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Neuromuscular electrical stimulation (NMES) is widely used for improving muscle strength, preventing muscle atrophy, and decreasing pain. Recently, NMES has become a substitute for exercise therapy for metabolism improvement and functional capacity improvement. However, NMES has several disadvantages. First, slow-twitch muscle contractions are insufficient because the recruitment pattern of NMES does not obey Henneman's size principle. Second, when using surface electrodes, it is difficult to contract deep skeletal muscles at the application site. Third, electrical stimulation causes discomfort. Therefore, we devised a simultaneous combination of NMES and voluntary muscle contractions to overcome the weak points of NMES. A hybrid training system (HTS) that resists the motion of a volitionally contracting agonist muscle with force generated by its electrically stimulated antagonist was developed as a technique to combine the application of NMES and volitional contractions. This motion sensor makes it possible to simultaneously combine voluntary movements with NMES. Our HTS synchronizes with voluntary movements, enhancing safety and reducing discomfort. This HTS enhances the exercise effect of even simple exercise. So far, our HTS has been reported to be effective for muscle strength enhancement, prevention of muscle atrophy, improvement of physical function, pain relief, enhancement of physical fitness, and improvement of metabolic function. HTS are expected to be useful methods in environments where sufficient exercise load is not available or for individuals with low exercise tolerance.

Alcohol-related liver disease and metabolic-dysfunction-associated steatotic liver disease are the most common causes of chronic liver disease. Globally, alcohol intake, and metabolic syndrome driven by excessive caloric intake and sedentary lifestyle have steadily increased over the past decades. Given the high prevalence rates of both excessive alcohol consumption and components of metabolic syndrome, both can frequently coexist in the same individuals and impact their lives. In this article, we review the impact of alcohol and metabolic syndrome on liver-related outcomes., Competing Interests: Disclosure Dr Z. M. Younossi is a consultant to BMS, GSK, Cymabay, Ipsen, Abbott, Novo Nordisk, Madrigal, Merck, Siemens, and Intercept. Other authors have no conflict of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: This study aimed to investigate the radiographic findings for the hip joint and hip range of motion in professional cyclists, and to determine their bone morphology and physical characteristics. The effects of physical characteristics on athletic performance were examined in terms of metabolic efficiency using simulation analysis., Methods: We performed a case-control research study on 22 hips in 11 male professional cyclists (average age 28.5, height 1.73 m, weight 77.6 kg). Thirty hips in 15 healthy male volunteers were selected as controls. As radiographic evaluations, acetabular dysplasia was assessed on standardized radiographs. During physical evaluations, the hip range of motion was examined. We used simulation analysis to investigate the metabolic efficiency in the different cycling forms., Results: The radiographic evaluations showed a significant difference in the incidence of acetabular dysplasia (p = 0.01): 59% (13/22 hips) in the pro-cyclist group versus 10% (3/30 hips) in the control group. The physical evaluations revealed significant differences in the hip internal rotation angle (p = 0.01), with greater ranges of internal rotation in the pro-cyclist group versus the control group. The simulation analyses showed that metabolism was reduced in the cycling form with hip internal rotation, especially in the lower extremities., Conclusions: Pro-cyclists showed a high frequency of acetabular dysplasia and superior hip internal rotation. According to the cycling model analyses, hip internal rotation allowed pedaling with reduced metabolic power., (© 2024. The Author(s).)

This study aimed to evaluate the superficial medial collateral ligament distal tibial attachment (sMCL-dTA) morphologically and morphometrically. Seventeen unpaired formalin-fixed cadaveric knees were used. The sMCL was divided into anterior and posterior sections in the paracoronal plane along the midline of the sMCL. The distance from the medial edge of the tibial plateau and the joint line to the proximal margin, center, and distal margin of the sMCL-dTA and the length of the sMCL-dTA were measured in the anterior section, respectively. The sMCL-dTA was histologically observed in the posterior section with hematoxylin and eosin and Masson's trichrome staining. The distance from the medial edge of the tibial plateauto the proximal margin, center, and distal margin of the sMCL-dTA were 38.1 ± 4.2, 49.7 ± 4.4, and 61.5 ± 5.1 mm, respectively. The perpendicular distance from the joint line to the proximal margin, center, and distal margin of the sMCL-dTA were 36.1 ± 4.0, 47.4 ± 4.2, and 59.1 ± 4.8 mm, respectively. The length of the sMCL-dTA was 23.6 ± 3.2 mm. Histologically, the sMCL-dTA was formed by two layers of collagen fibers: the unidirectional fibrous layer and the multidirectional fibrous layer. The respective thicknesses of the two layers both decreased distally. The anatomical location, the length, and the attachment morphology of sMCL-dTA have been clarified using human cadaveric knees. Anatomical data in the present study contribute to the quality of surgery associated with sMCL-dTA., (© 2024 American Association of Clinical Anatomists and British Association of Clinical Anatomists.)

Background: Physical function and knee kinematics recovery after discoid lateral meniscus (DLM) tear surgery are essential for a better prognosis. However, these alterations remain unclear. Therefore, this study aimed to investigate changes in physical function and knee kinematics following saucerization and DLM tear repair., Methods: We enrolled 16 patients who underwent saucerization and DLM tear repair. Postoperative changes in knee kinematics during gait, and physical function, were evaluated at 3, 6, and 12 months., Results: The peak flexion angle of the operated limb during weight acceptance was significantly higher than that of the contralateral limb at 3 (operated limb: 34.6 ± 8.9°, contralateral limb: 23.7 ± 8.3°; P < 0.01) and 6 months (operated limb: 32.1 ± 9.7°, contralateral limb: 24.6 ± 8.2°; P = 0.03) postoperatively, but not at 12 months (operated limb: 27.1 ± 7.1°, contralateral limb: 23.1 ± 9.5°; P = 0.22) postoperatively. The knee extensor strength of the operated limb was significantly lower than that of the contralateral limb at 3 (operated limb: 1.00 ± 0.59 Nm/kg, contralateral limb: 1.37 ± 0.59 Nm/kg; P = 0.01), 6 (operated limb: 1.22 ± 0.55 Nm/kg, contralateral limb: 1.48 ± 0.60 Nm/kg; P < 0.01), and 12 months (operated limb: 1.39 ± 0.57 Nm/kg, contralateral limb: 1.55 ± 0.64 Nm/kg; P = 0.04) postoperatively., Conclusion: Knee extension deficits and extensor weakness persisted at 6 months after saucerization and repair of DLM tears. Postoperative rehabilitation should be focused on knee extension function., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: Exercise, particularly resistance exercise, is beneficial for sarcopenia in patients with liver cirrhosis. However, the effects of exercise on events remain unclear. We aimed to examine the effects of exercise on serious events in patients with liver cirrhosis using a meta-analysis of randomized controlled trials (RCTs)., Methods: A literature search was conducted in 2022. Eleven RCTs were selected for the meta-analysis (exercise group, n = 232; control group, n = 193). Serious events were defined as death or serious complications according to the original articles. A meta-analysis was performed using a random-effects model. The primary outcome was the incidence of serious events., Results: In the 11 RCTs, the incidence of serious events was 5.6% (13/232) and 12.3% (24/193) in the exercise and control groups, respectively. However, a meta-analysis demonstrated no significant difference in the incidence of serious events between the two groups (risk difference [RD] - 0.03, 95% confidence intervals (CI) - 0.07 to 0.02). In a stratification analysis based on a combination of aerobic and resistance exercise, five RCTs (n = 185) were enrolled. The incidence of serious events was 6.25% (7/112) and 24.7% (18/73) in the combination exercise and control groups, respectively. A meta-analysis demonstrated a significant reduction in the incidence of serious events in the combination exercise group compared with the control group (RD - 0.12; 95% CI - 0.21 to - 0.03)., Conclusions: Resistance exercise in combination with aerobic exercise reduces serious events in patients with liver cirrhosis. A combination of aerobic and resistance exercise may be beneficial to improve the prognosis of patients with liver cirrhosis., (© 2023. Japanese Society of Gastroenterology.)

A 62-year-old woman with adult T-cell leukemia/lymphoma (ATL) received umbilical cord blood transplantation (CBT) in first complete remission. However, relapse of ATL was detected on day 74 post-transplantation, as evidenced by the rapid growth of lymphoma cells in peripheral blood and an increase in soluble interleukin-2 receptor (sIL2R) levels. Discontinuation of immunosuppressant therapy alone did not improve ATL findings, but treatment with lenalidomide caused lymphoma cells to disappear from the peripheral blood and sIL2R levels to return to normal. Pancytopenia was observed as a lenalidomide-associated adverse effect, but lymphocyte counts were not reduced. The patient was judged to be in complete remission based on results of Southern blot analysis and human T-cell leukemia virus 1 (HTLV-1)-infected cell analysis using flow cytometry (HAS-Flow). Flow cytometric analysis of peripheral blood and FISH analysis of X and Y chromosomes revealed that the therapeutic effect of lenalidomide was associated with an increase in the number of donor-derived peripheral natural killer cells. ATL relapse was not observed at 13 months into lenalidomide treatment. Our results suggest that lenalidomide is an effective option for the treatment of post-transplant relapsed ATL.

There are 48 nuclear receptors in the human genome, and many members of this superfamily have been implicated in human diseases. The NR4A nuclear receptor family consisting of three members, NR4A1, NR4A2, and NR4A3 (formerly annotated as Nur77, Nurr1, and NOR1, respectively), are still orphan receptors but exert pathological effects on immune-related and neurological diseases. We previously reported that prostaglandin A 1 (PGA 1 ) and prostaglandin A 2 (PGA 2 ) are potent activators of NR4A3, which bind directly to the ligand-binding domain (LBD) of the receptor. Recently, the co-crystallographic structures of NR4A2-LBD bound to PGA 1 and PGA 2 were reported, followed by reports of the neuroprotective effects of these possible endogenous ligands in mouse models of Parkinson's disease. Based on these structures, we modeled the binding structures of the other two members (NR4A1 and NR4A3) with these potential endogenous ligands using a template-based modeling method, and reviewed the similarity and diversity of ligand-binding mechanisms in the nuclear receptor family.

Nutritional disorders in patients with chronic obstructive pulmonary disease (COPD) are associated with cachexia, sarcopenia, and weight loss. In particular, weight loss is a prognostic factor in COPD independent of pulmonary function, and energy malnutrition is a contributing factor. Frequent exacerbation hospitalization is also a prognostic factor for COPD patients. The impact of energy malnutrition on adverse events such as exacerbation hospitalization is unknown, and this study aimed to investigate that. We included 163 male subjects with COPD. Respiratory quotient (RQ), an index of energy malnutrition, was calculated by expiratory gas analysis using an indirect calorimeter. RQ <0.85 was categorized as the energy malnutrition group. Kaplan-Meier analysis was used to compare the hospitalization avoidance rate between the with and without energy malnutrition groups. Independent factors associated with exacerbation hospitalization were evaluated by Cox regression analysis. We finally analyzed data from 56 selected subjects (median age: 74 y). The exacerbation hospitalization rate was significantly higher in the energy malnutrition group. Fifty percent of the energy malnutrition group was hospitalized for an exacerbation, and the median hospitalization avoidance time was 701 d. In Cox regression analysis (adjusted for age, BMI, mMRC dyspnea scale score, %FEV 1 , and 6-min walk test), energy malnutrition was an independent factor associated with exacerbation hospitalization (HR 4.14, 95% CI 1.13-15.1, p=0.03). Energy malnutrition may be the risk factor for exacerbation hospitalization. Energy malnutrition may be an early nutritional disorder and early detection and intervention may reduce exacerbation hospitalizations.

Background: Locomotive syndrome (LS) is characterized by reduced mobility. Clinical decision limit (CDL) stage 3 in LS indicates physical frailty. Lumbar spinal canal stenosis (LSS) is one of the causes of LS, for which lumbar surgery is considered to improve the CDL stage. This study aimed to investigate the efficacy of lumbar surgery and independent factors for improving the CDL stage in patients with LSS., Methods: This retrospective study was conducted at the Department of Orthopaedic Surgery at our University Hospital. A total of 157 patients aged ≥ 65 years with LSS underwent lumbar surgery. The 25-Question Geriatric Locomotive Function scale (GLFS-25) was used to test for LS, and the Timed Up and Go test (TUG) was used to evaluate functional ability. Lower limb pain was evaluated using a visual analog scale. Patients with at least one improvement in the CDL stage following lumbar surgery were included in the improvement group. Differences in lower limb pain intensity between the groups were evaluated using the Wilcoxon rank-sum test. The Spearman's rank correlation coefficient was used to determine correlations between Δ lower limb pain and Δ GLFS-25. Logistic regression analysis was used to identify factors associated with improvement in LS., Results: The proportion of patients with improved CDL stage was 45.1% (improvement/non-improvement: 32/39). Δ Lower limb pain was significantly reduced in the improvement group compared with that in the non-improvement group (51.0 [36.3-71.0] vs 40.0 [4.0-53.5]; p = 0.0107). Δ GLFS-25 was significantly correlated with Δ lower limb pain (r = 0.3774, p = 0.0031). Multiple logistic regression analysis revealed that TUG and age were significantly associated with improvement in LS (odds ratio, 1.22; 95% confidence interval: 1.07-1.47)., Conclusions: Lumbar surgery effectively improved the CDL stage in patients with LSS. In addition, TUG was an independent factor associated with improvement in the CDL., (© 2023. The Author(s).)

Lumbar spinal stenosis (LSS) can interfere with daily life and quality of life (QOL). Evaluating physical function and QOL and helping patients to improve is the focus of rehabilitation. Phase angle (PhA) assessment is widely used to measure body composition and is considered an indicator of physical function and QOL. This study investigated the relationship between PhA and physical function, physical activity, and QOL in patients with LSS. PhA, handgrip strength, walking speed, Timed Up and Go test (TUG), Life Space Assessment (LSA), Prognostic Nutritional Index (PNI), Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ), and EQ-5D were assessed and statistically analyzed. The study included 133 patients with LSS. Multiple regression analysis of PhA adjusted for age, sex, and body mass index (Model 1) and for Model 1 + PNI (Model 2) showed significant correlations (P < 0.05) with handgrip strength, walking speed, TUG, and LSA. Regarding QOL, PhA was significantly correlated (P < 0.05) with lumbar function in JOABPEQ. PhA was associated with physical function and QOL in patients with LSS and might be a new clinical indicator in this population., (© 2023. Springer Nature Limited.)

A hybrid training system (HTS) combining antagonist muscle electrical stimulation and voluntary muscle contraction has been developed using eccentric antagonist muscle contractions with electrical stimulation as resistance to voluntary muscle contractions. We devised an exercise method using HTS combined with a cycle ergometer (HCE). The purpose of this study was to compare the muscle strength, muscle volume, aerobic functions and lactate metabolism of HCE and a volitional cycle ergometer (VCE). A total of 14 male participants performed exercise on a bicycle ergometer for 30 min per session, 3 times per week for 6 weeks. We divided 14 participants into an HCE group (7 participants) and a VCE group (7 participants). The workload was set at 40% of each participant's peak oxygen uptake (V.O 2 peak). Electrodes were placed over each motor point on the quadriceps and hamstrings. The V.O 2 peak and anaerobic threshold significantly increased before and after training when using HCE rather than VCE. The HCE group had significantly increased extension and flexion muscle strength at 180 degrees/s in post-training measurements over pre-training measurements. Knee flexion muscle strength at 180 degrees/s tended to increase in the HCE group compared to the VCE group. The quadricep muscle cross-sectional area was significantly increased in the HCE group compared to the VCE group. Additionally, the HCE group had significantly decreased maximal lactate, measured every 5 min during exercise at the end of study, between pre and post-training. Thus, HCE may be a more effective training method for muscle strength, muscle mass and aerobic functions at 40% of each participant's V.O 2 peak than conventional cycling exercise. HCE could be applied not only as aerobic exercise but also as resistance training.

Background: Cervical spondylotic myelopathy preoperative prognostic factors include age, preoperative severity, and disease duration. However, there are no reports on the relationship between changes in physical function during hospitalization and postoperative course, and in recent years, the length of hospital stay has shortened. We aimed to investigate whether changes in physical function during hospitalization can predict the postoperative outcome., Methods: We recruited 104 patients who underwent laminoplasty for cervical spondylotic myelopathy by the same surgeon. Physical functions, including Simple Test for Evaluating Hand Function (STEF), grip strength, timed up and go test, 10-m walk, and time to stand on one leg, were assessed at admission and discharge. Patients with the Japanese Orthopaedic Association (JOA) score improvement rate of 50% or more were defined as the improved group. Decision tree analysis was investigated factor for identifying improvement in the JOA score. According to this analysis, we divided into two groups using age. Then, we conducted a logistic regression analysis to identify factors that improve the JOA score., Results: The improved and non-improved groups had 31 and 73 patients, respectively. The improved group was younger (p = 0.003) and had better improved Δgrip strength (p = 0.001) and ΔSTEF (p < .0007). Age was significantly positively correlated with disease duration (r = 0.4881, p =  < .001). Disease duration exhibited a significant negative correlation with the JOA score improvement rate (r = - 0.2127, p = 0.031). Based on the decision tree analysis results, age was the first branching variable, with 15% of patients ≥ 67 years showing JOA score improvement. This was followed by ΔSTEF as the second branching factor. ΔSTEF was selected as the factor associated with JOA improvement in patients ≥ 67 years (odds ratio (OR) 0.95, 95% confidence interval (CI) 0.90-0.99, p = .047); in patients < 67 years, Δgrip strength was identified (OR 0.53, CI 0.33‒0.85, p = .0086)., Conclusions: In the improved group, upper limb function improved more than lower limb function from the early postoperative period. Upper limb function changes during hospitalization were associated with outcomes one year postoperatively. Improvement factors in upper extremity function differed by age, with changes in grip strength in patients < 67 years and STEF in patients ≥ 67 years, reflecting the outcome at one year postoperatively., (© 2023. The Author(s).)

Fatty liver is known to be associated with extra-hepatic diseases including atherosclerotic cardiovascular disease and extra-hepatic cancers, which affect the prognosis and quality of life of the patients. The inter-organ crosstalk is mediated by metabolic abnormalities such as insulin resistance and visceral adiposity. Recently, metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed as a new definition for fatty liver. MAFLD is characterized by the inclusion criteria of metabolic abnormality. Therefore, MAFLD is expected to identify patients at high risk of extra-hepatic complications. In this review, we focus on the relationships between MAFLD and multi-organ diseases. We also describe the pathogenic mechanisms of the inter-organ crosstalk.

Increased liver stiffness and insulin resistance are important therapeutic targets in patients with nonalcoholic fatty liver disease (NAFLD). A hybrid training system (HTS) has been developed which combines application of electrical stimulation and volitional contractions. We compared the effect of walking exercise (5.6 km/h) both with and without simultaneous HTS on liver stiffness and insulin resistance. In a single-blind, controlled trial, 32 subjects with NAFLD were randomized to 12 weeks of triweekly 30 minute walking exercise with either HTS (HTS group) or without HTS (control group). Transient elastography for the assessment of liver stiffness, body weight, visceral fat, the homeostasis model assessment of insulin resistance, fasting blood glucose, serum aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transpeptidase were evaluated. Data were evaluated using the linear model after adjusting the baseline value. In the subjects with BMI of 27 kg/m 2 or more, the decrement of transient elastography in the HTS group was significantly larger than in the control group (mean ± standard error: Δ2.13 ± 0.64 kPa vs. Δ-0.67 ± 0.42 kPa, p=0.0009). There were no significant differences between groups in other endpoints. These results showed that simultaneously combining electrical stimulation with walking exercise could potentially improve liver stiffness in people who have NAFLD. In fact, because the exercise effect was increased by HTS without increasing the walking speed, this HTS could be especially useful for obese or overweight subjects, in whom NAFLD and joint problems often coexist. However, its effects on insulin resistance and body composition were not clear.

Aim: Hepatic fibrosis is associated with various factors, including metabolic dysfunction-associated fatty liver disease (MAFLD), insulin resistance, and alcohol intake in patients with morbid obesity. We investigated factors directly associated with hepatic fibrosis in patients with morbid obesity using a graphical model., Methods: We enrolled 134 consecutive patients with morbid obesity who underwent liver biopsy during sleeve gastrectomy (median age 43.5 years; MAFLD 78.4%; homeostasis model assessment of insulin resistance [HOMA-IR] 5.97; >20 g/day alcohol intake 14.2%). Patients were classified into none/mild (F0/1; n = 77) or significant/advanced fibrosis (F2/3; n = 57) groups, based on histology. Factors associated with F2/3 were analyzed using logistic regression analysis and a graphical model., Results: F2/3 was observed in 42.5% of the enrolled patients. The prevalence of MAFLD and HOMA-IR values were significantly higher in the F2/3 group than in the F0/1 group; however, no significant difference in alcohol intake was observed between the two groups. On logistic regression analysis, MAFLD, but not HOMA-IR or alcohol intake, was the only independent factor associated with F2/3 (odds ratio 7.555; 95% confidence interval 2.235-25.544; p = 0.0011). The graphical model revealed that F2/3 directly interacted with MAFLD, diabetes mellitus, HOMA-IR, and low-density lipoprotein cholesterol. Among these factors, MAFLD showed the strongest interaction with F2/3., Conclusions: We determined that MAFLD was more directly associated with significant/advanced fibrosis than insulin resistance or hyperlipidemia, and alcohol intake was not directly associated with hepatic fibrosis. Metabolic dysfunction-associated fatty liver disease could be the most important factor for hepatic fibrosis in patients with morbid obesity., (© 2022 The Japan Society of Hepatology.)

Purpose: Preventing falls in patients is one of the most important concerns in acute hospitals. Balance disorder and hypnotic drugs lead to falls. The Standing Test for Imbalance and Disequilibrium (SIDE) is developed for the evaluation of static standing balance ability. There have been no reports of a comprehensive assessment of falls risk including hypnotic drugs and SIDE. The purpose of this study was to investigate the fall rate of each patient who took the hypnotic drug and the factor associated with falls., Methods: Fall rates for each hypnotic drug were calculated as follows (number of patients who fell/number of patients prescribed hypnotic drug x 100). We investigated the hypnotic drugs as follows; benzodiazepine drugs, Z-drugs, melatonin receptor agonists, and orexin receptor antagonists. Hypnotic drug fall rate was analyzed using Pearson's chi-square test. Decision tree analysis is the method we used to discover the most influential factors associated with falls., Results: This study included 2840 patients taking hypnotic drugs. Accidents involving falls were reported for 211 of inpatients taking hypnotic drugs. Z-drug recipients had the lowest fall rate among the hypnotic drugs. We analyzed to identify independent factors for falls, a decision tree algorithm was created using two divergence variables. The SIDE levels indicating balance disorder were the initial divergence variable. The rate of falls in patients at SIDE level ≦ 2a was 14.7%. On the other hand, the rate of falls in patients at SIDE level ≧ 2b was 2.9%. Gender was the variable for the second classification. In this analysis, drugs weren't identified as divergence variables for falls., Conclusion: The SIDE balance assessment was the initial divergence variable by decision tree analysis. In order to prevent falls, it seems important not only to select appropriate hypnotic drugs but also to assess patients for balance and implement preventive measures., Competing Interests: We have declared that no competing interests exist.

Background and Aim: Metabolic dysfunction and associated systemic inflammation are risk factors for chronic obstructive pulmonary disease (COPD) and COPD is highly prevalent in men. We investigated the impact of metabolic-associated fatty liver disease (MAFLD) and MAFLD-related systemic inflammation on COPD in men., Methods: We enrolled 2,041 men with fatty liver. Patients were classified into the COPD (n = 420/2041) and non-COPD (n = 1621/2041) groups. COPD and its high-risk group were diagnosed using the Japanese Respiratory Society Disease statement. Systemic inflammation was evaluated using the C-reactive protein (CRP)/albumin ratio. Independent factors for COPD were investigated by multivariate analysis and decision-tree analysis., Results: The prevalence of MAFLD was significantly higher in the COPD group than in the non-COPD group. In multivariable analysis, in addition to heavy smoking and aging, MAFLD was identified as an independent factor for COPD (OR 1.46, 95% CI 1.020-2.101, P = 0.0385). Decision-tree analysis showed that MAFLD, rather than heavy smoking, was the most influential classifier for COPD in non-elderly men (14% in MAFLD vs 6% in non-MAFLD groups). MAFLD was also the second most influential factor in elderly men who were not heavy smokers. In both groups, the CRP/albumin ratio was the first classifier for COPD (16% in the high CRP/albumin ratio group vs 3% in the low CRP/albumin ratio group of non-elderly men)., Conclusions: MAFLD is an independent predictor of COPD in men. MAFLD had a significant impact on COPD through systemic inflammation in men of all ages who were not heavy smokers. MAFLD may be useful to broadly identify COPD in men., (© 2022. The Author(s).)

Purpose: Osteoporosis combined with sarcopenia contributes to a high risk of falling, fracture, and even mortality. However, sarcopenia's impact on low back pain and quality of life (QOL) in patients with osteoporosis is still unknown. The purpose of this study is to investigate low back pain and QOL in osteoporosis patients with sarcopenia., Methods: We assessed 100 ambulatory patients who came to our hospital for osteoporosis treatment. Low back pain was evaluated using the Visual Analogue Scale (VAS) with 100 being an extreme amount of pain and 0 no pain. The Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) score was used to assess QOL after adjustment for age, history of vertebral fracture, and adult spinal deformity. Differences in low back pain intensity assessed by VAS between groups were evaluated by the Willcoxon rank-sum test. Covariance analysis was used to assess QOL. All data are expressed as either median, interquartile range, or average, standard error., Results: Patients were classified into the sarcopenia group (n = 32) and the non-sarcopenia group (n = 68). Low back pain intensity assessed by VAS was significantly higher in the sarcopenia group than in the non-sarcopenia group (33.0 [0-46.6] vs. 8.5 [0-40.0]; p < 0.05). The subscales of the JOABPEQ for low back pain were significantly lower in the sarcopenia group than in the non-sarcopenia group (65.0 ± 4.63 vs. 84.0 ± 3.1; p < 0.05)., Conclusion: In this cross-sectional study, sarcopenia affected low back pain and QOL in ambulatory patients with osteoporosis. Sarcopenia may exacerbate low back pain and QOL., (© 2022. The Author(s).)

Background: An elastic band (EB) is generally used with a low load for rotator cuff physical exercise, but the resulting increase in muscle strength is insufficient. We assessed the efficacy on external rotator muscle strength of the shoulder joint; of a hybrid training system (HTS) that resists the motion of a volitionally contracting agonist muscle using the force generated by its electrically stimulated antagonist vs. general rotator cuff exercise with EB., Methods: Twenty healthy men with no shoulder joint disorders were randomized to 6 weeks of triweekly 10-min rotator cuff exercise with HTS or EB in a clinical research laboratory. Isokinetic concentric external rotator muscle strength at angular velocities of 60°/s and 180°/s (CON60, CON180, respectively) and isokinetic eccentric external rotator muscle strength at an angular velocity of 60°/s (ECC60) were measured as rotator cuff function before and after 6 weeks of intervention., Results: There were no significant intergroup differences in baseline characteristics. There were statistically significant differences (p = 0.0358, p = 0.0213, respectively) in the increase in CON180 (mean ± SD) and ECC60 between the HTS group (Δ6.0 ± 6.0Nm, p = 0.015; Δ7.5 ± 4.7Nm p = 0.0007, respectively) and the EB group (Δ0.3 ± 5.2Nm, p = 0.8589; Δ1.8 ± 5.3 Nm p = 0.3133, respectively). There was a trend toward CON60 increasing in the HTS group (Δ4.7 ± 6.5Nm, p = 0.0494) which was greater than in the control group (Δ-0.9 ± 6.3Nm, p = 0.6637) (inter-group, p = 0.0677)., Conclusions: The results of this study support the conclusion that HTS is more effective for increasing external rotator muscle strength more effectively than EB. HTS would be useful for rotator cuff physical exercise., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Patients with hip fracture are limited as to physical activity. It is difficult to evaluate the physical function of the legs at admission; however, it is easy to measure grip strength, which has been reported to be correlated with systemic muscular strength and physical function. The objective of this study was to investigate the utility of grip strength in predicting functional outcome after hip fracture., Methods: Fifty-seven patients who underwent surgery for hip fracture were evaluated for height, weight, Body Mass Index (BMI), grip strength, bone density (femoral neck), hemoglobin, Hemoglobin A1c (HbA1c), Hasegawa's Dementia Scale-Revised (HDS-R), and albumin at admission and Functional Independence Measure (FIM) at discharge. Spearman's rank correlation coefficient was used to evaluate the relation between grip strength and the above variables. Furthermore, factors of walking acquisition were analyzed by logistic regression analysis and decision-tree analysis., Results: Correlation analysis showed that grip strength was positively correlated with bone density at admission and FIM at discharge and negatively correlated with age. In the logistic regression analysis, the independent factor associated with walking acquisition was grip strength (OR 1.26; 95%CI 1.018-1.566; p=0.0339). In the decisiontree analysis, grip strength was the initial divergence variable for walking acquisition (the percentage with walking acquisition was 80.0% of the patients with grip strength ≧13.2 kg VS. 18.7% of the patients with grip strength < 13.2 kg)., Conclusions: Grip strength at admission was definitive in predicting the functional outcome of patients with hip fracture who underwent surgery.

It is well known that prolonged bed rest induces muscle weakness, muscle atrophy, cardiovascular deconditioning, bone loss, a loss of functional capacity, and the development of insulin resistance. Neuromuscular electrical stimulation is anticipated to be an interventional strategy for disuse due to bed rest. A hybrid training system (HTS), synchronized neuromuscular electrical stimulation for voluntary exercise using an articular motion sensor, may increase the exercise load though bed rest. We assessed oxygen uptake or heart rate during knee bending exercise in the supine position on a bed both simultaneously combined with HTS and without HTS to evaluate exercise intensity on different days in ten healthy subjects (8 men and 2 women) by a randomized controlled crossover trial. The values of relative oxygen uptake during knee bending exercise with HTS were significantly greater than those during knee bending exercise without HTS (7.29 ± 0.91 ml/kg/min vs. 8.29 ± 1.06 ml/kg/min; p = 0.0115). That increment with HTS was a mean of 14.42 ± 13.99%. Metabolic equivalents during knee bending exercise with HTS and without HTS were 2.08 ± 0.26 and 2.39 ± 0.30, respectively. The values of heart rate during knee bending exercise with HTS were significantly greater than those during knee bending exercise without HTS (80.82 ± 9.19 bpm vs. 86.36 ± 5.50 bpm; p = 0.0153). HTS could increase exercise load during knee bending exercise which is easy to implement on a bed. HTS might be a useful technique as a countermeasure against the disuse due to bed rest, for example during acute care or the quarantine for infection prophylaxis., Competing Interests: The authors have declared that no competing interests exist.

Reduction in activity links to the development and progression of non-alcoholic fatty liver disease (NAFLD). Brain-derived neurotrophic factor (BDNF) is known to regulate an activity. We aimed to investigate the association between reduction in activity and BDNF in patients with NAFLD using data-mining analysis. We enrolled 48 NAFLD patients. Patients were classified into reduced ( n = 21) or normal activity groups ( n = 27) based on the activity score of the Chronic Liver Disease Questionnaire-NAFLD/non-alcoholic steatohepatitis. Circulating BDNF levels were measured using an enzyme-linked immunoassay. Factors associated with reduced activity were analyzed using decision-tree and random forest analyses. A reduction in activity was seen in 43.8% of patients. Hemoglobin A1c and BDNF were identified as negative independent factors for reduced activity (hemoglobin A1c, OR 0.012, p = 0.012; BDNF, OR 0.041, p = 0.039). Decision-tree analysis showed that "BDNF levels ≥ 19.1 ng/mL" was the most important classifier for reduced activity. In random forest analysis, serum BDNF level was the highest-ranked variable for distinguishing between the reduced and normal activity groups (158 valuable importance). Reduced activity was commonly seen in patients with NAFLD. Data-mining analyses revealed that BNDF was the most important independent factor corresponding with the reduction in activity. BDNF may be an important target for the prevention and treatment of NAFLD.

Neuromuscular electrical stimulation (NMES) is used to increase not only muscle strength but also whole-body metabolism. A hybrid training system (HTS) in which NMES is synchronized to voluntary exercise by an articular motion sensor may increase exercise load during aerobic walking exercise. We assessed the metabolic cost during walking exercise (5 minutes at 4 km/h and 5.6 km/h) on a treadmill simultaneously combined with HTS (HTSW) or without HTS (CON). We evaluated oxygen uptake ( VO · 2 ) and heart rate (HR) during HTSW or CON on different days in fifteen subjects. The values ofVO · 2 during HTSW at 4 km/h and 5.6 km/h were signifi cantly greater than those during CON (16.6 ± 1.85 ml/min/kg vs 15.3 ± 1.48 ml/min/kg; p < 0.05, 21.0 ± 2.17 ml/min/kg vs 19.4 ± 2.13 ml/min/kg; p < 0.01, respectively). The values of HR during HTSW at 4 km/h, 5.6 km/h were significantly greater than those during CON (106.7 ± 8.1 bpm vs 101.7 ± 10.3 bpm; p < 0.05, 126.5 ± 11.1 bpm vs 121.5 ± 12.5 bpm; p < 0.05, respectively). HTS added significantly to the exercise load by 8.3 ± 12.0% or 9.1 ± 9.9% during aerobic walking exercise at 4 km/h or 5.6 km/h, respectively. HTS might be useful for health promotion by increasing metabolic cost during aerobic walking exercise without increasing the perceived difficulty.

Aim: In patients with liver cirrhosis, high levels of serum myostatin are associated with poor prognosis. We aimed to clarify the influence of myostatin on the prognosis of patients with non-alcoholic fatty liver disease-hepatocellular carcinoma (NAFLD-HCC) without cirrhosis and on the progression of liver fibrosis., Methods: Serum myostatin levels were evaluated in 234 patients who underwent primary surgical resection for single HCC. To clarify the impact of myostatin on liver fibrosis, we established human primary liver fibroblasts from resected livers, and cultured them in the presence of myostatin., Results: The median age was 67.4 years, the median L3 skeletal muscle mass index was 44.4 cm 2 /m 2 , and the median body mass index was 23.4 kg/m 2 . Eighty-two (35.0%) patients had sarcopenia (L3 skeletal muscle mass index: men <42, women <38 cm 2 /m 2 ). The etiologies of liver disease were hepatitis B virus (n = 61), hepatitis C virus (n = 86), and non-B non-C hepatitis (n = 87) including NAFLD (n = 74). High preoperative serum myostatin and vascular invasion were independent predictors of poor overall survival (OS). High serum myostatin was associated with poor OS in patients with no sarcopenia (n = 152). In patients without advanced liver fibrosis (Fibrosis stage, 0-2; n = 58), high levels of serum myostatin were also associated with poor OS, regardless of sarcopenia. Serum myostatin levels were increased with the progression of liver fibrosis. Liver fibroblasts were activated and produced collagen following stimulation with myostatin., Conclusions: In patients with NAFLD-HCC without advanced liver fibrosis, high levels of serum myostatin were associated with poor OS. Myostatin activated primary fibroblasts and stimulated collagen production., (© 2021 The Japan Society of Hepatology.)

Aims: Exercise is effective for the prevention of liver cancer. Exercise exerts biological effects through the regulation of microRNAs (miRNAs) and cytokines/myokines. We aimed to investigate the effects of low-intensity resistance exercise on serum miRNA and cytokine/myokine expressions in subjects with no exercise habits., Methods: We enrolled seven male subjects with no exercise habits in this prospective before-after study. All subjects performed a low-intensity resistance exercise program (three metabolic equivalents, approximately 20 min/session). Serum miRNA expressions were evaluated using microarrays. We performed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of differentially expressed miRNAs before and after exercise. Serum cytokine/myokine expressions were evaluated using a multiplex panel., Results: All subjects completed the exercise program with no adverse events. In the microarray analysis, seven miRNAs showed a significant change between before and after exercise. Of these, microRNA (miR)-630 and miR-5703 showed a >1.5-fold increase (miR-630: 40.7 vs. 69.3 signal intensity, p = 0.0133; miR-5703: 30.7 vs. 55.9 signal intensity, p = 0.0051). KEGG pathway enrichment analysis showed that miR-630- and miR-5703-related genes were enriched in 37 and 5 pathways, including transforming growth factor-beta and Wnt signaling pathways, respectively. In the multiplex analysis, 12 cytokines/myokines showed significant alteration after exercise compared to before exercise. Of these, fractalkine/CX3CL1 showed the most significant up-regulation by exercise (94.5 vs. 109.1 pg/ml, p = 0.0017)., Conclusions: A low-intensity resistance exercise program was associated with upregulation of serum miR-630, miR-5703, and fractalkine/CX3CL1 expressions in subjects with no exercise habits. Thus, even low-intensity exercise may alter miRNA and cytokine/myokine expressions in humans., (© 2021 The Japan Society of Hepatology.)

Overall response rates of systemic therapies against advanced hepatocellular carcinoma (HCC) remain unsatisfactory. Thus, searching for new immunotherapy targets is indispensable. NK cells are crucial effectors and regulators in the tumor microenvironment and a determinant of responsiveness to checkpoint inhibitors. We revealed the landscape of NK cell phenotypes in HCC patients to find potential immunotherapy targets. Using single cell mass cytometry, we analyzed 32 surface markers on CD56 dim and CD56 bright NK cells, which included Sialic acid-binding immunoglobulin-type lectins (Siglecs). We compared peripheral NK cells between HCC patients and healthy volunteers. We also compared NK cells, in terms of their localizations, on an individual patient bases between peripheral and intrahepatic NK cells from cancerous and noncancerous liver tissues. In the HCC patient periphery, CD160 + CD56 dim NK cells that expressed Siglec-7, NKp46, and NKp30 were reduced, while CD49a + CD56 dim NK cells that expressed Siglec-10 were increased. CD160 and CD49a on CD56 dim NK cells were significantly correlated to other NK-related markers in HCC patients, which suggested that CD160 and CD49a were signature molecules. CD49a + CX3CR1 + Siglec-10 + NK cells had accumulated in HCC tissues. Considering further functional analyses, CD160, CD49a, CX3CR1, and Siglec-10 on CD56 dim NK cells may be targets for immunotherapies of HCC patients.

Serum carnitine is decreased in hemodialysis patients, which induces muscle atrophy. Thus, we examined the different effects of l-carnitine and exercise on exercise activity and muscle status in hemodialysis patients. Twenty patients were divided into l-carnitine and cycle ergometer groups and were followed for 3 months. Muscle and fat mass, physical activities, and muscle status were evaluated by an impedance, physical function test, and magnetic resonance imaging, respectively. The l-carnitine significantly increased muscle mass (P = .023) and thigh circumference (P = .027), decreased fat mass (P = .007), and shortened chair stand-up time (P = .002) and 10-m walk test (P = .037). The fat fraction was improved by the l-carnitine (P = .047). Compared with the exercise group, l-carnitine improved the changes in 10-m walk test (P = .026), chair stand-up time (P = .014), and thigh circumference (P = .022). Baseline fibroblast growth factor-21 and myostatin levels predicted the l-carnitine-associated changes in exercise activities. l-carnitine, rather than exercise, improved physical activity and muscle status in hemodialysis patients., (© 2020 The Authors. Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf of International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Severe ascites is an adverse event of ramucirumab (RAM), a second-line treatment for hepatocellular carcinoma (HCC). Ascites can be associated with various factors, including nutritional status and muscle quality. The aim of the present study was to investigate the prevalence and profiles of RAM-associated severe ascites in patients with HCC. This retrospective study enrolled 14 consecutive patients with HCC treated with RAM (median age, 72 years; Barcelona Clinic Liver Cancer stage B/C, 6/8). Nutritional status and muscle quality were evaluated using the controlling nutritional status (CONUT) score and intramuscular adipose tissue (IMAT) content, respectively. Factors associated with severe ascites were evaluated using decision-tree analysis. The median progression-free survival (PFS) time was 2.1 months, and the overall objective response and disease control rates were 14 and 50%, respectively. Severe ascites developed in 57.1% of the patients, and the median onset was 37.5 days (range, 14-61 days) after initiation of RAM treatment. In the decision-tree analysis, the CONUT score and IMAT content were the first and second splitting variables for the development of severe ascites. In patients with a CONUT score ≥5 and IMAT <-0.54, the prevalence of severe ascites was 80 and 100%, respectively. A high incidence of severe ascites was observed in patients treated with RAM. A CONUT score ≥5 and an IMAT <-0.54 were associated with severe ascites. Thus, caution must be taken for severe ascites in patients with HCC treated with RAM, in particular patients with malnutrition and fat infiltration in muscle., Competing Interests: TK received an honorarium (lecture fee) from Mitsubishi Tanabe Pharma Corporation and Otsuka Pharmaceutical Co., Ltd. All other authors declare that they have no competing interests., (Copyright: © Kamachi et al.)

Much public research suggests that autoimmune diseases such as rheumatoid arthritis (RA) are induced by aberrant "self" immune responses attacking autologous tissues and organ components. However, recent studies have reported that autoimmune diseases may be triggered by dysbiotic composition changes of the intestinal bacteria and an imbalance between these bacteria and intestinal immune systems. However, there are a few solid concepts or methods to study the putative involvement and relationship of these inner environmental factors in RA pathogenesis. Fortunately, Collagen-Induced Arthritis (CIA) and Collagen Antibody-Induced Arthritis (CAIA) models have been widely used as animal models for studying the pathogenesis of RA. In addition to RA, these models can be extensively used as animal models for studying complicated hypotheses in many diseases. In this review, we introduce some basic information about the CIA and CAIA models as well as how to apply these models effectively to investigate relationships between the pathogenesis of autoimmune diseases, especially RA, and the dysbiosis of intestinal bacterial flora., Competing Interests: The authors declare that they have received financial support from Chondrex, Inc., (Copyright © 2021 Ryoichi Hashida et al.)

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and one of the leading causes of hepatocellular carcinoma and liver transplantation. Moreover, patients with NAFLD frequently complain of non-specific symptoms including fatigue, abdominal discomfort, as well as anxiety, and NAFLD is reported to affect patient-reported outcomes (PROs). Thus, for clarifying the total burden of NAFLD, it is crucial to assess all associated outcomes, including not only clinical and economic outcomes but also PROs. PROs are thought to reflect what is happening in one's daily life and is an important way patients and health-care professionals communicate. There are various instruments for the assessment of PROs. Recently, a NAFLD/non-alcoholic steatohepatitis (NASH)-specific instrument called "Chronic Liver Disease Questionnaire (CLDQ)-NAFLD/NASH" has been developed. CLDQ-NAFLD/NASH comprises six domains: (i) abdominal symptoms, (ii) activity/energy, (iii) emotional health, (iv) fatigue, (v) systemic symptoms, and (vi) worry. CLDQ-NAFLD/NASH has demonstrated excellent internal consistency, face validity, content validity, and test-retest reliability. It has been sufficiently validated in two international phase 3 clinical trials. In this review, we summarize features of various instruments for assessing PROs by focusing on CLDQ-NAFLD/NASH. We also examine the validity of CLDQ-NAFLD/NASH in Japanese patients and alterations in CLDQ-NAFLD/NASH score in Japanese patients with significant hepatic fibrosis. Moreover, we discuss the utility of CLDQ-NAFLD/NASH in phase 3 clinical trials and in a real-world clinical setting., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Frailty including physical inactivity is associated with the survival of patients with hepatocellular carcinoma (HCC). We aimed to investigate the effects of in-hospital exercise on frailty in patients with HCC. This was a multi-center observational study. Patients with HCC were classified into exercise ( n = 114) and non-exercise ( n = 67) groups. The exercise group was treated with a mixture of aerobic and resistance exercises (20-40 min/day, median four days). Frailty was assessed using the liver frailty index (LFI). Factors for changes in LFI were examined by multivariate and decision-tree analyses. The factors were also examined after propensity score matching. During hospitalization, LFI was significantly improved in the exercise group compared to the non-exercise group (ΔLFI -0.17 vs. -0.02, p = 0.0119). In multivariate analysis, exercise (odds ratio (OR) 2.38, 95% confidence interval (CI) 1.240-4.570, p = 0.0091) and females (OR 2.09; 95%CI, 1.062-4.109; p = 0.0328) were identified as independent factors for the improvement of LFI. In the decision-tree analysis, exercise was identified as an initial classifier associated with the improvement of LFI. Similar findings were also seen in the propensity score matching analyses. We demonstrated that in-hospital exercise improved frailty in patients with HCC. Thus, in-hospital exercise may be beneficial for improving physical function in patients with HCC.

Abstract: Hashida, R, Takano, Y, Matsuse, H, Kudo, M, Bekki, M, Omoto, M, Nago, T, Kawaguchi, T, Torimura, T, and Shiba, N. Electrical stimulation of the antagonist muscle during cycling exercise interval training improves oxygen uptake and muscle strength. J Strength Cond Res 35(1): 111-117, 2021-A hybrid training system (HTS) is a resistance exercise method that combines voluntary concentric muscle contractions and electrically stimulated eccentric muscle contractions. We devised an exercise technique using HTS on cycle ergometer (HCE). The purpose of this study was to compare cardiorespiratory function and muscle strength when cycling exercise is combined with electrical stimulation over an extended period. Twenty-nine healthy young men were divided into an HCE group (n = 14) and a volitional cycle ergometer (VCE alone) group (n = 15). All subjects performed 30-minute cycling exercise interval training sessions 3 times a week for 6 weeks. The V̇o2peak of both groups significantly increased compared with the pretraining period (HCE group: from 31.3 ± 4.4 [ml·kg-1·min-1] pretraining to 37.6 ± 6.7 [ml·kg-1·min-1] post-training [p = 0.0024] and VCE group: from 34.0 ± 7.1 [ml·kg-1·min-1] pretraining to 38.4 ± 8.2 [ml·kg-1·min-1] [p = 0.0057]). After the training, there was no significant difference of changes in V̇o2peak between the HCE and the VCE groups (p = 0.7107). In the VCE group, the maximal isokinetic torque of knee extension (60°·s-1) post-training did not significantly increase compared with the pretraining period (VCE group: from 2.4 ± 0.5 [N·m·kg-1] pretraining to 2.5 ± 0.4 [N·m·kg-1] [p = 0.4543]). By contrast, in the HCE group, the maximal isokinetic torque of knee extension (60°·s-1) post-training significantly increased compared with pretraining period (HCE group: from 2.5 ± 0.3 [N·m·kg-1] pretraining to 2.8 ± 0.3 [N·m·kg-1] [p < 0.0001]). The change in knee extension torque was significantly greater for the HCE group than for the VCE group (p = 0.0307). In conclusion, cardiopulmonary function and knee extension strength were improved by the use of HCE., (Copyright © 2017 National Strength and Conditioning Association.)