Gene correction and overexpression of TNNI3 improve impaired relaxation in engineered heart tissue model of pediatric restrictive cardiomyopathy.

Research on cardiomyopathy models using engineered heart tissue (EHT) created from disease-specific induced pluripotent stem cells (iPSCs) is advancing rapidly. However, the study of restrictive cardiomyopathy (RCM), a rare and intractable cardiomyopathy, remains at the experimental stage because there is currently no established method to replicate the hallmark phenotype of RCM, particularly diastolic dysfunction, in vitro. In this study, we generated iPSCs from a patient with early childhood-onset RCM harboring the TNNI3 R170W mutation (R170W-iPSCs). The properties of R170W-iPSC-derived cardiomyocytes (CMs) and EHTs were evaluated and compared with an isogenic iPSC line in which the mutation was corrected. Our results indicated altered calcium kinetics in R170W-iPSC-CMs, including prolonged tau, and an increased ratio of relaxation force to contractile force in R170W-EHTs. These properties were reversed in the isogenic line, suggesting that our model recapitulates impaired relaxation of RCM, i.e., diastolic dysfunction in clinical practice. Furthermore, overexpression of wild-type TNNI3 in R170W-iPSC-CMs and -EHTs effectively rescued impaired relaxation. These results highlight the potential efficacy of EHT, a modality that can accurately recapitulate diastolic dysfunction in vitro, to elucidate the pathophysiology of RCM, as well as the possible benefits of gene therapies for patients with RCM.

Diagnostic performance of deep-learning-based virtual chromoendoscopy in gastric neoplasms.

BACKGROUNDS: Cycle-consistent generative adversarial network (CycleGAN) is a deep neural network model that performs image-to-image translations. We generated virtual indigo carmine (IC) chromoendoscopy images of gastric neoplasms using CycleGAN and compared their diagnostic performance with that of white light endoscopy (WLE). METHODS: WLE and IC images of 176 patients with gastric neoplasms who underwent endoscopic resection were obtained. We used 1,633 images (911 WLE and 722 IC) of 146 cases in the training dataset to develop virtual IC images using CycleGAN. The remaining 30 WLE images were translated into 30 virtual IC images using the trained CycleGAN and used for validation. The lesion borders were evaluated by 118 endoscopists from 22 institutions using the 60 paired virtual IC and WLE images. The lesion area concordance rate and successful whole-lesion diagnosis were compared. RESULTS: The lesion area concordance rate based on the pathological diagnosis in virtual IC was lower than in WLE (44.1% vs. 48.5%, p < 0.01). The successful whole-lesion diagnosis was higher in the virtual IC than in WLE images; however, the difference was insignificant (28.2% vs. 26.4%, p = 0.11). Conversely, subgroup analyses revealed a significantly higher diagnosis in virtual IC than in WLE for depressed morphology (41.9% vs. 36.9%, p = 0.02), differentiated histology (27.6% vs. 24.8%, p = 0.02), smaller lesion size (42.3% vs. 38.3%, p = 0.01), and assessed by expert endoscopists (27.3% vs. 23.6%, p = 0.03). CONCLUSIONS: The diagnostic ability of virtual IC was higher for some lesions, but not completely superior to that of WLE. Adjustments are required to improve the imaging system's performance.

Neuroport® makes brain biopsy less invasive and easy even in eloquent areas.

Tissue diagnosis of brain tumours in eloquent is often done via needle biopsy but this method yields small samples that may not be representative of the whole tumour. The Neuroport® system enables a larger tumour biopsy to be taken via a burr hole. We report our experience on 5 cases October 2017 and June 2018. Brainlab® navigation was used. The diagnosis in all patients was made without worsening of their modified Rankin scale scores.

Effectiveness of the 'hoisting method' for shunt placement.

PURPOSE: The abdominal procedure of ventriculoperitoneal or lumboperitoneal shunt is difficult because of a deep and narrow operative view, especially for obese patients. We have developed the 'Hoisting method,' which enables us to make abdominal procedures easy and safe. MATERIAL AND METHODS: We report our experience with five cases between April 2020 and March 2021. RESULTS: The placement of the shunt was easy and safe in all patients without any complications. CONCLUSION: The shunt method is very effective and easy without requiring additional devices.

Subcutaneous tanezumab for osteoarthritis of the hip or knee: efficacy and safety results from a 24-week randomised phase III study with a 24-week follow-up period.

OBJECTIVE: Tanezumab, a nerve growth factor inhibitor, was investigated for osteoarthritis (OA) of the hip or knee in a study with 24-week treatment and 24-week safety follow-up. METHODS: This double-blind, randomised, phase III study enrolled adults in Europe and Japan with moderate-to-severe OA who had not responded to or could not tolerate standard-of-care analgesics. Patients were randomised to tanezumab 2.5 mg or 5 mg subcutaneously or matching placebo every 8 weeks (three doses). Co-primary end points were change from baseline to week 24 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function, and Patient's Global Assessment of OA (PGA-OA). Joint safety and neurological assessments continued throughout the 48-week study. RESULTS: From March 2016 to December 2017, 849 patients were randomised and evaluated (placebo n=282, tanezumab 2.5 mg n=283, tanezumab 5 mg n=284). At week 24, there was a statistically significant improvement from baseline for tanezumab 5 mg compared with placebo for WOMAC Pain (least squares mean difference±SE -0.62±0.18, p=0.0006), WOMAC Physical Function (-0.71±0.17, p<0.0001) and PGA-OA (-0.19±0.07, p=0.0051). For tanezumab 2.5 mg, there was a statistically significant improvement in WOMAC Pain and Physical Function, but not PGA-OA. Rapidly progressive osteoarthritis (RPOA) was observed in 1.4% (4/283) and 2.8% (8/284) of patients in the tanezumab 2.5 mg and tanezumab 5 mg groups, respectively and none receiving placebo. Total joint replacements (TJRs) were similarly distributed across all three treatment groups (6.7%-7.8%). Tanezumab-treated patients experienced more paraesthesia (5 mg) and hypoaesthesia (both doses) than placebo. CONCLUSION: Tanezumab 5 mg statistically significantly improved pain, physical function and PGA-OA, but tanezumab 2.5 mg only achieved two co-primary end points. RPOA occurred more frequently with tanezumab 5 mg than tanezumab 2.5 mg. TJRs were similarly distributed across all three groups. TRIAL REGISTRATION NUMBER: NCT02709486.

A Multicenter, Prospective, Randomized, Placebo-Controlled, Double-Blind Study of a Novel Pain Management Device, AT-02, in Patients with Fibromyalgia.

OBJECTIVES: Existing treatments for fibromyalgia have limited efficacy, and only a minority of individuals clinically respond to any single intervention. This study was a prospective, multicenter, randomized, double-blind, controlled clinical trial to evaluate the feasibility of alternating magnetic field therapy in fibromyalgia patients by comparing the Angel Touch device (AT-02) with a sham control (S-01). METHODS: Two sites enrolled 44 subjects with diagnosed fibromyalgia. After informed consent, subjects taking prohibited concomitant drugs underwent a washout period of two or more weeks. All subjects then began a one-week run-in period. Numerical rating scale (NRS) pain scores were collected without device intervention for one day, followed by S-01 application to four or more painful sites for 10 minutes at each site, twice daily for six days. Subjects were then randomized to AT-02 or S-01, applied to four or more painful sites for 10 minutes at each site, twice daily for eight weeks. NRS scores were obtained twice daily during the entire treatment period. RESULTS: The primary end point (change in NRS ± SD at week 8 vs baseline) was -0.94 ± 1.33 in the AT-02 group and -0.22 ± 1.38 in the S-01 group. A trend toward a between-group difference in eight-week NRS scores favored the AT-02 group (-0.73, 95% confidence interval = -1.56 to 0.11, P = 0.086). An adjusted repeated measure analysis detected a significant difference in NRS scores (P = 0.039). CONCLUSIONS: The reduction in NRS scores for AT-02 relative to sham was comparable to reductions observed in meta-analyses of fibromyalgia drug therapy. The unadjusted results and the persistence of the pain score reductions remain encouraging.

Absence of Microbleeds Reduces the Risk for Recurrent Intracerebral Hemorrhage.

BACKGROUND: Many known risk factors, including hypertension and hyperlipidemia cause intracerebral hemorrhage (ICH). Recently, microbleeds have been identified as one of the factors leading to ICH. While some patients have been found to have recurrent ICH, risk factors for recurrent ICH are scarcely reported. We conducted an observational study on the risk-factors of recurrent ICH, comparing stroke patients with a single hemorrhagic episode and those with recurrent ICH. METHODS: A retrospective analysis of a single-center database was performed to analyze the clinical presentation and characteristics of patients with a single and recurrent ICH. From January 2016 to December 2017, a total of 317 patients were analyzed based on suspected factors including patients' sex, age, medical history, antiplatelet therapy use, and presence of microbleeds on images. RESULTS: Of the 317 patients, 36 patients (11.4%) developed a second episode of cerebral hemorrhage. Brain magnetic resonance imaging (MRI) of the patients without microbleeds, predicted reduced risk of recurrence. This is the first report strongly associating the presence of microbleeds with the possibility of a recurrent ICH. Other factors under study did not show an apparent association with recurrent ICH probably because of the high statistical significance obtained with the presence of microbleeds. CONCLUSION: Our findings revealed that the absence of microbleeds on images is a factor that strongly predicts a reduced risk for recurrent ICH and that the detection of microbleeds on MRI performed in patients with a single hemorrhagic episode, is useful in defining further therapeutic management. These findings may benefit physicians treating stroke patients.

Cutoff Value for Short Form of Central Sensitization Inventory.

OBJECTIVES: This study aimed to determine the optimal cutoff score of the 9-item short version of the CSI, the CSI-9, by comparing patients with central sensitivity syndrome (CSS) not only to healthy volunteers as with the original version, but also to patients with musculoskeletal (MSK) disorders. METHODS: All participants filled out the CSI, EuroQol 5-dimension, Brief Pain Inventory, and Pain Catastrophizing Scale questionnaires. To identify a clinically relevant cutoff score, receiver operating characteristic analyses were conducted. The area under the curve was used to examine the ability of the CSI-9 to distinguish patients with fibromyalgia (FM) from patients with MSK disorders and healthy individuals. RESULTS: Twenty-six participants with FM, 30 patients with MSK disorders, and 28 healthy individuals were included. We determined 2 cutoff scores: 20 for distinguishing patients with FM from patients with MSK disorders and 17 for distinguishing patients with FM from healthy individuals. These cutoff scores had good sensitivity (patients with MSK disorders, 92.3%; healthy individuals, 96.2%) and specificity (patients with MSK disorders, 93.3%; healthy individuals, 100%). In addition, the patients who scored above the cutoff of 20 points exhibited worse clinical symptoms (higher pain intensity, higher pain interference, higher Pain Catastrophizing Scale scores, and lower EuroQol 5-dimension scores) than those who scored below it. Furthermore, a significantly higher number of subjects who scored more than 20 on the CSI-9 had a history of 2 or more diagnoses of CSS. CONCLUSION: The optimal CSI-9 cutoff score of 20 is beneficial to clinicians in the evaluation of central sensitization-related symptoms. The cutoff score helps to identify patients who need additional treatments, such as pain neuroscience education and cognitive behavioral therapy.

Acquired Factor V Deficiency Associated with CFPM Administration.

BACKGROUND: Acquired factor V deficiency (AFVD) caused by Factor V (FV) inhibition is a rare event, characterized by prolonged prothrombin time and activated partial thromboplastin time. To date, various factors were reported as triggers for developing FV inhibitor. Clinical symptoms range from asymptomatic to life-threatening bleeding. Case Report and Conclusions: Here, we report an 84-year-old Japanese male on hemodialysis due to renal failure who developed subcutaneous hemorrhage after administration of cefepime (CFPM) to treat bacteremia. Deficient FV activity (< 1.0%) was identified and AFVD with FV inhibitor titer of 9 BU/mL was diagnosed. Although the patient had multiple risks for developing FV inhibitor, CFPM was thought to be the major culprit in this case. After the diagnosis, oral prednisolone (30 mg/day) was initiated, but the patient died of respiratory/cardiac failure, unrelated to AFVD.

[Two Case Reports of Paroxysmal Sympathetic Hyperactivity Following Craniotomy for Cerebral Hemorrhages].

Paroxysmal sympathetic hyperactivity(PSH)is a clinical condition characterized by abnormal paroxysmal surges in sympathetic nervous system activity. PSH is well known to happen after severe head injury and hypoxic encephalopathy. There are reports of cases of PSH developing after stroke, but PSH is not well recognized in the stroke field in Japan. Case 1 is a 79-year-old woman who became unconscious and suffered a large left mixed-type hemorrhage. Emergency craniotomy was performed. Two months postoperatively, she developed a high fever, tachycardia, tachypnea, and decerebrate posture. After taking clonazepam, her symptoms improved, and she was transferred to another hospital. Case 2 is a 67-year-old man with right hemiplegia, a history of thrombectomy for left M1, occlusion and left carotid artery stenting for asymptomatic left severe carotid artery stenosis performed one year previously. Five hours after right corotid artery stenting, he became restless and hemiplegic on his left side. His computed tomography showed extensive cerebral hemorrhage in the right hemisphere necessitating emergency craniotomy. About a month after surgery, he had a high fever, tachypnea, tachycardia, and decerebrate posture. Taking gabapentin improved his symptoms. Prolonged PSH may be a factor greatly impairing activities of daily living in stroke patients. It is important to diagnose and treat PSH early.

A Cross-Cultural Validation of the Multidimensional Pain Readiness to Change Questionnaire 2 for Japanese Individuals With Chronic Pain.

OBJECTIVES: The Multidimensional Pain Readiness to Change Questionnaire 2 (MPRCQ2) is a reliable and valid measure that assesses readiness to adopt a variety of discrete pain self-management responses. We sought to translate and evaluate psychometric properties of the Japanese version of the MPRCQ2 (MPRCQ2-J) in individuals with chronic pain. METHODS: One hundred seventy-three individuals with chronic pain were asked to complete the MPRCQ2-J, as well as measures assessing pain intensity, pain interference, self-efficacy, and general readiness to adopt a self-management approach for pain. Forty-eight of these participants provided additional MPRCQ2-J data to assess test-retest reliability. RESULTS: The findings supported a 2-factor structure of the MPRCQ2-J when error covariances between the some of the nine primary scales were allowed. Adequate internal consistencies of the MPRCQ2-J scales (Cronbach's α ranged 0.71 to 0.86), except for the total score (α = 0.68), were observed. However, adequate test-retest reliabilities (intraclass correlation coefficients ≥ 0.60) were found for only 59% of the MPRCQ2-J scales. The MPRCQ2-J evidenced its construct validity via confirmation of the predicted patterns of associations with validity criterion measures and the anticipated effects of participation in an exercise treatment. DISCUSSION: The findings support the internal consistency (except for the total score) and construct validity for MPRCQ2-J scales. However, potential limitations with respect to test-retest reliability of some of the scales were also suggested. The MPRCQ2-J can be used to examine the role that specific readiness domains of pain self-management responses may play in an adjustment process in Japanese individuals with chronic pain.

How Has Virtual Hepatectomy Changed the Practice of Liver Surgery?: Experience of 1194 Virtual Hepatectomy Before Liver Resection and Living Donor Liver Transplantation.

OBJECTIVE: To assess how virtual hepatectomy (VH), conducted using surgical planning software, influences the outcomes of liver surgery. BACKGROUND: Imaging technology visualizes the territories of the liver vessels, which were previously impossible. However, the clinical impact of VH has not been evaluated. METHODS: From 2004 to 2013, we performed 1194 VHs preoperatively. Outcomes of living donor liver transplantation (LDLT) and hepatectomy for hepatocellular carcinoma (HCC)/colorectal liver metastases (CRLM) were compared between patients in whom VH was performed (VH) and those without VH evaluation (non-VH). RESULTS: In LDLT, the rate of right liver graft use was higher in the VH (62.1%) than in the non-VH (46.5%) (P < 0.01), which did not increase morbidity of donor surgery. Duration of recipient surgery in the VH in which middle hepatic vein branch reconstruction was skipped was shorter than that in the VH with venous reconstruction. Among HCC patients with impaired liver function, portal territory-oriented resection was conducted more often in the VH than in the non-VH. The 5-year disease-free survival rate for localized HCC was higher in the VH than in the non-VH (37.2% vs 23.9%; P = 0.04). In CRLM, long-term outcomes were similar in the VH and non-VH despite the larger tumor load in the VH. CONCLUSIONS: VH in LDLT allows double equipoise for the recipient and donor by optimizing decision-making on graft selection and venous reconstruction. VH offers a chance for radical hepatectomy even in HCC patients with impaired liver function and CRLM patients with advanced tumors, without compromising survival.

Identification of Two Additional Genomic Loci Responsible for experimentally induced testicular teratoma 2 and 3 (ett2 and ett3).

Experimental testicular teratomas (ETTs) can be induced in 129/Sv mouse by E12.5 fetal testes transplant into adult testes. Previously, we conducted linkage analysis to explore candidate genes possibly involved in ETT development using F2 intercross fetuses derived from F1[LTXBJ × 129/Sv- + /Ter (+ /+)] hybrids. By linkage analysis on Chr 18 and Chr 19, we identified the genomic locus for experimental testicular teratoma 1 (ett1) on Chr 18. In the present study, we conducted additional mapping and linkage analysis on teratoma susceptibility and genome composition on Chr 1-17. The results revealed two new candidate loci, experimental testicular teratoma 2 (ett2) and experimental testicular teratoma 3 (ett3), on Chr 3 and 7. Interestingly, the rates of ETT generation were increased in the case of ett2 and ett3 regions replaced with LTXBJ strain. To determine whether a polymorphic gene was present, we performed exome analysis of 129/Sv- + /Ter (+ /+) and LTXBJ. This revealed the presence of SNPs in all three loci, ett1 to ett3. ett1 contains polymorphic Mc4r; ett2 contains polymorphic Polr3c, Cd160, and Pdzk1; and ett3 contains polymorphic Prmt3. We found additional loci responsible for ETT formation, namely, ett2 and ett3, and identified candidate genes in these regions by exome analysis.

Randomized open-label [corrected] non-inferiority trial of acetaminophen or loxoprofen for patients with acute low back pain.

BACKGROUND: Current worldwide clinical practice guidelines recommend acetaminophen as the first option for the treatment of acute low back pain. However, there is no concrete evidence regarding whether acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) is more effective for treating acute low back pain (LBP) in Japan. The present study aimed to investigate whether acetaminophen treatment for acute musculoskeletal pain was comparable with loxoprofen (a traditional NSAID in Japan) treatment. METHODS: Of the 140 patients with acute LBP who visited out-patient hospitals, 127 were considered eligible and were randomly allocated to a group taking acetaminophen or one taking loxoprofen. As primary outcome measure, pain intensity was measured using a 0-10-numeric rating scale (NRS). Moreover, pain disability, pain catastrophizing, anxiety, depression, and quality of life, as well as adverse events, were assessed as secondary outcomes. The primary outcome was tested with a noninferiority margin (0.84 on changes in pain-NRS), and the secondary outcomes were compared using conventional statistical methods at week 2 and week 4. RESULTS: Seventy patients completed the study (acetaminophen: 35, loxoprofen: 35). The dropout rates showed no significant difference between the two medication-groups. We found that the mean differences of changes in pain-NRS from baseline to week 2 or 4 between the two medication groups were not statistically beyond the noninferiority margin (mean [95% confidence interval]: -0.51 [-1.70, 0.67], at week 2 and -0.80 [-2.08, 0.48] at week 4). There were no consistent differences between the two medication groups in terms of secondary outcomes. CONCLUSIONS: The results suggest that acetaminophen has comparable analgesic effects on acute LBP, based on at least a noninferiority margin, compared with loxoprofen at 4 weeks. Acetaminophen seems to be a reasonable first-line option for patients with acute LBP in Japan.

New Portal-Superior Mesenteric Vein Reconstructions Using First Jejunal Vein Flap in Pancreaticoduodenectomy.

Pancreaticoduodenectomy (PD) is the only potential treatment for pancreatic head adenocarcinomas, which are sometimes located close to or invade the portal-superior mesenteric vein (PSMV). Surgeons often attempt to obtain a negative resectional margin after resection of the PSMV. This attempt requires PSMV reconstruction through graft replacements or end-to-end anastomosis; however, possible complications should be concerned including anastomosis stenosis, damage to some of the PSMV branches, prosthetic graft infection, and that associated with autologous graft harvesting. The first jejunal artery and vein are often resected in PD with the intent of lymphadenectomy. In this study, jejunal vein flap was used for PSMV reconstruction without causing damage to any of the PSMV branches in two patients. Here, we describe the new methods of PSMV reconstruction using first jejunal vein flap in PD.

The future of medical reimbursement for orthopedic surgery in Japan from the viewpoint of the health economy.

BACKGROUND: The financial burden of medical insurance on the government of Japan has recently become severe, which has led to the control of outpatient orthopedic reimbursements for common procedures. On the other hand, the overall disease burden for total hip or knee arthroplasty, decompression for cervical myelopathy or lumbar spinal canal stenosis, and new surgical technologies to treat other painful conditions and the post-surgical care related to these procedures has been reduced. METHODS: Medical insurance systems in Japan are generally influenced by budget-balancing action. Consequently, the further development of interventional evaluation methods should be promoted. From the viewpoint of health economics, the value (meaning) of medical intervention can partly be explained by its cost-effectiveness. In order for appropriate medical reimbursement levels to be set for orthopedic surgery, the financial status of medical institutions needs to be concurrently reviewed. In particular, the relationship between the expense structure and medical reimbursement must be discussed to evaluate its role in community medicine system. RESULTS: Over the past 10 years, medical expenditures have increased by 9.6% in all fields, whereas the monthly medical reimbursements per patient have dropped by an average of 17.5%. Remarkably, surgery-related costs have increased by 36.5%, while other medical costs have decreased by 19.8%. There are a few reports of cost-utility analyses which investigate interventions such as total hip arthroplasty for hip osteoarthritis patients (US$ 4,600-70,500/QALY) and laminectomy for patients with spinal canal stenosis. Interventions may be an inevitable part of relative expense control under the current trend; however, there has been a slight increase in other parameters in response to changes in medical reimbursement evaluations - specifically, in the total income of medical institutions. CONCLUSIONS: If medical professionals such as orthopedic surgeons contribute to the economic value of orthopedic surgery, it is crucial to clearly establish interventions among the different performances of medical reimbursement to motivate the increased allocation of management resources. To further develop this concept, discussions between stakeholders should involve the value of medicine based on cost and benefit.

Making steady progress on direct cardiac reprogramming toward clinical application.

A new report demonstrates direct cardiac reprogramming in human cells for the first time and points to the possibility of moving this technology toward clinical applications.

Enhanced survival of transplanted human induced pluripotent stem cell-derived cardiomyocytes by the combination of cell sheets with the pedicled omental flap technique in a porcine heart.

BACKGROUND: Transplantation of cardiomyocytes that are derived from human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) shows promise in generating new functional myocardium in situ, whereas the survival and functionality of the transplanted cells are critical in considering this therapeutic impact. Cell-sheet method has been used to transplant many functional cells; however, potential ischemia might limit cell survival. The omentum, which is known to have rich vasculature, is expected to be a source of blood supply. We hypothesized that transplantation of hiPS-CM cell sheets combined with an omentum flap may deliver a large number of functional hiPS-CMs with enhanced blood supply. METHODS AND RESULTS: Retrovirally established human iPS cells were treated with Wnt signaling molecules to induce cardiomyogenic differentiation, followed by superparamagnetic iron oxide labeling. Cell sheets were created from the magnetically labeled hiPS-CMs using temperature-responsive dishes and transplanted to porcine hearts with or without the omentum flap (n=8 each). Two months after transplantation, the survival of superparamagnetic iron oxide-labeled hiPS-CMs, assessed by MRI, was significantly greater in mini-pigs with the omentum than in those without it; histologically, vascular density in the transplanted area was significantly greater in mini-pigs with the omentum than in those without it. The transplanted tissues contained abundant cardiac troponin T-positive cells surrounded by vascular-rich structures. CONCLUSIONS: The omentum flap enhanced the survival of hiPS-CMs after transplantation via increased angiogenesis, suggesting that this strategy is useful in clinical settings. The combination of hiPS-CMs and the omentum flap may be a promising technique for the development of tissue-engineered vascular-rich new myocardium in vivo.