Synovial mesenchymal stem cells secrete more lubricin than adipose mesenchymal stem cells after injection into rat osteoarthritis knees.

Intra-articular injection of mesenchymal stem cells (MSCs) is envisioned as a solution for knee osteoarthritis (OA). Although synovial MSCs (SyMSCs) are promising for cartilage regeneration, the clinical choice is usually adipose MSCs (AdMSCs). However, the similarities/differences in the mode of action between SyMSCs and AdMSCs remain unclear. Here, we compared factors secreted by human SyMSCs and AdMSCs after injection into OA knees. Human SyMSCs or AdMSCs were injected into the knees of rat partial meniscectomy models. The next day, the knee joints were collected to analyze the distribution of injected MSCs and transcriptome changes in the human MSCs and rat synovium. Non-injected MSCs were mixed with rat synovium as a control. After injection, no difference was apparent in intra-articular distribution of the SyMSCs or AdMSCs. RNA sequencing demonstrated an enrichment of cytokine-cytokine receptor interaction-related genes in both human SyMSCs and AdMSCs after injection. Differentially expressed genes (DEGs) specific to SyMSCs were associated with cartilage matrix synthesis and homeostasis. PCR analysis of the matrisome-related DEGs showed significantly higher expression of PRG4 in SyMSCs than in AdMSCs after injection. Immunostaining also confirmed a significantly greater expression of lubricin by SyMSCs than by AdMSCs. These findings indicate that SyMSCs will be a more promising treatment for OA.

Equivalent Clinical Outcomes Between Anatomical Alignment Versus Mechanical Alignment of Simultaneous Bilateral Total Knee Arthroplasty Using a Posterior-Stabilized Prosthesis During an Average Follow-Up of Five Years: A Prospective Randomized Clinical Trial.

BACKGROUND: This study aimed to investigate the differences in clinical outcomes between anatomical alignment and mechanical alignment in each knee, respectively, in patients who underwent bilateral total knee arthroplasty. METHODS: Bilateral simultaneous total knee arthroplasty using a posterior-stabilized prosthesis was performed between June 2016 and May 2018, with one knee undergoing anatomical alignment and the contralateral knee undergoing mechanical alignment, which was randomized. There were 80 knees in 40 patients (mean age 75 years, range 60 to 87, with 4 men and 36 women) followed up for at least two years (mean follow-up 4.9 years, range 2 to 7y). On the anatomical side, the distal femoral cut was set 2° more valgus to the mechanical axis, and the tibial cut was set to 2 or 3° varus using a specific guide. Implant position and lower extremity alignment were measured using postoperative radiographs and computed tomography images. The range of motion before and after surgery, Knee Society score, patient satisfaction, postoperative 2011 Knee Society questionnaire, and Knee Injury and Osteoarthritis Outcome Scores were evaluated. RESULTS: A significant difference was observed in joint line orientation (0.6 versus 2.9°, P < 0.001), but not in the postoperative hip-knee-ankle angle between two groups. There was one knee in the mechanical alignment group that required revision surgery at five years due to implant loosening. Before surgery, the anatomical alignment group had a significantly lower knee extension angle (-7.2 versus -6.0º, P = 0.035) and Knee Society score (46.1 versus 49.1, P = 0.046). No significant difference was observed between the groups except for the 2011 Knee Society questionnaire satisfaction scores (26.7 versus 25.7, P = 0.035). More participants preferred the anatomical alignment side postoperatively. CONCLUSION: Anatomical and mechanical alignments had similar clinical outcomes in patients undergoing bilateral total knee arthroplasty at a mean of 4.9 year follow-up.

Benziodarone and 6-hydroxybenziodarone are potent and selective inhibitors of transthyretin amyloidogenesis.

Transthyretin amyloidosis is a progressive systemic disorder that is caused by the amyloid deposition of transthyretin in various organs. Stabilization of the native transthyretin is an effective strategy for the treatment of transthyretin amyloidosis. In this study we demonstrate that the clinically used uricosuric agent benziodarone is highly effective to stabilize the tetrameric structure of transthyretin. An acid-induced aggregation assay showed that benziodarone had strong inhibitory activity similar to that of tafamidis, which is currently used as a therapeutic agent for transthyretin amyloidosis. Moreover, a possible metabolite, 6-hydroxybenziodarone, retained the strong amyloid inhibitory activity of benziodarone. An ex vivo competitive binding assay using a fluorogenic probe showed that benziodarone and 6-hydroxybenziodarone were highly potent for selective binding to transthyretin in human plasma. An X-ray crystal structure analysis revealed that the halogenated hydroxyphenyl ring was located at the entrance of the thyroxine binding channel of transthyretin and that the benzofuran ring was located in the inner channel. These studies suggest that benziodarone and 6-hydroxybenziodarone would potentially be effective against transthyretin amyloidosis.

Augmentation of a Nonanatomical Repair of a Medial Meniscus Posterior Root Tear With Centralization Using Three Knotless Anchors May Be Associated With Less Meniscal Extrusion and Better Compressive Load Distribution in Mid-Flexion Compared With Non-Anatomical Root Repair Alone in a Porcine Knee Model.

PURPOSE: To investigate the biomechanics of the centralization augmentation using knotless soft anchors to a nonanatomical transtibial pull-out root repair in a porcine medial meniscus posterior root tear (MMPRT) model. METHODS: Porcine knee joints (N = 10) were used to perform one of the following procedures: (1) intact; (2) MMPRT; (3) nonanatomical root repair; (4) nonanatomical root repair with centralization using 2 anchors: anchors were inserted at the posterior medial collateral ligament (MCL) border and 10 mm anterior to the posterior MCL border; and (5) nonanatomical root repair with centralization using 3 anchors: another anchor was placed 10 mm posterior to the posterior MCL border. Contact area on the medial meniscus (MM), contact pressure in the MM and tibial cartilage, and MM extrusion were evaluated at 30°, 45°, 60°, and 90° knee flexions under 200 N compressive force. RESULTS: MM extrusion at the posterior MCL border was significantly reduced after root repair with centralization using 3 anchors than after root repair alone at 30° (-0.063 mm vs 1.5 mm, P = .017), 45° (0.21 mm vs 1.7 mm, P = .018), and 60° (0.78 mm vs 2.3 mm, P = .019). There were no significant differences in MM extrusion between the root repair alone and root repair with centralization using 2 anchors at all flexion angles. The contact area in the middle and posterior MM was significantly greater after centralization with 3 anchors than after root repair alone at all flexion angles (except the posterior MM at 90°). The mean contact pressure in the tibial cartilage was significantly lower after centralization with 3 anchors than after root repair at all angles. CONCLUSIONS: Augmentation of a nonanatomical repair of a medial meniscus posterior root tear with centralization using three knotless anchors may be associated with less meniscal extrusion and better compressive load distribution between 30° and 60° flexion compared with nonanatomical root repair alone in a porcine model. CLINICAL RELEVANCE: This biomechanical study at time zero suggests that the addition of centralization using 3 knotless anchors may reduce MM extrusion and restore the load-distributing function of the MM.

Lateral-medial asymmetry of posterior tibial slope and small lateral tibial plateau articular surface depth are morphological factors of lateral meniscus posterior root tears in ACL-injured patients.

PURPOSE: To investigate whether knee morphological features, patient characteristics, and intraoperative findings are associated with a lateral meniscus (LM) posterior root tear (LMPRT) in anterior cruciate ligament (ACL) injuries with the integrated data from two academic centres. METHODS: This retrospective study used registry data acquired prospectively at two academic centres. Patients with ACL reconstruction (ACLR) with LMPRT and no other LM injury were selected (LMPRT group) from each database. The control group included patients who underwent ACLR without LM tears. Patients were matched to the LMPRT group according to age and gender (1:1). Morphological factors evaluated on preoperative magnetic resonance image scans included lateral femoral condyle (LFC) anterior-posterior diameter, height, and depth; lateral tibial plateau (LTP) articular surface (AS) depth and sagittal plane depth; and lateral and medial posterior tibial slopes (PTSs). LFC height and depth ratios, LTP AS depth and sagittal plane depth ratios, and lateral-to-medial slope asymmetry were computed from previous measurements. Patient characteristics and intraoperative findings were extracted and compared between both groups. RESULTS: The study included 252 patients (126 in each group). The lateral-medial asymmetry of PTS was greater in the LMPRT group (1.2° vs 0.3°, p < 0.05), and the LTP AS depth was smaller in the LMPRT group (31.4 mm vs 33.2 mm, p < 0.01). There were no differences in LFC morphology between the control and LMPRT groups. Pivot shift grade (p < 0.05), percentage of complete ACL tears (p < 0.05), and medial meniscus ramp lesions (p < 0.05) were significantly higher in the LMPRT group. CONCLUSION: LMPRT was associated with significantly increased lateral-medial asymmetry of PTS and significantly smaller LTP AS depth. LMPRT was also associated with an increase in the preoperative pivot shift grade and the presence of a medial meniscus ramp lesion. These morphological characteristics are rather simple to measure and would serve as helpful indicators to preoperatively detect LMPRT, which is frequently challenging to diagnose preoperatively. LEVEL OF EVIDENCE: Level III.

Low central sensitisation inventory score is associated with better post-operative outcomes of osteotomy around the knee.

PURPOSE: The purpose of this study was to investigate the potential association between central sensitisation inventory (CSI) scores and post-operative patient-reported outcomes (PROs) in patients underwent osteotomy around the knee (OAK), with a CSI cut-off score specific for knee osteoarthritis. METHODS: CSI scores were collected from 173 patients who underwent OAK, along with their knee injury and osteoarthritis outcome score (KOOS) and pain numeric rating scale (NRS) scores. Patients were divided into high-CSI score group and low-CSI score group with a cut-off score of 17. Multivariate linear regression was performed to test the association between CSI scores and post-operative outcomes. Pre-surgery KOOS and NRS scores and the rate of attainment of minimal clinically important difference (MCID) of KOOS scores was analysed as secondary outcomes. RESULTS: Low-CSI score group had significantly higher post-operative KOOS scores and lower pain NRS scores compared to the high-CSI score group (< p = 0.01) after adjusting for confounding factors. For pre-operative scores, only the KOOS-Symptom score was significantly different between the groups (64.7 ± 20.1 when CSI < 17 vs.55.1 ± 19.7 when CSI ≥ 17; p = 0.008). The low-CSI score group had significantly higher MCID achievement rates of KOOS-Pain, Symptom, and ADL than the high-CSI score group (86% vs. 68%; 74% vs. 55%; 86% vs. 67%, respectively; P < 0.05). CONCLUSIONS: This study established an association between post-operative CSI scores ≥ 17 and poorer outcomes following OAK, highlighting the potential value of the CSI in identifying patients in need of more comprehensive peri-operative pain management. LEVEL OF EVIDENCE: Level III. Retrospective comparative study.

Simultaneous bilateral total knee arthroplasty is safe and effective for patients in different ages.

BACKGROUND: Simultaneous bilateral total knee arthroplasty is considered beneficial for patients with bilateral end-stage knee osteoarthritis, even though there could be potential postoperative complications. Presently, there is a paucity of evidence of the efficacy and safety of SB-TKA for elderly patients. This study aimed to compare the clinical outcomes of simultaneous bilateral total knee arthroplasty by different age groups. METHODS: A total of 216 knees of 108 patients, who underwent simultaneous bilateral total knee arthroplasty for osteoarthritis at our hospital between April 2015 and September 2018, were divided into three groups based on age: 60s (44 knees), 70s (106 knees), and 80s (66 knees). Perioperative data and postoperative clinical outcomes 1 year after surgery were compared between the age groups. RESULTS: The patients in the Group 60s were characterized by a higher body mass index (BMI) (P < 0.01), a lower pre-operative knee function score (P < 0.01), longer operation time (P < 0.01), greater intra-operative (P < 0.01), and postoperative bleeding (P = 0.026). No significant difference was found in terms of occurrence of various postoperative complications, although deep vein thrombosis and delirium occurred slightly more frequently in the Group 70s and the Group 80s than in the Group 60s group. The Knee Society Knee Score, a function score, and patient satisfaction scores were significantly improved in all groups 1 year after surgery. Moreover, these indexes of clinical outcomes were similar among the three groups. CONCLUSION: Performing simultaneous bilateral total knee arthroplasty in 80s patients was found to be as safe and effective as in the 60s and 70s patients. LEVEL OF EVIDENCE: 3 (A retrospective cohort study).

Mid-term clinical outcomes of a posterior stabilized total knee prosthesis for Japanese patients: A minimum follow-up of 5 years.

BACKGROUND: A high-flexion posterior-stabilized total knee prosthesis has been developed for the Asian population. The component design was based on computed tomography images of Japanese osteoarthritic knees. The femoral component is composed of zirconia ceramics, which exhibit low friction and high durability. The present study aimed to evaluate the mid-term clinical outcomes of this implant. METHODS: This study included 334 knees of 210 patients who underwent primary total knee arthroplasty with this implant at our hospital between October 2010 and December 2014. The patients comprised 28 men and 172 women with an average age of 73 years. The average follow-up period was 5.9 years, and the follow-up rate was 71.1%. Clinical outcomes were assessed using the Knee Society scoring system, 2011 Knee Society questionnaire, and Knee Injury and Osteoarthritis Outcome Score. Kaplan-Meier survivorship analysis was performed to determine the cumulative prosthesis survival rate. RESULTS: In terms of clinical outcomes at the final follow-up, the average ranges of motion were -2.0 in extension and 126.7 in flexion. The Knee Society knee and function scores were 94.2% and 72.6%, respectively. With revision surgery or radiographic failure for any reason as the endpoint, the survival rates at 5 and 9 years were 98.2% and 95.5%, respectively. The most common reason for revision surgery or radiological failure was aseptic loosening. CONCLUSIONS: Despite several revision cases mainly due to aseptic loosening, the present study found that this new high-flexion posterior-stabilized total knee arthroplasty prosthesis design showed comparable results for Asian populations with other PS prosthesis. LEVELS OF EVIDENCE: Level Ⅱ (Prospective cohort study).

Impact of Structural Abnormalities in Left Ventricle and Left Atrium on Clinical Outcomes in Heart Failure with Preserved Ejection Fraction.

Two key echocardiographic parameters, left ventricular mass index (LVMI) and left atrial volume index (LAVI), are important in assessing structural myocardial changes in heart failure (HF) with preserved ejection fraction (HFpEF). However, the differences in clinical characteristics and outcomes among groups classified by LVMI and LAVI values are unclear.We examined the data of 960 patients with HFpEF hospitalized due to acute decompensated HF from the PURSUIT-HFpEF registry, a prospective, multicenter observational study. Four groups were classified according to the cut-off values of LVMI and LAVI [LVMI = 95 g/m2 (female), 115 g/m2 (male) and LAVI = 34 mL/m2]. Clinical endpoints were the composite of HF readmission and all-cause death. Study endpoints among the 4 groups were evaluated. The composite endpoint occurred in 364 patients (37.9%). Median follow-up duration was 445 days. Kaplan-Meier analysis revealed significant differences in the composite endpoint among the 4 groups (P < 0.001). Cox proportional hazards analysis demonstrated that patients with increased LAVI alone were at significantly higher risk of HF readmission and the composite endpoints than those with increased LVMI alone (P = 0.030 and P = 0.024, respectively). Age, male gender, systolic blood pressure at discharge, atrial fibrillation (AF) hemoglobin, renal function, and LAVI were significant determinants of LVMI and female gender, AF, hemoglobin, and LVMI were significant determinants of LAVI.In HFpEF patients, increased LAVI alone was more strongly associated with HF readmission and the composite of HF readmission and all-cause death than those with increased LVMI alone.

Abdominal obesity, and not general obesity, is associated with a lower 123I MIBG heart-to-mediastinum ratio in heart failure patients with preserved ejection fraction.

BACKGROUND: The relationship between general obesity or abdominal obesity (abdominal circumference of ≥85 cm in men and ≥ 90 cm in women) and the heart-to-mediastinum ratio (HMR), a measure of cardiac sympathetic innervation, on cardiac iodine-123-metaiodobenzylguanidine scintigraphy (MIBG) in patients with heart failure with preserved ejection fraction (HFpEF) has not been clarified. METHODS: A total of 239 HFpEF patients with both MIBG and abdominal circumference data were examined. We divided these patients into those with abdominal obesity and those without it. In the cardiac MIBG study, early phase image was acquired 15-20 min after injection, and late phase image was acquired 3 h after the early phase. A HMR obtained from a low-energy type collimator was converted to that obtained by a medium-energy type collimator. RESULTS: Early and late HMRs were significantly lower in those with abdominal obesity, although washout rates were not significantly different. The incidence of patients with early and late HMRs <2.2 was significantly higher in those with abdominal obesity. Multivariate linear regression analysis revealed that abdominal obesity was independently associated with early HMR (standardized ß = -0.253, P = 0.003) and late HMR (standardized ß = -0.222, P = 0.010). Multivariate logistic regression analysis revealed that abdominal obesity was independently associated with early (odds ratio [OR] [95% confidence interval {CI}] = 4.25 [2.13, 8.47], P < 0.001) and late HMR < 2.2 (OR [95% CI] = 2.06 [1.11, 3.83], P = 0.022). Elevated BMI was not significantly associated with low early and late HMR. The presence of abdominal obesity was significantly associated with low early and late HMR even in patients without elevated BMI values. CONCLUSION: Abdominal obesity, but not general obesity, in HFpEF patients was independently associated with low HMR, suggesting that visceral fat may contribute to decreased cardiac sympathetic activity in patients with HFpEF. TRIAL REGISTRATION: UMIN000021831.

Effects of different surgical procedures for meniscus injury on two-year clinical and radiological outcomes after anterior cruciate ligament reconstructions. -TMDU MAKS study.

BACKGROUND: The treatment of meniscus injuries combined with anterior cruciate ligament (ACL) reconstruction would be important to improve outcomes after ACL reconstruction. However, the effects of treatment methods for meniscus after ACL reconstruction have not been thoroughly investigated. The objective of this study was to investigate the effects of treatment methods for meniscus on clinical and radiological outcomes at 2 years after ACL reconstruction. METHODS: Three-hundred and eighteen patients with primary ACL reconstruction using autologous hamstring tendon registered in our multicenter study database and who were followed up for 2 years were included. They were then divided into 3 groups, the no meniscal lesion/untreated group (n = 149), the meniscal repair group (n = 139), and the meniscal resection group (n = 30). Patient-based subjective evaluations (Lysholm score, Knee injury and Osteoarthritis Outcome score and International Knee Documentation Committee subjective score), objective evaluations (Lachman test, pivot shift test and KT measurement), and radiological measurements (medial and lateral joint space width) were compared among the 3 groups preoperatively and at 2 years follow-up. RESULTS: All subjective scores and objective evaluations significantly improved in all groups without significant differences among the groups postoperatively. Regarding radiological findings, the medial joint space width significantly decreased only in the resection group during the 2-year period, and the medial joint space width in the resection group was significantly smaller than that of the other groups at the 2-year follow-up. Moreover, the medial joint space width significantly decreased during the 2-year period when MM was resected. CONCLUSIONS: In radiological findings, medial meniscus resection decreased medial joint space width two years after ACL reconstruction. On the other hand, treatment methods for meniscus neither significantly affected subjective nor objective findings until the 2-year follow-up. LEVEL OF EVIDENCE: Ⅱ, Cohort study.

Substrate-induced product-release mechanism of lipocalin-type prostaglandin D synthase.

Prostaglandin D2 (PGD2), an endogenous somnogen, is a unique PG that is secreted into the cerebrospinal fluid. PGD2 is a relatively fragile molecule and should be transported to receptors localized in the basal forebrain without degradation. However, it remains unclear how PGD2 is stably carried to such remote receptors. Here, we demonstrate that the PGD2-synthesizing enzyme, Lipocalin-type prostaglandin D synthase (L-PGDS), binds not only its substrate PGH2 but also its product PGD2 at two distinct binding sites for both ligands. This behaviour implys its PGD2 carrier function. Nevertheless, since the high affinity (Kd = âˆ¼0.6 µM) of PGD2 in the catalytic binding site is comparable to that of PGH2, it may act as a competitive inhibitor, while our binding assay exhibits only weak inhibition (Ki = 189 µM) of the catalytic reaction. To clarify this enigmatic behavior, we determined the solution structure of L-PGDS bound to one substrate analog by NMR and compared it with the two structures: one in the apo form and the other in substrate analogue complex with 1:2 stoichiometry. The structural comparisons showed clearly that open or closed forms of loops at the entrance of ligand binding cavity are regulated by substrate binding to two sites, and that the binding to a second non-catalytic binding site, which apparently substrate concentration dependent, induces opening of the cavity that releases the product. From these results, we propose that L-PGDS is a unique enzyme having a carrier function and a substrate-induced product-release mechanism.

Prognostic Impact of Echocardiographic Diastolic Dysfunction on Outcomes in Patients With Heart Failure With Preserved Ejection Fraction　- Insights From the PURSUIT-HFpEF Registry.

BACKGROUND: Although diastolic dysfunction is important pathophysiology in heart failure with preserved ejection fraction (HFpEF), its prognostic impact in HFpEF patients, including those with atrial fibrillation (AF), remains to be elucidated.Methods and Results:We included the data for 863 patients (321 patients with AF) registered in a prospective multicenter observational study of patients with HFpEF. Patients were divided into 3 groups according to the 2016 ASE/EACVI recommendations. The primary endpoint was a composite of all-cause death or HF rehospitalization. Median age was 83 years, and 55.5% were female. 196 (22.7%) were classified with normal diastolic function (ND), 253 (29.3%) with indeterminate (ID) and 414 (48.0%) with diastolic dysfunction (DD). The primary endpoint occurred more frequently in patients with DD than in those with ND or ID (log-rank P<0.001 for DD vs. ND, and log-rank P=0.007 for DD vs. ID, respectively). Taking ND as the reference, multivariable Cox regression analysis revealed that DD (hazard ratio (HR): 1.57, 95% confidence interval (CI):1.06-2.32, P=0.024) was independently associated with the composite endpoint, whereas ID (HR: 1.28, 95% CI: 0.84-1.95, P=0.255) was not. DD was associated with the composite endpoint in both patients with and without AF. CONCLUSIONS: HFpEF patients classified with DD using the 2016 ASE/EACVI recommendations had worse clinical outcomes than those with ND or ID. DD may be considered a prognostic marker in patients with HFpEF regardless of AF.

Inhibitory activities of anthraquinone and xanthone derivatives against transthyretin amyloidogenesis.

Transthyretin is a tetrameric protein which functions as a transporter of thyroxine and retinol-binding protein. Misfolding and amyloid aggregation of transthyretin are known to cause wild-type and hereditary transthyretin amyloidosis. Stabilization of the transthyretin tetramer by low molecular weight compounds is an efficacious strategy to inhibit the aggregation pathway in the amyloidosis. Here, we investigated the inhibitory activities of anthraquinone and xanthone derivatives against amyloid aggregation, and found that xanthone-2-carboxylic acid with one chlorine or methyl group has strong inhibitory activity comparable with that of diflunisal, which is one of the best known stabilizers of transthyretin. X-ray crystallographic structures of transthyretin in complex with the compounds revealed that the introduction of chlorine, which is buried in a hydrophobic region, is important for the strong inhibitory effect of the stabilizer against amyloidogenesis. An in vitro absorption, distribution, metabolism and elimination (ADME) study and in vivo pharmacokinetic study demonstrated that the compounds have drug-like features, suggesting that they have potential as therapeutic agents to stabilize transthyretin.

Prognostic relevance of elevated plasma osmolality on admission in acute decompensated heart failure with preserved ejection fraction: insights from PURSUIT-HFpEF registry.

BACKGROUND: Complicated pathophysiology makes it difficult to identify the prognosis of heart failure with preserved ejection fraction (HFpEF). While plasma osmolality has been reported to have prognostic importance, mainly in heart failure with reduced ejection fraction (HFrEF), its prognostic meaning for HFpEF has not been elucidated. METHODS: We prospectively studied 960 patients in PURSUIT-HFpEF, a multicenter observational study of acute decompensated HFpEF inpatients. We divided patients into three groups according to the quantile values of plasma osmolality on admission. During a follow-up averaging 366 days, we examined the primary composite endpoint of cardiac mortality or heart failure re-admission using Kaplan-Meier curve analysis and Cox proportional hazard testing. RESULTS: 216 (22.5%) patients reached the primary endpoint. Kaplan-Meier curve analysis revealed that the highest quantile of plasma osmolality on admission (higher than 300.3 mOsm/kg) was significantly associated with adverse outcomes (Log-rank P = 0.0095). Univariable analysis in the Cox proportional hazard model also revealed significantly higher rates of adverse outcomes in the higher plasma osmolality on admission (hazard ratio [HR] 7.29; 95% confidence interval [CI] 2.25-23.92, P = 0.0009). Multivariable analysis in the Cox proportional hazard model also showed that higher plasma osmolality on admission was significantly associated with adverse outcomes (HR 5.47; 95% CI 1.46-21.56, P = 0.0113) independently from other confounding factors such as age, gender, comorbid of atrial fibrillation, hypertension history, diabetes, anemia, malnutrition, E/e', and N-terminal pro-B-type natriuretic peptide elevation. CONCLUSIONS: Higher plasma osmolality on admission was prognostically important for acute decompensated HFpEF inpatients.

Comparison of tissue pharmacokinetics of esflurbiprofen plaster with flurbiprofen tablets in patients with knee osteoarthritis: A multicenter randomized controlled trial.

This open-label, multicenter, prospective, randomized controlled trial aimed to determine the effectiveness of esflurbiprofen plaster (SFPP) and flurbiprofen tablets (FPTs) on knee osteoarthritis in patients scheduled for total knee arthroplasty by comparing the transfer of esflurbiprofen and flurbiprofen to tissues and fluids. Thirty-eight patients were randomly assigned in a 1:1 ratio to receive SFPP or FPT. Both groups were then divided into four subgroups, according to whether they received the final dose of SFPP or FPT at 2, 7, 12, or 24 h before planned surgery. The primary endpoints were the esflurbiprofen concentrations in synovium, synovial fluid, and plasma. Areas under concentration-time curves (AUC0-24 h ) of esflurbiprofen were calculated for each group. Pain was assessed using a numeric rating scale (NRS) 7 days before and immediately before surgery. The AUC0-24 h in the synovium were 4401.24 and 4862.70 ng·h/g in the SFPP and FPT groups, respectively. Maximum esflurbiprofen concentrations were observed in the synovium, synovial fluids, and plasma after SFPP application for 12 h. The NRS results indicated a long-lasting effect of SFPP. The AUC of the synovial esflurbiprofen concentration of SFPP indicated that the SFPP is transferred to the synovium and synovial fluid in high concentration. The efficient deep-tissue transfer of esflurbiprofen suggests that its pharmacokinetic characteristics differ from those of conventional topical NSAIDs. This study was prospectively registered in the Japan Registry of Clinical Trials (registration number: jRCTs031180228).

Knee laxity, lateral meniscus tear and distal femur morphology influence pivot shift test grade in ACL injury patients.

PURPOSE: Although several factors have been considered to be associated with pivot shift test grade in ACL injured patients, a conclusion regarding which factors contribute to the pivot shift test grade has not been reached. The purpose of this study was to identify factors associated with preoperative pivot shift test grade. METHODS: Three hundred and sixty-six consecutive patients who underwent ACL reconstruction in our hospital were enrolled in the study. Patients were divided into two groups on the basis of preoperative pivot shift test grade (Mild: grade 0-3, Severe: grade 4-6). First, 13 independent variables (age, gender, period from injury to surgery, hyperextension, KT measurement, contralateral side pivot shift test grade, medial and lateral tibial slope, lateral condyle length, lateral condyle height, distal femoral condyle offset, medial and lateral meniscus tear) were analyzed by one-way ANOVA and Chi-squared test. Binary Logistic regression was then performed based on the results of univariate analyses (independent variables of p < 0.2 were included). RESULTS: Hyperextension, lateral meniscus tear, contralateral side pivot shift test grade, distal femoral condyle offset and KT measurement were identified as risk factors for preoperative pivot shift grade via logistic regression analysis. CONCLUSION: The current study revealed that hyperextension, lateral meniscus tear, contralateral side pivot shift test grade, distal femoral condyle offset and anterior instability were associated with preoperative pivot shift grade. Patients with above factors that cannot be modified during surgery may need special consideration when ACL reconstruction is performed, as greater preoperative pivot shift has been proven to be a risk factor for residual pivot shift after ACL reconstruction. LEVEL OF EVIDENCE: III.

Trends in arthroplasty in Japan by a complete survey, 2014-2017.

BACKGROUND: Precise knowledge of the prevalence and trends of arthroplasty can facilitate the design of medical plans for efficient treatments. The National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) Open Data Japan provides statistics about the annual number of arthroplasties (knee, hip, shoulder, finger, elbow, and foot/ankle) through health insurance claim numbers for these surgeries. The purpose of this study was to document the annual arthroplasty numbers between 2014 and 2017 in Japan and to analyze their four-year trends, gender differences, age distributions, and regional differences as revealed by the complete survey. METHODS: Numbers of arthroplasty surgeries were extracted from the NDB Open Data Japan for 2014-2017. For "knee", "hip", "shoulder", "finger", "elbow", and "foot/ankle" arthroplasties, we showed the annual arthroplasty numbers, annual arthroplasty numbers by age group, annual arthroplasty numbers in individual prefectures, and annual arthroplasty numbers per 100,000 population in individual prefectures. RESULTS: The annual arthroplasty numbers in 2017 were 146,189 for all joints, 82,304 for knees, 59,029 for hips, 2454 for shoulders, 1551 for fingers, 536 for elbows, and 291 for feet/ankles. For the four years up to 2017, the rate of alteration in the number of arthroplasties was +14% for total arthroplasties, +9% for knees, +21% for hip joints, +97% for shoulders, + 8% for fingers, -10% for elbows, and +25% for feet/ankles. The proportion of females was 70-90% and the peak age was between the late 60s and late 70s for all joints. Variations in arthroplasty numbers per population by prefecture appeared to be small for knees and hips and large for other joints. CONCLUSIONS: We revealed the annual total number of arthroplasties for each joint in Japan using the NDB Open Data Japan for the first time.

Underweight Is Associated with Poor Prognosis in Heart Failure with Preserved Ejection Fraction.

The obesity paradox states higher body mass index (BMI) is associated with better outcomes than normal weight in patients with heart failure with preserved ejection fraction (HFpEF). However, underweight was defined by BMI < 18.5 kg/m2, and results have been inconclusive, in part due to small number of participants. The number of underweight patients with HFpEF is higher in Asian than in Western countries. In this study, we aim to determine the prognostic impact of underweight in patients with HFpEF in Asian population.We enrolled 846 consecutive patients from the PURSUIT-HFpEF registry. We then divided them into three groups by BMI, namely, underweight (BMI < 18.5 kg/m2), normal weight (18.5 ≤ BMI < 23), and overweight (23 ≤ BMI). The underweight group consisted of 187 patients (22%). Over a mean follow-up of 407 days, 105 deaths were reported as all-cause mortality. On multivariable Cox analysis, the underweight group was determined to be significantly associated with higher risk of all-cause mortality than the normal and overweight groups (Hazard ratios [HR]: 2.33; 95% confidence intervals [CI]: 1.45-3.75, P < 0.001; HR: 3.54; 95% CI: 1.99-6.29, P < 0.001, respectively), after adjustment for age, sex, vital signs, and comorbidities.Underweight is a useful predictor of poor prognosis in patients with HFpEF in Asian population.

Crystal structures clarify cofactor binding of plant tyrosine decarboxylase.

Plant tyrosine decarboxylase (TyrDC) is a group II pyridoxal 5'-phosphate (PLP)-dependent decarboxylase that mainly catalyzes the decarboxylation of tyrosine to tyramine. This is biologically important for diverting essential primary metabolites into secondary metabolic pathways. Intensive studies have characterized the effective of PLP-binding and the substrate specificity of mammalian 3,4-dihydroxyphenyl-l-alanine (Dopa) decarboxylases, a member of group II PLP-dependent decarboxylase. However, the characteristics of PLP binding and substrate specificity of plant TyrDCs remain unknown. In this study, we focus on the PLP binding manner, and determined the crystal structures of the apo and PLP binding form of type II TyrDC from Papaver somniferum (PsTyrDCII and PsTyrDCII-PLP). The structures showed that, unlike mammalian Dopa decarboxylase, the binding of PLP does not induce distinct conformational changes of PsTyrDCII regarding the overall structure, but the PLP binding pocket displays conformational changes at Phe124, His203 and Thr262. Combining structural comparation and the obtained biochemical findings, it is demonstrated that PsTyrDCII does not binds PLP tightly. Such characteristics of PLP binding may be required by its catalytic reaction and substrate binding. The activity of TyrDC probably regulated by the concentration of PLP in cells.