Mechanistic study of the effect of flexible fixation and load-bearing stress environment on fracture healing and shaping.

BACKGROUND: The biomechanical environment created by suture-button fixation Latarjet is conducive to the healing and shaping of the transplanted coracoid, but its mechanism remains unclear. The latest research has found that the absence of stem cell chemokine (CXCL12) impeded bone regeneration in Sonic Hedgehog (SHH)-deficient animals. However, whether the biomechanical environment affects SHH and CXCL12 function has not been studied. METHODS: Rat fracture models were constructed to simulate stress environments under non-load-bearing and load-bearing conditions. The fracture healing and shaping, as well as the expression levels of SHH and CXCL12, were assessed through gross viewing, micro-computed tomography (micro-CT), and histochemical staining. RESULTS: Under flexible fixation, the relative bone volume (BV/TV) of rats exposed to the load-bearing stress environment was significantly higher than that of rats under a non-load-bearing stress environment (p ≤ 0.05). Adverse bone shaping was not observed in rats subjected to flexible fixation. The levels of SHH and CXCL12 in load-bearing rats exhibited significant elevation (p ≤ 0.05). Under a load-bearing stress environment, no significant difference was observed in the BV/TV between the flexible fixation group and the rigid fixation group (p ≥ 0.05), but there was excessive hyperplasia of the fracture callus in the rigid fixation group. The levels of SHH and CXCL12 in rats subjected to rigid fixation were significantly elevated (p ≤ 0.05). CONCLUSIONS: Flexible fixation and load-bearing stress environment may contribute to bone healing and shaping by influencing the levels of SHH and CXCL12, suggested that this mechanism may be relevant to the healing and shaping of the transplanted coracoid after suture-button fixation Latarjet.

Riparian plant-soil-microbial C:N:P stoichiometry: are they conserved at plant functional group level?

As a consequence of the tight linkages between plants, soil, and microorganisms, we hypothesized the variations in plant species would change soil and microbial stoichiometry. Here, we examined the plant leaf carbon (C):nitrogen (N):phosphorus (P) ratios of nine species coming from three plant functional groups (PFGs) in the riparian zones of Hulunbuir steppe during near-peak biomass. The soil C:N:P, microbial biomass carbon (MBC):microbial biomass nitrogen (MBN), and extracellular enzyme's C:N:P were also assessed using the soils from each species. We found that plant tissue, soil nutrient, microbial, and enzyme activity stoichiometry significantly differed among different PFGs. Plant leaf and soil nutrient ratios tended to be similar (p > 0.05) between different species within the same PFGs. The variations in leaf C:N:P significantly correlated with the changes in soil C:N:P and MBC:MBN ratios. The homeostatic coefficients (H) < 1 suggested the relationships between plants and their resources C:N:P ratios might be non-homeostatic in the examined riparian zone. By assessing plant tissue and its soil nutrient stoichiometry, this study provided a perspective to understand the linkages of plant community, soil nutrient, and microbial characteristics.

Comparing the modified socket-shield technique with the conventional immediate implantation technique in the anterior dentition: A 5-year retrospective clinical study.

AIMS: The aim of this retrospective clinical study was to compare the 5-year radiological and clinical outcomes of patients undergoing immediate implantation with or without the modified socket-shield technique. MATERIALS AND METHODS: Patients who underwent anterior tooth replacement via the modified socket-shield technique (MSST) or the conventional immediate implantation technique (CIIT) between 2016 and 2017 were included. The labial bone thickness was assessed at different measurement levels (0, 2, 4 and 6 mm apical to the implant shoulder (IS)) postoperatively (T1), 6 months postoperatively (T2) and 5 years postoperatively (T3). The pink aesthetic score (PES) was evaluated before surgery (T0) and at T2 and T3. Implant success, complications and patient satisfaction were evaluated at every visit. RESULTS: Thirty-six patients (18 in the MSST group) underwent follow-up for 5 years, with no cases of implant failure. Two cases of exposure were detected in the MSST group, but there were no significant effects on hard or soft tissue. Patients in the MSST group showed less and more stable bone resorption than did those in the CIIT group at any measurement level and any time. A higher PES was achieved in the MSST group. Patient satisfaction was similar in both groups. CONCLUSIONS: The MSST is a reliable immediate implantation method because of its ability to preserve the alveolar bone and provide superior recovery of aesthetics.

Efficacy and mechanism of acupuncture in animal models of depressive-like behaviors: a systematic review and meta-analysis.

Background: Many studies have investigated the efficacy of acupuncture in treating depression, but the mechanism of acupuncture for depression is still controversial and there is a lack of meta-analysis of mechanisms. Consequently, we investigated acupuncture's efficacy and mechanism of depression. Methods: We searched the Cochrane Library, PubMed, EMBASE, Web of Science. The SYRCLE Risk of Bias Tool was used to assess bias risk. Meta-analysis was performed using Stata 15.0 for indicators of depression mechanisms, body weight and behavioral tests. Results: A total of 22 studies with 497 animals with depressive-like behaviors were included. Meta-analysis showed that acupuncture significantly increased BDNF [SMD = 2.40, 95% CI (1.33, 3.46); I2 = 86.6%], 5-HT [SMD = 2.28, 95% CI (1.08, 3.47); I2 = 87.7%] compared to the control group (p < 0.05), and significantly reduced IL-1ß [SMD = -2.33, 95% CI (-3.43, -1.23); I2 = 69.6%], CORT [SMD = -2.81, 95% CI (-4.74, -0.87); I2 = 86.8%] (p < 0.05). Acupuncture improved body weight [SMD = 1.35, 95% CI (0.58, 2.11); I2 = 84.5%], forced swimming test [SMD = -1.89, 95% CI (-2.55, -1.24); I2 = 76.3%], open field test (crossing number [SMD = 3.08, 95% CI (1.98, 4.17); I2 = 86.7%], rearing number [SMD = 2.53, 95% CI (1.49, 3.57); I2 = 87.0%]) (p < 0.05) compared to the control group. Conclusion: Acupuncture may treat animals of depressive-like behaviors by regulating neurotrophic factors, neurotransmitters, inflammatory cytokines, neuroendocrine system. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023403318, identifier (CRD42023403318).

Partial root-zone drying subsurface drip irrigation increased the alfalfa quality yield but decreased the alfalfa quality content.

Water shortage seriously restricts the development of grassland agriculture in arid land and dramatically impacts alfalfa (Medicago sativa L.) quality content and hay yield. Reasonable irrigation methods have the potential to enhance the alfalfa quality content, hay yield, and thus quality yield. Whether partial root-zone drying subsurface drip irrigation (PRDSDI) improves the alfalfa quality yield, quality content, and hay yield is still unknown compared with conventional subsurface drip irrigation (CSDI). The effects of PRDSDI compared with that of CSDI and the interaction with irrigation volume (10 mm/week, 20 mm/week, and 30 mm/week) on the alfalfa quality yield were investigated in 2017-2018 and explained the change in quality yield with the alfalfa quality content and hay yield. Here, the results showed that PRDSDI did not increase the alfalfa quality yield in 2 years. PRDSDI significantly increased acid detergent fiber by 13.3% and 12.2% in 2018 with 10-mm and 20-mm irrigation volumes and neutral detergent fiber by 16.2%, 13.2%, and 12.6% in 2017 with 10-mm, 20-mm, and 30-mm irrigation volumes, respectively. PRDSDI significantly decreased the crude protein by 5.4% and 8.4% in 2018 with 10-mm and 20-mm irrigation volumes and relative feed value by 15.0% with 20-mm irrigation volume in 2017 and 9.8% with 10-mm irrigation volume in 2018, respectively. In addition, PRDSDI significantly increased the alfalfa average hay yield by 49.5% and 59.6% with 10-mm and 20-mm irrigation volumes in 2018, respectively. Our results provide a counterexample for PRDSDI to improve crop quality. Although there was no significant improvement in average quality yield by PRDSDI, the positive impact of average hay yield on quality yield outweighed the negative impact of quality content. Thus, it has the potential to improve quality yields. The novel findings regarding the effects of PRDSDI on quality yield are potentially favorable for the forage feed value in water-limited areas.

Comparing Bone Alteration and Esthetic Recovery Between the Socket-Shield Technique and the Conventional Immediate Implant Technique: A Retrospective Study.

PURPOSE: To evaluate bone preservation and esthetic recovery between the socket-shield technique (SST) with different labial bone plate thicknesses and the conventional immediate implant technique (CIIT). MATERIALS AND METHODS: Patients who underwent immediate implant placement in the anterior region were divided into three groups: the SST with a thickwall phenotype (> 1 mm; SSTA group), the SST with a thin-wall phenotype (< 1 mm; SSTB group), and the CIIT with a thickwall phenotype (> 1 mm; CIIT group). Radiologic images and clinical photos were collected before surgery, immediately postoperatively, and 6 months postoperatively. The labial bone width, labial bone width change (BWC), labial bone volume change (BVC), pink esthetic score (PES), and complication rate were evaluated among the three groups. Statistical analysis was performed using SPSS software. RESULTS: A total of 60 patients (n = 20/group) were enrolled in this 6-month retrospective study. The BWC in the SSTA group (0.22 to 0.30 mm) and the SSTB group (0.18 to 0.33 mm) was less than that in the CIIT group (0.61 to 0.80 mm; P < .004). The SSTA group and the SSTB group had a lower BVC (24.08 vs 21.14 vs 54.81, respectively; P = .004) and greater PES (11.75 vs 11.65 vs 10.65, respectively; P = .009) than the CIIT group. No complications occurred among these patients. CONCLUSIONS: With the limitations of this study, it can be concluded that the SST is a reliable method for preserving bone and achieving satisfactory esthetic outcomes. The labial bone plate phenotype associated with the SST has minimal impact on both clinical and radiologic outcomes.

Biotic interactions contribute more than environmental factors and geographic distance to biogeographic patterns of soil prokaryotic and fungal communities.

Recent studies have shown distinct soil microbial assembly patterns across taxonomic types, habitat types and regions, but little is known about which factors play a dominant role in soil microbial communities. To bridge this gap, we compared the differences in microbial diversity and community composition across two taxonomic types (prokaryotes and fungi), two habitat types (Artemisia and Poaceae) and three geographic regions in the arid ecosystem of northwest China. To determine the main driving factors shaping the prokaryotic and fungal community assembly, we carried out diverse analyses including null model, partial mantel test and variance partitioning analysis etc. The findings suggested that the processes of community assembly were more diverse among taxonomic categories in comparison to habitats or geographical regions. The predominant driving factor of soil microbial community assembly in arid ecosystem was biotic interactions between microorganisms, followed by environmental filtering and dispersal limitation. Network vertex, positive cohesion and negative cohesion showed the most significant correlations with prokaryotic and fungal diversity and community dissimilarity. Salinity was the major environmental variable structuring the prokaryotic community. Although prokaryotic and fungal communities were jointly regulated by the three factors, the effects of biotic interactions and environmental variables (both are deterministic processes) on the community structure of prokaryotes were stronger than that of fungi. The null model revealed that prokaryotic community assembly was more deterministic, whereas fungal community assembly was structured by stochastic processes. Taken together, these findings unravel the predominant drivers governing microbial community assembly across taxonomic types, habitat types and geographic regions and highlight the impacts of biotic interactions on disentangling soil microbial assembly mechanisms.

Efficacy of belimumab in patients with systemic lupus erythematosus from North East Asia: Results of exploratory subgroup analyses.

OBJECTIVES: To assess belimumab efficacy in patients from North East Asia (NEA) with systemic lupus erythematosus (SLE) in baseline demographic/disease characteristic subgroups. METHODS: This analysis of patient subgroups from BLISS-NEA (GSK Study 113750; NCT01345253) studied adults with SLE randomized to belimumab (10 mg/kg intravenous) or placebo. Primary endpoint, SLE Responder Index 4 (SRI-4) response rate at Week 52, was analysed in subgroups defined by gender, country, prednisone-equivalent dose, concomitant medications, Safety of Estrogens in Lupus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score, complement (C) levels, anti-double-stranded deoxyribonucleic acid (dsDNA) positivity, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index score. RESULTS: Patients (overall population: N = 677; belimumab: n = 451, placebo: n = 226) were from China (76.4%), Korea (14.8%), and Japan (8.9%). The mean age was 32.1 years; 92.9% were female. In the overall population, more belimumab (53.8%) than placebo (40.1%) patients were SRI-4 Week 52 responders (p = .0001). SRI-4 response rates by subgroups were generally consistent with the overall population. A greater response with belimumab was seen in patients with a baseline SELENA-SLEDAI score ≥10 versus ≤9 and patients with low C3/C4 levels and anti-dsDNA positive at baseline versus those 'NOT' (low C3 and/or C4 and anti-dsDNA positive). CONCLUSIONS: These findings continue to support the efficacy of belimumab in SLE.

Large-scale Preparation of Synovial Fluid Mesenchymal Stem Cell-Derived Exosomes by 3D Bioreactor Culture.

Exosomes secreted by mesenchymal stem cells (MSCs) have been suggested as promising candidates for cartilage injuries and osteoarthritis treatment. Exosomes for clinical application require large-scale production. To this aim, human synovial fluid MSCs (hSF-MSCs) were grown on microcarrier beads, and then cultured in a dynamic three-dimension (3D) culture system. Through utilizing 3D dynamic culture, this protocol successfully obtained large-scale exosomes from SF-MSC culture supernatants. Exosomes were harvested by ultracentrifugation and verified by a transmission electron microscope, nanoparticle transmission assay, and western blotting. Also, the microbiological safety of exosomes was detected. Results of exosome detection suggest that this approach can produce a large number of good manufacturing practices (GMP)-grade exosomes. These exosomes could be utilized in exosome biology research and clinical osteoarthritis treatment.

Phase 3, long-term, open-label extension period of safety and efficacy of belimumab in patients with systemic lupus erythematosus in China, for up to 6 years.

OBJECTIVES: To evaluate the long-term safety and efficacy of belimumab in patients with systemic lupus erythematosus (SLE) in China. METHODS: In this phase 3, open-label extension period, eligible completers of study BEL113750 (NCT01345253) received intravenous belimumab 10 mg/kg monthly for ≤6 years. The primary endpoint was safety. Secondary endpoints included the SLE Responder Index (SRI)-4 response rate, severe SLE flares and changes in prednisone use. Analyses were based on observed data from the first dose of belimumab through to study end. RESULTS: Of the 424 patients who received belimumab, 215 (50.7%) completed the study, 208 (49.1%) withdrew and 1 patient died. Overall, 359/424 (84.7%) patients had adverse events (AEs), and 96/424 (22.6%) had serious AEs. 26/424 (6.1%) patients discontinued study treatment/withdrew from the study due to AEs. Postinfusion systemic reaction rate was 1.5 events/100 patient-years. Herpes zoster infection rate was 3.0 events/100 patient-years, of which 0.4 events/100 patient-years were serious events. One papillary thyroid cancer and one vaginal cancer were reported in year 0-1 and year 3-4, respectively. There were no completed suicides/suicide attempts and no reports of serious depression. The proportion of SRI-4 responders increased progressively (year 1, week 24: 190/346 (54.9%); year 5, week 48: 66/82 (80.5%)). Severe flares were experienced by 55/396 (13.9%) patients. For 335 patients with baseline prednisone-equivalent dose >7.5 mg/day, the number of patients with a dose reduction to ≤7.5 mg/day increased over time (year 1, week 24: 30/333 (9.0%); year 5, week 48: 36/67 (53.7%)). CONCLUSIONS: Favourable safety profile and disease control appeared to be maintained in patients with SLE in China for ≤6 years, consistent with previous belimumab studies.

Patient-reported outcomes from a randomized, double-blind, placebo controlled, phase III study of baricitinib versus placebo in patients with moderately to severely active rheumatoid arthritis and an inadequate response to methotrexate therapy: results from the RA-BALANCE study.

INTRODUCTION: To assess the effect of baricitinib on patient-reported outcomes (PROs) in patients with moderately to severely active rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX). METHODS: This was a 52-week, randomized, double-blind, placebo controlled, phase III study in patients with RA who had an inadequate response to MTX. Patients (n = 290) receiving stable background MTX were randomly assigned (1:1) to receive placebo or baricitinib 4 mg once daily with a primary endpoint at week 12. PROs assessed included Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity, patient's assessment of pain, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), European Quality of Life-5 Dimensions-5 Level index scores and visual analogue scale, and measures collected in electronic patient daily diaries: duration of morning joint stiffness, Worst Tiredness, and Worst Joint Pain. Treatment comparisons were made with logistic regression and analysis of covariance models for categorical and continuous variables, respectively. RESULTS: Statistically significant (p ⩽ 0.05) improvements in all PROs were observed in the baricitinib 4 mg group compared to placebo as early as week 1 to week 4; and were sustained to week 24. These improvements were maintained until week 52 for the baricitinib group. A significantly larger proportion of patients met or exceeded the minimum clinically important difference for HAQ-DI (⩾0.22) and FACIT-F (3.56) profiles in the baricitinib group. CONCLUSION: Baricitinib provided significant improvements in PROs compared to placebo to 52 weeks of treatment in patients with RA who had an inadequate response to MTX.Clinicaltrials.gov identifier: https://clinicaltrials.gov/ct2/show/NCT02265705; NCT02265705; RA-BALANCE. Registered 13 October 2014.

Association of homocysteine with ankylosing spondylitis: a systematic review and meta-analysis.

BACKGROUND: Hyperhomocysteinemia is associated with autoimmune diseases such as ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Current findings regarding plasma/serum homocysteine (HCY) levels in AS patients are inconsistent. This study aims to systematically evaluate the association between circulating HCY levels and AS. METHODS: Online electronic databases (PubMed, Web of Science, Embase, ScienceDirect, China National Knowledge Infrastructure (CNKI), and Wanfang data) were used to retrieve all relevant articles published up to May 7, 2020. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated using the random-effect model, Stata16 software. RESULTS: Nine articles containing 778 AS patients and 522 controls were included in this meta-analysis. No significant differences in HCY levels were found between AS and control groups (pooled SMD = 0.46, 95% CI = - 0.30 to 1.23, P = 0.23). However, subgroup analysis suggested that HCY levels were significantly higher (P < 0.05) in the AS group treated with methotrexate (MTX) compared with the control group. In contrast, HCY levels were significantly (P < 0.05) lower in the AS group receiving anti-TNF-α treatment compared with the control group. No significant differences were detected between HCY levels and disease activity scores (Bath AS disease activity index, BASDAI), and methylenetetrahydrofolate reductase (MTHFR) C677T genotype. CONCLUSION: This meta-analysis indicates that HCY levels are similar between AS and controls, and do not correlate with disease activity. However, different medical treatments cause fluctuations of circulating HCY levels in AS patients. Further and larger-scale studies are needed to confirm these findings. TRIAL REGISTRATION: This study was registered at international prospective register of systematic reviews (PROSPERO), registration number: CRD42020184426 .

Safety and Efficacy of Prefilled Liquid Etanercept-Biosimilar Yisaipu for Active Ankylosing Spondylitis: A Multi-Center Phase III Trial.

INTRODUCTION: The aim of this work is to examine the efficacy and safety of prefilled liquid etanercept-biosimilar Yisaipu versus lyophilized Yisaipu in active ankylosing spondylitis (AS) patients. METHODS: This double-blind, phase III trial with non-inferiority design randomized adult patients with active AS in a 3:1:1 ratio to receive twice-weekly 25-mg prefilled liquid Yisaipu for a total of 48 injections (group I, n = 330), once-weekly 50-mg prefilled liquid Yisaipu for 24 injections (group II, n = 110), or twice-weekly 25-mg lyophilized Yisaipu for 48 injections (group III, n = 110). Both physicians and patients who received 25-mg twice-weekly lyophilized or liquid Yisaipu were blinded to treatment assignment while patients who received 50-mg once-weekly liquid Yisaipu received treatment in an open-label design. In addition, 90 patients in the PK/PD study were randomized in a 1:1:1 ratio to each group. The primary outcome was the proportion of patients who achieved ASAS20 at week 24. RESULTS: A total of 640 subjects were enrolled. The proportion of patients who attained ASAS20 at week 24 was 85.56% in group I, 85.71% in group II, and 83.45% in group III (group I vs. III, P = 0.545; group II vs. III, P = 0.605). The difference between group I and III was 2.10% (95% CI - 5.06%, 9.27%) and 2.26% (95% CI - 6.21%, 10.73%) between group II and III, meeting the non-inferiority threshold (Δ = - 15%) (P < 0.001). Except for a statistical difference between group I (75.83%) and group III at week 8 (64.75%, P = 0.011), there was no statistical difference in the ASAS20 attainment rate among the three groups at other time points. The incidence of serious adverse events was comparable among the three groups (group I, 2.50%, II, 2.86% and III, 1.43%; P > 0.05). No deaths were reported. CONCLUSIONS: Once-weekly 50-mg or twice-weekly 25-mg prefilled liquid Yisaipu is safe and non-inferior to twice-weekly 25-mg lyophilized Yisaipu. TRIAL REGISTRATION: CTR20130124 and NCT04345458.

Administration of zoledronic acid alleviates osteoporosis in HIV patients by suppressing osteoclastogenesis via regulating RANKL expression.

BACKGROUND: Osteoporosis is a common phenomenon in HIV patients on tenofovir treatment, but its underlying mechanisms remain to be explored. METHODS: Quantitative real-time PCR was performed to analyze the expression of miR-302, miR-101, miR-145 and osteoclast-specific genes in the serum of HIV patients treated with tenofovir and ZOL. ELISA was used to evaluate the expression of RANKL, SMAD3 and PRKACB in the serum of these patients. Luciferase assay was carried out to explore the inhibitory effects of miR-302, miR-101 and miR-145 on the expression of PRKACB, RANKL and SMAD3, respectively. Western blot was used to examine the expression of genes involved in NF­κB and JNK signaling pathways. RESULTS: ZOL treatment significantly suppressed the expression of CTx and osteocalcin in HIV patients treated with tenofovir. The BMD loss of HIV patients treated with tenofovir was effectively hindered by ZOL treatment. Mechanistically, the expression of miR-302, miR-101, miR-145, RANKL, SMAD3 and PRKACB in the serum was remarkably activated by ZOL treatment. Luciferase assays showed that miR-302, miR-101 and miR-145 effectively suppressed the expression of PRKACB, RANKL and SMAD3, respectively, through binding to their 3' UTR. Furthermore, ZOL treatment notably restored the normal expression of osteoclast­specific genes while activating NF­κB and JNK signaling pathways. CONCLUSION: The findings of this study demonstrated that administration of ZOL suppressed the expression of RANKL via modulating signaling pathways of miR-101-3p/RANKL, miR-302/PRKACB/RANKL and miR-145/SMAD3/RANKL. Furthermore, down-regulated expression of RANKL by ZOL treatment alleviated osteoporosis in HIV-positive subjects treated with tenofovir.

Rapid Onset of Efficacy of Baricitinib in Chinese Patients with Moderate to Severe Rheumatoid Arthritis: Results from Study RA-BALANCE.

INTRODUCTION: Baricitinib is an oral, selective inhibitor of Janus kinase which demonstrates clinical efficacy in patients with rheumatoid arthritis (RA). This report aims to analyze the onset time of baricitinib in Chinese patients with moderately to severely active RA who had an inadequate response to methotrexate. METHODS: This post hoc analysis evaluated clinical improvements of Chinese patients treated with baricitinib 4 mg once daily compared with placebo, based on data from a phase 3 study RA-BALANCE. Efficacy measures including American College of Rheumatology 20% (ACR20) response, ACR core set values, Disease Activity Score modified to include the 28 diarthrodial joint count (DAS28) using high-sensitivity C-reactive protein (hsCRP), DAS28-erythrocyte sedimentation rate, Simplified Disease Activity Index, Clinical Disease Activity Index, DAS28-hsCRP ≤ 3.2 response (low disease activity), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated at weeks 1, 2, 4, 8, 12, 14, 16, 20, and 24 (except for FACIT-F evaluated every 4 weeks). A logistic regression model and an analysis of covariance model were used to analyze treatment comparisons of categorical and continuous measures, respectively. RESULTS: Statistically significant (p ≤ 0.05) improvements were observed as early as week 1 or 2 for the baricitinib group compared to placebo in almost all main efficacy measures. For other outcomes including 66 swollen joint count, 68 tender joint count, FACIT-F, and DAS28-hsCRP ≤ 3.2 response rate, differences were evident (p ≤ 0.05) by week 4 in the baricitinib group compared with placebo. Significant improvements in all efficacy measures were sustained through 24 weeks. CONCLUSIONS: Baricitinib demonstrated a rapid onset of efficacy on ACR20 response, ACR core set values, disease activity, and patient-reported outcome improvements in Chinese patients from RA-BALANCE. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02265705.

Cross-Tissue Characterization of Heterogeneities of Mesenchymal Stem Cells and Their Differentiation Potentials.

Mesenchymal stem/stromal cells (MSCs) are promising cell sources for regenerative medicine and the treatment of autoimmune disorders. Comparing MSCs from different tissues at the single-cell level is fundamental for optimizing clinical applications. Here we analyzed single-cell RNA-seq data of MSCs from four tissues, namely umbilical cord, bone marrow, synovial tissue, and adipose tissue. We identified three major cell subpopulations, namely osteo-MSCs, chondro-MSCs, and adipo/myo-MSCs, across all MSC samples. MSCs from the umbilical cord exhibited the highest immunosuppression, potentially indicating it is the best immune modulator for autoimmune diseases. MSC subpopulations, with different subtypes and tissue sources, showed pronounced differences in differentiation potentials. After we compared the cell subpopulations and cell status pre-and-post chondrogenesis induction, osteogenesis induction, and adipogenesis induction, respectively, we found MSC subpopulations expanded and differentiated when their subtypes consist with induction directions, while the other subpopulations shrank. We identified the genes and transcription factors underlying each induction at the single-cell level and subpopulation level, providing better targets for improving induction efficiency.

Exosome-Mediated Drug Delivery for Cell-Free Therapy of Osteoarthritis.

Osteoarthritis (OA) is a degenerative disease of cartilage and bones, which results in severely compromised quality of life in the aged population. However, currently, no ideal treatment strategies have been developed to prevent OA progression. Cell therapies, such as chondrocyte and MSC transplantation, have been extensively tested and evaluated in clinical trials. Yet, to day, the clinical efficacy of articular injection of stem cells in OA has not been convincingly demonstrated. Recent studies have indicated that exosomes, one type of Extracellular Vesicles (EVs) play an important regulatory role in the pathogenesis of OA, suggesting the prospective therapeutic application of exosomes in OA treatment. In this review, we systematically summarized the paracrine effects of exosomes derived from MSCs and chondrocytes on cartilage regeneration, the use of exosomes as a delivery vehicle for OA treatment, the effectiveness of such treatments in OA animal models, and the future perspective of exosome-mediated drug delivery as a cell- free therapy of OA.

Exosome-mediated delivery of kartogenin for chondrogenesis of synovial fluid-derived mesenchymal stem cells and cartilage regeneration.

Transplantation of synovial fluid-derived mesenchymal stem cells (SF-MSCs) is a viable therapy for cartilage degeneration of osteoarthritis (OA). But controlling chondrogenic differentiation of the transplanted SF-MSCs in the joints remains a challenge. Kartogenin (KGN) is a small molecule that has been discovered to induce differentiation of SF-MSCs to chondrocytes both in vitro and in vivo. The clinical application of KGN however is limited by its low water solubility. KGN forms precipitates in the cell, resulting in low effective concentration and thus limiting its chondrogesis-promoting activity. Here we report that targeted delivery of KGN to SF-MSCs by engineered exosomes leads to even dispersion of KGN in the cytosol, increases its effective concentration in the cell, and strongly promotes the chondrogenesis of SF-MSCs in vitro and in vivo. Fusing an MSC-binding peptide E7 with the exosomal membrane protein Lamp 2b yields exosomes with E7 peptide displayed on the surface (E7-Exo) that has SF-MSC targeting capability. KGN delivered by E7-Exo efficiently enters SF-MSCs and induces higher degree of cartilage differentiation than KGN alone or KGN delivered by exosomes without E7. Co-administration of SF-MSCs with E7-Exo/KGN in the knee joints via intra-articular injection also shows more pronounced therapeutic effects in a rat OA model than KGN alone or KGN delivered by exosomes without E7. Altogether, transplantation of SF-MSCs with in situ chondrogenesis enabled by E7-Exo delivered KGN holds promise towards as an advanced stem cell therapy for OA.

Association of homocysteine with ankylosing spondylitis: a systematic review and meta-analysis

Abstract Background: Hyperhomocysteinemia is associated with autoimmune diseases such as ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Current findings regarding plasma/serum homocysteine (HCY) levels in AS patients are inconsistent. This study aims to systematically evaluate the association between circulating HCY levels and AS. Methods: Online electronic databases (PubMed, Web of Science, Embase, ScienceDirect, China National Knowledge Infrastructure (CNKI), and Wanfang data) were used to retrieve all relevant articles published up to May 7, 2020. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated using the random-effect model, Stata16 software. Results: Nine articles containing 778 AS patients and 522 controls were included in this meta-analysis. No significant differences in HCY levels were found between AS and control groups (pooled SMD = 0.46, 95% CI = − 0.30 to 1.23, P = 0.23). However, subgroup analysis suggested that HCY levels were significantly higher (P < 0.05) in the AS group treated with methotrexate (MTX) compared with the control group. In contrast, HCY levels were significantly (P < 0.05) lower in the AS group receiving anti-TNF-α treatment compared with the control group. No significant differences were detected between HCY levels and disease activity scores (Bath AS disease activity index, BASDAI), and methylenetetrahydrofolate reductase (MTHFR) C677T genotype. Conclusion: This meta-analysis indicates that HCY levels are similar between AS and controls, and do not correlate with disease activity. However, different medical treatments cause fluctuations of circulating HCY levels in AS patients. Further and larger-scale studies are needed to confirm these findings. Trial registration: This study was registered at international prospective register of systematic reviews (PROSPERO), registration number: CRD42020184426.(AU)