bluuebunny/crossref_metadata_2025_split huggingface dataset:
PRECISION MAGNETOPLEXES FOR MICRORNA DELIVERY TARGETING TENDON INFLAMMATION
Authors: Almeida A.F. , Miranda M.S. , Crowe L.A.N. , Akbar M. , Rodrigues M.T. , Millar N.L. , Gomes M.E. 
Published: January 2024

MicroRNA (miR) delivery to regulate chronic inflammation hold extraordinary promise, with new therapeutic possibilities emanating from their ability to fine-tune multiple target gene regulation pathways which is an important factor in controlling aberrant inflammatory reactions in complex multifactorial disease. However, several hurdles have prevented advancements in miR-based therapies. These include off-target effects of miRs, limited trafficking, and inefficient delivery. We propose a magnetically guided nanocarrier to transport therapeutically relevant miRs to assist self- resolving inflammation processes at injury sites and reduce the impact of chronic inflammation- related diseases such as tendinopathies. The high prevalence, significant socio-economic burden and increasing recognition of dysregulated immune mediated pathways in tendon disease provide a compelling rationale for exploring inflammation-targeting strategies as novel treatments in this condition. By combining cationic polymers, miR species (e.g., miR 29a, miR155 antagonist), and magnetic nanoparticles in the form of magnetoplexes with highly efficient magnetofection procedures, we developed inexpensive, easy-to-fabricate, and biocompatible systems with competent miR-binding and fast cellular uptake into different types of human cells, namely macrophages and tendon-derived cells. The system was shown to be cell-compatible and to successfully modulate the expression and production of inflammatory markers in tendon cells, with evidence of functional pro-healing changes in immune cell phenotypes. Hence, magnetoplexes represent a simple, safe, and non-viral nanoplatform that enables contactless miR delivery and high- precision control to reprogram cell profiles toward improved pro-regenerative environments.Acknowledgements: ERC CoG MagTendon No.772817; FCT Doctoral Grant SFRD/BD/144816/2019, and TERMRES Hub (Norte-01-0145-FEDER-022190).
DO LEUCOCYTE-RICH AND -POOR PLATELET-RICH PLASMA DIFFER BY THEIR METABOLITES?
Authors: Fidan B.B. , Demirdis I. , Çiftçi E. , Aydinli H. , Kaplan O. , Çelebier M. , Boyacioglu Ö. , Korkusuz P. , Karanfil Y. , Korkusuz F. 
Published: January 2024

Platelet Rich Plasma (PRP), either rich (L-PRP) or poor (P-PRP) of leukocytes, is frequently used as an anti-inflammatory and regenerative tool in osteoarthritis (OA). PRP contains proteins but not genes as it is derived from megakaryocytes. Proteomics but not metabolomics of PRP was recently studied. Metabolomics is a field of ‘omics’ research involved in comprehensive portrayal of the small molecules, metabolites, in the metabolome. These small molecules can be endogenous metabolites or exogenous compounds found in an organism (1). Our aim was to determine the difference between L-PRP and P-PRP.A cross-sectional clinical study was designed in six recreational male athletes between the ages of 18 and 35 years. 3 mL P-PRP and 3 mL -LPRP was prepared from 60 mL of venous blood after treating with 9 mL of sodium citrate and centrifugation at 2.700 rpm for 10 min. Half of the prepared PRP's were frozen at −20°C for a week. Fresh and frozen samples were analyzed at the Q-TOF LC/MS device after thawing to room temperature.Untargeted metabolomic results revealed that the metabolomic profile of the L-PRP and P-PRP were significantly different from each other. A total of 33.438 peaks were found. Statistically significant (p<0.05) peaks were uploaded to the MetaboAnalyst 5.0 platform. Exogenous out of 2.308 metabolites were eliminated and metabolites found significant for our study were subjected to pathway analysis. Steroid biosynthesis, sphingolipid metabolism and metabolism of lipid pathways were affected. In the L-PRP samples, Nicotinamide riboside (FC: 2.2), MHPG (FC: 3.0), estrone sulfate (FC: 7.5), thiamine diphosphate (FC: 2.0), leukotriene E4 (FC: 7.5), PC(18:1 (9Z)e/2:0) (FC: 9.8) and Ap4A (FC: 2.1) were higher compared to P-PRP. C24 sulfatide (FC: −11.8), 3-hexaprenyl-4,5-dihydroxybenzoic acid (FC: −2.8) metabolites were furthermore lower in P-PRP. Clinical outcomes of PRP application should consider these metabolic pathways in future studies (2).
STAT3 ACTIVATION IN THE SYNOVIAL TISSUES FROM THE HIP JOINT IN THE EARLY STAGE OF RAPIDLY DESTRUCTIVE COXOPATHY
Authors: Yasuda T. , Hara S. , Yamashita S. , Mitsuzawa S. , Tsukamoto Y. , Takeuchi H. , Ota S. , Onishi E. 
Published: January 2024

The interleukin-6/gp130-associated Janus Kinases/STAT3 axis is known to play an important role in mediating inflammatory signals, resulting in production of matrix metalloproteinase-3 (MMP-3). The hip joints with rapidly destructive coxopathy (RDC) demonstrate rapid chondrolysis, probably by increased production of MMP-3 observed in the early stage of RDC. In the recent study, no apparent activation of STAT3 has been shown in the synovial tissues obtained from the osteoarthritic joint at operation. However, no data are currently available on STAT3 activation in the synovial tissues in the early stage of RDC. This study aimed to elucidate STAT3 activation in the synovial tissues in the early stage of RDC. Synovial tissues within 7 months from the disease onset were obtained from four RDC patients with femoral head destruction and high serum levels of MMP-3. RDC synovial tissues showed the synovial lining hyperplasia with an increase of CD68-positive macrophages and CD3-positive T lymphocytes. STAT3 phosphorylation was found in the synovial tissues by immunohistochemistry using anti-phospho-STAT3 antibody. The majority of phospho-STAT3-positive cells were the synovial lining cells and exhibited negative expression of macrophage or T cell marker. Treatment with tofacitinib, a Janus Kinase inhibitor, resulted in a decrease in phospho-STAT3-positive cells, especially with high intensity, indicating effective suppression of STAT3 activation in RDC synovial tissues. Inhibitory effect of tofacitinib could act through the Janus Kinase/STAT3 axis in the synovial tissues in the early stage of RDC. Therefore, STAT3 may be a potential therapeutic target for prevention of joint structural damage in RDC.Acknowledgements: This study was supported by Katakami Foundation for Clinical Research.
DUAL-MOBILITY ARTICULATION CONFERS LOWER DISLOCATION AND REVISION RATES: A STUDY USING REVIEW OF REVIEWS METHODOLOGY
Authors: Mehta S. , Goel A. , Mahajan U. , Reddy N.R. , Bhaskar D. 
Published: January 2024

Dislocation post THA confers a higher risk of re-dislocation (Kotwal et al, 2009). The dual mobility (DM) cup design (1974) was aimed at improving the stability by increasing the femoral head to neck ratio (Cuthbert et al., 2019) combining the ideas of low friction arthroplasty with increased jump distance associated with a big head arthroplasty.Understand the dislocation rates, rates of aseptic loosening, infection rate and revision rates between the 2 types of constructs to provide current and up-to date evidence.Medline, pubmed, embase and Cochrane databases were used based on PRISMA guidelines. RevMan software was used for the meta-analysis. Studies (English literature) which used DM construct with atleast 6 months follow-up used as intervention and non DM construct as control were included. 2 independent reviewers conducted the review with a third reviewer in case of difference in opinion regarding eligibility. Primary outcome was dislocation rate and secondary outcome was rate of revision.564 articles identified out of which 44 articles were screened for full texts and eventually 4 systematic review articles found eligible for the study. Thus, study became a review of systematic reviews. From the 4 systematic reviews, another 35 studies were identified for data extraction and 13 papers were used for meta-analysis. Systematic reviews evaluated, projected an average follow up of 6-8 years with significantly lower dislocation rates for DM cups. The total number of patients undergoing DM cup primary THA were 30,559 with an average age 71 years while the control group consisted of 218,834 patients with an average age of 69 years. DM group had lower rate of dislocation (p < 0.00001), total lower rate of cup revision (p < 0.00001, higher incidence of fracture (p>0.05).DM THA is a viable alternative for conventional THA. The long-term results of DM cups in primary THA need to be further evaluated using high quality prospective studies and RCTs.
ORTHOPOD: PREDICTING INJURY PROPORTIONALITY FROM NECK OF FEMUR FRACTURES
Authors: Morris T. , Fouweather F. , Walshaw T. , Baldock T. , Wei N. , Eardley W. 
Published: January 2024

The need to accurately forecast the injury burden has never been higher. With an aging, ever expanding trauma population and less than half of the beds available compared to 1990, the National Health Service (NHS) is stretched to breaking point1,2.We utilised a dataset of 22,585 trauma patients across the four countries of the United Kingdom (UK) admitted to 83 hospitals between 22/08/22 – 16/10/22 to determine whether it is possible to predict the proportionality of injuries treated operatively within orthopaedic departments based on their number of Neck of Femur fracture (NOF) patients.More operations were performed for elderly hip fractures alone than for the combined totals of the next four most common fractures: ankle, distal radius, tibial shaft and forearm (6387 vs 5922). Conversely, 10 out of the 13 fracture types were not encountered by at least one hospital and 93% of hospitals encountered less than 2 fractures of a certain type.60% trauma is treated within Trauma Units (TUs) however, per unit, Major Trauma Centres (MTCs) treat approximately 43% more patients.After excluding NOF, lower limb fractures accounted for approximately 57% of fractures in all countries and ankle and distal radius fracture combined comprised more than 50% in 74% of regions.The number of hip fractures seen on average by an individual unit remains relatively consistent as does the regional variation of any given fracture; resultantly, it is possible to predict injury proportionality based off a unit's hip fracture numbers. This powerful tool could transform both resource allocation and recruitment.
COULD A DECELLULARIZATION PROTOCOL BE VALIDATED WITHOUT TALKING ABOUT HUMAN LEUKOCYTE ANTIGEN?
Authors: Manon J. , Evrard R. , Fievé L. , Xhema D. , Maistriaux L. , Schubert T. , Lengelé B. , Behets C. , Cornu O. 
Published: January 2024

Decellularization techniques have advanced to reduce the risk of immune rejection in transplantation. Validation of these protocols typically relies on Crapo's criteria1, which include the absence of visible nuclei and low DNA content. In our study, five decellularization protocols were compared to determine the optimal approach for human fascia lata (HFL) samples. However, our findings raised questions as to why recipients can still develop immunity despite meeting validation criteria.HFL samples were decellularized using four protocols with SDS-Triton X100-DNase (D1 to D4-HFL) and one protocol using solvent-detergent-based baths (D5-HFL). The decellularized samples (D-HFL) were compared to native samples (N-HFL) using histology, and DNA content was measured. The human leukocyte antigen (HLA) content within the matrix was assessed using western blot analysis. Both D-HFL and N-HFL samples, along with negative control patches, were implanted in the backs of 28 Wistar rats. Anti-human IgG serum levels were evaluated after one month.H&E and Hoechst staining revealed the absence of residual cells in all decellularization protocols. DNA content was consistently below the critical threshold (p<0.05). All implanted D-HFL samples resulted in significantly lower anti-human IgG levels compared to N-HFL (p<0.01). However, 2.5 out of 4 rats developed immunity after being implanted with D1 to D4-HFL, with varying levels of anti-human IgG. Only rats implanted with D5-HFL showed undetectable levels of IgG and were considered non-immunized. Western blot analysis indicated that only D5-HFL had a residual HLA content below 1%.The literature on decellularization has primarily relied on Crapo's criteria, which do not consider the role of HLA mismatch in acute immune rejection. Our results suggest that a residual HLA content below 1% should also be considered to prevent immunization, even if other validation criteria are met. Further research is needed to evaluate the impact of residual HLA levels on human allotransplantation outcomes.
THE INTERPLAY OF ANGIOGENESIS AND OSTEOGENESIS FOR BONE REGENERATION
Authors: Banfi A. 
Published: January 2024

Bone regeneration is an area of acute medical need, but its clinical success is hampered by the need to ensure rapid vascularization of osteogenic grafts. Vascular Endothelial Growth Factor (VEGF) is the master regulator of vascular growth and during bone development angiogenesis and osteogenesis are physiologically coupled through so-called angiocrine factors produced by blood vessels. However, how to exploit this process for therapeutic bone regeneration remains a challenge (1).Here we will describe recent work aiming at understanding the cross-talk between vascular growth and osteogenesis under conditions relevant for therapeutic bone regeneration. To this end we take advantage of a unique platform to generate controlled signalling microenvironments, by the covalent decoration of fibrin matrices with tunable doses and combinations of engineered growth factors. The combination of human osteoprogenitors and hydroxyapatite in these engineered fibrin matrices provides a controlled model to investigate how specific molecular signals regulate vascular invasion and bone formation in vivo. In particular, we found that:Controlling the distribution of VEGF protein in the microenvironment is key to recapitulate its physiologic function to couple angiogenesis and osteogenesis (2);Such coupling is exquisitely dependent on VEGF dose and on a delicate equilibrium between opposing effects. A narrow range of VEGF doses specifically activates Notch1 signaling in invading blood vessels, inducing a pro-osteogenic functional state called Type H endothelium, that promotes differentiation of surrounding mesenchymal progenitors. However, lower doses are ineffective and higher ones paradoxically inhibit both vascular invasion and bone formation (Figure 1) (3);Semaphorin3a (Sema3a) acts as a novel pro-osteogenic angiocrine factor downstream of VEGF and it mediates VEGF dose-dependent effects on both vascular invasion and osteogenic progenitor stimulation.In conclusion, vascularization of osteogenic grafts is not simply necessary in order to enable progenitor survival. Rather, blood vessels can actively stimulate bone regeneration in engineered grafts through specific molecular signals that can be harnessed for therapeutic purposes.Acknowledgements: This work was supported in part by the European Union Horizon 2020 Program (Grant agreement 874790 – cmRNAbone).For any figures and tables, please contact the authors directly.
FUNCTIONAL ACTIVITY OF MONOMERIC C-REACTIVE PROTEIN IN INTERVERTEBRAL DISC
Authors: Ruiz-Fernández C. , Eldjoudi D.A. , Gonzalez-Rodríguez M. , Barreal A.C. , Farrag Y. , Mobasheri A. , Pino J. , Sakai D. , Gualillo O. 
Published: January 2024

Monomeric C reactive protein (mCRP) presents important proinflammatory effects in endothelial cells, leukocytes, or chondrocytes. However, CRP in its pentameric form exhibits weak anti-inflammatory activity. It is used as a biomarker to follow severity and progression in infectious or inflammatory diseases, such as intervertebral disc degeneration (IVDD). This work assesses for the first time the mCRP effects in human intervertebral disc cells, trying to verify the pathophysiological relevance and mechanism of action of mCRP in the etiology and progression of IVD degeneration.We demonstrated that mCRP induces the expression of multiple proinflammatory and catabolic factors, like nitric oxide synthase 2 (NOS2), cyclooxygenase 2 (COX2), matrix metalloproteinase 13 (MMP13), vascular cell adhesion molecule 1 (VCAM1), interleukin (IL)-6, IL-8, and lipocalin 2 (LCN2), in human annulus fibrosus (AF) and nucleus pulposus (NP) cells. We also showed that nuclear factor-κβ (NF-κβ), extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphoinositide 3-kinase (PI3K) are at play in the intracellular signaling of mCRP.Our results indicate that the effect of mCRP is persistent and sustained, regardless of the proinflammatory environment, as it was similar in healthy and degenerative human primary AF cells. This is the first article that demonstrates the localization of mCRP in intravertebral disc cells of the AF and NP and that provides evidence for the functional activity of mCRP in healthy and degenerative human AF and NP disc cells.
CELLULAR AND MOLECULAR ENDOTYPES FOR OSTEOARTHRITIS
Authors: Pattappa G. 
Published: January 2024

The biological understanding for the disease progression osteoarthritis (OA) has uncovered specific biomarkers from either synovial fluid, articular chondrocytes or synoviocytes that can be used to diagnose the disease. Examples of these biomarkers include interleukin-1β (IL-1β) or collagen II fragments (1, 2). In parallel, isolation of chondrocytes or bone marrow derived mesenchymal stromal cells (MSCs) has yielded cell-based strategies that have shown long- term beneficial effects in a specific cohort of patients, specifically in traumatic cartilage lesions (2). This latter finding shows that patient stratification of OA is an important tool to both match patients for a specific treatment and to develop novel therapies, especially disease modifying drugs. In order to create disease stage specific therapies, the use of next generation analysis tools such as RNAseq and metabolomics, has the potential to decipher specific cellular and molecular endotypes. Alongside greater understanding of the clinical phenotype (e.g. imaging, pain, co- morbidities), therapies can be designed to alleviate the symptoms of OA at specific points of the disease in patients. This talk will outline the current biological understanding of OA and discuss how patient stratification could assist in the design of innovative therapies for the disease.Acknowledgements: This presentation was supported by the COST action, CA21110 – Building an open European Network on Osteoarthritis Research (NetwOArk)
Effects of acupuncture treatment for myasthenia gravis: A systematic review and meta-analysis
Authors: Xue Hua , Zeng Li , He Hongxian , Xu Dongxun , Ren Kaixin 
Published: January 2024

Background
Randomized controlled trials (RCTs) of acupuncture for myasthenia gravis (MG) were searched and the efficacy of acupuncture in the treatment of MG was evaluated by meta-analysis.

Methods
We searched for RCTs in six main electronic databases, and collected RCTs of acupuncture treatment for MG from database creation to 28 February 2023. The main outcome was the effective rate and the secondary outcome was the Traditional Chinese Medicine (TCM) relative clinical score, absolute clinical score (ACS) of MG, Quantitive myasthenia gravis score (QMG), quality of life, and adverse events. Odds ratios (ORs) and weighted mean differences (WMD) and 95% confidence intervals (CI) were used to assess pooled effect estimates using Review Manager software.

Results
A total of 14 RCTs were included. Meta-analysis showed that the effective rate in the acupuncture group was significantly improved compared with conventional Western medicine alone [OR = 4.28, 95% CI (2.95, 6, 22), P<0.005]. The pooled WMDs revealed that TCM relative clinical score [WMD = -2.22, 95% CI = (-2.53, -1.90), P<0.005], ACS of MG [WMD = -3.14, 95% CI = (-3.67, -2.62), P<0.005], and QMG [WMD = -0.88, 95% CI = (-1.46, -0.29), P<0.005] in the acupuncture group was lower than the control group. Adverse reactions related to acupuncture and quality of life were less mentioned among included RCTs.

Conclusion
This meta-analysis demonstrated that acupuncture as an auxiliary may play a positive role in treating MG. It can improve the effective rate of treatment, and reduce TCM relative clinical score, ACS of MG, and QMG. However, the quality of included studies was generally low and caution should be exercised when considering this treatment option. In the future, more rigorous study designs and high-quality RCTs are needed to verify the efficacy of acupuncture in the treatment of MG, because the results of high-quality RCTs are more reliable and accurate.
Prevalence, clinical correlates and outcomes of cardiorenal anemia syndrome among patients with heart failure attending tertiary referral hospital in Dodoma, Tanzania: A protocol of a prospective observational study
Authors: Edwin Gidion , Alphonce Baraka , Meremo Alfred , Meda John Robson 
Published: January 2024

Background
Cardiorenal anemia syndrome (CRAS) is a common complication among patients with heart failure and is associated with poor clinical outcomes. However, there is a paucity of published data concerning CRAS, despite of significant increase in heart failure patients attending medical services in developing countries. This study aims to assess the prevalence, clinical correlates, and outcomes of CRAS among patients with heart failure attending the Benjamin Mkapa Hospital in Dodoma, Tanzania.

Methodology
A prospective observational study is ongoing at the Benjamin Mkapa Hospital in Dodoma, Tanzania. Currently, 92 patients have been recruited into this study and process is not yet completed. The socio-demographic data, clinical correlates, and prevalence of CRAS will be determined at baseline meanwhile, the outcomes of CRAS will be determined during a follow-up period of six months from the date of enrollment. CRAS is the primary outcome of the study. Data will be categorized into CRAS and non-CRAS during statistical analysis. Mean and standard deviation will be used for normally distributed continuous variables while median and interquartile range will be used for skewed data. Frequencies and percentages will summarize categorical variables. Clinical correlates and outcomes of CRAS will be analyzed and compared by using univariate and multivariate logistic regression and Cox proportional hazards models. A two-tailed p-value of less than 0.05 will indicate statistical significance.