Musculoskeletal Tissue Research Articles

3D Bioprinting in Otolaryngology: A Review.

The evolution of tissue engineering and 3D bioprinting has allowed for increased opportunities to generate musculoskeletal tissue grafts that can enhance functional and aesthetic outcomes in otolaryngology-head and neck surgery. Despite literature reporting successes in the fabrication of cartilage and bone scaffolds for applications in the head and neck, the full potential of this technology has yet to be realized. Otolaryngology as a field has always been at the forefront of new advancements and technology and is well poised to spearhead clinical application of these engineered tissues. In this review, current 3D bioprinting methods are described and an overview of potential cell types, bioinks, and bioactive factors available for musculoskeletal engineering using this technology is presented. The otologic, nasal, tracheal, and craniofacial bone applications of 3D bioprinting with a focus on engineered graft implantation in animal models to highlight the status of functional outcomes in vivo; a necessary step to future clinical translation are reviewed. Continued multidisciplinary efforts between material chemistry, biological sciences, and otolaryngologists will play a key role in the translation of engineered, 3D bioprinted constructs for head and neck surgery.

Regenerative engineering: Polymeric chemistry and materials science for regeneration

A version of this essay will be presented at the American Chemical Society Spring 2023 meeting by 2023 Priestley Medal winner Cato T. Laurencin, the University Professor and Albert and Wilda Van Dusen Distinguished Endowed Professor of Orthopaedic Surgery at the University of Connecticut. I’m very proud and honored to receive the 2023 Priestley Medal, the highest honor of the American Chemical Society. I am here to discuss with you regenerative engineering, which is my field. I am Dr. Cato Laurencin. I am the University Professor and the Albert and Wilda Van Dusen Distinguished Endowed Professor of Orthopaedic Surgery at the University of Connecticut. I am professor of chemical and biomolecular engineering, professor of materials science and engineering, and professor of biomedical engineering. I work in the area of musculoskeletal tissue regeneration, relying heavily on principles of chemistry and materials science. At this point, I and my team have been

Canakinumab for Adult-Onset Still Disease


 This review identified limited evidence from 2 systematic reviews about the clinical effectiveness and safety of canakinumab for patients with adult-onset Still disease (AOSD). Most studies in the systematic reviews on AOSD did not have a control group; therefore, the findings related to the effectiveness and safety of canakinumab in this population are uncertain.
 For adults with AOSD, treatment with canakinumab may be associated with a complete or partial response to treatment, corticosteroid-sparing effect, and a decrease or normalization of key laboratory parameters, such as leukocyte count, erythrocyte sedimentation rate, and serum levels of ferritin and C-reactive protein, compared with baseline.
 In adults with AOSD, limited evidence suggested there was no statistically significant difference between canakinumab and placebo in articular manifestations.
 Adverse events associated with canakinumab treatment included infections, leukopenia, musculoskeletal and connective tissue disorders, skin disorders, thoracic and mediastinal disorders, gastrointestinal disorders, and site injection reactions. Severe adverse events included macrophage activation syndrome, hepatocytotoxicity, and serious infections that led to discontinuation of treatment.
 No studies were found comparing canakinumab and alternative pharmacologic treatments for AOSD.
 No studies were found on the cost-effectiveness of canakinumab for the treatment of AOSD.
 No evidence-based guidelines were found on the use of canakinumab for the treatment of ASOD.

Engineering High-Quality Cartilage Microtissues Using Hydrocortisone Functionalized Microwells.

Engineering clinically relevant musculoskeletal tissues at a human scale is a considerable challenge. Developmentally inspired scaffold-free approaches for engineering cartilage tissues have shown great promise in recent years, enabling the generation of highly biomimetic tissues. Despite the relative success of these approaches, the absence of a supporting scaffold or hydrogel creates challenges in the development of large-scale tissues. Combining numerous scaled-down tissue units (herein termed microtissues) into a larger macrotissue represents a promising strategy to address this challenge. The overall success of such approaches, however, relies on the development of strategies which support the robust and consistent chondrogenic differentiation of clinically relevant cell sources such as mesenchymal stem/stromal cells (MSCs) within microwell arrays to biofabricate numerous microtissues rich in cartilage-specific extracellular matrix components. In this article, we first describe a simple method to manufacture cartilage microtissues at various scales using novel microwell array stamps. This system allows the rapid and reliable generation of cartilage microtissues and can be used as a platform to study microtissue phenotype and development. Based on the unexpected discovery that Endothelial Growth Medium (EGM) enhanced MSC aggregation and chondrogenic capacity within the microwell arrays, this work also sought to identify soluble factors within the media capable of supporting robust differentiation using heterogeneous MSC populations. Hydrocortisone was found to be the key factor within EGM that enhanced the chondrogenic capacity of MSCs within these microwell arrays. This strategy represents a promising means of generating large numbers of high-quality, scaffold-free cartilage microtissues for diverse biofabrication applications. Impact statement This study addresses a key challenge facing emerging modular biofabrication strategies that use microtissues as biological building blocks. Namely, achieving the necessary robust and consistent differentiation of clinically relevant cell sources, for example, mesenchymal stem/stromal cells (MSCs), and the accumulation of sufficient tissue-specific extracellular matrix (ECM) to engineer tissue of scale. We achieved this by establishing hydrocortisone as a simple and potent method for improving MSC chondrogenesis, resulting in the biofabrication of high-quality (ECM rich) cartilage microtissues. These findings could enable the generation of more scalable engineered cartilage by ensuring the formation of high-quality microtissue building blocks generated using heterogeneous MSC populations.

A Gout Flare Caused by the Administration of Platelet Rich Plasma: A Clinical Case

The therapy with Platelet Rich Plasma (PRP) administered in degenerated or injured musculoskeletal tissues is a new and promising regenerative treatment option. Traditionally, it is considered that as PRP represents an autologous (to the patient) blood product, the potential for serious side effects is neglectable. Consequently, it is important that any significant negative consequences are well described. We present a fifty-five years old male patient, complaining of pain and stiffness in his right ankle joint due to multiple traumas during his earlier sport career. He had no any contraindications and PRP was injected intraarticularly under ultrasound guidance. On the next day, the patient developed an intensive pain and swelling in the regions of the right ankle and the dorsum of the right foot. The acute phase reactants were elevated and there was no leukocytosis. On ultrasound examination, there was an effusion in the tibiotalar and talonavicular joints. Arthrocentesis was performed and the microscopic examination revealed the typical needle shaped monosodium urate crystals inside the joint fluid and no bacteria. Consequently, the diagnosis of acute gouty flare was made (the patient has a history of gout, but did not have any flares in the past two years). As PRP concentrate contains naturally many proinflammatory molecules, we speculate that some of them may activate the macrophages that residue normally in the synovium and the capsule of the injected joint. The activated macrophages further may react to the MSU crystals deposited there, leading to the development of a gouty flare. In conclusion, the possibility of a flare should be explained to gouty patients, candidate for PRP treatment.

Proceedings of the Post-Genome Analysis for Musculoskeletal Biology Workshop.

Herein, we report on the proceedings of the workshop entitled "Post-Genome analysis for musculoskeletal biology" that was held in July of 2022 in Safed, Galilee, Israel. Supported by the Israel Science Foundation, the goal of this workshop was to bring together established investigators and their trainees who were interested in understanding the etiology of musculoskeletal disease, from Israel and from around the world. Presentations at this workshop spanned the spectrum from basic science to clinical studies. A major emphasis of the discussion centered on genetic studies in humans, and the limitations and advantages of such studies. The power of coupling studies using human data with functional follow-up studies in pre-clinical models such as mice, rats, and zebrafish was discussed in depth. The advantages and limitations of mice and zebrafish for faithfully modelling aspects of human disease were debated, specifically in the context of age-related diseases such as osteoporosis, osteoarthritis, adult-onset auto-immune disease, and osteosarcopenia. There remain significant gaps in our understanding of the nature and etiology of human musculoskeletal disease. While therapies and medications exist, much work is still needed to find safe and effective interventions for all patients suffering from diseases associated with age-related deterioration of musculoskeletal tissues. The potential of forward and reverse genetic studies has not been exhausted for diseases of muscles, joints, and bones.

Effects of dapagliflozin on hospitalisations in people with type 2 diabetes: post-hoc analyses of the DECLARE-TIMI 58 trial

In people with type 2 diabetes at high risk of cardiovascular or kidney disease, sodium-glucose co-transporter 2 (SGLT2) inhibitors consistently reduce the risk of hospitalisations for heart failure. Less is known about their effects on hospitalisation from any cause, especially in people with type 2 diabetes without atherosclerotic cardiovascular disease, which includes most of the global population of people with type 2 diabetes. We aimed to assess the effect of the SGLT2 inhibitor, dapagliflozin, on the risks of hospitalisations for any cause and for specific causes in people with type 2 diabetes with and without atherosclerotic cardiovascular disease. The DECLARE-TIMI 58 trial was a double-blind, multicentre, randomised, placebo-controlled study. People with type 2 diabetes and either risk factors for or established atherosclerotic cardiovascular disease were randomly assigned (1:1) to receive oral dapagliflozin 10 mg or placebo once daily. In these post-hoc analyses, the effects of dapagliflozin on risks of first non-elective any-cause and cause-specific hospitalisation were assessed with Cox proportional hazards regression models overall and in the subset of participants without prevalent atherosclerotic cardiovascular disease. The risk of total (first plus subsequent) non-elective hospitalisations was assessed with Lin-Wei-Ying-Yang model. Investigator-reported System Organ Class terms were used to classify cause-specific hospitalisations. The trial is registered with ClinicalTrials.gov, NCT01730534. Between April 25, 2013, and Sept 18, 2018, 17 160 people (6422 [37·4%] women, 10 738 [62·6%] men; mean age 63·9 years [SD 6·8]) were enrolled in the original trial, of whom 10186 (59·4%) had multiple risk factors for but did not have established atherosclerotic cardiovascular disease, and 6835 (39·8%) had both no evidence of atherosclerotic cardiovascular disease and low KDIGO risk. Over a median follow-up of 4·2 years (IQR 3·9-4·4), dapagliflozin was associated with a lower risk of first non-elective hospitalisation for any cause (2779 [32·4%] of 8582 people in the dapagliflozin group vs 3036 [35·4%] of 8578 people in the placebo group; hazard ratio [HR] 0·89 [95% CI 0·85-0·94]) and total (first plus subsequent) non-elective hospitalisations for any cause (risk ratio 0·92 [95% CI 0·86-0·97]). The association between dapagliflozin use and the risk of first non-elective hospitalisation for any cause was consistent in subgroups of participants with (HR 0·92 [95% CI 0·85-0·99] and without (0·87 [0·81-0·94]) atherosclerotic cardiovascular disease at baseline (p interaction=0·31). Compared with the placebo group, the dapagliflozin group had lower risk of first hospitalisations due to cardiac disorders (HR 0·91 [95% CI 0·84-1·00]), metabolism and nutrition disorders (0·73 [0·60-0·89]), renal and urinary disorders (0·61 [0·49-0·77]), and due to any other cause excluding these three causes (0·90 [0·85-0·96]). Treatment with dapagliflozin was also associated with a lower risk of hospitalisations due to musculoskeletal and connective tissue disorders (HR 0·81 [0·67-0·99]) and infections and infastations (HR 0·86 [0·78-0·96]). Dapagliflozin reduced the risk of first and total non-elective hospitalisations for any cause in people with type 2 diabetes, regardless of the presence of atherosclerotic cardiovascular disease, including hospitalisations not directly attributed to cardiac, kidney, or metabolic causes. These findings might have implications on health-related quality of life for people with type 2 diabetes and on health-care costs attributable this condition. AstraZeneca.

Bioreactors for engineering patient-specific tissue grafts

Bioreactors have the potential to advance the clinical application of cell-based therapies. Cell expansion bioreactors have been used commercially for therapeutic applications; however, bioreactor-based engineering of 3D tissue grafts remains challenging owing to the complexity of tissue architectures, cellular heterogeneity and the lack of non-invasive, tissue-specific biomarkers with which to assess graft viability and maturation. Consequently, only a few bioreactor-based start-up companies that engineer patient-specific tissue grafts have emerged. In this Review, we discuss patient-specific bioreactors that can be used to engineer skin, small-diameter arteries and musculoskeletal tissues. We evaluate the impact of precision manufacturing, including 3D bioprinting, automation and non-invasive sensing, on optimizing the biological, chemical and physical parameters of the bioreactors that are required for specific tissue regeneration. We discuss the commercially available tissue-engineering bioreactors and the potential of digital twins and automation, and we outline the scientific and regulatory pathways that must be followed to enable the translation of tissue-specificbioreactors to the clinic. Bioreactors enable the cultivation of mammalian cells in a closely monitored and controlled microenvironment. This Review discusses bioreactor technologies and closed-loop set-ups for producing patient-specific engineered-tissue grafts, including skin, small-diameter arteries and musculoskeletal tissues, with a particular focus on commercialization and regulatory considerations.

Significance of musculoskeletal and connective tissue parameters as health indicators in Federal Fire-Fighting Service officers of the State Fire-Fighting Service of the EMERCOM of Russia

Relevance. The job of Federal Fire-Fighting Service (FFS) officers of the State Fire-Fighting Service of the EMERCOM of Russia is among the global top 10 occupations with evident risk of health functional reserves depletion, prevalence of early occupational diseases, injuries and even death. Traditionally, investigators focus on circulatory diseases and how they affect firefighters’ occupational health.The objective is to provide research-based evidence showing that musculoskeletal and connective tissue parameters provide a reliable estimate of the health status in Russian Federal Fire-Fighting Service officers.Methodology. The authors analyzed the research papers included in the Russian Science Citation Index mostly within the last 10 years and the studies carried out at the Nikiforov Russian Center of Emergency and Radiation Medicine and at the All-Russian Research Institute for Fire Protection of the EMERCOM of Russia. Morbidity was calculated in ppm (‰), industrial injury and primary disability rates were estimated per 10,000 (×104), mortality (deaths) – per 100,000 (×105) people. The indicators dynamics was estimated based on dynamic sets of data applying the 2nd order polynomial trend; the Pearson correlation coefficient was utilized to verify consistency of the trends.Results and analysis. In 2003–2015 the average annual incidence rate of cases with labor losses (across all ICD-10 chapters of diseases) among the EMERCOM Federal Fire Service officers was (407.0 ± 30.4) ‰ which was statistically significantly lower than among the Russian armed forces officers (508.5 ± 35.6) ‰ (p < 0.05); the number of lost workdays was higher, i.e. (5139 ± 402) and (4174 ± 123) ‰ respectively (p < 0.05). Consistency in the dynamics of case number, rate of lost workdays, and day/incident ratio among firefighters and military officers is low and negative, potentially due to the impact of different factors on lost workdays rate. Assuming the macrosocial factors are identical, organisational and/or occupational factors could be the key contributors to labor losses. Rates of injuries, poisoning and other external impacts (chapter XIX in ICD-10), as well as musculoskeletal and connective tissue diseases (chapter XIII) play the leading role in morbidity dynamics among firefighters. The mortality rate among the Russian EMERCOM FFS officers with chapter XIX injuries was 8.5 times lower than that among the Russian male population, although the population cohort was 2.5 times more numerous. Occupational injury rate of (14.66 ± 2.01) • 10–4 of injuries/(firefighter • year) and firefighter fatalities (8.53 ± 0.83) • 10–5 deaths/(firefighter • year) in 2006–2020 were statistically significantly lower than among economically active working male population in Russia: (22.73 ± 2.8) • 10–4 (p < 0.01) and (13.23 ± 1.12) • 10–5 (p < 0.05) respectively. Considering the work schedule of firefighters, the annual amount of work in extreme environments was carried out within 6 months; whereas the level of industrial traumatism due to fire extinguishing and elimination of other emergency situations calculated for 12 months should be doubled, to say the least. The level of primary disability among Russian Federal Fire Service employees was (15.98 ± 0.99) • 10–4, i.e. statistically reliably lower (p < 0.001) than among the working population of Russia aged 18–44 years (25.51 ± 1.19) • 10–4. On the one hand, the data demonstrates efficient labor set-up and labor protection of the EMERCOM FFS employees, whereas disability rate among the adult population of Russia stays at a high level, on the other hand.Conclusion. Although not entirely eliminated, negative occupational impacts (i.e. diseases, injuries) can be reduced to minimal rates. Preventing the early onset of occupational diseases, especially traumas and musculoskeletal diseases, has a huge health sparing potential to ensure professional longevity of the EMERCOM FFS employees.

Tensile Loaded Tissue-Engineered Human Tendon Constructs Stimulate Myotube Formation.

Skeletal muscle possesses adaptability to mechanical loading and regenerative potential following muscle injury due to muscle stem cell activity. So far, it is known that muscle stem cell activity is supported by the roles of several interstitial cells within skeletal muscle in response to muscle damage. The adjacent tendon is also exposed to repetitive mechanical loading and possesses plasticity like skeletal muscle. However, the interplay between the skeletal muscle and adjacent tendon tissue has not been fully investigated. In this study, we tested whether factors released by three-dimensional engineered human tendon constructs in response to uniaxial tensile loading can stimulate the proliferation and differentiation of human-derived myogenic cells (myoblasts). Tendon constructs were subjected to repetitive mechanical loading (4% strain at 0.5 Hz for 4 h) and nonrepetitive loading (0% strain at 0 Hz for 4 h), and the conditioned media from mechanically loaded and nonmechanically loaded control constructs were applied to myoblasts. Immunofluorescence analysis revealed both an increase of myotube fusion index (≥5 nuclei within one desmin+ myotube) and the myotube diameter when conditioned medium from mechanically loaded tendon constructs was applied. Myostatin, myosin heavy chain 7, and AXIN2 gene expressions were downregulated in myotubes treated with conditioned medium from mechanically loaded tendon constructs. However, proliferative potential (number of Ki67+ and bromodeoxyuridine+ myoblasts) did not differ between the two groups. These results indicate that tendon fibroblasts enhance myotube formation by mechanical loading-induced factors. Our finding suggests that mechanical loading affects the signaling interplay between skeletal muscle and tendon tissue and is thus important for musculoskeletal tissue development and regeneration in humans. Impact statement The interplay between satellite cells and various types of resident cells within the skeletal muscle for muscle regeneration has been extensively studied. However, even though tendon tissue is located adjacent to skeletal muscle tissue and cells in these tissues are exposed to repetitive mechanical loading together, the interaction between muscle and tendon tissues for muscle regeneration remains to be elucidated. In this study, we report that the conditioned media from engineered human tendon tissues undergoing repetitive tensile mechanical loading enhanced myotube formation. Our in vitro findings extend the fundamental understanding of the crosstalk between adjacent tissues of the muscle-tendon unit.

Shear wave elastography ultrasound does not quantify mechanical properties of the ulnar collateral ligament of the elbow.

To validate shear wave elastography (SWE) stiffness measurements for the ulnar collateral ligament (UCL) of the elbow compared to mechanical measurements. Eleven fresh frozen human cadaveric upper extremities were evaluated by a musculoskeletal-specialized radiologist to provide SWE measurements used to calculate stiffness at 4 points along the anterior band of the UCL at various load states and flexion angles. Specimens were then dissected and optical markers were placed on the UCL to track displacement during applied force by a load frame, thereby providing measurements to calculate the mechanical stiffness. These two stiffness values were compared by ANOVA for all load states and flexion angles. Measurements of stiffness by SWE for the UCL were three orders of magnitude smaller than the true mechanical testing stiffness and no correlations between SWE and mechanical measurements of stiffness were found at 30, 60 or 90 degrees of elbow flexion (R2 = 0.004, p = 0.85; R2 = 0.001, p = 0.92; R2 = 0.15, p = 0.24 respectively). SWE stiffness was greatest near the insertion of the ligament and lowest in the mid-substance of the ligament (p = 0.0002). SWE stiffness did not correlate with mechanical measurements. Clinical utility of musculoskeletal SWE may be better defined when biomechanical properties or clinical outcomes can be correlated with SWE measurements. The ultimate clinical utility of SWE in musculoskeletal tissues may be qualitative, as demonstrated by differences throughout the length of the UCL in this study.

DL_Track - Automated analysis of muscle architecture from B-mode ultrasonography images using deep learning

B-mode ultrasound is commonly used to image musculoskeletal tissues, but one major bottleneck is data analysis. Manual analysis is commonly deployed for assessment of muscle thickness, pennation angle and fascicle length in muscle ultrasonography images. However, manual analysis is somewhat subjective, laborious and requires thorough experience. We provide an openly available algorithm (DL_Track) to automatically analyze muscle architectural parameters in ultrasonography images or videos of human lower limb muscles.
 We trained two different neural networks (classic U-net [Ronneberger et al., 2021] and U-net with VGG16 [Simonyan & Zisserman, 2015] pretrained encoder) one to detect muscle fascicles and another to detect muscle aponeuroses using a set of labelled musculoskeletal ultrasound images. We included images from four different devices of the vastus lateralis, gastrocnemius medialis, tibilias anterior and soleus. In total, we included 310 images for the fascicle model and 570 images for the aponeuroses model, which we augmented to about 1,700 images per set. Each dataset was randomly split into a training and test set for model training, using a common 80/20 train/test split. We determined the best performing model based on intersection-over-union and loss metrics calculated during model training. We compared neural network predictions on an unseen test set consisting of 35 images to those obtained via manual analysis and two existing semi/automated analysis approaches (SMA and Ultratrack).
 Across the set of 35 unseen images, the mean differences between DL_Track and manual analysis were for fascicle length -2.4 mm (95% compatibility interval (CI) = -3.7 to -1.2), for pennation angle 0.6° (-0.2 to 1.4), and for muscle thickness -0.6 mm (-1.2 to 0.002). The corresponding values comparing DL_Track with SMA were for fascicle length 5.2 mm (1.3 to 9.0), for pennation angle -1.4° (-2.6 to -0.4) and for muscle thickness -0.9 mm (-1.5 to -0.3) respectively. ICC values between DL_Track and Ultratrack were 0.19 (0.00 to 0.35) for medial gastrocnemius passive contraction, 0.79 (0.77 to 0.81) for medial gastrocnemius maximal voluntary contraction, 0.88 (0.87 to 0.89) for calf raise, 0.67 (0.07 to 0.86) for medial gastrocnemius during walking, 0.80 (0.79 to 0.82) for tibialis passive plantar and dorsiflexion, and 0.85 (0.83 to 0.86) for tibialis anterior maximum voluntary contraction.
 Our method is fully automated and can estimate fascicle length, pennation angle and muscle thickness from single images or videos in multiple superficial muscles. For single images, the method gave results that are in agreement with those produced by SMA or manual analysis. Similarly, for videos, there was overlap between the results produced with Ultratrack and our method. In contrast to Ultratrack, DL_Track analyzes each frame independently of the previous frames, which might explain the observerd variability.
 References
 Ronneberger, O., Fischer, P., & Brox, T. (2021). U-Net: Convolutional networks for biomedical image segmentation. arXiv. https://doi.org/10.48550/arXiv.1505.04597
 Simonyan, K., & Zisserman, A. (2015). Very deep convolutional networks for large-scale image recognition. arXiv. https://doi.org/10.48550/arXiv.1409.1556

Application of an in silico approach identifies a genetic locus within ITGB2, and its interactions with HSPG2 and FGF9, to be associated with anterior cruciate ligament rupture risk

ABSTRACT We developed a Biomedical Knowledge Graph model that is phenotype and biological function-aware through integrating knowledge from multiple domains in a Neo4j, graph database. All known human genes were assessed through the model to identify potential new risk genes for anterior cruciate ligament (ACL) ruptures and Achilles tendinopathy (AT). Genes were prioritised and explored in a case–control study comparing participants with ACL ruptures (ACL-R), including a sub-group with non-contact mechanism injuries (ACL-NON), to uninjured control individuals (CON). After gene filtering, 3376 genes, including 411 genes identified through previous whole exome sequencing, were found to be potentially linked to AT and ACL ruptures. Four variants were prioritised: HSPG2:rs2291826A/G, HSPG2:rs2291827G/A, ITGB2:rs2230528C/T and FGF9:rs2274296C/T. The rs2230528 CC genotype was over-represented in the CON group compared to ACL-R (p < 0.001) and ACL-NON (p < 0.001) and the TT genotype and T allele were over-represented in the ACL-R group and ACL-NON compared to CON (p < 0.001) group. Several significant differences in distributions were noted for the gene-gene interactions: (HSPG2:rs2291826, rs2291827 and ITGB2:rs2230528) and (ITGB2:rs2230528 and FGF9:rs2297429). This study substantiates the efficiency of using a prior knowledge-driven in silico approach to identify candidate genes linked to tendon and ACL injuries. Our biomedical knowledge graph identified and, with further testing, highlighted novel associations of the ITGB2 gene which has not been explored in a genetic case control association study, with ACL rupture risk. We thus recommend a multistep approach including bioinformatics in conjunction with next generation sequencing technology to improve the discovery potential of genomics technologies in musculoskeletal soft tissue injuries. Highlights A biomedical knowledge graph was modelled for musculoskeletal soft tissue injuries to efficiently identify candidate genes for genetic susceptibility analyses. The biomedical knowledge graph and sequencing data identified potential biologically relevant variants to explore susceptibility to common tendon and ligament injuries. Specifically genetic variants within the ITGB2 and FGF9 genes were associated with ACL risk. Novel allele combinations (HSPG2-ITGB2 and ITGB2-FGF9) showcase the potential effect of ITGB2 in influencing risk of ACL rupture.

Анализ заболеваемости населения старше трудоспособного возраста в Российской Федерации и ее региональные особенности

Objective assessment of the health status and medical care of the elderly in the context of progressive aging of the population is one of the leading health problems. Purpose of the study. Based on the analysis of the medical and demographic situation and the incidence of the population, as well as the results of our own research, to give recommendations on the health protection of the population older than working age. Research methods: statistical, sociological, expert assessments, direct observation. The forms of federal and sectoral statistical observation for 2018–2021 were analyzed. Results of sociological surveys of patients older than working age. Results. Over the 10 years of analysis (2012–2021), the overall incidence rate of the entire population in Russia increased by 4,5%, the adult population – by 8,2% and the working-age population – by 1.3%, in children and adolescents the indicators decreased by 8,8 and 4,7%. The overall incidence of the population older than working age in 2021 in the Russian Federation was 209164‰00, which is 1.2 times higher than the total population (167714‰00). The difference in the general morbidity rates of the population older than working age in the federal districts of the Russian Federation was 1.3 times, in the constituent entities of the Russian Federation 2.3 times. 2020, there is a significant decline in the overall incidence rate in all age groups, which is associated with the COVID‑19 pandemic. The first detected incidence of the population older than working age (in 2021) amounted to 66183,5 per 100 thousand of the corresponding population, which is lower than the total population by 22,6% (85531,6‰00). The population older than working age has significantly higher rates of newly diagnosed morbidity than the entire population in the classes: diseases of the circulatory system by 103%, the indicators were 6191,7‰00, 3048,3‰00, respectively; neoplasms (by 66%), musculoskeletal and connective tissue (by 16%) and diseases of the endocrine system, eating disorders and metabolic disorders (by 15,6%). The results of the study should be taken into account for planning the volume of preventive and dispensary work for people of older age groups. The article gives recommendations on the health protection of the population of pre-retirement and older working age using hospital-replacing technologies.

Basic Science of Allograft Orthobiologics.

Orthobiologic procedures are based on altering the microenvironment of musculoskeletal tissues to induce an anti-inflammatory effect and reduce pain, promote healing of these tissues, or provide mechanical support. Allograft tissues have these inherent qualities and can be used as such. This could provide patients whose own autologous tissues may be compromised or have contraindications to harvesting an alternative to treat their orthopedic conditions. Although these allograft therapies are promising, they lack high-quality clinical studies and regulatory guidelines currently limit their use.

RNA Extraction from Cartilage: Issues, Methods, Tips.

The increase in degenerative diseases involving articular cartilage has pushed research to focus on their pathogenesis and treatment, exploiting increasingly complex techniques. Gene expression analyses from tissue are representative of the in vivo situation, but the protocols to be applied to obtain a reliable analysis are not completely cleared through customs. Thus, RNA extraction from fresh samples and specifically from musculoskeletal tissue such as cartilage is still a challenging issue. The aim of the review is to provide an overview of the techniques described in the literature for RNA extraction, highlighting limits and possibilities. The research retrieved 65 papers suitable for the purposes. The results highlighted the great difficulty in comparing the different studies, both for the sources of tissue used and for the techniques employed, as well as the details about protocols. Few papers compared different RNA extraction methods or homogenization techniques; the case study reported by authors about RNA extraction from sheep cartilage has not found an analog in the literature, confirming the existence of a relevant blank on studies about RNA extraction from cartilage tissue. However, the state of the art depicted can be used as a starting point to improve and expand studies on this topic.

Revisiting the role of hyperbaric oxygen therapy in knee injuries: Potential benefits and mechanisms.

Knee injury negatively impacts routine activities and quality of life of millions of people every year. Disruption of tendons, ligaments, and articular cartilage are major causes of knee lesions, leading to social and economic losses. Besides the attempts for an optimal recovery of knee function after surgery, the joint healing process is not always adequate given the nature of intra-articular environment. Based on that, different therapeutic methods attempt to improve healing capacity. Hyperbaric oxygen therapy (HBOT) is an innovative biophysical approach that can be used as an adjuvant treatment post-knee surgery, to potentially prevent chronic disorders that commonly follows knee injuries. Given the well-recognized role of HBOT in improving wound healing, further research is necessary to clarify the benefits of HBOT in damaged musculoskeletal tissues, especially knee disorders. Here, we review important mechanisms of action for HBOT-induced healing including the induction of angiogenesis, modulation of inflammation and extracellular matrix components, and activation of parenchyma cells-key events to restore knee function after injury. This review discusses the basic science of the healing process in knee injuries, the role of oxygen during cicatrization, and shed light on the promising actions of HBOT in treating knee disorders, such as tendon, ligament, and cartilage injuries.

Predictive validity of the Questionnaire for Medical Checkup of Old-Old for functional disability: Using the National Health Insurance Database System.

To enhance health services that can address multifaceted issues, the Questionnaire for Medical Checkup of Old-Old (QMCOO) was strategically developed to ascertain frailty status. Using the National Health Insurance database system, we aimed to clarify whether the QMCOO can predict new certifications for long-term care for disabilities. Of 20 151 adults aged ≥75 years who underwent health checkups in Kashiwa City, Japan, in fiscal year 2020 (examination rate 36.8%), 18 130 persons were included (mean age 80.1 ± 4.1 years, 55.1% women). The outcome was the new certification of long-term care until January 2022. From the medical care receipt data, QMCOO, age, sex, living arrangement, body mass index, comorbidity, and musculoskeletal and connective tissue diseases were evaluated. During the follow-up period, 727 (4.0%) participants had an incident disability (median follow up 457 days [quartile range 408-519 days]). The QMCOO's predictive accuracy for new long-term care needs was optimal when the total score of 3/4 was used as the threshold. Older adults with scores ≥4 had a higher adjusted hazard ratio for incident disability (adjusted hazard ratio 2.5, 95% confidence interval 2.1-2.9). Furthermore, the adjusted hazard ratio was greatly enhanced with comorbidity (6.6, 95% confidence interval 4.8-8.9). The QMCOO, which reflects multifaceted frailty, might be predictive of incident disability, and its predictive accuracy could be improved by considering comorbidities. The comprehensive QMCOO could contribute to extending healthy life expectancy through efficiently assessing health care and preventing long-term care, even among the old-old in the latter stage who tended to suffer from multimorbidity. Geriatr Gerontol Int 2023; 23: 124-130.

Disproportionality analysis of quinolone safety in children using data from the FDA adverse event reporting system (FAERS).

Quinolones are widely prescribed for the treatment or prevention of infectious diseases in children. To gain further insight into quinolone-associated adverse event (AE) in children and better protect pediatric patients, continued surveillance of safety data is essential. The purpose of this study was to characterize the safety profiles of quinolone-associated AEs in children by mining the FDA adverse event reporting system (FAERS). FAERS reports from quarter 1 of 2004 to quarter 1 of 2022 were included in the study. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify adverse events. Reporting odds ratios (ROR) corresponding 95% confidence intervals (CIs) and information component (IC) along with 95% CIs were calculated to detect drug-AE pairs with higher-than-expected reporting rates within the FAERS from System Organ Classes (SOCs) to Preferred Terms (PTs). Reports were considered as signals if the 95% confidence interval did not contain the null value. After inclusion criteria were applied, a total of 4,704 reports associated with quinolones were considered. Most FAERS reports associated with ciprofloxacin (N = 2,706) followed by levofloxacin (N = 1,191), moxifloxacin (N = 375), oflaxacin (N = 245) and ozenoxacin (N = 187). The most common age group was 12-18 years. The median weight was 39.0 kilogram. The adverse effects of quinolones emerging for SOCs primarily included Infections and infestations, gastrointestinal symptoms, blood and lymphatic system disorders, cardiac disorders, nervous system disorders, musculoskeletal and connective tissue disorders and psychiatric disorders. The most frequently AE signals at the PT level were pyrexia (N = 236), febrile neutropenia (N = 120), off label use (N = 48), drug resistance (N = 18) and cardiac arrest (N = 22) following the use of ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin, and ozenoxacin, respectively. Serious oznoxacin-associated AE signals were found and have not been documented in the package insert. They included cardiac arrest (N = 22; ROR = 19.83; IC = 3.68), overdose (N = 21; ROR = 4.98; IC = 2.07), seizure (N = 16; ROR = 6.01; IC = 2.29), small for dates baby (N = 9; ROR = 14.7; IC = 3.05), completed suicide (N = 15, ROR = 18.87; IC = 3.51), asthma (N = 9; ROR = 6.69; IC = 2.24;) and hypotension (N = 9; ROR = 3.83; IC = 1.68). This study provided additional evidence with respect to quinolones-related AEs for children. Generally, the findings of this study are compatible with AEs recorded in package inserts. The unexpected signals of ozenoxacin justify active vigilance by clinicians and timely monitoring by pharmacovigilance experts.

Contemporary Pharmacotherapies for Nontuberculosis Mycobacterial Infections: A Narrative Review.

Nontuberculous mycobacteria (NTM) are a group of atypical bacteria that may cause a spectrum of clinical manifestations, including pulmonary, musculoskeletal, skin and soft tissue, and cardiac infections. Antimycobacterial medication regimens for NTM infections require multiple agents with prolonged treatment courses and are often associated with poor tolerance in patients and suboptimal clinical outcomes. This review summarizes NTM pharmacotherapy, including treatment concepts, preferred medication regimens according to NTM species and site of infection, and emerging treatment methods for difficult-to-treat species.