Prediction of Physical Frailty in Orthogeriatric Patients Using Sensor Insole–Based Gait Analysis and Machine Learning Algorithms: Cross-sectional Study

Background: Assessment of the physical frailty of older patients is of great importance in many medical disciplines to be able to implement individualized therapies. For physical tests, time is usually used as the only objective measure. To record other objective factors, modern wearables offer great potential for generating valid data and integrating the data into medical decision-making. Objective: The aim of this study was to compare the predictive value of insole data, which were collected during the Timed-Up-and-Go (TUG) test, to the benchmark standard questionnaire for sarcopenia (SARC-F: strength, assistance with walking, rising from a chair, climbing stairs, and falls) and physical assessment (TUG test) for evaluating physical frailty, defined by the Short Physical Performance Battery (SPPB), using machine learning algorithms. Methods: This cross-sectional study included patients aged >60 years with independent ambulation and no mental or neurological impairment. A comprehensive set of parameters associated with physical frailty were assessed, including body composition, questionnaires (European Quality of Life 5-dimension [EQ 5D 5L], SARC-F), and physical performance tests (SPPB, TUG), along with digital sensor insole gait parameters collected during the TUG test. Physical frailty was defined as an SPPB score≤8. Advanced statistics, including random forest (RF) feature selection and machine learning algorithms (K-nearest neighbor [KNN] and RF) were used to compare the diagnostic value of these parameters to identify patients with physical frailty. Results: Classified by the SPPB, 23 of the 57 eligible patients were defined as having physical frailty. Several gait parameters were significantly different between the two groups (with and without physical frailty). The area under the receiver operating characteristic curve (AUROC) of the TUG test was superior to that of the SARC-F (0.862 vs 0.639). The recursive feature elimination algorithm identified 9 parameters, 8 of which were digital insole gait parameters. Both the KNN and RF algorithms trained with these parameters resulted in excellent results (AUROC of 0.801 and 0.919, respectively). Conclusions: A gait analysis based on machine learning algorithms using sensor soles is superior to the SARC-F and the TUG test to identify physical frailty in orthogeriatric patients

Differences in the Inflammatory Response of White Adipose Tissue and Adipose-Derived Stem Cells

The application of liposuctioned white adipose tissue (L-WAT) and adipose-derived stem cells (ADSCs) as a novel immunomodulatory treatment option is the currently subject of various clinical trials. Because it is crucial to understand the underlying therapeutic mechanisms, the latest studies focused on the immunomodulatory functions of L-WAT or ADSCs. However, studies that examine the specific transcriptional adaptation of these treatment options to an extrinsic inflammatory stimulus in an unbiased manner are scarce. The aim of this study was to compare the gene expression profile of L-WAT and ADSCs, when subjected to tumor necrosis factor alpha (TNF\textgreeka), and to identify key factors that might be therapeutically relevant when using L-WAT or ADSCs as an immuno-modulator. Fat tissue was harvested by liposuction from five human donors. ADSCs were isolated from the same donors and shortly subjected to expansion culture. L-WAT and ADSCs were treated with human recombinant TNF\textgreeka, to trigger a strong inflammatory response. Subsequently, an mRNA deep nextgeneration sequencing was performed to evaluate the different inflammatory responses of L-WAT and ADSCs. We found significant gene expression changes in both experimental groups after TNF\textgreeka incubation. However, ADSCs showed a more homogenous gene expression profile by predominantly expressing genes involved in immunomodulatory processes such as CCL19, CCL5, TNFSF15 and IL1b when compared to L-WAT, which reacted rather heterogeneously. As RNA sequencing between L-WAT and ADSCS treated with TNF\textgreeka revealed that L-WAT responded very heterogeneously to TNF\textgreeka treatment, we therefore conclude that ADSCs are more reliable and predictable when used therapeutically. Our study furthermore yields insight into potential biological processes regarding immune system response, inflammatory response, and cell activation. Our results can help to better understand the different immunomodulatory effects of L-WAT and ADSCs

Hypoxic Signaling in Skeletal Muscle Maintenance and Regeneration: A Systematic Review

In skeletal muscle tissue, oxygen (O2) plays a pivotal role in both metabolism and the regulation of several intercellular pathways, which can modify proliferation, differentiation and survival of cells within the myogenic lineage. The concentration of oxygen in muscle tissue is reduced during embryogenesis and pathological conditions. Myogenic progenitor cells, namely satellite cells, are necessary for muscular regeneration in adults and are localized in a hypoxic microenvironment under the basal lamina, suggesting that the O2 level could affect their function. This review presents the effects of reduced oxygen levels (hypoxia) on satellite cell survival, myoblast regeneration and differentiation in vertebrates. Further investigations and understanding of the pathways involved in adult muscle regeneration during hypoxic conditions are maybe clinically relevant to seek for novel drug treatments for patients with severe muscle damage. We especially outlined the effect of hypoxia-inducible factor 1-alpha (HIF1A), the most studied transcriptional regulator of cellular and developmental response to hypoxia, whose investigation has recently been awarded with the Nobel price

Reduced awareness for osteoporosis in hip fracture patients compared to elderly patients undergoing elective hip replacement

Background: Osteoporotic fractures are associated with a loss of quality of life, but only few patients receive an appropriate therapy. Therefore, the present study aims to investigate the awareness of musculoskeletal patients to participate in osteoporosis assessment and to evaluate whether there are significant differences between acute care patients treated for major fractures of the hip compared to elective patients treated for hip joint replacement.; Methods: From May 2015 to December 2016 patients who were undergoing surgical treatment for proximal femur fracture or total hip replacement due to osteoarthritis and were at risk for an underlying osteoporosis (female > 60 and male > 70 years) were included in the study and asked to complete a questionnaire assessing the awareness for an underlying osteoporosis. ASA Score, FRAX Score, and demographic information have also been examined. Results: In total 268 patients (female = 194 (72.0%)/male = 74 (28%)), mean age 77.7 years (±7.7) undergoing hip surgery were included. Of these, 118 were treated for fracture-related etiology and 150 underwent total hip arthroplasty in an elective care setting. Patients were interviewed about their need for osteoporosis examination during hospitalization. Overall, 76 of 150 patients receiving elective care (50.7%) considered that an examination was necessary, whereas in proximal femur fracture patients the awareness was lower, and the disease osteoporosis was assessed as threatening by significantly fewer newly fractured patients. By comparison, patients undergoing trauma surgery had a considerably greater risk of developing another osteoporotic fracture than patients undergoing elective surgery determined by the FRAX(®) Score (p ≤ 0.001).; Conclusions: The patients’ motivation to endure additional osteoporosis diagnostic testing is notoriously low and needs to be increased. Patients who underwent acute care surgery for a fragility proximal femur fracture, although acutely affected by the potential consequences of underlying osteoporosis, showed lower awareness than the elective comparison population that was also on average 6.1 years younger. Although elective patients were younger and at a lower risk, they seemed to be much more willing to undergo further osteoporosis assessment. In order to better identify and care for patients at risk, interventions such as effective screening, early initiation of osteoporosis therapy in the inpatient setting and a fracture liaison service are important measures

Detailed analysis of surgically treated hand trauma patients in a regional German trauma centre.

Hand and forearm injuries are the most frequent reason for consultations in German emergency departments. Therefore, full recovery has a high social and economic relevance. In this study, data on surgically treated hand injuries in a regional German trauma centre between 01.01.2019 and 31.01.2021 were collected using the new German HandTraumaRegister of the German Society for Hand Surgery. These data were retrospectively analysed and correlated with mobility data of the Bavarian population, the 7-day incidence of Covid-19 infections in Germany and the number of elective hand surgeries. We found that a fall from standing height with consecutive distal radius fracture was the most common injury in women, whereas mechanism of injury and diagnosis were more diverse in men. The populations' mobility correlated well with the number of accidents, which in turn was reciprocal to the 7-day-incidence of Covid-19 infections. The number of elective hand surgeries expectedly dropped significantly during the state-imposed lockdowns. Knowing that mainly young men and elderly women suffer from hand injuries, tailored prevention measures may be elaborated. In order to reduce socioeconomic burden, care for hand injuries and elective hand surgeries must be guaranteed according to the frequency of their occurrence

Tenogenic Contribution to Skeletal Muscle Regeneration: The Secretome of Scleraxis Overexpressing Mesenchymal Stem Cells Enhances Myogenic Differentiation In Vitro

Integrity of the musculoskeletal system is essential for the transfer of muscular contraction force to the associated bones. Tendons and skeletal muscles intertwine, but on a cellular level, the myotendinous junctions (MTJs) display a sharp transition zone with a highly specific molecular adaption. The function of MTJs could go beyond a mere structural role and might include homeostasis of this musculoskeletal tissue compound, thus also being involved in skeletal muscle regeneration. Repair processes recapitulate several developmental mechanisms, and as myotendinous interaction does occur already during development, MTJs could likewise contribute to muscle regeneration. Recent studies identified tendon-related, scleraxis-expressing cells that reside in close proximity to the MTJs and the muscle belly. As the muscle-specific function of these scleraxis positive cells is unknown, we compared the influence of two immortalized mesenchymal stem cell (MSC) lines-differing only by the overexpression of scleraxis-on myoblasts morphology, metabolism, migration, fusion, and alignment. Our results revealed a significant increase in myoblast fusion and metabolic activity when exposed to the secretome derived from scleraxis-overexpressing MSCs. However, we found no significant changes in myoblast migration and myofiber alignment. Further analysis of differentially expressed genes between native MSCs and scleraxis-overexpressing MSCs by RNA sequencing unraveled potential candidate genes, i.e., extracellular matrix (ECM) proteins, transmembrane receptors, or proteases that might enhance myoblast fusion. Our results suggest that musculotendinous interaction is essential for the development and healing of skeletal muscles

Early Transcriptional Changes of Adipose-Derived Stem Cells (ADSCs) in Cell Culture

Background and Objectives: While autologous fat grafting has been carried out in the clinical field for many years, the utilization of isolated and cultured adipose-derived stem cells (ADSCs) is highly restricted in many countries. However, ADSCs are under investigation currently and heavily researched in many cell-based therapy approaches in the field of regenerative medicine. Objective: For the utilization of future cell-based therapies with ADSCs, in vitro cell expansion might be necessary in many cases. Thus, the cellular characteristics of ADSCs may be altered though the process of being cultured. The aim of this study was to assess changes in the gene expression profile of ADSCs after cell expansion for 48 h. Materials and Methods: Isolated ADSCs from five different donors were used for in vitro expansion. For the evaluation of the gene expression profile, mRNA deep Next-Generation Sequencing was performed to evaluate the differences between cultured and freshly isolated cells. Results: Our study gives insight into transcriptional changes in ADSCs after a short cell cultivation period. This includes the most prominent upregulated genes such as PPL, PRR15, CCL11 and ABCA9, as well the most downregulated genes, which are FOSB, FOS, EGR1 and DUSP6. Furthermore, we showed different biological processes that changed during short-term cell expansion, which led to downregulation of fat-associated metabolism hormone processes and to an upregulation of extracellular matrix-associated genes. Conclusion: In conclusion, our study reveals a detailed insight into early changes in the gene expression profile of cultured ADSCs. Our results can be utilized in future experiments

SFRP2 Overexpression Induces an Osteoblast-like Phenotype in Prostate Cancer Cells

Prostate cancer bone metastasis is still one of the most fatal cancer diagnoses for men. Survival of the circulating prostate tumor cells and their adaptation strategy to survive in the bone niche is the key point to determining metastasis in early cancer stages. The promoter of SFRP2 gene, encoding a WNT signaling modulator, is hypermethylated in many cancer types including prostate cancer. Moreover, SFRP2 can positively regulate osteogenic differentiation in vitro and in vivo. Here, we showed SFRP2 overexpression in the prostate cancer cell line PC3 induces an epithelial mesenchymal transition (EMT), increases the attachment, and modifies the transcriptome towards an osteoblast-like phenotype (osteomimicry) in a collagen 1-dependent manner. Our data reflect a novel molecular mechanism concerning how metastasizing prostate cancer cells might increase their chance to survive within bone tissue

Effects of medical interventions on health-related quality of life in chronic disease – systematic review and meta-analysis of the 19 most common diagnoses

Introduction: The demographic shift leads to a tremendous increase in age-related diseases, which are often chronic. Therefore, a focus of chronic disease management should be set on the maintenance or even improvement of the patients’ quality of life (QoL). One indicator to objectively measure QoL is the EQ-5D questionnaire, which was validated in a disease- and world region-specific manner. The aim of this study was to conduct a systematic literature review and meta-analysis on the QoL across the most frequent chronic diseases that utilized the EQ-5D and performed a disease-specific meta-analysis for treatment-dependent QoL improvement. Materials and methods: The most common chronic disease in Germany were identified by their ICD-10 codes, followed by a systematic literature review of these ICD-10 codes and the EQ-5D index values. Finally, out of 10,016 independently -screened studies by two persons, 538 studies were included in the systematic review and 216 studies in the meta-analysis, respectively. Results: We found significant medium to large effect sizes of treatment effects, i.e., effect size >0.5, in musculoskeletal conditions with the exception of fractures, for chronic depression and for stroke. The effect size did not differ significantly from zero for breast and lung cancer and were significantly negative for fractures. Conclusion: Our analysis showed a large variation between baseline and post-treatment scores on the EQ-5D health index, depending on the health condition. We found large gains in health-related quality of life mainly for interventions for musculoskeletal disease

Aggrecan Hypomorphism Compromises Articular Cartilage Biomechanical Properties and Is Associated with Increased Incidence of Spontaneous Osteoarthritis

The gene encoding the proteoglycan aggrecan (Agc1) is abundantly expressed in cartilage during development and adulthood, and the loss or diminished deposition of the protein results in a wide range of skeletal malformations. Furthermore, aggrecan degradation is a hallmark of cartilage degeneration occurring in osteoarthritis. In the present study, we investigated the consequences of a partial loss of aggrecan in the postnatal skeleton and in the articular cartilage of adult mice. We took advantage of the previously described Agc1tm(IRES-CreERT2) mouse line, which allows for conditional and timely-regulated deletion of floxed, cartilage-expressed genes. As previously reported, the introduction of the CreERT2 cassette in the 3’UTR causes a disruption of the normal expression of Agc1 resulting in a hypomorphic deposition of the protein. In homozygous mice, we observed a dwarf phenotype, which persisted throughout adulthood supporting the evidence that reduced aggrecan amount impairs skeletal growth. Homozygous mice exhibited reduced proteoglycan staining of the articular cartilage at 6 and 12 months of age, increased stiffening of the extracellular matrix at six months, and developed severe cartilage erosion by 12 months. The osteoarthritis in the hypomorph mice was not accompanied by increased expression of catabolic enzymes and matrix degradation neoepitopes. These findings suggest that the degeneration found in homozygous mice is likely due to the compromised mechanical properties of the cartilage tissue upon aggrecan reduction