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Advanced therapies are expected to play a crucial role in supporting repair after injury, halting the degeneration of musculoskeletal tissue to enable and promote physical activity. Despite advancements, the progress in developing advanced therapies in orthopaedics lags behind specialties like oncology, since innovative regenerative treatment strategies fall short of their expectations in musculoskeletal clinical trials. Researchers should focus on understanding the mechanism of action behind the investigated target before conducting clinical trials. Strategic research networks are needed that not only enhance scientific exchange among like-minded researchers but need to include early on commercial views, companies and venture perspectives, regulatory insights and reimbursement perspectives. Only in such collaborations essential roadblocks towards clinical trials and go-to-patients be overcome.

Recent developments in cell therapy have revolutionized medical treatment. While various methods of stimulation have been explored, the role of mechanical force has often been overlooked. Although mechanical loading is not easily visible, it can actively reshape organisms, and abnormal mechanical loading can lead to injury and disease. By leveraging the mechanobiology of cells, we can equip them with synthetic mechanosensors that can redirect genetic circuits to express protective factors, such as antibodies and cytokines, according to the mechanical force signal. The advancement of artificial intelligence (AI) presents a fascinating opportunity to redesign more complex mechanoreceptors, allowing cells to respond to intricate stimuli. Additionally, genetic engineering tools like CRISPR-Cas9, base editing, and prime editing enable the creation of multiple gene circuits for cells to react to complex mechanical environments. Advanced mechanical loading techniques, such as focused ultrasound, deliver signals in a confined spatial and temporal manner. Therefore, harnessing mechanobiology in cells can develop more flexible, personalized, and precise cell therapies.

Purpose: The aim of this study was to investigate the efficacy of calcitonin (CT) in animal models of experimental osteoarthritis (OA) and rheumatoid arthritis (RA), as new stabilized CT formulations are currently being introduced. Methods: A comprehensive and systemic literature search was conducted in PubMed/MEDLINE and Embase databases to identify articles with original data on CT treatment of preclinical OA and RA. Methodological quality was assessed using the Systematic Review Centre for Laboratory Animal Experimentation’s risk of bias tool for animal intervention studies. To provide summary estimates of efficacy, a meta-analysis was conducted for outcomes reported in four or more studies, using a random-effects model. Subgroup analyses were employed to correct for study specifics. Results: Twenty-six studies were ultimately evaluated and data from 16 studies could be analyzed in the meta-analysis, which included the following outcomes: bone mineral density, bone volume, levels of cross-linked C-telopeptide of type I collagen, histopathological arthritis score, and mechanical allodynia. For all considered outcome parameters, CT-treated groups were significantly superior to control groups (P = 0.002; P = 0.01; P < 0.00001; P < 0.00001; P = 0.04). For most outcomes, effect sizes were significantly greater in OA than in RA (P ≤ 0.025). High in-between study heterogeneity was detected. Conclusion: There is preclinical evidence for an antioxidant, anti-inflammatory, antinociceptive, cartilage-and bone-protective effect of CT in RA and OA. Given these effects, CT presents a promising agent for the treatment of both diseases, although the potential seems to be greater in OA.

Abstract 5q-spinal muscular atrophy (SMA) is a neuromuscular disorder (NMD) that has become one of the first 5% treatable rare diseases. The efficacy of new SMA therapies is creating a dynamic SMA patient landscape, where disease progression and scoliosis development play a central role, however, remain difficult to anticipate. New approaches to anticipate disease progression and associated sequelae will be needed to continuously provide these patients the best standard of care. Here we developed an interpretable machine learning (ML) model that can function as an assistive tool in the anticipation of SMA-associated scoliosis based on disease progression markers. We collected longitudinal data from 86 genetically confirmed SMA patients. We selected six features routinely assessed over time to train a random forest classifier. The model achieved a mean accuracy of 0.77 (SD 0.2) and an average ROC AUC of 0.85 (SD 0.17). For class 1 ‘scoliosis’ the average precision was 0.84 (SD 0.11), recall 0.89 (SD 0.22), F1-score of 0.85 (SD 0.17), respectively. Our trained model could predict scoliosis using selected disease progression markers and was consistent with the radiological measurements. During post validation, the model could predict scoliosis in patients who were unseen during training. We also demonstrate that rare disease data sets can be wrangled to build predictive ML models. Interpretable ML models can function as assistive tools in a changing disease landscape and have the potential to democratize expertise that is otherwise clustered at specialized centers.

Objective: This expert opinion paper proposes a design for a state-of-the-art magnetic resonance image (MRI) acquisition protocol for knee osteoarthritis clinical trials in early and advanced disease. Semi-quantitative and quantitative imaging endpoints are supported, partly amendable to automated analysis. Several (peri-) articular tissues and pathologies are covered, including synovitis. Method: A PubMed literature search was conducted, with focus on the past 5 years. Further, osteoarthritis imaging experts provided input. Specific MRI sequences, orientations, spatial resolutions and parameter settings were identified to align with study goals. We strived for implementation on standard clinical scanner hardware, with a net acquisition time ≤30 ​min. Results: Short- and long-term longitudinal MRIs should be obtained at ≥1.5T, if possible without hardware changes during the study. We suggest a series of gradient- and spin-echo-sequences, supporting MOAKS, quantitative analysis of cartilage morphology and T2, and non-contrast-enhanced depiction of synovitis. These sequences should be properly aligned and positioned using localizer images. One of the sequences may be repeated in each participant (re-test), optimally at baseline and follow-up, to estimate within-study precision. All images should be checked for quality and protocol-adherence as soon as possible after acquisition. Alternative approaches are suggested that expand on the structural endpoints presented. Conclusions: We aim to bridge the gap between technical MRI acquisition guides and the wealth of imaging literature, proposing a balance between image acquisition efficiency (time), safety, and technical/methodological diversity. This approach may entertain scientific innovation on tissue structure and composition assessment in clinical trials on disease modification of knee osteoarthritis.

Abstract Background The vasoactive neuropeptide calcitonin gene-related peptide alpha (αCGRP) enhances nociception in primary knee osteoarthritis (OA) and has been shown to disrupt cartilage and joint integrity in experimental rheumatoid arthritis (RA). Little is known about how αCGRP may alter articular structures in primary OA. We investigated whether αCGRP modulates local inflammation and concomitant cartilage and bone changes in a murine model of age-dependent OA. Methods Sixteen- to 18-month-old αCGRP-deficient mice (αCGRP−/− aged) were compared to, first, age-matched wild type (WTaged) and, second, young 4- to 5-month-old non-OA αCGRP-deficient (αCGRP−/− CTRL) and non-OA WT animals (WTCTRL). αCGRP levels were measured in serum. Knee and hip joint inflammation, cartilage degradation, and bone alterations were assessed by histology (OARSI histopathological grading score), gene expression analysis, and µ-computed tomography. Results WTaged mice exhibited elevated αCGRP serum levels compared to young WTCTRL animals. Marked signs of OA-induced cartilage destruction were seen in WTaged animals, while αCGRP−/− aged mice were mostly protected from this effect. Age-dependent OA was accompanied by an increased gene expression of pro-inflammatory Tnfa, Il1b, and Il6 and catabolic Mmp13, Adamts5, Ctsk, Tnfs11 (Rankl), and Cxcl12/Cxcr4 in WTaged but not in αCGRP−/− aged mice. αCGRP-deficiency however further aggravated subchondral bone sclerosis of the medial tibial plateau and accelerated bone loss in the epi- and metaphyseal trabecular tibial bone in age-dependent OA. Conclusions Similar to its function in experimental RA, αCGRP exerts a dual pro-inflammatory and bone-protective function in murine primary OA. Although anti-CGRP treatment was previously not successful in reducing pain in OA clinically, these data underline a crucial pathophysiological role of αCGRP in age-related OA.

Probabilistic pushdown automata (pPDA) are a standard operational model for programming languages involving discrete random choices and recursive procedures. Temporal properties are useful for specifying the chronological order of events during program execution. Existing approaches for model checking pPDA against temporal properties have focused mostly on $\omega$-regular and LTL properties. In this paper, we give decidability and complexity results for the model checking problem of pPDA against $\omega$-visibly pushdown languages that can be described by specification logics such as CaRet. These logical formulae allow specifying properties that explicitly take the structured computations arising from procedural programs into account. For example, CaRet is able to match procedure calls with their corresponding future returns, and thus allows to express fundamental program properties such as total and partial correctness.

Abstract Objective Platelet-rich plasma (PRP) therapy is increasingly popular to treat musculoskeletal diseases, including tendinopathies and osteoarthritis (OA). To date, it remains unclear to which extent PRP compositions are determined by the immune cell and cytokine profile of individuals or by the preparation method. To investigate this, we compared leukocyte and cytokine distributions of different PRP products to donor blood samples and assessed the effect of pro-inflammatory cytokines on chondrocytes. Design For each of three PRP preparations (ACP®, Angel™, and nSTRIDE® APS), products were derived using whole blood samples from twelve healthy donors. The cellular composition of PRP products was analyzed by flow cytometry using DURAClone antibody panels (DURAClone IM Phenotyping Basic and DURAClone IM T Cell Subsets). The MESO QuickPlex SQ 120 system was used to assess cytokine profiles (V-PLEX Proinflammatory Panel 1 Human Kit, Meso Scale Discovery). Primary human chondrocyte 2D and 3D in vitro cultures were exposed to recombinant IFN-γ and TNF-α. Proliferation and chondrogenic differentiation were quantitatively assessed. Results All three PRP products showed elevated portions of leukocytes compared to baseline levels in donor blood. Furthermore, the pro-inflammatory cytokines IFN-γ and TNF-α were significantly increased in nSTRIDE® APS samples compared to donor blood and other PRP products. The characteristics of all other cytokines and immune cells from the donor blood, including pro-inflammatory T cell subsets, were maintained in all PRP products. Chondrocyte proliferation was impaired by IFN-γ and enhanced by TNF-α treatment. Differentiation and cartilage formation were compromised upon treatment with both cytokines, resulting in altered messenger ribonucleic acid (mRNA) expression of collagen type 1A1 (COL1A1), COL2A1, and aggrecan (ACAN) as well as reduced proteoglycan content. Conclusions Individuals with elevated levels of cells with pro-inflammatory properties maintain these in the final PRP products. The concentration of pro-inflammatory cytokines strongly varies between PRP products. These observations may help to unravel the previously described heterogeneous response to PRP in OA therapy, especially as IFN-γ and TNF-α impacted primary chondrocyte proliferation and their characteristic gene expression profile. Both the individual’s immune profile and the concentration method appear to impact the final PRP product. Trial registration This study was prospectively registered in the Deutsches Register Klinischer Studien (DRKS) on 4 November 2021 (registration number DRKS00026175).

ObjectivesAnti-septin-5 encephalitis is a rare disease with only few published cases, mainly based on retrospective CSF and serum analyses. Predominant symptoms are cerebellar ataxia and oculomotor abnormalities. Due to the rareness of the disease, treatment recommendations are scarce. Herein, we prospectively describe the clinical course of a female patient with anti-septin-5 encephalitis.MethodsWe describe diagnostic workup, treatment and follow-up of a 54-year-old patient presenting with vertigo, unsteady gait, lack of drive and behavioral changes.ResultsClinical examination revealed severe cerebellar ataxia, saccadic smooth pursuit, upbeat-nystagmus, and dysarthria. Additionally, the patient presented with a depressive syndrome. MRI of the brain and spinal cord were normal. CSF analysis showed lymphocytic pleocytosis (11 cells/μl). Extensive antibody testing revealed anti septin-5 IgG in both CSF and serum without coexisting anti-neuronal antibodies. PET/CT detected no signs of malignancy. Corticosteroids, plasma exchange, and rituximab led to transient clinical improvement followed by relapse. Re-applied treatment with plasma exchange followed by bortezomib resulted in moderate but sustained clinical improvement.DiscussionAnti septin-5 encephalitis represents a rare but treatable and therefore relevant differential diagnosis in patients with cerebellar ataxia. Psychiatric symptoms can be observed in anti septin-5 encephalitis. Immunosuppressive treatment including bortezomib is moderately effective.

Aims The aim of the HIPGEN consortium is to develop the first cell therapy product for hip fracture patients using PLacental-eXpanded (PLX-PAD) stromal cells. Methods HIPGEN is a multicentre, multinational, randomized, double-blind, placebo-controlled trial. A total of 240 patients aged 60 to 90 years with low-energy femoral neck fractures (FNF) will be allocated to two arms and receive an intramuscular injection of either 150 × 106 PLX-PAD cells or placebo into the medial gluteal muscle after direct lateral implantation of total or hemi hip arthroplasty. Patients will be followed for two years. The primary endpoint is the Short Physical Performance Battery (SPPB) at week 26. Secondary and exploratory endpoints include morphological parameters (lean body mass), functional parameters (abduction and handgrip strength, symmetry in gait, weightbearing), all-cause mortality rate and patient-reported outcome measures (Lower Limb Measure, EuroQol five-dimension questionnaire). Immunological biomarker and in vitro studies will be performed to analyze the PLX-PAD mechanism of action. A sample size of 240 subjects was calculated providing 88% power for the detection of a 1 SPPB point treatment effect for a two-sided test with an α level of 5%. Conclusion The HIPGEN study assesses the efficacy, safety, and tolerability of intramuscular PLX-PAD administration for the treatment of muscle injury following arthroplasty for hip fracture. It is the first phase III study to investigate the effect of an allogeneic cell therapy on improved mobilization after hip fracture, an aspect which is in sore need of addressing for the improvement in standard of care treatment for patients with FNF. Cite this article: Bone Jt Open 2022;3(4):340–347.

Abstract Background Quadriceps tendon ruptures (QTRs) are rare but debilitating injuries, often associated with chronic metabolic conditions or long‐term steroid treatment. While the surgical treatment for acute QTRs is described thoroughly, no common strategy exists for the often frustrating treatment of chronic, reoccurring QTRs. The pro‐angiogenic and immunomodulatory properties of placenta‐derived adherent mesenchymal stromal‐like (PLX‐PAD) cells have been described to protect musculoskeletal tissues from inflammation and catabolic cytokine migration, yet little is known about the regenerative potential of PLX‐PAD cells in repetitively damaged tendon tissue. Case We report the case of an 80‐year‐old male patient with a chronic three‐time QTR of his right knee. The quadriceps tendon was reconstructed applying a conventional suture anchor repair procedure combined with a synthetic mesh augmentation and additional intramuscular and intratendineous PLX‐PAD cell injections as an individualized treatment approach. No adverse events were reported, and excellent radiological and functional outcomes with a passive range of motion of 0/0/120° knee extension‐flexion were observed at the 12 month follow‐up. Gait analysis confirmed restoration of joint motion, including gait speed, deficit in step length, and knee extensor muscle strength (pre‐surgery: 0.98 m/s, 40 cm, 42.4 ± 12.4 N; 9 months post‐surgery: 1.07 m/s, 0 cm, 10.4 ± 18.9 N) as well as hyperextension throughout stance and late swing phases (pre‐surgery: −11.2 ± 0.9°; 9 months post‐surgery: −2.7 ± 1.6°). Postoperative lymphocyte and cytokine analyses from the patient's peripheral blood serum suggested a systemic short‐term immunoregulatory reaction with postoperatively increased interleukin (IL)‐6 (pre‐surgery: 0.79 pg/mL; day 1: 139.97 pg/mL; day 5: 5.58 pg/mL; 9 months: 1.76 pg/mL) and IL‐10 (pre‐surgery: 0.9 pg/mL; day 1: 1.21 pg/ mL; day 5: 0.3 pg/mL; 9 months: 0.34 pg/mL) levels that decreased again over time. Conclusions Herein, we demonstrate a successfully treated chronic QTR with a synergistic surgical and biological reconstructive treatment approach. This local add‐on treatment with PLX‐PAD cells may be considered in specific cases of chronic QTRs, not susceptible to traditional suture anchor procedures and which exhibit a high risk of treatment failure. Further scientific engagement is warranted to explore underlying immunomodulatory mechanisms of action behind PLX‐PAD cell treatment for tendon injuries.

Background: Total knee arthroplasty (TKA) is a highly effective treatment for severe knee osteoarthritis that is increasingly performed in younger, more active patients. As postoperative muscular impairments may negatively affect surgical outcomes and implant longevity, functional muscle recovery gains increasing importance in meeting future patient demands. This study aimed to assess the status of periarticular muscles in the long-term follow-up after TKA and to evaluate its impact on in vivo tibio-femoral joint loads.Methods: A case series was created, with eight patients with knee osteoarthritis. All subjects received an instrumented knee implant in unilateral TKA. Native computed tomography scans, acquired pre and postoperatively, were used to evaluate distal muscle volumes and fatty infiltration. In vivo tibio-femoral joint loads were measured telemetrically during standing, walking, stair climbing and chair rising and were correlated to muscle status.Results: Postoperatively a reduction in fatty infiltration across all periarticular muscles was pronounced. High average peak loads acted in the tibio-femoral joint ranging from 264% during stand-to-sit activities up to 341% body weight (BW) during stair descent. Fatty infiltration of the m. quadriceps femoris and hamstrings were associated with increased tibio-femoral joint contact forces during walking (r = 0.542; 0.412 and 0.766).Conclusion: The findings suggest that a fatty infiltration of periarticular muscles may lead to increased tibio-femoral joint contact forces. However, we only observed weak correlations between these parameters. Improvements in functional mobility and the restoration of a pain-free joint likely explain the observed postoperative reductions in fatty infiltration. Perioperative rehabilitation approaches targeting residual impairments in muscle quality could, contribute to reduced tibio-femoral joint loads and improved long-term outcomes of TKA. However, it has to be pointed out that the study included a small number of patients, which may limit its validity.

BackgroundKnife crime has increased considerably in recent years in Northern Europe. Affected patients often require immediate surgical care due to traumatic organ injury. Yet, little is known about clinically relevant routine laboratory parameters in stab injury patients and how these are associated with intensive care unit (ICU) admission, hospitalization and number of surgeries.MethodsWe retrospectively analyzed 258 stab injury cases between July 2015 and December 2021 at an urban Level I Trauma Center. Annual and seasonal incidences, injury site, injury mechanism, Injury Severity Score (ISS), and surgical management were evaluated. First, correlations between routine laboratory parameters for hematology, coagulation, and serum biochemistry (peak, and Δ (change from admission to peak within 3 days following admission)) and length of hospital stay, ICU stay, and number of surgeries were assessed using Spearman’s rank correlation coefficients. Second, multivariable Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were conducted to identify parameters predictive of clinical outcomes. Third, longitudinal developments of routine laboratory parameters were assessed during hospital admission.ResultsIn 2021, significantly more stab injuries were recorded compared with previous years and occurred less during winter compared with other seasons. Mean ISS was 8.3 ± 7.3, and ISS was positively correlated with length of hospital and ICU stay (r = 0.5–0.8, p < 0.001). Aspartate transaminase (AST) (Δ) (r = 0.690), peak C-reactive protein (CrP) (r = 0.573), and erythrocyte count (Δ) (r = 0.526) showed the strongest positive correlations for length of ICU stay for penetrating, thoracoabdominal, and organ injuries, respectively. No correlations were observed between routine laboratory parameters and number of surgeries. For patients with penetrating injuries, LASSO-selected predictors of ICU admission included ISS, pH and lactate at admission, and Δ values for activated partial thromboplastin time (aPTT), K+, and erythrocyte count. CrP levels on day 3 were significantly higher in patients with penetrating (p = 0.005), thoracoabdominal (p = 0.041), and organ injuries (p < 0.001) compared with those without.ConclusionOur data demonstrate an increase in stab injury cases in 2021 and an important link between changes in routine laboratory parameters and ICU admission and hospitalization. Monitoring ISS and changes in AST, CrP, erythrocyte count, pH, lactate, aPTT, and K+ may be useful to identify patients at risk and adjust surgical and ICU algorithms early on.

The isolation of chondrocytes from human articular cartilage for single-cell RNA sequencing requires extensive and prolonged tissue digestion at 37 C. Modulations of the transcriptional activity likely take place during this period such that the transcriptomes of isolated human chondrocytes no longer match their original status in vivo. Here, we optimized the human chondrocyte isolation procedure to maximally preserve the in vivo transcriptome. Cartilage tissues were transferred into a hypoxia chamber (4% O2) immediately after being removed from OA patients and minced finely. Collagenase II at concentrations of 0.02%, 0.1%, 0.25%, 0.5%, 1%, and 2% was applied for 0.5, 1, 2, 4, and 18 h to digest the minced tissue. Actinomycin D (ActD) was added to test its capacity in stabilizing the transcriptome. Cell yield, viability, cell size, and transcriptome were determined using counter chamber, flow cytometry, and RNA sequencing (RNA-seq). Collagenase II at 2% concentration released small chondrocytes from cartilage matrix during the first digestion hour and started to release large cells thereafter, reaching a complete release at 4 h. During 4-h digestions, collagenase II at 2% and 1% but not at lower concentrations yielded maximal release also of the large chondrocyte population. RNA-seq analysis revealed that a 4-h digestion period with 1% or 2% collagenase II plus Actinomycin D optimally preserved the transcriptome. Thus, this study provides an isolation protocol for single chondrocytes from human articular cartilage optimized for transcriptome preservation and RNA-seq analysis.

Abstract The long-term success of highly effective total hip arthroplasty (THA) is mainly restricted by aseptic loosening, which is widely associated with friction between the head and cup liner. However, knowledge of the in vivo joint friction and resulting temperature increase is limited. Employing a novel combination of in vivo and in silico technologies, we analyzed the hypothesis that the intraoperatively defined implant orientation defines the individual joint roofing, friction and its associated temperature increase. A total of 38,000 in vivo activity trials from a special group of 10 subjects with instrumented THA implants with an identical material combination were analyzed and showed a significant link between implant orientation, joint kinematics, joint roofing and friction-induced temperature increase but surprisingly not with acting joint contact force magnitude. This combined in vivo and in silico analysis revealed that cup placement in relation to the stem is key to the in vivo joint friction and heating-up of THA. Thus, intraoperative placement, and not only articulating materials, should be the focus of further improvements, especially for young and more active patients.

Abstract A further increase in the number of total hip arthroplasty (THA) is predicted, in particular the number of young THA patients has raised and with it their demands. There is no standardized evidence-based rehabilitation program and no reliable guidelines for sports activities after THA. Stretching and strengthening gymnastics are routinely performed in rehabilitation and aerobics as a sport after THA. The aim of the investigation was to determine the in vivo force and moments acting on the hip prosthesis during gymnastics and aerobic exercises to provide a source for evidence-based recommendations. Hip joint loads were measured in six patients with instrumented hip implants. The resulting force FRes, bending moment MBend at the neck and torsional moment MTors at the stem were examined during seven strengthening (with two different resistance bands) and four stretching gymnastic exercises and seven aerobic exercises with and without an aerobic step board compared to the loads during the reference activity walking. The stretching and strengthening gymnastics exercises and the aerobic exercises with and without a board demonstrated in their median peak force and moments mostly lower or similar values compared to walking. Significantly increased loads were recorded for the flexor stretching exercise in monopod stand (Fres and MBend), the strengthening abduction exercise on the chair (MTors) and the strengthening flexion exercise with the stronger resistance band (MTors). We also found a significant increase in median peak values in aerobic exercises with a board for the "Basic Step" (ipsilateral started Fres and MTors; contralateral started MTors), "Kickstep ipsilateral started" (Fres and MTors) and "Over the Top contralateral started" (Fres). The in vivo loads in THA patients during frequently performed stretching, strengthening and aerobic exercises were demonstrated for the first time. It was proved that stretching gymnastic exercises are safe in terms of resulting force, bending and torque moments for THA patients, although an external assistance for stabilization may be considered. Strengthening gymnastics exercises are reliable in terms of Fres, MBend and MTors, but, based on our data, we recommend to adhere to the communicated specific postoperative restrictions and select the resistance bands with lower tension. Aerobic exercises without an aerobic board can be considered as reliable activity in terms of force and moments for THA patients. Aerobic exercises with a board are not recommended for the early postoperative period and in our opinion need to be adapted to the individual muscular and coordinative resources.

Background: Training with gym machines is one of the most popular physical activities after total hip arthroplasty (THA). However, to date, there are no evidence-based recommendations for physical activity after THA, worldwide. The aim of the study is to evaluate the in vivo hip joint loads during exercises on four widely used gym machines in order to provide a source for an evidence-based patient counselling for arthroplasty surgeons.Methods: The in vivo hip joint loads in seven patients (59.6 ± 6.4 years, 28.6 ± 2.1 kg/m2) with instrumented hip implants were assessed. The resulting force (Fres), bending moment (Mbend), and torsional moment (Mtors) were evaluated during the training on leg curl/leg extension machines (loads: 20, 30, and 40 kg), leg press machine [backrest: 10°, 30°, and 60°; load: 50, 75, and 100%BW (bodyweight)], and a rope pull machine (abduction/adduction/flexion/extension; each ipsi- and contralateral; load 10 kg). These loads were compared with the loads during walking on treadmill at 4 km/h (median peak values: Fres 303%BW, Mbend 4.25%BWm, and Mtors 2.70%BWm).Results: In each of the four performed exercises with a total of 23 different load conditions or exercise modes analyzed, a significantly lower or not different load was detected with respect to Fres, Mbend, and Mtors measured while walking with 4 km/h. Nevertheless, Fres and Mbend demonstrated a trend to increased loading during the ipsilateral monopod standing rope pull exercises hip flexion, extension, and abduction.Conclusion: Based on our investigation, we assume that the investigated gym machines and external loads can be considered mainly as low-impact sports (with some exceptions) and thus as safe physical activity after THA. Due to the fact that the examinations were conducted in the mean 17.4 months after THA, the applicability of the results to the immediate postoperative period is limited.

Abstract Background Developmental dysplasia of the hip (DDH) can lead to pain and premature secondary osteoarthritis at an early stage. Joint-preserving osteotomy is an established solution to this problem. In contrast, a conservative approach would result in pain persistence, ultimately raising the patients question for a possible date of expected prosthesis implantation. The aim of the study was to identify the relationship between the dysplastic hip anatomy and the time of prosthesis implantation in order to enable prognostic predictions in younger patients with symptomatic DDH. Materials and methods Data from 129 hips who received THA due to secondary DDH osteoarthritis were evaluated. The preoperative hip anatomy was evaluated for AI and LCE angle. Multiple linear regression analyses were then used to correlate the influence of these parameters with the patient’s age at the time of surgery. In addition, a graphical relationship was derived by the method of power least squares curve fitting with second-degree polynomials. Results The mean age for THA was 54.3 ± 11 years. The time of surgery correlated significantly with LCE (0.37) and AI (− 0.3) (p

Abstract Diseases that jeopardize the musculoskeletal system and cause chronic impairment are prevalent throughout the Western world. In Germany alone, ~1.8 million patients suffer from these diseases annually, and medical expenses have been reported to reach 34.2bn Euros. Although musculoskeletal disorders are seldom fatal, they compromise quality of life and diminish functional capacity. For example, musculoskeletal disorders incur an annual loss of over 0.8 million workforce years to the German economy. Among these diseases, traumatic skeletal muscle injuries are especially problematic because they can occur owing to a variety of causes and are very challenging to treat. In contrast to chronic muscle diseases such as dystrophy, sarcopenia, or cachexia, traumatic muscle injuries inflict damage to localized muscle groups. Although minor muscle trauma heals without severe consequences, no reliable clinical strategy exists to prevent excessive fibrosis or fatty degeneration, both of which occur after severe traumatic injury and contribute to muscle degeneration and dysfunction. Of the many proposed strategies, cell‐based approaches have shown the most promising results in numerous pre‐clinical studies and have demonstrated success in the handful of clinical trials performed so far. A number of myogenic and non‐myogenic cell types benefit muscle healing, either by directly participating in new tissue formation or by stimulating the endogenous processes of muscle repair. These cell types operate via distinct modes of action, and they demonstrate varying levels of feasibility for muscle regeneration depending, to an extent, on the muscle injury model used. While in some models the injury naturally resolves over time, other models have been developed to recapitulate the peculiarities of real‐life injuries and therefore mimic the structural and functional impairment observed in humans. Existing limitations of cell therapy approaches include issues related to autologous harvesting, expansion and sorting protocols, optimal dosage, and viability after transplantation. Several clinical trials have been performed to treat skeletal muscle injuries using myogenic progenitor cells or multipotent stromal cells, with promising outcomes. Recent improvements in our understanding of cell behaviour and the mechanistic basis for their modes of action have led to a new paradigm in cell therapies where physical, chemical, and signalling cues presented through biomaterials can instruct cells and enhance their regenerative capacity. Altogether, these studies and experiences provide a positive outlook on future opportunities towards innovative cell‐based solutions for treating traumatic muscle injuries—a so far unmet clinical need.

Abstract Background Two-stage exchange arthroplasty is still the preferred treatment choice for chronic PJI. However, the results remain unpredictable. We analyzed the treatment success of patients with an infected hip prosthesis, who were treated according to a standardized algorithm with a multidisciplinary team approach and evaluated with a strict definition of failure. Methods In this single-center prospective cohort study, all hip PJI episodes from March 2013 to May 2015 were included. Treatment failure was assessed according to the Delphi-based consensus definition. The Kaplan-Meier survival method was used to estimate the probability of infection-free survival. Patients were dichotomized into two groups depending on the number of previous septic revisions, duration of prosthesis-free interval, positive culture with difficult-to-treat microorganisms, microbiology at explantation, and microbiology at reimplantation. Results Eighty-four patients with hip PJI were the subject of this study. The most common isolated microorganisms were coagulase-negative staphylococci (CNS) followed by Staphylococcus aureus and Propionibacterium. Almost half of the study cohort (46%) had at least one previous septic revision before admission. The Kaplan-Meier estimated infection-free survival after 3 years was 89.3% (95% CI, 80% to 94%) with 30 patients at risk. The mean follow-up was 33.1 months (range, 24–48 months) with successful treatment of PJI. There were no statistical differences in infect eradication rate among the dichotomized groups. Conclusions High infect eradication rates were achieved in a challenging cohort using a standardized two-stage exchange supported by a multidisciplinary approach.

BackgroundThe COVID-19 pandemic led to the implementation of drastic shutdown measures worldwide. While quarantine, self-isolation and shutdown laws helped to effectively contain and control the spread of SARS-CoV-2, the impact of COVID-19 shutdowns on trauma care in emergency departments (EDs) remains elusive.MethodsAll ED patient records from the 35-day COVID-19 shutdown (SHUTDOWN) period were retrospectively compared to a calendar-matched control period in 2019 (CTRL) as well as to a pre (PRE)- and post (POST)-shutdown period in an academic Level I Trauma Center in Berlin, Germany. Total patient and orthopedic trauma cases and contacts as well as trauma causes and injury patterns were evaluated during respective periods regarding absolute numbers, incidence rate ratios (IRRs) and risk ratios (RRs).FindingsDaily total patient cases (SHUTDOWN vs. CTRL, 106.94 vs. 167.54) and orthopedic trauma cases (SHUTDOWN vs. CTRL, 30.91 vs. 52.06) decreased during the SHUTDOWN compared to the CTRL period with IRRs of 0.64 and 0.59. While absolute numbers decreased for most trauma causes during the SHUTDOWN period, we observed increased incidence proportions of household injuries and bicycle accidents with RRs of 1.31 and 1.68 respectively. An RR of 2.41 was observed for injuries due to domestic violence. We further recorded increased incidence proportions of acute and regular substance abuse during the SHUTDOWN period with RRs of 1.63 and 3.22, respectively.ConclusionsWhile we observed a relevant decrease in total patient cases, relative proportions of specific trauma causes and injury patterns increased during the COVID-19 shutdown in Berlin, Germany. As government programs offered prompt financial aid during the pandemic to individuals and businesses, additional social support may be considered for vulnerable domestic environments.

Background:. With increasing life expectancy, the demand for knee replacement is continuously rising. Despite the use of antibiotic prophylaxis and improved aseptic surgical techniques, periprosthetic joint infection (PJI) still occurs in 1% to 5% of patients after primary arthroplasty. An open question is the influence of PJI and resulting surgical procedures on the occurrence of long-term complications such as aseptic loosening. Patients needing multiple revision surgeries are especially at risk for decreases in bone mass and damage to the medullary cavity. Thus, we theorized that prior surgeries on the affected knee increase the risk of aseptic loosening in patients with PJI. Methods:. We retrospectively analyzed the cases of 100 patients who underwent total knee replacement exchange surgery as a result of PJI. In addition to clinical, paraclinical, and radiographic examination, we assessed comorbidities and the number of prior surgeries. Results:. Prosthetic survival was drastically decreased after PJI-related revision arthroplasty: during the first 7.3 years after reimplantation, 22% and 16% of all patients had aseptic loosening and recurrent PJI, respectively. The prevalence of aseptic loosening was 27.8% for female and 15.2% for male patients. A significant association between increasing patients’ American Society of Anesthesiologists (ASA) classification and prosthetic failure rates was found, as was a strong correlation between number of prior surgeries and aseptic loosening Conclusions:. In this study, we found notable rates of aseptic loosening and recurrent PJI following PJI-related revision arthroplasty. The difference in the rate of aseptic loosening among male and female patients supports theories of the role of bone metabolism in the development of aseptic loosening. The economic and clinical burdens of prosthetic failure make it paramount to gain a better understanding of bone metabolism in PJI. Additional research should address the need to optimize treatment strategies to increase prosthetic survival. Level of Evidence:. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Abstract Background No regenerative approach has thus far been shown to be effective in skeletal muscle injuries, despite their high frequency and associated functional deficits. We sought to address surgical trauma‐related muscle injuries using local intraoperative application of allogeneic placenta‐derived, mesenchymal‐like adherent cells (PLX‐PAD), using hip arthroplasty as a standardized injury model, because of the high regenerative and immunomodulatory potency of this cell type. Methods Our pilot phase I/IIa study was prospective, randomized, double blind, and placebo‐controlled. Twenty patients undergoing hip arthroplasty via a direct lateral approach received an injection of 3.0 × 108 (300 M, n = 6) or 1.5 × 108 (150 M, n = 7) PLX‐PAD or a placebo (n = 7) into the injured gluteus medius muscles. Results We did not observe any relevant PLX‐PAD‐related adverse events at the 2‐year follow‐up. Improved gluteus medius strength was noted as early as Week 6 in the treatment‐groups. Surprisingly, until Week 26, the low‐dose group outperformed the high‐dose group and reached significantly improved strength compared with placebo [150 M vs. placebo: P = 0.007 (baseline adjusted; 95% confidence interval 7.6, 43.9); preoperative baseline values mean ± SE: placebo: 24.4 ± 6.7 Nm, 150 M: 27.3 ± 5.6 Nm], mirrored by an increase in muscle volume [150 M vs. placebo: P = 0.004 (baseline adjusted; 95% confidence interval 6.0, 30.0); preoperative baseline values GM volume: placebo: 211.9 ± 15.3 cm3, 150 M: 237.4 ± 27.2 cm3]. Histology indicated accelerated healing after cell therapy. Biomarker studies revealed that low‐dose treatment reduced the surgery‐related immunological stress reaction more than high‐dose treatment (exemplarily: CD16+ NK cells: Day 1 P = 0.06 vs. placebo, P = 0.07 vs. 150 M; CD4+ T‐cells: Day 1 P = 0.04 vs. placebo, P = 0.08 vs. 150 M). Signs of late‐onset immune reactivity after high‐dose treatment corresponded to reduced functional improvement. Conclusions Allogeneic PLX‐PAD therapy improved strength and volume of injured skeletal muscle with a reasonable safety profile. Outcomes could be positively correlated with the modulation of early postoperative stress‐related immunological reactions.

The diagnosis of implant-associated infections is hampered due to microbial adherence and biofilm formation on the implant surface. Sonication of explanted devices was shown to improve the microbiological diagnosis by physical removal of biofilms. Recently, chemical agents have been investigated for biofilm dislodgement such as the chelating agent ethylenediaminetetraacetic acid (EDTA) and the reducing agent dithiothreitol (DTT). We compared the activity of chemical methods for biofilm dislodgement to sonication in an established in vitro model of artificial biofilm. Biofilm-producing laboratory strains of Staphylococcus epidermidis (ATCC 35984), S. aureus (ATCC 43300), E. coli (ATCC 25922) and Pseudomonas aeruginosa (ATCC 53278) were used. After 3 days of biofilm formation, porous glass beads were exposed to control (0.9% NaCl), sonication or chemical agents. Quantitative and qualitative biofilm analyses were performed by colony counting, isothermal microcalorimetry and scanning electron microscopy. Recovered colony counts after treatment with EDTA and DTT were similar to those after exposure to 0.9% NaCl for biofilms of S. epidermidis (6.3 and 6.1 vs. 6.0 log10 CFU/mL, S. aureus (6.4 and 6.3 vs. 6.3 log10 CFU/mL), E. coli (5.2 and 5.1 vs. 5.1 log10 CFU/mL and P. aeruginosa (5.1 and 5.2 vs. 5.0 log10 CFU/mL, respectively). In contrast, with sonication higher CFU counts were detected with all tested microorganisms (7.5, 7.3, 6.2 and 6.5 log10 CFU/mL, respectively) (p

The percentage area of fast twitch fibres of a muscle is a major determinant of muscle mechanical power and, thus, an important biomarker for the evaluation of training processes. However, the invasive character of the assessment (muscle biopsy) limits the wide application of the biomarker in the training praxis. Our purpose was to develop a non-invasive method for the assessment of fast twitch fibre content in human soleus muscle. From a theoretical point of view, the maximum muscle mechanical power depends on the fibre composition, the muscle volume and muscle specific tension. Therefore, we hypothesised that the percentage area of type II fibres would show a correlation with the maximum muscle mechanical power normalised to muscle volume and specific muscle contractile strength (i.e., plantar flexion moment divided by muscle cross-sectional area). In 20 male adults, the percentage area of type II fibres, volume and maximum cross-sectional area of the soleus muscle as well as the maximum plantar flexion moment and the maximum mechanical power were measured using muscle biopsies, magnetic resonance imaging and dynamometry. The maximum mechanical power normalised to muscle volume and specific muscle contractile strength provided a significant relationship (r = 0.654, p = 0.002) with the percentage area of type II fibres. Although the proposed assessment parameter cannot fully replace histological measurements, the predictive power of 43% can provide a relevant contribution to performance diagnostics in the training praxis.