The Association Between the Development of Cam Morphology During Skeletal Growth in High-Impact Athletes and the Presence of Cartilage Loss and Labral Damage in Adulthood: A Prospective Cohort Study With a 12-Year Follow-up.

BACKGROUND: Cam morphology develops during skeletal growth, but its influence on cartilage and the labrum in high-impact athletes later in life is unknown. PURPOSE: To (1) explore the association between the presence and duration of cam morphology during adolescence and the cartilage and labral status 7 to 12 years later and (2) report the prevalence of cartilage loss and labral damage in a population of young male athletes (<32 years old) who played professional soccer during skeletal growth. STUDY DESIGN: Cohort study (Prognosis); Level of evidence, 2. METHODS: A total of 89 healthy male academy soccer players from the Dutch soccer club Feyenoord (aged 12-19 years) were included at baseline. At baseline and 2.5- and 5-year follow-ups, standardized supine anteroposterior pelvis and frog-leg lateral radiographs of each hip were obtained. At 12-year follow-up, magnetic resonance imaging of both hips was performed. Cam morphology was defined by a validated alpha angle ≥60° on radiographs at baseline or 2.5- or 5-year follow-up when the growth plates were closed. Hips with the presence of cam morphology at baseline or at 2.5-year follow-up were classified as having a "longer duration" of cam morphology. Hips with cam morphology only present since 5-year follow-up were classified as having a "shorter duration" of cam morphology. At 12-year follow-up, cartilage loss and labral abnormalities were assessed semiquantitatively. Associations were estimated using logistic regression, adjusted for age and body mass index. RESULTS: Overall, 35 patients (70 hips) with a mean age of 28.0 ± 2.0 years and mean body mass index of 24.1 ± 1.8 participated at 12-year follow-up. Cam morphology was present in 56 of 70 hips (80%). The prevalence of cartilage loss was 52% in hips with cam morphology and 21% in hips without cam morphology (adjusted odds ratio, 4.52 [95% CI, 1.16-17.61]; P = .03). A labral abnormality was present in 77% of hips with cam morphology and in 64% of hips without cam morphology (adjusted odds ratio, 1.99 [95% CI, 0.59-6.73]; P = .27). The duration of cam morphology did not influence these associations. CONCLUSION: The development of cam morphology during skeletal growth was associated with future magnetic resonance imaging findings consistent with cartilage loss in young adults but not with labral abnormalities.

Femoroacetabular impingement syndrome in middle-aged individuals is strongly associated with the development of hip osteoarthritis within 10-year follow-up: a prospective cohort study (CHECK).

OBJECTIVE: The objective is to determine the association and absolute risk of femoroacetabular impingement syndrome (FAIS) for the development of radiographic hip osteoarthritis (RHOA). METHODS: This is a nationwide, multicentre prospective cohort study (Cohort Hip and Cohort Knee) with 1002 individuals aged between 45 and 65 years. Hips without definitive RHOA (Kellgren-Lawrence (KL) grade≤1) at baseline and with anteroposterior pelvic radiographs at baseline and 10-year follow-up available (n=1386 hips) were included. FAIS was defined by the baseline presence of a painful hip, limited internal hip rotation≤25° and cam morphology defined by an alpha angle>60°. The outcomes were incident RHOA (KL grade≥2 or total hip replacement (THR)) and incident end-stage RHOA (KL≥3 or THR) within 10 years. RESULTS: Of the 1386 included hips (80% women; mean age 55.7±5.2 years), 21 hips fulfilled criteria for FAIS and 563 hips did not fulfil any of the FAIS criteria (reference group; no symptoms, no signs, no cam morphology). Within 10-year follow-up, 221 hips (38%) developed incident RHOA and 15 hips (3%) developed end-stage RHOA (including 9 hips with THR). Adjusted for sex, age and body mass index, FAIS with cam morphology resulted in an OR of 6.85 (95% CI 2.10 to 22.35) for incident RHOA and 47.82 (95% CI 12.51 to 182.76) for incident end-stage RHOA, compared with hips not having any FAIS criteria. The absolute risk of FAIS was 81% for incident RHOA and 33% for incident end-stage RHOA. CONCLUSION: FAIS was strongly associated with the development of RHOA within 10 years. Although the baseline prevalence of FAIS was low, the high absolute risk of FAIS for RHOA warrants further studies to determine preventive strategies.

Severity and progression of structural hand OA is not associated with progression of structural knee OA: The IMI-APPROACH cohort.

Objective: To investigate whether structural hand OA or its progression is associated with structural knee OA progression after two years in a population with symptomatic knee OA. Methods: We used baseline and two-year follow-up data from the IMI-APPROACH cohort. Symptomatic hand and knee OA were defined using ACR criteria. Radiographs of hands and knees were scored semi-quantitatively for osteophytes and joint space narrowing (JSN) following the OARSI atlas, and Kellgren-Lawrence (KL) scale. Knee images were also scored quantitatively with the Knee Image Digital Analysis (KIDA). Progression was defined as change above the minimal detectable change on patient level, except for KIDA (most affected knee compartment level). With logistic regression analyses the severity or progression of hand OA was associated with knee OA progression. Results: In 221 participants (mean age 66, 77% women, mean BMI 27.7, 19% hand OA), OA progression occurred in 18%-28%, and 9%-38% in hands and knees respectively, depending on features. Baseline structural hand OA features were not significantly associated with knee OA progression, except for hand osteophytes with KIDA osteophytes progression (odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01-1.06). Progression of structural hand OA features was not significantly associated with knee OA progression, except for hand osteophyte or JSN progression, which was significantly associated with knee osteophyte progression (OR 0.44, 95%CI 0.22-0.84 and OR 0.43, 95%CI 0.18-0.94, respectively), and hand osteophyte progression for knee JSN (OR 2.51, 95%CI 1.15-5.48). Conclusions: In patients with symptomatic knee OA, no consistent associations between baseline structural hand OA or hand OA progression and knee OA progression were shown.

Cohort profile: Worldwide Collaboration on OsteoArthritis prediCtion for the Hip (World COACH) - an international consortium of prospective cohort studies with individual participant data on hip osteoarthritis.

PURPOSE: Hip osteoarthritis (OA) is a major cause of pain and disability worldwide. Lack of effective therapies may reflect poor knowledge on its aetiology and risk factors, and result in the management of end-stage hip OA with costly joint replacement. The Worldwide Collaboration on OsteoArthritis prediCtion for the Hip (World COACH) consortium was established to pool and harmonise individual participant data from prospective cohort studies. The consortium aims to better understand determinants and risk factors for the development and progression of hip OA, to optimise and automate methods for (imaging) analysis, and to develop a personalised prediction model for hip OA. PARTICIPANTS: World COACH aimed to include participants of prospective cohort studies with ≥200 participants, that have hip imaging data available from at least 2 time points at least 4 years apart. All individual participant data, including clinical data, imaging (data), biochemical markers, questionnaires and genetic data, were collected and pooled into a single, individual-level database. FINDINGS TO DATE: World COACH currently consists of 9 cohorts, with 38 021 participants aged 18-80 years at baseline. Overall, 71% of the participants were women and mean baseline age was 65.3±8.6 years. Over 34 000 participants had baseline pelvic radiographs available, and over 22 000 had an additional pelvic radiograph after 8-12 years of follow-up. Even longer radiographic follow-up (15-25 years) is available for over 6000 of these participants. FUTURE PLANS: The World COACH consortium offers unique opportunities for studies on the relationship between determinants/risk factors and the development or progression of hip OA, by using harmonised data on clinical findings, imaging, biomarkers, genetics and lifestyle. This provides a unique opportunity to develop a personalised hip OA risk prediction model and to optimise methods for imaging analysis of the hip.

Prevalence and progression of arterial calcifications on computed tomography in humans with knee osteoarthritis.

OBJECTIVES: Ectopic bone deposition plays an important role in osteoarthritis (OA) and in arterial wall disease. We aimed to investigate the prevalence and progression of arterial calcifications on whole-body computed tomography (CT) in persons with knee OA. METHODS: We included 118 (36 male) participants who satisfied the clinical American College of Rheumatology classification criteria for knee OA. Baseline investigations included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Kellgren-Lawrence grading. At baseline and after two years, a whole-body CT was performed using the same scanner and protocol. Calcifications were quantified in the carotid, brachiocephalic, coronary, thoracic aortic, abdominal aortic, iliac, femoropopliteal and crural arteries. Multivariable linear and logistic regression modeling was used for analyses. RESULTS: At baseline males were 66.9 ± 7.7 and females were 68.0 ± 5.6 years old. Calcifications were common, all participants except two females had some calcification, and prevalence ranged between 41.8% and 94.4% for various arterial beds. Baseline femoropopliteal calcifications were associated with a higher Kellgren-Lawrence grade (more severe knee OA). Median annual progression rate was 13.1% in males and 15.7% in females. Structural OA severity was not associated with progression, but a five points lower (worse) WOMAC was associated with 1% faster progression of arterial calcifications (p= 0.008). CONCLUSION: Around age 70 nearly all persons with knee OA have arterial calcifications, which progress substantially. For further investigation into shared causality intervention studies are needed.

Photoimmuno-antimicrobial therapy for Staphylococcus aureus implant infection.

INTRODUCTION: Implant infections caused by Staphylococcus aureus are responsible for high mortality and morbidity worldwide. Treatment of these infections can be difficult especially when bacterial biofilms are involved. In this study we investigate the potential of infrared photoimmunotherapy to eradicate staphylococcal infection in a mouse model. METHODS: A monoclonal antibody that targets Wall Teichoic Acid surface components of both S. aureus and its biofilm (4497-IgG1) was conjugated to a photosensitizer (IRDye700DX) and used as photoimmunotherapy in vitro and in vivo in mice with a subcutaneous implant pre-colonized with biofilm of Staphylococcus aureus. A dose of 400 µg and 200 µg of antibody-photosensitizer conjugate 4497-IgG-IRDye700DXwas administered intravenously to two groups of 5 mice. In addition, multiple control groups (vancomycin treated, unconjugated IRDye700DX and IRDye700DX conjugated to a non-specific antibody) were used to verify anti-microbial effects. RESULTS: In vitro results of 4497-IgG-IRDye700DX on pre-colonized (biofilm) implants showed significant (p<0.01) colony-forming units (CFU) reduction at a concentration of 5 µg of the antibody-photosensitizer conjugate. In vivo, treatment with 4497-IgG-IRDye700DX showed no significant CFU reduction at the implant infection. However, tissue around the implant did show a significant CFU reduction with 400 µg 4497-IgG-IRDye700DX compared to control groups (p = 0.037). CONCLUSION: This study demonstrated the antimicrobial potential of photoimmunotherapy for selectively eliminating S. aureus in vivo. However, using a solid implant instead of a catheter could result in an increased bactericidal effect of 4497-IgG-IRDye700DX and administration locally around an implant (per operative) could become valuable applications in patients that are difficult to treat with conventional methods. We conclude that photoimmunotherapy could be a potential additional therapy in the treatment of implant related infections, but requires further improvement.

Radiologic Assessment of Interbody Fusion: A Systematic Review on the Use, Reliability, and Accuracy of Current Fusion Criteria.

BACKGROUND: Lumbar interbody fusion (IF) is a common procedure to fuse the anterior spine. However, a lack of consensus on image-based fusion assessment limits the validity and comparison of IF studies. This systematic review aims to (1) report on IF assessment strategies and definitions and (2) summarize available literature on the diagnostic reliability and accuracy of these assessments. METHODS: Two searches were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Search 1 identified studies on adult lumbar IF that provided a detailed description of image-based fusion assessment. Search 2 analyzed studies on the reliability of specific fusion criteria/classifications and the accuracy assessed with surgical exploration. RESULTS: A total of 442 studies were included for search 1 and 8 studies for search 2. Fusion assessment throughout the literature was highly variable. Eighteen definitions and more than 250 unique fusion assessment methods were identified. The criteria that showed most consistent use were continuity of bony bridging, radiolucency around the cage, and angular motion <5°. However, reliability and accuracy studies were scarce. CONCLUSION: This review highlights the challenges in reaching consensus on IF assessment. The variability in IF assessment is very high, which limits the translatability of studies. Accuracy studies are needed to guide innovations of assessment. Future IF assessment strategies should focus on the standardization of computed tomography-based continuity of bony bridging. Knowledge from preclinical and imaging studies can add valuable information to this ongoing discussion. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Magnetic resonance imaging-based bone imaging of the lower limb: Strategies for generating high-resolution synthetic computed tomography.

This study aims at assessing approaches for generating high-resolution magnetic resonance imaging- (MRI-) based synthetic computed tomography (sCT) images suitable for orthopedic care using a deep learning model trained on low-resolution computed tomography (CT) data. To that end, paired MRI and CT data of three anatomical regions were used: high-resolution knee and ankle data, and low-resolution hip data. Four experiments were conducted to investigate the impact of low-resolution training CT data on sCT generation and to find ways to train models on low-resolution data while providing high-resolution sCT images. Experiments included resampling of the training data or augmentation of the low-resolution data with high-resolution data. Training sCT generation models using low-resolution CT data resulted in blurry sCT images. By resampling the MRI/CT pairs before the training, models generated sharper images, presumably through an increase in the MRI/CT mutual information. Alternatively, augmenting the low-resolution with high-resolution data improved sCT in terms of mean absolute error proportionally to the amount of high-resolution data. Overall, the morphological accuracy was satisfactory as assessed by an average intermodal distance between joint centers ranging from 0.7 to 1.2 mm and by an average intermodal root-mean-squared distances between bone surfaces under 0.7 mm. Average dice scores ranged from 79.8% to 87.3% for bony structures. To conclude, this paper proposed approaches to generate high-resolution sCT suitable for orthopedic care using low-resolution data. This can generalize the use of sCT for imaging the musculoskeletal system, paving the way for an MR-only imaging with simplified logistics and no ionizing radiation.

In Vivo Prevention of Implant-Associated Infections Caused by Antibiotic-Resistant Bacteria through Biofunctionalization of Additively Manufactured Porous Titanium.

Additively manufactured (AM) porous titanium implants may have an increased risk of implant-associated infection (IAI) due to their huge internal surfaces. However, the same surface, when biofunctionalized, can be used to prevent IAI. Here, we used a rat implant infection model to evaluate the biocompatibility and infection prevention performance of AM porous titanium against bioluminescent methicillin-resistant Staphylococcus aureus (MRSA). The specimens were biofunctionalized with Ag nanoparticles (NPs) using plasma electrolytic oxidation (PEO). Infection was initiated using either intramedullary injection in vivo or with in vitro inoculation of the implant prior to implantation. Nontreated (NT) implants were compared with PEO-treated implants with Ag NPs (PT-Ag), without Ag NPs (PT) and infection without an implant. After 7 days, the bacterial load and bone morphological changes were evaluated. When infection was initiated through in vivo injection, the presence of the implant did not enhance the infection, indicating that this technique may not assess the prevention but rather the treatment of IAIs. Following in vitro inoculation, the bacterial load on the implant and in the peri-implant bony tissue was reduced by over 90% for the PT-Ag implants compared to the PT and NT implants. All infected groups had enhanced osteomyelitis scores compared to the noninfected controls.

Microencapsulated stem cells reduce cartilage damage in a material dependent manner following minimally invasive intra-articular injection in an OA rat model.

Osteoarthritis (OA) is a degenerative disease of the joints for which no curative treatment exists. Intra-articular injection of stem cells is explored as a regenerative approach, but rapid clearance of cells from the injection site limits the therapeutic outcome. Microencapsulation of mesenchymal stem cells (MSCs) can extend the retention time of MSCs, but the outcomes of the few studies currently performed are conflicting. We hypothesize that the composition of the micromaterial's shell plays a deciding factor in the treatment outcome of intra-articular MSC injection. To this end, we microencapsulate MSCs using droplet microfluidic generators in flow-focus mode using various polymers and polymer concentrations. We demonstrate that polymer composition and concentration potently alter the metabolic activity as well as the secretome of MSCs. Moreover, while microencapsulation consistently prolongs the retention time of MSC injected in rat joints, distinct biodistribution within the joint is demonstrated for the various microgel formulations. Furthermore, intra-articular injections of pristine and microencapsulated MSC in OA rat joints show a strong material-dependent effect on the reduction of cartilage degradation and matrix loss. Collectively, this study highlights that micromaterial composition and concentration are key deciding factors for the therapeutic outcome of intra-articular injections of microencapsulated stem cells to treat degenerative joint diseases.

Development and validation of a machine learning-supported strategy of patient selection for osteoarthritis clinical trials: the IMI-APPROACH study.

Objectives: To efficiently assess the disease-modifying potential of new osteoarthritis treatments, clinical trials need progression-enriched patient populations. To assess whether the application of machine learning results in patient selection enrichment, we developed a machine learning recruitment strategy targeting progressive patients and validated it in the IMI-APPROACH knee osteoarthritis prospective study. Design: We designed a two-stage recruitment process supported by machine learning models trained to rank candidates by the likelihood of progression. First stage models used data from pre-existing cohorts to select patients for a screening visit. The second stage model used screening data to inform the final inclusion. The effectiveness of this process was evaluated using the actual 24-month progression. Results: From 3500 candidate patients, 433 with knee osteoarthritis were screened, 297 were enrolled, and 247 completed the 2-year follow-up visit. We observed progression related to pain (P, 30%), structure (S, 13%), and combined pain and structure (P â€‹+ â€‹S, 5%), and a proportion of non-progressors (N, 52%) ∼15% lower vs an unenriched population. Our model predicted these outcomes with AUC of 0.86 [95% CI, 0.81-0.90] for pain-related progression and AUC of 0.61 [95% CI, 0.52-0.70] for structure-related progression. Progressors were ranked higher than non-progressors for P â€‹+ â€‹S (median rank 65 vs 143, AUC = 0.75), P (median rank 77 vs 143, AUC = 0.71), and S patients (median rank 107 vs 143, AUC = 0.57). Conclusions: The machine learning-supported recruitment resulted in enriched selection of progressive patients. Further research is needed to improve structural progression prediction and assess this strategy in an interventional trial.

Evaluation of silver bio-functionality in a multicellular in vitro model: towards reduced animal usage in implant-associated infection research.

Background: Despite the extensive use of silver ions or nanoparticles in research related to preventing implant-associated infections (IAI), their use in clinical practice has been debated. This is because the strong antibacterial properties of silver are counterbalanced by adverse effects on host cells. One of the reasons for this may be the lack of comprehensive in vitro models that are capable of analyzing host-bacteria and host-host interactions. Methods and results: In this study, we tested silver efficacy through multicellular in vitro models involving macrophages (immune system), mesenchymal stem cells (MSCs, bone cells), and S. aureus (pathogen). Our model showed to be capable of identifying each element of culture as well as tracking the intracellular survival of bacteria. Furthermore, the model enabled to find a therapeutic window for silver ions (AgNO3) and silver nanoparticles (AgNPs) where the viability of host cells was not compromised, and the antibacterial properties of silver were maintained. While AgNO3 between 0.00017 and 0.017 µg/mL retained antibacterial properties, host cell viability was not affected. The multicellular model, however, demonstrated that those concentrations had no effect on the survival of S. aureus, inside or outside host cells. Similarly, treatment with 20 nm AgNPs did not influence the phagocytic and killing capacity of macrophages or prevent S. aureus from invading MSCs. Moreover, exposure to 100 nm AgNPs elicited an inflammatory response by host cells as detected by the increased production of TNF-α and IL-6. This was visible only when macrophages and MSCs were cultured together. Conclusions: Multicellular in vitro models such as the one used here that simulate complex in vivo scenarios can be used to screen other therapeutic compounds or antibacterial biomaterials without the need to use animals.

Acetabular rim extension using a personalized titanium implant for treatment of hip dysplasia in dogs: short-term results.

Hip dysplasia (HD) is a common orthopedic problem in young dogs. To decrease the laxity of the hip joint related to HD, the surgical treatments are recommended to increase femoral head coverage. ACEtabular rim eXtension (ACE-X) using a personalized 3-dimensional printed titanium shelf implant is a new surgical treatment to increase femoral head coverage and decrease laxity of the dysplastic hip joint, however, the efficacy is less know. Client-owned dogs older than 6 months with clinical signs of coxofemoral joint subluxation and radiographic evidence of HD with no or mild osteoarthritis (OA) were included. The Norberg angle (NA), linear percentage of femoral head overlap (LFO), and percentage of femoral head coverage (PC) were investigated radiographically and with computed tomography (CT) before and after surgery. OA was graded (scores 0-3) according to the maximum osteophyte size measured on CT. In addition, joint laxity (Ortolani) test results, gait analysis, and the Helsinki chronic pain index (HCPI) questionnaire were obtained at preoperative, immediately postoperative and at 1.5- and 3-month evaluations. Acetabular rim extension was performed in 61 hips of 34 dogs; NA, LFO, and PC were significantly higher immediately postoperatively and at the 1.5- and 3-month follow-up examinations compared with preoperative values (p < 0.05). Osteophyte size gradually increased over time (p < 0.05). The OA score significantly increased between preoperatively and directly postoperatively, and between preoperatively and at 3-month follow-up (p < 0.05). The laxity test normalized in 59 out of 61 hips after surgery, and the HCPI questionnaire showed that the pain score decreased significantly at 1.5 and 3 months, postoperatively. The force plate showed no significant improvement during the 3 months follow-up. Although pain reduction by the implant was unclear in short-term results, a personalized shelf implant significantly increased femoral head coverage and eliminated subluxation of the dysplastic hip joint. Further studies are required to study the long-term efficacy of gait, chronic pain, and progression of osteoarthritis.

Impact of bone and cartilage segmentation from CT and MRI on both bone forearm osteotomy planning.

INTRODUCTION: The use of MRI scans for pre-operative surgical planning of forearm osteotomies provides additional information of joint cartilage and soft tissue structures and reduces radiation exposure in comparison with the use of CT scans. In this study, we investigated whether using 3D information obtained from MRI with and without cartilage information leads to a different outcome of pre-operative planning. METHODS: Bilateral CT and MRI scans of the forearms of 10 adolescent and young adult patients with a unilateral bone deformation were acquired in a prospective study. The bones were segmented from CT and MRI, and cartilage only from MRI. The deformed bones were virtually reconstructed, by registering the joint ends to the healthy contralateral side. An optimal osteotomy plane was determined that minimized the distance between the resulting fragments. This process was performed in threefold: using the CT and MRI bone segmentations, and the MRI cartilage segmentations. RESULTS: Comparison of bone segmentation from MRI and CT scan resulted in a 0.95 ± 0.02 Dice Similarity Coefficient and 0.42 ± 0.07 mm Mean Absolute Surface Distance. All realignment parameters showed excellent reliability across the different segmentations. However, the mean differences in translational realignment between CT and MRI bone segmentations (4.5 ± 2.1 mm) and between MRI bone and MRI bone and cartilage segmentations (2.8 ± 2.1 mm) were shown to be clinically and statistically significant. A significant positive correlation was found between the translational realignment and the relative amount of cartilage. CONCLUSION: This study indicates that although bone realignment remained largely similar when using MRI with and without cartilage information compared to using CT, the small differences in segmentation could induce statistically and clinically significant differences in the osteotomy planning. We also showed that endochondral cartilage might be a non-negligible factor when planning osteotomies for young patients.

Mesenchymal stem/stromal cells-derived extracellular vesicles as a potentially more beneficial therapeutic strategy than MSC-based treatment in a mild metabolic osteoarthritis model.

BACKGROUND: Mesenchymal stromal/stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) hold promise as a disease modifying treatment in osteoarthritis (OA). Obesity, and its associated inflammation, contribute to OA development and metabolic OA represents a specific and significant group of the OA patient population. Given their immunomodulatory properties, MSC and MSC-EVs are especially interesting for this group of patients as a therapeutic option. Here, we were the first to compare the therapeutic efficacy of MSCs and MSC-EVs in a mild OA model taking these metabolic aspects into consideration. METHODS: Male Wistar-Han rats (Crl:WI(Han) (n = 36) were fed a high fat diet for 24 weeks, with unilateral induction of OA by groove surgery after 12 weeks. Eight days after surgery rats were randomized in three treatment groups receiving MSCs, MSC-EVs or vehicle injection. Pain-associated behavior, joint degeneration, and local and systemic inflammation were measured. RESULTS: We demonstrated that despite not having a significant therapeutic effect, MSC-EV treatment results in lower cartilage degeneration, less pain behaviour, osteophytosis and joint inflammation, than MSC treatment. Suggesting that MSC-EVs could be a more promising therapeutic strategy than MSCs in this mild metabolic OA model. CONCLUSION: In summary, we find that MSC treatment has negative effects on the joint in metabolic mild OA. This is an essential finding for the significant group of patients with metabolic OA phenotype, and might help to understand why clinical translation of MSC treatment shows varying therapeutic efficacy thus far. Our results also suggest that MSC-EV-based treatment might be a promising option for these patients, however MSC-EV therapeutic efficacy will need improvement.

Macrophage-Driven Inflammation in Metabolic Osteoarthritis: Implications for Biomarker and Therapy Development.

Osteoarthritis (OA) is a common and debilitating joint disorder that leads to progressive joint breakdown and loss of articular cartilage. Accompanied by a state of low-grade inflammation, its etiology extends beyond that of a wear-and-tear disease, and the immune system might have a role in its initiation and progression. Obesity, which is directly associated with an increased incidence of OA, alters adipokine release, increases pro-inflammatory macrophage activity, and affects joint immune regulation. Studying inflammatory macrophage expression and strategies to inhibit inflammatory macrophage phenotype polarization might provide insights into disease pathogenesis and therapeutic applications. In pre-clinical studies, the detection of OA in its initial stages was shown to be possible using imaging techniques such as SPECT-CT, and advances are made to detect OA through blood-based biomarker analysis. In this review, obesity-induced osteoarthritis and its mechanisms in inducing joint degeneration are summarized, along with an analysis of the current developments in patient imaging and biomarker use for diagnostic and therapeutic strategies.

Evaluating the Targeting of a Staphylococcus-aureus-Infected Implant with a Radiolabeled Antibody In Vivo.

Implant infections caused by Staphylococcus aureus are difficult to treat due to biofilm formation, which complicates surgical and antibiotic treatment. We introduce an alternative approach using monoclonal antibodies (mAbs) targeting S. aureus and provide evidence of the specificity and biodistribution of S.-aureus-targeting antibodies in a mouse implant infection model. The monoclonal antibody 4497-IgG1 targeting wall teichoic acid in S. aureus was labeled with indium-111 using CHX-A"-DTPA as a chelator. Single Photon Emission Computed Tomography/computed tomographyscans were performed at 24, 72 and 120 h after administration of the 111In-4497 mAb in Balb/cAnNCrl mice with a subcutaneous implant that was pre-colonized with S. aureus biofilm. The biodistribution of this labelled antibody over various organs was visualized and quantified using SPECT/CT imaging, and was compared to the uptake at the target tissue with the implanted infection. Uptake of the 111In-4497 mAbs at the infected implant gradually increased from 8.34 %ID/cm3 at 24 h to 9.22 %ID/cm3 at 120 h. Uptake at the heart/blood pool decreased over time from 11.60 to 7.58 %ID/cm3, whereas the uptake in the other organs decreased from 7.26 to less than 4.66 %ID/cm3 at 120 h. The effective half-life of 111In-4497 mAbs was determined to be 59 h. In conclusion, 111In-4497 mAbs were found to specifically detect S. aureus and its biofilm with excellent and prolonged accumulation at the site of the colonized implant. Therefore, it has the potential to serve as a drug delivery system for the diagnostic and bactericidal treatment of biofilm.

MRI-based synthetic CT in the detection of knee osteoarthritis: Comparison with CT.

Magnetic resonance Imaging is the gold standard for assessment of soft tissues; however, X-ray-based techniques are required for evaluating bone-related pathologies. This study evaluated the performance of synthetic computed tomography (sCT), a novel MRI-based bone visualization technique, compared with CT, for the scoring of knee osteoarthritis. sCT images were generated from the 3T T1-weighted gradient-echo MR images using a trained machine learning algorithm. Two readers scored the severity of osteoarthritis in tibiofemoral and patellofemoral joints according to OACT, which enables the evaluation of osteoarthritis, from its characteristics of joint space narrowing, osteophytes, cysts and sclerosis in CT (and sCT) images. Cohen's κ was used to assess the interreader agreement for each modality, and intermodality agreement of CT- and sCT-based scores for each reader. We also compared the confidence level of readers for grading CT and sCT images using confidence scores collected during grading. Inter-reader agreement for tibiofemoral and patellofemoral joints were almost-perfect for both modalities (κ = 0.83-0.88). The intermodality agreement of osteoarthritis scores between CT and sCT was substantial to almost-perfect for tibiofemoral (κ = 0.63 and 0.84 for the two readers) and patellofemoral joints (κ = 0.78 and 0.81 for the two readers). The analysis of diagnosis confidence scores showed comparable visual quality of the two modalities, where both are showing acceptable confidence levels for scoring OA. In conclusion, in this single-center study, sCT and CT were comparable for the scoring of knee OA.

Automatic Assessment of Lower-Limb Alignment from Computed Tomography.

BACKGROUND: Preoperative planning of lower-limb realignment surgical procedures necessitates the quantification of alignment parameters by using landmarks placed on medical scans. Conventionally, alignment measurements are performed on 2-dimensional (2D) standing radiographs. To enable fast and accurate 3-dimensional (3D) planning of orthopaedic surgery, automatic calculation of the lower-limb alignment from 3D bone models is required. The goal of this study was to develop, validate, and apply a method that automatically quantifies the parameters defining lower-limb alignment from computed tomographic (CT) scans. METHODS: CT scans of the lower extremities of 50 subjects were both manually and automatically segmented. Thirty-two manual landmarks were positioned twice on the bone segmentations to assess intraobserver reliability in a subset of 20 subjects. The landmarks were also positioned automatically using a shape-fitting algorithm. The landmarks were then used to calculate 25 angles describing the lower-limb alignment for all 50 subjects. RESULTS: The mean absolute difference (and standard deviation) between repeat measurements using the manual method was 2.01 ± 1.64 mm for the landmark positions and 1.05° ± 1.48° for the landmark angles, whereas the mean absolute difference between the manual and fully automatic methods was 2.17 ± 1.37 mm for the landmark positions and 1.10° ± 1.16° for the landmark angles. The manual method required approximately 60 minutes of manual interaction, compared with 12 minutes of computation time for the fully automatic method. The intraclass correlation coefficient showed good to excellent reliability between the manual and automatic assessments for 23 of 25 angles, and the same was true for the intraobserver reliability in the manual method. The mean for the 50 subjects was within the expected range for 18 of the 25 automatically calculated angles. CONCLUSIONS: We developed a method that automatically calculated a comprehensive range of 25 measurements that defined lower-limb alignment in considerably less time, and with differences relative to the manual method that were comparable to the differences between repeated manual assessments. This method could thus be used as an efficient alternative to manual assessment of alignment. LEVEL OF EVIDENCE: Diagnostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Current clinical practice of knee osteotomy in the Netherlands.

BACKGROUND: Realignment osteotomies is gaining popularity amongst Dutch orthopaedic surgeons. Exact numbers and used standards in clinical practice concerning osteotomies are unknown due to the absence of a national registry. The aim of this study was to investigate the national statistics of performed osteotomies, utilized clinical workups, surgical techniques, and post-operative rehabilitation standards in the Netherlands. METHOD: Dutch orthopaedic surgeons, all members of the Dutch Knee Society, received a web-based survey between January and March 2021. This electronic survey contained 36 questions, subdivided into: general surgeon-related information, number of performed osteotomies, inclusion of patients, clinical workup, surgical techniques, and post-operative management. RESULTS: 86 orthopaedic surgeons filled in the questionnaire, of whom 60 perform realignment osteotomies around the knee. All the 60 responders (100%) perform high tibial osteotomies and 63.3% additionally perform distal femoral osteotomies, while 30% perform double level osteotomies. Discrepancies in surgical standards were reported regarding to inclusion criteria, clinical workup, surgical techniques, and post-operative strategies. CONCLUSIONS: In conclusion, this study got more insight in knee osteotomy clinical practices as applied by Dutch orthopaedic surgeons. However, there are still important discrepancies which pleads for more standardization based on available evidence. A (inter)national knee osteotomy registry, and even more so, a (inter)national registry for joint preserving surgeries could be helpful to achieve more standardization and treatment insights. Such a registry could improve all aspects of osteotomies and its combinations with other joint-preserving interventions towards evidence for personalised treatments.