Bone turnover and microdamage are impacted by skeletal metastases which can contribute to increased fracture risk. Treatments for metastatic disease may further impact bone quality. This study aimed to establish an understanding of microdamage accumulation and load to failure in healthy and osteolytic vertebrae following cancer treatment (stereotactic body radiotherapy (SBRT), zoledronic acid (ZA), or docetaxel (DTX)). Forty-two 6-week old athymic female rats (Hsd:RH-Foxn1rnu, Envigo) were studied; 22 were inoculated with HeLa cervical cancer cells through intracardiac injection (day 0). Animals were randomly assigned to four groups: untreated (healthy=5, osteolytic=6), SBRT on day 14 (healthy=6, osteolytic=6), ZA on day 7 (healthy=4, osteolytic=5), and DTX on day 14 (healthy=5, osteolytic=5). Animals were euthanized on day 21. L1-L3 motion segments were compression loaded to failure and force-displacement data recorded. T13 vertebrae were stained with BaSO. 4. and µCT imaged (90kVp, 44uA, 4.9µm) to visualize microdamage location and volume. Damage volume fraction (DV/BV) was calculated as the ratio of BaSO. 4. to bone volume. Differences in mean load-to-failure were compared using three-way ANOVA (disease status, treatment, cells injected). Differences in mean DV/BV between treatment groups were compared using one-way ANOVA. Treatment had a significant effect on load-to-failure (p=0.004) with ZA strengthening the healthy and osteolytic vertebrae. Reduced strength post SBRT seen in the metastatic (but not the healthy) group may be explained by greater tumor involvement secondary to higher cell injection concentrations. Untreated metastatic samples had higher DV/BV (16.25±2.54%) compared to all treatment groups (p<0.05) suggesting a benefit of treatment to bone quality. Focal and systemic cancer treatments were shown to effect load-to-failure and microdamage accumulation in healthy and osteolytic vertebrae. Developing a better understanding of how treatments effect bone quality and mechanical stability is critical for effective management of patients with spinal metastases

Staphylococcus aureus (SA), the predominant pathogen in human osteomyelitis, is known to persist by forming intracellular reservoirs, including in bone cells (Schwarz et al., 2019, Yang et al., 2018, Krauss et al., 2019, Gao et al., 2020, Bosse et al., 2005), promoting decreased antibiotic susceptibility. However, there are no evidence-based treatment guidelines for intracellular SA infections in osteomyelitis. We sought to address this by systematically reviewing the literature and, testing a selection of antibiotic treatments in a clinically relevant in vitro assay. We conducted a systematic review of the literature to determine the current evidence for the efficacy of antibiotics against intracellular SA infections relevant to osteomyelitis. For the antibiotics identified as potentially useful, we determined their minimal inhibitory concentration (MIC) against 11 clinical osteomyelitis SA- isolates. We selected those for further testing reported able to reach a higher concentration in the bone than the identified MIC against the majority of strains. Thus, rifampicin, oxacillin, linezolid, levofloxacin, oritavancin and doxycycline were tested in human SaOS-2-osteocyte infection models (Gunn et al., 2021) of acute (1d) or chronic (14d) infection to clear intracellular SA. Antibiotics were tested at 1x/4x/10x the MIC for the duration of 1d or 7d in each model. A systematic review found that osteoblasts and macrophages have mostly been used to test immediate short-term activity against intracellular SA, with a high variability in methodology. However, some extant evidence supports that rifampicin, oritravancin, linezolid, moxifloxacin and oxacillin may be effective intracellular treatments. While studies are ongoing, in vitro testing in a clinically relevant model suggests that rifampicin, oxacillin and doxycycline could be effectively used to treat osteomyelitic intracellular SA infections. Importantly, these have lower MICs against multiple clinical isolates than their respective clinically-achievable bone concentrations. The combined approach of a systematic review and disease-relevant in vitro screening will potentially inform as to the best approach for treating osteomyelitis where intracellular SA infection is confirmed or suspected

Introduction. Shared decision making (SDM) was introduced in hospital Lillebelt in 2019 and research reports that patients are more satisfied with their treatment, if they play an active role in choosing treatment. A Decision-Helper was constructed and introduced in the treatment for Colles fractures. This study aimed to understand how patients experience shared decision-making (SDM) for an acute illness, and how it affects them when making decisions about the treatment of their distal radius fracture. Method. An exploratory, qualitative study design was performed to understand the patient's experience, during the choice of treatment with SDM. 12 were recruited when they came to their first follow-up 5 days after the injury, in the outpatient clinic. 10 were interviewed; 3 face to face and 7 by telephone. All women aged 57-87 years and all had a displaced Colles fracture, which had been reduced in the Emergency Room. Result. Analyzing the interviews three themes emerged: 1) Acute situation. Patients was positive towards SDM, but found it demanding to participate in. Patients was still in crisis, 5 days after suffering from a fracture. Patients were unable to remember the information given in the ER, regarding the use of the Decision helper. Few had prepared themselves for the consult in the outpatient clinic. 2) Influence on treatment choice. It was unclear to the majority of patients, that cast or surgery, resulted in similar clinical outcomes. 3) The treatment decision was based on personal factors, more than the information received during the consult. Conclusion. Patients wants to be included in the treatment decision. It is important to highlight that booth treatments are equal in clinical outcome, before introducing the Decision-Helper. The doctor´s demeanor is of great importance to the patient's experience. Introducing SDM in the clinical setting requires training and repeated observations, to succeed

Fracture related infections (FRI) are debilitating complications of musculoskeletal trauma surgery that can result in permanent functional loss or amputation. This study aims to determine risk factors associated with FRI treatment failure, allowing clinicians to optimise them prior to treatment and identify patients at higher risk. A major trauma centre database was retrospectively reviewed over a six-year period. Of the 102 patients identified with a FRI (66 male, 36 female), 29.4% (n=30) had acute infections (onset <6 weeks post-injury), 34.3% (n=35) had an open fracture. Open fractures were classified using Gustilo-Anderson (GA) classification (type 2:n=6, type 3A:n=16, type 3B:n=10, type 3C:n=3). Patients with periprosthetic infections of the hip and knee joint, those without prior fracture fixation, soft tissue infections, diabetic foot ulcers, pressure sore infections, patients who died within one month of injury, <12 months follow-up were excluded. FRI treatment failure was defined as either infection recurrence, non-union, or amputation. Lifestyle, clinical, and intra-operative data were documented via retrospective review of medical records. Factors with a P-value of p<0.05 in univariate analysis were included in a stepwise multivariate logistic regression model. FRI treatment failure was encountered in 35.3% (n=36). The most common FRI site was the femoral shaft (16.7%; n=17), and 15.7% (n=16) presented with signs of systemic sepsis. 20.6% (n=21) had recurrent infection, 9.8% (n=10) had non-union, and 4.9% (n=5) required an amputation. The mean age at injury was 49.71 years old. Regarding cardiovascular risk factors, 37 patients were current smokers (36.3%), 31 patients were diabetics (30.4%), and 32 patients (31.4%) were obese (BMI≥30.0). Average follow-up time was 2.37 (range: 1.04-5.14) years. Risk factors for FRI treatment failure were BMI>30, GA type 3c, and implant retention. Given that FRI treatment in 35.3% (36/102) ended up in failure, clinicians need to take into account the predictive variables analysed in this study, and implement a multidisciplinary team approach to optimise these factors. This study could aid clinicians to redirect efforts to improve high risk patient management, and prompt future studies to trial adjuvant technologies for patients at higher risk of failure

Aneurysmal bone cyst (ABC) of the spine is a locally aggressive benign lesion which can be treated by en bloc resection with wide margin to reduce the risk of local recurrence. To avoid morbidity associated with surgery, selective arterial embolization (SAE) can be considered the first-line treatment for ABCs of the spine. We previously introduced the use of autologous bone marrow concentrate (BMC) injection therapy to stimulate bone healing and regeneration in ABC of the spine. In this prospective study we described the clinical and radiological outcomes of percutaneous injection of autologous BMC in a series of patients affected by ABCs of the spine. Fourteen patients (6 male, 8 female) were treated between June 2014 and December 2019 with BMC injection for ABC of the spine. The mean age was 17.85 years. The mean follow up was 37.4 months (range 12–60 months). The dimension of the cyst and the degree of ossification were measured by Computed Tomography (CT) scans before the treatment and during follow-up visits. Six patients received a single dose of BMC, five patients received two doses and in three patients three doses of BMC were administered. The mean ossification of the cyst (expressed in Hounsfield units) increased statistically from 43.48±2.36 HU to 161.71±23.48 HU during follow-up time and the ossification was associated to an improvement of the clinical outcomes. The mean ossification over time was significantly higher in patients treated with a single injection compared to patients treated with multiple injections. No significant difference in ossification was found between cervical and non-cervical localization of the cyst. Moreover, the initial size of the cyst was not statistically associated with the degree of ossification during follow-up. The results of this study reinforce our previous evidence on the use of BMC as a valid alternative for spinal ABC management when SAE is contraindicated or ineffective. The initial size of the cyst and its localization does not influence the efficacy of the treatment. However, data suggest that BMC injection could be indicated as treatment of choice for spinal ABC in young adolescent women

Stem cells represent an exciting biological therapy for the management of many musculoskeletal tissues that suffer degenerative disease and/or where the reparative process results in non-functional tissue (‘failed healing’). The original hypothesis was that implanted cells would differentiate into the target tissue cell type and synthesise new matrix. However, this has been little evidence that this happens in live animals compared to the laboratory, and more recent theories have focussed on the immunomodulatory effects via the release of paracrine factors that can still improve the outcome, especially since inflammation is now considered one of the central processes that drive poor tendon healing. Because of the initial ‘soft’ regulatory environment for the use of stem cells in domestic mammals, bone and fat-derived stem cells quickly established themselves as a useful treatment for naturally occurring musculoskeletal diseases in the horse more than 20 years ago (Smith, Korda et al. 2003). Since the tendinopathy in the horse has many similarities to human tendinopathy, we propose that the following challenges and, the lessons learnt, in this journey are highly relevant to the development of stem cells therapies for human tendinopathy:. Source – while MSCs can be recovered from many tissues, the predominant sources for autologous MSCs have been bone and fat. Other sources, including blood, amnion, synovium, and dental pulp have also been commercialised for allogenic treatments. Preparation – ex vivo culture requires transport from a licensed laboratory while ‘minimally manipulated’ preparations can be prepared patient-side. Cells also need a vehicle for transport and implantation. Delivery – transport of cells from the laboratory to the clinic for autologous ex vivo culture techniques; implantation technique (usually by ultrasound-guided injection to minimise damage to the cells (or, more rarely, incorporated into a scaffold). They can also be delivered by regional perfusion via venous or arterial routes. Retention – relatively poor although small numbers of cells do survive for at least 5 months. Immediate loss to the lungs if the cells are administered via vascular routes. Synovially administered cells do not engraft into tendon. Adverse effects – very safe although needle tracts often visible (but do not seen to adversely affect the outcome). Allogenic cells require careful characterisation for MHC Class II antigens to avoid anaphylaxis or reduced efficacy. Appropriate injuries to treat – requires a contained lesion when administered via intra-lesional injection. Intrasynovial tendon lesions are more often associated with surface defects and are therefore less appropriate for treatment. Earlier treatment appears to be more effective than delayed, when implantation by injection is more challenging. Efficacy - beneficial effects shown at both tissue and whole animal (clinical outcome) level in naturally-occurring equine tendinopathy using bone marrow-derived autologous MSCs Recent (licenced) allogenic MSC treatment has shown equivalent efficacy while intra-synovial administration of MSCs is ineffective for open intra-synovial tendon lesions. Regulatory hurdles – these have been lighter for veterinary treatments which has facilitated their development. There has been greater regulation of commercial allogenic MSC preparations which have required EMA marketing authorisation

Metacarpal fractures represent up to 33% of all hand fractures; of which the majority can be treated non-operatively. Previous research has shown excellent putcomes with non-operative treatment yet surgical stabilisation is recommended to avoid malrotation and symptomatic shortening. It is unknown whether operative is superior to non-operative treatment in oblique or spiral metacarpal shaft fractures. The aim of the study was to compare non-operative treatment of mobilisation with open surgical stabilisation. 42 adults (≥ 18 years) with a single displaced oblique or spiral metacarpal shaft fractures were randomly assigned in a 1:1 pattern to either non-operative treatment with free mobilisation or operative treatment with open reduction and fixation with lag screws in a prospective study. The primary outcome measure was grip-strength in the injured hand in comparison to the uninjured hand at 1-year follow-up. The Disabilities of the Arm, Shoulder and Hand Score, ranges of motion, metacarpal shortening, complications, time off work, patient satisfaction and costs were secondary outcomes. All 42 patients attended final follow-up after 1 year. The mean grip strength in the non-operative group was 104% (range 73–250%) of the contralateral hand and 96% (range 58–121%) in the operatively treated patients. Mean metacarpal shortening was 5.0 (range 0–9) mm in the non-operative group and 0.6 (range 0–7) mm in the operative group. There were five minor complications and three revision operations, all in the operative group. The costs for non-operative treatment were estimated at 1,347 USD compared to 3,834USD for operative treatment; sick leave was significantly longer in the operative group (35 days, range 0–147) than in the non-operative group (12 days, range 0–62) (p=0.008). When treated with immediate free mobilization single, patients with displaced spiral or oblique metacarpal shaft fractures have outcomes that are comparable to those after operative treatment, despite some metacarpal shortening. Complication rates, costs and sick leave are higher with operative treatment. Early mobilisation of spiral or long oblique single metacarpal fractures is the preferred treatment. Trial registration number: ClinicalTrials.gov NCT03067454

Bone regeneration is pivotal for the healing of fractures. In case this process is disturbed a non-union can occur. This can be induced by environmental factors such as smoking, overloading etc. Co-morbidities such as diabetes, osteoporosis etc. may be more intrinsic factors besides other disturbances in the process. Those pathways negatively influence the bone regeneration process. Several intrinsic signal transduction pathways (WNT, BMP etc.) can be affected. Furthermore, on the transcriptional level, important mRNA expression can be obstructed by deregulated miRNA levels. For instance, several miRNAs have been shown to be upregulated during osteoporotic fractures. They are detrimental for osteogenesis as they block bone formation and accelerate bone resorption. Modulating those miRNAs may revert the physiological homeostasis. Indeed, physiological fracture healing has a typical miRNA signature. Besides using molecular pathways for possible treatment of non-union fractures, providing osteogenic cells is another solution. In 5 clinical cases with non-union fractures with defects larger than 10 cm, successful administration of a 3D printed PCL-TCP scaffold with autologous bone marrow aspirate concentrate and a modulator of the pathogenetic pathway has been achieved. All patients recovered well and showed a complete union of their fractures within one year after start of the regenerative treatment. Thus, non-union fractures are a diverse entity. Nevertheless, there seem to be common pathogenetic disturbances. Those can be counteracted at several levels from molecular to cell. Compositions of those may be the best option for future therapies. They can also be used in a more personalized fashion in case more specific measurements such as miRNA signature and stem cell activity are applied

Artificial Intelligence (AI) is becoming more powerful but is barely used to counter the growth in health care burden. AI applications to increase efficiency in orthopedics are rare. We questioned if (1) we could train machine learning (ML) algorithms, based on answers from digitalized history taking questionnaires, to predict treatment of hip osteoartritis (either conservative or surgical); (2) such an algorithm could streamline clinical consultation. Multiple ML models were trained on 600 annotated (80% training, 20% test) digital history taking questionnaires, acquired before consultation. Best performing models, based on balanced accuracy and optimized automated hyperparameter tuning, were build into our daily clinical orthopedic practice. Fifty patients with hip complaints (>45 years) were prospectively predicted and planned (partly blinded, partly unblinded) for consultation with the physician assistant (conservative) or orthopedic surgeon (operative). Tailored patient information based on the prediction was automatically sent to a smartphone app. Level of evidence: IV. Random Forest and BernoulliNB were the most accurate ML models (0.75 balanced accuracy). Treatment prediction was correct in 45 out of 50 consultations (90%), p<0.0001 (sign and binomial test). Specialized consultations where conservatively predicted patients were seen by the physician assistant and surgical patients by the orthopedic surgeon were highly appreciated and effective. Treatment strategy of hip osteoartritis based on answers from digital history taking questionnaires was accurately predicted before patients entered the hospital. This can make outpatient consultation scheduling more efficient and tailor pre-consultation patient education

Sarcopenia is an age-related geriatric syndrome which is associated with subsequent disability and morbidity. Currently there is no promising therapy approved for the treatment of sarcopenia. The receptor activator of nuclear factor NF-κB ligand (RANKL) and its receptor (RANK) are expressed in bone and skeletal muscle. Activation of the NF-κB pathway mainly inhibits myogenic differentiation, which leads to skeletal muscle dysfunction and loss. LYVE1 and CD206 positive macrophage has been reported to be associated with progressive impairment of skeletal muscle function with aging. The study aims to investigate the effects of an anti-RANKL treatment on sarcopenic skeletal muscle and explore the related mechanisms on muscle inflammation and the polarization status of macrophages. Sarcopenic senescence-accelerated mouse P8 (SAMP8) mice at month 8 were treated intraperitoneally with 5mg/kg anti-RANKL (IK22/5) or isotype control (2A3; Bio X Cell) antibody every 4 weeks and harvested at month 10. Senescence accelerated mouse resistant-1 (SAMR1) were collected at month 10 as the age-matched non-sarcopenic group. Ex-vivo functional assessment, grip strength and immunostaining of C/EBPa, CD206, F4/80, LYVE1 and PAX7 were performed. Data analysis was done with one-way ANOVA, and the significant level was set at p≤0.05. At month 10, tetanic force/specific tetanic force, twitch force/specific twitch force in anti-RANKL group were significantly higher than control group (all p<0.01). The mice in the anti-RANKL treatment group also showed significantly higher grip strength than Con group (p<0.001). The SAMP8 mice at month 10 expressed significantly more C/EBPa, CD206 and LYVE1 positive area than in SAMR1, while anti-RANKL treatment significantly decreased C/EBPa, CD206 and LYVE1 positive area. The anti-RANKL treatment protected against skeletal muscle dysfunctions through suppressing muscle inflammation and modulating M2 macrophages, which may represent a novel therapeutic approach for sarcopenia. Acknowledgment: Collaborative Research Fund (CRF, Ref: C4032-21GF)

Flat-top talus (FTT) is a complication well-known to those treating clubfoot. Despite varying anecdotal opinions, its association with different treatments, especially the Ponseti method, remains uncertain. This systematic review aimed to establish the aetiology and prevalence of FTT, as well as detailing management strategies and their efficacy. A systematic review was conducted according to PRISMA guidelines to search for articles using MEDLINE, EMBASE and Web of Science until November 2021. Studies with original data relevant to one of three questions were included: 1) Possible aetiology 2) Prevalence following different treatments 3) Management strategies and their outcomes. 32 original studies were included, with a total of 1473 clubfeet. FTT may be a pre-existing feature of the pathoanatomy of some clubfeet as well as a sequela of treatment. It can be a radiological artefact due to positioning or other residual deformity. The Ponseti method is associated with a higher percentage of radiologically normal tali (57%) than both surgical methods (52%) and non-Ponseti casting (29%). Only one study was identified that reported outcomes after surgical treatment for FTT (anterior distal tibial hemiepiphysiodesis). The cause of FTT remains unclear. It is seen after all treatment methods but the rate is lowest following Ponseti casting. Guided growth may be an effective treatment. Key words:. Clubfoot, Flat-top talus, Ponseti method, guided growth. Disclosures: The authors have no relevant disclosures

The effect of high-fat diet and testosterone replacement therapy upon bone remodelling was investigated in orchiectomised male APOE-/- mice. Mice were split in to three groups: sham surgery + placebo treatment (control, n=9), orchiectomy plus placebo treatment (n=8) and orchiectomy plus testosterone treatment (n=10). Treatments were administered via intramuscular injection once a fortnight for 17 weeks before sacrifice at 25 weeks of age. Tibiae were scanned ex-vivo using µCT followed by post-analysis histology and immunohistochemistry. Previously presented µCT data demonstrated orchiectomised, placebo treated mice exhibited significantly reduced trabecular bone volume, number, thickness and BMD compared to control mice despite no significant differences in body weight. Trabecular parameters were rescued back to control levels in orchiectomised mice treated with testosterone. No significant differences were observed in the cortical bone. Assessment of TRAP stained FFPE sections revealed no significant differences in osteoclast or osteoblast number along the endocortical surface. IHC assessment of osteoprotegerin (OPG) expression in osteoblasts is to be quantified alongside markers of osteoclastogenesis including RANK and RANKL. Results support morphological analysis of cortical bone where no change in cortical bone volume or density between groups is in line with no significant change in osteoblast or osteoclast number and percentage across all three groups. Future work will include further IHC assessment of bone remodelling and adiposity, as well as utilisation of mechanical testing to establish the effects of observed morphological differences in bone upon mechanical properties. Additionally, the effects of hormone treatments upon murine-derived bone cells will be investigated to provide mechanistic insights

Low back pain affects 80% of the population with half of cases attributed to intervertebral disc (IVD) degeneration. However, the majority of treatments focus on pain management, with none targeting the underlying pathophysiological causes. PCRX-201 presents a novel gene therapy approach that addresses this issue. PCRX-201 codes for interleukin-1 receptor antagonist (IL-1Ra), the natural inhibitor of the pro-inflammatory cytokine IL-1, which orchestrates the catabolic degeneration of the IVD. Our objective here is to determine the ability of PCRX-201 to infect human nucleus pulposus (NP) cells and tissue to increase the production of IL-1Ra and assess downstream effects on catabolic protein production. Degenerate human NP cells and tissue explants were infected with PCRX-201 at 0 or 3000 multiplicities of infection (MOI) and subsequently cultured for 5 days in monolayer (n=7), 21 days in alginate beads (n=6) and 14 days in tissue explants (n=5). Cell culture supernatant was collected throughout culture duration and downstream targets associated with pain and degeneration were assessed using ELISA. IL-1Ra production was increased in NP cells and tissue infected with PCRX-201. The production of downstream catabolic proteins such as IL-1β, IL-6, MMP3, ADAMTS4 and VEGF was decreased in both 3D-cultured NP cells and tissue explants. Here, we have demonstrated that a novel gene therapy, PCRX-201, is able to infect and increase the production of IL-1Ra in degenerate NP cells and tissue in vitro. The increase of IL-1Ra also resulted in a decrease in the production of a number of pro-inflammatory and catabolic proteins, suggesting PCRX-201 enables the inhibition of IL-1-driven IVD degeneration. At present, no treatments for IVD degeneration target the underlying pathology. The ability of FX201 to elicit anti-catabolic responses is promising and warrants further investigation in vitro and in vivo, to determine the efficacy of this exciting, novel gene therapy

Plantar fasciitis (PF) is one of the widespread conditions causing hindfoot pain. The most common presenting symptoms are functional limitation and pain (first step and activity) on plantar surface of the foot. The non-operative treatments provide complete resolution of pain in 90% of patients, but functional limitation still remains as a risk factor for recurrency of PF. Although the number of non-operative treatment options showing efficacy on pain and functional limitation are excessive, the evidences are limited for functional limitation. Additionally, Mulligan mobilization with movement (MMWM) in Chronic Plantar Fasciitis has been poorly studied in the literature. According to these findings, the study was aimed to determine effectiveness of Mulligan mobilization with movement on Chronic Plantar Fasciitis. A total of 25 patients (40 feet) with chronic PF were included in the study. The patients were randomly divided into Mulligan concept rehabilitation group (PF-M, n=20 feet) and Home Rehabilitation group (PF-H, n=20 feet). (MMWM), Foot and ankle exercises program were applied to PF-M, twice a week totally 8 week (16 sessions) and foot- ankle exercises as a home program were given for PF-H, 8 weeks. The range of motion (ROM) for dorsiflexion and plantar flexion was measured by using a manual goniometer. Pain, disability and activity restriction were assessed by Foot Function Index (FFI) . The first step morning pain was evaluated by Visual Analogue Scale (VAS) and Kinesiophobia was also reported by using Tampa Scale (TSK). Patients were evaluated at baseline and 8 weeks. FFI, VAS, TSK, ROM values improved in all groups (intragroup variability) at 8th week (P < .05). The other result indicated that ROM values for DF and PF and TSK scores in PF-M had more significant improvement than PF-H (p<.05). To the best of our knowledge this is the first randomised controlled trial for investigating Mulligan Concept efficiancy on chronic PF. Both Mulligan mobilization with movement (MMWM) and exercise protocols are effective for chronic PF. Furthermore, The Mulligan concept seems more effective treatment option in reducing kinesiophobia and improving functional capacity

Fracture related infection remains a major challenge in musculoskeletal trauma surgery. Despite best practice, treatment strategies suffer from high failure rates due to antibiotic resistance and tolerance. Bacteriophages represent a promising alternative as they retain activity against such bacteria. However, optimal phage administration protocols remain unknown, although injectable hydrogels, loaded with phage and conventional antibiotics, may support conventional therapy. In this study we tested the activity of meropenem, and two newly isolated bacteriophages (ϕ9 and ϕ3) embedded within alginate-chitosan microbeads and a hydrogel. Antibiotic and phage stability and activity were monitored in vitro, over a period of 10 days. In vivo, the same material was tested in treatment of a 5-day old Pseudomonas aeruginosa infection of a tibial plate osteotomy in mice. Treatment involved debridement and 5 days of systemic antibiotic therapy plus: i- saline, ii-phages in saline, iii-phages and antibiotics loaded into a hydrogel (n=7 mice/group). To assess the efficacy of the treatments, the infection load was monitored during revision surgery with debridement of the infected tissue after 5,10 and 13 days (euthanasia) by CFU and PFU quantification. In vitro testing confirmed that the stability of meropenem and activity of ϕ9 and ϕ3, was not affected within the alginate beads or hydrogel over 10 days. The in vivo study showed that all mice receiving phages and antibiotics loaded into a hydrogel survived the infection with a reduction of the bacterial load in the soft tissue. Active phages could be recovered from the infected site at euthanasia (10. 4. PFU/g). The hydrogel loaded with bacteriophages and meropenem showed a positive result in locally reducing the infection load indicating a synergistic effect of the selected antimicrobials. Overall, our new strategy shows encouraging results for improving the treatment of antibiotic-resistant biofilm infections that are related to medical implants

Introduction. Hip prosthetic joint infection (PJI) is a debilitating complication following joint replacement surgery, with significant impact on patients and healthcare systems. The INFection ORthopaedic Management: Evidence into Practice (INFORM: EP) study, builds upon the 6-year INFORM programme by developing evidence-based guidelines for the identification and management of hip PJI. Methods. A panel of 21 expert stakeholders collaborated to develop best practice guidelines based on evidence from the previous INFORM research programme. An expert consensus process was used to refine guidelines using RAND/UCLA criteria. The guidelines were then implemented over a 12-month period through a Learning Collaborative of 24 healthcare professionals from 12 orthopaedic centres in England. Qualitative interviews were conducted with 17 members of the collaborative and findings used to inform the development of an implementation support toolkit. Patient and public involvement contextualised the implementation of the guidelines. The study is registered with the ISCRTN (34710385). Result. The INFORM guidelines, structured around the stages of PJI management, were largely supported by surgeons, although barriers included limited awareness among non-surgical team members, lack of job planning for multidisciplinary teams, and challenges in ensuring timely referrals from primary care. Psychological support for patients was identified as a critical gap. Advanced Nurse Practitioners and multidisciplinary team (MDT) coordinators were seen as potential bridges to address these knowledge gaps. The guidelines were also viewed as a useful tool for service development. Conclusions. This study presents the first evidence-based guidelines for hip PJI management, offering a comprehensive approach to prevention, treatment, and postoperative care. Effective implementation is crucial, involving wider dissemination amongst primary and community care, as well as non-specialist treatment centres. Further resources are needed to ensure job planning for MDTs and psychological support for patients. Overall, this study lays the foundation for improved PJI management, benefiting patients and healthcare systems

Knee joint distraction (KJD) has been associated with clinical and structural improvement and synovial fluid (SF) marker changes. However, structural changes have not yet been shown satisfactorily in regular care, since radiographic acquisition was not fully standardized. AI-based modules have shown great potential to reduce reading time, increase inter-reader agreement and therefore function as a tool for treatment outcome assessment. The objective was to analyse structural changes after KJD in patients using this AI-based measurement method, and relate these changes to clinical outcome and SF markers. 20 knee OA patients (<65 years old) were included in this study. KJD treatment was performed using an external fixation device, providing 5 mm distraction for 6 weeks. SF was aspirated before, during and immediately after treatment. Weight-bearing antero-posterior knee radiographs and WOMAC questionnaires were collected before and ~one year after treatment. Radiographs were analysed with the Knee Osteoarthritis Labelling Assistant (KOALA, IB Lab GmbH, Vienna, Austria), and 10 pre-defined biomarker levels in SF were measured by immunoassay. Radiographic one-year changes were analysed and linear regression was used to calculate associations between changes in standardized joint space width (JSW) and WOMAC, and changes in JSW and SF markers. After treatment, radiographs showed an improvement in Kellgren-Lawrence grade in 7 of 16 patients that could be evaluated; 3 showed a worsening. Joint space narrowing scores and continuous JSW measures improved especially medially. A greater improvement in JSW was significantly associated with a greater improvement in WOMAC pain (β=0.64;p=0.020). A greater increase in MCP1 (β=0.67;p=0.033) and lower increase in TGFβ1 (β=-0.787;p=0.007) were associated with JSW improvement. Despite the small number of patients, also in regular care KJD treatment shows joint repair as measured automatically on radiographs, significantly associated with certain SF marker change and even with clinical outcome

Partial meniscectomy patients have a greater likelihood for the development of early osteoarthritis (OA). To prevent the onset of early OA, patient-specific treatment algorithms need to be created that predict patient risk to early OA after meniscectomy. The aim of this work was to identify patient-specific risk factors in partial meniscectomy patients that could potentially lead to early OA. Partial meniscectomy patients operated between 01/2017 and 12/2019 were evaluated in the study (n=317). Exclusion criteria were other pathologies or surgeries for the evaluated knee and meniscus (n = 114). Following informed consent, an online questionnaire containing demographics and the “Knee Injury and Osteoarthritis Outcome Score” (KOOS) questionnaire was sent to the patient. Based on the KOOS pain score, patients were classified into “low” (> 75) and “high” (< 75) risk patients, indicating risk to symptomatic OA. The “high risk” patients also underwent a follow-up including an MRI scan to understand whether they have developed early OA. From 203 participants, 96 patients responded to the questionnaire (116 did not respond) with 61 patients considered “low-risk” and 35 “high-risk” patients. Groups that showed a significant increased risk for OA were patients aged > 40 years, females, overweight (BMI >25 kg/m2 ≤ 30 kg/m2), and smokers (*p < 0.05). The “high-risk”-follow-up revealed a progression of early osteoarthritic cartilage changes in seven patients, with the remaining nineteen patients showing no changes in cartilage status or pain since time of operation. Additionally, eighteen patients in the high-risk group showed a varus or valgus axis deviation. Patient-specific factors for worse postoperative outcomes after partial meniscectomy and indicators for an “early OA” development were identified, providing the basis for a patient-specific treatment approach. Further analysis in a multicentre study and computational analysis of MRI scans is ongoing to develop a patient-specific treatment algorithm for meniscectomy patients

Introduction. Epiphysiodesis, defined as the process of closing the growth plate (physis), have been used for several years as a treatment option of cases where the predicted leg-length discrepancy (LLD) falls between 2 to 5 cm. The aim of this study was to systematically review the existing literature on the effectiveness of three different epiphysiodesis techniques with implant usage for the treatment of leg-length discrepancy in the pediatric population. The secondary aim was to address the reported complications of staples, tension-band plates (TBP) and percutaneous epiphysiodesis screws (PETS). Method. This systematic review was performed according to PRISMA guidelines. We searched MEDLINE (PubMed), Embase, Cochrane Library, Web of Science and Scopus for studies on skeletally immature patients with LLD treated with epiphysiodesis with an implant. The extracted outcome categories were effectiveness of epiphysiodesis (LLD measurements pre/post-operatively, successful/unsuccessful) and complications that were graded on severity. Result. Forty-four studies (2184 patients) were included, from whom 578 underwent TBP, 455 PETS and 1048 staples. From pooled analysis of the studies reporting success rate, 64% (150/234) successful TBP surgeries (10 studies), 78% (222/284) successful PETS (9 studies) and 52% (212/407) successful Blount staples (8 studies). Severe complications rate was 7% for PETS, 17% for TBP and 16% for Blount staples. TBP had 43 cases of angular deformity (10%), Blount staples 184 (17%) while PETS only 18 cases (4%). Conclusion. Our results highlighted that PETS seems to be the most successful type of epiphysiodesis surgery with an implant, with higher success rate and lower severe complications than TBP or Blount staples

Prosthetic joint infections represent complications connected to the implantation of biomedical devices. Bacterial biofilm is one of the main issues causing infections from contaminated orthopaedic prostheses. Biofilm is a structured community of microbial cells that are firmly attached to a surface and have unique metabolic and physiological attributes that induce improved resistance to environmental stresses including toxic compounds like antimicrobial molecules (e.g. antibiotics). Therefore, there is increasing need to develop methods/treatments exerting antibacterial activities not only against planktonic (suspended) cells but also against adherent cells of pathogenic microorganisms forming biofilms. In this context, metal-based coatings with antibacterial activities have been widely investigated and used in the clinical practice. However, traditional coatings exhibit some drawbacks related to the insufficient adhesion to the substrate, scarce uniformity and scarce control over the toxic metal release reducing the biofilm formation prevention efficacy. Additionally, standardized and systematic approaches to test antibacterial activity of newly developed coatings are still missing, while standard microbiological tests (e.g. soft-agar assays) are typically used that are limited in terms of simultaneous conditions that can be tested, potentially leading to scarce reproducibility and reliability of the results. In this work, we combined the Calgary Biofilm Device (CBD) as a device for high-throughput screening, together with a novel plasma-assisted technique named Ionized Jet Deposition (IJD), to generate and test new generation of nanostructured silver- and zinc-based films as coatings for biomedical devices with antibacterial and antibiofilm properties. During the experiments we tested both planktonic and biofilm growth of four bacterial strains, two gram-positive and two gram-negative bacterial strains, i.e. Staphylococcus aureus ATCC 6538P, Enterococcus faecalis DP1122 and Escherichia coli ATCC 8739 and Pseudomonas aeruginosa PAO1, respectively. The use of CBD that had the only wells covered with the metal coatings while the biofilm supports (pegs) were not sheltered allowed to selectively define the toxic effect of the metal release (from the coating) against biofilm development in addition to the toxic activity exerted by contact killing mechanism (on biofilms formed on the coating). The results indicated that the antibacterial and antibiofilm effects of the metal coatings was at least partly gram staining dependent. Indeed, Gram negative bacterial strains showed high sensitivity toward silver in both planktonic growth and biofilm formation, whereas zinc coatings provided a significant inhibitory activity against Gram positive bacterial strains. Furthermore, the coatings showed the maximal activity against biofilms directly forming on them, although, Zn coating showed a strong effect against biofilms of gram-positive bacteria also formed on uncoated pegs. We conclude that the metal-based coatings newly developed and screened in this work are efficient against bacterial growth and adherence opening possible future applications for orthopedic protheses manufacturing