Aim. The aim of the present work was (i) to survey the situation of healthcare regarding the use of antibiotics in orthopaedics and trauma surgery in Germany, (ii) to determine which empiric antibiotic regimens are preferred in the treatment of periprosthethic joint infections (PJI) and (iii) to evaluate the hypothetical antibiotic adequacy of the applied empirical antibiotic therapy regimens based on a patient collective of a German university hospital. Method. A survey on empirical and prophylactic antibiotic therapy was conducted at German university and occupational health clinics (BG clinics), each in the specialties of orthopedics and trauma surgery. A total of 71 clinics were contacted by email. The questionnaire sent included open-ended questions on systemic antibiotic prophylaxis in primary hip arthroplasty; a distinction was made between hip arthroplasty due to femoral fractures and elective hip arthroplasty. In addition, the empirical antibiotic therapy used in PJIs was surveyed. To determine the success rate of prophylaxis and therapy according to sensitivity to the antibiotics applied, the survey results were compared with previously published data on antimicrobial treatment in n=81 PJI patients treated in our department between 2017 and 2020. Results. In 93.2% (elective) and 88.6% (fracture care) of the hospitals, 1st- and 2nd-generation cephalosporins are administered perioperatively for infection prophylaxis in primary hip arthroplasty. In contrast, empiric antibiotic treatment for PJI showed a clearly inhomogeneous therapeutic picture. Monotherapy with an aminopenicillin/betalactamase inhibitor is most frequently used (38.7%); 1st- and 2nd-generation cephalosporins are second most frequently used as monotherapy (18.2%). In addition, dual combination therapies have become established, mostly aminopenicillin/betalactamase inhibitor or 1st- and 2nd-generation cephalosporins, whose administration is supplemented with another antibiotic. The most common combination in PJI is aminopenicillin/betalactamase inhibitor + vancomycin (11.4%). The most widely used therapy (monotherapy with aminopenicillin/betalactamase inhibitor) would have covered 69.0% of PJI patients. Monotherapy with 1st- and 2nd-generation cephalosporins would have been susceptible to 57.8% of PJI patients. In contrast, a combination of vancomycin + 1st- and 2nd-generation cephalosporins would have been most effective, with an efficacy of 91.5% according to the resistograms, but this was used by only two hospitals. Conclusions. Empirical antibiotic therapy for the treatment of PJI is applied in more than half of the clinics with a single broad-spectrum beta-lactamase inhibitor antibiotic. This discrepancy between the everyday care in the clinics and the administration of clearly more effective combination therapies underlines the need for recommendation guidelines

Introduction. Non-union is an unfortunate outcome of the fracture healing process for some patients; with an estimated annual incidence of 17.4- 18.9 per 100,00. The management of these patients depicts a significant clinical challenge for surgeons and financial burden to health services. External ultrasound stimulation devices (Exogen. TM. ) have been highlighted as a novel non invasive therapy to achieve union in cases of delayed and non-union. The aim of the current study was to assess the rate of union in patients using Exogen. TM. therapy for delayed fracture union in a district general hospital. Materials & Methods. This is a single centre retrospective continuous cohort study. Patients were identified from a prospective database of all patients prescribed Exogen. TM. therapy between June 2013- September 2021 in a district general hospital. Patient data was collected retrospectively using electronic patient records. Fracture union was assessed both clinically and radiographically and recorded in patient records. Failure of treatment was defined as progression to operative treatment due to lack of progression with ultrasound therapy or established asymptomatic non-union. Patient were excluded from the study if Exogen. TM. therapy was prescribed within 6 weeks of injury. Results. 142 potential patient were identified from the database. 35 patients were excluded from the data set (17 patients due to insufficient data available, 9 lost to follow up, 4 died and 5 excluded due to early application of Exogen. TM. therapy). 58 Patients progressed to union with an average time to union of 41 weeks. 49 cases failed to progress to union, of which 7 cases had conversion to operative management prior to completion of single course of Exogen. TM. therapy and were excluded from all other data review. 12% of cases that failed to unite with ultrasound therapy required multiple operations to establish union. Conclusions. A union rate of 58% was reported by the current study, which is lower than previously published. This likely reflects the heterogenous nature of the patient population and fracture distribution included. However, this is potentially a more reflective union rate for the general population than previously published. There were no adverse events associated with the use of Exogen. TM. therapy in the current study. Therefore supporting its use as a first line management to promote union in delayed fracture union in the general population. Additionally, failure to achieve fracture union with utilisation of Exogen. TM. therapy was associated with risk for requirement of multiple surgeries to achieve union. This could serve as an indicator for surgeon to consider the requirement additional measures at the initial surgical procedure

Chronic pain is recognised as a problem worldwide. Interdisciplinary multimodal pain therapy (MMPT) is currently the gold standard of treatment. The aim of the present prospective observational study is to research whether chronic pain patients form an intention for lifestyle change during a 4-week-long treatment at the Outpatient Clinic for Pain Therapy and Conservative Orthopedics in Heidelberg, Germany, and how sustainable this change is after 3 months. In addition, we theorized a connection between standardised survey endpoints and the number of therapy units perceived as helpful (TPAH). Finally, the effect of socio-demographic factors on patient perceptions were put into perspective. Clinical data was collected via 3-part-questionnaires from 95 German-speaking patients at 4 checkpoints between 05/2020 and 11/2021 at admission (T1), after 2 weeks (T2), at discharge (T3) and 3 months post-treatment (T4). The questionnaires consisted of already established scores for surveying chronic pain patients, such as the von Korff Chronification Scale, ODI, HADS, PSEQ/FESS, and FABQ, a grading scale for each therapy unit, and free answers. Patients were most likely to implement Group Walking in their everyday lives. A higher number of TPAH neither lowered nor improved significantly the change in lifestyle, but both a higher number and bigger lifestyle changes improved significantly the scores across the standardised surveys. Furthermore, no significant change in intention happened between the second and the fourth week. Physical components were perceived throughout as more helpful. The results of this research support the efficacy of MMPT in multi-faceted improving of the patient's well-being and lowering the possibility for pain chronification. A higher number of TPAH could be translated as having more available techniques to combat chronic pain in everyday life. The number of TPAH and the amount of lifestyle change both influence positively the survey scores, yet no connection between them was found. A third factor could be the reason for this constellation. The possibility that the more mental therapies are offered, the more likely it is for those to be perceived as helpful, cannot be excluded either. Further research is required on both topics

Introduction. Legg-Calve-Perthes (Perthes Disease) was first recognised by three physicians, Arthur Legg (1874–1939), Jacqui Calve (1875–1954) and George Perthes (1869 – 1927) in 1910. Perthes disease is a rare childhood condition that affects the hip. It occurs when the blood supply to the femoral head is disrupted. Without this blood supply, the bone cells die and avascular necrosis can occur. The Herring classification is used to diagnose the stages of Perthes Disease. It is an important prognostic factor. There are three classifications, Herring A, B and C. Herring A has no involvement of the lateral pillar with no density changes noted on x-ray. Herring B has at least 50% of the lateral pillar height maintained on x-ray. Herring C has less than 50% of the lateral pillar height on x-ray (Herring et al, 1992). Children with Perthes disease require specialist Limb Reconstruction team throughout their treatment journey, this includes Orthopaedic surgery and therapy (Physiotherapy and Occupational Therapy). The National Limb Reconstruction Therapy Team is based at the National Orthopaedic Hospital, Cappagh. The therapy team consists of 1 Clinical Specialist Physiotherapist, 1 Senior Physiotherapist and 1 Senior Occupational Therapist who provide input to this cohort. This study aims to analyse the importance of a comprehensive pre-operative assessment by the therapy team (Physiotherapist and Occupational Therapist) to maximise patient outcomes post operatively. Methodology. This is a quantitative research study conducted by the National Limb Reconstructive Therapy Service of the National Orthopaedic Hospital in Cappagh, Dublin. The inclusion criteria for this study consisted of:. Age – Patient must be part of the Paediatric Service, i.e., under the age of 16. Diagnosis – Patient must have a diagnosis of Perthes Disease with a Herring Classification documented. Application of a Hip Distractor Frame formed part of the patient's surgical management. Surgery was completed by Mr Connor Green. Surgery was completed between January 2021 and December 2022. Patient were required to have their external hip distractor frame removed by December 2022. Exclusion Criteria: Those not meeting the above inclusion criteria. Following the inclusion criteria, a number of cases were identified of which 10 cases were selected at random. A retrospective analysis of these samples was completed. The medical charts were reviewed as well as patient electronic healthcare records. Microsoft Excel was utilised to analyse the data and capture results. Results. From analysing the data, the following results were identified:. 80% of the sample cohort had a length of stay of 5 days following surgery. There were two outliers due to infection who had a length of stay of 14 days. 90% of the sample received a pre-operative Physiotherapy and Occupational Therapy assessment. This assessment included information gathering regarding the child's home and social environment; their functional baseline and anticipated post-operative needs. Standardised and non-standardised assessments were used. 88.89% of those who completed a pre-operative assessment required referral to community Occupational Therapy teams for equipment provision (wheelchair, transfer aids) to allow for timely discharge. On average, each patient in the sample required 17 physiotherapy outpatient sessions prior to handover to the community teams. 100% of our sample required post operation onward referral for MDT input in the community (Occupational Therapy and Physiotherapy). Conclusions. The importance of a multi-disciplinary approach towards family and children was highlighted in this study. A comprehensive pre-operative therapy assessment optimizes care for this cohort by preparing them in terms of equipment provisions, local team input and expectations for therapy. The data suggests future Limb Reconstruction team should include Physiotherapy and Occupational Therapy as part of the multi-disciplinary team, in the treatment of children with Perthe's Disease. We suggest an MDT pre-assessment is completed to optimize patient care, reduce length of stay and improve patient satisfaction in the acute hospital setting

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

Autologous micro-fragmented adipose tissue (MFAT) for the treatment of symptomatic knee osteoarthritis (OA) is gaining interest although there is still a lack of supportive data on safety and clinical efficacy. This study primarily aimed to identify patient- and pathology-related parameters to tighten patient selection criteria for future clinical MFAT application. Secondly, the overall (1) therapeutic response rate (TRR), (2) short-term clinical effect, (3) effect durability and (4) therapeutic safety was investigated at a minimal follow-up of 1 year. Sixty-four subjects (91 knees) with symptomatic knee OA (mild-severe on MRI) were enrolled in a prospective single-centre case series. Ethical approval was obtained from the local and academic ethical committee (#B300201733775). After liposuction, the adipose tissue was mechanically processed in a Lipogem® device which eventually produced 6–9cc MFAT. Subjects were clinically assessed by means of the KOOS, NRS, UCLA and EQ-5D at baseline and 1, 3, 6 and 12 months after injection. Adverse events were meticulously recorded. The TRR was defined according to the OMERACT-OARSI criteria. A baseline MRI was scored following the MOAKS system. Paired sample t-tests, independent t-test and Fischer's exact test were applied on appropriate variables. Multiple regression models were fit separately for patient-and pathology-specific factors. Significance level was set at α=0.05. The overall TRR was 66% at 3 months and 50% at 12 months after injection. Subgroup analysis revealed that specifically patients with no-mild bone marrow lesions (BML) had a TRR of 88% at 3 months and 75% at 12 months after MFAT injection. Therapy responders at these timepoints improved with 29.3±14.1 points and 30.8±15.3 points on KOOS pain, while non-responders deteriorated mildly. All clinical scores were significantly higher at follow-up compared to baseline (p<0.05). BMI (factor 0.17, p=0.002) and age (factor −0.48, p=0.048) were prognosticators for the TRR% at 1 month and for absolute KOOS pain improvement at 6 months, respectively. Posterior horn lesions (PHL) in the medial meniscus (p<0.001) and bone marrow lesions (p=0.003) were negative prognosticators for the TRR at respectively 6 and 12 months post-injection. An inflammatory reaction (pain, swelling or stiffness) to MFAT was reported in 79% knees and resolved spontaneously within 16.6±13.5 days after administration. The study showed a durable and satisfying TRR (up to 75% at 1 year in selected patients without BML) and clinical improvement after a single intra-articular injection with autologous MFAT. The availability of an index knee MRI is mandatory to select MFAT patients, preferably with no or mild BML and without PHL of the medial meniscus. High BMI and younger age are associated with better early outcomes. In comparison to other injection therapies such as cortisone, hyaluronic acid and PRP, MFAT appears very attractive with an effect durability of at least 1 year

Abstract. Osteoarthritis (OA) is a degenerative disorder associated with cartilage loss and is a leading cause of disability around the world. In old age, the capacity of cartilage to regenerate is diminished. With an aging population, the burden of OA is set to rise. Currently, there is no definitive treatment for OA. However, cell-based therapies derived from adipose tissue are promising. A PRISMA systematic review was conducted employing four databases (MEDLINE, EMBASE, Cochrane, Web of Science) to identify all clinical studies that utilized adipose tissue derived mesenchymal stem cells (AMSCs) or stromal vascular fraction (SVF) for the treatment of knee OA. Eighteen studies were included, which met the inclusion criteria. Meta-analyses were conducted on fourteen of these studies, which all documented WOMAC scores after the administration of AMSCs. Pooled analysis revealed that cell-based treatments definitively improve WOMAC scores, post treatment. These improvements increased with time. The studies in this meta-analysis have established the safety and efficacy of both AMSC therapy and SVF therapy for knee OA in old adults and show that they reduce pain and improve knee function in symptomatic knee OA suggesting that they may be effective therapies to improve mobility in an aging population

Symptomatic and non-symptomatic hip osteonecrosis related to sickle cell disease (SCD) has a high risk of progression to collapse and total hip arthroplasty (THA) in this disease has a high rate of complications. We asked question about the benefit of performing an IRM to detect and treat with cell therapy an early (stage I or II) contralateral osteonecrosis. 430 consecutive SCD adult (32 years, 18 to 51) patients (225 males) with bilateral osteonecrosis (diagnosed with MRI) were included in this study from 1990 to 2010. One side with collapse was treated with THA and the contralateral without collapse (stage I or II) treated with cell therapy. The volume of osteonecrosis was measured with MRI. For cell therapy, the average total number of mesenchymal stem cells (MSCs) counted as number of colony forming units-fibroblast injected in each hip was 160,000 ± 45,000 cells (range 75,000 to 210,000 cells). At the most recent FU (20 years, range 10 to 30), among the 430 hips treated with cell therapy, 45 hips (10.5%) had collapsed and had required THA at 10 years (range 5 to 14 years) and 380 hips (88%) were without collapse and asymptomatic (or with few symptoms) with a decrease percentage of necrosis on MRI from 45% to 11%. Among the 430 contralateral THA, 96 (22.3%) had required one revision, 28 had a re-revision, and 12 a third re-revision with aseptic loosening (85% of revisions) and/or infection (6% of revisions). Hips undergoing cell therapy were approximately three times less likely to undergo revision or re-revision surgery (p < 0.01) as compared with hips undergoing a primary THA. THA is the usual treatment of collapsed ON in patients with SCD. In this population, it is worth looking with MRI for an early stage on the contralateral hip and performing (when necessary) bone marrow cell implantation during the same anesthesia as for arthroplasty

There is conjecture on the optimal timing to administer bisphosphonate therapy following operative fixation of low- trauma hip fractures. Factors include recommendations for early opportunistic commencement of osteoporosis treatment, and clinician concern regarding the effect of bisphosphonates on fracture healing. We performed a systematic review and meta-analysis to determine if early administration of bisphosphonate therapy within the first month post-operatively following proximal femur fracture fixation is associated with delay in fracture healing or rates of delayed or non-union. We included randomised controlled trials examining fracture healing and union rates in adults with proximal femoral fractures undergoing osteosynthesis fixation methods and administered bisphosphonates within one month of operation with a control group. Data was pooled in meta-analyses where possible. The Cochrane Risk of Bias Tool and the GRADE approach were used to assess validity. For the outcome of time to fracture union, meta-analysis of three studies (n= 233) found evidence for earlier average time to union for patients receiving early bisphosphonate intervention (MD = −1.06 weeks, 95% CI −2.01 – −0.12, I. 2. = 8%). There was no evidence from two included studies comprising 718 patients of any difference in rates of delayed union (RR 0.61, 95% CI 0.25–1.46). Meta-analyses did not demonstrate a difference in outcomes of mortality, function, or pain. We provide low-level evidence that there is no reduction in time to healing or delay in bony union for patients receiving bisphosphonates within one month of proximal femur fixation

Abstract. Objectives. Bone marrow aspirate concentrate (BMAC), together with fibrin glue (Tisseel, Baxter, UK) and Hyaluronic acid (HA) were used as a one-step cell therapy treating patients with ankle cartilage defects in our hospital. This therapy was proven to be safe, with patients demonstrating a significant improvement 12 months post-treatment. Enriched mesenchymal stem cells (MSCs) in BMAC are suggested inducers of cartilage regeneration, however, currently there is no point-of-care assessment for BMAC quality; especially regarding the proportion of MSCs within. This study aims to characterise the cellular component of CCR-generated BMAC using a point-of-care device, and to investigate if the total nucleated cell (TNC) count and patient age are predictive of MSC concentration. Methods. During surgery, 35ml of bone marrow aspirate (BMA) was collected from each patients’ iliac crest under anaesthesia, and BMAC was obtained via a commercial kit (Cartilage Regeneration kit, CCR, Innotec. ®. , UK). BMAC was then mixed with thrombin (B+T) for injection with HA and fibrinogen. In our study, donor-matched BMA, BMAC and B+T were obtained from consented patients (n=12, age 41 ± 16years) undergoing surgery with BMAC therapy. TNC, red blood cell (RBC) and platelet (PLT) counts were measured via a haematology analyser (ABX Micros ES 60, Horiba, UK), and the proportion of MSCs in BMA, BMAC and B+T were assessed via colony forming unit-fibroblast (CFU-F) assays. Significant differences data in matched donors were tested using Friedman test. All data were shown as mean ± SD. Results. Mean TNC counts in BMA and BMAC were not significantly different (14.0 ± 4.4 million/ml and 19.4 ± 32.9 million/ml, respectively, P>0.9999). However, TNC counts were significantly lower in B+T compared to BMAC (9.7 ± 24.5 million/ml and 19.4 ± 32.9 million/ml, respectively, P=0.0167). Similarly, PLT counts were decreased in B+T compared to BMAC (40.7 ± 30.7 million/ml and 417.5 ± 365.5 million/ml, respectively, P<0.0001), however, PLTs were significantly concentrated in BMAC compared to BMA (417.5 ± 365.5 million/ml and 114.8 ± 61.6 million/ml, respectively, P=0.0429). RBC counts were significantly decreased in BMAC and B+T compared to BMA (P=0.0322 and P<0.0001, respectively). Higher concentration of MSCs were observed in BMAC compared to BMA (0.006% ± 0.01% and 0.00007% ± 0.0001%, respectively, P=0.0176). Similar to TNCs and PLTs, the proportion of MSCs significantly decreased in B+T compared to BMAC (0.0004% ± 0.001% and 0.006% ± 0.01%, respectively, P=0.0023). Furthermore, patient age and TNC counts did not correlate with MSC concentration (Spearman's Rank test, P=0.3266 and P=0.4880, respectively). Conclusions. BMAC successfully concentrated PLTs, but BMAC preparations were highly variable. Mixing BMAC and thrombin however, as described in the CCR protocol, resulted in a dramatic reduction in TNCs, PLTs and MSCs. TNC counts and patient age could not be used to predict the MSC proportion in the BMAC based on current data. Future work aims to look at the biomolecule profile of BMAC plasma, and to correlate them to patient clinical outcomes. Declaration of Interest. (a) fully declare any financial or other potential conflict of interest

Purpose. Cognitive Muscular Therapy (CMT) is a new treatment for low back pain which integrates psychological techniques for pain management alongside training to improve postural control. Rather than focus on postural alignment or strength, CMT aims to improve the regulation of postural tone (low-level activity which supports the body against gravity). This is achieved by teaching patients an awareness of compensatory paraspinal activation, which can be triggered by overactivity of the abdominal muscles. The aim of this study was to understand whether CMT could reduce symptoms associated with low back pain and improve paraspinal muscle activation. Methods and results. Fifteen patients with chronic low back pain received seven weekly sessions of CMT from a physiotherapist. Clinical data was captured at baseline and two weeks after the intervention using the Roland-Morris questionnaire and the pain catastrophising scale. Activation of the erector spinae muscle during walking was also measured at baseline and after the final intervention session. Change data were analysed using paired t-tests. There was a 75% reduction (p<0.001) in the Roland-Morris score from a mean (SD) of 9.3(2.9) to 2.3(2.6), along with a 78% reduction in pain catastrophising (p<0.002) from 16.6(13) to 3.7(4.8). Activation of the contralateral erector spinae muscles reduced by 30% (p<0.01) during the contralateral swing phase of walking. Conclusion. In this small sample, CMT delivered large clinical improvements and reduced activation of the low back muscles during walking. Larger randomised trials are now required to confirm whether CMT could outperform existing physiotherapy treatments for chronic back pain. Conflict of interest. No conflicts of interest. Source of funding. University of Salford

Purpose of study: To test the relative effectiveness of interferential therapy (IFT) and manipulative therapy (MT) when used as sole treatments and in combination for the management of acute low back pain (ALBP). Although IFT is the most widely used electrotherapeutic modality in Britain and Ireland for the physiotherapeutic management of patients with LBP, often in combination with MT, its evidence base is weak and limited. Methods: In this assessor-blinded RCT, consenting subjects recruited from 4 NHS hospitals (n=240) were randomised to receive (1) MT (n=80), (2) IFT (n=80). 1. or (3) combined MT and IFT (n=80), as well as a copy of the Back Book. Subjects completed the Roland Morris Disability Questionnaire (primary outcome), VAS, McGill Pain Questionnaire, EuroQol, SF-36 and a range of patient-related variables (secondary outcomes) at baseline, discharge (n=194, 83%), 6 months (n=166, 71%) and 12 months (n=158, 67%). Results: There were significant improvements in all outcomes at discharge, which were not significantly different from the 6 month and 12 month values for the whole sample. Univariate analysis of covariance detected significant differences between groups in the mean adjusted change scores for SF-36 Physical Functioning (P = 0.03), Bodily Pain (P=0.04), and Mental Health (P = 0.03) scales at 12 months in favour of combined MT and IFT over MT. Although not statistically significant the trend of the change score data for the remaining pain outcomes suggested that subjects in the MT group deteriorated after discharge while those in the IFT and combined therapy groups displayed a more gradual improvement over the follow-up period, such that the MT group outcomes were poorer at 12 months. Conclusions: The results provide some evidence for the continued use of IFT for short and long-term improvements in function and LBP particularly when used in combination with MT. However, MT alone was less effective for long-term improvements in pain

Aim. Antibiotics have limited activity in the treatment of multidrug-resistant or chronic biofilm-associated infections, in particular when implants cannot be removed. Lytic bacteriophages can rapidly and selectively kill bacteria, and can be combined with antibiotics. However, clinical experience in patients with surgical infections is limited. We investigated the outcome and safety of local application of bacteriophages in addition to antimicrobial therapy. Method. 8 patients (2 female and 6 male) with complex orthopedic and cardiovascular infections were included, in whom standard treatment was not feasible or impossible. The treatment was performed in agreement with the Article 37 of the Declaration of Helsinki. Commercial or individually prepared bacteriophages were provided by ELIAVA Institute in Tbilisi, Georgia. Bacteriophages were applied during surgery and continued through drains placed during surgery three times per day for the following 5–14 days. Follow-up ranged from 1 to 28 months. Results. Median age was 57 years, range 33–75 years. Two patients were diagnosed with a persistent knee arthrodesis infection, one chronic periprosthetic joint infection (PJI), one cardiovascular implantable electronic device (CIED) infection and four patients with left ventricular assist device (LVAD) infection. The isolated pathogens were multi-drug-resistant Pseudomonas aeruginosa (n=3), methicillin-sensitive Staphylococcus aureus (n=4), methicillin-resistant Staphylococcus aureus (MRSA) (n=1) and methicillin-resistant Staphylococcus epidermidis (MRSE) (n=1). 4 infections were polymicrobial. 5 patients underwent surgical debridement with retention of the implant, 1 patient with PJI underwent the exchange of the prosthesis and one patient with LVAD infection was treated conservatively. All patients received intravenous and oral antibiotic therapy and local application of bacteriophages. At follow-up of 12 month, 5 patients were without signs or symptoms of infection, whereas in one patient with LVAD infection, a relapse was observed with emergence of phage-resistant Pseudomonas aeruginosa. In this patient, no surgical revision was performed. Conclusions. Bacteriophage therapy may represent a valid additional approach, when standard antimicrobial and surgical treatment is not possible or feasible, including in difficult-to-treat infections. In our case series, 5 of 6 patients were infection free after 1 year. Further studies need to address the optimal bacteriophage administration route, concentration, duration of treatment and combination with antimicrobials

Intra-articular injection is a common way to deliver biologics to joints, but their effectiveness is limited by rapid clearance from the joint space. This barrier can be overcome by genetically modifying cells within the joint such that they produce anti-arthritic gene products endogenously, thereby achieving sustained, therapeutic, intra-articular concentrations of the transgene products without re-dosing. A variety of non-viral and viral vectors have been subjected to preclinical testing to evaluate their suitability for delivering genes to joints. The first transfer of a gene to a human joint used an ex vivo protocol involving retrovirally transduced, autologous, synovial fibroblasts. Recent advances in vector technology allow in vivo delivery using adeno-associated virus (AAV). We have developed an AAV vector encoding the interleukin-1 receptor antagonist (AAV.IL-1Ra) for injection into joints with osteoarthritis (OA). It showed efficacy and safety in equine and rat models of OA, leading to a recently-completed, investigator-initiated, Phase I, dose-escalation clinical trial in 9 subjects with mid-stage OA of the knee (. ClinicalTrials.gov. Identifier: NCT02790723). Three cohorts of three subjects with mild to moderate OA in the index knee were injected intra-articularly under ultrasound guidance with a low (10e11 viral genomes) medium (10e12 viral genomes) or high (10e13 viral genomes) dose of AAV.IL-1Ra and followed for one year. The data confirm safety, with evidence of sustained intra-articular expression of IL-1Ra and a clinical response in certain subjects. Funding for a subsequent Phase Ib trial involving 50 subjects (. ClinicalTrials.gov. Identifier: NCT05835895), expected to start later this year, has been acquired. Progress in this area has stimulated commercial activity and there are now at least seven different companies developing gene therapies for OA and a number of clinical trials are in progress. Acknowledgement: Clinical trial funded by US Department of Defense Clinical Trial Award W81XWH-16-1-0540

To analyse the efficacy and safety of cellular therapy utilizing Mesenchymal Stromal Cells (MSCs) in the management of rotator cuff(RC) tears from clinical studies available in the literature. We conducted independent and duplicate electronic database searches including PubMed, Embase, Web of Science, and Cochrane Library on August 2021 for studies analyzing the efficacy and safety of cellular therapy (CT) utilizing MSCs in the management of RC tears. VAS for pain, ASES Score, DASH Score, Constant Score, radiological assessment of healing and complications and adverse events were the outcomes analyzed. Analysis was performed in R-platform using OpenMeta [Analyst] software. RESULTS:. 6 studies involving 238 patients were included for analysis. We noted a significant reduction in VAS score for pain at 3 months (WMD=-2.234,p<0.001) and 6 months (WMD=-3.078,p<0.001) with the use of CT. Concerning functional outcomes, utilization of CT produced a significant short-term improvement in the ASES score (WMD=17.090,p<0.001) and significant benefit in functional scores such as Constant score (WMD=0.833,p=0.760) at long-term. Moreover, we also observed a significantly improved radiological tendon healing during the long-term follow-up (OR=3.252,p=0.059). We also noted a significant reduction in the retear rate upon utilization of CT in RC tears both at short- (OR=0.079,p=0.032) and long-term (OR=0.434,p=0.027). We did not observe any significant increase in the adverse events as compared with the control group (OR=0.876,p=0.869). Utilization of CT in RC tear is safe and it significantly reduced pain severity, improved functional outcome, enhanced radiological tendon healing, and mitigated retear rates at short- and long-term follow-up

Despite osteoarthritis (OA) representing a large burden for healthcare systems, there remains no effective intervention capable of regenerating the damaged cartilage in OA. Mesenchymal stromal cells (MSCs) are adult-derived, multipotent cells which are a candidate for musculoskeletal cell therapy. However, their precise mechanism of action remains poorly understood. The effects of an intra-articular injection of human bone-marrow derived MSCs into a knee osteochondral injury model were investigated in C57Bl/6 mice. The cell therapy was retrieved at different time points and single cell RNA sequencing was performed to elucidate the transcriptomic changes relevant to driving tissue repair. Mass cytometry was also used to study changes in the mouse immune cell populations during repair. Histological assessment reveals that MSC treatment is associated with improved tissue repair in C57Bl/6 mice. Single cell analysis of retrieved human MSCs showed spatial and temporal transcriptional heterogeneity between the repair tissue (in the epiphysis) and synovial tissue. A transcriptomic map has emerged of some of the distinct genes and pathways enriched in human MSCs isolated from different tissues following osteochondral injury. Several MSC subpopulations have been identified, including proliferative and reparative subpopulations at both 7 days and 28 days after injury. Supported by the mass cytometry results, the immunomodulatory role of MSCs was further emphasised, as MSC therapy was associated with the induction of increased numbers of regulatory T cells correlating with enhanced repair in the mouse knee. The transcriptomes of a retrieved MSC therapy were studied for the first time. An important barrier to the translation of MSC therapies is a lack of understanding of their heterogeneity, and the consequent lack of precision in its use. MSC subpopulations with different functional roles may be implicated in the different phases of tissue repair and this work offers further insights into repair process

Autologous tendon cell injection (ATI) is a promising non-surgical treatment for tendinopathies and tendon tear that address its underlying pathology. The procedure involves harvesting autologous tendon tissue, the isolation of the tendon cells, expansion under quality assured GMP cell laboratory and the injection of the tendon cells via U/S into the degenerative tendon tissue. In clinical practice, the patella (PT) and palmaris longus (PL) tendons are common sites used for tendon tissue biopsy. The objective of this study is to compare the tendon cell quality, identity, purity, doubling time and yield of cells between PT and PL tendons for ATI. Tendon tissue biopsies were harvested from PT via U/S using a 14-gauge needle or resected surgically from the PL tendon. The biopsies were transported to a GMP cell laboratory, where tendon cells were isolated, cultured and expanded for 4 to 6 weeks, and analysed for viability, cell doubling time, cellular characteristics including cell purity, potency and identity (PPI). Tendon samples from 149 patients were analysed (63 PT). Average biopsy weight was 62mg for PT and 119mg for PI (p<0.001). Average cell doubling time (83.9 vs 82.7 hours), cellular yield (16.2 vs 15.2x106), viability (98.7 vs 99.0%) and passage number (3 vs 3) were not significantly different between tendons. Additionally, ddPCR analyses showed no differences of PPI including tendon cell markers of collagen type I, scleraxis and tenomodulin. No post-biopsy complications or contamination were reported for either group. Assessing tendon tissue from palmaris tendon is relatively easier. Tendon tissue biopsy tissue for autologous tendon cell therapy can be obtained from either the PT or PL tendons. Tendon cells isolated from PT and PL were equal in growth characteristics and PPI. There are no differences in the quality of tendon cells isolated from the PT or PL

Aim. Debridement, antibiotics, and implant retention (DAIR) is a viable treatment option for acute periprosthetic joint infections (PJI). The landmark DATIPO trial of Bernard et al. concluded that six weeks is not non-inferior to 12-week antibiotic therapy for DAIR. However, it is unknown if suppressive antibiotic treatment (SAT) would improve patient outcomes. Therefore, our study aims to evaluate the utility of SAT after 12 weeks of therapy. Method. We performed a retrospective study of patients with acute hip or knee PJI managed with DAIR at five institutions; in the U.S. (n=1), Netherlands (n=3), and Spain (n=1) from 2005–2020. We analyzed the effect of SAT using a Cox model among patients after 12 weeks of antibiotic treatment. The primary covariate of interest was whether the patient was on antibiotics after week 12, which was coded as a time-varying covariate. We decided a-priori to control for the clinically important risk factors such as age, sex, type of infection, modular exchange, joint, and presence of bacteremia and Staphylococcus aureus. We excluded patients who died, had treatment failure, or were lost to follow-up before 12 weeks. We defined treatment failure as infection recurrence (same or different organism), unexpected reoperation, or death due to infection. Results. There were 504 patients included in the study. The majority were female (58%, n=292), with a mean age of 70 years ago (SD 11). Hips and knees were equally proportioned. Primary arthroplasties represented 69% of the total cohort (n=349). Treatment failure was 11.9% in the total cohort (n=60). There was no statistically significant association between SAT after 12 weeks and treatment failure (HR 1.25, p=0.45, 95% CI 0.70–2.24). This finding was consistent across different subgroups, including hip or knee joints, early or late acute infections, cohort, and a subgroup of knee joints after 180 days. Conclusions. SAT after 12 weeks of antibiotic treatment for acute PJI managed with DAIR does not appear to improve patient outcomes

Novel oral anticoagulant (NOAC) use in Australia has increased significantly since their introduction to the Pharmaceutical Benefits Scheme (PBS). Currently, there are no specific guidelines regarding recommencement of NOAC therapy post-operatively for patients concurrently on a NOAC and undergoing arthroplasty. To address this gap in the literature, the aim of this study was to compare the clinical and patient-reported outcomes in a patient cohort recommencing a therapeutic dose of NOAC within 24 hours of total hip or knee arthroplasty. Data was retrieved from a prospective registry (ACTRN1262000079698) containing hip and knee arthroplasties. Cases were labelled based on whether they presented on a therapeutic dose of NOAC prior to surgery or not. Descriptive statistics were used to summarise patient outcomes. Of 291 patients undergoing 331 primary arthroplasties, 9.3% were undertaking NOAC therapy prior to their surgery. In the NOAC cohort, there was a 34.5% adverse event rate, however on closer analysis of each event, it was found that none of these events were complications in relation to NOAC use. This was compared to 15.6% of the comparison cohort who experienced a range of complications, some involving bleeding events. PROMs improved to a similar degree amongst both groups. This study showed that recommencing therapeutic doses of NOACs in patients post hip and knee arthroplasty within 24 hours was safe. These findings will help guide larger scale analysis to better inform clinical guidelines pertaining to hip and knee arthroplasty

The spine is a common site of metastasis. Complications include pathologic fracture, spinal cord compression, and neurological deficits. Vertebroplasty (VP) and Balloon Kyphoplasty (KP) are minimally invasive stabilization procedures used as a palliative treatment to improve mechanical stability, quality of life, and reduce pain. Photodynamic therapy (PDT) is a tumour-ablative modality that may complement mechanical stability afforded by VP/KP. This first-in-human study evaluates PDT safety when applied in conjunction with VP/KP. This dose escalation trial involved one light only control group and four light-drug doses (50,100,150,200J;n=6) delivered at 150mW from a 690nm diode laser by 800-micron optical fibers prior to KP/VP. Patients eligible for VP/KP in treating pathologic fracture or at-risk lesions at a single level were recruited. Exclusion criteria included spinal canal compromise or neurologic impairment. PDT is a two-step binary therapy of systemic drug followed by intravertebral light activation. Light was applied via bone trochar prior to cementation. This study used a benzoporphyrin derivative monoacid (BPD-MA), Verteporfin (VisudyneTm), as the photosensitizer drug in the therapy. Drug/light safety, neurologic safety, generic (SF-36), and disease-specific outcomes (VAS, EORTC-QLQ-BM22, EORTC-QLQ-C15-PAL) were recorded through six weeks. Phototoxicity and the side effects of the BPD-MA were also examined following PDT use. Thirty (10 male, 20 female) patients were treated (13 KP, 17 VP). The average age was 61 and significantly different between genders (Male 70yrs vs. Female 57yrs: p 0.05), and tumour status (lytic vs. mixed blastic/lytic: p>0.05). In most cases, fluence rates were similar throughout PDT treatment time, indicating a relatively stable treatment. Twelve (40%) of patients experienced complications during the study, none of which were attributed to PDT therapy. This included two kyphoplasty failures due to progression of disease, one case of shingles, one ankle fracture, one prominent suture, one case of constipation due to a lung lesion, one case of fatigue, and five patients experienced pain that was surgically related or preceded therapy. Vertebral PDT appears safe from pharmaceutical and neurologic perspectives. KP/VP failure rate is broadly in line with reported values and PDT did not compromise efficacy. The 50J group demonstrated an improved response. Ongoing study determining safe dose range and subsequent efficacy studies are necessary