Quantification of cefuroxime and flucloxacillin in synovial tissue and bone using ultra-performance convergence chromatography-tandem mass spectrometry.

After a revision surgery, approximately 1-2 % of patients will develop a periprosthetic joint infection (PJI). During the revision surgery, the infected prosthesis is removed, a debridement is performed and a new or temporary spacer is placed. Additionally, patients are treated with antibiotics during and after the surgery. Adequate exposure of the administered antibiotic to the pathogen is of crucial importance during the treatment of any infection. Inadequately low concentrations are associated with an increase in antibiotic resistance, antibiotic related side effects, treatment failures and prolonged infections. While high concentrations may lead to serious adverse events and potential lasting damage. Despite the importance of optimal dosing, there is a lack of knowledge with respect to the correlation between the plasma concentrations and target site concentrations of the antibiotics. Two of the commonly administered antimicrobial agents during the arthroplasty exchange are cefuroxime and flucloxacillin. Therefore, an accurate, specific, and sensitive quantification method is required in order to assess pharmacokinetics of cefuroxime and flucloxacillin in synovial tissue and bone. The aim of this study is to develop and validate a quantification method for the measurement of cefuroxime and flucloxacillin in human synovial tissue and bone using the UPC2-MS/MS conform Food and Drug Administration guidelines. The method was found linear for both compounds in both matrices (r2 > 0.990) from 1 µg/g to 20 µg/g, except for cefuroxime in bone, which was validated from 1 µg/g to 15 µg/g. We developed and validated a quantification method for cefuroxime and flucloxacillin in synovial tissue and bone using a simple sample preparation and a short analysis run time of 5.0 min, which has been already successfully applied in a clinical study. To our knowledge, no methods have been described earlier for the simultaneous quantification of cefuroxime and flucloxacillin in synovial tissue and bone.

Are serum cobalt and chromium levels predictors for patient-reported outcome measures in the ASR hip resurfacing arthroplasty?

Aims: The aims of this study were to determine if an increasing serum cobalt (Co) and/or chromium (Cr) concentration is correlated with a decreasing Harris Hip Score (HHS) and Hip disability and Osteoarthritis Outcome Score (HOOS) in patients who received the Articular Surface Replacement (ASR) hip resurfacing arthroplasty (HRA), and to evaluate the ten-year revision rate and show if sex, inclination angle, and Co level influenced the revision rate. Methods: A total of 62 patients with an ASR-HRA were included and monitored yearly postoperatively. At follow-up, serum Co and Cr levels were measured and the HHS and the HOOS were scored. In addition, preoperative patient and implant variables and the need for revision surgery were recorded. We used a linear mixed model to relate the serum Co and Cr levels to different patient-reported outcome measures (PROMs). For the survival analyses we used the Kaplan-Meier and Cox regression model. Results: We found that an increase of one part per billion (ppb) in serum Co and Cr levels correlated significantly with worsening of the HHS in the following year. This significant correlation was also true for the HOOS-Pain and HOOS-quality of life sub scores. The overall ten-year survival rate in our cohort was 65% (95% confidence interval (CI) 52.5 to 77.6). Cox regression analysis showed a significant hazard ratio (HR) of 1.08 (95% CI 1.01 to 1.15; p = 0.028) for serum Co level. No significance was found with sex or inclination angle. Conclusion: This study shows that increasing serum Co and Cr levels measured in patients with an ASR-HRA are predictive for deterioration in HHS and HOOS subscales in the following year. Increasing serum Co and Cr should forewarn both surgeon and patient that there is a heightened risk of failure. Continued and regular review of patients with an ASR-HRA implant by measurement of serum Co/Cr levels and PROMs remains essential.

An Overview of the Protein Binding of Cephalosporins in Human Body Fluids: A Systematic Review.

Introduction: Protein binding can diminish the pharmacological effect of beta-lactam antibiotics. Only the free fraction has an antibacterial effect. The aim of this systematic literature review was to give an overview of the current knowledge of protein binding of cephalosporins in human body fluids as well as to describe patient characteristics influencing the level of protein binding. Method: A systematic literature search was performed in Embase, Medline ALL, Web of Science Core Collection and the Cochrane Central Register of Controlled Trials with the following search terms: "protein binding," "beta-lactam antibiotic," and "body fluid." Only studies were included where protein binding was measured in humans in vivo. Results: The majority of studies reporting protein binding were performed in serum or plasma. Other fluids included pericardial fluid, blister fluid, bronchial secretion, pleural exudate, wound exudate, cerebrospinal fluid, dialysate, and peritoneal fluid. Protein binding differs between diverse cephalosporins and between different patient categories. For cefazolin, ceftriaxone, cefpiramide, and cefonicid a non-linear pattern in protein binding in serum or plasma was described. Several patient characteristics were associated with low serum albumin concentrations and were found to have lower protein binding compared to healthy volunteers. This was for critically ill patients, dialysis patients, and patients undergoing cardiopulmonary bypass during surgery. While mean/median percentages of protein binding are lower in these patient groups, individual values may vary considerably. Age is not likely to influence protein binding by itself, however limited data suggest that lower protein binding in newborns. Obesity was not correlated with altered protein binding. Discussion/Conclusion: Conclusions on protein binding in other body fluids than blood cannot be drawn due to the scarcity of data. In serum and plasma, there is a large variability in protein binding per cephalosporin and between different categories of patients. Several characteristics were identified which lead to a lower protein binding. The finding that some of the cephalosporins display a non-linear pattern of protein binding makes it even more difficult to predict the unbound concentrations in individual patients. Taken all these factors, it is recommended to measure unbound concentrations to optimize antibiotic exposure in individual patients. Systematic Review Registration: PROSPERO, identifier (CRD42021252776).

No added value for Computer-Assisted surgery to improve femoral component positioning and Patient Reported Outcomes in Hip Resurfacing Arthroplasty; a multi-center randomized controlled trial.

BACKGROUND: Computer Assisted Surgery (CAS) has proven to improve the accuracy in several orthopedic procedures. Therefore we used this technique to evaluate femoral component positioning in Hip Resurfacing Arthroplasty (HRA). The aim of this study was to evaluate imageless CAS compared to manually implanted femoral components and subsequently evaluates Patient Related Outcome Measures (PROMs). We hypothesized that the use of CAS optimizes the position of the femoral component and improves PROMs. METHODS: This is a multicenter, single-blinded, randomized, controlled trial of two groups. In the CAS group guiding of the femoral component was done with imageless navigation. In the Conventional (control) group the femoral component was placed manually according to the preplanned position. The primary outcome measure consists of a maximum of 3 degrees difference between the postoperative Stem Shaft Angle (SSA) and preplanned SSA. Secondary outcome measures consist of the Hip disability and Osteoarthritis Outcome Scale (HOOS), the Harris Hip Score (HHS) and Visual Analogue Scale (VAS) pain score. RESULTS: A total of 122 patients were randomized, 61 in the CAS group and 61 in the conventional group. There was no significant differences in accuracy of femoral implant position. The mean difference between the postoperative- and preplanned SSA was - 2.26 and - 1.75 degrees (more varus) respectively in the CAS and Conventional group. After surgery both groups show significant improvement in all PROMs compared to the baseline measurements, with no significant differences between the groups. CONCLUSION: Our cohort indicates no benefit for the use of CAS in accuracy of placement of the femoral component in HRA compared to manual implantation. There are no clinical differences in PROMs after 1 year follow up. This study showed no added value and no justification for the use of CAS in femoral component positioning in HRA. TRIAL REGISTRATION: This trial is registered at ClinicalTrails.gov ( https://clinicaltrials.gov/ ) on the 25th of October 2006: NCT00391937. LEVEL OF INCIDENCE: Level IIb, multicenter randomized controlled trial.

Mesenchymal stem cell secretome reduces pain and prevents cartilage damage in a murine osteoarthritis model.

Mesenchymal stem cells (MSCs) represent a promising biological therapeutic option as an osteoarthritis (OA)-modifying treatment. MSCs secrete factors that can counteract inflammatory and catabolic processes and attract endogenous repair cells. The effects of intra-articular injection of MSC secretome on OA-related pain, cartilage damage, subchondral bone alterations and synovial inflammation were studied in a mouse collagenase-induced OA model. The MSC secretome was generated by stimulating human bone-marrow-derived MSCs with interferon gamma (IFNγ) and tumour necrosis factor alpha (TNFα). 54 mice were randomly assigned to injections with i) MSC secretome from 20,000 MSCs, ii) 20,000 MSCs or iii) medium (control). Pain was assessed by hind limb weight distribution. Cartilage damage, subchondral bone volume and synovial inflammation were evaluated by histology. MSC-secretome- and MSC-injected mice showed pain reduction at day 7 when compared to control mice. Cartilage damage was more abundant in the control group as compared to healthy knees, a difference which was not found in knees treated with MSC secretome or MSCs. No effects were observed regarding synovial inflammation, subchondral bone volume or the presence of different macrophage subtypes. Injection of MSC secretome, similarly to injection of MSCs, resulted in early pain reduction and had a protective effect on the development of cartilage damage in a murine OA model. By using the regenerative capacities of the MSC-secreted factors, it will be possible to greatly enhance the standardisation, affordability and clinical translatability of the approach. This way, this biological therapy could evolve towards a true disease-modifying anti-osteoarthritic drug.

Adverse events and survival after closing- and opening-wedge high tibial osteotomy: a comparative study of 412 patients.

PURPOSE: Varus medial knee osteoarthritis (OA) can be treated with a closing-wedge (CW) or opening-wedge (OW) high tibial osteotomy (HTO). Little is known about the adverse event (AE) rate of these techniques. The purpose of this study was to examine the AE rate and survival rate of a consecutive series of 412 patients undergoing CW- or OW-HTO. METHODS: Medical records were retrospectively screened, and all patients who underwent HTO from 1993 to 2012 at the Erasmus University Medical Centre were assessed with a self-administered questionnaire. Patients filled in the intermittent and constant osteoarthritis pain score, knee injury and osteoarthritis outcome score, and a general questionnaire focusing on AE. RESULTS: Medical records of 412 patients (354 CW- and 112 OW-HTOs) were screened. Of the 358 eligible patients, 291 (81 %) returned their questionnaire. A total of 80 AE (17 %) were found in 466 osteotomies. In the CW-group, 47 (13 %) serious adverse events (SAE) and 2 (0.6 %) AE were found. In the OW-group, 17 (15 %) SAE and 14 (13 %) AE were found. The most common AE was in 14 (4 %) patients of the CW-group sensory palsy of the common peroneal nerve. The most common AE in the OW-group was persistent pain at the iliac crest [11 (9.8 %) patients]. Hardware was removed in 48 % of the CW-osteotomies and 71 % of the OW-osteotomies (p < 0.05). The probability of survival was 75 % after 10 years in the CW-group versus 90 % in the OW-group (p < 0.05). In both groups, an equal number of patients were "in need for prosthesis" according to OARSI criteria. CONCLUSION: OW-HTO was associated with more AE than CW-HTO. OW-HTO resulted in better survival than CW-HTO. However, in both groups an equal number of patients were in need for prosthesis. LEVEL OF EVIDENCE: Retrospective comparative study, Level III.

Reconstruction of defects involving the Achilles tendon and local soft tissues: a quick solution for a lingering problem.

A total of seven patients (six men and one woman) with a defect in the Achilles tendon and overlying soft tissue underwent reconstruction using either a composite radial forearm flap (n = 3) or an anterolateral thigh flap (n = 4). The Achilles tendons were reconstructed using chimeric palmaris longus (n = 2) or tensor fascia lata (n = 2) flaps or transfer of the flexor hallucis longus tendon (n = 3). Surgical parameters such as the rate of complications and the time between the initial repair and flap surgery were analysed. Function was measured objectively by recording the circumference of the calf, the isometric strength of the plantar flexors and the range of movement of the ankle. The Achilles tendon Total Rupture Score (ATRS) questionnaire was used as a patient-reported outcome measure. Most patients had undergone several previous operations to the Achilles tendon prior to flap surgery. The mean time to flap surgery was 14.3 months (2.1 to 40.7). At a mean follow-up of 32.3 months (12.1 to 59.6) the circumference of the calf on the operated lower limb was reduced by a mean of 1.9 cm (sd 0.74) compared with the contralateral limb (p = 0.042). The mean strength of the plantar flexors on the operated lower limb was reduced to 88.9% of that of the contralateral limb (p = 0.043). There was no significant difference in the range of movement between the two sides (p = 0.317). The mean ATRS score was 72 points (sd 20.0). One patient who had an initial successful reconstruction developed a skin defect of the composite flap 12 months after free flap surgery and this resulted in recurrent infections, culminating in transtibial amputation 44 months after reconstruction. These otherwise indicate that reconstruction of the Achilles tendon combined with flap cover results in a successful and functional reconstruction.

Comparison of closing-wedge and opening-wedge high tibial osteotomy for medial compartment osteoarthritis of the knee: a randomized controlled trial with a six-year follow-up.

BACKGROUND: Varus deformity increases the risk of progression of medial compartment knee osteoarthritis. The aim of this study was to investigate the clinical and radiographic mid-term results of closing-wedge and opening-wedge high tibial osteotomy when used to treat this condition. METHODS: From January 2001 to April 2004, ninety-two patients were randomized to receive either a closing-wedge or an opening-wedge high tibial osteotomy. The clinical outcome and radiographic results were examined preoperatively; at one year; and, for the present study, at six years postoperatively. The outcomes that we reviewed included maintenance of the achieved correction, progression of osteoarthritis (based on the Kellgren and Lawrence classification), severity of pain (as assessed on a visual analog scale [VAS]), knee function (as measured with the Hospital for Special Surgery [HSS] score and Knee injury and Osteoarthritis Outcome Score [KOOS]), walking distance, complications, and survival with conversion to a total knee arthroplasty as the end point. The results were analyzed on the basis of the intention-to-treat principle. RESULTS: Six years postoperatively, the mean hip-knee-ankle (HKA) angle (and standard deviation) was 3.2° ± 4.1° of valgus after a closing-wedge high tibial osteotomy and 1.3° ± 5.0° of valgus after an opening-wedge high tibial osteotomy (p = 0.343). In both groups, the six-year postoperative HKA angles did not differ from the respective one-year postoperative angles. No difference in the severity of pain or in knee function was found between the two groups. Four complications (9%) occurred in the closing-wedge group and seventeen (38%), in the opening-wedge group. Ten (22%) of the patients in the closing-wedge group and three (8%) in the opening-wedge group needed conversion to a total knee arthroplasty within the six-year period (p = 0.05). The difference in the percentage of cases with conversion to total knee arthroplasty was 14% (95% confidence interval [CI] = 21.7 to 0.2). CONCLUSIONS: In the group of patients without conversion to a total knee arthroplasty, there was no difference between the high tibial closing-wedge and opening-wedge osteotomies in terms of clinical outcomes or radiographic alignment at six years postoperatively. Opening-wedge osteotomy was associated with more complications, but closing-wedge osteotomy was associated with more early conversions to total knee arthroplasty. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

[A soccer player with a painful and swollen knee]. / Een voetballer met een pijnlijke zwelling van de knie.

UNLABELLED: A 19-year-old man was evaluated for medial knee pain 1.5 year after repeated distortion of the right knee. The medial side of his knee was swollen and painful upon running and playing soccer. An anteroposterior knee radiograph showed a calcification located at the proximal medial collateral ligament. He was diagnosed with Pellegrini-Stieda syndrome. Treatment of this syndrome includes rest, range of motion exercises, nonsteroidal anti-inflammatory drugs, local infiltration with corticosteroids or excision in refractory cases. DIAGNOSIS: Pellegrini-Stieda syndrome.

Safety of intra-articular cell-therapy with culture-expanded stem cells in humans: a systematic literature review.

BACKGROUND: An important goal of stem cell research in orthopaedics is to develop clinically relevant techniques that could be applied to heal cartilage or joint pathology. Stem cell treatment in orthopaedics for joint pathology is promising since these cells have the ability to modulate different processes in the various tissues of the joint simultaneously. The non life-threatening nature of musculoskeletal system disorders makes safety of stem cell therapy a necessary prerequisite. OBJECTIVE: To systematically review the literature and provide an overview of reported adverse events (AEs) of intra-articular treatment with culture-expanded stem cells in humans. DESIGN: A systematic literature search was performed in Pubmed, EMBASE, Web of Science and CINAHL in February 2013. AEs were reported into three categories: local/systemic, serious adverse event or AE (SAE/AE), related/unrelated. RESULTS: 3039 Potentially eligible articles were identified of which eventually eight fulfilled our inclusion criteria. In total, 844 procedures with a mean follow-up of 21 months were analysed. Autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) were used for cartilage repair and osteoarthritis treatment in all included studies. Four SAEs were reported by the authors. One infection following bone marrow aspiration (BMA) was reported as probably related and resolved with antibiotics. One pulmonary embolism occurred 2 weeks after BMA and was reported as possibly related. Two tumours, both not at the site of injection, were reported as unrelated. Twenty-two other cases of possible procedure-related and seven of possible stem cell-product related adverse events (AEs) were documented. The main AEs related to the procedure were increased pain/swelling and dehydration after BMA. Increased pain and swelling was the only AE reported as related to the stem cell-product. CONCLUSIONS: Based on current literature review we conclude that application of cultured stem cells in joints appears to be safe. We believe that with continuous caution for potential side effects, it is reasonable to continue with the development of articular stem cell therapies.

Mesenchymal stem cells secrete factors that inhibit inflammatory processes in short-term osteoarthritic synovium and cartilage explant culture.

OBJECTIVE: Mesenchymal stem cells (MSCs) are promising candidates for osteoarthritis (OA) therapies, although their mechanism of action remains unclear. MSCs have recently been discovered to secrete anti-inflammatory cytokines and growth factors. We studied the paracrine effects of MSCs on OA cartilage and synovial explants in vitro. DESIGN: MSC-conditioned medium was prepared by stimulating primary human MSCs with tumour necrosis factor alpha (TNFα) and (50ng/ml each). Human synovium and cartilage explants were cultured in MSC-conditioned medium or in control medium, containing the same amount of added TNFα and IFNγ but not incubated with MSCs. Explants were analyzed for gene expression and the production of nitric oxide (NO). The presence of the inhibitor of nuclear factor kappa B alpha (IκBa) was assessed by Western blot analysis. RESULTS: Synovial explants exposed to MSC-conditioned medium showed decreased gene expression of interleukin-1 beta (IL-1ß), matrix metalloproteinase (MMP)1 and MMP13, while suppressor of cytokine signaling (SOCS)1 was upregulated. In cartilage, expression of IL-1 receptor antagonist (IL-1RA) was upregulated, whereas a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)5 and collagen type II alpha 1 (COL2A1) were downregulated. MSC-conditioned medium reduced NO production in cartilage explants and the presence of IκBa was increased in synoviocytes and chondrocytes treated with MSC-conditioned medium. CONCLUSIONS: In an inflammatory environment, MSCs secrete factors which cause multiple anti-inflammatory effects and influence matrix turnover in synovium and cartilage explants. Thereby, the presented data encourage further study of MSCs as a treatment for joint diseases.

Ferumoxides-protamine sulfate is more effective than ferucarbotran for cell labeling: implications for clinically applicable cell tracking using MRI.

The use of superparamagnetic iron oxide (SPIO) for labeling cells holds great promise for clinically applicable cell tracking using magnetic resonance imaging. For clinical application, an effectively and specifically labeled cell preparation is highly desired (i.e. a large amount of intracellular iron and a negligible amount of extracellular iron). In this study we performed a direct comparison of two SPIO labeling strategies that have both been reported as efficient and clinically translatable approaches. These approaches are cell labeling using ferumoxides-protamine complexes or ferucarabotran particles. Cell labeling was performed on primary human bone marrow stromal cells (hBMSCs) and chondrocytes. For both cell types ferumoxides-protamine resulted in a higher percentage of labeled cells, a higher total iron load, a larger amount of intracellular iron and a lower amount of extracellular iron aggregates, compared with ferucarbotran. Consequently, hBMSC and chondrocyte labeling with ferumoxides-protamine is more effective and results in more specific cell labeling than ferucarbotran.

Growth factor expression in cartilage wound healing: temporal and spatial immunolocalization in a rabbit auricular cartilage wound model.

OBJECTIVE: The ability of cartilage to regenerate following injury is limited, potentially leading to osteoarthritis. Integrative cartilage repair, necessary for durable restoration of cartilage lesions, can be regarded as a wound healing process. Little is known about the effects of growth factors regulating acute cartilage wound healing in vivo. In this study the temporal expression patterns of growth factors and proteoglycan content in cartilage wound edges in vivo were studied. DESIGN: Cartilage wounds were created in rabbit ear cartilage using a 6 mm biopsy punch. Specimens were subsequently harvested 1, 3, 7, 14 and 28 days after surgery. Paraffin sections were thionin stained to visualize proteoglycan loss and replacement. Immunohistochemical staining of TGFbeta1, TGFbeta3, IGF-1, IGF-II and FGF-2 was used to define growth factor expression at the cartilage wound sites. RESULTS: Almost no effect of cartilage wounding was observed one day after surgery. A decrease of proteoglycan content, with a maximal loss at day 7, and a subsequent restoration was observed at the wound edges. Growth factor expression increased simultaneously. Maximal immunostaining for IGF1, IGFII, FGF2 and TGF-beta3 was observed at day 7, followed by a gradual decrease. Increased expression of TGFbeta1 lasted from day 3 until day 14. CONCLUSION: We have demonstrated the ability of chondrocytes to increase growth factor expression and to restore the rapid decrease in proteoglycan content in the initial phase following acute wounding. A temporal increase in intracellular growth factor expression suggests an autocrine and/or paracrine metabolic stimulation, which can be regarded a sign of chondrocytes repair capacity.