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.

Evaluating the Clinical Relevance of Routine Sonication for Periprosthetic Hip or Knee Joint Infection Diagnosis.

Periprosthetic joint infection (PJI) is a serious complication after joint arthroplasty. PJI screening and conventional cultures may be inconclusive. Sonication fluid culturing stands out as a valuable adjunct technique for PJI diagnosis. This study aims to determine the clinical relevance of routine sonication for all (a)septic revisions. All patients who underwent (partial) hip or knee revision arthroplasty between 2012 and 2021 were retrospectively reviewed. We formed three groups based on the European Bone and Joint Society PJI criteria: infection confirmed, likely, and unlikely. We analyzed clinical, laboratory, and radiological screening. Sensitivity and specificity were calculated for synovial fluid (preoperative), tissue, and sonication fluid cultures. We determined the clinical relevance of sonication as the percentage of patients for whom sonication confirmed PJI; 429 patients who underwent (partial) revision of hip or knee arthroplasty were included. Sensitivity and specificity were 69% and 99% for synovial fluid cultures, 76% and 92% for tissue cultures, and 80% and 89% for sonication fluid cultures, respectively. Sonication fluid cultures improved tissue culture sensitivity and specificity to 83% and 99%, respectively. In 11% of PJIs, sonication fluid cultures were decisive for diagnosis. This is applicable to acute and chronic infections. Sonication fluid cultures enhanced the sensitivity and specificity of PJI diagnostics. In 11% of PJI cases, causative pathogens were confirmed by sonication fluid culture results. Sonication fluid culture should be performed in all revision arthroplasties.

Femoral Neck Design Does Not Impact Revision Risk After Primary Total Hip Arthroplasty Using a Dual Mobility Cup.

Background: The use of dual mobility (DM) cups has increased quickly. It is hypothesized that femoral neck taper geometry may be involved in the risk of prosthetic impingement and DM cup revision. We aim to (1) explore the reasons for revision of DM cups or head/liners and (2) explore whether certain femoral neck characteristics are associated with a higher risk of revision of DM cups. Methods: Primary total hip arthroplasties with a DM cup registered in the Dutch Arthroplasty Register between 2007 and 2021 were identified (n = 7603). Competing risk survival analyses were performed, with acetabular component and head/liner revision as the primary endpoint. Reasons for revision were categorized in cup-/liner-related revisions (dislocation, liner wear, acetabular loosening). Femoral neck characteristics were studied to assess whether there is an association between femoral neck design and the risk of DM cup/liner revision. Multivariable Cox proportional hazard analyses were performed. Results: The 5- and 10-year crude cumulative incidence of DM cup or head/liner revision for dislocation, wear, and acetabular loosening was 0.5% (CI 0.4-0.8) and 1.9% (CI 1.3-2.8), respectively. After adjusting for confounders, we found no association between the examined femoral neck characteristics (alloy used, neck geometry, CCD angle, and surface roughness) and the risk for revision for dislocation, wear, and acetabular loosening. Conclusions: The risk of DM cup or head/liner revision for dislocation, wear, and acetabular loosening was low. We found no evidence that there is an association between femoral neck design and the risk of cup or head/liner revision.

Adherence to guideline recommendations for Barrett's esophagus (BE) surveillance endoscopies: Effects of dedicated BE endoscopy lists.

Background and study aims For non-dysplastic Barrett's Esophagus (BE) patients, guidelines recommend endoscopic surveillance every 3 to 5 years with four-quadrant random biopsies every 2 cm of BE length. Adherence to these guidelines is low in clinical practice. Pooling BE surveillance endoscopies on dedicated endoscopy lists performed by dedicated endoscopists could possibly enhance guideline adherence, detection of visible lesions, and dysplasia detection rates (DDRs). Patients and methods Data were used from the ACID-study (Netherlands Trial Registry NL8214), a prospective trial of BE surveillance in the Netherlands. BE patients with known or previously treated dysplasia were excluded. Guideline adherence, detection of visible lesions, and DDRs were compared for patients on dedicated and general endoscopy lists. Results A total of 1,244 patients were included, 318 on dedicated lists and 926 on general lists. Endoscopies on dedicated lists showed significantly higher adherence to the random biopsy protocol (85% vs. 66%, P <0.01) and recommended surveillance intervals (60% vs. 47%, P <0.01) compared to general lists. Detection of visible lesions (8.8% vs. 8.1%, P =0.79) and DDRs were not significantly different (6.9% and 6.6%, P =0.94). None (0.0%) of the patients scheduled on dedicated lists and 10 (1.1%) on general lists were diagnosed with esophageal adenocarcinoma ( P =0.07). In multivariable analysis, dedicated lists were significantly associated with biopsy protocol adherence and adherence to surveillance interval recommendations with odds ratios of 4.45 (95% confidence interval [CI] 2.07-9.57) and 1.64 (95% CI 1.03-2.61), respectively. Conclusions Dedicated endoscopy lists are associated with better adherence to the random biopsy protocol and surveillance interval recommendations.

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.

Long-term oncological outcomes of endoscopic full-thickness resection after previous incomplete resection of low-risk T1 CRC (LOCAL-study): study protocol of a national prospective cohort study.

BACKGROUND: T1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly lower morbidity, mortality and costs compared to radical surgery. An important prerequisite for endoscopic resection as definite treatment is the histological confirmation of tumour-free resection margins. Incomplete resection with involved (R1) or indeterminate (Rx) margins is considered a strong risk factor for residual disease and local recurrence. Therefore, international guidelines recommend additional surgery in case of R1/Rx resection, even in absence of high-risk factors for LNM. Endoscopic full-thickness resection (eFTR) is a relatively new technique that allows transmural resection of colorectal lesions. Local scar excision after prior R1/Rx resection of low-risk T1 CRC could offer an attractive minimal invasive strategy to achieve confirmation about radicality of the previous resection or a second attempt for radical resection of residual luminal cancer. However, oncologic safety has not been established and long-term data are lacking. Besides, surveillance varies widely and requires standardization. METHODS/DESIGN: In this nationwide, multicenter, prospective cohort study we aim to assess feasibility and oncological safety of completion eFTR following incomplete resection of low-risk T1 CRC. The primary endpoint is to assess the 2 and 5 year luminal local tumor recurrence rate. Secondary study endpoints are to assess feasibility, percentage of curative eFTR-resections, presence of scar tissue and/or complete scar excision at histopathology, safety of eFTR compared to surgery, 2 and 5 year nodal and/or distant tumor recurrence rate and 5-year disease-specific and overall-survival rate. DISCUSSION: Since the implementation of CRC screening programs, the diagnostic rate of T1 CRC is steadily increasing. A significant proportion is not recognized as cancer before endoscopic resection and is therefore resected through conventional techniques primarily reserved for benign polyps. As such, precise histological assessment is often hampered due to cauterization and fragmentation and frequently leads to treatment dilemmas. This first prospective trial will potentially demonstrate the effectiveness and oncological safety of completion eFTR for patients who have undergone a previous incomplete T1 CRC resection. Hereby, substantial surgical overtreatment may be avoided, leading to treatment optimization and organ preservation. Trial registration Nederlands Trial Register, NL 7879, 16 July 2019 ( https://trialregister.nl/trial/7879 ).

Accelerated menopausal changes as human disease model 'FOCUM' for the development of osteoarthritis and other degenerative disorders: protocol for a prospective cohort study.

INTRODUCTION: The incidence of degenerative disorders, including osteoarthritis (OA), increases rapidly in women after menopause. However, the influence of the menopause is still insufficiently investigated due to the slowness of menopausal transition. In this study, a novel human model is used in which it is expected that menopausal-related changes will occur faster. This is the Females discontinuing Oral Contraceptives Use at Menopausal age model. The ultimate aim is to link these changes to OA and other degenerative disorders, including cardiovascular diseases, diabetes, osteoporosis and tendinopathies. METHODS AND ANALYSIS: This is a pilot observational prospective cohort study with 2 years of follow-up. Fifty women aged 50-60 who use oral contraceptive (OC) and have the intention to stop are included. Measurements are performed once before stopping OC, and four times thereafter at 6 weeks, 6 months, 1 year and 2 years. At every time point, a questionnaire is filled in and a sample of blood is drawn. At the first and final time points, a physical examination, hand radiographs and a MRI scan of one knee are performed. The primary OA outcome is progression of the MRI Osteoarthritis Knee Score. Secondary OA outcomes are the development of clinical knee and hand OA, development of knee OA according to the MRI definition, and progression of radiographic features for hand OA. Principal component analysis will be used to assess which changes occur after stopping OC. Univariate and multivariate generalised estimating equation models will be used to test for associations between these components and OA. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee of the Erasmus MC University Medical Center Rotterdam (MEC-2019-0592). All participants must give informed consent before data collection. Results will be disseminated in national and international journals. TRIAL REGISTRATION NUMBER: NL70796.078.19.

Quantification of vancomycin and clindamycin in human plasma and synovial fluid applying ultra-performance liquid chromatography tandem mass spectrometry.

Periprosthetic joint infection is a challenging infection involving the joint prosthesis and adjacent tissue, such as synovial fluid, synovial tissue, and bone tissue. The current treatment consists of multiple surgical revisions and long-term antibiotic therapy. Treatment failure can cause poor functional outcome and reduced quality of life. Further research on the extent of antibiotic penetration into the infected tissues is of great importance. Our work aimed to develop and validate a novel ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of the commonly administered antibiotics vancomycin and clindamycin in plasma and synovial fluid. An extraction procedure consisting of zinc sulfate precipitation and dilution with eluent was used for both analytes. Chromatographic separation was performed on a Waters Acquity UPLC HSS T3 C18 column (1.8 µm, 2.1 × 100 mm), and quantification was carried out by a Waters Xevo TQ-S micro mass spectrometer. Stable isotope-labeled vancomycin-d10 served as internal standard. The method validation was performed based on the guidelines of the EMA and FDA. The calibration curves were linear over the range of 0.5-50 mg/L, with a coefficient of determination above 0.990. The validation results for precision and accuracy, specificity, matrix effects and stability were all within the acceptance range. An accurate and rapid method for the simultaneous quantification of vancomycin and clindamycin in human plasma and synovial fluid on the UPLC-MS/MS was developed, optimized and validated. The analysis has a run time of 5.2 min and 50 µL sample volume is needed. This developed method was successfully applied in eight patients with PJI and is suitable to determine the exposure of antibiotics in plasma and synovial fluid in patients during current PK/PD studies.

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).

Higher risk of knee arthroplasty during ten-year follow-up if baseline radiographic osteoarthritis involves the patellofemoral joint: a CHECK Cohort Study.

BACKGROUND: Patellofemoral OA is a strong risk factor for progression to generalized whole knee OA, but it is unknown whether involvement of the patellofemoral joint in early radiographic OA (ROA) is associated with risk of undergoing future knee arthroplasty. This is clinically relevant because patellofemoral OA likely requires a different treatment approach than tibiofemoral OA, and identifying prognostic factors for future arthroplasty might assist clinicians with prioritizing and guiding early interventions that could improve long-term outcomes. Therefore, we evaluated association of baseline patellofemoral or tibiofemoral ROA with undergoing knee arthroplasty over 10 years. METHODS: Using the multicenter Cohort Hip and Cohort Knee (CHECK) study, we acquired three views of radiographs in both knees of individuals aged 45-65 years with complaints of knee symptoms in at least one knee. From baseline radiographs, we categorized each knee as having one of four patterns of ROA: no ROA, isolated patellofemoral ROA, isolated tibiofemoral ROA, or combined ROA. We evaluated the 10-year relative hazard for undergoing going arthroplasty, based on baseline ROA pattern, using Cox proportional hazard models, adjusting for age, sex body mass index, and pain severity. RESULT: Our sample (n = 842) included 671 (80%) women and had mean (SD) age 56 (5) years, and BMI 26.3 (4.0) kg/m2. Arthroplasties were undertaken in 44/1678 knees. In comparison to having no ROA at baseline, adjusted hazard ratios (aHR) for arthroplasty were highest for combined ROA (aHR 14.2 [95% CI 5.8, 34.6]) and isolated patellofemoral ROA (aHR 12.7 [5.6, 29.0]). Isolated tibiofemoral ROA was not significantly associated with arthroplasty (aHR 2.9 [0.6, 13.6]). CONCLUSIONS: In a sample of middle-aged individuals with complaints in one or both knees, the 10-year relative hazard for undergoing arthroplasty, compared to no ROA, was increased when OA involved the patellofemoral joint, regardless of whether it was isolated to the patellofemoral joint or occurred in combination with tibiofemoral OA. Further research is needed to confirm this association and to clarify the causal mechanism of this relationship. However, our results provide preliminary evidence that identifying patellofemoral ROA may be a clinically useful prognostic indicator in early knee OA.

Effect of Intramuscular vs Intra-articular Glucocorticoid Injection on Pain Among Adults With Knee Osteoarthritis: The KIS Randomized Clinical Trial.

Importance: Intra-articular (IA) glucocorticoid injection is widely used in patients with knee osteoarthritis (OA), but the safety of this technique is in question among physicians. Intramuscular (IM) glucocorticoid injection could be an alternative approach. Objective: To investigate whether an IM glucocorticoid injection is noninferior to an IA glucocorticoid injection in reducing knee pain for patients with knee OA in primary care. Design, Setting, and Participants: The KIS trial, a multicenter, open-label, randomized clinical noninferiority trial including patients with symptomatic knee OA, was conducted in 80 primary care general practices in the southwest of the Netherlands. The study was conducted from March 1, 2018, to July 28, 2020. Interventions: Patients were randomly allocated to receive an injection of triamcinolone acetonide, 40 mg, either IM in the ipsilateral ventrogluteal region or IA in the knee joint. All patients were followed up for 24 weeks. Main Outcomes and Measures: The pain score at 4 weeks measured with Knee Injury and Osteoarthritis Outcome Score (range, 0-100; 0 indicates extreme pain), with a noninferiority margin of -7 (IM minus IA). A per-protocol analysis was prespecified as the primary analysis. Results: A total of 145 patients (94 women [65%]; mean [SD] age, 67 [10] years) were included; of these, 138 patients (IM, 72; IA, 66) were included in the per-protocol analysis. Clinically relevant improvements in knee pain were reached up to 12 weeks after the injection in both groups. At 4 weeks, the estimated mean difference in the Knee Injury and Osteoarthritis Outcome Score between the 2 groups was -3.4 (95% CI, -10.1 to 3.3). Noninferiority could not be declared because the lower limit exceeded the noninferiority margin. Intramuscular injection was noninferior to IA injection at 8 (mean difference, 0.7; 95% CI, -6.5 to 7.8) and 24 (mean difference, 1.6; 95% CI, -5.7 to 9.0) weeks. No significant difference was found among all the secondary outcomes. These results were similar for the sensitivity analysis in an intention-to-treat population. The most frequently reported adverse events were hot flush (IM, 7 [10%] vs IA, 14 [21%]) and headache (IM, 10 [14%] vs IA, 12 [18%]), and all events were classified as nonserious. Conclusions and Relevance: Based on the findings of this trial, among patients with knee OA in primary care, IM glucocorticoid injection could present an inferior effect in reducing pain at 4 weeks compared with IA injection. Noninferiority of an IM injection was observed at 8 and 24 weeks after injection. This trial provides data for shared decision-making, taking into account the advantages and disadvantages of both types of injections. Trial Registration: Dutch Trial Registry: NTR6968.

Genicular artery embolization as a novel treatment for mild to moderate knee osteoarthritis: protocol design of a randomized sham-controlled clinical trial.

INTRODUCTION: Knee osteoarthritis is a common disease with pain as the most prevalent symptom. Previous cohort studies have shown genicular artery embolization to reduce pain symptoms in patients with mild to moderate knee osteoarthritis. Patients resistant to conservative therapy but not eligible yet for surgical treatment due to young age or comorbidities may profit from an effective and sustained pain reduction treatment. This study is a randomized sham-controlled trial to evaluate the efficacy of genicular artery embolization in patients with knee osteoarthritis. METHODS AND ANALYSIS: Fifty-eight patients with mild-to-moderate knee osteoarthritis will be recruited and randomly allocated to the treatment or control group in a 1:1 ratio. Participants in the treatment group will undergo genicular artery embolization. Patients in the control group will undergo sham treatment. Outcome measurements will be assessed at baseline and after 1, 4, 8, and 12 months with questionnaires, pressure pain threshold testing, and MR imaging. The MR imaging protocol is designed to (semi)quantitatively assess osteoarthritis in the knee joint. The primary outcome is the change from baseline of the Knee injury and Osteoarthritis Outcome Score (KOOS) pain subscale after 4 months. Secondary outcomes include change in osteoarthritis-related questionnaires, pressure pain threshold, and OA-related MRI features, particularly synovitis and bone marrow lesions. ETHICS AND DISSEMINATION: This trial will determine the efficacy of genicular artery embolization compared to a sham treatment. This is of importance to assess before proceeding to larger-scale efficiency studies and, ultimately, implementing this treatment into day to day clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT03884049. Registered on 21 March 2019.

Timing of debridement, antibiotics, and implant retention (DAIR) for early post-surgical hip and knee prosthetic joint infection (PJI) does not affect 1-year re-revision rates: data from the Dutch Arthroplasty Register.

Debridement, antibiotics, and implant retention (DAIR) is a procedure to treat a periprosthetic joint infection (PJI) after total hip arthroplasty (THA) or total knee arthroplasty (TKA). The timing between the primary procedure and the DAIR is likely a determinant for its successful outcome. However, the optimal timing of a DAIR and the chance of success still remain unclear. We aimed to assess the risk of re-revision within 1 year after a DAIR procedure and to evaluate the timing of the DAIR in primary THA and TKA. We used data from the Dutch Arthroplasty Register (LROI) and selected all primary THA and TKA in the period 2007-2016 which underwent a DAIR within 12 weeks after primary procedure. A DAIR was defined as a revision for infection in which only modular parts were exchanged. A DAIR was defined as successful if not followed by a re-revision within 1 year after DAIR; 207 DAIRs were performed < 4  weeks after THA, of which 16 (8 %) received a complete revision within 1 year. DAIR procedures performed between 4 and 12 weeks ( n = 98 ) had a failure rate of 9 % ( n = 9 ). After TKA 126 DAIRs were performed in less than 4  weeks, of which 11 (9 %) received a complete revision within 1 year; 83 DAIRs were performed between 4 and 12 weeks, of which 14 (17 %) were revised. There was no significant difference in 1-year re-revision rate after a DAIR procedure by timing of the DAIR procedure for total hip and knee arthroplasty based on Dutch registry data.

Facial subcutaneous emphysema due to rectum injury after pelvic fracture.

A 35-year old dockworker sustained a pelvic injury when he was caught by a large loading clamshell grab. Primary survey revealed an open book pelvic fracture with soft tissue defects of the left thigh and groin. CT scanning of the thorax and abdomen did not reveal significant additional injuries. Partly due to patient's haemodynamical instability, osteosynthesis of the pelvic fracture was performed immediately after resuscitation, whereby the severely contaminated wound of the thigh was debrided and irrigated. The following days, progressive facial subcutaneous emphysema developed, but patient remained clinically stable. Several specialists were consulted, but did not find a cause. At day 7, a second surgery was planned to treat a pelvic surgical wound infection. Unexpectedly, we found faecal contamination in the pelvic surgical wound. The consulted gastro/intestinal-surgeon performed a laparoscopic colostomy for a rectal laceration. Awareness for bowel injuries with open pelvic fracture should be high, also when subcutaneous emphysema is found remotely.

The multiple myeloma microenvironment is defined by an inflammatory stromal cell landscape.

Progression and persistence of malignancies are influenced by the local tumor microenvironment, and future eradication of currently incurable tumors will, in part, hinge on our understanding of malignant cell biology in the context of their nourishing surroundings. Here, we generated paired single-cell transcriptomic datasets of tumor cells and the bone marrow immune and stromal microenvironment in multiple myeloma. These analyses identified myeloma-specific inflammatory mesenchymal stromal cells, which spatially colocalized with tumor cells and immune cells and transcribed genes involved in tumor survival and immune modulation. Inflammatory stromal cell signatures were driven by stimulation with proinflammatory cytokines, and analyses of immune cell subsets suggested interferon-responsive effector T cell and CD8+ stem cell memory T cell populations as potential sources of stromal cell-activating cytokines. Tracking stromal inflammation in individuals over time revealed that successful antitumor induction therapy is unable to revert bone marrow inflammation, predicting a role for mesenchymal stromal cells in disease persistence.

Quantification of beta-lactam antibiotics cefuroxime and flucloxacillin in human synovial fluid, using ultra-performance convergence chromatography-tandem mass spectrometry.

Total hip- and knee arthroplasty generally result in successful outcomes. A small percentage of patients however suffer from periprosthetic joint infections (PJI) postoperatively, often with severe consequences. The standard treatment of chronic PJIs consists of a staged arthroplasty exchange during which antibiotic therapy plays a crucial role. For successful antibiotic treatment, adequate concentrations at the infection site are a prerequisite. Regarding the treatment of PJIs, knowledge is lacking with respect to the relationship between administered dosages and plasma- and infection site concentrations of the antibiotics. To gain insight into the antibiotic exposure at the infection site, validated analytical methods for analysis of the antibiotics in matrices at the site of the PJI are essential. We describe a validated ultra-performance convergence chromatography-tandem mass spectrometry (UPC2-MS/MS) method for quantification of the beta-lactam antibiotics cefuroxime and flucloxacillin in synovial fluid. This method was successfully validated for antibiotic quantification in synovial fluids according to the EMA guidelines and consists of a simple sample preparation. For both antibiotics, the accuracy and precision were within requirements (RSD < 15%). In addition, matrix effects and recovery were within the range of 80-120%. Carry over was less than 20% and stability in -80 °C was at least 2 months for standards and quality controls. The limits of quantification were adequate (1-100 mg/L) to cover potential cefuroxime and flucloxacillin concentrations in synovial fluid as described in literature (r > 0.995). The method has a run time of 4.5 min and 50 µL synovial fluid is needed and the validated method will be applied during a PK/PD study to determine the exposure of the study antibiotics in synovial fluid at the site of PJIs.

MSC encapsulation in alginate microcapsules prolongs survival after intra-articular injection, a longitudinal in vivo cell and bead integrity tracking study.

Mesenchymal stem cells (MSC) are promising candidates for use as a biological therapeutic. Since locally injected MSC disappear within a few weeks, we hypothesize that efficacy of MSC can be enhanced by prolonging their presence. Previously, encapsulation in alginate was suggested as a suitable approach for this purpose. We found no differences between the two alginate types, alginate high in mannuronic acid (High M) and alginate high in guluronic acid (High G), regarding MSC viability, MSC immunomodulatory capability, or retention of capsule integrity after subcutaneous implantation in immune competent rats. High G proved to be more suitable for production of injectable beads. Firefly luciferase-expressing rat MSC were used to track MSC viability. Encapsulation in high G alginate prolonged the presence of metabolically active allogenic MSC in immune competent rats with monoiodoacetate-induced osteoarthritis for at least 8 weeks. Encapsulation of human MSC for local treatment by intra-articular injection did not significantly influence the effect on pain, synovial inflammation, or cartilage damage in this disease model. MSC encapsulation in alginate allows for an injectable approach which prolongs the presence of viable cells subcutaneously or in an osteoarthritic joint. Further fine tuning of alginate formulation and effective dosage for might be required in order to improve therapeutic efficacy depending on the target disease. Graphical Abstract.

Self-Assessment of Competence and Referral Behavior for Musculoskeletal Injections among Dutch General Practitioners.

General practitioners (GPs) are qualified and trained to administer therapeutic musculoskeletal injections when indicated. However, it is unknown to what extend Dutch GPs feel competent to administer these injections in clinical practice. Reluctance among GPs to inject might lead to unnecessary and costly referral to secondary care. An online and offline questionnaire was spread among Dutch GPs, querying demographics, GPs' self-assessment of injection competence, the number of administered/referred injections and management strategy for musculoskeletal injections. A total of 355 GPs responded. In total, 81% of the GPs considered themselves competent in administering musculoskeletal injections. Self-assessed incompetent GPs performed less injections the last month than self-assessed competent GPs (1.2 ± 1.4 vs 4.8 ± 4.6 injections, P < 0.001). Additionally, they referred four times more often to a colleague GP (0.4 ± 1.0 vs 0.1 ± 0.6 injections per month, P < 0.001) and twice as often to secondary care (1.0 ± 1.3 vs 0.5 ± 0.9 injections per month, P = 0.001). Self-assessed incompetence was associated with female sex (OR [95% CI] = 4.94 [2.39, 10.21]) and part-time work (OR [95% CI] = 2.58 [1.43, 4.66]). The most frequently addressed barriers were a lack of confidence in injection skills, lack of practical training, and uncertainty about the effectiveness and diagnosis of musculoskeletal injections. Although most GPs considered themselves competent to administer musculoskeletal injections, the referral rate to secondary care for several injections was strikingly high. To decrease secondary care referrals, addressing some of the most frequently indicated barriers is highly recommended.

Effectiveness of intramuscular gluteal glucocorticoid injection versus intra-articular glucocorticoid injection in knee osteoarthritis: design of a multicenter randomized, 24 weeks comparative parallel-group trial.

BACKGROUND: The knee is symptomatically the most frequent affected joint in osteoarthritis and, in the Netherlands and other Western countries, is mainly managed by general practitioners (GPs). An intra-articular glucocorticoid injection is recommended in (inter) national guidelines for patients with knee osteoarthritis as an option for a flare of knee pain and/or for those who are not responding well to pain medication. An innovative approach that could replace the intra-articular injection is an intramuscular gluteal glucocorticoid injection. An intramuscular injection is easier to perform than an intra-articular injection with lesser risk of severe local adverse reactions. We hypothesize that intramuscular gluteal glucocorticoid injection is non-inferior in reducing knee pain compared to intra-articular glucocorticoid injection, with potentially a longer lasting effect than intra-articular injection. METHODS/DESIGN: The study will be a pragmatic randomized controlled non-inferiority trial with two parallel groups. A total of 140 patients aged 45 years and older with knee osteoarthritis who contacted their general practitioner and have persistent knee pain (score ≥ 3 on 0-10 numerical rating scale; 0 = no knee pain) will be included. Patients will be randomly allocated (1:1) to an injection of 40 mg triamcinolone acetonide intra-articular in the knee joint or intramuscular in the ipsilateral ventrogluteal area. The effect of treatment will be evaluated by questionnaires at 2, 4, 8, 12, and 24 weeks after injection. The primary outcome is patients' reported severity of knee pain measured with the pain subscale of the Knee injury and Osteoarthritis Outcome Score 4 weeks after injection. Statistical analysis will be based on both the per-protocol and the intention-to-treat principle. DISCUSSION: This study will evaluate non-inferiority of intramuscular glucocorticoid injection compared to intra-articular glucocorticoid injection for knee osteoarthritis symptoms. TRIAL REGISTRATION: This trial is registered in the Dutch Trial Registry (number NTR6968) at 2018-01-22 (https://www.trialregister.nl/trial/6784). Issue date: 1 October 2019. TRIAL SPONSOR: Erasmus MC University Medical Center Rotterdam. PO-box 2040. 3000 CA Rotterdam. The Netherlands.

Preoperative embolization in surgical treatment of long bone metastasis: a systematic literature review.

Surgery of long bone metastases is associated with a significant risk of perioperative blood loss, which may necessitate blood transfusion.Successful embolization (> 70% obliteration of vascularity) can be achieved in 36-75% of cases.The reported rate of embolization-related complications is 0-9%.Three out of six level III evidence studies showed a reduction in perioperative blood loss and/or blood transfusion requirement after preoperative embolization of renal cell carcinoma metastasis in long bones; three out of six studies did not.One level III evidence study did not show a reduction in perioperative blood loss and/or transfusion requirement after preoperative embolization of hepatocellular carcinoma metastases in long bones.There were no studies found that support preoperative embolization of thyroid metastases or other frequent long bone metastases (e.g. mamma carcinoma, lung carcinoma, or prostate carcinoma).The clinical level of evidence of the studies found is low and randomized studies taking into account primary tumour, location of metastases and type of surgery are therefore desired. Cite this article: EFORT Open Rev 2020;5:17-25. DOI: 10.1302/2058-5241.5.190013.