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Agroforestry (AF) is considered to be a sustainable land use practice as it combines agricultural production with multiple beneficial effects such as carbon sequestration, enhanced nutrient cycling and increased biodiversity. Quantification of these beneficial effects in temperate arable fields is still limited, however, and most studies focus on one sole parameter (i.e., impact on crop productivity, soil quality, biodiversity, etc.). Combined effects are only rarely considered, resulting in a lack of integrated quantification. Here we assess the effect of rows of walnut trees (Juglans regia L.) on soil organic carbon (SOC), soil nutrient status, the presence of potentially beneficial ground-dwelling arthropods and on the yield and quality of neighboring arable crops. Significantly higher SOC and soil nutrient concentrations were found near the trees, which is assumed to be primarily a result of tree leaf litter input. Abundance of macro-detritivorous arthropods was increased in and near the tree rows, whereas only limited effects of tree presence were found on the presence of the predatory arthropod taxa under study. The yield of all crops under study was reduced as a result of tree presence, with the strongest reductions observed for grain maize and sugar beet near the trees (<10 m). In addition, alteration of crop quality was observed near tree rows with decreased dry matter concentration of grain samples and increased crude protein concentration of winter cereals.

Identify gene expression profiles associated with OA processes in articular cartilage and determine pathways changing during the disease process. Genome wide gene expression was determined in paired samples of OA affected and preserved cartilage of the same joint using microarray analysis for 33 patients of the RAAK study. Results were replicated in independent samples by RT-qPCR and immunohistochemistry. Profiles were analyzed with the online analysis tools DAVID and STRING to identify enrichment for specific pathways and protein-protein interactions. Among the 1717 genes that were significantly differently expressed between OA affected and preserved cartilage we found significant enrichment for genes involved in skeletal development (e.g. TNFRSF11B and FRZB). Also several inflammatory genes such as CD55, PTGES and TNFAIP6, previously identified in within-joint analyses as well as in analyses comparing preserved cartilage from OA affected joints versus healthy cartilage were among the top genes. Of note was the high up-regulation of NGF in OA cartilage. RT-qPCR confirmed differential expression for 18 out of 19 genes with expression changes of 2-fold or higher, and immunohistochemistry of selected genes showed a concordant change in protein expression. Most of these changes associated with OA severity (Mankin score) but were independent of joint-site or sex. We provide further insights into the ongoing OA pathophysiological processes in cartilage, in particular into differences in macroscopically intact cartilage compared to OA affected cartilage, which seem relatively consistent and independent of sex or joint. We advocate that development of treatment could benefit by focusing on these similarities in gene expression changes and/or pathways.

IntroductionPatients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA) are considered to have a symptomatic venous thromboembolism (VTE) risk of 1.0%–1.5% despite thromboprophylaxis. Fast-track treatment protocols have substantially lowered the VTE risk in most patients. Hence, the majority of patients may be unnecessarily exposed to the burden and risk of thromboprophylaxis. On the contrary, there are still patients with a high VTE risk who develop VTE despite thromboprophylaxis. Thus, tailored thromboprophylaxis treatment may potentially reduce both VTE and bleeding risk.Methods and analysisThe DISTINCT (inDividual, targeted thrombosIS prophylaxis versus the standard ‘one-size-fits-all’ approach in patients undergoing Total hIp or total kNee replaCemenT) trial is a national, multicentre, randomised, multiarm, open-label trial. The main objective is to study whether tailored thromboprophylaxis reduces the occurrence of symptomatic VTE (primary outcome) and major bleeding (primary safety outcome) within 90 days after THA/TKA in comparison with standard thromboprophylaxis. Patients with a low, intermediate or high predicted VTE risk (based on the Thrombosis Risk Prediction following total hip and knee arthroplasty score (TRiP(plasty) score)) will be included in the DISTINCT-1, DISTINCT-2 or DISTINCT-3 studies, respectively. In the DISTINCT-1 trial, 3478 patients will be randomly allocated to receive either in-hospital thromboprophylaxis or standard prophylaxis. In the DISTINCT-2 cohort study, 2500 patients will receive standard prophylaxis. In the DISTINCT-3 trial, 4100 patients will be randomly allocated to receive either 6 weeks of high-dose thromboprophylaxis or standard prophylaxis. Standard prophylaxis consists of a low dose of any approved thromboprophylactic agent for 4 weeks. We hypothesise that (1) the efficacy of in-hospital only thromboprophylaxis is non-inferior in preventing VTE and equally safe compared with standard prophylaxis in patients with a low VTE risk (DISTINCT-1) and (2) prolonged high-dose thromboprophylaxis is superior in preventing VTE as compared with standard prophylaxis in patients with a high VTE risk (DISTINCT-3). Patients with intermediate VTE risk will be observed to evaluate VTE and bleeding rates (DISTINCT-2).Ethics and disseminationThe protocol has been approved by the Medical Research Ethics Committee Leiden-Den Haag-Delft, EU-trial-number 2023-510186-98. Study results will be disseminated through peer-reviewed journals and during international conferences.Trial registration numberNCT06581965.

ObjectiveTo assess the effectiveness of a prospective multifaceted quality improvement intervention on patient outcomes after total hip and knee arthroplasty (THA and TKA).DesignCluster randomised controlled trial nested in a national registry. From 1 January 2018 to 31 May 2020 routinely submitted registry data on revision and patient characteristics were used, supplemented with hospital data on readmission, complications and length of stay (LOS) for all patients.Setting20 orthopaedic departments across hospitals performing THA and TKA in The Netherlands.Participants32 923 patients underwent THA and TKA, in 10 intervention and 10 control hospitals (usual care).InterventionThe intervention period lasted 8 months and consisted of the following components: (1) monthly updated feedback on 1-year revision, 30-day readmission, 30-day complications, long (upper quartile) LOS and these four indicators combined in a composite outcome; (2) interactive education; (3) an action toolbox including evidence-based quality improvement initiatives (QIIs) to facilitate improvement of above indicators; and (4) bimonthly surveys to report on QII undertaken.Main outcome measuresThe primary outcome was textbook outcome (TO), an all-or-none composite representing the best outcome on all performance indicators (ie, the absence of revision, readmissions, complications and long LOS). The individual indicators were analysed as secondary outcomes. Changes in outcomes from pre-intervention to intervention period were compared between intervention versus control hospitals, adjusted for case-mix and clustering of patients within hospitals using random effect binary logistic regression models. The same analyses were conducted for intervention hospitals that did and did not introduce QII.Results16,314 patients were analysed in intervention hospitals (12,475 before and 3,839 during intervention) versus 16,609 in control hospitals (12,853 versus 3,756). After the intervention period, the absolute probability to achieve TO increased by 4.32% (95% confidence interval (CI) 4.30-4.34) more in intervention than control hospitals, corresponding to 21.6 (95%CI 21.5-21.8), i.e., 22 patients treated in intervention hospitals to achieve one additional patient with TO. Intervention hospitals had a larger increase in patients achieving TO (ratio of adjusted odds ratios 1.24, 95%CI 1.05-1.48) than control hospitals, a larger reduction in patients with long LOS (0.74, 95%CI 0.61-0.90) but also a larger increase in patients with reported 30-day complications (1.34, 95%CI 1.00-1.78). Intervention hospitals that introduced QII increased more in TO (1.32, 95%CI 1.10-1.57) than control hospitals, with no effect shown for hospitals not introducing QII (0.93, 95%CI 0.67-1.30).ConclusionThe multifaceted QI intervention including monthly feedback, education, and a toolbox to facilitate QII effectively improved patients achieving TO. The effect size was associated with the introduction of (evidence-based) QII, considered as the causal link to achieve better patient outcomes.Trial registration number NCT04055103.

Objectives Obesity is a risk factor for the development of osteoarthritis (OA) in hands and knees. Adipose tissue can secrete different adipokines with powerful immunomodulatory effects. The infrapatellar fat pad (IFP) is an intra-articular organ in the vicinity of the synovium and cartilage. It is hypothesised that IFP-derived soluble factors could contribute to pathological processes in the knee joint. A study was therefore undertaken to compare the release of inflammatory mediators in the IFP and subcutaneous adipose tissue (ScAT) and to characterise the adipocytes and immune cell infiltrate in these tissues. Methods Paired IFP and ScAT samples were obtained from 27 patients with primary OA. The stromal vascular cell fraction (SVF) was isolated and characterised by fluorescence activated cell sorting. Cytokine and adipokine release in fat- and adipocyte-conditioned media was measured by luminex. Results IFP secreted higher levels of inflammatory mediators such as interleukin 6 (IL-6), adipsin, adiponectin and visfatin than ScAT. This could be due to differences in the phenotype of adipocytes and/or in the composition and phenotype of the SVF cells. IFP adipocyte-conditioned media showed a trend towards more IL-6 and adipsin than ScAT. Moreover, the SVF fraction of IFP contained more cells/g tissue, a lower percentage of T cells and a higher percentage of mast cells than ScAT. In addition, T cells had a predominantly pro-inflammatory phenotype while macrophages had a mixed pro- and anti-inflammatory phenotype in the IFP. Conclusion There are profound differences in secreted inflammatory factors and immune cell composition between the IFP and ScAT. These data indicate that IFP-derived soluble mediators could contribute to pathophysiological processes in the OA knee joint.

Background Obesity is associated with the development and progression of osteoarthritis (OA). Although the infrapatellar fat pad (IFP) could be involved in this association, due to its intracapsular localization in the knee joint, there is currently little known about the effect of obesity on the IFP. Therefore, we investigated cellular and molecular body mass index (BMI)-related features in the IFP of OA patients. Methods Patients with knee OA (N = 155, 68% women, mean age 65 years, mean (SD) BMI 29.9 kg/m2 (5.7)) were recruited: IFP volume was determined by magnetic resonance imaging in 79 patients with knee OA, while IFPs and subcutaneous adipose tissue (SCAT) were obtained from 106 patients undergoing arthroplasty. Crown-like structures (CLS) were determined using immunohistochemical analysis. Adipocyte size was determined by light microscopy and histological analysis. Stromal vascular fraction (SVF) cells were characterized by flow cytometry. Results IFP volume (mean (SD) 23.6 (5.4) mm 3 ) was associated with height, but not with BMI or other obesity-related features. Likewise, volume and size of IFP adipocytes (mean 271 pl, mean 1933 μm) was not correlated with BMI. Few CLS were observed in the IFP, with no differences between overweight/obese and lean individuals. Moreover, high BMI was not associated with higher SVF immune cell numbers in the IFP, nor with changes in their phenotype. No BMI-associated molecular differences were observed, besides an increase in TNFα expression with high BMI. Macrophages in the IFP were mostly pro-inflammatory, producing IL-6 and TNFα, but little IL-10. Interestingly, however, CD206 and CD163 were associated with an anti-inflammatory phenotype, were the most abundantly expressed surface markers on macrophages (81% and 41%, respectively) and CD163 + macrophages had a more activated and pro-inflammatory phenotype than their CD163 - counterparts. Conclusions BMI-related features usually observed in SCAT and visceral adipose tissue could not be detected in the IFP of OA patients, a fat depot implicated in OA pathogenesis.

ObjectivesTo investigate how the genetic susceptibility gene DIO2 confers risk to osteoarthritis (OA) onset in humans and to explore whether counteracting the deleterious effect could contribute to novel therapeutic approaches.MethodsEpigenetically regulated expression of DIO2 was explored by assessing methylation of positional CpG-dinucleotides and the respective DIO2 expression in OA-affected and macroscopically preserved articular cartilage from end-stage OA patients. In a human in vitro chondrogenesis model, we measured the effects when thyroid signalling during culturing was either enhanced (excess T3 or lentiviral induced DIO2 overexpression) or decreased (iopanoic acid).ResultsOA-related changes in methylation at a specific CpG dinucleotide upstream of DIO2 caused significant upregulation of its expression (β=4.96; p=0.0016). This effect was enhanced and appeared driven specifically by DIO2 rs225014 risk allele carriers (β=5.58, p=0.0006). During in vitro chondrogenesis, DIO2 overexpression resulted in a significant reduced capacity of chondrocytes to deposit extracellular matrix (ECM) components, concurrent with significant induction of ECM degrading enzymes (ADAMTS5, MMP13) and markers of mineralisation (ALPL, COL1A1). Given their concurrent and significant upregulation of expression, this process is likely mediated via HIF-2α/RUNX2 signalling. In contrast, we showed that inhibiting deiodinases during in vitro chondrogenesis contributed to prolonged cartilage homeostasis as reflected by significant increased deposition of ECM components and attenuated upregulation of matrix degrading enzymes.ConclusionsOur findings show how genetic variation at DIO2 could confer risk to OA and raised the possibility that counteracting thyroid signalling may be a novel therapeutic approach.

Objective Genetic variation at the type II deiodinase (D2) gene (DIO2) was previously identified as osteoarthritis (OA) risk factor. To investigate mechanisms possibly underlying this association, we assessed D2 protein in healthy and OA-affected cartilage and investigated allelic balance of the OA risk polymorphism rs225014 at DIO2 in human OA joints. Methods Immunohistochemical staining of healthy and OA-affected cartilage was performed for D2. We then assessed allelic balance of DIO2 mRNA within OA-affected cartilage both at and away from the lesion, ligaments and subchondral bone. Allelic balance was measured by the amount of alleles ‘C’ and ‘T’ of the intragenic OA risk polymorphism rs225014 in heterozygous carriers. Results A markedly higher amount of D2 positive cells and staining intensity was observed in OA cartilage. A significant, 1.3-fold higher presence was observed for the OA-associated rs225014 ‘C’ allele relative to the ‘T’ allele of DIO2, which was significant in 28 of 31 donors. Conclusion In OA cartilage, D2 protein presence is increased. The allelic imbalance of the DIO2 mRNA transcript, with the OA risk allele ‘C’ of rs225014 more abundant than the wild-type ‘T’ allele in heterozygote carriers provides a possible mechanism by which genetic variation at DIO2 confers OA risk.

Purpose The purpose of this study was to assess in which proportion of patients with degenerative knee disease aged 50+ in whom a knee arthroscopy is performed, no valid surgical indication is reported in medical records, and to explore possible explanatory factors. Methods A retrospective study was conducted using administrative data from January to December 2016 in 13 orthopedic centers in the Netherlands. Medical records were selected from a random sample of 538 patients aged 50+ with degenerative knee disease in whom arthroscopy was performed, and reviewed on reported indications for the performed knee arthroscopy. Valid surgical indications were predefined based on clinical national guidelines and expert opinion (e.g., truly locked knee). A knee arthroscopy without a reported valid indication was considered potentially low value care. Multivariate logistic regression analysis was performed to assess whether age, diagnosis (“Arthrosis” versus “Meniscal lesion”), and type of care trajectory (initial or follow-up) were associated with performing a potentially low value knee arthroscopy. Results Of 26,991 patients with degenerative knee disease, 2556 (9.5%) underwent an arthroscopy in one of the participating orthopedic centers. Of 538 patients in whom an arthroscopy was performed, 65.1% had a valid indication reported in the medical record and 34.9% without a reported valid indication. From the patients without a valid indication, a joint patient–provider decision or patient request was reported as the main reason. Neither age [OR 1.013 (95% CI 0.984–1.043)], diagnosis [OR 0.998 (95% CI 0.886–1.124)] or type of care trajectory [OR 0.989 (95% CI 0.948–1.032)] were significantly associated with performing a potentially low value knee arthroscopy. Conclusions In a random sample of knee arthroscopies performed in 13 orthopedic centers in 2016, 65% had valid indications reported in the medical records but 35% were performed without a reported valid indication and, therefore, potentially low value care. Patient and/or surgeons preference may play a large role in the decision to perform an arthroscopy without a valid indication. Therefore, interventions should be developed to increase adherence to clinical guidelines by surgeons that target invalid indications for a knee arthroscopy to improve care. Level of evidence IV.

Background The aseptic lymphocyte vasculitis-associated lesion (ALVAL) score and the modified Oxford ALVAL score are frequently used scoring methods to evaluate the morphologic features of periprosthetic tissues around metal-on-metal (MoM) hip implants. Except for the initial studies of these two morphology scoring methods, to our knowledge, no other studies have reported on intraclass correlation coefficient (ICC) values for interobserver reliability of these scoring methods. Questions/purposes Are the ALVAL and Oxford ALVAL scores reproducible? Methods The periprosthetic tissue of 37 revisions of 36 patients with failed MoM THAs were independently scored by three experienced pathologists using ALVAL and Oxford ALVAL scoring methods. All patients were included who underwent revision surgery in our hospital until January 2013, with a large-head MoM prosthesis and also met the criteria: blood serum cobalt levels, available MRI scan, and intraarticular cobalt levels. The population included 26 patients with pseudotumors diagnosed by two radiologists using the method described by Matthies et al. The ALVAL describes morphologic features of the synovial lining, tissue organization, and inflammatory cell infiltrate in periprosthetic tissues. The Oxford-ALVAL score uses a semiquantitative measure of the immune response which should be easier to score. Results The ALVAL score showed an ICC of 0.38 (95% CI, 0.18–0.58) (fair) for the sum score and this improved up to 0.50 (95% CI, 0.31–0.68) (moderate) using the modified Oxford ALVAL score. The individual parameters of the ALVAL score showed an ICC for the scoring of inflammatory infiltrate of 0.37 (95% CI, 0.17–0.57), an ICC of 0.32 (95% CI, 0.12–0.53) for the scoring of tissue organization, and an ICC of 0.14 (95% CI, −0.04 to 0.34) for synovial lining. Conclusions Scoring morphologic features of MoM tissue is not reproducible using the ALVAL score or the Oxford ALVAL score. This may reflect heterogeneous morphologic features in tumor tissue and between different tumor tissue samples that cannot be reliably quantified by pathologists using the parameters of these two scoring methods. An alternative, simplified scoring system should be developed to improve the interrater agreement. Level of Evidence Level III, diagnostic study.