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This study investigated the longitudinal assessment of step-up performance in patients undergoing total joint arthroplasty (TJA) and correlation with subjective patient reported outcome measures (PROMs). In this sub-analysis of the ADAPT study, PROMs were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Block step-up (BS) transfers were assessed by wearable-derived measures of time. 76 patients undergoing TJA were included. Subgroups were formed isolating the worst performing quartile (low functioning (LF)) from the high functioning (HF), and outcomes were compared– One-year post-surgery, WOMAC function demonstrated strong correlations to WOMAC pain (Pearson's r = 0.67–0.84) and moderate correlations to BS performance (Pearson's r = 0.31–0.54). Both WOMAC and BS significantly improved with a larger effect size for the HF subgroup (0.62 vs. 0.43; p < 0.05). Patients designated to the LF subgroup at 3 months had increased odds of representing the LF subgroup at 12 months (WOMAC = 19; BS = 4). WOMAC defined 18 LF patients at 12 months follow-up. BS performance identified 9 additional LF patients. WOMAC function scores seem pain dominated. Measures of BS performance allow assessment of otherwise hidden residual functional impairment. Lower functioning 3 months post-surgery is predictive of longer-term impairment. Severe hip or knee osteoarthritis is a disabling condition which not only impacts patients' mobility but restricts quality of life due to constant pain and consequential lifestyle changes. Total joint arthroplasty (TJA) has developed into a successful intervention for patients with advanced hip or knee osteoarthritis. Some patients are dissatisfied after TJA due to residual functional impairment and the inclusion of performance-based tests in the post-operative evaluation and rehabilitation allows for the assessment of otherwise hidden residual impairment. Early detection of functional impairment using the repeated block step-up (BS) transfers allows to facilitate more targeted rehabilitation for better functional outcomes. [ABSTRACT FROM AUTHOR]

Background: The proportion of patients who are dissatisfied with the outcome following total knee replacement (TKR) is high. Malalignment is considered a probable cause for persistent pain, but whether this reason for revision could be the result of specific patient characteristics remains unclear. Therefore, we aim to assess whether specific patient characteristics are associated with revision for symptomatic TKR malalignment., Methods: Data was obtained from the Dutch Arthroplasty Register (LROI), which contains data from all Dutch hospitals. All patients who underwent TKR revision surgery between 2008 and 2019 were included in this study. The (primary) reason for revision as well as patient characteristics (age, gender, ASA classification, and pre-operative patient-reported outcome measures) were abstracted. The Chi-square test for categorical variables, and ANOVA or Kruskal-Wallis for continuous variables were used to determine differences in patient characteristics between the subgroups based on reason for revision., Results: A total of 11,044 TKR revisions were registered in The Netherlands between 2008 and 2019. Malalignment was registered as the primary reason for revision in 13% of the patients. Subgroup analyses showed that patients who underwent TKR revisions for malalignment where younger (63.8 year, SD ± 9.3) and more often female (70%) compared to other major reasons for TKR revisions., Conclusion: Patients who had a TKR revision for malalignment were younger and more often female. This suggests that patient characteristics may play a role when reasons to perform revision surgery are considered. Surgeons should invest in the expectation management in (young) patients and inform patients of these potential risk factors as part of shared decision-making., Competing Interests: None., (© 2023 Published by Elsevier B.V. on behalf of Professor P K Surendran Memorial Education Foundation.)

Migrants and their offspring are at increased risk of developing mental disorders. Previous research has shown associations between adverse social factors (e.g., discrimination, lack of social support) and mental health problems in migrants, but it is unknown how these associations are understood by migrants themselves. In this study, we aimed to gain explorative insight into the way young Moroccan-Dutch people experience their social environment, and how they relate this social environment to the development of mental health problems. At www.marokko.nl, the largest online discussion platform for young Moroccan-Dutch people, contributors discuss a broad variety of subjects, including societal, cultural, religious, and mental health issues. Combining deductive and inductive approaches to qualitative data analysis, we analysed 22 forum discussions at marokko.nl about mental health problems, after which data saturation was reached. Contributors described feeling isolated and experiencing discrimination in their social environment. Contributor comments identified social challenges arising from Dutch society, Dutch culture (e.g., being too individualistic), Moroccan culture (e.g., strict parenting style), and living between these two cultures. These social challenges are perceived to be associated with mental health problems. Furthermore, we created a model describing the different types of explanations contributors used for mental health problems, being: religious (e.g., possession); medical (i.e., a bio-psycho-social cause); or a combination of both. This model can help clinicians in delivering culturally sensitive mental health care. Lastly, this study shows the taboo on mental health problems in the Moroccan-Dutch population and the opportunity to open up in the online environment.

Introduction: Total knee replacement (TKR) for osteoarthritis results in a satisfactory outcome in the majority of patients, although up to one in five patients may be dissatisfied with the outcome. Persistent pain is a main contributor to patient dissatisfaction, and femoral and tibial component malrotation have been identified as a potential cause for both persistent pain and patellofemoral problems. Based on the assumption that component malrotation is the causative factor for persistent pain, early revision for patients with symptomatic malrotated components has been advocated in the literature. However, convincing evidence that component malrotation indeed results in less than optimal outcomes is lacking. This study aims to assess the relation between knee prosthesis component rotation and patient-reported outcomes in a large group of patients and to determine the range of femoral, tibial and combined rotation that results in the best clinical outcomes., Methods and Analysis: In this single-centre, prospective observational cohort study, a total of 500 patients will undergo TKR. All patients will have a 3D-CT assessment of femoral and tibial component rotation within 8 weeks after surgery. Outcome measures will include the Oxford Knee Score, the Knee Injury and Osteoarthritis Outcome Score, EQ-5D, visual analogue scale for pain, the American Knee Society Score and the knee joint range of motion. We will assess the relation between femoral, tibial and combined component rotation and patient-reported outcome measures at 8 weeks and 1 year of follow-up, and we will determine the range of femoral, tibial and combined rotation that results in the best clinical outcomes., Ethics and Dissemination: Ethical approval for this study has been granted by the Isala Hospital ethics committee. The results will be published in a peer-reviewed journal and presented at relevant meetings., Trial Registration Number: NL7635., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Release of growth factors while simultaneously maintaining their full biological activity over a period of days to weeks is an important issue in controlled drug delivery and in tissue engineering. In addition, the selected strategy to immobilize growth factors largely determines their biological activity. Silica surfaces derivatized with glycidyloxy propyl trimethoxysilane and poly(glycidyl methacrylate) brushes yielded epoxide-functionalized surfaces onto which human bone morphogenetic protein-6 (hBMP-6) was immobilized giving stable secondary amine bonds. The biological activity of hBMP-6 was unleashed by hydrolysis of the surface siloxane and ester bonds. We demonstrate that this type of labile bonding strategy can be applied to biomaterial surfaces with relatively simple and biocompatible chemistry, such as siloxane, ester, and imine bonds. Our data indicates that the use of differential hydrolytically labile linkers is a versatile method for functionalization of biomaterials with a variety of growth factors providing control over their biological activity.

Histone methyltransferases EZH1 and EZH2 catalyse the trimethylation of histone H3 at lysine 27 (H3K27), which serves as an epigenetic signal for chromatin condensation and transcriptional repression. Genome-wide associated studies have implicated EZH2 in the control of height and mutations in EZH2 cause Weaver syndrome, which includes skeletal overgrowth. Here we show that the combined loss of Ezh1 and Ezh2 in chondrocytes severely impairs skeletal growth in mice. Both of the principal processes underlying growth plate chondrogenesis, chondrocyte proliferation and hypertrophy, are compromised. The decrease in chondrocyte proliferation is due in part to derepression of cyclin-dependent kinase inhibitors Ink4a/b, while ineffective chondrocyte hypertrophy is due to the suppression of IGF signalling by the increased expression of IGF-binding proteins. Collectively, our findings reveal a critical role for H3K27 methylation in the regulation of chondrocyte proliferation and hypertrophy in the growth plate, which are the central determinants of skeletal growth.

Unlabelled: MicroRNAs (miRs) are small regulatory molecules emerging as potential biomarkers in cancer. Previously, it was shown that COX-2 expression promotes breast cancer progression via multiple mechanisms, including induction of stem-like cells (SLC), owing to activation of the prostaglandin E2 receptor EP4 (PTGER4). COX-2 overexpression also upregulated microRNA-526b (miR-526b), in association with aggressive phenotype. Here, the functional roles of miR-526b in breast cancer and the mechanistic role of EP4 signaling in miR-526b upregulation were examined. A positive correlation was noted between miR-526b and COX-2 mRNA expression in COX-2 disparate breast cancer cell lines. Stable overexpression of miR-526b in poorly metastatic MCF7 and SKBR3 cell lines resulted in increased cellular migration, invasion, EMT phenotype and enhanced tumorsphere formation in vitro, and lung colony formation in vivo in immunodeficient mice. Conversely, knockdown of miR-526b in aggressive MCF7-COX-2 and SKBR3-COX-2 cells reduced oncogenic functions and reversed the EMT phenotype, in vitro. Furthermore, it was determined that miR-526b expression is dependent on EP4 receptor activity and downstream PI3K-AKT and cyclic AMP (cAMP) signaling pathways. PI3K-AKT inhibitors blocked EP4 agonist-mediated miR-526b upregulation and tumorsphere formation in MCF7 and SKBR3 cells. NF-κB inhibitor abrogates EP agonist-stimulated miRNA expression in MCF7 and T47D cells, indicating that the NF-κB pathway is also involved in miR-526b regulation. In addition, inhibition of COX-2, EP4, PI3K, and PKA in COX-2-overexpressing cells downregulated miR-526b and its functions in vitro. Finally, miR-526b expression was significantly higher in cancerous than in noncancerous breast tissues and associated with reduced patient survival. In conclusion, miR-526b promotes breast cancer progression, SLC-phenotype through EP4-mediated signaling, and correlates with breast cancer patient survival., Implications: This study presents novel findings that miRNA 526b is a COX-2 upregulated, oncogenic miRNA promoting SLCs, the expression of which follows EP4 receptor-mediated signaling, and is a promising biomarker for monitoring and personalizing breast cancer therapy., (©2015 American Association for Cancer Research.)

Purpose: To compare small incision lenticule extraction (SMILE) versus LASIK for post-refractive dry eye disease., Design: Prospective, comparative, nonrandomized clinical study., Participants: Thirty patients scheduled for bilateral myopic SMILE and 30 age-, sex-, and refraction-matched patients scheduled for bilateral myopic LASIK were enrolled and followed for 6 months after the surgery., Methods: Complete evaluation of dry eye disease was performed at 1 and 6 months postoperatively, which included vision-related quality of life (Ocular Surface Disease Index [OSDI]), clinical examinations (tear film breakup time [TBUT], Schirmer I test, corneal staining), and tear osmolarity measurements, together with an overall severity score. Function and morphology of the corneal innervation were evaluated by corneal esthesiometry and subbasal nerve imaging using in vivo confocal microscopy (IVCM)., Main Outcome Measures: Overall analysis of dry eye disease and corneal innervation., Results: High incidence of mild to moderate dry eye disease was observed in both groups 1 month postoperatively, which remained significantly higher in the LASIK group than in the SMILE group 6 months after surgery (overall severity score [0-4]: 1.2±1.1 vs. 0.2±0.4, respectively, P < 0.01), leading to more frequent use of tear substitutes over the long term. Corneal sensitivity was better in SMILE than in LASIK eyes 1 month postoperatively (3.5±1.79 vs. 2.45±2.48, respectively, P < 0.01) and then recovered to statistically similar values at 6 months. Corneal nerve density, number of long fibers, and branchings as assessed by IVCM were significantly higher in the SMILE group compared with the LASIK group 1 and 6 months after surgery. Corneal sensitivity was negatively correlated with dry eye-related corneal damage (R² = 0.48, P < 0.01), and the long fiber nerve density was independently correlated with the OSDI score (R² = 0.50, P < 0.01) and the Schirmer test (R² = 0.21, P < 0.01) 6 months postoperatively., Conclusions: The SMILE procedure has a less pronounced impact on the ocular surface and corneal innervation compared with LASIK, further reducing the incidence of dry eye disease and subsequent degradation in quality of life after refractive surgery., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

A supramolecular strategy is presented for the assembly of growth factors employing His6-tagged single-domain antibodies (VHH). A combination of orthogonal supramolecular interactions of β-cyclodextrin (βCD)-adamantyl (Ad) host-guest and N-nitrilotriacetic acid (NTA)-histidine (His) interactions was employed to generate reversible and homogeneous layers of growth factors. A single-domain antibody V(H)H fragment was identified to bind to the human bone morphogenetic protein-6 (hBMP6) growth factor and could be recombinantly expressed in E. coli. The V(H)H fragment was equipped with a C-terminal hexahistidine (His6) tether to facilitate the assembly on βCD surfaces using a linker that contains an Ad group to bind to the βCD receptors and an NTA moiety to interact with the His6-tag upon cocomplexation of Ni(2+) ions. After exploring the thermodynamic and kinetic stability of the V(H)H assemblies on βCD surfaces using a variety of experimental techniques including microcontact printing (μCP), surface plasmon resonance (SPR), microscale thermophoresis (MST), and theoretical models for determining the thermodynamic behavior of the system, hBMP6 was assembled onto the V(H)H-functionalized surfaces. After analyzing the immobilized hBMP6 using immunostaining, the biological activity of hBMP6 was demonstrated in cell differentiation experiments. Early osteogenic differentiation was analyzed in terms of alkaline phosphatase (ALP) activity of KS483-4C3 mouse progenitor cells, and the results indicated that the reversibly immobilized growth factors were functionally delivered to the cells. In conclusion, the supramolecular strategy used here offers the necessary affinity, reversibility, and temporal control to promote biological function of the growth factors that were delivered by this strategy.

Strategies to generate platforms combining tissue targeting and regeneration properties are in great demand in the regenerative medicine field. Here we employ an approach to directly visualize the immobilization of cysteine-terminated peptides on a novel fluorogenic surface. Peptides with relevant biological properties, CLPLGNSH and CLRGRYW, were synthesized to function as peptide binders to transforming growth factor (TGF)-β1 and collagen type II (CII). The selective immobilization of the peptides was directly detected using a fluorogenic surface. Adhered proteins were confined to patterns of these peptides matching with the fluorogenic areas. These results show that the fluorogenic signal can be used to detect the chemo-selective immobilization of non-fluorescent biomolecules and to correlate the cell response with the patterned peptides. After analyzing the sequence specificity and cross-reactivity of the binding of TGF-β1 and CII to the respective peptide regions employing immunofluorescence assays, both peptides were co-immobilized in a step-wise process as detected by the fluorogenic surface. TGF-β1 and CII could be self-sorted from a mixture in a regio-selective manner resulting in a bi-functional protein platform. Surfaces of CLPLGNSH pre-loaded with TGF-β1 showed excellent bioactivity in combination with human articular chondrocytes (HACs) and stimulated expression of chondrogenic markers.

CYP2C9 is an important drug-metabolizing enzyme that metabolizes, e.g., warfarin, antidiabetics, and antiphlogistics. However, the endogenous regulation of this enzyme is largely unknown. In this study, we examined the role of GATA transcription factors in the gene expression of CYP2C9. We investigated four putative GATA binding sites within the first 200 base pairs of CYP2C9 promoter at the positions I: -173/-170, II: -167/-164, III: -118/-115, and IV: -106/-103. Luciferase activity driven by a wild-type CYP2C9 promoter construct was strongly up-regulated in Huh-7 cells upon cotransfection with expression plasmids for GATA-2 and GATA-4, whereas mutations introduced into GATA binding site III or I and II reduced this induction to a significant extent. Electrophoretic mobility shift assays revealed specific binding of GATA-4 and GATA-6 to the oligonucleotides containing GATA binding sites I and II. Furthermore, the association of GATA-4 with CYP2C9 promoter was confirmed by chromatin immunoprecipitation assays in HepG2 cells. Taken together, these data strongly suggest an involvement of liver-specific transcription factor GATA-4 in the transcriptional regulation of CYP2C9.

Isotonic saline is the fluid most commonly used for treatment of asymptomatic hypotonic dehydration, but as shown in the case presented in this article, rapid increase in serum sodium may follow administration of isotonic saline, leading to the development of central pontine myelinolysis (CPM). Because the necessity of rapid correction is less, whereas the risk of CPM is greater with chronic asymptomatic hyponatremia than with acute hyponatremia, use of a half normal saline might be more appropriate than normal saline for treating certain patients with hypotonic dehydration with asymptomatic hyponatremia. The calculations indicate that half normal saline will expand the extracellular volume quite effectively, but the rate of increase in serum sodium will be considerably slower than that with normal saline.