ABSTRACT
T cell-mediated islet destruction is a hallmark of autoimmune diabetes. Here, we examined the dynamics and pathogenicity of CD4+ T cell responses to four different insulin-derived epitopes during diabetes initiation in non-obese diabetic (NOD) mice. Single-cell RNA sequencing of tetramer-sorted CD4+ T cells from the pancreas revealed that islet-antigen-specific T cells adopted a wide variety of fates and required XCR1+ dendritic cells for their activation. Hybrid-insulin C-chromogranin A (InsC-ChgA)-specific CD4+ T cells skewed toward a distinct T helper type 1 (Th1) effector phenotype, whereas the majority of insulin B chain and hybrid-insulin C-islet amyloid polypeptide-specific CD4+ T cells exhibited a regulatory phenotype and early or weak Th1 phenotype, respectively. InsC-ChgA-specific CD4+ T cells were uniquely pathogenic upon transfer, and an anti-InsC-ChgA:IAg7 antibody prevented spontaneous diabetes. Our findings highlight the heterogeneity of T cell responses to insulin-derived epitopes in diabetes and argue for the feasibility of antigen-specific therapies that blunts the response of pathogenic CD4+ T cells causing autoimmunity.
ABSTRACT
Trichorhinophalangeal syndrome (TRPS) is a genetic disorder caused by point mutations or deletions in the gene-encoding transcription factor TRPS1. TRPS patients display a range of skeletal dysplasias, including reduced jaw size, short stature, and a cone-shaped digit epiphysis. Certain TRPS patients experience early onset coxarthrosis that leads to a devastating drop in their daily activities. The etiologies of congenital skeletal abnormalities of TRPS were revealed through the analysis of Trps1 mutant mouse strains. However, early postnatal lethality in Trps1 knockout mice has hampered the study of postnatal TRPS pathology. Here, through epigenomic analysis we identified two previously uncharacterized candidate gene regulatory regions in the first intron of Trps1. We deleted these regions, either individually or simultaneously, and examined their effects on skeletal morphogenesis. Animals that were deleted individually for either region displayed only modest phenotypes. In contrast, the Trps1Δint/Δint mouse strain with simultaneous deletion of both genomic regions exhibit postnatal growth retardation. This strain displayed delayed secondary ossification center formation in the long bones and misshaped hip joint development that resulted in acetabular dysplasia. Reducing one allele of the Trps1 gene in Trps1Δint mice resulted in medial patellar dislocation that has been observed in some patients with TRPS. Our novel Trps1 hypomorphic strain recapitulates many postnatal pathologies observed in human TRPS patients, thus positioning this strain as a useful animal model to study postnatal TRPS pathogenesis. Our observations also suggest that Trps1 gene expression is regulated through several regulatory elements, thus guaranteeing robust expression maintenance in skeletal cells.
ABSTRACT
Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption. We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis. Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies. In line with AXIN1 being a central component of the ß-catenin destruction complex, analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity. All three AXIN1-truncating variants resulted in reduced protein levels and impaired AXIN1 polymerization mediated by its C-terminal DIX domain but partially retained Wnt-inhibitory function upon overexpression. Addition of a tankyrase inhibitor attenuated Wnt overactivity in the AXIN1-mutant model systems. Our data suggest that AXIN1 coordinates the action of osteoblasts and osteoclasts and that tankyrase inhibitors can attenuate the effects of AXIN1 hypomorphic variants.
Subject(s)
Hip Dislocation , Osteosclerosis , Tankyrases , Humans , Tankyrases/genetics , Tankyrases/metabolism , Axin Protein/genetics , Axin Protein/metabolism , Wnt Signaling Pathway/genetics , Osteosclerosis/genetics , beta Catenin/metabolismABSTRACT
Membrane-less organelles (MLOs) are liquid-like subcellular compartments that form through phase separation of proteins and RNA. While their biophysical properties are increasingly understood, their regulation and the consequences of perturbed MLO states for cell physiology are less clear. To study the regulatory networks, we targeted 1,354 human genes and screened for morphological changes of nucleoli, Cajal bodies, splicing speckles, PML nuclear bodies (PML-NBs), cytoplasmic processing bodies, and stress granules. By multivariate analysis of MLO features we identified hundreds of genes that control MLO homeostasis. We discovered regulatory crosstalk between MLOs, and mapped hierarchical interactions between aberrant MLO states and cellular properties. We provide evidence that perturbation of pre-mRNA splicing results in stress granule formation and reveal that PML-NB abundance influences DNA replication rates and that PML-NBs are in turn controlled by HIP kinases. Together, our comprehensive dataset is an unprecedented resource for deciphering the regulation and biological functions of MLOs.
Subject(s)
Organelles/genetics , Stress, Physiological/genetics , Systems Biology/methods , Transcriptome , DNA Replication , Gene Expression Profiling , Gene Expression Regulation , Gene Regulatory Networks , HeLa Cells , Humans , Organelles/metabolism , Phase Transition , RNA Interference , RNA Precursors/genetics , RNA, Messenger/genetics , Signal Transduction/genetics , Single-Cell AnalysisABSTRACT
Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that has a strong HLA association, where a number of self-epitopes have been implicated in disease pathogenesis. Human pancreatic islet-infiltrating CD4+ T cell clones not only respond to proinsulin C-peptide (PI40-54; GQVELGGGPGAGSLQ) but also cross-react with a hybrid insulin peptide (HIP; PI40-47-IAPP74-80; GQVELGGG-NAVEVLK) presented by HLA-DQ8. How T cell receptors recognize self-peptide and cross-react to HIPs is unclear. We investigated the cross-reactivity of the CD4+ T cell clones reactive to native PI40-54 epitope and multiple HIPs fused at the same N-terminus (PI40-54) to the degradation products of two highly expressed pancreatic islet proteins, neuropeptide Y (NPY68-74) and amyloid polypeptide (IAPP23-29 and IAPP74-80). We observed that five out of the seven selected SKW3 T cell lines expressing TCRs isolated from CD4+ T cells of people with T1D responded to multiple HIPs. Despite shared TRAV26-1-TRBV5-1 gene usage in some T cells, these clones cross-reacted to varying degrees with the PI40-54 and HIP epitopes. Crystal structures of two TRAV26-1+-TRBV5-1+ T cell receptors (TCRs) in complex with PI40-54 and HIPs bound to HLA-DQ8 revealed that the two TCRs had distinct mechanisms responsible for their differential recognition of the PI40-54 and HIP epitopes. Alanine scanning mutagenesis of the PI40-54 and HIPs determined that the P2, P7, and P8 residues in these epitopes were key determinants of TCR specificity. Accordingly, we provide a molecular basis for cross-reactivity towards native insulin and HIP epitopes presented by HLA-DQ8.
ABSTRACT
Developmental dysplasia of the hip (DDH) is one of the most common congenital skeletal malformations; however, its etiology remains unclear. Here, we conducted whole-exome sequencing in eight DDH families followed by targeted sequencing of 68 sporadic DDH patients. We identified likely pathogenic variants in the LRP1 (low-density lipoprotein receptor-related protein 1) gene in two families and seven unrelated patients. All patients harboring the LRP1 variants presented a typical DDH phenotype. The heterozygous Lrp1 knockout (KO) mouse (Lrp1+/-) showed phenotypes recapitulating the human DDH phenotypes, indicating Lrp1 loss of function causes DDH. Lrp1 knockin mice with a missense variant corresponding to a human variant identified in DDH (Lrp1R1783W) also presented DDH phenotypes, which were milder in heterozygotes and severer in homozygotes than those of the Lrp1 KO mouse. The timing of triradiate cartilage development was brought forward 1 or 2 wk earlier in the LRP-deficient mice, which leads to malformation of the acetabulum and femoral head. Furthermore, Lrp1 deficiency caused a significant decrease of chondrogenic ability in vitro. During the chondrogenic induction of mice bone marrow stem cells and ATDC5 (an inducible chondrogenic cell line), Lrp1 deficiency caused decreased autophagy levels with significant ß-catenin up-regulation and suppression of chondrocyte marker genes. The expression of chondrocyte markers was rescued by PNU-74654 (a ß-catenin antagonist) in an shRNA-Lrp1-expressed ATDC5 cell. Our study reveals a critical role of LRP1 in the etiology and pathogenesis of DDH, opening an avenue for its treatment.
Subject(s)
Autophagy , Chondrocytes , Developmental Dysplasia of the Hip , Heterozygote , Low Density Lipoprotein Receptor-Related Protein-1 , Animals , Autophagy/genetics , Chondrocytes/metabolism , Chondrocytes/pathology , Developmental Dysplasia of the Hip/genetics , Developmental Dysplasia of the Hip/pathology , Humans , Low Density Lipoprotein Receptor-Related Protein-1/genetics , Mice , Mice, Knockout , beta Catenin/metabolismABSTRACT
BACKGROUND: Genomic heterozygosity has been shown to confer a health advantage in humans and play a protective role in complex diseases. Given osteoarthritis (OA) is a highly polygenic disease, we set out to determine if an association exists between OA and genomic heterozygosity. RESULTS: End-stage knee and hip OA patients and healthy controls were recruited from the Newfoundland and Labrador (NL) population. The Arthritis Research UK Osteoarthritis Genetics (arcOGEN) consortium database was utilized as a replication cohort. DNA was extracted from blood samples and genotyped. Individual rates of observed heterozygosity (HetRate) and heterozygosity excess (HetExcess) relative to the expected were mathematically derived, and standardized to a z-score. Logistic regression modeling was used to examine the association between OA and HetRate or HetExcess. A total of 559 knee and hip OA patients (mean age 66.5 years, body mass index (BMI) 33.7 kg/m2, and 55% females) and 118 healthy controls (mean age 56.4 years, BMI 29.5 kg/m2, and 59% female) were included in the NL cohort analysis. We found that OA had an inverse relationship with HetRate and HetExcess with odds ratios of 0.64 (95% CI: 0.45-0.91) and 0.65 (95% CI: 0.45-0.93) per standard deviation (SD), respectively. The arcOGEN data included 2,019 end-stage knee and hip OA patients and 2,029 healthy controls, validating our findings with HetRate and HetExcess odds ratios of 0.60 (95% CI: 0.56-0.64) and 0.44 (95% CI: 0.40-0.47) per SD, respectively. CONCLUSIONS: Our results are the first to clearly show evidence, from two separate cohorts, that reduced genomic heterozygosity confers a risk for the future development of OA.
Subject(s)
Osteoarthritis, Hip , Osteoarthritis, Knee , Humans , Female , Aged , Middle Aged , Male , Osteoarthritis, Hip/genetics , Osteoarthritis, Hip/epidemiology , Osteoarthritis, Knee/genetics , Osteoarthritis, Knee/epidemiology , Cohort Studies , Genomics , HeterozygoteABSTRACT
Total joint arthroplasty is a commonly used surgical procedure in orthopedics. Revision surgeries are required in >10% of patients mainly because of prosthetic joint infection caused by bacteria or aseptic implant loosening caused by chronic inflammation. Encephalitozoon cuniculi is a microsporidium, an obligate intracellular parasite, capable of exploiting migrating proinflammatory immune cells for dissemination within the host. We used molecular detection methods to evaluate the incidence of E. cuniculi among patients who had total hip or knee arthroplasty revision. Out of 49 patients, E. cuniculi genotypes I, II, or III were confirmed in joint samples from 3 men and 2 women who had implant loosening. Understanding the risks associated with the presence of microsporidia in periprosthetic joint infections is essential for proper management of arthroplasty. Furthermore, E. cuniculi should be considered a potential contributing cause of joint inflammation and arthrosis.
Subject(s)
Encephalitozoon cuniculi , Encephalitozoonosis , Microsporidia , Male , Humans , Female , Microsporidia/genetics , Encephalitozoon cuniculi/genetics , Czech Republic/epidemiology , Encephalitozoonosis/epidemiology , InflammationABSTRACT
Osteoarthritis is the most common chronic joint disease, characterized by the abnormal remodeling of joint tissues including articular cartilage and subchondral bone. However, there are currently no therapeutic drug targets to slow the progression of disease because disease pathogenesis is largely unknown. Thus, the goals of this study were to identify metabolic differences between articular cartilage and subchondral bone, compare the metabolic shifts in osteoarthritic grade III and IV tissues, and spatially map metabolic shifts across regions of osteoarthritic hip joints. Articular cartilage and subchondral bone from 9 human femoral heads were obtained after total joint arthroplasty, homogenized and metabolites were extracted for liquid chromatography-mass spectrometry analysis. Metabolomic profiling revealed that distinct metabolic endotypes exist between osteoarthritic tissues, late-stage grades, and regions of the diseased joint. The pathways that contributed the most to these differences between tissues were associated with lipid and amino acid metabolism. Differences between grades were associated with nucleotide, lipid, and sugar metabolism. Specific metabolic pathways such as glycosaminoglycan degradation and amino acid metabolism, were spatially constrained to more superior regions of the femoral head. These results suggest that radiography-confirmed grades III and IV osteoarthritis are associated with distinct global metabolic and that metabolic shifts are not uniform across the joint. The results of this study enhance our understanding of osteoarthritis pathogenesis and may lead to potential drug targets to slow, halt, or reverse tissue damage in late stages of osteoarthritis.
Subject(s)
Cartilage, Articular , Osteoarthritis , Humans , Osteoarthritis/pathology , Cartilage, Articular/metabolism , Femur Head/diagnostic imaging , Femur Head/metabolism , Radiography , Amino Acids/metabolism , LipidsABSTRACT
BACKGROUND: Few previous studies have assessed overall morbidity at the individual level with respect to future risk of hip fracture. The aim of this register-based cohort study was to examine the association between morbidity measured by the medication-based Rx-Risk Comorbidity Index (Rx-Risk) and the risk of first hip fracture. METHODS: Individual-level data on medications dispensed from pharmacies (2005-2016) was retrieved from the Norwegian Prescription Database and used to calculate Rx-Risk for each calendar year. Information on first hip fractures (2006-2017) was obtained from a nationwide hip fracture database. Individuals ≥ 51 years who filled at least one prescription during the study period comprised the population at risk. Using Rx-Risk as a time-varying exposure variable, relative risk estimates were obtained by a negative binomial model. RESULTS: During 2006-2017, 94,104 individuals sustained a first hip fracture. A higher Rx-Risk was associated with increased risk of hip fracture within all categories of age and sex. Women with the highest Rx-Risk (> 25) had a relative risk of 6.1 (95% confidence interval (CI): 5.4, 6.8) compared to women with Rx-Risk ≤ 0, whereas the corresponding relative risk in women with Rx-Risk 1-5 was 1.4 (95% CI: 1.3, 1.4). Similar results were found in men. Women > 80 years with Rx-Risk 21-25 had the highest incidence rate (514 (95% CI: 462, 566) per 10, 000 person years). The relative increase in hip fracture risk with higher Rx-Risk was most pronounced in the youngest patients aged 51-65 years. CONCLUSIONS: Rx-Risk is a strong predictor of hip fracture in the general outpatient population and may be useful to identify individuals at risk in a clinical setting and in future studies.
Subject(s)
Hip Fractures , Male , Humans , Female , Cohort Studies , Comorbidity , Hip Fractures/epidemiology , Risk , Incidence , Risk FactorsABSTRACT
OBJECTIVE: The aim of this systematic review and meta-analysis is to describe the effect of digitally delivered exercise on pain, physical function and quality of life (QoL) for people with knee or hip osteoarthritis (OA). METHODS: Articles were eligible for inclusion if they were of a randomized control trial that evaluated the prescription of digitally delivered exercise (requiring the internet) in people with symptomatic primary hip and/or knee OA. Risk of bias was assessed using the Physiotherapy Evidence Database scale, and levels of evidence were assessed according to Grading of Recommendations Assessment, Development and Evaluation. RESULTS: Digitally delivered exercise was delivered via synchronous and asynchronous methods (or a combination of both). Digitally delivered exercise was superior to education only for pain and physical function, with high-quality evidence for quality-of-life outcomes in the long-term (standardized mean difference -0.35, 95% confidence interval -0.59 to -0.12, P = 0.003) in people with knee OA. Furthermore, there was very low to low-quality evidence that digitally delivered exercise was comparable to face-to-face delivery in the short and long-term for people with hip or knee OA and comparable in the medium-term for people with knee OA only. DISCUSSION: The review demonstrated very low to low-quality evidence that digitally delivered exercise was comparable to face-to-face delivery for pain, function and QoL. In the absence of higher-level evidence, we would provisionally recommend that healthcare providers offer the choice of face-to-face or digitally delivered exercise intervention for people with hip or knee OA. Further work is required to understand these programs' reach, access, uptake and implementation across diverse population groups.
Subject(s)
Osteoarthritis, Hip , Osteoarthritis, Knee , Humans , Osteoarthritis, Knee/therapy , Osteoarthritis, Hip/therapy , Quality of Life , Exercise Therapy/methods , Pain , Randomized Controlled Trials as TopicABSTRACT
OBJECTIVE: To determine if subtypes of cam morphology on anteroposterior radiographs exist using statistical shape modeling (SSM), and to assess their association with incident radiographic hip osteoarthritis (RHOA) within 10 years. DESIGN: The nationwide prospective Cohort Hip and Cohort Knee (CHECK) study included 1002 participants aged 45-65 years with 10-year follow-up. Subtypes of cam morphology were defined as SSM-based shape variations of femoral head-neck junction that are associated with baseline cam morphology (alpha angle ≥60°). The association between each subtype in hips free of osteoarthritis at baseline (Kellgren & Lawrence (KL) grade <2) and incident RHOA (KL grade≥2, or a total hip replacement) was estimated using logistic regression at 10-year follow-up and stratified by sex. RESULTS: In sex-combined group, but also for males and females separately, cam morphology subtypes were captured in modes 1, 3, 4, and 5 with odds ratios (ORs) ranging from 0.39 (0.27-0.58) to 2.25 (1.64-3.10). For sex-combined group, only mode 3, a flattened head-neck junction, was associated with incident RHOA (OR:1.14, 1.02-1.27). Males' modes 1 and 3 and females' modes 3 and 4 were associated with RHOA. Notably, the female mode 4, a slightly flattened neck but with subtle curvature, was significantly protective for RHOA (OR:0.88, 0.80-0.98). CONCLUSIONS: We identified four distinct morphological subtypes of cam morphology defined by alpha angle. Only some subtypes were found acting as risk factors for RHOA at 10-year follow-up, which differed between males and females. This highlights the need to study cam morphology beyond the alpha angle alone.
ABSTRACT
OBJECTIVE: Understanding the mechanisms of hip disease, such as osteoarthritis (OA), is crucial to advance their treatment. Such hip diseases often involve specific morphological changes. Genetic variations, called single nucleotide polymorphisms (SNPs), influence various hip morphological parameters. This study investigated the biological relevance of SNPs correlated to hip morphology in genome-wide association studies (GWAS). The SNP-associated genes were compared to genes associated with OA in other joints, aiming to see if the same genes play a role in both hip development and the risk of OA in other lower limb joints. METHODOLOGY: A systematic literature review was conducted to identify SNPs correlated with hip morphology, based on the Population, Intervention, Comparison, Outcome, and Study (PICOS) framework. Afterwards, Gene Ontology (GO) analysis was performed, using EnrichR, on the SNP-associated genes and compared with non-hip OA-associated genes, across different databases. RESULTS: Reviewing 49 GWAS identified 436 SNPs associated with hip joint morphology, encompassing variance in bone size, structure and shape. Among the SNP-associated genes, SOX9 plays a pivotal role in size, GDF5 impacts bone structure, and BMP7 affects shape. Overall, skeletal system development, regulation of cell differentiation, and chondrocyte differentiation emerged as crucial processes influencing hip morphology. Eighteen percent of GWAS-identified genes related to hip morphology were also associated with non-hip OA. CONCLUSION: Our findings indicate the existence of multiple shared genetic mechanisms across hip morphology and OA, highlighting the necessity for more extensive research in this area, as in contrast to the hip, the genetic background on knee or foot morphology remains largely understudied.
Subject(s)
Genome-Wide Association Study , Growth Differentiation Factor 5 , Hip Joint , Osteoarthritis, Hip , Polymorphism, Single Nucleotide , Humans , Osteoarthritis, Hip/genetics , Osteoarthritis, Hip/pathology , Growth Differentiation Factor 5/genetics , Hip Joint/pathology , Bone Morphogenetic Protein 7/genetics , SOX9 Transcription Factor/genetics , Genetic Predisposition to DiseaseABSTRACT
OBJECTIVE: To explore associations between hip muscle strength and cartilage defects (presence and severity) on magnetic resonance imaging (MRI) in young adults with hip/groin pain participating in sub-elite football. DESIGN: Sub-elite football players with hip/groin pain (>6 months) completed assessments of isometric hip strength and functional task performance. Hip cartilage defects were assessed using the Scoring Hip Osteoarthritis with MRI tool. This exploratory, cross-sectional study used logistic and negative binomial models to assess the relationships between hip muscle strength or functional task performance and hip cartilage defects, controlling for body mass index, age, testing site and cam morphology, incorporating sex-specific interaction terms. RESULTS: One hundred and eighty-two (37 women) sub-elite (soccer or Australian football) players with hip/groin pain (age 26 ± 7 years) were included. Greater hip extension strength was associated with higher cartilage total score (adjusted incidence rate ratio [aIRR] 1.01, 95%CI: 1.0 to 1.02, p = 0.013) and superolateral cartilage score (adjusted odds ratio (aOR) 1.03, 95% confidence interval (CI): 1.01 to 1.06, p < 0.01). In female sub-elite football players, greater hip external rotation strength was associated with lateral cartilage defects (aOR 1.61, 95%CI: 1.05 to 2.48, p = 0.03) and higher cartilage total score (aIRR 1.25, 95%CI: 1.01 to 1.66, p = 0.042). A one-repetition increase in one-leg rise performance was related to lower odds of superomedial cartilage defects (aOR 0.96, 95%CI: 0.94 to 0.99, p < 0.01). CONCLUSIONS: Overall, there were few associations between peak isometric hip muscle strength and overall hip cartilage defects. It is possible that other factors may have relevance in sub-elite football players. Additional studies are needed to support or refute our findings that higher one leg rise performance was associated with reduced superomedial cartilage defect severity and greater hip extension strength was related to higher cartilage defect severity scores.
Subject(s)
Cartilage, Articular , Hip Joint , Magnetic Resonance Imaging , Muscle Strength , Soccer , Humans , Male , Female , Muscle Strength/physiology , Adult , Cross-Sectional Studies , Cartilage, Articular/diagnostic imaging , Cartilage, Articular/physiopathology , Young Adult , Hip Joint/physiopathology , Hip Joint/diagnostic imaging , Groin/physiopathology , Arthralgia/physiopathology , Osteoarthritis, Hip/physiopathology , Osteoarthritis, Hip/diagnostic imaging , AdolescentABSTRACT
OBJECTIVE: To explore the impact of oligohydramnios on fetal movement and hip development, given its association with developmental dysplasia of the hip (DDH) but unclear mechanisms. METHODS: Chick embryos were divided into four groups based on the severity of oligohydramnios induced by amniotic fluid aspiration (control, 0.2 mL, 0.4 mL, 0.6 mL). Fetal movement was assessed by detection of movement and quantification of residual amniotic fluid volume. Hip joint development was assessed by gross anatomic analysis, micro-computed tomography (micro-CT) for cartilage assessment, and histologic observation at multiple time points. In addition, a subset of embryos from the 0.4 mL aspirated group underwent saline reinfusion and subsequent evaluation. RESULTS: Increasing volumes of aspirated amniotic fluid resulted in worsening of fetal movement restrictions (e.g., 0.4 mL aspirated and control group at E10: frequency difference -7.765 [95% CI: -9.125, -6.404]; amplitude difference -0.343 [95% CI: -0.588, -0.097]). The 0.4 mL aspirated group had significantly smaller hip measurements compared to controls, with reduced acetabular length (-0.418 [95% CI: -0.575, -0.261]) and width (-0.304 [95% CI: -0.491, -0.117]) at day E14.5. Histological analysis revealed a smaller femoral head (1.084 ± 0.264 cm) and shallower acetabulum (0.380 ± 0.106 cm) in the 0.4 mL group. Micro-CT showed cartilage matrix degeneration (13.6% [95% CI: 0.6%, 26.7%], P = 0.043 on E14.5). Saline reinfusion resulted in significant improvements in the femoral head to greater trochanter (0.578 [95% CI: 0.323, 0.833], P = 0.001). CONCLUSIONS: Oligohydramnios can cause DDH by restricting fetal movement and disrupting hip morphogenesis in a time-dependent manner. Timely reversal of oligohydramnios during the fetal period may prevent DDH.
Subject(s)
Developmental Dysplasia of the Hip , Disease Models, Animal , Oligohydramnios , X-Ray Microtomography , Animals , Chick Embryo , Oligohydramnios/diagnostic imaging , Developmental Dysplasia of the Hip/diagnostic imaging , Fetal Movement , Hip Joint/diagnostic imaging , Hip Joint/pathology , Hip Joint/embryology , Female , Cartilage, Articular/diagnostic imaging , Cartilage, Articular/pathology , Cartilage, Articular/embryology , Amniotic Fluid , PregnancyABSTRACT
OBJECTIVE: To develop and validate a neural network to estimate hip contact forces (HCF), and lower body kinematics and kinetics during walking in individuals with hip osteoarthritis (OA) using synthesised anatomical key points and electromyography. To assess the capability of the neural network to detect directional changes in HCF resulting from prescribed gait modifications. DESIGN: A calibrated electromyography-informed neuromusculoskeletal model was used to compute lower body joint angles, moments, and HCF for 17 participants with mild-to-moderate hip OA. Anatomical key points (e.g., joint centres) were synthesised from marker trajectories and augmented with bias and noise expected from computer vision-based pose estimation systems. Temporal convolutional and long short-term memory neural networks (NN) were trained using leave-one-subject-out validation to predict neuromusculoskeletal modelling outputs from the synthesised key points and measured electromyography data from 5 hip-spanning muscles. RESULTS: HCF was predicted with an average error of 13.4 ± 7.1% of peak force. Joint angles and moments were predicted with an average root-mean-square-error of 5.3 degrees and 0.10 Nm/kg, respectively. The NN could detect changes in peak HCF that occur due to gait modifications with good agreement with neuromusculoskeletal modelling (r2 = 0.72) and a minimum detectable change of 9.5%. CONCLUSION: The developed neural network predicted HCF and lower body joint angles and moments in individuals with hip OA using noisy synthesised key point locations with acceptable errors. Changes in HCF magnitude due to gait modifications were predicted with high accuracy. These findings have important implications for implementation of load-modification based gait retraining interventions for people with hip OA in a natural environment (i.e., home, clinic).
Subject(s)
Electromyography , Gait , Hip Joint , Neural Networks, Computer , Osteoarthritis, Hip , Humans , Osteoarthritis, Hip/physiopathology , Electromyography/methods , Female , Male , Biomechanical Phenomena , Middle Aged , Hip Joint/physiopathology , Aged , Gait/physiology , Walking/physiology , Muscle, Skeletal/physiopathology , Weight-Bearing/physiologyABSTRACT
OBJECTIVE: To assess the degree of core outcome set alignment and identify issues with alignment to the 2019 COS among clinical trial registrations focused on knee and/or hip osteoarthritis (OA). METHODS: Our search was performed on registered knee and hip OA randomized controlled trials (RCTs) available on ClinicalTrials.gov and WHO International Clinical Trials Registry Platform. The screening process considered trials registered between 8/2014 and 6/2023. We extracted data on general trial characteristics and the five trial endpoints detailed in the COS (pain, physical function, quality of life, patient global assessment, and adverse events), in a masked and duplicate manner. The frequencies of COS alignment were assessed over time prior to and after COS publication. RESULTS: Of the 10,718 RCTs screened, 481 met inclusion criteria. Most were phase 3 (368/481, 76.51%) and heavily university-funded (184/481, 38.25%). Despite the 2019 COS, no marked enhancement in overall alignment was noted. The outcome 'Pain' exhibited the highest degree of COS alignment (455/481, 94.59%), whereas 'adverse events' lagged behind (89/481, 18.50%). Additionally, trial factors such as 'Continent', 'Funding Type', and 'Recruitment Status' displayed no significant influence on COS alignment. CONCLUSIONS: Despite the acknowledged advantages of using COS in RCTs and the availability of an updated COS, the alignment to these outcomes remains notably low. Significant efforts are needed to encourage broader adoption in future studies on knee and hip OA, with the aim of improving research quality and patient care.
Subject(s)
Osteoarthritis, Hip , Osteoarthritis, Knee , Randomized Controlled Trials as Topic , Humans , Cross-Sectional Studies , Quality of Life , Outcome Assessment, Health CareABSTRACT
OBJECTIVE: To study socio-economic inequalities in patient-reported outcomes in primary hip and knee arthroplasty (THA/TKA) patients for osteoarthritis, using two analytical techniques. METHODS: We obtained data from 44,732 THA and 30,756 TKA patients with preoperative and 12-month follow-up PROMs between 2014 and 2020 from the Dutch Arthroplasty Registry. A deprivation indicator based on neighborhood income, unemployment rate, and education level was linked and categorized into quintiles. The primary outcome measures were the EQ-5D-3L index and Oxford Hip/Knee Score (OHS/OKS) preoperative, at 12-month follow-up, and the calculated change score between these measurements. We contrasted the most and least deprived quintiles using multivariable linear regression, adjusting for patient characteristics. Concurrently, we calculated concentration indices as a non-arbitrary tool to quantify inequalities. RESULTS: Compared to the least deprived, the most deprived THA patients had poorer preoperative (EQ-5D -0.03 (95%CI -0.02, -0.04), OHS -1.26 (-0.99, -1.52)) and 12-month follow-up health (EQ-5D -0.02 (-0.01, -0.02), OHS -0.42 (-0.19, -0.65)), yet higher mean change (EQ-5D 0.02 (0.01, 0.03), OHS 0.84 (0.52, 1.16)). The most deprived TKA patients had similar results. The higher mean change among the deprived resulted from lower preoperative health in this group (confounding). After accounting for this, the most deprived patients had a lower mean change. The concentration indices showed similar inequality effects and provided information on the magnitude of inequalities over the entire socio-economic range. CONCLUSION: The most deprived THA and TKA patients have worse preoperative health, which persisted after surgery. The concentration indices allow comparison of inequalities across different outcomes (e.g., revision risk).
Subject(s)
Arthroplasty, Replacement, Hip , Arthroplasty, Replacement, Knee , Osteoarthritis, Knee , Osteoarthritis , Humans , Osteoarthritis/surgery , Knee Joint/surgery , Patient Reported Outcome Measures , Socioeconomic Factors , Quality of Life , Osteoarthritis, Knee/surgeryABSTRACT
OBJECTIVE: To investigate whether biological DMARDs affect the risk of aseptic loosening after total hip/knee arthroplasty (THA/TKA) in patients with RA. METHODS: We retrospectively identified all patients suffering from RA who underwent THA/TKA at our academic centre between 2002 and 2015 and linked them with an existing prospective observational RA database at our institution. The risk of aseptic loosening was estimated using radiological signs of component loosening (RCL). A time-dependent Cox regression analysis was used to compare the risk of implant loosening between patients treated with traditional DMARDS and biological DMARDs, or alternately both over time. RESULTS: A total of 155 consecutive total joint arthroplasties (TJAs) (103 TKA vs 52 THA) was retrospectively included in the study. Mean age at implantation was 59 ± 13 years. Mean follow-up time was 69 ± 43 months. Overall, 48 (31%) TJAs showed signs of RCL, with 28 (27.2%) RCLs occurring after TKA compared with 20 after THA (38.5%). A significant difference regarding the incidence of RCL between the traditional DMARDs group (39 cases of RCL, 35%) and the biological DMARDs group (nine cases of RCL, 21%) (P = 0.026) was observed using the log-rank test. This was also true when using a time-dependent Cox regression with therapy as well as arthroplasty location (hip vs knee) as variables (P = 0.0447). CONCLUSION: Biological DMARDs may reduce the incidence of aseptic loosening after TJA in patients with RA compared with traditional DMARDs. This effect seems to be more pronounced after TKA than THA.
Subject(s)
Antirheumatic Agents , Arthroplasty, Replacement, Hip , Arthroplasty, Replacement, Knee , Humans , Middle Aged , Aged , Retrospective Studies , Arthroplasty, Replacement, Hip/adverse effects , Regression Analysis , Antirheumatic Agents/therapeutic use , Reoperation , Prosthesis FailureABSTRACT
OBJECTIVE: To develop a CT-based scoring system for assessment of hip arthropathy in AS. METHODS: All AS patients were prospectively recruited, consented, and underwent whole-body stereoradiographs and pelvis CT, which were assessed by two independent radiologists. Stereoradiographs were assessed according to Kellgreen-Lawrence and BASRI-h. For the Hip arthropathy CT score in AS (HACTSAS), joints were divided into 7 segments and scored for joint space, osteophytes, subchondral cysts/erosions. Patients were clinically assessed for range of motion (ROM), pain, and clinical scores (BASMI, BASFI, ASQol, BASDAI and ASDAS). Radiological scores correlations with clinical parameters were compared. ROM sensitivity and specificity for hip arthropathy (BASRI-h ≥ 2) were calculated. RESULTS: Sample included 112 patients, with 36/112 females and 76/112 males. Average age was 51.0 ± 11.2 years and mean duration of AS was 20.9 ± 9.6 years. ICC for HACTSAS, Kellgreen-Lawrence and BASRI-h were 0.89, 0.89 and 0.82 respectively. HACTSAS showed moderate absolute correlation with ROM (ρ=-0.41) and BASMI (ρ = 0.45), and weak with pain (ρ = 0.18) and BASFI (ρ = 0.25). BASRI-h and Kellgreen-Lawrence exhibited moderate correlation with ROM (ρ=-0.44 and ρ=-0.40, respectively), weak with pain (ρ=-.27and ρ=-0.23, respectively) and BASFI (ρ=-0.16 and ρ=-0.18, respectively), but only weak with BASMI (ρ=-0.34 and ρ=-0.36, respectively). Internal rotation <15°, abduction <31°, and intermalleolar distance <75cm were, respectively, 73%, 70% and 73% sensitivity and 81%, 65% and 68% specific for hip arthropathy. CONCLUSION: HACTSAS exhibited higher correlation with BASMI and BASFI when compared with BASRI-h, but less correlation with pain and ROM. Internal rotation was the best clinical discriminator for hip arthropathy.