Assessing functional recovery following total knee replacement surgery using objective classification of level gait data and patient-reported outcome measures

Background Patient recovery can be quantified objectively, via gait analysis, or subjectively, using patient reported outcome measures. Association between these measures would explain the level of disability reported in patient reported outcome measures and could assist with therapeutic decisions. Methods Total knee replacement outcome was assessed using objective classification and patient-reported outcome measures (Knee Outcome Survey and Oxford Knee Scores). A classifier was trained to distinguish between healthy and osteoarthritic characteristics using knee kinematics, ground reaction force and temporal gait data, combined with anthropometric data from 32 healthy and 32 osteoarthritis knees. For the osteoarthritic cohort, classification of 20 subjects quantified changes at up to 3 timepoints post-surgery. Findings Osteoarthritic classification was reduced for 17 subjects when comparing pre- to post-operative assessments, however only 6 participants achieved non-pathological classification and only 4 of these were classified as non-pathological at 12 months. In 15 cases, the level of osteoarthritic classification did not decrease between every post-operative assessment. For an individual's recovery, classification outputs correlated (r > 0.5) with knee outcome survey for 75% of patients and oxford knee score for 78% of patients (based on 20 and 9 subjects respectively). Classifier outputs from all visits of the combined total knee replacement sample correlated moderately with knee outcome survey (r > 0.4) and strongly with oxford knee score (r > 0.6). Interpretation Biomechanical deficits existed in most subjects despite improvements in Patient Reported Outcome Measures, with larger changes reported subjectively as compared to measured objectively. Objective Classification provides additional insight alongside Patient Reported Outcomes when reporting recovered outcomes

Correlations between patient-perceived outcome and objectively-measured biomechanical change following total knee replacement

Background: Total Knee Replacement (TKR) surgery is being utilised in a younger, more active population with greater functional expectations. Understanding whether patient-perceived measures of function reflect objective biomechanical measures is critical in understanding whether functional limitations can be adequately captured within a clinical setting. Research Question: Do changes in objective gait biomechanics measures reflect patient-reported outcome measures at approximately 12 months following TKR surgery? Methods: Three-dimensional gait analysis was performed on 41 patients with OA who were scheduled for TKR surgery, 22 of which have returned for a (9–24 month) follow-up assessment. Principal Component Analysis was used to define features of variation between OA subjects and an additional 31 non-pathological control subjects. These were used to train the Cardiff Classifier, an objective classification technique, and subsequently quantify changes following TKR surgery. Patient-perceived changes were also assessed using the Oxford Knee Score (OKS), Knee Outcome Survey (KOS), and Pain Audit Collection System scores (PACS). Pearson and Spearman correlation coefficients were calculated to establish the relationship between changes in objectively-measured and perceived outcome

Combined effect of toe out gait and high tibial osteotomy on knee adduction moment in patients with varus knee deformity

Background Gait adaptations, including toe out gait, have been proposed as treatments for knee osteoarthritis. The clinical application of toe out gait, however, is unclear. This study aims to identify the changes in Knee adduction moment in varus knee deformity assessing toe out gait as an alternative to high tibial osteotomy, and if any change in dynamic loading persists post operatively, when anatomical alignment is restored. Methods Three-dimensional motion analysis was performed on 17 patients with medial compartment knee osteoarthritis and varus deformity prior to undergoing high tibial osteotomy, 13 patients were assessed post-operatively, and results compared to 13 healthy controls. Findings Pre-operatively, there was no significant difference between natural and toe out gait for measures of knee adduction moment. Post high tibial osteotomy, first (2.70 to 1.51% BW·h) and second peak (2.28 to 1.21% BW·h) knee adduction moment were significantly reduced, as was knee adduction angular impulse (1.00 to 0.52% BW·h·s), to a healthy level. Adopting toe out gait post-operatively reduced the second peak further to a level below that of healthy controls. Interpretation Increasing the foot progression angle from 20° (natural) to 30° in isolation did not significantly alter the knee adduction moment or angular impulse. This suggests that adopting a toe out gait, in isolation, in an already high natural foot progression angle, is not of benefit. Adopting toe out gait post-operatively, however, resulted in a further reduction in the second peak to below that of the healthy control cohort, however, this may increase lateral compartment load

The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids

There is a high unmet need for developing treatments for nonalcoholic fatty liver disease (NAFLD), for which there are no approved drugs today. Here, we used a human in vitro disease model to understand mechanisms linked to genetic risk variants associated with NAFLD. The model is based on 3D spheroids from primary human hepatocytes from five different donors. Across these donors, we observed highly reproducible differences in the extent of steatosis induction, demonstrating that inter-donor variability is reflected in the in vitro model. Importantly, our data indicates that the genetic variant TM6SF2 E167K, previously associated with increased risk for NAFLD, induces increased hepatocyte fat content by reducing APOB particle secretion. Finally, differences in gene expression pathways involved in cholesterol, fatty acid and glucose metabolism between wild type and TM6SF2 E167K mutation carriers (N = 125) were confirmed in the in vitro model. Our data suggest that the 3D in vitro spheroids can be used to investigate the mechanisms underlying the association of human genetic variants associated with NAFLD. This model may also be suitable to discover new treatments against NAFLD

The Application of NCaRBS to the Trendelenburg Test and Total Hip Arthroplasty Outcome

This paper compares the frontal plane hip func- tion of subject’s known to have had hip arthroplasty via either the lateral (LA) or posterior (PA) surgical approaches and a group of subjects associated with no pathology (NP). This is investigated through the Trendelenburg test using 3D motion analysis and classification. Here, a recent develop- ment on the Classification and Ranking Belief Simplex (CaRBS) technique, able to undertake n-state classification, so termed NCaRBS is employed. The relationship between post-operative hip function measured during a Trendelen- burg Test using three patient characteristics (pelvic obliquity, frontal plane hip moment and frontal plane hip power) of LA, PA and NP subjects are modelled together. Using these characteristics, the classification accuracy was 93.75% for NP, 57.14% for LA, 38.46% for PA. There was a clear distinction between NP and post-surgical function. 3/6 LA subjects and 6/8 PA subjects were misclassified as having NP function, implying that greater function is restored following the PA to surgery. NCaRBS achieved a higher accuracy (65.116%) than through a linear discriminant analysis (48.837%). A Neural Network with two-nodes achieved the same accuracy (65.116%) and as expected was further improved with three-nodes (69.767%). A valuable benefit to the employment of the NCaRBS technique is the graphical exposition of the contribution of patient characteristics to the classification analysis

Immunohistochemical and transcriptional expression of Matrix Metalloproteinases in full-term human umbilical cord and Human Umbilical Vein Endothelial Cells

Matrix metalloproteinases (MMPs) are extracellular zinc-dependent endopeptidases involved in the degradation and remodelling of extracellular matrix in physiological and pathological processes. MMPs also have a role on cell proliferation, migration, differentiation, angiogenesis and apoptosis. Umbilical cord is a special organ subjected to many changes during pre-natal life and whose cells can maintain a certain degree of plasticity also in post-natal period; for example recently they have been used as a source of stem cells. In this work we investigated the expression of MMPs in human umbilical cord and Human Umbilical Vein Endothelial Cells (HUVEC) though immunohistochemistry, RT-PCR and gelatin zymography. MMP-2 protein is expressed in the amniotic epithelium of human umbilical cord and in few sub-epithelial fibroblasts, while MMP-3 and MMP-10 only in the umbilical epithelium. MMP-8, MMP-9 and MMP-13 immunoreactivity is localised in the epithelium and in Wharton\u2019s jelly mesenchymal cells. Immunocytochemistry also revealed protein expression for MMP-2, 3, 8, 9 and 10 in cultured HUVEC. In agreement with immunohistochemical data, RT-PCR analysis performed on samples of whole umbilical cord confirmed the transcriptional expression for the genes encoding all the six matrix metalloproteinases investigated, while in HUVEC only the expression of MMP-2, 3, 9, 10 and 13 mRNAs was detected. Gelatin zymograpgy showed a clear MMP-2 and MMP-9 enzymatic activity in the conditioned medium of HUVEC at different culture passages, suggesting that HUVEC secrete gelatinases, that afterwards undergo extracellular activation, and this ability is not affected by passage number

A Common Polymorphism in the Promoter Region of the TNFSF4 Gene Is Associated with Lower Allele-Specific Expression and Risk of Myocardial Infarction

BACKGROUND: The TNFSF4/TNFRSF4 system, along with several other receptor-ligand pairs, is involved in the recruitment and activation of T-cells and is therefore tentatively implicated in atherosclerosis and acute coronary syndromes. We have previously shown that genetic variants in TNFSF4 are associated with myocardial infarction (MI) in women. This prompted functional studies of TNFSF4 expression. METHODS AND RESULTS: Based on a screening of the TNFSF4 genomic region, a promoter polymorphism (rs45454293) and a haplotype were identified, conceivably involved in gene regulation. The rs45454293T-allele, in agreement with the linked rs3850641G-allele, proved to be associated with increased risk of MI in women. Haplotype-specific chromatin immunoprecipitation of activated polymerase II, as a measure of transcriptional activity in vivo, suggested that the haplotype including the rs45454293 and rs3850641 polymorphisms is functionally important, the rs45454293T- and rs3850641G-alleles being associated with lower transcriptional activity in cells heterozygous for both polymorphisms. The functional role of rs45454293 on transcriptional levels of TNFSF4 was clarified by luciferase reporter assays, where the rs45454293T-allele decreased gene expression when compared with the rs45454293C-allele, while the rs3850641 SNP did not have any effect on TNFSF4 promoter activity. Electromobility shift assay showed that the rs45454293 polymorphism, but not rs3850641, affects the binding of nuclear factors, thus suggesting that the lower transcriptional activity is attributed to binding of one or more transcriptional repressor(s) to the T-allele. CONCLUSIONS: Our data indicate that the TNFSF4 rs45454293T-allele is associated with lower TNFSF4 expression and increased risk of MI

Modelling clinical narrative as computable knowledge: The NICE computable implementation guidance project

Introduction: Translating narrative clinical guidelines to computable knowledge is a long‐standing challenge that has seen a diverse range of approaches. The UK National Institute for Health and Care Excellence (NICE) Content Advisory Board (CAB) aims ultimately to (1) guide clinical decision support and other software developers to increase traceability, fidelity and consistency in supporting clinical use of NICE recommendations, (2) guide local practice audit and intervention to reduce unwarranted variation, (3) provide feedback to NICE on how future recommendations should be developed. Objectives: The first phase of work was to explore a range of technical approaches to transition NICE toward the production of natively digital content. Methods: Following an initial ‘collaborathon’ in November 2022, the NICE Computable Implementation Guidance project (NCIG) was established. We held a series of workstream calls approximately fortnightly, focusing on (1) user stories and trigger events, (2) information model and definitions, (3) horizon‐scanning and output format. A second collaborathon was held in March 2023 to consolidate progress across the workstreams and agree residual actions to complete. Results: While we initially focussed on technical implementation standards, we decided that an intermediate logical model was a more achievable first step in the journey from narrative to fully computable representation. NCIG adopted the WHO Digital Adaptation Kit (DAK) as a technology‐agnostic method to model user scenarios, personae, processes and workflow, core data elements and decision‐support logic. Further work will address indicators, such as prescribing compliance, and implementation in document templates for primary care patient record systems. Conclusions: The project has shown that the WHO DAK, with some modification, is a promising approach to build technology‐neutral logical specifications of NICE recommendations. Implementation of concurrent computable modelling by multidisciplinary teams during guideline development poses methodological and cultural questions that are complex but tractable given suitable will and leadership

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe