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

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 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

Assessing changes in subjective and objective function from pre- to post-knee arthroplasty using the Cardiff Dempster–Shafer theory classifier

The purpose of this study is to assess changes in subjective and objective function from pre- to post-knee arthroplasty (KA) using a combined classifier technique. Twenty healthy adults (50–80 years) and 31 KA patients (39–81 years) were studied (4 weeks pre- and 6 months post-KA). Questionnaire measures of subjective pain, joint stability, activity and function were collected. Objective functional assessment included goniometry, ultrasound imaging and 3-D motion analysis/inverse modelling of gait and sit–stand. An optimal set of variables were used to classify function using the Cardiff Dempster–Shafer theory (DST) method. Out of sample accuracy of the classifiers ranged between 90% and 94% for segregating healthy individuals and pre-KA patients. Post-KA subjective function improved with 74% classified as healthy. However, there was minimal improvement in objective measures (23% classified as healthy). The novel use of Cardiff DST segregated KA patients from healthy individuals and estimated changes in function from pre- to post-surgery. KA patients had improved pain and function post-operation but objective knee joint measures remained different to healthy individuals