Evaluation of multi-segmental kinematic modelling in the paediatric foot using three concurrent foot models

Background: Various foot models are used in the analysis of foot motion during gait and selection of the appropriate model can be difficult. The clinical utility of a model is dependent on the repeatability of the data as well as an understanding of the expected error in the process of data collection. Kinematic assessment of the paediatric foot is challenging and little is reported about multi-segment foot models in this population. The aim of this study was to examine three foot models and establish their concurrent test-retest repeatability in evaluation of paediatric foot motion during gait. Methods: 3 DFoot, Kinfoot and the Oxford Foot Model (OFM) were applied concurrently to the right foot and lower limb of 14 children on two testing sessions. Angular data for foot segments were extracted at gait cycle events and peaks and compared between sessions by intraclass correlation coefficient (ICC) with 95% confidence intervals (95% CI) and standard error of measurement (SEM). Results: All foot models demonstrated moderate repeatability: OFM (ICC 0.55, 95% CI 0.16 to 0.77), 3DFoot (ICC 0.47, 95% CI 0.15 to 0.64) and Kinfoot (ICC 0.43, 95% CI − 0.03 to 0.59). On the basis of a cut-off of 5°, acceptable mean error over repeated sessions was observed for OFM (SEM 4.61° ± 2.86°) and 3DFoot (SEM 3.88° ± 2.18°) but not for Kinfoot (SEM 5.08° ± 1.53°). Reliability of segmental kinematics varied, with low repeatability (ICC < 0.4) found for 14.3% of OFM angles, 22.7% of 3DFoot angles and 37.6% of Kinfoot angles. SEM greater than 5° was found in 26.2% of OFM, 15.2% of 3DFoot, and 43.8% of Kinfoot segmental angles. Conclusion: Findings from this work have demonstrated that segmental foot kinematics are repeatable in the paediatric foot but the level of repeatability and error varies across the segments of the different models. Information on repeatability and test-retest errors of three-dimensional foot models can better inform clinical assessment and advance understanding of foot motion during gai

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Alterations in human muscle and central control mechanisms

Research has shown that skeletal muscle, despite showing a high degree of specialisation, has a remarkable ability to modify its properties. Understanding these changes is important for optimal response to therapeutic intervention. These studies investigated alterations in neuromuscular performance of quadriceps femoris muscle in normal subjects, before investigating changes in muscle and neural mechanisms in the first six months following stroke. Muscle function studies were conducted to monitor the effects of selected patterns of long term electrical stimulation (PI - uniform 8 Hz, P2 - mixed frequency, and P3 random high and low frequency) on quadriceps femoris of 21 healthy subjects. Stimulated muscles showed significant increases in strength, fatigue resistance and relaxation times after 3 weeks and in force-frequency output after 6 weeks. Significant changes were observed in the stimulated muscles in Groups P2 and P3 indicating that a mixed or random pattern of activation induced greater changes than a uniform 8 Hz pattern. These studies together with soleus H reflexes were used to study concurrent changes in quadriceps femoris and la spinal reflex pathways of stroke patients and age-matched controls (n=10). One month following stroke, both paretic and non-paretic muscles were more fatiguable and weaker than the muscles of controls and disynaptic and presynaptic inhibition were reduced in the paretic limbs. In subsequent months, the paretic muscles regained strength and inhibitory effects were restored. Subjective analysis suggested that different patterns of recovery related to walking ability at six months. In patients taking less than 15s to walk 10m (Group 1 n=5), the paretic muscles became significantly stronger and less fatiguable over time whereas the muscles of patients who took longer to walk 10m (Group 2 n=5) remained weaker and more fatiguable. Reciprocal inhibition was regained by 1 month in Group 1 and by 6 months in Group 2. These findings provide insight into long-term recovery and rationale for therapeutic intervention following stroke

Effectiveness of a community-based low intensity exercise programme for ambulatory stroke survivors

Purpose. To establish the feasibility and effectiveness of a community-based exercise programme for ambulatory patients with stroke discharged from rehabilitation Method. Eighteen participants were recruited 3-12 months after onset of first stroke. Using a time series experimental design, the group completed a baseline period of 4 weeks (A1), a group exercise programme of low-intensity progressive resistive exercise and functional tasks for lower limb muscles (B) and repeat assessment after cessation of exercise (A2). Fitness instructors delivered sessions at Leisure Centres twice weekly for 14 weeks with physiotherapy support and the minimum attendance requirement was 16 sessions. Measures included muscle strength, gait velocity, Berg Balance Scale and Nottingham Extended Activities of Daily Living. Results. Lower limb muscle strength improved after training (ANOVA,

Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score.

BACKGROUND Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. METHODS We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. FINDINGS 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79-0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=-0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present). INTERPRETATION We have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis. FUNDING UK Medical Research Council and University of Milan-Bicocca

Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score.

BACKGROUND: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. METHODS: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. FINDINGS: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79-0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=-0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present). INTERPRETATION: We have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis. FUNDING: UK Medical Research Council and University of Milan-Bicocca

X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis.

BACKGROUND & AIMS: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. METHODS: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). RESULTS: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10(-4), with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10(-6); odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10(-8)), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10(-9); OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). CONCLUSIONS: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.The article is available via Open Access. Click on the 'Additional link' above to access the full-text.Published version, accepted versio