A Combined Geometric Morphometric and Discrete Element Modeling Approach for Hip Cartilage Contact Mechanics.

Finite element analysis (FEA) provides the current reference standard for numerical simulation of hip cartilage contact mechanics. Unfortunately, the development of subject-specific FEA models is a laborious process. Owed to its simplicity, Discrete Element Analysis (DEA) provides an attractive alternative to FEA. Advancements in computational morphometrics, specifically statistical shape modeling (SSM), provide the opportunity to predict cartilage anatomy without image segmentation, which could be integrated with DEA to provide an efficient platform to predict cartilage contact stresses in large populations. The objective of this study was, first, to validate linear and non-linear DEA against a previously validated FEA model and, second, to present and evaluate the applicability of a novel population-averaged cartilage geometry prediction method against previously used methods to estimate cartilage anatomy. The population-averaged method is based on average cartilage thickness maps and therefore allows for a more accurate and individualized cartilage geometry estimation when combined with SSM. The root mean squared error of the population-averaged cartilage geometry predicted by SSM as compared to the manually segmented cartilage geometry was 0.31 ± 0.08 mm. Identical boundary and loading conditions were applied to the DEA and FEA models. Predicted DEA stress distribution patterns and magnitude of peak stresses were in better agreement with FEA for the novel cartilage anatomy prediction method as compared to commonly used parametric methods based on the estimation of acetabular and femoral head radius. Still, contact stress was overestimated and contact area was underestimated for all cartilage anatomy prediction methods. Linear and non-linear DEA methods differed mainly in peak stress results with the non-linear definition being more sensitive to detection of high peak stresses. In conclusion, DEA in combination with the novel population-averaged cartilage anatomy prediction method provided accurate predictions while offering an efficient platform to conduct population-wide analyses of hip contact mechanics

Clinical observation of diminished bone quality and quantity through longitudinal HR-pQCT-derived remodeling and mechanoregulation.

High resolution peripheral quantitative computed tomography (HR-pQCT) provides methods for quantifying volumetric bone mineral density and microarchitecture necessary for early diagnosis of bone disease. When combined with a longitudinal imaging protocol and finite element analysis, HR-pQCT can be used to assess bone formation and resorption (i.e., remodeling) and the relationship between this remodeling and mechanical loading (i.e., mechanoregulation) at the tissue level. Herein, 25 patients with a contralateral distal radius fracture were imaged with HR-pQCT at baseline and 9-12 months follow-up: 16 patients were prescribed vitamin D3 with/without calcium supplement based on a blood biomarker measures of bone metabolism and dual-energy X-ray absorptiometry image-based measures of normative bone quantity which indicated diminishing (n = 9) or poor (n = 7) bone quantity and 9 were not. To evaluate the sensitivity of this imaging protocol to microstructural changes, HR-pQCT images were registered for quantification of bone remodeling and image-based micro-finite element analysis was then used to predict local bone strains and derive rules for mechanoregulation. Remodeling volume fractions were predicted by both average values of trabecular and cortical thickness and bone mineral density (R2 > 0.8), whereas mechanoregulation was affected by dominance of the arm and group classification (p < 0.05). Overall, longitudinal, extended HR-pQCT analysis enabled the identification of changes in bone quantity and quality too subtle for traditional measures

Precision of bone mechanoregulation assessment in humans using longitudinal high-resolution peripheral quantitative computed tomography in vivo.

Local mechanical stimuli in the bone microenvironment are essential for the homeostasis and adaptation of the skeleton, with evidence suggesting that disruption of the mechanically-driven bone remodelling process may lead to bone loss. Longitudinal clinical studies have shown the combined use of high-resolution peripheral quantitative computed tomography (HR-pQCT) and micro-finite element analysis can be used to measure load-driven bone remodelling in vivo; however, quantitative markers of bone mechanoregulation and the precision of these analyses methods have not been validated in human subjects. Therefore, this study utilised participants from two cohorts. A same-day cohort (n = 33) was used to develop a filtering strategy to minimise false detections of bone remodelling sites caused by noise and motion artefacts present in HR-pQCT scans. A longitudinal cohort (n = 19) was used to develop bone imaging markers of trabecular bone mechanoregulation and characterise the precision for detecting longitudinal changes in subjects. Specifically, we described local load-driven formation and resorption sites independently using patient-specific odds ratios (OR) and 99 % confidence intervals. Conditional probability curves were computed to link the mechanical environment to the remodelling events detected on the bone surface. To quantify overall mechanoregulation, we calculated a correct classification rate measuring the fraction of remodelling events correctly identified by the mechanical signal. Precision was calculated as root-mean-squared averages of the coefficient of variation (RMS-SD) of repeated measurements using scan-rescan pairs at baseline combined with a one-year follow-up scan. We found no significant mean difference (p < 0.01) between scan-rescan conditional probabilities. RMS-SD was 10.5 % for resorption odds, 6.3 % for formation odds, and 1.3 % for correct classification rates. Bone was most likely to be formed in high-strain and resorbed in low-strain regions for all participants, indicating a consistent, regulated response to mechanical stimuli. For each percent increase in strain, the likelihood of bone resorption decreased by 2.0 ± 0.2 %, and the likelihood of bone formation increased by 1.9 ± 0.2 %, totalling 38.3 ± 1.1 % of strain-driven remodelling events across the entire trabecular compartment. This work provides novel robust bone mechanoregulation markers and their precision for designing future clinical studies

Combination of Statistical Shape Modeling and Statistical Parametric Mapping to Quantify Cartilage Contact Mechanics in Hip Dysplasia

Finite element models can predict subject-specific chondrolabral stresses and help to elucidate the effect of under-coverage and incongruency of the hip joint in patients with dysplasia. However, complex stress patterns are difficult to generalize and evaluate statistically. With an established correspondence across shapes from statistical shape modeling (SSM), statistical parametric mapping (SPM) allows for evaluation of local variability while preserving model subject-specificity. Herein, we evaluated the combined application of SSM and SPM to compare cartilage contact stress between control subjects and patients with dysplasia. Previously published hip joint contact stresses were mapped onto chondrolabral surface meshes and incorporated into an SSM. Principal component analysis (PCA) quantified shape variation. Contact stress values from heel-strike of stair ascent (AH), stair descent (DH), and level walking (WH) and mid-stance of level walking (WM) were evaluated. Using SPM, regions of significant contact stress variation were identified based on test statistics from general linear statistical models and corrected for multiple comparisons using Gaussian random fields. Shape differences of the femoral and acetabular cartilage with labrum were captured by two and one PCA mode, respectively. Contact stress differences were observed in anterosuperior regions of the femoral cartilage for AH and DH and of the acetabular cartilage for DH and WM (Figure 1). The SPM identified regions of varied contact stresses were small and likely would have been diluted through averaging or region-splitting using traditional analysis methods. The combined application of SSM and SPM provides a method to generalize and statistically-compare subject-specific mechanics and joint morphology

Application of Statistical Shape Modeling to Predict Clinical Metric of Femoral Head Coverage in Patients with Developmental Dysplasia

Developmental dysplasia of the hip (DDH) is described as under-coverage of the femoral head by the acetabulum, resulting in mechanical instability. Though DDH is often diagnosed using plain film radiographs, these images cannot adequately capture 3D joint coverage. Herein, we applied a 3D statistical shape model (SSM) to the femur and hemi-pelvis of patients with DDH to objectively measure shape variation and evaluated whether SSM outputs could predict measurements of joint coverage. The femur and hemi-pelvis were semi-automatically segmented from CT images (83 hips from 47 females with DDH). Surfaces of each hip were reconstructed from segmentations, aligned, and input into a multi-domain SSM (shapeworks.sci.utah.edu). Correspondence particles were automatically placed over the bone surfaces and a subset on the femoral head and acetabulum were isolated for a joint-specific model. Modes of shape variation were determined with principal component analysis (PCA). A sparse model of PCA modes predicting coverage was determined using linear regression with Lasso regularization. Coverage measurements ranged from 27.3% to 39.4%. Eight and 13 modes were selected for the full bone and joint-specific models, respectively. These modes represented 6.1% and 39.6% of the overall shape variation for full bone and joint-specific models with mean prediction errors of 0.9% and 0.6% coverage, respectively (Figure 1). Selected modes represented the depth of the acetabulum and oblateness of the femoral head, aligning well with the clinical description of DDH. In addition, the full bone model captured morphological and pose-related differences potentially related to altered muscle paths or differences in femoral torsion

Qualitative meta-synthesis of user experience of computerised therapy for depression and anxiety

Objective: Computerised therapies play an integral role in efforts to improve access to psychological treatment for patients with depression and anxiety. However, despite recognised problems with uptake, there has been a lack of investigation into the barriers and facilitators of engagement. We aimed to systematically review and synthesise findings from qualitative studies of computerised therapies, in order to identify factors impacting on engagement. Method: Systematic review and meta-synthesis of qualitative studies of user experiences of computer delivered therapy for depression and/or anxiety. Results: 8 studies were included in the review. All except one were of desktop based cognitive behavioural treatments. Black and minority ethnic and older participants were underrepresented, and only one study addressed users with a comorbid physical health problem. Through synthesis, we identified two key overarching concepts, regarding the need for treatments to be sensitive to the individual, and the dialectal nature of user experience, with different degrees of support and anonymity experienced as both positive and negative. We propose that these factors can be conceptually understood as the ‘non-specific’ or ‘common’ factors of computerised therapy, analogous to but distinct from the common factors of traditional face-to-face therapies. Conclusion: Experience of computerised therapy could be improved through personalisation and sensitisation of content to individual users, recognising the need for users to experience a sense of ‘self’ in the treatment which is currently absent. Exploiting the common factors of computerised therapy, through enhancing perceived connection and collaboration, could offer a way of reconciling tensions due to the dialectal nature of user experience. Future research should explore whether the findings are generalisable to other patient groups, to other delivery formats (such as mobile technology) and other treatment modalities beyond cognitive behaviour therapy. The proposed model could aid the development of enhancements to current packages to improve uptake and support engagement

The Pochonia chlamydosporia Serine Protease Gene vcp1 Is Subject to Regulation by Carbon, Nitrogen and pH: Implications for Nematode Biocontrol

The alkaline serine protease VCP1 of the fungus Pochonia chlamydosporia belongs to a family of subtilisin-like enzymes that are involved in infection of nematode and insect hosts. It is involved early in the infection process, removing the outer proteinaceous vitelline membrane of nematode eggs. Little is known about the regulation of this gene, even though an understanding of how nutrients and other factors affect its expression is critical for ensuring its efficacy as a biocontrol agent. This paper provides new information on the regulation of vcp1 expression. Sequence analysis of the upstream regulatory region of this gene in 30 isolates revealed that it was highly conserved and contained sequence motifs characteristic of genes that are subject to carbon, nitrogen and pH-regulation. Expression studies, monitoring enzyme activity and mRNA, confirmed that these factors affect VCP1 production. As expected, glucose reduced VCP1 expression and for a few hours so did ammonium chloride. Surprisingly, however, by 24 h VCP1 levels were increased in the presence of ammonium chloride for most isolates. Ambient pH also regulated VCP1 expression, with most isolates producing more VCP1 under alkaline conditions. There were some differences in the response of one isolate with a distinctive upstream sequence including a variant regulatory-motif profile. Cryo-scanning electron microscopy studies indicated that the presence of nematode eggs stimulates VCP1 production by P. chlamydosporia, but only where the two are in close contact. Overall, the results indicate that readily-metabolisable carbon sources and unfavourable pH in the rhizosphere/egg-mass environment may compromise nematode parasitism by P. chlamydosporia. However, contrary to previous indications using other nematophagous and entomopathogenic fungi, ammonium nitrate (e.g. from fertilizers) may enhance biocontrol potential in some circumstances

Abstracts from the NIHR INVOLVE Conference 2017

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The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder