Explore the vast range of titles available.

In many biomechanical analyses, the forces acting on a body during dynamic and static activities are often simplified as point loads. However, it is usually more accurate to characterize these forces as distributed loads, varying in magnitude and direction, over a given contact area. Evaluating these pressure distributions while they are applied to different parts of the body can provide effective insights for clinicians and researchers when studying health and disease conditions, for example when investigating the biomechanical factors that may lead to plantar ulceration in diabetic foot disease. At present, most processing and analysis for pressure data is performed using proprietary software, limiting reproducibility, transparency, and consistency across different studies. This paper describes an open-source software package, ‘pressuRe’, which is built in the freely available R statistical computing environment and is designed to process, analyze, and visualize pressure data collected on a range of different hardware systems in a standardized manner. We demonstrate the use of the package on pressure dataset from patients with diabetic foot disease, comparing pressure variables between those with longer and shorter durations of the disease. The results matched closely with those from commercially available software, and individuals with longer duration of diabetes were found to have higher forefoot pressures than those with shorter duration. By utilizing R’s powerful and openly available tools for statistical analysis and user customization, this package may be a useful tool for researchers and clinicians studying plantar pressures and other pressure sensor array based biomechanical measurements. With regular updates intended, this package allows for continued improvement and we welcome feedback and future contributions to extend its scope. In this article, we detail the package’s features and functionality.

In order to assess potential associations between autism spectrum disorder (ASD) phenotype, functional GI disorders and fecal microbiota, we recruited simplex families, which had only a single ASD proband and neurotypical (NT) siblings, through the Simons Simplex Community at the Interactive Autism Network (SSC@IAN). Fecal samples and metadata related to functional GI disorders and diet were collected from ASD probands and NT siblings of ASD probands (age 7-14). Functional gastrointestinal disorders (FGID) were assessed using the parent-completed ROME III questionnaire for pediatric FGIDs, and problem behaviors were assessed using the Child Behavior Check List (CBCL). Targeted quantitative polymerase chain reaction (qPCR) assays were conducted on selected taxa implicated in ASD, including Sutterella spp., Bacteroidetes spp. and Prevotella spp. Illumina sequencing of the V1V2 and the V1V3 regions of the bacterial 16S rRNA genes from fecal DNA was performed to an average depth of 208,000 and 107,000 high-quality reads respectively. Twenty-five of 59 ASD children and 13 of 44 NT siblings met ROME III criteria for at least one FGID. Functional constipation was more prevalent in ASD (17 of 59) compared to NT siblings (6 of 44, P = 0.035). The mean CBCL scores in NT siblings with FGID, ASD children with FGID and ASD without FGID were comparably higher (58-62 vs. 44, P < 0.0001) when compared to NT children without FGID. There was no significant difference in macronutrient intake between ASD and NT siblings. There was no significant difference in ASD severity scores between ASD children with and without FGID. No significant difference in diversity or overall microbial composition was detected between ASD children with NT siblings. Exploratory analysis of the 16S rRNA sequencing data, however, identified several low abundance taxa binned at the genus level that were associated with ASD and/or first order ASD*FGID interactions (FDR <0.1).

Abnormalities of the intestinal microbiota are implicated in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC), two spectra of inflammatory bowel disease (IBD). However, the high complexity and low inter-individual overlap of intestinal microbial composition are formidable barriers to identifying microbial taxa representing this dysbiosis. These difficulties might be overcome by an ecologic analytic strategy to identify modules of interacting bacteria (rather than individual bacteria) as quantitative reproducible features of microbial composition in normal and IBD mucosa. We sequenced 16S ribosomal RNA genes from 179 endoscopic lavage samples from different intestinal regions in 64 subjects (32 controls, 16 CD and 16 UC patients in clinical remission). CD and UC patients showed a reduction in phylogenetic diversity and shifts in microbial composition, comparable to previous studies using conventional mucosal biopsies. Analysis of weighted co-occurrence network revealed 5 microbial modules. These modules were unprecedented, as they were detectable in all individuals, and their composition and abundance was recapitulated in an independent, biopsy-based mucosal dataset 2 modules were associated with healthy, CD, or UC disease states. Imputed metagenome analysis indicated that these modules displayed distinct metabolic functionality, specifically the enrichment of oxidative response and glycan metabolism pathways relevant to host-pathogen interaction in the disease-associated modules. The highly preserved microbial modules accurately classified IBD status of individual patients during disease quiescence, suggesting that microbial dysbiosis in IBD may be an underlying disorder independent of disease activity. Microbial modules thus provide an integrative view of microbial ecology relevant to IBD.

The plantar aponeurosis functions to support the foot arch during weight bearing. Accurate anatomy and material properties are critical in developing analytical and computational models of this tissue. We determined the cross-sectional areas and material properties of four regions of the plantar aponeurosis: the proximal middle and distal middle portions of the tissue and the medial (to the first ray) and lateral (to the fifth ray) regions. Bone-plantar aponeurosis-bone specimens were harvested from fifteen cadaveric feet. Cross-sectional areas were measured using molding, casting, and sectioning methods. Mechanical testing was performed using displacement control triangle waves (0.5, 1, 2, 5, and 10 Hz) loaded to physiologic tension by estimating from body weight and area ratio of the region. Five specimens were tested for each region. Regional deformations were recorded by a high-speed video camera. There were overall differences in cross-sectional areas and biomechanical behavior across regions. The stress–strain responses are non-linear and mainly elastic (energy loss 3.6% to 7.2%). Moduli at the proximal middle and distal middle regions (400 and 522 MPa) were significantly higher than the medial and lateral regions (225 and 242 MPa). The effect of frequency on biomechanical outcomes was small (e.g., 3.5% change in modulus), except for energy loss (107% increase as frequency increased from 0.5 to 10 Hz). These results indicate that the plantar aponeurosis tensile response is non-linear, nearly elastic, and frequency independent. The cross-sectional area and material properties differ by region, and we suggest that such differences be included to accurately model this structure.

Individuals with diabetes are at a higher risk of developing foot ulcers. To better understand internal soft tissue loading and potential treatment options, subject-specific finite element (FE) foot models have been used. However, existing models typically lack subject-specific soft tissue material properties and only utilize subject-specific anatomy. Therefore, this study determined subject-specific hindfoot soft tissue material properties from one non-diabetic and one diabetic subject using inverse FE analysis. Each subject underwent cyclic MRI experiments to simulate physiological gait and to obtain compressive force and three-dimensional soft tissue imaging data at 16 phases along the loading–unloading cycles. The FE models consisted of rigid bones and nearly-incompressible first-order Ogden hyperelastic skin, fat, and muscle (resulting in six independent material parameters). Then, calcaneus and loading platen kinematics were computed from imaging data and prescribed to the FE model. Two analyses were performed for each subject. First, the skin, fat, and muscle layers were lumped into a single generic soft tissue material and optimized to the platen force. Second, the skin, fat, and muscle material properties were individually determined by simultaneously optimizing for platen force, muscle vertical displacement, and skin mediolateral bulging. Our results indicated that compared to the individual without diabetes, the individual with diabetes had stiffer generic soft tissue behavior at high strain and that the only substantially stiffer multi-material layer was fat tissue. Thus, we suggest that this protocol serves as a guideline for exploring differences in non-diabetic and diabetic soft tissue material properties in a larger population.

Inflammatory bowel disease Crohn's disease, a chronic inflammation of the gut, has been linked to over thirty gene loci. Two papers in this issue focus a recent addition to that list, ATG16L1 (Atg16-like 1). Atg16 protein itself was first identified in yeast as an essential gene for the process of autophagy, a system that clears away unwanted cellular components and is involved in the pathogenesis of microbial infection, neurodegeneration and tumorigenesis. Cadwell et al . report a unique role for Atg16L1 in Paneth cells, a type of epithelial cell that secretes granules containing antimicrobial peptides into the intestines. Saitoh et al . show that ATG16L1 plays a role in the inflammatory response in isolated macrophages and in the mouse intestine, as an essential component of the autophagic machinery. This work implicates Atg16L1 in the control of inflammatory immune response and the maintenance of intestinal barrier, both of which are important for the prevention of inflammatory bowel disease. Susceptibility to Crohn’s disease, a complex inflammatory disease involving the small intestine, is controlled by over 30 loci 1 . One Crohn’s disease risk allele is in ATG16L1 , a gene homologous to the essential yeast autophagy gene ATG16 (ref. 2 ). It is not known how ATG16L1 or autophagy contributes to intestinal biology or Crohn’s disease pathogenesis. To address these questions, we generated and characterized mice that are hypomorphic for ATG16L1 protein expression, and validated conclusions on the basis of studies in these mice by analysing intestinal tissues that we collected from Crohn’s disease patients carrying the Crohn’s disease risk allele of ATG16L1 . Here we show that ATG16L1 is a bona fide autophagy protein. Within the ileal epithelium, both ATG16L1 and a second essential autophagy protein ATG5 are selectively important for the biology of the Paneth cell, a specialized epithelial cell that functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment 3 . ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to ATG16L1-deficient Paneth cells including increased expression of genes involved in peroxisome proliferator-activated receptor (PPAR) signalling and lipid metabolism, of acute phase reactants and of two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, Crohn’s disease patients homozygous for the ATG16L1 Crohn’s disease risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy-protein-deficient mice and expressed increased levels of leptin protein. Thus, ATG16L1, and probably the process of autophagy, have a role within the intestinal epithelium of mice and Crohn’s disease patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells.

Background: Diabetes is associated with an increased risk of colorectal cancer (CRC). We conducted a retrospective analysis of adenoma detection rates (ADR) in initial screening colonoscopies to further investigate the role of diabetes in adenoma detection. Methods: A chart review was performed on initial average risk screening colonoscopies (ages 45–75) during 2012–2015. Data collected included basic demographics, insurance, BMI, family history of CRC, smoking, diabetes, and aspirin use. Multivariable generalized linear mixed models for binary outcomes were used to examine the relationship between diabetes and variables associated with CRC risk and ADR. Results: Of 2865 screening colonoscopies, 282 were performed on patients with type 2 diabetes (T2DM). Multivariable analysis suggested that T2DM (OR = 1.49, 95% CI:1.13–1.97, p = 0.0047) was associated with an increased ADR, as well as smoking, older age, higher BMI and male sex (all p < 0.05). For patients with T2DM, those not taking diabetes medications were more likely to have an adenoma than those taking medication (OR = 2.38, 95% CI:1.09–5.2, p = 0.03). Conclusion: T2DM has an effect on ADR after controlling for multiple confounding variables. Early interventions for prevention of T2DM and prescribing anti-diabetes medications may reduce development of colonic adenomas and may contribute to CRC prevention.

We tested the hypothesis that Crohn's disease (CD)-related genetic polymorphisms involved in host innate immunity are associated with shifts in human ileum-associated microbial composition in a cross-sectional analysis of human ileal samples. Sanger sequencing of the bacterial 16S ribosomal RNA (rRNA) gene and 454 sequencing of 16S rRNA gene hypervariable regions (V1-V3 and V3-V5), were conducted on macroscopically disease-unaffected ileal biopsies collected from 52 ileal CD, 58 ulcerative colitis and 60 control patients without inflammatory bowel diseases (IBD) undergoing initial surgical resection. These subjects also were genotyped for the three major NOD2 risk alleles (Leu1007fs, R708W, G908R) and the ATG16L1 risk allele (T300A). The samples were linked to clinical metadata, including body mass index, smoking status and Clostridia difficile infection. The sequences were classified into seven phyla/subphyla categories using the Naïve Bayesian Classifier of the Ribosome Database Project. Centered log ratio transformation of six predominant categories was included as the dependent variable in the permutation based MANCOVA for the overall composition with stepwise variable selection. Polymerase chain reaction (PCR) assays were conducted to measure the relative frequencies of the Clostridium coccoides - Eubacterium rectales group and the Faecalibacterium prausnitzii spp. Empiric logit transformations of the relative frequencies of these two microbial groups were included in permutation-based ANCOVA. Regardless of sequencing method, IBD phenotype, Clostridia difficile and NOD2 genotype were selected as associated (FDR ≤ 0.05) with shifts in overall microbial composition. IBD phenotype and NOD2 genotype were also selected as associated with shifts in the relative frequency of the C. coccoides--E. rectales group. IBD phenotype, smoking and IBD medications were selected as associated with shifts in the relative frequency of F. prausnitzii spp. These results indicate that the effects of genetic and environmental factors on IBD are mediated at least in part by the enteric microbiota.

The combination therapy of lumacaftor and ivacaftor (Orkambi ® ) is approved for patients bearing the major cystic fibrosis (CF) mutation: ΔF508 . It has been predicted that Orkambi ® could treat patients with rarer mutations of similar “theratype”; however, a standardized approach confirming efficacy in these cohorts has not been reported. Here, we demonstrate that patients bearing the rare mutation: c.3700 A>G, causing protein misprocessing and altered channel function—similar to ΔF508‐CFTR, are unlikely to yield a robust Orkambi ® response. While  in silico  and biochemical studies confirmed that this mutation could be corrected and potentiated by lumacaftor and ivacaftor, respectively, this combination led to a minor in vitro response in patient‐derived tissue. A CRISPR/Cas9‐edited bronchial epithelial cell line bearing this mutation enabled studies showing that an “amplifier” compound, effective in increasing the levels of immature CFTR protein, augmented the Orkambi ® response. Importantly, this “amplifier” effect was recapitulated in patient‐derived nasal cultures—providing the first evidence for its efficacy in augmenting Orkambi ® in tissues harboring a rare CF‐causing mutation. We propose that this multi‐disciplinary approach, including creation of CRISPR/Cas9‐edited cells to profile modulators together with validation using primary tissue, will facilitate therapy development for patients with rare CF mutations. Synopsis Potential strategies for improving function in a rare CF‐causing mutation based on a CRISPR/Cas9‐edited bronchial cell line and patient‐derived nasal cultures. Molecular dynamic simulations predicted the consequences of the rare mutation c.3700 A>G on CFTR protein (ΔI1234_R1239‐CFTR) structure. Misprocessing and altered function of ΔI1234_R1239‐CFTR can be partially ameliorated by small molecule modulators of ΔF508‐CFTR. A CRISPR/Cas9‐edited HBE cell line recapitulates the endogenous expression of ΔI1234_R1239‐CFTR and response to ΔF508‐CFTR modulators. A novel small molecule amplifier (PTI‐CH) improves the effect of the corrector (VX‐809) and potentiator (VX‐770) on ΔI1234_R1239‐CFTR in CRISPR/Cas9‐engineered and patient‐specific tissues. Graphical Abstract Potential strategies for improving function in a rare CF‐causing mutation based on a CRISPR/Cas9‐edited bronchial cell line and patient‐derived nasal cultures.

Specific scapula shapes are associated with full-thickness tears of the supraspinatus tendon. A primary role of the supraspinatus is to actively stabilize the glenohumeral joint against muscles that generate destabilizing shear forces. Mechanisms that increase the supraspinatus load required to perform this stabilizing function may increase an individual's susceptibility to tears. Previous work has shown that tear-associated scapula shapes increase the destabilizing action of the deltoid during arm-raising, but no work has investigated whether tear-associated shapes inhibit the stabilizing potential of the supraspinatus itself. We combined statistical shape modeling, kinematics-driven simulations of the glenohumeral joint, and a finite element model of the supraspinatus to investigate the interactions among shape, kinematics, and the stabilizing potential of the supraspinatus. First, we identified tear-associated 3D scapula shapes using partial least squares discriminant analysis. Second, we examined how tear-associated shapes alter the stabilizing potential of the supraspinatus given the same kinematic path. Finally, we examined the extent to which kinematic perturbations could modulate differences in stabilizing potential. Relative to asymptomatic controls, individuals with full-thickness tears possessed a suite of 3D shape differences including narrower supraspinous fossae and anteverted glenoids. For the same abduction path, tear-associated scapula shapes caused supraspinatus fibres to act more anteriorly and less compressively compared to the control shapes, potentially inhibiting the supraspinatus' ability to stabilize the humeral head. When the abduction path of the tear-associated scapula was internally rotated and shifted anteriorly, the supraspinatus line-of-action closely resembled that of the control-associated scapula; however, the tear-associated shape still possessed a narrower breadth in its supraspinatus line-of-action. Our findings indicate that tear-associated scapula geometry may inhibit the stabilizing potential of the supraspinatus, but this shape-driven change could be partially modulated when the abduction path of the tear-associated shape was perturbed. The magnitude of kinematic perturbations required to modulate function exceeded the magnitude of shape differences, indicating that the perturbations are not correcting for a simple offset, but rather complex changes in muscle geometry that occur due to 3D shape differences.