Impact of foot progression angle modification on plantar loading in individuals with diabetes mellitus and peripheral neuropathy

AIMS: To determine if participants can reduce foot progression angle (FPA), and if FPA reduction decreases regional plantar stresses and forces in individuals with diabetes. METHODS: DESIGN: Three-group cross-sectional design with repeated measures. SUBJECTS: twenty-eight participants either with diabetes mellitus (DM), diabetes and peripheral neuropathy with (DMPN+NPU) or without a prior history of ulceration (DMPN−NPU) were studied. INTERVENTION: Participants were first instructed to walk over a 3.6 m walkway at their preferred FPA, and then to walk with their foot aligned parallel with the line of gait progression at their self-selected speed. Dynamic plantar kinetics in six masked regions were collected using an EMED-st-P-2 pedobarograph. MAIN MEASURES: Primary outcome measures were FPA, peak plantar pressure (PPP), and force-time integral (FTI). A repeated measures ANOVA was conducted to determine group differences in FPA for both walking conditions. Regional differences in PPPs and FTIs between preferred and corrected walking conditions were analyzed using repeated measures ANCOVA. RESULTS: Participants showed a reduction in FPA magnitude on the ‘Involved’ foot between the preferred and corrected walking conditions (p<0.01). There were no differences in PPPs or FTIs in any mask between walking conditions (p>0.05). CONCLUSION: Results from this investigation offer important evidence that people with diabetes can modify their FPA with a simple intervention of visual and verbal cueing. Future research should examine if gait retraining strategies in regular footwear more effectively offload areas of elevated regional plantar stresses and forces in adults with diabetes mellitus and peripheral neuropathy

Progression of foot deformity in charcot neuropathic osteoarthropathy

BACKGROUND: Charcot neuropathic osteoarthropathy associated foot deformity can result in joint instability, ulceration, and even amputation. The purpose of the present study was to follow patients with and without active Charcot osteoarthropathy for as long as two years to examine the magnitude and timing of foot alignment changes. METHODS: We studied fifteen subjects with Charcot osteoarthropathy and nineteen subjects with diabetes mellitus and peripheral neuropathy without Charcot osteoarthropathy for one year; eight of the subjects with osteoarthropathy and five of the subjects with diabetes and peripheral neuropathy were followed for two years. Bilateral weight-bearing radiographs of the foot were made at baseline for all subjects, with repeat radiographs being made at six months for the osteoarthropathy group and at one and two years for both groups. Radiographic measurements included the Meary angle, cuboid height, calcaneal pitch, and hindfoot-forefoot angle. RESULTS: The Meary angle, cuboid height, and calcaneal pitch worsened in feet with Charcot osteoarthropathy over one year as compared with the contralateral, uninvolved feet and feet in patients with diabetes and peripheral neuropathy. Cuboid height continued to worsen over the two-year follow-up in the feet with Charcot osteoarthropathy. These feet also had a greater change in the hindfoot-forefoot angle at one year as compared with the feet in patients with diabetes and peripheral neuropathy and at two years as compared with the contralateral, uninvolved feet. CONCLUSIONS: In patients with Charcot neuropathic osteoarthropathy, radiographic alignment measurements demonstrate the presence of foot deformity at the time of the initial clinical presentation and evidence of progressive changes over the first and second years. The six-month data suggest worsening of medial column alignment prior to lateral column worsening. This radiographic evidence of worsening foot alignment over time supports the need for aggressive intervention (conservative bracing or surgical fixation) to attempt to prevent limb-threatening complications. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence

Neuropathic midfoot deformity: Associations with ankle and subtalar joint motion

BACKGROUND: Neuropathic deformities impair foot and ankle joint mobility, often leading to abnormal stresses and impact forces. The purpose of our study was to determine differences in radiographic measures of hind foot alignment and ankle joint and subtalar joint motion in participants with and without neuropathic midfoot deformities and to determine the relationships between radiographic measures of hind foot alignment to ankle and subtalar joint motion in participants with and without neuropathic midfoot deformities. METHODS: Sixty participants were studied in three groups. Forty participants had diabetes mellitus (DM) and peripheral neuropathy (PN) with 20 participants having neuropathic midfoot deformity due to Charcot neuroarthropathy (CN), while 20 participants did not have deformity. Participants with diabetes and neuropathy with and without deformity were compared to 20 young control participants without DM, PN or deformity. Talar declination and calcaneal inclination angles were assessed on lateral view weight bearing radiograph. Ankle dorsiflexion, plantar flexion and subtalar inversion and eversion were assessed by goniometry. RESULTS: Talar declination angle averaged 34±9, 26±4 and 23±3 degrees in participants with deformity, without deformity and young control participants, respectively (p< 0.010). Calcaneal inclination angle averaged 11±10, 18±9 and 21±4 degrees, respectively (p< 0.010). Ankle plantar flexion motion averaged 23±11, 38±10 and 47±7 degrees (p<0.010). The association between talar declination and calcaneal inclination angles with ankle plantar flexion range of motion is strongest in participants with neuropathic midfoot deformity. Participants with talonavicular and calcaneocuboid dislocations result in the most severe restrictions in ankle joint plantar flexion and subtalar joint inversion motions. CONCLUSIONS: An increasing talar declination angle and decreasing calcaneal inclination angle is associated with decreases in ankle joint plantar flexion motion in individuals with neuropathic midfoot deformity due to CN that may contribute to excessive stresses and ultimately plantar ulceration of the midfoot

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification

Peak oxygen uptake (VO2peak) across childhood, adolescence and young adulthood in Barth syndrome: Data from cross-sectional and longitudinal studies.

Barth syndrome (BTHS) is an ultra-rare, X-linked recessive disorder characterized by cardio-skeletal myopathy, exercise intolerance, and growth delay. Oxygen uptake during peak exercise (VO2peak) has been shown to be severely limited in individuals with BTHS however; the trajectory of VO2peak from childhood to young adulthood is unknown. The objective of this study was to describe VO2peak from childhood through young adulthood in BTHS. METHODS AND MATERIALS:VO2peak over time was presented through cross-sectional (n = 33 participants) and a longitudinal analyses (n = 12 participants). Retrospective data were obtained through maximal exercise testing on a cycle ergometer from individuals with BTHS who were or are currently enrolled in a research study during July 2006-September 2017. Participants included in the cross-sectional analysis were divided into 3 groups for analysis: 1) children (n = 13), 2) adolescents (n = 8), and 3) young adults (n = 12). Participants in the longitudinal analysis had at least two exercise tests over a span of 2-9 years. RESULTS:VO2peak relative to body weight (ml/kgBW/min), fat-free mass (FFM) and by percent of predicted VO2peak obtained were not significantly different between children, adolescents and young adults. VO2peak did not longitudinally change over a mean time of ~5 years in late adolescent and young adult participants with repeated tests. A model including both cardiac and skeletal muscle variables best predicted VO2peak. CONCLUSIONS:In conclusion, VO2peak relative to body weight and fat-free mass demonstrates short- and long-term stability from childhood to young adulthood in BTHS with some variability among individuals

Participant demographics, peak exercise testing and echocardiography.

<p>Participant demographics, peak exercise testing and echocardiography.</p

Longitudinal data on VO_2peak relative to body mass in individuals with BTHS.

<p>Longitudinal data on VO_2peak relative to body mass in individuals with BTHS.</p

Cross-sectional data on VO_2peak in children, adolescents and young adults with BTHS.

<p>A. absolute (L/min), B. relative to body weight (kg), C. relative to fat-free mass (kg) and D. as percent predicted for age and body mass [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0197776#pone.0197776.ref025" target="_blank">25</a>].</p