Effect of Relative Marker Movement on the Calculation of the Foot Torsion Axis Using a Combined Cardan Angle and Helical Axis Approach

The two main movements occurring between the forefoot and rearfoot segment of a human foot are flexion at the metatarsophalangeal joints and torsion in the midfoot. The location of the torsion axis within the foot is currently unknown. The purpose of this study was to develop a method based on Cardan angles and the finite helical axis approach to calculate the torsion axis without the effect of flexion. As the finite helical axis method is susceptible to error due to noise with small helical rotations, a minimal amount of rotation was defined in order to accurately determine the torsion axis location. Using simulation, the location of the axis based on data containing noise was compared to the axis location of data without noise with a one-sample t-test and Fisher's combined probability score. When using only data with helical rotation of seven degrees or more, the location of the torsion axis based on the data with noise was within 0.2 mm of the reference location. Therefore, the proposed method allowed an accurate calculation of the foot torsion axis location

Young Australians navigating the ‘Careers Information Ecology’

The policy orientations of advanced neoliberal democracies situate young people as rational actors who are responsible for their own career outcomes. While career scholars have been critical of how this routinely ignores the unequal effects of structural constraints on personal agency, they have long suggested that young people should have access to the best available ‘roadmaps’ and advice to navigate the uncertainties baked into the contemporary economic landscape. Complementing the significant attention that is given to the (potentially emancipatory) experience of formal careers guidance, we present findings from a multi-method study. We explore young Australians’ (aged 15–24) navigation of careers information through a nationally representative survey (n = 1103), focus groups with 90 participants and an analysis of 15,227 social media comments. We suggest that the variety of formal and informal sources pursued and accessed by young people forms a relational ‘ecology’. This relationality is twofold. First, information is often sequential, and engagements with one source can inform the experience or pursuit of another. Second, navigation of the ecology is marked by a high level of intersubjectivity through interpersonal support networks including peers, family and formal service provision. These insights trouble a widespread, but perhaps simplistic, reading of young people having largely internalised a neoliberal sensibility of ‘entrepreneurial selfhood’ in their active pursuit of a range of career advice. Throughout our analysis, we attend to the ways that engagement in the career information ecology is shaped by social inequalities, further underscoring challenges facing careers guidance and social justice goals

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .)

Effect of torsional stiffness on biomechanical variables of the lower extremity during running

Torsion, the relative in-/eversion between forefoot and rearfoot, is a concept that has been incorporated into running shoes for almost 30 years. Studies have shown an influence of footwear torsional stiffness on lower extremity biomechanics during running but results are inconclusive. However, the influence of the torsion axis of the shoe on kinematics and kinetics of running has not been examined. Therefore, the goal was to examine the effect of shoes with a specially designed torsion element on running biomechanics of the lower extremities. Twenty runners performed heel–toe running at 4.0 ms−1 with three shoes and barefoot. All shoes had a torsion element based on a rearfoot and a forefoot element connected by bushings that had a defined rotation axis. The torsional stiffness was altered by modifications made to the torsion element and the surrounding midsole. A force plate and camera system were used to collect kinetics and kinematics. Foot torsion, ankle eversion, ankle and knee moments in the frontal and transverse plane and ground reaction forces were compared between conditions using paired t-tests. The shoe with the lowest torsional stiffness did not result in larger torsion range of motion compared to a stiffer shoe. Ankle eversion decreased with decreasing torsional stiffness while the changes in ankle kinetics were not consistent between the frontal and transverse plane. Torsional stiffness did not have a systematic influence on knee joint kinetics. While shoe torsional stiffness influences foot kinematics significantly, it does not affect lower extremity running biomechanics in a way that would alter the risk of running injuries

Effect of Relative Marker Movement on the Calculation of the Foot Torsion Axis Using a Combined Cardan Angle and Helical Axis Approach

The two main movements occurring between the forefoot and rearfoot segment of a human foot are flexion at the metatarsophalangeal joints and torsion in the midfoot. The location of the torsion axis within the foot is currently unknown. The purpose of this study was to develop a method based on Cardan angles and the finite helical axis approach to calculate the torsion axis without the effect of flexion. As the finite helical axis method is susceptible to error due to noise with small helical rotations, a minimal amount of rotation was defined in order to accurately determine the torsion axis location. Using simulation, the location of the axis based on data containing noise was compared to the axis location of data without noise with a one-sample t-test and Fisher's combined probability score. When using only data with helical rotation of seven degrees or more, the location of the torsion axis based on the data with noise was within 0.2 mm of the reference location. Therefore, the proposed method allowed an accurate calculation of the foot torsion axis location.Peer Reviewe

Serine administration as a novel prophylactic approach to reduce the severity of acute pancreatitis during diabetes in mice

Aims/hypothesis: Compared with the general population, individuals with diabetes have a higher risk of developing severe acute pancreatitis, a highly debilitating and potentially lethal inflammation of the exocrine pancreas. In this study, we investigated whether 1-deoxysphingolipids, atypical lipids that increase in the circulation following the development of diabetes, exacerbate the severity of pancreatitis in a diabetic setting. Methods: We analysed whether administration of an l-serine-enriched diet to mouse models of diabetes, an established method for decreasing the synthesis of 1-deoxysphingolipids in vivo, reduced the severity of acute pancreatitis. Furthermore, we elucidated the molecular mechanisms underlying the lipotoxicity exerted by 1-deoxysphingolipids towards rodent pancreatic acinar cells in vitro. Results: We demonstrated that l-serine supplementation reduced the damage of acinar tissue resulting from the induction of pancreatitis in diabetic mice (average histological damage score: 1.5 in l-serine-treated mice vs 2.7 in the control group). At the cellular level, we showed that l-serine decreased the production of reactive oxygen species, endoplasmic reticulum stress and cellular apoptosis in acinar tissue. Importantly, these parameters, together with DNA damage, were triggered in acinar cells upon treatment with 1-deoxysphingolipids in vitro, suggesting that these lipids are cytotoxic towards pancreatic acinar cells in a cell-autonomous manner. In search of the initiating events of the observed cytotoxicity, we discovered that 1-deoxysphingolipids induced early mitochondrial dysfunction in acinar cells, characterised by ultrastructural alterations, impaired oxygen consumption rate and reduced ATP synthesis. Conclusions/interpretation: Our results suggest that 1-deoxysphingolipids directly damage the functionality of pancreatic acinar cells and highlight that an l-serine-enriched diet may be used as a promising prophylactic intervention to reduce the severity of pancreatitis in the context of diabetes

Serine administration as a novel prophylactic approach to reduce the severity of acute pancreatitis during diabetes in mice

AIMS/HYPOTHESIS: Compared with the general population, individuals with diabetes have a higher risk of developing severe acute pancreatitis, a highly debilitating and potentially lethal inflammation of the exocrine pancreas. In this study, we investigated whether 1-deoxysphingolipids, atypical lipids that increase in the circulation following the development of diabetes, exacerbate the severity of pancreatitis in a diabetic setting. METHODS: We analysed whether administration of an L-serine-enriched diet to mouse models of diabetes, an established method for decreasing the synthesis of 1-deoxysphingolipids in vivo, reduced the severity of acute pancreatitis. Furthermore, we elucidated the molecular mechanisms underlying the lipotoxicity exerted by 1-deoxysphingolipids towards rodent pancreatic acinar cells in vitro. RESULTS: We demonstrated that L-serine supplementation reduced the damage of acinar tissue resulting from the induction of pancreatitis in diabetic mice (average histological damage score: 1.5 in L-serine-treated mice vs 2.7 in the control group). At the cellular level, we showed that L-serine decreased the production of reactive oxygen species, endoplasmic reticulum stress and cellular apoptosis in acinar tissue. Importantly, these parameters, together with DNA damage, were triggered in acinar cells upon treatment with 1-deoxysphingolipids in vitro, suggesting that these lipids are cytotoxic towards pancreatic acinar cells in a cell-autonomous manner. In search of the initiating events of the observed cytotoxicity, we discovered that 1-deoxysphingolipids induced early mitochondrial dysfunction in acinar cells, characterised by ultrastructural alterations, impaired oxygen consumption rate and reduced ATP synthesis. CONCLUSIONS/INTERPRETATION: Our results suggest that 1-deoxysphingolipids directly damage the functionality of pancreatic acinar cells and highlight that an L-serine-enriched diet may be used as a promising prophylactic intervention to reduce the severity of pancreatitis in the context of diabetes

Identification of cell‐specific differential DNA methylation associated with methotrexate treatment response in rheumatoid arthritis

ObjectiveWe undertook this study to estimate changes in cell-specific DNA methylation (DNAm) associated with methotrexate (MTX) response using whole blood samples collected from rheumatoid arthritis (RA) patients before and after initiation of MTX treatment.MethodsPatients included in this study were from the Rheumatoid Arthritis Medication Study (n = 66) and the University of California San Francisco Rheumatoid Arthritis study (n = 11). All patients met the American College of Rheumatology RA classification criteria. Blood samples were collected at baseline and following treatment. Disease Activity Scores in 28 joints using the C-reactive protein level were collected at baseline and after 3-6 months of treatment with MTX. Methylation profiles were generated using the Illumina Infinium HumanMethylation450 and MethylationEPIC v1.0 BeadChip arrays using DNA from whole blood. MTX response was defined using the EULAR response criteria (responders showed good/moderate response; nonresponders showed no response). Differentially methylated positions were identified using the Limma software package and Tensor Composition Analysis, which is a method for identifying cell-specific differential DNAm at the CpG level from tissue-level ("bulk") data. Differentially methylated regions were identified using Comb-p software.ResultsWe found evidence of differential global methylation between treatment response groups. Further, we found patterns of cell-specific differential global methylation associated with MTX response. After correction for multiple testing, 1 differentially methylated position was associated with differential DNAm between responders and nonresponders at baseline in CD4+ T cells, CD8+ T cells, and natural killer cells. Thirty-nine cell-specific differentially methylated regions associated with MTX treatment response were identified. There were no significant findings in analyses of whole blood samples.ConclusionWe identified cell-specific changes in DNAm that were associated with MTX treatment response in RA patients. Future studies of DNAm and MTX treatment response should include measurements of DNAm from sorted cells