Reduced skeletal muscle protein balance in paediatric Crohn’s disease

Background and AimsAn inability to respond to nutrition could be implicated in low muscle mass in Crohn’s disease. We aim to determine skeletal muscle metabolic response to feeding in Crohn’s disease and healthy volunteers.MethodsTwenty asymptomatic Crohn’s disease participants (15.6 ± 0.5 yrs; BMI 20.6 ± 0.9 kg/m2); 9 with active disease (faecal calprotectin, 808 ± 225ug/g and C-reactive protein, 2.2 ± 1.2 mg/dl), 11 in deep remission (faecal calprotectin, 61 ± 12ug/g and C-reactive protein, 0.3 ± 0.2 mg/dl) and 9 matched healthy volunteers (16.0±0.6 yrs; BMI 20.7±0.6 kg/m2) were recruited. Participants had a dual energy X-ray absorptiometry scan, handgrip dynamometer test, wore a pedometer and completed a food diary. Arterialised hand and venous forearm blood samples were collected concurrently and brachial artery blood flow measured at baseline and every 20mins for 2hrs after the ingestion of a standardised liquid meal. Net balance of branched chain amino acids and glucose were derived.ResultsControls had a positive mean BCAA balance. CD participants had an initial anabolic response to the meal, with increasing BCAA balance between t=0 & t=20, but returned to negative by t=60. This was associated with reduced FFM z-scores in CD but not with insulin resistance or disease activity. Exploratory analyses suggest that negative postprandial BCAA response seen in CD is predominant in males (p=0.049), with associated lower appendicular muscle mass (p=0.034), higher muscle fatigue (p=0.014) and reduced protein intake (p=0.026).ConclusionsThe inability to sustain a positive protein balance postprandially could provide an explanation for the reduced muscle mass seen in CD. Further mechanistic studies will be needed to confirm these findings

EXPO-ENGAGE: Facilitating participation in air quality citizen science

Achieving net zero emissions targets in the UK is essential to combat the climate crisis. This will require major changes in the way that we live, so citizen support will be essential. Citizen science is one way of engaging communities with energy transitions

A combination of mutations in AKR1D1 and SKIV2L in a family with severe infantile liver disease.

Infantile cholestatic diseases can be caused by mutations in a number of genes involved in different hepatocyte molecular pathways. Whilst some of the essential pathways have a well understood function, such as bile biosynthesis and transport, the role of the others is not known. Here we report the findings of a clinical, biochemical and molecular study of a family with three patients affected with a severe infantile cholestatic disease. A novel homozygous frameshift germline mutation (c.587delG) in the AKR1D1 gene; which encodes the enzyme Δ 4-3-oxosteroid 5β-reductase that is required for synthesis of primary bile acids and is crucial for establishment of normal bile flow, was found in all 3 patients. Although the initial bile acid analysis was inconclusive, subsequent testing confirmed the diagnosis of a bile acid biogenesis disorder. An additional novel homozygous frameshift mutation (c.3391delC) was detected in SKIV2L in one of the patients. SKIV2L encodes a homologue of a yeast ski2 protein proposed to be involved in RNA processing and mutations in SKIV2L were recently described in patients with Tricohepatoenteric syndrome (THES). A combination of autozygosity mapping and whole-exome-sequencing allowed the identification of causal mutations in this family with a complex liver phenotype. Although the initial 2 affected cousins died in the first year of life, accurate diagnosis and management of the youngest patient led to successful treatment of the liver disease and disease-free survival.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Colonic Volume Changes in Paediatric Constipation Compared to Normal Values Measured Using MRI

Background: Functional constipation in children is common. Management of this condition can be challenging and is often based on symptom reports. Increased, objective knowledge of colonic volume changes in constipation compared to health could provide additional information. However, very little data on paediatric colonic volume is available except from methods that are invasive or require unphysiological colonic preparations. Objectives: (1) To measure volumes of the undisturbed colon in children with functional constipation (FC) using magnetic resonance imaging (MRI) and provide initial normal range values for healthy controls, and (2) to investigate possible correlation of colonic volume with whole gut transit time (WGTT). Methods: Total and regional (ascending, transverse, descending, sigmoid, and rectum) colon volumes were measured from MRI images of 35 participants aged 7–18 years (16 with FC and 19 healthy controls), and corrected for body surface area. Linear regression was used to explore the relationship between total colon volume and WGTT. Results: Total colonic volume was significantly higher, with a median (interquartile range) of 309 mL (243–384 mL) for the FC group than for the healthy controls of 227 mL (180–263 mL). The largest increase between patients and controls was in the sigmoid colon–rectum region. In a linear regression model, there was a positive significant correlation between total colonic volume and WGTT (R = 0.56, p = 0.0005). Conclusions: This initial study shows increased volumes of the colon in children with FC, in a physiological state, without use of any bowel preparation. Increased knowledge of colonic morphology may improve understanding of FC in this age group and help to direct treatment

Colon length in pediatric health and constipation measured using magnetic resonance imaging and three dimensional skeletonization

Recent magnetic resonance imaging (MRI) studies showed that colonic volumes in children are different between health and functional constipation. The length of the colon has however been rarely measured and principally using unphysiological colon preparations or cadaver studies. The main objective of this study was to measure the length of the undisturbed colon in children with functional constipation (FC) and healthy controls. Here, the colon of 19 healthy controls (10-18 years old) and 16 children with FC (7-18 years old) was imaged using MRI. Different regions of the colon (ascending, transverse, descending, and sigmoid-rectum) were first segmented manually on the MRI images. Three-dimensional skeletonization image analysis methods were then used to reduce the regions of interest to a central, measurable line. Total colon length (corrected for body surface area) in healthy controls was 56±2 cm/m2 (mean±SEM). Total colon length was significantly longer in children with FC 69±3 cm/m2 compared to controls (p = 0.0037). The colon regions showing the largest differences between groups were the ascending colon (p = 0.0479) and the sigmoid-rectum (p = 0.0003). In a linear regression model, there was a positive significant correlation between total colon length and age (R = 0.45, p = 0.0064), height (R = 0.49, p = 0.0031), weight (R = 0.46, p = 0.0059) and colon volume (R = 0.4543, p = 0.0061). Our findings showed significant differences in colon lengths between healthy controls and children with constipation. A new objective diagnostic imaging endpoint such as colon length may help to improve knowledge of colon morphology and function and, in turn, understanding of colon functional pathology

Establishment of a core outcome set for burn care research: development and international consensus

Objective: To develop a core outcome set for international burn research.Design: Development and international consensus, from April 2017 to November 2019.Methods: Candidate outcomes were identified from systematic reviews and stakeholder interviews. Through a Delphi survey, international clinicians, researchers, and UK patients prioritised outcomes. Anonymised feedback aimed to achieve consensus. Pre-defined criteria for retaining outcomes were agreed. A consensus meeting with voting was held to finalise the core outcome set.Results: Data source examination identified 1021 unique outcomes grouped into 88 candidate outcomes. Stakeholders in round 1 of the survey, included 668 health professionals from 77 countries (18% from low or low middle income countries) and 126 UK patients or carers. After round 1, one outcome was discarded, and 13 new outcomes added. After round 2, 69 items were discarded, leaving 31 outcomes for the consensus meeting. Outcome merging and voting, in two rounds, with prespecified thresholds agreed seven core outcomes: death, specified complications, ability to do daily tasks, wound healing, neuropathic pain and itch, psychological wellbeing, and return to school or work.Conclusions: This core outcome set caters for global burn research, and future trials are recommended to include measures of these outcomes

The synthetic TRPML1 agonist ML-SA1 rescues Alzheimer-related alterations of the endosomal-autophagic-lysosomal system

Abnormalities in the endosomal-autophagic-lysosomal (EAL) system are an early event in Alzheimer's disease (AD) pathogenesis. However, the mechanisms underlying these abnormalities are unclear. The transient receptor potential channel mucolipin 1(TRPML1, also known as MCOLN1), a vital endosomal-lysosomal Ca2+ channel whose loss of function leads to neurodegeneration, has not been investigated with respect to EAL pathogenesis in late-onset AD (LOAD). Here, we identify pathological hallmarks of TRPML1 dysregulation in LOAD neurons, including increased perinuclear clustering and vacuolation of endolysosomes. We reveal that induced pluripotent stem cell (iPSC)-derived human cortical neurons expressing APOE ε4, the strongest genetic risk factor for LOAD, have significantly diminished TRPML1-induced endolysosomal Ca2+ release. Furthermore, we found that blocking TRPML1 function in primary neurons by depleting the TRPML1 agonist PI(3,5)P2 via PIKfyve inhibition, recreated multiple features of EAL neuropathology evident in LOAD. This included increased endolysosomal Ca2+ content, enlargement and perinuclear clustering of endolysosomes, autophagic vesicle accumulation and early endosomal enlargement. Strikingly, these AD-like neuronal EAL defects were rescued by TRPML1 reactivation using its synthetic agonist ML-SA1. These findings implicate defects in TRPML1 in LOAD EAL pathogenesis and present TRPML1 as a potential therapeutic target

Supporting healthy lifestyles for First Nations women and communities through co-design: lessons and early findings from remote Northern Australia

BackgroundThe period before, during, and after pregnancy presents an opportunity to reduce diabetes-related risks, which in Australia disproportionately impact Aboriginal and Torres Strait Islander women. Collaboration with Aboriginal and Torres Strait Islander women/communities is essential to ensure acceptability and sustainability of lifestyle modifications. Using a novel co-design approach, we aimed to identify shared priorities and potential lifestyle strategies. We also reflected on learnings from this approach.MethodsWe conducted 11 workshops and 8 interviews at two sites in Australia’s Northern Territory (Central Australia and Top End), using experience-based co-design (EBCD) and incorporating principles of First Nations participatory research. Workshops/interviews explored participant’ experiences and understanding of diabetes in pregnancy, contextual issues, and potential lifestyle strategies. Participants included three groups: 1) Aboriginal and Torres Strait Islander women of reproductive age (defined as aged 16-45 years); 2) Aboriginal and Torres Strait Islander community members; and 3) health/community services professionals. The study methodology sought to amplify the voices of Aboriginal women.FindingsParticipants included 23 women between ages 16-45 years (9 with known lived experience of diabetes in pregnancy), 5 community members and 23 health professionals. Key findings related to identified priority issues, strategies to address priorities, and reflections on use of EBCD methodology. Priorities were largely consistent across study regions: access to healthy foods and physical activity; connection to traditional practices and culture; communication regarding diabetes and related risks; and the difficulty for women of prioritising their health among competing priorities. Strategies included implementation of a holistic women’s program in Central Australia, while Top End participants expressed the desire to improve nutrition, peer support and community awareness of diabetes. EBCD provided a useful structure to explore participants’ experiences and collectively determine priorities, while allowing for modifications to ensure co-design methods were contextually appropriate. Challenges included the resource-intensive nature of stakeholder engagement, and collaborating effectively with services and communities when researchers were “outsiders”.ConclusionsA hybrid methodology using EBCD and First Nations participatory research principles enabled collaboration between Aboriginal women, communities and health services to identify shared priorities and solutions to reduce diabetes-related health risks. Genuine co-design processes support self-determination and enhance acceptability and sustainability of health strategies

The effect of topical anti blister products on the risk of friction blister formation on the foot

Introduction Foot blisters are a common injury, which can impact on activity and lead to infection. Increased skin surface hydration has been identified as a risk factor for blister formation, indicating that a reduction in hydration could reduce the risk of blister formation. Method Thirty healthy adults were randomised into 3 groups, each receiving a preventative foot blister treatment (2Toms® Blister Shield®; Flexitol® Blistop and Boots Anti–Perspirant Foot Spray). Cycles of compression and shear loads where applied to heel skin using a mechanism driven by compressed air. Temperature changes were measured during load application using a thermal imaging camera (FLIR Systems Inc. and Therm CAM™ Quick Report). Near surface hydration of the skin was measured using a Corneometer® (C & K, Germany). Results There was no significant difference in the rate of temperature change of the skin between the three groups compared to not using products (p = 0.767, p = 0.767, p = 0.515) or when comparing each product (p = 0.551). There was a significant decrease in near surface skin hydration, compared to baseline, after the application of powder (−8.53 AU, p = 0.01). There was no significant difference in hydration after the application of film former and antiperspirant (−1.47 AU, p = 0.26; −1.00 AU, p = 0.80, respectively). Conclusion With the application of external load we found no significant difference in the effect of the three products on temperature change. The powder product demonstrated an effect on reducing the risk of blister. It is postulated that powder may have a barrier effect

HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn's Disease

Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.This article is freely available via Open Access. Click on Publisher URL to access the full-text