Genome-wide and Mendelian randomisation studies of liver MRI yield insights into the pathogenesis of steatohepatitis

Background A non-invasive method to grade the severity of steatohepatitis and liver fibrosis is magnetic resonance imaging (MRI) based corrected T1 (cT1). We aimed to identify genetic variants influencing liver cT1 and use genetics to understand mechanisms underlying liver fibroinflammatory disease and its link with other metabolic traits and diseases. Methods First, we performed a genome-wide association study (GWAS) in 14,440 Europeans in UK Biobank with liver cT1 measures. Second, we explored the effects of the cT1 variants on liver blood tests, and a range of metabolic traits and diseases. Third, we used Mendelian randomisation to test the causal effects of 24 predominantly metabolic traits on liver cT1 measures. Results We identified six independent genetic variants associated with liver cT1 that reached GWAS significance threshold (p<5x10-8). Four of the variants (rs75935921 in SLC30A10, rs13107325 in SLC39A8, rs58542926 in TM6SF2, rs738409 in PNPLA3) were also associated with elevated transaminases and had variable effects on liver fat and other metabolic traits. Insulin resistance, type 2 diabetes, non-alcoholic fatty liver and BMI were causally associated with elevated cT1 whilst favourable adiposity (instrumented by variants associated with higher adiposity but lower risk of cardiometabolic disease and lower liver fat) was found to be protective. Conclusion The association between two metal ion transporters and cT1 indicates an important new mechanism in steatohepatitis. Future studies are needed to determine whether interventions targeting the identified transporters might prevent liver disease in at risk individuals

Detecting periodicity in experimental data using linear modeling techniques

Fourier spectral estimates and, to a lesser extent, the autocorrelation function are the primary tools to detect periodicities in experimental data in the physical and biological sciences. We propose a new method which is more reliable than traditional techniques, and is able to make clear identification of periodic behavior when traditional techniques do not. This technique is based on an information theoretic reduction of linear (autoregressive) models so that only the essential features of an autoregressive model are retained. These models we call reduced autoregressive models (RARM). The essential features of reduced autoregressive models include any periodicity present in the data. We provide theoretical and numerical evidence from both experimental and artificial data, to demonstrate that this technique will reliably detect periodicities if and only if they are present in the data. There are strong information theoretic arguments to support the statement that RARM detects periodicities if they are present. Surrogate data techniques are used to ensure the converse. Furthermore, our calculations demonstrate that RARM is more robust, more accurate, and more sensitive, than traditional spectral techniques.Comment: 10 pages (revtex) and 6 figures. To appear in Phys Rev E. Modified styl

A stochastic model for the evolution of the web allowing link deletion

Recently several authors have proposed stochastic evolutionary models for the growth of the web graph and other networks that give rise to power-law distributions. These models are based on the notion of preferential attachment leading to the ``rich get richer'' phenomenon. We present a generalisation of the basic model by allowing deletion of individual links and show that it also gives rise to a power-law distribution. We derive the mean-field equations for this stochastic model and show that by examining a snapshot of the distribution at the steady state of the model, we are able to tell whether any link deletion has taken place and estimate the link deletion probability. Our model enables us to gain some insight into the distribution of inlinks in the web graph, in particular it suggests a power-law exponent of approximately 2.15 rather than the widely published exponent of 2.1

Effect of prophylactic corticosteroids on the incidence of reactions in newly diagnosed multibacillary leprosy patients [5]

To the editor: Leprosy reactions, including reversal re-actions and episodes of neuritis, are known to occur in leprosy patients most frequently in the first few months after starting multidrug therapy (MDT), especially in cases with multibacillary (MB) disease. Such reactions can lead to impairment of nerve function, and subsequent deformity and disability. That this can occur in leprosy patients who present without any nerve function impairment (NFI) at diagnosis is a discouraging phenomenon for both the patient and the doctor or health worker.It is an axiom of modern leprosy controlthat early case detection and treatment with MDT can prevent much NFI by halting the multiplication of the leprosy bacillus, and that this is the single most important activity in the prevention of NFI. [...]<br/

Effect of prophylactic corticosteroids on the incidence of reactions in newly diagnosed multibacillary leprosy patients [5]

To the editor: Leprosy reactions, including reversal re-actions and episodes of neuritis, are known to occur in leprosy patients most frequently in the first few months after starting multidrug therapy (MDT), especially in cases with multibacillary (MB) disease. Such reactions can lead to impairment of nerve function, and subsequent deformity and disability. That this can occur in leprosy patients who present without any nerve function impairment (NFI) at diagnosis is a discouraging phenomenon for both the patient and the doctor or health worker.It is an axiom of modern leprosy controlthat early case detection and treatment with MDT can prevent much NFI by halting the multiplication of the leprosy bacillus, and that this is the single most important activity in the prevention of NFI. [...]<br/

Assessing hand osteoarthritis using digital photographs in a community-dwelling population: reliability and associations with radiographic and clinical features

Purpose: An atlas for grading hand osteoarthritis (OA) on photographs has been shown to be reliable and associated with clinical examination and radiographic features in a population of older adults (aged ≥69 years) from the AGES-Reykjavik study. The objective of this research was to determine if this atlas was reliable and to assess its association with radiographic and clinical features in a different younger community-dwelling population.Methods: Participants were community-dwelling older adults (≥50 years) in North Staffordshire, UK with self-reported hand pain or hand problems in the last year who attended a research clinic. High quality photographs taken at a set distance in a standardised position were graded for the presence of hand OA using an established atlas. Hand radiographs were graded for OA using the Kellgren Lawrence grading system and the presence of clinical features (nodes, bony enlargement, deformity) was determined on physical examination by trained assessors.Results: Following exclusions 558 participants (mean age 64 years, 62% female) were included in the analyses. Overall reliability for scoring each joint and joint group was good (mean intra-rater ICC =0.79, mean inter-rater ICC =0.71). For each joint and joint group photographic hand OA was positively associated with grade of radiographic OA (rho 0.19-0.57, p<0.001) and the number of clinical features present on an examination (rho 0.36-0.59, p<0.001). At the person level, individuals with higher global photographic hand OA scores had higher summed K&L scores and had higher percentages meeting the ACR clinical hand OA criteria.Conclusions: This photographic scoring system for hand OA has been shown to be reliable and associated with both radiographic and clinical features in a different and younger community-dwelling population to that in which it was developed. This method of data collection offers researchers an feasible alternative to the physical examination and maybe of particular use to large studies and those spread over a wide geographic areas

Analysis of Granular Flow in a Pebble-Bed Nuclear Reactor

Pebble-bed nuclear reactor technology, which is currently being revived around the world, raises fundamental questions about dense granular flow in silos. A typical reactor core is composed of graphite fuel pebbles, which drain very slowly in a continuous refueling process. Pebble flow is poorly understood and not easily accessible to experiments, and yet it has a major impact on reactor physics. To address this problem, we perform full-scale, discrete-element simulations in realistic geometries, with up to 440,000 frictional, viscoelastic 6cm-diameter spheres draining in a cylindrical vessel of diameter 3.5m and height 10m with bottom funnels angled at 30 degrees or 60 degrees. We also simulate a bidisperse core with a dynamic central column of smaller graphite moderator pebbles and show that little mixing occurs down to a 1:2 diameter ratio. We analyze the mean velocity, diffusion and mixing, local ordering and porosity (from Voronoi volumes), the residence-time distribution, and the effects of wall friction and discuss implications for reactor design and the basic physics of granular flow.Comment: 18 pages, 21 figure

Glucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release

How can cancer cells survive the consequences of cyt-c release? Huber et al provide a quantitative analysis of the protective role of enhanced glucose utilization in cancer cells and investigate the impact of cell-to-cell heterogeneity in mitochondrial bioenergetics