Showing papers by "University of Newcastle published in 2016"

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

Genomic analyses identify molecular subtypes of pancreatic cancer

Abstract: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

Genome-wide association study identifies 74 loci associated with educational attainment

Abstract: Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

Physical Activity for Cognitive and Mental Health in Youth: A Systematic Review of Mechanisms.

Abstract: CONTEXT: Physical activity can improve cognitive and mental health, but the underlying mechanisms have not been established. OBJECTIVE: To present a conceptual model explaining the mechanisms for the effect of physical activity on cognitive and mental health in young people and to conduct a systematic review of the evidence. DATA SOURCES: Six electronic databases (PubMed, PsycINFO, SCOPUS, Ovid Medline, SportDiscus, and Embase) were used. STUDY SELECTION: School-, home-, or community-based physical activity intervention or laboratory-based exercise interventions were assessed. Studies were eligible if they reported statistical analyses of changes in the following: (1) cognition or mental health; and (2) neurobiological, psychosocial, and behavioral mechanisms. DATA EXTRACTION: Data relating to methods, assessment period, participant characteristics, intervention type, setting, and facilitator/delivery were extracted. RESULTS: Twenty-five articles reporting results from 22 studies were included. Mechanisms studied were neurobiological (6 studies), psychosocial (18 studies), and behavioral (2 studies). Significant changes in at least 1 potential neurobiological mechanism were reported in 5 studies, and significant effects for at least 1 cognitive outcome were also found in 5 studies. One of 2 studies reported a significant effect for self-regulation, but neither study reported a significant impact on mental health. LIMITATIONS: Small number of studies and high levels of study heterogeneity. CONCLUSIONS: The strongest evidence was found for improvements in physical self-perceptions, which accompanied enhanced self-esteem in the majority of studies measuring these outcomes. Few studies examined neurobiological and behavioral mechanisms, and we were unable to draw conclusions regarding their role in enhancing cognitive and mental health.

Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Abstract: Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.

Pioglitazone after Ischemic Stroke or Transient Ischemic Attack

Abstract: BackgroundPatients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease. MethodsIn this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction. ResultsBy 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group...

A contribution of novel CNVs to schizophrenia from a genome-wide study of 41,321 subjects

Abstract: Genomic copy number variants (CNVs) have been strongly implicated in the etiology of schizophrenia (SCZ). However, apart from a small number of risk variants, elucidation of the CNV contribution to risk has been difficult due to the rarity of risk alleles, all occurring in less than 1% of cases. We sought to address this obstacle through a collaborative effort in which we applied a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. We observed a global enrichment of CNV burden in cases (OR=1.11, P=5.7e-15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7e-6). CNV burden is also enriched for genes associated with synaptic function (OR = 1.68, P = 2.8e-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3e-5). We identified genome-wide significant support for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. We find support at a suggestive level for nine additional candidate susceptibility and protective loci, which consist predominantly of CNVs mediated by non-allelic homologous recombination (NAHR).

Treatable traits: toward precision medicine of chronic airway diseases.

Abstract: Asthma and chronic obstructive pulmonary disease (COPD) are two prevalent chronic airway diseases that have a high personal and social impact. They likely represent a continuum of different diseases that may share biological mechanisms (i.e. endotypes), and present similar clinical, functional, imaging and/or biological features that can be observed (i.e. phenotypes) which require individualised treatment. Precision medicine is defined as "treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations". In this Perspective, we propose a precision medicine strategy for chronic airway diseases in general, and asthma and COPD in particular.

Efficacy of interventions that use apps to improve diet, physical activity and sedentary behaviour: a systematic review.

Abstract: Health and fitness applications (apps) have gained popularity in interventions to improve diet, physical activity and sedentary behaviours but their efficacy is unclear. This systematic review examined the efficacy of interventions that use apps to improve diet, physical activity and sedentary behaviour in children and adults. Systematic literature searches were conducted in five databases to identify papers published between 2006 and 2016. Studies were included if they used a smartphone app in an intervention to improve diet, physical activity and/or sedentary behaviour for prevention. Interventions could be stand-alone interventions using an app only, or multi-component interventions including an app as one of several intervention components. Outcomes measured were changes in the health behaviours and related health outcomes (i.e., fitness, body weight, blood pressure, glucose, cholesterol, quality of life). Study inclusion and methodological quality were independently assessed by two reviewers. Twenty-seven studies were included, most were randomised controlled trials (n = 19; 70%). Twenty-three studies targeted adults (17 showed significant health improvements) and four studies targeted children (two demonstrated significant health improvements). Twenty-one studies targeted physical activity (14 showed significant health improvements), 13 studies targeted diet (seven showed significant health improvements) and five studies targeted sedentary behaviour (two showed significant health improvements). More studies (n = 12; 63%) of those reporting significant effects detected between-group improvements in the health behaviour or related health outcomes, whilst fewer studies (n = 8; 42%) reported significant within-group improvements. A larger proportion of multi-component interventions (8 out of 13; 62%) showed significant between-group improvements compared to stand-alone app interventions (5 out of 14; 36%). Eleven studies reported app usage statistics, and three of them demonstrated that higher app usage was associated with improved health outcomes. This review provided modest evidence that app-based interventions to improve diet, physical activity and sedentary behaviours can be effective. Multi-component interventions appear to be more effective than stand-alone app interventions, however, this remains to be confirmed in controlled trials. Future research is needed on the optimal number and combination of app features, behaviour change techniques, and level of participant contact needed to maximise user engagement and intervention efficacy.

Astrocytes: a central element in neurological diseases

Abstract: The neurone-centred view of the past disregarded or downplayed the role of astroglia as a primary component in the pathogenesis of neurological diseases. As this concept is changing, so is also the perceived role of astrocytes in the healthy and diseased brain and spinal cord. We have started to unravel the different signalling mechanisms that trigger specific molecular, morphological and functional changes in reactive astrocytes that are critical for repairing tissue and maintaining function in CNS pathologies, such as neurotrauma, stroke, or neurodegenerative diseases. An increasing body of evidence shows that the effects of astrogliosis on the neural tissue and its functions are not uniform or stereotypic, but vary in a context-specific manner from astrogliosis being an adaptive beneficial response under some circumstances to a maladaptive and deleterious process in another context. There is a growing support for the concept of astrocytopathies in which the disruption of normal astrocyte functions, astrodegeneration or dysfunctional/maladaptive astrogliosis are the primary cause or the main factor in neurological dysfunction and disease. This review describes the multiple roles of astrocytes in the healthy CNS, discusses the diversity of astroglial responses in neurological disorders and argues that targeting astrocytes may represent an effective therapeutic strategy for Alexander disease, neurotrauma, stroke, epilepsy and Alzheimer's disease as well as other neurodegenerative diseases.

Nanoencapsulation, Nano-guard for Pesticides: A New Window for Safe Application

Abstract: The application of nanotechnology in pesticide delivery is relatively new and in the early stages of development. This technology aims to reduce the indiscriminate use of conventional pesticides and ensure their safe application. This critical review investigated the potential of nanotechnology, especially the nanoencapsulation process for pesticide delivery. In-depth investigation of various nanoencapsulation materials and techniques, efficacy of application, and current research trends are also presented. The focus of ongoing research was on the development of a nanoencapsulated pesticide formulation that has slow releasing properties with enhanced solubility, permeability, and stability. These properties are mainly achieved through either protecting the encapsulated active ingredients from premature degradation or increasing their pest control efficacy for a longer period. Nanoencapsulated pesticide formulation is able to reduce the dosage of pesticides and human exposure to them, which is environmenta...

Genomic characterization of the uncultured Bacteroidales family S24-7 inhabiting the guts of homeothermic animals

Abstract: Our view of host-associated microbiota remains incomplete due to the presence of as yet uncultured constituents. The Bacteroidales family S24-7 is a prominent example of one of these groups. Marker gene surveys indicate that members of this family are highly localized to the gastrointestinal tracts of homeothermic animals and are increasingly being recognized as a numerically predominant member of the gut microbiota; however, little is known about the nature of their interactions with the host. Here, we provide the first whole genome exploration of this family, for which we propose the name “Candidatus Homeothermaceae,” using 30 population genomes extracted from fecal samples of four different animal hosts: human, mouse, koala, and guinea pig. We infer the core metabolism of “Ca. Homeothermaceae” to be that of fermentative or nanaerobic bacteria, resembling that of related Bacteroidales families. In addition, we describe three trophic guilds within the family, plant glycan (hemicellulose and pectin), host glycan, and α-glucan, each broadly defined by increased abundance of enzymes involved in the degradation of particular carbohydrates. “Ca. Homeothermaceae” representatives constitute a substantial component of the murine gut microbiota, as well as being present within the human gut, and this study provides important first insights into the nature of their residency. The presence of trophic guilds within the family indicates the potential for niche partitioning and specific roles for each guild in gut health and dysbiosis.

Correlates of Gross Motor Competence in Children and Adolescents: A Systematic Review and Meta-Analysis

Abstract: Background Gross motor competence confers health benefits, but levels in children and adolescents are low. While interventions can improve gross motor competence, it remains unclear which correlates should be targeted to ensure interventions are most effective, and for whom targeted and tailored interventions should be developed.

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

A critical look at the use of SEM in international business research

Abstract: Purpose – Structural equation modeling (SEM) has been widely used to examine complex research models in international business and marketing research. While the covariance-based SEM (CB-SEM) approach is dominant, the authors argue that the field’s dynamic nature and the sometimes early stage of theory development more often require a partial least squares SEM (PLS-SEM) approach. The purpose of this paper is to critically review the application of SEM techniques in the field. Design/methodology/approach – The authors searched six journals with an international business (and marketing) focus (Management International Review, Journal of International Business Studies, Journal of International Management, International Marketing Review, Journal of World Business, International Business Review) from 1990 to 2013. The authors reviewed all articles that apply SEM, analyzed their research objectives and methodology choices, and assessed whether the PLS-SEM papers followed the best practices outlined in the past. ...

Nudging consumers towards healthier choices: A systematic review of positional influences on food choice

Abstract: Nudging or 'choice architecture' refers to strategic changes in the environment that are anticipated to alter people's behaviour in a predictable way, without forbidding any options or significantly changing their economic incentives. Nudging strategies may be used to promote healthy eating behaviour. However, to date, the scientific evidence has not been systematically reviewed to enable practitioners and policymakers to implement, or argue for the implementation of, specific measures to support nudging strategies. This systematic review investigated the effect of positional changes of food placement on food choice. In total, seven scientific databases were searched using relevant keywords to identify interventions that manipulated food position (proximity or order) to generate a change in food selection, sales or consumption, among normal-weight or overweight individuals across any age group. From 2576 identified articles, fifteen articles comprising eighteen studies met our inclusion criteria. This review has identified that manipulation of food product order or proximity can influence food choice. Such approaches offer promise in terms of impacting on consumer behaviour. However, there is a need for high-quality studies that quantify the magnitude of positional effects on food choice in conjunction with measuring the impact on food intake, particularly in the longer term. Future studies should use outcome measures such as change in grams of food consumed or energy intake to quantify the impact on dietary intake and potential impacts on nutrition-related health. Research is also needed to evaluate potential compensatory behaviours secondary to such interventions.

Co-becoming Bawaka: Towards a relational understanding of place/space

Abstract: We invite readers to dig for ganguri (yams) at and with Bawaka, an Indigenous Homeland in northern Australia, and, in doing so, consider an Indigenous-led understanding of relational space/place. W...

What is asthma-COPD overlap syndrome? Towards a consensus definition from a round table discussion.

Abstract: Patients with asthma–chronic obstructive pulmonary disease overlap syndrome (ACOS) have been largely excluded from pivotal therapeutic trials and, as a result, its treatment remains poorly defined and lacking firm evidence. To date, there is no universally accepted definition of ACOS, which has made it difficult to understand its epidemiology or pathophysiology. Despite many uncertainties, there is emerging agreement that some of the key features of ACOS include persistent airflow limitation in symptomatic individuals 40 years of age and older, a well-documented history of asthma in childhood or early adulthood and a significant exposure history to cigarette or biomass smoke. In this perspective, we propose a case definition of ACOS that incorporates these key features in a parsimonious algorithm that may enable clinicians to better diagnose patients with ACOS and most importantly enable researchers to design therapeutic and clinical studies to elucidate its epidemiology and pathophysiology and to ascertain its optimal management strategies.

A Review of Power Electronics for Grid Connection of Utility-Scale Battery Energy Storage Systems

Abstract: The increasing penetration of renewable energy sources (RES) poses a major challenge to the operation of the electricity grid owing to the intermittent nature of their power output. The ability of utility-scale battery energy storage systems (BESS) to provide grid support and smooth the output of RES in combination with their decrease in cost has fueled research interest in this technology over the last couple of years. Power electronics (PE) is the key enabling technology for connecting utility-scale BESS to the medium-voltage grid. PE ensure energy is delivered while complying with grid codes and dispatch orders. Simultaneously, the PE must regulate the operating point of the batteries, thus for instance preventing overcharge of batteries. This paper presents a comprehensive review of PE topologies for utility BESS that have been proposed either within industry or the academic literature. Moreover, a comparison of the presently most commercially viable topologies is conducted in terms of estimated power conversion efficiency and relative cost.

Scaling-up an efficacious school-based physical activity intervention: Study protocol for the 'Internet-based Professional Learning to help teachers support Activity in Youth' (iPLAY) cluster randomized controlled trial and scale-up implementation evaluation

Abstract: Despite the health benefits of regular physical activity, most children are insufficiently active. Schools are ideally placed to promote physical activity; however, many do not provide children with sufficient in-school activity or ensure they have the skills and motivation to be active beyond the school setting. The aim of this project is to modify, scale up and evaluate the effectiveness of an intervention previously shown to be efficacious in improving children’s physical activity, fundamental movement skills and cardiorespiratory fitness. The ‘Internet-based Professional Learning to help teachers support Activity in Youth’ (iPLAY) study will focus largely on online delivery to enhance translational capacity. The intervention will be implemented at school and teacher levels, and will include six components: (i) quality physical education and school sport, (ii) classroom movement breaks, (iii) physically active homework, (iv) active playgrounds, (v) community physical activity links and (vi) parent/caregiver engagement. Experienced physical education teachers will deliver professional learning workshops and follow-up, individualized mentoring to primary teachers (i.e., Kindergarten – Year 6). These activities will be supported by online learning and resources. Teachers will then deliver the iPLAY intervention components in their schools. We will evaluate iPLAY in two complementary studies in primary schools across New South Wales (NSW), Australia. A cluster randomized controlled trial (RCT), involving a representative sample of 20 schools within NSW (1:1 allocation at the school level to intervention and attention control conditions), will assess effectiveness and cost-effectiveness at 12 and 24 months. Students’ cardiorespiratory fitness will be the primary outcome in this trial. Key secondary outcomes will include students’ moderate-to-vigorous physical activity (via accelerometers), fundamental movement skill proficiency, enjoyment of physical education and sport, cognitive control, performance on standardized tests of numeracy and literacy, and cost-effectiveness. A scale-up implementation study guided by the RE-AIM framework will evaluate the reach, effectiveness, adoption, implementation, and maintenance of the intervention when delivered in 160 primary schools in urban and regional areas of NSW. This project will provide the evidence and a framework for government to guide physical activity promotion throughout NSW primary schools and a potential model for adoption in other states and countries. Australia and New Zealand Clinical Trials Registry ( ACTRN12616000731493 ). Date of registration: June 3, 2016.

Defining secondary progressive multiple sclerosis.

Abstract: A number of studies have been conducted with the onset of secondary progressive multiple sclerosis as an inclusion criterion or an outcome of interest. However, a standardized objective definition of secondary progressive multiple sclerosis has been lacking. The aim of this work was to evaluate the accuracy and feasibility of an objective definition for secondary progressive multiple sclerosis, to enable comparability of future research studies. Using MSBase, a large, prospectively acquired, global cohort study, we analysed the accuracy of 576 data-derived onset definitions for secondary progressive multiple sclerosis and first compared these to a consensus opinion of three neurologists. All definitions were then evaluated against 5-year disease outcomes post-assignment of secondary progressive multiple sclerosis: sustained disability, subsequent sustained progression, positive disability trajectory, and accumulation of severe disability. The five best performing definitions were further investigated for their timeliness and overall disability burden. A total of 17 356 patients were analysed. The best definition included a 3-strata progression magnitude in the absence of a relapse, confirmed after 3 months within the leading Functional System and required an Expanded Disability Status Scale step ≥4 and pyramidal score ≥2. It reached an accuracy of 87% compared to the consensus diagnosis. Seventy-eight per cent of the identified patients showed a positive disability trajectory and 70% reached significant disability after 5 years. The time until half of all patients were diagnosed was 32.6 years (95% confidence interval 32-33.6) after disease onset compared with the physicians' diagnosis at 36 (35-39) years. The identified patients experienced a greater disease burden [median annualized area under the disability-time curve 4.7 (quartiles 3.6, 6.0)] versus non-progressive patients [1.8 (1.2, 1.9)]. This objective definition of secondary progressive multiple sclerosis based on the Expanded Disability Status Scale and information about preceding relapses provides a tool for a reproducible, accurate and timely diagnosis that requires a very short confirmation period. If applied broadly, the definition has the potential to strengthen the design and improve comparability of clinical trials and observational studies in secondary progressive multiple sclerosis.