Showing papers by "University of Melbourne published in 2018"
Clotilde Théry1, Kenneth W. Witwer2, Elena Aikawa3, María José Alcaraz4 +414 more•Institutions (209)
TL;DR: The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities, and a checklist is provided with summaries of key points.
Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
5,988 citations
Gregory A. Roth1, Gregory A. Roth2, Degu Abate3, Kalkidan Hassen Abate4 +1025 more•Institutions (333)
TL;DR: Non-communicable diseases comprised the greatest fraction of deaths, contributing to 73·4% (95% uncertainty interval [UI] 72·5–74·1) of total deaths in 2017, while communicable, maternal, neonatal, and nutritional causes accounted for 18·6% (17·9–19·6), and injuries 8·0% (7·7–8·2).
5,211 citations
Mayo Clinic1, Rush University2, University of Gothenburg3, Alzheimer's Association4, Silver Spring Networks5, Biogen Idec6, Washington University in St. Louis7, University of California, Berkeley8, University of Cologne9, University of Pennsylvania10, Stanford University11, National Institutes of Health12, University of California, San Francisco13, University of Melbourne14, VU University Medical Center15, Eli Lilly and Company16, Brigham and Women's Hospital17
TL;DR: This research framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms and envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD.
Abstract: In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a "research framework" because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.
5,126 citations
TL;DR: Deep phenotype and genome-wide genetic data from 500,000 individuals from the UK Biobank is described, describing population structure and relatedness in the cohort, and imputation to increase the number of testable variants to 96 million.
Abstract: The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. Here we describe the centralized analysis of the genetic data, including genotype quality, properties of population structure and relatedness of the genetic data, and efficient phasing and genotype imputation that increases the number of testable variants to around 96 million. Classical allelic variation at 11 human leukocyte antigen genes was imputed, resulting in the recovery of signals with known associations between human leukocyte antigen alleles and many diseases.
4,489 citations
TL;DR: A comprehensive review of the main 3D printing methods, materials and their development in trending applications was carried out in this paper, where the revolutionary applications of AM in biomedical, aerospace, buildings and protective structures were discussed.
Abstract: Freedom of design, mass customisation, waste minimisation and the ability to manufacture complex structures, as well as fast prototyping, are the main benefits of additive manufacturing (AM) or 3D printing. A comprehensive review of the main 3D printing methods, materials and their development in trending applications was carried out. In particular, the revolutionary applications of AM in biomedical, aerospace, buildings and protective structures were discussed. The current state of materials development, including metal alloys, polymer composites, ceramics and concrete, was presented. In addition, this paper discussed the main processing challenges with void formation, anisotropic behaviour, the limitation of computer design and layer-by-layer appearance. Overall, this paper gives an overview of 3D printing, including a survey on its benefits and drawbacks as a benchmark for future research and development.
4,159 citations
Lorenzo Galluzzi1, Lorenzo Galluzzi2, Ilio Vitale3, Stuart A. Aaronson4 +183 more•Institutions (111)
TL;DR: The Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives.
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
3,301 citations
Jeffrey D. Stanaway1, Ashkan Afshin1, Emmanuela Gakidou1, Stephen S Lim1 +1050 more•Institutions (346)
TL;DR: This study estimated levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs) by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017 and explored the relationship between development and risk exposure.
2,910 citations
Imperial College London1, RWTH Aachen University2, Cranfield University3, Loughborough University4, University of Sheffield5, Massachusetts Institute of Technology6, United States Department of Energy7, Newcastle University8, Commonwealth Scientific and Industrial Research Organisation9, University of California, Berkeley10, University of Cambridge11, Carnegie Mellon University12, École Polytechnique Fédérale de Lausanne13, University of Melbourne14, Colorado School of Mines15
TL;DR: In this article, the authors review the current state-of-the-art of CO2 capture, transport, utilisation and storage from a multi-scale perspective, moving from the global to molecular scales.
Abstract: Carbon capture and storage (CCS) is broadly recognised as having the potential to play a key role in meeting climate change targets, delivering low carbon heat and power, decarbonising industry and, more recently, its ability to facilitate the net removal of CO2 from the atmosphere. However, despite this broad consensus and its technical maturity, CCS has not yet been deployed on a scale commensurate with the ambitions articulated a decade ago. Thus, in this paper we review the current state-of-the-art of CO2 capture, transport, utilisation and storage from a multi-scale perspective, moving from the global to molecular scales. In light of the COP21 commitments to limit warming to less than 2 °C, we extend the remit of this study to include the key negative emissions technologies (NETs) of bioenergy with CCS (BECCS), and direct air capture (DAC). Cognisant of the non-technical barriers to deploying CCS, we reflect on recent experience from the UK's CCS commercialisation programme and consider the commercial and political barriers to the large-scale deployment of CCS. In all areas, we focus on identifying and clearly articulating the key research challenges that could usefully be addressed in the coming decade.
2,088 citations
TL;DR: This work presents a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and shows that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods.
Abstract: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
1,620 citations
TL;DR: This analysis expands upon previous analyses by working under the hypothesis that both bodies were neutron stars that are described by the same equation of state and have spins within the range observed in Galactic binary neutron stars.
Abstract: On 17 August 2017, the LIGO and Virgo observatories made the first direct detection of gravitational waves from the coalescence of a neutron star binary system. The detection of this gravitational-wave signal, GW170817, offers a novel opportunity to directly probe the properties of matter at the extreme conditions found in the interior of these stars. The initial, minimal-assumption analysis of the LIGO and Virgo data placed constraints on the tidal effects of the coalescing bodies, which were then translated to constraints on neutron star radii. Here, we expand upon previous analyses by working under the hypothesis that both bodies were neutron stars that are described by the same equation of state and have spins within the range observed in Galactic binary neutron stars. Our analysis employs two methods: the use of equation-of-state-insensitive relations between various macroscopic properties of the neutron stars and the use of an efficient parametrization of the defining function pðρÞ of the equation of state itself. From the LIGO and Virgo data alone and the first method, we measure the two neutron star radii as R1 ¼ 10.8 þ2.0 −1.7 km for the heavier star and R2 ¼ 10.7 þ2.1 −1.5 km for the lighter star at the 90% credible level. If we additionally require that the equation of state supports neutron stars with masses larger than 1.97 M⊙ as required from electromagnetic observations and employ the equation-of-state parametrization, we further constrain R1 ¼ 11.9 þ1.4 −1.4 km and R2 ¼ 11.9 þ1.4 −1.4 km at the 90% credible level. Finally, we obtain constraints on pðρÞ at supranuclear densities, with pressure at twice nuclear saturation density measured at 3.5 þ2.7 −1.7 × 1034 dyn cm−2 at the 90% level.
1,595 citations
University of Southern California1, Duke University2, Stockholm School of Economics3, University of Virginia4, Center for Open Science5, University of Amsterdam6, University of Pennsylvania7, University of North Carolina at Chapel Hill8, University of Regensburg9, California Institute of Technology10, Research Institute of Industrial Economics11, New York University12, Cardiff University13, Mathematica Policy Research14, Northwestern University15, Ohio State University16, University of Sussex17, Texas A&M University18, Royal Holloway, University of London19, University of Zurich20, University of Melbourne21, University of Wisconsin-Madison22, University of Michigan23, Stanford University24, Rutgers University25, Columbia University26, University of Washington27, University of Edinburgh28, National University of Singapore29, Utrecht University30, Arizona State University31, Princeton University32, University of California, Los Angeles33, Imperial College London34, University of Innsbruck35, Harvard University36, University of Chicago37, University of Pittsburgh38, University of Notre Dame39, University of California, Berkeley40, Johns Hopkins University41, University of Bristol42, University of New South Wales43, Dartmouth College44, Whitman College45, University of Puerto Rico46, University of Milan47, University of California, Irvine48, Paris Dauphine University49, University of British Columbia50, Ludwig Maximilian University of Munich51, Purdue University52, Washington University in St. Louis53, University of California, Davis54, Microsoft55
TL;DR: The default P-value threshold for statistical significance is proposed to be changed from 0.05 to 0.005 for claims of new discoveries in order to reduce uncertainty in the number of discoveries.
Abstract: We propose to change the default P-value threshold for statistical significance from 0.05 to 0.005 for claims of new discoveries.
Verneri Anttila1, Verneri Anttila2, Brendan Bulik-Sullivan2, Brendan Bulik-Sullivan1 +717 more•Institutions (270)
TL;DR: It is demonstrated that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine, and it is shown that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures.
Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
Harvard University1, University of Cape Town2, King's College London3, Makerere University4, Johns Hopkins University5, University of Washington6, Emory University7, Carter Center8, University of London9, University of Melbourne10, World Psychiatric Association11, Rutgers University12, Al-Quds University13, Peking University14, University of Amsterdam15, Dow University of Health Sciences16, University of Health Sciences Lahore17, University of Ibadan18, University of Liverpool19, Public Health Foundation of India20, Wellcome Trust21, University of Oxford22, South African Medical Research Council23, Groote Schuur Hospital24
TL;DR: Adolescence is the phase of life stretching between childhood and adulthood, and its definition has long posed a conundrum as mentioned in this paper, and it encompasses elements of biological growth and major social role transitions, both of which have changed in the past century.
TL;DR: A novel approach to modelling life expectancy, all-cause mortality and cause of death forecasts —and alternative future scenarios—for 250 causes of death from 2016 to 2040 in 195 countries and territories is provided.
King's College London1, University of Nottingham2, University of Naples Federico II3, Royal College of Surgeons in Ireland4, Swansea University5, University of Calgary6, Scripps Research Institute7, University of Melbourne8, University of California, San Diego9, Nanjing Medical University10, University of Liverpool11, La Trobe University12, University College London13, Universidade Federal de Minas Gerais14, University of Bath15, Queen Mary University of London16
TL;DR: The guidelines have been simplified for ease of understanding by authors, to make it more straightforward for peer reviewers to check compliance and to facilitate the curation of the journal's efforts to improve standards.
Abstract: This article updates the guidance published in 2015 for authors submitting papers to British Journal of Pharmacology (Curtis et al., 2015) and is intended to provide the rubric for peer review. Thus, it is directed towards authors, reviewers and editors. Explanations for many of the requirements were outlined previously and are not restated here. The new guidelines are intended to replace those published previously. The guidelines have been simplified for ease of understanding by authors, to make it more straightforward for peer reviewers to check compliance and to facilitate the curation of the journal's efforts to improve standards.
TL;DR: The measurement of high-performance plasma amyloid-β biomarkers by immunoprecipitation coupled with mass spectrometry demonstrates the potential clinical utility of plasma biomarkers in predicting brain amyloids-β burden at an individual level and shows cost–benefit and scalability advantages over current techniques.
Abstract: To facilitate clinical trials of disease-modifying therapies for Alzheimer's disease, which are expected to be most efficacious at the earliest and mildest stages of the disease, supportive biomarker information is necessary. The only validated methods for identifying amyloid-β deposition in the brain-the earliest pathological signature of Alzheimer's disease-are amyloid-β positron-emission tomography (PET) imaging or measurement of amyloid-β in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable. Despite much effort, to our knowledge, no study has validated the clinical utility of blood-based amyloid-β markers. Here we demonstrate the measurement of high-performance plasma amyloid-β biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-β precursor protein (APP)669-711/amyloid-β (Aβ)1-42 and Aβ1-40/Aβ1-42 ratios, and their composites, to predict individual brain amyloid-β-positive or -negative status was determined by amyloid-β-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer's disease. All test biomarkers showed high performance when predicting brain amyloid-β burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-β-PET burden and levels of Aβ1-42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-β burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.
Institute for Health Metrics and Evaluation1, University of Louisville2, Karolinska Institutet3, Kermanshah University of Medical Sciences4, Centre for Mental Health5, University of Queensland6, Tehran University of Medical Sciences7, South African Medical Research Council8, University of KwaZulu-Natal9, University of Colorado Boulder10, University of California, Irvine11, Fred Hutchinson Cancer Research Center12, Montefiore Medical Center13, Northeastern University14, University of Alabama at Birmingham15, Brown University16, San Diego State University17, University of Melbourne18, Albert Einstein College of Medicine19, Cambridge Health Alliance20, University of Pittsburgh21, University of Cape Town22, Johns Hopkins University23, Case Western Reserve University24, Marshall University25, University of London26, University of Illinois at Urbana–Champaign27, National Drug and Alcohol Research Centre28, Harvard University29, University of California, San Diego30, Yale University31, Georgetown University32, Veterans Health Administration33, Jackson State University34, University of Massachusetts Boston35, State University of New York System36, Simmons College37, University of California, Los Angeles38, Charles R. Drew University of Medicine and Science39, University of Oxford40, Norwegian Institute of Public Health41, Pacific Institute42, Curtin University43, Heidelberg University44, Jimma University45, Northwestern University46, Washington University in St. Louis47, Howard University48, University of New Mexico49, University at Buffalo50, University of Washington51, University of South Florida52, Tufts University53, University of Rochester Medical Center54, Kosin University55, Central South University56, Michigan State University57, Ball State University58, Nova Southeastern University59, Dalhousie University60, Mayo Clinic61, University of British Columbia62, Ohio State University63, Baylor University64, Jagiellonian University Medical College65, Wrocław Medical University66, Dartmouth College67, University of Western Ontario68, Oregon Health & Science University69, Virginia Commonwealth University70, Columbia University71, University of Canberra72, Aga Khan University73
TL;DR: There are wide differences in the burden of disease at the state level and specific diseases and risk factors, such as drug use disorders, high BMI, poor diet, high fasting plasma glucose level, and alcohol use disorders are increasing and warrant increased attention.
Abstract: Introduction Several studies have measured health outcomes in the United States, but none have provided a comprehensive assessment of patterns of health by state. Objective To use the results of the Global Burden of Disease Study (GBD) to report trends in the burden of diseases, injuries, and risk factors at the state level from 1990 to 2016. Design and Setting A systematic analysis of published studies and available data sources estimates the burden of disease by age, sex, geography, and year. Main Outcomes and Measures Prevalence, incidence, mortality, life expectancy, healthy life expectancy (HALE), years of life lost (YLLs) due to premature mortality, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 333 causes and 84 risk factors with 95% uncertainty intervals (UIs) were computed. Results Between 1990 and 2016, overall death rates in the United States declined from 745.2 (95% UI, 740.6 to 749.8) per 100 000 persons to 578.0 (95% UI, 569.4 to 587.1) per 100 000 persons. The probability of death among adults aged 20 to 55 years declined in 31 states and Washington, DC from 1990 to 2016. In 2016, Hawaii had the highest life expectancy at birth (81.3 years) and Mississippi had the lowest (74.7 years), a 6.6-year difference. Minnesota had the highest HALE at birth (70.3 years), and West Virginia had the lowest (63.8 years), a 6.5-year difference. The leading causes of DALYs in the United States for 1990 and 2016 were ischemic heart disease and lung cancer, while the third leading cause in 1990 was low back pain, and the third leading cause in 2016 was chronic obstructive pulmonary disease. Opioid use disorders moved from the 11th leading cause of DALYs in 1990 to the 7th leading cause in 2016, representing a 74.5% (95% UI, 42.8% to 93.9%) change. In 2016, each of the following 6 risks individually accounted for more than 5% of risk-attributable DALYs: tobacco consumption, high body mass index (BMI), poor diet, alcohol and drug use, high fasting plasma glucose, and high blood pressure. Across all US states, the top risk factors in terms of attributable DALYs were due to 1 of the 3 following causes: tobacco consumption (32 states), high BMI (10 states), or alcohol and drug use (8 states). Conclusions and Relevance There are wide differences in the burden of disease at the state level. Specific diseases and risk factors, such as drug use disorders, high BMI, poor diet, high fasting plasma glucose level, and alcohol use disorders are increasing and warrant increased attention. These data can be used to inform national health priorities for research, clinical care, and policy.
University of Melbourne1, University of British Columbia2, New York University3, Federal University of São Paulo4, French Institute of Health and Medical Research5, University of California, Los Angeles6, Albert Einstein College of Medicine7, Children's Hospital Los Angeles8, University of Pavia9, Karolinska Institutet10, University of Calgary11, Peking University12, University of Glasgow13, Royal Hospital for Sick Children14
TL;DR: The International League Against Epilepsy Classification of the Epilepsies has been updated to reflect the gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989.
Abstract: The International League Against Epilepsy (ILAE) classification of the epilepsies has been updated to reflect the gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for the clinical diagnosis of patients but it is also critical for epilepsy research, development of antiepileptic treatment and communication around the world. The new classification is based on a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It consists of three levels starting with seizure type, where it is assumed that the epileptic seizures of the patient are defined by the new 2017 ILAE seizure classification. After diagnosis of the seizure type, the next step is the diagnosis of the epilepsy type, which includes focal epilepsy, generalized epilepsy, combined generalized and focal epilepsy and also an unclassified epilepsy group. At the third level the disease is assigned to a specific epilepsy syndrome. The new classification incorporates etiology at each stage, emphasizing the need to consider etiology at each step of the diagnosis, as it often carries significant treatment implications. The various etiologies can be assigned to six subgroups, defined with respect to the potential therapeutic consequences. New terminology is introduced, such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limiting and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the twenty-first century.
University of Texas MD Anderson Cancer Center1, University of Melbourne2, Harvard University3, Royal North Shore Hospital4, University of Kiel5, University of Colorado Denver6, University of South Florida7, Washington University in St. Louis8, Sir Charles Gairdner Hospital9, Stanford University10, Memorial Sloan Kettering Cancer Center11, University of Queensland12, University of Duisburg-Essen13, Regeneron14, University of Arizona15, Autonomous University of Barcelona16, Sarah Cannon Research Institute17, Emory University18
TL;DR: Among patients with advanced cutaneous squamous‐cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors.
Abstract: Background No systemic therapies have been approved for the treatment of advanced cutaneous squamous-cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is high and the disease risk is strongly associated with immunosuppression. In the dose-escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous-cell carcinoma. Methods We report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic-disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review. Results In the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval [CI], 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event. Conclusions Among patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT02383212 and NCT02760498 .).
TL;DR: In this article, the authors present possible observing scenarios for the Advanced LIGO, Advanced Virgo and KAGRA gravitational-wave detectors over the next decade, with the intention of providing information to the astronomy community to facilitate planning for multi-messenger astronomy with gravitational waves.
Abstract: We present possible observing scenarios for the Advanced LIGO, Advanced Virgo and KAGRA gravitational-wave detectors over the next decade, with the intention of providing information to the astronomy community to facilitate planning for multi-messenger astronomy with gravitational waves. We estimate the sensitivity of the network to transient gravitational-wave signals, and study the capability of the network to determine the sky location of the source. We report our findings for gravitational-wave transients, with particular focus on gravitational-wave signals from the inspiral of binary neutron star systems, which are the most promising targets for multi-messenger astronomy. The ability to localize the sources of the detected signals depends on the geographical distribution of the detectors and their relative sensitivity, and 90% credible regions can be as large as thousands of square degrees when only two sensitive detectors are operational. Determining the sky position of a significant fraction of detected signals to areas of 5– 20 deg2 requires at least three detectors of sensitivity within a factor of ∼2 of each other and with a broad frequency bandwidth. When all detectors, including KAGRA and the third LIGO detector in India, reach design sensitivity, a significant fraction of gravitational-wave signals will be localized to a few square degrees by gravitational-wave observations alone.
University of Gothenburg1, University of California, San Francisco2, Universidade Estadual de Maringá3, University of Iowa4, University of California, Los Angeles5, University of Melbourne6, University of Texas Health Science Center at San Antonio7, Complutense University of Madrid8, University of Zurich9, University of Sydney10, Stony Brook University11, Seoul National University12, University of Michigan13, Katholieke Universiteit Leuven14, Kristianstad University College15, University of Bern16, Goethe University Frankfurt17, Columbia University18, University of Basel19
TL;DR: Case definitions in day-to-day clinical practice and in epidemiological or disease-surveillance studies for peri-implant health, peri"-implant mucositis, and peri'simplantitis were introduced.
Abstract: A classification for peri-implant diseases and conditions was presented. Focused questions on the characteristics of peri-implant health, peri-implant mucositis, peri-implantitis, and soft- and hard-tissue deficiencies were addressed. Peri-implant health is characterized by the absence of erythema, bleeding on probing, swelling, and suppuration. It is not possible to define a range of probing depths compatible with health; Peri-implant health can exist around implants with reduced bone support. The main clinical characteristic of peri-implant mucositis is bleeding on gentle probing. Erythema, swelling, and/or suppuration may also be present. An increase in probing depth is often observed in the presence of peri-implant mucositis due to swelling or decrease in probing resistance. There is strong evidence from animal and human experimental studies that plaque is the etiological factor for peri-implant mucositis. Peri-implantitis is a plaque-associated pathological condition occurring in tissues around dental implants, characterized by inflammation in the peri-implant mucosa and subsequent progressive loss of supporting bone. Peri-implantitis sites exhibit clinical signs of inflammation, bleeding on probing, and/or suppuration, increased probing depths and/or recession of the mucosal margin in addition to radiographic bone loss. The evidence is equivocal regarding the effect of keratinized mucosa on the long-term health of the peri-implant tissue. It appears, however, that keratinized mucosa may have advantages regarding patient comfort and ease of plaque removal. Case definitions in day-to-day clinical practice and in epidemiological or disease-surveillance studies for peri-implant health, peri-implant mucositis, and peri-implantitis were introduced. The proposed case definitions should be viewed within the context that there is no generic implant and that there are numerous implant designs with different surface characteristics, surgical and loading protocols. It is recommended that the clinician obtain baseline radiographic and probing measurements following the completion of the implant-supported prosthesis.
TL;DR: The sources of plastic particles in agroecosystems, the mechanisms, constraints and dynamic behaviour of plastic during aging on land, and the responses of soil organisms and plants at different levels of biological organisation to plastic particles of micro and nano-scale are discussed.
TL;DR: The findings show that radionuclide treatment with Lutetium-177 [177Lu]-PSMA-617 has high response rates, low toxic effects, and reduction of pain in men with metastatic castration-resistant prostate cancer who have progressed after conventional treatments.
Abstract: Summary Background Progressive metastatic castration-resistant prostate cancer is a highly lethal disorder and new effective therapeutic agents that improve patient outcomes are urgently needed. Lutetium-177 [ 177 Lu]-PSMA-617, a radiolabelled small molecule, binds with high affinity to prostate-specific membrane antigen (PSMA) enabling beta particle therapy targeted to metastatic castration-resistant prostate cancer. We aimed to investigate the safety, efficacy, and effect on quality of life of [ 177 Lu]-PSMA-617 in men with metastatic castration-resistant prostate cancer who progressed after standard treatments. Methods In this single-arm, single-centre, phase 2 trial, we recruited men (aged 18 years and older) with metastatic castration-resistant prostate cancer and progressive disease after standard treatments, including taxane-based chemotherapy and second-generation anti-androgens, from the Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Patients underwent a screening PSMA and FDG-PET/CT to confirm high PSMA-expression. Eligible patients had progressive disease defined by imaging (according to Response Evaluation Criteria In Solid Tumours [RECIST] or bone scan) or new pain in an area of radiographically evident disease, and were required to have an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or lower. Eligible patients received up to four cycles of intravenous [ 177 Lu]-PSMA-617, at six weekly intervals. The primary endpoint was PSA response according to Prostate Cancer Clinical Trial Working Group criteria defined as a greater than 50% PSA decline from baseline and toxicity according to CTCAE. Additional primary endpoints were imaging responses (as measured by bone scan, CT, PSMA, and FDG PET/CT) and quality of life (assessed with the EORTC-Q30 and Brief Pain Inventory-Short Form questionnaires), all measured up to 3 months post completion of treatment. This trial is registered with the Australian New Zealand Clinical Trials Registry, number 12615000912583. Findings Between Aug 26, 2015, and Dec 8, 2016, 43 men were screened to identify 30 patients eligible for treatment. 26 (87%) had received at least one line of previous chemotherapy (80% docetaxel and 47% cabazitaxel) and 25 (83%) received prior abiraterone acetate, enzalutamide, or both. The mean administered radioactivity was 7·5 GBq per cycle. 17 (57%) of 30 patients (95% CI 37–75) achieved a PSA decline of 50% or more. There were no treatment-related deaths. The most common toxic effects related to [ 177 Lu]-PSMA-617 were grade 1 dry mouth recorded in 26 (87%) patients, grade 1 and 2 transient nausea in 15 (50%), and G1–2 fatigue in 15 (50%). Grade 3 or 4 thrombocytopenia possibly attributed to [ 177 Lu]-PSMA-617 occurred in four (13%) patients. Objective response in nodal or visceral disease was reported in 14 (82%) of 17 patients with measurable disease. Clinically meaningful improvements in pain severity and interference scores were recorded at all timepoints. 11 (37%) patients experienced a ten point or more improvement in global health score by the second cycle of treatment. Interpretation Our findings show that radionuclide treatment with [ 177 Lu]-PSMA-617 has high response rates, low toxic effects, and reduction of pain in men with metastatic castration-resistant prostate cancer who have progressed after conventional treatments. This evidence supports the need for randomised controlled trials to further assess efficacy compared with current standards of care. Funding None.
TL;DR: Current understanding of the mechanisms by which p53 induces cell death is discussed and how this affects p53-mediated tumour suppression and the response of malignant cells to anticancer therapy is discussed.
Abstract: The tumour suppressor gene TP53 is mutated in ~50% of human cancers. In addition to its function in tumour suppression, p53 also plays a major role in the response of malignant as well as nontransformed cells to many anticancer therapeutics, particularly those that cause DNA damage. P53 forms a homotetrameric transcription factor that is reported to directly regulate ~500 target genes, thereby controlling a broad range of cellular processes, including cell cycle arrest, cell senescence, DNA repair, metabolic adaptation and cell death. For a long time, induction of apoptotic death in nascent neoplastic cells was regarded as the principal mechanism by which p53 prevents tumour development. This concept has, however, recently been challenged by the findings that in striking contrast to Trp53-deficient mice, gene-targeted mice that lack the critical effectors of p53-induced apoptosis do not develop tumours spontaneously. Remarkably, even mice lacking all mediators critical for p53-induced apoptosis, G1/S boundary cell cycle arrest and cell senescence do not develop any tumours spontaneously. In this review we discuss current understanding of the mechanisms by which p53 induces cell death and how this affects p53-mediated tumour suppression and the response of malignant cells to anticancer therapy.
TL;DR: A high proportion of patients achieved an intracranial response with the combination of nivolumab alone or in combination with ipilimumab, which should be considered as a first-line therapy for patients with asymptomatic untreated brain metastases.
Abstract: Summary Background Nivolumab monotherapy and combination nivolumab plus ipilimumab increase proportions of patients achieving a response and survival versus ipilimumab in patients with metastatic melanoma; however, efficacy in active brain metastases is unknown. We aimed to establish the efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with active melanoma brain metastases. Methods This multicentre open-label randomised phase 2 trial was done at four sites in Australia, in three cohorts of immunotherapy-naive patients aged 18 years or older with melanoma brain metastases. Patients with asymptomatic brain metastases with no previous local brain therapy were randomly assigned using the biased coin minimisation method, stratified by site, in a 30:24 ratio (after a safety run-in of six patients) to cohort A (nivolumab plus ipilimumab) or cohort B (nivolumab). Patients with brain metastases in whom local therapy had failed, or who had neurological symptoms, or leptomeningeal disease were enrolled in non-randomised cohort C (nivolumab). Patients in cohort A received intravenous nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks; patients in cohort B or cohort C received intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was intracranial response from week 12. Primary and safety analyses were done on an intention-to-treat basis in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02374242, and is ongoing for the final survival analysis. Findings Between Nov 4, 2014, and April 21, 2017, 79 patients were enrolled; 36 in cohort A, 27 in cohort B, and 16 in cohort C. One patient in cohort A and two in cohort B were found to be ineligible and excluded from the study before receiving the study drug. At the data cutoff (Aug 28, 2017), with a median follow up of 17 months (IQR 8–25), intracranial responses were achieved by 16 (46%; 95% CI 29–63) of 35 patients in cohort A, five (20%; 7–41) of 25 in cohort B, and one (6%; 0–30) of 16 in cohort C. Intracranial complete responses occurred in six (17%) patients in cohort A, three (12%) in cohort B, and none in cohort C. Treatment-related adverse events occurred in 34 (97%) of 35 patients in cohort A, 17 (68%) of 25 in cohort B, and eight (50%) of 16 in cohort C. Grade 3 or 4 treatment-related adverse events occurred in 19 (54%) patients in cohort A, four (16%) in cohort B, and two (13%) in cohort C. No treatment-related deaths occurred. Interpretation Nivolumab combined with ipilimumab and nivolumab monotherapy are active in melanoma brain metastases. A high proportion of patients achieved an intracranial response with the combination. Thus, nivolumab combined with ipilimumab should be considered as a first-line therapy for patients with asymptomatic untreated brain metastases. Funding Melanoma Institute Australia and Bristol-Myers Squibb.
Columbia University1, Centre Hospitalier Universitaire de Toulouse2, University of Melbourne3, University of Western Ontario4, Karolinska Institutet5, University of Milan6, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico7, Eli Lilly and Company8, Indiana University9, Avid Radiopharmaceuticals10
TL;DR: Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer's disease did not significantly affect cognitive decline and the secondary outcomes were considered to be descriptive and are reported without significance testing.
Abstract: Background Alzheimer’s disease is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid. Methods We conducted a double-blind, placebo-controlled, phase 3 trial involving patients with mild dementia due to Alzheimer’s disease, defined as a Mini–Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron-emission tomography or Aβ1-42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessmen...
University of Southampton1, University of Nottingham2, Newcastle University3, University of London4, University College London5, University Hospital Southampton NHS Foundation Trust6, University of Melbourne7, University of the West Indies8, Agency for Science, Technology and Research9, University of Auckland10
TL;DR: It is proposed that the evidence for periconceptional effects on lifetime health is now so compelling that it calls for new guidance on parental preparation for pregnancy, beginning before conception, to protect the health of offspring.
TL;DR: DynaMut is presented, a web server implementing two distinct, well established normal mode approaches, which can be used to analyze and visualize protein dynamics by sampling conformations and assess the impact of mutations on protein dynamics and stability resulting from vibrational entropy changes.
Abstract: Proteins are highly dynamic molecules, whose function is intrinsically linked to their molecular motions. Despite the pivotal role of protein dynamics, their computational simulation cost has led to most structure-based approaches for assessing the impact of mutations on protein structure and function relying upon static structures. Here we present DynaMut, a web server implementing two distinct, well established normal mode approaches, which can be used to analyze and visualize protein dynamics by sampling conformations and assess the impact of mutations on protein dynamics and stability resulting from vibrational entropy changes. DynaMut integrates our graph-based signatures along with normal mode dynamics to generate a consensus prediction of the impact of a mutation on protein stability. We demonstrate our approach outperforms alternative approaches to predict the effects of mutations on protein stability and flexibility (P-value < 0.001), achieving a correlation of up to 0.70 on blind tests. DynaMut also provides a comprehensive suite for protein motion and flexibility analysis and visualization via a freely available, user friendly web server at http://biosig.unimelb.edu.au/dynamut/.
TL;DR: Detailed, high-dimensional characterization of T cells in breast cancer reveals activated TRM population and a gene signature associated with improved prognosis and suggest that CD8+ TRM cells contribute to BC immunosurveillance and are the key targets of modulation by immune checkpoint inhibition.
Abstract: The quantity of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is a robust prognostic factor for improved patient survival, particularly in triple-negative and HER2-overexpressing BC subtypes1. Although T cells are the predominant TIL population2, the relationship between quantitative and qualitative differences in T cell subpopulations and patient prognosis remains unknown. We performed single-cell RNA sequencing (scRNA-seq) of 6,311 T cells isolated from human BCs and show that significant heterogeneity exists in the infiltrating T cell population. We demonstrate that BCs with a high number of TILs contained CD8+ T cells with features of tissue-resident memory T (TRM) cell differentiation and that these CD8+ TRM cells expressed high levels of immune checkpoint molecules and effector proteins. A CD8+ TRM gene signature developed from the scRNA-seq data was significantly associated with improved patient survival in early-stage triple-negative breast cancer (TNBC) and provided better prognostication than CD8 expression alone. Our data suggest that CD8+ TRM cells contribute to BC immunosurveillance and are the key targets of modulation by immune checkpoint inhibition. Further understanding of the development, maintenance and regulation of TRM cells will be crucial for successful immunotherapeutic development in BC.