Showing papers by "Monash University published in 2018"
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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
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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
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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
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Northeastern University1, Tufts Medical Center2, McGill University3, Johns Hopkins University4, Utrecht University5, Vanderbilt University Medical Center6, Brigham and Women's Hospital7, New York University8, McMaster University9, Ohio State University10, Radboud University Nijmegen11, London Health Sciences Centre12, University of Western Ontario13, University of Montpellier14, RMIT University15, University of Poitiers16, Maine Medical Center17, University of Washington18, University of Chicago19, Intermountain Healthcare20, Deakin University21, Johns Hopkins University School of Medicine22, Yale University23, University of Grenoble24, University of California, San Francisco25, Monash University26, Case Western Reserve University27, New York Medical College28, University of Toronto29, Stanford University30
TL;DR: Substantial agreement was found among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults.
Abstract: Objective:To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU.Design:Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups g
1,935 citations
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TL;DR: This review highlights the significance of size and PDI in the successful design, formulation and development of nanosystems for pharmaceutical, nutraceutical and other applications.
Abstract: Lipid-based drug delivery systems, or lipidic carriers, are being extensively employed to enhance the bioavailability of poorly-soluble drugs. They have the ability to incorporate both lipophilic and hydrophilic molecules and protecting them against degradation in vitro and in vivo. There is a number of physical attributes of lipid-based nanocarriers that determine their safety, stability, efficacy, as well as their in vitro and in vivo behaviour. These include average particle size/diameter and the polydispersity index (PDI), which is an indication of their quality with respect to the size distribution. The suitability of nanocarrier formulations for a particular route of drug administration depends on their average diameter, PDI and size stability, among other parameters. Controlling and validating these parameters are of key importance for the effective clinical applications of nanocarrier formulations. This review highlights the significance of size and PDI in the successful design, formulation and development of nanosystems for pharmaceutical, nutraceutical and other applications. Liposomes, nanoliposomes, vesicular phospholipid gels, solid lipid nanoparticles, transfersomes and tocosomes are presented as frequently-used lipidic drug carriers. The advantages and limitations of a range of available analytical techniques used to characterize lipidic nanocarrier formulations are also covered.
1,891 citations
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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
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TL;DR: This study assesses the state-of-the-art machine learning methods used for brain tumor image analysis in mpMRI scans, during the last seven instances of the International Brain Tumor Segmentation (BraTS) challenge, i.e., 2012-2018, and investigates the challenge of identifying the best ML algorithms for each of these tasks.
Abstract: Gliomas are the most common primary brain malignancies, with different degrees of aggressiveness, variable prognosis and various heterogeneous histologic sub-regions, i.e., peritumoral edematous/invaded tissue, necrotic core, active and non-enhancing core. This intrinsic heterogeneity is also portrayed in their radio-phenotype, as their sub-regions are depicted by varying intensity profiles disseminated across multi-parametric magnetic resonance imaging (mpMRI) scans, reflecting varying biological properties. Their heterogeneous shape, extent, and location are some of the factors that make these tumors difficult to resect, and in some cases inoperable. The amount of resected tumoris a factor also considered in longitudinal scans, when evaluating the apparent tumor for potential diagnosis of progression. Furthermore, there is mounting evidence that accurate segmentation of the various tumor sub-regions can offer the basis for quantitative image analysis towards prediction of patient overall survival. This study assesses thestate-of-the-art machine learning (ML) methods used for brain tumor image analysis in mpMRI scans, during the last seven instances of the International Brain Tumor Segmentation (BraTS) challenge, i.e., 2012-2018. Specifically, we focus on i) evaluating segmentations of the various glioma sub-regions in pre-operative mpMRI scans, ii) assessing potential tumor progression by virtue of longitudinal growth of tumor sub-regions, beyond use of the RECIST/RANO criteria, and iii) predicting the overall survival from pre-operative mpMRI scans of patients that underwent gross tota lresection. Finally, we investigate the challenge of identifying the best ML algorithms for each of these tasks, considering that apart from being diverse on each instance of the challenge, the multi-institutional mpMRI BraTS dataset has also been a continuously evolving/growing dataset.
1,165 citations
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National Health and Medical Research Council1, Monash University2, University of New South Wales3, University of Pennsylvania4, Erasmus University Rotterdam5, Oulu University Hospital6, University of Adelaide7, Odense University Hospital8, State University of New York System9, Australian Catholic University10, University Medical Center Utrecht11, Sanjay Gandhi Post Graduate Institute of Medical Sciences12, University of Chile13, university of lille14, Utrecht University15, Imperial College London16, University of Western Australia17, Karolinska Institutet18, University of Rochester19, Pennsylvania State University20, Peking University21, Cornell University22, Royal College of Surgeons in Ireland23, University of Hong Kong24, Columbia University Medical Center25, Pennington Biomedical Research Center26, Agostino Gemelli University Polyclinic27, Deakin University28, Universidade Federal do Rio Grande do Sul29, Victoria University, Australia30, University of Helsinki31, Queen Mary University of London32, Taipei Medical University Hospital33, University of Cape Town34, Norwegian University of Science and Technology35, Children's Hospital of Philadelphia36, University of Colombo37, University of Pittsburgh38, Boston Children's Hospital39, Hacettepe University40
TL;DR: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS.
Abstract: Study Question What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? Summary Answer International evidence-based guidelines including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS. What Is Known Already Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. Study Design, Size, Duration International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. Participants/Materials, Setting, Methods Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis, and translation experts. Thirty-seven societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels. Main Results and the Role of Chance The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; ii) reducing unnecessary testing; iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and iv) emphasizing evidence based medical therapy and cheaper and safer fertility management. Limitations, Reasons for Caution Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided. Wider Implications of the Findings The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. Study Funding/Competing Interest(S) The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREEII criteria and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC.
1,088 citations
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Bela Abolfathi1, D. S. Aguado2, Gabriela Aguilar3, Carlos Allende Prieto2 +361 more•Institutions (94)
TL;DR: SDSS-IV is the fourth generation of the Sloan Digital Sky Survey and has been in operation since 2014 July. as discussed by the authors describes the second data release from this phase, and the 14th from SDSS overall (making this Data Release Fourteen or DR14).
Abstract: The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since 2014 July. This paper describes the second data release from this phase, and the 14th from SDSS overall (making this Data Release Fourteen or DR14). This release makes the data taken by SDSS-IV in its first two years of operation (2014-2016 July) public. Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey; the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data-driven machine-learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from the SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS web site (www.sdss.org) has been updated for this release and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020 and will be followed by SDSS-V.
965 citations
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TL;DR: A random-effects model meta-analysis allows benchmarking of the prevalence of depression during the era when online health information emerged, facilitating future comparisons.
Abstract: The prevalence of depression may be affected by changes in psychiatric practices and the availability of online mental health information in the past two decades. This study aimed to evaluate the aggregate prevalence of depression in communities from different countries between 1994 and 2014 and to explore the variations in prevalence stratified by geographical, methodological and socio-economic factors. A total of 90 studies were identified and met the inclusion criteria (n = 1,112,573 adults) with 68 studies on single point prevalence, 9 studies on one-year prevalence, and 13 studies on lifetime prevalence of depression. A random-effects model meta-analysis that was performed to calculate the aggregate point, one-year and lifetime prevalence of depression calculated prevalences of 12.9%, 7.2% and 10.8% respectively. Point prevalence of depression was significantly higher in women (14.4%), countries with a medium human development index (HDI) (29.2%), studies published from 2004 to 2014 (15.4%) and when using self-reporting instruments (17.3%) to assess depression. Heterogeneity was identified by meta-regression and subgroup analysis, and response rate, percentage of women and year of publication, respectively, were determined contribute to depression prevalence. This meta-analysis allows benchmarking of the prevalence of depression during the era when online health information emerged, facilitating future comparisons.
828 citations
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Goethe University Frankfurt1, University of Maryland, College Park2, University of Guelph3, Duke University4, Radboud University Nijmegen5, Swedish University of Agricultural Sciences6, Federal University of Mato Grosso do Sul7, University of Alberta8, Royal Veterinary College9, Wildlife Conservation Society10, Mississippi State University11, Sao Paulo State University12, Michigan Department of Natural Resources13, University of California, Davis14, Aarhus University15, Max Planck Society16, University of Potsdam17, Middle Tennessee State University18, Mammal Research Institute19, Harvard University20, Edmund Mach Foundation21, Smithsonian Conservation Biology Institute22, University of Évora23, University of Montpellier24, Monash University25, Parks Victoria26, Ohio State University27, Fiji National University28, University of Massachusetts Amherst29, United States Geological Survey30, University of Oxford31, Save the Elephants32, German Primate Center33, Technische Universität München34, Institute of Ecosystem Studies35, University of British Columbia36, University of Zurich37, University of Wyoming38, University of Washington39, University of Montana40, University of Freiburg41, Bavarian Forest National Park42, University of Toulouse43, University of Veterinary Medicine Vienna44, University College Cork45, North Carolina Museum of Natural Sciences46, North Carolina State University47, Karatina University48, University of Lethbridge49, Lamont–Doherty Earth Observatory50, University of Valencia51, Stony Brook University52, International Union for Conservation of Nature and Natural Resources53, University of Alicante54, Empresa Brasileira de Pesquisa Agropecuária55, University of Glasgow56, New York University57, University of Oslo58, Hebrew University of Jerusalem59, Norwegian University of Science and Technology60, Field Museum of Natural History61, University of Grenoble62, University of Bayreuth63, University of New South Wales64, Pennsylvania Game Commission65, Princeton University66, University of Konstanz67, University of Haifa68, Polish Academy of Sciences69, University of Lisbon70, University of Porto71, Instituto Superior de Agronomia72, University of California, Santa Cruz73, University of Pretoria74, Colorado State University75
TL;DR: Using a unique GPS-tracking database of 803 individuals across 57 species, it is found that movements of mammals in areas with a comparatively high human footprint were on average one-half to one-third the extent of their movements in area with a low human footprint.
Abstract: Animal movement is fundamental for ecosystem functioning and species survival, yet the effects of the anthropogenic footprint on animal movements have not been estimated across species. Using a unique GPS-tracking database of 803 individuals across 57 species, we found that movements of mammals in areas with a comparatively high human footprint were on average one-half to one-third the extent of their movements in areas with a low human footprint. We attribute this reduction to behavioral changes of individual animals and to the exclusion of species with long-range movements from areas with higher human impact. Global loss of vagility alters a key ecological trait of animals that affects not only population persistence but also ecosystem processes such as predator-prey interactions, nutrient cycling, and disease transmission.
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TL;DR: The Viewpoint is a call for action on this global problem of low back pain and suggests population shifts are more rapid in low-income and middle-income countries, where adequate resources to address the problem might not exist.
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TL;DR: Novel therapies derived from microbiome studies such as fecal microbiota transplantation, probiotic and prebiotics to target associated diseases have been reviewed to introduce the idea of how certain disease symptoms can be ameliorated through dysbiosis correction, thus revealing a new scientific approach toward disease treatment.
Abstract: Interest toward the human microbiome, particularly gut microbiome has flourished in recent decades owing to the rapidly advancing sequence-based screening and humanized gnotobiotic model in interrogating the dynamic operations of commensal microbiota. Although this field is still at a very preliminary stage, whereby the functional properties of the complex gut microbiome remain less understood, several promising findings have been documented and exhibit great potential toward revolutionizing disease etiology and medical treatments. In this review, the interactions between gut microbiota and the host have been focused on, to provide an overview of the role of gut microbiota and their unique metabolites in conferring host protection against invading pathogen, regulation of diverse host physiological functions including metabolism, development and homeostasis of immunity and the nervous system. We elaborate on how gut microbial imbalance (dysbiosis) may lead to dysfunction of host machineries, thereby contributing to pathogenesis and/or progression toward a broad spectrum of diseases. Some of the most notable diseases namely Clostridium difficile infection (infectious disease), inflammatory bowel disease (intestinal immune-mediated disease), celiac disease (multisystemic autoimmune disorder), obesity (metabolic disease), colorectal cancer, and autism spectrum disorder (neuropsychiatric disorder) have been discussed and delineated along with recent findings. Novel therapies derived from microbiome studies such as fecal microbiota transplantation, probiotic and prebiotics to target associated diseases have been reviewed to introduce the idea of how certain disease symptoms can be ameliorated through dysbiosis correction, thus revealing a new scientific approach toward disease treatment. Toward the end of this review, several research gaps and limitations have been described along with suggested future studies to overcome the current research lacunae. Despite the ongoing debate on whether gut microbiome plays a role in the above-mentioned diseases, we have in this review, gathered evidence showing a potentially far more complex link beyond the unidirectional cause-and-effect relationship between them.
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Fredrick R. Schumacher1, Ali Amin Al Olama2, Sonja I. Berndt3, Sara Benlloch2 +204 more•Institutions (79)
TL;DR: A large meta-analysis combining genome-wide and custom high-density genotyping array data identifies 63 new susceptibility loci for prostate cancer, enhancing fine-mapping efforts and providing insights into the underlying biology of PrCa1.
Abstract: Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10−9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55–2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04–6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1. A large meta-analysis combining genome-wide and custom high-density genotyping array data identifies 63 new susceptibility loci for prostate cancer, enhancing fine-mapping efforts and providing insights into the underlying biology.
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TL;DR: While the review identified increased presentations by the elderly with complex and chronic conditions as an emerging and widespread driver of crowding, more research is required to isolate the precise local factors leading to ED crowding.
Abstract: Background Emergency department crowding is a major global healthcare issue. There is much debate as to the causes of the phenomenon, leading to difficulties in developing successful, targeted solutions. Aim The aim of this systematic review was to critically analyse and summarise the findings of peer-reviewed research studies investigating the causes and consequences of, and solutions to, emergency department crowding. Method The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. A structured search of four databases (Medline, CINAHL, EMBASE and Web of Science) was undertaken to identify peer-reviewed research publications aimed at investigating the causes or consequences of, or solutions to, emergency department crowding, published between January 2000 and June 2018. Two reviewers used validated critical appraisal tools to independently assess the quality of the studies. The study protocol was registered with the International prospective register of systematic reviews (PROSPERO 2017: CRD42017073439). Results From 4,131 identified studies and 162 full text reviews, 102 studies met the inclusion criteria. The majority were retrospective cohort studies, with the greatest proportion (51%) trialling or modelling potential solutions to emergency department crowding. Fourteen studies examined causes and 40 investigated consequences. Two studies looked at both causes and consequences, and two investigated causes and solutions. Conclusions The negative consequences of ED crowding are well established, including poorer patient outcomes and the inability of staff to adhere to guideline-recommended treatment. This review identified a mismatch between causes and solutions. The majority of identified causes related to the number and type of people attending ED and timely discharge from ED, while reported solutions focused on efficient patient flow within the ED. Solutions aimed at the introduction of whole-of-system initiatives to meet timed patient disposition targets, as well as extended hours of primary care, demonstrated promising outcomes. While the review identified increased presentations by the elderly with complex and chronic conditions as an emerging and widespread driver of crowding, more research is required to isolate the precise local factors leading to ED crowding, with system-wide solutions tailored to address identified causes.
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University of Alabama at Birmingham1, University of California, San Diego2, Harvard University3, Monash University4, University of California, Los Angeles5, Brigham and Women's Hospital6, University of California, San Francisco7, Emory University8, University of North Carolina at Chapel Hill9, University of Cologne10, University of Zurich11, University of Paris12
TL;DR: Advances in HIV prevention and treatment with antiretroviral drugs continue to improve clinical management and outcomes for individuals at risk for and living with HIV.
Abstract: Importance Antiretroviral therapy (ART) is the cornerstone of prevention and management of HIV infection. Objective To evaluate new data and treatments and incorporate this information into updated recommendations for initiating therapy, monitoring individuals starting therapy, changing regimens, and preventing HIV infection for individuals at risk. Evidence Review New evidence collected since the International Antiviral Society–USA 2016 recommendations via monthly PubMed and EMBASE literature searches up to April 2018; data presented at peer-reviewed scientific conferences. A volunteer panel of experts in HIV research and patient care considered these data and updated previous recommendations. Findings ART is recommended for virtually all HIV-infected individuals, as soon as possible after HIV diagnosis. Immediate initiation (eg, rapid start), if clinically appropriate, requires adequate staffing, specialized services, and careful selection of medical therapy. An integrase strand transfer inhibitor (InSTI) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is generally recommended for initial therapy, with unique patient circumstances (eg, concomitant diseases and conditions, potential for pregnancy, cost) guiding the treatment choice. CD4 cell count, HIV RNA level, genotype, and other laboratory tests for general health and co-infections are recommended at specified points before and during ART. If a regimen switch is indicated, treatment history, tolerability, adherence, and drug resistance history should first be assessed; 2 or 3 active drugs are recommended for a new regimen. HIV testing is recommended at least once for anyone who has ever been sexually active and more often for individuals at ongoing risk for infection. Preexposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine and appropriate monitoring is recommended for individuals at risk for HIV. Conclusions and Relevance Advances in HIV prevention and treatment with antiretroviral drugs continue to improve clinical management and outcomes for individuals at risk for and living with HIV.
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28 May 2018TL;DR: DeepCom applies Natural Language Processing (NLP) techniques to learn from a large code corpus and generates comments from learned features for better comments generation of Java methods.
Abstract: During software maintenance, code comments help developers comprehend programs and reduce additional time spent on reading and navigating source code. Unfortunately, these comments are often mismatched, missing or outdated in the software projects. Developers have to infer the functionality from the source code. This paper proposes a new approach named DeepCom to automatically generate code comments for Java methods. The generated comments aim to help developers understand the functionality of Java methods. DeepCom applies Natural Language Processing (NLP) techniques to learn from a large code corpus and generates comments from learned features. We use a deep neural network that analyzes structural information of Java methods for better comments generation. We conduct experiments on a large-scale Java corpus built from 9,714 open source projects from GitHub. We evaluate the experimental results on a machine translation metric. Experimental results demonstrate that our method DeepCom outperforms the state-of-the-art by a substantial margin.
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University of Bern1, Institute of Cancer Research2, Oregon Health & Science University3, Cornell University4, Princess Margaret Cancer Centre5, Yonsei University6, University of Salford7, University of Copenhagen8, Monash University9, University of São Paulo10, Columbia University11, The Royal Marsden NHS Foundation Trust12, University of Texas MD Anderson Cancer Center13, University of California, Davis14, University of Bologna15, University of California, San Francisco16, University of Paris-Sud17, University of British Columbia18, Duke University19, University of Cologne20, Fred Hutchinson Cancer Research Center21, University of Birmingham22, Memorial Sloan Kettering Cancer Center23, University of Tampere24, American University of Beirut25, Medical University of Vienna26, Vanderbilt University27, Tata Memorial Hospital28, Icahn School of Medicine at Mount Sinai29, Ghent University30, University of Washington31, Université de Montréal32, Tulane University33, Tel Aviv University34, Harvard University35, Prostate Cancer Foundation36, Toho University37, University College London38, University of Toronto39, Université catholique de Louvain40, University of Milan41, University of Ulm42
TL;DR: The presented expert voting results can be used for support in areas of management of men with APC where there is no high-level evidence, but individualised treatment decisions should as always be based on all of the data available.
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Richard A. Klein1, Michelangelo Vianello2, Fred Hasselman3, Byron G. Adams4 +187 more•Institutions (118)
TL;DR: This paper conducted preregistered replications of 28 classic and contemporary published findings, with protocols that were peer reviewed in advance, to examine variation in effect magnitudes across samples and settings, and found that very little heterogeneity was attributable to the order in which the tasks were performed or whether the task were administered in lab versus online.
Abstract: We conducted preregistered replications of 28 classic and contemporary published findings, with protocols that were peer reviewed in advance, to examine variation in effect magnitudes across samples and settings. Each protocol was administered to approximately half of 125 samples that comprised 15,305 participants from 36 countries and territories. Using the conventional criterion of statistical significance (p < .05), we found that 15 (54%) of the replications provided evidence of a statistically significant effect in the same direction as the original finding. With a strict significance criterion (p < .0001), 14 (50%) of the replications still provided such evidence, a reflection of the extremely high-powered design. Seven (25%) of the replications yielded effect sizes larger than the original ones, and 21 (75%) yielded effect sizes smaller than the original ones. The median comparable Cohen’s ds were 0.60 for the original findings and 0.15 for the replications. The effect sizes were small (< 0.20) in 16 of the replications (57%), and 9 effects (32%) were in the direction opposite the direction of the original effect. Across settings, the Q statistic indicated significant heterogeneity in 11 (39%) of the replication effects, and most of those were among the findings with the largest overall effect sizes; only 1 effect that was near zero in the aggregate showed significant heterogeneity according to this measure. Only 1 effect had a tau value greater than .20, an indication of moderate heterogeneity. Eight others had tau values near or slightly above .10, an indication of slight heterogeneity. Moderation tests indicated that very little heterogeneity was attributable to the order in which the tasks were performed or whether the tasks were administered in lab versus online. Exploratory comparisons revealed little heterogeneity between Western, educated, industrialized, rich, and democratic (WEIRD) cultures and less WEIRD cultures (i.e., cultures with relatively high and low WEIRDness scores, respectively). Cumulatively, variability in the observed effect sizes was attributable more to the effect being studied than to the sample or setting in which it was studied.
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TL;DR: This combination phase 1b study enrolled previously untreated patients aged 65 years and over with acute myeloid leukaemia who were ineligible for standard induction therapy and suggested synergy between hypomethylating agents and venetoclax to determine the maximum tolerated dose and recommended phase 2 dose and analysed safety, pharmacokinetics, and anti-leukaemic activity in all patients.
Abstract: Summary Background Elderly patients (aged ≥65 years) with acute myeloid leukaemia have poor outcomes and no effective standard-of-care therapy exists. Treatment with hypomethylating agents such as azacitidine and decitabine is common, but responses are modest and typically short-lived. The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor, venetoclax, has shown promising single-agent activity in patients with relapsed or refractory acute myeloid leukaemia and preclinical data suggested synergy between hypomethylating agents and venetoclax, which led to this combination phase 1b study. Methods Previously untreated patients aged 65 years and over with acute myeloid leukaemia who were ineligible for standard induction therapy were enrolled into this non-randomised, open-label, phase 1b study. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0–2 and either intermediate-risk or poor-risk cytogenetics. Patients were enrolled into one of three groups for the dose-escalation phase of this study: group A (venetoclax and intravenous decitabine 20 mg/m 2 [days 1–5 of each 28-day cycle]), group B (venetoclax and subcutaneous or intravenous azacitidine 75 mg/m 2 [days 1–7 of each 28-day cycle]), and group C (a venetoclax and decitabine substudy with the oral CYP3A inhibitor posaconazole, 300 mg twice on cycle 1, day 21, and 300 mg once daily from cycle 1, days 22–28, to assess its effect on venetoclax pharmacokinetics). Dose escalation followed a standard 3 + 3 design with at least three evaluable patients enrolled per cohort; daily target doses of venetoclax for groups A and B were 400 mg (cohort 1), 800 mg (cohorts 2 and 3), and 1200 mg (cohort 4), and 400 mg for group C. The primary endpoints were the safety and pharmacokinetics of venetoclax plus decitabine or azacitidine, and to determine the maximum tolerated dose and recommended phase 2 dose. Secondary endpoints included the preliminary anti-leukaemic activity of venetoclax with decitabine or azacitidine through the analysis of overall response, duration of response, and overall survival. We analysed safety, pharmacokinetics, and anti-leukaemic activity in all patients who received one or more venetoclax doses. The expansion phase of the study is ongoing but is closed to accrual. This trial is registered with ClinicalTrials.gov, number NCT02203773. Findings 57 patients were enrolled in the study. 23 patients in group A and 22 patients in group B were enrolled between Nov 19, 2014, and Dec 15, 2015, and 12 patients in group C were enrolled between June 14, 2015, and Jan 16, 2016. As of data cutoff on June 15, 2016, the most common grade 3–4 treatment-emergent adverse events were thrombocytopenia (27 [47%] of 57 patients; nine in group A, 13 in group B, and five in group C), febrile neutropenia (24 [42%] of 57; 11 in group A, ten in group B, and three in group C), and neutropenia (23 [40%] of 57; 12 in group A, eight in group B, and three in group C). The most common serious treatment-emergent adverse event in groups A and B was febrile neutropenia (seven [30%] of 23 patients vs seven [32%] of 22), whereas in group C it was lung infection (four [33%] of 12 patients). 49 (86%) of 57 patients had treatment-related adverse events; the most common in groups A and B included nausea (12 [52%] patients vs seven [32%] patients), fatigue (six [26%] patients vs seven [32%]), and decreased neutrophil count (six [26%] patients vs six [27%]), whereas in group C the most common were nausea (seven [58%] of 12 patients), leucopenia (six [50%]), vomiting (five [42%]), and decreased platelet count (five [42%]). The maximum tolerated dose was not reached. The recommended phase 2 dose was 400 mg once a day or 800 mg with an interrupted dosing schedule (safety expansion). In total, four (7%) of 57 patients had died within 30 days of the first venetoclax dose caused by sepsis (group B), bacteraemia (group A), lung infection (group C), and respiratory failure (group A). Tumour lysis syndrome was not observed. Decitabine and azacitidine did not substantially affect venetoclax exposures. Overall, 35 (61%; 95% CI 47·6–74·0) of 57 patients achieved complete remission or complete remission with incomplete marrow recovery. In groups A and B, 27 (60%; 95% CI 44·3–74·3) of 45 patients had complete remission or complete remission with incomplete marrow recovery. Interpretation Venetoclax plus hypomethylating agent therapy seems to be a novel, well-tolerated regimen with promising activity in this underserved patient population. Evaluation of expansion cohorts is ongoing at 400 mg and 800 mg doses using both hypomethylating agent combinations. Funding AbbVie and Genentech.
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TL;DR: This study provides a mechanistic description of mtDNA release from mitochondria during apoptosis, and suggests that mtDNA is found outside the mitochondria—and, indeed, outside the cell—in a wide range of circumstances.
Abstract: Mitochondrial apoptosis is mediated by BAK and BAX, two proteins that induce mitochondrial outer membrane permeabilization, leading to cytochrome c release and activation of apoptotic caspases. In the absence of active caspases, mitochondrial DNA (mtDNA) triggers the innate immune cGAS/STING pathway, causing dying cells to secrete type I interferon. How cGAS gains access to mtDNA remains unclear. We used live-cell lattice light-sheet microscopy to examine the mitochondrial network in mouse embryonic fibroblasts. We found that after BAK/BAX activation and cytochrome c loss, the mitochondrial network broke down and large BAK/BAX pores appeared in the outer membrane. These BAK/BAX macropores allowed the inner mitochondrial membrane to herniate into the cytosol, carrying with it mitochondrial matrix components, including the mitochondrial genome. Apoptotic caspases did not prevent herniation but dismantled the dying cell to suppress mtDNA-induced innate immune signaling.
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Princess Alexandra Hospital1, University of Queensland2, Royal Brisbane and Women's Hospital3, National University of Singapore4, Tan Tock Seng Hospital5, Nanyang Technological University6, Istanbul Medipol University7, King Saud bin Abdulaziz University for Health Sciences8, Sapienza University of Rome9, University of Udine10, Monash University11, American University of Beirut12, North Shore Hospital13, University of Sydney14, Westmead Hospital15, University of Cape Town16, Wollongong Hospital17, University of Wollongong18, Illawarra Health & Medical Research Institute19, Middlemore Hospital20, King Fahad Specialist Hospital21, St. Vincent's Health System22, Fiona Stanley Hospital23, University of Western Australia24, Sunnybrook Health Sciences Centre25, Mater Health Services26, QIMR Berghofer Medical Research Institute27, Deakin University28, Monash University, Clayton campus29
TL;DR: Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality, and findings do not support use of piperACillin- tazobactsam in this setting.
Abstract: Importance Extended-spectrum β-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective “carbapenem-sparing” option to treat extended-spectrum β-lactamase producers. Objectives To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae . Design, Setting, and Participants Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study. Interventions Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician. Main Outcomes and Measures The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used. Results Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1-sided 97.5% CI, −∞ to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group. Conclusions and relevance Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting. Trial Registration anzctr.org.au Identifiers:ACTRN12613000532707andACTRN12615000403538and ClinicalTrials.gov Identifier:NCT02176122
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TL;DR: The present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide, and is believed to be the first ever large-scale coordinated study of WM microstructural differences in schizophrenia.
Abstract: The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.
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TL;DR: Improvements in efficiency are found upon backbone fluorination of the donor polymer to afford the novel material PFBDB-T and the resulting blend with C8-ITIC shows an impressive PCE up to 13.2% as a result of the higher open-circuit voltage.
Abstract: A new synthetic route, to prepare an alkylated indacenodithieno[3,2-b]thiophene-based nonfullerene acceptor (C8-ITIC), is reported. Compared to the reported ITIC with phenylalkyl side chains, the new acceptor C8-ITIC exhibits a reduction in the optical band gap, higher absorptivity, and an increased propensity to crystallize. Accordingly, blends with the donor polymer PBDB-T exhibit a power conversion efficiency (PCE) up to 12.4%. Further improvements in efficiency are found upon backbone fluorination of the donor polymer to afford the novel material PFBDB-T. The resulting blend with C8-ITIC shows an impressive PCE up to 13.2% as a result of the higher open-circuit voltage. Electroluminescence studies demonstrate that backbone fluorination reduces the energy loss of the blends, with PFBDB-T/C8-ITIC-based cells exhibiting a small energy loss of 0.6 eV combined with a high JSC of 19.6 mA cm-2 .
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TL;DR: In this article, the authors review the latest developments in this platform, examine where further development is necessary to achieve more functionalities in LNOI integrated optical circuits and make a few suggestions of interesting applications that could be realized in the platform.
Abstract: Lithium niobate on insulator (LNOI) technology is revolutionizing the lithium niobate industry, enabling higher performance, lower cost and entirely new devices and applications. The availability of LNOI wafers has sparked significant interest in the platform for integrated optical applications, as LNOI offers the attractive material properties of lithium niobate, while also offering the stronger optical confinement and a high optical element integration density that has driven the success of more mature silicon and silicon nitride (SiN) photonics platforms. Due to some similarities between LNOI and SiN, established techniques and standards can readily be adapted to the LNOI platform including a significant array of interface approaches, device designs and also heterogeneous integration techniques for laser sources and photodetectors. In this contribution, we review the latest developments in this platform, examine where further development is necessary to achieve more functionalities in LNOI integrated optical circuits and make a few suggestions of interesting applications that could be realized in this platform. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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TL;DR: How SMRT sequencing is revolutionizing constitutional, reproductive, cancer, microbial and viral genetic testing is capsulize.
Abstract: Short read massive parallel sequencing has emerged as a standard diagnostic tool in the medical setting. However, short read technologies have inherent limitations such as GC bias, difficulties mapping to repetitive elements, trouble discriminating paralogous sequences, and difficulties in phasing alleles. Long read single molecule sequencers resolve these obstacles. Moreover, they offer higher consensus accuracies and can detect epigenetic modifications from native DNA. The first commercially available long read single molecule platform was the RS system based on PacBio's single molecule real-time (SMRT) sequencing technology, which has since evolved into their RSII and Sequel systems. Here we capsulize how SMRT sequencing is revolutionizing constitutional, reproductive, cancer, microbial and viral genetic testing.
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TL;DR: A ‘minimum information standard’ for experimental literature investigating bio–nano interactions is suggested, consisting of specific components to be reported, divided into three categories: material characterization, biological characterization and details of experimental protocols.
Abstract: Studying the interactions between nanoengineered materials and biological systems plays a vital role in the development of biological applications of nanotechnology and the improvement of our fundamental understanding of the bio-nano interface. A significant barrier to progress in this multidisciplinary area is the variability of published literature with regards to characterizations performed and experimental details reported. Here, we suggest a 'minimum information standard' for experimental literature investigating bio-nano interactions. This standard consists of specific components to be reported, divided into three categories: material characterization, biological characterization and details of experimental protocols. Our intention is for these proposed standards to improve reproducibility, increase quantitative comparisons of bio-nano materials, and facilitate meta analyses and in silico modelling.
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TL;DR: An introduction to the MplusAutomation package is provided using applied examples including a large-scale simulation study to support methodological developments in structural equation modeling using Mplus.
Abstract: MplusAutomation is a package for R that facilitates complex latent variable analyses in Mplus involving comparisons among many models and parameters. More specifically, MplusAutomation provides too...
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TL;DR: iFeature is a versatile Python‐based toolkit for generating various numerical feature representation schemes for both protein and peptide sequences, capable of calculating and extracting a comprehensive spectrum of 18 major sequence encoding schemes that encompass 53 different types of feature descriptors.
Abstract: Summary Structural and physiochemical descriptors extracted from sequence data have been widely used to represent sequences and predict structural, functional, expression and interaction profiles of proteins and peptides as well as DNAs/RNAs. Here, we present iFeature, a versatile Python-based toolkit for generating various numerical feature representation schemes for both protein and peptide sequences. iFeature is capable of calculating and extracting a comprehensive spectrum of 18 major sequence encoding schemes that encompass 53 different types of feature descriptors. It also allows users to extract specific amino acid properties from the AAindex database. Furthermore, iFeature integrates 12 different types of commonly used feature clustering, selection and dimensionality reduction algorithms, greatly facilitating training, analysis and benchmarking of machine-learning models. The functionality of iFeature is made freely available via an online web server and a stand-alone toolkit. Availability and implementation http://iFeature.erc.monash.edu/; https://github.com/Superzchen/iFeature/. Supplementary information Supplementary data are available at Bioinformatics online.