Showing papers by "University of Louisville published in 2018"
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
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
TL;DR: The proposed case definition extends beyond description based on severity to include characterization of biological features of the disease and represents a first step towards adoption of precision medicine concepts to the management of periodontitis.
Abstract: Background Authors were assigned the task to develop case definitions for periodontitis in the context of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. The aim of this manuscript is to review evidence and rationale for a revision of the current classification, to provide a framework for case definition that fully implicates state-of-the-art knowledge and can be adapted as new evidence emerges, and to suggest a case definition system that can be implemented in clinical practice, research and epidemiologic surveillance. Methods Evidence gathered in four commissioned reviews was analyzed and interpreted with special emphasis to changes with regards to the understanding available prior to the 1999 classification. Authors analyzed case definition systems employed for a variety of chronic diseases and identified key criteria for a classification/case definition of periodontitis. Results The manuscript discusses the merits of a periodontitis case definition system based on Staging and Grading and proposes a case definition framework. Stage I to IV of periodontitis is defined based on severity (primarily periodontal breakdown with reference to root length and periodontitis-associated tooth loss), complexity of management (pocket depth, infrabony defects, furcation involvement, tooth hypermobility, masticatory dysfunction) and additionally described as extent (localized or generalized). Grade of periodontitis is estimated with direct or indirect evidence of progression rate in three categories: slow, moderate and rapid progression (Grade A-C). Risk factor analysis is used as grade modifier. Conclusions The paper describes a simple matrix based on stage and grade to appropriately define periodontitis in an individual patient. The proposed case definition extends beyond description based on severity to include characterization of biological features of the disease and represents a first step towards adoption of precision medicine concepts to the management of periodontitis. It also provides the necessary framework for introduction of biomarkers in diagnosis and prognosis.
1,366 citations
Columbia University1, Complutense University of Madrid2, Ege University3, University of Birmingham4, Rutgers University5, University of Hong Kong6, Boston University7, University of Michigan8, University of Pisa9, University of Louisville10, University of Bonn11, University of Pennsylvania12, University at Buffalo13, University of Greifswald14, Ohio State University15, VU University Amsterdam16, Technion – Israel Institute of Technology17, Peking University18, University of Geneva19, University College London20, University of North Carolina at Chapel Hill21, University of Queensland22
TL;DR: A new periodontitis classification scheme has been adopted, in which forms of the disease previously recognized as "chronic" or "aggressive" are now grouped under a single category ("periodontitis") and are further characterized based on a multi-dimensional staging and grading system as mentioned in this paper.
Abstract: A new periodontitis classification scheme has been adopted, in which forms of the disease previously recognized as "chronic" or "aggressive" are now grouped under a single category ("periodontitis") and are further characterized based on a multi-dimensional staging and grading system. Staging is largely dependent upon the severity of disease at presentation as well as on the complexity of disease management, while grading provides supplemental information about biological features of the disease including a history-based analysis of the rate of periodontitis progression; assessment of the risk for further progression; analysis of possible poor outcomes of treatment; and assessment of the risk that the disease or its treatment may negatively affect the general health of the patient. Necrotizing periodontal diseases, whose characteristic clinical phenotype includes typical features (papilla necrosis, bleeding, and pain) and are associated with host immune response impairments, remain a distinct periodontitis category. Endodontic-periodontal lesions, defined by a pathological communication between the pulpal and periodontal tissues at a given tooth, occur in either an acute or a chronic form, and are classified according to signs and symptoms that have direct impact on their prognosis and treatment. Periodontal abscesses are defined as acute lesions characterized by localized accumulation of pus within the gingival wall of the periodontal pocket/sulcus, rapid tissue destruction and are associated with risk for systemic dissemination.
1,301 citations
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, University of KwaZulu-Natal8, South African Medical Research Council9, 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 Cape Town21, Johns Hopkins University22, University of Pittsburgh23, 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, Veterans Health Administration32, Georgetown University33, 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, Wrocław Medical University65, Jagiellonian University Medical College66, 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.
962 citations
TL;DR: Current knowledge and emerging mechanisms governing oral polymicrobial synergy and dysbiosis that have both enhanced the understanding of pathogenic mechanisms and aided the design of innovative therapeutic approaches for oral diseases are discussed.
Abstract: The dynamic and polymicrobial oral microbiome is a direct precursor of diseases such as dental caries and periodontitis, two of the most prevalent microbially induced disorders worldwide. Distinct microenvironments at oral barriers harbour unique microbial communities, which are regulated through sophisticated signalling systems and by host and environmental factors. The collective function of microbial communities is a major driver of homeostasis or dysbiosis and ultimately health or disease. Despite different aetiologies, periodontitis and caries are each driven by a feedforward loop between the microbiota and host factors (inflammation and dietary sugars, respectively) that favours the emergence and persistence of dysbiosis. In this Review, we discuss current knowledge and emerging mechanisms governing oral polymicrobial synergy and dysbiosis that have both enhanced our understanding of pathogenic mechanisms and aided the design of innovative therapeutic approaches for oral diseases.
938 citations
Columbia University1, Complutense University of Madrid2, Ege University3, University of Birmingham4, Rutgers University5, University of Hong Kong6, Boston University7, University of Michigan8, University of Pisa9, University of Louisville10, University of Bonn11, University of Pennsylvania12, University at Buffalo13, University of Greifswald14, Ohio State University15, VU University Amsterdam16, Technion – Israel Institute of Technology17, Peking University18, University of Geneva19, University College London20, University of North Carolina at Chapel Hill21, University of Queensland22
TL;DR: A new periodontitis classification scheme has been adopted, in which forms of the disease previously recognized as "chronic" or "aggressive" are now grouped under a single category ("periodontitis") and are further characterized based on a multi-dimensional staging and grading system.
Abstract: A new periodontitis classification scheme has been adopted, in which forms of the disease previously recognized as \"chronic\" or \"aggressive\" are now grouped under a single category (\"periodontitis\") and are further characterized based on a multi-dimensional staging and grading system. Staging is largely dependent upon the severity of disease at presentation as well as on the complexity of disease management, while grading provides supplemental information about biological features of the disease including a history-based analysis of the rate of periodontitis progression; assessment of the risk for further progression; analysis of possible poor outcomes of treatment; and assessment of the risk that the disease or its treatment may negatively affect the general health of the patient. Necrotizing periodontal diseases, whose characteristic clinical phenotype includes typical features (papilla necrosis, bleeding, and pain) and are associated with host immune response impairments, remain a distinct periodontitis category. Endodontic-periodontal lesions, defined by a pathological communication between the pulpal and periodontal tissues at a given tooth, occur in either an acute or a chronic form, and are classified according to signs and symptoms that have direct impact on their prognosis and treatment. Periodontal abscesses are defined as acute lesions characterized by localized accumulation of pus within the gingival wall of the periodontal pocket/sulcus, rapid tissue destruction and are associated with risk for systemic dissemination.
698 citations
TL;DR: In injured patients at risk for hemorrhagic shock, the prehospital administration of thawed plasma was safe and resulted in lower 30‐day mortality and a lower median prothrombin‐time ratio than standard‐care resuscitation.
Abstract: Background After a person has been injured, prehospital administration of plasma in addition to the initiation of standard resuscitation procedures in the prehospital environment may reduc
496 citations
University of Cincinnati1, University of Edinburgh2, St George's, University of London3, King's College London4, National Institutes of Health5, University of Louisville6, Brown University7, Toronto Western Hospital8, Royal Hallamshire Hospital9, University of Cambridge10, Western General Hospital11, University of Messina12
TL;DR: The new model highlights a wider range of past sensitizing events, such as physical trauma, medical illness, or physiological/psychophysiological events, that correlate with abnormal predictions of sensory data and body-focused attention.
Abstract: Importance: Functional neurological disorders (FND) are common sources of disability in medicine. Patients have often been misdiagnosed, correctly diagnosed after lengthy delays, and/or subjected to poorly delivered diagnoses that prevent diagnostic understanding and lead to inappropriate treatments, iatrogenic harm, unnecessary and costly evaluations, and poor outcomes. Observations: Functional Neurological Symptom Disorder/Conversion Disorder was adopted by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, replacing the term psychogenic with functional and removing the criterion of psychological stress as a prerequisite for FND. A diagnosis can now be made in an inclusionary manner by identifying neurological signs that are specific to FNDs without reliance on presence or absence of psychological stressors or suggestive historical clues. The new model highlights a wider range of past sensitizing events, such as physical trauma, medical illness, or physiological/psychophysiological events. In this model, strong ideas and expectations about these events correlate with abnormal predictions of sensory data and body-focused attention. Neurobiological abnormalities include hypoactivation of the supplementary motor area and relative disconnection with areas that select or inhibit movements and are associated with a sense of agency. Promising evidence has accumulated for the benefit of specific physical rehabilitation and psychological interventions alone or in combination, but clinical trial evidence remains limited. Conclusions and Relevance: Functional neurological disorders are a neglected but potentially reversible source of disability. Further research is needed to determine the dose and duration of various interventions, the value of combination treatments and multidisciplinary therapy, and the therapeutic modality best suited for each patient.
411 citations
TL;DR: It is demonstrated that plant-derived exosome-like nanoparticles (ELNs) are taken up by the gut microbiota and contain RNAs that alter microbiome composition and host physiology and reveal how plant products and their effects on the microbiome may be used to target specific host processes to alleviate disease.
407 citations
TL;DR: Four patients with motor complete spinal cord injury, signifying no voluntary movement or sphincter function below the level of injury but including retention of some sensation, do not recover independent walking after intense locomotor treadmill training with weight support and simultaneous spinal cord epidural stimulation.
Abstract: Persons with motor complete spinal cord injury, signifying no voluntary movement or sphincter function below the level of injury but including retention of some sensation, do not recover independent walking. We tested intense locomotor treadmill training with weight support and simultaneous spinal cord epidural stimulation in four patients 2.5 to 3.3 years after traumatic spinal injury and after failure to improve with locomotor training alone. Two patients, one with damage to the mid-cervical region and one with damage to the high-thoracic region, achieved over-ground walking (not on a treadmill) after 278 sessions of epidural stimulation and gait training over a period of 85 weeks and 81 sessions over a period of 15 weeks, respectively, and all four achieved independent standing and trunk stability. One patient had a hip fracture during training. (Funded by the Leona M. and Harry B. Helmsley Charitable Trust and others; ClinicalTrials.gov number, NCT02339233 .).
TL;DR: It is shown that MHC class I expression in advanced melanoma predicted resistance to anti–CTLA-4, but not anti-PD-1, treatment, which may need MHCclass II to be effective, which explains why patients on combined therapy do better on average, with one drug overcoming the limitations of the other.
Abstract: Combination anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) and anti–programmed cell death protein 1 (PD-1) therapy promotes antitumor immunity and provides superior benefit to patients with advanced-stage melanoma compared with either therapy alone. T cell immunity requires recognition of antigens in the context of major histocompatibility complex (MHC) class I and class II proteins by CD8+ and CD4+ T cells, respectively. We examined MHC class I and class II protein expression on tumor cells from previously untreated melanoma patients and correlated the results with transcriptional and genomic analyses and with clinical response to anti–CTLA-4, anti–PD-1, or combination therapy. Most (>50% of cells) or complete loss of melanoma MHC class I membrane expression was observed in 78 of 181 cases (43%), was associated with transcriptional repression of HLA-A, HLA-B, HLA-C, and B2M, and predicted primary resistance to anti–CTLA-4, but not anti–PD-1, therapy. Melanoma MHC class II membrane expression on >1% cells was observed in 55 of 181 cases (30%), was associated with interferon-γ (IFN-γ) and IFN-γ–mediated gene signatures, and predicted response to anti–PD-1, but not anti–CTLA-4, therapy. We conclude that primary response to anti–CTLA-4 requires robust melanoma MHC class I expression. In contrast, primary response to anti–PD-1 is associated with preexisting IFN-γ–mediated immune activation that includes tumor-specific MHC class II expression and components of innate immunity when MHC class I is compromised. The benefits of combined checkpoint blockade may be attributable, in part, to distinct requirements for melanoma-specific antigen presentation to initiate antitumor immunity.
TL;DR: In this paper, a search for new phenomena in final states with an energetic jet and large missing transverse momentum is reported, and the results are translated into exclusion limits in models with pair-produced weakly interacting dark-matter candidates, large extra spatial dimensions, and supersymmetric particles in several compressed scenarios.
Abstract: Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses proton-proton collision data corresponding to an integrated luminosity of 36.1 fb−1 at a centre-of-mass energy of 13 TeV collected in 2015 and 2016 with the ATLAS detector at the Large Hadron Collider. Events are required to have at least one jet with a transverse momentum above 250 GeV and no leptons (e or μ). Several signal regions are considered with increasing requirements on the missing transverse momentum above 250 GeV. Good agreement is observed between the number of events in data and Standard Model predictions. The results are translated into exclusion limits in models with pair-produced weakly interacting dark-matter candidates, large extra spatial dimensions, and supersymmetric particles in several compressed scenarios.
University of Mississippi Medical Center1, Veterans Health Administration2, University of Louisville3, University at Buffalo4, The Heart Research Institute5, Albert Einstein College of Medicine6, University of Würzburg7, Virginia Tech8, University of Virginia9, Huntington Medical Research Institutes10, University of Southern California11, Louisiana State University12, Harvard University13, National Institutes of Health14, University of California, Los Angeles15, Wayne State University16, Sant'Anna School of Advanced Studies17, Temple University18, University of California, Davis19, Cedars-Sinai Medical Center20, University of Duisburg-Essen21
TL;DR: The goal of this review is to provide best practice information regarding myocardial ischemia-reperfusion and infarction models and to provide increasing awareness of the need for rigor and reproducibility in designing and performing scientific research to ensure validation of results.
Abstract: Myocardial infarction is a prevalent major cardiovascular event that arises from myocardial ischemia with or without reperfusion, and basic and translational research is needed to better understand...
TL;DR: The effects of several CVD; including heart failure, acute myocardial infarction, arrhythmias and pulmonary hypertension; on levels of circulating miRNAs are provided, as well as challenges and recommendations in their use in the diagnosis of CVD.
Abstract: Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality in the world. Although considerable progress has been made in the diagnosis, treatment and prognosis of CVD, there is still a critical need for novel diagnostic biomarkers and new therapeutic interventions to decrease the incidence of this disease. Recently, there is increasing evidence that circulating miRNAs (miRNAs), i.e. endogenous, stable, single-stranded, short, non-coding RNAs, can be used as diagnostic biomarkers for CVD. Furthermore, miRNAs represent potential novel therapeutic targets for several cardiovascular disorders. In this review we provides an overview of the effects of several CVD; including heart failure, acute myocardial infarction, arrhythmias and pulmonary hypertension; on levels of circulating miRNAs. In addition, the use of miRNA as therapeutic targets is also discussed, as well as challenges and recommendations in their use in the diagnosis of CVD.
Mayo Clinic1, Yale University2, Johns Hopkins University3, Rhode Island Hospital4, University of North Carolina at Chapel Hill5, Medical College of Wisconsin6, Cleveland Clinic7, Beaumont Health8, Dartmouth College9, University of Louisville10, Tufts University11, NorthShore University HealthSystem12, Rutgers University13
TL;DR: This document, developed by experts in laboratory and adult and pediatric clinical medicine, provides information on which tests are valuable and in which contexts, and on tests that add little or no value for diagnostic decisions.
Abstract: The critical nature of the microbiology laboratory in infectious disease diagnosis calls for a close, positive working relationship between the physician/advanced practice provider and the microbiologists who provide enormous value to the healthcare team. This document, developed by experts in laboratory and adult and pediatric clinical medicine, provides information on which tests are valuable and in which contexts, and on tests that add little or no value for diagnostic decisions. This document presents a system-based approach rather than specimen-based approach, and includes bloodstream and cardiovascular system infections, central nervous system infections, ocular infections, soft tissue infections of the head and neck, upper and lower respiratory infections, infections of the gastrointestinal tract, intra-abdominal infections, bone and joint infections, urinary tract infections, genital infections, and other skin and soft tissue infections; or into etiologic agent groups, including arthropod-borne infections, viral syndromes, and blood and tissue parasite infections. Each section contains introductory concepts, a summary of key points, and detailed tables that list suspected agents; the most reliable tests to order; the samples (and volumes) to collect in order of preference; specimen transport devices, procedures, times, and temperatures; and detailed notes on specific issues regarding the test methods, such as when tests are likely to require a specialized laboratory or have prolonged turnaround times. In addition, the pediatric needs of specimen management are also emphasized. There is intentional redundancy among the tables and sections, as many agents and assay choices overlap. The document is intended to serve as a guidance for physicians in choosing tests that will aid them to quickly and accurately diagnose infectious diseases in their patients.
TL;DR: There is evidence to suggest that continuously high levels of exercise (e.g., marathon running) could have detrimental effects on cardiovascular health and further studies are needed to identify the mechanisms that impart cardiovascular benefits of exercise in order to develop more effective exercise regimens.
Abstract: It is widely accepted that regular physical activity is beneficial for cardiovascular health. Frequent exercise is robustly associated with a decrease in cardiovascular mortality as well as the risk of developing cardiovascular disease. Physically active individuals have lower blood pressure, higher insulin sensitivity, and a more favorable plasma lipoprotein profile. Animal models of exercise show that repeated physical activity suppresses atherogenesis and increases the availability of vasodilatory mediators such as nitric oxide. Exercise has also been found to have beneficial effects on the heart. Acutely, exercise increases cardiac output and blood pressure, but individuals adapted to exercise show lower resting heart rate and cardiac hypertrophy. Both cardiac and vascular changes have been linked to a variety of changes in tissue metabolism and signaling, although our understanding of the contribution of the underlying mechanisms remains incomplete. Even though moderate levels of exercise have been found to be consistently associated with a reduction in cardiovascular disease risk, there is evidence to suggest that continuously high levels of exercise (e.g., marathon running) could have detrimental effects on cardiovascular health. Nevertheless, a specific dose response relationship between the extent and duration of exercise and the reduction in cardiovascular disease risk and mortality remains unclear. Further studies are needed to identify the mechanisms that impart cardiovascular benefits of exercise in order to develop more effective exercise regimens, test the interaction of exercise with diet, and develop pharmacological interventions for those unwilling or unable to exercise.
Cleveland Clinic1, Washington University in St. Louis2, University of Manitoba3, Mayo Clinic4, University of California, San Francisco5, University of Kansas6, University of Louisville7, St. Luke's University Health Network8, University of Virginia9, Wayne State University10, University of Southern California11, Kaiser Permanente12, National Multiple Sclerosis Society13, Heart Rhythm Society14, American Academy of Neurology15, University of Calgary16
TL;DR: The development of a guideline covering 23 medications and 143 randomized trials, as well as 30-plus recommendations and multiple development steps, is complex to the point of being overwhelming.
Abstract: Objective To develop recommendations for disease-modifying therapy (DMT) for multiple sclerosis (MS). Methods A multidisciplinary panel developed DMT recommendations, integrating findings from a systematic review; followed an Institute of Medicine–compliant process to ensure transparency and patient engagement; and developed modified Delphi consensus–based recommendations concerning starting, switching, and stopping DMTs pertinent to people with relapsing-remitting MS, secondary progressive MS, primary progressive MS, and clinically isolated syndromes of demyelination. Recommendations were supported by structured rationales, integrating evidence from one or more sources: systematic review, related evidence (evidence not from the systematic review), principles of care, and inference from evidence. Results Thirty recommendations were developed: 17 on starting DMTs, including recommendations on who should start them; 10 on switching DMTs if breakthrough disease develops; and 3 on stopping DMTs. Recommendations encompassed patient engagement strategies and individualization of treatment, including adherence monitoring and disease comorbidity assessment. The panel also discussed DMT risks, including counseling about progressive multifocal leukoencephalopathy risk in people with MS using natalizumab, fingolimod, rituximab, ocrelizumab, and dimethyl fumarate; and made suggestions for future research to evaluate relative merits of early treatment with higher potency DMTs vs standard stepped-care protocols, DMT comparative effectiveness, optimal switching strategies, long-term effects of DMT use, definitions of highly active MS, and effects of treatment on patient-specified priority outcomes. This guideline reflects the complexity of decision-making for starting, switching, or stopping MS DMTs. The field of MS treatment is rapidly changing; the Academy of Neurology development process includes planning for future updates.
TL;DR: In this article, four possible routes to the electrochemical synthesis of liquid products from CO2 derived from post-combustion flue gas were compared with one consistent approach to technoeconomic analysis.
Abstract: Electrochemical reduction of CO2 to fuels and chemicals is currently a focus of significant research effort as a technology that can simultaneously mitigate greenhouse gas emissions while storing renewable electricity for use on demand. Liquid products are particularly desirable as an easily storable and portable energy-dense form. To be widely implemented, CO2 electroreduction technologies must be able to produce chemicals at costs that are economically competitive with existing commercial prices. In this work, four possible routes to the electrochemical synthesis of liquid products from CO2 derived from post-combustion flue gas were compared with one consistent approach to technoeconomic analysis. In the first case, diesel fuel was produced from electrosynthesized CO plus H2 to make syngas which was subsequently converted through the Fischer–Tropsch process. Liquid ethanol was modeled through two comparable approaches, a one-step electrolysis and a two-step cascade electrolysis. Lastly, the direct electrosynthesis of formic acid from CO2 was considered. In the base case scenarios established on current state-of-the-art CO2 reduction research, none of the processes were modeled to be competitive with present fuel prices. High capital expense for the electrolyzer units was the primary limiting factor. With conceivable improvements in an optimistic scenario, the diesel process was projected to have the best pathway to making cost-effective fuels, while ethanol would be prohibitively expensive without major improvements to the present electrosynthesis performance. Formic acid, though projected to be expensive relative to its stored energy content, was projected to have perhaps the simplest pathway to production at costs competitive with its commercial bulk price. In each case, the levelized cost of the liquid product was most strongly influenced by parameters that affect the electrolyzer capital cost (i.e., current density, faradaic efficiency, and cost per electrode area).
TL;DR: Variants of the genetically encoded sensor iGluSnFR that are functionally brighter; detect submicromolar to millimolar amounts of glutamate; and have blue, cyan, green, or yellow emission profiles improve compatibility with various illumination schemes are reported.
Abstract: Single-wavelength fluorescent reporters allow visualization of specific neurotransmitters with high spatial and temporal resolution. We report variants of intensity-based glutamate-sensing fluorescent reporter (iGluSnFR) that are functionally brighter; detect submicromolar to millimolar amounts of glutamate; and have blue, cyan, green, or yellow emission profiles. These variants could be imaged in vivo in cases where original iGluSnFR was too dim, resolved glutamate transients in dendritic spines and axonal boutons, and allowed imaging at kilohertz rates.
TL;DR: The results show that CD spectra of nucleic acids can be analyzed to obtain quantitative structural information about secondary structure content in an analogous way to methods used to analyze proteinCD spectra.
Abstract: A curated library of circular dichroism spectra of 23 G-quadruplexes of known structure was built and analyzed. The goal of this study was to use this reference library to develop an algorithm to derive quantitative estimates of the secondary structure content of quadruplexes from their experimental CD spectra. Principal component analysis and singular value decomposition were used to characterize the reference spectral library. CD spectra were successfully fit to obtain estimates of the amounts of base steps in anti-anti, syn-anti or anti-syn conformations, in diagonal or lateral loops or in other conformations. The results show that CD spectra of nucleic acids can be analyzed to obtain quantitative structural information about secondary structure content in an analogous way to methods used to analyze protein CD spectra.
Christopher J L Murray1, Charlton S K H Callender1, Xie Rachel Kulikoff1, Vinay Srinivasan1 +1092 more•Institutions (424)
TL;DR: This work estimated population in 195 locations by single year of age and single calendar year from 1950 to 2017 with standardised and replicable methods and used the cohort-component method of population projection, with inputs of fertility, mortality, population, and migration data.
TL;DR: In this article, a genetic blood disorder, Diamond-Blackfan anemia (DBA), where the majority of mutations affect ribosomal proteins and the erythroid lineage is selectively perturbed, was studied and mechanistic insight into how lineage commitment is programmed normally and disrupted in disease.
University of Washington1, Institute for Health Metrics and Evaluation2, Jimma University3, Cairo University4, University of Western Australia5, University of Cartagena6, Karolinska Institutet7, Mekelle University8, Public Health Foundation of India9, University of Gondar10, University of Belgrade11, Harvard University12, Jazan University13, University of Oxford14, University of São Paulo15, University of Valencia16, Kazakh National Medical University17, University of Peradeniya18, International Institute for Population Sciences19, University of the Philippines Manila20, University of Louisville21, Auckland University of Technology22, Catholic University of Portugal23, Wageningen University and Research Centre24, University of Massachusetts Boston25, Mizan–Tepi University26, Debre markos University27, Tehran University of Medical Sciences28, New York Medical College29, Islamic University30, Ball State University31, Northeastern University32, Brown University33, Uppsala University34, University of Haifa35, Mansoura University36, Chinese Academy of Sciences37, Martin Luther University of Halle-Wittenberg38, United Nations Population Fund39, National Institutes of Health40, University of Melbourne41, Kyrgyz State Medical Academy42, Ahmadu Bello University43, Columbia University44, University of Ibadan45, University of British Columbia46, BRAC47, University of Sydney48, University of Maragheh49, University of KwaZulu-Natal50, Universidade Federal de Santa Catarina51, University of Western Ontario52, Addis Ababa University53, Post Graduate Institute of Medical Education and Research54, Jagiellonian University Medical College55, University of Copenhagen56, Cleveland Clinic57, Hospital Sant Joan de Déu Barcelona58, National Research University – Higher School of Economics59, Norwegian Institute of Public Health60, Royal Children's Hospital61, King's College London62, Nanjing University63, University of Mississippi Medical Center64, University of Hong Kong65, Kyoto University66, Jackson State University67, Wuhan University68
TL;DR: Large disparities in total burden of CVD persist between US states despite marked improvements in CVD burden, and increases in risk-deleted CVD DALY rates between 2006 and 2016 in 16 states suggest additional unmeasured risks beyond these traditional factors.
Abstract: Importance Cardiovascular disease (CVD) is the leading cause of death in the United States, but regional variation within the United States is large. Comparable and consistent state-level measures of total CVD burden and risk factors have not been produced previously. Objective To quantify and describe levels and trends of lost health due to CVD within the United States from 1990 to 2016 as well as risk factors driving these changes. Design, Setting, and Participants Using the Global Burden of Disease methodology, cardiovascular disease mortality, nonfatal health outcomes, and associated risk factors were analyzed by age group, sex, and year from 1990 to 2016 for all residents in the United States using standardized approaches for data processing and statistical modeling. Burden of disease was estimated for 10 groupings of CVD, and comparative risk analysis was performed. Data were analyzed from August 2016 to July 2017. Exposures Residing in the United States. Main Outcomes and Measures Cardiovascular disease disability-adjusted life-years (DALYs). Results Between 1990 and 2016, age-standardized CVD DALYs for all states decreased. Several states had large rises in their relative rank ordering for total CVD DALYs among states, including Arkansas, Oklahoma, Alabama, Kentucky, Missouri, Indiana, Kansas, Alaska, and Iowa. The rate of decline varied widely across states, and CVD burden increased for a small number of states in the most recent years. Cardiovascular disease DALYs remained twice as large among men compared with women. Ischemic heart disease was the leading cause of CVD DALYs in all states, but the second most common varied by state. Trends were driven by 12 groups of risk factors, with the largest attributable CVD burden due to dietary risk exposures followed by high systolic blood pressure, high body mass index, high total cholesterol level, high fasting plasma glucose level, tobacco smoking, and low levels of physical activity. Increases in risk-deleted CVD DALY rates between 2006 and 2016 in 16 states suggest additional unmeasured risks beyond these traditional factors. Conclusions and Relevance Large disparities in total burden of CVD persist between US states despite marked improvements in CVD burden. Differences in CVD burden are largely attributable to modifiable risk exposures.
TL;DR: Diagnostic criteria were created following a Delphi consensus exercise and validated against peer-reviewed established cases of pyoderma gangrenosum and mimickers using k-fold cross-validation with methods of multiple imputation to serve as a guideline for clinicians.
Abstract: Importance Pyoderma gangrenosum is a rare inflammatory skin condition that is difficult to diagnose. Currently, it is a “diagnosis of exclusion,” a definition not compatible with clinical decision making or inclusion for clinical trials. Objective To propose and validate diagnostic criteria for ulcerative pyoderma gangrenosum. Evidence Review Diagnostic criteria were created following a Delphi consensus exercise using the RAND/UCLA Appropriateness Method. The criteria were validated against peer-reviewed established cases of pyoderma gangrenosum and mimickers using k-fold cross-validation with methods of multiple imputation. Findings Delphi exercise yielded 1 major criterion—biopsy of ulcer edge demonstrating neutrophilic infiltrate—and 8 minor criteria: (1) exclusion of infection; (2) pathergy; (3) history of inflammatory bowel disease or inflammatory arthritis; (4) history of papule, pustule, or vesicle ulcerating within 4 days of appearing; (5) peripheral erythema, undermining border, and tenderness at ulceration site; (6) multiple ulcerations, at least 1 on an anterior lower leg; (7) cribriform or “wrinkled paper” scar(s) at healed ulcer sites; and (8) decreased ulcer size within 1 month of initiating immunosuppressive medication(s). Receiver operating characteristic analysis revealed that 4 of 8 minor criteria maximized discrimination, yielding sensitivity and specificity of 86% and 90%, respectively. Conclusions and Relevance This Delphi exercise produced 1 major criterion and 8 minor criteria for the diagnosis of ulcerative pyoderma gangrenosum. The criteria may serve as a guideline for clinicians, allowing for fewer misdiagnoses and improved patient selection for clinical trials.
University of Toronto1, Veterans Health Administration2, University of Minnesota3, Dartmouth–Hitchcock Medical Center4, University of California, San Francisco5, Columbia University6, McGill University7, Cleveland Clinic8, University of Louisville9, University of Cincinnati10, Pennsylvania State University11, University of Ottawa12, Ohio State University13, University of Southern California14
TL;DR: The results confirm that the epidemic of sensitivity to methylisothiazolinone has continued in North America and that patch testing with allergens beyond a screening tray is necessary for a complete evaluation of occupational and nonoccupational ACD.
Abstract: Background Patch testing is an important diagnostic tool for the assessment of allergic contact dermatitis (ACD). Objective This study documents the North American Contact Dermatitis Group (NACDG) patch testing results from January 1, 2015, to February 28, 2017. Methods At 13 centers in North America, patients were tested in a standardized manner with a screening series of 70 allergens. Data were manually verified and entered into a central database. Descriptive frequencies were calculated, and trends were analyzed using χ test. Results A total of 5597 patients were tested. There were 3725 patients (66.6%) who had at least 1 positive reaction, and 2798 patients (50.2%) were ultimately determined to have a primary diagnosis of ACD. A total of 572 patients (10.2%) had occupationally related skin disease. There were 10,983 positive allergic reactions. Nickel remained the most commonly detected allergen (17.5%). Methylisothiazolinone, which was added to the screening series for the 2013-2014 cycle, had the second highest positive reaction rate of allergens tested (13.4%). Compared with the previous reporting periods (2013-2014) and (2005-2014), positive reaction rates for the top 35 screening allergens statistically increased for only 1 allergen: hydroxyethyl methacrylate (3.4%; risk ratios, 1.24 [confidence interval, 1.00-1.54] and 1.46 [confidence interval, 1.23-1.73]). Three newly added allergen preparations-ammonium persulfate (1.7%), chlorhexidine (0.8%), and hydroquinone (0.3%)-all had a reaction rate of less than 2%. Twenty-three percent of the tested patients had at least 1 relevant allergic reaction to an allergen not on the NACDG series; 12% of these were occupationally related. T.R.U.E. Test (SmartPractice Denmark, Hillerod, Denmark) would have hypothetically missed one quarter to almost 40% of reactions detected by the NACDG screening series. Conclusions These results confirm that the epidemic of sensitivity to methylisothiazolinone has continued in North America. Patch testing with allergens beyond a screening tray is necessary for a complete evaluation of occupational and nonoccupational ACD.
University of California, Irvine1, University of Twente2, New York University3, Fundamental Research on Matter Institute for Atomic and Molecular Physics4, University of Grenoble5, Swiss Federal Laboratories for Materials Science and Technology6, Forschungszentrum Jülich7, University of Groningen8, Air Products & Chemicals9, Leiden University10, École Polytechnique Fédérale de Lausanne11, Delft University of Technology12, Eindhoven University of Technology13, Uppsala University14, University of Kitakyushu15, Lawrence Berkeley National Laboratory16, Tokyo University of Science17, Office of Energy Efficiency and Renewable Energy18, Arizona State University19, University of Cambridge20, California Institute of Technology21, Technical University of Denmark22, University of Louisville23, Drexel University24
TL;DR: In this article, the authors describe potential pathways for solar-hydrogen technologies into the marketplace in the form of photoelectrochemical or photovoltaic-driven electrolysis devices and systems.
Abstract: Solar-powered electrochemical production of hydrogen through water electrolysis is an active and important research endeavor. However, technologies and roadmaps for implementation of this process do not exist. In this perspective paper, we describe potential pathways for solar-hydrogen technologies into the marketplace in the form of photoelectrochemical or photovoltaic-driven electrolysis devices and systems. We detail technical approaches for device and system architectures, economic drivers, societal perceptions, political impacts, technological challenges, and research opportunities. Implementation scenarios are broken down into short-term and long-term markets, and a specific technology roadmap is defined. In the short term, the only plausible economical option will be photovoltaic-driven electrolysis systems for niche applications. In the long term, electrochemical solar-hydrogen technologies could be deployed more broadly in energy markets but will require advances in the technology, significant cost reductions, and/or policy changes. Ultimately, a transition to a society that significantly relies on solar-hydrogen technologies will benefit from continued creativity and influence from the scientific community.
TL;DR: In this article, a search was performed for resonant and non-resonant Higgs boson pair production in the $ \upgamma \ upgamma b\overline{b} $ final state.
Abstract: A search is performed for resonant and non-resonant Higgs boson pair production in the $ \upgamma \upgamma b\overline{b} $ final state. The data set used corresponds to an integrated luminosity of 36.1 fb$^{−1}$ of proton-proton collisions at a centre-of-mass energy of 13 TeV recorded by the ATLAS detector at the CERN Large Hadron Collider. No significant excess relative to the Standard Model expectation is observed. The observed limit on the non-resonant Higgs boson pair cross-section is 0.73 pb at 95% confidence level. This observed limit is equivalent to 22 times the predicted Standard Model cross-section. The Higgs boson self-coupling (κ$_{λ}$ = λ$_{HHH}$/λ$_{HHH}^{SM}$ ) is constrained at 95% confidence level to −8.2 < κ$_{λ}$ < 13.2. For resonant Higgs boson pair production through $ X\to HH\to \upgamma \upgamma b\overline{b} $ , the limit is presented, using the narrow-width approximation, as a function of m$_{X}$ in the range 260 GeV < m$_{X}$ < 1000 GeV. The observed limits range from 1.1 pb to 0.12 pb over this mass range.
TL;DR: This review integrates knowledge of different forms of cardiac remodeling to develop general models of how relationships between catabolic and anabolic glucose metabolism may fortify cardiac health or promote (mal)adaptive myocardial remodeling.
Abstract: Metabolic pathways integrate to support tissue homeostasis and to prompt changes in cell phenotype. In particular, the heart consumes relatively large amounts of substrate not only to regenerate ATP for contraction but also to sustain biosynthetic reactions for replacement of cellular building blocks. Metabolic pathways also control intracellular redox state, and metabolic intermediates and end products provide signals that prompt changes in enzymatic activity and gene expression. Mounting evidence suggests that the changes in cardiac metabolism that occur during development, exercise, and pregnancy as well as with pathological stress (eg, myocardial infarction, pressure overload) are causative in cardiac remodeling. Metabolism-mediated changes in gene expression, metabolite signaling, and the channeling of glucose-derived carbon toward anabolic pathways seem critical for physiological growth of the heart, and metabolic inefficiency and loss of coordinated anabolic activity are emerging as proximal causes of pathological remodeling. This review integrates knowledge of different forms of cardiac remodeling to develop general models of how relationships between catabolic and anabolic glucose metabolism may fortify cardiac health or promote (mal)adaptive myocardial remodeling. Adoption of conceptual frameworks based in relational biology may enable further understanding of how metabolism regulates cardiac structure and function.
TL;DR: Patients with AF recurrence following RFA have a higher mean LAV/LAVi compared to patients with no recurrence, and large LAV or LAVi increases the odds ofAF recurrence post RFA.
Abstract: Aims Left atrial (LA) diameter is a predictor of atrial fibrillation (AF) recurrence following radiofrequency catheter ablation (RFA). However, LA volume (LAV) is more accurate in assessing LA size. Studies evaluating LAV as a predictor of AF recurrence are contradictory; therefore, we performed a meta-analysis to assess whether LAV is an independent predictor of AF recurrence following RFA. Methods and results All studies reporting LAV/LAV index (LAVi) as a predictor of AF recurrence following RFA were included. For studies reporting mean LAV/ LAVi in patients with and without AF recurrence, standard difference in means (SDM) and standard errors were calculated, and combined using meta-analytical techniques. For studies reporting adjusted odds ratio (OR) for AF recurrence based on LAV/LAVi, log ORs were combined using generic inverse variance. Twenty one studies (3822 subjects) were included. Meta-analysis of 11 studies (1559 subjects) reporting LAV, showed that patients with AF recurrence had a higher mean LA volume compared to patients with no recurrence (SDM 0.801; CI 0.387-1.216). Data from 9 studies (1425 subjects) comparing LAVi showed that, patients with AF recurrence had a higher mean LAVi compared to patients with no recurrence (SDM-0.596; CI 0.305-0.888). Thirteen studies (2886 patients) reporting ORs for AF recurrence based on LAV/ LAVi, showed that LAV/LAVi was independently predictive of AF recurrence post-RFA (OR-1.032, CI- 1.012-1.052). Conclusions Patients with AF recurrence following RFA have a higher mean LAV/LAVi compared to patients with no recurrence. Large LAV/LAVi increases the odds of AF recurrence post RFA.