Showing papers by "University of Miami published in 2015"
TL;DR: In the Global Burden of Disease Study 2013 (GBD 2013) as discussed by the authors, the authors used the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data.
5,792 citations
TL;DR: In the Global Burden of Disease Study 2013 (GBD 2013) as mentioned in this paper, the authors estimated the quantities for acute and chronic diseases and injuries for 188 countries between 1990 and 2013.
4,510 citations
Michael S. Lawrence1, Carrie Sougnez1, Lee Lichtenstein1, Kristian Cibulskis1 +306 more•Institutions (26)
TL;DR: It is shown that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1.
Abstract: The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1 Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22 A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53 Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours Therapeutic candidate alterations were identified in most HNSCCs
2,997 citations
TL;DR: Major tumour regressions are reported in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody and radiation and reproduced this effect in mouse models, showing that PD-L1 on melanoma cells allows tumours to escape anti- NCTLA4-based therapy, and the combination of radiation, anti- CTLA4 and anti-PD-L 1 promotes response and immunity through distinct mechanisms.
Abstract: Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.
1,872 citations
Ghent University1, University of Pittsburgh2, Research Foundation - Flanders3, University of Alberta4, Austin Hospital5, University of Miami6, University of California, San Diego7, University of Surrey8, The Chinese University of Hong Kong9, Medanta10, University of Bordeaux11, University of Helsinki12, Pontifical Catholic University of Chile13, Jikei University School of Medicine14, University of Western Australia15
TL;DR: This is the first multinational cross-sectional study on the epidemiology of AKI in ICu patients using the complete KDIGO criteria and found that AKI occurred in more than half of ICU patients.
Abstract: Current reports on acute kidney injury (AKI) in the intensive care unit (ICU) show wide variation in occurrence rate and are limited by study biases such as use of incomplete AKI definition, selected cohorts, or retrospective design. Our aim was to prospectively investigate the occurrence and outcomes of AKI in ICU patients. The Acute Kidney Injury–Epidemiologic Prospective Investigation (AKI-EPI) study was an international cross-sectional study performed in 97 centers on patients during the first week of ICU admission. We measured AKI by Kidney Disease: Improving Global Outcomes (KDIGO) criteria, and outcomes at hospital discharge. A total of 1032 ICU patients out of 1802 [57.3 %; 95 % confidence interval (CI) 55.0–59.6] had AKI. Increasing AKI severity was associated with hospital mortality when adjusted for other variables; odds ratio of stage 1 = 1.679 (95 % CI 0.890–3.169; p = 0.109), stage 2 = 2.945 (95 % CI 1.382–6.276; p = 0.005), and stage 3 = 6.884 (95 % CI 3.876–12.228; p < 0.001). Risk-adjusted rates of AKI and mortality were similar across the world. Patients developing AKI had worse kidney function at hospital discharge with estimated glomerular filtration rate less than 60 mL/min/1.73 m2 in 47.7 % (95 % CI 43.6–51.7) versus 14.8 % (95 % CI 11.9–18.2) in those without AKI, p < 0.001. This is the first multinational cross-sectional study on the epidemiology of AKI in ICU patients using the complete KDIGO criteria. We found that AKI occurred in more than half of ICU patients. Increasing AKI severity was associated with increased mortality, and AKI patients had worse renal function at the time of hospital discharge. Adjusted risks for AKI and mortality were similar across different continents and regions.
1,704 citations
Mohammad H. Forouzanfar1, Lily Alexander1, H. Ross Anderson2, Victoria F Bachman1 +718 more•Institutions (295)
TL;DR: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) as mentioned in this paper provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.
1,656 citations
TL;DR: Emerging evidence suggests that atypical engagement of specific subdivisions of the insula within the salience network is a feature of many neuropsychiatric disorders.
Abstract: The brain is constantly bombarded by stimuli, and the relative salience of these inputs determines which are more likely to capture attention. A brain system known as the 'salience network', with key nodes in the insular cortices, has a central role in the detection of behaviourally relevant stimuli and the coordination of neural resources. Emerging evidence suggests that atypical engagement of specific subdivisions of the insula within the salience network is a feature of many neuropsychiatric disorders.
1,484 citations
TL;DR: At least 30 million men worldwide are infertile with the highest rates in Africa and Eastern Europe, and a novel and unique way to calculate the distribution of male infertility around the world is demonstrated.
Abstract: Infertility affects an estimated 15% of couples globally, amounting to 485 million couples Males are found to be solely responsible for 20-30% of infertility cases and contribute to 50% of cases overall However, this number does not accurately represent all regions of the world Indeed, on a global level, there is a lack of accurate statistics on rates of male infertility Our report examines major regions of the world and reports rates of male infertility based on data on female infertility Our search consisted of systematic reviews, meta-analyses, and population-based studies by searching the terms “epidemiology, male infertility, and prevalence” We identified 16 articles for detailed study We typically used the assumption that 50% of all cases of infertility are due to female factors alone, 20-30% are due to male factors alone, and the remaining 20-30% are due to a combination of male and female factors Therefore, in regions of the world where male factor or rates of male infertility were not reported, we used this assumption to calculate general rates of male factor infertility Our calculated data showed that the distribution of infertility due to male factor ranged from 20% to 70% and that the percentage of infertile men ranged from 2·5% to 12% Infertility rates were highest in Africa and Central/Eastern Europe Additionally, according to a variety of sources, rates of male infertility in North America, Australia, and Central and Eastern Europe varied from 4 5-6%, 9%, and 8-12%, respectively This study demonstrates a novel and unique way to calculate the distribution of male infertility around the world According to our results, at least 30 million men worldwide are infertile with the highest rates in Africa and Eastern Europe Results indicate further research is needed regarding etiology and treatment, reduce stigma & cultural barriers, and establish a more precise calculation
1,331 citations
Memorial Sloan Kettering Cancer Center1, Institut Gustave Roussy2, University of North Carolina at Chapel Hill3, Roswell Park Cancer Institute4, Vanderbilt University5, University of Rennes6, Ohio State University7, University of California, Davis8, Beth Israel Medical Center9, Lehigh Valley Hospital10, University Hospitals of Cleveland11, Providence Portland Medical Center12, University of Miami13, Ludwig Maximilian University of Munich14, Bristol-Myers Squibb15, Emory University16
TL;DR: Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer and these data support the assessment of nivolumsab in randomised, controlled, phase 3 studies of first-line and second-line treatment.
Abstract: Summary Background Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. Methods We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. Findings Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7–22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2–4·8), and median duration of response was not reached (95% CI 8·31–not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7–10·9). 20 (17%) of 117 patients reported grade 3–4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. Interpretation Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. Funding Bristol-Myers Squibb.
1,273 citations
TL;DR: In this article, the authors engaged in an international and interdisciplinary research effort to identify research priorities that have the potential to advance the service field and benefit customers, organizations, and society.
Abstract: The context in which service is delivered and experienced has, in many respects, fundamentally changed. For instance, advances in technology, especially information technology, are leading to a proliferation of revolutionary services and changing how customers serve themselves before, during, and after purchase. To understand this changing landscape, the authors engaged in an international and interdisciplinary research effort to identify research priorities that have the potential to advance the service field and benefit customers, organizations, and society. The priority-setting process was informed by roundtable discussions with researchers affiliated with service research centers and networks located around the world and resulted in the following 12 service research priorities:
• stimulating service innovation,
• facilitating servitization, service infusion, and solutions,
• understanding organization and employee issues relevant to successful service,
• developing service networks and systems,
• leveraging service design,
• using big data to advance service,
• understanding value creation,
• enhancing the service experience,
• improving well-being through transformative service,
• measuring and optimizing service performance and impact,
• understanding service in a global context, and
• leveraging technology to advance service.
For each priority, the authors identified important specific service topics and related research questions. Then, through an online survey, service researchers assessed the subtopics’ perceived importance and the service field’s extant knowledge about them. Although all the priorities and related topics were deemed important, the results show that topics related to transformative service and measuring and optimizing service performance are particularly important for advancing the service field along with big data, which had the largest gap between importance and current knowledge of the field. The authors present key challenges that should be addressed to move the field forward and conclude with a discussion of the need for additional interdisciplinary research.
1,168 citations
TL;DR: Glycogen synthase kinase-3 (GSK3) must be particularly adaptable for incorporating new substrates into its repertoire, and the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways are discussed.
TL;DR: Global stroke burden continues to increase globally, and more efficient stroke prevention and management strategies are urgently needed to halt and eventually reverse the stroke pandemic, while universal access to organized stroke services should be a priority.
Abstract: Background: Global stroke epidemiology is changing rapidly. Although age-standardized rates of stroke mortality have decreased worldwide in the past 2 decades, the absolute numbers of people who have a stroke every year, and live with the consequences of stroke or die from their stroke, are increasing. Regular updates on the current level of stroke burden are important for advancing our knowledge on stroke epidemiology and facilitate organization and planning of evidence-based stroke care. Objectives: This study aims to estimate incidence, prevalence, mortality, disability-adjusted life years (DALYs) and years lived with disability (YLDs) and their trends for ischemic stroke (IS) and hemorrhagic stroke (HS) for 188 countries from 1990 to 2013. Methodology: Stroke incidence, prevalence, mortality, DALYs and YLDs were estimated using all available data on mortality and stroke incidence, prevalence and excess mortality. Statistical models and country-level covariate data were employed, and all rates were age-standardized to a global population. All estimates were produced with 95% uncertainty intervals (UIs). Results: In 2013, there were globally almost 25.7 million stroke survivors (71% with IS), 6.5 million deaths from stroke (51% died from IS), 113 million DALYs due to stroke (58% due to IS) and 10.3 million new strokes (67% IS). Over the 1990-2013 period, there was a significant increase in the absolute number of DALYs due to IS, and of deaths from IS and HS, survivors and incident events for both IS and HS. The preponderance of the burden of stroke continued to reside in developing countries, comprising 75.2% of deaths from stroke and 81.0% of stroke-related DALYs. Globally, the proportional contribution of stroke-related DALYs and deaths due to stroke compared to all diseases increased from 1990 (3.54% (95% UI 3.11-4.00) and 9.66% (95% UI 8.47-10.70), respectively) to 2013 (4.62% (95% UI 4.01-5.30) and 11.75% (95% UI 10.45-13.31), respectively), but there was a diverging trend in developed and developing countries with a significant increase in DALYs and deaths in developing countries, and no measurable change in the proportional contribution of DALYs and deaths from stroke in developed countries. Conclusion: Global stroke burden continues to increase globally. More efficient stroke prevention and management strategies are urgently needed to halt and eventually reverse the stroke pandemic, while universal access to organized stroke services should be a priority.
TL;DR: The discovery of the STING (stimulator of interferon genes)-controlled innate immune pathway, which mediates cytosolic DNA-induced signalling events, has recently provided important insights into these processes, opening the way for the development of novel immunization regimes, as well as therapies to treat autoinflammatory disease and cancer.
Abstract: The rapid detection of microbial agents is essential for the effective initiation of host defence mechanisms against infection. Understanding how cells detect cytosolic DNA to trigger innate immune gene transcription has important implications - not only for comprehending the immune response to pathogens but also for elucidating the causes of autoinflammatory disease involving the sensing of self-DNA and the generation of effective antitumour adaptive immunity. The discovery of the STING (stimulator of interferon genes)-controlled innate immune pathway, which mediates cytosolic DNA-induced signalling events, has recently provided important insights into these processes, opening the way for the development of novel immunization regimes, as well as therapies to treat autoinflammatory disease and cancer.
TL;DR: The conceptual guidelines that have emerged for their classification and functional annotation based on expanding and more comprehensive use of large systems biology-based datasets are described.
Earth System Research Laboratory1, Geophysical Fluid Dynamics Laboratory2, Georgia Institute of Technology3, University of California, Irvine4, University of Arizona5, Texas A&M University6, University of Reading7, Woods Hole Oceanographic Institution8, University of Miami9, California Institute of Technology10, Hanyang University11
TL;DR: The authors surveys the current state of knowledge of ENSO diversity, identifies key gaps in understanding, and outlines some promising future research directions, as well as identifying key gaps and promising future directions.
Abstract: El Nino–Southern Oscillation (ENSO) is a naturally occurring mode of tropical Pacific variability, with global impacts on society and natural ecosystems. While it has long been known that El Nino events display a diverse range of amplitudes, triggers, spatial patterns, and life cycles, the realization that ENSO’s impacts can be highly sensitive to this event-to-event diversity is driving a renewed interest in the subject. This paper surveys our current state of knowledge of ENSO diversity, identifies key gaps in understanding, and outlines some promising future research directions.
Johns Hopkins University1, American Society of Clinical Oncology2, University of Washington3, Washington University in St. Louis4, Duke University5, University of Miami6, Princess Margaret Cancer Centre7, City of Hope National Medical Center8, Wayne State University9, University of Nebraska Medical Center10
TL;DR: Current recommendations for the management of patients exposed to lethal doses of total-body radiotherapy, but not doses high enough to lead to certain death as a result of injury to other organs, include the prompt administration of CSFs.
Abstract: Purpose To update the 2006 American Society of Clinical Oncology guideline on the use of hematopoietic colony-stimulating factors (CSFs). Methods The American Society of Clinical Oncology convened an Update Committee and conducted a systematic review of randomized clinical trials, meta-analyses, and systematic reviews from October 2005 through September 2014. Guideline recommendations were based on the review of the evidence by the Update Committee. Results Changes to previous recommendations include the addition of tbo-filgrastim and filgrastim-sndz, moderation of the recommendation regarding routine use of CSFs in older patients with diffuse aggressive lymphoma, and addition of recommendations against routine dose-dense chemotherapy in lymphoma and in favor of high–dose-intensity chemotherapy in urothelial cancer. The Update Committee did not address recommendations regarding use of CSFs in acute myeloid leukemia or myelodysplastic syndromes in adults. Recommendations Prophylactic use of CSFs to reduce ...
TL;DR: The Technology Readiness Index (TRI) as mentioned in this paper, a 36-item scale to measure people's propensity to embrace and use cutting-edge technologies, was published in the Journal of Service Research over a decade ago.
Abstract: The Technology Readiness Index (TRI), a 36-item scale to measure people’s propensity to embrace and use cutting-edge technologies, was published in the Journal of Service Research over a decade ago...
Emory University1, DePaul University2, University of Miami3, Baylor College of Medicine4, Pennsylvania State University5, University of California, Irvine6, Duke University7, University of Colorado Denver8, Medical University of South Carolina9, University of Oklahoma10, University of Texas Southwestern Medical Center11, University of Illinois at Chicago12, Tulane University13, University of California, San Francisco14, Icahn School of Medicine at Mount Sinai15, Harvard University16, Virginia Commonwealth University17, University of Pennsylvania18, Rush University Medical Center19, Oregon Health & Science University20
TL;DR: This document represents a continuation of the National Lipid Association recommendations developed by a diverse panel of experts who examined the evidence base and provided recommendations regarding the following topics: lifestyle therapies and strategies to improve patient outcomes by increasing adherence and using team-based collaborative care.
Primary Children's Hospital1, University of Colorado Denver2, Northwestern University3, Georgetown University4, University of Washington5, Columbia University6, University of North Carolina at Chapel Hill7, University of California, San Francisco8, Baylor University Medical Center9, Mayo Clinic10, University of California, San Diego11, University of Miami12, Johns Hopkins University13, University of Kansas14, Henry Ford Health System15, Indiana University16, Washington University in St. Louis17, Duke University18, New York University19, University of Michigan20, University of Pennsylvania21, Harvard University22
TL;DR: The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation.
Abstract: Background & Aims There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. Methods In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). Results We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%–89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%–98% of patients without cirrhosis or with compensated cirrhosis, by 85%−88% of patients with moderate hepatic impairment, by 60%–75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. Conclusion The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.
TL;DR: Nearly a third of patients admitted to an intensive care unit develop delirium, and these patients are at increased risk of dying during admission, longer stays in hospital, and cognitive impairment after discharge.
Abstract: Objectives To determine the relation between delirium in critically ill patients and their outcomes in the short term (in the intensive care unit and in hospital) and after discharge from hospital. Design Systematic review and meta-analysis of published studies. Data sources PubMed, Embase, CINAHL, Cochrane Library, and PsychINFO, with no language restrictions, up to 1 January 2015. Eligibility criteria for selection studies Reports were eligible for inclusion if they were prospective observational cohorts or clinical trials of adults in intensive care units who were assessed with a validated delirium screening or rating system, and if the association was measured between delirium and at least one of four clinical endpoints (death during admission, length of stay, duration of mechanical ventilation, and any outcome after hospital discharge). Studies were excluded if they primarily enrolled patients with a neurological disorder or patients admitted to intensive care after cardiac surgery or organ/tissue transplantation, or centered on sedation management or alcohol or substance withdrawal. Data were extracted on characteristics of studies, populations sampled, identification of delirium, and outcomes. Random effects models and meta-regression analyses were used to pool data from individual studies. Results Delirium was identified in 5280 of 16 595 (31.8%) critically ill patients reported in 42 studies. When compared with control patients without delirium, patients with delirium had significantly higher mortality during admission (risk ratio 2.19, 94% confidence interval 1.78 to 2.70; P Conclusions Nearly a third of patients admitted to an intensive care unit develop delirium, and these patients are at increased risk of dying during admission, longer stays in hospital, and cognitive impairment after discharge.
Primary Children's Hospital1, University of Colorado Denver2, Northwestern University3, Georgetown University4, University of Washington5, Columbia University6, University of North Carolina at Chapel Hill7, University of California, San Francisco8, Baylor University Medical Center9, Mayo Clinic10, University of California, San Diego11, University of Miami12, Johns Hopkins University13, University of Kansas14, Henry Ford Health System15, Indiana University16, Washington University in St. Louis17, Duke University18, New York University19, University of Michigan20, University of Pennsylvania21, Harvard University22
TL;DR: In this article, the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin were used to treat chronic hepatitis C virus (HCV) infection in patients with advanced liver disease.
University of East Anglia1, University of Oslo2, Commonwealth Scientific and Industrial Research Organisation3, University of Exeter4, Oak Ridge National Laboratory5, Woods Hole Research Center6, University of Bristol7, Scripps Institution of Oceanography8, National Oceanic and Atmospheric Administration9, Karlsruhe Institute of Technology10, University of Miami11, Centre national de la recherche scientifique12, University of Maryland, College Park13, Aix-Marseille University14, Flanders Marine Institute15, Alfred Wegener Institute for Polar and Marine Research16, Max Planck Society17, University of Illinois at Urbana–Champaign18, Plymouth Marine Laboratory19, Netherlands Environmental Assessment Agency20, Lawrence Berkeley National Laboratory21, ETH Zurich22, Bjerknes Centre for Climate Research23, University of Paris24, Woods Hole Oceanographic Institution25, Institute of Arctic and Alpine Research26, Japan Agency for Marine-Earth Science and Technology27, National Institute for Environmental Studies28, University of Washington29, University of Bergen30, Spanish National Research Council31, Montana State University32, Leibniz Institute for Baltic Sea Research33, Japan Meteorological Agency34, Leibniz Institute of Marine Sciences35, University of Bern36, Imperial College London37, Joint Institute for the Study of the Atmosphere and Ocean38, Lamont–Doherty Earth Observatory39, Hobart Corporation40, Wageningen University and Research Centre41, VU University Amsterdam42, University of New Hampshire43, Met Office44
TL;DR: In this article, the authors presented a methodology to quantify all major components of the global carbon budget, including their uncertainties, based on the combination of a range of data, algorithms, statistics, and model estimates and their interpretation by a broad scientific community.
Abstract: Accurate assessment of anthropogenic carbon dioxide (CO2) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere is important to better understand the global carbon cycle, support the development of climate policies, and project future climate change. Here we describe data sets and a methodology to quantify all major components of the global carbon budget, including their uncertainties, based on the combination of a range of data, algorithms, statistics, and model estimates and their interpretation by a broad scientific community. We discuss changes compared to previous estimates as well as consistency within and among components, alongside methodology and data limitations. CO2 emissions from fossil fuels and industry (EFF) are based on energy statistics and cement production data, while emissions from land-use change (ELUC), mainly deforestation, are based on combined evidence from land-cover-change data, fire activity associated with deforestation, and models. The global atmospheric CO2 concentration is measured directly and its rate of growth (GATM) is computed from the annual changes in concentration. The mean ocean CO2 sink (SOCEAN) is based on observations from the 1990s, while the annual anomalies and trends are estimated with ocean models. The variability in SOCEAN is evaluated with data products based on surveys of ocean CO2 measurements. The global residual terrestrial CO2 sink (SLAND) is estimated by the difference of the other terms of the global carbon budget and compared to results of independent dynamic global vegetation models forced by observed climate, CO2, and land-cover change (some including nitrogen–carbon interactions). We compare the mean land and ocean fluxes and their variability to estimates from three atmospheric inverse methods for three broad latitude bands. All uncertainties are reported as ±1σ, reflecting the current capacity to characterise the annual estimates of each component of the global carbon budget. For the last decade available (2005–2014), EFF was 9.0 ± 0.5 GtC yr−1, ELUC was 0.9 ± 0.5 GtC yr−1, GATM was 4.4 ± 0.1 GtC yr−1, SOCEAN was 2.6 ± 0.5 GtC yr−1, and SLAND was 3.0 ± 0.8 GtC yr−1. For the year 2014 alone, EFF grew to 9.8 ± 0.5 GtC yr−1, 0.6 % above 2013, continuing the growth trend in these emissions, albeit at a slower rate compared to the average growth of 2.2 % yr−1 that took place during 2005–2014. Also, for 2014, ELUC was 1.1 ± 0.5 GtC yr−1, GATM was 3.9 ± 0.2 GtC yr−1, SOCEAN was 2.9 ± 0.5 GtC yr−1, and SLAND was 4.1 ± 0.9 GtC yr−1. GATM was lower in 2014 compared to the past decade (2005–2014), reflecting a larger SLAND for that year. The global atmospheric CO2 concentration reached 397.15 ± 0.10 ppm averaged over 2014. For 2015, preliminary data indicate that the growth in EFF will be near or slightly below zero, with a projection of −0.6 [range of −1.6 to +0.5] %, based on national emissions projections for China and the USA, and projections of gross domestic product corrected for recent changes in the carbon intensity of the global economy for the rest of the world. From this projection of EFF and assumed constant ELUC for 2015, cumulative emissions of CO2 will reach about 555 ± 55 GtC (2035 ± 205 GtCO2) for 1870–2015, about 75 % from EFF and 25 % from ELUC. This living data update documents changes in the methods and data sets used in this new carbon budget compared with previous publications of this data set (Le Quere et al., 2015, 2014, 2013). All observations presented here can be downloaded from the Carbon Dioxide Information Analysis Center (doi:10.3334/CDIAC/GCP_2015).
TL;DR: Adoption of this staging classification provides a standardized taxonomy for type 1 diabetes and will aid the development of therapies and the design of clinical trials to prevent symptomatic disease, promote precision medicine, and provide a framework for an optimized benefit/risk ratio.
Abstract: Insights from prospective, longitudinal studies of individuals at risk for developing type 1 diabetes have demonstrated that the disease is a continuum that progresses sequentially at variable but predictable rates through distinct identifiable stages prior to the onset of symptoms. Stage 1 is defined as the presence of β-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic, stage 2 as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic, and stage 3 as onset of symptomatic disease. Adoption of this staging classification provides a standardized taxonomy for type 1 diabetes and will aid the development of therapies and the design of clinical trials to prevent symptomatic disease, promote precision medicine, and provide a framework for an optimized benefit/risk ratio that will impact regulatory approval, reimbursement, and adoption of interventions in the early stages of type 1 diabetes to prevent symptomatic disease.
The American College of Financial Services1, Icahn School of Medicine at Mount Sinai2, Wayne State University3, Emory University4, Cleveland Clinic5, University of California, San Diego6, Ochsner Medical Center7, Louisiana State University8, University of Tennessee Health Science Center9, University of Texas at Dallas10, American Association of Clinical Endocrinologists11, Harvard University12, Baylor College of Medicine13, University of Alabama at Birmingham14, Veterans Health Administration15, University of Washington16, Mayo Clinic17, University of Miami18, University of California, Santa Barbara19, SUNY Downstate Medical Center20, University of Arizona21, Washington University in St. Louis22, University of Southern California23, University of California, Los Angeles24, University of California, Irvine25, Eastern Virginia Medical School26, Cornell University27
TL;DR: These guidelines are a working document that reflects the state of the field at the time of publication and any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances.
TL;DR: It is indicated that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders.
Abstract: Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.
TL;DR: Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease.
TL;DR: This document provides support for a consensus set of recommendations for patient-centered management of dyslipidemia in clinical medicine and an elevated level of cholesterol carried by circulating apolipoprotein B-containing lipoproteins is a root cause of atherosclerosis.
TL;DR: It is proposed that more consistent operationalization and study of cognitive flexibility is required in clinical and developmental neuroscience and an important avenue for future research is the characterization of the relationship between neural flexibility and cognitive flexibility in typical and atypical development.
University of Virginia1, Case Western Reserve University2, University of Toronto3, Virginia Commonwealth University4, University of Washington5, Harvard University6, Washington University in St. Louis7, Veterans Health Administration8, University of Michigan9, University of Miami10, Wake Forest University11, University of South Carolina12, University of California, San Diego13, University of Texas Health Science Center at San Antonio14, University of Medicine and Dentistry of New Jersey15, University of California, Davis16, University of California, San Francisco17, University of Minnesota18, University of Louisville19, Johns Hopkins University20
TL;DR: In patients with intraabdominal infections who had undergone an adequate source-control procedure, the outcomes after fixed-duration antibiotic therapy were similar to those after a longer course of antibiotics that extended until after the resolution of physiological abnormalities.
Abstract: Surgical-site infection, recurrent intraabdominal infection, or death occurred in 56 of 257 patients in the experimental group (21.8%), as compared with 58 of 260 patients in the control group (22.3%) (absolute difference, −0.5 percentage point; 95% confidence interval [CI], −7.0 to 8.0; P = 0.92). The median duration of antibiotic therapy was 4.0 days (interquartile range, 4.0 to 5.0) in the experimental group, as compared with 8.0 days (interquartile range, 5.0 to 10.0) in the control group (absolute difference, −4.0 days; 95% CI, −4.7 to −3.3; P<0.001). No signifi cant between-group differences were found in the individual rates of the components of the primary outcome or in other secondary outcomes. CONCLUSIONS In patients with intraabdominal infections who had undergone an adequate sourcecontrol procedure, the outcomes after fixed-duration antibiotic therapy (approximately 4 days) were similar to those after a longer course of antibiotics (approximately 8 days) that extended until after the resolution of physiological abnormalities. (Funded by the National Institutes of Health; STOP-IT ClinicalTrials .gov number, NCT00657566.)
TL;DR: It is found that MSC exosomes ranged from 30 to 100-nm in diameter and internalization of MSCExosomes resulted in a dose-dependent enhancement of proliferation and migration of fibroblasts derived from normal donors and chronic wound patients.
Abstract: Although chronic wounds are common and continue to be a major cause of morbidity and mortality, treatments for these conditions are lacking and often ineffective. A large body of evidence exists demonstrating the therapeutic potential of mesenchymal stem cells (MSCs) for repair and regeneration of damaged tissue, including acceleration of cutaneous wound healing. However, the exact mechanisms of wound healing mediated by MSCs are unclear. In this study, we examined the role of MSC exosomes in wound healing. We found that MSC exosomes ranged from 30 to 100-nm in diameter and internalization of MSC exosomes resulted in a dose-dependent enhancement of proliferation and migration of fibroblasts derived from normal donors and chronic wound patients. Uptake of MSC exosomes by human umbilical vein endothelial cells also resulted in dose-dependent increases of tube formation by endothelial cells. MSC exosomes were found to activate several signaling pathways important in wound healing (Akt, ERK, and STAT3) and induce the expression of a number of growth factors [hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF1), nerve growth factor (NGF), and stromal-derived growth factor-1 (SDF1)]. These findings represent a promising opportunity to gain insight into how MSCs may mediate wound healing.