Showing papers by "University of Tennessee Health Science Center published in 2016"
TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.
For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.
Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.
5,187 citations
Baylor College of Medicine1, Beth Israel Deaconess Medical Center2, Emory University3, Ochsner Medical Center4, Icahn School of Medicine at Mount Sinai5, Cedars-Sinai Medical Center6, University of Tennessee Health Science Center7, University of Texas Health Science Center at San Antonio8, American Association of Clinical Endocrinologists9, Tulane University10, University of Alabama at Birmingham11, Wayne State University12, The American College of Financial Services13, University of California, San Diego14, University of Washington15, University of Miami16, Washington University in St. Louis17, University of California, Irvine18
TL;DR: This chapter discusses the development and use of eicosapentaenoic acid as a treatment for diabetic ketoacidosis and its applications in conventional and regenerative medicine.
680 citations
University of Texas MD Anderson Cancer Center1, Duke University2, University of South Florida3, Northwestern University4, City of Hope National Medical Center5, Fox Chase Cancer Center6, University of California, San Diego7, Seattle Cancer Care Alliance8, Brigham and Women's Hospital9, Memorial Sloan Kettering Cancer Center10, Case Western Reserve University11, University of Utah12, University of Michigan13, Roswell Park Cancer Institute14, Mayo Clinic15, Yale Cancer Center16, Johns Hopkins University17, University of California, San Francisco18, University of Colorado Boulder19, Vanderbilt University20, Washington University in St. Louis21, University of Nebraska Medical Center22, Ohio State University23, Stanford University24, University of Tennessee Health Science Center25, Harvard University26
TL;DR: The recommendations outlined in the NCCN Guidelines for staging, assessment of HER2 overexpression, systemic therapy for locally advanced or metastatic disease, and best supportive care for the prevention and management of symptoms due to advanced disease are discussed.
Abstract: Gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of death from cancer in the world. Several advances have been made in the staging procedures, imaging techniques, and treatment approaches. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer provide an evidence- and consensus-based treatment approach for the management of patients with gastric cancer. This manuscript discusses the recommendations outlined in the NCCN Guidelines for staging, assessment of HER2 overexpression, systemic therapy for locally advanced or metastatic disease, and best supportive care for the prevention and management of symptoms due to advanced disease.
677 citations
Nicholas J Kassebaum1, Ryan M Barber1, Zulfiqar A Bhutta2, Zulfiqar A Bhutta3 +613 more•Institutions (272)
TL;DR: In this article, the authors quantified maternal mortality throughout the world by underlying cause and age from 1990 to 2015 for ages 10-54 years by systematically compiling and processing all available data sources from 186 of 195 countries and territories.
641 citations
Case Western Reserve University1, Johns Hopkins University2, Mayo Clinic3, Harvard University4, Australian Catholic University5, University of Tennessee Health Science Center6, University of Kentucky7, University of Washington8, University of Pennsylvania9, Memorial Sloan Kettering Cancer Center10, New York Medical College11, Université de Montréal12, Martin Luther University of Halle-Wittenberg13, Centra14
TL;DR: This guideline provides timely, evidence-based reversal strategies to assist practitioners in the care of patients with antithrombotic-associated intracranial hemorrhage.
Abstract: The use of antithrombotic agents, including anticoagulants, antiplatelet agents, and thrombolytics has increased over the last decade and is expected to continue to rise. Although antithrombotic-associated intracranial hemorrhage can be devastating, rapid reversal of coagulopathy may help limit hematoma expansion and improve outcomes. The Neurocritical Care Society, in conjunction with the Society of Critical Care Medicine, organized an international, multi-institutional committee with expertise in neurocritical care, neurology, neurosurgery, stroke, hematology, hemato-pathology, emergency medicine, pharmacy, nursing, and guideline development to evaluate the literature and develop an evidence-based practice guideline. Formalized literature searches were conducted, and studies meeting the criteria established by the committee were evaluated. Utilizing the GRADE methodology, the committee developed recommendations for reversal of vitamin K antagonists, direct factor Xa antagonists, direct thrombin inhibitors, unfractionated heparin, low-molecular weight heparin, heparinoids, pentasaccharides, thrombolytics, and antiplatelet agents in the setting of intracranial hemorrhage. This guideline provides timely, evidence-based reversal strategies to assist practitioners in the care of patients with antithrombotic-associated intracranial hemorrhage.
524 citations
TL;DR: This report provides national estimates of levels and trends of HIV/AIDS incidence, prevalence, coverage of antiretroviral therapy (ART), and mortality for 195 countries and territories from 1980 to 2015.
522 citations
TL;DR: Understanding the levels and trends of the leading causes of death and disability among children and adolescents is critical to guide investment and inform policies and give guidance to policy makers in countries where more attention is needed.
Abstract: Importance The literature focuses on mortality among children younger than 5 years. Comparable information on nonfatal health outcomes among these children and the fatal and nonfatal burden of diseases and injuries among older children and adolescents is scarce. Objective To determine levels and trends in the fatal and nonfatal burden of diseases and injuries among younger children (aged Evidence Review Data from vital registration, verbal autopsy studies, maternal and child death surveillance, and other sources covering 14 244 site-years (ie, years of cause of death data by geography) from 1980 through 2013 were used to estimate cause-specific mortality. Data from 35 620 epidemiological sources were used to estimate the prevalence of the diseases and sequelae in the GBD 2013 study. Cause-specific mortality for most causes was estimated using the Cause of Death Ensemble Model strategy. For some infectious diseases (eg, HIV infection/AIDS, measles, hepatitis B) where the disease process is complex or the cause of death data were insufficient or unavailable, we used natural history models. For most nonfatal health outcomes, DisMod-MR 2.0, a Bayesian metaregression tool, was used to meta-analyze the epidemiological data to generate prevalence estimates. Findings Of the 7.7 (95% uncertainty interval [UI], 7.4-8.1) million deaths among children and adolescents globally in 2013, 6.28 million occurred among younger children, 0.48 million among older children, and 0.97 million among adolescents. In 2013, the leading causes of death were lower respiratory tract infections among younger children (905 059 deaths; 95% UI, 810 304-998 125), diarrheal diseases among older children (38 325 deaths; 95% UI, 30 365-47 678), and road injuries among adolescents (115 186 deaths; 95% UI, 105 185-124 870). Iron deficiency anemia was the leading cause of years lived with disability among children and adolescents, affecting 619 (95% UI, 618-621) million in 2013. Large between-country variations exist in mortality from leading causes among children and adolescents. Countries with rapid declines in all-cause mortality between 1990 and 2013 also experienced large declines in most leading causes of death, whereas countries with the slowest declines had stagnant or increasing trends in the leading causes of death. In 2013, Nigeria had a 12% global share of deaths from lower respiratory tract infections and a 38% global share of deaths from malaria. India had 33% of the world’s deaths from neonatal encephalopathy. Half of the world’s diarrheal deaths among children and adolescents occurred in just 5 countries: India, Democratic Republic of the Congo, Pakistan, Nigeria, and Ethiopia. Conclusions and Relevance Understanding the levels and trends of the leading causes of death and disability among children and adolescents is critical to guide investment and inform policies. Monitoring these trends over time is also key to understanding where interventions are having an impact. Proven interventions exist to prevent or treat the leading causes of unnecessary death and disability among children and adolescents. The findings presented here show that these are underused and give guidance to policy makers in countries where more attention is needed.
486 citations
University of Manitoba1, Johns Hopkins University2, Tufts University3, University of Wisconsin-Madison4, Tel Aviv University5, University of Minnesota6, University of Auckland7, Karolinska Institutet8, Norwegian University of Science and Technology9, Tohoku University10, Yonsei University11, Veterans Health Administration12, University of Tennessee Health Science Center13, Innsbruck Medical University14, University of Groningen15, University of Aberdeen16, Icahn School of Medicine at Mount Sinai17, Cleveland Clinic18, National Institutes of Health19, University of Erlangen-Nuremberg20, University of Oxford21, University of Sydney22
TL;DR: Kidney failure risk equations developed in a Canadian population showed high discrimination and adequate calibration when validated in 31 multinational cohorts, but the original risk equations overestimated risk in some non-North American cohorts.
Abstract: Importance Identifying patients at risk of chronic kidney disease (CKD) progression may facilitate more optimal nephrology care. Kidney failure risk equations, including such factors as age, sex, estimated glomerular filtration rate, and calcium and phosphate concentrations, were previously developed and validated in 2 Canadian cohorts. Validation in other regions and in CKD populations not under the care of a nephrologist is needed. Objective To evaluate the accuracy of the risk equations across different geographic regions and patient populations through individual participant data meta-analysis. Data Sources Thirty-one cohorts, including 721 357 participants with CKD stages 3 to 5 in more than 30 countries spanning 4 continents, were studied. These cohorts collected data from 1982 through 2014. Study Selection Cohorts participating in the CKD Prognosis Consortium with data on end-stage renal disease. Data Extraction and Synthesis Data were obtained and statistical analyses were performed between July 2012 and June 2015. Using the risk factors from the original risk equations, cohort-specific hazard ratios were estimated and combined using random-effects meta-analysis to form new pooled kidney failure risk equations. Original and pooled kidney failure risk equation performance was compared, and the need for regional calibration factors was assessed. Main Outcomes and Measures Kidney failure (treatment by dialysis or kidney transplant). Results During a median follow-up of 4 years of 721 357 participants with CKD, 23 829 cases kidney failure were observed. The original risk equations achieved excellent discrimination (ability to differentiate those who developed kidney failure from those who did not) across all cohorts (overallCstatistic, 0.90; 95% CI, 0.89-0.92 at 2 years;Cstatistic at 5 years, 0.88; 95% CI, 0.86-0.90); discrimination in subgroups by age, race, and diabetes status was similar. There was no improvement with the pooled equations. Calibration (the difference between observed and predicted risk) was adequate in North American cohorts, but the original risk equations overestimated risk in some non-North American cohorts. Addition of a calibration factor that lowered the baseline risk by 32.9% at 2 years and 16.5% at 5 years improved the calibration in 12 of 15 and 10 of 13 non-North American cohorts at 2 and 5 years, respectively (P = .04 andP = .02). Conclusions and Relevance Kidney failure risk equations developed in a Canadian population showed high discrimination and adequate calibration when validated in 31 multinational cohorts. However, in some regions the addition of a calibration factor may be necessary.
413 citations
University of Nevada, Reno1, Purdue University2, Monsanto3, Old Dominion University4, North Carolina State University5, University College London6, Spanish National Research Council7, Oklahoma State University–Stillwater8, National Institutes of Health9, University of Cambridge10, Wellcome Trust11, J. Craig Venter Institute12, Leidos13, Broad Institute14, University of Nevada, Las Vegas15, University of Notre Dame16, University of Barcelona17, Carlos III Health Institute18, University of Massachusetts Medical School19, University of Connecticut20, University of Lausanne21, University of Oxford22, Virginia Tech23, West Virginia University24, Indiana University25, University of Maryland, Baltimore26, Kansas State University27, Texas A&M University28, University of Minnesota29, University of Manchester30, National University of Singapore31, University of California, San Francisco32, Iowa State University33, Colorado State University34, Pennsylvania State University35, Max Planck Society36, University of California, Riverside37, ANSES38, University of Santiago de Compostela39, Pompeu Fabra University40, California State Polytechnic University, Pomona41, University of Queensland42, University of the Sunshine Coast43, University of Geneva44, Swiss Institute of Bioinformatics45, University of Copenhagen46, University of Tennessee Health Science Center47, Wellcome Trust Sanger Institute48, University of Vigo49, University of Illinois at Urbana–Champaign50, Quinnipiac University51, International Livestock Research Institute52
TL;DR: Insights from genome analyses into parasitic processes unique to ticks, including host ‘questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival are reported.
Abstract: Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing ∼57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host 'questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent.
406 citations
University of Washington1, University of Utah2, University of California, San Diego3, Fox Chase Cancer Center4, University of Colorado Boulder5, Roswell Park Cancer Institute6, Brigham and Women's Hospital7, Duke University8, University of South Florida9, University of Alabama10, Washington University in St. Louis11, Vanderbilt University12, University of California, San Francisco13, University of Texas MD Anderson Cancer Center14, Harvard University15, Yale Cancer Center16, University of Michigan17, Stanford University18, Ohio State University19, Northwestern University20, City of Hope National Medical Center21, Memorial Sloan Kettering Cancer Center22, Mayo Clinic23, Case Western Reserve University24, University of Tennessee Health Science Center25, National Comprehensive Cancer Network26
TL;DR: New immunotherapeutic agents, such as nivolumab and pembrolizumab, for patients with metastatic NSCLC are discussed, based on improved overall survival rates, higher response rates, longer duration of response, and fewer adverse events when compared with docetaxel therapy.
Abstract: These NCCN Guidelines Insights focus on recent updates in the 2016 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC; Versions 1-4). These NCCN Guidelines Insights will discuss new immunotherapeutic agents, such as nivolumab and pembrolizumab, for patients with metastatic NSCLC. For the 2016 update, the NCCN panel recommends immune checkpoint inhibitors as preferred agents (in the absence of contraindications) for second-line and beyond (subsequent) therapy in patients with metastatic NSCLC (both squamous and nonsquamous histologies). Nivolumab and pembrolizumab are preferred based on improved overall survival rates, higher response rates, longer duration of response, and fewer adverse events when compared with docetaxel therapy.
378 citations
Northwestern University1, University of Washington2, University of California, San Francisco3, University of California, San Diego4, Brigham and Women's Hospital5, Washington University in St. Louis6, University of Colorado Boulder7, Ohio State University8, University of Alabama at Birmingham9, University of Texas MD Anderson Cancer Center10, Mayo Clinic11, Fox Chase Cancer Center12, Harvard University13, Duke University14, Vanderbilt University15, Memorial Sloan Kettering Cancer Center16, Yale Cancer Center17, University of Michigan18, Roswell Park Cancer Institute19, University of Tennessee Health Science Center20, Seattle Cancer Care Alliance21, Johns Hopkins University22, University of South Florida23, City of Hope National Medical Center24, Stanford University25, University of Utah26
TL;DR: The NCCN Guidelines specific to breast cancer that is locoregional (restricted to one region of the body) are outlined, and the management of clinical stage I, II, and IIIA (T3N1M0) tumors are discussed.
Abstract: Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. This article outlines the NCCN Guidelines specific to breast cancer that is locoregional (restricted to one region of the body), and discusses the management of clinical stage I, II, and IIIA (T3N1M0) tumors. For NCCN Guidelines on systemic adjuvant therapy after locoregional management of clinical stage I, II and IIIA (T3N1M0) and for management for other clinical stages of breast cancer, see the complete version of these guidelines at NCCN.org.
TL;DR: In this paper, the association of age-related peripheral hearing impairment (HI) with incident dementia and with domain-specific cognitive decline in memory, perceptual speed, and processing speed was quantified.
Abstract: Background Age-related peripheral hearing impairment (HI) is prevalent, treatable, and may be a risk factor for dementia in older adults. In prospective analysis, we quantified the association of HI with incident dementia and with domain-specific cognitive decline in memory, perceptual speed, and processing speed. Methods Data were from the Health, Aging and Body Composition (Health ABC) study, a biracial cohort of well-functioning adults aged 70-79 years. Dementia was defined using a prespecified algorithm incorporating medication use, hospital records, and neurocognitive test scores. A pure-tone average in decibels hearing level (dBHL) was calculated in the better hearing ear using thresholds from 0.5 to 4kHz, and HI was defined as normal hearing (≤25 dBHL), mild (26-40 dBHL), and moderate/severe (>40 dBHL). Associations between HI and incident dementia and between HI and cognitive change were modeled using Cox proportional hazards models and linear mixed models, respectively. Results Three-hundred eighty seven (20%) participants had moderate/severe HI, and 716 (38%) had mild HI. After adjustment for demographic and cardiovascular factors, moderate/severe audiometric HI (vs. normal hearing) was associated with increased risk of incident dementia over 9 years (hazard ratio: 1.55, 95% confidence interval [CI]: 1.10, 2.19). Other than poorer baseline memory performance (difference of -0.24 SDs, 95% CI: -0.44, -0.04), no associations were observed between HI and rates of domain-specific cognitive change during 7 years of follow-up. Conclusions HI is associated with increased risk of developing dementia in older adults. Randomized trials are needed to determine whether treatment of hearing loss could postpone dementia onset in older adults.
TL;DR: A tool that simultaneously incorporates multiple health characteristics to estimate a person's probable long-term risk of ESRD if that person does not donate a kidney was developed and may be used to inform acceptance criteria for kidney donors.
Abstract: BackgroundEvaluation of candidates to serve as living kidney donors relies on screening for individual risk factors for end-stage renal disease (ESRD). To support an empirical approach to donor selection, we developed a tool that simultaneously incorporates multiple health characteristics to estimate a person’s probable long-term risk of ESRD if that person does not donate a kidney. MethodsWe used risk associations from a meta-analysis of seven general population cohorts, calibrated to the population-level incidence of ESRD and mortality in the United States, to project the estimated long-term incidence of ESRD among persons who do not donate a kidney, according to 10 demographic and health characteristics. We then compared 15-year projections with the observed risk among 52,998 living kidney donors in the United States. ResultsA total of 4,933,314 participants from seven cohorts were followed for a median of 4 to 16 years. For a 40-year-old person with health characteristics that were similar to those of...
TL;DR: In this article, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, the authors describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens.
Abstract: Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-seq, that is responsible for subgroup divergence, and implicates candidate cells of origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins.
Ohio State University1, Johns Hopkins University2, University of Tennessee Health Science Center3, University of Utah4, University of California, San Francisco5, University of Alabama6, Brigham and Women's Hospital7, Northwestern University8, University of Colorado Boulder9, Stanford University10, University of Texas MD Anderson Cancer Center11, University of California, San Diego12, Duke University13, University of Michigan14, Memorial Sloan Kettering Cancer Center15, University of South Florida16, Harvard University17, University of Washington18, Roswell Park Cancer Institute19, City of Hope National Medical Center20, Washington University in St. Louis21, Mayo Clinic22, Vanderbilt University23, National Comprehensive Cancer Network24
TL;DR: Major discussion topics this year included multigene testing, risk management recommendations for less common genetic mutations, and salpingectomy for ovarian cancer risk reduction.
Abstract: The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling and risk assessment and management for hereditary cancer syndromes. Guidelines focus on syndromes associated with an increased risk of breast and/or ovarian cancer and are intended to assist with clinical and shared decision-making. These NCCN Guidelines Insights summarize major discussion points of the 2015 NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian panel meeting. Major discussion topics this year included multigene testing, risk management recommendations for less common genetic mutations, and salpingectomy for ovarian cancer risk reduction. The panel also discussed revisions to genetic testing criteria that take into account ovarian cancer histology and personal history of pancreatic cancer.
University of Pittsburgh1, University of Washington2, University of California, San Francisco3, University of Tennessee Health Science Center4, National Institutes of Health5, University of Minnesota6, Oregon Health & Science University7, Veterans Health Administration8, Merck & Co.9, University of Maryland, College Park10
TL;DR: In older adults, gait speed predicts 3 year incidence of bathing or dressing dependence, mobility difficulty, and a composite outcome of disability and mortality.
Abstract: Background. Functional independence with aging is an important goal for individuals and society. Simple prognostic indicators can inform health promotion and care planning, but evidence is limited by heterogeneity in measures of function. Methods. We performed a pooled analysis of data from seven studies of 27,220 community-dwelling older adults aged 65 or older with baseline gait speed, followed for disability and mortality. Outcomes were incident inability or dependence on another person in bathing or dressing; and difficulty walking ¼ – ½ mile or climbing 10 steps within 3 years. Results. Participants with faster baseline gait had lower rates of incident disability. In subgroups (defined by 0.2 m/s-wide intervals from <0.4 to ≥1.4 m/s) with increasingly greater gait speed, 3-year rates of bathing or dressing dependence trended from 10% to 1% in men, and from 15% to 1% in women, while mobility difficulty trended from 47% to 4% in men and 40% to 6% in women. The age-adjusted relative risk ratio per 0.1 m/s greater speed for bathing or dressing dependence in men was 0.68 (0.57–0.81) and in women: 0.74 (0.66– 0.82); for mobility difficulty, men: 0.75 (0.68–0.82), women: 0.73 (0.67–0.80). Results were similar for combined disability and mortality. Effects were largely consistent across subgroups based on age, gender, race, body mass index, prior hospitalization, and selected chronic conditions. In the presence of multiple other risk factors for disability, gait speed significantly increased the area under the receiver operator characteristic curve. Conclusion. In older adults, gait speed predicts 3 year incidence of bathing or dressing dependence, mobility difficulty, and a composite outcome of disability and mortality.
University of California, San Francisco1, University of California, San Diego2, Washington University in St. Louis3, Ohio State University4, Mayo Clinic5, Northwestern University6, Harvard University7, University of Texas MD Anderson Cancer Center8, Johns Hopkins University9, Seattle Cancer Care Alliance10, University of Nebraska Medical Center11, Case Western Reserve University12, University of Washington13, Brigham and Women's Hospital14, University of Utah15, University of Colorado Boulder16, Roswell Park Cancer Institute17, University of Michigan18, Vanderbilt University19, University of South Florida20, Duke University21, University of Alabama at Birmingham22, Fox Chase Cancer Center23, Stanford University24, Yale Cancer Center25, Memorial Sloan Kettering Cancer Center26, University of Tennessee Health Science Center27, National Comprehensive Cancer Network28
TL;DR: These NCCN Guidelines Insights summarize the N CCN Prostate Cancer Early Detection Panel's most significant discussions for the 2016 guideline update, which included issues surrounding screening in high-risk populations (ie, African Americans, BRCA1/2 mutation carriers), approaches to refine patient selection for initial and repeat biopsies, and approaches to improve biopsy specificity.
Abstract: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer Early Detection provide recommendations for prostate cancer screening in healthy men who have elected to participate in an early detection program. The NCCN Guidelines focus on minimizing unnecessary procedures and limiting the detection of indolent disease. These NCCN Guidelines Insights summarize the NCCN Prostate Cancer Early Detection Panel's most significant discussions for the 2016 guideline update, which included issues surrounding screening in high-risk populations (ie, African Americans, BRCA1/2 mutation carriers), approaches to refine patient selection for initial and repeat biopsies, and approaches to improve biopsy specificity.
TL;DR: The challenges to developing drugs to treat tuberculosis are discussed and how the field has adapted to these difficulties, with an emphasis on drug discovery approaches that might produce more effective agents and treatment regimens.
TL;DR: The B. tabaci genome contains numerous genetic novelties, including expansions in gene families associated with insecticide resistance, detoxification and virus transmission, as well as numerous horizontally transferred genes from bacteria and fungi.
Abstract: The whitefly Bemisia tabaci (Hemiptera: Aleyrodidae) is among the 100 worst invasive species in the world. As one of the most important crop pests and virus vectors, B. tabaci causes substantial crop losses and poses a serious threat to global food security. We report the 615-Mb high-quality genome sequence of B. tabaci Middle East-Asia Minor 1 (MEAM1), the first genome sequence in the Aleyrodidae family, which contains 15,664 protein-coding genes. The B. tabaci genome is highly divergent from other sequenced hemipteran genomes, sharing no detectable synteny. A number of known detoxification gene families, including cytochrome P450s and UDP-glucuronosyltransferases, are significantly expanded in B. tabaci. Other expanded gene families, including cathepsins, large clusters of tandemly duplicated B. tabaci-specific genes, and phosphatidylethanolamine-binding proteins (PEBPs), were found to be associated with virus acquisition and transmission and/or insecticide resistance, likely contributing to the global invasiveness and efficient virus transmission capacity of B. tabaci. The presence of 142 horizontally transferred genes from bacteria or fungi in the B. tabaci genome, including genes encoding hopanoid/sterol synthesis and xenobiotic detoxification enzymes that are not present in other insects, offers novel insights into the unique biological adaptations of this insect such as polyphagy and insecticide resistance. Interestingly, two adjacent bacterial pantothenate biosynthesis genes, panB and panC, have been co-transferred into B. tabaci and fused into a single gene that has acquired introns during its evolution. The B. tabaci genome contains numerous genetic novelties, including expansions in gene families associated with insecticide resistance, detoxification and virus transmission, as well as numerous horizontally transferred genes from bacteria and fungi. We believe these novelties likely have shaped B. tabaci as a highly invasive polyphagous crop pest and efficient vector of plant viruses. The genome serves as a reference for resolving the B. tabaci cryptic species complex, understanding fundamental biological novelties, and providing valuable genetic information to assist the development of novel strategies for controlling whiteflies and the viruses they transmit.
Memorial Sloan Kettering Cancer Center1, Cleveland Clinic2, Emory University3, University of Tennessee Health Science Center4, Fred Hutchinson Cancer Research Center5, Cleveland Clinic Lerner Research Institute6, Leipzig University7, European Organisation for Research and Treatment of Cancer8, University of Zurich9, University of Washington10
TL;DR: This analysis substantiates the request for prudent and restricted use of corticosteroids in glioblastoma and highlights the importance of identifying alternative agents such as vascular endothelial growth factor antagonists for managing oedema in glooblastom patients.
Abstract: Glioblastoma is the most common and most aggressive primary brain tumour. Standard of care consists of surgical resection followed by radiotherapy and concomitant and maintenance temozolomide (temozolomide/radiotherapy→temozolomide). Corticosteroids are commonly used perioperatively to control cerebral oedema and are frequently continued throughout subsequent treatment, notably radiotherapy, for amelioration of side effects. The effects of corticosteroids such as dexamethasone on cell growth in glioma models and on patient survival have remained controversial. We performed a retrospective analysis of glioblastoma patient cohorts to determine the prognostic role of steroid administration. A disease-relevant mouse model of glioblastoma was used to characterize the effects of dexamethasone on tumour cell proliferation and death, and to identify gene signatures associated with these effects. A murine anti-VEGFA antibody was used in parallel as an alternative for oedema control. We applied the dexamethasone-induced gene signature to The Cancer Genome Atlas glioblastoma dataset to explore the association of dexamethasone exposure with outcome. Mouse experiments were used to validate the effects of dexamethasone on survival in vivo Retrospective clinical analyses identified corticosteroid use during radiotherapy as an independent indicator of shorter survival in three independent patient cohorts. A dexamethasone-associated gene expression signature correlated with shorter survival in The Cancer Genome Atlas patient dataset. In glioma-bearing mice, dexamethasone pretreatment decreased tumour cell proliferation without affecting tumour cell viability, but reduced survival when combined with radiotherapy. Conversely, anti-VEGFA antibody decreased proliferation and increased tumour cell death, but did not affect survival when combined with radiotherapy. Clinical and mouse experimental data suggest that corticosteroids may decrease the effectiveness of treatment and shorten survival in glioblastoma. Dexamethasone-induced anti-proliferative effects may confer protection from radiotherapy- and chemotherapy-induced genotoxic stress. This study highlights the importance of identifying alternative agents such as vascular endothelial growth factor antagonists for managing oedema in glioblastoma patients. Beyond the established adverse effect profile of protracted corticosteroid use, this analysis substantiates the request for prudent and restricted use of corticosteroids in glioblastoma.
The American College of Financial Services1, University of California, San Diego2, Icahn School of Medicine at Mount Sinai3, University of Tennessee Health Science Center4, University of Texas Health Science Center at San Antonio5, American Association of Clinical Endocrinologists6, Tulane University7, Baylor College of Medicine8, Emory University9, University of Maryland, Baltimore10
TL;DR: ABBREVIATIONS AACE = American Association of Clinical Endocrinologists ACE = American College of Endocrinology DKA = diabetic ketoacidosis EMA = European Medicines Agency FDA = U.S. Food and Drug Administration SGLT-2 = sodium glucosecotransporter 2 T1D = type 1 diabetes T2D =type 2 diabetes.
TL;DR: It is shown that the interferon-inducible protein IRGB10 is essential for activation of the DNA-sensing AIM2 inflammasome by Francisella novicida and contributed to theactivation of the LPS-s sensing caspase-11 and NLRP3 inflammaome by Gram-negative bacteria.
TL;DR: Rigorous preclinical investigations are potentially generating novel strategies for the treatment of osteosarcoma that will inform the next generation of clinical trials, with the opportunity to identify agents that will improve survival outcomes.
Abstract: Purpose of reviewOverall survival rates for osteosarcoma have remained essentially unchanged over the past 3 decades despite attempts to improve outcome via dose intensification and modification based on response. This review describes recent findings from contemporary clinical trials, advances in t
University of Memphis1, United States Department of Agriculture2, Max Planck Society3, Pennsylvania State University4, University of Arizona5, University of Wisconsin–Oshkosh6, Broad Institute7, University of Geneva8, University of Illinois at Chicago9, University of Cincinnati10, University of Texas at Arlington11, North Dakota State University12, Baylor College of Medicine13, University of Rochester14, Wayne State University15, Georgia Institute of Technology16, Texas A&M University17, Michigan State University18, National Taiwan University19, Indiana University20, University of Tennessee Health Science Center21, University of Kentucky22, University of Cologne23, Xavier University24, University of Illinois at Urbana–Champaign25
TL;DR: Amplification and functional divergence of genes associated with specialized feeding on plants, including genes originally obtained via horizontal gene transfer from fungi and bacteria, contributed to the addition, expansion, and enhancement of the metabolic repertoire of the Asian longhorned beetle and to a lesser degree, other phytophagous insects.
Abstract: Relatively little is known about the genomic basis and evolution of wood-feeding in beetles. We undertook genome sequencing and annotation, gene expression assays, studies of plant cell wall degrading enzymes, and other functional and comparative studies of the Asian longhorned beetle, Anoplophora glabripennis, a globally significant invasive species capable of inflicting severe feeding damage on many important tree species. Complementary studies of genes encoding enzymes involved in digestion of woody plant tissues or detoxification of plant allelochemicals were undertaken with the genomes of 14 additional insects, including the newly sequenced emerald ash borer and bull-headed dung beetle. The Asian longhorned beetle genome encodes a uniquely diverse arsenal of enzymes that can degrade the main polysaccharide networks in plant cell walls, detoxify plant allelochemicals, and otherwise facilitate feeding on woody plants. It has the metabolic plasticity needed to feed on diverse plant species, contributing to its highly invasive nature. Large expansions of chemosensory genes involved in the reception of pheromones and plant kairomones are consistent with the complexity of chemical cues it uses to find host plants and mates. Amplification and functional divergence of genes associated with specialized feeding on plants, including genes originally obtained via horizontal gene transfer from fungi and bacteria, contributed to the addition, expansion, and enhancement of the metabolic repertoire of the Asian longhorned beetle, certain other phytophagous beetles, and to a lesser degree, other phytophagous insects. Our results thus begin to establish a genomic basis for the evolutionary success of beetles on plants.
City of Hope National Medical Center1, Johns Hopkins University2, University of Alabama at Birmingham3, Mayo Clinic4, University of Colorado Boulder5, University of California, San Francisco6, Ohio State University7, Vanderbilt University8, Stanford University9, University of Texas MD Anderson Cancer Center10, University of Washington11, University of South Florida12, Duke University13, University of Michigan14, Roswell Park Cancer Institute15, Fox Chase Cancer Center16, Brigham and Women's Hospital17, Harvard University18, Northwestern University19, University of California, San Diego20, Washington University in St. Louis21, Yale Cancer Center22, Case Western Reserve University23, Memorial Sloan Kettering Cancer Center24, University of Tennessee Health Science Center25, University of Utah26
TL;DR: This selection from the NCCN Guidelines for Ovarian Cancer focuses on the less common ovarian histopathologies (LCOHs), because new algorithms were added for LCOHs and current algorithms were revised for the 2016 update.
Abstract: This selection from the NCCN Guidelines for Ovarian Cancer focuses on the less common ovarian histopathologies (LCOHs), because new algorithms were added for LCOHs and current algorithms were revised for the 2016 update. The new LCOHs algorithms include clear cell carcinomas, mucinous carcinomas, and grade 1 (low-grade) serous carcinomas/endometrioid epithelial carcinomas. The LCOHs also include carcinosarcomas (malignant mixed Mullerian tumors of the ovary), borderline epithelial tumors (also known as low malignant potential tumors), malignant sex cord-stromal tumors, and malignant germ cell tumors.
TL;DR: Recommendations for EVD management are developed based on a thorough literature review using the Grading of Recommendations Assessment, Development, and Evaluation system, with emphasis placed not only on the quality of the evidence, but also on the balance of benefits versus risks, patient values and preferences, and resource considerations.
Abstract: External ventricular drains (EVDs) are commonly placed to monitor intracranial pressure and manage acute hydrocephalus in patients with a variety of intracranial pathologies. The indications for EVD insertion and their efficacy in the management of these various conditions have been previously addressed in guidelines published by the Brain Trauma Foundation, American Heart Association and combined committees of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons. While it is well recognized that placement of an EVD may be a lifesaving intervention, the benefits can be offset by procedural and catheter-related complications, such as hemorrhage along the catheter tract, catheter malposition, and CSF infection. Despite their widespread use, there are a lack of high-quality data regarding the best methods for placement and management of EVDs to minimize these risks. Existing recommendations are frequently based on observational data from a single center and may be biased to the authors’ view. To address the need for a comprehensive set of evidence-based guidelines for EVD management, the Neurocritical Care Society organized a committee of experts in the fields of neurosurgery, neurology, neuroinfectious disease, critical care, pharmacotherapy, and nursing. The Committee generated clinical questions relevant to EVD placement and management. They developed recommendations based on a thorough literature review using the Grading of Recommendations Assessment, Development, and Evaluation system, with emphasis placed not only on the quality of the evidence, but also on the balance of benefits versus risks, patient values and preferences, and resource considerations.
TL;DR: This work presents a meta-analysis of the putative mechanisms behind the Evolutionary Relationship of the Putative SmCPS1- and SmC PS2- Gene Clusters and co-Expression Analysis of CYPs with SmCps1 and 437 Putative CYPs in the S. miltiorrhiza Genome.
TL;DR: Higher SBPV in individuals with and without hypertension was associated with increased risks of all-cause mortality, CHD, stroke, and ESRD, and further studies are needed to determine interventions that can lowerSBPV and their impact on adverse health outcomes.
TL;DR: A thorough summary and comprehensive understanding of the prevalence and structural characteristics of SCCmec may aid in global surveillance, implementation and investigation on MRSA isolates, as well as further development of preventive and therapeutic approaches.
TL;DR: A comprehensive assessment is needed to understand the pain experience of women presenting with vulvodynia, and several treatment options are worth pursuing.