Showing papers by "University of Utah published in 2019"
Harvard University1, University of Western Australia2, University of Texas Health Science Center at San Antonio3, McMaster University4, University of Washington5, Centers for Disease Control and Prevention6, Primary Children's Hospital7, University of Utah8, University of Pittsburgh9, University of Michigan10, Vanderbilt University11, University of Connecticut12, United States Department of Veterans Affairs13, Baylor College of Medicine14
TL;DR: Although some recommendations remain unchanged from the 2007 guideline, the availability of results from new therapeutic trials and epidemiological investigations led to revised recommendations for empiric treatment strategies and additional management decisions.
Abstract: Background: This document provides evidence-based clinical practice guidelines on the management of adult patients with community-acquired pneumonia.Methods: A multidisciplinary panel conducted pra...
1,708 citations
Roswell Park Cancer Institute1, Johns Hopkins University2, Duke University3, Brigham and Women's Hospital4, Mayo Clinic5, City of Hope National Medical Center6, Memorial Sloan Kettering Cancer Center7, Fred Hutchinson Cancer Research Center8, Fox Chase Cancer Center9, Yale Cancer Center10, Washington University in St. Louis11, University of California, San Diego12, University of Wisconsin-Madison13, University Hospitals of Cleveland14, University of Alabama at Birmingham15, Vanderbilt University16, Moffitt Cancer Center17, University of Colorado Boulder18, University of Tennessee Health Science Center19, University of California, San Francisco20, Northwestern University21, Ohio State University22, University of Michigan23, Stanford University24, University of Utah25, National Comprehensive Cancer Network26
TL;DR: The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer.
Abstract: The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer. The portions of the guidelines included herein focus on the roles of germline and somatic genetic testing, risk stratification with nomograms and tumor multigene molecular testing, androgen deprivation therapy, secondary hormonal therapy, chemotherapy, and immunotherapy in patients with prostate cancer.
1,218 citations
TL;DR: Overall survival and radiographic progression-free survival were significantly longer with the addition of apalutamide to ADT than with placebo plus ADT, and the side-effect profile did not differ substantially between the two groups.
Abstract: Background Apalutamide is an inhibitor of the ligand-binding domain of the androgen receptor. Whether the addition of apalutamide to androgen-deprivation therapy (ADT) would prolong radiographic progression-free survival and overall survival as compared with placebo plus ADT among patients with metastatic, castration-sensitive prostate cancer has not been determined. Methods In this double-blind, phase 3 trial, we randomly assigned patients with metastatic, castration-sensitive prostate cancer to receive apalutamide (240 mg per day) or placebo, added to ADT. Previous treatment for localized disease and previous docetaxel therapy were allowed. The primary end points were radiographic progression-free survival and overall survival. Results A total of 525 patients were assigned to receive apalutamide plus ADT and 527 to receive placebo plus ADT. The median age was 68 years. A total of 16.4% of the patients had undergone prostatectomy or received radiotherapy for localized disease, and 10.7% had received previous docetaxel therapy; 62.7% had high-volume disease, and 37.3% had low-volume disease. At the first interim analysis, with a median of 22.7 months of follow-up, the percentage of patients with radiographic progression-free survival at 24 months was 68.2% in the apalutamide group and 47.5% in the placebo group (hazard ratio for radiographic progression or death, 0.48; 95% confidence interval [CI], 0.39 to 0.60; P Conclusions In this trial involving patients with metastatic, castration-sensitive prostate cancer, overall survival and radiographic progression-free survival were significantly longer with the addition of apalutamide to ADT than with placebo plus ADT, and the side-effect profile did not differ substantially between the two groups. (Funded by Janssen Research and Development; TITAN ClinicalTrials.gov number, NCT02489318.).
789 citations
Wake Forest University1, University of Mississippi Medical Center2, University of Pennsylvania3, University of Utah4, University of Alabama at Birmingham5, Veterans Health Administration6, National Institutes of Health7, University of Tennessee Health Science Center8, Stanford University9, Case Western Reserve University10, Tufts Medical Center11, Tulane University12
TL;DR: Among ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of more than 140mm Hg did not result in a significant reduction in the risk of probable dementia.
Abstract: Importance There are currently no proven treatments to reduce the risk of mild cognitive impairment and dementia. Objective To evaluate the effect of intensive blood pressure control on risk of dementia. Design, Setting, and Participants Randomized clinical trial conducted at 102 sites in the United States and Puerto Rico among adults aged 50 years or older with hypertension but without diabetes or history of stroke. Randomization began on November 8, 2010. The trial was stopped early for benefit on its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. The final date for follow-up of cognitive outcomes was July 22, 2018. Interventions Participants were randomized to a systolic blood pressure goal of either less than 120 mm Hg (intensive treatment group; n = 4678) or less than 140 mm Hg (standard treatment group; n = 4683). Main Outcomes and Measures The primary cognitive outcome was occurrence of adjudicated probable dementia. Secondary cognitive outcomes included adjudicated mild cognitive impairment and a composite outcome of mild cognitive impairment or probable dementia. Results Among 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 8563 (91.5%) completed at least 1 follow-up cognitive assessment. The median intervention period was 3.34 years. During a total median follow-up of 5.11 years, adjudicated probable dementia occurred in 149 participants in the intensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6 cases per 1000 person-years; hazard ratio [HR], 0.83; 95% CI, 0.67-1.04). Intensive BP control significantly reduced the risk of mild cognitive impairment (14.6 vs 18.3 cases per 1000 person-years; HR, 0.81; 95% CI, 0.69-0.95) and the combined rate of mild cognitive impairment or probable dementia (20.2 vs 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74-0.97). Conclusions and Relevance Among ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of less than 140 mm Hg did not result in a significant reduction in the risk of probable dementia. Because of early study termination and fewer than expected cases of dementia, the study may have been underpowered for this end point. Trial Registration ClinicalTrials.gov Identifier:NCT01206062
732 citations
University of Texas MD Anderson Cancer Center1, Duke University2, Northwestern University3, City of Hope National Medical Center4, University of California, San Francisco5, Fox Chase Cancer Center6, Brigham and Women's Hospital7, University of California, San Diego8, Fred Hutchinson Cancer Research Center9, Memorial Sloan Kettering Cancer Center10, Vanderbilt University11, University of Utah12, University of Michigan13, Roswell Park Cancer Institute14, Mayo Clinic15, Yale Cancer Center16, Johns Hopkins University17, University of Colorado Boulder18, University of Wisconsin-Madison19, University Hospitals of Cleveland20, Washington University in St. Louis21, Ohio State University22, University of South Florida23, Stanford University24, University of Pennsylvania25, Harvard University26, National Comprehensive Cancer Network27
TL;DR: This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.
Abstract: Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.
710 citations
TL;DR: The authors assesses whether shareholders drive the environmental and social (E&S) performance of firms worldwide and finds that institutional ownership is positively associated with E&S performance with additional tests suggesting this relation is causal.
669 citations
Nasim Mavaddat1, Kyriaki Michailidou1, Kyriaki Michailidou2, Joe Dennis1 +307 more•Institutions (105)
TL;DR: This PRS, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset is developed and empirically validated and is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
Abstract: Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
653 citations
Seattle Cancer Care Alliance1, Memorial Sloan Kettering Cancer Center2, Duke University3, University of Wisconsin-Madison4, Brigham and Women's Hospital5, University of Michigan6, University of South Florida7, Fox Chase Cancer Center8, Harvard University9, Ohio State University10, Vanderbilt University11, Yale Cancer Center12, Stanford University13, University of Texas MD Anderson Cancer Center14, University of Colorado Boulder15, Roswell Park Cancer Institute16, University of Utah17, City of Hope National Medical Center18, University of Alabama at Birmingham19, Northwestern University20, Mayo Clinic21, Washington University in St. Louis22, Case Western Reserve University23, Johns Hopkins University24, University of Nebraska Medical Center25, University of Tennessee Health Science Center26, University of California, San Francisco27, University of California, San Diego28, National Comprehensive Cancer Network29
TL;DR: This manuscript discusses guiding principles for the workup, staging, and treatment of early stage and locally advanced cervical cancer, as well as evidence for these recommendations.
Abstract: Cervical cancer is a malignant epithelial tumor that forms in the uterine cervix. Most cases of cervical cancer are preventable through human papilloma virus (HPV) vaccination, routine screening, and treatment of precancerous lesions. However, due to inadequate screening protocols in many regions of the world, cervical cancer remains the fourth-most common cancer in women globally. The complete NCCN Guidelines for Cervical Cancer provide recommendations for the diagnosis, evaluation, and treatment of cervical cancer. This manuscript discusses guiding principles for the workup, staging, and treatment of early stage and locally advanced cervical cancer, as well as evidence for these recommendations. For recommendations regarding treatment of recurrent or metastatic disease, please see the full guidelines on NCCN.org.
649 citations
TL;DR: A deep learning approach that predicts the risk of acute kidney injury and provides confidence assessments and a list of the clinical features that are most salient to each prediction, alongside predicted future trajectories for clinically relevant blood tests are developed.
Abstract: The early prediction of deterioration could have an important role in supporting healthcare professionals, as an estimated 11% of deaths in hospital follow a failure to promptly recognize and treat deteriorating patients1. To achieve this goal requires predictions of patient risk that are continuously updated and accurate, and delivered at an individual level with sufficient context and enough time to act. Here we develop a deep learning approach for the continuous risk prediction of future deterioration in patients, building on recent work that models adverse events from electronic health records2–17 and using acute kidney injury—a common and potentially life-threatening condition18—as an exemplar. Our model was developed on a large, longitudinal dataset of electronic health records that cover diverse clinical environments, comprising 703,782 adult patients across 172 inpatient and 1,062 outpatient sites. Our model predicts 55.8% of all inpatient episodes of acute kidney injury, and 90.2% of all acute kidney injuries that required subsequent administration of dialysis, with a lead time of up to 48 h and a ratio of 2 false alerts for every true alert. In addition to predicting future acute kidney injury, our model provides confidence assessments and a list of the clinical features that are most salient to each prediction, alongside predicted future trajectories for clinically relevant blood tests9. Although the recognition and prompt treatment of acute kidney injury is known to be challenging, our approach may offer opportunities for identifying patients at risk within a time window that enables early treatment. A deep learning approach that predicts the risk of acute kidney injury may help to identify patients at risk of health deterioration within a time window that enables early treatment.
617 citations
29 Jan 2019
TL;DR: This paper outlines this mismatch with five "traps" that fair-ML work can fall into even as it attempts to be more context-aware in comparison to traditional data science and suggests ways in which technical designers can mitigate the traps through a refocusing of design in terms of process rather than solutions.
Abstract: A key goal of the fair-ML community is to develop machine-learning based systems that, once introduced into a social context, can achieve social and legal outcomes such as fairness, justice, and due process. Bedrock concepts in computer science---such as abstraction and modular design---are used to define notions of fairness and discrimination, to produce fairness-aware learning algorithms, and to intervene at different stages of a decision-making pipeline to produce "fair" outcomes. In this paper, however, we contend that these concepts render technical interventions ineffective, inaccurate, and sometimes dangerously misguided when they enter the societal context that surrounds decision-making systems. We outline this mismatch with five "traps" that fair-ML work can fall into even as it attempts to be more context-aware in comparison to traditional data science. We draw on studies of sociotechnical systems in Science and Technology Studies to explain why such traps occur and how to avoid them. Finally, we suggest ways in which technical designers can mitigate the traps through a refocusing of design in terms of process rather than solutions, and by drawing abstraction boundaries to include social actors rather than purely technical ones.
615 citations
University of Southern California1, University of Washington2, Harvard University3, University of Michigan4, Max Planck Society5, University of Groningen6, University of Maryland, Baltimore7, Icahn School of Medicine at Mount Sinai8, Xi'an Jiaotong University9, University of Texas MD Anderson Cancer Center10, University of North Carolina at Charlotte11, Broad Institute12, European Bioinformatics Institute13, Yale University14, University of California, Davis15, University of Utah16, Pacific Biosciences17, University of California, San Diego18, Illumina19, Ludwig Institute for Cancer Research20, Ewha Womans University21, Drexel University22, University of Texas Health Science Center at Houston23, Washington University in St. Louis24, University of Malaya25, University of California, San Francisco26, University of British Columbia27, BC Cancer Agency28
TL;DR: A suite of long-read, short- read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms are applied to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner.
Abstract: The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 bp) and 27,622 SVs (≥50 bp) per genome. We also discover 156 inversions per genome and 58 of the inversions intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a three to sevenfold increase in SV detection compared to most standard high-throughput sequencing studies, including those from the 1000 Genomes Project. The methods and the dataset presented serve as a gold standard for the scientific community allowing us to make recommendations for maximizing structural variation sensitivity for future genome sequencing studies.
University of Texas MD Anderson Cancer Center1, University of Chicago2, Roswell Park Cancer Institute3, Seattle Cancer Care Alliance4, University of Southern Denmark5, University of New South Wales6, Jikei University School of Medicine7, University of Oklahoma8, Kaplan Medical Center9, University of Utah10, Texas Oncology11, University of Pennsylvania12, University of Ulsan13, University of Alabama at Birmingham14, University of Oxford15, Washington University in St. Louis16, Kaiser Permanente17, Memorial Sloan Kettering Cancer Center18, AbbVie19
TL;DR: Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliporib maintenance therapy led to significantly longer progression-free survival than carboplati plus pac Litaxel induction therapy alone.
Abstract: Background Data are limited regarding the use of poly(adenosine diphosphate [ADP]–ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance...
National Center for Immunization and Respiratory Diseases1, University of California, San Diego2, Boston Children's Hospital3, University of Washington4, Northeast Ohio Medical University5, Brown University6, University of Virginia Health System7, Centers for Disease Control and Prevention8, University of Maryland, Baltimore9, Northwestern University10, Nova Scotia Health Authority11, University of Toronto12, Harvard University13, Duke University14, Infectious Diseases Society of America15, McMaster University16, University of Utah17
TL;DR: These clinical practice guidelines are an update of the guidelines published by the Infectious Diseases Society of America in 2009 and address new information regarding diagnostic testing, treatment and chemoprophylaxis with antiviral medications, and issues related to institutional outbreak management for seasonal influenza.
Abstract: These clinical practice guidelines are an update of the guidelines published by the Infectious Diseases Society of America (IDSA) in 2009, prior to the 2009 H1N1 influenza pandemic. This document addresses new information regarding diagnostic testing, treatment and chemoprophylaxis with antiviral medications, and issues related to institutional outbreak management for seasonal influenza. It is intended for use by primary care clinicians, obstetricians, emergency medicine providers, hospitalists, laboratorians, and infectious disease specialists, as well as other clinicians managing patients with suspected or laboratory-confirmed influenza. The guidelines consider the care of children and adults, including special populations such as pregnant and postpartum women and immunocompromised patients.
Johns Hopkins University1, Seattle Cancer Care Alliance2, University of Pennsylvania3, University of Colorado Boulder4, University of Utah5, Fox Chase Cancer Center6, Northwestern University7, Case Western Reserve University8, University of Texas MD Anderson Cancer Center9, Brigham and Women's Hospital10, Duke University11, University of South Florida12, Yale University13, Washington University in St. Louis14, University of California, San Francisco15, Roswell Park Cancer Institute16, Vanderbilt University17, University of Nebraska Medical Center18, Harvard University19, University of Wisconsin-Madison20, University of Michigan21, Stanford University22, Ohio State University23, University of California, San Diego24, City of Hope National Medical Center25, Memorial Sloan Kettering Cancer Center26, Mayo Clinic27, University of Tennessee Health Science Center28, National Comprehensive Cancer Network29
TL;DR: The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) as discussed by the authors address all aspects of management for NSCLC, focusing on recent updates in immunotherapy.
Abstract: The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates in immunotherapy. For the 2020 update, all of the systemic therapy regimens have been categorized using a new preference stratification system; certain regimens are now recommended as "preferred interventions," whereas others are categorized as either "other recommended interventions" or "useful under certain circumstances."
29 Jan 2019
TL;DR: It is found that fairness-preserving algorithms tend to be sensitive to fluctuations in dataset composition and to different forms of preprocessing, indicating that fairness interventions might be more brittle than previously thought.
Abstract: Computers are increasingly used to make decisions that have significant impact on people's lives. Often, these predictions can affect different population subgroups disproportionately. As a result, the issue of fairness has received much recent interest, and a number of fairness-enhanced classifiers have appeared in the literature. This paper seeks to study the following questions: how do these different techniques fundamentally compare to one another, and what accounts for the differences? Specifically, we seek to bring attention to many under-appreciated aspects of such fairness-enhancing interventions that require investigation for these algorithms to receive broad adoption. We present the results of an open benchmark we have developed that lets us compare a number of different algorithms under a variety of fairness measures and existing datasets. We find that although different algorithms tend to prefer specific formulations of fairness preservations, many of these measures strongly correlate with one another. In addition, we find that fairness-preserving algorithms tend to be sensitive to fluctuations in dataset composition (simulated in our benchmark by varying training-test splits) and to different forms of preprocessing, indicating that fairness interventions might be more brittle than previously thought.
Charité1, Wayne State University2, Ottawa Hospital Research Institute3, University of Luxembourg4, University of Melbourne5, University of Freiburg6, Radboud University Nijmegen7, University of South Carolina8, University of Pittsburgh9, Northeastern University10, Harvard University11, University of Utah12
TL;DR: This work represents a multi‐institutional collaborative effort to develop a comprehensive, open source pipeline for DBS imaging and connectomics, which has already empowered several studies, and may facilitate a variety of future studies in the field.
F. Kyle Satterstrom1, Jack A. Kosmicki1, Jiebiao Wang2, Michael S. Breen3 +150 more•Institutions (45)
TL;DR: Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, 102 risk genes are identified at a false discovery rate of ≤ 0.1, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.
Abstract: We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.
TL;DR: While the prevalence of spinal pathologies is not known, the rate of elective lumbar fusion surgery in the United States increased most for spondylolisthesis and scoliosis, indications with relatively good evidence of effectiveness.
Abstract: Study Design.Analysis of National Inpatient Sample (NIS), 2004 to 2015.Objective.Describe recent trends in US rates of lumbar fusion procedures and associated costs, by surgical indication.Summary of Background Data.Spinal fusion is appropriate for spinal deformity and instability, but evidence of e
TL;DR: The definition of bronchopulmonary dysplasia that best predicted early childhood morbidity categorized disease severity according to the mode of respiratory support administered at 36 weeks’ postmenstrual age, regardless of supplemental oxygen use.
Abstract: Rationale: Current diagnostic criteria for bronchopulmonary dysplasia rely heavily on the level and duration of oxygen therapy, do not reflect contemporary neonatal care, and do not adequately pred...
University of California, San Diego1, McGill University2, Oregon Health & Science University3, Florida International University4, Yale University5, Washington University in St. Louis6, Virginia Commonwealth University7, University of Vermont8, University of Michigan9, Medical University of South Carolina10, National Institutes of Health11, SRI International12, University of Southern California13, McGovern Institute for Brain Research14, Harvard University15, Medical College of Wisconsin16, University of California, Irvine17, University of California, Los Angeles18, University of California, San Francisco19, University of Colorado Boulder20, University of Florida21, University of Maryland, Baltimore22, University of Massachusetts Boston23, University of Minnesota24, University of Pittsburgh25, University of Rochester26, University of Tennessee27, University of Utah28, University of Wisconsin–Milwaukee29, United States Department of Veterans Affairs30, Boston University31
TL;DR: The baseline neuroimaging processing and subject-level analysis methods used by the Adolescent Brain Cognitive Development Study are described to be a resource of unprecedented scale and depth for studying typical and atypical development.
TL;DR: Targeted inhibition of RAF–MEK–ERK signaling induces autophagy through the LKB1–AMPK axis, creating a therapeutic vulnerability that can be exploited for treating patients with pancreatic cancer and potentially other RAS-mutant tumors.
Abstract: Pancreatic ductal adenocarcinoma (PDA) was responsible for ~ 44,000 deaths in the United States in 2018 and is the epitome of a recalcitrant cancer driven by a pharmacologically intractable oncoprotein, KRAS1–4. Downstream of KRAS, the RAF→MEK→ERK signaling pathway plays a central role in pancreatic carcinogenesis5. However, paradoxically, inhibition of this pathway has provided no clinical benefit to patients with PDA6. Here we show that inhibition of KRAS→RAF→MEK→ERK signaling elicits autophagy, a process of cellular recycling that protects PDA cells from the cytotoxic effects of KRAS pathway inhibition. Mechanistically, inhibition of MEK1/2 leads to activation of the LKB1→AMPK→ULK1 signaling axis, a key regulator of autophagy. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic anti-proliferative effects against PDA cell lines in vitro and promotes regression of xenografted patient-derived PDA tumors in mice. The observed effect of combination trametinib plus chloroquine was not restricted to PDA as other tumors, including patient-derived xenografts (PDX) of NRAS-mutated melanoma and BRAF-mutated colorectal cancer displayed similar responses. Finally, treatment of a patient with PDA with the combination of trametinib plus hydroxychloroquine resulted in a partial, but nonetheless striking disease response. These data suggest that this combination therapy may represent a novel strategy to target RAS-driven cancers. Targeted inhibition of RAF–MEK–ERK signaling induces autophagy through the LKB1–AMPK axis, creating a therapeutic vulnerability that can be exploited for treating patients with pancreatic cancer and potentially other RAS-mutant tumors.
TL;DR: An update of the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk calculator and compares it with recently published European Society of Cardiology/Respiratory Society guideline-derived risk assessment strategies, showing greater risk discrimination than the COMPERA and FPHR risk Assessment strategies in patients enrolled in REVEAL.
TL;DR: This manuscript compares simulations using polarizable and nonpolarizable models for several classes of ionic systems, discussing the underlying physics that each approach includes or ignores, implications for implementation and computational efficiency, and the accuracy of properties predicted by these methods compared to experiments.
Abstract: Many applications in chemistry, biology, and energy storage/conversion research rely on molecular simulations to provide fundamental insight into structural and transport properties of materials with high ionic concentrations. Whether the system is comprised entirely of ions, like ionic liquids, or is a mixture of a polar solvent with a salt, e.g., liquid electrolytes for battery applications, the presence of ions in these materials results in strong local electric fields polarizing solvent molecules and large ions. To predict properties of such systems from molecular simulations often requires either explicit or mean-field inclusion of the influence of polarization on electrostatic interactions. In this manuscript, we review the pros and cons of different treatments of polarization ranging from the mean-field approaches to the most popular explicit polarization models in molecular dynamics simulations of ionic materials. For each method, we discuss their advantages and disadvantages and emphasize key assumptions as well as their adjustable parameters. Strategies for the development of polarizable models are presented with a specific focus on extracting atomic polarizabilities. Finally, we compare simulations using polarizable and nonpolarizable models for several classes of ionic systems, discussing the underlying physics that each approach includes or ignores, implications for implementation and computational efficiency, and the accuracy of properties predicted by these methods compared to experiments.
University of Michigan1, Ohio State University2, Brigham and Women's Hospital3, Memorial Sloan Kettering Cancer Center4, University of Colorado Boulder5, University of Utah6, Northwestern University7, Harvard University8, Johns Hopkins University9, University of Alabama at Birmingham10, University of Nebraska Medical Center11, Vanderbilt University12, University of Wisconsin-Madison13, University of California, San Diego14, Yale University15, Roswell Park Cancer Institute16, Stanford University17, University of Tennessee18, Case Western Reserve University19, Seattle Cancer Care Alliance20, University of Texas MD Anderson Cancer Center21, National Comprehensive Cancer Network22
TL;DR: The panel for the Distress Management Guidelines recently added a new principles section including guidance on implementation of standards of psychosocial care for patients with cancer.
Abstract: Distress is defined in the NCCN Guidelines for Distress Management as a multifactorial, unpleasant experience of a psychologic (ie, cognitive, behavioral, emotional), social, spiritual, and/or physical nature that may interfere with the ability to cope effectively with cancer, its physical symptoms, and its treatment. Early evaluation and screening for distress leads to early and timely management of psychologic distress, which in turn improves medical management. The panel for the Distress Management Guidelines recently added a new principles section including guidance on implementation of standards of psychosocial care for patients with cancer.
University of Barcelona1, Erasmus University Rotterdam2, Oslo University Hospital3, Université catholique de Louvain4, Cliniques Universitaires Saint-Luc5, Mayo Clinic6, French Institute of Health and Medical Research7, University of Limoges8, Synlab Group9, University of Cincinnati Academic Health Center10, Cincinnati Children's Hospital Medical Center11, Charité12, Leipzig University13, University of Utah14, Medical University of Warsaw15, St George's Hospital16, Kyushu University17, Christian Medical College & Hospital18, Leiden University Medical Center19, Erasmus University Medical Center20, Heidelberg University21, University of Colorado Denver22
TL;DR: It is concluded that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade, and the Expert Committee concludes that Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacolimus therapy and to improve long-term outcomes for treated patients.
Abstract: Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus pharmacokinetics (PK), pharmacogenetics (PG), pharmacodynamics, and immunologic biomarkers, with the aim to provide analytical and drug-exposure recommendations to assist TDM professionals and clinicians to individualize tacrolimus TDM and treatment. The consensus is based on in-depth literature searches regarding each topic that is addressed in this document. Thirty-seven international experts in the field of TDM of tacrolimus as well as its PG and biomarkers contributed to the drafting of sections most relevant for their expertise. Whenever applicable, the quality of evidence and the strength of recommendations were graded according to a published grading guide. After iterated editing, the final version of the complete document was approved by all authors. For each category of solid organ and stem cell transplantation, the current state of PK monitoring is discussed and the specific targets of tacrolimus trough concentrations (predose sample C0) are presented for subgroups of patients along with the grading of these recommendations. In addition, tacrolimus area under the concentration-time curve determination is proposed as the best TDM option early after transplantation, at the time of immunosuppression minimization, for special populations, and specific clinical situations. For indications other than transplantation, the potentially effective tacrolimus concentrations in systemic treatment are discussed without formal grading. The importance of consistency, calibration, proficiency testing, and the requirement for standardization and need for traceability and reference materials is highlighted. The status for alternative approaches for tacrolimus TDM is presented including dried blood spots, volumetric absorptive microsampling, and the development of intracellular measurements of tacrolimus. The association between CYP3A5 genotype and tacrolimus dose requirement is consistent (Grading A I). So far, pharmacodynamic and immunologic biomarkers have not entered routine monitoring, but determination of residual nuclear factor of activated T cells-regulated gene expression supports the identification of renal transplant recipients at risk of rejection, infections, and malignancy (B II). In addition, monitoring intracellular T-cell IFN-g production can help to identify kidney and liver transplant recipients at high risk of acute rejection (B II) and select good candidates for immunosuppression minimization (B II). Although cell-free DNA seems a promising biomarker of acute donor injury and to assess the minimally effective C0 of tacrolimus, multicenter prospective interventional studies are required to better evaluate its clinical utility in solid organ transplantation. Population PK models including CYP3A5 and CYP3A4 genotypes will be considered to guide initial tacrolimus dosing. Future studies should investigate the clinical benefit of time-to-event models to better evaluate biomarkers as predictive of personal response, the risk of rejection, and graft outcome. The Expert Committee concludes that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade. Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacrolimus therapy and to improve long-term outcomes for treated patients.
Columbia University1, Harvard University2, National Taiwan University3, Johns Hopkins University School of Medicine4, Nemours Foundation5, University of Freiburg6, Children's Memorial Hospital7, University of Colorado Denver8, Royal Children's Hospital9, University of Utah10, Hacettepe University11, Hamad Medical Corporation12, University of Milan13, Kaohsiung Medical University14, University of California, Los Angeles15, Biogen Idec16
TL;DR: Interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial emphasize the importance of proactive treatment with nusineren immediately after establishing the genetic diagnosis of SMA in presymptic infants and emerging newborn screening efforts.
Jeroen R. Huyghe1, Stephanie A. Bien1, Tabitha A. Harrison1, Hyun Min Kang2 +221 more•Institutions (68)
TL;DR: Genome-wide association analyses based on whole-genome sequencing and imputation identify 40 new risk variants for colorectal cancer, including a strongly protective low-frequency variant at CHD1 and loci implicating signaling and immune function in disease etiology.
Abstract: To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
University of Pittsburgh1, Ford Motor Company2, University of Michigan3, Stanford University4, Montefiore Medical Center5, All Children's Hospital6, Johns Hopkins University School of Medicine7, Vanderbilt University8, University of Utah9, Hospital of the University of Pennsylvania10, Northwestern University11, University of Alabama at Birmingham12
TL;DR: Outcomes are presented for patients who underwent isolated continuous flow left ventricular assist device (CF LVAD) support, CF LVAD support with concomitant right ventricular Assist device (RVAD) implant, or total artificial heart implant to treat advanced heart failure.
Abstract: Background The Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs), a joint effort among the National Heart, Lung, and Blood Institute, the Food and Drug Administration, the Centers for Medicare and Medicaid Services, and others, was established in 2005 at the University of Alabama at Birmingham. The registry examined clinical outcomes and quality-of-life metrics of patients who received an Food and Drug Administration-approved durable mechanical circulatory support (MCS) device to treat advanced heart failure. On January 1, 2018, the Intermacs Database became part of The Society of Thoracic Surgeons National Database, providing additional resources for quality assessment and improvement and scientific advancement. Methods The Intermacs Database Annual Report summarizes outcomes in patients (≥19 years of age) who underwent durable MCS implant between June 23, 2006, and December 31, 2017. Outcomes are presented for patients who underwent isolated continuous flow left ventricular assist device (CF LVAD) support, CF LVAD support with concomitant right ventricular assist device (RVAD) implant, or total artificial heart implant. Analyses of patients with CF LVADs are stratified by axial flow and centrifugal flow configurations. Because of the association of era with outcomes, the survival analyses are restricted to isolated CF LVADs implanted in the 2012 to 2016 era. Results There were 25,145 adult patients with MCS reported to Intermacs, of whom 18,539 (74%) received CF LVADs, 667 (2.6%) had an RVAD with CF LVAD, 339 received a total artificial heart (1.3%), and 20 (0.07%) received an isolated RVAD. Of the CF LVADs, mean age was 57 ± 1 years, 26% were listed for transplantation, and 51% were in cardiogenic shock (profile 1 to 2) preoperatively. CF LVADs included 14,527 axial flow (78%) and 4,012 centrifugal flow (22%) devices. Intermacs patient phenotype has evolved over time to include more patients with profile 3 (26% in 2006 to 2011 versus 35% in 2012 to 2016) and fewer patients with profile 2 (40% versus 35%), patients with better markers of preoperative renal and hepatic function, and more patients who received implants for destination therapy (29% versus 48%) indication. In 2017, centrifugal flow implants (51%) approximated that of axial flow devices (49%). Mean CF LVAD support duration was 20 months (31,563 patient-years). One-year survival for isolated CF LVADs was 83% and 5-year survival was 46%. One-year survivals for centrifugal versus axial flow devices were 85% and 84%, respectively. Patients who required concomitant RVAD support had 1- and 5-year survivals of 58% and 28%, respectively. Freedom from all-cause readmission was 70% at 1 month and 20% at 1 year. At 1 year, stroke occurred in 20% of patients on centrifugal flow and 13% of patients on axial flow support (p Conclusions With the evolution of MCS, patient phenotype and outcomes are also changing over time. CF LVAD support is increasingly being used in the less ill patient phenotype and more patients are supported for destination therapy. Mean survival is now approaching 5 years, but adverse events, especially neurologic events, continue to have a detrimental impact on the success of CF LVAD support.
TL;DR: The similar magnitude and acceleration of ice loss across the Himalayas suggests a regionally coherent climate forcing, consistent with atmospheric warming and associated energy fluxes as the dominant drivers of glacier change.
Abstract: Himalayan glaciers supply meltwater to densely populated catchments in South Asia, and regional observations of glacier change over multiple decades are needed to understand climate drivers and assess resulting impacts on glacier-fed rivers. Here, we quantify changes in ice thickness during the intervals 1975–2000 and 2000–2016 across the Himalayas, using a set of digital elevation models derived from cold war–era spy satellite film and modern stereo satellite imagery. We observe consistent ice loss along the entire 2000-km transect for both intervals and find a doubling of the average loss rate during 2000–2016 [−0.43 ± 0.14 m w.e. year−1 (meters of water equivalent per year)] compared to 1975–2000 (−0.22 ± 0.13 m w.e. year−1). The similar magnitude and acceleration of ice loss across the Himalayas suggests a regionally coherent climate forcing, consistent with atmospheric warming and associated energy fluxes as the dominant drivers of glacier change.
University of Alabama at Birmingham1, McMaster University2, University of Pennsylvania3, Toronto Western Hospital4, Cleveland Clinic5, Oregon Health & Science University6, Boston Medical Center7, Stanford University8, University of Washington9, Brigham and Women's Hospital10, University of Rochester Medical Center11, University of Maryland, Baltimore12, Florida State University13, Eastern Virginia Medical School14, American College of Rheumatology15, ECRI Institute16, University of Oxford17, New York Medical College18, Case Western Reserve University19, Johns Hopkins University20, New York University21, University of Utah22
TL;DR: The 2018 ACR/NPF guideline as mentioned in this paper provides evidence-based guidelines for the pharmacologic and non-pharmacologic treatment of psoriatic arthritis (PsA) using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology.
Abstract: Objective To develop an evidence-based guideline for the pharmacologic and nonpharmacologic treatment of psoriatic arthritis (PsA), as a collaboration between the American College of Rheumatology (ACR) and the National Psoriasis Foundation (NPF). Methods We identified critical outcomes in PsA and clinically relevant PICO (population/intervention/comparator/outcomes) questions. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available pharmacologic and nonpharmacologic therapies for PsA. GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to rate the quality of the evidence. A voting panel, including rheumatologists, dermatologists, other health professionals, and patients, achieved consensus on the direction and the strength of the recommendations. Results The guideline covers the management of active PsA in patients who are treatment-naive and those who continue to have active PsA despite treatment, and addresses the use of oral small molecules, tumor necrosis factor inhibitors, interleukin-12/23 inhibitors (IL-12/23i), IL-17 inhibitors, CTLA4-Ig (abatacept), and a JAK inhibitor (tofacitinib). We also developed recommendations for psoriatic spondylitis, predominant enthesitis, and treatment in the presence of concomitant inflammatory bowel disease, diabetes, or serious infections. We formulated recommendations for a treat-to-target strategy, vaccinations, and nonpharmacologic therapies. Six percent of the recommendations were strong and 94% conditional, indicating the importance of active discussion between the health care provider and the patient to choose the optimal treatment. Conclusion The 2018 ACR/NPF PsA guideline serves as a tool for health care providers and patients in the selection of appropriate therapy in common clinical scenarios. Best treatment decisions consider each individual patient situation. The guideline is not meant to be proscriptive and should not be used to limit treatment options for patients with PsA.