Showing papers by "University of Colorado Denver published in 2019"
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Ljubljana University Medical Centre1, King's College London2, Vita-Salute San Raffaele University3, Stanford University4, American Diabetes Association5, University of Padua6, Harvard University7, University of Amsterdam8, University of Sydney9, University of Colorado Denver10, University of Sheffield11, University of Washington12, University of Cambridge13, Shanghai Jiao Tong University14, University of Virginia15, JDRF16, Katholieke Universiteit Leuven17, University of East Anglia18, San Antonio River Authority19, Steno Diabetes Center20, University of Montpellier21, University of Florida22, Nihon University23, Yale University24, Tel Aviv University25
TL;DR: This article summarizes the ATTD consensus recommendations for relevant aspects of CGM data utilization and reporting among the various diabetes populations.
Abstract: Improvements in sensor accuracy, greater convenience and ease of use, and expanding reimbursement have led to growing adoption of continuous glucose monitoring (CGM). However, successful utilization of CGM technology in routine clinical practice remains relatively low. This may be due in part to the lack of clear and agreed-upon glycemic targets that both diabetes teams and people with diabetes can work toward. Although unified recommendations for use of key CGM metrics have been established in three separate peer-reviewed articles, formal adoption by diabetes professional organizations and guidance in the practical application of these metrics in clinical practice have been lacking. In February 2019, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address this issue. This article summarizes the ATTD consensus recommendations for relevant aspects of CGM data utilization and reporting among the various diabetes populations.
1,776 citations
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University of Texas MD Anderson Cancer Center1, Johns Hopkins University2, City of Hope National Medical Center3, University of California, Davis4, Emory University5, Fred Hutchinson Cancer Research Center6, University of Washington7, Northwestern University8, Monash University9, AbbVie10, Genentech11, University of Colorado Denver12, Harvard University13
TL;DR: The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML and achieved complete remission (CR) + CR with incomplete count recovery (CRi).
1,153 citations
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TL;DR: Data from the T1D Exchange registry demonstrate that only a minority of adults and youth with type 1 diabetes in the United States achieve ADA goals for HbA1c, and racial differences were evident in use of pumps and CGM and Hb a1c levels.
Abstract: Objective To provide a snapshot of the profile of adults and youth with type 1 diabetes (T1D) in the United States and assessment of longitudinal changes in T1D management and clinical outcomes in the T1D Exchange registry. Research design and methods Data on diabetes management and outcomes from 22,697 registry participants (age 1-93 years) were collected between 2016 and 2018 and compared with data collected in 2010-2012 for 25,529 registry participants. Results Mean HbA1c in 2016-2018 increased from 65 mmol/mol at the age of 5 years to 78 mmol/mol between ages 15 and 18, with a decrease to 64 mmol/mol by age 28 and 58-63 mmol/mol beyond age 30. The American Diabetes Association (ADA) HbA1c goal of 10-fold in children Conclusions Data from the T1D Exchange registry demonstrate that only a minority of adults and youth with T1D in the United States achieve ADA goals for HbA1c.
1,082 citations
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TL;DR: This siteless study design provides a foundation for large-scale pragmatic studies in which outcomes or adherence can be reliably assessed with user-owned devices and the probability of receiving an irregular pulse notification was low.
Abstract: Background Optical sensors on wearable devices can detect irregular pulses. The ability of a smartwatch application (app) to identify atrial fibrillation during typical use is unknown. Met...
928 citations
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TL;DR: In patients with oligometastatic NSCLC that did not progress after front-line systemic therapy, LCT prolonged PFS and OS relative to MT/O, and the longer-term overall survival (OS) results accompanied by additional secondary end points are presented.
Abstract: PURPOSEOur previously published findings reported that local consolidative therapy (LCT) with radiotherapy or surgery improved progression-free survival (PFS) and delayed new disease in patients wi...
760 citations
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TL;DR: Recent findings in pathology and cellular mechanisms contributing to the onset and progression of pulmonary vascular remodelling associated with various forms of pulmonary hypertension are reviewed and ways to improve management and to support and optimise drug development are discussed.
Abstract: Clinical and translational research has played a major role in advancing our understanding of pulmonary hypertension (PH), including pulmonary arterial hypertension and other forms of PH with severe vascular remodelling (e.g. chronic thromboembolic PH and pulmonary veno-occlusive disease). However, PH remains an incurable condition with a high mortality rate, underscoring the need for a better transfer of novel scientific knowledge into healthcare interventions. Herein, we review recent findings in pathology (with the questioning of the strict morphological categorisation of various forms of PH into pre- or post-capillary involvement of pulmonary vessels) and cellular mechanisms contributing to the onset and progression of pulmonary vascular remodelling associated with various forms of PH. We also discuss ways to improve management and to support and optimise drug development in this research field.
702 citations
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Daniel Taliun1, Daniel N. Harris2, Michael D. Kessler2, Jedidiah Carlson3 +191 more•Institutions (61)
TL;DR: The nearly complete catalog of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and non-coding sequence variants to phenotypic variation as well as resources and early insights from the sequence data.
Abstract: Summary paragraph The Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, >400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the >400 million variants detected, 97% have frequency
662 citations
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Brigham and Women's Hospital1, Barts Health NHS Trust2, Hospital for Special Surgery3, Cornell University4, University of Rochester Medical Center5, University of Alabama at Birmingham6, University of Massachusetts Medical School7, Broad Institute8, University of California, San Diego9, Northwestern University10, The Feinstein Institute for Medical Research11, University of Pittsburgh12, Queen Mary University of London13, University Hospitals Birmingham NHS Foundation Trust14, University of Colorado Denver15
TL;DR: Several single-cell -omics approaches are used to define the cellular processes and pathways in the human RA joint and attributed IL6 expression to THY1+HLA-DRAhi fibroblasts and IL1B production to pro-inflammatory monocytes, potentially key mediators of RA pathogenesis.
Abstract: To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)+HLA-DRAhi sublining fibroblasts, IL1B+ pro-inflammatory monocytes, ITGAX+TBX21+ autoimmune-associated B cells and PDCD1+ peripheral helper T (TPH) cells and follicular helper T (TFH) cells. We defined distinct subsets of CD8+ T cells characterized by GZMK+, GZMB+, and GNLY+ phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1+HLA-DRAhi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.
649 citations
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University of Texas Southwestern Medical Center1, Queen's University2, Laval University3, Osaka University4, Ben-Gurion University of the Negev5, VU University Amsterdam6, University of Milan7, University of São Paulo8, Harvard University9, University of Surrey10, University of Padua11, University of New South Wales12, University of Colorado Denver13
TL;DR: The evidence for visceral adiposity and ectopic fat as emerging risk factors for type 2 diabetes, atherosclerosis, and cardiovascular disease, with a focus on practical recommendations for health professionals and future directions for research and clinical practice is summarised.
553 citations
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539 citations
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TL;DR: The varied roles of IL-1 family members in immune homeostasis and their contribution to pathologies, including autoimmunity and auto-inflammation, dysmetabolism, cardiovascular disorders, and cancer are discussed.
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TL;DR: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, it is found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in Patients with HFr EF.
Abstract: Background: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the compo...
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National Institute for Occupational Safety and Health1, New York University2, Veterans Health Administration3, University of Colorado Denver4, University of Massachusetts Amherst5, University of Florida6, Johns Hopkins University7, Cornell University8, George Washington University9, Saint Louis University10, Boston Children's Hospital11, Baylor College of Medicine12, Denver Health Medical Center13, University of Texas Southwestern Medical Center14
TL;DR: Among outpatient health care personnel, N95 respirators vs medical masks as worn by participants in this trial resulted in no significant difference in the incidence of laboratory-confirmed influenza.
Abstract: Importance Clinical studies have been inconclusive about the effectiveness of N95 respirators and medical masks in preventing health care personnel (HCP) from acquiring workplace viral respiratory infections. Objective To compare the effect of N95 respirators vs medical masks for prevention of influenza and other viral respiratory infections among HCP. Design, Setting, and Participants A cluster randomized pragmatic effectiveness study conducted at 137 outpatient study sites at 7 US medical centers between September 2011 and May 2015, with final follow-up in June 2016. Each year for 4 years, during the 12-week period of peak viral respiratory illness, pairs of outpatient sites (clusters) within each center were matched and randomly assigned to the N95 respirator or medical mask groups. Interventions Overall, 1993 participants in 189 clusters were randomly assigned to wear N95 respirators (2512 HCP-seasons of observation) and 2058 in 191 clusters were randomly assigned to wear medical masks (2668 HCP-seasons) when near patients with respiratory illness. Main Outcomes and Measures The primary outcome was the incidence of laboratory-confirmed influenza. Secondary outcomes included incidence of acute respiratory illness, laboratory-detected respiratory infections, laboratory-confirmed respiratory illness, and influenzalike illness. Adherence to interventions was assessed. Results Among 2862 randomized participants (mean [SD] age, 43 [11.5] years; 2369 [82.8%]) women), 2371 completed the study and accounted for 5180 HCP-seasons. There were 207 laboratory-confirmed influenza infection events (8.2% of HCP-seasons) in the N95 respirator group and 193 (7.2% of HCP-seasons) in the medical mask group (difference, 1.0%, [95% CI, −0.5% to 2.5%];P = .18) (adjusted odds ratio [OR], 1.18 [95% CI, 0.95-1.45]). There were 1556 acute respiratory illness events in the respirator group vs 1711 in the mask group (difference, −21.9 per 1000 HCP-seasons [95% CI, −48.2 to 4.4];P = .10); 679 laboratory-detected respiratory infections in the respirator group vs 745 in the mask group (difference, −8.9 per 1000 HCP-seasons, [95% CI, −33.3 to 15.4];P = .47); 371 laboratory-confirmed respiratory illness events in the respirator group vs 417 in the mask group (difference, −8.6 per 1000 HCP-seasons [95% CI, −28.2 to 10.9];P = .39); and 128 influenzalike illness events in the respirator group vs 166 in the mask group (difference, −11.3 per 1000 HCP-seasons [95% CI, −23.8 to 1.3];P = .08). In the respirator group, 89.4% of participants reported “always” or “sometimes” wearing their assigned devices vs 90.2% in the mask group. Conclusions and Relevance Among outpatient health care personnel, N95 respirators vs medical masks as worn by participants in this trial resulted in no significant difference in the incidence of laboratory-confirmed influenza. Trial Registration ClinicalTrials.gov Identifier:NCT01249625
01 Feb 2019
TL;DR: In the T1D Exchange Registry, a snapshot of the profile of adults and youth with Type 1 diabetes (T1D) in the United States and assessment of longitudinal changes in management and clinical outcomes was provided as discussed by the authors.
Abstract: Objective To provide a snapshot of the profile of adults and youth with type 1 diabetes (T1D) in the United States and assessment of longitudinal changes in T1D management and clinical outcomes in the T1D Exchange registry. Research design and methods Data on diabetes management and outcomes from 22,697 registry participants (age 1-93 years) were collected between 2016 and 2018 and compared with data collected in 2010-2012 for 25,529 registry participants. Results Mean HbA1c in 2016-2018 increased from 65 mmol/mol at the age of 5 years to 78 mmol/mol between ages 15 and 18, with a decrease to 64 mmol/mol by age 28 and 58-63 mmol/mol beyond age 30. The American Diabetes Association (ADA) HbA1c goal of 10-fold in children Conclusions Data from the T1D Exchange registry demonstrate that only a minority of adults and youth with T1D in the United States achieve ADA goals for HbA1c.
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Tufts University1, Harvard University2, National Institutes of Health3, Maine Medical Center4, HealthPartners5, Duke University6, University of Nebraska Medical Center7, Baylor College of Medicine8, Memorial Hospital of South Bend9, Pennington Biomedical Research Center10, University of Tennessee Health Science Center11, Cleveland Clinic12, Stanford University13, Kaiser Permanente14, University of Vermont15, Lenox Hill Hospital16, Medical University of South Carolina17, Emory University18, University of Southern California19, United States Department of Veterans Affairs20, Translational Research Institute21, University of Colorado Denver22, University of Kansas23
TL;DR: Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo.
Abstract: Background Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the...
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TL;DR: There is now overwhelming evidence to support lowering LDL-c (low-density lipoprotein cholesterol) to reduce cardiovascular morbidity and mortality and an urgent need to identify those at increased risk of developing side effects as well as provide alternative treatment strategies.
Abstract: There is now overwhelming evidence to support lowering LDL-c (low-density lipoprotein cholesterol) to reduce cardiovascular morbidity and mortality. Statins are a class of drugs frequently prescribed to lower cholesterol. However, in spite of their wide-spread use, discontinuation and nonadherence remains a major gap in both the primary and secondary prevention of atherosclerotic cardiovascular disease. The major reason for statin discontinuation is because of the development of statin-associated muscle symptoms, but a range of other statin-induced side effects also exist. Although the mechanisms behind these side effects have not been fully elucidated, there is an urgent need to identify those at increased risk of developing side effects as well as provide alternative treatment strategies. In this article, we review the mechanisms and clinical importance of statin toxicity and focus on the evaluation and management of statin-associated muscle symptoms.
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TL;DR: Glasdegib plus LDAC has a favorable benefit–risk profile and may be a promising option for AML patients unsuitable for intensive chemotherapy and clinical efficacy was evident across patients with diverse mutational profiles.
Abstract: Glasdegib is a Hedgehog pathway inhibitor. This phase II, randomized, open-label, multicenter study (ClinicalTrials.gov, NCT01546038) evaluated the efficacy of glasdegib plus low-dose cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome unsuitable for intensive chemotherapy. Glasdegib 100 mg (oral, QD) was administered continuously in 28-day cycles; LDAC 20 mg (subcutaneous, BID) was administered for 10 per 28 days. Patients (stratified by cytogenetic risk) were randomized (2:1) to receive glasdegib/LDAC or LDAC. The primary endpoint was overall survival. Eighty-eight and 44 patients were randomized to glasdegib/LDAC and LDAC, respectively. Median (80% confidence interval [CI]) overall survival was 8.8 (6.9–9.9) months with glasdegib/LDAC and 4.9 (3.5–6.0) months with LDAC (hazard ratio, 0.51; 80% CI, 0.39–0.67, P = 0.0004). Fifteen (17.0%) and 1 (2.3%) patients in the glasdegib/LDAC and LDAC arms, respectively, achieved complete remission (P < 0.05). Nonhematologic grade 3/4 all-causality adverse events included pneumonia (16.7%) and fatigue (14.3%) with glasdegib/LDAC and pneumonia (14.6%) with LDAC. Clinical efficacy was evident across patients with diverse mutational profiles. Glasdegib plus LDAC has a favorable benefit–risk profile and may be a promising option for AML patients unsuitable for intensive chemotherapy.
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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, Cincinnati Children's Hospital Medical Center10, University of Cincinnati Academic Health 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.
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Hartford Hospital1, University of Michigan2, Nanjing Medical University3, Duke University4, Beth Israel Deaconess Medical Center5, University of Pennsylvania6, Cleveland Clinic7, Washington University in St. Louis8, Northwestern University9, Vita-Salute San Raffaele University10, University of Maryland, Baltimore11, University of Queensland12, University of Alabama at Birmingham13, Indiana University14, University of Tsukuba15, University of California, San Francisco16, Australian National University17, Queen Elizabeth II Health Sciences Centre18, University of Antwerp19, Kyorin University20, Vanderbilt University21, Brigham and Women's Hospital22, University of Colorado Denver23, Leiden University Medical Center24
TL;DR: This document is to help electrophysiologists around the world to appropriately select patients for catheter ablation, to perform procedures in a safe and efficacious manner, and to provide follow-up and adjunctive care in order to obtain the best possible outcomes for patients with ventricular arrhythmias.
Abstract: Ventricular arrhythmias are an important cause of morbidity and mortality and come in a variety of forms, from single premature ventricular complexes to sustained ventricular tachycardia and fibrillation. Rapid developments have taken place over the past decade in our understanding of these arrhythmias and in our ability to diagnose and treat them. The field of catheter ablation has progressed with the development of new methods and tools, and with the publication of large clinical trials. Therefore, global cardiac electrophysiology professional societies undertook to outline recommendations and best practices for these procedures in a document that will update and replace the 2009 EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias. An expert writing group, after reviewing and discussing the literature, including a systematic review and meta-analysis published in conjunction with this document, and drawing on their own experience, drafted and voted on recommendations and summarized current knowledge and practice in the field. Each recommendation is presented in knowledge byte format and is accompanied by supportive text and references. Further sections provide a practical synopsis of the various techniques and of the specific ventricular arrhythmia sites and substrates encountered in the electrophysiology lab. The purpose of this document is to help electrophysiologists around the world to appropriately select patients for catheter ablation, to perform procedures in a safe and efficacious manner, and to provide follow-up and adjunctive care in order to obtain the best possible outcomes for patients with ventricular arrhythmias.
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TL;DR: Fluid resuscitation therapy is an essential part of sepsis treatment, but overaggressive fluid therapy practices (leading to hypervolemia) may augment glycocalyx degradation, and fresh frozen plasma and albumin administration may attenuate glycocalyX degradation.
Abstract: The glycocalyx is a gel-like layer covering the luminal surface of vascular endothelial cells. It is comprised of membrane-attached proteoglycans, glycosaminoglycan chains, glycoproteins, and adherent plasma proteins. The glycocalyx maintains homeostasis of the vasculature, including controlling vascular permeability and microvascular tone, preventing microvascular thrombosis, and regulating leukocyte adhesion. During sepsis, the glycocalyx is degraded via inflammatory mechanisms such as metalloproteinases, heparanase, and hyaluronidase. These sheddases are activated by reactive oxygen species and pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-1beta. Inflammation-mediated glycocalyx degradation leads to vascular hyper-permeability, unregulated vasodilation, microvessel thrombosis, and augmented leukocyte adhesion. Clinical studies have demonstrated the correlation between blood levels of glycocalyx components with organ dysfunction, severity, and mortality in sepsis. Fluid resuscitation therapy is an essential part of sepsis treatment, but overaggressive fluid therapy practices (leading to hypervolemia) may augment glycocalyx degradation. Conversely, fresh frozen plasma and albumin administration may attenuate glycocalyx degradation. The beneficial and harmful effects of fluid and plasma infusion on glycocalyx integrity in sepsis are not well understood; future studies are warranted. In this review, we first analyze the underlying mechanisms of glycocalyx degradation in sepsis. Second, we demonstrate how the blood and urine levels of glycocalyx components are associated with patient outcomes. Third, we show beneficial and harmful effects of fluid therapy on the glycocalyx status during sepsis. Finally, we address the concept of glycocalyx degradation as a therapeutic target.
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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.
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TL;DR: B7-H3 CAR T-cell efficacy is largely dependent upon high surface target antigen density on tumor tissues and that activity is greatly diminished against target cells that express low levels of antigen, thus providing a possible therapeutic window despite low-level normal tissue expression of B7- H3.
Abstract: Purpose: Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T cell therapy of pediatric solid tumors, including those arising in the central nervous system.
Experimental Design: We developed a novel B7-H3 CAR whose binder is derived from a monoclonal antibody that has been shown to preferentially bind tumor tissues and has been safely used in humans in early phase clinical trials. We tested B7-H3 CAR T cells in a variety of pediatric cancer models.
Results: B7-H3 CAR T cells mediate significant anti-tumor activity in vivo, causing regression of established solid tumors in xenograft models including osteosarcoma, medulloblastoma, and Ewing sarcoma. We demonstrate that B7-H3 CAR T cell efficacy is largely dependent upon high surface target antigen density on tumor tissues and that activity is greatly diminished against target cells that express low levels of antigen, thus providing a possible therapeutic window despite low-level normal tissue expression of B7-H3.
Conclusions: B7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies which should be tested in carefully designed clinical trials.
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University of Pittsburgh1, University of Florida2, Nationwide Children's Hospital3, New York University4, Johns Hopkins University5, University of Washington6, ImmunoGen, Inc.7, Baylor College of Medicine8, University of Colorado Denver9, Fred Hutchinson Cancer Research Center10, Princess Margaret Cancer Centre11, Shaare Zedek Medical Center12, University of Pennsylvania13, Mayo Clinic14, Memorial Sloan Kettering Cancer Center15, Yeshiva University16, University of Birmingham17, Ohio State University18, University of Chicago19, University of Texas MD Anderson Cancer Center20, University of California, San Francisco21
TL;DR: Analysis of 1,988 cases of B-cell acute lymphoblastic leukemia characterizes 23 subtypes defined by genomic features and shows that two of the subtypes have frequent PAX5 alterations, demonstrating the utility of transcriptome sequencing to classify B-ALL.
Abstract: Recent genomic studies have identified chromosomal rearrangements defining new subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL), however many cases lack a known initiating genetic alteration. Using integrated genomic analysis of 1,988 childhood and adult cases, we describe a revised taxonomy of B-ALL incorporating 23 subtypes defined by chromosomal rearrangements, sequence mutations or heterogeneous genomic alterations, many of which show marked variation in prevalence according to age. Two subtypes have frequent alterations of the B lymphoid transcription-factor gene PAX5. One, PAX5alt (7.4%), has diverse PAX5 alterations (rearrangements, intragenic amplifications or mutations); a second subtype is defined by PAX5 p.Pro80Arg and biallelic PAX5 alterations. We show that p.Pro80Arg impairs B lymphoid development and promotes the development of B-ALL with biallelic Pax5 alteration in vivo. These results demonstrate the utility of transcriptome sequencing to classify B-ALL and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis.
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TL;DR: It is found that progenitor-like CD8+ T cells became distinct from memory precursor cells before the peak of the T cell response and the transcription factor TOX was identified as essential to endow ‘stemness’ and long-term persistence in the face of chronic infection.
Abstract: Progenitor-like CD8+ T cells mediate long-term immunity to chronic infection and cancer and respond potently to immune checkpoint blockade. These cells share transcriptional regulators with memory precursor cells, including T cell-specific transcription factor 1 (TCF1), but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. By comparing the single-cell transcriptomes and epigenetic profiles of CD8+ T cells responding to acute and chronic viral infections, we found that progenitor-like CD8+ T cells became distinct from memory precursor cells before the peak of the T cell response. We discovered a coexpression gene module containing Tox that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursor cells. Moreover, thymocyte selection-associated high mobility group box protein TOX (TOX) promoted the persistence of antiviral CD8+ T cells and was required for the programming of progenitor-like CD8+ T cells. Thus, long-term CD8+ T cell immunity to chronic viral infection requires unique transcriptional and epigenetic programs associated with the transcription factor TOX.
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TL;DR: Replicating aspects of endocrine cell clustering permits the generation of stem-cell-derived β cells that resemble their endogenous counterparts, including robust dynamic insulin secretion and mitochondrial oxidative respiration.
Abstract: Despite advances in the differentiation of insulin-producing cells from human embryonic stem cells, the generation of mature functional β cells in vitro has remained elusive. To accomplish this goal, we have developed cell culture conditions to closely mimic events occurring during pancreatic islet organogenesis and β cell maturation. In particular, we have focused on recapitulating endocrine cell clustering by isolating and reaggregating immature β-like cells to form islet-sized enriched β-clusters (eBCs). eBCs display physiological properties analogous to primary human β cells, including robust dynamic insulin secretion, increased calcium signalling in response to secretagogues, and improved mitochondrial energization. Notably, endocrine cell clustering induces metabolic maturation by driving mitochondrial oxidative respiration, a process central to stimulus–secretion coupling in mature β cells. eBCs display glucose-stimulated insulin secretion as early as three days after transplantation in mice. In summary, replicating aspects of endocrine cell clustering permits the generation of stem-cell-derived β cells that resemble their endogenous counterparts. Nair et al. report the generation of human ESC-derived mature and functional β cells in vitro with a culture system including a step to induce clustering of immature β-like cells.
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University of Colorado Denver1, Gdańsk Medical University2, University of Lausanne3, The Chinese University of Hong Kong4, Hoffmann-La Roche5, University of Michigan6, University of Toronto7, Royal North Shore Hospital8, European Institute of Oncology9, University of Grenoble10, Harvard University11
TL;DR: Retrospective analyses suggest that the echinoderm microtubule-associated protein-like 4 gene-ALK variant (EML4-ALK) may influence ALK-inhibitor treatment benefit, and alectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALk-positive NSCLC, irrespective of EML4-alk variant.
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TL;DR: This research paper uses a quasi-natural experiment in the Denver, Colorado, region to analyze basic impacts of ride-hailing on transportation efficiency in terms of deadheading, vehicle occupancy, mode replacement, and vehicle miles traveled (VMT).
Abstract: Ride-haling such as Uber and Lyft are changing the ways people travel Despite widespread claims that these services help reduce driving, there is little research on this topic This research paper uses a quasi-natural experiment in the Denver, Colorado, region to analyze basic impacts of ride-hailing on transportation efficiency in terms of deadheading, vehicle occupancy, mode replacement, and vehicle miles traveled (VMT) Realizing the difficulty in obtaining data directly from Uber and Lyft, we designed a quasi-natural experiment—by one of the authors driving for both companies—to collect primary data This experiment uses an ethnographic and survey-based approach that allows the authors to gain access to exclusive data and real-time passenger feedback The dataset includes actual travel attributes from 416 ride-hailing rides—Lyft, UberX, LyftLine, and UberPool—and travel behavior and socio-demographics from 311 passenger surveys For this study, the conservative (lower end) percentage of deadheading miles from ride-hailing is 408% The average vehicle occupancy is 14 passengers per ride, while the distance weighted vehicle occupancy is 13 without accounting for deadheading and 08 when accounting deadheading When accounting for mode replacement and issues such as driver deadheading, we estimate that ride-hailing leads to approximately 835% more VMT than would have been driven had ride-hailing not existed Although our data collection focused on the Denver region, these results provide insight into the impacts of ride-hailing
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TL;DR: The results of this trial will provide initial evidence for the ability of a smartwatch algorithm to identify pulse irregularity and variability which may reflect previously unknown AF.
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TL;DR: A revised diagnostic algorithm provides guidelines for the diagnosis of patients with suspected pulmonary hypertension, both prior to and following referral to expert centres, and includes recommendations for expedited referral of high-risk or complicated patients and patients with confounding comorbidities.
Abstract: A revised diagnostic algorithm provides guidelines for the diagnosis of patients with suspected pulmonary hypertension, both prior to and following referral to expert centres, and includes recommendations for expedited referral of high-risk or complicated patients and patients with confounding comorbidities. New recommendations for screening high-risk groups are given, and current diagnostic tools and emerging diagnostic technologies are reviewed.
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TL;DR: The analytic performance of a laboratory-validated mNGS assay for pan-pathogen detection, to be used clinically for diagnosis of neurological infections from CSF, is demonstrated.
Abstract: Metagenomic next-generation sequencing (mNGS) for pan-pathogen detection has been successfully tested in proof-of-concept case studies in patients with acute illness of unknown etiology but to date has been largely confined to research settings. Here, we developed and validated a clinical mNGS assay for diagnosis of infectious causes of meningitis and encephalitis from cerebrospinal fluid (CSF) in a licensed microbiology laboratory. A customized bioinformatics pipeline, SURPI+, was developed to rapidly analyze mNGS data, generate an automated summary of detected pathogens, and provide a graphical user interface for evaluating and interpreting results. We established quality metrics, threshold values, and limits of detection of 0.2-313 genomic copies or colony forming units per milliliter for each representative organism type. Gross hemolysis and excess host nucleic acid reduced assay sensitivity; however, spiked phages used as internal controls were reliable indicators of sensitivity loss. Diagnostic test accuracy was evaluated by blinded mNGS testing of 95 patient samples, revealing 73% sensitivity and 99% specificity compared to original clinical test results, and 81% positive percent agreement and 99% negative percent agreement after discrepancy analysis. Subsequent mNGS challenge testing of 20 positive CSF samples prospectively collected from a cohort of pediatric patients hospitalized with meningitis, encephalitis, and/or myelitis showed 92% sensitivity and 96% specificity relative to conventional microbiological testing of CSF in identifying the causative pathogen. These results demonstrate the analytic performance of a laboratory-validated mNGS assay for pan-pathogen detection, to be used clinically for diagnosis of neurological infections from CSF.