tbuckley/cabot-search huggingface dataset:
On Mediation Models in Clinical Neurology Studies—Reply
Authors: Hee Jin Kim, Seonwoo Kim, Sang Won Seo
Journal: JAMA Neurology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Updated Analysis of the Efficacy and Safety of Tisagenlecleucel in Pediatric and Young Adult Patients with Relapsed/Refractory (r/r) Acute Lymphoblastic Leukemia
Authors: Stephan A. Grupp, Shannon L. Maude, Susana Rives, Andre Baruchel, Michael W. Boyer, Henrique Bittencourt, Peter Bader, Jochen Büchner, Theodore W. Laetsch, Heather Stefanski, Gary Douglas Myers, Muna Qayed, Michael A. Pulsipher, Barbara De Moerloose, Gregory A. Yanik, Kara L. Davis, Paul L. Martin, Eneida R. Nemecek, Christina Peters, Joerg Krueger, Adriana Balduzzi, Nicolas Boissel, Francoise Marie Mechinaud, Mimi Leung, Lamis K. Eldjerou, Lan Yi, Karen Thudium Mueller, Eric Bleickardt, Hidefumi Hiramatsu
Journal: Blood (2018)
Abstract 16492: Spatiotemporal AED Location Optimization
Authors: Timothy C Chan, Christopher L Sun, Derya Demirtas, Laurie J Morrison, Steven C Brooks
Journal: Circulation (2015)

Background: Mathematical optimization can be used to plan future AED placement to maximize out-of-hospital cardiac arrest (OHCA) coverage. Many public access AEDs are placed in locations without 24/7 access. AED coverage can be overestimated unless temporal availability is considered. Objective: To develop a new spatiotemporal AED location optimization model that accounts for both spatial and temporal information. Methods: We identified all atraumatic public-location OHCAs occurring in Toronto, Canada from Jan. 2006 – Aug. 2014. We gathered location and operating hours data for 4898 buildings that were used as potential sites for AED placement. We extended a previously published spatial optimization model, which identifies locations to place AEDs that maximize the number of historical OHCAs occurring within 100 m of an AED. The new spatiotemporal model finds AED locations that maximize the number of OHCAs occurring within 100 m of an available AED, considering when the OHCAs occurred (“actual coverage”). We then compared the spatial and spatiotemporal models on actual coverage of out-of-sample OHCAs using 10-fold cross validation. Statistical analysis was performed using McNemar’s test. Results: We identified 2440 atraumatic public-location OHCAs. AED locations chosen by the spatiotemporal model outperformed those chosen by the spatial model by 26.1% in actual coverage (p&lt;0.001). The figure shows coverage improvement at all times of day: daytime (11.2%), evening (37.4%), and night (292.3%). Equivalently, 40.2% fewer AEDs are needed when using the spatiotemporal model to reach the same level of actual coverage provided by AEDs located according to the spatial model. Conclusion: Spatiotemporal optimization can maximize actual OHCA coverage by accounting for AED availability when identifying future AED locations. The largest gains occurred during the evening and night, which is when the largest coverage losses were experienced by Toronto’s existing AEDs.
Venetoclax in Combination with Hypomethylating Agents Induces Rapid, Deep, and Durable Responses in Patients with AML Ineligible for Intensive Therapy
Authors: Daniel A Pollyea, Keith W. Pratz, Brian A. Jonas, Anthony Letai, Vinod A. Pullarkat, Andrew Wei, Marina Y. Konopleva, Christian Recher, Olga Frankfurt, David Rizzieri, Tu Xu, Monique Dail, Brenda Chyla, Jalaja Potluri, Courtney D. DiNardo
Journal: Blood (2018)
Using Whole Genome Sequencing (WGS) of 3256 Patients with Hematologic Malignancies to Determine Genome Instability
Authors: Constance Baer, Stephan Hutter, Alexander Höllein, Wencke Walter, Manja Meggendorfer, Wolfgang Kern, Claudia Haferlach, Torsten Haferlach
Journal: Blood (2018)
Inflammation and NLRP3 Inflammasome Activation Initiated in Response to Pressure Overload by Ca <sup>2+</sup> /Calmodulin-Dependent Protein Kinase II δ Signaling in Cardiomyocytes Are Essential for Adverse Cardiac Remodeling
Authors: Takeshi Suetomi, Andrew Willeford, Cameron S. Brand, Yoshitake Cho, Robert S. Ross, Shigeki Miyamoto, Joan Heller Brown
Journal: Circulation (2018)

Inflammation is associated with cardiac remodeling and heart failure, but how it is initiated in response to nonischemic interventions in the absence of cell death is not known. We tested the hypothesis that activation of Ca2+/calmodulin-dependent protein kinase II δ (CaMKIIδ) in cardiomyocytes (CMs) in response to pressure overload elicits inflammatory responses leading to adverse remodeling.Mice in which CaMKIIδ was selectively deleted from CMs (cardiac-specific knockout [CKO]) and floxed control mice were subjected to transverse aortic constriction (TAC). The effects of CM-specific CaMKIIδ deletion on inflammatory gene expression, inflammasome activation, macrophage accumulation, and fibrosis were assessed by quantitative polymerase chain reaction, histochemistry, and ventricular remodeling by echocardiography.TAC induced increases in cardiac mRNA levels for proinflammatory chemokines and cytokines in ≤3 days, and these responses were significantly blunted when CM CaMKIIδ was deleted. Apoptotic and necrotic cell death were absent at this time. CMs isolated from TAC hearts mirrored these robust increases in gene expression, which were markedly attenuated in CKO. Priming and activation of the NOD-like receptor pyrin domain-containing protein 3 inflammasome, assessed by measuring interleukin-1β and NOD-like receptor pyrin domain-containing protein 3 mRNA levels, caspase-1 activity, and interleukin-18 cleavage, were increased at day 3 after TAC in control hearts and in CMs isolated from these hearts. These responses were dependent on CaMKIIδ and associated with activation of Nuclear Factor-kappa B and reactive oxygen species. Accumulation of macrophages observed at days 7 to 14 after TAC was diminished in CKO and, by blocking Monocyte Chemotactic Protein-1 signaling, deletion of CM Monocyte Chemotactic Protein-1 or inhibition of inflammasome activation. Fibrosis was also attenuated by these interventions and in the CKO heart. Ventricular dilation and contractile dysfunction observed at day 42 after TAC were diminished in the CKO. Inhibition of CaMKII, Nuclear Factor-kappa B, inflammasome, or Monocyte Chemotactic Protein-1 signaling in the first 1 or 2 weeks after TAC decreased remodeling, but inhibition of CaMKII after 2 weeks did not.Activation of CaMKIIδ in response to pressure overload triggers inflammatory gene expression and activation of the NOD-like receptor pyrin domain-containing protein 3 inflammasome in CMs. These responses provide signals for macrophage recruitment, fibrosis, and myocardial dysfunction in the heart. Our work suggests the importance of targeting early inflammatory responses induced by CM CaMKIIδ signaling to prevent progression to heart failure.
FRI0042 Tender joints have low agreement with patient’s evaluation of spontaneous joint pain, joint swelling and ultrasound verified synovitis in patients with established rheumatoid arthritis
Authors: H.B. Hammer, J. Sexton, B. Michelsen, S. Provan, T. Uhlig, T.K. Kvien
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Tender joint count is included in the clinical composite scores (CDAI, SDAI, DAS28) which serves as a proxy for inflammatory activity. However, there may be several causes of joint tenderness, including both nociception and central sensitisation. Ultrasonography (US) is sensitive for evaluation of joint inflammation (synovitis (grey scale, GS) and vascularisation (power Doppler, PD)). <h3>Objectives</h3> In patients with rheumatoid arthritis (RA) to explore the agreement at a joint level between tenderness, spontaneous patient reported joint pain, swelling and US synovitis. <h3>Methods</h3> 174 patients with established RA (mean (SD) age 52<sup>13</sup> years, disease duration 10<sup>8</sup> years, 82% women, 79% anti-CCP positive were assessed when they initiated bDMARD treatment and after 1, 2, 3, 6 and 12 months. An experienced study nurse assessed presence/absence of joint tenderness and swelling (wrist, MCP1–5, PIP2–3, elbow, knee, ankle and MTP1–5 bilaterally). The same 32 joints were assessed by use of a manikin for Patient Reported Spontaneous Joint Pain (PRSJP) the last day as well as US (GS and PD, both scored 0–3) by an experienced sonographer (HBH). Agreement at joint level was explored between categorical variables using Cohens kappa (US scores transformed to presence (PD score 1–3/GS score 2–3) versus absence (PD score 0/GS score 0–1), and in addition agreement between presence of tenderness/swelling and the different US scores were explored. <h3>Results</h3> A total of 4091 (baseline) and 22 885 (all visits) joints were assessed. Tender joints had moderate agreement with PRSJP and swollen joints, and lower with US synovitis. Swollen joints had high agreement with US synovitis (table 1), and US synovitis was found in 75% of swollen joints. There were no differences in agreement between results at baseline and all visits, or if subgroup analyses were performed of only finger joints. A clear relationship was found between increasing GS/PD scores and percentages of joints being swollen, but this association was not found for tender joints (table 2). <h3>Conclusions</h3> Tender joints had weak agreement with presence of US synovitis, while swollen joints had strong agreement. PRSJP had moderate/weak agreement with all the other assessments. Presence of swelling was highly associated with the degree of US synovitis, while this association was not found for tenderness. Our results raise questions regarding the prominent role of tender joint count in RA clinical composite scores for disease activity. <h3>Disclosure of Interest</h3> None declared
Abstract 20282: Increased Circulating Levels of Total and Very Long-Chain Ceramides as Markers of Abnormal Lipid Metabolism and Lipotoxicity in Patients With Chronic Stable Heart Failure
Authors: Lily Y Deng, Ruiping Ji, Raymond Givens, Danielle L Templeton, Christina Wu, P. Christian Schulze
Journal: Circulation (2014)

Introduction: Heart failure (HF) is associated with myocardial and systemic metabolic derangements. Ceramides, a class of sphingolipids, have been associated with autophagy and mitochondrial dysfun...
£26m spent on private consultancy firms to aid NHS reorganisation, BMA finds
Authors: Abi Rimmer
Journal: BMJ (2018)

A BMA investigation has found that private consultancy firms have been paid hundreds of thousands, and in some cases millions, of pounds by the NHS to support the reorganisation of services.

A Freedom of Information request sent by the BMA got 30 responses from the 44 Sustainability and Transformation Partnerships (STPs) and Integrated Care Systems (ICS) that work across England. The information requested was also already available from a further nine organisations.

The BMA requested information on the organisations’ spending on private consultancy firms and whether new jobs had been created. They found …
ACC/AHA/SCAI/SIR/SVM 2018 Appropriate Use Criteria for Peripheral Artery Intervention
Authors: Steven R. Bailey, Joshua A. Beckman, Timothy D. Dao, Sanjay Misra, Piotr S. Sobieszczyk, Christopher J. White, L. Samuel Wann, Steven R. Bailey, Timothy Dao, Herbert D. Aronow, Reza Fazel, Heather L. Gornik, Bruce H. Gray, Jonathan L. Halperin, Alan T. Hirsch, Michael R. Jaff, Venkataramu Krishnamurthy, Sahil A. Parikh, Amy B. Reed, Fadi Shamoun, Rita E. Shugart, E. Kent Yucel
Journal: Journal of the American College of Cardiology (2018)
PCSK9 Involvement in Aortic Valve Calcification
Authors: Paolo Poggio, Paola Songia, Laura Cavallotti, Silvia S. Barbieri, Ilaria Zanotti, Benoît J. Arsenault, Vincenza Valerio, Nicola Ferri, Romain Capoulade, Marina Camera
Journal: Journal of the American College of Cardiology (2018)
Sinus Venosus Defects
Authors: Animesh Tandon, Barbara E.U. Burkhardt, Maria Batsis, Thomas M. Zellers, Mari Nieves Velasco Forte, Israel Valverde, Ryan P. McMahan, Kristine J. Guleserian, Gerald F. Greil, Tarique Hussain
Journal: JACC. Cardiovascular imaging (2018)
Assessment of Self-monitoring of Blood Glucose in Individuals With Type 2 Diabetes Not Using Insulin
Authors: Kevin D. Platt, Amy N. Thompson, Paul Lin, Tanima Basu, Ariel Linden, A. Mark Fendrick
Journal: JAMA Internal Medicine (2018)

This database analysis quantifies the rate of use and cost of self-monitoring blood glucose supplies that are potentially used inappropriately, specifically focusing on test strips.
Building Strong Neighborhoods in the Lung with a Little Help from My Mesenchymal Stem Cells
Authors: Rosa Faner, Mauricio Rojas
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

development requires certain standards for analytical validity (meaning that the biomarker needs to be accurate, reproducible, and reliable), clinical validity (ability to separate groups with distinct clinical/biological outcomes or differences), and clinical utility (the use of the biomarker should improve measurable clinical outcomes) (14).When studying the airway microbiota, we are still frequently faced with analytical validity challenges, in part related to the low biomass and risk for reagent contamination (most important for lower airway samples), as well as the lack of uniformity of sequencing techniques and analytical approaches.Further, unlike gut microbiome studies, airway microbiome studies have been small and frequently limited to few centers, even when noninvasive samples, such as sputum, are used.Thus, for the most part, the clinical validity is limited by the single discovery cohort design (such as the one described in this study) and the lack of validation.And finally, as promising biomarkers arise, we need effective strategies to test whether the use of microbiome data can affect clinical outcomes.Thus, the current study is an important initial step in biomarker discovery.The road ahead will require larger cohorts and different designs so we can have a personalized approach in which noninvasive microbial signatures may have clinical implications for patients with COPD.
Genetics and genomics of pulmonary arterial hypertension
Authors: Nicholas W. Morrell, Micheala A. Aldred, Wendy K. Chung, C. Gregory Elliott, William C. Nichols, Florent Soubrier, Richard C. Trembath, James E. Loyd
Journal: European Respiratory Journal (2018)

Since 2000 there have been major advances in our understanding of the genetic and genomics of pulmonary arterial hypertension (PAH), although there remains much to discover. Based on existing knowledge, around 25–30% of patients diagnosed with idiopathic PAH have an underlying Mendelian genetic cause for their condition and should be classified as heritable PAH (HPAH). Here, we summarise the known genetic and genomic drivers of PAH, the insights these provide into pathobiology, and the opportunities afforded for development of novel therapeutic approaches. In addition, factors determining the incomplete penetrance observed in HPAH are discussed. The currently available approaches to genetic testing and counselling, and the impact of a genetic diagnosis on clinical management of the patient with PAH, are presented. Advances in DNA sequencing technology are rapidly expanding our ability to undertake genomic studies at scale in large cohorts. In the future, such studies will provide a more complete picture of the genetic contribution to PAH and, potentially, a molecular classification of this disease.
Exercise measures up to medication as antihypertensive therapy: its value has long been underestimated
Authors: Linda S Pescatello
Journal: British Journal of Sports Medicine (2018)

Hypertension is the major risk factor for cardiovascular disease (CVD)—the leading global cause of death.1 2 High systolic blood pressure (SBP) is the top health risk factor for the global burden of disease.2 3 The CVD mortality and morbidity benefits of antihypertensive medications are well established, and their use to treat hypertension is increasing worldwide.4 5 These trends will continue as the American Heart Association (AHA) and American College of Cardiology (ACC) recently established lower blood pressure (BP) thresholds for treatment.6 

Exercise was rated in the AHA/ACC report as one of the best non-pharmacological approaches to treat hypertension because aerobic exercise training lowers BP 5–8 mm Hg among adults with hypertension.6 7 The magnitude of these BP reductions may lower CVD risk by 4%–22% and stroke by 6%–41%,4 8 and reduce the resting BP of adults with hypertension into normal ranges. Accordingly, professional organisations from around the world recommend adults with hypertension participate in 30–60 min/day of moderate to vigorous intensity aerobic exercise, such as walking or jogging, on most days of the week with the recommendations for resistance training less consistent9 (table 1).

View this table:

Table 1 
Professional Committee Exercise Recommendations for Hypertension (adapted from Pescatello et al 9)



Despite the well documented BP benefits of medications and exercise to treat hypertension, the 2018 Physical Activity Guidelines Advisory Committee (PAGAC) noted in their …
β-catenin-activated autocrine PDGF/Src signaling is a therapeutic target in pancreatic cancer
Authors: Tzu-Lei Kuo, Kuang-Hung Cheng, Yan-Shen Shan, Li-Tzong Chen, Wen-Chun Hung
Journal: Theranostics (2018)

K-ras mutation and p53 loss are the most prevalent genetic alterations in pancreatic cancer. In addition to these two alterations, pancreatic tumors frequently contain a third genetic defect. Mutations in the WNT/ß-catenin signaling molecules occur in 15-20% of pancreatic cancer patients and co-exist with K-ras mutation and p53 loss. However, the contribution of the WNT/ß-catenin pathway in pancreatic tumorigenesis is still unclear. Methods: We generated Pdx1-CreKrasG12Dp53L/+APCL/+ (KPA) mice and compared their phenotypes with Pdx1-CreKrasG12Dp53L/+ (KPC) mice. The signaling pathways specifically activated in the KPA mice were investigated and the therapeutic effect by targeting the activated pathways was evaluated. We finally validated our findings in human blood and tumor samples. Results: Survival of the KPA mice was shorter than that of the KPC mice. The KPA cancer cells are highly invasive and exhibit distorted morphology in organoid culture with extensive invadopodia formation and elevated matrix metalloproteinase (MMP) activity. The platelet-derived growth factor (PDGF) pathway is upregulated in the KPA cancer cells, and PDGF production induced by ß-catenin triggers constitutive activation of the Src kinase via the PDGF receptor in the cells. Serum PDGF concentration of the KPA mice is much higher than that of the normal and KPC mice. The Src inhibitor dasatinib effectively inhibits tumor growth and metastasis of the KPA cancer cells. Patient's serum PDGF level is significantly correlated with the expression of PDGF and phosphor-Src in tumors and elevated PDGF/phosphor-Src level in tumors predicts increased recurrence and poor survival. Moreover, mutations of the WNT/ß-catenin signaling molecules are higher in patients with elevated PDGF/phosphor-Src level. Conclusion: ß-catenin activation, coupled with K-ras mutation and p53 loss, activates an autocrine PDGF/Src signaling in pancreatic cancer and defines a subset of patients who might be sensitive to Src inhibition. In addition, serum PDGF level could be a reliable biomarker for patient selection in clinic.
Abstract 16323: Racial Differences in Outcomes of Transcatheter Aortic Valve Replacement: Insights From a National Database
Authors: Nirmanmoh Bhatia, Sahil Agrawal, Mohit Pahuja, Lohit Garg, Divyanshu Mohananey, Michael Durkin, Manyoo Agarwal, Ronak G Soni, Jamshid Shirani
Journal: Circulation (2016)

Introduction: African-American (AA) patients have poorer outcomes as compared to Caucasian patients for many cardiovascular diseases. Whether such racial differences exist in outcomes of patients u...
Late thymic deficiency after HLA-haploidentical hematopoietic stem cell transplantation for severe combined immunodeficiency
Authors: Markus J. Ege, Catharina Schuetz, Eva-Maria Jacobsen, Susanna M. Müller-Langer, Ingrid Furlan, Mehtap Sirin, Ulrich Pannicke, Klaus Schwarz, Klaus-Michael Debatin, Manfred Hönig, Ansgar Schulz, Wilhelm Friedrich
Journal: Journal of Allergy and Clinical Immunology (2018)
P072 Low Detection Rate of EGFR Driver and T790M Mutation in Plasma by Cobas v2 After Acquired Resistance to Afatinib
Authors: O. Yuko, T. Yoshida, K. Asada, T. Oguri, N. Inui, S. Morikawa, K. Ito, T. Kimura, E. Kunii, T. Matsui, A. Kubo, T. Kato, J. Shindo, T. Tsuda, M. Okuno, T. Hida
Journal: Journal of Thoracic Oncology (2018)
Integrating tumor genomics into studies of the microbiome in colorectal cancer
Authors: Michael B. Burns, Ran Blekhman
Journal: Gut Microbes (2018)

Although the gut microbiome has been linked to colorectal cancer (CRC) development, associations of microbial taxa with CRC status are often inconsistent across studies. We have recently shown that tumor genomics, a factor that is rarely incorporated in analyses of the CRC microbiome, has a strong effect on the composition of the microbiota. Here, we discuss these results in the wider context of studies characterizing interaction between host genetics and the microbiome, and describe the implications of our findings for understanding the role of the microbiome in CRC.
Comment on “ALK is a therapeutic target for lethal sepsis”
Authors: Rafael B. Blasco, Enrico Patrucco, Ines Mota, Wei-Tien Tai, Roberto Chiarle
Journal: Science Translational Medicine (2018)

ALK is not highly expressed on monocytes and macrophages, and the effects of bioactive compounds on STING activation may not depend on ALK.