tbuckley/cabot-search huggingface dataset:
Upsizing Neonatal Heart Regeneration
Authors: Ahmed I. Mahmoud, Enzo R. Porrello
Journal: Circulation (2018)

egenerating the adult human heart remains a central barrier in cardiovascular medicine.Developing effective cardiac regenerative therapies has proven to be challenging because of a lack of mechanistic understanding of the key processes required for endogenous heart regeneration.Peering into natural mechanisms of heart regeneration in animal models is beginning to provide a blueprint for regeneration, which could be exploited therapeutically in humans.Efficient and complete regeneration after cardiac injury in adult vertebrates has been demonstrated in newts, zebrafish, and axolotls (Figure ,A). 1 Although it was previously believed that mammals had lost their capacity for heart regeneration during evolution, recent studies have shown that neonatal mice are able to mount a robust regenerative response after injury (Figure ,A). 2 However, this regenerative potential in neonatal mice rapidly diminishes after birth. 2 It is important to note that the evolutionary conservation of the cardiac regenerative program in the neonatal mouse heart has raised the exciting prospect that this dormant regenerative program could be reactivated in adulthood if the underlying mechanisms could be unraveled.However, it was unclear whether large mammals, including humans, shared a similar developmental window for heart regeneration.In this issue of Circulation, studies by Ye et al 3 and Zhu et al 4 demonstrate that similar to neonatal mice, 1-day-old (P1) and 2-day-old (P2) neonatal pigs are capable of mounting a cardiac regenerative response after myocardial infarction (MI) characterized by restoration of contractile function, cardiomyocyte replenishment, and minimal fibrosis.It is interesting to note that this regenerative capacity is rapidly lost after the first 2 days of life.This brief window of regeneration has also been documented recently in the neonatal mouse heart. 5Similar to regeneration in neonatal mice, the proliferation of preexisting cardiomyocytes appears to be the primary source of cardiomyocyte replenishment in neonatal pigs, with markers of cardiomyocyte mitosis, sarcomere disassembly, and cytokinesis elevated after injury in the P1 and P2 hearts but not at later time points.BrdU pulse-chase experiments further demonstrated that cardiomyocyte DNA synthesis was increased after neonatal pig MI as well. 3Cardiomyocyte proliferation significantly decreased after this 2-day window, which was associated with a marked reduction in telomerase activity. 4Thus, in mice and pigs, cardiac regenerative capacity appears to be driven by cardiomyocyte proliferation and sharply declines after the first 2 days of postnatal development.The timing of regenerative arrest in mice and pigs is intriguing given substantive differences in the rates of cardiomyocyte cell cycle withdrawal and binucleation in both species.In rodents, cardiomyocytes exit the cell cycle shortly after birth with the cessation of cytokinesis and persistence of karyokinesis resulting in binucle-
Cardiovascular Disease Risk After Treatment-Induced Premature Ovarian Insufficiency in Female Survivors of Hodgkin Lymphoma
Authors: Inge M. Krul, Annemieke W.J. Opstal–van Winden, Cécile P.M. Janus, Laurien A. Daniëls, Yolande Appelman, Angela H.E.M. Maas, Simone de Vries, Katarzyna Jóźwiak, Berthe M.P. Aleman, Flora E. van Leeuwen
Journal: Journal of the American College of Cardiology (2018)
Delphi, a Data Warehouse to Discover Associations between Variables in Clinical Trials: Application to the Fondazione Italiana Linfomi (FIL) MCL0208 Phase III Trial
Authors: Gian Maria Zaccaria, Simone Ferrero, Andrea Evangelista, Samanta Rosati, Cristina Castagneri, Marco Ghislieri, Barbero Daniela, Elisa Genuardi, Mariella Lo Schirico, Alberto Zamò, Umberto Vitolo, Riccardo Bomben, Valter Gattei, Sara Galimberti, Antonello Di Paolo, Davide Rossi, Gianluca Gaidano, Alice Di Rocco, Sergio Cortelazzo, Mario Boccadoro, Gabriella Balestra, Marco Ladetto
Journal: Blood (2017)
Safety of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-1-infected adults with end-stage renal disease on chronic haemodialysis: an open-label, single-arm, multicentre, phase 3b trial
Authors: Joseph J Eron, Jean-Daniel Lelievre, Robert Kalayjian, Jihad Slim, Anson K Wurapa, Jeffrey L Stephens, Cheryl McDonald, Eric Cua, Aimee Wilkin, Brigitte Schmied, Mehri McKellar, Stephanie Cox, Sophia R Majeed, Shuping Jiang, Andrew Cheng, Moupali Das, Devi SenGupta
Journal: The Lancet HIV (2018)
Cardiovascular and Limb Outcomes in Patients With Diabetes and Peripheral Artery Disease
Authors: Cecilia C. Low Wang, Juuso I. Blomster, Gretchen Heizer, Jeffrey S. Berger, Iris Baumgartner, F. Gerry R. Fowkes, Peter Held, Brian G. Katona, Lars Norgren, W. Schuyler Jones, Renato D. Lopes, Jeffrey W. Olin, Frank W. Rockhold, Kenneth W. Mahaffey, Manesh R. Patel, William R. Hiatt
Journal: Journal of the American College of Cardiology (2018)
Incidence, Predictors, and Outcome Associations of Dyskalemia in Heart Failure With Preserved, Mid-Range, and Reduced Ejection Fraction
Authors: Gianluigi Savarese, Hong Xu, Marco Trevisan, Ulf Dahlström, Patrick Rossignol, Bertram Pitt, Lars H. Lund, Juan J. Carrero
Journal: JACC Heart Failure (2018)
Abstract O.34: NT-proBNP based Algorithm for Diagnosis and Treatment of Kawasaki Disease - Are we there yet?
Authors: Audrey Dionne, Léamarie Meloche-Dumas, Anne Fournier, Nagib Dahdah
Journal: Circulation (2015)

Background: Diagnosis of Kawasaki Disease (KD) can be confusing in the absence of a confirmatory test or pathognomonic finding, especially when clinical criteria are incomplete (iKD). We have lately proposed serum NT-proBNP as an adjunctive diagnostic test. Method: We retrospectively tested a new diagnostic algorithm to aid in diagnosis based on NT-proBNP (Z-score for age), coronary artery dilation (CAD) at onset, and abnormal serum albumin or CRP. The goal was to assess the performance of the algorithm with respect to CAD outcome (aneurysm, dilation, or occult dilation). Occult dilation is defined as variation of coronary artery Z-score &gt;2 within the normal range (&lt;2.5). Results: The algorithm was tested on 81 KD patients who had NT-proBNP on admission at our institution between 2008 and 2013. Age at diagnosis was 3.2 ± 2.6 years, with a median of 5 diagnostic criteria (range 3-6), of whom 31/81 (38.3%) had iKD. Aneurysms occurred in 16/81 (19.8%); higher prevalence in iKD, 12/31 (38.7%) versus 4/50 (8.0%) (p=0.001). CAD affected 35/81 (43.2%), and 30/81 (37.0%) had occult CAD. With the algorithm, 80/81 (98.8%) were to be treated: based on high NT-proBNP alone for 54/81 (66.7%), on onset CAD for 13/81 (16.0%), and on high CRP or low albumin for 13/81 (16.0%). (Figure 1) Results were similar when the algorithm was applied to patients with complete or incomplete criteria. The only patient “not-to-treat” with the algorithm had iKD and transient occult CAD. Conclusion: This NT-proBNP based algorithm is efficient to identify and treat patients at risk of coronary involvement, despite an apparent selection bias of CA involvement. This paves the way for a prospective validation trial of the algorithm.
Intravenous immunoglobulin induces IL-4 in human basophils by signaling through surface-bound IgE
Authors: Caroline Galeotti, Emmanuel Stephen-Victor, Anupama Karnam, Mrinmoy Das, Laurent Gilardin, Mohan S. Maddur, Sandra Wymann, Cédric Vonarburg, Alain Chevailler, Jordan D. Dimitrov, Olivier Benveniste, Pierre Bruhns, Srini V. Kaveri, Jagadeesh Bayry
Journal: Journal of Allergy and Clinical Immunology (2018)
VEGF expands erythropoiesis via hypoxia-independent induction of erythropoietin in noncanonical perivascular stromal cells
Authors: Alissa C. Greenwald, Tamar Licht, Saran Kumar, Sunday S. Oladipupo, Seema Iyer, Myriam Grunewald, Eli Keshet
Journal: The Journal of Experimental Medicine (2018)

Insufficient erythropoiesis due to increased demand is usually met by hypoxia-driven up-regulation of erythropoietin (Epo). Here, we uncovered vascular endothelial growth factor (VEGF) as a novel inducer of Epo capable of increasing circulating Epo under normoxic, nonanemic conditions in a previously unrecognized reservoir of Epo-producing cells (EPCs), leading to expansion of the erythroid progenitor pool and robust splenic erythropoiesis. Epo induction by VEGF occurs in kidney, liver, and spleen in a population of Gli1+SMA+PDGFRβ+ cells, a signature shared with vascular smooth muscle cells (VSMCs) derived from mesenchymal stem cell–like progenitors. Surprisingly, inhibition of PDGFRβ signaling, but not VEGF signaling, abrogated VEGF-induced Epo synthesis. We thus introduce VEGF as a new player in Epo induction and perivascular Gli1+SMA+PDGFRβ+ cells as a previously unrecognized EPC reservoir that could be harnessed for augmenting Epo synthesis in circumstances such as chronic kidney disease where production by canonical EPCs is compromised.
Abstract 16486: Safely Removing the Brakes on Fibrinolysis: Inactivation of α2-Antiplasmin Dissolves Pulmonary Emboli Without Causing Bleeding
Authors: Satish Singh, Aiilyan K Houng, Guy L Reed
Journal: Circulation (2015)

Introduction: Venous thromboembolism affects millions of patients per year and pulmonary embolism (PE) is a leading cause of hospital mortality. PE activates the fibrinolytic system, but regulatory molecules such as α2-antiplasmin (a2AP) appear to prevent thrombus dissolution. Pharmacologic tissue plasminogen activator (tPA) dissolves pulmonary emboli, relieves right heart strain and improves mortality in high risk patients, but tPA has unacceptable bleeding risks. We examined whether inactivation of a2AP may prove to be a safer and more effective method for dissolving experimental pulmonary emboli. Methods: Pulmonary embolism was examined in a humanized model. Anesthetized, a2AP -/- mice, supplemented with physiological levels of a2AP, were infused with 125 I-labeled human thrombi via the jugular vein. Then mice were treated with tPA, no agent (control), a humanized chimeric monoclonal antibody inactivator of a2AP (a2AP-I) or the combination of low dose tPA and a2AP-I. Thrombus dissolution was determined by gamma counting and surgical bleeding was measured. Results: Clinical dose tPA dissolved pulmonary emboli more effectively than no therapy (control, p&lt;0.001). However, mice treated with a2AP-I showed greater thrombus dissolution than tPA (p&lt;0.001) or controls (p&lt;0.001). Alone, low doses of tPA did not dissolve thrombi, but in combination with a2AP-I, low dose tPA increased thrombus dissolution more than clinical dose tPA alone (p&lt;0.001) or a2AP-I alone (p&lt;0.001). Clinical dose tPA therapy was associated with a significant increase in bleeding (p&lt;0.01). Though more potent than tPA in dissolving pulmonary emboli, a2AP-I alone, or in combination with low dose tPA, did not increase bleeding risk vs. controls and caused less bleeding than tPA (p&lt;0.01). Conclusion: In experimental pulmonary embolism a2AP plays a critical regulatory role in blocking fibrinolysis. Inactivation of a2AP was more potent than tPA in dissolving thrombi in PE, but unlike tPA, it did not cause bleeding. This suggests that a2AP inactivation may be a safer strategy for treating venous thromboembolism.
Effectiveness and Safety of Reference Infliximab and Biosimilar in Crohn Disease: A French Equivalence Study
Authors: Antoine Meyer, Jérémie Rudant, Jérôme Drouin, Alain Weill, Franck Carbonnel, Joël Coste
Journal: Annals of Internal Medicine (2018)

CT-P13 is a biosimilar of the reference product (RP) infliximab, with demonstrated efficacy and safety for some inflammatory arthritides. It was approved for the treatment of Crohn disease (CD) on that basis, without specific studies examining its effects in CD.To compare the effectiveness and safety of CT-P13 and RP in infliximab-naive patients with CD.Comparative equivalence cohort study.Système National des Données de Santé (SNDS), a French nationwide health administrative database (1 March 2015 to 30 June 2017).5050 infliximab-naive patients with CD who were older than 15 years, had started treatment with RP (n = 2551) or CT-P13 (n = 2499), and had no other indications for infliximab.The primary outcome was a composite end point of death, CD-related surgery, all-cause hospitalization, and reimbursement of another biologic therapy. Equivalence was defined as a 95% CI of the hazard ratio (HR) of CT-P13 versus RP in a multivariable marginal Cox model situated within prespecified margins (0.80 to 1.25).Overall, 1147 patients in the RP group and 952 patients in the CT-P13 group met the composite end point (including 838 and 719 hospitalizations, respectively). In multivariable analysis of the primary outcome, CT-P13 was equivalent to RP (HR, 0.92 [95% CI, 0.85 to 0.99]). No differences in safety outcomes were observed between the 2 groups: serious infections (HR, 0.82 [CI, 0.61 to 1.11]), tuberculosis (HR, 1.10 [CI, 0.36 to 3.34]), and solid or hematologic cancer (HR, 0.66 [CI, 0.33 to 1.32]).The SNDS does not contain all relevant clinical data (for example, disease activity).This analysis of real-world data indicates that the effectiveness of CT-P13 is equivalent to that of RP for infliximab-naive patients with CD. No difference was observed for safety outcomes.Caisse Nationale de l'Assurance Maladie.
Dual antiplatelet therapy with aspirin and clopidogrel for acute high risk transient ischaemic attack and minor ischaemic stroke: a clinical practice guideline
Authors: Kameshwar Prasad, Reed Siemieniuk, Qiukui Hao, Gordon Guyatt, Martin O’Donnell, Lyubov Lytvyn, Anja Fog Heen, Thomas Agoritsas, Per Olav Vandvik, Sankar Prasad Gorthi, Loraine Fisch, Mirza Jusufovic, Jennifer Muller, Brenda Booth, Eleanor Horton, Auxiliadora Fraiz, Jillian Siemieniuk, Awah Cletus Fobuzi, Neelima Katragunta, Bram Rochwerg
Journal: BMJ (2018)

What is the role of dual antiplatelet therapy after high risk transient ischaemic attack or minor stroke? Specifically, does dual antiplatelet therapy with a combination of aspirin and clopidogrel lead to a greater reduction in recurrent stroke and death over the use of aspirin alone when given in the first 24 hours after a high risk transient ischaemic attack or minor ischaemic stroke? An expert panel produced a strong recommendation for initiating dual antiplatelet therapy within 24 hours of the onset of symptoms, and for continuing it for 10-21 days. Current practice is typically to use a single drug
Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes
Authors: Emily K. Sims, Henry T. Bahnson, Julius Nyalwidhe, Leena Haataja, Asa K. Davis, Cate Speake, Linda A. DiMeglio, Janice Blum, Margaret A. Morris, Raghavendra G. Mirmira, Jerry Nadler, Teresa L. Mastracci, Santica Marcovina, Wei-Jun Qian, Lian Yi, Adam C. Swensen, Michele Yip-Schneider, C. Max Schmidt, Robert V. Considine, Peter Arvan, Carla J. Greenbaum, Carmella Evans-Molina, Steven Willi, Tammy Calvano, Georgeanna Klingensmith, Heidi Haro, Ruth Weinstock, Suzan Bzdick, Robin Goland, Ellen Greenberg, Joyce Lee, Ashley Eason, Linda DiMeglio, Stephanie Woerner, Andrew Ahmann, Rebecca Fitch, Kathleen Bethin, Michelle Ecker, Irl Hirsch, Christina Peterson, David Liljenquist, Brandon Robison, Richard Bergenstal, Beth Olson, Eda Cengiz, Amy Steffen, Anne Peters, Perez Hinton, Janet McGill, Lori Buechler, Eva Tsalikian, Joanne Cabbage, Mark Clements, Lois Hester, Davida Kruger, Heather Remtema, Desmond Schatz, Jamie Thomas, William Zipf, Diane Seiple, Henry Rodriguez, Danielle Henson, Jill Simmons, Faith Brendle, Brandon Nathan, Kara Schmid, Kathleen Arnold, Sharon Sellers, David Harlan, Lisa Hubacz, John Buse, Julie Tricome, Michael Rickels, Cornelia Dalton-Bakes, Leroy Schroeder, Amanda Roark, Amy Potter, Faith Brendle
Journal: Diabetes Care (2018)

OBJECTIVE Abnormally elevated proinsulin secretion has been reported in type 2 and early type 1 diabetes when significant C-peptide is present. We questioned whether individuals with long-standing type 1 diabetes and low or absent C-peptide secretory capacity retained the ability to make proinsulin. RESEARCH DESIGN AND METHODS C-peptide and proinsulin were measured in fasting and stimulated sera from 319 subjects with long-standing type 1 diabetes (≥3 years) and 12 control subjects without diabetes. We considered three categories of stimulated C-peptide: 1) C-peptide positive, with high stimulated values ≥0.2 nmol/L; 2) C-peptide positive, with low stimulated values ≥0.017 but &amp;lt;0.2 nmol/L; and 3) C-peptide &amp;lt;0.017 nmol/L. Longitudinal samples were analyzed from C-peptide–positive subjects with diabetes after 1, 2, and 4 years. RESULTS Of individuals with long-standing type 1 diabetes, 95.9% had detectable serum proinsulin (&amp;gt;3.1 pmol/L), while 89.9% of participants with stimulated C-peptide values below the limit of detection (&amp;lt;0.017 nmol/L; n = 99) had measurable proinsulin. Proinsulin levels remained stable over 4 years of follow-up, while C-peptide decreased slowly during longitudinal analysis. Correlations between proinsulin with C-peptide and mixed-meal stimulation of proinsulin were found only in subjects with high stimulated C-peptide values (≥0.2 nmol/L). Specifically, increases in proinsulin with mixed-meal stimulation were present only in the group with high stimulated C-peptide values, with no increases observed among subjects with low or undetectable (&amp;lt;0.017 nmol/L) residual C-peptide. CONCLUSIONS In individuals with long-duration type 1 diabetes, the ability to secrete proinsulin persists, even in those with undetectable serum C-peptide.
Letting the right one in: evaluating the generalisability of clinical trials
Authors: Rahul Shrimanker, Richard Beasley, Ciléin Kearns
Journal: European Respiratory Journal (2018)

<b>Clinical trials can be poorly generalisable to a patient population due to strict, label-based diagnostic criteria. Selection using the trait the treatment is targeting may produce results more applicable to the disease population.</b>http://ow.ly/p30b30mKrC5
Abstract A094: The study of single-nucleotide polymorphisms (SNPs) of tumor suppressor gene in prostate cancer patient of Bangladeshi population
Authors: Hasnain Imtiaz, Sharmin Afroz, Md. Amir Hossain, Sm Faysal Bellah, Md. Mustafizur Rahman
Journal: Cancer Research (2018)

Abstract Background: Prostate cancer (PCa) is the second leading cause of death among males in present world. The polymorphisms of invasion suppressor gene CDH1 and DNA mismatch repair gene Exo1 have been reported to play a critical role in the tumorigenesis, development, and prognosis of several kinds of cancers, including prostate cancer in some countries. The present study was designed to analyze the contribution of single-nucleotide polymorphisms (SNP) of the CDH1 (-160C/A) and Exo1 (K589E) to prostate cancer susceptibility in Bangladeshi population. Methods: The study included 100 prostate cancer cases and age-matched 100 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was used to determine the genetic polymorphisms. Results: A significant association was found between CDH1 -160 C/A (rs16260) and Exo1 (K589E) polymorphisms and prostate cancer risk. In case of CDH1 -160C/A (rs16260) polymorphism, the frequencies of the three genotypes C/C, C/A, and A/A were 45, 48, and 7% in cases vs. 63, 32, and 5% in controls, respectively. The frequency of C/A heterozygote and combined C/A+A/A genotypes was found to be significantly associated (OR=2.1000, 95% CI= 1.2956. to 4.0905 p=0.013; OR=2.0811, 95% CI= 1.1820-3.6641, p= 0.011, respectively) with increased susceptibility to prostate cancer. The variant A allele also increased the risk of prostate cancer (OR=1.6901, 95% CI= 1.0740 to 2.6597, p= 0.0233). In case of Exo1 (K589E) polymorphism, G/A heterozygote, A/A homozygote, and combined G/A+A/A genotypes were found to be strongly associated (OR= 2.3021, 95% CI=2956. to 4.0905, p=0.0031; OR= 4.8462, 95% CI=1.0198 to 23.0284, p=0.0291; OR= 3.0362, 95% CI=1.7054 to 5.4053, p=0.0001, respectively) with prostate cancer risk. The “A” allele frequency was also found to be significantly associated with increased susceptibility to prostate cancer (OR=2.2955, 95% CI= 1.4529-3.6270, p= 0.0004). Conclusions: Results of our present study suggest that CDH1 -160 C/A and Exo1 K589E polymorphisms are associated with increased susceptibility to prostate cancer in Bangladeshi population. Citation Format: Hasnain Imtiaz, Sharmin Afroz, Md. Amir Hossain, Sm Faysal Bellah, Md. Mustafizur Rahman. The study of single-nucleotide polymorphisms (SNPs) of tumor suppressor gene in prostate cancer patient of Bangladeshi population [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A094.
Implementing Measurement-Based Care in Behavioral Health
Authors: Cara C. Lewis, Meredith Boyd, Ajeng Puspitasari, Elena Navarro, Jacqueline Howard, Hannah Kassab, Mira Hoffman, Kelli Scott, Aaron Lyon, Susan Douglas, Greg Simon, Kurt Kroenke
Journal: JAMA Psychiatry (2018)

<h3>Importance</h3> Measurement-based care (MBC) is the systematic evaluation of patient symptoms before or during an encounter to inform behavioral health treatment. Despite MBC's demonstrated ability to enhance usual care by expediting improvements and rapidly detecting patients whose health would otherwise deteriorate, it is underused, with typically less than 20% of behavioral health practitioners integrating it into their practice. This narrative review addresses definitional issues, offers a concrete and evaluable operationalization of MBC fidelity, and summarizes the evidence base and utility of MBC. It also synthesizes the extant literature's characterization of barriers to and strategies for supporting MBC implementation, sustainment, and scale-up. <h3>Observations</h3> Barriers to implementing MBC occur at multiple levels: patient (eg, concerns about confidentiality breach), practitioner (eg, beliefs that measures are no better than clinical judgment), organization (eg, no resources for training), and system (eg, competing requirements). Implementation science—the study of methods to integrate evidence-based practices such as MBC into routine care—offers strategies to address barriers. These strategies include using measurement feedback systems, leveraging local champions, forming learning collaboratives, training leadership, improving expert consultation with clinical staff, and generating incentives. <h3>Conclusions and Relevance</h3> This narrative review, informed by implementation science, offers a 10-point research agenda to improve the integration of MBC into clinical practice: (1) harmonize terminology and specify MBC's core components; (2) develop criterion standard methods for monitoring fidelity and reporting quality of implementation; (3) develop algorithms for MBC to guide psychotherapy; (4) test putative mechanisms of change, particularly for psychotherapy; (5) develop brief and psychometrically strong measures for use in combination; (6) assess the critical timing of administration needed to optimize patient outcomes; (7) streamline measurement feedback systems to include only key ingredients and enhance electronic health record interoperability; (8) identify discrete strategies to support implementation; (9) make evidence-based policy decisions; and (10) align reimbursement structures.
Tumor-Infiltrating Lymphocytes—Location for Prognostic Evaluation
Authors: Michael Peled, Amir Onn, Roy S. Herbst
Journal: Clinical Cancer Research (2018)

Tumor-infiltrating lymphocytes (TIL) are crucial for the success of immunotherapy, and their density can predict prognosis. It has now been shown that computer-based analysis of the spatial organization of TILs adds prognostic value in early-stage non-small cell lung cancer, possibly improving the treatment algorithm to prevent recurrence.See related article by Corredor et al., p. 1526.