tbuckley/cabot-search huggingface dataset:
Evolving Challenges in Pediatric Pulmonary Medicine. New Opportunities to Reinvigorate the Field
Authors: Joseph M. Collaco, Steven H. Abman
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Thirty years after the first board certification examination for pediatric pulmonology was administered there remain substantial challenges in attracting trainees and sustaining and retaining clinician-scientists in the field. In fact, significant workforce shortages are predicted to exist with current fellowship graduation rates and the aging of the existing workforce. However, the rapid diagnostic and therapeutic advances occurring in the field should serve as draw for trainees. In addition, pediatric pulmonologists provide unique expertise for the diversity and severity of respiratory conditions that is not duplicated by generalists, allergists, intensivists, or neonatologists. It is critical to raise awareness of the depth of pediatric pulmonology, not only to trainees, but also of the broader medical community at large, to recognize the value pediatric pulmonologists bring to clinical care, research endeavors, and interdisciplinary collaborations. In this perspective, we highlight the nature of the c...
FIBROSpect ® NASH serum test identifies advanced liver fibrosis in patients with nonalcoholic steatohepatitis: Results of a validation study
Authors: M. Abdelmalek, C. Guy, A.M. Diehl, X. LI, L. Mimms, K. Hester, A. Jain, R. Loomba
Journal: Journal of Hepatology (2018)
Hyaluronan
Authors: Maria Grandoch, Paul L. Bollyky, Jens W. Fischer
Journal: Circulation Research (2018)

H yaluronan (HA) matrix responds quickly to chang- ing conditions during atherogenesis and atheroprogression.Our evolving understanding of HA's specific functions at the interface of inflammatory responses and phenotypic control of mesenchymal cells in the vessel wall points to its importance in inflammation and atherosclerosis.Additionally, the enzymes that mediate HA biosynthesis and degradation are potential target molecules for novel therapies, as are signal-transducing HA receptors: deciphering the HA matrix, thus, has significant translational possibilities.
T1 Mapping by Cardiac Magnetic Resonance and Multidimensional Speckle-Tracking Strain by Echocardiography for the Detection of Acute Cellular Rejection in Cardiac Allograft Recipients
Authors: Leyla Elif Sade, Tuncay Hazirolan, Hatice Kozan, Handan Ozdemir, Mutlu Hayran, Serpil Eroglu, Bahar Pirat, Atilla Sezgin, Haldun Muderrisoglu
Journal: JACC. Cardiovascular imaging (2018)
PiggyBac-Engineered T Cells Expressing CD19-Specific CARs that Lack IgG1 Fc Spacers Have Potent Activity against B-ALL Xenografts
Authors: David C. Bishop, Ning Xu, Benjamin Tse, Tracey A. O’Brien, David J. Gottlieb, Alla Dolnikov, Kenneth P. Micklethwaite
Journal: Molecular Therapy (2018)

Clinical trials of CD19-specific chimeric antigen receptor (CAR19) T cells have demonstrated remarkable efficacy against relapsed and refractory B cell malignancies. The piggyBac transposon system offers a less complex and more economical means for generating CAR19 T cells compared to viral vectors. We have previously optimized a protocol for the generation of CAR19 T cells using the piggyBac system, but we found that CAR19 T cells had poor in vivo efficacy and persistence, probably due to deleterious FcγR interactions with the CAR's IgG1 Fc-containing spacer domain. We therefore designed three CD19-specifc CARs that lacked the IgG1 Fc region, and we incorporated combinations of CD28 or 4-1BB transmembrane and co-stimulatory domains. PiggyBac-generated CAR19 T cells expressing these re-designed constructs all demonstrated reactivity in vitro specifically against CD19+ cell lines. However, those combining CD28 transmembrane and co-stimulatory domains showed CD4 predominance and inferior cytotoxicity. At high doses, CAR19 T cells were effective against B-ALL in a xenograft mouse model, regardless of co-stimulatory domain. At diminishing doses, 4-1BB co-stimulation led to greater potency and persistence of CAR19 T cells, and it provided protection against B-ALL re-challenge. Production of potent CAR T cells using piggyBac is simple and cost-effective, and it may enable wider access to CAR T cell therapy.
Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2)
Authors: Pierre Charles, Benjamin Terrier, Élodie Perrodeau, Pascal Cohen, Stanislas Faguer, Antoine Huart, Mohamed Hamidou, Christian Agard, Bernard Bonnotte, Maxime Samson, Alexandre Karras, Noémie Jourde-Chiche, François Lifermann, Pierre Gobert, Catherine Hanrotel-Saliou, Pascal Godmer, Nicolas Martin-Silva, Grégory Pugnet, Marie Matignon, Olivier Aumaitre, Jean-François Viallard, François Maurier, Nadine Meaux-Ruault, Sophie Rivière, Jean Sibilia, Xavier Puéchal, Philippe Ravaud, Luc Mouthon, Loïc Guillevin
Journal: Annals of the Rheumatic Diseases (2018)

To compare individually tailored, based on trimestrial biological parameter monitoring, to fixed-schedule rituximab reinfusion for remission maintenance of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAVs).Patients with newly diagnosed or relapsing granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in complete remission after induction therapy were included in an open-label, multicentre, randomised controlled trial. All tailored-arm patients received a 500 mg rituximab infusion at randomisation, with rituximab reinfusion only when CD19+B lymphocytes or ANCA had reappeared or ANCA titre rose markedly based on trimestrial testing until month 18. Controls received a fixed 500 mg rituximab infusion on days 0 and 14 postrandomisation, then 6, 12 and 18 months after the first infusion. The primary endpoint was the number of relapses (new or reappearing symptom(s) or worsening disease with Birmingham Vasculitis Activity Score (BVAS)>0) at month 28 evaluated by an independent Adjudication Committee blinded to treatment group.Among the 162 patients (mean age: 60 years; 42% women) included, 117 (72.2%) had GPA and 45 (27.8%) had MPA. Preinclusion induction therapy included cyclophosphamide for 100 (61.7%), rituximab for 61 (37.6%) and methotrexate for 1 (0.6%). At month 28, 21 patients had suffered 22 relapses: 14/81 (17.3%) in 13 tailored-infusion recipients and 8/81 (9.9%) in 8 fixed-schedule patients (p=0.22). The tailored-infusion versus fixed-schedule group, respectively, received 248 vs 381 infusions, with medians (IQR) of 3 (2-4) vs 5 (5-5) administrations.AAV relapse rates did not differ significantly between individually tailored and fixed-schedule rituximab regimens. Individually tailored-arm patients received fewer rituximab infusions.NCT01731561; Results.
In type 2 diabetes with CVD and kidney disease, empagliflozin reduced mortality and hospitalization
Authors: Louise Moist
Journal: Annals of Internal Medicine (2018)

Source Citation Wanner C, Lachin JM, Inzucchi SE, et al; EMPA-REG OUTCOME Investigators. Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. Circulation. 2018;137:119-29. 28904068
CRISPR-Mediated Gene Editing to Assess the Roles of Tet2 and Dnmt3a in Clonal Hematopoiesis and Cardiovascular Disease
Authors: Soichi Sano, Kosei Oshima, Ying Wang, Yasufumi Katanasaka, Miho Sano, Kenneth Walsh
Journal: Circulation Research (2018)

Clonal hematopoiesis has been associated with increased mortality and cardiovascular disease. This condition can arise from somatic mutations in preleukemic driver genes within hematopoietic stem/progenitor cells. Approximately 40 candidate driver genes have been identified, but mutations in only 1 of these genes, TET2 (ten-eleven translocation-2), has been shown to casually contribute to cardiovascular disease in murine models.To develop a facile system to evaluate the disease characteristics of different clonal hematopoiesis driver genes using lentivirus vector and CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) methodology. Using this methodology, evaluate whether Dnmt3a (DNA [cytosine-5]-methyltransferase 3a)-a commonly occurring clonal hematopoiesis driver gene-causally contributes to cardiovascular disease.Lentivirus vectors were used to deliver Cas9 and guide RNA to introduce inactivating mutations in Tet2 and Dnmt3a in lineage-negative bone marrow cells. After implantation into lethally irradiated mice, these cells were engrafted and gave rise to labeled blood cell progeny. When challenged with an infusion of Ang II (angiotensin II), mice with inactivating mutations in Tet2 or Dnmt3a displayed greater cardiac hypertrophy, diminished cardiac function, and greater cardiac and renal fibrosis. In comparison with Tet2, inactivation of Dnmt3a did not lead to detectable expansion of the mutant hematopoietic cells during the time course of these experiments. Tet2 inactivation promoted the expression of IL (interleukin) 1β, IL-6, and Ccl5, whereas Dnmt3a inactivation promoted the expression of Cxcl1 (CXC chemokine ligand), Cxcl2, IL-6, and Ccl5 in a lipopolysaccharide-stimulated macrophage cell line.Experiments using lentivirus vector/CRISPR methodology provided evidence suggesting that inactivating DNMT3A mutations in hematopoietic cells contributes to cardiovascular disease. Comparative analyses showed that inactivation of Tet2 and Dnmt3 was similar in their ability to promote Ang II-induced cardiac dysfunction and renal fibrosis in mice. However, gene-specific actions were indicated by differences in kinetics of hematopoietic stem/progenitor cell expansion and different patterns of inflammatory gene expression.
Procalcitonin algorithm to guide initial antibiotic therapy in acute exacerbations of COPD admitted to the ICU: a randomized multicenter study
Authors: Cédric Daubin, Xavier Valette, Fabrice Thiolliere, Jean-Paul Mira, Pascal Hazera, Djillali Annane, Vincent Labbé, Bernard Floccard, François Fournel, Nicolas Terzi, Damien Du Cheyron, Jean-Jacques Parienti
Journal: Intensive Care Medicine (2018)

To compare the efficacy of an antibiotic protocol guided by serum procalcitonin (PCT) with that of standard antibiotic therapy in severe acute exacerbations of COPD (AECOPDs) admitted to the intensive care unit (ICU). We conducted a multicenter, randomized trial in France. Patients experiencing severe AECOPDs were assigned to groups whose antibiotic therapy was guided by (1) a 5-day PCT algorithm with predefined cutoff values for the initiation or stoppage of antibiotics (PCT group) or (2) standard guidelines (control group). The primary endpoint was 3-month mortality. The predefined noninferiority margin was 12%. A total of 302 patients were randomized into the PCT (n = 151) and control (n = 151) groups. Thirty patients (20%) in the PCT group and 21 patients (14%) in the control group died within 3 months of admission (adjusted difference, 6.6%; 90% CI − 0.3 to 13.5%). Among patients without antibiotic therapy at baseline (n = 119), the use of PCT significantly increased 3-month mortality [19/61 (31%) vs. 7/58 (12%), p = 0.015]. The in-ICU and in-hospital antibiotic exposure durations, were similar between the PCT and control group (5.2 ± 6.5 days in the PCT group vs. 5.4 ± 4.4 days in the control group, p = 0.85 and 7.9 ± 8 days in the PCT group vs. 7.7 ± 5.7 days in the control group, p = 0.75, respectively). The PCT group failed to demonstrate non-inferiority with respect to 3-month mortality and failed to reduce in-ICU and in-hospital antibiotic exposure in AECOPDs admitted to the ICU.
Risk stratification using transient elastography and the new scoring systems for patients with primary biliary cholangitis
Authors: L. Perini, N. Cazzagon, F.P. Russo, G. Leardini, V. Baldo, M.F. Secchi, N. Perin, C. Mangini, A. Zago, A. Floreani
Journal: Journal of Hepatology (2018)
Association of Marital Status With T Stage at Presentation and Management of Early-Stage Melanoma
Authors: Cimarron E. Sharon, Andrew J. Sinnamon, Michael E. Ming, Emily Y. Chu, Douglas L. Fraker, Giorgos C. Karakousis
Journal: JAMA Dermatology (2018)

<h3>Importance</h3> Early detection of melanoma is associated with improved patient outcomes. Data suggest that spouses or partners may facilitate detection of melanoma before the onset of regional and distant metastases. Less well known is the influence of marital status on the detection of early clinically localized melanoma. <h3>Objective</h3> To evaluate the association between marital status and T stage at the time of presentation with early-stage melanoma and the decision for sentinel lymph node biopsy (SLNB) in appropriate patients. <h3>Design, Setting, and Participants</h3> This retrospective, population-based study used the Surveillance, Epidemiology, and End Results database of 18 population-based registered cancer institutes. Patients with cutaneous melanoma who were at least 18 years of age and without evidence of regional or distant metastases and presented from January 1, 2010, through December 31, 2014, were identified for the study. Data were analyzed from September 27 to December 5, 2017. <h3>Exposure</h3> Marital status, categorized as married, never married, divorced, or widowed. <h3>Main Outcomes and Measures</h3> Clinical T stage at presentation and performance of SLNB for lesions with Breslow thickness greater than 1 mm. <h3>Results</h3> A total of 52 063 patients were identified (58.8% men and 41.2% women; median age, 64 years; interquartile range, 52-75 years). Among married patients, 16 603 (45.7%) presented with T1a disease, compared with 3253 never married patients (43.0%), 1422 divorced patients (39.0%), and 1461 widowed patients (32.2%) (<i>P</i> &lt; .001). Conversely, 428 widowed patients (9.4%) presented with T4b disease compared with 1188 married patients (3.3%) (<i>P</i> &lt; .001). The association between marital status and higher T stage at presentation remained significant among never married (odds ratio [OR], 1.32; 95% CI, 1.26-1.39;<i>P</i> &lt; .001), divorced (OR, 1.38; 95% CI, 1.30-1.47;<i>P</i> &lt; .001), and widowed (OR, 1.70; 95% CI, 1.60-1.81;<i>P</i> &lt; .001) patients after adjustment for various socioeconomic and patient factors. Independent of T stage and other patient factors, married patients were more likely to undergo SLNB in lesions with Breslow thickness greater than 1 mm, for which SLNB is routinely recommended, compared with never married (OR, 0.59; 95% CI, 0.53-0.65;<i>P</i> &lt; .001), divorced (OR, 0.87; 95% CI, 0.76-0.99;<i>P</i> = .03), and widowed (OR, 0.69; 95% CI, 0.62-0.76;<i>P</i> &lt; .001) patients. <h3>Conclusions and Relevance</h3> Marital status is associated with earlier presentation of localized melanoma. Moreover, never married, divorced, and widowed patients are less likely to undergo SLNB for appropriate lesions. Marital status should be considered when counseling patients for melanoma procedures and when recommending screening and follow-up to optimize patient care.
Impact of baclofen treatment in 212 alcohol-dependant patients of the french “OBADE-ANGH” series
Authors: C. Barrault, J.-F. Cadranel, C. Locher, T. Thévenot, F. Skinasi, D. Labarriere, B. Valerie, Y. Le Bricquir, V. Quentin, A. Garioud, C. Costentin, C. Jouan, H. Hagege, C. Jung
Journal: Journal of Hepatology (2018)
Efficacy and Tolerability of Mirabegron Compared with Antimuscarinic Monotherapy or Combination Therapies for Overactive Bladder: A Systematic Review and Network Meta-analysis
Authors: Con Kelleher, Zalmai Hakimi, Richard Zur, Emad Siddiqui, Khaled Maman, Samuel Aballéa, Jameel Nazir, Chris Chapple
Journal: European Urology (2018)

Mirabegron is an established treatment alternative to antimuscarinic therapy for patients with overactive bladder (OAB), as shown by efficacy and tolerability data from phase III trials. To assess efficacy and tolerability of mirabegron 50 mg versus antimuscarinic monotherapies and combination therapies. Systematic literature review and network meta-analysis of randomised controlled trials (2000–2017) assessing eligible treatments for OAB. Efficacy assessments included micturition frequency, urgency urinary incontinence, dry rate, and 50% reduction in incontinence. Tolerability assessments included dry mouth, constipation, blurred vision, and hypertension. A total of 64 studies (n = 46 666) were included in the network meta-analysis. Mirabegron 50 mg was significantly more efficacious than placebo for all efficacy endpoints. Comparable overall efficacy was observed for mirabegron 50 mg versus most active treatments, but solifenacin 10 mg monotherapy and solifenacin 5 mg plus mirabegron 25 or 50 mg in combination were more efficacious for some/all outcomes. Mirabegron 50 mg was significantly better tolerated regarding dry mouth, constipation, and urinary retention than 21/22, 9/20, and 7/10 active comparators, respectively; similar overall tolerability was observed between mirabegron 50 mg and all treatments (including placebo) for the remaining endpoints. Limitations of the study included between-trial variations in the definition of certain endpoints and heterogeneity of the available data (eg, number of studies and patients assessed) for comparator treatments across different endpoints. The relief of key OAB symptoms produced by mirabegron 50 mg is significantly better than placebo, and similar to a range of common antimuscarinics, with the benefit of significantly fewer bothersome anticholinergic side effects such as dry mouth. Combination treatment of solifenacin 5 mg plus mirabegron 25 or 50 mg appears to provide an efficacy benefit compared with mirabegron 50 mg, with the expected side effects of individual antimuscarinics. This study assessed the efficacy and tolerability of different drug treatments for OAB. Mirabegron 50 mg was as effective as antimuscarinic therapy, with fewer common, bothersome side effects such as dry mouth, constipation, and urinary retention. Combination treatment of solifenacin 5 mg plus mirabegron 25 or 50 mg was more effective than mirabegron 50 mg alone, but with more anticholinergic side effects.
Public versus internal conceptions of addiction: An analysis of internal Philip Morris documents
Authors: Jesse Elias, Yogi Hale Hendlin, Pamela M. Ling
Journal: PLoS Medicine (2018)

Background Tobacco addiction is a complex, multicomponent phenomenon stemming from nicotine's pharmacology and the user's biology, psychology, sociology, and environment. After decades of public denial, the tobacco industry now agrees with public health authorities that nicotine is addictive. In 2000, Philip Morris became the first major tobacco company to admit nicotine's addictiveness. Evolving definitions of addiction have historically affected subsequent policymaking. This article examines how Philip Morris internally conceptualized addiction immediately before and after this announcement. Methods and findings We analyzed previously secret, internal Philip Morris documents made available as a result of litigation against the tobacco industry. We compared these documents to public company statements and found that Philip Morris's move from public denial to public affirmation of nicotine's addictiveness coincided with pressure on the industry from poor public approval ratings, the Master Settlement Agreement (MSA), the United States government's filing of the Racketeer Influenced and Corrupt Organizations (RICO) suit, and the Institute of Medicine's (IoM's) endorsement of potentially reduced risk products. Philip Morris continued to research the causes of addiction through the 2000s in order to create successful potentially reduced exposure products (PREPs). While Philip Morris's public statements reinforce the idea that nicotine's pharmacology principally drives smoking addiction, company scientists framed addiction as the result of interconnected biological, social, psychological, and environmental determinants, with nicotine as but one component. Due to the fragmentary nature of the industry document database, we may have missed relevant information that could have affected our analysis. Conclusions Philip Morris's research suggests that tobacco industry activity influences addiction treatment outcomes. Beyond nicotine's pharmacology, the industry's continued aggressive advertising, lobbying, and litigation against effective tobacco control policies promotes various nonpharmacological determinants of addiction. To help tobacco users quit, policy makers should increase attention on the social and environmental dimensions of addiction alongside traditional cessation efforts.
Inflammasomes make the case for littermate-controlled experimental design in studying host-microbiota interactions
Authors: Michail Mamantopoulos, Francesca Ronchi, Kathy D. McCoy, Andy Wullaert
Journal: Gut Microbes (2018)

Several human diseases are thought to evolve due to a combination of host genetic mutations and environmental factors that include alterations in intestinal microbiota composition termed dysbiosis. Although in some cases, host genetics may shape the gut microbiota and enable it to provoke disease, experimentally disentangling cause and consequence in such host-microbe interactions requires strict control over non-genetic confounding factors. Mouse genetic studies previously proposed Nlrp6/ASC inflammasomes as innate immunity regulators of the intestinal ecosystem. In contrast, using littermate-controlled experimental setups, we recently showed that Nlrp6/ASC inflammasomes do not alter the gut microbiota composition. Our analyses indicated that maternal inheritance and long-term separate housing are non-genetic confounders that preclude the use of non-littermate mice when analyzing host genetic effects on intestinal ecology. Here, we summarize and discuss our gut microbiota analyses in inflammasome-deficient mice for illustrating the importance of littermate experimental design in studying host-microbiota interactions.