tbuckley/cabot-search huggingface dataset:
The Role of Nonglycolytic Glucose Metabolism in Myocardial Recovery Upon Mechanical Unloading and Circulatory Support in Chronic Heart Failure
Authors: Rachit Badolia, Dinesh K.A. Ramadurai, E. Dale Abel, Peter Ferrin, Iosif Taleb, Thirupura S. Shankar, Aspasia Thodou Krokidi, Sutip Navankasattusas, Stephen H. McKellar, Michael Yin, Abdallah G. Kfoury, Omar Wever-Pinzon, James C. Fang, Craig H. Selzman, Dipayan Chaudhuri, Jared Rutter, Stavros G. Drakos
Journal: Circulation (2020)

Background: Significant improvements in myocardial structure and function have been reported in some patients with advanced heart failure (termed responders [R]) following left ventricular assist device (LVAD)–induced mechanical unloading. This therapeutic strategy may alter myocardial energy metabolism in a manner that reverses the deleterious metabolic adaptations of the failing heart. Specifically, our previous work demonstrated a post-LVAD dissociation of glycolysis and oxidative-phosphorylation characterized by induction of glycolysis without subsequent increase in pyruvate oxidation through the tricarboxylic acid cycle. The underlying mechanisms responsible for this dissociation are not well understood. We hypothesized that the accumulated glycolytic intermediates are channeled into cardioprotective and repair pathways, such as the pentose-phosphate pathway and 1-carbon metabolism, which may mediate myocardial recovery in R. Methods: We prospectively obtained paired left ventricular apical myocardial tissue from nonfailing donor hearts as well as R and nonresponders at LVAD implantation (pre-LVAD) and transplantation (post-LVAD). We conducted protein expression and metabolite profiling and evaluated mitochondrial structure using electron microscopy. Results: Western blot analysis shows significant increase in rate-limiting enzymes of pentose-phosphate pathway and 1-carbon metabolism in post-LVAD R (post-R) as compared with post-LVAD nonresponders (post-NR). The metabolite levels of these enzyme substrates, such as sedoheptulose-6-phosphate (pentose phosphate pathway) and serine and glycine (1-carbon metabolism) were also decreased in Post-R. Furthermore, post-R had significantly higher reduced nicotinamide adenine dinucleotide phosphate levels, reduced reactive oxygen species levels, improved mitochondrial density, and enhanced glycosylation of the extracellular matrix protein, α-dystroglycan, all consistent with enhanced pentose-phosphate pathway and 1-carbon metabolism that correlated with the observed myocardial recovery. Conclusions: The recovering heart appears to direct glycolytic metabolites into pentose-phosphate pathway and 1-carbon metabolism, which could contribute to cardioprotection by generating reduced nicotinamide adenine dinucleotide phosphate to enhance biosynthesis and by reducing oxidative stress. These findings provide further insights into mechanisms responsible for the beneficial effect of glycolysis induction during the recovery of failing human hearts after mechanical unloading.
TCT-27 Safety and Effectiveness of Coronary Intravascular Lithotripsy for Treatment of Severely Calcified Coronary Stenoses: The Disrupt CAD II Study
Authors: Ziad Ali, Holger Nef, Javier Escaned, Nikos Werner, Adrian Banning, Jonathan Hill, Matteo Montorfano, Thierry Lefevre, Gregg Stone, Alexandra Lansky
Journal: Journal of the American College of Cardiology (2019)
Abstract 1842: Inflammatory Activation In Patients With Lone Atrial Fibrillation: New Insights By Coronary Sinus Thermography.
Authors: Konstantinos Toutouzas, Maria Drakopoulou, Sophia Vaina, Polychronis Dilaveris, Kostas Gatzoulis, John Karabelas, Maria Riga, Elli Stefanadi, Dimitrios Tousoulis, Christodoulos Stefanadis
Journal: Circulation (2007)

Background: In the clinical setting there are conflicting results regarding the role of inflammatory activation in atrial fibrillation (AF). Coronary sinus (CS) thermography assesses myocardial heat production and is correlated with inflammatory states. The purpose of this study was to investigate in patients (pts) with AF whether there is increased CS blood temperature and the correlation of heat production with systemic inflammation. Methods: We included pts with AF and subjects with sinus rhythm (controls). C-reactive protein (CRP) levels were measured in all pts. CS and right atrium (RA) blood temperature measurements were performed by a dedicated 7F thermography catheter. ΔT was calculated by subtracting RA from CS blood temperature. Results: We included 70 pts: 47 with lone AF and 23 controls. We stratified pts with AF into two groups: normotensive (AFN; n=25) and hypertensive (AFH; n=22). Heart rate was similar between the three groups (AFH: 72.91±4.11/min, AFN: 72.84±4.50/min control:72.52±4.19/min, p=0.89). Mean blood temperature was lower in the RA compared with the CS in AFH (37.27±0.52°C vs 37.47±0.54°C, p&lt;0.01), in AFN (37.13±0.53°C vs 37.34±0.54°C, p&lt;0.01), and in controls (37.41±0.69°C vs 37.55±0.68°C, p&lt;0.01). ΔT was greater in AFH, and AFN compared to controls (0.20±0.07°C, 0.20±0.08°C, vs 0.14±0.06°C, p&lt;0.01 for both comparisons). ΔT was similar between AFH and AFN (p=0.95). CRP was higher in AFH and AFN compared to controls (1.72±0.85mg/Dl, 1.69±0.94mg/dL vs 0.98±0.71 mg/dL, p&lt;0.01). CRP was similar between AFH and AFN (p=0.87). Pts with high ΔT (≥0.15°C) had significantly higher CRP compared to pts with low ΔT (1.73±0.95mg/dL vs 1.01±0.57 mg/dL, p=0.01). A correlation between CRP levels with ΔT was observed in AFH and AFN (R=0.58, p&lt;0.01, R=0.44, p=0.02, respectively). Multiple linear regression analysis confirmed that pts with lone AF (b±SE: 0.07±0.02, p=0.01) and pts with hypertension and AF (b±SE: 0.07±0.03, p=0.03) had higher ΔT compared to the control group. Conclusions: Pts with AF have increased myocardial heat production, which is correlated to the systemic inflammation. CS blood temperature measurement may provide significant information for the pathogenesis of AF.
A report from the Brescia Renal COVID Task Force on the clinical characteristics and short-term outcome of hemodialysis patients with SARS-CoV-2 infection
Authors: Federico Alberici, Elisa Delbarba, Chiara Manenti, Laura Econimo, Francesca Valerio, Alessandra Pola, Camilla Maffei, Stefano Possenti, Bernardo Lucca, Roberta Cortinovis, Vincenzo Terlizzi, Mattia Zappa, Chiara Saccà, Elena Pezzini, Eleonora Calcaterra, Paola Piarulli, Alice Guerini, Francesca Boni, Agnese Gallico, Alberto Mucchetti, Stefania Affatato, Sergio Bove, Martina Bracchi, Ester Maria Costantino, Roberto Zubani, Corrado Camerini, Paola Gaggia, Ezio Movilli, Nicola Bossini, Mario Gaggiotti, Francesco Scolari
Journal: Kidney International (2020)

The SARS-CoV-2 epidemic is pressuring healthcare systems worldwide. Disease outcomes in certain subgroups of patients are still scarce, and data are needed. Therefore, we describe here the experience of four dialysis centers of the Brescia Renal COVID Task Force. During March 2020, within an overall population of 643 hemodialysis patients, SARS-CoV-2 RNA positivity was detected in 94 (15%). At disease diagnosis, 37 of the 94 (39%) patients (group 1) were managed on an outpatient basis, whereas the remaining 57 (61%) (group 2) required hospitalization. Choices regarding management strategy were made based on disease severity. In group 1, 41% received antivirals and 76% hydroxychloroquine. Eight percent died and 5% developed acute respiratory distress syndrome (ARDS). In group 2, 79% received antivirals and 77% hydroxychloroquine. Forty two percent died and 79% developed ARDS. Overall mortality rate for the entire cohort was 29%. History of ischemic cardiac disease, fever, older age (over age 70), and dyspnea at presentation were associated with the risk of developing ARDS, whereas fever, cough and a C-reactive protein higher than 50 mg/l at disease presentation were associated with the risk of death. Thus, in our population of hemodialysis patients with SARS-CoV-2 infection, we documented a wide range of disease severity. The risk of ARDS and death is significant for patients requiring hospital admission at disease diagnosis.
Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma
Authors: Alain P. Algazi, Christopher G. Twitty, Katy K. Tsai, Mai Le, Robert Pierce, Erica Browning, Reneta Hermiz, David A. Canton, Donna Bannavong, Arielle Oglesby, Murray Francisco, Lawrence Fong, Mikael J. Pittet, Sean P. Arlauckas, Christopher Garris, Lauren P. Levine, Carlos Bifulco, Carmen Ballesteros-Merino, Shailender Bhatia, Sharron Gargosky, Robert H.I. Andtbacka, Bernard A. Fox, Michael D. Rosenblum, Adil I. Daud
Journal: Clinical Cancer Research (2020)

Tumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL).Tavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progression-free survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done.The combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses.The combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors.
Diabetes as a risk factor for periodontal disease—plausible mechanisms
Authors: David Polak, Terukazu Sanui, Fusanori Nishimura, Lior Shapira
Journal: Periodontology 2000 (2020)

The present narrative review examines the scientific evidence of the biological mechanisms that may link periodontitis and diabetes, as a source of comorbidity. Publications regarding periodontitis and diabetes, in human, animals, and in vitro were screened for their relevance. Periodontal microbiome studies indicate a possible association between altered glucose metabolism in prediabetes and diabetes and changes in the periodontal microbiome. Coinciding with this, hyperglycemia enhances expression of pathogen receptors, which enhance host response to the dysbiotic microbiome. Hyperglycemia also promotes pro-inflammatory response independently or via the advanced glycation end product/receptor for advanced glycation end product pathway. These processes excite cellular tissue destruction functions, which further enhance pro-inflammatory cytokines expression and alteration in the RANKL/osteoprotegerin ratio, promoting formation and activation of osteoclasts. The evidence supports the role of several pathogenic mechanisms in the path of true causal comorbidity between poorly controlled diabetes and periodontitis. However, further research is needed to better understand these mechanisms and to explore other mechanisms.
Hepatitis C virus RNA and liver histology in blood donors reactive to a single antigen by second-generation recombinant immunoblot assay*1
Authors: A ZANELLA
Journal: Hepatology (1995)

The clinical significance of single band reactivity (indeterminate pattern) at anti-hepatitis C virus (HCV) second-generation recombinant immunoblot assay (RIBA-2) was investigated in symptomless subjects with normal liver function tests to obtain data for their counseling and clinical management. Serum and hepatic HCV RNA were determined by the nested polymerase chain reaction, and liver histology was evaluated in 40 symptomless blood donors with stable indeterminate RIBA-2 pattern, including 38 reactive to c22-3. All but one had normal alanine aminotransferase (ALT) levels. Two new immunoblot tests, RIBA-3 and INNO-LIA HCV Ab III (LIA-III), which incorporate additional HCV antigens, were also done to assess whether they could identify the viremic subjects. Ten cases (25%, confidence interval 12 to 38) were HCV RNA positive. Three of the HCV RNA-positive and none of the HCV RNA-negative subjects had chronic hepatitis. RIBA-2 strong intensity of reaction (score >2+) was observed in all the HCV RNA-positive and in 12 HCV RNA-negative subjects. RIBA-3 and LIA-III gave positive results in 9 of 10 and 10 of 10 HCV RNApositive, but also in 8 of 30 and 24 of 30 HCV RNAnegative subjects. A c-22-3 reactivity score of 4+ by RIBA-3 and E2/NS1 reactivity by LIA-III were both strongly associated with HCV RNA (P < .001). Based on relatively high prevalence of chronic hepatitis in our series (30%), apparently healthy subjects with stable indeterminate RIBA-2 pattern and HCV RNA positivity should be considered for liver biopsy independently of ALT profile. Reactivity to particular HCV antigens by third-generation tests helped to identify the subjects with current infection.
Targeting the inflammatory cascade with anakinra in moderate to severe COVID-19 pneumonia: case series
Authors: Achille Aouba, Aurelie Baldolli, Loïk Geffray, Renaud Verdon, Emmanuel Bergot, Nicolas Martin-Silva, Aurélien Justet
Journal: Annals of the Rheumatic Diseases (2020)

<h3>Background</h3> To investigate the thinning rate of three-dimensional neuroretinal rim thickness (3D-NRT) in glaucoma eyes with optic disc haemorrhage (DH) and its relationship to retinal nerve fibre layer thickness (RNFLT) progression. <h3>Methods</h3> Ninety-five (95) eyes of 95 glaucoma patients with initial DH in the inferotemporal (n=69) and superotemporal (n=26) regions and 48 eyes of 48 glaucoma patients without DH were retrospectively reviewed. The rates of change for 3D-NRT and RNFLT were compared by linear mixed-effect model. For the direct comparison between 3D-NRT and RNFLT, dynamic-range-based normalised coefficient was used. The effect of DH frequency on the rates of thinning of 3D-NRT and RNFLT was evaluated. <h3>Results</h3> During a mean 7-year follow-up, the rates of thinning of 3D-NRT (–5.69±4.88 µm/year) and RNFLT (–2.03±2.03 µm/year) at 7 o’clock were faster than those at other locations (all p&lt;0.05) in DH eyes. The dynamic-range-based normalised rate of thinning was significantly faster for RNFLT (–2.06%±1.62%/year) than for 3D-NRT (–1.15%±1.10%/year, p&lt;0.001) in DH eyes, but not in non-DH eyes (p=0.43). DH frequency in the inferotemporal region was associated with the thinning rate of 3D-NRT as well as RNFLT. <h3>Conclusion</h3> DH eyes are associated with the progression of both 3D-NRT and RNFLT, especially in the inferotemporal region. DH eyes show a relatively faster thinning rate of average RNFLT than 3D-NRT. The frequency of DH can affect the progression of 3D-NRT as well as RNFLT.
First results of abciximab (ReoPro) in the treatment of acute myocardial infarction and primary PTCA: the GRAPE pilot study
Authors: L.F.M. van den Merkhof, A. Liem, F. Zijlstra, H. Olsson, G. Veen, C. de Zwaan, F. Bär, C. van der Zwaan, M.L. Simoons, F.W.A. Verheugt, H. Nilsson, L. Grip
Journal: Circulation (1997)
Improving rheumatoid arthritis comparative effectiveness research through causal inference principles: systematic review using a target trial emulation framework
Authors: Sizheng Steven Zhao, Houchen Lyu, Daniel H Solomon, Kazuki Yoshida
Journal: Annals of the Rheumatic Diseases (2020)

Objectives Target trial emulation is an intuitive design framework that encourages investigators to formulate their comparative effectiveness research (CER) question as a hypothetical randomised controlled trial (RCT). Our aim was to systematically review CER studies in rheumatoid arthritis (RA) to provide examples of design limitations that could be avoided using target trial emulation, and how these limitations might introduce bias. Methods We searched for head-to-head CER studies of biologic disease modifying anti-rheumatic drugs (DMARDs) in RA. Study designs were reviewed for seven components of the target trial emulation framework: eligibility criteria, treatment strategies, assignment procedures, follow-up period, outcome, causal contrasts of interest (ie, intention-to-treat (ITT) or per-protocol effect) and analysis plan. Hypothetical trials corresponding to the reported methods were assessed to identify design limitations that would have been avoided with an explicit target trial protocol. Analysis of the primary effectiveness outcome was chosen where multiple analyses were performed. Results We found 31 CER studies, of which 29 (94%) had at least one design limitation belonging to seven components. The most common limitations related to: (1) eligibility criteria: 19/31 (61%) studies used post-baseline information to define baseline eligibility; (2) causal contrasts: 25 (81%) did not define whether ITT or per-protocol effects were estimated and (3) assignment procedures: 13 (42%) studies did not account for confounding by indication or relied solely on statistical confounder selection. Conclusions Design limitations were found in 94% of observational CER studies in RA. Target trial emulation is a structured approach for designing observational CER studies that helps to avoid potential sources of bias.
COVID-19 “Fulminant Myocarditis” Successfully Treated With Temporary Mechanical Circulatory Support
Authors: Jorge Salamanca, Pablo Díez-Villanueva, Pablo Martínez, Alberto Cecconi, Begoña González de Marcos, Guillermo Reyes, Clara Salas, Javier Segovia, Luis Jesús Jiménez-Borreguero, Fernando Alfonso
Journal: JACC. Cardiovascular imaging (2020)
Effect of a Face-Aging Mobile App–Based Intervention on Skin Cancer Protection Behavior in Secondary Schools in Brazil
Authors: Titus J. Brinker, Bianca Lisa Faria, Olber Moreira de Faria, Joachim Klode, Dirk Schadendorf, Jochen S. Utikal, Ute Mons, Eva Krieghoff-Henning, Oscar Campos Lisboa, Ana Carla Cruz Oliveira, Henrique Augusto Lino, Breno Bernardes-Souza
Journal: JAMA Dermatology (2020)

Because exposure to UV radiation early in life is an important risk factor for melanoma development, reducing UV exposure in children and adolescents is of paramount importance. New interventions are urgently required.To determine the effect of the free face-aging mobile app Sunface on the skin cancer protection behavior of adolescents.This cluster-randomized clinical trial included a single intervention and a 6-month follow-up from February 1 to November 30, 2018. Randomization was performed on the class level in 52 school classes within 8 public secondary schools (grades 9-12) in Itauna, Southeast Brazil. Data were analyzed from May 1 to October 10, 2019.In a classroom seminar delivered by medical students, adolescents' selfies were altered by the app to show UV effects on their future faces and were shown in front of their class, accompanied by information about UV protection. Information about relevant parameters was collected via anonymous questionnaires before and 3 and 6 months after the intervention.The primary end point of the study was the difference in daily sunscreen use at 6 months of follow-up. Secondary end points included the difference in daily sunscreen use at 3 months of follow-up, at least 1 skin self-examination within 6 months, and at least 1 tanning session in the preceding 30 days. All analyses were predefined and based on intention to treat. Cluster effects were taken into account.Participants included 1573 pupils (812 girls [51.6%] and 761 boys [48.4%]; mean [SD] age, 15.9 [1.3] years) from 52 school classes. Daily sunscreen use increased from 110 of 734 pupils (15.0%) to 139 of 607 (22.9%; P < .001) at the 6-month follow-up in the intervention group. The proportion of pupils performing at least 1 skin self-examination in the intervention group rose from 184 of 734 (25.1%) to 300 of 607 (49.4%; P < .001). Use of tanning decreased from 138 of 734 pupils (18.8%) to 92 of 607 (15.2%; P = .04). No significant changes were observed in the control group. The intervention was more effective for female students (number needed to treat for the primary end point: 8 for girls and 31 for boys).These findings suggest that interventions based on face-aging apps may increase skin cancer protection behavior in Brazilian adolescents. Further studies are required to maximize the effect and to investigate the generalizability of the effects.ClinicalTrials.gov Identifier: NCT03178240.
Details of a New Anti-Coronovirus Neutralizing Antibody
Authors: Derek Lowe
Journal: Science Translational Medicine (2020)

There’s a lot of work being done on antibodies for the coronavirus and on the protein domains they recognize  This of course has bearing both on the idea of monoclonal antibody therapies and for the vaccines that are in development, so let’s have a look at the new data  For reference, here’s a background post on some of the proteins that the virus makes and the mutations that have been spotted in them, here’s my post on the basics of antibodies and immunology as relating to the epidemic, with an update here, and here’s my earlier post on monoclonal antibodies as a treatment, now updated with some new items
Peripheral clearance of brain-derived Aβ in Alzheimer's disease: pathophysiology and therapeutic perspectives
Authors: Yuan Cheng, Ding-Yuan Tian, Yan-Jiang Wang
Journal: Translational Neurodegeneration (2020)

Abstract Alzheimer’s disease (AD) is the most common type of dementia, and no disease-modifying treatments are available to halt or slow its progression. Amyloid-beta (Aβ) is suggested to play a pivotal role in the pathogenesis of AD, and clearance of Aβ from the brain becomes a main therapeutic strategy for AD. Recent studies found that Aβ clearance in the periphery contributes substantially to reducing Aβ accumulation in the brain. Therefore, understanding the mechanism of how Aβ is cleared in the periphery is important for the development of effective therapies for AD. In this review, we summarized recent findings on the mechanisms of Aβ efflux from the brain to the periphery and discuss where and how the brain-derived Aβ is cleared in the periphery. Based on these findings, we propose future strategies to enhance peripheral Aβ clearance for the prevention and treatment of AD. This review provides a novel perspective to understand the pathogenesis of AD and develop interventions for this disease from a systemic approach.
Genomic characterization of patients with polycythemia vera developing resistance to hydroxyurea
Authors: Alberto Alvarez-Larrán, Alvaro Díaz-González, Esperanza Such, Elvira Mora, Marcio Andrade-Campos, Carmen García-Hernández, M. Teresa Gómez-Casares, Valentín García-Gutiérrez, Gonzalo Carreño-Tarragona, Marta Garrote, Lierni Fernández-Ibarrondo, José Cervera, Beatriz Bellosillo, Francisco Cervantes, Juan Carlos Hernández-Boluda
Journal: Leukemia (2020)
Regulatory T Cell-Specific Epigenomic Region Variants Are a Key Determinant of Susceptibility to Common Autoimmune Diseases
Authors: Naganari Ohkura, Yoshiaki Yasumizu, Yohko Kitagawa, Atsushi Tanaka, Yamami Nakamura, Daisuke Motooka, Shota Nakamura, Yukinori Okada, Shimon Sakaguchi
Journal: Immunity (2020)