tbuckley/cabot-search huggingface dataset:
Integrated safety analysis of filgotinib in patients with moderately to severely active rheumatoid arthritis receiving treatment over a median of 1.6 years
Authors: Kevin L Winthrop, Yoshiya Tanaka, Tsutomu Takeuchi, Alan Kivitz, Franziska Matzkies, Mark C Genovese, Deyuan Jiang, Kun Chen, Beatrix Bartok, Angelika Jahreis, Robin Besuyen, Gerd R Burmester, Jacques-Eric Gottenberg
Journal: Annals of the Rheumatic Diseases (2021)

To characterise safety of the Janus kinase-1 preferential inhibitor filgotinib in patients with moderately to severely active rheumatoid arthritis.Data were integrated from seven trials (NCT01668641, NCT01894516, NCT02889796, NCT02873936, NCT02886728, NCT02065700, NCT03025308). Results are from placebo (PBO)-controlled (through week (W)12) and long-term, as-treated (all available data for patients receiving ≥1 dose filgotinib 200 (FIL200) or 100 mg (FIL100) daily) datasets. We calculated exposure-adjusted incidence rates (EAIRs)/100 patient-years filgotinib exposure (100PYE) for treatment-emergent adverse events (TEAEs).3691 patients received filgotinib for 6080.7 PYE (median 1.6, maximum 5.6 years). During the PBO-controlled period, TEAEs, including those of grade ≥3, occurred at comparable rates with filgotinib or PBO; long-term EAIRs of TEAEs grade ≥3 were 6.4 and 7.6/100PYE for FIL200 and FIL100. EAIRs for deaths were 0.6/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 0.5 and 0.3/100PYE for FIL200 and FIL100. EAIRs for serious infection were 3.9, 3.3 and 2.4/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 1.6 and 3.1/100PYE for FIL200 and FIL100. EAIRs for herpes zoster were 0.6, 1.1, and 1.1/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 1.8 and 1.1/100PYE for FIL200 and FIL100. EAIRs for major adverse cardiovascular events were 0, 1.7 and 1.1/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 0.4 and 0.6/100PYE for FIL200 and FIL100. No venous thromboembolism occurred during the PBO-controlled period; long-term EAIRs were 0.2 and 0/100PYE for FIL200 and FIL100.Over a median of 1.6 and maximum of 5.6 years of exposure, safety/tolerability of FIL200 and FIL100 were similar, with a lower incidence of infections with FIL200 among the long-term, as-treated dataset.
TCT-67 Mechanical Circulatory Support in Patients With COVID-19 Presenting With Myocardial Infarction: Analysis From the North American COVID-19 Myocardial Infarction Registry
Authors: Raviteja Guddeti, Cristina Sanina, Timothy Henry, Payam Dehghani, Ross Garberich, Christian Schmidt, Keshav Nayak, Jay Shavadia, Akshay Bagai, Chadi Alraies, Aditya Mehra, Santiago Garcia
Journal: Journal of the American College of Cardiology (2021)
TCT-172 Risk Stratification and Management of Advanced Conduction Disturbances After TAVI in Patients With Preexisting RBBB
Authors: Toshiaki Isogai, Iryna Dykun, Ankit Agrawal, Shashank Shekhar, Beni Verma, Omar Abdelfattah, Ankur Kalra, Amar Krishnaswamy, Grant Reed, Samir Kapadia, Rishi Puri
Journal: Journal of the American College of Cardiology (2021)
TCT-349 Transcatheter Correction of Superior Sinus Venosus Atrial Septal Defect (SVASD) Using Self-Expandable Aortic Stent Graft: A Case Series
Authors: Radha Yalamanchi, Refai Showkathali, Raja Reddy, C.S. Muthukumaran, K. Chandra
Journal: Journal of the American College of Cardiology (2021)
Covid-19: Symptom tracking app shows UK surge may be bigger than reported
Authors: Chris Baraniuk
Journal: BMJ (2021)

Covid-19: Symptom tracking app shows UK surge may be bigger than reported Chris BaraniukCases of covid-19 in the UK could be nearly twice as high as the official figures, shows modelling by researchers who run a smartphone symptoms app. 1 1 ZOE Covid Study.Covid reaches new highs for 2021.Oct 2021.https://covid.joinzoe
When Women and Children Made the Policy Agenda — The Sheppard–Towner Act, 100 Years Later
Authors: Jeffrey P. Baker
Journal: New England Journal of Medicine (2021)

Interview with Dr. Jeffrey Baker on a short-lived 1921 law that supported U.S. women and children. (09:20)Download One hundred years ago, the Sheppard–Towner Maternity and Infancy Protection Act launched a striking policy experiment. Had the program survived, the country might have developed a model for promoting child health that integrated preventive care with social services.
TCT-197 Independent Clinical and Echocardiographic Predictors of Restenosis After Percutaneous Mitral Balloon Commissurotomy Followed for 24 Years
Authors: Rafael Alexandre Meneguz-Moreno, Alfredo Nunes Ferreira Filho, Nisia Gomes, Auristela Ramos, Zilda Meneghelo, J. Italo Franca, Amanda Sousa, Sergio Braga, Dimytri Siqueira, J. Eduardo Sousa, Jose Costa
Journal: Journal of the American College of Cardiology (2021)
Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial
Authors: Stephanie Kullmann, Julia Hummel, Robert Wagner, Corinna Dannecker, Andreas Vosseler, Louise Fritsche, Ralf Veit, Konstantinos Kantartzis, Jürgen Machann, Andreas L. Birkenfeld, Norbert Stefan, Hans-Ulrich Häring, Andreas Peter, Hubert Preissl, Andreas Fritsche, Martin Heni
Journal: Diabetes Care (2021)

OBJECTIVE Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since sodium–glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance. RESEARCH DESIGN AND METHODS In this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age 60 ± 9 years; BMI 31.5 ± 3.8 kg/m2) with prediabetes were randomized to receive 25 mg empagliflozin every day or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain. RESULTS We identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin-treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated the empagliflozin-induced decrease in fasting glucose and liver fat. CONCLUSIONS Our results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity, a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.
TCT-375 High Syntax Score and Left Main Percutaneous Coronary Intervention in High-Risk Patients: Long-Term Follow-Up Real-World Experience of a Single Center Without On-Site Cardiac Surgery
Authors: Ignacio Sanchez-Perez, Ricardo Concepcion-Suárez, Fernando Lozano, Ariana Gonzálvez-García, Manuel Muñoz Garcia, Jorge Martinez del Río, Alfonso Morón Alguacil, Martin Negreira, Pedro Pérez-Díaz, Alfonso Freites Esteves
Journal: Journal of the American College of Cardiology (2021)
TCT-464 Outcomes of Patients With Bifurcation Lesions: Preliminary Results From the Prospective Global Registry for the Study of Bifurcation Lesion Interventions (PROGRESS-BIFURCATION) Registry
Authors: Judit Karacsonyi, Spyridon Kostantinis, Alessandra Gutierrez, Vennela Avula, Bahadir Simsek, M. Nicholas Burke, Santiago Garcia, Mario Goessl, Paul Sorajja, Ivan Chavez, Michael Mooney, Anil Poulose, Jay Traverse, Yale Wang, Imre Ungi, Ilias Nikolakopoulos, Evangelia Vemmou, Raviteja Guddeti, Bavana Rangan, Emmanouil Brilakis
Journal: Journal of the American College of Cardiology (2021)
Cluster Analysis of Cardiovascular Phenotypes in Patients With Type 2 Diabetes and Established Atherosclerotic Cardiovascular Disease: A Potential Approach to Precision Medicine
Authors: Abhinav Sharma, Yinggan Zheng, Justin A. Ezekowitz, Cynthia M. Westerhout, Jacob A. Udell, Shaun G. Goodman, Paul W. Armstrong, John B. Buse, Jennifer B. Green, Robert G. Josse, Keith D. Kaufman, Darren K. McGuire, Giuseppe Ambrosio, Lee-Ming Chuang, Renato D. Lopes, Eric D. Peterson, Rury R. Holman
Journal: Diabetes Care (2021)

OBJECTIVE Phenotypic heterogeneity among patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) is ill defined. We used cluster analysis machine-learning algorithms to identify phenotypes among trial participants with T2DM and ASCVD. RESEARCH DESIGN AND METHODS We used data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study (n = 14,671), a cardiovascular outcome safety trial comparing sitagliptin with placebo in patients with T2DM and ASCVD (median follow-up 3.0 years). Cluster analysis using 40 baseline variables was conducted, with associations between clusters and the primary composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) assessed by Cox proportional hazards models. We replicated the results using the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial. RESULTS Four distinct phenotypes were identified: cluster I included Caucasian men with a high prevalence of coronary artery disease; cluster II included Asian patients with a low BMI; cluster III included women with noncoronary ASCVD disease; and cluster IV included patients with heart failure and kidney dysfunction. The primary outcome occurred, respectively, in 11.6%, 8.6%, 10.3%, and 16.8% of patients in clusters I to IV. The crude difference in cardiovascular risk for the highest versus lowest risk cluster (cluster IV vs. II) was statistically significant (hazard ratio 2.74 [95% CI 2.29–3.29]). Similar phenotypes and outcomes were identified in EXSCEL. CONCLUSIONS In patients with T2DM and ASCVD, cluster analysis identified four clinically distinct groups. Further cardiovascular phenotyping is warranted to inform patient care and optimize clinical trial designs.
CST6 protein and peptides inhibit breast cancer bone metastasis by suppressing CTSB activity and osteoclastogenesis
Authors: Xiaoxun Li, Yajun Liang, Cheng Lian, Fangli Peng, Yansen Xiao, Yunfei He, Chengxin Ma, Yuan Wang, Peiyuan Zhang, Yuhan Deng, Yunpeng Su, Cheng Luo, Xiangyin Kong, Qingcheng Yang, Tong Liu, Guohong Hu
Journal: Theranostics (2021)

Background: Bone metastasis is a frequent symptom of breast cancer and current targeted therapy has limited efficacy. Osteoclasts play critical roles to drive osteolysis and metastatic outgrowth of tumor cells in bone. Previously we identified CST6 as a secretory protein significantly downregulated in bone-metastatic breast cancer cells. Functional analysis showed that CST6 suppresses breast-to-bone metastasis in animal models. However, the functional mechanism and therapeutic potential of CST6 in bone metastasis is unknown. Methods: Using in vitro osteoclastogenesis and in vivo metastasis assays, we studied the effect and mechanism of extracellular CST6 protein in suppressing osteoclastic niches and bone metastasis of breast cancer. A number of peptides containing the functional domain of CST6 were screened to inhibit bone metastasis. The efficacy, stability and toxicity of CST6 recombinant protein and peptides were evaluated in preclinical metastasis models. Results: We show here that CST6 inhibits osteolytic bone metastasis by inhibiting osteoclastogenesis. Cancer cell-derived CST6 enters osteoclasts by endocytosis and suppresses the cysteine protease CTSB, leading to up-regulation of the CTSB hydrolytic substrate SPHK1. SPHK1 suppresses osteoclast maturation by inhibiting the RANKL-induced p38 activation. Importantly, recombinant CST6 protein effectively suppresses bone metastasis in vitro and in vivo. We further identified several peptides mimicking the function of CST6 to suppress cancer cell-induced osteoclastogenesis and bone metastasis. Pre-clinical analyses of CTS6 recombinant protein and peptides demonstrated their potentials in treatment of breast cancer bone metastasis. Conclusion: These findings reveal the CST6-CTSB-SPHK1 signaling axis in osteoclast differentiation and provide a promising approach to treat bone diseases with CST6-based peptides.
Early Adversity and Development: Parsing Heterogeneity and Identifying Pathways of Risk and Resilience
Authors: Dylan G. Gee
Journal: American Journal of Psychiatry (2021)

Adversity early in life is common and is a major risk factor for the onset of psychopathology. Delineating the neurodevelopmental pathways by which early adversity affects mental health is critical for early risk identification and targeted treatment approaches. A rapidly growing cross-species literature has facilitated advances in identifying the mechanisms linking adversity with psychopathology, specific dimensions of adversity and timing-related factors that differentially relate to outcomes, and protective factors that buffer against the effects of adversity. Yet, vast complexity and heterogeneity in early environments and neurodevelopmental trajectories contribute to the challenges of understanding risk and resilience in the context of early adversity. In this overview, the author highlights progress in four major areas—mechanisms, heterogeneity, developmental timing, and protective factors; synthesizes key challenges; and provides recommendations for future research that can facilitate progress in the field. Translation across species and ongoing refinement of conceptual models have strong potential to inform prevention and intervention strategies that can reduce the immense burden of psychopathology associated with early adversity.
Abstract MP008: Fatty Liver, Visceral Adipose Tissue and Atherosclerotic Calcification: The Jackson Heart Study
Authors: Jiankang Liu, Aurelian Bidulescu, Solomon K Musani, John J Carr, James G Wilson, Herman A Taylor, Caroline S Fox
Journal: Circulation (2012)

Background: Both fatty liver and abdominal visceral fat (VAT) are independently associated with cardiometabolic risk factors. We investigated whether fatty liver and VAT are jointly associated with coronary artery (CAC) or abdominal aortoiliac (AAC) calcification. Methods: Jackson Heart Study (JHS) participants (n=2884, mean age 60 years, 65% women) underwent CT assessment for assessment of fatty liver, VAT, and CAC and AAC. Fatty liver was measured by liver attenuation (LA; low LA=high fatty liver). Cross-sectional associations between LA, VAT, CAC and AAC were examined in logistic regression models. Results: LA (per 1-standard deviation [SD] decrement) was associated with CAC in the age-, sex-adjusted (OR 0.84, 95%CI 0.7–0.9, p=0.0001 ) and multivariable adjusted model including age, sex, smoking and alcohol, systolic blood pressure, treatments for hypertension, dyslipidemia and diabetes, total cholesterol and HDLC (OR 0.89, 95%CI 0.8–0.9, p=0.02 ). The association persisted for LA with CAC when additionally adjusted for VAT (OR 0.89, 95%CI 0.8–0.9, p=0.04 ) or body mass index (BMI) (OR 0.89, 95%CI 0.8–0.9, p=0.04 ). Abdominal VAT (per 1-SD increment) was associated with CAC in age-, sex-adjusted models (OR 1.27, 95%CI 1.2–1.4, p=0.0001 ), but the association was attenuated in the multivariable adjusted model (OR 1.10, 95%CI 0.9–1.2, p=0.09 ) or with additional adjustment for LA ( p = 0.24 ) or BMI ( p = 0.36 ). For AAC, the associations with LA and VAT were only present in the age-, sex-adjusted model. In addition, we did not observe interactions between LA and VAT for CAC ( p=0.18 ) or AAC ( p=0.24 ). Conclusion: Fatty liver, but not VAT, is independently associated with atherosclerotic calcification in African American men and women and these observations persist after accounting for VAT or BMI.
Primary vulvar squamous cell carcinomas with high T cell infiltration and active immune signaling are potential candidates for neoadjuvant PD-1/PD-L1 immunotherapy
Authors: Kim E Kortekaas, Saskia J Santegoets, Liselotte Tas, Ilina Ehsan, Pornpimol Charoentong, Helena C van Doorn, Mariette I E van Poelgeest, Dana A M Mustafa, Sjoerd H van der Burg
Journal: Journal for ImmunoTherapy of Cancer (2021)

A profound insight into the immune landscape of vulvar squamous cell carcinoma (VSCC) is lacking. Here, an in-depth interrogation of T cell infiltration, local immune contexture, signaling pathways and checkpoint molecule expression was performed in early-stage and late-stage VSCC.The type, location, and infiltration pattern of T cells were studied in 109 patients with primary VSCC FIGO stage I-III. RNA expression of genes involved in immune oncology and oncogenic signaling pathways was analyzed in 40 VSCC, matched for prognostic clinicopathological variables, analyzed for HPV and p53 status, and selected based on T cell infiltration.High intraepithelial infiltration with CD4 or CD8 T cells was associated with longer overall and recurrence-free survival and formed an independent prognostic factor, outperforming molecular subtype and stage of the disease. Strong T cell infiltrated VSCC displayed a coordinated immune response reflected by a positive association between T cells and different lymphocyte and myeloid cell subsets. The expression of genes involved in the migration of T cells and myeloid cells, T cell activation and costimulation, interferon (IFN)-γ signaling, cytotoxicity and apoptosis was higher than in low infiltrated tumors. An active immune signaling profile was observed in all inflamed, part of the altered-excluded and not in altered-immunosuppressed or deserted VSCC. While several checkpoint molecules were overexpressed, only PD-L1 expression displayed discriminatory ability and clinical usefulness. High PD-L1 expression was detected in all inflamed and ~60% of the altered-excluded VSCC.An active immune signaling profile is present in 35% of primary FIGO I-III VSCCs, suggesting potential responsiveness to neoadjuvant PD-1/PD-L1 immunotherapy.
External validation of a refined four-stratum risk assessment score from the French pulmonary hypertension registry
Authors: Athénaïs Boucly, Jason Weatherald, Laurent Savale, Pascal de Groote, Vincent Cottin, Grégoire Prévot, Ari Chaouat, François Picard, Delphine Horeau-Langlard, Arnaud Bourdin, Etienne-Marie Jutant, Antoine Beurnier, Mitja Jevnikar, Xavier Jaïs, Gérald Simonneau, David Montani, Olivier Sitbon, Marc Humbert
Journal: European Respiratory Journal (2021)

Contemporary risk assessment tools categorise patients with pulmonary arterial hypertension (PAH) as low, intermediate or high risk. A minority of patients achieve low risk status with most remaining intermediate risk. Our aim was to validate a four-stratum risk assessment approach categorising patients as low, intermediate-low, intermediate-high or high risk, as proposed by the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) investigators.We evaluated incident patients from the French PAH Registry and applied a four-stratum risk method at baseline and at first reassessment. We applied refined cut-points for three variables: World Health Organization functional class, 6-min walk distance and N-terminal pro-brain natriuretic peptide. We used Kaplan-Meier survival analyses and Cox proportional hazards regression to assess survival according to three-stratum and four-stratum risk approaches.At baseline (n=2879), the four-stratum approach identified four distinct risk groups and performed slightly better than a three-stratum method for predicting mortality. Four-stratum model discrimination was significantly higher than the three-stratum method when applied during follow-up and refined risk categories among subgroups with idiopathic PAH, connective tissue disease-associated PAH, congenital heart disease and portopulmonary hypertension. Using the four-stratum approach, 53% of patients changed risk category from baseline compared to 39% of patients when applying the three-stratum approach. Those who achieved or maintained a low risk status had the best survival, whereas there were more nuanced differences in survival for patients who were intermediate-low and intermediate-high risk.The four-stratum risk assessment method refined risk prediction, especially within the intermediate risk category of patients, performed better at predicting survival and was more sensitive to change than the three-stratum approach.
Scratching the surface of RGD-directed AAV capsid engineering
Authors: Sergei Zolotukhin, Prasad D. Trivedi, Manuela Corti, Barry J. Byrne
Journal: Molecular Therapy (2021)

Over the last few decades, cell adhesion receptors have been studied as potential biotherapeutic targets for muscle tissues. Integrins, which belong to this heterodimeric superfamily, play multi-faceted roles in signal transduction. In addition, integrins play a major role in regulating cancer (progression, metastasis, and angiogenesis), sepsis, fibrosis, and viral infections. 1 Ludwig B.S. Kessler H. Kossatz S. Reuning U. RGD-binding integrins revisited: how recently discovered functions and novel synthetic ligands (re-)shape an ever-evolving field. Cancers (Basel). 2021; 13: 1711 Crossref PubMed Scopus (17) Google Scholar In the recent issue of Cell, Tabebordbar et al. 2 Tabebordbar M. Lagerborg K.A. Stanton A. King E.M. Ye S. Tellez L. Krunnfusz A. Tavakoli S. Widrick J.J. Messemer K.A. et al. Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species. Cell. 2021; 184: 4919-4938.e22 Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar describe the engineering of efficient adeno-associated virus (AAV) capsid variants targeting specific tissues or cell types of interest, but more specifically skeletal muscle following intravenous delivery to mice and non-human primates (NHPs). The necessity of the integrin heterodimers for the infectivity of this new MyoAAV class of capsid plays a very important role in their skeletal muscle tropism. Undoubtedly, strategies such as that described by Tabebordbar et al. will continue to expand the frontier of genetic medicines for inherited muscle disease based on recombinant AAV, which were originally described with first-generation AAV vectors. 3 Kessler P.D. Podsakoff G.M. Chen X. McQuiston S.A. Colosi P.C. Matelis L.A. Kurtzman G.J. Byrne B.J. Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein. Proc. Natl. Acad. Sci. U S A. 1996; 93: 14082-14087 Crossref PubMed Scopus (532) Google Scholar ,4 Xiao X. Li J. Samulski R.J. Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J. Virol. 1996; 70: 8098-8108 Crossref PubMed Google Scholar
ERCP: see one, do one, teach a few? Not everybody needs to learn everything!
Authors: Raf Bisschops
Journal: Endoscopy (2021)

Endoscopic retrograde cholangiopancreatography (ERCP) is by far the best example of a complex invasive endoscopic procedure. The procedure is life-saving and prevents significant surgery; on the other hand, it also entails a significant risk. The recent evolution where ERCP goes hand in hand with interventional endoscopic ultrasound (EUS) for third-space endoscopy makes proper skills acquisition even more challenging. It is therefore not surprising that, during the last decade, quality assurance in ERCP and, following that, training in ERCP have received increasing interest.
Annual Review of Pathology: Mechanisms of Disease
Authors: Abul K. Abbas, James R. Downing, Vinay Kumar
Journal: Annual Review of Pathology Mechanisms of Disease (2017)

Tumor cells release extracellular vesicles (EVs) that can function as mediators of intercellular communication in the tumor microenvironment. EVs contain a host of bioactive cargo, including membrane, cytosolic, and nuclear proteins, in addition to ...Read More