tbuckley/cabot-search huggingface dataset:
Abstract MP73: Ultra-processed Food Intake And All-cause And Cause-specific Mortality In Subjects With Type 2 Diabetes: Longitudinal Findings From The Moli-sani Study
Authors: Marialaura Bonaccio, Simona Costanzo, Augusto Di Castelnuovo, Mariarosaria Persichillo, Sara Magnacca, Amalia De Curtis, Chiara Cerletti, Maria Benedetta Donati, Giovanni de Gaetano, Licia Iacoviello
Journal: Circulation (2022)

Introduction: Excessive consumption of ultra-processed food (UPF) is associated with increased risk of mortality and disease in general populations but its health impact for individuals with type 2 diabetes is poorly defined. Hypothesis: We assessed the hypothesis of an association between elevated UPF intake and all-cause and cause-specific mortality among subjects with type 2 diabetes. We expect that elevated sugar content of UPF is on the pathway of this relation and that established risk factors might act as potential biological mechanisms linking UPF to mortality. Methods: Longitudinal analysis on 1,068 men and women (mean age 65±10 y) with type 2 diabetes, at the moment of their enrolled in the Moli-sani Study( between 2005 and 2010), and followed for 10.7 y (median). Food intake was assessed, at enrolment, by a 188-item food frequency questionnaire. UPF was defined using the NOVA classification according to degree of processing, and categorized as quartiles of the ratio (%) between UPF (g/d) and total food consumed (g/d). The possible mediating effects of 18 inflammatory, metabolic, cardiovascular and renal biomarkers were evaluated on the basis of percentage changes and associated p values. Results: Study participants reported a median UPF intake of 6.3% (interquartile range: 4.1-9.4%). Food mostly contributing to the total of UPF eaten were processed meat (22.4%), crispbread/rusks (16.6%), non-homemade pizza (11.2%), and cakes/pies/pastries (8.8%). In multivariable-adjusted COX analyses, higher intake of UPF (Q4, ≥9.4% of total food eaten), as opposed to the lowest (Q1, UPF&lt;4.1%), was associated with higher hazards of all-cause (Hazard ratio [HR]=1.72; 95%CI 1.22-2.41) and CVD mortality (HR=2.15; 1.23-3.77). A linear dose-response relationship of 1% increment in UPF intake with all-cause and CVD mortality was also observed. Elevated sugar content of UPF explained about 30% of these associations. Altered levels of serum creatinine accounted for 9.6% and 12.6% of the relation between UPF with all-cause and CVD mortality, respectively. Conclusions: An increased dietary share of UPF was associated with higher hazards of all-cause and CVD mortality among individuals with type 2 diabetes, possibly through the high sugar content of these products. Creatinine, as a marker of renal function, was likely on the pathway between UPF and mortality.
The International Brain Initiative: enabling collaborative science
Authors: Gianluca Quaglio, Patrizia Toia, Edvard I Moser, Theodoros Karapiperis, Katrin Amunts, Shigeo Okabe, Mu-ming Poo, Jong-Cheol Rah, Yves De Koninck, John Ngai, Linda Richards, Jan G Bjaalie
Journal: The Lancet Neurology (2021)
Bilateral Avid Axillary Nodes on FDG PET/CT Due to Concurrent Booster COVID-19 Immunization and Seasonal Influenza Vaccination
Authors: Ayah Adel Nawwar, Julie Searle, Iain Douglas Lyburn
Journal: Clinical Nuclear Medicine (2022)

In an attempt to protect the high-risk demographic and reduce burden on health care systems, concomitant administration of COVID-19 and influenza vaccines has been recommended by health bodies. The ComFluCOV trial indicates this is well tolerated with no reduction in immune response to either vaccine. A 48-year-old woman with right oropharyngeal squamous cell carcinoma underwent postradiotherapy FDG PET/CT, which demonstrated complete metabolic response. Incidental avid bilateral axillary lymphadenopathy of benign configuration was noted and concluded to be reactive in response to recent Pfizer-BioNTech booster and influenza vaccination. This is expected to be seen more frequently over the coming months.
Whole-genome sequencing as an investigational device for return of hereditary disease risk and pharmacogenomic results as part of the All of Us Research Program
Authors: Eric Venner, Donna Muzny, Joshua D. Smith, Kimberly Walker, Cynthia L. Neben, Christina M. Lockwood, Phillip E. Empey, Ginger A. Metcalf, Chris Kachulis, Sana Mian, Anjene Musick, Heidi L. Rehm, Steven Harrison, Stacey Gabriel, Richard A. Gibbs, Deborah Nickerson, Alicia Y. Zhou, Kimberly Doheny, Bradley Ozenberger, Scott E. Topper, Niall J. Lennon
Journal: Genome Medicine (2022)

Abstract Background The All of Us Research Program (AoURP, “the program”) is an initiative, sponsored by the National Institutes of Health (NIH), that aims to enroll one million people (or more) across the USA. Through repeated engagement of participants, a research resource is being created to enable a variety of future observational and interventional studies. The program has also committed to genomic data generation and returning important health-related information to participants. Methods Whole-genome sequencing (WGS), variant calling processes, data interpretation, and return-of-results procedures had to be created and receive an Investigational Device Exemption (IDE) from the United States Food and Drug Administration (FDA). The performance of the entire workflow was assessed through the largest known cross-center, WGS-based, validation activity that was refined iteratively through interactions with the FDA over many months. Results The accuracy and precision of the WGS process as a device for the return of certain health-related genomic results was determined to be sufficient, and an IDE was granted. Conclusions We present here both the process of navigating the IDE application process with the FDA and the results of the validation study as a guide to future projects which may need to follow a similar path. Changes to the program in the future will be covered in supplementary submissions to the IDE and will support additional variant classes, sample types, and any expansion to the reportable regions.
Cost-Minimization Analysis for Cardiac Revascularization in 12 Health Care Systems Based on the EuroCMR/SPINS Registries
Authors: Karine Moschetti, Raymond Y. Kwong, Steffen E. Petersen, Massimo Lombardi, Jerome Garot, Dan Atar, Frank E. Rademakers, Lilia M. Sierra-Galan, Sophie Mavrogeni, Kuncheng Li, Juliano Lara Fernandes, Steffen Schneider, Christophe Pinget, Yin Ge, Panagiotis Antiochos, Christina Deluigi, Oliver Bruder, Heiko Mahrholdt, Juerg Schwitter
Journal: JACC. Cardiovascular imaging (2022)

The aim of this study was to compare the costs of a noninvasive cardiac magnetic resonance (CMR)-guided strategy versus 2 invasive strategies with and without fractional flow reserve (FFR).Coronary artery disease (CAD) is a major contributor to the public health burden. Stress perfusion CMR has excellent accuracy to detect CAD. International guidelines recommend as a first step noninvasive testing of patients in stable condition with known or suspected CAD. However, nonadherence in routine clinical practice is high.In the EuroCMR (European Cardiovascular Magnetic Resonance) registry (n = 3,647, 59 centers, 18 countries) and the U.S.-based SPINS (Stress-CMR Perfusion Imaging in the United States) registry (n = 2,349, 13 centers, 11 states), costs were calculated for 12 health care systems (8 in Europe, the United States, 2 in Latin America, and 1 in Asia). Costs included diagnostic examinations (CMR and x-ray coronary angiography [CXA] with and without FFR), revascularizations, and complications during 1-year follow-up. Seven subgroup analyses covered low- to high-risk cohorts. Patients with ischemia-positive CMR underwent CXA and revascularization at the treating physician's discretion (CMR+CXA strategy). In the hypothetical invasive CXA+FFR strategy, costs were calculated for initial CXA and FFR in vessels with ≥50% stenoses, assuming the same proportion of revascularizations and complications as with the CMR+CXA strategy and FFR-positive rates as given in the published research. In the CXA-only strategy, costs included CXA and revascularizations of ≥50% stenoses.Consistent cost savings were observed for the CMR+CXA strategy compared with the CXA+FFR strategy in all 12 health care systems, ranging from 42% ± 20% and 52% ± 15% in low-risk EuroCMR and SPINS patients with atypical chest pain, respectively, to 31% ± 16% in high-risk SPINS patients with known CAD (P < 0.0001 vs 0 in all groups). Cost savings were even higher compared with CXA only, at 63% ± 11%, 73% ± 6%, and 52% ± 9%, respectively (P < 0.0001 vs 0 in all groups).In 12 health care systems, a CMR+CXA strategy yielded consistent moderate to high cost savings compared with a hypothetical CXA+FFR strategy over the entire spectrum of risk. Cost savings were consistently high compared with CXA only for all risk groups.
A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation
Authors: Florence Atrafi, Oliver Boix, Vivek Subbiah, Jennifer R. Diamond, Sant P. Chawla, Anthony W. Tolcher, Patricia M. LoRusso, Joseph P. Eder, Martin Gutierrez, Kumar Sankhala, Prabhu Rajagopalan, Isabelle Genvresse, Simon Langer, Ron H.J. Mathijssen, Jaap Verweij, Ingmar Bruns, Martijn P. Lolkema
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination. Patients and Methods: Patients with solid tumors were randomized to receive oral BAY (twice daily 2-days-on/5-days-off) with weekly paclitaxel (90 mg/m2) or paclitaxel monotherapy in cycle 1. Dose escalation was guided by CRM modeling. Primary objectives were to assess safety, establish the MTD of BAY, and to evaluate the pharmacokinetic profiles for both compounds. Simulations were performed to determine the contribution of the rCRM for dose determination. Results: In total, 75 patients were enrolled. The main dose-limiting toxicities were hematologic toxicities (55.6%). The MTD of BAY was established at 64 mg twice daily with paclitaxel. Inclusion of a control arm enabled the definitive attribution of grade ≥3 neutropenia to higher BAY exposure [AUC0–12 (P&amp;lt; 0.001)]. After determining the MTD, we included 19 patients with breast cancer at this dose for dose expansion. Other common toxicities were nausea (45.3%), fatigue (41.3%), and diarrhea (40.0%). Overall confirmed responses were seen in 31.6% of evaluable patients. Simulations showed that rCRM outperforms traditional designs in determining the true MTD. Conclusions: The combination of BAY with paclitaxel was associated with considerable toxicity without a therapeutic window. However, the use of the rCRM design enabled us to determine the exposure–toxicity relation for BAY. Therefore, we propose that the rCRM could improve dose determination in phase I trials that combine agents with overlapping toxicities.
Single-Cell Analyses Reveal Mechanisms of Cancer Stem Cell Maintenance and Epithelial–Mesenchymal Transition in Recurrent Bladder Cancer
Authors: Huanjun Wang, Yan Mei, Cheng Luo, Qun Huang, Zifeng Wang, Guan-Ming Lu, Lili Qin, Zhun Sun, Chao-Wen Huang, Zhi-Wen Yang, Junxing Chen, Weiguo Yin, Chao-Nan Qian, Jianming Zeng, Lingwu Chen, Qibin Leng, Yan Guo, Guangshuai Jia
Journal: Clinical Cancer Research (2021)

Bladder cancer treatment remains a major clinical challenge due to therapy resistance and a high recurrence rate. Profiling intratumor heterogeneity can reveal the molecular mechanism of bladder cancer recurrence.Here, we performed single-cell RNA sequencing and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) on tumors from 13 patients with low recurrence risk, high recurrence risk, and recurrent bladder cancer.Our study generated a comprehensive cancer-cell atlas consisting of 54,971 single cells and identified distinct cell subpopulations. We found that the cancer stem-cell subpopulation is enriched during bladder cancer recurrence with elevated expression of EZH2. We further defined a subpopulation-specific molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of the NCAM1 gene, thereby inactivating the cell invasive and stemness transcriptional program. Furthermore, taking advantage of this large single-cell dataset, we elucidated the spectrum of epithelial-mesenchymal transition (EMT) in clinical samples and revealed distinct EMT features associated with bladder cancer subtypes. We identified that TCF7 promotes EMT in corroboration with single-cell ATAC with high-throughput sequencing (scATAC-seq) analysis. Additionally, we constructed regulatory networks specific to recurrent bladder cancer.Our study and analytic approaches herein provide a rich resource for the further study of cancer stem cells and EMT in the bladder cancer research field.
Abstract P105: Bypasses To Below-Knee Arteries May Expedite Amputation In Patients With Claudication
Authors: Corey A Kalbaugh, Brian Witrick, Kerry A Howard, Katharine L McGinigle, Catherine R Lesko
Journal: Circulation (2022)

Objective: Claudication is an early-stage subtype of peripheral artery disease that may result in surgical intervention. The purpose of this study was to compare the types of elective bypass in a population of Black and White patients with claudication and to identify actionable areas that may explain the higher limb amputation rates observed in Black patients. Methods: We identified Black and White patients undergoing elective infrainguinal bypass for claudication using data from the Vascular Quality Initiative registry (2011-2018). Distal bypass target was classified as 1) at or above the popliteal artery (above-knee) or 2) below the popliteal, including all tibial, peroneal, dorsalis pedis and tarsal/plantar arteries (below-knee). Graft conduit was categorized as vein or prosthetic. We calculated one-year risk of major lower limb amputation with 95% confidence intervals (CI) for all combinations of target and conduit, stratified by race. We then forced an intervention on the data to estimate the post-intervention incidence of amputation and the proportion of racial disparity eliminated and 95% CI if everyone received the gold standard treatment (above-knee, vein). Results: We identified 8,401 infrainguinal bypass revascularizations for claudication (12% Black/88% White); 82% were performed above-knee and 44% of those used a vein conduit. The remaining 18% of bypasses were to below-knee arteries, of which 78% used a vein conduit. The remaining 1,534 (18.3%) bypasses were to below-knee arteries, including 1,197 (78.4%) using vein and 330 (21.6%) using prosthetic material. One-year incidence of major limb amputation was 1.6% (1.3%,1.9%) among all grafts, 1.2% (1.0%,1.5%) in above-knee grafts, and 3.3% (2.4%,4.2%) in below-knee grafts. Black patients had higher incidence of amputation across bypass target/conduit groups compared to White patients; the difference was greatest for below-knee revascularizations (8.9%, 95% CI: 4.8%,12.3% v 2.1%, 95% CI: 0.9%,2.9%). Pre-intervention amputation incidence was 1.3% (1.0%,1.5%) in White patients and 3.6% (1.9%,5.2%) in Black patients. Overall amputation incidence decreased significantly after our gold standard intervention was applied for both White (1.0%; 0.7%,1.2%) and Black (2.0%; 0.7%,3.2%) patients. The risk difference (i.e. the disparity gap) between Black and White patients was lessened post-intervention by 56.8% (31.9%,116.3%). Conclusions: We observed risk of amputation higher than would be expected based on other studies of the natural history of claudication without bypass surgery; future work should identify the mechanisms that alter the natural history of claudication via open bypass surgery. Interventions below-knee or using a prosthetic graft were particularly harmful and their harm was concentrated in Black patients.
Medical countermeasures against henipaviruses: a review and public health perspective
Authors: Raúl Gómez Román, Nadia Tornieporth, Neil George Cherian, Amy C Shurtleff, Maïna L’Azou Jackson, Debra Yeskey, Adam Hacker, Eric Mungai, Tung Thanh Le
Journal: The Lancet Infectious Diseases (2021)

Henipaviruses, including Nipah virus, are regarded as pathogens of notable epidemic potential because of their high pathogenicity and the paucity of specific medical countermeasures to control infections in humans. We review the evidence of medical countermeasures against henipaviruses and project their cost in a post-COVID-19 era. Given the sporadic and unpredictable nature of henipavirus outbreaks, innovative strategies will be needed to circumvent the infeasibility of traditional phase 3 clinical trial regulatory pathways. Stronger partnerships with scientific institutions and regulatory authorities in low-income and middle-income countries can inform coordination of appropriate investments and development of strategies and normative guidelines for the deployment and equitable use of multiple medical countermeasures. Accessible measures should include global, regional, and endemic in-country stockpiles of reasonably priced small molecules, monoclonal antibodies, and vaccines as part of a combined collection of products that could help to control henipavirus outbreaks and prevent future pandemics.
Abstract 11397: Impact of Von Willebrand Factor Multimer Abnormalities on Blood Loss After Aortic Valve Replacement Using the Semi-Automated Hydragel 5 Multimer Assay
Authors: Marwan Hamiko, Lena Gerdes, Holger Seidel, Philipp Westhoven, Johannes Kruppenbacher, Hans-Jörg Hertfelder, Zaki Kohistani, Georg Daniel Duerr
Journal: Circulation (2021)

Introduction: Acquired von Willebrand syndrome (aVWS) is common in patients with severe aortic stenosis (sAS), which is characterized by the loss of high-molecular-weight multimers (HMWM) of the von Willebrand factor (VWF). VWF abnormalities are improved after surgical aortic valve replacement (SAVR). While conventional multimer analysis is technically challenging, lengthy and non-standardized, recently a new semi-automated multimer assay, the Hydragel 5 VWF multimers (H5VWM) has become available. Therefore, the aim of our study was to analyze VWF abnormalities by H5VWM in patients undergoing SAVR in terms of echocardiography parameter and perioperative bleeding. Methods: We prospectively included 52 patients (age: 67.9±7.2 years; 53.8% male) undergoing SAVR. Patients were divided in two groups (A: abnormal VWF, n=24; B: normal VWF, n=28). Blood samples and echocardiographic data were collected at three time points (TP): day before SAVR (TP1), 7 days (TP2), and 3 months (TP3) after SAVR. Blood loss from chest drainage and the use of blood and haemostatic products were evaluated peri- and postoperatively. Results: Baseline characteristics were similar in both groups. Loss of HMWM was present in 38.5%. After SAVR the level of HMWM had increased significantly compared to baseline in group A. At TP3, we observed no loss of HMWM at all. Bleeding occurred in 15% (A: 17% vs. B: 14%; p&gt;0.999) with need of re-thoracotomy in about 10% (A: 8% vs. B: 11%; p&gt;0.999). There was no significant difference in postoperative bleeding in the first 24hrs (A: 491 ml vs. B: 701ml; p=0.255). Also, peri- and postoperative need of blood transfusion and haemostatic agents were similar between both groups. HMWM was inversely correlated with the peak aortic gradient (R=-0.557; p&lt;0.001) and positively correlated with the aortic valve area (R=0.292; p=0.04). Conclusion: Loss of HMWM was not associated with increased postoperative bleeding in patients with sAS. Echocardiographic parameters could predict the loss of HMWM. The complete restoration of altered VWF at three months postoperatively, demonstrated by H5VWM, seems to be indicative for successful SVAR. Therefore, H5VWM, as a rapid and sensitive assay, could be included as diagnostic tool of suspected aVWS in AS patients.
Perivascular Fibrosis Is Mediated by a KLF10-IL-9 Signaling Axis in CD4+ T Cells
Authors: Rulin Zhuang, Jingshu Chen, Henry S. Cheng, Carmel Assa, Anurag Jamaiyar, Arvind K. Pandey, Daniel Pérez-Cremades, Bofang Zhang, Aspasia Tzani, Akm Khyrul Wara, Jorge Plutzky, Victor Barrera, Preetida Bhetariya, Richard N. Mitchell, Zhongmin Liu, Mark W. Feinberg
Journal: Circulation Research (2022)

Perivascular fibrosis, characterized by increased amount of connective tissue around vessels, is a hallmark for vascular disease. Ang II (angiotensin II) contributes to vascular disease and end-organ damage via promoting T-cell activation. Despite recent data suggesting the role of T cells in the progression of perivascular fibrosis, the underlying mechanisms are poorly understood.
Modulating Endothelial Cells with EGFL7 to Diminish aGVHD after Allogeneic Bone Marrow Transplantation in Mice
Authors: Martin Guimond, Moutuaata Moutuou, Chinmayee Goda, Nathalie Sell, Sonu Kaylan, Malith Karunasiri, Rohan SUDHIR Kulkarni, Marie Goulard, Sofia Kovovich, Eric Naumann, Antoire Ackaoui, Charles-Etienne Bigras, Francis Daudelin, Alex Ruddich, Ramiro Garzon, Parvathi Ranganathan, Adrienne M. Dorrance
Journal: Blood (2021)
Integrated Stress Response Couples Mitochondrial Protein Translation With Oxidative Stress Control
Authors: Guangyu Zhang, Xiaoding Wang, Chao Li, Qinfeng Li, Yu A. An, Xiang Luo, Yingfeng Deng, Thomas G. Gillette, Philipp E. Scherer, Zhao V. Wang
Journal: Circulation (2021)

The integrated stress response (ISR) is an evolutionarily conserved process to cope with intracellular and extracellular disturbances. Myocardial infarction is a leading cause of death worldwide. Coronary artery reperfusion, the most effective means to mitigate cardiac damage of myocardial infarction, causes additional reperfusion injury. This study aimed to investigate the role of the ISR in myocardial ischemia/reperfusion (I/R).Cardiac-specific gain- and loss-of-function approaches for the ISR were used in vivo. Myocardial I/R was achieved by ligation of the cardiac left anterior descending artery for 45 minutes followed by reperfusion for different times. Cardiac function was assessed by echocardiography. Cultured H9c2 cells, primary rat cardiomyocytes, and mouse embryonic fibroblasts were used to dissect underlying molecular mechanisms. Tandem mass tag labeling and mass spectrometry was conducted to identify protein targets of the ISR. Pharmacologic means were tested to manipulate the ISR for therapeutic exploration.We show that the PERK (PKR-like endoplasmic reticulum resident kinase)/eIF2α (α subunit of eukaryotic initiation factor 2) axis of the ISR is strongly induced by I/R in cardiomyocytes in vitro and in vivo. We further reveal a physiologic role of PERK/eIF2α signaling by showing that acute activation of PERK in the heart confers robust cardioprotection against reperfusion injury. In contrast, cardiac-specific deletion of PERK aggravates cardiac responses to reperfusion. Mechanistically, the ISR directly targets mitochondrial complexes through translational suppression. We identify NDUFAF2 (NADH:ubiquinone oxidoreductase complex assembly factor 2), an assembly factor of mitochondrial complex I, as a selective target of PERK. Overexpression of PERK suppresses the protein expression of NDUFAF2 and PERK inhibition causes an increase of NDUFAF2. Silencing of NDUFAF2 significantly rescues cardiac cell survival from PERK knockdown under I/R. We show that activation of PERK/eIF2α signaling reduces mitochondrial complex-derived reactive oxygen species and improves cardiac cell survival in response to I/R. Moreover, pharmacologic stimulation of the ISR protects the heart against reperfusion damage, even after the restoration of occluded coronary artery, highlighting clinical relevance for myocardial infarction treatment.These results suggest that the ISR improves cell survival and mitigates reperfusion damage by selectively suppressing mitochondrial protein synthesis and reducing oxidative stress in the heart.