tbuckley/cabot-search huggingface dataset:
An Analysis of Hospital Costs for Childhood Cancer Care
Authors: Owen Tan, Deborah J. Schofield, Rupendra Shrestha
Journal: Journal of the National Comprehensive Cancer Network (2021)

This study used a linked dataset consisting of all childhood cancers recorded over the course of 10 years in New South Wales (NSW), Australia, to evaluate the hospital and emergency department costs (from a payer perspective) and resources used by patients with childhood cancer. We also analyzed determinants responsible for high-frequency hospital admissions, hospital length of stay (LoS), and hospital costs.We analyzed linked data at the individual patient level for a retrospective cohort of 2,966 patients with cancer aged <18 years with a diagnosis date between 2001 and 2012 from the NSW Central Cancer Registry, Australia. We reported costs and use of hospitalization and emergency department presentation 1 year before the date of diagnosis, 1 year after diagnosis, and 2 to 5 years after diagnosis. We also examined the association between cancer types and hospital admission and hospital costs from the payer perspective. Patient characteristics associated with the frequency of hospital admissions, hospital LoS, and hospital costs were also determined using a generalized linear model.Most hospital admission costs occurred in the first year after diagnosis, accounting for >70% of hospital costs within 5 years after diagnosis. The estimated median annual cost of hospitalization in the first year after diagnosis was A$88,964 (interquartile range [IQR], A$34,399-A$163,968) for patients diagnosed at age 0 to 14 years and A$23,384 (IQR, A$5,585-A$91,565) for those diagnosed at age 15 to 17 years. Higher frequency of hospital admissions, hospital LoS, and hospital costs were significantly associated with younger age at cancer diagnosis, cancer metastases, and living in remote/disadvantaged socioeconomic areas.Our study represents one of the first in Australia to include detailed hospitalization cost information for all childhood cancer cases. This study highlights the high hospital use by pediatric patients and the importance of early diagnosis. Our findings also demonstrate the health inequities experienced by patients from remote areas and the lowest socioeconomic areas.
Patient-Reported Goals of Youths in Canada Receiving Medication-Assisted Treatment for Opioid Use Disorder
Authors: Darren Chai, Tea Rosic, Balpreet Panesar, Nitika Sanger, Emma A. van Reekum, David C. Marsh, Andrew Worster, Lehana Thabane, Zainab Samaan
Journal: JAMA Network Open (2021)

<h3>Importance</h3> In the literature on opioid use disorder (OUD), opioid abstinence is used as an outcome measure for individuals receiving medication-assisted treatment (MAT), without consideration of patient-reported goals (PRGs). <h3>Objectives</h3> To identify common PRGs for youths receiving MAT for OUD and assess whether these patients achieve their stated goals. <h3>Design, Setting, and Participants</h3> This prospective cohort study examined data from 152 individuals aged 16 to 25 years (noninclusive) recruited between May 22, 2018, and March 11, 2020, from 45 outpatient MAT clinics in the Pharmacogenetics of Opioid Substitution Treatment Response study. Youths receiving MAT for OUD were included and were followed up for 3 months. <h3>Exposures</h3> Medication-assisted treatment for OUD. <h3>Main Outcomes and Measures</h3> The frequency of each PRG; the success of goal attainment, compared between those who reported specific PRGs and those who did not; and associations between reporting certain goals and achieving them. <h3>Results</h3> Among the 152 youths in the study, 82 were male (53.9%), and the mean (SD) age was 22.8 (1.8) years. Ten overarching goals were identified, with the most common being to taper the dose of or stop MAT (96 [63.2%]), avoid use of recreational substances (71 [46.7%]), manage OUD symptoms (25 [16.4%]), live a normal life (14 [9.2%]), improve mental health (11 [7.2%]), and gain employment (8 [5.3%]). Overall, individuals who reported PRGs had similar odds of achieving them as those who did not for the goals of taper dose of or stop MAT (OR, 1.98; 95% CI, 0.88-4.46;<i>P</i> = .10), avoid recreational substances (OR, 1.34; 95% CI, 0.65-2.74;<i>P</i> = .43), manage OUD symptoms (β coefficient, –0.93; 95% CI, –4.24 to 2.38;<i>P</i> = .58), and improve mental health (β coefficient, –0.76; 95% CI, –6.31 to 4.78;<i>P</i> = .79). Furthermore, multivariable logistic regression showed that goals to taper the dose of or stop MAT (odds ratio, 1.90; 95% CI, 0.78-4.63;<i>P</i> = .16) or avoid recreational substances (odds ratio, 1.27; 95% CI, 0.60-2.67;<i>P</i> = .53) were not associated with achieving these respective outcomes. <h3>Conclusions and Relevance</h3> This study suggests that youths have highly variable PRGs regarding MAT for OUD and that reporting a goal may not mean one is at higher odds of achieving it. There is a need to develop treatment plans that effectively incorporate PRGs. In addition, the finding that most youths aim to minimize or stop their MAT dose warrants the creation of a tapering protocol to guide clinicians. Because a diagnosis of OUD has substantial psychosocial implications in this population, clinicians must ensure that these dimensions of care are part of routine clinical practice.
Vascular endothelial tissue factor contributes to trimethylamine N-oxide-enhanced arterial thrombosis
Authors: Marco Witkowski, Mario Witkowski, Julian Friebel, Jennifer A Buffa, Xinmin S Li, Zeneng Wang, Naseer Sangwan, Lin Li, Joseph A DiDonato, Caroline Tizian, Arash Haghikia, Daniel Kirchhofer, François Mach, Lorenz Räber, Christian M Matter, W H Wilson Tang, Ulf Landmesser, Thomas F Lüscher, Ursula Rauch, Stanley L Hazen
Journal: Cardiovascular Research (2021)

Abstract Aims Gut microbiota and their generated metabolites impact the host vascular phenotype. The metaorganismal metabolite trimethylamine N-oxide (TMAO) is both associated with adverse clinical thromboembolic events, and enhances platelet responsiveness in subjects. The impact of TMAO on vascular Tissue Factor (TF) in vivo is unknown. Here, we explore whether TMAO-enhanced thrombosis potential extends beyond TMAO effects on platelets, and is linked to TF. We also further explore the links between gut microbiota and vascular endothelial TF expression in vivo. Methods and results In initial exploratory clinical studies, we observed that among sequential stable subjects (n = 2989) on anti-platelet therapy undergoing elective diagnostic cardiovascular evaluation at a single-site referral centre, TMAO levels were associated with an increased incident (3 years) risk for major adverse cardiovascular events (MACE) (myocardial infarction, stroke, or death) [4th quartile (Q4) vs. Q1 adjusted hazard ratio (HR) 95% confidence interval (95% CI), 1.73 (1.25–2.38)]. Similar results were observed within subjects on aspirin mono-therapy during follow-up [adjusted HR (95% CI) 1.75 (1.25–2.44), n = 2793]. Leveraging access to a second higher risk cohort with previously reported TMAO data and monitoring of anti-platelet medication use, we also observed a strong association between TMAO and incident (1 year) MACE risk in the multi-site Swiss Acute Coronary Syndromes Cohort, focusing on the subset (n = 1469) on chronic dual anti-platelet therapy during follow-up [adjusted HR (95% CI) 1.70 (1.08–2.69)]. These collective clinical data suggest that the thrombosis-associated effects of TMAO may be mediated by cells/factors that are not inhibited by anti-platelet therapy. To test this, we first observed in human microvascular endothelial cells that TMAO dose-dependently induced expression of TF and vascular cell adhesion molecule (VCAM)1. In mouse studies, we observed that TMAO-enhanced aortic TF and VCAM1 mRNA and protein expression, which upon immunolocalization studies, was shown to co-localize with vascular endothelial cells. Finally, in arterial injury mouse models, TMAO-dependent enhancement of in vivo TF expression and thrombogenicity were abrogated by either a TF-inhibitory antibody or a mechanism-based microbial choline TMA-lyase inhibitor (fluoromethylcholine). Conclusion Endothelial TF contributes to TMAO-related arterial thrombosis potential, and can be specifically blocked by targeted non-lethal inhibition of gut microbial choline TMA-lyase.
Atypical antipsychotic drugs deregulate the cholesterol metabolism of macrophage-foam cells by activating NOX-ROS-PPARγ-CD36 signaling pathway
Authors: Chia-Hui Chen, Shr-Jeng Jim Leu, Chiao-Po Hsu, Ching-Chian Pan, Song-Kun Shyue, Tzong-Shyuan Lee
Journal: Metabolism (2021)

Clinical reports indicate that schizophrenia patients taking atypical antipsychotic drugs suffer from metabolism diseases including atherosclerosis. However, the mechanisms underlying the detrimental effect of atypical antipsychotic drugs on atherosclerosis remain to be explored.In this study, we used apolipoprotein E-deficient (apoe-/-) hyperlipidemic mice and apoe-/-cd36-/- mice to investigate the underlying mechanism of atypical antipsychotic drugs on atherosclerosis and macrophage-foam cells.In vivo studies showed that genetic deletion of cd36 gene ablated the pro-atherogenic effect of olanzapine in apoe-/- mice. Moreover, in vitro studies revealed that genetic deletion or siRNA-mediated knockdown of cd36 or pharmacological inhibition of CD36 prevented atypical antipsychotic drugs-induced oxLDL accumulation in macrophages. Additionally, olanzapine and clozapine activated NADPH oxidase (NOX) to generate reactive oxygen species (ROS) which upregulated the activity of peroxisome proliferator-activated receptor γ (PPARγ) and subsequently elevated CD36 expression. Inhibition of NOX activity, ROS production or PPARγ activity suppressed CD36 expression and abolished the detrimental effects of olanzapine and clozapine on oxLDL accumulation in macrophages.Collectively, our results suggest that atypical antipsychotic drugs exacerbate atherosclerosis and macrophage-foam cell formation by activating the NOX-ROS-PPARγ-CD36 pathway.
Therapeutic approaches targeting molecular signaling pathways common to diabetes, lung diseases and cancer
Authors: Rajeswari Raguraman, Akhil Srivastava, Anupama Munshi, Rajagopal Ramesh
Journal: Advanced Drug Delivery Reviews (2021)

Diabetes mellitus (DM), is the most common metabolic disease and is characterized by sustained hyperglycemia. Accumulating evidences supports a strong association between DM and numerous lung diseases including chronic obstructive pulmonary disease (COPD), fibrosis, and lung cancer (LC). The global incidence of DM-associated lung disorders is rising and several ongoing studies, including clinical trials, aim to elucidate the molecular mechanisms linking DM with lung disorders, in particular LC. Several potential mechanisms, including hyperglycemia, hyperinsulinemia, glycation, inflammation, and hypoxia, are cited as plausible links between DM and LC. In addition, studies also propose a connection between the use of anti-diabetic medications and reduction in the incidence of LC. However, the exact cause for DM associated lung diseases especially LC is not clear and is an area under intense investigation. Herein, we review the biological links reported between DM and lung disorders with an emphasis on LC. Furthermore, we report common signaling pathways (eg: TGF-β, IL-6, HIF-1, PDGF) and miRNAs that are dysregulated in DM and LC and serve as molecular targets for therapy. Finally, we propose a nanomedicine based approach for delivering therapeutics (eg: IL-24 plasmid DNA, HuR siRNA) to disrupt signaling pathways common to DM and LC and thus potentially treat DM-associated LC. Finally, we conclude that the effective modulation of commonly regulated signaling pathways would help design novel therapeutic protocols for treating DM patients diagnosed with LC.
Affinity maturation of SARS-CoV-2 neutralizing antibodies confers potency, breadth, and resilience to viral escape mutations
Authors: Frauke Muecksch, Yiska Weisblum, Christopher O. Barnes, Fabian Schmidt, Dennis Schaefer-Babajew, Zijun Wang, Julio C. C. Lorenzi, Andrew I. Flyak, Andrew T. DeLaitsch, Kathryn E. Huey-Tubman, Shurong Hou, Celia A. Schiffer, Christian Gaebler, Justin Da Silva, Daniel Poston, Shlomo Finkin, Alice Cho, Melissa Cipolla, Thiago Y. Oliveira, Katrina G. Millard, Victor Ramos, Anna Gazumyan, Magdalena Rutkowska, Marina Caskey, Michel C. Nussenzweig, Pamela J. Bjorkman, Theodora Hatziioannou, Paul D. Bieniasz
Journal: Immunity (2021)
Hepatitis E virus RNA‐dependent RNA polymerase is involved in RNA replication and infectious particle production
Authors: Noémie Oechslin, Nathalie Da Silva, Dagmara Szkolnicka, François‐Xavier Cantrelle, Xavier Hanoulle, Darius Moradpour, Jérôme Gouttenoire
Journal: Hepatology (2021)

Abstract Background and Aims Hepatitis E virus (HEV) is one of the most common causes of acute hepatitis worldwide. Its positive‐strand RNA genome encodes three open reading frames (ORF). ORF1 is translated into a large protein composed of multiple domains and is known as the viral replicase. The RNA‐dependent RNA polymerase (RDRP) domain is responsible for the synthesis of viral RNA. Approach and Results Here, we identified a highly conserved α‐helix located in the RDRP thumb subdomain. Nuclear magnetic resonance demonstrated an amphipathic α‐helix extending from amino acids 1628 to 1644 of the ORF1 protein. Functional analyses revealed a dual role of this helix in HEV RNA replication and virus production, including assembly and release. Mutations on the hydrophobic side of the amphipathic α‐helix impaired RNA replication and resulted in the selection of a second‐site compensatory change in the RDRP palm subdomain. Other mutations enhanced RNA replication but impaired virus assembly and/or release. Conclusions Structure‐function analyses identified a conserved amphipathic α‐helix in the thumb subdomain of the HEV RDRP with a dual role in viral RNA replication and infectious particle production. This study provides structural insights into a key segment of the ORF1 protein and describes the successful use of reverse genetics in HEV, revealing functional interactions between the RDRP thumb and palm subdomains. On a broader scale, it demonstrates that the HEV replicase, similar to those of other positive‐strand RNA viruses, is also involved in virus production.
Three Kinds of Decision-Making Capacity for Refusing Medical Interventions
Authors: Mark Christopher Navin, Abram L. Brummett, Jason Adam Wasserman
Journal: The American Journal of Bioethics (2021)

According to a standard account of patient decision-making capacity (DMC), patients can provide ethically valid consent or refusal only if they are able to understand and appreciate their medical condition and can comparatively evaluate all offered treatment options. We argue instead that some patient refusals can be capacitated, and therefore ethically authoritative, without meeting the strict criteria of this standard account-what we call comparative DMC. We describe how patients may possess burdens-based DMC for refusal if they have an overriding objection to at least one burden associated with each treatment option or goals-based DMC for refusal if they have an overriding goal that is inconsistent with treatment. The overridingness of a patient's objections to burdens, or of their commitment to a goal, can justify the moral authority of their refusal, even when a patient lacks some of the cognitive capacities that standard accounts of DMC involve.
P-193 Final results of hepatectomy followed by adjuvant chemotherapy with 3-month capecitabine plus oxaliplatin for colorectal cancer liver metastases: A multicenter phase 2 study
Authors: H. Hashida, H. Satake, H. Tanioka, Y. Miyake, S. Yoshioka, T. Watanabe, M. Matsuura, T. Kyogoku, M. Inukai, T. Kotake, Y. Okita, T. Matsumoto, H. Yasui, M. Kotaka, T. Kato, S. Kaihara, A. Tsuji
Journal: Annals of Oncology (2021)
ラパマイシン治療によるPKCダウンレギュレーションはミトコンドリア疾患を軽減する【JST・京大機械翻訳】
Authors: Martin-Perez Miguel, S Grillo Anthony, K Ito Takashi, S Valente Anthony, Han Jeehae, W Entwisle Samuel, Z Huang Heather, Kim Dayae, Yajima Masanao, Kaeberlein Matt, Villen Judit
Journal: Nature Metabolism (2020)
EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis
Authors: Kulveer Mankia, Heidi J Siddle, Andreas Kerschbaumer, Deshire Alpizar Rodriguez, Anca Irinel Catrina, Juan D Cañete, Andrew P Cope, Claire Immediato Daien, Kevin D Deane, Hani El Gabalawy, Axel Finckh, V Michael Holers, Marios Koloumas, Francesca Ometto, Karim Raza, Condruta Zabalan, Annette van der Helm-van Mil, Dirkjan van Schaardenburg, Daniel Aletaha, Paul Emery
Journal: Annals of the Rheumatic Diseases (2021)

Despite growing interest, there is no guidance or consensus on how to conduct clinical trials and observational studies in populations at risk of rheumatoid arthritis (RA).
Early-phenotype CAR-T cells for the treatment of pediatric cancers
Authors: D. Meyran, R.L. Terry, J.J. Zhu, M. Haber, D.S. Ziegler, P.G. Ekert, J.A. Trapani, P.K. Darcy, P.J. Neeson
Journal: Annals of Oncology (2021)
Intermittent fasting in the prevention and treatment of cancer
Authors: Katherine K. Clifton, Cynthia X. Ma, Luigi Fontana, Lindsay L. Peterson
Journal: CA A Cancer Journal for Clinicians (2021)

Abstract Chronic caloric restriction (CR) has powerful anticarcinogenic actions in both preclinical and clinical studies but may be difficult to sustain. As an alternative to CR, there has been growing interest in intermittent fasting (IF) in both the scientific and lay community as a result of promising study results, mainly in experimental animal models. According to a survey by the International Food Information Council Foundation, IF has become the most popular diet in the last year, and patients with cancer are seeking advice from oncologists about its beneficial effects for cancer prevention and treatment. However, as discussed in this review, results from IF studies in rodents are controversial and suggest potential detrimental effects in certain oncologic conditions. The effects of IF on human cancer incidence and prognosis remain unknown because of a lack of high‐quality randomized clinical trials. Preliminary studies suggest that prolonged fasting in some patients who have cancer is safe and potentially capable of decreasing chemotherapy‐related toxicity and tumor growth. However, because additional trials are needed to elucidate the risks and benefits of fasting for patients with cancer, the authors would not currently recommend patients undergoing active cancer treatment partake in IF outside the context of a clinical trial. IF may be considered in adults seeking cancer‐prevention benefits through means of weight management, but whether IF itself affects cancer‐related metabolic and molecular pathways remains unanswered.
Decreased vaccine protection of egg-based influenza vaccine in the elderly and nonhemagglutinin-focused immunity
Authors: Karen J. Gonzalez, Eva M. Strauch
Journal: Journal of Clinical Investigation (2021)

Severe influenza illness or death is a serious concern among the elderly population despite vaccination. To investigate how the adaptive immune response after vaccination varies with the patient's age, Jung et al., in a recent issue of the JCI, extensively analyzed the serum antibody response in different age groups after immunization with the egg-based influenza vaccine Fluzone. As expected, the immune response in young adults was dominated by antibodies targeting the influenza hemagglutinin (HA) protein. On the contrary, the serological repertoire of elderly donors was characterized by cross-reactive (CR) antibodies recognizing non-HA antigens. Surprisingly, a substantial fraction of these CR antibodies targeted sulfated glycans typical of egg-produced proteins, which does not provide protection against human influenza viruses. Overall, these findings are of great value in understanding suboptimal immunity after influenza vaccination and shaping future vaccine efforts that will achieve increased protection in the elderly.
How much should a pedestrian be fined for intentionally blocking a fully automated vehicle? A random parameters beta hurdle model with heterogeneity in the variance of the beta distribution
Authors: Amir Pooyan Afghari, Eleonora Papadimitriou, Xiaomeng Li, Sherrie-Anne Kaye, Oscar Oviedo-Trespalacios
Journal: Analytic Methods in Accident Research (2021)

Intentionally blocking the path of fully automated vehicles is an important dimension of pedestrians' receptivity towards these vehicles. The monetary value of this behaviour can be obtained by asking pedestrians about their perception of the "fine" for blocking the path of a fully automated vehicle. Econometric modelling of the reported fine can shed more light on factors influencing pedestrians' receptivity towards fully automated vehicles. However, development of such an econometric model is not straightforward due to the unique characteristics of the dependent variable: it has two fundamentally different states; it is right-truncated; and it may be fat-tailed. Despite fairly extensive methodological advancements in econometric modelling of pedestrian behaviour, there is no model that can adequately explain these characteristics. While a beta distribution in a hurdle setting has the potential to address the above complexities, its applicability in dealing with limited dependent variables in transport applications has remained, by and large, unexplored. This study aims to fill this gap by developing a new beta hurdle regression model that systematically considers the dual-state of a right-truncated dependent variable representing the fine associated with intentionally blocking a fully automated vehicle. The hypothesized model is empirically tested using data obtained from a survey administered in Queensland, Australia, and the results are compared with truncated lognormal, and truncated lognormal hurdle regression models. Results indicate that the hurdle models are superior to the non-hurdle model. The beta variant of the hurdle model provides a better statistical fit for the data that are near their right limit. In addition, parametrizing the variance of the beta distribution captures the additional heterogeneity in the data. Age, gender, education level, violations, attitudes, behaviours that appease social interactions, and perceived ease or difficulty of interacting with fully automated vehicles influence the likelihood and/or the propensity of the fine and thus are associated with the perceived monetary value of intentionally blocking the path of a fully automated vehicle.