tbuckley/cabot-search huggingface dataset:
The Use of Human Pluripotent Stem Cells for Modeling Liver Development and Disease
Authors: James A. Heslop, Stephen A. Duncan
Journal: Hepatology (2018)

The use of pluripotent stem cells (PSCs) has transformed the investigation of liver development and disease. Clinical observations and animal models have provided the foundations of our understanding in these fields. While animal models remain essential research tools, long experimental lead times and low throughput limit the scope of investigations. The ability of PSCs to produce large numbers of human hepatocyte-like cells, with a given or modified genetic background, allows investigators to use previously incompatible experimental techniques, such as high-throughput screens, to enhance our understanding of liver development and disease. In this review, we explore how PSCs have expedited our understanding of developmental mechanisms and have been used to identify new therapeutic options for numerous hepatic diseases. We discuss the future directions of the field, including how to further unlock the potential of the PSC model to make it amenable for use with a broader range of assays and a greater repertoire of diseases. Furthermore, we evaluate the current weaknesses of the PSC model and the directions open to researchers to address these limitations. Conclusion: The use of PSCs to model human liver disease and development has and will continue to have substantial impact, which is likely to further expand as protocols used to generate hepatic cells are improved.
Obesity modifies the stoichiometry of mitochondrial proteins in a way that is distinct to the subcellular localization of the mitochondria in skeletal muscle
Authors: Katon A. Kras, Paul R. Langlais, Nyssa Hoffman, Lori R. Roust, Tonya R. Benjamin, Elena A. De Filippis, Valentin Dinu, Christos S. Katsanos
Journal: Metabolism (2018)
Revisiting the form and function of conflict: Neurobiological, psychological, and cultural mechanisms for attack and defense within and between groups
Authors: Carsten K. W. De Dreu, Jörg Gross
Journal: Behavioral and Brain Sciences (2018)

Abstract Conflict can profoundly affect individuals and their groups. Oftentimes, conflict involves a clash between one side seeking change and increased gains through victory and the other side defending the status quo and protecting against loss and defeat. However, theory and empirical research largely neglected these conflicts between attackers and defenders, and the strategic, social, and psychological consequences of attack and defense remain poorly understood. To fill this void, we model (1) the clashing of attack and defense as games of strategy and reveal that (2) attack benefits from mismatching its target's level of defense, whereas defense benefits from matching the attacker's competitiveness. This suggests that (3) attack recruits neuroendocrine pathways underlying behavioral activation and overconfidence, whereas defense invokes neural networks for behavioral inhibition, vigilant scanning, and hostile attributions; and that (4) people invest less in attack than defense, and attack often fails. Finally, we propose that (5) in intergroup conflict, out-group attack needs institutional arrangements that motivate and coordinate collective action, whereas in-group defense benefits from endogenously emerging in-group identification. We discuss how games of attack and defense may have shaped human capacities for prosociality and aggression, and how third parties can regulate such conflicts and reduce their waste.
Copenhagen Prospective Personalized Oncology (CoPPO)—Clinical Utility of Using Molecular Profiling to Select Patients to Phase I Trials
Authors: Ida Viller Tuxen, Kristoffer Staal Rohrberg, Olga Oestrup, Lise Barlebo Ahlborn, Ane Yde Schmidt, Iben Spanggaard, Jane P. Hasselby, Eric Santoni-Rugiu, Christina Westmose Yde, Morten Mau-Sørensen, Finn Cilius Nielsen, Ulrik Lassen
Journal: Clinical Cancer Research (2018)

Abstract Purpose: We evaluated the clinical benefit of tumor molecular profiling to select treatment in the phase I setting. Experimental Design: Patients with advanced solid cancers and exhausted treatment options referred to a phase I unit were included in a prospective, single-center, single-arm open-label study (NCT02290522). Tumor biopsies were obtained for comprehensive genomic analysis including whole-exome sequencing and RNA sequencing. When possible, patients were treated with regimen matched to the genomic profile. Primary endpoint was progression-free survival (PFS). Results: From May 2013 to January 2017, a total of 591 patients were enrolled, with 500 patients undergoing biopsy. Genomic profiles were obtained in 460 patients and a potential actionable target was identified in 352 (70%) of 500 biopsied patients. A total of 101 patients (20%) received matched treatment based on either gene mutations or RNA expression levels of targets available in early clinical trials or off-label treatment. Objective response according to RECIST1.1 was observed in 15 of 101 patients (0% complete response, 15% partial response), with a median PFS of 12 weeks (95% confidence interval, 9.9–14.4). Conclusions: Our study supports the feasibility of genomic profiling to select patients in the phase I setting and suggests that genomic matching can be beneficial for a minor subset of patients with no other treatment options. Randomized studies may validate this assumption. See related commentary by Ratain, p. 1136
Medical error reporting, culture, and infrastructure.
Authors: Diane Denny, DBA, Caitlyn Shinners
Journal: Journal of Clinical Oncology (2018)

245 Background: Much work has focused on the importance of culture as a key factor in advancing the patient safety discussion. No assumption can be made that a culture of safety equates to embracing responsibility to report when errors and near misses occur. Underreporting exists. Without data, the opportunity to redesign care and address system failures is diminished. This research aimed to answer: what impact do various factors have on influencing the likelihood of reporting across a hospital network of oncology providers? Methods: The AHRQ Hospital Culture on Safety was used coupled with 15 custom questions of interest. Dependent variables (DVs) included: structure for reporting (definition, policy and ease), incentives to report, supervisor/employee relationship and management support. Independent variables (IVs) included number of errors reported and perceived frequency by which events are reported, influenced by tenure and extent of patient interaction. Higher scores associated with the IVs were posited to be positively associated with the errors reported as well as the reporting frequency. A principle component analysis was conducted as a variable reduction technique to affirm factors; the reliability of factors tested; and multiple regression analyses conducted to test the strength of relationships. Results: 2,103 surveys were completed. The 4 factors are found to weakly predict the DVs. Infrastructure had the greatest association in both models. Tenure and patient interaction influenced the likelihood of reporting. Conclusions: This research moves beyond culture in ascertaining factors pivotal in the underreporting of errors and near misses. An infrastructure promoting reporting must also exist ensuring staff know what, how, when, and why to report, linking data to action.[Table: see text]
Extra-axial cerebrospinal fluid in high-risk and normal-risk children with autism aged 2–4 years: a case-control study
Authors: Mark D Shen, Christine W Nordahl, Deana D Li, Aaron Lee, Kathleen Angkustsiri, Robert W Emerson, Sally J Rogers, Sally Ozonoff, David G Amaral
Journal: The Lancet Psychiatry (2018)
Automatic grading of prostate cancer in digitized histopathology images: Learning from multiple experts
Authors: Guy Nir, Soheil Hor, Davood Karimi, Ladan Fazli, Brian F. Skinnider, Peyman Tavassoli, Dmitry Turbin, Carlos F. Villamil, Gang Wang, R. Storey Wilson, Kenneth A. Iczkowski, M. Scott Lucia, Peter C. Black, Purang Abolmaesumi, S. Larry Goldenberg, Septimiu E. Salcudean
Journal: Medical Image Analysis (2018)
Mycobacterial blood cultures in the diagnosis of tuberculosis in human immunodeficiency virus-infected patients: are they useful?
Authors: F. Ceia, A. Santos-Silva, J. Alves, A. Silva-Pinto, O. Oliveira, A. Cláudia Carvalho, A. Ramos, T. Carvalho, A. Sarmento, R. Duarte
Journal: Clinical Microbiology and Infection (2018)
Psychological origins of the Industrial Revolution
Authors: Nicolas Baumard
Journal: Behavioral and Brain Sciences (2018)

Since the Industrial Revolution, human societies have experienced high and sustained rates of economic growth. Recent explanations of this sudden and massive change in economic history have held that modern growth results from an acceleration of innovation. But it is unclear why the rate of innovation drastically accelerated in England in the eighteenth century. An important factor might be the alteration of individual preferences with regard to innovation resulting from the unprecedented living standards of the English during that period, for two reasons. First, recent developments in economic history challenge the standard Malthusian view according to which living standards were stagnant until the Industrial Revolution. Pre-industrial England enjoyed a level of affluence that was unprecedented in history. Second, behavioral sciences have demonstrated that the human brain is designed to respond adaptively to variations in resources in the local environment. In particular, Life History Theory, a branch of evolutionary biology, suggests that a more favorable environment (high resources, low mortality) should trigger the expression of future-oriented preferences. In this paper, I argue that some of these psychological traits - a lower level of time discounting, a higher level of optimism, decreased materialistic orientation, and a higher level of trust in others - are likely to increase the rate of innovation. I review the evidence regarding the impact of affluence on preferences in contemporary as well as past populations, and conclude that the impact of affluence on neurocognitive systems may partly explain the modern acceleration of technological innovations and the associated economic growth.
Abstract 20587: Myocyte-Specific Over-Expression of Hdac4 Promotes Myocardial Ischemia and Reperfusion Injury
Authors: Ling Zhang, Jian Feng Du, Yu Zhao, Ting C Zhao
Journal: Circulation (2014)

Background: Histone deacetylases (HDACs) have been recently demonstrated to play a critical role in modulating myocardial protection and cardiomyocyte survival. However, the specific HDAC in mediating myocardial ischemia/reperfusion injury is currently unknown. Objective: The goal of this study is sought to define whether cardiac specific over-expression of HDAC4 would exacerbate myocardial ischemia and reperfusion injury. Methods: We created myocyte-specific HDAC4 transgenic mice, in which cDNA encoding HDAC4 was cloned into an expression vector encoding alpha-myosine heavy chain (the α-MHC promoter). Langendorff isovolumetrically perfused hearts from wild type (WT) control (n=5) and α-MHC-HDAC4 mice (n=5) were subjected to 30 minutes of ischemia followed by 30 minutes of reperfusion. Infarct size was measured by triphenyl tetrazolium chloride staining. HDAC4 protein and activity in myocardium were determined. Results: The HDAC4 protein levels in the hearts of α-MHC-HDAC4 mice were significantly higher than those of control wild type. HDAC activity was elevated in MHC-HDAC4 mice as compared with wild type mice. In adult mice, there was no significant difference in the heart weight-body weight ratio between α-MHC-HDAC and wild-type mice. As compared to wild type mice, myocyte-specific over-expression of HDAC4 resulted in an elevation of left ventricular end-diastolic pressure (LVEDP) and reduction in the recovery of rate and pressure products (RPP) at the end of reperfusion. Furthermore, over-expression of HDAC4 increased myocardial infarct size as compared to wild type mice. Conclusions: These findings indicate that specific over-expression of HDAC4 exacerbates myocardial ischemia and reperfusion injury.
Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care
Authors: Hartmut Döhner, Anna Dolnik, Lin Tang, John F. Seymour, Mark D. Minden, Richard M. Stone, Teresa Bernal del Castillo, Haifa Kathrin Al-Ali, Valeria Santini, Paresh Vyas, C. L. Beach, Kyle J. MacBeth, Barry S. Skikne, Steve Songer, Nora Tu, Lars Bullinger, Hervé Dombret
Journal: Leukemia (2018)

Older patients with newly diagnosed acute myeloid leukemia (AML) in the phase 3 AZA-AML-001 study were evaluated at entry for cytogenetic abnormalities, and a subgroup of patients was assessed for gene mutations. Patients received azacitidine 75 mg/m2/day x7 days (n = 240) or conventional care regimens (CCR; n = 245): intensive chemotherapy, low-dose cytarabine, or best supportive care only. Overall survival (OS) was assessed for patients with common (occurring in ≥10% of patients) cytogenetic abnormalities and karyotypes, and for patients with recurring gene mutations. There was a significant OS improvement with azacitidine vs CCR for patients with European LeukemiaNet-defined Adverse karyotype (HR 0.71 [95%CI 0.51–0.99]; P = 0.046). Azacitidine-treated patients with -5/5q-, -7/7q-, or 17p abnormalities, or with monosomal or complex karyotypes, had a 31–46% reduced risk of death vs CCR. The most frequent gene mutations were DNMT3A (27%), TET2 (25%), IDH2 (23% [R140, 15%; R172, 8%]), and TP53 (21%). Compared with wild-type, OS was significantly reduced among CCR-treated patients with TP53 or NRAS mutations and azacitidine-treated patients with FLT3 or TET2 mutations. Azacitidine may be a preferred treatment for older patients with AML with Adverse-risk cytogenetics, particularly those with chromosome 5, 7, and/or 17 abnormalities and complex or monosomal karyotypes. The influence of gene mutations in azacitidine-treated patients warrants further study.
Clinical workflows to support cost-of-care conversations: Multisite design study.
Authors: Nora B. Henrikson, Matthew P. Banegas, Leah Tuzzio, Catherine Lim, Jennifer L Schneider, Callie Walsh-Bailey, Aaron Scrol, Stephanie M Hodge
Journal: Journal of Clinical Oncology (2018)

168 Background: Patients prefer to discuss costs in the clinical setting, but current workflows are not designed to support cost-of-care conversations. Methods: We conducted a human centered design study to identify clinical workflows that optimize cost of care conversations. We conducted ethnographic observations at primary care departments or oncology clinics at two integrated health systems, assessing barriers and facilitators to discussing costs with patients. We then designed three unique patient experiences of having financial concerns addressed in the clinic setting. We refined these experiences following in-person patient interviews (n = 20). All data was synthesized into (1) a set of clinical workflow requirements and (2) journey maps describing sample workflows for the three patient experiences. Results: Most patient cost concerns take one of three unique pathways, each with workflow implications: (1) informing clinical decision-making, such as alternative treatment selection, mode of administration, or therapy sequence; (2) planning and budgeting concerns for therapy; and (3) addressing immediate financial hardship. Workflow requirements include organizational recognition of the need for clinic-based cost of care conversations; access to cost and benefits data to support each conversation pathway; clear team member roles and responsibilities for addressing cost of care concerns, including the role of the physician; pursuit of a patient experience that includes a clinical culture where cost questions are normal and each patient's values, preferences, and privacy are respected; patients know who to go to with cost questions; patients' concerns are documented to minimize repetition to multiple team members; and patients learn their expected OOP costs before treatment begins. Conclusions: Clinic-based workflows for cost-of-care conversations that optimize patients’ care experience require organizational commitment to addressing cost concerns, clear roles and responsibilities, appropriate and complete data access, and a team-based approach.
Who are the cancer patients most likely to utilize lay navigation services and what types of issues do they ask for help?
Authors: Marcy Winget, Darlene Veruttipong, Laura M Holdsworth, Dani Zionts, Steven M Asch
Journal: Journal of Clinical Oncology (2018)

229 Background: In 2017, the Stanford Cancer Institute implemented a lay patient navigation program directed towards patients receiving at least two treatment modalities with the thought that these patients likely need more support than those with single treatment modality. We would like to target future services, prospectively, to patients that need them most. The aim of this paper is to understand the characteristics and concerns of the highest users of the lay navigation services. Methods: Patients were included if they had been assigned a care navigator between February 2017 through November 2017 and had at least four months of potential follow-up with their navigator. High contact patients were defined as those with the total number of contacts in the top 10% and/or the duration of contact in the top 25%. Demographic and clinical characteristics of patients were obtained from the electronic medical record. Data that captured patient-navigator interactions were abstracted from a templated note in the electronic medical record. Descriptive statistics were calculated to describe demographic and clinical characteristics of patients and the concerns raised to navigators. Results: There were 436 patients who met the inclusion criteria, 115 (26%) of whom were classified as high contact. High contact patients were more likely to be younger (under 60 years), non-white, have private insurance and live more than 20 miles from the cancer center than medium/low contact patients. They were also more likely to have multiple non-life threatening comorbidities such as diabetes without complications. The high contact patients accounted for 44% of all navigator contacts and 75% of all contacts in which a patient expressed any concern. 55% of high contact patient concerns were clinical in nature, 19% related to scheduling issues; 14% social/mental health issues; and 12% were non-clinical. Conclusions: The patients that are in the top 25% of utilization of lay navigators are a complex mix of patients and account for roughly 75% of the concerns of the broader patient population.
Abstract P038: Serum Calcium, 25-hydroxyvitamin D and Incidence of Abdominal Aortic Aneurysm: The Atherosclerosis Risk in Communities Study
Authors: Mary R Rooney, Weihong Tang, Aaron R Folsom, Erin D Michos, Alvaro Alonso, Pamela L Lutsey
Journal: Circulation (2017)

Introduction: Serum concentrations of calcium and 25-hydroxyvitamin D [25(OH)D] may potentially contribute to the development of abdominal aortic aneurysms (AAA), likely predominately through established AAA risk factors such as hypertension and inflammation. To date, no prospective epidemiologic studies have examined the association between calcium and 25(OH)D and AAA risk. Hypothesis: We hypothesized that 20-year risk of AAA is higher among individuals with elevated serum calcium and among those with low serum of 25(OH)D. Methods: Serum calcium and 25(OH)D were measured in Atherosclerosis Risk in Communities (ARIC) study participants without prior AAA and who attended visit 2 (1990-92) (N=13,452). Serum calcium was corrected for serum albumin. AAA events were identified through 2011 via annual follow-up phone calls for hospitalized AAAs, and through Medicare for both hospitalized and outpatient AAAs. Multi-variable Cox proportional hazards models were used. Calcium was modeled as quartiles and 25(OH)D as &lt;10, 10-&lt;20, 20-&lt;30, ≥30 ng/ml. Additionally, sex-stratified analysis was conducted. Results: The participants were mean±SD age 57±6y, 44% men and 75% white. Mean serum concentrations were 9.2±0.4 mg/dl for calcium and 24.3±8.5 ng/ml for 25(OH)D. Over a median 19.7 years of follow-up, 484 AAA cases were identified. High serum calcium was associated with an increased incidence of AAA [HR Q4 v Q1=1.60 (95% CI: 1.24-2.08)] after adjustment for demographics and with additional adjustment for height, weight and smoking [1.39 (1.05-1.82)], but not after other CVD risk factors were controlled for [1.20 (0.91-1.58)]. In the fully adjusted model, a sex-interaction was present [p-value sex*calcium interaction=0.03], whereby the association was present in women [2.28 (1.20-4.34)] not men [1.05 (0.75-1.47)]. Those with 25(OH)D ≥30 ng/ml vs. &lt;10 ng/ml had a HR for AAA of 1.54 (1.03-2.29) after demographic adjustment, but the association was attenuated with further adjustment for height, weight and smoking [1.24 (0.82-1.88)]. No sex-25(OH)D interaction was detected. As such, stratified results are not presented. Conclusions: In this large prospective cohort, there was little evidence that markers of vitamin D metabolism are associated with risk of incident AAA. The positive association of calcium with AAA among women may warrant further investigation and replication in other populations.
Development of a person-centered patient portal in oncology using stakeholder co-design.
Authors: John Kildea, Tarek Hijal, Laurie Hendren
Journal: Journal of Clinical Oncology (2018)

221 Background: Patient portals are software products that provide care recipients (patients) with access to some or all of their personal health information (PHI) within a healthcare institution’s electronic medical record (EMR). Most patient portals are just that–windows into an EMR. However, in today’s connected world, a patient portal can offer much more than just access to PHI. By exploiting modern technology and by recognizing that care recipients are people with complex needs that extend beyond just the delivery of care, patient portals can be person-centered. Such person-centered needs include: the ability to plan ahead and know one’s position in a waiting list, to feel in control of one’s own care, to understand one’s treatment options, and to share in all decision-making about one’s care. Methods: We used stakeholder co-design, involving care recipients, care providers (clinicians) and technical experts at all levels, to design and develop a person-centered patient portal from within the healthcare system. Results: Our mobile-friendly patient portal, known as Opal (opalmedapps.com), contains the following: One-stop multi-speciality and multi-institutional operation; Appointment schedule with personalized appointment preparation guidelines; Appointment check-in and waiting room management tools; Monitoring of step-by-step radiotherapy treatment planning; Access to PHI contextualized with explanatory information; Access to personalized educational materials; Patient-reported outcomes questionnaires with response visualizations; An automated rules-based system to minimize clinician workload; Triggered notifications to alert patients and clinicians to actionable events. Conclusions: Opal is currently in beta release involving a small number of oncology patients at our centre who are providing feedback about its use and usefulness. Their initial feedback is very positive and enthusiastic. A full pilot study is starting by July 2018.
Abstract 17627: Assessment of Stiffness in Patients Undergoing Renal Sympathetic Denervation - Ascending Aortic Distensibility Predicts Blood Pressure Response
Authors: Karl Fengler, Karl Philipp Rommel, Stephan Blazek, Maximilian von Roeder, Gerhard Schuler, Philipp Lurz
Journal: Circulation (2016)

Introduction: The effectiveness of catheter-based renal sympathetic denervation (RDN) as a treatment for therapy resistant hypertension has been questioned after the results of the Simplicity-HTN3-...