cssi/SciSciGPT-SciSciNet huggingface dataset:
Examining the Relationship between Pre-Malignant Breast Lesions, Carcinogenesis and Tumor Evolution in the Mammary Epithelium Using an Agent-Based Model

Introduction Breast cancer, the product of numerous rare mutational events that occur over an extended time period, presents numerous challenges to investigators interested in studying the transformation from normal breast epithelium to malignancy using traditional laboratory methods, particularly with respect to characterizing transitional and pre-malignant states. Dynamic computational modeling can provide insight into these pathophysiological dynamics, and as such we use a previously validated agent-based computational model of the mammary epithelium (the DEABM) to investigate the probabilistic mechanisms by which normal populations of ductal cells could transform into states replicating features of both pre-malignant breast lesions and a diverse set of breast cancer subtypes. Methods The DEABM consists of simulated cellular populations governed by algorithms based on accepted and previously published cellular mechanisms. Cells respond to hormones, undergo mitosis, apoptosis and cellular differentiation. Heritable mutations to 12 genes prominently implicated in breast cancer are acquired via a probabilistic mechanism. 3000 simulations of the 40-year period of menstrual cycling were run in wild-type (WT) and BRCA1-mutated groups. Simulations were analyzed by development of hyperplastic states, incidence of malignancy, hormone receptor and HER-2 status, frequency of mutation to particular genes, and whether mutations were early events in carcinogenesis. Results Cancer incidence in WT (2.6%) and BRCA1-mutated (45.9%) populations closely matched published epidemiologic rates. Hormone receptor expression profiles in both WT and BRCA groups also closely matched epidemiologic data. Hyperplastic populations carried more mutations than normal populations and mutations were similar to early mutations found in ER+ tumors (telomerase, E-cadherin, TGFB, RUNX3, p < .01). ER- tumors carried significantly more mutations and carried more early mutations in BRCA1, c-MYC and genes associated with epithelial-mesenchymal transition. Conclusions The DEABM generates diverse tumors that express tumor markers consistent with epidemiologic data. The DEABM also generates non-invasive, hyperplastic populations, analogous to atypia or ductal carcinoma in situ (DCIS), via mutations to genes known to be present in hyperplastic lesions and as early mutations in breast cancers. The results demonstrate that agent-based models are well-suited to studying tumor evolution through stages of carcinogenesis and have the potential to be used to develop prevention and treatment strategies.
The Use Of A Cross-Over Design In A Study Of Student Teachers’ Classroom Behaviors

ARE APPRAISALS OF students made at the time of their admission to the teacher education program related to descriptions of their subsequent c las s room behavior ? This question stimulated a study of the observed classroom behaviors of women in elementary education during their student teaching (9). This paper describes that part of the study which was concerned with the development of the ex perimental design for studying classroom behav iors. Since few, if any, studies of student teach ers' classroom performance have employed an ex perimental approach, this discussion is presented as an example of the application of the experiment al method to this type of research and of the use of the cross-over design in particular. The study il lustrates how factors assumed to be relevant to classroom performance variables can either be con trolled or their influence measured and examined for significance.
The Liquidity Trap, the Great Depression, and Unconventional Policy: Reading Keynes at the Zero Lower Bound

The developed economies of Japan, the United States, and the Eurozone are currently experiencing very low short-term rates, so low that they are considered to be at the “zero lower bound” of possibility. This effectively paralyzes conventional monetary policy. As a consequence, monetary authorities have turned to unconventional and controversial policies such as “Quantitative Easing,” “Maturity Extension,” and “Low for Long Forward Guidance.” John Maynard Keynes in The General Theory offered a rich analysis of the problems that appear at the zero lower bound and advocated the very same unconventional policies that are now being pursued. Keynes’s comments on these issues are rarely mentioned in the current discussions because the subsequent simplifications and the bowdlerization of his model obliterated this detail. It was only later that his characterization of a lower bound to interest rates would be dubbed a “Liquidity Trap.” This essay employs Keynes’s analysis to retell the economic history of the Great Depression in the United States. Keynes’s rationale for unconventional policies and his expectations of their effect remain surprisingly relevant today. I suggest that in both the Depression and the Great Recession the primary impact on interest rates was produced by lowering expectations about the future path of rates rather than by changing the risk premiums that attach to yields of different maturities. The long sustained period when short term rates were at the lower bound convinced investors that rates were likely to remain near zero for several more years. In both cases the treatment proved to be very slow to produce a significant response, requiring a sustained zero-rate policy for four years or longer.
‘An Assertion of Liberty Incarnate’: Irish and Indian Nationalists in North America

The 1920 Saint Patrick’s Day parade in New York was noteworthy for a number of reasons. The first was the size of the crowd that watched it. The New York Times commented on ‘what appeared to be the biggest turnout since the city had a St. Patrick’s Day,’ observing that there was not an unoccupied inch of sidewalk along the line of march on Fifth Avenue. The Irish World and Industrial Liberator estimated that one million spectators watched the parade.
Abstract 804: Gene-environment interactions and the risk of Barrett's esophagus in three US cohorts

Background: Several single nucleotide polymorphisms (SNPs) have been associated with Barrett9s esophagus (BE) risk. Additionally, environmental factors including smoking, alcohol consumption and heartburn have been shown to increase BE risk. However, no studies have evaluated whether interactions between these genetic and environmental factors influence BE risk. Understanding how genes and environmental risk factors interact may provide key insight into the pathophysiology of BE. Objectives: To examine the main effects and the potential effect-modification between known genetic loci (SNPS) and established environmental risk factors for BE. Patients and Methods: We performed a nested case-control study using data on 401 incident BE cases and 436 age-matched controls from the Nurses’ Health Study, Nurses’ Health Study II, and Health Professionals Follow-up Study cohorts, who gave blood and completed biennial questionnaires. We genotyped SNPs identified in previous BE GWAS as well as SNPs in candidate genes related to BE susceptibility (i.e., related to excess body fat, fat distribution, factors associated with insulin resistance, and inflammatory mediators). A genetic risk score (GRS) was constructed to evaluate the combined effect of the selected SNPs on BE risk. Interactions between SNPs and BE risk factors were also assessed. Results and Conclusions: We found a borderline association between our GRS and BE risk: a one-allele increase in the unweighted GRS increased the risk of Barrett9s esophagus by a factor of 1.20 (95%CI = 1.00-1.44; p = 0.057). We observed a significant interaction between smoking and BE genotypes (p-interaction = 0.016). However, while alcohol consumption and heartburn duration were strongly associated with BE, we did not observe any significant gene-environment interactions. Citation Format: Marta Crous-Bou, Diane Feskanich, Meir J. Stampfer, Charles S. Fuchs, Immaculata De Vivo, Brian C. Jacobson. Gene-environment interactions and the risk of Barrett9s esophagus in three US cohorts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 804.
Bottom Temperatures in Drake Passage

AbstractLong time series of bottom temperatures in the Southern Ocean are rare. The cDrake array with over 40 current- and pressure-recording inverted echo sounders, moored across Drake Passage to monitor the Antarctic Circumpolar Current (ACC) variability and transport, measured temperature at 1 and 50 m above the seafloor at depths ≥ 3500 m and at the southern continental margin. The 4-yr dataset provided an opportunity to examine the temporal and spatial scales of bottom temperature variability. High variability was observed; ranges were 0.5°–0.9°C in the northern passage and 0.3°–0.6°C in the southern passage. Standard deviations in the two regions were 0.1°–0.15°C and <0.05°C, respectively. Meandering of the ACC with its deep-reaching thermocline accounted for up to 50% of the observed bottom temperature variance. Northern passage temperatures, spaced less than 40 km apart, were correlated with each other, while those in the southern portion, separated by 60–70 km, were not. A gap in the West Scotia ...
Censors at Work: How States Shaped Literature. By Robert Darnton. (New York, NY: W. W. Norton, 2014. Pp. iii, 316. $32.95.)

In this unique study of censorship, the author focuses on three states in three different centuries, detailing their situations and practices. The first is Bourbon France and centers on privilege a...
Synchronous deglacial thermocline and deep-water ventilation in the eastern equatorial Pacific

The deep ocean is most likely the primary source of the radiocarbon-depleted CO2 released to the atmosphere during the last deglaciation. While there are well-documented millennial scale Δ14C changes during the most recent deglaciation, most marine records lack the resolution needed to identify more rapid ventilation events. Furthermore, potential age model problems with marine Δ14C records may obscure our understanding of the phase relationship between inter-ocean ventilation changes. Here we reconstruct changes in deep water and thermocline radiocarbon content over the last deglaciation in the eastern equatorial Pacific (EEP) using benthic and planktonic foraminiferal 14C. Our records demonstrate that ventilation of EEP thermocline and deep waters occurred synchronously during the last deglaciation. In addition, both gradual and rapid deglacial radiocarbon changes in these Pacific records are coeval with changes in the Atlantic records. This in-phase behaviour suggests that the Southern Ocean overturning was the dominant driver of changes in the Atlantic and Pacific ventilation during deglaciation.
The Effect of Disclosure and Price on Uninformed Traders’ Beliefs and Trading: An Experimental Study on Public Forecasts

We study how uniformed traders (defined as strategic traders not endowed with private information) use public disclosure and prices to form beliefs and trade. We manipulate the availability of public forecasts (e.g. earnings forecasts) of forthcoming public signals (e.g., earnings announcements). Forecasts preempt the majority of information in earnings and become redundant after earnings announcements. This unique information structure allows us to detect two interactive effects of public disclosure and prices on uninformed traders’ beliefs. First, disclosure can reinforce learning from prices. We find this effect dominates when earnings informativeness is high. As forecasts lead to more informative prices, uninformed traders have more accurate beliefs after earnings announcements because they glean more information from prices. Second, disclosure can hinder learning from prices. We find this effect dominates when earnings informativeness is low. Uninformed traders overuse information in public disclosure and underuse information in prices. Such misweighting of information is more severe when forecasts are available.
Syndiotactic Polystyrene-Based Ionogel Membranes for High Temperature Electrochemical Applications

This work focuses on ionogel membranes for use in Li-ion batteries fabricated from syndiotactic polystyrene (sPS) gels filled with ionic liquids (ILs). The aim is to increase the operating temperature of Li-ion batteries. Thermal stability and safe operation of Li-ion batteries are two key attributes for their success in hybrid vehicles and other high-temperature applications. The volatility of the liquid electrolytes in current lithium-ion battery technology causes thermal runaway leading to fire, explosion, and swelling of the cell. The approach followed in this work combines the thermal stability and ruggedness of sPS and the extremely low volatility of ILs. The performances of lithium metal/graphite half-cells fabricated with ionogel membranes and those with Celgard-3501 membranes are evaluated at both room temperature and at elevated temperatures of 100 °C. Our data show that the cells with ionogel membranes can be operated continuously at 100 °C without failure. In addition, better charge–discharge ...
A self-determination theory approach to problematic drinking and intimate partner violence

Problematic drinking has long been established as an important antecedent to the perpetration of intimate partner violence (IPV). As little research has evaluated individual differences beyond anger in this association, this research examines problematic drinking and IPV perpetration through the lens of self-determination theory (SDT), the relational perspective suggesting individuals are motivated to be in their relationship for autonomous (i.e., self-driven) and controlled (i.e., guilt-driven) reasons. We test the hypothesis that problematic drinking is more strongly associated with IPV among those who are controlled in their motivation in four independent samples (N = 617). College students in relationships completed measures of alcohol consumption, negative alcohol-related consequences, relationship motivation, and IPV perpetration. Results generally suggested that the association between both alcohol consumption and negative alcohol-related consequences and IPV perpetration is only significant among those endorsing greater controlled motivation. This study supports problematic drinking as not being an equal risk factor for all individuals, and suggests that some people may be more vulnerable to problematic drinking resulting in relationship aggression.
Safe and Effective, Prolonged Administration of Epsilon Aminocaproic Acid in Bleeding from the Urinary Tract

AbstractA total of 9 patients with macroscopic hematuria from various causes, none with evidence of disseminated intravascular coagulation, received low oral, divided doses (approximately 150mg. per kg. per day) of epsilon aminocaproic acid for up to 21 consecutive days. The hematuria was controlled effectively without overt clinical reactions. Parameters of hepatic and renal function, indicators of muscular damage, were studied in detail in 3 patients. No significant abnormalities were found.The use of small doses of epsilon aminocaproic acid was not accompanied by significant complications and appeared to be effective in special situations for the control of urinary bleeding. This therapy may have indications in a number of urological states accompanied by excessive hematuria.
Contributions to Avian Biogeography From the Archipelago and Lowlands of Bocas Del Toro, Panama

-New distributional information is summarized from avifaunal surveys conducted from 1987 to 1991 in the ornithologically unknown islands of the province of Bocas del Toro, Panama, and points on the adjacent mainland. These establish the region of the Laguna de Chiriqui to be of great biogeographic interest and complexity. New records include 3 species new to Panama, and 11 species and 3 subspecies new to Bocas del Toro. Two taxa of birds (Platyrinchus cancrominus and a form of Chlorophanes spiza) are relicts on islands and are not resident on the Panamanian mainland. Four pairs of species or subspecies (Anthracothorax prevostiilA. veraguensis, Glaucis aenea/G. hirsuta, Gymnopithys bicolor olivascensIG. b. bicolor, and Tangara inornata rava /T. i. languens) are shown for the first time to change abruptly over a narrow distance along the southern shore of the Laguna de Chiriqui. Received 6 January 1992, accepted 22 April 1992. THE PROVINCE of Bocas del Toro occupies the western quarter of the Caribbean coast of Panama. Its most distinctive physiographic feature is a large embayment (Laguna de Chiriqui/Bahia de Almirante) encompassing many islands, some quite large (Fig. 1). Along the southern shore of this embayment, lowland habitats are very restricted because of the proximity of mountains to the sea. Other factors that may have biogeographic significance are the presence of a deep channel (20 to 30 fathoms) between the Valiente Peninsula and Cayo Agua, and an extensive area of swamp at the southeastern corner of the Laguna de Chiriqui. Systematic ornithological collecting in Bocas del Toro began in 1926 (Kennard and Peters 1928) and continued actively for a few years, but then fell off for a quarter century (Eisenmann 1957). Alexander Wetmore made substantial collections for the Smithsonian Institution in 1958, but with minor exceptions almost exclusively near Almirante. In the 1960s, the Gorgas Memorial Laboratory operated hundreds of mist nets near Almirante in connection with epidemiological research, which added considerably to ornithological knowledge of the
Heterogeneity of Vascular Endothelial Cells: Its Possible Role in Selective Neovascularization in the Eye

The central hypothesis of our laboratory is that vascular endothelial cells are not all alike, and that their differences reflect in large part their developmental origins (1–4). In order to document these differences between endothelial cells of different organs we have used monoclonal and polyclonal antibodies to delineate organ-specific determinants (1–3). We have used a variety of plant lectins to characterize cell surface-associated lectin-binding sites (5). Further, we have demonstrated that differences exist in the adhesion of different tumor cells to various endothelial cell mono layers (6,7).
Radiation Oncologist Characteristics and their Association with Outcomes in Patients with Head and Neck Cancer.

Abstract Purpose Intensity modulated radiation therapy (IMRT) is widely used in the treatment of head and neck cancers (HNC). There is not enough evidence to suggest that some radiation oncologists (ROs) are associated with better outcomes in patients with HNC. We conducted a cross-sectional analysis to evaluate the effect of ROs' characteristics on outcomes in patients with HNC treated with IMRT. Methods and materials The study used the Surveillance Epidemiology and End Results-Medicare linked database to identify patient characteristics. Physician records were obtained from the American Medical Association. Logistic regression models with propensity scores were analyzed to look for an association between RO characteristics and patient outcomes. Results RO characteristics showed that approximately 30% of ROS completed their training in or after the year 2000 (recently trained), and 17% were in top decile of treatment volume (high volume). Less than 3% of ROs work in academic settings. We found that ROs who were recently trained have higher odds (odds ratio [OR]: 1.10; 95% confidence interval [CI], 1.011-1.191) compared with those who were not. In addition, ROs who were treating high volumes of patients have higher odds (OR: 1.08; 95% CI, 1.010-1.165) compared with those treating low volumes of an event of adverse effect of IMRT or death among patients. ROs who work in academic settings have a protective effect (OR: 0.72; 95% CI, 0.569-0.925). Conclusions ROs who were recently trained and had a high treatment volume are associated with poorer outcomes among patients with HNC who receive IMRT treatment.
Mechanistic Evaluation of the Complex Drug-Drug Interactions of Maraviroc: Contribution of Cytochrome P450 3A, P-Glycoprotein and Organic Anion Transporting Polypeptide 1B1

The aim of the present study was to quantitatively evaluate the drug-drug interactions (DDIs) of maraviroc (MVC) with various perpetrator drugs, including telaprevir (TVR), using an in vitro data-informed physiologically based pharmacokinetic (PBPK) model. MVC showed significant active uptake and biliary excretion in sandwich-cultured human hepatocytes, and biphasic organic anion transporting polypeptide (OATP)1B1-mediated uptake kinetics in transfected cells (high-affinity Km ∼5 µM). No measureable active uptake was noted in OATP1B3- and OATP2B1-transfceted cells. TVR inhibited OATP1B1-mediated MVC transport in vitro, and also exhibited CYP3A time-dependent inhibition in human hepatocytes (inactivation constant, KI = 2.24 µM, and maximum inactivation rate constant, kinact = 0.0112 minute−1). The inactivation efficiency (kinact/KI) was approximately 34-fold lower in human hepatocytes compared with liver microsomes. A PBPK model accounting for interactions involving CYP3A, P-glycoprotein (P-gp), and OATP1B1 was developed based on in vitro mechanistic data. MVC DDIs with ketoconazole (inhibition of CYP3A and P-gp), ritonavir (inhibition of CYP3A and P-gp), efavirenz (induction of CYP3A), rifampicin (induction of CYP3A and P-gp; inhibition of OATP1B1), and TVR (inhibition of CYP3A, P-gp, and OATP1B1) were well described by the PBPK model with optimized transporter Ki values implying that OATP1B1-mediated uptake along with CYP3A metabolism determines the hepatic clearance of MVC, and P-gp–mediated efflux limits its intestinal absorption. In summary, MVC disposition involves intestinal P-gp/CYP3A and hepatic OATP1B1/CYP3A interplay, and TVR simultaneously inhibits these multiple mechanisms leading to a strong DDI—about 9.5-fold increase in MVC oral exposure.
FLT3 inhibitor quizartinib (AC220)

Acute myeloid leukemia (AML) is a heterogeneous disease and remains a therapeutic challenge. Cytogenetics is a well-established prognostic factor. Recent discovery of molecular mutations has gained momentum with some being potential therapeutic targets. FLT3 mutation seen in approximately one third of the cytogenetically normal AML confers high risk of relapse and poor survival. Quizartinib is the first drug developed specifically as a FLT3 inhibitor. It has confirmed safety and efficacy in phase I and II clinical trials and has shown survival benefit over conventional chemotherapy in patients with FLT3 ITD mutated relapsed/refractory AML. Despite such promise, disease relapses are still seen. Besides the complex nature of AML itself, resistance mechanisms blunting the efficacy of quizartinib have been identified and are being investigated including TKD mutations, alternate signaling pathways and the bone marrow microenvironment. Strategies using combination of quizartinib with other TKIs/agents like crenolinib, PIM kinase, and MEK inhibitors should be further explored.
Influence of Lipid Saturation, Hydrophobic Length and Cholesterol on Double-Arginine-Containing Helical Peptides in Bilayer Membranes.

Membrane proteins are essential for many cell processes yet are more difficult to investigate than soluble proteins. Charged residues often contribute significantly to membrane protein function. Model peptides such as GWALP23 (acetyl-GGALW5 LAL8 LALALAL16 ALW19 LAGA-amide) can be used to characterize the influence of specific residues on transmembrane protein domains. We have substituted R8 and R16 in GWALP23 in place of L8 and L16, equidistant from the peptide center, and incorporated specific 2 H-labeled alanine residues within the central sequence for detection by solid-state 2 H NMR spectroscopy. The resulting pattern of [2 H]Ala quadrupolar splitting (Δνq ) magnitudes indicates the core helix for R8,16 GWALP23 is significantly tilted to give a similar transmembrane orientation in thinner bilayers with either saturated C12:0 or C14:0 acyl chains (1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) or 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)) or unsaturated C16:1 Δ9 cis acyl chains. In bilayers of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC; C18:1 Δ9 cis) multiple orientations are indicated, whereas in longer, unsaturated 1,2-dieicosenoyl-sn-glycero-3-phosphocholine (DEiPC; C20:1 Δ11 cis) bilayers, the R8,16 GWALP23 helix adopts primarily a surface orientation. The inclusion of 10-20 mol % cholesterol in DOPC bilayers drives more of the R8,16 GWALP23 helix population to the membrane surface, thereby allowing both charged arginines access to the interfacial lipid head groups. The results suggest that hydrophobic thickness and cholesterol content are more important than lipid saturation for the arginine peptide dynamics and helix orientation in lipid membranes.
Student confidence with oncology pharmacy competencies.

Abstract Objective The purpose of this study was to assess the change in student confidence to perform oncology pharmacy competencies before and after completing oncology didactic instruction using a flipped classroom approach. Methods First year doctor of pharmacy students completed a survey prior to the Applied Science and Therapeutics (AST) oncology module (pre-survey) and the same survey following the completion of the oncology module (post-survey). The survey consisted of questions addressing prior oncology pharmacy experience related to employment (research or patient care) and education, level of interest in oncology pharmacy, and level of confidence to perform thirteen oncology pharmacy competencies. Results One-hundred sixteen students completed the pre-survey and 35 completed the post-survey. Students completing both surveys reported greater confidence in all oncology pharmacy competencies (p Conclusions The delivery of oncology content using flipped classroom instruction in the AST course successfully increased student confidence in ability to perform oncology pharmacy competencies. Cancer screening, cancer risk factors, and the preparation and dispensing of chemotherapy were competencies identified as needing greater emphasis in classroom instruction. Future studies are needed to assess student's knowledge and application of oncology pharmacy competencies in both the experiential and classroom settings.
Chapter Seventeen The Fluttering of Autumn Leaves: Logic, Mathematics, and Metaphysics in Florensky’s “The Pillar and Ground of the Truth”

Pavel Florensky’s The Pillar and the Ground of the Truth is surely one of the most unusual books of philosophy published in the twentieth century. More often than not, it produces in the reader a consternation that has caused many to reject it altogether after a few glances, thinking it an example of the aestheticism and even decadence that has come to be associated with Russian Symbolism. This stigmatization is both unfortunate and unjust, for it is a work of great logical, mathematical, and philosophical rigor as well as a source of deep spiritual insight. Moreover, one of its primary claims is that the formal rigor of logic and mathematics is ontologically rooted—not just applicable to the real, but of one piece with being itself. And another of its claims is that spirituality does not concern some rarified dimension separate from empirical reality, divorced from the human body and natural science and works of art, but that it extends into and illumines every aspect of life; it does not inhabit a world unto itself. Transcendence and immanence, visible and invisible, are not just “two worlds,” but ultimately two aspects of one world. Like Heraclitus and Parmenides before him, Florensky seeks to show that “it is wise to agree that all is one,” hen panta.
Understanding patients' end-of-life goals of care in the emergency department.

Background Emergency departments (ED) are frequently the entryway to the health system for older, more ill patients. Because decisions made in the ED often influence escalation of care both in the ED and after admission, it is important for emergency physicians to understand their patients' goals of care. Study objectives To determine how well emergency physicians understand their patients' goals of care. Methods This was a prospective survey study of a convenience sample of ED patients 65 years and older presenting between February 18 and March 1, 2019 to an academic center with 77,000 annual visits. If a patient did not have decision-making capacity, a surrogate decision-maker was interviewed when possible. Two sets of surveys were designed, one for patients and one for physicians. The patient survey included questions regarding their goals of care and end-of-life care preferences. The physician survey asked physicians to select which goals of care were important to their patients and to identify which was the most important. Patient-physician agreement on patients' most important goal of care was analyzed with Cohen's kappa. Results A total of 111 patient participants were invited to complete the survey, of whom 80 (72%) agreed to participate. The patients consisted of 43 women and 37 men with an age range from 65 to 98 years. Additionally, 16 attending and 14 resident physicians participated in the study for a total of 49 attending responses and 41 resident responses. A total of 88% of patients believed it was either very important or important to discuss goals of care with their physicians. Both patients and physicians most frequently chose "Improve or maintain function, quality of life, or independence" as the most important goal; however, there was wide variation in patient responses. Patients and attending physicians selected the same most important goal of care in 20% of cases (kappa 0.03) and patients and resident physicians selected the same goal in 27% of cases (kappa 0.11). Conclusions We found poor agreement between patients and physicians in the ED regarding patients' most important goal of care. Additionally, we found that most patients visiting the ED believe it is important to discuss goals of care with their physicians. Future work may focus on interventions to facilitate goals of care discussions in the ED.
Workforce, Workload, and Burnout in Critical Care Organizations: Survey Results and Research Agenda.

Objectives This report provides analyses and perspective of a survey of critical care workforce, workload, and burnout among the intensivists and advanced practice providers of established U.S. and Canadian critical care organizations and provides a research agenda. Design A 97-item electronic survey questionnaire was distributed to the leaders of 27 qualifying organizations. Setting United States and Canada. Participants Leaders of critical care organizations in the United States and Canada. Interventions None. Data synthesis and main results We received 23 responses (85%). The critical care organization survey recorded substantial variability of most organizational aspects that were not restricted by the critical care organization definition or regulatory mandates. The most common physician staffing model was a combination of full-time and part-time intensivists. Approximately 80% of critical care organizations had dedicated advanced practice providers that staffed some or all their ICUs. Full-time intensivists worked a median of 168 days (range 42-192 d) in the ICU (168 shifts = 24 7-d wk). The median shift duration was 12 hours (range, 7-14 hr), and the median number of consecutive shifts allowed was 7 hours (range 7-14 hr). More than half of critical care organizations reported having burnout prevention programs targeted to ICU physicians, advanced practice providers, and nurses. Conclusions The variability of current approaches suggests that systematic comparative analyses could identify best organizational practices. The research agenda for the study of critical care organizations should include studies that provide insights regarding the effects of the integrative structure of critical care organizations on outcomes at the levels of our patients, our workforce, our work practices, and sustainability.
Treatment Response among Preschoolers with Disruptive Behavior Disorders: The Role of Temperament and Parenting.

Objective: This study examined associations between temperament (negative affect, effortful control, and surgency) and symptoms of attention-deficit/hyperactivity disorder (ADHD) and oppositional d...
Measuring Insulin Resistance in Humans.

Background Insulin resistance is a pathophysiological condition associated with diabetes and cardiometabolic diseases that is characterized by a diminished tissue response to insulin action. Our understanding of this complex phenomenon and its role in the pathogenesis of cardiometabolic diseases is rooted in the discovery of insulin, its isolation and purification, and the challenges encountered with its therapeutic use. Summary In this historical perspective, we explore the evolution of the term "insulin resistance" and demonstrate how advances in insulin and glucose analytics contributed to the recognition and validation of this metabolic entity. We identify primary discoveries which were pivotal in expanding our knowledge of insulin resistance, the challenges in measurement and interpretation, contemporary techniques, and areas of future exploration. Key Message: Measurements of insulin resistance are important tools for defining and treating cardiometabolic diseases. Accurate quantification of this pathophysiological entity requires careful consideration of the assumptions and pitfalls of the methodological techniques and the historical and clinical context when interpreting and applying the results.
The value of student feedback in open forums: A natural analysis of descriptions of poorly rated teachers

In this paper we used natural language processing to review hundreds of thousands of negative student reviews of their teachers submitted to the website RateMyTeacher.com. Our analysis identified several issues raised by students when rating teachers poorly, which adds to the literature that defines “bad teachers” from the student perspective. We also identify the language students used to describe these issues and notice a clear distinction between the language used to address teaching-related complaints and behavior perceived as unfit for teachers. We argue that digital forums can be valuable tools for schools and conclude with suggestions and examples of the type of policies that may be derived from this type of analysis of a digital forum for students.
Extending Privacy Harms Toward a Non-Economic Perspective

Addressing data breach harms has become a great challenge in the administration of privacy law in the United States. Several data breach cases have been dismissed by US courts because the victims cannot prove cognizable harm. The current US legal system emphasizes that data breach victims must prove that they have suffered an “injury in fact,” which means that the injury suffered must be concrete and particularized. Data breach harms are futuristic and hard-to-quantify, reasons for which they may not fit in the “injury in fact” requirement. Furthermore, victims of data violations have attempted to plead economic loss to prove the harm suffered, but with no success. This article suggests a new approach that aims at addressing privacy harms without necessarily proving economically quantifiable harm.
A conserved long noncoding RNA, GAPLINC, modulates the immune response during endotoxic shock

Recent studies have identified thousands of long noncoding RNAs (lncRNAs) in mammalian genomes that regulate gene expression in different biological processes. Although lncRNAs have been identified in a variety of immune cells and implicated in immune response, the biological function and mechanism of the majority remain unexplored, especially in sepsis. Here, we identify a role for a lncRNA-gastric adenocarcinoma predictive long intergenic noncoding RNA (GAPLINC)-previously characterized for its role in cancer, now in the context of innate immunity, macrophages, and LPS-induced endotoxic shock. Transcriptome analysis of macrophages from humans and mice reveals that GAPLINC is a conserved lncRNA that is highly expressed following macrophage differentiation. Upon inflammatory activation, GAPLINC is rapidly down-regulated. Macrophages depleted of GAPLINC display enhanced expression of inflammatory genes at baseline, while overexpression of GAPLINC suppresses this response. Consistent with GAPLINC-depleted cells, Gaplinc knockout mice display enhanced basal levels of inflammatory genes and show resistance to LPS-induced endotoxic shock. Mechanistically, survival is linked to increased levels of nuclear NF-κB in Gaplinc knockout mice that drives basal expression of target genes typically only activated following inflammatory stimulation. We show that this activation of immune response genes prior to LPS challenge leads to decreased blood clot formation, which protects Gaplinc knockout mice from multiorgan failure and death. Together, our results identify a previously unknown function for GAPLINC as a negative regulator of inflammation and uncover a key role for this lncRNA in modulating endotoxic shock.
The AdcACB/AdcAII system is Essential for Zinc Homeostasis and an Important Contributor of Enterococcus faecalis Virulence

Bacterial pathogens require a variety of micronutrients for growth, including trace metals such as iron, manganese, and zinc (Zn). Despite their relative abundance in host environments, access to these metals is severely restricted during infection due to host-mediated defense mechanisms collectively known as nutritional immunity. Despite a growing appreciation of the importance of Zn in host-pathogen interactions, the mechanisms of Zn homeostasis and the significance of Zn to the pathophysiology of E. faecalis, a major pathogen of nosocomial and community-associated infections, have not been investigated. Here, we show that E. faecalis encoded an ABC-type transporter AdcACB and an orphan substrate-binding lipoprotein AdcAII that work cooperatively to maintain Zn homeostasis. Simultaneous inactivation of adcA and adcAII or the entire adcACB operon led to significant reduction in intracellular Zn under Zn-restricted conditions, heightened sensitivity to Zn-chelating agents including human calprotectin, aberrant cell morphology, and impaired fitness in serum ex vivo. Additionally, inactivation of adcACB and adcAII significantly reduced bacterial tolerance towards cell envelope-targeting antibiotics, which may be associated to altered fatty acid abundance and species. Lastly, we show that the AdcACB/AdcAII system contributes to E. faecalis virulence in an invertebrate (Galleria mellonella) infection model and in two catheter-associated mouse infection models that recapitulate many of the host conditions associated with enterococcal human infections. Collectively, this report reveals that high-affinity Zn import is essential for the pathogenesis of E. faecalis indicating that the surface-associated AdcA and AdcAII lipoproteins are potential therapeutic targets.
Pursuing the Good: Patenting BRCA

In the United States a system of patents designed to promote science and the useful arts is embedded in the Constitution. Before 1980 “products of nature” fell outside the scope of patentable materials and new knowledge about the functioning of living things was classified as discovery rather than invention. In 1980 the U.S. Supreme Court ruled on the basis of a narrow statutory interpretation that whether something is living or not is beside the point. Instead, a divided Court ruled that a living substance, not previously found in nature, is patentable if assessed as a man-made invention. Currently, at least twenty percent of the human genome is patented. The conceptual, scientific, and legal contrivances underpinning this development are premised on three general principles. First, scientific progress is good. Second, doing science is expensive. Third, patents stimulate innovation and will attract public and private investment in science. Patents on genes associated with breast and ovarian cancers (BRCA1 and BRCA2) awarded to Myriad Genetics provide particularly provocative challenges to these guiding principles. This presentation will explore national and international efforts to craft viable genomic policies as a result of patent opposition, litigation, and international agreements, like Trade-Related Aspects of Intellectual Property Rights (TRIPS), in responses to charges that patents on genomic substances inhibit scientific innovation, restrict access to diagnostic and preventative health care, and skew the economies of investment in favor of corporate profit rather than promoting the social good of health care.
ON STOCHASTICITY IN THE VON FOERSTER HYPERBOLIC PARTIAL DIFFERENTIAL EQUATION SYSTEM FURTHER APPLICATIONS TO THE MODELING OF AN ASYNCHRONOUSLY DIVIDING CELLULAR SYSTEM

Abstract We investigate the problem of including stochastically varying components in the Von Foerster hyperbolic partial differential equation system. In particular, we address the incorporation of stochasticity in the birth and death rates of the model. We assume, for the purposes of this analysis, that the stochasticity is slowly varying. The results of this analysis have bearing upon the modeling of biological populations which have a describable age-time dynamics. This analysis also has bearing upon some recent results concerning the modeling of asynchronously dividing cellular systems.
Introduction to the minitrack on markets and economics

Deregulation of the electric power industry has had mixed success in the USA, and many people are seriously questioning the desirability of continuing with this process. High prices in the Californian spot market in the Summer, 2000, for example, have led to government intervention to reduce customers’ bills in San Diego. In contrast, the high price volatility that was experienced in Pennsylvania, New Jersey and Maryland (PJM) market in Summer, 1999, was not repeated in Summer, 2000. These contrasting situations illustrate the importance of learning more about the performance of markets for electricity and the behavior of the players in these markets. The nature of supplying electric power to customers is more complicated than it is for many commodities. Customers want to purchase real power but other ancillary services, such as generating reserves and voltage support, must also be provided to make the supply reliable (e.g., avoid blackouts). In this Minitrack, a collection of 10 papers discuss various aspects of the markets for real power and ancillary services, including financial hedges against uncertainty. Since there are major differences in the fundamental structures of the deregulated markets for electricity in different regions, the objectives of this Minitrack are to discuss the structures of different markets, and to identify specific features that lead to good and bad performance of a market.
Charged Residues Render Pro-OmpA Potential Dependent for Initiation of Membrane Translocation*

We have examined the effects of positively and negatively charged residues on the translocation of outer membrane protein A precursor (pro-OmpA) across the bacterial inner membrane. Pro-OmpA does not translocate across the membrane when 2 positively charged residues are inserted immediately after the leader peptide, whereas it does insert when 2 neutral or negatively charged residues are introduced. Using a cell-free translocation system, we show that the membrane potential stimulated the rate of initial insertion of pro-OmpA with negatively charged residues, inhibited pro-OmpA with positively charged residues, and had no effect on neutral pro-OmpA. Thus, acidic residues render pro-OmpA potential-dependent for loop formation, which then initiates the translocation process.
The life cycle, ecological, and economic determinants of spousal leisure sharing: Panel estimations from Tawahka Amerindians, Honduras

Researchers have used the amount of leisure as a yardstick to proxy for quality of life, but so far they have paid scant attention to the quality of leisure. Here I use spousal leisure sharing to proxy for quality of leisure and, by implication, for quality of life. I draw on life-cycle perspective, price theory, and on human ecology to frame hypotheses about the determinants of spousal leisure sharing. Drawing on longitudinal information collected over 2 years from 32 households in two villages of Tawahka Amerindians, a horticultural and foraging society in the tropical rain forest of eastern Honduras, I estimate the simultaneous effects of age and age squared, cash income, and climatic/seasonal variables on the amount of time spouses spend together in leisure. Analysis using different random and fixed-effect multivariate logit models suggests that (1) life-cycle determinants play a strong role in spousal leisure sharing and (2) neither climate/seasonal variables nor income correlate with spousal leisure sharing. As is true among couples in the United States, among Tawahka couples a change in the income of either spouse has a small effect on the amount of leisure shared by spouses. I find no evidence that economic development erodes spousal leisure sharing or that couples exhibit fissure in their pursuit of a common goal of leisure sharing.
Business and public health collaboration for emergency preparedness in Georgia: a case study

Governments may be overwhelmed by a large-scale public health emergency, such as a massive bioterrorist attack or natural disaster, requiring collaboration with businesses and other community partners to respond effectively. In Georgia, public health officials and members of the Business Executives for National Security have successfully collaborated to develop and test procedures for dispensing medications from the Strategic National Stockpile. Lessons learned from this collaboration should be useful to other public health and business leaders interested in developing similar partnerships. The authors conducted a case study based on interviews with 26 government, business, and academic participants in this collaboration. The partnership is based on shared objectives to protect public health and assure community cohesion in the wake of a large-scale disaster, on the recognition that acting alone neither public health agencies nor businesses are likely to manage such a response successfully, and on the realization that business and community continuity are intertwined. The partnership has required participants to acknowledge and address multiple challenges, including differences in business and government cultures and operational constraints, such as concerns about the confidentiality of shared information, liability, and the limits of volunteerism. The partnership has been facilitated by a business model based on defining shared objectives, identifying mutual needs and vulnerabilities, developing carefully-defined projects, and evaluating proposed project methods through exercise testing. Through collaborative engagement in progressively more complex projects, increasing trust and understanding have enabled the partners to make significant progress in addressing these challenges. As a result of this partnership, essential relationships have been established, substantial private resources and capabilities have been engaged in government preparedness programs, and a model for collaborative, emergency mass dispensing of pharmaceuticals has been developed, tested, and slated for expansion. The lessons learned from this collaboration in Georgia should be considered by other government and business leaders seeking to develop similar partnerships.