cssi/SciSciGPT-SciSciNet huggingface dataset:
The Nonstationary Staff-Planning Problem with Business Cycle and Learning Effects

Managing highly skilled employees is extremely complex because of the need to balance the costs and time lags associated with their training against the need to meet demand as quickly as possible. Unlike previous approaches to this problem in the staffing literature, this paper develops an optimal staffing policy at the strategic level to cope with nonstationary stochastic demand for a staff characterized by unproductive apprentice employees and fully productive experienced employees. The paper then explores the implications of this policy in different industries, using empirical data. Aside from the optimal policy, this paper's primary results include: (1) demand volatility reduces average productivity, most especially under conditions of low (or slightly negative) growth and--nonintuitively-- low employee turnover or knowledge obsolescence rates; (2) there is a trade-off between meeting demand and high productivity; (3) firms withlonger business cycles should smooth their hiring and firing policies; and (4) firms in industries with longer training times should smooth their hiring and firing policies. The paper also explores the possible rewards from reducing training times and turnover rates. Finally, it discusses managerial implications and possible future directions in research.
What is Truth? Standards of Scientific Integrity in American Heart Association Journals

The pursuit of scientific knowledge engenders both a profound sense of wonder and responsibility. As life scientists, we endeavor to discover hidden truths that will illuminate specific pathways underlying basic life or death processes, or the mechanism of action of a therapeutic intervention. But what is truth? We expect what is true in a given set of experiments to be self-evident in our publications; however, increasingly, we are confronted with cases of skewed truth or outright fraud. One could argue the increase in scientific misconduct relates to the ever-rising demand to publish data. This demand in publishing is reflected by a steady increase in both the number of scientific journals and total articles published over the past 60 years (Figure). Interestingly, recent evidence suggests an apparent escalation in the number of retracted articles during the last 10 years,1 when a particularly sharp increase in journal/paper number was observed (Figure). Whether the rise in the number of retracted papers, and by extension scientific misconduct, relates to increases in published articles or simply the greater detection/reporting of scientific misconduct is unclear. However, few would dispute that the pressure to publish (or perish) and the ease in which data figures are generated provide fertile conditions for scientific misconduct to occur. Figure. The 60-year trend in total publication and journal number. Shown are the PubMed-indexed scientific publications for each of the indicated years and the corresponding number of journals available to authors in which to publish their work. Journal numbers for the years shown were obtained through the National Library of Medicine. The issues surrounding scientific misconduct have spawned several initiatives to detect and combat such practices. But what realistic remedy can we promulgate for the journals stewarded by the American Heart Association (AHA)? A recent National Academies panel was formed to define …
Die Technik, ein vorwiegend menschliches Problem

„In der Tatsache, das die Maschinen gegenwartig nur wenig Bewustsein besitzen, liegt keine Gewahr gegen die schliesliche Entwicklung eines mechanischen Bewustseins. — Wenn eine Maschine imstande ist, andere systematisch zu erzeugen, durfen wir sicherlich sagen, sie habe ein Fortpflanzungsvermogen. — Wenn geltend gemacht wird, die Tatigkeit der Kartoffel sei blos chemisch und mechanisch und ruhre von den chemischen und mechanischen Wirkungen des Lichtes und der Warme her, scheint mir die beste Antwort darauf eine Untersuchung zu sein, ob nicht jede Empfindung in ihrem Vorgang chemischer und mechanischer Natur sei? — ... mochte ich wiederholen, das ich keine der heute vorhandenen Maschinen furchte. Was ich furchte, ist die auserordentliche Schnelligkeit, mit der sie etwas ganz Anderes werden, als sie heute sind. — ... allem weiteren technischen Fortschritt sogleich ein Ende zu machen und alle technischen Erfindungen und Verbesserungen der letzten 300 Jahre zu vernichten.“
An evaluation of roof support plans at two coal mines in Illinois using numerical models

•Roof control plans at two mines are compared using strain-based rock mass failure criteria.•Shearing strains at pillar corners near the roof and floor are critical for failure initiation.•Shear and tensile strains at the coal-floor interface are also critical.•High compressive strains along the pillar ribs in entries result in cutter roof.•Failure initiation occurs around the mid-height of pillar ribs and progresses downward.
β-Adrenergic-mediated vasodilation in young men and women: cyclooxygenase restrains nitric oxide synthase

We tested the hypothesis that women exhibit greater vasodilator responses to β-adrenoceptor stimulation compared with men. We further hypothesized women exhibit a greater contribution of nitric oxide synthase and cyclooxygenase to β-adrenergic-mediated vasodilation compared with men. Forearm blood flow (Doppler ultrasound) was measured in young men (n = 29, 26 ± 1 yr) and women (n = 33, 25 ± 1 yr) during intra-arterial infusion of isoproterenol (β-adrenergic agonist). In subset of subjects, isoproterenol responses were examined before and after local inhibition of nitric oxide synthase [N(G)-monomethyl-l-arginine (l-NMMA); 6 male/10 female] and/or cyclooxygenase (ketorolac; 5 male/5 female). Vascular conductance (blood flow ÷ mean arterial pressure) was calculated to assess vasodilation. Vascular conductance increased with isoproterenol infusion (P 0.99) or women (P = 0.21). In contrast, ketorolac infusion markedly increased isoproterenol-mediated responses in both men (P < 0.01) and women (P = 0.04) and this rise was lost with subsequent l-NMMA infusion (men, P < 0.01; women, P < 0.05). β-Adrenergic vasodilation is not different between men and women and sex differences in the independent contribution of nitric oxide synthase and cyclooxygenase to β-mediated vasodilation are not present. However, these data are the first to demonstrate β-adrenoceptor activation of cyclooxygenase suppresses nitric oxide synthase signaling in human forearm microcirculation and may have important implications for neurovascular control in both health and disease.
Engineering an Escherichia coli platform to synthesize designer biodiesels

Biodiesels, fatty acid esters (FAEs), can be synthesized by condensation of fatty acid acyl CoAs and alcohols via a wax ester synthase in living cells. Biodiesels have advantageous characteristics over petrodiesels such as biodegradability, a higher flash point, and less emission. Controlling fatty acid and alcohol moieties are critical to produce designer biodiesels with desirable physiochemical properties (e.g., high cetane number, low kinematic viscosity, high oxidative stability, and low cloud point). Here, we developed a flexible framework to engineer Escherichia coli cell factories to synthesize designer biodiesels directly from fermentable sugars. In this framework, we designed each FAE pathway as a biodiesel exchangeable production module consisting of acyl CoA, alcohol, and wax ester synthase submodules. By inserting the FAE modules in an engineered E. coli modular chassis cell, we generated E. coli cell factories to produce targeted biodiesels (e.g., fatty acid ethyl (FAEE) and isobutyl (FAIbE) esters) with tunable and controllable short-chain alcohol moieties. The engineered E. coli chassis carrying the FAIbE production module produced 54mg/L FAIbEs with high specificity, accounting for>90% of the total synthesized FAEs and ∼4.7 fold increase in FAIbE production compared to the wildtype. Fed-batch cultures further improved FAIbE production up to 165mg/L. By mixing ethanol and isobutanol submodules, we demonstrated controllable production of mixed FAEEs and FAIbEs. We envision the developed framework offers a flexible, alternative route to engineer designer biodiesels with tunable and controllable properties using biomass-derived fermentable sugars.
Effect of hypophysectomy on pigmentation and ascorbic acid excretion in black rats.

SummaryPigmentation was observed in black rats following hypophysectomy, similar to the pigmentation occurring in black rats following adrenalectomy. The adrenals of the hypophysectomized rats were smaller than normal, with atrophic cortices. Excretion of ascorbic acid decreased to low levels following hypophysectomy. The increase in pigmentation is believed to be related to the derangement of the steroid hormones of the adrenal cortex of the hypophysectomized rat.
Nonlocal Interferometry Using Schrodinger Cats

A method for performing nonlocal interferometry using macroscopic phase-entangled coherent states is described. This allows Bell’s inequality to be violated using Schrodinger cat states over relatively large distances in optical fibers.
Application of a New Earth Dam Interior Settlement Monitoring Instrument-Rod Settlement Gage

As a settlement monitoring instrument in the interior of an earth dam,the rod settlement gage can meet the requirements of monitoring the interior settlement of an earth dam in an automated and convenient way. It can reduce the effects on dam construction,and cut down the unnecessary cost of civil engineering of observation rooms and other related works. This paper summarizes the background of development,the principle and structure of the rod settlement gage and the results of its engineering application.
Immunophenotypic characteristics of cerebrospinal fluid cells in children with acute lymphoblastic leukemia at diagnosis

The presence of meningeal involvement in children with acute lymphoblastic leukemia (ALL) may have important prognostic and therapeutic implications. Conventional methods of diagnosing central nervous system (CNS) leukemia rely on the interpretation of cerebrospinal fluid (CSF) cell morphology, which may produce ambiguous results in the presence of minimal leukemic involvement. A methodology has been developed for immunophenotyping small numbers of CSF cells while preserving cell morphology. CSF samples from 33 children with CD10 (common ALL antigen [CALLA]) positive ALL were examined at initial presentation using both conventional morphology and this combined immunohistopathologic technique. Six (18%) of the samples contained lymphoblasts or cells considered morphologically suspicious for leukemic involvement. Nine additional samples (27% of the total) had normal CSF morphology, but contained increased numbers of CALLA positive cells. Twelve of the 33 samples were also examined for the simultaneous presence of nuclear terminal deoxynucleotidyl transferase (TdT) and demonstrated increased numbers of cells positive for both TdT and CD10. These data suggest that a large proportion of children with ALL may have abnormalities of CSF cells at initial diagnosis consistent with the presence of occult leukemic involvement.
Honking Helps Overcome the Driving Too Slowly Problem in Driving Simulators

In driving simulators, subjects sometimes drive more slowly than they would on real roads when not attending to driving. To address this problem, in two experiments, groups of 24 subjects drove through 138 intersections with green (53 %), yellow (36 %), or red lights (11 %). The speed limit was 35 mi/hr. In the second experiment, the following vehicle honked as needed.The number of honks per subject varied from 0 to 6 for driving too slowly (less than 25 mi/hr) and 0 to 8 for delayed responses when a traffic light changed from red to green. Older drivers received 2.4 times more honks than younger drivers. Within 5 s after the following vehicle honked between intersections, the mean speed driven increased by 5 mi/hr. Similarly, with honking, the speed 5 s after the light changed increased by 8 mi/hr, both changes that lead to more realistic driving.
Lymphokine production by T lymphocytes isolated from murine small intestinal epithelium.

Mouse small intestinal intraepithelial lymphocytes (IEL) are predominantly Lyt 2+ (suppressor/cytotoxic phenotype) T cells. IEL T lymphocytes display immunocompetence in vitro insofar as they respond to Concanavalin A (Con A) and alloantigens (1). There is also some evidence from histologic studies that IEL respond to local stimuli in vivo, because their numbers can be markedly increased (parasite infection; food allergy) or decreased (germ free animals) and many of them have the characteristics of immunoblasts (2). However it is not known whether T cells in the intestinal epithelium have the potential to function in the regulation of gut immune responses as suppressor cells, reflecting their predominantly Lyt 2+ phenotype, or whether they act in the afferent limb of cell mediated immunity by secreting lymphokines.
A SORRY TALE: NATIVES, SETTLERS, AND THE SALMON OF LAKE ONTARIO, 1780–1900*

Through the end of the eighteenth century, Lake Ontario had a large population of Atlantic salmon. However, the salmon population declined precipitously in the first half of the nineteenth century, and the fish had disappeared completely by 1900. This article analyses the responses of both Natives and settlers to initial salmon abundance and subsequent diminution. Although the extirpation of the lake's salmon is generally attributed to the construction of dams, this article identifies earlier and broader causes of salmon decline. In both Canada and the United States, commercial fishing captured unprecedented numbers of fish while agriculture and deforestation compromised salmon spawning habitat. While primary responsibility for the extirpation rests with the settlers, both Natives and Euro-Americans treated the fish as a commodity. As the salmon dwindled, sportsmen's groups came to the fore in setting fisheries policy. Sportsmen supported enhanced conservation measures but based their strategy on unrealistic methods for reviving the fish population through pisciculture.
Mechanical chest compression devices are associated with poor neurological survival in a statewide registry: A propensity score analysis.

Abstract Objective To compare functional survival (discharge cerebral performance category 1 or 2) among victims of out-of-hospital cardiac arrest (OHCA) who had resuscitations performed using mechanical chest compression (mech-CC) devices vs. those using manual chest compressions (man-CC). Methods Observational cohort of 2600 cases of OHCA from a statewide, prospectively-collected cardiac arrest registry (Utah Cardiac Arrest Registry to Enhance Survival). Comparison of functional survival among those receiving mech-CC vs man-CC was performed using a mixed-effects Poisson model with inverse probability weighted propensity scores to control for selection bias. Results Overall, mech-CC was utilized in 405/2600 (16%) of the total arrests in Utah during this period. 371/405 (92%) were of the load-distributing band type (AutoPulse ® ) and 22/405 (5%) were mechanical piston devices (LUCAS™), while 12/405 (3%) employed other devices. The relative risk (RR) for functional survival comparing mech-CC to man-CC after propensity score adjustment was 0.41 (95% CI 0.24–0.70, p =0.001). Conclusions Mechanical chest compression device use was associated with lower rates of functional survival in this propensity score analysis, controlling for Utstein variables and early return of spontaneous circulation.
Sensory Evaluation of the Mouthfeel of Beer

The sensory attributes that constitute the mouthfeel of beer were identified and defined using descriptive analysis procedures. Nine terms were found to be important in describing the mouthfeel of ...
Religion, Stress, and Superheroes

Religion can be a cause of stress or a cure for stress. Religion's ability to relieve the stress that it induces partly accounts for its tenacious hold on its truest or newest believers. Religious sentiment and sectarianism rises during times of increased personal or societal stress. Since change and uncertainty are potent causes of stress, on a psychological, sociological, and physiological level, it stands to reason that some of history's most unusual religious movements occurred at times of rapid social change and uncertainty. Individuals undergoing personal stress and lifestyle shifts are statistically more likely to get involved with unusual or innovative religious movements. Thus, adolescents who recently left home, those who are newly divorced, bereaved or relocated, and inmates who “relocate” to prison are especially susceptible to the appeal of “radical religions.” “Garden-variety” religions and also cults grow in response to the stresses of poverty, old age, war, illness, isolation, or impending death.
Principles of Cell Signaling

The successful transition from single cells to complex multicellular organisms has required the development of mechanisms for cells to communicate with each other, so as to act in concert during processes such as nutrient acquisition, motility, and defense. The most fundamental of these are cell–cell junctions that serve as structural organizers, but also provide information that individual cells can utilize to orient themselves in relation to the remainder of the organism. In larger species that contain multiple organs and cell types, the need to communicate information over long distances has led to the development of diffusible factors that are secreted by one cell and travel to distant cells. These factors can be delivered locally, via the circulation (e.g., hormones and cytokines) or via the nervous system (e.g., neurotransmitters), and are recognized by the appropriate cell surface receptor on the recipient cell. The complex nature of the numerous signals presented to the cell at any given point in time has led to the development of an intricate array of receptor-activated intracellular second messengers that, by undergoing a coordinated series of interactions and enzymatic alterations, can transduce the information presented on the cell surface to effector molecules that mediate the appropriate cellular response.
Atomistic calculations and materials informatics: A review

Abstract In recent years, there has been a large effort in the materials science community to employ materials informatics to accelerate materials discovery or to develop new understanding of materials behavior. Materials informatics methods utilize machine learning techniques to extract new knowledge or predictive models out of existing materials data. In this review, we discuss major advances in the intersection between data science and atom-scale calculations with a particular focus on studies of solid-state, inorganic materials. The examples discussed in this review cover methods for accelerating the calculation of computationally-expensive properties, identifying promising regions for materials discovery based on existing data, and extracting chemical intuition automatically from datasets. We also identify key issues in this field, such as limited distribution of software necessary to utilize these techniques, and opportunities for areas of research that would help lead to the wider adoption of materials informatics in the atomistic calculations community.
The Specter of War and Revolution

In this chapter, we deal first with the immediate reaction among Russian philosophers to the “Geat War” against Germany before turning to the criticisms of Kant from intuitivism, Solov’evian metaphysics, and common sense. The diatribe by a young philosopher Ern against Kant, linking the latter to German militarism met with consternation and criticism. However, criticisms of Kant came from several philosophical directions, some of which upheld various aspects of Kant’s thought. We, then, turn to two disciples of Marburg neo-Kantianism.
Combination therapy with GLP‐1 receptor agonist and SGLT2 inhibitor

The SGLT2 inhibitors (SGLTi) and glucagon-like-1 receptor agonists (GLP-1 RAs) effectively reduce HbA1c, but via very different mechanisms, making them an effective duet for combination therapy. Recently, drugs in both of these antidiabetic classes have been shown to reduce cardiovascular events, most probably by different mechanisms. SGLT2i appear to exert their CV protective actions by haemodynamic effects, while GLP-1 RAs work via anti-atherogenic/anti-inflammatory mechanisms, raising the possibility that combined therapy with these 2 classes may produce additive CV benefits. The SGLT2i and GLP-1 RAs also reduced macroalbuminuria, decreased the time for doubling of serum creatinine, and slowed the time to end-stage renal disease. In this perspective, we review the potential benefit of combination SGLT2i/GLP-1 RA therapy on metabolic-cardiovascular-renal disease in patients with type 2 diabetes mellitus.
Enantioselectivity Model for Pd-Catalyzed C–H Functionalization Mediated by the Mono-N-protected Amino Acid (MPAA) Family of Ligands

The mono-N-protected amino acid (MPAA) family of ligands is arguably the most prolific scaffold for enabling enantioselective C–H activation via metal insertion. However, its mechanism for asymmetric induction is not fully understood. Here, we developed a practical model for asymmetric induction from the viewpoint of rationalizing chiral, bidentate ligands for C–H activation via metal insertion. The model is validated against Pd(II)-catalyzed C–H activation in 2-benzhydrylpyridine mediated by the [(cyclohexyloxy)carbonyl]-l-leucine (MPAA) ligand. We found that full control elements of enantioselectivity are (a) inherent strain in the bidentate coordination of substrate and the ability of the ligand to enhance it, (b) the gearing effect that restricts the C–H bond activation to one face of the Pd catalyst, (c) potential interactions between the ligand and substrate, and (d) chelate inversion which is controlled by the ligand-anchored base that restricts the C–H bond activation to one side of the Pd catalys...
The Progression of End-of-Life Wishes and Concordance with End-of-Life Care.

Abstract Since 2013, Kaiser Permanente Northern California has engaged in a systematic effort to elicit, document, and honor the care preferences of patients as they near the end of life. This is done through its Advanced Steps program, in which selected patients discuss their preferences for future medical care with their healthcare agent during a structured conversation with a trained advance care planning facilitator. The facilitator then translates the patient's wishes into an actionable medical order set using a Physician's Order for Life-Sustaining Treatment (POLST) form. We wanted to know whether these patients' recorded wishes were concordant with care received at the end of life. To evaluate, we conducted an in-depth chart review of 300 patients who died in 2015 and had participated in the program. We determined that 290 patients received concordant care, whereas three patients received care discordant with their wishes before death. Seven patients did not have sufficient information in their rec...
In vitro demonstration that pemetrexed is a good substrate for glucarpidase

4773 The objective of this work was to assess the ability of glucarpidase to hydrolyse pemetrexed and to compare the kinetics of the reaction with the hydrolysis of methotrexate (MTX) by glucarpidase. Studies were performed in vitro in tris buffer. Disappearance of pemetrexed and methotrexate in the presence of glucarpidase was measured spectrophotometrically, and results were used to estimate Km and k cat values. Pemetrexed was shown to be a good substrate for glucarpidase with comparable kinetic parameters (Km=25 µM, k cat =1808 s -1 ) to MTX (Km=10 µM, k cat =1039 s -1 ). Glucarpidase (formerly carboxypeptidase G2, CPG2) is an enzyme that hydrolyses the glutamate subgroup from MTX. It has consistently been shown to cause a marked and rapid reduction in systemic MTX concentrations in patients whose elimination of MTX is delayed following high-dose MTX treatment 1 . Like methotrexate, pemetrexed is a folate analogue that inhibits dihydrofolate reductase. Pemetrexed is licensed by FDA for the first-line treatment of malignant pleural mesothelioma and second-line, single-agent treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) 2 . The principal dose limiting toxicity found in Phase I was myelosuppression. In a randomized controlled comparison of pemetrexed against docetaxel, pemetrexed was as effective as docetaxel, but was associated with significantly fewer side effects 3 . Nevertheless, 5.3% of the pemetrexed treated patients had grade 3 or 4 neutropenia. The results of this investigation show that glucarpidase is able to hydrolyse pemetrexed with similar reaction kinetics to its hydrolysis of methotrexate. Glucarpidase thus has the potential to be used to control systemic exposure of patients to pemetrexed and may allow further enhancement of its antitumor efficacy/safety profile. 1. Adamson, P. C., Balis, F. M., Boron, M., Shalabi, A., O9Brien, M., Eby, M., Jayaprakash, N., Cole, D. E., Ivy, P., Widemann, B. C. Carboxypeptidase-G2 (CPDG2) and leucovorin (LV) rescue with and without addition of thymidine (Thd) for high-dose methotrexate (HDMTX) induced renal dysfunction. ASCO Meeting Abstracts 1 Jun 2005 23: 2076 2. Rollins, K. D., Lindley, C. Pemetrexed: a multitargeted antifolate. Clin.Ther. Sep 2005 27: 1343-1382 3. Hanna, N., Shepherd, F. A., Fossella, F. V., Pereira, J. R., De Marinis, F., von Pawel, J., Gatzemeier, U., Tsao, T. C., Pless, M., Muller, T., Lim, H. L., Desch, C., Szondy, K., Gervais, R., Shaharyar, Manegold, C., Paul, S., Paoletti, P., Einhorn, L., Bunn, P. A., Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J.Clin.Oncol. 1 May 2004 22: 1589-1597
Simulation of the Solar Wind Dynamic Pressure Increase in 2014 and Its Effect on Energetic Neutral Atom Fluxes from the Heliosphere

In late 2014, the solar wind dynamic pressure increased by ~50% over a relatively short time (~6 months). In early 2017, the Interstellar Boundary Explorer (IBEX) observed an increase in heliospheric energetic neutral atom (ENA) fluxes from directions near the front of the heliosphere. These enhanced ENA emissions resulted from the increase in SW pressure propagating through the inner heliosheath (IHS), affecting the IHS plasma pressure and emission of ~keV ENA fluxes. We expand on the analysis by McComas et al. on the effects of this pressure change on ENA fluxes observed at 1 au using a three-dimensional, time-dependent simulation of the heliosphere. The pressure front has likely already crossed the termination shock (TS) in all directions, but ENA fluxes observed at 1 au will change over the coming years, as the TS, heliopause, and IHS plasma pressure continue to change in response to the SW pressure increase. Taken in isolation, the pressure front creates a "ring" of increasing ENA fluxes projected in the sky that expands in angular radius over time, as a function of the distances to the heliosphere boundaries and the ENA propagation speed. By tracking the position of this ring over time in our simulation, we demonstrate a method for estimating the distances to the TS, heliopause, and ENA source region that can be applied to IBEX data. This will require IBEX observations at 4.3 keV up through ~2020, and longer times at lower ENA energies, in order to observe significant changes from the heliotail.
Fields of Extremals and Sufficient Conditions for a Class of Variational Games

In this paper, using G. Leitmann's direct sufficiency method, extended for differential games, we present sufficient conditions for open loop strategies for a class of continuous time variational games. The result presented here is an extension of the classical Weierstrass sufficiency results for free problems in the calculus of variations.
Distinguishing the meaning making processes of survivors of suicide loss: An expansion of the meaning of loss codebook.

Suicide loss represents particularly a difficult form of bereavement due to the challenges that volitional death poses to survivors. Understanding these challenges requires recognition of the idios...
Untangling the Gordian Knot of Human Sexuality: What Is the Biologic Basis of Variations in Sexual Phenotype?

There is increasing interest in and tolerance of the lay public for variations in human sexuality. In contrast, the molecular biology that underlies gender identity, the development of gonadal and ...
Temporary Transvenous Cardiac Pacing

For detailed descriptions of the anatomy of the neck, please refer to Surgical Anatomy chapters on Central Venous Access and Pulmonary Artery Catheterization.
Platelet Function Testing in Clinical Research Trials

Abstract As our understanding of the role of platelets in various disease settings has expanded ( Chapters 26–31 26 27 28 29 30 31 ) so has the use of platelet function tests in clinical research trials. A wide variety of platelet function tests are currently available (see Chapters 33–36 33 34 35 36 ) ranging from light transmission aggregation, to adhesion under shear, to flow cytometric determination of receptor activation and heterotypic cell aggregate formation. The use of platelet function tests in clinical research trials has specific requirements which present major challenges for many tests. The purpose of this chapter is to describe the key characteristics required for platelet function testing in clinical research trials, and thereby promote the generation of high-quality data which can be used to evaluate disease mechanisms, assess patient risk for thrombosis or bleeding, determine drug pharmacodynamics, and inform treatment decisions.
Abstract 3091: Effects of melanoma cell-derived exosomes in melanoma patients’ plasma on immune cell functions

Background: Exosomes are a subset of small (30-150nm) extracellular vesicles (EVs) of the endocytic origin that mediate intercellular communication in health and disease. Exosomes are actively produced by tumor cells, circulate freely in body fluids and carry messages that alter functions of normal cells in the tumor microenvironment (TME), including immune cell functions. The ability of melanoma exosomes to reprogram immune cell functions might contribute to disease progression. Methods: To evaluate effects of melanoma cell-derived exosomes (MTEX) on human immune cell subsets, we isolated exosomes from plasma of 12 patients with melanoma and separated MTEX from non-MTEX by immune capture using anti-CSPG4 mAb on beads. These exosome fractions, and exosomes from plasma of 6 normal donors used as controls (NC), were studied by on-bead flow cytometry to quantify their surface protein profiles and in co-incubation assays with immune cell subsets for functional attributes. Phenotypic and functional profiles of MTEX and non-MTEX were compared. Results & Conclusion: MTEX were enriched (p to exosomes of NC, were not immunosuppressive. Thus, MTEX, present in excess in plasma of patients with metastatic melanoma, mediate immune suppression and contribute to immune escape of the tumor. Citation Format: Priyanka Sharma, Brenda Diergaarde, Soldano Ferrone, John M. Kirkwood, Theresa L. Whiteside. Effects of melanoma cell-derived exosomes in melanoma patients’ plasma on immune cell functions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3091.
Metal-dependent assembly of a protein nano-cage

Short, alpha-helical coiled coils provide a simple, modular method to direct the assembly of proteins into higher order structures. We previously demonstrated that by genetically fusing de novo-designed coiled coils of the appropriate oligomerization state to a natural trimeric protein, we could direct the assembly of this protein into various geometrical cages. Here, we have extended this approach by appending a coiled coil designed to trimerize in response to binding divalent transition metal ions and thereby achieve metal ion-dependent assembly of a tetrahedral protein cage. Ni2+ , Co2+ , Cu2+ , and Zn2+ ions were evaluated, with Ni2+ proving the most effective at mediating protein assembly. Characterization of the assembled protein indicated that the metal ion-protein complex formed discrete globular structures of the diameter expected for a complex containing 12 copies of the protein monomer. Protein assembly could be reversed by removing metal ions with ethylenediaminetetraacetic acid or under mildly acidic conditions.
Time-resolved FRET and NMR analyses reveal selective binding of peptides containing the LC3-interacting region to ATG8 family proteins.

Selective autophagy sequesters cytoplasmic cargo for lysosomal degradation via the binding of autophagy receptors to Atg8 (autophagy-related 8) family proteins on the autophagic membrane. The sole yeast Atg8 gene has six mAtg8 (mammalian Atg8) homologs, including the MAP1LC3 (microtubule-associated protein-1 light chain 3) family and the GABA receptor–associated proteins. Selective autophagy receptors interact with two conserved hydrophobic pockets (termed the W-site and L-site) of mATG8 proteins through a linear motif called the LC3-interacting region (LIR) with the general composition (W/F/Y)XX(I/L/V). To address a lack in our knowledge regarding LIR peptide specificity toward each mATG8 homolog, here we used competitive time-resolved FRET to sensitively and quantitatively characterize the interactions between LIRs and mAtg8. We report that 14 representative LIR-containing peptides display differential binding affinities toward the mAtg8 proteins and identified the LIR domain peptide of TP53INP1 as exhibiting high affinity for all six mATG8 proteins. Using peptide truncation studies, we found that both N- and C-terminal acidic residues, as well as the C-terminal Cys residue of the TP53INP1 LIR peptide, are required for its high-affinity binding to LC3A and LC3B, whereas binding to the GABARAP subfamily proteins was facilitated by residues either N-terminal or C-terminal to the core motif. Finally, we used NMR chemical shift perturbation analysis to gain molecular insights into these findings. Collectively, our results may aid in the development of molecules that selectively disrupt specific mATG8–LIR interactions to dissect the biological roles of the six mATG8 homologs for potential therapeutic applications.
David Oliver: What's the verdict on personal health budgets?

A key component of the NHS long term plan was a set of commitments on personalised care.1 These included a target for 200 000 people to benefit from personal health budgets by 2023-24. The current number is around 40 000.2 This raises questions. For instance, will these budgets benefit the right people? Will they introduce risks or bring opportunity costs for other service users? Are they a cost effective use of scarce public resources, or would the money be better spent elsewhere? Are any safeguards required? In England, personal budgets3 and direct payments linked to personalised care plans have existed in social care for some time. Their introduction was partly a response to …
Fetal MRI assessment of mediastinal shift angle in isolated left congenital diaphragmatic hernia: A new postnatal survival predictive tool?

Objective To quantify the mediastinal shift angle (MSA) in fetuses with isolated left congenital diaphragmatic hernia (CDH) by magnetic resonance imaging and evaluate survival. Method Fetuses from singleton pregnancies with isolated left CDH were matched for gestational age with controls without thoracic malformations. For all fetuses the MSA was determined by two operators and inter-operator variability and differences between cases and controls were investigated. For all cases total fetal lung volume (TFLV) was calculated and the correlation between MSA and TFLV was assessed, and its predictive value towards survival was determined. Results Thirty-four fetuses were included as cases and 42 as controls. The mean gestational age for assessment of CDH fetuses was 32 weeks (range 27-38). Twenty-four fetuses survived until discharge and 10 did not. There was an excellent inter-operator reliability for measuring the MSA and a significant difference between MSA in cases and controls. There was an inverse correlation between MSA values and survival, a correlation between TFLV and survival and an inverse correlation between MSA and TFLV. The area under the ROC curve for MSA in predicting survival was 0.931 (95% CI 0.851-1.000). Conclusion The MSA measured late in gestation correlates with postnatal survival in patients with isolated left CDH.
Measuring implementation feasibility of clinical decision support alerts for clinical practice recommendations.

Objective The study sought to describe key features of clinical concepts and data required to implement clinical practice recommendations as clinical decision support (CDS) tools in electronic health record systems and to identify recommendation features that predict feasibility of implementation. Materials and methods Using semistructured interviews, CDS implementers and clinician subject matter experts from 7 academic medical centers rated the feasibility of implementing 10 American College of Emergency Physicians Choosing Wisely Recommendations as electronic health record-embedded CDS and estimated the need for additional data collection. Ratings were combined with objective features of the guidelines to develop a predictive model for technical implementation feasibility. Results A linear mixed model showed that the need for new data collection was predictive of lower implementation feasibility. The number of clinical concepts in each recommendation, need for historical data, and ambiguity of clinical concepts were not predictive of implementation feasibility. Conclusions The availability of data and need for additional data collection are essential to assess the feasibility of CDS implementation. Authors of practice recommendations and guidelines can enable organizations to more rapidly assess data availability and feasibility of implementation by including operational definitions for required data.
ICD-11 complex post-traumatic stress disorder: simplifying diagnosis in trauma populations

ICD-11 complex post-traumatic stress disorder (PTSD) is a new disorder that describes the more complex reactions that are typical of individuals exposed to chronic trauma. The addition of this disorder as distinct from PTSD is expected to provide greater precision in the diagnosis of trauma populations and more personalised and effective treatment.
Performing tracheostomy during the Covid-19 pandemic: Guidance and recommendations from the Critical Care and Acute Care Surgery Committees of the American Association for the Surgery of Trauma

As the Covid-19 pandemic evolves, acute care surgeons, intensivists and other surgical specialists increasingly may be asked to perform a tracheostomy in patients with known or suspected coronavirus-19 infection. Practitioners must be prepared for this inevitability while taking measures to perform the procedure safely for patients in altered or suboptimal conditions and protecting themselves and other healthcare personnel from undue risk of exposure and infection. This document provides a brief overview for those considering performing tracheostomy in known or suspected Covid-19. The information provided here is not intended to supersede clinical judgment. As the current pandemic evolves, some or all of the data and recommendations may not be applicable to future conditions. As of 26 March 2020, the Centers for Disease Control and Prevention (CDC) reported 68 440 total confirmed plus presumptive cases of Covid-19 in the USA, with 994 deaths.1 These numbers are expected to change daily as more data are collected and more testing for the virus is performed. As of 16 March 2020, the last report of outcome data by the CDC,2 508 patients were known to have been hospitalized in the USA, with 121 (23.8%) admitted to an intensive care unit (ICU). ICU admissions were highest among adults 75–84 years old and lowest among adults 20–44 years old. Among the 44 cases with a known outcome, 80% of deaths have been in patients 65 years of age or older and 20% among adults 20–64 years of age. The largest percentage of severe outcomes are in those 85 years of age or older. The early experience from Wuhan, China, on 138 hospitalized patients reported that 36 (26.1%) were admitted to ICU for complications, 22 (61.1%) of whom were diagnosed with ARDS and 17 (47.2%) of whom were placed on mechanical ventilation.3 Discharge data were incomplete, …
Inoculum quantification of canker-causing pathogens in prune and walnut orchards using real-time PCR.

Aims A real-time quantitative PCR (qPCR) assay was established to quantify the inoculum densities in the air and rainwater for six canker-causing pathogen groups in prune and walnut orchards in California. Methods and results The previously published DNA primers to target six pathogen groups including Botryosphaeria dothidea, Cytospora spp., Diplodia spp., Lasiodiplodia spp., Neofusicoccum spp. and Phomopsis spp. were used in a qPCR assay. Air samples from Burkard spore traps and rain samples from special rain collector devices were collected periodically from various prune and walnut orchards. Using the qPCR approach, we were able to quantify the concentrations of these pathogen groups in rainwater and air samples and study the dynamics of pathogen inoculum in orchards showing severe canker potential. Phomopsis spp. and Diplodia spp. were not found in all rain samples in prune orchards, although they were detected in the 2016 in the walnut orchard. The other four pathogen groups were quantified at varying concentrations in the prune and walnut orchards. Cytospora spp. in some cases showed higher concentrations in the rainwater in prune orchards. Conclusions The rainy season during winter and early spring is a highly risky period of time for infection by the pathogens when the inoculum of these pathogens can easily spread by air and rain water, thus serving as an important inoculum source for disease initiation. The different studied pathogen groups showed different concentrations during the growing season, indicating the complexity of the components of canker-causing species in various tree crops. Significance and impact of the study This study showed the applicability of the qPCR assay in the quantification of inoculum in tree orchards to help reveal the mechanisms of canker disease epidemics and to help design disease management strategies.
Adjuvant and Neoadjuvant Chemotherapy for Osteosarcoma: A Historical Perspective

Osteosarcoma was initially resistant to chemotherapy that worked for Ewing sarcoma and rhabdomyosarcoma as well as other chemotherapeutic agents available in the 1960s. In the early 1970s, responses of osteosarcoma to adriamycin were reported, and at about the same time, so were responses of osteosarcoma to high-dose methotrexate. These agents were introduced into adjuvant therapy due to the dire prognosis associated with apparently localized osteosarcoma. After initial questions regarding the role of chemotherapy delayed its uniform acceptance, there is now general agreement that chemotherapy is primarily responsible for the cure of patients with osteosarcoma when combined with surgical elimination of the primary tumor. Advances with combination chemotherapy later adding cisplatin and ifosfamide have improved ultimate survival. The history of the development of effective chemotherapy combinations at Memorial Sloan Kettering Cancer Center, UT MD Anderson Cancer Center, and the Rizzoli Institute are highlighted, and recent large cooperative group studies are reviewed in the context of those findings.
Orientation-Preserving Vectorized Distance Between Curves.

We introduce an orientation-preserving landmark-based distance for continuous curves, which can be viewed as an alternative to the \Frechet or Dynamic Time Warping distances. This measure retains many of the properties of those measures, and we prove some relations, but can be interpreted as a Euclidean distance in a particular vector space. Hence it is significantly easier to use, faster for general nearest neighbor queries, and allows easier access to classification results than those measures. It is based on the \emph{signed} distance function to the curves or other objects from a fixed set of landmark points. We also prove new stability properties with respect to the choice of landmark points, and along the way introduce a concept called signed local feature size (slfs) which parameterizes these notions. Slfs explains the complexity of shapes such as non-closed curves where the notion of local orientation is in dispute -- but is more general than the well-known concept of (unsigned) local feature size, and is for instance infinite for closed simple curves. Altogether, this work provides a novel, simple, and powerful method for oriented shape similarity and analysis.
An examination of single day vs. multi-day heart rate variability and its relationship to heart rate recovery following maximal aerobic exercise in females.

The purpose of this study was to examine the relationship of a single day measure of heart rate variability (HRV), and the averaged baseline measures of HRV to heart rate recovery (HRR) following maximal exercise. Thirty females (22.9 ± 3.2 years, 64.8 ± 8.4 kg) completed four visits (V1–V4), where a 10-min HRV was recorded. Upon completing the V4 recording, a treadmill graded exercise test (GXT) was performed, followed by a 5-min active cool down. HRV was assessed through time domain measures [natural log of root mean square of successive R–R differences (lnRMSSD) and standard deviation of normal to normal intervals (lnSDNN)] and natural log frequency domain measures [low frequency (lnLF) and high frequency (lnHF)]. Variables collected over V1–V4 were measured as; day of (DO) GXT, 3 day (AV3), and 4 day average (AV4). HRR was calculated as the maximal HR achieved minus the HR at: 30-s (HRR30), 1-min (HRR1), 2-min (HRR2), 3-min (HRR3), 4-min (HRR4) or 5-min (HRR5) of recovery. Pearson’s Product correlations revealed significant correlations (P = < 0.05) between all HRVDO measures to each HRR measure and are presented in ranges: lnSDNN (r = 0.442–0.522), lnRMSSD (r = 0.458–0.514), lnLF (r = 0.368–0.469), lnHF (r = 0.422–0.493). For HRVAV3, lnRMSSDAV3 and HRR1 were positively correlated (r = 0.390, P = 0.033). Last, HRVAV4 showed positive relationships (P = < 0.05) between lnRMSSDAV4 and HRR30 (r = 0.365, P = 0.048); and for HRR1 and lnSDNNAV4 (r = 0.400, P = 0.029), lnRMSSDAV4 (r = 0.442, P = 0.014), and lnHFAV4 (r = 0.368, P = 0.045); and lnRMSSDAV4 and HRR3 (r = 0.381, P = 0.038). Within the current study HRVDO displayed the strongest correlations to HRR therefore, averaged resting HRV measures do not strengthen the prediction of cardiovascular recovery following a GXT in this population.
Weight Selection Attempts of Elite Classic Powerlifters.

This study provides the first comparison of weight selection attempt strategies used by powerlifters competing at the international level. We observed attempts selected by elite male and female cla...