cssi/SciSciGPT-SciSciNet huggingface dataset:
Acquired growth hormone deficiency in a girl with chronic myelogenous leukemia treated with tyrosine kinase inhibitor therapy.

Chronic myelogenous leukemia (CML) is caused by the BCR-ABL1 fusion gene that encodes for a constitutively-active tyrosine kinase. Adults and children with CML are typically treated with imatinib mesylate, a BCR-ABL1 tyrosine kinase inhibitor (TKI), or a second-generation TKI. Several case reports have documented growth delay of unknown mechanism in children with CML treated with imatinib. We report a seven-year-old identical twin with CML who developed significant growth delay, as compared to her twin, during five years of TKI therapy. Detailed endocrine evaluation showed acquired growth hormone deficiency, a pathway potentially inhibited by TKIs. Pediatr Blood Cancer 2011;56:671–673. © 2010 Wiley-Liss, Inc.
Witnesses to History: Children's Views of Race and the 2008 United States Presidential Election

The 2008 presidential election presented a unique opportunity to examinechildren’s attention to racial issues in politics. We conducted interviews with 6- to11-year-old children (70 boys, 60 girls; 29 African Americans, 58 EuropeanAmericans, 43 Latinos) within 3 weeks prior to and after the election. Interviewquestions concerned knowledge, preferences, and perceptions of others’ attitudesconcerning the election, views of the implications of the election for racerelations, and personal aspirations to become president. Results indicated thatchildren were highly knowledgeable about Obama’s status as the first AfricanAmericanpresident.MostchildrenfeltpositivelyaboutthepresenceofanAfricanAmerican candidate for president, although a few children showed clear racialprejudice. Overall, children expected others to show racial ingroup preferencesbut simultaneously endorsed the optimistic view that Obama’s race was a slightasset in his bid for the presidency. Older children were somewhat more likely toview Obama’s race as negatively impacting his chances of being elected thanyounger children. African American and Latino children were more interested inbecoming president than European American children; aspiration rates did notchange from pre- to post-election.
HotDrink: a library for web user interfaces

HotDrink is a JavaScript library for constructing forms, dialogs, and other common user interfaces for Web applications. With HotDrink, instead of writing event handlers, developers declare a "view-model" in JavaScript and a set of "bindings" between the view-model and the HTML elements comprising the view. These specifications tend to be small, but they are enough for HotDrink to provide a fully operational GUI with multi-way dataflows, enabling/disabling of values, activation/deactivation of commands, and data validation. HotDrink implements these rich behaviors, expected of high-quality user interfaces, as generic reusable algorithms. This paper/tool demonstration introduces developers to the HotDrink library by stepping through the construction of an example web application GUI.The library is a concrete realization of our prior work on the "property models" approach to declarative GUI programming. To encourage adoption among developers, we have packaged the technology following established web programming conventions.
The fine structure of the salivary glands in the cockroach Gromphadorhina portentosa: Secretion.

Secretion in the salivary glands of Gromphadorhina portentosa involves three cell types: parietal cells, secretory cells, and duct cells. The organization and role of the parietal and secretory cells are here considered. Parietal cells have numerous mitochondria, indicating an active metabolic role and the subsequent production of ATP. Plasma membrane invaginations and intracellular ductules containing microvilli appear to function in the absorption of solutes from the hemolymph and finely-tapered ductules. Secretory cells contain abundant rough endoplasmic reticulum, the three forms (stacked, vesicular, and diffuse) of which appear to develop sequentially during maturation. Secretory vesicle formation is asynchronous between adjacent secretory cells, and apparently the large vesicles often coalesce. The secretory vesicles also show differing degrees of electron density, indicating distinct biochemical composition.
Multiligament Knee Injuries and Their Treatment

Multiligament knee injuries are rare but potentially devastating. They require expeditious and thorough evaluation and treatment for best outcomes. Management consists of a careful history and physical examination, including a complete assessment of the neurovascular status with ankle-brachial indexes ± magnetic resonance angiography. Imaging should include plain radiographs, stress radiography as necessary, and possibly computed tomography scans if fracture is suspected. Magnetic resonance imaging is the modality of choice for evaluating the ligaments and soft tissues. Once evaluation is complete, the decision to proceed with surgery versus conservative management is made. We favor surgery in patients who are able to tolerate the procedure, are relatively high functioning, and are not obese. Surgery is performed at 10 to 14 days if repair is possible or it is delayed until at least 4 to 6 weeks from the time of injury if reconstructions are to be performed to minimize the risk of arthrofibrosis. We prefer allografts for our reconstructions rather than autografts to minimize morbidity and operative time. After surgery, patients may be anticoagulated with either aspirin or coumadin. With extensive, focused rehabilitation, patients can return to heavy labor and/or sports beginning at 9 to 12 months postoperatively.
Does Second Language Instruction Make a Difference? A Review of Research

Does second language instruction promote second language acquisition? Some studies conclude that instruction does not help (or even that it is counter-productive); others find it beneficial. The picture becomes clearer if two distinctions are made. First, researchers may address one or both of two issues: the absolute effect of instruction, on the one hand, and its relative utility, on the other. Second, studies need to be subclassified according to whether or not the comparisons they make involve controlling for the total amount of instruction, exposure, or instruction plus exposure-that is, for the total opportunity to acquire the second language. Observing these distinctions, a review of research findings concludes that there is considerable (although not overwhelming) evidence that instruction is beneficial 1) for children as well as adults, 2) for beginning, intermediate, and advanced students, 3) on integrative as well as discrete-point tests, and 4) in acquisition-rich as well as acquisition-poor environments. These findings have implications for theories of second language acquisition, such as Krashen's Monitor Theory, which make predictions about second language acquisition with and without instruction, and also for those involved in educational administration, program design, and classroom teaching.
Sintering of Si3N4-Y2O3-Al2O3

Sintering kinetics of the system Si3N4-Y2O3-Al2O3 were determined from measurements of the linear shrinkage of pressed disks sintered isothermally at 1500° to 1700°C. Amorphous and crystalline Si3N4 were studied with additions of 4 to 17 wt% Y2O3 and 4 wt% A12O3. Sintering occurs by a liquid-phase mechanism in which the kinetics exhibit the three stages predicted by Kingery's model. However, the rates during the second stage of the process are higher for all compositions than predicted by the model. X-ray data show the presence of several transient phases which, with sufficient heating, disappear leaving mixtures of β′ -Si3N4 and glass or β′-Si3N4, α′-Si3N4, and glass. The compositions and amounts of the residual glassy phases are estimated.
Effects of soil wetness, plant litter, and under‐canopy atmospheric stability on ground evaporation in the Community Land Model (CLM3.5)

[1] The National Center for Atmospheric Research (NCAR) Community Land Model Version 3.5 (CLM3.5) has significantly improved the simulation of hydrologic cycles compared to its earlier version (CLM3.0) owing to a series of new and modified parameterizations for canopy and soil processes. One of the key elements is the addition of a soil resistance to effectively reduce soil evaporation (Es) and improve the partitioning of evapotranspiration. This soil resistance, however, is found to be physically inconsistent under wet soil conditions and implicitly include the effects of dead leaves. A new treatment with three components are proposed here: (1) two different approaches to better reflect the soil moisture limitation to Es, the so-called α and β methods combined and a new soil resistance; (2) a new surface resistance to explicitly represent the effect of plant litter cover on water vapor transfer; and (3) an explicit consideration of the effect of under-canopy atmospheric stability on the under-canopy turbulent resistance. The effects of each modification vary locally and seasonally, and their combination leads to regional differences between CLM3.5 and our new formulations. Our new formulations tend to have higher Es over high latitudes and similar or slightly higher Es in dry regions. A larger reduction of Es by the new formulations is also found over regions with relatively wet soil and more vegetation, in better agreement with previous ET partitioning studies.
Negative symptoms in schizophrenia: a target for new drug development.

Delusions, hallucinations, and certain types of thought disorders, e. g., incoherence and illogicality, constitute the so-called positive symptoms in schizophrenia. It is unclear whether other kinds of thought disorder, e. g., looseness of associations, are also positive symptoms. The most important clinical effect of the current major classes of antipsychotic drugs, e. g., phenothiazines, butyrophenones, and thioxanthenes, is their ability to eliminate or significantly diminish positive symptoms in psychiatric patients, including those who meet narrow diagnostic criteria for schizophrenia. Positive symptoms are thought to be readily rated in most patients, at least in those who are not so guarded that they deny them or are mute and unable to confirm their presence or absence. The ability of antipsychotic drugs to diminish positive symptoms correlates highly with their ability to block dopamine D2 receptors (Seeman and Lee 1975), a characteristic which is readily ascertainable preclinically through a variety of methods. Because of these three factors — effectiveness, ease of clinical evaluation and preclinical predictability — much of the search for novel drug treatments in schizophrenia has focused on the alleviation of positive symptoms by dopamine receptor blockers which have a favorable side effect profile, desirable pharmacokinetic features, or both. Putative antipsychotics are then tested in patients, with the major focus on the rapid alleviation of positive symptoms. The net result is that antipsychotic drugs have a similar efficacy profile, with little to choose between them except side effects (Rifkin and Siris 1987).
Cemented and cementless fixation: results and techniques.

Abstract There are multiple reports of successful cemented and cementless total knee arthroplasty in the current literature. Although technically more demanding to implant, selected cementless designs, with nearly 20 years of follow-up, demonstrate near-equal success compared with cemented implants, the gold standard. Far more important than the decision to use a cemented or cementless implant is the use of precise technique, adequate balancing of the soft tissues, and proper overall alignment. Failure to achieve these basic principles can lead to early failure in any total knee replacement system.
THE CAUSE OF CHARACTERISTIC LENGTHS IN SCATTERING CURVES

This work explains the cause of crossovers in the power-law structure of scattering curves for spherical and nonspherical particles. For spheres, the crossovers have been empirically correlated with length scales of the particle, e.g., radius. Here, a technique, called phasor analysis, will shown that destructive interference within the particle causes the crossovers. Nonspherical particles will also be investigated and found to display similar behavior, and several practical implications of the crossovers will be presented.
Rehospitalization in Infants Born < 29 Weeks' Gestation during the First 2 Years of Life: Risk Assessment.

OBJECTIVE This study aims to determine risk factors for rehospitalization in extremely premature infants. STUDY DESIGN A retrospective cohort study of 157 infants born < 29 weeks' gestational age assessing risk factors for rehospitalization through 2 years of life. RESULTS Multivariable logistic regression showed that an increasing number of respiratory infections (odds ratio [OR]: 1.8 [1.1-3.1] per infection p = 0.03) and inhaled steroid use at 1 year (OR: 4.0 [1.3-12.1] p = 0.01) were predictive of hospital readmission. Diuretic (OR: 27 [1.01-1,000] p = 0.04) and oxygen (OR: 32 [3.1-333] p = 0.004) use at 1 year were predictive of pediatric intensive care unit admission. The number of respiratory infections (OR: 2.8 [1.7-4.5] p < 0.0001) with reflux/aspiration necessitating G-tube/Nissen fundoplication surgical intervention with or without G-tubes alone (OR: 21.3 [2.9-166.7] p = 0.02 and OR: 22.7 [CI, 2.4-200] p = 0.04) was predictive of increased number of rehospitalizations. CONCLUSIONS Key modifiable risk factors identified were reflux/aspiration and ongoing respiratory infections. Critical time periods for diuretic, oxygen, and inhaled steroid use in this population occurred at the age of 1 year.
Explaining and arguing with examples

In this paper, we discuss two tasks - on-line help and legal argument - that involve use of examples. In the case of on-line HELP, we discuss how to make it more intelligent by embedding custom-tailored examples in the explanations it gives its user. In the case of legal argumentation, we discuss how hypotheticals serve a central role in analyzing the strengths and weakness of a case and describe the generation of hypotheticals, stronger or weaker for one of the parties with respect to a doctrinal aspect, through modification of already existing cases or hypotheticals.
Unilateral Hypersecretion of Aldosterone Associated with Adrenal Hyperplasia as a Cause of Primary Aldosteronism

In 3 patients with longstanding hypertension and spontaneous or diuretic-induced hypokalemia, the diagnosis of primary aldosteronism was established by the dual criteria of non-suppressible plasma aldosterone level and suppressed plasma renin activity. Preoperative studies of the etiology for the hyperaldosteronism using the postural plasma aldosterone test and adrenal venous steroid measurements gave conflicting results. On the basis of the differential adrenal venous steroid content, which suggested an unilateral adrenal source for the aldosterone hypersecretion, presumed to be adrenal adenoma, each patient was operated upon. In each case the excised adrenal revealed adenomatous or macronodular hyperplasia. Reinvestigation of the patients 3 to 12 months after the adrenalectomy showed that the dynamics of the renin-aldosterone axis was now restored to the normal state even though the patients remained hypertensive. These findings indicate that unilateral hypersecretion of aldosterone associated with adrenal hyperplasia can occur in some patients with primary aldosteronism simulating that due to an aldosteronoma. Such observations also raise questions about the pathogenesis of the adrenal hyperplasia and seem to add further complexity to the evaluation of patients with hyperaldosteronism.
2012 Benjamin Franklin Medal in Computer and Cognitive Science presented to Vladimir Vapnik

Abstract The Franklin Institute, Philadelphia, Pennsylvania, awards the 2012 Benjamin Franklin Medal in Computer and Cognitive Science to Professor Vladimir Vapnik for his fundamental contributions to our understanding of machine learning, which allows computers to classify new data based on statistical models derived from earlier examples, and for his invention of widely used machine learning techniques.
Industrial Engineering in Higher Education

Abstract Higher education is increasingly facing a condition of financial exigency. A number of colleges and universities have closed; almost all have had to curtail their aspirations and make sacrifices in their operations. While the university is big business, it does not readily lend itself to many of the conventional measures of and improvements in productivity. But the industrial engineer can, and indeed must, help higher education. Some of the unique features of the university are treated herein along with recommendations for industrial engineering study.
Field Surveys and Experimental Transmission of Pleurogonius malaclemys (Digenea: Pronocephalidae), an Intestinal Parasite of the Diamondback Terrapin Malaclemys terrapin

Abstract Life history stages of Pleurogonius malaclemys were investigated in wild populations of the eastern mudsnail (Ilyanassa obsoleta) and diamondback terrapin (Malaclemys terrapin) in New Jersey, New York, and Rhode Island between 2011 and 2015, and laboratory experiments investigating the settling preference of metacercarial cysts of P. malaclemys were conducted. Cysts of P. malaclemys were found on mudsnails on the north and south shores of Long Island, New York and in Rhode Island, approximately 280 km farther north than previously reported. The cysts were found on mudsnails year round, but cyst prevalence increased during the summer months, reaching maximum levels (∼70%) in November. Nearly 58% of Jamaica Bay, New York mudsnails had cysts; mean intensities were 2.63 cysts/mudsnail. Although cyst prevalence was high, only 11 mudsnails (0.28%) were found to have the internal redial stages of P. malaclemys, the stage of infection preceding external cysts. In addition to mudsnails, P. malaclemys coul...
Structural and Optical Properties of Amorphous Ge2Sb2Te5

The optical and structural properties of amorphous sputtered films of Ge 2 Sb 2 Te 5 depend strongly on the preparation conditions. Films grown at higher growth rates exhibit greater local strains as indicated by the slope of the optical absorption in the exponential “band-tail” region, but these films also incorporate smaller densities of oxygen impurities. At slower growth rates the band-tail slopes are sharper (smaller local strains) but there is greater oxygen incorporation. We will discuss several experiments that suggest that the local strain relief in the films grown at slower growth rates is due to a greater ability of the atoms to rearrange on the growing surface and not to increased oxygen incorporation. Small angle x-ray scattering experiments show that the films exhibit small elliptical “voids” with long axes perpendicular to the growing surface. The approximate dimensions of these voids are 3 × 20 nm. These films can be switched optically with little change in surface topography as measured by atomic force microscopy. Electron spin resonance measurements indicate that paramagnetic defects exist in some films but are either absent or below the detection limit (~ 10 18 cm -3 ) in most films. The implications of these results for the switching mechanisms will be discussed.
Studies on experimental rickets, V. The production of rickets by means of a diet faulty in only two respects

The following diet, when fed to the young rat, in a comparatively short time (three to five weeks) produces rickets. The diet is composed of:This diet is extremely poor in fat-soluble A, the anti-xerophthalmic substance. Young rats develop xerophthalmia when placed upon it in from four to five weeks. Its proteins are of good quality and are supplied in abundance (21 per cent.). The phosphorus content is relatively low (0.209 gms. per 100 gms. of the food mixture). The calcium content is approximately the optimum.The gross evidences of rickets in the rats eating the faulty ration were briefly these: deformities of the thorax consisting in flattening or hollowing along the line of costochondral junctions; pigeon breast; enlargement and distortion of the costochondral junctions; fractures of the ribs; enlargements of the ends of all the long bones; diminished resistance of the bone to cutting; great diminution in the tensile strength; and finally, the presence of a zone of a white or pale yellow color, betwe...
Correction for Pattabiraman and Bopp, Draft Whole-Genome Sequences of Nine Enterotoxigenic Escherichia coli Serogroup O6 Strains.

Volume 3, no. 3, [e00564-15][1], 2015. Page 1: The title should read as given above and the number of enterotoxigenic Escherichia coli (ETEC) serogroup O6 strains in the study should be given as nine throughout because one of the ETEC strains was confirmed to be a non-O6 strain. Page 1: The third
An analytical study on residual solvents in edible vegetable oils by headspace gas chromatography

Objective:To develop a new method to determine residual solvents in edible vegetable oils.Method:The standard solution is hexyl hydride.The residual solvents in edible vegetable oils was analyzed by capillary column and headspace gas chromatography.Results:Using 40 g edible vegetable oils as the sample,the balance temperature was 70℃ and the balance time was 30 min.A siginificant linear relationship(r=0.9992)was observed with a range of 0 to 1650 μg.The sample detection limit was 2.5 mg/kg.The recoveries were 90.6%～100.9% and RSD 0.89%～3.13%.Conclusion:This method is stable,precise,fast,repeatable and accurate to determine the residual solvents in edible vegetable oils.
Catecholamine response to chronic ANG II infusion and its role in myocyte and coronary vascular damage

Acute elevations in circulating angiotensin II (ANG II) are known to increase circulating norepinephrine (NE) levels. However, the time course of catecholamine release relative to chronic ANG II infusion is not known. Furthermore, it is unknown if this ANG II-induced catecholamine release is ANG II type 1 (AT1) receptor mediated or whether the increase in serum catecholamines is responsible for the myocyte and coronary vascular damage seen within the first 3 days of chronic ANG II infusion. Therefore, we examined the influence of chronic ANG II stimulation on serum catecholamine levels with and without AT1 blockade and the effect of beta-blockade on ANG II-induced myocyte and coronary vascular damage. The results indicate that NE release is AT1 mediated, but NE is not significantly elevated until day 4 of ANG II infusion after which it remains elevated. beta-Blockade prevented most ANG II-related myocyte necrosis and coronary vascular damage. Therefore, myocyte and coronary vascular damage do not appear to be related to increased serum NE levels, but instead may be due to the release of neural catecholamines within the heart.
Magnetic state of La 1.36 Sr 1.64 Mn 2 O 7 probed by magnetic force microscopy

We have investigated the ferromagnetic (FM) domain structure of a single-crystal bilayered manganite ${\mathrm{La}}_{2\ensuremath{-}2x}{\mathrm{Sr}}_{1+2x}{\mathrm{Mn}}_{2}{\mathrm{O}}_{7}$ $(x=0.32)$ by using low-temperature magnetic force microscopy. We observed that below $65\phantom{\rule{0.3em}{0ex}}\mathrm{K}$, the FM domains form stable treelike patterns with out-of-plane magnetization. With increasing temperature, the FM domain patterns gradually change in the form of domain wall motion. Above $80\phantom{\rule{0.3em}{0ex}}\mathrm{K}$, the FM domain patterns change more and more with each temperature step. The magnetization changes from the out-of-plane to an in-plane direction around $88\phantom{\rule{0.3em}{0ex}}\mathrm{K}$. The in-plane FM domains almost completely disappear near the Curie temperature of this sample $({T}_{C}\ensuremath{\approx}110\phantom{\rule{0.3em}{0ex}}\mathrm{K})$, where the resistivity exhibits a sharp increase. We also observed large changes in the magnetic structures upon thermal cycling. We concluded that the formation of FM domains at low temperatures $(Tl80\phantom{\rule{0.3em}{0ex}}\mathrm{K})$ is determined by the energy associated with surface magnetic free poles and domain walls. At high temperatures $(80\phantom{\rule{0.3em}{0ex}}\mathrm{K}lTl{T}_{C})$, the two-dimensional FM fluctuations in the basal plane may also play an important role in forming the domain structures. The evolution of the FM domain patterns with temperature coincides with the change in resistivity.
Ignorance was our excuse

Difficultes particulieres liees a la formation bibliographique des etudiants etrangers dans les bibliotheques
Target Delineation and Contouring

Adjuvant whole breast radiotherapy (RT) reduces the risk of recurrence and improves survival after breast-conserving surgery [1]. Recently, the addition of radiation to the high axillary, supraclavicular, and internal mammary lymph nodes has been shown to result in further reductions in locoregional and distant relapse and improvements in disease-free survival [2, 3]. In women with lymph node-positive breast cancer, postmastectomy RT to the chest wall and regional lymph nodes improves overall survival [4]. These established benefits of breast cancer RT are accompanied by an increased risk of delayed morbidity, such as lymphedema [5], secondary malignancy [6], and major coronary events [7]. Therefore, meticulous treatment planning is needed in order to optimize the therapeutic ratio in patients with indications for RT [8].
III-V/Si tunable vernier-ring flexible grid comb laser

We demonstrate the first 200 GHz III-V/Si hybrid tunable, individually addressable four channel comb laser defined by a single shared tunable Si ring mirror, Vernier-paired with four rings filters using < 2.5 mW per channel.
Structural minimum controllability problem for switched linear continuous-time systems

Abstract This paper addresses a structural design problem in control systems, and explicitly takes into consideration the possible application to large-scale systems. More precisely, we aim to determine and characterize the minimum number of manipulated state variables ensuring structural controllability of switched linear continuous-time systems. Towards this goal, we provide a new necessary and sufficient condition that leverages both graph-theoretic and algebraic properties required to ensure feasibility of the solutions. With this new condition, we show that a solution can be determined by an efficient procedure, i.e., polynomial in the number of state variables. In addition, we also discuss the switching signal properties that ensure structural controllability and the computational complexity of determining these sequences. In particular, we show that determining the minimum number of modes that a switching signal requires to ensure structural controllability is NP-hard.
Security policy checking in distributed SDN based clouds

Separation of network control from devices in Software Defined Network (SDN) allows for centralized implementation and management of security policies in a cloud computing environment. The ease of programmability also makes SDN a great platform implementation of various initiatives that involve application deployment, dynamic topology changes, and decentralized network management in a multi-tenant data center environment. Dynamic change of network topology, or host reconfiguration in such networks might require corresponding changes to the flow rules in the SDN based cloud environment. Verifying adherence of these new flow policies in the environment to the organizational security policies and ensuring a conflict free environment is especially challenging. In this paper, we extend the work on rule conflicts from a traditional environment to an SDN environment, introducing a new classification to describe conflicts stemming from cross-layer conflicts. Our framework ensures that in any SDN based cloud, flow rules do not have conflicts at any layer; thereby ensuring that changes to the environment do not lead to unintended consequences. We demonstrate the correctness, feasibility and scalability of our framework through a proof-of-concept prototype.
Practical comparison of distributed ledger technologies for IoT

Existing distributed ledger implementations – specifically, several blockchain implementations – embody a cacophony of divergent capabilities augmenting innovations of cryptographic hashes, consensus mechanisms, and asymmetric cryptography in a wide variety of applications. Whether specifically designed for cryptocurrency or otherwise, several distributed ledgers rely upon modular mechanisms such as consensus or smart contracts. These components, however, can vary substantially among implementations; differences involving proof-of-work, practical byzantine fault tolerance, and other consensus approaches exemplify distinct distributed ledger variations. Such divergence results in unique combinations of modules, performance, latency, and fault tolerance. As implementations continue to develop rapidly due to the emerging nature of blockchain technologies, this paper encapsulates a snapshot of sensor and internet of things (IoT) specific implementations of blockchain as of the end of 2016. Several technical risks and divergent approaches preclude standardization of a blockchain for sensors and IoT in the foreseeable future; such issues will be assessed alongside the practicality of IoT applications among Hyperledger, Iota, and Ethereum distributed ledger implementations suggested for IoT. This paper contributes a comparison of existing distributed ledger implementations intended for practical sensor and IoT utilization. A baseline for characterizing distributed ledger implementations in the context of IoT and sensors is proposed. Technical approaches and performance are compared considering IoT size, weight, and power limitations. Consensus and smart contracts, if applied, are also analyzed for the respective implementations’ practicality and security. Overall, the maturity of distributed ledgers with respect to sensor and IoT applicability will be analyzed for enterprise interoperability.
Androgen receptor inhibitor–induced “BRCAness” and PARP inhibition are synthetically lethal for castration-resistant prostate cancer

Cancers with loss-of-function mutations in BRCA1 or BRCA2 are deficient in the DNA damage repair pathway called homologous recombination (HR), rendering these cancers exquisitely vulnerable to poly(ADP-ribose) polymerase (PARP) inhibitors. This functional state and therapeutic sensitivity is referred to as “BRCAness” and is most commonly associated with some breast cancer types. Pharmaceutical induction of BRCAness could expand the use of PARP inhibitors to other tumor types. For example, BRCA mutations are present in only ~20% of prostate cancer patients. We found that castration-resistant prostate cancer (CRPC) cells showed increased expression of a set of HR-associated genes, including BRCA1 , RAD54L , and RMI2 . Although androgen-targeted therapy is typically not effective in CRPC patients, the androgen receptor inhibitor enzalutamide suppressed the expression of those HR genes in CRPC cells, thus creating HR deficiency and BRCAness. A “lead-in” treatment strategy, in which enzalutamide was followed by the PARP inhibitor olaparib, promoted DNA damage–induced cell death and inhibited clonal proliferation of prostate cancer cells in culture and suppressed the growth of prostate cancer xenografts in mice. Thus, antiandrogen and PARP inhibitor combination therapy may be effective for CRPC patients and suggests that pharmaceutically inducing BRCAness may expand the clinical use of PARP inhibitors.
A preexisting rare PIK3CAe545k subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling

Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS-mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CAE545K mutation as conferring drug resistance. We demonstrate that PIK3CAE545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CAE545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CAE545K-induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways.Significance: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CAE545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CAE545K-expressing NRAS-mutant melanoma cells to MEKi + CDK4i. Cancer Discov; 8(5); 556-67. ©2018 AACR.See related commentary by Sullivan, p. 532See related article by Teh et al., p. 568This article is highlighted in the In This Issue feature, p. 517.
γδTCR regulates production of interleukin-27 by neutrophils and attenuates inflammatory arthritis

γδ T cells have been implicated in inflammatory diseases as an important link between the innate and adaptive immune responses, however, their role in inflammatory arthritis remain unclear. To define the contribution of γδ T cells in the pathogenesis of inflammatory arthritis, we performed gene transfer of IL-23 in B10.RIII mice to establish joint inflammation in the presence or absence of γδ T cells. We demonstrated that γδ T cell blockade has a protective effect on arthritis incidence and severity by preventing neutrophil accumulation in the blood, spleen and bone marrow as well as by reducing neutrophil infiltration into the joints. Furthermore, our data demonstrate that absence of γδ T cells was associated with an increase of IL-27 levels produced by neutrophils and dendritic cells, and systemic IL-27 expression also prevents IL-23-induced inflammatory arthritis and limits neutrophil expansion. Collectively our findings reveal an immunomodulatory effect of γδ T cells on neutrophils associated with IL-27 synthesis and secretion and indicate a novel link between IL-27 and the modulation of γδ T cells and neutrophils that can be targeted in the treatment of inflammatory arthritis.
Viral Hyperinfection of the Central Nervous System and High Mortality After Hematopoietic Stem Cell Transplantation for Treatment of Theiler’s Murine Encephalomyelitis Virus-Induced Demyelinating Disease

Theiler’s murine encephalomyelitis virus (TMEV) establishes a persistent infection in the central nervous system (CNS) leading to an inflammatory demyelinating disease of the CNS in which the histology and clinical course is similar to multiple sclerosis (MS). Disease pathogenesis is primarily due to T-cell–mediated destruction of myelin, which has been attributed to cytopathic effects of the virus, but immune-mediated destruction of myelin mediated via both virus-specific and myelin-specific T cells appear to play the major role. To determine if bone marrow transplantation would be an effective therapy for a virus-initiated autoimmune disease and to better separate viral cytopathic effects from immune-mediated demyelination, we ablated the immune system of TMEV-infected animals with 1,100 cGy total body irradiation, and then the animal’s immunity was reconstituted by transplantation of disease-susceptible SJL/J mice with syngeneic marrow or disease-susceptible DBA/2J with marrow from disease-resistant (C57Bl/6 × DBA/2)F1 (B6D2) donors. Hematopoietic transplant performed after onset of disease resulted in 42% mortality in SJL/J syngeneic transplants, 47% mortality in diseased DBA2 recipients restored with marrow from naive B6D2 donors, and 12% in diseased DBA2 recipients receiving marrow from B6D2 donors previously infected with TMEV. Delayed type hypersensitivity (DTH) to both virion and myelin proteins was decreased in surviving mice that underwent transplantation; however, CNS viral titers were significantly elevated compared with nontransplanted controls. We conclude that a functional immune system with appropriate T-cell responses are important in prevention of lethal cytopathic CNS effects from TMEV. Relevant to the clinical use of bone marrow transplantation, attempts to ablate the immune system in viral-mediated immune diseases or virus-initiated autoimmune disease may have acute and lethal consequences. Our results raise concern about the attempted use of autologous hematopoietic transplantation in patients with MS, an autoimmune disease with a suspected virus etiology, particularly if the graft is aggressively depleted of lymphocytes.
Assertive communication about others' smoking and vaping in public venues: Results from a National Survey of US adults.

Abstract Introduction This study describes prevalence and correlates of US adults' intentions to engage in assertive communication (i.e., speak up) about others' smoking and vaping in public venues. Methods: Participants from a nationally representative online survey of 1551 US adults conducted October–December 2013 reported intentions to ask others not to smoke/vape in three types of public venues (restaurants, bars/casinos/nightclubs, and parks). We examined weighted prevalence of intentions and conducted weighted logistic regression. Results: Fifty-two percent of participants reported being likely to ask someone not to smoke in at least one venue compared with 19% for vaping. Assertive communication intentions for smoking in restaurants (48%), bars/casinos/nightclubs (35%), and parks (32%) were higher than for vaping (16%, 14%, and 12%, respectively). Significant correlates of assertive communication intentions in one or more venues were current smoking status, ever trying e-cigarettes, gender, age, health status, political ideology, and party identification. Conclusions: US adults were more willing to ask others not to smoke than vape. Intentions to speak up about smoking and vaping differed by venue, demographics, and cigarette/e-cigarette use. These findings help establish an evidence base to inform policymakers in developing strategies to promote compliance with smoke-free and vape-free laws.
Light-activation of Cre recombinase in zebrafish embryos through genetic code expansion.

Abstract Cre recombinase-mediated DNA recombination is an established method for conditional control of gene expression in animal models. Regulation of its activity has been accomplished to impart spatial and/or temporal control over recombination of the target gene. In this chapter, optical control of Cre recombinase in developing zebrafish embryos through genetic code expansion is discussed. This method takes advantage of an evolved aminoacyl tRNA synthetase and tRNA pair that can incorporate an unnatural amino acid (UAA) into proteins in response to an amber stop codon (TAG). Genetic code expansion is used to replace a lysine residue critical to Cre recombinase function with a photocaged analogue of lysine, successfully blocking DNA recombination until irradiation with 405 nm light. Use of optically controlled Cre recombinase for cell-lineage tracing experiments in zebrafish embryos is highlighted, demonstrating the ability to target small populations of cells at different developmental time points for recombination. Optically controlled Cre recombinase showed no background activity and precise activation upon irradiation, making it a useful new tool for studying development and disease in the zebrafish embryo.
Hematopoietic growth factors for graft failure after bone marrow transplantation: a randomized trial of granulocyte-macrophage colony-stimulating factor (GM-CSF) versus sequential GM-CSF plus granulocyte-CSF.

Delay in hematologic recovery after bone marrow transplantation (BMT) can extend and amplify the risks of infection and hemorrhage, compromise patients' survival, and increase the duration and cost of hospitalization. Because current studies suggest that granulocyte-macrophage (GM) colony-stimulating factor (CSF) may potentiate the sensitivity of hematopoietic progenitor cells to G-CSF, we performed a prospective, randomized trial comparing GM-CSF (250 micrograms/m2/d x 14 days) versus sequential GM-CSF x 7 days followed by G-CSF (5 micrograms/kg/d x 7 days) as treatment for primary or secondary graft failure after BMT. Eligibility criteria included failure to achieve a white blood cell (WBC) count > or = 100/microL by day +21 or > or = 300/microL by day +28, no absolute neutrophil count (ANC) > or = 200/microL by day +28, or secondary sustained neutropenia after initial engraftment. Forty-seven patients were enrolled: 23 received GM-CSF (10 unrelated, 8 related allogeneic, and 5 autologous), and 24 received GM-CSF followed by G-CSF (12 unrelated, 7 related allogeneic, and 5 autologous). For patients receiving GM-CSF alone, neutrophil recovery (ANC > or = 500/microL) occurred between 2 and 61 days (median, 8 days) after therapy, while those receiving GM-CSF+G-CSF recovered at a similar rate of 1 to 36 days (median, 6 days; P = .39). Recovery to red blood cell (RBC) transfusion independence was slow, occurring 6 to 250 days (median, 35 days) after enrollment with no significant difference between the two treatment groups (GM-CSF: median, 30 days; GM-CSF+G-CSF; median, 42 days; P = .24). Similarly, platelet transfusion independence was delayed until 4 to 249 days (median, 32 days) after enrollment, with no difference between the two treatment groups (GM-CSF: median, 28 days; GM-CSF+G-CSF: median, 42 days; P = .38). Recovery times were not different between patients with unrelated donors and those with related donors or autologous transplant recipients. Survival at 100 days after enrollment was superior after treatment with GM-CSF alone. Only 1 of 23 patients treated with GM-CSF died versus 7 of 24 treated with GM-CSF+G-CSF who died 16 to 84 days (median, 38 days) after enrollment, yielding Kaplan-Meier 100-day survival estimates of 96% +/- 8% for GM-CSF versus 71% +/- 18% for GM-CSF+G-CSF (P = .026). These data suggest that sequential growth factor therapy with GM-CSF followed by G-CSF offers no advantage over GM-CSF alone in accelerating trilineage hematopoiesis or preventing lethal complications in patients with poor graft function after BMT.(ABSTRACT TRUNCATED AT 400 WORDS)
Routine Assessment of Symptoms of Substance Use Disorders in Primary Care: Prevalence and Severity of Reported Symptoms

Most patients with substance use disorders (SUDs) never receive treatment and SUDs are under-recognized in primary care (PC) where patients can be treated or linked to treatment. Asking PC patients to directly report SUD symptoms on questionnaires might help identify SUDs but to our knowledge, this approach is previously untested. To describe the prevalence and severity of DSM-5 SUD symptoms reported by PC patients as part of routine care. Cross-sectional study using secondary data. A total of 241,265 adult patients who visited one of 25 PC sites in an integrated health system in Washington state and had alcohol, cannabis, or other drug use screening documented in their EHRs (March 2015–July 2018) were included in main analyses if they had a positive screen for high-risk substance use defined as AUDIT-C score 7–12 points, or report of past-year daily cannabis use or any other drug use. The main outcome was number of SUD symptoms based on Diagnostic and Statistical Manual, 5th edition (DSM-5), reported on Symptom Checklists (0–11) for alcohol or other drugs: 2–3 mild; 4–5 moderate; 6–11 severe. Of screened patients, 16,776 (5.7%) reported high-risk use of alcohol (2.4%), cannabis (3.9%), and/or other drugs (1.7%), and 65.0–69.9% of those completed Symptom Checklists. Of those with high-risk alcohol use, 52.5% (95% CI 50.9–54.0%) reported ≥ 2 symptoms consistent with mild-severe alcohol use disorders. Of those reporting daily cannabis use, 29.8% (28.6–30.9%) reported ≥ 2 symptoms consistent with mild-severe SUDs. Of those reporting any other drug use, 37.5% (35.7–39.3%) reported ≥ 2 symptoms consistent with mild-severe SUDs. Many PC patients who screened positive for high-risk substance use reported symptoms consistent with DSM-5 SUDs on self-report Symptom Checklists. Use of SUD Symptom Checklists could support PC providers in making SUD diagnoses and initiating discussions of substance use.
Time-scale separation based design of biomolecular feedback controllers

Time-scale separation is a powerful property that can be used to simplify control systems design. In this work, we consider the problem of designing biomolecular feedback controllers that provide tracking of slowly varying references and rejection of slowly varying disturbances for nonlinear systems. We propose a design methodology that uses timescale separation to accommodate physical constraints on the implementation of integral control in cellular systems. The main result of this paper gives sufficient conditions under which controllers designed using our time-scale separation methodology have desired asymptotic performance when the reference and disturbance are constant or slowly varying. Our analysis is based on construction of Lyapunov functions for a class of singularly perturbed systems that are dependent on an additional parameter that perturbs the system regularly. When the exogenous inputs are slowly varying, this approach allows us to bound the system trajectories by a function of the regularly perturbing parameter. This bound decays to zero as the parameter’s value increases, while an inner-estimate of the region of attraction stays unchanged as this parameter is varied. These results cannot be derived using standard singular perturbation results. We apply our results to an application demonstrating a physically realizable parameter tuning that controls performance.
Staff Nurses' Perceptions of Nurse Manager Caring Behaviors: A Scoping Study.

OBJECTIVE The purpose of this scoping study is to review the published evidence regarding staff nurses' perceptions of nurse manager caring behaviors. BACKGROUND As healthcare administration becomes more complex and financial challenges continue, the ability of nurse managers to lead patient care environments that produce desirable outcomes becomes critical. Demonstrating caring behaviors that build relationships with individuals and groups is a necessary competency of nursing administrators to advance healthcare. METHODS This scoping study was guided by Arksey and O'Malley's methodology to review existing literature. RESULTS Published literature provided knowledge of staff nurses' perceptions of nurse manager caring behaviors. The final sample was 13 publications. The results were summarized in both numeric and thematic analysis. CONCLUSIONS Further research is needed to explore the relationship between nurse manager caring behaviors and patient outcomes.