Articoli di riviste sul tema "(Norman Barnett)"

BackgroundQuality Improvement (QI) methods have been used in healthcare since the late 1980s across a wide range of healthcare settings. However, in the UK they have not been applied widely within rheumatology including axial Spondyloarthritis (axial SpA). In 2017, the UK healthcare regulator, NICE, produced a national clinical guideline for axial SpA, but there was no mechanism to encourage uptake of its recommendations.The National Axial Spondyloarthritis Society created a programme to use QI approaches to help encourage uptake of the Guidelines and act as a catalyst for wider improvement in axial SpA care.ObjectivesTo encourage service improvement in axial Spondyloarthritis care through the use of quality improvement theory and methods.MethodsIn late 2019 six rheumatology departments were selected to participate in the first cohort. The programme design was underpinned by:• A framework for management grounded in systems theory1• A learning system that brings healthcare organisations together2• A set of tools to develop, test and implement changes: the Model for Improvement3.The teams met four times for training in QI methods, plus team-based online coaching. They had time to develop their projects and networking opportunities to share their data and experiences of implementation.We conducted a qualitative review of the programme in year one. We interviewed 31 programme participants and reviewed programme documentation.ResultsThe review found that:•A proven QI framework provides a strong basis to build improvement•A competitive programme helps foster motivation and accountability•The programme provides the time to use tools to understand the problem and construct improvement aims•Measurement is key to understand improvement and to create a story of change•Collaboration and engagement is key within the team and with other stakeholders.The teams have: Trained community–based physiotherapists, leading to improved rheumatology referrals Implemented an inflammatory back pain pathway from primary care Introduced an MRI spine IBP protocol to reduce variation in imaging Established a tertiary referral service which has improved time to diagnosis Implemented mental health interventions for patients and reduced the percentage of patients with abnormal scores Established a pathway for physiotherapy self–referral and reduced Did Not Attend rates Used audit to make the business case for an extended scope practitionerConclusionDespite the challenges of posed by the Covid-19 pandemic, a structured QI programme has enabled clinicians to stay engaged and implement projects to reduce diagnostic delay and improve care.References[1]Deming WE. The new economics for industry. Government, Education, Massachusetts Institute of Technology, Cambridge, MA. 1993;1:235.[2]Institute for Healthcare Improvement. The Breakthrough Series: IHI’s Collaborative Model for Achieving Breakthrough Improvement. IHI Innovation Series white paper. Boston: Institute for Healthcare Improvement. 2003.[3]Langley GJ, Nolan KM, Nolan TW, Norman L, Provost LP. The improvement guide. San Francisco: Jossey–Bass. 1996.Disclosure of InterestsDale Webb Grant/research support from: Grant funding from AbbVie, Biogen, Lilly, Janssen, Novartis & UCB, Rosie Barnett: None declared, Lucy Davies: None declared

New states of electromagnetic field, generalized excited negative binomial states are introduced here. These states interpolate between the superposition of two excited coherent states and number states. The non-classical properties for these states are discussed, such as, second order correlation function, squeezing phenomena [normal squeezing and amplitude squared squeezing], phase properties in Pegg–Barnett formalism and the quasi-probability distribution functions (Q-function and Wigner function).

Surface microseismic arrays enable long-term field-scale monitoring over multiple stimulations during the life of an unconventional field. In this study, we show highly economic methods of monitoring with sparse surface arrays in the Barnett Shale and develop an alternatative method of processing to enable good vertical and horizontal resolution of located events. We show that sparse surface monitoring arrays enable not only the detection and location of high numbers of microseismic events but also source mechanism characterization. This case study illustrates how hydraulic fracturing activated normal faulting at a distance of approximately 1 mile from stimulated wells. We show that the source mechanism enables us to resolve between newly created hydraulic fractures and activated faults. The differences in source mechanisms and b-values of newly created fractures and activated faults are consistent with independently processed temporary star-like arrays, which are also deployed over the same stimulation.

Summary Accurate prediction of fracture initiation pressure and orientation is paramount to the design of a hydraulic fracture stimulation treatment and is a major factor in the treatment's eventual success. In this study, closed-form analytical approximations of the fracturing stresses are used to develop orientation criteria for relative-to-the-wellbore (longitudinal or transverse) fracture initiation from perforated wells. These criteria were assessed numerically and found to overestimate the occurrence of transverse fracture initiation, which only takes place under a narrow range of conditions in which the tensile strength of the rock formation is lower than a critical value, and the breakdown pressure falls within a “window.” For a case study performed on the Barnett Shale, transverse fracture initiation is shown to take place for breakdown pressures below 4,762 psi, provided that the formation's tensile strength is below 2,482 psi. A robust 3D finite volume numerical model is used to evaluate solutions for the longitudinal and transverse fracturing stresses for a variable wellbore pressure, hence developing correction factors for the existing closed-form approximations. Geomechanical inputs from the Barnett Shale are considered for a horizontal well aligned parallel to the direction of the least compressive horizontal principal stress. The corrected numerically derived expressions can predict initiation pressures for a specific orientation of fracture initiation. Similarly, at known breakdown pressures, the corrected expressions are used to predict the orientation of fracture initiation. Besides wellbore trajectory, the results depend on the perforation direction. For the Barnett Shale case study, which is under a normal faulting stress regime, the perforations on the side of the borehole yield a wider breakdown pressure window by 71% and higher critical tensile strength by 32.5%, compared to perforations on top of the borehole, implying better promotion of transverse fracture initiation. Leakage of fracturing fluid around the wellbore, between the cemented casing and the surrounding rock, reduces the breakdown pressure window by 11% and the critical tensile strength by 65%. Dimensionless plots are employed to present the range of in-situ stress states in which longitudinal or transverse hydraulic fracture initiation is promoted. This is useful for completion engineers; when targeting low permeability formations such as shale reservoirs, multiple transverse fractures must be induced from the horizontal wells, as opposed to longitudinal fracture initiation, which is desired in higher permeability reservoirs or “frac-and-pack” operations.

TPS11077 Background: The response rates of advanced soft tissue sarcomas (STS) to single-agent, first-line anthracycline are typically less than 25%. P-glycoprotein 1 (P-gp), a cell membrane drug efflux pump, is believed to be a resistance mechanism in STS. CBT-1 is a small molecule, orally administered, P-gp antagonist currently under clinical development. This is a multi-institutional open label phase I study of CBT-1 in combination with doxorubicin in patients with anthracycline-refractory sarcoma. The study is designed to determine a maximum tolerable dose (MTD), recommended phase II dose (RP2D), and the safety/tolerability of the combination of CBT-1 and doxorubicin. The study will evaluate anti-cancer activity as a secondary objective as measured by Disease Control Rate (DCR; complete response [CR] + partial response [PR] + stable disease [SD]) at 12 weeks. Objective Response Rate (ORR; CR+PR) and Progression Free Survival (PFS) will be monitored. Correlative studies include assessment of pharmacokinetic and pharmacodynamicendpoints. Methods: Patients 18 years or older with locally advanced metastatic, unresectable STS, prior progression on ≤ 150 mg/m2 of doxorubicin (or another anthracycline equivalent), ECOG PS ≤ 1 and normal organ function, are eligible for this study. Dosing includes fixed doxorubicin (37.5 mg/m2 IV day 5 and day 6) and escalation of oral CBT-1 on days 1-7 of a 21 day cycle. This study follows a standard 3+3 phase I design where dose escalation will occur if < 0/3 or 1/6 patients experience a dose-limiting toxicity (DLT). Tumor assessments are conducted at Week 6 and Week 12. For patients with response or stable disease, treatment is allowed to continue for 4-5 cycles to a maximum of 450 mg/m2 lifetime doxorubicin exposure. Once RP2D is defined, an additional 10 patients will be enrolled into the dose expansion phase. To date, Cohorts 1 (50 mg CBT-1) and 2 (100 mg CBT-1) have been completed with one DLT of grade 4 neutropenia lasting longer than 7 days in Cohort 1. Enrollment to Cohort 3 began December 2018. (References: Oldham, R. K., Reid, W. K., Preisler, H. D., and Barnett, D. (1998) Cancer Biother. Radiopharm. 13, 71-80; Kelly, R. J., Robey, R. W., Chen, C. C., Draper, D., Luchenko, V., Barnett, D., Oldham, R. K., Caluag, Z., Frye, R. A., Steinberg, S. M., Fojo, T., Bates, S. E. (2012) The Oncologist 17 (4) 512-e523; Robey, R. W., Shukla, S., Finely, E. M., Oldham, R. K., Barnett, D., Ambudkar, S. V., Fojo, T., Bates, S. E., (2008) Biochemical Pharmacology 75, 6, 1302-1312). Clinical trial information: NCT03002805.

When performing validation studies on diagnostic classification procedures, one or more biomarkers are typically measured in individuals. Some of these biomarkers may provide better information; moreover, more than one biomarker may be significant and may exhibit dependence between them. This proposal intends to estimate the Area Under the Receiver Operating Characteristic Curve (AUC) for classifying individuals in a screening study. We analyze the dependence between the results of the tests by means of copula-type dependence (using FGM and Gumbel-Barnett copula functions), and studying the respective AUC under this type of dependence. Three different dependence-level values were evaluated for each copula function considered. In most of the reviewed literature, the authors assume a normal model to represent the performance of the biomarkers used for clinical diagnosis. There are situations in which assuming normality is not possible because that model is not suitable for one or both biomarkers. The proposed statistical model does not depend on some distributional assumption for the biomarkers used for diagnosis procedure, and additionally, it is not necessary to observe a strong or moderate linear dependence between them.

Trabajo de investigación realizado con el objetivo de describir la aeromicologia de los locales administrativos de la ciudad universitaria de la Universidad Nacional de San Cristobal de Huamanga. El tipo de estudio fue no experimental con un diseño descriptivo simple, la población estuvo conformada por la totalidad de los locales administrativos, para la toma de muestra se uso el método gravimétrico de sedimentación en placa propuesto por Omeliansky, la identificación fue realizada por la observación macroscópica y microscópica de las colonias de hongos basado en la clave de Barnett (2003). Se Cuantificación de las UFC/m3 por la fórmula propuesta por la Norma Ramal de la Pesca NRP-201, la densidad relativa de los géneros microbianos por la fórmula de Smith 1980, se ordenaron los datos en tablas y gráficos porcentuales. Se concluye que se aislaron entre 160 a 880 UFC/m3, por lo tanto, el nivel de contaminación de los locales de la ciudad universitaria está consideradas en categorías de intermedia a alta. Los géneros aislados con mayor frecuencia fueron: Penicillium, Aspergillus, Alternaria y Cladosporium.

Sous l'influence première d'un article de Barnes (1954), les études anthropologiques sur les réseaux sociaux ont ouvert une voie de recherches qui apparaît encore pleine de promesses. Il faut bien avouer, pourtant, que jusqu'à maintenant peu d'analyses fondées sur des données empiriques ont emporté la conviction. Les études de réseaux n'ont pas encore fait la preuve de leur fécondité. Il leur manque un fondement théorique, pourtant disponible dans la théorie des graphes qui est justement une théorie des réseaux, qu'ils soient sociaux ou autres. Comme l'a noté Mitchell, la jonction n'existe pas — ou pas assez — entre les spécialistes de la théorie des graphes et les chercheurs sur le terrain (1969, p. 35). Pourtant, quelques bons exposés ont été écrits par des anthropologues, qui indiquent bien ce qu'on pourrait tirer d'une utilisation plus poussée de la théorie des graphes (en particulier Mitchell, 1969; Barnes, 1969a; et surtout Barnes, 1972). Malgré ces mises en place, la plupart des études empiriques ne dépassent guère l'analyse situationnelle qui, comme le note Barnes (1972, p. 13), peut fort bien se passer de la notion de réseau, en plus d'être inapte au dégagement d'hypothèses générales. Nous allons donner, à la fin de cet article, une brève illustration d'une étude proprement structurale des réseaux sociaux, au sens où l'entendent Harary, Norman et Cartwright (1968), dans leur ouvrage sur les graphes orientés. En utilisant des données recueillies sur le terrain, nous montrerons comment la notion d'articulation, tirée de la théorie des graphes, permet de poser et de traiter des problèmes théoriques, mais aussi pratiques, qui nous semblent propres aux réseaux sociaux. Auparavant, nous voudrions discuter de certaines questions préalables à une analyse vraiment spécifique des réseaux sociaux. Ils ont trait au concept même de réseau, à la constitution des unités d'analyse, et aux différentes voies d'analyse qui s'offrent au chercheur.

Summary Hydraulic fracturing is recognized as the main stimulating technique to enhance recovery in tight fissured reservoirs. These fracturing treatments are often mapped by use of hypocenters of induced microseismic events. In some cases, the microseismic mapping shows asymmetry of the induced-fracture geometry with respect to the injection well. In addition, the conventional theories predict fracture propagation along a path normal to the least compressive in-situ stresses, whereas in some cases the microseismic data suggest fracture propagation parallel to the minimum compressive stress. In this paper, we present an extended-finite-element-method (XFEM) model that can simulate asymmetric fracture-wing development as well as diversion of the fracture path along natural fractures. Simulation results demonstrate the sensitivity of the fracture-pattern geometry to differential stress and natural-fracture orientation with respect to the in-situ maximum compressive stress. We examine the properties of sealed natural fractures that are common in formations such as the Barnett shale and show that they may still serve as weak paths for hydraulic-fracture beginning and/or diversion. The presented model predicts faster fracture propagation in formations where natural fractures are favorably aligned with the tectonic stresses.

We highly appreciate the useful remarks of Dr. Barnes relating our work to well‐known practical seismic processing effects. This is of particular interest as normal‐moveout (NMO) correction and post‐stack time migration are still two very important processing steps. Most exploration geophysicists know about the significance of pulse distortions known as “NM0 stretch” and “frequency shifting due to zero‐offset time migration.” As a result of the discussion of Dr. Barnes, it should now be possible to better appreciate the importance of our very general formulas (27) describing the pulse distortion of seismic reflections from an arbitrarily curved subsurface reflector when subjected to a prestack depth migration in 3‐D laterally inhomogeneous media. This discussion thus relates in particular to such important questions as how to correctly sample signals in the time or depth domain in order to avoid spatial aliasing, or how to stack seismic data without loss of information due to destructive interference of wavelets of different lengths.

This study investigated the transfer of ten learning outcomes from an ESAP writing course to subject-specific courses. It was a longitudinal study carried over one academic year. It followed 40 undergraduate students of English under normal classroom conditions. A mixed-methods approach was used. It included analysis of students’ written exams from four subjects, student semi-structured interviews, and a student questionnaire. Elements from Barnett and Ceci’s (2002) transfer taxonomy were also used. They helped classify the targeted learning outcomes in terms of specificity/generality and helped distinguish between near and far transfer contexts. Results showed that the transfer of the ten learning outcomes to the near and far transfer contexts was affected by the specificity/generality of the learned skill in the first place. The learning outcomes that were classified as specific transferred more easily to both the near and far transfer contexts, while the more complex learning outcomes transferred in a constrained manner. The findings suggest that an ESAP writing course that is informed by teaching for transfer principles offers students a more authentic learning environment to hone their writing skills and to transfer these skills to other contexts. However, this transfer can be a very slow process.

Using highly precise and accurate Monte Carlo simulations of 20,000,000 replications and 102 independent simulation experiments with extremely low simulation errors and total uncertainties, we evaluated the performance of four single outlier discordancy tests (Grubbs test N2, Dixon test N8, skewness test N14, and kurtosis test N15) for normal samples of sizes 5 to 20. Statistical contaminations of a single observation resulting from parameters calledδfrom ±0.1 up to ±20 for modeling the slippage of central tendency orεfrom ±1.1 up to ±200 for slippage of dispersion, as well as no contamination (δ=0andε=±1), were simulated. Because of the use of precise and accurate random and normally distributed simulated data, very large replications, and a large number of independent experiments, this paper presents a novel approach for precise and accurate estimations of power functions of four popular discordancy tests and, therefore, should not be considered as a simple simulation exercise unrelated to probability and statistics. From both criteria of the Power of Test proposed by Hayes and Kinsella and the Test Performance Criterion of Barnett and Lewis, Dixon test N8 performs less well than the other three tests. The overall performance of these four tests could be summarized asN2≅N15>N14>N8.

Interval type 2 fuzzy numbers are a special kind of type 2 fuzzy numbers. These numbers can be described by triangular and trapezoidal shapes. In this paper, first, perfectly normal interval type 2 trapezoidal fuzzy numbers with their left-hand and right-hand spreads and their core have been introduced, which are normal and convex; then a new type of fuzzy arithmetic operations for perfectly normal interval type 2 trapezoidal fuzzy numbers has been proposed based on the extension principle of normal type 1 trapezoidal fuzzy numbers. Moreover, in this proposal, linear programming problems with resources and technology coefficients are perfectly normal interval type 2 fuzzy numbers. To solve this kind of fuzzy linear programming problems, a method based on the degree of satisfaction (or possibility degree) of the constraints has been introduced. In this method the fulfillment of the constraints can be measured with the help of ranking method of fuzzy numbers. Optimal solution is obtained at different degree of satisfaction by using Barnes algorithm with the help of MATLAB. Finally, the optimal solution procedure is illustrated with numerical example.

Earlier studies (Barber et al., 1990) showed the superiority of near infrared reflectance spectroscopy (NIRS) for predicting the organic matter digestibility (OMD) in vivo of grass silage over fibre and in vitro procedures. However, during routine application occasional erroneous values were predicted for which there were no obvious reasons. Baker and Barnes (1990) reported that the likely sources of the problems contributing to the errors were instrumental and environmental noise, sample particle size effects and variable moisture content of the samples. These authors also reported that standard normal variate - detrend (SNV-D) scatter correction procedure of Barnes et al. (1989) could be used to reduce the effects of particle size variation and they also emphasised the need to test NIRS calibrations for repeatability. The purpose of the present work was to evaluate the use of the SNV-D scatter correction procedure, the techniques for reducing the sensitivity of calibrations to residual moisture and methods to improve the repeatability of the predicted OMD in vivo values of grass silage. In addition, a further objective was to compare three calibration methods, namely modified stepwise regression (MSR), modified partial least squares (MPLS) and principal component analysis (PCA).

We extend a full-waveform modeling method to invert source focal-plane mechanisms for microseismic data recorded with dual-borehole seismic arrays. Combining inverted focal-plane mechanisms with geomechanics knowledge, we map the pore pressure distribution in the reservoir. Determining focal mechanisms for microseismic events is challenging due to poor geometry coverage. We use the P-wave polarities, the P- and S-wave similarities, the SV/P amplitude ratio, and the SH/P amplitude ratio to invert the focal-plane mechanisms. A synthetic study proves that this method can effectively resolve focal mechanisms with dual-array geometry. We apply this method to 47 relatively large events recorded during a hydraulic fracturing operation in the Barnett Shale. The focal mechanisms are used to invert for the orientation and relative magnitudes of the principal stress axes, the orientation of the planes slipping in shear, and the approximate pore pressure perturbation that caused the slip. The analysis of the focal mechanisms consistently shows a normal faulting stress state with the maximum principal stress near vertical, the maximum horizontal stress near horizontal at an azimuth of N60°E, and the minimum horizontal stress near horizontal at an azimuth of S30°E. We propose a general method that can be used to obtain microseismic focal-plane mechanisms and use them to improve the geomechanical understanding of the stimulation process during multistage hydraulic fracturing.

The role played by environment on nuclear activity in galaxies is not clear and largely debated (see e.g. Barnes & Hernquist 1992, Kelm 1996). To overcome statistical uncertainties, environment properties of two large samples of Seyfert galaxies (Sy 1 and Sy 2 have been kept separated) have been computed and compared with equivalent size “normal galaxy” sample ones. Seyfert samples have been extracted from the Veron & Veron catalogue (Veron & Veron 1996), whilst “normal galaxies” have been randomly extracted from ZCAT (Huchra 1993). The samples are limited in cz ([1500–9500] km/sec) and contain 149 Sy 1, 173 Sy 2 and 160 “normal galaxies” (hundreds of random extractions from ZCAT). For each galaxy neighbors have been computed (from ZCAT) within two variables radii, R (isolation radius) and r (pair separation), which span [0.2 - 2] h100 Mpc. and [20–90]h100 kpc. respectively. Neighbors must lie also within 700 km/sec from the galaxy. In this way, for each value of R and r, environment of each galaxy has been “quantified”.

Learning and memory as well as long-term potentiation (LTP) depend on Ca2+ influx through the NMDA-type glutamate receptor (NMDAR) and the resulting activation of the Ca2+ and calmodulin-dependent protein kinase (CaMKII). Ca2+ influx via the NMDAR triggers CaMKII binding to the NMDAR for enhanced CaMKII accumulation at post-synaptic sites that experience heightened activity as occurring during LTP. Previously, we generated knock-in (KI) mice in which we replaced two residues in the NMDAR GluN2B subunit to impair CaMKII binding to GluN2B. Various forms of LTP at the Schaffer collateral synapses in CA1 are reduced by 50%. Nevertheless, working memory in the win-shift 8 arm maze and learning of the Morris water maze (MWM) task was normal in the KI mice although recall of the task was impaired in these mice during the period of early memory consolidation. We now show that massed training in the MWM task within a single day resulted in impaired learning. However, learning and recall of the Barnes maze task and contextual fear conditioning over one or multiple days were surprisingly unaffected. The differences observed in the MWM compared to the Barnes maze and contextual fear conditioning suggest a differential involvement of CaMKII and the specific interaction with GluN2B, probably depending on varying degrees of stress, cognitive demand or even potentially different plasticity mechanisms associated with the diverse tasks.

An acupuncture clinic was established, for a limited period, within a rheumatology department of Barnet and Chase Farm Hospital Trust. Courses of six to eight sessions of traditional and trigger-point acupuncture were offered for a specified range of conditions. Pain and use of analgesics were measured routinely. A prospective observational study is presented of the outcome for a series of 41 patients, who had a mean age of 57 years and pain duration of 3 years. The mean score for daytime pain fell from 6.8 (SD 1.2) to 4.9 (2.5) points which is highly significant (p < 0.001). A total of 30 patients (73%) had reduction in pain of at least 33% and 22 patients (54%) had a reduction in pain of at least 50%. Analgesic intake (without distinguishing between different analgesic medication) was reduced from a mean of 17 (15.3) tablets per week to a mean of 6 (7.9). Patients with normal X-rays had a much better response to acupuncture than those whose X-rays showed significant degenerative changes. In response to these findings, financial support has been provided to continue the acupuncture clinic.

✓ Between 1928 and 1980, 84 children (aged 19 years or younger) with an astrocytoma of the cerebellum were managed at Washington University Medical Center-Barnes Hospital. Fifty-eight children were treated with surgery only and 26 received surgery and postoperative irradiation. The 5-, 10-, and 25-year actuarial disease-free survival rates for the entire group were 92%, 88%, and 88%, respectively. Age at diagnosis and extent of surgery were prognostic factors, but no correlation with survival times was found for gross appearance of the tumor or postoperative irradiation. Posttreatment neurological function was excellent in the 58 patients alive at the end of the study; 92% were completely normal or had only a mild neurological deficit and 75% were employed or attending school.

O objetivo do estudo foi descrever a morfologia da germinação de plântulas normais de Senna cana (Nees & Mart.) H. S. Irwin & Barneby e, descrever as plântulas anormais. A coleta das sementes foi realizada no Parque Nacional Vale do Catimbau, Buíque - PE. As sementes foram escarificadas, desinfestadas e lavadas com água deionizada. Foram utilizadas quatro repetições de 25 sementes, semeadas sobre papel toalha e postas para germinar em B.O.D a 20-30ºC. A emissão da radícula ocorreu no terceiro dia após semeadura, coloração bege amarelada, tenra, cilíndrica, com pelos radiculares. Do 7º ao 11º dia, alongamento do hipocótilo e surgimento das raízes secundárias. O hipocótilo cilíndrico, herbáceo, coloração amarela, com tricomas curtos. No 17º dia, o surgimento do epicótilo pubescente. Aos 45 dias, o sistema radicular pivotante, com comprimento de 3,0 a 3,5 cm de coloração marrom enegrecida. O hipocótilo de 2,5 a 3,0 cm, cilíndrico, reto ou tortuoso, verde-claro no ápice e amarelado na base. Cotilédones persistentes, limbo levemente pendente, verde-escuro em ambas as faces e nervação evidente. Os protófilos compostos, pinados, alternos, peciolados, verde-claro, com dois folíolos e muitos tricomas. A semente de S. cana apresenta germinação epígea, sendo as plântulas classificadas como fanerocotiledonares.Palavras-chave: Caatinga; estudo morfológico; espécie nativa. MORPHOLOGY OF SEED GERMINATION OF Senna cana (Nees & Mart.) H.S. Irwin & Barneby ABSTRACT: The objective of the study was to describe the germination morphology of normal seedlings of Senna cana (Nees & Mart.) H. S. Irwin & Barneby and, describe the abnormal seedlings. The seeds were collected in the Vale do Catimbau National Park, Buíque - PE. The seeds were scarified, disinfested and washed with deionized water. Four replicates of 25 seeds were used, sown on paper towel and put to germinate in B.O.D at 20-30ºC. The emission of the radicle occurred on the third day after sowing, beige yellowish color, tender, cylindrical, with root hairs. From 7th to 11th day, hypocotyl elongation and secondary root development. The cylindrical hypocotyl, herbaceous, yellow color, with short trichomes. On the 17th day, the appearance of the pubescent epicotyl. At 45 days, the pivotal root system, with 3.0 to 3.5 cm length of blackish brown coloration. Hypocotyl 2.5-3.0 cm, cylindrical, straight or tortuous, light green at apex and yellow at base. Persistent cotyledons, slightly pendulous limb, dark green on both cheeks and obvious veining. The prototyphs composed, pinnate, alternate, petiolate, light green, with two leaflets and many trichomes. The S. cana seed presents epigene germination, the seedlings being classified as phanerocotonares.Keywords: Caatinga; morphological study; native species.

Masyarakat sebagai elemen dasar dari peradaban manusia, sejatinya terbentuk dalam berbagai upaya dan interaksi sosial. Interaksi yang terjalin disebabkan oleh berbagai aspek, hubungan biologis, lokasi tempat tinggal, suku, pemahaman ideologi yang sama termasuk usaha untuk mencapai tujuan bersama melalui kesepakatan-kesepakatan sosial tertentu yang mengikat. Tulisan ini bertujuan untuk mengkaji fenomena ini dengan teori Karl Marx sebagai acuan dari munculnya konflik dalam kehidupan Bangsa Israel, lebih lanjut didukung oleh beberapa teori sosial lainnya. Adapun tulisan ini menggunakan metode hermeneutik untuk memahami situasi sosio-historis dari keberadaan Israel dan menganalisanya sesuai dengan teori-teori sosial. Dinamika sosial kehidupan bangsa Israel menunjukkan bahwa sebagai komunitas,yaitu komunitas yang bersatu pada masa kepemimpinan Daud (Israel Bersatu) dan terpecah pada masa pemerintahan Salomo menjadi Israel Selatan dan Israel Utara. KEPUSTAKAAN Bernhard W. Anderson. The Books of the Bible. New York: CSS, 1991. Elly M. Setiadi & Usman Kolip. Pengantar Sosiologi: Teori, Aplikasi dan Pemecahannya. Jakarta: Kencana Prenada Media Group, 2011. George Ritzer & Douglas J.Goodman. Teori Sosiologi: Dari Teori Sosiologi Klask sampai perkembangan terakhir teori sosial postmodern. Bantul: Kreasi Wacana, 2016. Heine Andersen & Lars Bo Kaspersen. Classical and Modern Social Theory. Malden: Blackwell Publishers, 2000. John A. Titaley. Persepuluhan dalam Alkitab Ibrani Israel Alkitab. Salatiga: Satya Wacana Press, 2016. Norman K. Gottwald. The Hebrew Bible: A Socio-Literary Introduction. Philadelphia: Fortress Press, 1985. Norman K. Gottwald. The Tribes of YHWH: A Sosiology of The Religion of Liberated Israel. New York: Orbis Book, 1979. Norman K. Gottwald. The Politics of Ancient Israel. Louisville Kentucky:Westminster John Knox Press, 2001. Robert B. Coote & David Robert Ord. Sejarah Pertama Alkitab: Dari Eden hingga Kerajaan Daud berdasarkan Sumber Y. BPK Gunung Mulia; Satya Wacana Press, 2015. Robert B. Coote. Demi Membela Revolusi: Sejarah Elohist. Jakarta: BPK Gunung Mulia, 2011. Soerjono Soekanto. Sosiologi: Suatu Pengantar. Jakarta: Raja Grafindo Persada, 1982. Samuel Koenig. Mand and Society, the basic teaching of sociology. New York: Barners & Noble Inc, 1957

Balanites aegyptiaca L. Delile (B. aegyptiaca) is used in traditional medicine for the treatment of memory impairment. This work aims to evaluate the antioxidant and anticholinesterase potential of BA fruit pulp extract on excitotoxicity induced by monosodium glutamate (MSG). MSG was administered 30 minutes after treatment with B. aegyptiaca aqueous fruit pulp extract (50, 125, 250, and 500 mg/kg) and vitamin C (100 mg/kg) for 30 days. The negative control group received only MSG, while the control group was given distilled water daily. Behavioral tests parameters (using the novel object recognition, Y-maze, and Barnes maze tests), oxidative stress biomarkers (malondialdehyde, superoxide dismutase, and catalase), nitric oxide, and acetylcholinesterase activity and hippocampal architecture were evaluated. Results obtained revealed that different doses of B. aegyptiaca significantly reversed the deleterious effect of MSG on memory. This was displayed by a significant ( p < 0.05 ) increment in the percentage of spontaneous alternation in the Y-maze test and a significant ( p < 0.001 ) increase in discrimination index in novel object recognition observed with 500 mg/kg extract dose. Moreover, the extract (250 and 500 mg/kg doses) significantly ( p < 0.001 ) increased direct search strategy and significantly decreased ( p < 0.01 ) the time taken to find the target hole in the Barnes maze. A modulation of hyperactivity was observed after administration of all extract doses compared to the negative control group in the open arena. Furthermore, the highest dose of the extract caused a significant ( p < 0.001 ) improvement in antioxidant enzymes activity, associated with a significant ( p < 0.001 ) decrement in nitric oxide and malondialdehyde concentrations and a significant ( p < 0.01 ) decrease in acetylcholinesterase activity. Treatment with the extract also restored normal hippocampal cell architecture. B. aegyptiaca fruit pulp extract could thus confer neuroprotection through its antioxidant and anticholinesterase potential.

Abstract Background Potential deleterious effect of multiple anesthesia exposures on the developing brain remains a clinical concern. We hypothesized that multiple neonatal anesthesia exposures are more detrimental to brain maturation than an equivalent single exposure, with more pronounced long-term behavioral consequences. We designed a translational approach using proton magnetic resonance spectroscopy in rodents, noninvasively tracking the neuronal marker N-acetyl-aspartate, in addition to tracking behavioral outcomes. Methods Trajectories of N-acetyl-aspartate in anesthesia naïve rats (n = 62, postnatal day 5 to 35) were determined using proton magnetic resonance spectroscopy, creating an “N-acetyl-aspartate growth chart.” This chart was used to compare the effects of a single 6-h sevoflurane exposure (postnatal day 7) to three 2-h exposures (postnatal days 5, 7, 10). Long-term effects on behavior were separately examined utilizing novel object recognition, open field testing, and Barnes maze tasks. Results Utilizing the N-acetyl-aspartate growth chart, deviations from the normal trajectory were documented in both single and multiple exposure groups, with z-scores (mean ± SD) of –0.80 ± 0.58 (P = 0.003) and –1.87 ± 0.58 (P = 0.002), respectively. Behavioral testing revealed that, in comparison with unexposed and single-exposed, multiple-exposed animals spent the least time with the novel object in novel object recognition (F(2,44) = 4.65, P = 0.015), traveled the least distance in open field testing (F(2,57) = 4.44, P = 0.016), but exhibited no learning deficits in the Barnes maze. Conclusions Our data demonstrate the feasibility of using the biomarker N-acetyl-aspartate, measured noninvasively using proton magnetic resonance spectroscopy, for longitudinally monitoring anesthesia-induced neurotoxicity. These results also indicate that the neonatal rodent brain is more vulnerable to multiple anesthesia exposures than to a single exposure of the same cumulative duration.

Carukia barnesi was the first in an expanding list of cubozoan jellyfish whose sting was identified as causing Irukandji syndrome. Nematocysts present on both the bell and tentacles are known to produce localised stings, though their individual roles in Irukandji syndrome have remained speculative. This research examines differences through venom profiling and pulse wave Doppler in a murine model. The latter demonstrates marked measurable differences in cardiac parameters. The venom from tentacles (CBVt) resulted in cardiac decompensation and death in all mice at a mean of 40 min (95% CL: ± 11 min), whereas the venom from the bell (CBVb) did not produce any cardiac dysfunction nor death in mice at 60 min post-exposure. This difference is pronounced, and we propose that bell exposure is unlikely to be causative in severe Irukandji syndrome. To date, all previously published cubozoan venom research utilised parenterally administered venom in their animal models, with many acknowledging their questionable applicability to real-world envenomation. Our model used live cubozoans on anaesthetised mice to simulate normal envenomation mechanics and actual expressed venoms. Consequently, we provide validity to the parenteral methodology used by previous cubozoan venom research.

Abstract: Studies show the positive effect of the nitric oxide donor in the seed germination process. However, there are no precise reports about which compound present in sodium nitroprusside would cause these effects in seeds under salt stress. The aim of this study was to evaluate the effects of SNP on germination of Senna macranthera seeds under salt stress. The osmotic potentials of -0.3, -0.4, and -0.5 MPa of NaCl were used, as well as the concentration of 100 μM of sodium nitroprusside, inactive sodium nitroprusside, and ferrocyanide. The sodium nitroprusside in germination was applied before, during, and after salt stress. Germination rate, germination speed index, percentage of normal seedlings, and seedling development components were evaluated. The treatments that proved to be more promising in recovery of germination under salt stress are -0.4 MPa together with SNP; -0.4 MPa together with inactive SNP; -0.5 MPa together with SNP and -0.5 MPa together with inactive SNP. Effects similar to those brought about by the sodium nitroprusside treatment were also observed in the treatments with inactive sodium nitroprusside and ferrocyanide, indicating that the effects observed were related to release of the cyanide present in the sodium nitroprusside.

The formation processes of epitaxial nickel silicides, resulting from the interaction of nickel silicide films (10 nm–100 nm) on (111) silicon (Si) substrates after furnace annealing, have been studied using transmission electron microscopy (TEM) and x-ray diffraction (XRD) techniques. The formation of type-A epitaxial grains (i.e., grown with the same orientation of the underlying Si substrate) and type-B epitaxial grains (i.e., rotated by 180± around the surface normal) in “thick” epitaxial films (i.e., greater than 35 nm) is proposed to be linked to the formation of a fluorite-based CuPt (L11)-like NiSi phase. This phase is found to be a metastable phase and is believed to be a transitional phase toward the formation of the equilibrium NiSi2 phase in both type-A and type-B orientations. In addition, we have found that a fluorite-based CuPt-like NiSi may even coexist with a fluorite-based CuAu I-like structure. The interrelationship between these two structures is discussed in the context of a displacive transformation process in fcc structures as originally proposed by Hansson and Barnes [Acta Metall. 12, 315 (1964)] and Pashley et al. [Philos. Mag. 19, 83 (1969)].

BackgroundHistorical records suggest dyskinesia was observed in severely ill institutionalised patients with schizophrenia in the pre-neuroleptic era More recent work has not found dyskinesia in never-medicated younger and middle aged patients. The present study complements this recent work and avoids the confounders of severity of illness and institutionalism by examining elderly patients in a wide variety of community settings.MethodMovement disorders were examined in 308 elderly individuals in Madras, India, using the Abnormal Involuntary Movements Scale, the Simpson and Angus Parkinsonism Scale and the Barnes Akathisia Scale. Patients' mental state was assessed by the Positive and Negative Syndrome Scale.ResultsDyskinesia was found in 15% of normal subjects (n=101, mean age 63 years), 15% of first degree blood relatives of younger schizophrenic patients (n=103, mean age 63 years), 38% of never medicated patients (n=21, mean age 65 years) and 41 % of medicated patients (n=83, mean age 57 years). The respective prevalences for Parkinsonism were 6%, 11 %, 24% and 36%; and for akathisia 9%, 5%, 21 % and 23%. Dyskinesia was associated with negative schizophrenic symptoms.ConclusionsDyskinesia in elderly schizophrenic patients is an integral part of the illness and not associated with antipsychotic medication.

Many forms of short-term synaptic plasticity rely on regulation of presynaptic voltage-gated Ca2+ type 2.1 (CaV2.1) channels. However, the contribution of regulation of CaV2.1 channels to other forms of neuroplasticity and to learning and memory are not known. Here we have studied mice with a mutation (IM-AA) that disrupts regulation of CaV2.1 channels by calmodulin and related calcium sensor proteins. Surprisingly, we find that long-term potentiation (LTP) of synaptic transmission at the Schaffer collateral-CA1 synapse in the hippocampus is substantially weakened, even though this form of synaptic plasticity is thought to be primarily generated postsynaptically. LTP in response to θ-burst stimulation and to 100-Hz tetanic stimulation is much reduced. However, a normal level of LTP can be generated by repetitive 100-Hz stimulation or by depolarization of the postsynaptic cell to prevent block of NMDA-specific glutamate receptors by Mg2+. The ratio of postsynaptic responses of NMDA-specific glutamate receptors to those of AMPA-specific glutamate receptors is decreased, but the postsynaptic current from activation of NMDA-specific glutamate receptors is progressively increased during trains of stimuli and exceeds WT by the end of 1-s trains. Strikingly, these impairments in long-term synaptic plasticity and the previously documented impairments in short-term synaptic plasticity in IM-AA mice are associated with pronounced deficits in spatial learning and memory in context-dependent fear conditioning and in the Barnes circular maze. Thus, regulation of CaV2.1 channels by calcium sensor proteins is required for normal short-term synaptic plasticity, LTP, and spatial learning and memory in mice.

The purpose of this study was to investigate whether or not Coriandrum sativum seed extract (CSSE) can ameliorate memory impairment in senescence-accelerated mouse-prone 8 (SAMP8) mice. Sixteen 10-week-old male SAMP8 mice were divided into two groups, which were orally administrated water (SAMP8(−)) or CSSE (200 mg/kg/day; SAMP8(+)). Eight 10-week-old male Institute of Cancer Research (ICR) mice were used as a normal control group and were also orally administrated water. The mean escape time in the Barnes maze test of SAMP8(−) mice was significantly longer than that of ICR mice. However, SAMP8(+) mice showed a shorter mean escape time compared to that of SAMP8(−) mice. Neurofilament messenger (m)RNA levels significantly decreased in the frontal lobe of SAMP8(−) mice when compared with ICR mice, but significantly increased in SAMP8(+) mice relative to SAMP8(−) mice. In addition, mRNA levels of inducible nitric oxide synthase (iNOS) and neuronal (n)NOS significantly increased in the frontal lobe of SAMP8(−) mice, but only the mRNA level of nNOS significantly decreased in SAMP8(+) mice. These results indicated that continuous oral administration of CSSE for 12 weeks could ameliorate aging-induced memory declines in the senescence-accelerated SAMP8 mouse model.

Because of their improved leverage against ground roll and multiples, as well as the ability to estimate azimuthal anisotropy, wide-azimuth 3D seismic surveys routinely now are acquired over most resource plays. For a relatively shallow target, most of these surveys can be considered to be long offset as well, containing incident angles up to 45°. Unfortunately, effective use of the far-offset data often is compromised by noise and normal moveout (NMO) (or, more accurately, prestack migration) stretch. The conventional NMO correction is well-known to decrease the frequency content and distort the seismic wavelet at far offsets, sometimes giving rise to tuning effects. Most quantitative interpreters work with prestack migrated gathers rather than unmigrated NMO-corrected gathers. However, prestack migration of flat reflectors suffers from the same limitation called migration stretch. Migration stretch leads to lower S-impedance ([Formula: see text]) and density ([Formula: see text]) resolution estimated from inversion, misclassification of amplitude variation with offset (AVO) types, and infidelity in amplitude variation with azimuth (AVAZ) inversion results. We have developed a matching pursuit algorithm commonly used in spectral decomposition to correct the migration stretch by scaling the stretched wavelets using a wavelet compensation factor. The method is based on hyperbolic moveout approximation. The corrected gathers show increased resolution and higher fidelity amplitudes at the far offsets leading to improvement in AVO classification. Correction for migration stretch rather than conventional “stretch-mute” corrections provides three advantages: (1) preservation of far angles required for accurate [Formula: see text] inversion, (2) improvement in the vertical resolution of [Formula: see text] and [Formula: see text] volumes, and (3) preservation of far angles that provide greater leverage against multiples. We apply our workflow to data acquired in the Fort Worth Basin and retain incident angles up to 42° at the Barnett Shale target. Comparing [Formula: see text], [Formula: see text], and [Formula: see text] of the original gather and migration stretch-compensated data, we find an insignificant improvement in [Formula: see text], but a moderate to significant improvement in resolution of [Formula: see text] and [Formula: see text]. The method is valid for reservoirs that exhibit a dip of no more than 2°. Consistent improvement is observed in resolving thick beds, but the method might introduce amplitude anomalies at far offsets for tuning beds.

O presente artigo tem o objetivo de propor a continuidade dos temas tratados no diálogo Crátilo de Platão pelo filósofo analítico David Lewis, a partir da associação entre suas teorias do significado e as teorias da linguagem contidas na obra platônica, em especial, aquelas defendidas pelo personagem Sócrates, deduzidas assim, pela leitura de Norman Kretzmann e revisadas segundo algumas críticas direcionadas ao intérprete, de modo a provar a semelhança de escopo e dimensão linguística entre a teoria filosófica da linguagem em Platão e a teoria filosófica da linguagem em Lewis. Para executar esta tarefa, iniciarei com a apresentação das principais teses sobre a correção dos nomes contidas no Crátilo, na forma de dois desdobramentos: o critério de nomeação das coisas e a pergunta pela origem dos nomes. Em seguida, farei um panorama das fontes que formam o arcabouço conceitual no qual Platão obtém as teses discutidas no interior da obra, passando pelos sucessores do pensamento platônico no que compete às concepções convencionalista e naturalista da linguagem, culminando na Filosofia analítica da linguagem. Após isto, será feita a exposição da interpretação de Kretzmann sobre as teorias da linguagem contidas no Crátilo, na forma de suas certification question e demonstration question, seguida da apresentação das teorias do significado (semântica e fundacional) de Lewis. E, por fim, as teorias de ambos os filósofos serão postas lado a lado, acompanhadas da revisão da concepção de convencionalismo com base nas críticas de Rachel Barney e findando com alguns resultados da comparação entre as teorias em jogo.

La biomasa se utiliza para la generación de calor y la preparación de alimentos por aproximadamente dos mil millones de personas en el mundo. En el área metropolitana de Monterrey, Nuevo León el consumo de carbón vegetal con fines recreativos tiene una demanda de 5 500 t mes-1. En México su comercialización se basa en conocimientos empíricos: especie, duración del encendido, producción de chispas y cenizas. Sin embargo, para su exportación se deben cumplir esquemas de calidad. Por lo anterior, en la presente investigación se comparó el rendimiento y calidad del carbón de Prosopis laevigata y Ebenopsis ebano producido en un horno tipo fosa. La calidad se determinó mediante el contenido de humedad, material volátil, cenizas, carbón fijo y poder calorífico, en función de estándares internacionales. Los datos se analizaron con un diseño experimental con arreglo factorial. Se obtuvieron diferencias altamente significativas (p<0.01) en el rendimiento entre las dos especies, lo mismo que para las cenizas y el poder calorífico (p<0.05). Se determinó un rendimiento de 2.8, 2.3 m3t-1, contenido de humedad de 3.6, 3.5%; material volátil de 22.8, 24.9%; porcentaje de cenizas de 2.8, 3.2%; carbón fijo de 70.8, 68.6%, y poder calorífico de 30 241, 29 725 kJ kg-1 para P. laevigata y E. ebano, respectivamente. El rendimiento en los dos casos fue alto, el contenido de humedad y cenizas se estimó dentro de los límites establecidos a nivel mundial. El material volátil y carbón fijo no cumplieron con los porcentajes permitidos en las normas vigentes del comercio exterior.

The microglial fatty-acid-binding protein 4-uncoupling protein 2 (FABP4-UCP2) axis is a key regulator of neuroinflammation in high-fat-diet (HFD)-fed animals, indicating a role for FABP4 in brain immune response. We hypothesized that the FABP4-UCP2 axis is involved in regulating diet-induced cognitive decline. We tested cognitive function in mice lacking microglial FABP4 (AKO mice). Fifteen-week-old male AKO and wild-type (WT) mice were maintained on 60% HFD or normal chow (NC) for 12 weeks. Body composition was measured using EchoMRI. Locomotor activity, working memory, and spatial memory were assessed using behavioral tests (open field, T-maze, and Barnes maze, respectively). Hippocampal microgliosis was assessed via immunohistochemical staining. An inflammatory cytokine panel was assayed using hippocampal tissue. Real-time RT-PCR was performed to measure microglial UCP2 mRNA expression. Our data support that loss of FABP4 prevents cognitive decline in vivo. HFD-fed WT mice exhibited impaired long- and short-term memory, in contrast with HFD-fed AKO mice. HFD-fed WT mice had an increase in hippocampal inflammatory cytokine expression (IFNγ, IL-1β, IL-5, IL-6, KC/GRO(CXCL1), IL-10, and TNFα) and microgliosis, and decreased microglial UCP2 expression. HFD-fed AKO mice had decreased hippocampal inflammatory cytokine expression and microgliosis and increased microglial UCP2 expression compared to HFD-fed WT mice. Collectively, our work supports the idea that the FABP4-UCP2 axis represents a potential therapeutic target in preventing diet-induced cognitive decline.

IntroductionObjective symptoms of akathisia in the absence of subjective symptoms is known as pseudoakathisia, more often diagnosed in older patients with long-term antipsychotic treatment.ObjectiveTo describe a case of pseudoakathisia in a patient with clotiapine abuse.AimsPseudoakathisia management.MethodsX is a 47-year-old male with chronic insomnia treated with clotiapine 40 mg/day for four years. He admits abusive neuroleptic consumption in the past eight months (160 mg/day), without any psychiatric control for years. In recent months he has experienced different organic complications, requiring multiple hospitalizations. During psychiatric examinations due to confusional states, repeated lower limbs movements were objectified. X reported he presented these movements for at least six months, without complaints of inner restlessness feeling. Neurological examination showed normal DAT-SCAN result. Clinical progression was evaluated using BARS scale (Barnes Akathisia Rating Scale).ResultsFollowing the results of tests and statements of drug history, X was diagnosed with clotiapine-induced pseudoakathisia. Neuroleptic treatment was suspended, and clonazepam 6 mg/day and propranolol in ascending doses up to 80 mg/day were initiated. In subsequent evaluations, progressive decrease in movement intensity was observed. However, complete remission after four months from clotiapine suspension was not achieved.ConclusionsPseudoakathisia is a concept not well defined at this moment and different hypotheses about its nature are considered. It has been suggested that it is a form of delayed dyskinesia, or a clinical progression from akathisia, with acquired subjective discomfort tolerance. The most widely used treatment includes benzodiazepines, beta-blockers and anticholinergics, although their effectiveness is limited.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Introduction Management of phenylketonuria (PKU) is mainly achieved through dietary control with limited intake of phenylalanine (Phe) from food, supplemented with low protein (LP) food and a mixture of free synthetic (FS) amino acids (AA) (FSAA). Casein glycomacropeptide (CGMP) is a natural peptide released in whey during cheese making by the action of the enzyme chymosin. Because CGMP in its pure form does not contain Phe, it is nutritionally suitable as a supplement in the diet for PKU when enriched with specific AAs. Lacprodan® CGMP-20 (= CGMP) used in this study contained only trace amounts of Phe due to minor presence of other proteins/peptides. Objective The aims were to address the following questions in a classical PKU mouse model: Study 1, off diet: Can pure CGMP or CGMP supplemented with Large Neutral Amino Acids (LNAA) as a supplement to normal diet significantly lower the content of Phe in the brain compared to a control group on normal diet, and does supplementation of selected LNAA results in significant lower brain Phe level?. Study 2, on diet: Does a combination of CGMP, essential (non-Phe) EAAs and LP diet, provide similar plasma and brain Phe levels, growth and behavioral skills as a formula which alone consist of FSAA, with a similar composition?. Material and methods 45 female mice homozygous for the Pahenu2 mutation were treated for 12 weeks in five different groups; G1(N-CGMP), fed on Normal (N) casein diet (75%) in combination with CGMP (25%); G2 (N-CGMP-LNAA), fed on Normal (N) casein diet (75%) in combination with CGMP (19,7%) and selected LNAA (5,3% Leu, Tyr and Trp); G3 (N), fed on normal casein diet (100%); G4 (CGMP-EAA-LP), fed on CGMP (70,4%) in combination with essential AA (19,6%) and LP diet; G5 (FSAA-LP), fed on FSAA (100%) and LP diet. The following parameters were measured during the treatment period: Plasma AA profiles including Phe and Tyr, growth, food and water intake and number of teeth cut. At the end of the treatment period, a body scan (fat and lean body mass) and a behavioral test (Barnes Maze) were performed. Finally, the brains were examined for content of Phe, Tyr, Trp, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and 5-hydroxyindole-acetic acid (5-HIAA), and the bone density and bone mineral content were determined by dual-energy x-ray absorptiometry. Results Study 1: Mice off diet supplemented with CGMP (G1 (N-CGMP)) or supplemented with CGMP in combination with LNAA (G2 (N-CGMP-LNAA)) had significantly lower Phe in plasma and in the brain compared to mice fed only casein (G3 (N)). Extra LNAA (Tyr, Trp and Leu) to CGMP did not have any significant impact on Phe levels in the plasma and brain, but an increase in serotonin was measured in the brain of G2 mice compared to G1. Study 2: PKU mice fed with mixture of CGMP and EAA as supplement to LP diet (G4 (CGMP-EAA-LP)) demonstrated lower plasma-Phe levels but similar brain- Phe levels and growth as mice fed on an almost identical combination of FSAA (G5 (FSAA-LP)). Conclusion CGMP can be a relevant supplement for the treatment of PKU.

Background: Glutamate is essential to learning and memory as an excitatory neurotransmitter. This study evaluated the atrazine effect on the hippocampus and examined the mitigative role of avocado oil against the neuronal degeneration and behavioral deficits in Wistar rats. Methods: Fifty adult male Wistar rats were divided into four groups of ten. Group 1 (controls) received 0.5 ml distilled water; group 2 received atrazine (215 mg/kg/d); group 3 received avocado oil (1 ml/ 250 g/d); group 4 received avocado oil (1 ml/ 250 g/d) 60 minutes before atrazine. Treatments were given by oral gavage over 28 days. Barnes maze and Y-maze tests were performed to assess the learning and memory. Histological and Glial Fibrillary Acidic Protein (GFAP)-immuno-reaction in the hippocampus were assessed, using Hematoxylin and Eosin (H&E) stain and anti-GFAP antibody. The glutamate and acetylcholinesterase levels were subsequently assessed. Results: The learning and memory performance was significantly affected in group 2, but improved in group 4. In group 3, learning and memory performance was not different from group 1. In group 2, atrazine caused massive neurodegeneration and astrogliosis at Cornu Ammonis-1 (CA-1) and Dentate Gyrus (DG). Combined avocado and atrazine significantly reduced neuronal death and astrogliosis in CA-1 and DG areas. In group 2, glutamate level was high while acetylcholinesterase was low. In group 4, glutamate was low but acetylcholinesterase was high compared to those in group 2. Glutamate and acetylcholinesterase levels in group 3 was not significantly different from that of group 1. Conclusion: Atrazine inhibited acetylcholinesterase and induced glutamate release. These were associated with excitotoxicity and neuronal degeneration in CA-1 and DG areas as shown by poor learning and memory. Treatment with avocado oil protected against high glutamate release, thus, mitigating neuronal degeneration and maintaining normal learning and memory in rats.

TPS505 Background: Focal adhesion kinase (FAK) is consistently hyperactivated in pancreatic ductal adenocarcinoma (PDAC), and FAK signaling is a key driver in forming its fibrotic and proinflammatory tumor microenvironment. Inhibition of FAK signaling leads to significant reduction of pancreatic tumor growth in animal models. Indeed, tumors treated with FAK inhibitors displayed markedly reduced tumor fibrosis and decreased immunosuppressive myeloid cells. Furthermore, our preclinical work has demonstrated that FAK- and PD-1 inhibitors elicit significant tumor regression, and the maximal response was achieved by combining FAK- and PD-1 inhibitors with gemcitabine, suggesting the need for a cytotoxic agent to bolster antigen presentation (Jiang H et al, Nature Medicine 2016). Defactinib is an orally available, potent ATP-competitive, FAK inhibitor with a recommended phase II dose (RP2D) of 400 mg twice daily. Methods: Eligible patients will be treated according to the dose escalation schema. A 3+3 design is used until the first occurrence of dose-limiting toxicity, and then switches to a continuous assessment design. The study has an expansion portion (group A and B) at the RP2D. Group A includes metastatic PDAC patients who are stable at least 4 months on front-line nab-paclitaxel/gemcitabine, and group B includes metastatic PDAC patients progressed on ≥ 1 chemotherapy line. Key eligibility criteria include patients with advanced solid tumors (dose escalation portion) or advanced PDAC (expansion cohort); age ≥18 years; ECOG score ≤1; normal organ function; and no history autoimmunity. The primary endpoint is to determine the RP2D. Secondary endpoints include objective response rate, progression-free survival and overall survival. The exploratory endpoints include developing a molecular and immune signature for treatment response. This trial is actively enrolling and funded by Precision Medicine Research Associate and Barnes Jewish Foundation. Clinical trial information: NCT02546531. [Table: see text]

e21062 Background: Acral melanoma is the main subtype in Asia, and tends to be insensitive to conventional and novel therapies compared with cutaneous melanomas. It has been proved that biomechanical alterations inside the tumor microenvironment significantly affect tumor progression in breast, pancreatic and other cancers(Hepatology. 2016 July ; 64(1): 261–275; Cold Spring Harbor Symposia on Quantitative Biology, Volume LXXXI) . Hence, we hypothesized that the biomechanical microenvironment plays critical roles in proliferation and invasion in acral melanoma. In this study, the main purpose is to observe whether melanoma cells have the same ability called “durotaxis” as other tumors, which to respond to a gradient of extracellular stiffness and migrate in a directed fashion. Methods: In this study, the stiffness was compared between the acral melanoma tissue and the normal tissue by using the atomic force microscope (AFM) with fresh samples and the freezing microtome sectioning specimen (J. Matthew Barnes et al., Nature Cell Biology 2018.) . A stiffness gradient polyacrylamide hydrogel system was constructed to observe how the acral melanoma cells response. Using automated tracking (Curr Protoc Cell Biol. ; 76: 12.12.1–12.12.16.) of positional data for large sample size of single migrating cells to systematically analyze polarized melanoma cell migration in response to stiffness gradient. Results: The results showed that 1) all the acral melanoma cell lines tested displayed strong anti-durotactic migratory response, which was in accordance with the AFM measurement that the melanoma microenvironment gradually softened; 2) Acral melanoma cells tend to move toward softer areas on gradient gels, which is contrary to the migration behavior of most other tumor cells. Conclusions: In this study, we presented the different migratory pattern of acral melanoma cells. It may illustrate the invasion mechanism for aral melanoma cells. It could also herald that extracellular matrix may be a potential therapeutic target in acral melanomas.

Purpose Ingenuity can be viewed as the use of creativity to develop innovation within constraints. The authors investigate how entrepreneurial ingenuity is enhanced by self-imposed ethical constraints, by using a case study of sustainability-driven technology enterprises in an emerging economy. The authors find that self-imposed ethical constraints can enhance entrepreneurial ingenuity because they encourage entrepreneurs to solve more complex problems as a result of considering the impact of the business on a more diverse set of stakeholders. The aim of this study is to show that while additional resources are normally considered an advantage, a dearth of resources can be a source of competitive advantage leading to ingenuity. By self-imposing ethical constraints, founders increase engagement of stakeholders who shape the firm’s industry toward greater sustainability knowledge. Design/methodology/approach The authors used semi-structured interviews which are typically the most important data source in the Gioia methodology because they provide both retrospective and present accounts by individuals experiencing the phenomenon of theoretical interest (Gioia et al., 2012). The authors focused on founders at each enterprise who had sufficient knowledge to speak comprehensively and authoritatively about their organizations. The goals of the semi-structured interview protocol were to focus on the research question, avoid the use of terminology that could lead interviewees in their answers and maintain flexibility to explore spontaneous themes during the interviews. Findings The authors examined the influence of entrepreneurial ingenuity on the creation of knowledge in an organization's environment. They defined entrepreneurial ingenuity as a type of organizational ingenuity (Lampel et al., 2014a, 2014b) and by focusing on the role of ethical constraints, examined the conditions under which it is influenced. They emphasized that ethical constraints warrant consideration in the knowledge management process (Rechberg and Syed, 2013) because they can stimulate entrepreneurial ingenuity. The authors also investigated the relevance of ethical constraints for founders of social enterprises in Brazil, an emerging economy of growing interest to knowledge management scholars. Research limitations/implications This study brings the following three main contributions. First, by incorporating the scope of social entrepreneurship, the research contributes to the perspective that both ethics and innovation can positively coexist within an organization while contributing to knowledge management creation and success (Borghini, 2005; Schumacher and Wasieleski, 2013). Second, the authors establish ethics as an important type of constraint that can spark ingenuity and help break through the constraints of bounded awareness for knowledge management (Kumar and Chakrabarti, 2012). Third, by highlighting the role of self-imposed ethical constraints, this study helps answer a recent call for research on “entrepreneurial actions that benefit others” (Shepherd, 2015, p. 490) addressing “What are the constraints that disable or obstruct an organization’s normal routines from alleviating human suffering?..It could be less about whether it is good or bad to ignore constraints and more about which constraints are ignored and which are abided by” (Shepherd, 2015, pp. 499, 501, emphasis added). Practical implications In this study, the authors show that entrepreneurs facing ethical dilemmas experience a unique cycle of equilibration, essentially throwing customary norms of equilibrium into disequilibrium. Treating ethics as both a lever and a constraint allows a more unique set of problems to be solved through knowledge management and entrepreneurship, so solutions to these problems can themselves become new sustainability-driven businesses. Social implications This study opens up several opportunities for future research. The authors conducted a study with five sustainability-driven enterprises from Brazil. New research may benefit from examining a larger number of organizations in other countries to investigate potential environmental differences that affect ingenuity and knowledge management. This study highlights the notion of ethical constraints as enabling mechanisms, and thus self-imposed ethical constraints merit a more systematic consideration as a key additional factor that may inspire disruptive innovation (Christensen, 2013), blue-ocean strategy (Kim and Mauborgne, 2004), as well as value-creation for stakeholders (Tantalo and Priem, 2016). Originality/value Resources are critical to both knowledge management and entrepreneurial activity and have been examined from numerous perspectives (Alvarez & Busenitz, 2001; Barney, Wright, & Ketchen, 2001; Moustaghfir and Schiuma, 2013). Entrepreneurs following a creation strategy depend less on accumulating existing knowledge and resources before beginning, and more on forming new knowledge or relationships that do not yet exist. They do this through a process of entrepreneurial trial and error (Alvarez & Barney, 2007, 2010). From a knowledge management perspective, individual knowledge sharing through both experimentation and learning by doing provide consistently high levels of knowledge sharing (Burns, Acar and Datta, 2011). This research emphasizes that constraints, such as limited resources and self-imposed ethical standards, can be a source of advantage leading to ingenuity and knowledge creation.

Abstract Chimeric-antigen receptor (CAR)-T cell immunotherapy is a promising type of cancer therapy and substantial progress has been made in developing adoptive T cell approaches for B cell malignancies. B cell maturation antigen (BCMA) is an attractive target for patients with multiple myeloma (MM) due to its high level of expression on tumor cells and restricted expression on normal tissues. Traditionally, the antigen-binding domain of a CAR is a single chain variable fragment (scFv) comprised of heavy chain (HC) and light chain (LC) variable fragments joined by a flexible linker that has been derived from a non-human monoclonal Ab (mAb). However, there are a number of disadvantages to scFv-based CARs including the limited availability of scFv, their potential to elicit antibody responses, and their association with tonic signaling due, in part, to inherent instability and flexibility of the structure and the potential for both HC/LC domain swapping and multimer formation through framework region interactions. Thus, replacement with alternative binding technologies may improve CAR-T efficacy in the clinic. Centyrins are alternative scaffold molecules that bind protein targets with high affinity and specificity, similar to scFv molecules. However, unlike scFv, Centyrins are smaller, derived from human consensus tenascin FN3 domains and are predicted to have decreased immunogenicity. Additionally, a monomeric Centryin in CAR format (i.e. CARTyrin molecule) is less likely to engage in domain swapping or interact with other Centyrins at the cell surface, thereby limiting the potential for the tonic signaling that drives the functional exhaustion of CAR T cells. Centyrins can be isolated against virtually any antigen through ex vivo panning of an extensive Centyrin library, yielding many distinct binders with a range of affinities and target epitopes. Panning with soluble BCMA protein yielded a large pool of BCMA-specific Centyrins, from which 11 distinct monomeric binders and 1 non-monomeric binder were selected for further study in CAR format. In addition, we tested numerous signal peptides, linkers, transmembrane domains and signaling domains to determine optimal configuration. We then created all CARTyrins by fusing each Centyrin with a CD8a leader peptide, spacer and transmembrane domain, as well as an intracellular signaling domain derived from both 4-1BB and CD3ζ. High quality mRNA of each CARTyrin construct was produced in order to rapidly screen CARTyrin cell surface expression and functionality in human pan T cells against BCMA+ targets. We also constructed scFv-based CARs against CD19 and BCMA for comparison. Previously CD3/CD28-stimulated T cells were electroporated (EP) with mRNA encoding each of the 12 anti-BCMA CARTyrins and, the following day, analyzed for surface expression of CARTyrin and their ability to degranulate against BCMA+ tumor cells. All 12 CARTyrins were detected on the cell surface and the 11 monomeric CARTyrins imparted BCMA-specific killing capacity to T cells. Notably, in these assays, CARTyrins were functionally comparable to scFv-based CARs against BCMA or to CD19-specific scFv-based CARs in a parallel assay with CD19+ tumor cells. The 11 functional anti-BCMA CARTyrins were further characterized for functional avidity by determining their activity against a panel of target cells with titrated levels of surface BCMA expression. To create this panel, various amounts of high quality BCMA mRNA were electroporated into BCMA- K562 tumor cells. After 4 hours of co-culture with the panel of BCMA expressing cells, CARTyrin+ T cell activity was measured as a function of CD107a expression. We observed a range of activities by each CARTyrin and show that this assay can be utilized to determine the minimal effective dose of BCMA needed to induce killing by CARTyrin+ cells. Furthermore, we establish that certain BCMA-specific CARTyrins are responsive to target cells with extremely low levels of surface BCMA expression. These results confirm that Centyrins are viable replacements for scFv in the construction of functional CARs and establish their potential utility in generating novel BCMA-specific CAR molecules, as well as other novel targetable tumor antigens. Disclosures Barnett: Poseida Therapeutics: Employment. Wang:Poseida Therapeutics: Employment. Hermanson:Poseida Therapeutics: Employment. Tan:Poseida Therapeutics: Employment. Osertag:Poseida Therapeutics: Employment, Equity Ownership. Shedlock:Poseida Therapeutics: Employment.

Abstract Background/Aims: Polycystic ovary syndrome (PCOS) is associated with disordered carbohydrate metabolism and an increased risk for T2D. However, there are limited data on the magnitude of this risk. Furthermore, 50-80% of women with PCOS are obese and obesity is known to have a synergistic deleterious effect on glucose tolerance in affected women. We systematically reviewed the literature regarding the association between PCOS, obesity and T2D risk. Methods: A comprehensive search was conducted in PubMed, CENTRAL and Scopus databases. Data are expressed as relative risk (RR) with 95% confidence intervals (CI). The I2 index was employed for heterogeneity. The available data, did not allow us to analyze the impact of weight status as normal, overweight and obese and as a consequence the studied subjects were stratified as obese (BMI&gt;30 kg/m2) and non-obese (BMI&lt;30kg/m2). Results: Twelve studies fulfilled eligibility criteria, yielding a total of 224,284 participants (45,361 PCOS and 5,717 T2DM cases). Women with PCOS had a higher risk of T2D compared with to unaffected women (RR 3.13, 95% CI, 2.83-3.47, p&lt;0.001; I2 40.1%). When women with PCOS were stratified according to the presence or absence of obesity, the RR for developing T2D in obese compared with non-obese women with PCOS was 4.20 (95% CI 1.97-9.10; p&lt;0.001). Moreover, compared to control women, the RR for developing T2D was significantly increased only in obese PCOS, RR 4.06 (95% CI 2.75-5.98; p&lt;0.001). There was a trend toward significantly increased risk in non-obese PCOS women [RR 2.68 (95% CI 0.97-7.49; p=0.06). Conclusion: Women with PCOS have a &gt;3-fold increased risk of T2D compared to women without PCOS, but this risk is substantially increased by the presence of obesity. Accordingly, weight reduction should be pursued in these women. References: 1. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38(9):1165-1174.2. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;84(1):165-169.3. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;22(1):141-146.4. Rubin KH, Glintborg D, Nybo M, Abrahamsen B, Andersen M. Development and risk factors of type 2 diabetes in a nationwide population of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2017;102(10):3848-3857.

Laburpena: Laburpena: Aldi baterako kontratazioan gehiegikeriari aurre egiteko Europar Batasuneko eta barneko neurriek ez dute sistema bateratu bat osatu, logika estratifikatu bati erantzun diote. Arkitektura horri esker, barne-zuzenbideak Europako gidalerroetatik eta horiei eusteko tresnetatik aldendu da. Horren ondorioz (beste arrazoi batzuekin batera), behin-behinekotasun tasa onartezinak sortu dira eta fenomeno patologiko eta kroniko bihurtu da. Azterlan honek Europar Batasuneko Justizia Auzitegiaren (EBJA) doktrina aztertzen du, «Sánchez Ruiz/Fernández Álvarez» gai garrantzitsuraino, bai eta horrek sektore publikoko bitarteko langileen izendapenetan (ondoz ondokoak izan edo ez) gehiegizko behin-behinekotasunaren aurkako arauetan duen eragin sakona ere. Europar Batasuneko doktrinak azken urteetan izan duen bilakaerak agerian uzten du barne-arau-esparruarekin eta haren interpretazio judizialarekin bat ez datorrela, eta atzeraezina dela neurri eraginkorrak sartzea kolektibo horren egoera larria zuzentzeko. Azterlanak, halaber, une honetatik aurrera jarraitu beharreko araugintza- eta interpretazio-jarraibide nagusien deskribapena egiten du, eremu horretako behin-behinekotasunaren izaera erabat atipikoa zuzentzen lagundu beharko luketenak. Resumen: Las medidas comunitarias e internas para combatir el abuso en la contratación temporal no han conformado un sistema unitario sino que han respondido a una lógica estratificada. Esta arquitectura ha permitido al derecho interno operar alejándose de las directrices comunitarias y de sus resortes de contención. Lo que ha desembocando (en conjunción con otras causas) en unas tasas de temporalidad intolerables y convirtiéndose en un fenómeno patológico y crónico. Este estudio lleva a cabo un análisis de la doctrina del Tribunal de Justicia de la Unión Europea (TJUE) hasta el importante asunto «Sánchez Ruiz/Fernández Álvarez» y de su profundo impacto en las normas contra la temporalidad abusiva en los nombramientos (sucesivos o no) del pesonal interino del sector público. El recorrido en la evolución de la doctrina comunitaria de los últimos años que se lleva a cabo evidencia el desajuste con el marco normativo interno y su interpretación judicial y la inaplazable necesidad de introducir medidas efectivas que corrijan la grave situación de este colectivo. El estudio también hace una descripción de las principales directrices normativas e interpretativas a seguir a partir de este momento y que deberían contribuir a corregir el carácter absolutamente atípico de la temporalidad en este ámbito. Abstract: Both national and the European Union (EU) measures to combat abuse in temporary contracts haven’t conformed a unitary system but have responded to a stratified logic. This architecture has allowed domestic law to operate away from EU guidelines and its containment elements. These factors have led (in conjunction with other causes) into intolerable temporality rates which have become a pathological and chronic phenomenon.This essay analyses the Court of Justice of the European Union (CJEU) doctrine up to the «Sánchez Ruiz/Fernández Álvarez» case and its deep impact on the national regulations to prevent abusive use of fixed-term appointments (successive or not) of public sector interim staff. The study of the evolution of recent CJEU doctrine that is carried out shows the mismatch with the internal regulatory framework and its judicial interpretation and the urgent need to introduce effective measures to correct the serious situation of this collective. The study provides as well a description of the policy and interpretation guidelines to follow from now on. These measures should contribute to mitigate theatypic temporality rates in this sector.

Abstract Monoclonal antibody (mAb) therapies have become the dominant product class within the biopharmaceutical industry mainly due to their intrinsic capacity to bind endogenous immune receptors and targeted antigens. In fact, this kind of therapeutic agent accounts for one fifth of the FDA’s new drug approvals each year. In addition, their stability and specificity make them the ideal scaffold to develop more complex and efficacious drug modalities such as bispecific antibodies and antibody-drug conjugates. However, in order to advance mAb therapies to the clinic, there are a number of parameters that need to be considered during early-stage development. The purpose of this study was to showcase important preclinical characterization and efficacy experiments aimed at assessing the biological activity, binding profile, mechanism of action and in vivo potency of cetuximab, a mAb therapy. Cetuximab targets EGFR, a well characterized receptor present in the epithelial cell membrane that is overexpressed in several cancer types, such as non-small cell lung cancer, breast cancer and colorectal cancer. In normal tissues EGFR activation initiates several intracellular signaling events involved in development and homeostasis. However, when overexpressed, it stimulates the growth, metastasis and invasion of tumors. For this reason, EGFR has been considered an important target for the development of new drugs. Here we measured the binding affinity of cetuximab to two EGFR expressing cancer cell lines (A-431 and A-549) and its off-target binding to a broad range of full-length human proteins employing Retrogenix Cell Microarray Technology. Using the AlphaLISA system, we observed that cetuximab significantly inhibits EGF binding to EGFR. The consequences of cetuximab treatment on EGF binding and the initiation of the signaling cascade were investigated by looking at the phosphorylation status of EGFR via intracellular staining and flow cytometry. Moreover, we tested the ability of cetuximab to induce Antibody Dependent Cellular Cytotoxicity (ADCC) where the target cell lines were co-cultured with freshly isolated NK cells. ADCC was assessed via both flow cytometry and live cell imaging. Lastly, we studied the efficacy of cetuximab in vivo. A tumor progression mouse model generated from A-431 cells and several Patient Derived Xenografts (PDX) mouse models representing a wide variety of cancers were treated with cetuximab and a significant reduction in tumor growth was observed for most of these cancers. The in vivo efficacy correlated directly with the EGFR expression level determined by IHC. With this case study we have generated a complete and valuable preclinical data package that could be used to advance this mAb therapy into the clinic. Moreover, this study serves as the basis for a streamlined workflow for mAb lead optimization and development as well as comparability studies for biosimilars. Citation Format: David Cobeta Lopez, Kerstin Klingner, Marie Carkill, Robert Nunan, Anya Avrutskaya, Paula Miliani de Marval, Amber Blackwell, Sarah Dawson, Donna Barnes, Jim Freeth, Deborah Bruce, Richard Bazin, René McLaughlin, Julia Schueler, Gemma Moiset, Maria L. Vlaming. A streamlined workflow for preclinical assessment of monoclonal antibody therapies: A case study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5612.

Abstract Background: Hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) are X-linked inherited bleeding disorders which cause recurrent bleeding into the joints leading to significant morbidity. The cornerstone of management is treatment of bleeding with infusions of factor concentrate.(Barnes et al 2013) Adoption of prophylactic treatment with regular factor infusions has dramatically improved life expectancy and quality of life in patients with hemophilia. (Manco-Johnson et al 2007) Dosing of factor replacement therapy is currently based on actual body weight (AW). However, given the obesity epidemic in the United States and the high cost of factor replacement, should patients be dosed based on AW or is there a role for dosing factor based on ideal body weight (IBW). Nearly half of the patients in a demographic study of the United States hemophilia population were considered either overweight or obese based on their body mass index (BMI). (Curtis et al 2015) The average cost of patients receiving prophylaxis over a three-month period ranged from $50,000 to $150,000. Estimation of dosing based on IBW could cut these expenses by almost 50 percent, an annual savings of approximately $136,000.(Graham et al 2014) Methods: We began a retrospective review of patient recovery studies of factor VIII and factor IX at our center to determine the effect of factor dosing based on AW versus that based on IBW. Hemophilia patients with and without inhibitors and a minimum height of 60 inches were included in this analysis. Information collected included: height, weight, dose of factor infused and the 1 hour recovery. IBW was calculated using the formula of: 50kg + (2.3kg (Actual height in inches - 60 inches)) and BMI was calculated by: (weight in kg)/(height in meter)2. Recovery was calculated by comparing the incremental increase in the pre-infusion factor activity and the 1 hour post infusion activity. Data were analyzed to determine DOSE DISCREPANCY, which is the difference between the factor dose given based on AW and calculated factor dose based on IBW and FACTOR DISCREPANCY, which is the difference between rise in factor activity based on AW and predicted rise in factor activity based on IBW. Statistical evaluation using a student's t-test and regression analysis was applied to determine if there were any differences between Dose Discrepancy and Factor Discrepancy. Results: We examined our database of patients with bleeding disorders (n=314). Of these, only patients who were 60 inches or taller with hemophilia were included (n=40) so that IBW could be accurately calculated. This included 38 males and 2 females, age range of 13 to 70 years, and BMIs ranging between 16.9 and 42.1. Patients were then stratified by BMI comparing BMIs below 25 (normal, n =23) versus greater than 25 (overweight or obese, n=17). Patients with a BMI below 25 had a high correlation between the Factor Discrepancy or Dose Discrepancy. Pearson correlation coefficient of 0.789 (p<0.05). However, in patients with BMIs above 25 there was no correlation between Dose Discrepancy and Factor Discrepancy. Pearson correlation coefficient of 0.240 (p=0.322). (see figure) ANOVAb Analysis Non Obese Population Obese Population Conclusions: These data suggest that IBW is an effective way to dose patients who are at a normal BMI of 25 or less but in patients who are overweight or obese (BMI >25) IBW does not provide a reliable method to predict post-infusion factor activities. The number of patients in our study with a BMI >25 was small and the range in BMI was quite large with BMIs up to 42.1. Studies of more patients who are overweight and obese will need to be studied and differences between overweight, obese and morbidly obese will need to be evaluated. Further, prospective studies are needed to determine factor dosing regimens for hemophilia patients who have a BMI over 25. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Simpson: Biogen: Consultancy, Research Funding; OctaPharma: Consultancy, Research Funding; CSL: Consultancy, Research Funding. Boggio:Selexys: Research Funding; OPKO: Research Funding; OctaPharma: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Baxter: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; Bayer: Consultancy, Research Funding.

Abstract BACKGROUND: Myeloproliferative neoplasms (MPN), including polycythemia vera (PV), essential thrombocythemia (ET), and primary meylofibrosis (PMF), are frequently associated with splanchnic vein thromboses (SVT). Risk factors for SVT in MPN patients differ from risk factors for all-cause thrombosis. This is likely due to differing disease mechanisms at play, and suggest a separate disease phenotype for MPN/SVT patients. While several studies have characterized the features of MPN patients with SVT, a direct comparison of MPN/SVT versus all MPN patients has been lacking. METHODS: We performed a retrospective, cross-sectional analysis of patients at Barnes-Jewish Hospital from 2000-2014 with MPN and SVT. Patients were identified using ICD-9 codes in the electronic medical record. 52 available patients with both MPN and SVT were included. Randomly selected 134 patients with MPNs only were used as controls. Clinical and laboratory variables were compared between the two groups. Quantitative JAK2 V617F allele burdens were available in 20 patients. As continuous variables were not normal in distribution, a Mann-Whitney U test was performed. Non-continuous variables were compared with an N-1 Chi-squared test to accommodate rare events. All p-values were corrected for multiple testing. RESULTS: MPN/SVT patients were significantly younger at time of MPN diagnosis (median age 47 vs 57 years, p=0.003). MPN/SVT patients were more likely to have splenomegaly (83% vs 30%, p=0.003), deep vein thrombosis (37% vs 15%, p=0.003), and concomitant thrombophilia (17% vs 2%, p=0.003). MPN/SVT patients had a higher proportion of females (63% vs 54%), but this finding did not reach significance. However, PV/SVT patients had a significantly higher proportion of females compared to PV alone (67% vs 37%, p=0.02). There were no significant differences in JAK2 mutation status, race, smoking status, presence of stroke or coronary artery disease risk factors. MPN/SVT patients had significantly lower hemoglobin (13.1 vs 14.6, p=0.024), hematocrit (39.3 vs 43.5, p=0.027), and platelet count (513 vs 698, p=0.003) at time of MPN diagnosis. When analysis was restricted to PV, only hemoglobin (14.6 vs 17.24, p=0.007) and hematocrit (44.3 vs 50.68, p=0.012) were significantly lower in SVT patients. No significant differences in cell counts were detected in ET and PMF patients. MPN/SVT patients had significantly lower JAK2 mutant allele burdens, with no MPN/SVT patient having an allele burden greater than 10% (p=0.019) (Figure 1). In contrast, mutant allele burdens for MPN patients ranged from 0.1 to 99.7%, with median allele burden being 36.3%. DISCUSSION: This is the first study to directly compare clinical and laboratory features of MPN patients with and without SVT. Our results confirm that MPN/SVT patients are younger, and within PV are more likely to be female. We also demonstrate that MPN/SVT patients have lower cell counts and lower JAK2 mutant allele burdens, findings not previously shown in the literature. MPN/SVT patients are more likely to have splenomegaly, concurrent thrombophilia, and additional DVT. These results indicate that MPN/SVT patients exhibit a disease phenotype distinct from MPN patients without SVTs. While the nature of this study is retrospective and causality cannot be definitively established, the findings of younger age, lower laboratory values, and lower JAK2 allele burden are consistent with the hypothesis that MPN/SVT patients present early in disease. It is possible that in MPN/SVT patients, other environmental and host factors (such as concurrent thrombophilia), in combination with early MPN disease, result in the first manifestation of SVT. These findings have important implications, as investigating the natural course of MPN/SVT patients would allow insight into MPN disease pathogenesis. These findings also suggest that SVTs in MPN patients are not solely mediated by elevated cell counts. In addition, while the presence of the JAK2 V617F mutation likely does affect thrombotic risk, the finding of lower allele burdens in MPN/SVT patients suggests that additional interactions mediate SVT development. These interactions are likely multifactorial and include both environmental and genetic factors. Of particular interest would be the presence of yet unidentified driver mutations present in MPN/SVT patients. Disclosures Oh: Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

When children only see their friends in little squares via Google Meet or Zoom, can teachers really address concepts like the importance of teamwork or how to manage conflict? This is a learning phenomenon during the COVID-19 pandemic and the era after it. This study aims to see the role of parents as children's learning companions in terms of mentors and motivators when online education takes place. This research using photovoice within phenomenological methodology and have been doing with thematic analysis and collecting data through interviews and observations. The participants were eight parents and one female teacher as a homeroom teacher. The research findings show that although there are many obstacles in online learning for children, learning during the COVID-19 pandemic can still run by involving the role of parents and teachers as pillars of education for preschool-age children. For further research, it is hoped that the findings will be a way in solving learning problems for children. Keywords: early childhood education, parents’ role, online learning References: Adedoyin, O. B., & Soykan, E. (2020). Covid-19 pandemic and online learning: The challenges and opportunities. In Interactive Learning Environments. https://doi.org/10.1080/10494820.2020.1813180 Aras, S. (2016). Free play in early childhood education: A phenomenological study. Early Child Development and Care, 186(7). https://doi.org/10.1080/03004430.2015.1083558 Arkorful, V. (2021). The role of e-learning, advantages and disadvantages of its adoption in higher The role of e-learning, the advantages and disadvantages of its adoption in Higher Education . International Journal of Education and Research, 2(December 2014). Atiles, J. T., Almodóvar, M., Chavarría Vargas, A., Dias, M. J. A., & Zúñiga León, I. M. (2021). 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Abstract In subduction zones undergoing oblique convergence, strain partitioning is often expressed by an important deformation inducing strike-slip faulting. In accretionary wedges, parameters such as obliquity of the convergence and friction at the bottom of the wedge play an important role in the strain partitioning. The impact of these parameters is studied using sandbox experiments. Two backstop geometries have been designed to account for different geological settings. These experiments show that the wedge taper remains constant and close to αcoulomb for variable obliquities. Measurements of critical tapers on the models suggest that the Coulomb wedge theory cannot be simply applied to determine parameters on wedges developed under oblique convergence. Parameters deduced from this theory are valid only when measured in the direction parallel to the convergence. In addition, the partition degree increases with the obliquity of the convergence, and strain partitioning occurs independently of the basal friction. We remark that the model morphology changes when an obliquity value, mainly, is exceeded. A transcurrent structure develops. The models show that oblique structures located above the velocity discontinuity are associated with strike-slip faults. Similar structures have been observed within the Hikurangi accretionary wedge (New Zealand). Introduction. – In subduction zones, for high values of the convergence obliquity γ, transcurrent faults are observed, parallel to the trench, on the continental plate. Such structures are present in Sumatra and the Philippines along the volcanic arc [Bellier and Sébrier, 1995 ; Malod et al., 1993 ; Barrier et al. 1991] or at the rear of the accretionary wedge for the South Ryukyu (Taiwan). These strike-slip faults are a consequence of strain partitioning. Partition is controlled by obliquity of convergence, basal friction and probably geometry of backstop. Using analog models, the influence of each parameter on strain partitioning, on the occurrence of transcurrent faults and its morphology are analyzed. The strain partitioning can be quantified by its degree (1) \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \[K_{\mathit{v}}\ =\ (1\ {-}\ \frac{{\phi}}{{\gamma}})\ {\cdot}\ 100\] \end{document} It requires the knowledge of the slip vector, which is situated between the azimuth of the convergence and the perpendicular to the trench. Experimental procedure. – The aim of our experiments is to better understand the effects of several parameters which determine the strain partitioning in accretionary wedges undergoing oblique convergence. For this purpose, a large-size table (140 cm × 250 cm) covered with a plastic film moving towards the backstop is used (fig. 1). The basal friction of the wedge can change according to the different textures of the plastic films used. Various angles of convergence (0o, 20o, 40o and 60o) are studied (fig. 1). Two types of backstop geometries are designed. In the first case, the plastic sheet moves under a thin PVC plate resting at the base of the material, in order to localize the strain above the velocity discontinuity, at the tip of the plate. In the second case, the backstop presents a 4 cm high, low-friction vertical wall. The whole device is covered by 2 cm of dry sand. The sand satisfies a Coulomb failure envelope, with an internal friction angle of about 30o and a very low cohesion. Colored markers perpendicular and parallel to the convergence direction, and perpendicular to the backstop, are spread on the surface of the sand. They allow recording of kinematics during the experiments. During these experiments, the plastic film converges towards the backstop with a constant velocity. Pictures of the deforming model are taken perpendicularly to the surface, every 5 cm of shortening. Intersections of the colored lines are followed and recorded at every stage of shortening, in order to describe the deformation and determine the velocity field. Vs corresponds to the displacement-vector of these points. The knowledge of the kinematics allows to deduce (using geometric construction) the slip-vector Vg and its obliquity ψ relative to the normal to the trench. The partition degree Kv is a function of the obliquity of convergence vector and of the obliquity of slip vector (fig. 2). The critical taper is measured at the end of each experiment, perpendicularly to the backstop and parallely to the direction of convergence. Results and discussion. – The morphology of the wedge suggests different structural domains : (a) a stable domain, (b) a zone of wrenching, (c) a wedge of imbricated thrusts. Above a value of the obliquity of convergence, the three domains become more distinct. Oblique structures develop in relation with the strike-slip fault. Their orientation compared with the orientation of the strike-slip fault is controlled by the geometry of the backstop (fig. 3). In the first type, these structures seem to be perpendicular to the convergence, in contrast with the second type where they tend to be parallel. Physical models of accretionary wedges show that the critical taper increases with increasing basal friction [e.g., Malavieille et al., 1992]. Furthermore, the sand used in the experiments obeys Coulomb failure criterion. Davis et al. [1983] apply this criterion to convergent thrust-wedges. They determine a relationship between critical taper wedge (αcoulomb), dip (β) of the subducting plate and basal friction (μb) : (2) \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \[{\alpha}_{\mathit{coulomb}}\ +\ {\gamma}\ =\ \frac{({\mu}\mathit{b}\ +\ {\beta}}{(1\ +\ \mathit{K})}\] \end{document} In our experiments, for both geometries of backstop, the slope measured perpendicularly to the trench increases with the obliquity of the convergence, whereas the slope measured parallel to the direction of the convergence remains constant. Its value is close to the slope deduced from relation 1. The slope measured perpendicularly to the trench increases with increasing basal friction (fig. 4). The partition degree Kv depends on the relation between the convergence vector Vc and the slip vector Vg. Each of them is defined by their obliquities which are respectively γ and ψ. The partition degree Kv can be deduced from the obliquity of the convergence vector relative to the slip vector, Liu et al. [1995]. See equation (1). For both backstop geometries (fig. 5), Kv increases with the obliquity of the convergence γ. Moreover, the strain partitioning develops for γ superior or equal to 20o. In the second type of experiments, the partition degree is homogeneous in the whole structure. It moves like a single block along a strike-slip fault located above the velocity discontinuity (fig. 6). Studies on the critical taper allow Davis et al. [1983], to determine a relationship applied to a frontal convergence. In our experiments, the measurements of the critical taper of the accretionary wedge is equal to αcoulomb and remains constant in the direction of the convergence. The critical taper equation (2) seems to apply in the direction of convergence. So the measures taken in the direction of the convergence permit to obtain some correct parameters. Using sand-silicone analogue models, Pinet and Cobbold [1992] show that a minimum angle of oblique convergence (30o) is required before strain partitioning occurs. Our models involving dry sand clearly reveal that strain partitioning : increases with the obliquity of convergence, may develop with low obliquities and may also develop if basal friction is very low. From physical models, Chemenda et al. [2000] proposed that the strain partitioning at lithospheric scale may occur for a high interplate friction only. Thus, the rheology of the material probably has a strong influence on the critical value of the convergence obliquity beyond which strain partitioning may appear. Comparison with natural examples. – To the south of the Ryukyu Trench, northeast Taiwan, bathymetric data highlight a dextral strike-slip fault at the rear of the accretionary wedge [Lallemand et al., 1999]. Seismic profiles analysis crossing the same area gives constraints on the shape of the Ryukyu arc basement. It ends with a several kilometers high subvertical basement wall [Font et al., 2001]. This vertical backstop favors strain partitioning and locates strike slip faulting. Our models also clearly outline the impact of backstop geometry on strain partitioning and on strain location. In New-Zealand, along the Hikurangi margin, the Pacific plate meets the Australian plate at a very oblique convergence (60o). Between the Cook canyon (175o00E and 176o45E), three crustal faults, having the same direction, are observed. The Palliser-Kaiwhata fault which outlines the edge of the continental margin is interpreted as a subvertical strike-slip fault. Close to the trench, two other faults are interpreted as reverse faults which may correspond to a strike slip oblique component. Sonar data reveals a lineament associated only with the Palliser-Kaiwhata fault trend [Barnes et al., 1998]. In our experiments, oblique structures associated to strike-slip faulting developed (backstop geometry 2, fig. 3d). These structures seem to be linked with strike-slip displacement of faults. Knowing the boundary conditions of the models and about the structural surface of the Hikurangi wedge, a similar configuration to our models could exist, with the possible presence of a velocity discontinuity above the Palliser-Kaiwhata fault. The present study points out several results : the critical taper of the wedge remains stable in the direction of the convergence when the obliquity increases. It is equal to the theoretical value determined by the Coulomb wedge theory; the partition degree increases with increasing obliquity of the convergence, whatever the basal friction may be; different structural domains characterized by their morphology have been observed : a stable domain, a convergence zone of wrenching, and a wedge of imbricated thrusts; oblique structures are associated to the strike slip fault zone.

The pandemic of COVID-19 has afflicted every individual and has initiated a cascade of directly or indirectly involved events in precipitating mental health issues. The human species is a wanderer and hunter-gatherer by nature, and physical social distancing and nationwide lockdown have confined an individual to physical isolation. The present review article was conceived to address psychosocial and other issues and their aetiology related to the current pandemic of COVID-19. The elderly age group has most suffered the wrath of SARS-CoV-2, and social isolation as a preventive measure may further induce mental health issues. Animal model studies have demonstrated an inappropriate interacting endogenous neurotransmitter milieu of dopamine, serotonin, glutamate, and opioids, induced by social isolation that could probably lead to observable phenomena of deviant psychosocial behavior. Conflicting and manipulated information related to COVID-19 on social media has also been recognized as a global threat. Psychological stress during the current pandemic in frontline health care workers, migrant workers, children, and adolescents is also a serious concern. Mental health issues in the current situation could also be induced by being quarantined, uncertainty in business, jobs, economy, hampered academic activities, increased screen time on social media, and domestic violence incidences. The gravity of mental health issues associated with the pandemic of COVID-19 should be identified at the earliest. Mental health organization dedicated to current and future pandemics should be established along with Government policies addressing psychological issues to prevent and treat mental health issues need to be developed. References World Health Organization (WHO) Coronavirus Disease (COVID-19) Dashboard. 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Propagation of production- and injection-induced stresses from reservoir layers to basement faults is not well understood, especially in reservoirs with hydraulically segregated production and injection units situated across low-permeability structural or stratigraphic boundaries. This is one of the challenges in understanding the 2013–2014 Azle-Reno earthquake sequence (maximum magnitude M w 3.8) in the Fort Worth Basin of Texas, which occurred after several billion cubic meters of gas and several million cubic meters of brine were produced from the Barnett Shale and several million cubic meters of water was injected into the Ellenburger Formation below the Barnett. The effect of Barnett production on induced stress and reactivation of the synthetic-antithetic fault pair hosting the seismicity is not well understood from prior studies. The interaction among production-induced contraction, injection-induced expansion, and decrease in fault compression due to fluid diffusing from the injection layer strengthens two-way coupling among fluid flow, deformation, and fault failure processes. Using a high-resolution coupled flow-geomechanics-fault reactivation model of the Azle region and a modified corner point meshing algorithm, we integrate structural, seismic, and well data to model novel mechanisms of stress interaction and propagation. The model indicates how Barnett’s production-induced contraction interacts with Ellenburger’s injection-induced expansion in the footwall block of the antithetic fault to cause updip shear on the fault. In the hanging-wall block of the synthetic fault below Ellenburger, the model finds that the downdip shear from Ellenburger expansion colludes with the decrease in fault’s effective compression due to downdip fluid diffusion. The collusion induces normal faulting in the model. Modeling also reveals that the reorientation of the principal stresses is more severe in the Barnett compared with that in the Ellenburger. The model quantifies the impact of stress reorientation on the magnitude and location of fault reactivation events.