The purpose of this community service was to educate the application of probiotics and immunostimulants in aquaculture. This activity was carried out in Cot Darat village, SamatigaDistrict, West Aceh Regency. This activity is divided into three steps, namely: (1) Introduction and socialization of probiotics and immunostimulant; (2) practice to produce probiotics and the application techniques; and (3) the monitoring of fish health and growth during cultivation. The type of bacteria used in this probiotic is Lactobacillus bacteria and the immunostimulant ingredients are turmeric and curcumin. Lactobacillus, turmeric and curcuma are known can improve fish health in aquaculture. The results of this activity indicate that group members have understood the definition of probiotics and immunostimulants, their benefits and how to make and apply them in aquaculture. In addition, fish health and growth are increase during fish culture compare before the probiotics was applied. The differences that occurred during probiotics application in fish cultivation were seen that the fish became healthier, the growth was better, and fish mortality decreased.


A calculation model is put forward to analyze the interfacial response of an elastic frictionless punch, pressed normally into a half-plane, and subject to bending moment throughout this paper to observe the important effect that different normal loads and bending moments on the contact pressure distribution and contact deformation. Results for the detailed considerations have been given to the specific different cases of η c . A characteristic response of the punch to a surplus bending moment has been found. The small differences can be observed between both methods show characteristic features of the FEM model and the theoretical model. The presented numerical results illustrate the influences of the normal load and bending moment on the contact stresses. The results obtained can be used to analyze the crack nucleation in fretting when the punch is acted upon by the normal force and the bending moment.


Atherosclerosis is known as the leading factor in heart disease with the highest mortality rate among the Malaysian population. Usually, the gold standard for diagnosing atherosclerosis is by using the coronary computed tomography angiography (CCTA) technique to look for plaque within the coronary artery. However, qualitative diagnosis for noncalcified atherosclerosis is vulnerable to false-positive diagnoses, as well as inconsistent reporting between observers. In this study, we assess the reproducibility and repeatability of segmenting atherosclerotic lesions manually and semiautomatically in CCTA images to identify the most appropriate CCTA image segmentation method for radiomics analysis to quantitatively extract the atherosclerotic lesion. Thirty (30) CCTA images were taken retrospectively from the radiology image database of Hospital Canselor Tuanku Muhriz (HCTM), Kuala Lumpur, Malaysia. We extract 11,700 radiomics features which include the first-order, second-order and shape features from 180 times of image segmentation. The interest vessels were segmentized manually and semiautomatically using LIFEx (Version 7.0.15, Institut Curie, Orsay, France) software by two independent radiology experts, focusing on three main coronary blood vessels. As a result, manual segmentation with a soft-tissuewindowing setting yielded higher repeatability as compared to semiautomatic segmentation with a significant intraclass correlation coefficient (intra-CC) 0.961 for thefirst-order and shape features; intra-CC of 0.924 for thesecond-order features with p < 0.001. Meanwhile, the semiautomatic segmentation has higher reproducibility as compared to manual segmentation with significant interclass correlation coefficient (inter-CC) of 0.920 (first-order features) and a good interclass correlation coefficient of 0.839 for the second-order features with p < 0.001. The first-order, shape order and second-order features for both manual and semiautomatic segmentation have an excellent percentage of reproducibility and repeatability (intra-CC > 0.9). In conclusion, semi-automated segmentation is recommended for inter-observer study while manual segmentation with soft tissue-windowing can be used for single observer study.


Eric Mumford Designing the Modern City: Urbanism since 1850 New Haven, Conn.: Yale University Press, 2018, 360 pp., 125 b/w illus. $40 (cloth), ISBN 9780300207729

The expansive catalogue of recent books on global urbanization covers an array of approaches, from the political and social to the technological and environmental. Urbanization and its central object, the city, claim a priority in analyses of the modern condition, whether optimistic or pessimistic. The city also appears as a central protagonist in any number of works of architectural history, having captivated the attention of architects and architectural discourse for the past two centuries. In Designing the Modern City: Urbanism since 1850 , Eric Mumford aims to acknowledge both of these views—the city as the conceit of architects and the city as the embodiment of modernity—with a broad survey of the strategies conceived, proposed, and deployed to design the modern city in the nineteenth and twentieth centuries.

Although compact, Mumford's book accomplishes ample coverage of salient examples distributed temporally and geographically, such that it functions as a survey textbook, one that may occupy the pedagogical positions formerly held by classic publications on city form. The influential morphological approach of publications by Leonardo Benevolo, Edmund Bacon, and Spiro Kostof has of course waned in recent decades with the ascendance of more emphatically sociocultural and technopolitical examinations of urbanization, leaving open the question of whether and how we should talk about the intentional design of cities. This is the challenge that Mumford takes up, proposing to offer "an account of how key figures in design responded to changing social, technical, and economic circumstances with design proposals and built projects" (2). The urbanism of the book's subtitle is for Mumford a field …


We present results obtained with a stretched-pulse polarization additive pulse mode-locked (P-APM) fiber laser using an environmentally stable cavity design. With 980-nm diode-pumping levels of 200-mW 1.2-nJ pulses with 50 nm of spectrum are obtained. These pulses can be externally compressed to sub-100 fs. The effects of high output coupling (>80%) and pumping configuration on output performance an d intracavity pulse dynamics are studied.


A novel bifunctional poly-monomer materials,4-(4-vinylphenyl) benzoic acid-(4-vinyl) phenyl ester was prepared by the esterification of 4-(4-acetylphenyl) benzoic acid and 4-acetyl phenol,then reduction of the resulting carbonyl containing ester and dehydrolysis.The former acid was synthesized by biphenyl via Friedel-Crafts,bromination,Grignard reaction and oxidation reactions,and the later 4-acetylphenol was prepared by anisole via Friedel-Crafts and methyl elimination reactions.The total yield based on biphenyl is around 7%~10%,and the target product and intermediates were characterized by 1H NMR and FT-IR,its liquid crystal properties was studied with Polarizing Optical Microscopy and Differential Scanning Calorimetry.


Malignant melanoma most commonly arises in the skin; however, primary melanomas can also arise from the mucosal epithelial lining of the gastrointestinal tract. Primary esophageal melanoma is rare and constitutes only 0.1% of primary esophageal tumors. There are only a few reports on the use of endosonography in this condition. We report here a case of a 45‐year‐old male with a history of painful deglutition and describe the endosonographic features of primary esophageal melanoma.


PURPOSE
The quality of presurgical evaluation in focal extratemporal epilepsy surgery is highly dependent on precise structural and functional identification of the epileptic focus. Navigated transcranial magnetic stimulation (nTMS) is a tool that combines the spatial information of high-resolution magnetic resonance imaging (MRI) with the functionality of non-invasive cortical stimulation. The non-invasive character of nTMS suggests that it could be a promising tool for presurgical evaluation of cortical excitability.

METHODS
Presurgical nTMS evaluation was performed on an 8-year-old boy with left-sided intractable focal epilepsy, somatosensory auras and epilepsia partialis continua. In line with standardized procedures, motor evoked potentials were sought in both hemispheres over perirolandic cortex during simultaneous belly-tendon surface recordings of the first dorsal interosseus muscles.

RESULTS
One singular motor-evoked potential (MEP) could be elicited in the unaffected hemisphere. In contrast, in the affected hemisphere MEPs could be elicited over a large area of the cortex even after the stimulation strength was reduced by at least 44%. Latency stratification in the affected hemisphere differentiated a motor from a sensory region of interest. Stimulation over the sensory region induced a sensory aura. The sensory site was concordant with a previous transient diffusion restriction found in an MRI two years prior to nTMS.

CONCLUSIONS
NTMS can locate pathological excitability with high spatial precision. Future studies should compare nTMS with direct cortex stimulation, as well as the combination of nTMS with electroencephalography (EEG) in a larger patient-collective.


Spinal cord injury (SCI) can be a lifelong, devastating condition for both the patient and the caregiver, with a daunting incidence rate. Still, there are only limited available therapies and the effectiveness of precise regeneration within the central nervous system is minimal throughout postnatal life. Recently, improved regeneration after SCI was seen by manipulating a pathway in sensorimotor neocortices that is involved in phosphorylation of an RNA binding protein (RBP) required for mRNA translation, the Eukaryotic translation initiation factor 4E (eIF4E). Our data identifies rapid molecular alterations of eIF4E in the sensorimotor neocortices 1 and 3 days after a lateral hemisection SCI, used as a model for Brown-Séquard syndrome. The function of an RBP depends on both its distribution sites within the cell and its phosphorylation states. Indeed, we found both to be affected after SCI. There was a distinct subcellular redistribution of eIF4E and phosphorylated-eIF4E was reduced, indicating that the eIF4E's translation was disrupted. Upon identification and analysis of the mRNA cargo of eIF4E in uninjured sensorimotor neocortices, we found that eIF4E binds both Importin-13 (Ipo13) and Parvalbumin (Pv) mRNAs, indicating a role in their translation. Remarkably, eIF4E's interaction with both Ipo13 and Pv mRNAs was disrupted 1 and 3 days after SCI, despite preservation of total Ipo13 and Pv mRNA levels. Finally, we detected a selective loss of expression of both IPO13 and PV proteins in projection neurons of sensorimotor neocortices, as well as their disrupted dendritic polarity. Since IPO13 is predominantly expressed in neocortical projection neurons and PV in a subset of neocortical interneurons, these data suggest a strong acute effect of SCI on neocortical microcircuitry. Taken together, these data indicate that neocortical eIF4E and a subset of mRNAs may be rapidly recruited to translational machinery after SCI to promote adaptive regeneration response of sensorimotor neurons.


Amphibians are the most threatened terrestrial vertebrates on the planet and are iconic in the global biodiversity crisis. Their global decline caused by the fungal agent Batrachochytrium dendrobatidis (Bd) is well known. Declines of Mesoamerican salamanders of the family Plethodontidae, mainly affecting high elevation species, have equally been attributed to Bd. Here we report the prevalence of Bd in a population of a high elevation Bolitoglossa species in Nicaragua, since its description in 1999 until 2011 in the absence of any obvious population declines. Our findings show a low prevalence in an environmental context where pathogen driven declines would be expected to occur.


Accepted 24 August 2011 Introduction Elderly are often associated with multiple social and health problems. Family members are important in helping them doing their daily activities. For elderly diabetics, family support has a role in diabetes management and glucose control. The aim of this study is to explore the perceptions of elderly diabetics regarding the role of family support on their glucose control. Methods This qualitative technique was a part of the study on glucose control and its associated factors among elderly diabetics. It was conducted from February until May 2009 in Kulim. Ten respondents were purposively sampled based on their glucose control. HbA1c 6.5% or less was considered as good glucose control. In depth interview, using semi-structured interview guide was used in this study. The conversation had been taped, transcribed to verbatim and analyzed manually using thematic analysis. Results All ten respondents perceived that family support did not play a role on their glucose control. They believed that self-awareness and self-determination were important to control the glucose level. Those with good glucose control practiced healthy diet, and not affected by food prepared by their family members compared to those with poor glucose control. However, both groups claimed that, they did not receive much advice from their family members and no special food was prepared for them. Conclusions Elderly diabetics should be motivated on self-determination and focusing on good glucose control. Health education should be given to patients and their family members to increase their diabetes knowledge especially on useful advice and proper food preparation. It could motivate the elderly diabetics to control their glucose level. Keywords Family support - glucose control - elderly diabetics - qualitative.


The coordination polymers [(Cu(N(3))(2))(2)Cu(N(3))(2)(methylpyrazine)(2)](n) 1 and [Cu(4-bromopyridine)(N(3))(2)](n) 2, were prepared from NaN(3), Cu(NO(3))(2).3H(2)O and nitrogen-containing heterocycles. 1 contains a three- and four-connected 3D (4.10(2))(2)(4(2).10(4))-dmd-net based on tetrahedral and trigonal planar nodes, whereas 2 is a sheet-structure formed by a uninodal three-connected 8(2).4 2D-net with additional BrBr (mean 3.903(2) A) and BrN(azide) (3.035(5) A) contacts. Both compounds contain end-on-type azide bridges, and 2 has in addition one end-to-end bridge as well. The corresponding magnetic interactions are J(1,2) = +14.9(6) cm(-1) for the end-on azido interactions in 1 with an additional -1.7 cm(-1) coupling through the pyrazine, and J(1) = 36(6) cm(-1) for the end-on azido interactions and J(2) = 2.5(1) cm(-1) for the orthogonal end-to-end azido interactions found in 2.


We used a new experimental approach involving thin aquaria, luminophores, time lapse photography and image analysis to assess sediment reworking in 2 closely related bivalves, Abra ovata and A. nitida. The method proved efficient based on the highly significant correlation between the concentrations of luminophores assessed using image analysis and direct counting of sediment slices. A. ovata and A. nitida exhibited different sediment reworking behaviours. A. ovata remained immobile within the sediment and transferred luminophores within the sediment through its siphonal activity, which resulted in the creation of typical inverse conical structures. A. nitida moved within the sediment and reworked a thinner sediment layer. Both A. ovata and A. nitida were characterised as biodiffusers. Biodiffusion coefficients (D b ) were maximal at intermediate food concentration in A. ovata and at high food concentration in A. nitida. This new approach allowed assessment of the effects of spatial scale and vertical grid size on the computation of D b . In both species D b decreased with spatial scale up to 3.750 cm and then remained constant. It is suggested that this pattern partly resulted from heterogeneity linked to: (1) the mode of sediment reworking (A. ovata) and (2) the relative proportion of reworked sediment surface (A. nitida). Vertical grid size > 0.250 cm resulted in a significant overestimation of D b in A. nitida, due to the low thickness of the sediment layer reworked by this species. The implications of these results on the main characteristics (duration, spatial scale, vertical grid size) of classical luminophore experiments are discussed.


The semi-classical Jaynes-Cummings model including damping inside the cavity without the rotating-wave approximation is analysed. It is shown that, depending on the values for the coupling constant and the detuning parameter, a new stable static solution of the equations of motion can exist, where the electric field does not vanish and the atoms are not in their ground state. By numerical simulations of the model the analytical results are confirmed.


This technical note introduces a new dissipativity-based switching adaptive control strategy for uncertain systems. In this approach, the parametric uncertainties in systems are not considered on continuums but studied on finite discrete sets. Differently to multiple model supervisory control, dissipativity-based switching adaptive control needs no estimation errors for each switching decision. The switching logic is designed based on the relationship between dissipativity/passivity and adaptive systems, such that in the process of switching control, a transient boundary can be guaranteed by appropriately switching the parameter estimates. This makes it possible to apply the strategy for nonlinear systems modeled in local regions in the state space. We also discuss the implementation of the new idea to general dissipative systems and feedback passive systems. An example with simulation is employed to show the effectiveness of the approach.


Despite a history of natural disasters, most preservationists in Charleston, South Carolina, discovered, as Hurricane Hugo approached, that they were without a cultural resource, disaster-preparedness plan. Each cultural organization in the city took basic protective measures prior to the storm's onslaught, but few were prepared for the magnitude of the outcome. Immediately afterward, preservationists organized an emergency stabilization task force at the request of the city. With a phone bank and a battery of volunteers, expert and amateur, a multilevel effort was commenced, consisting of architectural salvage, survey, technical information dissemination, contractor database, and recordation of damage. After months of recovery efforts, the final phase of recordation and survey led to the input of information and the development of a computer-automated graphics and database marriage program. The database has provided quick access to important information such as roofing and chimney failures and losses of building features. The Foundation's database offers the opportunity for future expansion. Its experience with Hugo has helped set forth new standards for damage recordation after a natural disaster.


Our goal in this paper is to automatically extract a set of decision rules (rule set) that best explains a classification data set. First, a large set of decision rules is extracted from a set of decision trees trained on the data set. The rule set should be concise, accurate, have a maximum coverage and minimum number of inconsistencies. This problem can be formalized as a modified version of the weighted budgeted maximum coverage problem, known to be NP-hard. To solve the combinatorial optimization problem efficiently, we introduce a nested genetic algorithm which we then use to derive explanations for ten public data sets.


Novel bio-inspired conductive scaffolds composed of sodium hyaluronate containing water soluble polyaniline or polypyrrole colloidal particles (concentrations 0.108, 0.054 and 0.036 % w/w) were manufactured. For this purpose, either crosslinking with N-(3-dimethylaminopropyl-N-ethylcarbodiimide hydrochloride and N-hydroxysuccinimid or a freeze-thawing process in the presence of poly(vinylalcohol) were used. The scaffolds comprised interconnected pores with prevailing porosity values of ~30 % and pore sizes enabling the accommodation of cells. Good swelling capacity (92 – 97 %) without any sign of disintegration was typical for all samples. The elasticity modulus depended on the composition of the scaffolds, with the highest value of ~50 000 Pa obtained for the sample containing the highest content of polypyrrole particles. The scaffolds did not possess cytotoxicity and allowed cell adhesion and growth on the surface. Using the in vivo-mimicking conditions in a bioreactor, cells were also able to grow into the structure of the scaffolds. The technique of scaffold preparation used here thus overcomes the limitations of conducting polymers (e.g. poor solubility in an aqueous environment, and limited miscibility with other hydrophilic polymer matrices) and moreover leads to the preparation of cytocompatible scaffolds with potentially cell-instructive properties, which may be of advantage in the healing of damaged electro-sensitive tissues.


A language of instruction is used to deliver explanations about the concepts that are taught, discuss among students and teachers, and solve academic tasks such as exercises and assignments. At the Islamic University of Technology (IUT), students are drawn from different OIC countries whose language background is either the host country's language, e.g. Bangla, or other OIC member state languages e.g. French, Arabic, or English. This study investigates the implications of students' language background towards their academic performance in IUT with specific objectives of assessing the impact of student's level of English Language (EL) proficiency against their academic performance and determining the relationship between the constructs of the level of English Language proficiency and academic performance. The quantitative research design was used including close-ended questionnaires to collect data about the implication of language background on students' performance. It was discovered that the implication of writing on students' performance was minor and depended on the insight it was viewed in. Secondly, reading played an important part in building students' confidence, increases participation and self-expression. Third, it was noted that perceived understanding had a slightly negative impact on student performance and, finally reading as part of background language had a significant positive role in the performance of students. Other factors such as the background of students in terms of origin, students' interest in courses, etc. also influenced students' academic performance. Further study in the future could explore other factors that determine students' performance and issues of language to improve engineering knowledge and skills.


Sustainable solar energy is of the interest for the city of San Francisco to meet their renewable energy initiative. Buildings in the downtown area are expected to have great photovoltaic (PV) potential for future solar panel installation. This study presents a comprehensive method for estimating geographical PV potential using remote sensed LiDAR data for buildings in downtown San Francisco. LiDAR derived DSMs and DTMs were able to generate high quality building footprints using the object‐oriented classification method. The GRASS built‐in solar irradiation model (r.sun) was used to simulate and compute PV yields. Monthly and yearly maps, as well as an exquisite 3D city building model, were created to visualize the variability of solar irradiation across the study area. Results showed that monthly sum of solar irradiation followed a one‐year cycle with the peak in July and troughs in January and December. The mean yearly sum of solar irradiation for the buildings in the study area was estimated to be 1675 kWh/m2. A multiple regression model was used to test the significance of building height, roof area and roof complexity against PV potential. Roof complexity was found to be the dominant determinant. Uncertainties of the research are mainly from the inherent r.sun limitations, boundary problems, and the LiDAR data accuracy in terms of both building footprint extraction and 3D modeling. Future work can focus on a more automated process and segment rooftops of buildings to achieve more accurate estimation of PV potential. The outcome of this research can assist decision makers in San Francisco to visualize building PV potential, and further select ideal places to install PV systems. The methodology presented and tested in this research can also be generalized to other cities in order to meet contemporary society's need for renewable energy.


Tourism development is directed at human welfare and the integrity of nature around the destination, and a new concept in tourism development is ustainable tourism. In sustainable tourism, the role of women as tourism actors was considered because they often experienced a double burden of suffering from the roar of tourism progress in a destination. This paper aimed to map the involvement of women in sustainable tourism strategies in tourist destinations of Komodo National Park (KNP). This study uses a qualitative method. The data collection technique used in-depth interviews with women involved in tourism service businesses around KNP. This paper conducted interviews with local communities, previous research, NGOs and regional government's data as data triangulation. The results of this study indicated that the involvement of women in tourism around KNP destinations was influenced by several factors such as patriarchal culture rooted in everyday life, stereotypes about women's abilities, and low self-esteem that came from women. On the other hand, the government's program for women's empowerment had not found the right formulation. The involvement of women around KNP as tourism drivers must also be a joint concern of the local community, NGOs, and local governments.


This paper subjects the piracy-corruption relationship to a detailed empirical examination. A distinction is drawn between the direct impact of corruption on piracy and the indirect impact which operates through corruption's impact on per capita income and the resultant impact of income on piracy. Using data for 100 countries covering the period 1996–2010, both direct and indirect impacts of corruption on software piracy are estimated. Corruption is estimated to have a positive direct effect on the piracy rate. The indirect effect is found to be negative and smaller in absolute value than the direct effect for the majority of the sample income range. As a result, the total effect of corruption on software piracy is positive except for the lower income countries in the sample.


Neisseria meningitidis traversal across the blood–cerebrospinal fluid barrier is an essential step in the pathogenesis of bacterial meningitis. We have previously shown that invasion of human brain microvascular endothelial cells (HBMEC) by meningococci is mediated by bacterial outer membrane protein Opc that binds fibronectin, thereby anchoring the bacterium to the integrin α5β1‐receptor on the endothelial cell surface. However, subsequent signal transduction mechanisms essential for or regulated by N. meningitidis adhesion and invasion, or HBMEC responses to N. meningitidis are unknown. In this report we investigated the role of c‐Jun N‐terminal kinases 1 and 2 (JNK1 and JNK2), p38 mitogen‐activated (MAP) kinase and protein tyrosine kinases in endothelial–N. meningitidis interaction. Binding of meningococci to HBMEC phosphorylated and activated JNK1 and JNK2 and p38 MAPK as well as their direct substrates c‐Jun and MAP kinase activated kinase‐2 (MAPKAPK‐2), respectively. Non‐invasive meningococcal strains lacking opc gene (opc mutants and sequence type 11 complex meningococci) still activated p38 MAPK, however, failed to activate JNK. Inhibition of JNK1 and JNK2 significantly reduced internalization of N. meningitidis by HBMEC without affecting its adherence. Blocking the endothelial integrin α5β1 also decreased N. meningitidis‐induced JNK activation in HBMEC. These findings indicate the crucial role of JNK signalling pathway in N. meningitidis invasion in HBMEC. In contrast, p38 MAPK pathway was important for the control of interleukin‐6 (IL‐6) and IL‐8 release by HBMEC. Genistein, a protein tyrosine kinase inhibitor, decreased both invasion of N. meningitidis into HBMEC and IL‐6 and IL‐8 release, indicating that protein tyrosine kinases, which link signals from integrins to intracellular signalling pathways are essential for both bacterial internalization and cytokine secretion by HBMEC.


This research paper discusses the rise of the heritage and tourist industry in Cornwall. It aims to historically contextualize this process by analyzing it in relation to the neo-liberal political landscape of the 1980s. The paper highlights several consequences of industrial heritage tourism in the region, including the growing gap between rich and poor that resulted from the arrival of newcomers from the richer Eastern counties and the perceived downplaying of Cornish heritage. It will explain how these developments paved the way for regionalist activists who strived for more Cornish autonomy in the field of heritage preservation and exploitation.


Fish are an important part of Bangladeshi culture and diet. Bangladesh ranks among the top five freshwater fish producers in the world. Fish are abundant in the thousands of rivers, ponds, lakes and seasonal floodplains across the country. They are a major source of protein for people living near these waterbodies. In Bangladesh, many households depend on fish farming for their livelihood. By growing fish in homestead ponds, households have a consistent supply of nutritious fish and can sell the surplus for an income. The USAID-funded Cereal Systems Initiative for South Asia in Bangladesh (CSISA-BD) aimed to increase the income of farming households through increased productivity of aquaculture systems. Key activities of the project included developing and disseminating appropriate improved agricultural technology and quality fish seeds to improve livelihoods, food security and nutrition.


This work seeks to develop an MO-CVD system using in situ sensors and automated process control to deposit controlled, reproducible oxide fiber coatings (e.g. LaAl/sub 11/O/sub 18/). A CVD system capable of continuous fiber coating has been assembled which employs liquid precursor delivery for precise precursor stoichiometry control and inert gas seals for near atmospheric operation. In-situ thermocouples and a mass spectrometer are used for process measurements. All of the system parameters are logged by and controllable by computer. A fuzzy logic controller was developed to control the flow rate based on the desired temperature or gas composition. A neural model of the process will be presented which translates the process settings into expected gas compositions.


Chromosomal Instability (CIN) is widely held to be associated with poor prognosis in solid tumours, including breast cancer, that may be related to enhanced clonal evolutionary capacity and the rapid acquisition of multi-drug resistance. Paradoxically, CIN is also associated with tumour suppression in animal models that may result from excessive genomic instability leading to autonomous cell lethality, a phenomenon analogous to "mutational meltdown" in model systems.We addressed whether such a phenomenon could be identified in breast cancer through a meta-analysis of CIN frequency in 1850 breast cancer patients. We assessed the distribution of CIN across breast cancer subtypes and its relationship with clinical outcome and prognosis using a surrogate of CIN, the CIN70 expression signature that correlates robustly with CIN in breast cancers quantified by DNA image cytometry. Increasing degrees of CIN predicted for poor outcome in multivariate analysis of 1850 patients and occurred more frequently in younger patients. Furthermore, CIN was more common in higher risk disease subtypes, including basal-like breast cancer, consistent with this pattern of genomic instability being a major determinant of breast cancer outcome.However, in agreement with previous evidence documenting a role for CIN in mediating cell lethality and tumour suppression in animal models, we demonstrate that a subset of tumours with extremes of CIN, that occur predominantly within the ER negative and HER2 negative subgroup, are associated with unexpected good prognosis in untreated breast cancer patients.We define a threshold of CIN beyond which clinical outcome improves and the relationship between CIN and proliferation is uncoupled. This evidence defines a paradoxical role for CIN in limiting tumour cell viability in vivo and suggests therapeutic strategies to tilt the balance toward CIN-mediated lethality in high-risk breast cancer subtypes in order to improve patient outcome. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3030.


We introduce a novel bandlimited manifold framework and an algorithm to recover freebreathing and ungated cardiac MR images from highly undersampled measurements. The image frames in the free breathing and ungated dataset are assumed to be points on a bandlimited manifold. We introduce a novel kernel low-rank algorithm to estimate the manifold structure (Laplacian) from a navigator-based acquisition scheme. The structure of the manifold is then used to recover the images from highly undersampled measurements. A computationally efficient algorithm, which relies on the bandlimited approximation of the Laplacian matrix, is used to recover the images. The proposed scheme is demonstrated on several patients with different breathing patterns and cardiac rates, without requiring the need for manually tuning the reconstruction parameters in each case. The proposed scheme enabled the recovery of free-breathing and ungated data, providing reconstructions that are qualitatively similar to breath-held scans performed on the same patients. This shows the potential of the technique as a clinical protocol for free-breathing cardiac scans.


[Purpose] This study aimed to investigate the effects of exercise on the autonomic nervous system of breast cancer survivors by measuring heart rate variability during an 8-week circulation exercise program. [Subjects and Methods] This intervention study included 22 volunteer female participants, younger than 65 years, who were selected from patients who had been diagnosed with carcinoma in situ and primary invasive breast cancer, stage I-III, in accordance with the American Joint Committee on Cancer (2009) and had undergone breast surgery. [Results] Despite the statistically significant differences in the low-frequency range (log), the high-frequency range (log), the standard deviation of the N-N interval, and the root mean square of differences values, which are heart rate variability indicators after exercise, between the two groups, no statistically significant difference was found in the low-frequency range/the high-frequency range values between the two groups. [Conclusion] The improvement in heart rate variability during the 8-week circulation exercise program confirms the increase in the activity of the autonomic nervous system of breast cancer patients after surgery.


Context. The red supergiant (RSG) Betelgeuse is an irregular variable star. Convection may play an important role in understanding this variability. Interferometric observations can be interpreted using sophisticated simulations of stellar convection. Aims. We compare the visibility curves and closure phases obtained from our 3D simulation of RSG convection with CO5BOLD to various interferometric observations of Betelgeuse from the optical to the H band to characterize and measure the convection pattern on this star. Methods. We use a 3D radiative-hydrodynamics (RHD) simulation to compute intensity maps in different filters and thus derive interferometric observables using the post-processing radiative transfer code OPTIM3D. The synthetic visibility curves and closure phases are compared to observations. Results. We provide a robust detection of the granulation pattern on the surface of Betelgeuse in both the optical and the H band based on excellent fits to the observed visibility points and closure phases. We determine that the Betelgeuse surface in the H band is covered by small to medium scale (5−15 mas) convection-related surface structures and a large (≈30 mas) convective cell. In this spectral region, H2O molecules are the main absorbers and contribute to both the small structures and the position of the first null of the visibility curve (i.e., the apparent stellar radius).


A 78-year-old female with massive pericardial effusion fulfilled diagnostic criteria for immunoglobulin G4 (IgG4)-related disease. Although her adenosine deaminase (ADA) level in the pericardial effusion was high, all the tests for tuberculosis infection were negative. Immunostaining of the pericardium biopsy specimen revealed remarkably increased IgG4-positive cells. This is the first report describing IgG4-related pericarditis with elevated ADA level. We also demonstrate the elevated interleukin-10 (IL-10) level in pericardial fluid and IL-10-producing T-cells in the pericardium.


An enquiry that would light on the past of sexuality and the ways in which the contemporary is of sexuality is produced through its historical legacies. Sexual topics of any kind are avoided in polite conversation in India, and any talk concerning homosociality (male social gathering) is altogether taboo, especially in Kerala (even kiss of love). Here how Malabar became popular for homosociality expedition and its nature and nurture is tracing out. Sketching the process of transformation from homosociality sub culture to a kind of gay politics in Calicut (Kozhikode) is the focus of the study.


Patterned media storage (PMS) is one of the promising technologies to overcome the limitations of the conventional magnetic recording. For a high areal density PMS, both inter-track interference (ITI) and inter-symbol interference (ISI), and noise severely degrade the bit error rate (BER) performance of the system. In this work, we develop soft feedback equalization (SFE) to mitigate these adverse effects. We evaluate the performance of SFE by using numerical experiments under different amount of 2D-ISI and noise. Simulation results suggest that SFE is a good candidate for ultra-high capacity PMS.


In the present paper, the authors reviews the endocrine and metabolic manifestations in tuberculosis. Disorders as adrenal insufficiency, the syndrome of inappropriate antidiuretic hormone secretion (SIADH), hypercalcemia, endocrine effects of antituberculous drugs, hypopituitarism, tuberculous involvement of the thyroid gland and pancreas and chest radiograph presentation in diabetes mellitus are discussed. In the literature, several reports support the presence of abnormal calcium metabolism in tuberculosis.


The all-plastic double-lumen catheter described in this paper represents a significant improvement over previously reported catheters. It is used routinely for continuous blood withdrawal in two clinical investigation units and one experimental laboratory in Toronto. No experiments have been terminated due to catheter failure or clot formation and no maximum time limit of its use has been established. In clinical use with adult patients (4), the outer cannula has been kept open overnight with a slow saline drip after 18 hours of use. The same cannula has then been reused the next day for another 16 hours with a new adapter precut to size. Its design enzures that: (1) heparin is mixed with the blood at the site of blood sampling. (2) Blood is never brought into contact with glass or metal. (3) The blood channel is a uniform polyethylene tube with no discontinuities and no junctions, except where it is introduced into the peristaltic pump tube. The overall manufacturing process is simple, and percutaneous insertion is straightforward. Through its use, clotting in the blood withdrawal line and thrombus formations in the blood analyzer are no longer problems to limit the use of techniques requiring continuous blood withdrawal.


Using genetically engineered mouse models of cancer, we and others have recently shown that a variety of established tumors require sustained inactivation of the p53 pathway. Reactivation of p53 in established tumors typically results in one of two cell fate decisions: cell cycle arrest or cell death via apoptosis. Since p53 is a transcription factor, one hypothesis that may explain these tumor-specific outcomes is that p53 transcriptionally activates a particular set of genes that is specific to each tumor type, in addition to genes involved in a core p53 pathway. Another possibility is that the level of mitochondrial apoptotic priming in a cell might dictate whether p53 activation promotes cell death or cell cycle arrest. To test this, we derived murine p53-restorable cell lines from three different tumor types: lung adenocarcinoma, sarcoma and lymphoma. Upon restoration of the endogenous Trp53 gene, these cell lines undergo cell cycle arrest (lung and sarcoma) or apoptosis (lymphoma). We hypothesized that this tumor-specific response to p53 restoration could be explained by the level of mitochondrial priming on each specific tumor type, where lymphoma cell lines would be highly primed relative to the lung and sarcoma cell lines. Indeed mitochondrial BH3 profiling demonstrated that lymphoma cell lines were highly primed and this correlated with their apoptotic response to p53 restoration. On the other hand, lung and sarcoma cell lines were poorly primed and this was consistent with their cell cycle arrest phenotype upon p53 restoration. Modulating the expression levels of Bcl2 family members to modulate mitochondrial apoptotic priming was sufficient to change the fate of these cells. Lymphoma cell lines were forced to undergo cell cycle arrest upon p53 restoration by overexpression of the anti-apoptotic Bcl2 family members Bcl-2 or Bcl-XL. In contrast, lung and sarcoma cell lines were forced to undergo cell death upon p53 restoration when priming was increased by overexpression of the pro-apoptotic Bcl2 family members Bim or Bad. When transplanted subcutaneously, sarcoma cell lines expressing Bad were specifically sensitized to undergo cell death upon p53 restoration whereas cell lines expressing empty vector underwent cell cycle arrest. We are currently carrying out in vivo experiments with lymphoma cell lines and lung cell lines, as well as with autochthonous tumor models and human cell lines to further test our main hypothesis. These findings may offer key insights into the potential use of drugs that restore p53 function. Citation Format: Francisco J. Sanchez-Rivera, Jeremy Ryan, Yadira M. Soto-Feliciano, David M. Feldser, Michael T. Hemann, Anthony Letai, Tyler Jacks. The level of mitochondrial apoptotic priming determines cell fate upon p53 restoration. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2961. doi:10.1158/1538-7445.AM2014-2961


Sea Highway is one of the Indonesian government's programs that aimed at reducing price disparities that occur between the West Indonesia (especially Java) and the East Indonesia with the use of sea transport. The government appointed PT Pelayaran Nasional Indonesia (PELNI) to run the Sea Highway program started from November 2015 by providing ships with the scheduled system from the western of Indonesia to the eastern of Indonesia and vice versa. This study was held to analyze the implementation of the PT PELNI's Sea Highway program especially in aspects of routes, frequency, and volume of the transported vessel, which only restricted from Surabaya to Eastern Indonesia's route. The results show that the route and frequency of Sea Highway are running consistently, while the volume is increasing if it's compare with the first time it started. The 3 aspects of Sea Highway (route, frequency, volume) influence each other; therefore it's suggested for government to improve the efficiency of those three aspects so the Sea Highway's purpose in reducing price disparities in Eastern Indonesia can be achieved maximally. Moreover, the research results also show that Sea Highway program never takes the private shipping company's commercial route.


In the multiuser downlink, power allocation for linear precoders that minimize the sum of mean squared errors under a sum power constraint is a non-convex problem. Many existing algorithms solve an equivalent convex problem in the virtual uplink and apply a transformation based on uplink-downlink duality to find a downlink solution. In this letter, we analyze the optimality criteria for the power allocation subproblem in the virtual uplink, and demonstrate that the optimal solution leads to identical power allocations in the downlink and virtual uplink. We thus extend the known duality results and, importantly, simplify the existing algorithms used for iterative transceiver design.


are moved away from their mothers immediately after delivery and brought to the NICU, where their parents can see them only for a few hours and several barriers make the contact with them difficult. In this context, infant massage and gentle touch may represent a support to the mother-child bonding and to the newborn's development Goals. To understand the benefits infant massage and gentle touch bring to both the premature child and the mother; to evaluate the behavioural reactions of prematures to tactile stimulation and the effect of the latter on their body weight. Subjects, materials and methods. Case series. The study was carried out on a group of premature newborns and their mothers, whom were trained to perform infant massage and gentle touch. Mothers were administered a questionnaire investigating mothers' perceived benefits and newborns reactions. Newborns' behaviour was assessed according to the Brazelton neurodevelopmental scale. Results: The main benefits observed by mothers in their children were: better relaxation (90%), recognition of mother through touch (50%). Weight speed was 40% higher than in the period of time preceding mothers' training on infant massage. Also, gradual decrease in distress signs, increase of adaptation to contact and improvement of interaction with mother, were also observed. Mothers reported an increased confidence in giving care to their children (70%), a better knowledg of the latter (50%) and a reduction of psychological distress (40%) Conclusion. This study suggests that gentle touch and infant massage may represent a support to mother-child relationship and to the development of prematures. Teaching parents infant massage and gentle touch techniques could be usefully introduced in premature newborns nursing care plans.


ABSTRACT Urban regions are complicated functional systems that are closely associated with and reshaped by human activities. The propagation of online geographic information-sharing platforms and mobile devices equipped with the Global Positioning System (GPS) greatly proliferates proximate sensing images taken near or on the ground at a close distance to urban targets. Studies leveraging proximate sensing images have demonstrated great potential to address the need for local data in the urban land-use analysis. This paper reviews and summarizes the state-of-the-art methods and publicly available data sets from proximate sensing to support land-use analysis. We identify several research problems in the perspective of examples to support the training of models and means of integrating diverse data sets. Our discussions highlight the challenges, strategies, and opportunities faced by the existing methods using proximate sensing images in urban land-use studies.


Studies focused on large companies in the United Sates, Japan and Britain have documented that there is a strong positive relation between firm size and CEO compensation. They also find the relation between firm performance and CEO compensation is weak. Executive compensation of 104 New Zealand firms are examined over the period of 1998 – 2002, and evidence is obtained consistent with previous studies. Result show that for every percentage increases in the firm's total asset, the cash compensation paid to the average CEO increases by 0.39 percent. This result is very close to the finding of many previous studies that identify a firm-size elasticity between 0.2 to 0.35 for larger U.S., U.K. and Japanese firms. Result also shows that the firm size elasticity of CEO compensation is greater in larger firms.


Most commercially available electrochemical enzyme sensor strips for the measurement of blood glucose use an artificial electron mediator to transfer electrons from the active side of the enzyme to the electrode. One mediator recently gaining attention for commercial sensor strips is hexaammineruthenium(III) chloride. In this study, we investigate and compare the preference of enzyme electrodes with two different FAD-dependent glucose dehydrogenases (FADGDHs) for the mediators hexaammineruthenium(III) chloride, potassium ferricyanide (the most common mediator in commercial sensor strips), and methoxy phenazine methosulfate (mPMS). One FADGDH is a monomeric fungal enzyme, and the other a hetero-trimeric bacterial enzyme. With the latter, which contains a heme-subunit facilitating the electron transfer, similar response currents are obtained with hexaammineruthenium(III), ferricyanide, and mPMS (6.8 µA, 7.5 µA, and 6.4 µA, respectively, for 10 mM glucose). With the fungal FADGDH, similar response currents are obtained with the negatively charged ferricyanide and the uncharged mPMS (5.9 µA and 6.7 µA, respectively, for 10 mM glucose), however, no response current is obtained with hexaammineruthenium(III), which has a strong positive charge. These results show that access of even very small mediators with strong charges to a buried active center can be almost completely blocked by the protein.


Gastric tuberculosis is a rare presentation of tuberculosis infection. Gastric perforation associated with tuberculosis is exceedingly rare with five previously published cases. We present a case of a male patient that developed presumed gastric tuberculosis secondary to pulmonary tuberculosis infection. He subsequently developed gastric perforation and sepsis, for which he was treated both surgically and medically. Despite ongoing antituberculosis treatment, the patient's condition worsened and the patient died secondary to multiorgan failure. This case highlights gastric perforation as a rare but devastating complication of pulmonary tuberculosis.


The objective of this study was to compare focused ultrasound (FUS) neuromodulation-induced motor responses under two physical mechanisms: mechanical and mechanothermal effects. Mice were divided into two groups. One group was subjected to short-duration FUS stimulation (0.3 s) that induced mechanical effects (mechanical group). The other group underwent long-duration FUS stimulation (15 s) that produced not only mechanical but also thermal effects (mechanothermal group). FUS was targeted at the deep cerebellar nucleus in the cerebellum to induce motor responses, which were evaluated by recording the evoked electromyographic (EMG) signals and tail movements. Brain tissue temperature rise associated with the FUS stimulation was quantified by noninvasive magnetic resonance thermometry in vivo. Temperature rise was negligible for the mechanical group (0.2 °C ± 0.1 °C) but did rise within the range of 0.6 °C ± 0.2 °C−3.3 °C ± 0.9 °C for the mechanothermal group. The elongated FUS beam also induced heating in the dorsal brain (below the top skull) and ventral brain (above the bottom skull) along the beam path for the mechanothermal group. Both mechanical and mechanothermal groups achieved successful FUS neuromodulation. EMG response latencies were within the range of 0.03–0.1 s at different intensity levels for the mechanical group. The mechanothermal effect of FUS could induce both short-latency EMG (0.2–1.4 s) and long-latency EMG (8.7–13.0 s) under the same intensity levels as the mechanical group. The different temporal dynamics of evoked EMG suggested that FUS-induced mechanical and mechanothermal effects could evoke different responses in the brain.


Bovine paratuberculosis (PTB), caused by Mycobacterium avium subsp. paratuberculosis (MAP), is a chronic granulomatous enteritis that affects cattle worldwide. According to their severity and extension, PTB-associated histological lesions have been classified into the following groups; focal, multifocal, and diffuse. It is unknown whether these lesions represent sequential stages or divergent outcomes. In the current study, the associations between host genetics and pathology were explored by genotyping 813 Spanish Holstein cows with no visible lesions (N= 373) and with focal (N=371), multifocal (N=33), and diffuse (N=33) lesions in gut tissues and regional lymph nodes. DNA from peripheral blood samples of these animals was genotyped with the Bovine EuroG MD Bead Chip, and the corresponding genotypes were imputed to whole-genome sequencing (WGS) data using the 1,000 Bull genomes reference population. A genome-wide association study (GWAS) was performed using the WGS data and the presence or absence of each type of histological lesion in a case-control approach. No overlap was seen in the SNPs controlling the three PTB-associated lesions. A total of 192 and 92 SNPs defining 13 and 9 distinct quantitative trait loci (QTLs) were highly-associated (P ≤ 5 x 10-7) with the multifocal (heritability= 0.075) and the diffuse (heritability= 0.189) lesions, respectively. Some of the identified QTLs overlapped with QTLs previously associated with PTB, bovine tuberculosis, mastitis, and IgG levels. Pathway analysis with candidate genes overlapping the identified QTLs revealed a significant enrichment of the keratinization pathway and cholesterol metabolism in the animals with multifocal and diffuse lesions, respectively. While keratin variants may predispose cows to the development of multifocal lesions, cholesterol variants associate with the more severe lesions. Taken together, these findings suggest that the variation in MAP-associated pathological outcomes might be genetically determined and indicative of distinct host responses in genetically predisposed individuals.


In the first paper of this series, we proposed a model-independent framework for characterising the architecture of planetary systems at the system level. There are four classes of planetary system architecture: similar, mixed, anti-ordered, and ordered. In this paper, we investigate the formation pathways leading to these four architecture classes. To understand the role of nature versus nurture in sculpting the final (mass) architecture of a system, we apply our architecture framework to synthetic planetary systems -- formed via core-accretion -- using the Bern model. General patterns emerge in the formation pathways of the four architecture classes. Almost all planetary systems emerging from protoplanetary disks whose initial solid mass was less than one Jupiter mass are similar. Systems emerging from heavier disks may become mixed, anti-ordered, or ordered. Increasing dynamical interactions (planet-planet, planet-disk) tends to shift a system's architecture from mixed to anti-ordered to ordered. Our model predicts the existence of a new metallicity-architecture correlation. Similar systems have very high occurrence around low-metallicity stars. The occurrence of the anti-ordered and ordered classes increases with increasing metallicity. The occurrence of mixed architecture first increases and then decreases with increasing metallicity. In our synthetic planetary systems, the role of nature is disentangled from the role of nurture. Nature (or initial conditions) pre-determines whether the architecture of a system becomes similar; otherwise nurture influences whether a system becomes mixed, anti-ordered, or ordered. We propose the `Aryabhata formation scenario' to explain some planetary systems which host only water-rich worlds. We finish this paper with a discussion of future observational and theoretical works that may support or refute the results of this paper.


PurposeThis paper focuses on analysis of the incorporation of a Lesson Study cycle within the university training proposal, as a teaching strategy in initial training in the Infant Education Degree.Design/methodology/approachQualitative research was conducted through a case study methodology.FindingsProposing training strategies based on this methodology encourages both the reconstruction of future teachers' practical knowledge and also adequate professional development from initial training.Research limitations/implicationsThe main constraint in the study was the cost-benefit ratio, since this experience has required significant practical and emotional dedication by the people involved, while the expected results have only been partially evident in the students. This would seem to imply that the strategy requires continuity over time in order for future education professionals to take it fully on board.Practical implicationsMore continuity in such experiences would be required in order to fully analyse their actual value. To this end, the experiences need to be more closely related to the university curriculum, and there must be greater coordination between the subjects in order to ensure a holistic approach to LS.Originality/valueThis article sets out an LS experience as a collaborative action-research strategy that promotes the reconstruction of students' practical knowledge and their professional development in initial training.


Two broadband very low-noise amplifiers operating in the frequency range from 4 to 12 GHz at cryogenic temperature are presented. The amplifier circuits have been developed using a 100 nm gate length InAlAs/InGaAs metamorphic high electron mobility transistor (mHEMT) technology. The three-stage amplifiers are monolithic microwave integrated circuit (MMIC) chips manufactured in coplanar technology. At cryogenic temperature the first MMIC amplifier achieved a linear gain of 22 dB and an average noise temperature of 11.6 K with a power dissipation of 41 mW. The second MMIC amplifier, with external input matching network, exhibited a gain of 26 dB, and an excellent average noise temperature of 8.1 K with a power dissipation of 12 mW. Both LNA units demonstrate broad bandwidth, high gain, low noise temperature, and compact chip size. The results obtained prove that mHEMT technology is suitable for applications in large instantaneous bandwidth cryogenic receivers for radio astronomy applications.


It is well established that fish can learn to associate odours from potential predators with risk and alter their behaviour accordingly. However, newly-hatched individuals have few opportunities for acquired predator recognition and may depend on unlearnt (innate) responses. We therefore considered whether newly hatched Atlantic salmon fry (alevins) exhibit innate predator recognition and whether this recognition could be improved by prior exposure to combined conspecific and predator (pike) odours. Our investigation showed that the response to pike odour was not affected by previous exposure to pike odour and conspecific tissue extract but was consistent with innate recognition of pike as predators. Trials conducted using odour from a non-piscivorous species confirmed that the fish were not simply reacting to a novel stimulus.


Podoconiosis (endemic non-filarial elephantiasis, also known as mossy foot) is a non-communicable disease now found exclusively in the tropics, caused by the conjunction of environmental, genetic, and economic factors. Silicate particles formed by the disintegration of lava in areas of high altitude (over 1,000 m) and seasonal rainfall (over 1,000 mm per annum) penetrate the skin of barefoot subsistence farmers, and in susceptible individuals cause lymphatic blockage and subsequent elephantiasis [1]. Although an estimated one million Ethiopians (of a total population of 77 million) are afflicted with podoconiosis [2], which creates a huge economic burden in endemic areas [3], no national policy has yet been developed to control or prevent the condition, and most affected communities remain unaware of treatment options.


This study aims at exploring the challenges to the implementation of gender mainstreaming in managing Covid-19 crisis in North Sumatra. It focuses on indicators in aspects of access, participation, control over resources and decision making, and the benefits of policies and programs for managing Covid-19 pandemic. This study is based on feminist qualitative research design. Data collection techniques included in-depth interviews, case studies, focused group discussions (FGD) and observation. Research informants consists of the local government and the Covid-19 Task Force, the Women and Children Empowerment Agency, Social Service, NGOs and women working in Medan and Siantar city. The findings reveal the handling of Covid-19 in North Sumatra ignores gender issues as evident by the absence of gender-based data in various Covid-19 handling programs, and the limited participation of women in crisis management related institutions. This study suggests the urgency of enhancing local government awareness, capacity and commitment in integrating gender in managing crisis as the key to the success of effective and equitable disaster management.


Polyamines are essential for maintaining normal intestinal epithelial integrity, an effect that relies, at least in part, on their ability to keep low levels of nucleophosmin (NPM) and p53 mRNAs. The RNA-binding protein HuR associates with the p53 mRNA, as reported previously, and with the NPM mRNA, computationally predicted to be a target of HuR. Here, we show that HuR binds the NPM and p53 3′-untranslated regions and stabilizes these mRNAs in polyamine-depleted intestinal epithelial cells. Depletion of cellular polyamines by inhibiting ornithine decarboxylase with α-difluoromethylornithine dramatically enhanced the cytoplasmic abundance of HuR, whereas ectopic ornithine decarboxylase overexpression decreased cytoplasmic HuR; neither intervention changed whole-cell HuR levels. HuR was found to specifically bind the 3′-untranslated regions of NPN and p53 mRNAs. HuR silencing rendered the NPM and p53 mRNAs unstable and prevented increases in NPM and p53 mRNA and protein in polyamine-deficient cells. These results indicate that polyamines modulate cytoplasmic HuR levels in intestinal epithelial cells, in turn controlling the stability of the NPM and p53 mRNAs and influencing NPM and p53 protein levels.


The legal environment within which community-based fisheries management (CBFM) will function should be examined to determine whether it supports or will need necessary enhancement to support the implementation of CBFM. The question as to whether CBFM is legally sustainable must be asked with regard to the whole legal framework of the State – from fundamental laws, such as the constitution, to subsidiary legislation. Amendments to existing legislation or new legislation may be necessary to implement CBFM. There is no blueprint for a CBFM legal framework what number of rights with respect to fish resources should be accorded and what should be the level of participation by the local community. It is important, however, to ensure that the constitutionality of all these aspects is ascertained, and to ensure that enabling legislation for CBFM consider the following issues: security, exclusivity and permanence of rights vested; flexibility of its provisions so as to allow states to exercise choices that reflect their unique needs, conditions and aspirations for CBFM; and the way CBFM harmonizes with the overall fisheries management legal framework. Attaining the right balance in the CBFM legal framework, however, is difficult and depends largely on local circumstances. There is much interest in using customary marine tenure (CMT) as a basis for CBFM in the Pacific Island Countries (PICs). The laws of PICs lend general support to the use of CMT or tradition in fisheries management. Stil l, only modest efforts in the use of CMT-based community fisheries management in the PICs are observed. Further legislative action can enhance CMT use in community fisheries management. Broad lessons can be drawn from the experiences of some PICs in legislating on CMT or certain of its aspects to enhance CMT use. Government commitment to CBFM generally, and for the role of CMT in the CBFM context with support from interested entities and stakeholders including communities, will complement efforts for promoting sustainable utilization of fisheries resources and improved livelihoods in the PICs.


A convenient method for the synthesis of mono- and polycyclic azacrown macrocycles containing aromatic fragments using the Mannich condensation of phenols and secondary diamines has been studied. This new approach allowed the synthesis of bisphenols connected by oligoazaoxaalkane units in good yields without the need to protect the phenolic OH groups. These bisphenols (13-16) were alkylated with ditosylates of polyethylene glycols to give benzoazacrown ethers 25-30. Intermediate bisphenols 13-15 were also treated with three bis(methoxymethyl)-substituted diamines to form benzoazacrowns 10-12 containing internal phenolic functions. Phenol-containing mono- (11) and bicyclic (3, n = 1) compounds, which were synthesized via the Mannich aminomethylation process, were used as building blocks for construction of bi- (32) and tricyclic (33) ligands.


Abstract We developed the Scaffolding English E-assessment Learning (SEEL), where instant feedback and scaffolding hints were provided, to facilitate students to acquire the knowledge of English grammar. On the other hand, an empirical study was conducted to investigate how cognitive styles (i.e. Holists vs. Serialists) affected learners' reactions to the SEEL, including learning performance, learning perception and learning behavior. The results indicated that Holists and Serialists demonstrated similar learning perception. Nevertheless, they showed different learning behavior, which corresponded to the characteristics of their cognitive styles. Additionally, Holists obtained better post-test scores and gain scores than Serialists. This might be because Holists could make the best use of various hints and benefit from feedback provided by the SEEL while Serialists needed additional support. The findings could provide guidance for incorporating personalization into the SEEL so that the needs and preferences of Holists and Serialists could be accommodated. Nevertheless, such findings are correlational in nature and, we, thus, leave open questions concerning causality. Implications for instructional design are also discussed in this study.


What is so interesting about the rule of law is that although the concept is 'elusive', people from around the world all think they know what it means. People from all corners of the globe use the phrase without feeling the need to add any explanation. For example, the rule of law is enshrined in the preamble of the European Convention on Human Rights and in Article 5 of the Constitution of the People's Republic of China. It was stressed by many a statesman during the debates at the United Nations General Assembly in September 2003. Yet, the literature shows that at least among the scholars and thinkers there are significant differences of opinion on what the rule of law is. I will begin my inquiry by describing and critiquing three commonly-found, but incomplete (in my view) formulations of the idea of the rule of law: the rule of law as a shield against governmental authority (the Dicey view); the rule of law as the rule of higher and just law; and the rule of law as the rule of rules or the law of rules. I will then make my own attempts (more or less my own, but based on the raw materials of others) at giving more 'complete' accounts of the concept by presenting: two formulations of the imperfect rule of law - the coercive rule of law and the extra-legal rule of law - and what I consider to be the perfect rule of law - the rule of law as law serving as the ultimate reason for voluntary action. The central tenets of each view are presented, critiqued (to some extent anyway), and then applied to the international circumstances. The 'perfect rule of law' formulation states that law is complied with simply because it is law, serving as the ultimate reason for voluntary action. The perfect rule of law requires that the existence of law or the concept of law coincides with the law as the ultimate reason for action and with the state of affairs called the rule of law. This coincidence of various factors centers on law serving as the ultimate reason for voluntary action. This formulation takes better account of the need to give meaning to both the word 'rule' and the word 'law' in the phrase 'the rule of law'. Admittedly such a formulation at present only describes an ideal state of affairs that we can only strive for, both in a national society and in international society.


Motivated by the needs of Cornell High Energy Synchrotron Source (CHESS), we developed and are now constructing a novel type of planar undulator magnet called CHESS Compact Undulator. The device consists of two pure permanent magnet (PPM) arrays mounted inside of a rectangular box-like frame on linear bearings providing magnet array motion along the beam axis. The outside frame dimensions are 156 mm 148 mm. Undulator is 1 meter long. It has 5 mm constant gap. The magnetic field strength is controlled by the array longitudinal motion (adjustable phase scheme). Magnetic structure has 24.4 mm period and maximum peak field 1.1 Tesla. The PM material is Nd-Fe-B of 40UH grade. The undulator magnet will be enclosed in a 273 (10.75") mm diameter cylindrical vacuum vessel while the driver mechanism responsible for moving the magnet array will be placed outside. The following sections describe mechanical and magnetic design of undulator and present results of the magnetic field measurement and evaluation of vacuum properties.


Educators' perceptions of community resilience have generally remained absent in scholarship on the nexus between community development, natural disasters, and resilience. Thus, building on extant research and drawing on resilience theory, the purpose of this qualitative study is to understand perceptions related to community resilience held by resident educators, located in the US Virgin Islands. In-depth interviews were conducted with educators (elementary and secondary schools) and the findings indicate that participants' role in coping and recovery entailed the following themes: Community Alliances for Social Recovery and Learning for Social Recovery. The former speaks to the educators' (in) direct provision of basic resources (e.g. teachers' union offering materials), in the aftermath of the disaster. The latter deals with teachers' provision of assistance to students experiencing psychological distress induced by the disaster as well as their work in teaching about and/or seeking educational materials related to natural disasters. In the aftermath of a hazard, access to formal counselling services is likely constrained accordingly; informal counselling services rendered by various members of the community are the most effective approach to obtain help with disaster-induced psychological distress. A key contribution of this study is that educators took on important informal counselling-like roles, in addition to their formal didactic duties, so as to better help youth with coping and recovery. Recovery requires many actors, but this study highlights educators' integral role in effective disaster mitigation through the formal and informal roles they enact, particularly as relates to youth.


OBJECTIVES--To compare the sex ratios of births and mortality in 12 Scottish localities with residential exposure to pollution from a variety of industrial sources with those in 12 nearby and comparable localities without such exposure. METHODS--24 localities were defined by postcode sectors. SMRs for lung cancer and for all causes of death and sex ratios of births were calculated for each locality for the years 1979-83. Log linear regression was used to assess the relation between exposure, sex ratios, and mortality. RESULTS--Mortalities from all causes were consistently and significantly higher in the residential areas exposed to air pollution than in the non-exposed areas. A similar, but less consistently significant, excess of mortality from lung cancer in the exposed areas was also found. The associations between exposure to the general air pollution and abnormal sex ratios, and between abnormal sex ratios and mortality, were negligible. CONCLUSIONS--Sex ratios were not consistently affected when the concentrations or components of the air pollution were insufficiently toxic to cause substantially increased death rates. Monitoring of the sex ratio does not provide a reliable screening measure for detecting cryptic health hazards from industrial air pollution in the general residential environment.


We merge QCEW and JOLTS microdata to study the recruiting intensity of firms in the cross-section and over time. We show that vast establishment-level heterogeneity in vacancy filling rates is entirely explained by differences in gross hiring rates. We provide theory that supports these empirical facts and, through the lens of this theory, aggregate firm-level decisions and data into an empirical measure of aggregate recruiting intensity (ARI).We find that procyclicality of ARI is primarily due to cutting recruiting effort in slack labor markets. This leads us to formulate an ARI index easily computable from publicly available macroeconomic time series. Declining ARI in the Great Recession accounted for much of the increase in unemployment, but little of its persistence.


Horwitz and Young (1991) define anxiety as a combination of feelings including tension, fear, anxiouness and apprehension that trigger the nervous system. They believe that anxiety would make it difficult for certain people to achieve success especially in the learning of a foreign language. They categorized it as specific anxiety reaction when the anxiety is restricted to the learning of a language. Psychologist used the term specific anxiety reaction to differrentiate those who are suffering from anxiety in different situation compared to those who are suffering from anxiety in a specific situation. Researchers like Tobias (1978) and Mallow (1901) found that specific anxiety is related to anxiety situation, for example, when talking an examination in academic subjects such as Mathematics and Science.


In this paper, we focus on the design, modeling and implementation of a MPPT controller based maximum power tracking of photovoltaic system. The electrical characteristic of The PV system is non-linear and changes with the solar irradiation and the ambient temperature. Therefore, the incremental conductance (IC) method control is known for its stability and robustness, and is used to extract the maximum energy from the PV source using a boost converter topology. It provides a strong basis for the improvement and optimization of control parameters of a photovoltaic system. Implementing MPPT algorithm usually need the use of a lot of sensors if accuracy of the system has to be increased. However, IC method with an extended Kalman filter (EKF) can be utilized in order to estimate some parameters to reduce the number of Sensors. The EKF is deployed in the optimal position to estimate both current and the capacitor voltage, thus allowing to eliminate two sensors devise from the entire PV system, which increases the system efficiency and reliability, simplifies the control method and decreases the system cost. The performance of the proposed technique is validated by experimental and simulation results under different operating conditions and load changes.


In this article, I present a theory of fiduciary relationships that seeks to address both the justification and the content of fiduciary duties. It will also address the question of remedies, which sheds important and neglected light on the question why this part of the law has the shape that it does. All three aspects — the reasons we impose these duties, what these duties require, and the remedies associated with them — are linked to one another in a conceptual unity that reveals the interlocking aspects of private law's concern with relationships in which one person is empowered to exercise decision-making authority on behalf of another.


In this paper a sensor fusion scheme, called triangulation-based fusion (TBF) of sonar data, is presented. This algorithm delivers stable natural point landmarks, which appear in practically all indoor environments, i.e., vertical edges like door posts, table legs, and so forth. The landmark precision is in most cases within centimeters. The TBF algorithm is implemented as a voting scheme, which groups sonar measurements that are likely to have hit the same object in the environment. The algorithm has low complexity and is sufficiently fast for most mobile robot applications. As a case study, we apply the TBF algorithm to robot pose tracking. The pose tracker is implemented as a classic extended Kalman filter, which use odometry readings for the prediction step and TBF data for measurement updates. The TBF data is matched to pre-recorded reference maps of landmarks in order to measure the robot pose. In corridors, complementary TBF data measurements from the walls are used to improve the orientation and position estimate. Experiments demonstrate that the pose tracker is robust enough for handling kilometer distances in a large scale indoor environment containing a sufficiently dense landmark set.


: As many as 76 children of the first year of life suffering from salmonellosis were examined for the clinical manifestations of the disease and for the immune status. The data were obtained, pointing to the development of secondary immuno- and granulocytopathies influencing the course the disease takes.


Although research has identified factors that support and hinder proactive bystander behaviors among adolescents, less is known about the more specific bystander responses viewed by youth as feasible, or whether these responses are likely to be ultimately helpful in the context of bullying and teen dating violence (TDV). Goals of this exploratory study were to describe specific bystander behaviors that adolescents perceive as possible for addressing bullying and TDV among peers, to assess the potential impact of these behaviors, and to examine similarities and differences in bystander behaviors across these forms of aggression. In focus groups with 113 14- to 18-year-old youth, participants identified more possible responses to bullying than to TDV, and more options for supporting victims of aggression than for interrupting perpetrators. Although many bystander responses identified by youth are promising for lessening the impact of bullying and TDV, some, such as "advising" victims of TDV and physically confronting perpetrators are likely not safe or helpful and may cause more harm than good. Findings point to the importance of better understanding how youth perceive their options as bystanders, and providing coaching to respond to peer aggression in specific ways that maximize their own and others' safety and well-being.


The protection of universal principles varies across jurisdictions: the prominence of free speech in the United States is undisputed. My argument is that the First Amendment took off only during the New Deal and later, the Civil Rights revolution as an identity‐formation and unifying tool in a deeply divided society. The symbolic significance of free speech in the US remains central to this day. In the midst of its identity crisis with looming Brexit, Europe is now experimenting with privacy‐as‐constitutional identity in a similar way. This article seeks to unpack the values encompassed in privacy and freedom of speech, looking into the different functional responses that two different democratic societies place their bets on. As data protection and privacy come to a clash with important trade and security interests in an evermore‐globalized world, the power of the outward‐oriented European privacy discourse is likely to remain above all rhetorical


This study was conducted to investigate the antioxidative activity and cytotoxicity of fermented Allium victorialis extract. The results were as follows; The total polyphenol content of A. victorialis extract was 2.63 mg/g, and that of fermented A. victorialis extract was 1.65 mg/g which decreased a little by fermentation. The total flavonoid content of A. victorialis extract was 57.77 mg/g, and that of fermented A. victorialis extract was 62.27 mg/g, and this could increase a little from fermentation. Electron donating ability of A. victorialis extract was lower than vitamin C(97.71%), but before fermentation it was 82.29% and after fermentation it became 82.40%. Nitrite scavenging ability of A. victorialis extract before and after fermentation showed lower numerical value than that of butylated hydroxytoluene(BHT) at pH 2.5 but that of A. victorialis extract expressed higher than that of BHT. Superoxide dismutase-like activity showed relatively low level, 15%. Nitrite production increased by A. victorialis extract but was inhibited after fermentation. Methyl diamphetamine (MDA) content was inhibited with increased concentration of A. victorialis extract compared with treatment but there was not any difference before and after fermentation. Therefore, production of lipid peroxide(LPO) was inhibited by A. victorialis extract. Cell viability of fibroblast cell was tend to slightly decrease with increased concentration of A. victorialis extract, but not different with control.


ABSTRACT The temporal community dynamics and persistence of different viral types in the marine environment are still mostly obscure. Polymorphism of the major capsid protein gene, g23, was used to investigate the community composition dynamics of T4-like myoviruses in a North Atlantic fjord for a period of 2 years. A total of 160 unique operational taxonomic units (OTUs) were identified by terminal restriction fragment length polymorphism (TRFLP) of the gene g23. Three major community profiles were identified (winter-spring, summer, and autumn), which resulted in a clear seasonal succession pattern. These seasonal transitions were recurrent over the 2 years and significantly correlated with progression of seawater temperature, Synechococcus abundance, and turbidity. The appearance of the autumn viral communities was concomitant with the occurrence of prominent Synechococcus blooms. As a whole, we found a highly dynamic T4-like viral community with strong seasonality and recurrence patterns. These communities were unexpectedly dominated by a group of persistently abundant viruses.


Multidrug resistance is a serious obstacle to the successful chemotherapeutic treatment of many human cancers. A major cause of multidrug resistance is the overexpression of a 170-kDa plasma membrane protein, known as P-glycoprotein, which appears to function as an ATP-driven efflux pump with a very broad specificity for hydrophobic drugs, peptides, and natural products. P-Glycoprotein is a member of the ABC superfamily and is proposed to consist of two homologous halves, each comprising six membrane-spanning segments and a cytosolic nucleotide binding domain. In recent years, P-glycoprotein has been purified and functionally reconstituted into lipid bilayers, where it retains both ATPase and drug transport activity. The availability of purified active protein has led to substantial advances in our understanding of the molecular structure and mechanism of action of this unique transporter. This review will focus on the recent application of fluorescence spectroscopy, infra-red spectroscopy, circular dichroism spectroscopy, electron microscopy, and other biophysical techniques to the study of P-glycoprotein structure and function.


Objective: To investigate the efficacy of the special extract ERr 731 from the roots of Rheum rhaponticum compared with placebo on anxiety, health state, and general well-being in perimenopausal women. Design: This study is a multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial, in which 109 perimenopausal women with climacteric complaints and anxiety received either 1 enteric coated tablet of ERr 731 (n = 54) or placebo (n = 55) daily for 12 weeks. The Hamilton Anxiety Scale, the Menopause Rating Scale II, the Women's Health Questionnaire, and the Psychological General Well-Being Index were used to measure anxiety, health state, and subjective psychological well-being. Results: The results demonstrate that ERr 731 is highly effective in reducing anxiety in perimenopausal women compared with placebo. After 12 weeks, the Hamilton Anxiety Scale total score decreased significantly with ERr 731 (from 27.5 ± 6.8 to 9.4 ± 4.2 points) compared with placebo (from 25.1 ± 6.0 to 21.6 ± 8.6 points). ERr 731 also reduced the Hamilton Anxiety Scale factor scores for somatic and psychic anxiety. After 12 weeks, a reduction in the severity of anxiety from "moderate" or "severe" to "slight" was observed in 33 of 39 ERr 731 women completing the double-blind phase, which correlated well with the reduction in number and severity of hot flushes. This was reflected by a high rate of ERr 731 women reporting a marked improvement in health state and general well-being. Conclusions: ERr 731 is an effective medication for women with menopause-related anxiety and improves their health state and general well-being.


Graphene is a single layer of graphite sheet; one atom thick sp2-bonded carbon atoms organized on a plane. It has extremely interesting electrical properties, which offers various applications in a number of nanometer scale devices, potentially operating at high frequency ranges. Mechanically exfoliated single and multilayer graphene sheets are prepared on (100) oriented silicon wafers with 300 nm thermal oxide. These graphene layers are characterized by optical microscopy, Atomic Force Microscopy (AFM) and Raman Spectroscopy. A graphene feld effect transistor is fabricated on a 35x9 micron graphene sheet by manually applying the drain and source contacts using silver paint and using the silicon substrate as backgate. In this thesis, the production methods, characterization methods and electrical properties of graphene are investigated.


To alleviate the growing concern of energy waste in networked devices, we propose an energy saving strategy in the "server-centric" data center network. Focusing on servers, we introduce a basic scheme based on the transition of automata. By changing efficiently from sleeping state to active state in different network traffic, servers save the energy. This scheme is self-adaptive and simple. Based on this prime scheme, we enhance the strategy by further taking advantage of the unique topology of BCube. We present a structure algorithm relying on the active substructure in BCube. Combining with the basic scheme and structure algorithm, our energy saving strategy can achieve a high proportion of energy saving without sacrificing service quality like packet delay in the simulation with real traffic trace.


Summary Although ionizing radiation can apparently induce neoplasms of virtually all types, the relation between tumor incidence and dose varies, depending on the type of neoplasm, constitution of the host, conditions of irradiation, and other variables. Owing to statistical limitations, however, the existing data fail to provide an unambiguous picture of the dose-response relation for any form of cancer. More adequate data are, therefore, needed not only for estimating the hazards to be expected from small doses of radiation but for analyzing the mechanism of carcinogenesis.


A more fundamentally oriented study was carried out on steel 100Cr6/sapphire pairs with polished or microtextured functional surfaces of the steel sliding unidirectionally under oil lubrication up to a velocity of 0.30 m/s against the polished ceramic. Crossed microchannels with variations of area fraction, width and depth of the channels were used as texture pattern with respect to applications in wet-running friction systems. The aim was to achieve a deeper knowledge of the correlation between texture or experimental parameters and oil film or friction behaviour. This is needed to design an optimised microtexture on a functional surface for a special application. A theoretical model was developed that describes the effect of texturing using microchannels on oil film thickness and friction coefficient in relation to a polished surface without a texture.


Although curcumin has preventive actions in animal models of colon cancer, whether the mechanism of action is through anti‐proliferation in normal environment is not clearly understood. Here, we studied the effects of chemopreventive doses of curcumin on the proliferation rate of colon epithelial cells (CEC), using a recently developed stable isotope – mass spectrometric method for measuring DNA synthesis rate. Adult male F344 rats were given diets containing 0, 2 and 4% curcumin for 5 weeks. 4% 2H2O was given in drinking water to label DNA, after a priming bolus, for 4 days prior to sacrifice. The isotopic enrichment of the deoxyribose moiety of deoxyadenosine from DNA was measured by gas chromatography – mass spectrometry. Cell cycle analysis was performed after propidium iodide staining of CECs. Curcumin administration did not reduce but instead resulted in dose‐dependent increases in CEC proliferation rate (p < 0.05) for 2% and 4% curcumin vs 0%). The length of the colon crypts and the fraction of cells in S‐phase were also increased in the 2% and 4% curcumin groups (p < 0.05). Thus, pharmacological doses of curcumin increase CEC proliferation rate and pool size in normal rats. Reduction of CEC proliferation therefore cannot explain the proposed chemopreventive actions of curcumin in colon cancer. Copyright © 2007 John Wiley & Sons, Ltd.


We studied the effects of thickness and heat treatments on giant magnetoimpedance (GMI) of cobalt-coated silver wires from 1 kHz to 100 MHz, under axial static magnetic field of 2 kOe. Cobalt, of thickness ranging from 1 to 25 /spl mu/m, was electro-deposited on 47.7-/spl mu/m-diameter silver wires. The frequency dependence of GMI varied with cobalt thickness with a maximum of 176% in 10-/spl mu/m-thick cobalt at the characteristic frequency 2 MHz. The characteristic frequency decreased with increasing thickness of cobalt layer but it was rather insensitive to dc Joule heating and conventional furnace annealing. However, both heat treatments led to magnetic hardening and decrease in GMI ratio. Joule heating also induced anisotropy in wire structures normally dominated by axial anisotropy.


The present study is about the evaluation of antibacterial and antifungal activities of crude extracts of leaves of Acalypha indica L. using different solvents like petroleum ether, chloroform, ethyl acetate, acetone and methanol. The effect of different extracts were tested on Gram positive bacteria like Staphylococcus aureus, Streptococcus pyogenes and Gram negative bacteria like Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, Shigella flexneri and Proteus mirabilis and on the fungal species Candida albicans, Candida tropicalis and Aspergillus flavus by in vitro disc diffusion method.


Background: Human immunodeficiency virus–infected (HIV+) individuals are disproportionately at risk for human papillomavirus (HPV)-associated cancers, but the magnitude of risk estimates varies widely. We conducted a retrospective study using a large U.S.-based cohort to describe the relationship between HIV infection and incident cervical, oropharyngeal, and anal cancers. Methods: Using 2001–2012 U.S. Medicaid data from 14 states, we matched one HIV+ to three HIV-uninfected (HIV−) enrollees on sex, race, state, age, and year, and followed persons for up to 10 years. We developed Cox proportional hazards models comparing HIV+ to HIV− for time to cancer diagnosis adjusted for demographic and comorbidity attributes. Results: Our cohorts included 443,592 women for the cervical cancer analysis, and 907,348 and 906,616 persons for the oropharyngeal and anal cancer analyses. The cervical cancer cohort had a mean age of 39 years and was 55% Black. The oropharyngeal and anal cancer cohorts were 50% male, had a mean age of 41 years, and were 51% Black. We estimated the following HRs: cervical cancer, 3.27 [95% confidence interval (CI), 2.82–3.80]; oropharyngeal cancer, 1.90 (95% CI, 1.62–2.23; both sexes), 1.69 (95% CI, 1.39–2.04; males), and 2.55 (95% CI, 1.86–3.50; females); and anal cancer, 18.42 (95% CI, 14.65–23.16; both sexes), 20.73 (95% CI, 15.60–27.56; males), and 12.88 (95% CI, 8.69–19.07; females). Conclusions: HIV+ persons were at an elevated risk for HPV-associated cancers, especially anal cancer. Impact: Medicaid claims data corroborate previous estimates based on registries and clinical cohorts.


INTRODUCTION:
 Blinatumomab is a bispecific CD19 directed CD3 T cell engager indicated for the treatment of adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission (CR) with minimal residual disease (MRD) greater than or equal to 0.1%.
 In BLAST (NCT01207388), an open-label, multicenter, single-arm, phase 2 study of blinatumomab in patients with MRD positive B-precursor ALL in hematological CR, blinatumomab resulted in complete MRD response in cycle 1 in 78% of patients. Overall survival (OS) was significantly better in those with MRD vs those without MRD. The objective of this study is to evaluate the cost-effectiveness of blinatumomab vs. standard of care (SOC) therapy in patients with Ph- B-cell precursor ALL in first hematological CR with MRD based on the BLAST study from a US healthcare payer perspective.
 METHODS:
 A partitioned survival model was used to estimate the incremental cost-effectiveness ratio (ICER) of blinatumomab vs. SOC maintenance. A 50-year lifetime horizon and US payer perspective were employed. Costs and outcomes were discounted at 3% annually. Probabilities of complete MRD response, relapse-free survival (RFS), OS, numbers of cycles of blinatumomab and SOC, and transplant rates were estimated from BLAST and a historical cohort comparator study using propensity score analyses. RFS and OS were based on parametric survival distributions fit to individual patient failure-time data. Utility values were based from a generalized linear model/generalized estimating equation (GLM/GEE) model fitted to EQ-5D data collected in BLAST applying US tariffs. Inpatient and outpatient healthcare use by MRD status was from an observational study which evaluated treatment patterns and healthcare resource utilization in adult B-cell precursor ALL in first hematological CR with and without MRD. Deterministic and probabilistic sensitivity analyses were conducted to assess the effects of changes in model assumptions and uncertainty around key parameters.
 RESULTS:
 The unrestricted Gompertz distribution for RFS and lognormal mixture cure model distribution for OS were selected. In the base case, blinatumomab was projected to yield 3.52 additional life years and 2.93 additional quality-adjusted life years (QALYs) compared with SOC. Blinatumomab is associated with higher drug and administration costs and transplant costs, which were partially offset by lower post-relapse costs. The ICER for blinatumomab vs. SOC maintenance therapy was estimated to be $81,807/QALY gained (table). The main cost drivers were the drug acquisition costs and the additional hematopoietic stem cell transplant costs with blinatumomab. Cost-effectiveness was mostly sensitive to the uncertainty around the cure fraction (proportion of patients whose survival pattern is similar to the general cancer-free population) and transplant rates. Assumptions that most affected cost-effectiveness were the duration of benefit of blinatumomab and the long-term mortality estimation. The cost-effectiveness remained below the willingness-to-pay threshold value of $150,000/QALY gained in all scenarios tested. In the probabilistic sensitivity analyses, the estimated probability that blinatumomab is cost-effective was 87% at a willingness-to-pay threshold of $150,000/QALY.
 CONCLUSIONS:
 Blinatumomab is a cost effective treatment option vs. SOC for adults with Ph - B-precursor ALL in first hematological CR with MRD from the US healthcare perspective with an ICER well below the threshold of $150,000 per QALY gained. The value of blinatumomab is derived from its high complete MRD response rate, prolonged RFS, and OS.

 Delea: Seattle Genetics: Research Funding; Takeda: Research Funding; Sanofi: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Policy Analysis Inc.: Employment. Despiegel:Amgen, Inc.: Employment, Equity Ownership. Boyko:Amgen: Research Funding. Amdahl:Amgen: Research Funding. Cong:Amgen, Inc.: Employment, Equity Ownership.