Background Retinoic acid (RA) and fibroblast growth factor 4 (FGF4) signaling control endoderm patterning and pancreas induction/expansion. Based on these findings, RA and FGFs, excluding FGF4, have frequently been used in differentiation protocols to direct differentiation of hESCs into endodermal and pancreatic cell types. In vivo, these signaling pathways act in a temporal and concentration-dependent manner. However, in vitro, the underlying basis for the time of addition of growth and differentiation factors (GDFs), including RA and FGFs, as well as the concentration is lacking. Thus, in order to develop robust and reliable differentiation protocols of ESCs into mature pancreatic cell types, including insulin-producing β cells, it will be important to mechanistically understand each specification step. This includes differentiation of mesendoderm/definitive endoderm into foregut endoderm- the origin of pancreatic endoderm. Methodology/Principal Findings Here, we provide data on the individual and combinatorial role of RA and FGF4 in directing differentiation of ActivinA (AA)-induced hESCs into PDX1-expressing cells. FGF4's ability to affect endoderm patterning and specification in vitro has so far not been tested. By testing out the optimal concentration and timing of addition of FGF4 and RA, we present a robust differentiation protocol that on average generates 32% PDX1+ cells. Furthermore, we show that RA is required for converting AA-induced hESCs into PDX1+ cells, and that part of the underlying mechanism involves FGF receptor signaling. Finally, further characterization of the PDX1+ cells suggests that they represent foregut endoderm not yet committed to pancreatic, posterior stomach, or duodenal endoderm. Conclusion/Significance In conclusion, we show that RA and FGF4 jointly direct differentiation of PDX1+ foregut endoderm in a robust and efficient manner. RA signaling mediated by the early induction of RARβ through AA/Wnt3a is required for PDX1 expression. Part of RA's activity is mediated by FGF signaling.


This paper describes the development of a distributed knowledge-based system. A software system, namely Distributed Algorithmic and Rule-based Blackboard System (DARBS), was developed from its predecessor ARBS, which lacked the distributed computing feature. ARBS has been used in solving a number of engineering problems [1-3]. DARBS now utilises client/server technology. It consists of a centralised database server, called the "Blackboard" and a number of Knowledge Source Clients (experts). It distributes the workload to a number of clients which are rule-based or other AI systems with specific knowledge in various areas. DARBS is being applied to automatic interpretation of non-destructive evaluation (NDE) data and control of plasma deposition processes.


: Accumulating evidences have indicated that BIM expression largely decides the development of lung cancer and outcome of EGFR-mutant lung cancers after TKI treatments. BIM polymorphism is a 2,903-bp deletion in the second exon. To clarify the relationship between this BIM polymorphism and clinical outcomes of lung cancers, we conducted this meta-analysis and observed the survival and responses to TKIs. Sixteen cohort studies, covering 4393 WT and 916 BIM deletion patients were included. Overall, BIM deletion polymorphism was associated with significantly shorter progression-free survival (PFS) and slightly shorter overall survival (OS), compared to the WT group. Moreover, patients with BIM deletion polymorphism showed significantly inferior response to EGFR TKIs. In conclusion, our analysis confirmed that lung cancer patients harboring the BIM deletion have inferior survival and TKI responses. Examination of the novel biomarker BIM deletion in lung cancer patients, especially for the EGFR mutant cohort, could provide some prognostic utility.


Marine structures are designed with a requirement to have reasonably long and safe operational life with a risk of catastrophic failures reduced to the minimum. Still, in a constant wish for reduced weight structures that can withstand increased loads, failures occur due to one or several following causes: excessive force and/or tempera-ture induced elastic deformation, yielding, fatigue, corrosion, creep, etc. Therefore, it is important to identify threats affecting the integrity of marine structures. In order to understand the causes of failures, structure's load response, failure process, pos- sible consequences and methods to cope with and prevent failures, probably the most suitable way would be reviewing case studies of common failures. Roughly, marine structural failures can be divided into structural failures of ships, propulsion system failures, offshore structural failure, and marine equipment failures. This book chapter will provide an overview of such failures taking into account failure mechanisms, tools used for failure analysis and critical review of possible improvements in failure analysis techniques.


Since the original description and definition of the 'antiphospholipid syndrome' (APS)' a number of distinct clinical manifestations related to it have been reported. Most of these may be ascribed to the hypercoagulable state, of which antiphospholipid antibodies seem either to be 'markers' or intimately connected in some way with the highly complex coagulation mechanisms resulting in thrombotic occlusions. Here, we bring these 'expanded' clinical manifestations together and examine specifically those situations which may now also be included under the broad umbrella of the APS. Although less common than deep vein thrombosis, recurrent fetal loss, or stroke (the well recognised manifestations of the APS), these additional manifestations may occur not only in association with a defined systemic lupus erythematosus (SLE) or 'lupus-like' disease but also in the 'primary' APS. We may further subdivide patients with these lesser known associations into (a) those in whom coagulopathy and thrombosis have been adequately demonstrated as the underlying mechanisms (table 1); and (b) those in whom the association remains unproved or indefinite because no radiological or histopathological evidence of vascular occlusions is available (table 2).


: OBJECTIVE: To describe the results of the use of alpha-2a-interferon in the treatment of inoperable childhood lymphangiomas refractory to other therapeutic management. METHOD: We reviewed the literature about pathogenic events and the treatments available for lymphangiomas. Based on that, we used alpha-2a-interferon at a dose of 3 million units/m(2)/day administered subcutaneously to patients with inoperable disease and no response to other treatments. We conducted periodic clinical and laboratory control to evaluate the response and the adverse reactions to alpha-2a-interferon administration. RESULTS: We observed that the 6 patients with inoperable lymphangiomas who used alpha-2a-interferon had a satisfactory clinical response associated with minimum adverse reactions. Of these patients, 5 had partial regression of their lesions, and 1 remained stable. CONCLUSION: Alpha-2a-interferon may be one more available treatment for inoperable childhood lymphangiomas.


The anti-swing problem of the bridge cranes is discussed, and the anti-swing and position control strategy based on BVP arithmetic is presented. The anti-swing and position control programming of bridge cranes can be transformed into the two-point boundary value problem (BVP) of nonlinear systems. According to the boundary conditions of the anti-swing and position process, the tractive force function of Fouries series form with free parameters is constructed. The BVP is solved with the bvp4c function in Matlab toolbox, and the tractive force sequence is obtained. The anti-swing and position control process of bridge cranes belongs to open-loop feedforward control essentially. The simulation of anti-swing and position control process illustrates the effectivity of the control strategy.


Research suggests that women who adopt alternative work arrangements may be viewed less favorably than women who work a regular schedule. This study examined whether those negative perceptions persist even after the woman returns to a regular schedule. One hundred twenty-five employed MBA students participated in an experimental study in which work schedule was manipulated. Participants reviewed a personnel file for a female employee who was either on a regular schedule or who had previously been on a reduced-workload schedule. They then completed a questionnaire assessing their perceptions of the target employee. Contrary to the authors' expectations, results revealed that the female employee who had previously been on an reduced workload schedule was actually viewed as having significantly greater advancement motivation and advancement capability than a female employee who had always used a regular schedule. She was also somewhat more likely to be recommended for a promotion.


A method for studying the problem of modeling, identification and analysis of mechanical system dynamic characteristic in view of the impulse response matrix for the purpose of adaptive control is developed here. Two types of the impulse response matrices are considered: (i) on displacement, which describes the space-coupled relationship between vectors of the force and simulated displacement, which describes the space-coupled relationship between vectors of the force and simulated displacement and (ii) on acceleration, which also describes the space-coupled relationship between the vectors of the force and measured acceleration. The idea of identification consists of: (a) the practical obtaining of the impulse response matrix on acceleration by 'impact-response' technique; (b) the modeling and parameter estimation of the each impulse response function on acceleration through the fundamental representation of the impulse response function on displacement as a sum of the damped sine curves applying linear and non-linear least square methods; (c) simulating the impulse provides the additional possibility to calculate masses, damper and spring constants. The damped natural frequencies are used as a priori information and are found through the standard FFT analysis. The problem of double numerical integration is avoided by taking two derivations of the fundamental dynamic model of a mechanical system as linear combination of the mass-damper-spring subsystems. The identified impulse response matrix on displacement represents the dynamic properties of the mechanical system. From the engineering point of view, this matrix can be also understood as a 'dynamic passport' of the mechanical system and can be used for dynamic certification and analysis of the dynamic quality. In addition, the suggested approach mathematically reproduces amplitude-frequency response matrix in a low-frequency band and on zero frequency. This allows the possibility of determining the matrix of the static stiffness due to dynamic testing over the time of 10- 15 minutes. As a practical example, the dynamic properties in view of the impulse and frequency response matrices of the lathe spindle are obtained, identified and investigated. The developed approach for modeling and parameter identification appears promising for a wide range o industrial applications; for example, rotary systems.


Longan (Dimocarpus longan Lour.) is a productive fruit crop with high nutritional and medical value in tropical and subtropical regions. The MYB gene family is one of the most widespread plant transcription factor (TF) families participating in the flowering regulation. However, little is known about the MYB TFs involved in the flowering process in longan and its regulatory network. In this study, a total of 119 DlR2R3-MYB genes were identified in the longan genome and were phylogenetically grouped into 28 subgroups. The groupings were supported by highly conserved gene structures and motif composition of DlR2R3-MYB genes in each subgroup. Collinearity analysis demonstrated that segmental replications played a more crucial role in the expansion of the DlR2R3-MYB gene family compared to tandem duplications, and all tandem/segmental duplication gene pairs have evolved under purifying selection. Interspecies synteny analysis among longan and five representative species implied the occurrence of gene duplication events was one of the reasons contributing to functional differentiation among species. RNA-seq data from various tissues showed DlR2R3-MYB genes displayed tissue-preferential expression patterns. The pathway of flower development was enriched with six DlR2R3-MYB genes. Cis-acting element prediction revealed the putative functions of DlR2R3-MYB genes were related to the plant development, phytohormones, and environmental stresses. Notably, the orthologous counterparts between Arabidopsis and longan R2R3-MYB members tended to play conserved roles in the flowering regulation and stress responses. Transcriptome profiling on off-season flower induction (FI) by KClO3 indicated two up-regulated and four down-regulated DlR2R3-MYB genes involved in the response to KClO3 treatment compared with control groups. Additionally, qRT-PCR confirmed certain genes exhibited high expression in flowers/flower buds. Subcellular localization experiments revealed that three predicted flowering-associated MYB proteins were localized in the nucleus. Future functional studies on these potential candidate genes involved in the flowering development could further the understanding of the flowering regulation mechanism.


The production rate of cosmogenic radionuclides such as 10Be or 14C is known to vary as a function of the geomagnetic field intensity. It should, therefore, be possible to extract a record of palaeofield intensity from the deposition record of these radionuclides in marine or terrestrial sediments and ice cores. Field intensity variations, however, are not the only factor that has influenced the cosmogenic radionuclide records. In the case of 14C, variations of the global carbon cycle, caused by reorganization of the ocean circulation patterns from the last glacial to the present interglacial, are superimposed. 10Be is not affected by these variations because it is not part of the carbon cycle, but its deposition rates in marine sediments vary as a function of lateral sediment redistribution and boundary scavenging intensity. A global stacked record of 10Be deposition rates, corrected for sediment redistribution by normalizing to 230Thex, was shown to remove most of the disturbances, and provides a record of 10Be production rate variations over the last 200 000 years, which translates into geomagnetic field intensity variations. This dataset is compared with palaeofield intensities reconstructed from marine sediments by palaeomagnetic methods, from variations in atmospheric 14C/12C derived from independent calibrations of 14C ages, such as U/Th dating and tree ring chronology, and from 36Cl and 10Be fluxes in polar ice cores. Potential influences of the Earth's orbital parameters and insufficient correction for orbitally triggered climate variations on the palaeointensity reconstructions are assessed. It is argued that the palaeointensity records derived from marine sediments are not significantly affected by these factors.


The main driving force for the rapid acceptance rate of small sized mobile devices to do e-commerce is its increased convenience and efficiency in performing simple transactions compared with the stationary machines. Two of the weaknesses of this type of e-commerce are: (1) due to its small size, a mobile device can easily get lost and get stolen; (2) it is neither very convenient nor cheap for a mobile user to perform transactions that require more than just a few messages, scanning of catalogues, or negotiations. Personal identification numbers (PIN) are currently used both for protection of the devices and for authentication of the user to solve (1). Sophisticated thieves might still uncover the PIN inside the mobile devices. (2) has not deserved much attention by the research community so far. In this paper, we propose to use agent technology to cope with both problems. The related protocols are presented and the improvements on the security over the existing schemes are studied.


Sequence alignment underpins all of comparative genomics, yet it remains an incompletely solved problem. In particular, the statistical uncertainty within inferred alignments is often disregarded, while parametric or phylogenetic inferences are considered meaningless without confidence estimates. Here, we report on a theoretical and simulation study of pairwise alignments of genomic DNA at human-mouse divergence. We find that >15% of aligned bases are incorrect in existing whole-genome alignments, and we identify three types of alignment error, each leading to systematic biases in all algorithms considered. Careful modeling of the evolutionary process improves alignment quality; however, these improvements are modest compared with the remaining alignment errors, even with exact knowledge of the evolutionary model, emphasizing the need for statistical approaches to account for uncertainty. We develop a new algorithm, Marginalized Posterior Decoding (MPD), which explicitly accounts for uncertainties, is less biased and more accurate than other algorithms we consider, and reduces the proportion of misaligned bases by a third compared with the best existing algorithm. To our knowledge, this is the first nonheuristic algorithm for DNA sequence alignment to show robust improvements over the classic Needleman-Wunsch algorithm. Despite this, considerable uncertainty remains even in the improved alignments. We conclude that a probabilistic treatment is essential, both to improve alignment quality and to quantify the remaining uncertainty. This is becoming increasingly relevant with the growing appreciation of the importance of noncoding DNA, whose study relies heavily on alignments. Alignment errors are inevitable, and should be considered when drawing conclusions from alignments. Software and alignments to assist researchers in doing this are provided at http://genserv.anat.ox.ac.uk/grape/.


This thesis explored the application of risk assessment in sexual offenders with intellectual disabilities. A systematic review of the literature appraised the quality and methodology of research examining the predictive validity of risk assessment instruments, this highlighted a lack of research taking into sexual offenders with intellectual disabilities. The empirical research paper explored the predictive validity of the RRASOR, SVR-20, RM2000-V and the ARMIDILO instruments using a retrospective design on a sample of special needs offenders with intellectual disabilities. Comparisons with mainstream offenders highlighted the difference between the instruments ability to accurately predict risk between the two groups of offenders. The findings suggest that the ARMIDILO can be useful when predicting risk for an intellectual disabled population. In the next chapter a risk assessment instrument, the RRASOR, was critically reviewed. Following on from this, a case study using an individual approached to risk assessment in an intellectually impaired sexual offender was demonstrated. This chapter emphasises that comprehensive assessment would be a prerequisite to working effectively with offenders with intellectual disabilities in order to address specific intervention needs. A social skills intervention aimed to reduce the level of dynamic risk posed. This chapter also served to outline some of the difficulties associated with risk assessment and management in routine clinical practice. The final chapter concludes by discussing the implications of the findings for clinical practice and offers some directions for future research.


We propose a stochastic Galerkin method using sparse grids for the Boltzmann equation with high dimensional random inputs. The method uses locally supported piecewise polynomials as an orthonormal basis of the random space. By a sparse grid technique, only a moderate number of basis functions are required to achieve good accuracy in high dimensional random spaces. We discover a sparse structure of a set of basis-related coefficients, which allows us to accelerate the computation of the collision operator. Regularity of the solution of the Boltzmann equation in the random space and an accuracy result of the stochastic Galerkin method are proved in multidimensional case. The efficiency of the method is illustrated by numerical examples with uncertainties from the initial data, boundary data and collision kernel.


The metabolic fate of norepinephrine, which is a neurotransmitter in brain as well as at peripheral sympathetic nerve endings has been the subjects of investigation for over 25 years. The various metabolites are formed by sequential O-methylation deamination, and oxidation of the aldehyde or glycol derivatives. O-methylation to normetanephrine occurs after release of the catcholamine in an active form whereas norepinephrine which is metabolized in neuronal tissue is converted mainly to 3,4-dihydroxyphenylglycol (DHPG). This neutral metabolite readily diffuses into extraneural tissue where it is O-methylated to 3-methoxy-4-hydroxy-phenylglycol (MHPG). The glycol can be oxidized to form 3-methoxy-4-hydroxymandelic acid (VMA) which is also a major product of hepatic or renal metabolism of normetanephrine. In humans, VMA is the major urinary excretion product of the catecholamine, epinephrine and norepinephrine. MHPG produced in brain on peripheral tissues is conjugated or converted to VMA so that the total of urinary conjugated MHPG plus VMA reflects overall synthesis and metabolism of norepinephrine. Normetanephrine and metanephrine are formed primarily from activated catecholamines; the ratio of these amines to the deaminated compounds provides a useful index of symphato-adrenal medullary activity in disease states or after drug administration.


This article draws on recent research to present findings concerning the nature of some recent trade union modernization policies in the UK. In response to decline, it can be seen that the unions have increasingly been encouraged to represent and service members more as individuals than as part of a collective. This appears to be consonant with the frequently expressed view that greater individualism, both in employment and in society more generally, has largely been responsible for recent union weaknesses, and that if they are to endure the unions should adapt to it. Using data generated from interviews with full-time officers from a number of unions and from a case study of Unison organization within a local authority, the paper identifies two crucial problems with such an approach. First, it is argued that the substantial difficulties that the unions have experienced recently have been caused by a process of decollectivization in employment relations, and not one of individualization. Second, an indication of the complexity of the relationship between individualism and collectivism within trade unionism is given, something that is entirely ignored by proponents of the thesis that unions should concentrate solely on appealing to individuals.


We propose a novel real-time algorithm for estimating the local scale correction of a monocular SLAM system, to obtain a correctly scaled version of the 3D map and of the camera trajectory. Within a Bayesian framework, it integrates observations from a deep-learning based generic object detector and landmarks from the map whose projection lie inside a detection region, to produce scale correction estimates from single frames. For each observation, a prior distribution on the height of the detected object class is used to define the observation's likelihood. Due to the scale drift inherent to monocular SLAM systems, we also incorporate a rough model on the dynamics of scale drift. Quantitative evaluations are presented on the KITTI dataset, and compared with different approaches. The results show a superior performance of our proposal in terms of relative translational error when compared to other monocular systems based on object detection.


INTRODUCTION: Chronic non-malignant pain poses considerable risk 10 patients and
the health service but its management is still inadequate. The introduction of prescribing
for nurses and pharmacists suggests that non-medical prescribing can improve some
important aspects of healthcare services

AIM : To provide new insights and theory regarding how nurses and pharmacists prescribe
for chronic pain, together with how the service is perceived by chronic pain patients and
to uncover barriers and facilitators encountered when this group is prescribed for.

METHOD: A mixed methods strategy was employed in this study. A grounded theory
approach was used to collect data from non-medical prescribers and patients. Non-medical
prescribes were then surveyed to confirm the emerging theory and determine
barriers and facilitators.

FINDINGS: The theory 'safety and support within the prescribing environment' explains
the relationship that non-medical prescribers have with colleagues, patients and other
factors in their prescribing environment in their prescribing for chronic pain. Non-medical
prescribers are motivated by various factors and may adopt an innovative or conservative
approach in their prescribing. Nurses were more likely to engage in informal mentoring
relationships, but were limited by their lack of medication knowledge. Pharmacists were
limited by a lack o f experience with patients, inaccessibility to formal CPD in paid work
time and the threats introduced by concerns around 'second checking'. Chronic pain
patients had strategies to maintain relationships with their prescribers and this relationship
influenced the likelihood of considering other measures to cope with their pain.

CONCLUSION: Nurses and pharmacists who qualified as prescribers would be more
likely to prescribe for chronic pain if they perceived certain essential elements in their
prescribing environment. This theory can facilitate assessment of non-medical
prescribers' support, involvement of patients and the development of resources to
encourage prescribing.


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The effect of treating rabbits with materials which destroy the cell receptors for influenzal viruses upon the ability of these animals to respond with fever to injection of the PR8 and Lee strains of influenza virus and Newcastle disease virus (NDV) is described. In general, both cholera vibrio and Cl. welchii filtrates produced diminution of febrile responses. The effect of sodium periodate upon the pyrogenic reaction was not significant. Near-lethal amounts of these materials were necessary to demonstrate their protective effects against virus challenge. In order to rule out general debility as a factor in lessening the fever, it was shown that the ability of animals to respond to the pyrogenic effect of typhoid vaccine was unimpaired by injection of receptor-destroying substances. The substances tested were more effective in abolishing the febrile response to PR8 virus than to Lee virus or NDV. This finding is compatible with previous studies of the protective effect exerted by homologous and heterologous viruses. These findings give support to the hypothesis that union of virus and host receptor substance plays a part in the production of fever by these viruses.


Chronic renal failure can lead to multiple medical and physical problems requiring physical therapy treatment. The purpose of this article is to provide an understanding of the medical treatment and the complications of chronic renal failure. Medically, patients with chronic renal failure are treated by hemodialysis, by peritoneal dialysis, or with a kidney transplant. The physical therapy management of the patient on dialysis and that of the patient with a kidney transplant differs as to the extent and aggressiveness of the program. Providing the proper physical therapy program for patients with chronic renal failure is often a challenge because of such complications as congestive heart failure and peripheral neuropathies. Physical therapy is a necessary part of the rehabilitation of the patient with chronic renal failure.


The study was conducted to estimate the Best Linear Unbiased Prediction (BLUP) breeding values of different milk production traits for Holstein and its crossbreds and to construct an economic selection index or total merit for individual cows from 2 different dairy farms in Chittagong, Bangladesh. The BLUP-estimated breeding values were obtained by AIREML, and an economic selection index was constructed as the sum of the product of the estimated breeding value with the economic value for each trait (lactation milk yield, calving interval, and liveweight). The Holstein × Sahiwal crossbred showed better phenotypic performance in both farms while the same cows showed variable performance when compared to each other. It can be postulated that comparatively better performance might be due to good management and proper feeding, as well as the lactation stage and age of the cows. According to the economic selection index value, the Holstein × Local scored higher when compared to other genotypes. Therefore, the selection of cows of top index value would be beneficial for the production of offspring in the next generation.


A polar coding scheme is proposed for the Wiretap Broadcast Channel with two legitimate receivers and one eavesdropper. We consider a model in which the transmitter wishes to send a private and a confidential message that must be reliably decoded by the receivers, and the confidential message must also be (strongly) secured from the eavesdropper. The coding scheme aims to use the optimal rate of randomness and does not make any assumption regarding the symmetry or degradedness of the channel. This paper extends previous work on polar codes for the wiretap channel by proposing a new chaining construction that allows to reliably and securely send the same confidential message to two different receivers. This construction introduces new dependencies between the random variables involved in the coding scheme that need to be considered in the secrecy analysis.


Clinical evaluation of therapies for patient care has evolved during the twentieth century from a variety of scientific methods. As a result of medical, political, and economic changes that occurred in the 1990s, randomized clinical trials and evidence‐based methods are presently in the forefront of the physician's thinking in the decision‐making process for therapeutic interventions. A new standard of patient care has emerged during this process. This report provides a clinician's viewpoint of the importance and interpretation of evidence‐based methods and suggests a strategy when such evidence does not exist.


This issue discusses methods to extract three-dimensional (3D) models from plain images. In particular, the 3D information is obtained from images for which the camera parameters are unknown. The principles underlying such uncalibrated structure-from-motion methods are outlined. First, a short review of 3D acquisition technologies puts such methods in a wider context and highlights their important advantages. Then, the actual theory behind this line of research is given. The authors have tried to keep the text maximally self-contained, therefore also avoiding to rely on an extensive knowledge of the projective concepts that usually appear in texts about self-calibration 3D methods. Rather, mathematical explanations that are more amenable to intuition are given. The explanation of the theory includes the stratification of reconstructions obtained from image pairs as well as metric reconstruction on the basis of more than two images combined with some additional knowledge about the cameras used. Readers who want to obtain more practical information about how to implement such uncalibrated structure-from-motion pipelines may be interested in two more Foundations and Trends issues written by the same authors. Together with this issue they can be read as a single tutorial on the subject.


Aims and background This analysis intended to estimate the incidence, mortality and prevalence time trends for the major cancer sites up to 2015 in the Friuli Venezia Giulia region, northeastern Italy, where a population-based cancer registry has been covering the whole area since 1995. Methods The MIAMOD method, a statistical back-calculation approach, was applied to estimate incidence, mortality and prevalence figures, in the period 1970—2015, using mortality data from the Italian National Institute of Statistics and relative survival data from Italian cancer registries. Results We estimated that the cancer sites with the highest incidence rates in the forthcoming years will be breast in women (with an age-standardized incidence rate of 130 per 100,000 in 2015), prostate in men (97 per 100,000) and colon-rectum in both sexes (85 and 42 per 100,000 in men and women, respectively). The incidence rates for lung cancer will continue to decrease only in men (down to 43 per 100,000 in 2015). Although the decline in the mortality rates of lung, breast and colorectal cancers is likely to persist, these tumors will remain the big killers in the near future. The number of people living in Friuli Venezia Giulia after a cancer diagnosis is expected to continue to rise in particular for breast cancer (with a crude prevalence of 3,000 per 100,000 women in 2015), prostate cancer (1,700 per 100,000 men) and colorectal cancer (1,100 and 800 per 100,000 in men and women, respectively). Conclusion These estimates confirmed the epidemiological patterns in time trends of major cancer sites recorded in Friuli Venezia Giulia. They highlighted in particular the increasing number of people living after a cancer diagnosis as a result of population aging, earlier diagnosis and better prognosis, which warrants adequate public health policies.


Cancer research continues to highlight the extensive genetic diversity that exists both between and within tumors. This intrinsic heterogeneity poses one of the central challenges to predicting patient clinical outcome and the personalization of treatments. Despite progress in some individual tumor types, it is not yet possible to prospectively, accurately classify patients by expected survival. One hypothesis proposed to explain this is that the prognostic classifiers developed to date are insufficiently sensitive and specific; however it is also possible that patients are not equally easy to classify by any given biomarker. We demonstrate in a cohort of 45 AJCC stage III melanoma patients that clinico-pathologic biomarkers can identify those patients that are most likely to be misclassified by a molecular biomarker. The process of modelling the classifiability of patients was then replicated in a cohort of 49 stage II breast cancer patients and 53 stage III colon cancer patients. A multi-step procedure incorporating this information not only improved classification accuracy but also indicated the specific clinical attributes that had made classification problematic in each cohort. These findings show that, even when cohorts are of moderate size, including features that explain the patient-specific performance of a prognostic biomarker in a classification framework can improve the modelling and estimation of survival.


Introduction From 1980 to June 2016 the Ministry of Health of Brazil notified 842,710 HIV/AIDS cases; 1 36 945 new cases were notified after 2007 (71,396 in the Southeast region). An increase in the number of individuals aged 15 to 34 years was observed, with a male to female ratio of 2.4:1 and sexual exposure as the major risk factor. At present, 50% of males referred homosexual practice and 9% bisexual; conversely, 96% of females are heterosexual. HTLV-1 and HTLV-2 are endemic in Brazil; estimated in 2.5 million people. Since HIV and HTLV share routes of virus transmission, coinfection of such virus could occur. Methods The present study discloses the age and gender of 1,715 HIV-infected individuals of AIDS care services (São Paulo, Brazil) in period from 2010 to 2016, whose blood samples were sent to Instituto Adolfo Lutz for HTLV infection analysis, and they were divided according to sex in five age-groups (G1=16–25 years, G2=26–30 years, G3=31–40 years, G4=41–50 years, and G5=>50 years). HIV/HTLV positive cases were analysed in each group. Results The increase of the HIV-infected male of G1 was detected (<10% in 2010 vs. 33% in 2016) as well in patients of G2 (<10% in 2010 vs. 22% in 2016). Among females, although in minor percentages, an increase in HIV infection in patients of 16 to 25 years was detected. Concerning HIV/HTLV coinfection, during the years from 2010 to 2014 all cases were detected in patients over 30 years old, but from 2015 to 2016 three cases of HTLV infection were detected in patients with less than 30 years of age. Conclusion The increase in the last years in Brazil in the number of HIV infections in the second and third decades of life is of concern, and could be related to unprotected sexual contact and promiscuity after consuming drugs (alcohol, marijuana and others). Although HTLV was more efficiently transmitted by parenteral route, sexual transmission seems to account for the new HTLV infected individuals in Brazil. Surveillance of such viruses is important to properly control these viruses spread. Support CNPq PD#302661/2015–8


There have been rapid technological advances in blood banking in South Asian region over the past decade with an increasing emphasis on quality and safety of blood products. The conventional test tube technique has given way to newer techniques such as column agglutination technique, solid phase red cell adherence assay, and erythrocyte-magnetized technique. These new technologies are adaptable to automation and major manufacturers in this field have come up with semi and fully automated equipments for immunohematology tests in the blood bank. Automation improves the objectivity and reproducibility of tests. It reduces human errors in patient identification and transcription errors. Documentation and traceability of tests, reagents and processes and archiving of results is another major advantage of automation. Shifting from manual methods to automation is a major undertaking for any transfusion service to provide quality patient care with lesser turnaround time for their ever increasing workload. This article discusses the various issues involved in the process.


A 49-year-old woman was diagnosed in 1985 as having pheochromocytoma because of hypertension with high levels of plasma catecholamine concentration and 24-hour urine excretion of vanillyl-mandelic acid and metanephrine together with a right adrenal mass. The excised tumor cells had fine granular basophilic cytoplasm with argyrophilic granules by Grimelius' method. Four years later, she was diagnosed as having a duodenal bulb ulcer. Serum gastrin showed an abnormally high level of 1900 pg/ml. Abdominal echogram and computed tomography revealed a hypoechoic lesion in the pancreas and intrahepatic multiple tumors. A needle biopsy specimen of the liver tumor was compatible with the histology of metastatic islet cell tumor. A diagnosis of Zollinger-Ellison syndrome was made due to malignant gastrinoma with multiple liver metastases. The patient had no family history of endocrinological or neoplastic disorders. The present case indicates the possibility that pheochromocytoma and gastrinoma, that is, endocrine tumors characteristic of multiple endocrine neoplasia (MEN) I and MEN II, may be coincident even in a person without MEN. A continued awareness of previously rare or undescribed manifestations is important in patients with islet cell tumors or pheochromocytoma.


The Tuskegee syphilis study has come to symbolize the most egregious abuse on the part of medical researchers. It also stands as a point of reference for African Americans suspicious of the motivations of scientific investigators. The invocation of Tuskegee in public debate over research involving vulnerable populations can help to illuminate the risks of exploitation. But when used incautiously--when abused--the legacy of Tuskegee can thwart serious and sustained discussion of the unique dilemmas posed by contemporary research under conditions of social deprivation. In this article we examine the uses and abuses of Tuskegee in three highly visible AIDS-related debates spanning the last decade.


Heart failure (HF) with reduced contractile function is a common and lethal syndrome in which the heart cannot pump blood to adequately meet bodily demands, resulting in high mortality despite the current standard of care. In modern societies, the most common drivers of HF are ischemic heart disease and hypertension. However, in a substantial subset of cases, patients present with dilated and poorly contracting hearts without evidence of common inciting stressors, a syndrome called dilated cardiomyopathy (DCM). Genome sequencing has identified a host of deleterious germline variants in key cardiomyocyte genes as causes of heritable DCM, including mutations in LMNA, which encodes the nuclear lamina-associated protein lamin A/C. In this issue of the JCI, Auguste et al. generate a mouse model of DCM in which they delete Lmna in cardiomyocytes and discover that bromodomain and extraterminal (BET) protein activation is a druggable epigenetic mechanism of disease pathogenesis in this heritable HF syndrome.


ABSTRACT New approaches for vaccination to prevent influenza virus infection are needed. Emerging viruses, such as the H5N1 highly pathogenic avian influenza (HPAI) virus, pose not only pandemic threats but also challenges in vaccine development and production. Parainfluenza virus 5 (PIV5) is an appealing vector for vaccine development, and we have previously shown that intranasal immunization with PIV5 expressing the hemagglutinin from influenza virus was protective against influenza virus challenge (S. M. Tompkins, Y. Lin, G. P. Leser, K. A. Kramer, D. L. Haas, E. W. Howerth, J. Xu, M. J. Kennett, J. E. Durbin, R. A. Tripp, R. A. Lamb, and B. He, Virology 362:139–150, 2007). While intranasal immunization is an appealing approach, PIV5 may have the potential to be utilized in other formats, prompting us to test the efficacy of rPIV5-H5, which encodes the HA from H5N1 HPAI virus, in different vaccination schemes. In the BALB/c mouse model, a single intramuscular or intranasal immunization with a live rPIV5-H5 (ZL46) rapidly induced robust neutralizing serum antibody responses and protected against HPAI challenge, although mucosal IgA responses primed by intranasal immunization more effectively controlled virus replication in the lung. The rPIV5-H5 vaccine incorporated the H5 HA into the virion, so we tested the efficacy of an inactivated form of the vaccine. Inactivated rPIV5-H5 primed neutralizing serum antibody responses and controlled H5N1 virus replication; however, similar to other H5 antigen vaccines, it required a booster immunization to prime protective immune responses. Taken together, these results suggest that rPIV5-HA vaccines and H5-specific vaccines in particular can be utilized in multiple formats and by multiple routes of administration. This could avoid potential contraindications based on intranasal administration alone and provide opportunities for broader applications with the use of a single vaccine vector.


plus recommendations for the "management" of projects , production, personnel, facilities, and contractors. Few DP books give as much for the price. It is a timely and useful successor to the first author's MANAGEMENT STANDARDS FOR DATA PROCESSING The authors admit that "The great bulk of the book is devoted to illustrations. .. ," and, indeed, the opus has 133 figures that range from "Communi-cation Paths in the System Development Process" to a sample software contract. The chapter on Personnel Requirements is followed by 25 consecutive pages of figures, one of which (on Career Planning), spans five pages. This volume is both a goldmlne of valuable nuggets for DP people at all levels and a potential lifetime resource for the spinner of red tape. The text starts with a history of the programming process. A major change in the process is seen to have been an emphasis on programming management rather than programming technology along with a shift toward recognition of programming as a group activity. Some behavioral principles and organizational issues relevant to programming are reviewed briefly in Chapter 2. Chapter 3 consists of a case analysis of the process of a programmer iteratively interpreting a user's definition of a problem. Chapters 4 and 5 on Design and Coding appear to contain the topics of central interest to the author. In design, top-down strategy and structured programming are emphasized together with a discussion of their major trade-offs. In coding, top-down and bottom-up programming strategies are contrasted. Program reliability and performance are emphasized. Chapter 6 consists of a discussion of debugging, documentation, and delivery. Chapter 7 is a fairly unique analysis of the pros and cons of on-line programming. The major point seems to be that substantial managerial attention is necessary for effective use. Chapter 8 summarizes the preceding chapters and previews Volume II. The author states, "Taken together, the two volumes are intended to give the professional programmer the basic tools he needs to perform effectively in positions of increasing responsibility in a systems programming course." There seems to be reasonable accomplishment of this goal; accordingly, the text should be of most use to practicing systems programmers. Collegiate courses in systems programming will be hampered by a lack of exercises. This lack is intended to be ameliorated by a case study guide. Managers of applications programming may be somewhat frustrated, if they apply the test to commercial programming practice …


Denmark's registry data provide accurate and complete career history data along with detailed personal characteristics (e.g., education, gender, work experience, tenure and others) for the population of Danish workers longitudinally. By using such data from 1992 to 2002, we provide rigorous evidence for the first time for the population of workers in an entire economy (as opposed to case study evidence) on the effects of the nature and scope of human capital on career success (measured by appointments to top management). First, we confirm the beneficial effect of acquiring general human capital formally through schooling for career success, as well as the gender gap in career success rates. Second, broadening the scope of human capital by experiencing various occupations (becoming a generalist) is found to be advantageous for career success. Third, initial human capital earned through formal schooling and subsequent human capital obtained informally on the job are found to be complements in the production of career success. Fourth, though there is a large body of the literature on the relationship between firm-specific human capital and wages, the relative value of firm-specific human capital has been rarely studied in the context of career success. We find that it is more beneficial to broaden the breadth of human capital within the firm than without, pointing to the significance of firm-specific human capital for career success.


AIMS
To evaluate the rate of dislocation following dual mobility total hip arthroplasty (DM-THA) in patients with displaced femoral neck fractures, and to compare rates of dislocation, surgical-site infection, reoperation, and one-year mortality between DM-THA and bipolar hemiarthroplasty (BHA).

METHODS
Studies were selected based on the following criteria: 1) study design (retrospective cohort studies, prospective cohort studies, retrospective comparative studies, prospective comparative studies, and randomized controlled studies (RCTs)); 2) study population (patients with femoral neck fracture); 3) intervention (DM-THA or BHA); and 4) outcomes (complications during postoperative follow-up and clinical results). Pooled meta-analysis was carried out to evaluate the dislocation rate after DM-THA and to compare outcomes between DM-THA and BHA.

RESULTS
A total of 17 studies (ten cohort studies on DM-THA and seven comparative studies of DM-THA and BHA) were selected. These studies included 2,793 patients (2,799 hips), made up of 2,263 DM-THA patients (2,269 hips) and 530 BHA patients (530 hips). In all, 16 studies were analyzed to evaluate dislocation rate after DM-THA. The cumulative dislocation rate was 4% (95% confidence interval (CI) 3 to 5). Seven studies were analyzed to compare the rates dislocation and surgical-site infection. The rate of dislocation was significantly lower in the DM-THA group than in the BHA group (risk ratio (RR) 0.3; 95% CI 0.17 to 0.53, p < 0.001, Z -4.11). There was no significant difference in the rate of surgical-site infection between the two groups (p = 0.580). Six studies reported all-cause reoperations. The rate of reoperation was significantly lower in the DM-THA group than in the BHA group (RR 0.5; 95% CI 0.32 to 0.78, p = 0.003, Z -3.01). Five studies reported one-year mortality. The mortality rate was significantly lower in the DM-THA group than in the BHA group (RR 0.58 95% CI 0.45 to 0.75, p < 0.0001, Z -4.2).

CONCLUSION
While the evidence available consisted mainly of non-randomized studies, DM-THA appeared to be a viable option for patients with displaced fractures of the femoral neck, with better reported rates of dislocation, reoperation, and mortality than BHA.


Antiserum specific for influenza A2 neuraminidase was produced by immunization of rabbits with the purified enzyme which had been isolated by electrophoresis from the proteins of a detergent-disrupted A0A2 influenza virus recombinant [X-7 (F1)]. This recombinant contained hemagglutinin of the A0 subtype and A2 neuraminidase. Antiserum to the isolated A2 neuraminidase did not react in any of four serological tests with A0 or A2 subtype viruses that lacked the A2 enzyme. In contrast, the antiserum inhibited the neuraminidase activity only of wild-type and recombinant viruses containing the A2 enzyme, regardless of the nature of their hemagglutinin proteins. The antiserum caused hemagglutination-inhibition of some, but not all, viruses bearing the A2 enzyme, and it reduced the plaque size or plaque number of all viruses tested that contained A2 neuraminidase. In the chick embryo and in cell culture, low dilutions of antiserum reduced the yield of virus. True neutralization of virus in the chick embryo did not occur. We conclude that an antiserum specific for A2 neuraminidase influenced the yield and release of virus from influenza virus-infected cells.


The Electron Multiplying Test Chip 1 (EMTC1) was developed with the aim of creating a device which could produce superior Electron Multiplication (EM) gain at a greatly reduced voltage. An EM gain exceeding 3% per stage has been recorded for a relatively low voltage (~13.0V) from two recently developed pixel structures. An electro-optical characterisation of the EMTC1 is presented focusing on charge transfer via experimental and simulation results aiming to provide insight into the transfer and multiplication process. The Charge Transfer Inefficiency (CTI) is analysed with the aim of providing a greater understanding of the charge transfer process. Light starved applications such as Earth observation and automated inspection are known to benefit from Time Delay Integration (TDI) and electron multiplication. Though traditionally implemented in CCDs, implementing TDI in CMOS technology can lead to an increase of functionality, higher readout speeds and reduced noise. This paper presents a discussion of the implication of these results on the potential applications of this sensor.


Bacteria of different genera isolated at nine medical centers in different parts of the United States and at one center in Venezuela during the first decade of gentamicin usage carried the gentamicin resistance gene 2"-aminoglycoside nucleotidyltransferase on the same transferable plasmid. Such widespread dissemination of a newly observed resistance gene on one plasmid suggests that a new resistance gene may emerge once on a single plasmid, which then carries it to other centers and other plasmids. The resistance gene might, therefore, be contained if detected early.


Abstract The ostracode genus Fossocytheridea Swain and Brown 1964 is emended herein. A summary of the diagnostic characters include: (1) a median sulcus, (2) a tripartite antimerodont hinge with distinct heart-shaped terminal elements, (3) distinct sexual dimorphism; (4) a narrow inner margin that has 20–28 straight radial pore canals, and (5) variability in the external carapace (pore shape, pore density, and patterns of reticulation) that bears close resemblance to Cyprideis. Two new species are described from southwest Utah (U.S.A): Fossocytheridea mosbyense sp. nov. and Fossocytheridea kirklandi sp. nov. and 21 taxa previously assigned to Fabanella, Sarlatina, Ovocytheridea, Dolocytheridea, Antibythocypris, and Cytheridea are assigned to the emended genus. Fossocytheridea resembles Cyprideis with respect to both shell morphology and ecology since it occurs in association with euryhaline biota in coal-bearing strata. Expansion of marginal marine environments during the highest sea level of the Mesozoic saw Fossocytheridea successfully migrate and dominate restricted coastal environments. Since this expansion, the prominent characters of Fossocytheridea have been preserved in descendent genera belonging to the tribe Cyprideidini Kollmann 1960 that are preserved to this day in Cyprideis.


There is no question that the U.S. voter registration system could be improved. How- ever, the answer to America's voter registration problems is not federal mandates or federal interference in election administration. Indeed, the federal government has almost no experience administering elections; states administer elections in the laboratories of democracy. As a result of this exercise in federalism, states are implementing numerous improvements to the voter registration system—and they are doing it at less cost to our treasury, our Constitution, and the integrity of our elections than mandatory universal registration.


The prevalence of type 2 diabetes mellitus (T2DM) is increasing all over the world. Targeting good glycemic control is fundamental to avoid the complications of diabetes linked to hyperglycemia. This narrative review is based on material searched for and obtained via PubMed up to April 2015. The search terms we used were: 'hypoglycemia, diabetes, complications' in combination with 'iatrogenic, treatment, symptoms.' Serious complications might occur from an inappropriate treatment of hyperglycemia. The most frequent complication is iatrogenic hypoglycemia that is often associated with autonomic and neuroglycopenic symptoms. Furthermore, hypoglycemia causes acute cardiovascular effects, which may explain some of the typical symptoms: ischemia, QT prolongation, and arrhythmia. With regards to the latter, the night represents a dangerous period because of the major increase in arrhythmias and the prolonged period of hypoglycemia; indeed, sleep has been shown to blunt the sympatho-adrenal response to hypoglycemia. Two main strategies have been implemented to reduce these effects: monitoring blood glucose values and individualized HbA1c goals. Several drugs for the treatment of T2DM are currently available and different combinations have been recommended to achieve individualized glycemic targets, considering age, comorbidities, disease duration, and life expectancy. In conclusion, according to international guidelines, hypoglycemia-avoiding therapy must reach an individualized glycemic goal, which is the lowest HbA1c not causing severe hypoglycemia and preserving awareness of hypoglycemia.


The normal innervation of structures in mouse foot pads was investigated with immunohistochemistry and confocal microscopy. Nerves were visualized by incubating Zamboni fixed, thick, frozen sections with antibodies to protein gene product 9.5 (PGP 9.5), vasoactive intestinal peptide, substance P, calcitonin gene‐related peptide, and protein zero. The antibodies were localized using cyanine 3.18 labeled anti‐rabbit gamma globulin. PGP 9.5 immunolocalization showed dense nerve bundles at the base of the foot pad with branches to larger blood vessels, sweat glands and epidermis. Sweat gland tubules were surrounded by numerous sudomotor axons; single fibers accompanied the sweat duct toward the skin's surface. Nerve bundles containing myelinated and unmyelinated axons ran through and around the centrally located sweat gland cluster to end in free nerve endings and Meissner's‐like corpuscles at the apex of the foot pad. Other bundles running parallel to the epidermis gave arcuate branches that supplied epidermis on the sides of the pads with a rich nerve network, principally with free nerve endings that often reached the most superficial cell layers of epidermis. Calcitonin gene‐related peptide‐immunoreactive (‐ir) nerves were distributed to dermis and epidermis in lower density than PGP 9.5‐ir fibers. Substance P‐ir fibers were less numerous; most terminated as free endings in deeper layers of epidermis. Vasoactive intestinal peptide‐ir nerves almost exclusively innervated sweat glands, ducts and blood vessels, but not epidermis. The mouse hind paw has potential to serve as a model system for investigations of functional and morphological changes that affect peripheral and au tonomic nerves under diverse experimental conditions. © 1995 Wiley‐Liss, Inc.


We have proposed Flexible Mono-tread mobile Track (FMT) as a mobile mechanism for hazardous environment such as disaster area. FMT has only one track which can flex in three dimension. Generally speaking, one has to teleoperate robots under invisible condition. In order to operate the robots skillfully, it is necessary to detect not only condition around the robots and its position but also posture of the robots at any time. Flexed posture of FMT decides turning radius and direction, it is very important to know its posture, accordingly. FMT has a vertebral structure composed of vertebrae as rigid body and intervertebral disks made by flexible devices such as rubber cylinder and spring. Since the intervertebral disks flex in three dimension, it is not easy for traditional sensors such as potentiometers, rotary encoders and range finders to measure its deformation. The purpose of the paper, therefore, is to measure flexed posture of FMT using a new flexible displacement sensor. We prove that the flexed posture of FMT with five intervertebral disks can be detected through experiment.


The principle aim of this work is to simulate the invasion of two invasive mosquito species Aedes aegypti and Aedes albopictus in central Europe at a landscape scale. The spatial-temporal dynamics of invasion is investigated in dependence of predation pressure, seasonal variation of ambient temperature as well as human population density. The introduction of temperature dependent entomological parameters enables the simulation of seasonal pattern of population dynamics. The influence of temperature, predation pressure and human population density on invasion is studied in one-dimensional cases. In two dimensions, georeferenced parameters such as annual mean temperature and human population density are prepared by a geographical information system and introduced into the finite element tool COMSOL Multiphysics. The results show that under the current temperature, central Europe cannot become a permanent breeding region for Aedes aegypti. However, southwest Germany especially the regions along the Upper Rhine Valley may provide suitable habitats for the permanent establishment of Aedes albopictus. An annual temperature rise of two degrees would lead to dramatic increase of invasion speed and extension range of Aedes albopictus.


The problem of parameter optimization for a feedforward artificial neural network (ANN) to determined its best architecture is addressed. A new metaheuristic called Multiple Particle Collision Algorithm (MPCA), introduced by Luz et al. [12], was applied to design an optimum architecture for two models of supervised neural network: the Multilayer Perceptron (MLP), and recurrent Elman network. The NN obtained using this approach is said to be self-configurable. In addition, two strategies are employed for calculating the connection weights to the MLP and Elman networks: MPCA, and backpropagation algorithm. The resulting ANNs were applied to predict the monthly mesoscale climate for the precipitation field. The comparison is performed between the ANN configuration obtained by automatic process and another configuration proposed by a human specialist.


6005 Background: Identifying excess variation has proved to be a useful tool to better understand potential strengths and weaknesses of the health care system. This study aims to report on the extent of geographic variation in chemotherapy utilization in ovarian cancer between 38 U.S. Health Service Areas (HSA) utilizing the 11 tumor registries from SEER-Medicare, and to determine HSA characteristics associated with this variation.

METHODS
Medicare patients with a diagnosis of ovarian cancer between 1990 and 1999 were selected from the SEER registries (N=10,986). After exclusions for HMO status (N=1778), death < 30 days (N=810), and HSAs < 30 subjects (N=466), the sample size was 7932. Chemotherapy within a year of diagnosis was identified by Medicare billing codes. Sociodemographic and disease characteristics were obtained from SEER and Census data. HSA data were obtained from the Area Resource File of the Federal Bureau of Health Professions.

RESULTS
In order to study differences across HSAs, we fit a logit model describing each of the 38 HSAs, and explored the variation in the odds of receiving chemotherapy inside HSAs, controlling for patient age, stage and year of diagnosis. There were large and significant differences between HSAs, with ORs varying 4.6-fold, (chi-square for HSA was 151, df=37, p=0.000). In a second model we added race, income, and education. ORs for HSAs now varied by 5.9 fold (chi-square for HSA was 148, df=37, p=0.000). Finally, we removed the 38 fixed effects and replaced them with 7 HSA descriptors (%HMO, pop. density, MD/pop., oncologist/MD, ln pop., N hospitals, %hosp with oncology services). The chi-square for these HSA characteristics was 21 (df=7, p=0.004). The only HSA descriptor with a significant odds ratio was % hospitals with oncology services (OR=1.82, p=.012).

CONCLUSIONS
Medicare patients with the same age, stage, and year of diagnosis had very different chemotherapy utilization within one year of diagnosis in different geographic areas as defined by the HSAs. An important HSA factor contributing to this excess variation in utilization of chemotherapy between HSAs was the density of oncology facilities inside each HSA. No significant financial relationships to disclose.


Abstract Objectives. Evaluate the effects of a 6-month High Intensity Interval Training (HIIT) program on (1) functional capacity and health-related quality of life, (2) multiple blood biomarkers, (3) echocardiographic parameters, and (4) exercise performance, in patients in cardiac resynchronization therapy (CRT) stratified by the presence of atrial fibrillation (AF), targeting the following questions: (1) Does CRT provide similar benefits in patients in AF and sinus rhythm (SR)?; and (2) Does HIIT provides similar benefits in patients in AF and SR? Design. Estimates were available at baseline and 6 months after CRT implantation in 37 patients with heart failure. Patients were randomized after CRT to a 24-week HIIT group or to a usual care group (CON). In this sub-analysis, HIIT (AF = 7; SR = 11) and CON (AF = 9; SR = 10) were stratified by the presence of AF. Results. Patients in AF benefitted to a lesser degree from CRT in functional status than patients in SR (23.8–46.0%). However, HIIT induced superior improvements in patients in AF compared to CON (23.9–61.0%). Decreases in TNF-α (8.5–42.9%), BNP (15.3–34.6%) and left ventricular mass (9.6–26.2%) were only observed in patients in SR, whereas increases in peak oxygen uptake were only observed in patients in AF (19.5–23.2%). HIIT improved exercise capacity (8.8–59.4%) in patients in SR. Conclusions. Patients in AF or SR undergoing CRT demonstrated distinct benefits from device implantation and from HIIT as an adjunctive therapeutic strategy. This suggests that both mainstay and adjunctive therapeutics may need to be managed differently in patients in AF and SR.


The fishes, which have currently named Aphanius Nardo, 1827 are the relict of the ancient ichthyofauna of the Tethys Sea. For a long time since 1827, the genus name has been subjected to revision by several researchers using mainly morphological features. Until recently, no comprehensive single- or multi-locus DNA barcoding study has been conducted on whole members of the family Aphaniidae. In the present study, by applying four conceptually different molecular species delimitation methods, including one distance-based method, one network-based and two topology-based methods, we examined a single-locus DNA barcode library (COI) diversity for the 268 sequences within the family Aphaniidae from the Old World (57 sequences are new in the present study and 211 sequences were retrieved from NCBI database). The molecular analyses revealed a clearer picture of intra-family relationships and allowed us to clarify the generic names, and also describe a new genus for the family Aphaniidae. Results supported distinction of three major clades related to three genera within this family: i) the first clade includes the A. mento group which are placed in a new genus, Paraphanius gen. nov., found in the Orontes (= Asi) and Tigris-Euphrates River drainage, the Levant in coastal waters and the Dead Sea basin, western Jordan, and in southern Turkey in the Mediterranean basins as well as in central Turkey. This clade positioned at the base of the phylogenetic tree, (ii) the second clade contains the A. dispar-like brackish water tooth-carps which are transferred to the genus Aphaniops Hoedeman, 1951 (type species, Lebias dispar), distributed in the coastal waters around the Red Sea and the Persian Gulf basins; and (iii) the third clade, the genus Aphanius Nardo, 1827 (type species Aphanius nanus = A. fasciatus) contains all the inland and inland-related tooth-carps, which are mainly distributed in the inland waters in Turkey and Iran and also in the inland-related drainages around the Mediterranean basin.


In 2010 the Council of the European Union laid down the standard for the European Case Law Identifier (ECLI). In this paper we assess to what extent and how ECLI has been implemented by national and European courts, as well as the state of play regarding the ECLI search engine on the European e-Justice Portal. With a lot of work to be done, the ongoing developments justify a positive outlook.


In early 2012, an equity analyst, was examining the jet fuel hedging strategy of JetBlue Airways for the coming year. Because airlines cross-hedged their jet fuel price risk using derivatives contracts on other oil products such as WTI and Brent crude oil, they were exposed to basis risk. In 2011, dislocations in the oil market led to a Brent-WTI premium wherein jet fuel started to move with Brent instead of WTI, as it traditionally did. Faced with hedging losses, several U.S. airlines started to change their hedging strategies, moving away from WTI. But others worried that the Brent-WTI premium might be a temporary phenomenon. For 2012, would JetBlue continue using WTI for its hedges, or would it switch to an alternative such as Brent?


Background: Cerebral vasospasm is a major cause of morbidity and mortality in patients with subarachnoid hemorrhage. Vasospasm is managed with triple H and vasodilators but sometimes, patients do not respond. Intra-arterial vasodilator infusion has been shown to improve outcome in such patients. In this study, we try to evaluate the efficacy of intra-arterial nimodipine therapy in 43 patients of post-aneurysmal subarachnoid hemorrhage refractory cerebral vasospasm. Methods: It is a prospective observational study of a group of 43 patients presenting with refractory cerebral vasospasm as per the inclusion criteria. Pre-procedure neurological assessment and Transcranial Doppler (TCD) monitoring were done. Endovascular spasmolysis was conducted and post-operative morbidity and outcomes were noted. Follow up of the patients was done at the time of discharge and at 6 months according to the Modified Rankin Scale and NCCT head. Results: Most of the patients developing refractory cerebral vasospasm belonged to Hunt and Hess Grade 2 and 3 and Fisher grade 3 and 4. 87.5% of the patients showed clinical recovery following endovascular spasmolysis and 58% of the patients showed complete angiographic recovery. Outcome after 6 months was good in 76%, moderate in 12% and poor in 12% patients. NCCT head showed no infarct in 58%, minor infarct in 28% and major vascular territorial infarct in 14% patients. Conclusions: Intra-arterial nimodipine infusion is a safe and effective therapy with minimum risk of complications if adhered to standard endovascular practice. By timely intervention, major ischemic insult to the brain can be averted, thereby significantly improving the prognosis.


Translating a dramatic text is a daunting task. The challenge is rooted in the fact that the text is specifically written to be acted or performed on the stage. A dramatic text is written in acts, scenes, and contains dialogues spoken by the characters. Apart from this, translating a dramatic text from one language with a different cultural setting into another language requires high creativity to guarantee faithfulness in the target language and culture. This article analyzes the interface between translation and drama as well as the woes and possibilities of translating Wole Soyinka's The Lion and the Jewel into French. The result of this research indicates that linguistic and cultural issues which are based on the shared knowledge of the original author and the readers are mostly problematic in translation and usually require the translator to do serious research to acquire the necessary background knowledge, and find out whether this background knowledge is at the target language readers' disposal; if not, to make it available to them through translations, expansions, explanations, and footnotes.


Vittorio Sainati wrote two books and several articles on Aristotle's logical thought. In this paper I reconstruct Sainati's intepretation of Aristotle's logic. I show that Sainati anticipates some of the contributions by Michael Frede and Marko Malink. I focus on two aspects: 1) Sainati's reconstruction of Aristotle's doctrine of the categories and 2) Sainati's claim that it is possible to make sense of Aristotle's necessity syllogistic if we believe that the necessity operator is used to express the necessity of the per se predications. I show that Sainati's idea that logical categories are nothing but predications has been further developed by M. Frede in a famous essay. Additionally, I show that Malink's interpretation of modal syllogistic against the backdrop of Aristotle's theory of predication echoes Sainati's contributions. My paper aims at showing the depth of Sainati's intepretation of Aristotle's logic.


Dunaliella bardawil, a beta-carotene accumulating halotolerant alga, has been tested as a source of retinol in a chick diet. Chicks were fed diets deficient in retinol or supplemented with retinol, synthetic beta-carotene or dry algae. After an initial lag, chicks grew equally well on diets supplemented with algae, retinol or beta-carotene. Serum and liver analyses revealed a normal content of retinol in all chicks except those grown on the retinol-deficient diet. Chicks fed the algae-supplemented diet contained lutein but no beta-carotene in their serum, even though the ratio of beta-carotene to lutein in the algae was over 15:1. Laying hens fed with an algae-supplemented diet showed enhanced egg yolk colour attributable to a higher lutein content. No beta-carotene was present in the egg-yolk. These studies demonstrate the possibility of using dried Dunaliella bardawil as a dietary supplement which can fully satisfy the retinol requirement and also serve as a yolk-colour enhancing agent.


Various mobile phases including phosphate buffer, pure water and five kinds of biological buffers (pH around 7) were systematically studied in terms of their ability to clean-up plasma matrix on precolumns of restrictedaccess media in a column-switching system. The necessary washing time, buffer pH, type and content of organic modifier were evaluated with respect to plasma elution profiles on restricted-access media precolumns. The influence of different mobile phases on the recovery of plasma matrix from alkyl-diol silica precolumns was studied by means of a scanning spectrophotometer. Our results show that phosphate buffer near physiological pH with small amounts of 2-propanol or acetonitrile was preferable for direct injection of large plasma volumes (500 gL). More than 93 % of the proteins in a plasma matrix can be recovered within 3 min from the alkyl-diol silica C18 column (25 mx 4 mm I.D.) as measured at 280 nm for all selected mobile phases except for tris (hydroxymethyl) aminomethane buffer, from which only about 88 % was obtained.


A network model for soil pore volume is presented and applied to the analysis of biological invasion of microorganisms. The pore geometry of two soils with a relatively high or low bulk density were quantified with the use of X-ray tomography and networks were constructed to present the pore space by channels connecting intersecting points. This network was subsequently quantified by the measurement of biologically relevant parameters, such as the distribution of lengths of the links between two nodes, the coordination number of the nodes, and the distribution of the sizes of the links between two nodes. Spread of microorganisms was subsequently considered as a function of these characteristics and embedded into a simple epidemiological model for spread that can be mapped onto percolation theory. We found that the networks display critical behaviour for biological invasions with a greater resilience to invasion for the more densely packed soil. We also found that inherent heterogeneity of soil systems further contributes to resilience to invasion.


Tak Oyai dance is a cultural heritage of the community of Pesisir Selatan Regency, particularly Painan Timur. The research focused on Tak Oyai dance in the Aie Duku Village, where the dance is herited from their ancestors. This research used qualitative method; where data is collected by observation, interviews, and documentation using equipments such as video and audio recorder, also camera. Research findings prove that Tak Oyai dance is recognized as a cultural heritage in the social and cultural life of the community, however it is not recognized as the current tradition and culture of the Aie Duku community, therefore it is rarely presented in entertaining and ceremonial event. In the other hand there is still an attempt preserve the dance although not yet successful.


This study tries to quantify the impact of salinity on rice production in the south-west region of Bangladesh. Khorip is the dominant crop season in the region. The average production of rice during khorip season is 4,232 kg ha-1 in low saline areas, whereas, it is 3,760 kg ha-1 and 2,663 kg ha-1 for moderate and high saline areas, respectively. The Cobb-Douglas production function estimation results find that salinity has a negative and statistically significant influence on rice yield. This study also finds that salinity intrusion negatively influences farm profitability as well as farm performance. If the salinity of high saline area can be reduced to the threshold level, farmers will gain about 685US$ ha-1 fromincreased rice yield. Salinity level needs to be controlled for realizing the benefits from an increase in production. Drainage, fresh water management for irrigation in time of dry season and spreading salt tolerant rice varieties in saline prone area are the controlling measures against salinity intrusion. Land zoning, property rights, tax for external costs associated with shrimp farming in the coastal areas of the country may be some command and control approaches to address the salinity problem. Thesewill ultimately increase farmprofitability in the saline affected areas.


Abstract Purpose: The purpose of this study is to (1) explore and (2) compare circumstances of falls among full-time wheelchair users with spinal cord injury (SCI) and multiple sclerosis (MS). Methods: A mixed method approach was used to explore and compare the circumstances of falls of 41 full-time wheelchair users with SCI (n = 23) and MS (n = 18). In addition to collecting participants' demographic information (age, gender, type of wheelchair used, duration of wheelchair use, and duration of disability), self-reported fall frequency in the past 6 months, self-reported restriction in activity due to fear of falling and the Spinal Cord Injury-Fall Concerns Scale (SCI-FCS) was collected. Qualitative data in the form of participants' responses to an open-ended question yielding information regarding the circumstances of the most recent fall were also collected. To examine differences in survey outcomes and demographic characteristics between participants with SCI and MS, independent t-tests and Pearson's Chi-square tests were used. Qualitative data were analyzed with a thematic analysis. Results: Statistical analysis revealed that individuals with MS (mean =3.3) had significantly higher average SCI-FCS than individuals with SCI (mean =2.4). The analysis of the participants' descriptions of the circumstances of their most recent falls resulted in three main categories: action-related fall contributors (e.g., transfer), (2) location of falls (e.g., bathroom), and (3) fall attributions (e.g., surface condition). Conclusions: The results from this study helped to understand fall circumstances among full-time wheelchair users with MS and SCI. Findings from this study can inform the development of evidenced-based interventions to improve the effectiveness of clinically based treatment protocols. Implications for rehabilitation Falls are a common health concern in full-time wheelchair users living with multiple sclerosis and spinal cord injury. The circumstances surrounding falls reported by full-time wheelchair users living with multiple sclerosis and spinal cord injuries were found to be multifactorial. The complex nature of falls must be taken into consideration in the development of fall prevention programs. Findings from this study can inform the development of comprehensive evidence-based, population-specific interventions to manage falls among full-time wheelchair users living with multiple sclerosis and spinal cord injury.


In this special issue of the European Journal of Applied Mathematics we celebrate the 75th birthday of its founding editor, Professor John Ockendon. John started his research career with his D.Phil., awarded in 1965, working with Alan Tayler at the University of Oxford. John's background was in fluid mechanics, covering a wide range of topics, including, lubrication flows, flows in porous media, hypersonic aerodynamics, sloshing phenomena, and flow separation. He soon became involved in industrial research which led, in particular, to his interest in the field of free boundary problems, an area in which he became a driving force, through papers, conferences, and particularly through the fostering of regular international meetings and personal interactions. His pioneering work in the field was particularly concentrated in diffusion-controlled moving boundary problems that arise in various applications, such as in phase change problems, elastic-contact problems and the fundamental Hele-Shaw free boundary problem. The industrial collaborations also led to mathematical studies of lens design, fibre extrusion, fluidised beds, glass manufacture and semiconductor devices, to name but a few, and to problems in scattering and wave theory, non-linear wave propagation and non-linear oscillations, as well as mechanics and heat and mass transfer. He continues to work on PDEs and asymptotics applied to new well-founded models from the real world, with a particular focus in the physical and earth sciences.


Capturing the nuances of clinical observations in an electronic format has been a major challenge in implementing electronic health records. In a formative evaluation study using three different methodologies, we identified that the greatest obstacle to point-of-care data entry for eye care was supporting free text annotation of clinical observations. To overcome this obstacle, we developed an approach that captures an image of a free text entry and associates this image with related data elements in an encounter note. Through simulated patient studies, we observed that this approach successfully supported complex documentation at the point of care by clinicians.


'One Voice For Australia': A Marketing History of Australia's National Tourist Organisation -1929-1967
This study examines, III an historical marketing context, the establishment of Australia's fust national tourist organisation in 1929, the semi-official, non-profit, Australian National Travel Association (ANTA). In 1966, following the recommendations of the Harris, Kerr, Forster Report, the Association's major function, tourism marketing, became incorporated into a statutory authority, the Australian Tourist Commission (ATC) in 1967. External and internal factors were inevitably responsible for the establishment and evolution of both organisations. The creation of the Association, modelled on community advertising principles and the Commonwealth Government's assumption of responsibility for tourism, albeit the marlreting function, were not unique to Australia but merely reflected international trends; however the position of tourism under the Federal Constitution was instrumental in determining the powers of the ATC to market to tourists overseas and within Australia. This thesis traces these historical developments and suggests reasons for the Commonwealth Government's decision to fully fund the Commission rather than provide token financial assistance to a non-profit organisation.
Marketing history in tourism is a new historical field but follows the principles of historical research by incorporating both macro and micro perspectives. Analysis of demand and supply factors are systematically examined in the context of an historical marketing framework. Two methodologies have been used in this study. The first examines, in a historical context, secondary literature relating to the origins of Australia's international tourism market during two buoyant periods of international tourism growth during the 1930s, 1950s and 1960s, and those supply factors affecting the development of the Australia's tourist product. The second method employs primary research to retrieve and examine archival records relating to the origins and evolution of the Association, and Commonwealth and State Government's attitudes to tourism whilst the application semiotic analysis of marketing ephemera is used to examine the Association's marketing activities in greater detail.
Government involvement in tourism marketing has a long history in Australia having been used by State Governments as a tool to effect economic development since 1905. Tourism policy at the national level has been more problematic, although the Commonwealth had exercised its overseas marketing powers for commodities since the 1920s and tentatively supported the objectives of the Association until 1940 through encouragement and financial contributions. Just as the Association's creation was inspired by the energy and vision of remarkable tourism pioneers, the Association's survival and resurgence was due to the remarkable tenacity of those same visionaries and the acumen of others without whose advocacy Australia's tourism history may well have been different. The events of 1966 and 1967 are crucial to understanding the present nature of Australia's tourism organisation, but it is not well appreciated that the demise of the Tourist Council of Australia in 2000 marked the final chapter of the Association.


In order to determine the most suitable species of triatomine for xenodiagnosis of the Chagas disease, five species triatomine (Triatoma barberi, T. infestans, T. pallidipennis, T. phyllosoma, and Rhodnius prolixus) in third and fourth instars were used to evaluate their susceptibility to one T. cruzi strain isolated in Mexico. The susceptibility was determined by: a) percentage of infected triatomines, b) amount of flagellates in bug feces and c) amount of blood ingested. We found that in most species of triatomines tested the third instar was more susceptible than fourth instar. The order of susceptibility to T. cruzi was: T. pallidipennis > T. barberi > T. phyllosoma > T. infestans > R. prolixus.


Integrated Vehicle Health Management (IVHM) covers frameworks for detecting, diagnosing, and mitigating faults in hardware and structures in aerospace systems. Software Health Management (SHM) applies the goals of IVHM to software-intensive systems to detect software faults in real-time and to mitigate them. In this position paper, we describe the needs and challenges of SHM in automotive systems.


I had only to be escorted a few yards from the floor on which we spent our initial night in Rwanda to see my first massacre site. The languid senior information officer whom I had interrupted listening to the BBC World Service news at 6 am swung open the door, still holding the large receiver under his free arm, on to a small room where 17 Jesuit priests had been shot. Blood had sprayed on the walls and ceiling and there were empty cartridge cases among the blood soaked blankets on the floor. When, in my ignorance of equatorial Africa, I suggested that the adjacent burial pit looked too overgrown to be contemporary he shrugged and walked off. Within days we learnt to relax our usual caution over the veracity of allegations. The nature of what has happened in Rwanda, the sheer numbers, and the brazen openness of the atrocities mean that no one has any need to manufacture stories. Reports of massacres soon began to seem commonplace and it became the bizarre that continued to have an impact. We were told of the member of a death squad killer who refused to kill a little Tutsi girl. Why? Had this man not set himself the task of filling his latrine pit with bodies? Apparently once he had fulfilled his self imposed quota he lost interest in killing any more.

The massacres in Rwanda began after the presidents of both Rwanda and Burundi were assassinated when their plane was hit by a missile as it was landing at Kigali airport. By 5 …


Most existing analyses of (stochastic) gradient descent rely on the condition that for $L$-smooth costs, the step size is less than $2/L$. However, many works have observed that in machine learning applications step sizes often do not fulfill this condition, yet (stochastic) gradient descent still converges, albeit in an unstable manner. We investigate this unstable convergence phenomenon from first principles, and discuss key causes behind it. We also identify its main characteristics, and how they interrelate based on both theory and experiments, offering a principled view toward understanding the phenomenon.


"I will not be donating to Tulane until they reinstate Newcomb College! What Scott Cowen did to destroy Josephine Louise Newcomb's legacy was illegal and wrong. My diploma says Newcomb College and that no longer means anything!" Amelia Conrad, a Newcomb Scholar and a student worker at the Tulane University Calling Center, murmured a quick apology and hung up the phone. This was not the first time that someone had yelled at her for the closing of Newcomb College during her shifts at the Calling Center. Since the consolidation of Newcomb College after Hurricane Katrina in 2005 and the creation of the Newcomb College Institute in its place, many alumnae were frustrated and angry about the loss of their collegiate home. This anger had led to a lawsuit against the university by one particular alumnae group, which ended in Tulane's favor in February 2011. Amelia told her fellow Newcomb Scholars about the confrontation during their seminar the next day. As a Newcomb Scholar myself, I felt very upset by the incident. But how could I and other members of the Newcomb Scholars Program communicate our Newcomb experience to these women, and how could we show that it is just as valid as theirs? In a public domain dominated by the lawsuit, how could we offer a different interpretation of the "Newcomb spirit" in 2011? This case explores these questions.


The UV Index was introduced in Canada in 1992 in response to growing concerns about the potential increase of ultraviolet (UV) radiation due to ozone depletion. The index was adopted as a standard indicator of UV levels by the World Meteorological Organization and World Health Organization in 1994. This survey article gives an overview of the UV Index and the main features of its geographical distribution. UV index values are determined from measurements made by ground-based spectrometers, broad-band filter radiometers and multi-filter radiometers. Radiative transfer models are used to estimate UV Index values from other types of geophysical observations, primarily column ozone and cloud thickness. UV Index values can also be retrieved from satellite measurements of atmospheric ozone and cloud cover. Forecasts of UV Index values are now widely available and are intended to be used by the public as a guide to avoid excessive exposure to UV radiation. Over the US and Canada, mean noontime UV Index values in summer range from 1.5 in the Arctic to 11.5 over southern Texas and can be as high as 20 at high elevations in Hawaii. The UV Index is also often used to quantify UV levels in studies investigating the impact of UV on other biological and photochemical processes. Factors affecting the UV Index, such as the sun elevation, total amount of ozone in the atmosphere, cloud cover, reflection from snow and local pollution, are also discussed. Since its introduction in 1992, the UV Index has become a widely used parameter to characterize solar UV. Information about it can be useful for helping people avoid excessive levels of UV radiation.


This research is a case study on three Islamic Bank in Malang, namely PT. Bank Muamalat Indonesia, Tbk, PT. BRI (Persero) Syariah Business Unit, and PT. BNI Syariah with the heading "Factors Considered In Determining Upper Sharing Ratio Mudharabah on Islamic Banking." The purpose of this study was to determine the calculation of profit sharing ratio of financing, the factors considered and the most considered factor in determining the profit sharing ratio of financing is given to customers every Islamic bank. In this study, data analysis was done by classifying the data obtained from each Islamic bank, describing all the data obtained, comparing the data obtained from an Islamic bank with other Islamic banks., Identify strengths and weaknesses of the calculation and the factors considered in determination of the profit sharing ratio of financing in every Islamic bank and draw conclusions from the research that has been done. From interviews conducted by the author, it can be concluded that the calculation of profit sharing ratio of financing is applicable in every Islamic banks differ from bank to one another, but in the calculation of financing, every Islamic bank remains guided by the National Sharia Board Fatwa . And note the factors considered in determining the profit sharing ratio of financing is as follows: The percentage of average net income / profit effective equivalent, nominal amount of financing the proposed customers, the ability of customers to pay installments, the risk to be received upon the bank of financing, terms of repayment of financing, market competition situation, good relationship between banks and customers, conventional interest rates, and customer willingness to pay installments. While most considered factor in determining the profit sharing ratio of financing is as follows: The percentage of average net income / profit effective equivalent. Based on the above conclusions, the authors may imply that better management of Islamic banks more transparent again in the calculation of profit sharing ratio of financing is included in the method of determining the average percentage of income / profit effective equivalent or profit targets for each client, so that customers feel comfortable in working with Islamic banks


A dispersive absorbing boundary condition (DBC) which allows the dispersion characteristics of waves to be used as a criterion for designing absorbing boundary conditions is presented. Its absorbing quality is superior to that of the presently used Mur's first-order boundary condition for microstrip component analysis, and its implementation is much simpler when compared to that of the super boundary condition treatment. Due to the significant performance improvement of the new boundary condition, the memory requirement can be reduced greatly when applying this boundary condition to microstrip component analysis. >


Boarding house tax is a new tax that is placed in the section of hotel tax. According to as potential of Semarang which has attracted migrants who require temporary housing, it is not suprised that many rental on boarding house businesses appear. Boarding house effort on a since a lot of boarding house enacted in Semarang, therefore tax on boarding house was implemented.  Focus of the study is implementation of the policy by using qualitative methods of analytical and descriptive. The study will try to find the widest possible knowledge of by describing and analyzing the research object. The findings of the study shows that the implementation of tax policies boarding house has not run optimally since aspects of the implementation of policies were not adequate. Deficiency lies in lack of technical guidance, human resources (HR) and lack of participation from the taxpayer.  The implementation of Tax policies boarding house  in Semarang Inadequate in order to be succesfully implemented, the existing shortcoming must be fixed. Moreover, improvement of operation away government agencies in Semarang City also important to develop the tax policy. Keywords: Evaluation, Policies, Boarding house tax


This thesis comprises the design and synthesis of chalcone and chromone derivatives and their use in various biological applications, particularly as anticancer agents (targeting proteins associated with cancer pathogenesis) and as potential fluorophores for live-cell imaging. Conveniently, all structures presented were synthesized from commercially available 2 ́-hydroxyacetophenones. Different synthetic strategies were used to obtain an easily accessible chromone scaffold with appropriate handles that allows regioselective introduction of various substituents. Structural diversity was accomplished by using palladium-mediated reactions for the incorporation of suitable substituents for the generation of chromone derivatives that possess different biological activities. Challenging synthesis provided a series of fluorescent 2,6,8-trisubstituted 3hydroxychromone derivatives with high quantum yields and molar extinction coefficients. Two of these derivatives were studied as fluorophores in live-cell imaging and showed rapid absorption, non-cytotoxic profiles and excellent fluorescent properties in a cellular environment. Synthetic chromone precursors, i.e. chalcones, and related dienones were evaluated as antiproliferative agents that interfere with the tubulin-microtubule equilibrium, crucial for cellular mitosis. It was shown that several of the synthesized compounds destabilize tubulin assembly. However, one of the compounds was instead found to stabilize tubulin to the same extent as the known anticancer drug docetaxel, thus representing the first chalcone with microtubule stabilizing activity. Molecular docking was used in order to theoretically investigate the interactions of the chalcones with -tubulin mainly focusing on binding modes, potential interactions and specific binding sites. Structural-based design and extensive synthesis provided chromone-based derivatives that target two different MAP kinases (p38 and MEK1), involved in essential cellular signal transduction pathways. The study resulted in a series of highly selective ATP-competitive chromone-based p38 inhibitors with IC50 values in the nanomolar range. Among those, two derivatives also showed inhibition of p38 signaling in human breast cancer cells. Furthermore, molecular docking was used to study potential structural modifications on the chromone structure in order to obtain highly potent derivatives that selectively target the allosteric pocket on MEK1. Initial studies provided a first generation of non-ATPcompetitive chromone derivatives that prevents the activation of MEK1 with micromolar activities.


By means of a simulator we could expand the test research scope which could not be reached with flight tests, and recover and repeat some special domain of the test course, and make many kinds of experiments about FMCS properties, functions and with embedded failures by combining simulation tests with practical structure. The reliability and creditability of simulation results could be increased under real FMCS in conjunction with semi-entity simulation. Simulators combining a real FMCS with digital simulation have been used extensively for evaluating the large matrix of FMCS contents.