Background : ADHD is classically seen as a disease of children, although it persists in one out of two cases in adults. The diagnosis is based on a long and multidisciplinary process, involving different health professionals, leading to an under-diagnosis of adult ADHD individuals. We therefore present a psychometric screening scale for the identification of adult ADHD, in order to serve as an aid in the decision whether or not to engage in a diagnostic process.Method : We designed the scale from the DSM-5 and administered it to n=110 control individuals and n=110 ADHD individuals. The number of items was reduced using regression techniques. We then performed factor analyses and a machine-learning assessment of the predictive power of the scale.Results : Internal consistency coefficients were calculated satisfactorily for TRAQ10, with Cronbach's alpha measured at .9. The 3-factor model tested was confirmed, with standardized factor loadings greater than .53 for all items. Finally, analysis by machine learning showed that a GNB-type classification algorithm could identify the subject's group appartenance with an high average precision of .88 based only on the participant's responses on the scale.Conclusions : The scale showed sufficient performance for its use in clinical routine. It could thus help to reduce the time required to diagnose ADHD in adults. Similarly, it could be used in research for screening purposes.


Introduces a frame metadata model to facilitate the continuous association rules of Web transactions. A new set of association rules can be derived with the updating of the Web log file by the Web transactions in the frame metadata model. This model consists of two types of classes: static classes and active classes. The static classes describe the Web transactions of the association rule table. The active classes are event-driven, obtaining Web transactions when invoked by a certain event. Whenever an update occurs in the existing Web transactions in the Web log file, a corresponding update is invoked by an event attribute in the method class which computes the association rules continuously. The result is active Web mining that is capable of deriving association rules of Web transactions continuously or incrementally using the frame metadata model.


A new class of [1,2,4]oxadiazolo[4,5-a]thiazolo[2,3-b]pyrimidin-9(10H)-one was prepared in moderate yields by the reaction of nitrile oxide with 2-arylmethylidene-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidin-3-one. The reaction site of dipolarphile is the CN of thiazolo[3,2-a]pyrimidin-3-one rather than the expected CC of arylmethylidene. The structures of the products were characterized thoroughly by IR, elemental analysis, MS, and NMR analysis.


The catabolic pathway for the degradation of aromatic hydrocarbons encoded by Pseudomonas putida TMB differs from the TOL plasmid-encoded pathway as far as regulation of the upper pathway is concerned. We found, by analyzing Tn5-induced mutants and by Southern blot hybridization with appropriate probes derived from the TOL plasmid pWW0, that the catabolic genes of strain TMB were located on the bacterial chromosome and not on the 84-kb plasmid harbored by this strain. The catabolic genes of TMB and pWW0 had sequence homology, as shown by Southern blot hybridization, but differed significantly in their restriction patterns. The analysis of the mutants suggests that a regulatory mechanism similar to that present in pWW0 coexists in TMB with a second mode of regulation which is epistatic on the former and that the chromosomal region carrying the catabolic genes is prone to rearrangements and deletions.


This paper considers the observer-based fuzzy control problem for nonlinear discrete-time systems, which are represented by a type of fuzzy systems with local nonlinear models. By using the estimations of the states and nonlinear functions in local models, sufficient conditions for designing observer-based controllers are given for discrete-time nonlinear systems. A separation property, that is, the controller and the observer can be independently designed, is proved for the class of fuzzy systems. Lastly, a numerical example is given to illustrate the effectiveness of the proposed methods.


Purpose - – This paper aims to examine five distinct consumer reactions, including corporate social responsibility (CSR) awareness, consumers' complaining, boycotting behavior, work preferences and consumer donation behavior. Design/methodology/approach - – The analysis in this paper was based on data collected by a team of experts in the Dubai Chamber of Commerce and Industry from more than 555 United Arab Emirates (UAE) individuals, aged 18 years or older. Our study postulated that there will be no statistically significant differences in any or all of the five reactions among respondents with different age, varying degree of CSR awareness, working preference, donation and boycotting behavior, and methods of complaining about companies or their products. Findings - – Gender analysis indicated that there is a statistically significant difference between male and female in terms of boycotting and complaining behaviors. Our analysis also showed that young consumers in the age group of 18-24 years react significantly different than older age group in terms of job preference. Third, the results of location analysis indicated that the UAE consumers' contacting behavior to a company to voice an opinion about a company's product or services are significantly different across the seven Emirates of UAE. Research limitations/implications - – The findings of this study have many implications. First, there is no doubt that such findings will raise the consumers' awareness of CSR. UAE companies will become more cognizant of their consumers' behavior, especially when the consumers' voice their opinion and show interest in the products or services offered by these companies. The implications of this study for the academics are that this study can be replicated in different parts of the globe to confirm or refute our findings. Practical implications - – The findings of this study will enable UAE companies to design and implement strategies that aim at increasing their efficiency, competitiveness and the ability to compete in global markets. Social implications - – Many of the developing economies started to realize how important CSR is. A fast growing economy such as that of UAE has given such topic an unprecedented attention. The social implication of our findings is that UAE corporations will have to rethink their strategies when it comes to their social responsibility toward society in which they exist. Our findings also enlighten consumers when it comes to their dealing with socially responsible corporations. Originality/value - – This study is unique in that it is the first empirically based study to address the consumer behavior and their reaction toward socially responsible corporations.


An antibody response against a thymic-dependent Ag requires cognate recognition of the Ag by B and T cells. Functional T-B cell (T-B) interaction involves binding of Ag by B cell surface Ig, internalization and processing of Ag, expression of an Ag fragment in the context of Ia, binding of Ag/Ia by the TCR and binding of T cell-derived lymphokines by B cell lymphokine receptors. It is becoming increasingly evident that B and T cell accessory molecules also are involved in T-B interactions. To determine the role of accessory molecules in T-B collaboration, we have designed a system in which T-B interaction was artificially induced in the absence of carrier protein. TNP-modified, turkey gamma-globulin-specific, Th cells were allowed to form conjugates with TNP-specific B cells in the absence of hapten-carrier complex. Both B and T cells were induced to proliferate and B cells partially differentiated into antibody-secreting cells when B cells were cultured with TNP-modified but not unmodified T cells. The activation of B cells by TNP-modified T cells was not MHC restricted but was blocked by anti-Ia antibodies, suggesting a role for Ia distinct from Ag presentation. Furthermore, B cell proliferation was also inhibited by antibodies to L3T4 and LFA-1, suggesting a functional accessory role for these molecules in induction of B cell proliferation/differentiation.


BACKGROUND
Telomeres are essential for the integrity of chromosome ends during cell division and their involvement in different processes linked to aging has been established. These chromosome components are involved in spermatogenesis and seem to play an important role in fertilization and embryo development. Telomere length is shortened with each cell division. Recently, short sperm telomere length has been proposed as a potential biomarker of male infertility.

OBJECTIVES
To conduct a systematic review and meta-analysis of studies exploring the association between sperm and/or leukocyte telomere length with sperm quality parameters and different infertility conditions.

MATERIAL AND METHODS
A systematic review and meta-analysis was conducted with studies from Medline-PUBMED and Cochrane Library databases until May 2022. Eligible studies included cohort, cross-sectional and case-control studies, and telomere length in sperm and/or leukocytes cells was defined as the exposure. Semen quality parameters or infertility conditions (e.g., oligozoospermia, asthenozoospermia, teratozoospermia, or other spermatogenic impairment combinations) were defined as the outcomes.

RESULTS
Twenty-four observational studies were included. In the qualitative analysis, high heterogeneity was observed between studies regarding the associations between telomere length and semen parameters in different normozoospermic/fertile and oligozoospermic/infertile populations. In the meta-analysis, sperm and leukocyte telomere length were shorter in infertile compared to fertile individuals (mean difference, MD; 95% confidence interval, CI) (-1.43; -1.66 to -1.21; P-value<0.001, and -1.67; -2.02 to -1.31; P-value<0.001, respectively). Moreover, in terms of sperm telomere length, these differences were also significant between individuals with a normal seminogram and individuals with low quantity of spermatozoa in the ejaculate (-0.97; -1.32, -0.61; P-value<0.001).

CONCLUSION
The current systematic review and meta-analysis suggest the potential role of sperm or leukocyte telomere length as a reliable biomarker of semen quality, which may help distinguish between infertility conditions beyond the routine semen analysis. This article is protected by copyright. All rights reserved.


We consider Suter's (see Proc. CVPR94, Seattle, p.939-948, 1994) DIV-CURL optical flow methods, wherein the problem of computing a velocity field from an image sequence is regularized using smoothness conditions based on the divergence and curl of the field. In particular, we develop stochastic formulations of DIV-CURL splines using the linear smoothing theory of Adams, Willsky, and Levy. Our models are shown to be well posed and thus can be used in both simulating and estimating velocity fields having known stochastic properties. As a special case, our stochastic model reduces to that developed by Rougee, Levy, and Willsky (1984) for the classical Horn and Schunck's (1981) optical flow.


According to S., Plato's 'chief philosophical' aim in the Parmenides is twofold: to 'destabilize the false privileging of individual things' and to establish the 'priority of the sources of intelligibility [i.e. forms] over individual things'. S. defends his thesis in five chapters. Chapters 1 and 2: in the first part of the Parmenides, Parmenides creates perplexities for Socrates, who unwittingly privileges individual things and separates forms from things. The intention of this Zenonian 'eristic' dialectic-critique is to educate Socrates. Chapter 3: the subject of the first hypothesis (H1), 'if one is', refers to a pure one, which is neither a form nor a participant. This view belongs to the inexperienced Aristoteles; it commits him to a spatio-temporal one, which is paradoxically not subject to space and time. However, this contradiction already implies its philosophical solution. This is where the more positive 'scientific dialectic', which closely resembles the eristic one, begins to emerge. Chapter 4: the solution is given in H2, which specifies the 'locative and durative "is"' that characterises 'every individual one'. This 'is' refers to the 'eidetic structure of spatiotemporal objects', that is, to their 'a-spatial and atemporal' ground, which is also the ground of their philosophical intelligibility. Thus H2 furnishes 'the foundation' of an adequate theory of forms, which holds that the spatio-temporal 'things are . . . dependent on a set of eidetic conditions'. Chapter 5: a more 'transformed perspective' is established in the post-H2 exercises. More specifically, 'the dialectical study' shows that 'the instant', (H2a), 'the idea of limit and the unlimited (H3), the idea of "veridical predication" (H5), and the idea of appearance (H7)' are the necessary further eidetic conditions of the now 'transformed understanding of the spatio-temporal "one"'. In conclusion, the Parmenides illustrates more successfully than Plato's other dialogues, including the Republic, that 'the world of appearance is governed by the forms', which are also the sources of 'higher intelligibility'. S.'s creative interpretation of the Parmenides is interesting, though it is bound to be controversial.


The first isolable, photoswitchable N-heterocyclic carbene was synthesized and found to undergo reversible electrocyclic isomerization upon successive exposure to UV and visible radiation. The UV-induced ring closure afforded substantial changes to the electronic structure of the dithienylethene-based NHC, as evidenced by changes in the corresponding UV/Vis absorption and (13)C NMR spectra. Likewise, molecular orbital calculations revealed diminished electron density at the carbene nucleus upon photocyclization, consistent with the enhanced electrophilicity displayed by the ring-closed form. The photoswitchable NHC was successfully switched between its ring-opened and ring-closed states with high fidelity over multiple cycles. Furthermore, the ring-closed isomer was found to undergo facile N-H bond activation, allowing for the controlled capture and release of ammonia upon cycling between its isomeric states.


Purpose Combination therapy is a promising strategy to treat cancer due to the synergistic effects. The drug and gene co-delivered systems attract more attention in the field of combination therapy. Materials and methods In the present research, poly(ethylene glycol)-ε-poly(caprolactone) block copolymer was used for the co-loading of 5-fluorouracil (5-FU) and gene. The physicochemical characteristics, in vitro and in vivo anticancer, and gene transfection efficiency were tested on colon cancer cells and tumor-bearing mice. Results 5-FU and gene co-loaded nanocarriers had a size of 145 nm. In vivo gene delivery results showed about 60% of gene-positive cells. Tumor volume of nanocarrier groups at day 21 was around 320 mm3, which is significantly smaller compared with free 5-FU group (852 mm3) and control group (1,059 mm3). The maximum 5-FU plasma concentration in nanocarrier groups (49 µg/mL) was significantly greater than free 5-FU (13 µg/mL). At 24 hours, drug level of nanocarrier groups was about 2.8 µg/mL compared with 0.02 µg/mL of free 5-FU. Conclusion The resulting nanocarriers co-loaded with the anticancer drugs and genes could be considered as a promising nanomedicine for colorectal cancer therapy.


We propose what we believe is a new approach to 3D reconstruction through the design of a 3D voxel volume, such that all the image information and camera geometry are embedded into one feature space. By customising the volume to be suitable for segmentation, the key idea that we propose is the recovery of a 3D scene through the use of globally optimal geodesic active contours. We also present an extension to this idea by proposing the novel design of a 4D voxel volume to analyse the stereo motion problem in multi-view image sequences.


The transfer of environmental knowledge from one country to another is a widespread practice. This paper presents an evaluation framework to assess the effectiveness of projects that involve such a transfer. It focuses on project-based interventions that are supported by actors of the transferring country. The developed framework is based on the recognition that policy transfer interventions are multi-actor processes and are, therefore, best understood as processes of social interaction. Whether such processes contribute to goal achievement depends on the engagement of users in the process. We further argue that the realization of ultimate outcomes can be estimated or explained on the basis of changes in the characteristics of actors involved. The framework is applied to a Dutch-funded project on flood risk planning in Romania. The ultimate goal of this intervention was to contribute to the solving of water-related problems in Romania and to generate follow-up projects for the Dutch water sector. Central to the project was the active involvement of regional stakeholders in the development of regional spatial plans. Application of the framework shows that the case study is unlikely to contribute to the realization of the desired ultimate outcomes. Process explanations include poor institutional embedding, limited diffusion of project results and a lack of adaptive management. The active involvement of local and regional stakeholders created a shared motivation and knowledge base. However, the project got stuck due to a lack of resources as actors with decision-making power were not involved and ignored the project results.


Objectives This study aims to assess the nailfold capillary changes in patients with systemic lupus erythematosus (SLE), particularly among those with Raynaud's phenomenon (RP), and the correlation between nailfold capillary changes and autoantibodies and disease activity. Patients and methods A total of 85 patients (9 males, 76 females; median age 31 years; range, 15 to 58 years) with newly diagnosed SLE were selected between July 2016 and July 2018 from our hospital. Disease activity was scored by the SLE Disease Activity Index. Nailfold capillaroscopy (NFC) was performed in all patients. Results Normal pattern, non-specific pattern, and scleroderma pattern were found in 13 (15.3%), 64 (75.3%), and eight (9.4%) patients, respectively. There was no significant difference between anti-double stranded deoxyribonucleic acid, anti-Smith antibodies, and low complements (all p>0.05), while significant differences of NFC pattern were found between low disease activity and high disease activity (p=0.002). RP was present in 31.7% of SLE patients, and the NFC findings in SLE patients with and without RP were significantly different in dilatation (81.5% vs. 14.0%). Conclusion The results of our study showed that capillary changes were very common in patients with SLE, which seem to associate with disease activity and RP condition.


Cardiovascular disease remains the leading cause of death in western countries. Despite advances in acute management of patients, secondary prevention remains essential and should include cardiac rehabilitation. Recent data have confirmed the interest of this management in the various conventional indications : coronary disease, valvular heart disease, heart failure and heart transplantation. New indications emerge with some benefit that should be evaluated : ventricular assistance, pulmonary hypertension, trans-catheter aortic valve implantation. However, the different rehabilitation programs proposed are still too uneven in content and duration and the number of patients participating in these programs remains low. Home based cardiac rehabilitation technologies have already shown some effectiveness and could improve some of the weaknesses of rehabilitation programs. Again protocols and tools need to be improved and standardized. The budgetary impact will also have to be studied further.


Telementoring surgeons as they perform surgery can be essential in the treatment of patients when in situ expertise is not available. Nonetheless, expert mentors are often unavailable to provide trainees with real-time medical guidance. When mentors are unavailable, a fallback autonomous mechanism should provide medical practitioners with the required guidance. However, AI/autonomous mentoring in medicine has been limited by the availability of generalizable prediction models, and surgical procedures datasets to train those models with. This work presents the initial steps towards the development of an intelligent artificial system for autonomous medical mentoring. Specifically, we present the first Database for AI Surgical Instruction (DAISI). DAISI leverages on images and instructions to provide step-by-step demonstrations of how to perform procedures from various medical disciplines. The dataset was acquired from real surgical procedures and data from academic textbooks. We used DAISI to train an encoder-decoder neural network capable of predicting medical instructions given a current view of the surgery. Afterwards, the instructions predicted by the network were evaluated using cumulative BLEU scores and input from expert physicians. According to the BLEU scores, the predicted and ground truth instructions were as high as 67% similar. Additionally, expert physicians subjectively assessed the algorithm using Likert scale, and considered that the predicted descriptions were related to the images. This work provides a baseline for AI algorithms to assist in autonomous medical mentoring.


The general prevalence of cardiac arrhythmias in 2,820 consecutive patients was 78%, ranging from 44% in multiple trauma patients to 90% in primary cardiovascular patients. Patients without recorded arrhythmias (22%, n = 621) were used as control subjects.No clinical group was free from cardiac arrhythmias. Atrial tachyarrhythmias had the highest prevalence in the population as a whole (28%) and in all clinical groups except multiple trauma. Atrial fibrillation was the most common atrial arrhythmia (52%); ventricular arrhythmias followed. Patients with atrial tachyarrhythmias, nodal rhythm, ventricular bradyarrhythmias, and ventricular rapid rhythms had significantly (p < .01) increased mortality rates (40%, 44%, 77%, and 51%, respectively) when compared with patients without arrhythmias (35%). The relative risk of dying (RRD) of these clinical groups was increased by 1.16, 1.27, 2.20, and 1.47, respectively.Patients with cardiorespiratory precipitating disease and any arrhythmia except atrial bradyarrhythmia had a mortality rate between 32% and 74%, significantly (p < .05) different from that of patients within the same clinical groups without arrhythmias. The RRD was increased by 1.67 to 3.40.Septic patients with atrial tachyarrhythmia or nodal rhythm and neurologic patients with nodal or ventricular arrhythmias also had significantly (p < .01 and .05, respectively) increased mortality and were at higher RRD (1.53 to 2.81).Our data suggest that severe illness may be present in some clinical groups of critically ill patients with cardiac arrhythmias.


Among disease vectors, Aedes aegypti (L.) (Diptera: Culicidae) is one of the most insidious species in the world. The disease burden created by this species has dramatically increased in the past 50 years, and during this time countries have relied on pesticides for control and prevention of viruses borne by Ae. aegypti. The small number of available insecticides with different modes of action had led to increases in insecticide resistance, thus, strategies, like the "Incompatible Insect Technique" using Wolbachia's cytoplasmic incompatibility are desirable. We evaluated the effect of releases of Wolbachia infected Ae. aegypti males on populations of wild Ae. aegypti in the metropolitan area of Houston, TX. Releases were conducted by the company MosquitoMate, Inc. To estimate mosquito population reduction, we used a mosquito abundance Bayesian hierarchical estimator that accounted for inefficient trapping. MosquitoMate previously reported a reduction of 78% for an intervention conducted in Miami, FL. In this experiment we found a reduction of 93% with 95% credibility intervals of 86% and 96% after six weeks of continual releases. A similar result was reported by Verily Life Sciences, 96% [94%, 97%], in releases made in Fresno, CA.


Background Previous surveys on the relationship between physicians and pharmaceutical representatives (PRs) have been of limited quality. The purpose of our survey of practicing physicians in Japan was to assess the extent of their involvement in pharmaceutical promotional activities, physician characteristics that predict such involvement, attitudes toward relationships with PRs, correlations between the extent of involvement and attitudes, and differences in the extent of involvement according to self-reported prescribing behaviors. Methods and Findings From January to March 2008, we conducted a national survey of 2621 practicing physicians in seven specialties: internal medicine, general surgery, orthopedic surgery, pediatrics, obstetrics-gynecology, psychiatry, and ophthalmology. The response rate was 54%. Most physicians met with PRs (98%), received drug samples (85%) and stationery (96%), and participated in industry-sponsored continuing medical education (CME) events at the workplace (80%) and outside the workplace (93%). Half accepted meals outside the workplace (49%) and financial subsidies to attend CME events (49%). Rules at the workplace banning both meetings with PRs and gifts predicted less involvement of physicians in promotional activities. Physicians valued information from PRs. They believed that they were unlikely to be influenced by promotional activities, but that their colleagues were more susceptible to such influence than themselves. They were divided about the appropriateness of low-value gifts. The extent of physician involvement in promotional activities was positively correlated with the attitudes that PRs are a valuable source of information and that gifts are appropriate. The extent of such involvement was higher among physicians who prefer to ask PRs for information when a new medication becomes available, physicians who are not satisfied with patient encounters ending only with advice, and physicians who prefer to prescribe brand-name medications. Conclusions Involvement in pharmaceutical promotional activities is widespread among practicing physicians in Japan. The extent of such involvement varies according to certain physician characteristics. As a group, they are at risk for influence by promotional activities.


The academic advantages of knowledge are often compromised when learners and teachers hold counterproductive epistemic beliefs, that is, personal convictions about the nature of knowledge and knowing. This study was an investigation of associations between prospective physical educators' game-specific epistemic beliefs (worldviews and beliefs in simple and stable knowledge and the need for cognition) and their preferred instructional model (Direct, Teaching Games for Understanding, or Sport Education) for teaching games in physical education. Following theoretical and applied instruction of each instructional model, 311 junior and senior undergraduate students enrolled in elective formal games classes at a mid-sized public university in south-central Canada completed several previously validated quantitative measures and one open-ended qualitative item. Those reporting a high need for cognition in games had higher contextualist and lower realist worldviews, along with more sophisticated beliefs about the simplicity and stability of knowledge. Participants most preferred a contextualist epistemic worldview and the TGfU instructional method, and a significant main effect difference was found in epistemic beliefs by preferred instructional model. Students' qualitative comments about each instructional  model also reflect a collective awareness of the dynamics of the models and their potential advantages and disadvantages in particular learning settings. It appears useful to increase knowledge about the potential role of epistemic worldviews and beliefs on games teaching preferences in prospective physical educators, particularly if these educators are to foster availing epistemic beliefs in their students.


Purpose: Some physiological events in women's life such as pregnancy and lactation can be associated to a condition known as Transient Osteoporosis of the Hip (TOH); if not promptly diagnosed it can lead to significant consequences such as femoral neck fracture. In this paper we describe a case of bilateral TOH, focusing on the importance of early treatment and how it influenced the outcome. Methods: A 40 years old post-delivery woman came to our attention for hip pain and a left femoral neck fracture was diagnosed. Magnetic resonance (MRI) showed bilateral edema of the femoral head. She underwent total hip replacement on the left side; toe-touch weight bearing and pharmacological therapy were prescribed for the right hip. Results: MRI at nine months showed complete regression of the femoral head and neck edema; the patient was clinically asymptomatic. Conclusion: If not promptly diagnosed and treated, TOH can potentially evolve in fracture. Many therapeutic strategies have been suggested since now; we believe that avoiding weight bearing on the involved hip as early as possible is the key to recovery.


Aims: To determine the levels of expression of ZNF652 and its relevance to prognosis in vulvar squamous cell carcinomas. Methods: 22 cases of vulvar intraepithelial neoplasia (VIN) and tumours from 217 patients with vulvar squamous cell carcinomas were investigated for expression of ZNF652 using immunostaining methods. The effect of ZNF652 ectopic expression was determined in the vulvar carcinoma cell line SW954 by western and cell-based assays. Results: High levels of ZNF652 nuclear expression were observed in 5 (100%) of VIN I, 6 (75%) of VIN II and 109 (50.2%) of the vulvar carcinomas, whereas low levels were seen in 2 (25%) VIN II, 9 (100%) of VIN III and 108 (49.8%) of the vulvar carcinomas. High levels of ZNF652 expression in the vulvar carcinomas were significantly correlated to high expression of EphA2. However, when correcting for multiple testing this correlation was lost. No association was identified between ZNF652 expression and p16, p21, p27, p53, cyclin A, D1, D3, E, EphrinA-1 and human papillomavirus. Variations in levels of ZNF652 were not related to prognosis. Low levels of ZNF652 protein were identified in the vulvar carcinoma cell line SW954. Furthermore, SW954 cells ectopically expressing ZNF652 showed reduced cell proliferation and the ability to form colonies on plastic. Conclusions: ZNF652 protein expression is reduced in 25% of VIN II, 100% of VIN III and approximately 50% of the cases of vulvar squamous cell carcinoma, and may be an early event in the pathogenesis of vulvar squamous cell carcinoma. Variations in the levels of ZNF652 were not related to patient's prognosis.


We present a Monte Carlo simulator of the population of binary stars within the solar neighborhood. We have used the most updated models for stellar evolution, a complete treatment of the Roche lobe overflow episodes, as well as a full implementation of the orbital evolution. Special emphasis has been placed on processes leading to the formation of binary systems in which one of the members is a white dwarf. As a preliminary application of our Monte Carlo simulator we have performed a statistical study of the scenarios leading to type Ib supernovae events within our Galaxy.


The results of a series of comparative density measurements on various mercury samples are presented together with a comment on the long term stability of the density of mercury.


The plant lignans, secoisolariciresinol (SEC) and matairesinol (MAT) are converted to the metabolites, enterodiol (ED) and enterolactone (EL), known as the mammalian lignans in the gastrointestinal tract. In vitro, mammalian lignans may have both estrogenic and antiestrogenic properties. Increased consumption of lignan-rich foods through the addition of brans, oilseeds and cereals in bread, muffins, health bars and breakfast cereal or emphasis on fruits and vegetables in a balanced diet has lead to the need for reliable data on lignan content in foods. The quantitative determination of the lignans to date by a direct method has involved hydrolysis of the glycoside and analysis of the resulting aglycones (SEC and MAT). The in vitro fermentation methodology, which simulates colonic fermentation with fecal microflora, has been utilized in the indirect analysis of foods where ED and EL are measured as an indication of the plant lignans. A compilation of the available data on the lignan content of various food groups and the assessment of these data by contrasting two different analytical methodologies are given. In general, in vitro fermentation gave higher values, compared to direct analysis, for most foods for which comparisons could be made.


This study was designed to compare insulin release during the intravenous glucose tolerance test (GTT) in normal blacks and whites. The study included 14 normal blacks (9 males and 5 females) and 15 normal whites (10 males and 5 females). The index of first phase insulin release (sum of 1 + 3 min insulin levels and total area under the curve for the first 10 min of the GTT) was significantly higher in blacks. The difference is discussed in terms of genetic and acquired traits.


computing is a modern as well as advanced computing technology, which provides flexible, on-demand, and low-cost usage of computing resources, but the information is outsourced to some cloud server providers, and various privacy concerns emerge from it. Different techniques based on the attribute-based encryption have been proposed to secure the cloud storage. Sharing of personal health record is an emerging patient centric model of health data exchange which is often outsourced by the third party such as cloud server. The confidentiality of the personal record is major problem when patient use commercial cloud server to store their health records, it can be viewed anyone is the Attribute- Based Encryption (ABE) has emerged as a promising platform providing end-to-end data security and privacy in cloud storage system. It allows data owners to define access policies and encrypt the data under the policies, such that only users whose attributes satisfying these access policies can decrypt the data. We also leverage Windows Communication Foundation (WCF) Technique that allows secure communication or exchange of data in real time. Personal Health Record (PHR) contains the details of the patient health which is monitored and handled by the patients and they can add, delete, and modify their own record.


Some B-cell neoplasms, including hairy cell leukemia (HCL), lack expression of the adhesion molecule leukocyte function antigen-1 (LFA-1/CD11a). Additionally, HCL cells express relatively low amounts of intercellular adhesion molecule-1 (ICAM-1/CD54) and may therefore be an inappropriate target for recognition by T cells or lymphokine-activated killer (LAK) cells. We tested whether these molecules were inducible on HCL cells and if induction would lead to enhanced susceptibility to lysis by LAK cells or cytolytic T cells. CD11a expression was induced by incubation with interferon-alpha (IFN-alpha) or interleukin-4. CD54 was induced by culturing the cells irrespectively of the addition of cytokines. Expression of CD11a and CD54 did not enhance susceptibility to either autologous or allogeneous LAK cells. However, induction of these adhesion molecules was accompanied by enhanced susceptibility to lysis by cytotoxic T lymphocyte clones. This lysis could be reversed by the addition of anti-CD11a and anti-CD54 antibodies. Finally, we monitored the expression of CD11a and CD54 on HCL cells from patients during IFN-alpha therapy. In one of four patients monitored, we observed rapid in vivo induction of CD11a and CD54 on the leukemic cells during IFN-alpha therapy. These studies provide a model for studying immunosurveillance in HCL.


Landmark-based geometric morphometrics were used to evaluate the effect of flow and depth in the water column on the body size and shape of Brycon henni from river and stream populations. The dendrogram showed that stream populations clustered apart and showed significantly smaller centroid size and narrower bodies than river populations, indicating a role for flow and depth on whole body morphometric variation. The results are concordant with morphometric variation described in other fish species and provide the first insights into phenotypic variation in natural populations of B. henni.


The urinary metabolites of flavanone in the rate were investigated using a gas chromatographic mass spectrometric method employing an OV-1 capillary column. Forty-three metabolites were detected and the most prominent of these were identified. The most common metabolic reactions were reduction of the keto group and hydroxylation at the 3- or 6-positions. Little hydroxylation occurred in ring B. The major metabolites were flavan-4 alpha-ol, trans-3-hydroxyflavan-4 beta-ol, 6-hydroxyflavanone and 6-hydroxyflavan-4 beta-ol. Gas chromatography analysis of underivatized flavanone metabolites, especially with stainless steel columns, results in the formation of dehydrated products including flavone, flav-3-ene and flavanone itself.


We investigate the self-tapping phenomena for two weakly coupled Bose–Einstein condensates with a rapid periodic modulation of the atomic scattering length. By using an averaging method, the equations of motion of the slow dynamics are derived to analyze the self-trapping behavior. It is shown numerically that under certain conditions, an alternative self-trapping in either well appears.


This paper examines the integration of the Indian stock market with the stock markets of Japan, the United Kingdom, the United States and China over the period ranging from 1 January 1998 to 31 October 2008 using Johansen and Engle-Granger co-integration tests and Granger's causality test. The analysis of daily data shows that the Indian stock market is integrated with the US stock market, but not with that of Japan, the UK and China. Unidirectional causality is found in most cases. The findings have important implications for investment and speculative decisions.


Purpose: The current understanding of circadian regulation disorders and their involvement in glaucoma pathophysiology are poorly understood, yet they may have a substantial impact on the onset and progression of glaucoma. Herein, we review and summarize all the available literature on circadian rhythm disorder and glaucoma to uncover the impact on glaucoma risk, and we highlight future research and potential novel targets for glaucoma management. Materials and Methods: A review of the relevant literature was performed through PubMed through August 1, 2019. Results: Within a normal circadian rhythm, intraocular pressure (IOP) peaks at night, whereas blood pressure (BP) troughs at night. High nocturnal IOP coupled with low nocturnal systemic BP results in low ocular perfusion pressure and potential for unobserved damage to retinal tissues and the optic nerve. Circadian-related melatonin and sleep disorders also result in changes in IOP and ocular perfusion pressure that lead to the progression of glaucoma. In addition, impaired perception of light input due to glaucoma can subsequently lead to abnormal serum levels of melatonin, resulting in circadian rhythm misalignment. This disruption of the circadian rhythm also contributes to sleep and mood disorders, common in individuals with glaucoma. As regards treatment, glaucoma medications that lower nocturnal IOP without influencing nocturnal BP or diminishing circadian variation seem most effective. Conclusions: Glaucoma progression is influenced by multiple physiological factors regulated by the circadian rhythm. Progression of the disease may also cause physiological changes that lead to circadian-related issues. Further research is warranted on the diurnal cycle, melatonin-mediated processes, and their influence on glaucoma management.


Orthogonal frequency-division-multiplexing (OFDM) technology is widely used in visible light communication (VLC) to achieve high data rate transmission. However, the traditional direct-current (DC)-biased optical OFDM (DCO-OFDM) VLC systems suffer from the high peak-to-average power ratio (PAPR) which causes signal clipping distortion, and, thus, performance degradation. Furthermore, severe high-frequency fading due to the limited system bandwidth results in poor bit error rate (BER) performance. Precoding matrix (PM) techniques have been proposed to enhance the performance of VLC OFDM transmission, but a little or no work has been carried out in investigating the theory of PM used in OFDM VLC systems. In this paper, we aim to reveal the theory of PM-DCO-OFDM for a VLC system. To figure out the intrinsic laws of a PM method, we investigate the principles of PAPR reduction, clipping distortion optimization, and signal-to-noise ratio (SNR) distribution equalization. Based on the analysis of PAPR, we theoretically proved the simplicity of PM as a method to reduce the possibility of high PAPR by improving the autocorrelation performance of input symbols. The clipping distortion could be improved due to the reduction of high PAPR. Moreover, the relatively uniform SNR distribution can be achieved by PM through equalizing the clipping and channel noise, which is beneficial to improve the BER performance in high-frequency constrained systems. However, the PM method used in a DCO-OFDM VLC system should consider the transmitting power, modulation format, and transmission distance as a whole to achieve the transmission performance improvement. The simulation results demonstrate the complementary cumulative distribution function of PAPR can be reduced ∼3 dB, while the performance of clipping distortion power and clipping error probability are significantly improved. Furthermore, experiment is carried out with results showing that the PM method can improve the BER performance in the case that VLC OFDM transmission has enough transmitting power, but with the low transmitting power, the PM also can damage the BER performance. The simulation and experiment results are consistent with our theoretical analysis.


Stuart's medium was originally prepared for use as a transport medium for gonococci (Stuart, 1946; Stuart, Toshach, and Patsula, 1954), but has now gained wide employment as a suitable transport medium for many micro-organisms (Stuart, 1956; Cooper, 1957; Gastrin, Kallings and Marcetic, 1968) including Trichomonas vaginalis (Stuart, 1956; Whittington, 1957; Odegaard, 1962). The original Stuart's medium is a semi-solid, nonnutrient medium, which prevents oxidation and dessication of the micro-organisms transported. Since a solid medium is easier to handle, the original medium has been modified by increasing the agar concentration (Reyn, Korner, and Bentzon, 1960; Ringertz, 1960). This modification, together with charcoal-impregnated applicators (Moffett, Young, and Stuart, 1948), has been used since 1960 in this Department, for the transport of freshly-obtained material to be cultured for gonococci. Since 1962 the same equipment has been used for transport of T. vaginalis (Nielsen, 1965). Apart from the investigation by Odegaard (1962), no detailed information is available concerning the survival time of T. vaginalis in Stuart's medium. Since knowledge on this point is of importance for laboratories using the medium for transport purposes, this problem became the subject of the present investigation.


Rationale: Gastric cancer patient with cold agglutinin syndrome (CAS) is an extremely rare entity. This kind of patients is very sensitive to the environment, and they always need scrupulous perioperative treatment, however the experience of perioperative treatment for these patients has been seldom reported. Patient concerns: The patient was a 54-year-old male. He suffered diarrhea for 3 months, and later the gastroscopy found a tumor located in the gastric antrum and the biopsy was performed. The pathological result reported that it was poorly differentiated gastric adenocarcinoma. The patient was previously diagnosed with CAS 8 years ago. Diagnoses: Gastric cancer patient with cold agglutinin syndrome (CAS). Interventions: After 2-month neoadjuvant chemoradiotherapy, the patient underwent open radical distal gastrectomy and D2 lymph node resection. No blood transfusion was performed. Eight days after operation, the patient was discharged. During the perioperative period, scrupulous plan was performed, including careful vital signs monitoring, rigid environment thermal control, infusion warming, proper methods for blood sampling and transmission, and mental relief. Outcomes: Curative resection was achieved and the patient was discharged. The perioperative period was uneventful. Lessons: Because of the fragility of CAS, the perioperative management was vital for this patient. Scrupulous plan may guarantee the safety of the patients.


The absolute, average, and differential phase shifts that p- and s-polarized light experience in total internal reflection (TIR) at the planar interface between two transparent media are considered as functions of the angle of incidence phi. Special angles at which quarter-wave phase shifts are achieved are determined as functions of the relative refractive index N. When the average phase shift equals pi/2, the differential reflection phase shift delta is maximum, and the reflection Jones matrix assumes a simple form. For N > square root 3, the average and differential phase shifts are equal (hence deltap = 3 deltas) at a certain angle phi that is determined as a function of N. All phase shifts rise with infinite slope at the critical angle. The limiting slope of the delta-versus-phi curve at grazing incidence (partial partial differential delta/partial partial differential phi)phi=90 degrees = -(2/N)(N2 - 1)1/2 = -2 cos phic, where phic is the critical angle and (partial partial differential2 delta/partial partial differential phi 2)phi=90 degrees = 0. Therefore delta is proportional to the grazing incidence angle theta = 90 degrees - phi (for small theta) with a slope that depends on N. The largest separation between the angle of maximum delta and the critical angle is 9.88 degrees and occurs when N = 1.55377. Finally, several techniques are presented for determining the relative refractive index N by using TIR ellipsometry.


CircRNAs acting as miRNA sponges play important roles in the growth process of animal individuals. The prolificacy trait of goats is involved in many pathways, however, the variation of circRNA expression profiles in the different phases of the estrus cycle at high and low fecundity groups is still unknown. Here, we analyzed the circRNA profiles of ovarian tissues among high and low fecundity groups in the follicular phase (HF vs LF), high and low fecundity groups in the luteal phase (HL vs LL), and high and low fecundity in the whole estrus cycle (HF vs HL and LF vs LL) using RNA-seq. A total of 283 (114 upregulated and 169 downregulated), 559 (299 upregulated and 260 downregulated), 449 (254 upregulated and 195 downregulated), and 314 (210 upregulated and 104 downregulated) differentially expressed (DE) circRNAs were screened in HF vs LF, HF vs HL, HL vs LL, and LF vs LL groups, respectively. Enrichment analysis suggested that the targeting of DE circRNAs was mainly enriched in oocyte meiosis, the GnRH signaling pathway, and estrogen signaling pathway. After integrating our previous study of miRNA-seq, there were 56 miRNAs that could target to 192 DE circRNAs, including the miR-133 family (including miR-133a-3p and miR-133b), miR-129-3p, and miR-21, which also had important influence on the prolificacy trait of goats. Then, 18 circRNAs with coding potential were obtained by four software predictions, and 9 circRNAs were validated by RT-qPCR. Together, circRNAs play a key role in the prolificacy trait and the transformation of the follicular phase to the luteal phase in the estrus cycle of goats.


After analysis of 423 hemodialysis patients in a transfusion program and 461 cadaver-donor renal transplants, we found that HLA-DR2 frequency was significantly higher in the responder (36%) than in the non-responder patient group (19%), according to the percentage of PRA (panel reactive antibodies). Among DR2+ patients, the percentage of hypersensitized patients was twice that of DR2- patients. Graft survival curves in cadaver-donor renal transplants indicated a significantly lower survival when recipients were DR2+, even in recipient-donor pairs identical for class II antigens but mismatched for class I antigens. The prognostic probability of low response to transfusions by a stepwise logistic regression analysis showed the influence of sex and DR2 phenotype. By multivariant discriminant analysis, we found that the DR2 phenotype was one of the most influential transfusion sensitization risk factors. Our preliminary conclusion is that DR2 can be related to immune responsiveness to class I antigens.


H.264 video coding standard supports 3D video through dedicated Stereo Video Information (SVI) Supplemental Enhancement Information (SEI) message. This SEI message allows main and auxiliary frames be coded into alternative pictures in which disparity information can also be utilized. However, due to the presence of both disparity and motion vectors at the neighborhood of a given macroblock, the H.264 predicted motion vector motion vector concept becomes less efficient. This paper presents a novel motion and disparity vector prediction algorithm that overcomes this drawback. Results show that the proposed algorithm achieves up to 1dB gain compared to the conventional motion vector prediction algorithm.


Thirty amides patterned after the antiarrhythmic drug changrolin were synthesized and their antiarrhythmic and parasympatholytic activities were assessed. There was no correlation between antiarrhythmic and parasympatholytic activities. Several of the amides were found to be potent antiarrhythmic agents that possessed low parasympatholytic activity. All of the compounds appear to act by a class I mechanism.


An approach to the construction of the CNOT quantum logic gate for a 4-dimensional coupledqubit model with weak but otherwise arbitrary coupling has been given recently [M. R. Geller et al., Phys. Rev. A 81, 012320 (2010)]. How does the resulting fidelity depend on the form of qubit-qubit coupling? In this paper we calculate intrinsic fidelity curves (fidelity in the absence of decoherence versus total gate time) for a variety of qubit-qubit interactions, including the commonly occurring isotropic Heisenberg and XY models, as well as randomly generated ones. For interactions not too close to that of the Ising model, we find that the fidelity curves do not significantly depend on the form of the interaction, and we calculate the resulting interaction-averaged fidelity curve for the non-Ising-like cases and a criterion for determining its applicability.


Historically, Korea has experienced much suffering and forbearance, including invasions and annexation by the Japanese Empire in the first half of the 20th century; and country`s current territorial division. Despite periods of occupation and disturbance, Korea`s tourism transportation industry has evolved and grown significantly. This study suggests a policy plan to cope with the country`s future environment by considering both the history and present condition of the tourism transportation industry. If organizations within various industries and the government, academic circles, and civil assemblies can endeavor to collaborate cooperatively, the future of the tourism transportation industry will help elevate Korea`s position as an important economic power in Asia and beyond.


Objective: This article addresses institutional arrangements and participation issues in the case study of a commons dilemma in the peri-urban sphere. It aims to evaluate the institutional robustness according to Ostrom's eight design principles of a Payments for Ecosystem Services (PES) arrangement in the Miringuava River Basin, São José dos Pinhais, Brazil. Methodology: Using documentary analysis, and semi-structured interviews with stakeholders we analyze the applicability of Ostrom's eight design principles. Relevance: Our analysis and discussion shed light on social and institutional dimensions that might be insufficiently considered by the local public administration. Results: While our analysis showed that most principles apply in some measure to the case study, favoring the implementation of PES, there are divergences in terms of monitoring, conflict resolution, and sanctions that hint to particular problems of peri-urban commons management. We conclude that PES could become a problem of collective action, representing a mechanism to increase robustness of peri-urban institutions, which allowed us to interpret ES as a common. Theoretical contributions: The PES for forest areas, has run parallel to an agricultural transition to organic farming desired by environmental organizations but resisted by local farmers. While the conservation is justified by the reduction of water treatment costs and an increase in water availability, social implications of this choice turn out to be much more complex. Management contributions: There is a need for the creation of institutional arrangements that consider power imbalances and to expand the different forms of participation in the situated action arenas created for governance and management of a common.


THAI A HILH L)tc,Rt.t of. NUrRltNI W A ~ I A I H ~ ~ I K o G F N ~ I ~ Y exists in soil resources, in a broad range of ecosystems, has been confirmed by studies dating back to the 1970s (Hall 1970, Jackson & Caldwell 1992, Gonzalez & Zak 1994, Gross & Pregitzer 1995). Further, this heterogeneity occurs at a scale that would allow an individual plant to experience a variety of belowground nutrient environments. Thus, the ability of a plant to increase nutrient uptake in nutrient-rich patches may be critical to its competitive success. There are both morphological and physiological methods of foraging for edaphic resources (review in Robinson 1994). In this study, morphological mechanisms of foraging are emphasized, in which changes in the rate and form of root growth allow a plant to take advantage of localized increases in nutrient availability. There are three mechanisms by which morphological foraging can occur: (1) increasing rooting density, (2) increasing the proportion of fine roots, and (3) increasing fine root turnover rates. Root foraging is often limited to the frequently observed phenomenon of a plant's root system growing prolifically into areas of high nutrient concentration and relatively little into areas that are nutrient-poor. The existence of this type of foraging has been demonstrated in many studies (Hutchings 1988, Pregitzer et al. 1993, Cain 1994, Caldwell 1994, Einsmann et al. 1999); however, it is not universal and some plants show relatively little morphological change in response to increased nutrient availability (Jackson & Caldwell 1992, Robinson 1994). While most roots act as a device for nutrient absorption, it is believed that young fine roots are more effective at this than their older, thicker counterparts and therefore responsible for the bulk of nutrient uptake (Nye & Tinker 1977, Caldwell & Richards 1983). This leads to the second form of foraging, in which there is an increase in the proportion of fine roots grown into an area in the presence of an increased resource supply. Because younger, finer roots are most able to absorb nutrients, it may not be energetically worthwhile for a plant to maintain older, less efficient roots. Thus, fine root turnover may increase in a high nutrient environment (Brzkke 1992, Pregitzer et al. 1995). This third mechanism of morphological root foraging involves not only an increase in fine root growth in nutrient rich areas but also increased root mortality. Root density is not necessarily changed. This study examined the density and size distribution of roots (mechanisms 1 and 2) in response to three substrates of varying nutrient quality: clay, leaf litter, and dried cow manure. The nutrient content of clay was the lowest and that of manure the highest. The first two substrates, clay and leaf litter, are normally available to plants for rooting. The third treatment, cow manure, was used for its characteristic high availability and slow release of nutrients, traits that make it a popular form of organic fertilizer. Given the mechanisms of root foraging, the length and diameter of roots growing into a substrate should be directly related to the nutrient quality of the substrate. This suggests two hypotheses about root ingrowth into the substrates tested: (1) root length should be longest in the manure treatment and shortest in the clay treatment; and (2) root diameter should be greatest in the clay treatment and least in the manure treatment. Since cu 80 percent of root biomass in this forest is found within the upper 20 cm of the mineral soil (B. Blair, pers. obs.), these hypotheses were tested using a root ingrowth technique to examine root proliferation into the three substrates within the top 20 cm of soil. The experiment was conducted on a 20 X 50 m plot within a wet tropical forest on the Caribbean coast of Nicaragua (11°53'N, 83'58'W; 20 m elev.), ca 15 km northwest of the city of Bluefields. Characterized by a patchwork of forest and farmland, this region on Nicaragua's agricultural frontier was struck in 1988 by a category four storm (Hurricane Joan) that severely damaged the forest. The forest's tree species (>60 spp. in a 1 ha plot) are dominated by species characteristic of wet tropical, primary


Subchronic intoxications in rats induced by repeated intraperitoneal injections of stable water suspensions of silver or copper oxide nanoparticles in low dosage were manifested by adverse shifts in some functional and biochemical indices, by development of histo-structural changes in different tissues and by poly-organ fragmentation of DNA. All these manifestations of toxicity were substantially attenuated against the background of parallel oral administration of bioprotective complexes comprising vitamins, trace elements, pectin, some amino acids and a fish oil preparation rich in omega-3 fee fatty acids, this composition has been adjusted to mechanisms of action of this or that nanomaterial.


An original method of superconductor preparation is described. It involves special surface preparations of the metal support, powder sedimentation, pressing and sintering. Typical 90 mu m thick coatings with 20% Ag exhibit high adherence to the rough substrate, and the diffusion depth of metallic elements into the coating is less than 10 mu m. Comparison is made with pure YBa2Cu3O7-x coatings: silver addition improves the electrical and mechanical properties. As shown by in situ high-temperature x-ray diffractometry, Ag accommodates mechanical stresses induced by temperature variation during preparation, more particularly on cooling.


Wireless sensor networks (WSNs) are promising tools to change the way the power grid is monitored and controlled. This paper presents the design, simulation and evaluation of ZigBee WSNs that are used for condition monitoring of delay sensitive data in wind turbines. It also presents an approach to reduce the end-to-end delay and provide service differentiation for sensor nodes that are transmitting delay sensitive data by modifying the existing IEEE 802.15.4 MAC protocol. Therefore, the results presented in this paper will assist in optimizing the operation of the smart grid in terms of near real-time asset monitoring and enhance the entire demand response process.


Evaluating the ability of cytotoxic T lymphocytes (CTLs) to eliminate tumor cells is crucial, for instance to predict the efficiency of cell therapy in personalized medicine. However, the destruction of a tumor by CTLs involves CTL migration in the extra-tumoral environment, accumulation on the tumor, antigen recognition, and cooperation in killing the cancer cells. Therefore, identifying the limiting steps in this complex process requires spatio-temporal measurements of different cellular events over long periods. Here, we use a cancer-on-a-chip platform to evaluate the impact of adenomatous polyposis coli (APC) mutation on CTL migration and cytotoxicity against 3D tumor spheroids. The APC mutated CTLs are found to have a reduced ability to destroy tumor spheroids compared with control cells, even though APC mutants migrate in the extra-tumoral space and accumulate on the spheroids as efficiently as control cells. Once in contact with the tumor however, mutated CTLs display reduced engagement with the cancer cells, as measured by a new metric that distinguishes different modes of CTL migration. Realigning the CTL trajectories around localized killing cascades reveals that all CTLs transition to high engagement in the two hours preceding the cascades, which confirms that the low engagement is the cause of reduced cytotoxicity. Beyond the study of APC mutations, this platform offers a robust way to compare cytotoxic cell efficiency of even closely related cell types, by relying on a multiscale cytometry approach to disentangle complex interactions and to identify the steps that limit the tumor destruction.


This research is motivated by the phenomenon of the rise of a variety of trade center such as department store in Indonesia marks a change in consumer shopping behavior from tradisional market to modern market. Matahari Department Store is one of the largest department store fashion and always visited by most of people in Indonesia. The involvement of location, price, and service quality are very important in shopping decision. The problems in this research was the decline in the percentage of achievement target the sale of the Matahari Department Store Java Mall Semarang. While the purpose of this research is to find how influence of location, price , and service quality to the shopping decision whether partially and simultaneously.This type of research is the explanatory research. Based on Cooper & Emory formula, total sample used in this study is 100 respondents were aged between 17 years up to 60 years and has bought in the Matahari Department Stores Java Mall Semarang in 2016.The result of this study show that the influence exerted by variable location to the shopping decision is 54,6%, variable the price to the shopping decision is 64%, and variable service quality to the shopping decision is 71,4%. In addition, the influence exerted by variable location, price, and service quality to the shopping decision of 74%. From the research found that the biggest influences that affect the shopping decision variable at Matahari Department Store Java Mall Semarang is the variable service quality (X3). From the discussion, we can conclude that location, price, and service quality positively influence to the shopping decision at Matahari Department Store Java Mall Semarang. But there were a number of things for those unsatisfactory in terms of location, the price of, and service quality. For that reason, management of Matahari Department Store Java Mall is expected to be more increase by a factor of strategic's location, price set ,and service quality for the increasing of shopping decision.


Based on our experience with existing image information mining (IIM) systems and their principal building blocks, we propose new implementation technologies for some of their typical functionalities. These new technologies are supposed to be more efficient than existing solutions and offer new performance perspectives. Motivated by potential new applications of TerraSAR-X data, we deal with feature extraction in transform domains, Kolmogorov complexity, hierarchical clustering, and Dirichlet modeling.


Community noise exposure is the one of the key challenges to the potential growth of the aviation industry. Various forecasts have shown that the industry is expected to grow in the future years, and with this comes a predicted increase in noise levels around airports without a significant influx of noise reduction technologies across the fleet. In order to plan for these future scenarios, airports, airlines, the FAA, and local governments must analyze various noise mitigation strategies, operational restrictions, and changes to airport states, whilst still increasing capacity. Thus, it has become important for these entities to be able to rapidly tradeoff different noise mitigation strategies to effectively manage community noise exposure in current and future airport scenarios. However, noise modeling can be a cumbersome task due to the potential for high computational times and its case dependency. Each entity, airport, and community have their own concerns, conditions, and population structure. Current noise modeling software can take multiple hours to set up an airport case study and run a single operational state. REACT, a tradeoff environment developed in this paper, aims to provide the key stakeholders with airport-specific information, an accessible visual user interface, and most importantly, rapid computations. REACT connects the various mitigation strategies and techniques most important to each of the key stakeholders, and allows these authorities to investigate solutions that are most important to them in current and future airport states.


The inner ear is responsible for the perception of motion and sound in vertebrates. Its functional unit, the sensory patch, contains mechanosensory hair cells innervated by sensory neurons from the statoacoustic ganglion (SAG) that project to the corresponding nuclei in the brainstem. How hair cells develop at specific positions, and how otic neurons are sorted to specifically innervate each endorgan and to convey the extracted information to the hindbrain is not completely understood. In this work, we study the generation of macular sensory patches and investigate the role of Hedgehog (Hh) signaling in the production of their neurosensory elements. Using zebrafish transgenic lines to visualize the dynamics of hair cell and neuron production, we show that the development of the anterior and posterior maculae is asynchronic, suggesting they are independently regulated. Tracing experiments demonstrate the SAG is topologically organized in two different neuronal subpopulations, which are spatially segregated and innervate specifically each macula. Functional experiments identify the Hh pathway as crucial in coordinating the production of hair cells in the posterior macula, and the formation of its specific innervation. Finally, gene expression analyses suggest that Hh influences the balance between different SAG neuronal subpopulations. These results lead to a model in which Hh orients functionally the development of inner ear towards an auditory fate in all vertebrate species.


ABSTRACT Mutations in the receptor-binding site of the hemagglutinin of pandemic influenza A(H1N1) 2009 viruses have been detected sporadically. An Asp222Gly (D222G) substitution has been associated with severe or fatal disease. Here we show that 222G variants infected a higher proportion of ciliated cells in cultures of human airway epithelium than did viruses with 222D or 222E, which targeted mainly nonciliated cells. Carbohydrate microarray analyses showed that 222G variants bind a broader range of α2-3-linked sialyl receptor sequences of a type expressed on ciliated bronchial epithelial cells and on epithelia within the lung. These features of 222G mutants may contribute to exacerbation of disease.


A new test for hysteresis based on a nonlinear unobserved components model is proposed. Observed unemployment rates are decomposed into a natural rate component and a cyclical component. Threshold type nonlinearites are introduced by allowing past cyclical unemployment to have a different impact on the natural rate depending on the regime of the economy. The impact of lagged cyclical shocks on the current natural component is the measure of hysteresis. To derive an appropriate p-value for a test for hysteresis two alternative bootstrap algorithms are proposed: the first is valid under homoskedastic errors and the second allows for heteroskedasticity of unknown form. A Monte Carlo simulation study shows the good performance of both bootstrap algorithms. The bootstrap testing procedure is applied to data from Italy, France and the United States. We find evidence of hysteresis for all countries under study.


Betel leaf extract gel contains tannin, a chromogenic agent that causes extrinsic discoloration of the tooth enamel. This study aimed to determine the effect of betel leaf extract gel on color changes in the tooth enamel. Eighteen extracted premolar teeth were divided into three groups (n = 6 each) based on the concentration of the betel leaf extract gel: 15%, 25%, and 35%. Color measurements were performed before application, and after 5, 15, and 26 applications (equivalent to 1, 3, and 6 months of application, respectively). The discolorations were calculated using the CIE L*a*b* formula. Statistical analysis revealed significant changes in color on the enamel surface among the 5, 15, and 26 gel applications at all three concentrations. Thus, duration of application of the betel leaf extract gel has a significant effect on color change of tooth enamel.


Community-dwelling multi-morbid older adults are a vulnerable population for medication safety-related threats. We interviewed a sample of these older adults recruited from local retirement communities and from primary care practices to learn their perceptions of barriers and enablers for their medication safety. The present study is part of the Partnership in Resilience for Medication Safety (PROMIS) study. One of the aims of this project is to identify barriers and opportunities to improve older adults' medication safety. These interviews were conducted during COVID-19 pandemic conditions. Results from this qualitative study suggest that trust between these older adults and their healthcare providers is an essential component of medication safety. Overarching themes include disruptions in medication management, caregivers caring for each other, patient safety practices or habits, and medication management literacy. Participants also shared strain due to lack of skills to navigate telemedicine visits, trust in Primary Care Providers (PCPs) and pharmacists to prescribe and dispense safely for them, reliance on PCPs and pharmacists to give essential information about medications without having to be asked. Our interviews illustrated large variations in older adults' perceived role in medication safety, with some developing expertise in understanding how medications work for them and how long-term medications should be periodically reviewed. The types of information needs and supports from PCPs were likely different. Understanding these barriers and enablers for safe medication management can help us develop medication safety improvements for this vulnerable population.


In adjustment studies of scales and in terms of cross validity at scale development, confirmatory factor analysis is conducted. Confirmatory factor analysis, multivariate statistics, is estimated via various parameter estimation methods and utilizes several fit indexes for evaluating the model fit. In this study, model fit indexes utilized in confirmatory factor analysis are examined with different parameter estimation methods under different sample sizes. For the purpose of this study, answers of 60, 100, 250, 500 and 1000 students who attended PISA 2012 program were pulled from the answers to two dimensional "thoughts on the importance of mathematics" dimension. Estimations were based on methods of maximum likelihood (ML), unweighted least squares (ULS) and generalized least squares (GLS). As a result of the study, it was found that model fit indexes were affected by the conditions, however some fit indexes were affected less than others and vice versa. In order to analyze these, some suggestions were made.


In vitro thyroid function tests are among the most frequently prescribed laboratory procedures. Serum triiodothyronine (T3) tests are seldom necessary as a first-level measurement. Our objectives were to measure the proportion of T3 measurements relative to all in vitro thyroid function tests in a large hospital network and to investigate the contributions of various interventions to change prescribers'behavior. We performed two cross-sectional surveys in 1995 and 1998 in the 50 Paris University hospitals. Questionnaires were mailed to the heads of the 30 laboratories performing thyroid function tests. One-month orders of free and total thyroxine, free and total T3 and thyrotropin were recorded; changes in T3 measurement orders between the two periods were estimated and association with interventions were expressed as odds ratios and 95% confidence intervals. Twenty-five heads of laboratory responded to both surveys. In 1995, T3 measurements constituted 21% of in vitro thyroid function test ordering, which seems to us exceedingly high. The decrease in T3 measurement ordering observed in 1998 (15% of thyroid function test ordering) was independently associated with multiple behavioral changes: educational interventions, structured test form use and year of prescription.


The very first low-frequency infrared absorption and Raman scattering spectra of TTF-CA are presented. Several studies have been performed as a function of temperature at atmospheric pressure. In the neutral phase by infrared absorption, we have emphasized the critical behaviour of an antisymmetric lattice mode (located around at 150 K) which shows the displacive nature of the neutral-to-ionic phase transition of TTF-CA at atmospheric pressure. In the ionic phase, the Raman scattering study has permitted confirmation of this result, the soft mode being located around at 16 K. Besides, the Raman study of several totally symmetric internal modes has confirmed the clearly first-order character of this transition. Finally, this study permits an estimation of the e - mv (electron-molecular vibrations) coupling constants in the neutral and ionic phases.


Despite an improving knowledge of species distribution patterns in the Neotropics, the processes that underlie these patterns remain uncertain. The tribe Bignonieae (Bignoniaceae), with 21 genera and c. 400 species, is the largest clade of lianas in the Neotropics. The group is an excellent model for biogeographical and evolutionary studies as it is widely distributed and exhibits high levels of morphological diversity. Here, we investigate the biogeographical history of Bignonieae using a tribe-wide time-calibrated phylogenetic tree as a basis for ancestral area reconstructions. We examine four hypotheses for the origin and subsequent biogeographical spread of the tribe. Our analyses suggest that the crown group of Bignonieae originated in South American rainforests approximately 50 Mya. Ancestral area reconstructions for the early divergences are equivocal, although the resulting Adenocalymma–Neojobertia and core Bignonieae clades appear to have occurred in eastern South America and lowland Amazonia, respectively. Our analyses suggest that, following this initial split, most lineages of Bignonieae have been repeatedly exchanged between biogeographical areas. These events occurred over a broad time span and are likely to have had multiple drivers; climate drying and the Andean Orogeny may have been particularly important for shaping overall diversity. In Bignonieae, contemporary distribution patterns appear to have been strongly influenced by Holocene environmental change. © 2012 The Linnean Society of London, Botanical Journal of the Linnean Society, 2013, 171, 154–170.


Power quality has become a major concern, in particular, to the domestic consumers because the reliability, efficiency and liability of their devices very much rely on the quality of the electric supply. However, up to now, there is no cost-effective instrument for power quality measurement. It is partially due to the lacking of a world-wide accepted indicator, power performance index (PPI) in the authors' case, and partially due to the conventionally high cost of power quality measurement equipment. In this paper, a good performance index, PPI, is proposed for the consideration by the power industry. Individual components arriving at the PPI are defined and the method of calculation is explained in detail. Such PPI will also be useful to assess the supply quality of independent power providers, especially for deregulation purposes. All algorithms have been implemented on a cost-effective power quality meter (PQM) while both hardware and software designs are described in this paper.


OBJECTIVE
To investigate the epidemiological characteristics of invasive nosocomial candidiasis in teaching hospitals in Beijing.

METHODS
The clinical data of consecutive cases diagnosed as with nosocomial candidiasis hospitalized in Beijing Chaoyang Hospital (CYH) (n=43) and Peking Union Medical College Hospital (PUMCH) (n=34) from January 2004 to September 2006 were retrospectively analyzed to evaluate the incidence and mortality, and the relationship between antifungal therapy and outcomes. The minimum inhibitory concentrations (MICs) for Candida spp were determined by microdilution method.

RESULTS
The incidence rates of nosocomial candidiasis of CYH and PUMCH were 0.053% and 0.025% respectively in 2004, and increased to 0.074% and 0.049% respectively in 2006. Candidemia accounted for 55.8% (43/77) of the Candida infection, followed by intra-abdominal infection (26.0%, n=20), intra-thoracic infection (9.1%, n=7), and biliary tract infection (7.8%, n=6). The species mostly frequently isolated were Candida albicans (57.1%), followed by C. tropicalis (19.5%), C. glabrata (14.3%), and C. parasitosis (2.6%). The susceptibility rates of C. albicans, C. tropicalis, C. glabrata, and C. parasitosis to fluconazole were 97.7%, 86.7%, 63.6%, and 100% respectively. No isolates were resistant to amphotericin B. The crude mortality rate of Candida infection was 37.7%. The mortality rate of the candidemia patients who did not receive systemic antifungal therapy was 72.7%, significantly higher than those who received antifungal therapy (37.5%, P = 0.043). Most patients received fluconazole as the first choice (91.7% in PUMCH and 79.2% in CYH) with the survival rates of 63.6% and 52.6% respectively. Conclusion With high morbidity and mortality, invasive nosocomial candidiasis is a big problem in teaching hospitals. Further investigation is necessary to evaluate the incidence and to identify which antifungal agents are most protective for candidiasis.


Ensembling methods are well known for improving prediction accuracy. However, they are limited in the sense that they cannot discriminate among component models effectively. In this paper, we propose stacking with auxiliary features that learns to fuse relevant information from multiple systems to improve performance. Auxiliary features enable the stacker to rely on systems that not just agree on an output but also the provenance of the output. We demonstrate our approach on three very different and difficult problems -- the Cold Start Slot Filling, the Tri-lingual Entity Discovery and Linking and the ImageNet object detection tasks. We obtain new state-of-the-art results on the first two tasks and substantial improvements on the detection task, thus verifying the power and generality of our approach.


Two algorithms are given for automatically recognizing the gender of a speaker using acoustic parameters extracted from the speaker's speech. The speech data used for developing the algorithms were taken from a large data set. Only acoustic parameters for vowels and fricatives were used to develop and test the algorithms because the authors wanted the gender classification to be achieved rapidly using only a brief data record.<<ETX>>


In this paper, a task independent discriminative training framework for subword units based continuous speech recognition is presented. Instead of aiming at the optimisation of any task independent figure, say the phone classification or recognition rates, we focus our attention to the reduction of the number of errors committed by the system when a task is defined. This consideration leads to the use of a segmental approach based on the minimisation of the confusability over short chains of subword units. Using this framework, a reduction of 32% in the string error rate may be achieved in the recognition of unknown length digit strings using task independent phone like units.


Abstract The thin helical vortex filament is one of the fundamental exact solutions possible under the local induction approximation (LIA). The LIA is itself an approximation to the non-local Biot–Savart dynamics governing the self-induced motion of a vortex filament, and helical filaments have also been considered for the Biot–Savart dynamics, under a variety of configurations and assumptions. We study the motion of such a helical filament in the Cartesian reference frame by determining the curve defining this filament mathematically from the Biot–Savart model. In order to do so, we consider a matched approximation to the Biot–Savart dynamics, with local effects approximated by the LIA in order to avoid the logarithmic singularity inherent in the Biot–Savart formulation. This, in turn, allows us to determine the rotational and translational velocity of the filament in terms of a local contribution (which is exactly that which is found under the LIA) and a non-local contribution, each of which depends on the wavenumber, $k$ , and the helix diameter, $A$ . Performing our calculations in such a way, we can easily compare our results to those of the LIA. For small $k$ , the transverse velocity scales as $k^{2}$ , while for large $k$ , the transverse velocity scales as $k$ . On the other hand, the rotational velocity attains a maximum value at some finite $k$ , which corresponds to the wavenumber giving the maximal torsion.


This paper investigates the use of machine learning classification techniques applied to the task of recognising the make and model of vehicles. Although a number of vehicle classification systems already exist, most of them seek only to distinguish between vehicle categories, e.g. identifying whether a vehicle is a bus, truck or car. The system presented here demonstrates that a set of features extracted from the frontal view of a vehicle may be used to determine the vehicle type (make and model) with high accuracy. The performance of some standard multi-class classification algorithms is compared for this problem. A one-class k-Nearest Neighbour classification algorithm is also implemented and tested.


The dimensions of the membranous labyrinth partly determine the mechanical operation of the semicircular canal system. This study provides, for the first time, extensive measures in individual specimens of the sizes, cross-sectional shapes and areas of the horizontal semicircular duct, ampulla and utricle in the rat and the guinea pig. The membranous labyrinths were fixed in Karnovsky's fixative, exposed, photographed, sectioned, oriented perpendicular to the line of sight and then measured using a calibrated graticule in the eye piece of an operating microscope. As well as the expected size differences between these species, there are major differences in the shape of the utricle.


In the development of genome-wide databases of model organisms, non-traditional approaches to study genomic networks have emerged to model molecular interactions. Past approaches to model such systems have used the homology of genes in model organisms to study human diseases and conditions. Combining the homology of genes between human and model organisms with information in genomic databases, the Marcotte laboratory has discovered a systematic approach to predict new candidate genes for human diseases. In characterizing phenotypes of model organisms with homologous genes, it is possible reveal similar genetic interactions of homologous genes in human diseases. These phenotypes are characterized by the presence and absence of all orthologous genes between species, these binary data structures are called phenologs. The project below examined the potential of Boolean relationships of phenologs within one or multiple species to optimize the identified set of genes for a human disease and to predict more candidate genes involved in human diseases.


Knowledge movement has been increasingly regarded as a vital indicator of competitiveness. This paper aims to explore the origin of knowledge movement from the perspective of Islamic ethics. It overviews the concepts of knowledge and knowledge management and comprehends its implications. The main method is by interpreting the relevant citation from holy Qur"an. It highlights the Islamic conception of knowledge through understanding its nature in the reality of knowledge society. With regards to the Islamic conception of knowledge, the Qur"an invites human beings to read both the natural phenomena and the divine text (revelation). Generally speaking, knowledge management and classification are very much influenced by the way society conceptualizes and realizes knowledge. Eventually, knowledge management and classification guide man to the ways of knowledge utilization. Therefore, any success achieved by a person is an output of his/her knowledge understanding and knowledge growth within himself. In this status, human beings might be influenced by a certain situations, limitations and constrains internally or externally that lead him to persuade either body knowledge or the functional usage of knowledge in making his own individual success in a form of user-centric based values. In this way, this paper is expected to extend the understanding of knowledge and provide a guide for Muslims to better manage knowledge with Islamic ethics.


In a previous communication (1) it was noted that haemolytic streptococci isolated from the tonsils, adenoids or accessory nasal sinuses of cases of acute and subacute glomerular nephritis produced, in broth cultures, "toxins" which caused skin reactions similar to those caused by the "Dick Toxin." While studying the property of these filtrates, it was observed that intense skin reactions often occurred in patients suffering from acute and subacute nephritis associated with infections caused by haemolytic streptococci. A systematic study was, therefore, made of the incidence and intensity of the skin reactions to these bouillon filtrates of haemolytic streptococci in three groups of cases; first, patients suffering from acute and subacute nephritis; secondly, normal individuals and patients affected with miscellaneous conditions, and thirdly, patients suffering from uncomplicated acute tonsillitis. There will be no attempt to discuss at this time the nature of these filtrates. It is, however, to be noted that many observers have found that haemolytic streptococci recovered from various forms of infection are capable of elaborating "toxic" substances when grown in broth (2, 3, 4, 5, 6, 7, 8, 9, 10, 11). Although these filtrates are usually more resistant to heat and less potent than the "Dick Toxin," yet they possess other properties in commonwith the "Dick Toxin," for they are frequently neutralizable by antiscarlatinal serum (3, 7, 9, 10) and are considered by some to differ only quantitatively from the "Dick Toxin," though qualitative differences have also been observed (10, 11, 13, 13a). 1 Aided by a grant from the Ella Sachs Plotz Foundation. 2Jacques Loeb Fellow in Medicine.


The objective of this study was to evaluate the toxicity of water which flows toward the beaches of Santos, SP, Brazil. Water samples were collected from eight urban drainage channels and a small creek, in March, April and August 2005. For each sample, some physical-chemical parameters were analyzed: pH, dissolved oxygen, temperature, salinity, presence of free chlorine and total ammonia contents. Acute toxicity tests (48h) with Daphnia similis were also performed with the samples. The level of ammonia was relatively high in the majority of the samples (≥ 1.5 mg/L), and free chlorine was measurable in most of them. Acute toxicity was observed in four water samples (stations 3, 4, 5 and 7), at least in one occasion. The toxicity was positively correlated with the ammonia concentrations and salinity. Because acute toxicity was detected, actions aiming to control the pollution sources and improve the water quality are recommended.


This study examines the effect of carbachol, a potent cholinoceptor agonist drug, on fertility of male rats, when administered to epididymis using stlastic formulations, in the form of rods. 10% and 25% carbachol rods were found to be toxic, and resulted in death within 25 min. On the other hand, 5% rods were tolerable. These rods significantly reduced sperm numbers both in the cauda epididymis and ejaculate but failed to Impair fertility. Libido (sexual desire) remained essentially unaltered. In organ bath experiments, carbachol induced rhythmic contrations in isolated vasa deferentia and cauda epididymal tubules in e ' dose-related manner. Short running head: carbachol and fertility of male rats Key· words: carbachol, silastic rods, epididymis fertility oligozoospermia, cholinomimetics


The last decades of the twentieth century ushered in the first treatments proven to modify the disease course of multiple sclerosis (MS). These breakthroughs in MS therapy stimulated an increase in the search for drugs with improved efficacy and greater ease of administration. This review summarizes the latest developments in the search for improved disease-modifying therapies and defines the efficacies and potential risks of such compounds. As with all new drugs, accurate assessments of risk:benefit ratios will be essential for the successful use of any agent targeting MS.


A total of 66 fluorescent pseudomonads strains isolated from diverse Tunisian environmental biotypes (wastewater, compost, wastewater treatment plant, etc.) were analysed by two polymerase chain reaction (PCR)-based methods, 16S-23S intergenic spacer regions (ITS)-PCR and repetitive extragenic palindromic (BOX)-PCR. These typing techniques were evaluated to assess their usefulness as tool to study the Pseudomonas diversity within this complex group. Genetic analysis using ITSand BOX-PCR generated respectively 12 and 45 distinct profiles. Phylogenetic relationships within fluorescent pseudomonads were examined by analyzing partial 16S rRNA and rpoB genes sequences. The phylogenetic resolution of the rpoB tree was higher than that of the 16S rRNA tree. Moreover, the sequencing of the rpoB gene has recognized 13 different species and sub-species, while the 16 rRNA gene sequencing differentiated only 9 species.


The present work evaluates some new developments concerning research into the removal of heavy metals from sewage sludge and discusses the significance for practical application. As such, the complete process of sludge treatment as an integral part of a sludge management process is considered. Two conceptual designs of a treatment process that may be applied in practice for heavy metals removal from sewage sludge are discussed. One refers to a physical-chemical treatment and the other to a biological-physical-chemical treatment. In the physical-chemical treatment, the solubilization of heavy metals is achieved by acidification with HCl (pH around 1) with a previous oxidative pre-treatment (in the same reactor) either by aeration or by hydrogen peroxide. In the biological-physical-chemical treatment, the approach is to use a heavy metal mobilization technique, which is mediated by acidophilic bacteria (Thiobacillus) able to produce sulfuric acid. This system consists of an anaerobic bioreactor fed with elemental sulfur as a reduced sulfur source component, which is oxidized by Thiobacillus and converted into sulfuric acid. In this system, a biological sulfate-reducing step, where sulfate is converted into sulfur, is included and, thus, a closed sulfur cycle can be achieved. Based on a brief qualitative evaluation, the feasibility of both treatment systems is accessed. The biological-physical-chemical process seems to be more attractive than the physical-chemical process.


Despite increasing use of targeted oral anticoagulants, vitamin K antagonists remain the mainstay of thromboembolism intervention. Vitamin K antagonists exert their anticoagulant effect by preventing formation of gamma-carboxylation of vitamin K dependent clotting factors. This effectively inhibits Gla domain-mediated protein conformational changes thereby altering protein-membrane binding required for robust thrombin generation and formation of a stable clot.

Disadvantages of vitamin K antagonists include a narrow therapeutic window, variable pharmacokinetics and annual bleeding rates of up to 15%. While available reversal strategies exist, they are limited by a) duration to achieve coagulopathy reversal precluding use of vitamin K in emergencies b) logistical barriers of elapsed time to administer fresh frozen plasma (FFP) and/or patient inability to tolerate volume required for reversal, and c) in the case of prothrombin complex concentrates, limited availability and potential thrombogenicity. No reversal strategy achieves rapid onset to efficacy and short duration of anticoagulation reversal. Rapid restoration of hemostasis with expeditious return to an anticoagulated state may prove beneficial in medically complex patients with conflicting hemostatic requirements, eliminating the need for bridging therapy and improved perioperative management.

We previously developed "zymogen-like" factor Xa (FXa) molecules with impaired active site maturation enabling a greater half-life (30 minutes) than wild type FXa (1-2 minutes) while maintaining full procoagulant function when assembled in the prothrombinase complex ( Blood 2011, 117:290-8; Nat. Biotech 2011 , 29:1028-33) . We evaluated if one variant, FXaI16L, may reverse warfarin anticoagulation.

We analyzed whole blood specimens from 12 subjects on warfarin (median INR 2.61, range 2.35-3.89) by rotational thromboelastometry (ROTEM) initiated with 0.2 pM tissue factor (TF) in the presence of varying concentrations of FXaI16L. FXaI16L dose dependently corrected whole blood ROTEM parameters. Subject clot times with 1 nM FXaI16L did not significantly differ from controls. Analysis of samples with the addition of 10% volume FFP (intended to simulate administration of 3 FFP units in a 60 kg adult) improved clot time but was still significantly prolonged compared to both control and analysis with 1 nM FXaI16L ([Figure 1][1]). Our findings show that FXaI16L is able to correct ex vivo hemostatic abnormalities observed by ROTEM in warfarin whole blood and appears superior to FFP.

By effectively bypassing the coagulation cascade to assemble the prothrombinase complex, the ability of FXaI16L to restore ex vivo hemostasis in warfarin anticoagulated whole blood suggests un- or under-carboxylated prothrombin may not prohibit robust thrombin production. To explore this further, thrombin generation assays (TGA) were used to evaluate varying INR plasmas (INR 7.1, 4.1, 2.9) initiated with 0.5 pM TF, 4 μM phospholipid vesicles (PCPS) with or without increasing concentrations of FXaI16L. Minimal thrombin generation was observed in warfarin plasma in the absence of FXaI16L. Irrespective of plasma INR, 2 nM FXaI16L restored thrombin generation to approximate thrombin generated in normal human plasma under the same conditions without FXaI16L. To further determine if uncarboxylated (des-Gla) prothrombin can be activated in plasma, we reconstituted prothrombin deficient plasma with either des-Gla or carboxylated prothrombin. The addition of 2 nM FXaI16L to des-Gla prothrombin plasma generated 1/3 of thrombin observed in carboxylated prothrombin plasma. Our results are consistent with a modest decrease in the rate of thrombin generation from des-Gla prothrombin previously observed ( J Biol Chem 2013, 288:27789-800).

These findings demonstrate that despite under-carboxylated prothrombin in warfarin plasma and whole blood, FXaI16L is able to effectively contribute to robust thrombin generation. This work suggests FXaI16L may serve as a quick onset, short acting warfarin reversal agent. A Phase I clinical trial is currently evaluating the safety of FXaI16L (ClinicalTrials.gov; [NCT01897142][2]). Additionally, our findings challenge the longstanding notion that fully carboxylated prothrombin is required for robust thrombin generation.

![Figure 1:][3]

Figure 1:
FXaI16L corrects ROTEM findings in warfarin whole blood and appears superior to FFP

Disclosures Camire: Pfizer: Consultancy, Patents & Royalties, Research Funding.

 [1]: #F1
 [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01897142&atom=%2Fbloodjournal%2F124%2F21%2F4262.atom
 [3]: pending:yes