A simple Bayesian decision-theoretic design for dose-finding trials

A flexible and simple Bayesian decision-theoretic design for dose-finding trials is proposed in this paper. In order to reduce the computational burden, we adopt a working model with conjugate priors, which is flexible to fit all monotonic dose-toxicity curves and produces analytic posterior distributions. We also discuss how to use a proper utility function to reflect the interest of the trial. Patients are allocated based on not only the utility function but also the chosen dose selection rule. The most popular dose selection rule is the one-step-look-ahead (OSLA), which selects the best-so-far dose. A more complicated rule, such as the two-step-look-ahead, is theoretically more efficient than the OSLA only when the required distributional assumptions are met, which is, however, often not the case in practice. We carried out extensive simulation studies to evaluate these two dose selection rules and found that OSLA was often more efficient than two-step-look-ahead under the proposed Bayesian structure. Moreover, our simulation results show that the proposed Bayesian method's performance is superior to several popular Bayesian methods and that the negative impact of prior misspecification can be managed in the design stage.

Rank regression analysis of correlated water quality data from South East Queensland

With growing population and fast urbanization in Australia, it is a challenging task to maintain our water quality. It is essential to develop an appropriate statistical methodology in analyzing water quality data in order to draw valid conclusions and hence provide useful advices in water management. This paper is to develop robust rank-based procedures for analyzing nonnormally distributed data collected over time at different sites. To take account of temporal correlations of the observations within sites, we consider the optimally combined estimating functions proposed by Wang and Zhu (Biometrika, 93:459-464, 2006) which leads to more efficient parameter estimation. Furthermore, we apply the induced smoothing method to reduce the computational burden. Smoothing leads to easy calculation of the parameter estimates and their variance-covariance matrix. Analysis of water quality data from Total Iron and Total Cyanophytes shows the differences between the traditional generalized linear mixed models and rank regression models. Our analysis also demonstrates the advantages of the rank regression models for analyzing nonnormal data.

Nonparametric rank regression for analyzing water quality concentration data with multiple detection limits

Environmental data usually include measurements, such as water quality data, which fall below detection limits, because of limitations of the instruments or of certain analytical methods used. The fact that some responses are not detected needs to be properly taken into account in statistical analysis of such data. However, it is well-known that it is challenging to analyze a data set with detection limits, and we often have to rely on the traditional parametric methods or simple imputation methods. Distributional assumptions can lead to biased inference and justification of distributions is often not possible when the data are correlated and there is a large proportion of data below detection limits. The extent of bias is usually unknown. To draw valid conclusions and hence provide useful advice for environmental management authorities, it is essential to develop and apply an appropriate statistical methodology. This paper proposes rank-based procedures for analyzing non-normally distributed data collected at different sites over a period of time in the presence of multiple detection limits. To take account of temporal correlations within each site, we propose an optimal linear combination of estimating functions and apply the induced smoothing method to reduce the computational burden. Finally, we apply the proposed method to the water quality data collected at Susquehanna River Basin in United States of America, which dearly demonstrates the advantages of the rank regression models.

sopB of Salmonella enterica serovar Typhimurium is a potential DNA vaccine candidate in conjugation with live attenuated bacteria

The immune response against Salmonella is multi-faceted involving both the innate and the adaptive immune system. The characterization of specific Salmonella antigens inducing immune response could critically contribute to the development of epitope based vaccines for Salmonella. We have tried to identify a protective T cell epitope(s) of Salmonella, as cell mediated immunity conferred by CD8+ T cells is the most crucial subset conferring protective immunity against Salmonella. It being a proven fact that secreted proteins are better in inducing cell mediated immunity than cell surface and cytosolic antigens, we have analyzed all the genbank annotated Salmonella pathogenicity island 1 and 2 secreted proteins of Salmonella enterica serovar Typhimurium (S. typhimurium) and S. enterica serovar Typhi (S. typhi). They were subjected to BIMAS and SYFPEITHI analysis to map MHC-I and MHC-II binding epitopes. The huge profile of possible T cell epitopes obtained from the two classes of secreted proteins were tabulated and using a scoring system that considers the binding affinity and promiscuity of binding to more than one allele, SopB and SifB were chosen for experimental confirmation in murine immunization model. The entire SopB and SifB genes were cloned into DNA vaccine vectors and were administered along with live attenuated Salmonella and it was found that SopB vaccination reduced the bacterial burden of organs by about 5-fold on day 4 and day 8 after challenge with virulent Salmonella and proved to be a more efficient vaccination strategy than live attenuated bacteria alone.

Paracrine action of sFLT-1 secreted by stably-transfected Ehrlich ascites tumor cells and therapy using sFLT-1 inhibits ascites tumor growth in vivo

Background Vascular endothelial growth factor (VEGF) is known to play a major role in angiogenesis. A soluble form of Flt-1, a VEGF receptor, is potentially useful as an antagonist of VEGF, and accumulating evidence suggests the applicability of sFlt-1 in tumor suppression. In the present study, we have developed and tested strategies targeted specifically to VEGF for the treatment of ascites formation.Methods As an initial strategy, we produced recombinant sFLT-1 in the baculovirus expression system and used it as a trap to sequester VEGF in the murine ascites carcinoma model. The effect of the treatment on the weight of the animal, cell number, ascites volume and proliferating endothelial cells was studied. The second strategy involved, producing Ehrlich ascites tumor (EAT) cells stably transfected with vectors carrying cDNA encoding truncated form of Flt-1 and using these cells to inhibit ascites tumors in a nude mouse model. Results The sFLT-1 produced by the baculovirus system showed potent antiangiogenic activity as assessed by rat cornea and tube formation assay. sFLT-1 treatment resulted in reduced peritoneal angiogenesis with a concomitant decrease in tumor cell number, volume of ascites, amount of free VEGF and the number of invasive tumor cells as assayed by CD31 staining. EAT cells stably transfected with truncated form of Flt-1 also effectively reduced the tumor burden in nude mice transplanted with these cells, and demonstrated a reduction in ascites formation and peritoneal angiogenesis. Conclusions The inhibition of peritoneal angiogenesis and tumor growth by sequestering VEGF with either sFlt-1 gene expression by recombinant EAT cells or by direct sFLT-1 protein therapy is shown to comprise a potential therapy. Copyright (C) 2009 John Wiley & Sons, Ltd.

Caring for patients with limb amputation

This article provides an overview of the care of patients undergoing limb amputation. Absence of a limb can be congenital or the result of trauma or complications of chronic diseases. While the economic burden of limb amputation is significant, nurses have an important role in limiting other losses attributable to limb loss, such as long-term disability leading to loss of employment and delayed return to work or school. Comprehensive nursing assessments and appropriate interventions, pre and post-operatively, as well as early discharge planning and community reintegration can help avoid some of these losses. Nurses should be aware of the resources available in communities and work in multidisciplinary teams to ensure optimal outcomes for patients following limb amputation and their families.

"Secoituxesta järjettömäin luondocappalden canssa" : Perversiot, oikeuselämä ja kansankulttuuri 1700-luvun Suomessa

Bestiality was in the 18th century a more difficult problem in terms of criminal policy in Sweden and Finland than in any other Christian country in any other period. In the legal history of deviant sexuality, the phenomenon was uniquely widespread by international comparison. The number of court cases per capita in Finland was even higher than in Sweden. The authorities classified bestiality among the most serious crimes and a deadly sin. The Court of Appeal in Turku opted for an independent line and was clearly more lenient than Swedish courts of justice. Death sentences on grounds of bestiality ended in the 1730s, decades earlier than in Sweden. The sources for the present dissertation include judgment books and Court of Appeal decisions in 253 cases, which show that the persecution of those engaging in bestial acts in 18th century Finland was not organised by the centralised power of Stockholm. There is little evidence of local campaigns that would have been led by authorities. The church in its orthodoxy was losing ground and the clergy governed their parishes with more pragmatism than the Old Testament sanctioned. When exposing bestiality, the legal system was compelled to rely on the initiative of the public. In cases of illicit intercourse or adultery the authorities were even more dependent on the activeness of the local community. Bestiality left no tangible evidence, illegitimate children, to betray the crime to the clergy or secular authorities. The moral views of the church and the local community were not on a collision course. It was a common view that bestiality was a heinous act. Yet nowhere near all crimes came to the authorities' knowledge. Because of the heavy burden of proof, the legal position of the informer was difficult. Passiveness in reporting the crime was partly because most Finns felt it was not their place to intervene in their neighbours' private lives, as long as that privacy posed no serious threat to the neighbourhood. Hidden crime was at least as common as crime more easily exposed and proven. A typical Finnish perpetrator of bestiality was a young unmarried man with no criminal background or mental illness. The suspects were not members of ethnic minorities or marginal social groups. In trials, farmhands were more likely to be sentenced than their masters, but a more salient common denominator than social and economical status was the suspects' young age. For most of the defendants bestiality was a deep-rooted habit, which had been adopted in early youth. This form of subculture spread among the youth, and the most susceptible to experiment with the act were shepherds. The difference between man and animal was not clear-cut or self-evident. The difficulty in drawing the line is evident both in legal sources and Finnish folklore. The law that required that the animal partners be slaughtered led to the killing of thousands of cows and mares, and thereby to substantial material losses to their owners. Regarding bestiality as a crime against property motivated people to report it. The belief that the act would produce human-animal mongrels or that it would poison the milk and the meat horrified the public more than the teachings of the church ever could. Among the most significant aspects in the problems regarding the animals is how profoundly different the worldview of 18th century people was from that of today.

Inter-lamellar shear resistance confers compressive stiffness in the intervertebral disc: An image-based modelling study on the bovine caudal disc

The intervertebral disc withstands large compressive loads (up to nine times bodyweight in humans) while providing flexibility to the spinal column. At a microstructural level, the outer sheath of the disc (the annulus fibrosus) comprises 12–20 annular layers of alternately crisscrossed collagen fibres embedded in a soft ground matrix. The centre of the disc (the nucleus pulposus) consists of a hydrated gel rich in proteoglycans. The disc is the largest avascular structure in the body and is of much interest biomechanically due to the high societal burden of disc degeneration and back pain. Although the disc has been well characterized at the whole joint scale, it is not clear how the disc tissue microstructure confers its overall mechanical properties. In particular, there have been conflicting reports regarding the level of attachment between adjacent lamellae in the annulus, and the importance of these interfaces to the overall integrity of the disc is unknown. We used a polarized light micrograph of the bovine tail disc in transverse cross-section to develop an image-based finite element model incorporating sliding and separation between layers of the annulus, and subjected the model to axial compressive loading. Validation experiments were also performed on four bovine caudal discs. Interlamellar shear resistance had a strong effect on disc compressive stiffness, with a 40% drop in stiffness when the interface shear resistance was changed from fully bonded to freely sliding. By contrast, interlamellar cohesion had no appreciable effect on overall disc mechanics. We conclude that shear resistance between lamellae confers disc mechanical resistance to compression, and degradation of the interlamellar interface structure may be a precursor to macroscopic disc degeneration.

The impact of home loan key facts sheets on borrowers' comparisons of loan costs

This thesis evaluates the effectiveness of the prescribed design and distribution requirements of the Australian Government's home loan key facts sheets (KFS) aimed at helping borrowers compare loan costs. The findings show that despite effectively improving borrower decision-making, few borrowers were aware of their existence and function. It was also demonstrated that KFS have had limited market impact over the four year window since introduction, likely due to the requirement that KFS provision is not required unless formally requested by a borrower. Recommendations include transferring the burden of disclosure to lenders in the first instance to address this information gap.

Bottleneck assignment problems under categorization

This paper considers two special cases of bottleneck grouped assignment problems when n jobs belong to m distinct categories (m < n). Solving these special problems through the available branch and bound algorithms will result in a heavy computational burden. Sequentially identifying nonopitmal variables, this paper provides more efficient methods for those cases. Propositions leading to the algorithms have been established. Numerical examples illustrate the respective algorithms.

Distributed Robotic Vision as a service

The vision sense of standalone robots is limited by line of sight and onboard camera capabilities, but processing video from remote cameras puts a high computational burden on robots. This paper describes the Distributed Robotic Vision Service, DRVS, which implements an on-demand distributed visual object detection service. Robots specify visual information requirements in terms of regions of interest and object detection algorithms. DRVS dynamically distributes the object detection computation to remote vision systems with processing capabilities, and the robots receive high-level object detection information. DRVS relieves robots of managing sensor discovery and reduces data transmission compared to image sharing models of distributed vision. Navigating a sensorless robot from remote vision systems is demonstrated in simulation as a proof of concept.

The Freudian unconscious in the context of the cognitive orientation

For decades psychoanalysis was the discipline studying the unconscious, and other branches of study lacked competence to take a stand on the issues concerning the unconscious. From 1980s onwards intense study of the unconscious has been taken place in the scope of cognitive orientation. Thus, nowadays it is talked about both pyschoanalytic and cognitive unconscious. The aim of this thesis is to integrate psychoanalytic and cognitive views. When the "Freudian" conception of the unconscious is considered, there are four entangled issues: 1) what is the unconscious like, 2) how does the unconsciuos give rise to psychic disorders 3) why and how certain contents are missing from consciousness (repression of contents), 4) the emergence of those contents (becoming conscious of the repressed). The conventional psychoanalytic answer to the first question - and "the cornerstone of psychoanalysis" - is "the unconscious is mental". The issues 2)-4) depend radically on the answer given to the 1): "psychoanalytic" conceptualizations on them rest on the "cornerstone". That ground was challended in study I: it was argued that it has never been clear what does it mean that the unconscious is mental. Thus, it was stated that in the current state of art psychoanalysis should drop out the ephitet "mental" before the term unconscious. That claim creates a pressure to reappraise the convential "psychoanalytic" answers to the other questions, and that reappraisal was the aim of studies II and III. In study II the question 2) is approached in terms of implicit knowledge. Study III focuses on mechanisms, which determine which contents appear in the scope of consciousness, and also cause missing of contents from there (the questions 3) and 4)). In the core of study III there are distinctions concerning the processess occuring in the levels of the brain, consciousness, self-consciousness, and narrative self-consciousness. Studies I-III set "psychoanalytic" topics in the frames of cognitive view. The picture emerging from those studies is not especially useful for a clinican (psychotherapist). Studies IV and V focused that issue. Study IV is a rather serious critique toward neuropsychoanalysis. In it it was claimed that repressive functions of conscious states are in the core of clinical psychoanalysis, and functions in general cannot be reduced to neurophysiological terminology. Thus, the limits of neuropsychoanalysis are more strict than it has been realized: crucial clinical issues remain outside its scope. In study V it was focused on the confusing state of things that although unconscious fantasies do not exist, the idea on them has been an important conceptual tool for clinicans. When put in a larger context, the aim of study V is similar to that of study IV: to determine the relation between psychotherapists' and neuroscientists' terminologies. Studies III, IV and V apply the philosopher Daniel Dennett's model on different levels of explanation.

Subtypes of psychotic-like experiences are differentially associated with suicidal ideation, plans and attempts in young adults

Psychotic-like experiences (PLEs) have been associated with increased risk of suicidality, but it is unclear whether the level of risk varies with different types of PLE. A cross-sectional online survey was completed by 1610 university students. Respondents completed the Community Assessment of Psychic Experiences-15 (CAPE-P15) assessing PLEs on three subscales: Perceptual Abnormalities (PA), Persecutory Ideation (PI) and Bizarre Experiences (BE). Lifetime suicidal ideation, plans and attempts, cannabis, ecstasy and methamphetamine use and family history of mental disorder were also assessed. Multinomal logistic regression was used to examine unique determinants of lifetime suicidality, defined as any history of (i) suicidal ideation or plans and (ii) any attempt, relative to no lifetime history of suicidality. A lifetime history of PA and PI provided significant unique contributions to the prediction of suicide risk, after control for other significant predictors. BE were not associated with any suicide variable demonstrating the variation in risk of suicidality with different types of PLEs. Perceptual abnormalities and persecutory ideation as measured by the CAPE-P15 are the PLEs associated with a higher risk of lifetime suicidality.

Current CAPE-15: A measure of recent psychotic-like experiences and associated distress

Aim Psychotic-like experiences (PLEs) are common in young people and are associated with both distress and adverse outcomes. The Community Assessment of Psychic Experiences-Positive Scale (CAPE-P) provides a 20-item measure of lifetime PLEs. A 15-item revision of this scale was recently published (CAPE-P15). Although the CAPE-P has been used to assess PLEs in the last 12 months, there is no version of the CAPE for assessing more recent PLEs (e.g. 3 months). This study aimed to determine the reliability and validity of the current CAPE-P15 and assess its relationship with current distress. Method A cross-sectional online survey of 489 university students (17–25 years) assessed lifetime and current substance use, current distress, and lifetime and 3-month PLEs on the CAPE-P15. Results Confirmatory factor analysis indicated that the current CAPE-P15 retained the same three-factor structure as the lifetime version consisting of persecutory ideation, bizarre experiences and perceptual abnormalities. The total score of the current version was lower than the lifetime version, but the two were strongly correlated (r = .64). The current version was highly predictive of generalized distress (r = .52) and indices that combined symptom frequency with associated distress did not confer greater predictive power than frequency alone. Conclusion This study provided preliminary data that the current CAPE-P15 provides a valid and reliable measure of current PLEs. The current CAPE-P15 is likely to have substantial practical utility if it is later shown to be sensitive to change, especially in prevention and early intervention for mental disorders in young people.

Review: Near infrared spectroscopy of faeces to evaluate the nutrition and physiology of herbivores

Near infrared (NIR) spectroscopy, usually in reflectance mode, has been applied to the analysis of faeces to measure the concentrations of constituents such as total N, fibre, tannins and delta C-13. In addition, an unusual and exciting application of faecal NIR [F.NIR] analyses is to directly predict attributes of the diet of herbivores such as crude protein and fibre contents, proportions of plant species and morphological components, diet digestibility and voluntary DM intake. This is an unusual application of NIR spectroscopy insofar as the spectral measurements are made, not on the material of interest [i.e. the diet), but on a derived material (i.e. faeces). Predictions of diet attributes from faecal spectra clearly depend on there being sufficient NIR spectral information in the diet residues present in faeces to describe the diet, although endogenous components of faeces such as undigested debris of micro-organisms from the rumen and Large intestine and secretions into the gastrointestinal tract wilt also contribute spectral information. Spectra of forage and of faeces derived from the forage are generally similar and the observed differences are principally in the spectral regions associated with constituents of forages known to be of low, or of high, digestibility. Some diet components (for example, ureal which are likely to be entirely digested apparently cannot be predicted from faecal NIR spectra because they cannot contribute to faecal spectra except through modifying the microbial and endogenous components. The errors and robustness of F.NIR calibrations to predict the crude protein concentration and digestibility of the diet of herbivores are generally comparable with those to directly predict the same attributes in forage from NIR spectra of the forage. Some attributes of the animal, such as species, gender, pregnancy status and parasite burden have been successfully discriminated into classes based on their faecal NIR spectra. Such discrimination was likely associated with differences in the diet selected and/or differences in the metabolites excreted in the faeces. NIR spectroscopy of faeces has usually involved scanning dried and ground samples in monochromators in the 400-2500nm or 1100-2500nm ranges. Results satisfactory for the purpose have also been reported for dried and ground faeces scanned using a diode array instrument in the 800-1700nm range and for wet faeces and slurries of excreta scanned with monochromators. Chemometric analysis of faecal spectra has generally used the approaches established for forage analysis. The capacity to predict many attributes of the diet, and some aspects of animal physiology, from NIR spectra of faeces is particularly useful to study the quality and quantity of the diet selected by both domestic and feral grazing herbivores and to enhance production and management of both herbivores and their grazing environment.