Alive SMC^2: Bayesian model selection for low-count time series models with intractable likelihoods

In this paper we present a new method for performing Bayesian parameter inference and model choice for low count time series models with intractable likelihoods. The method involves incorporating an alive particle filter within a sequential Monte Carlo (SMC) algorithm to create a novel pseudo-marginal algorithm, which we refer to as alive SMC^2. The advantages of this approach over competing approaches is that it is naturally adaptive, it does not involve between-model proposals required in reversible jump Markov chain Monte Carlo and does not rely on potentially rough approximations. The algorithm is demonstrated on Markov process and integer autoregressive moving average models applied to real biological datasets of hospital-acquired pathogen incidence, animal health time series and the cumulative number of poison disease cases in mule deer.

Importance of animal models in schizophrenia research

Objective This review aims to summarize the importance of animal models for research on psychiatric illnesses, particularly schizophrenia. Method and Results Several aspects of animal models are addressed, including animal experimentation ethics and theoretical considerations of different aspects of validity of animal models. A more specific discussion is included on two of the most widely used behavioural models, psychotropic drug-induced locomotor hyperactivity and prepulse inhibition, followed by comments on the difficulty of modelling negative symptoms of schizophrenia. Furthermore, we emphasize the impact of new developments in molecular biology and the generation of genetically modified mice, which have generated the concept of behavioural phenotyping. Conclusions Complex psychiatric illnesses, such as schizophrenia, cannot be exactly reproduced in species such as rats and mice. Nevertheless, by providing new information on the role of neurotransmitter systems and genes in behavioural function, animal 'models' can be an important tool in unravelling mechanisms involved in the symptoms and development of such illnesses, alongside approaches such as post-mortem studies, cognitive and psychophysiological studies, imaging and epidemiology.

Neurodevelopmental animal models of schizophrenia: Effects on prepulse inhibition

Epidemiological studies have shown increased incidence of schizophrenia in patients subjected to different forms of pre- or perinatal stress. However, as the onset of schizophrenic illness does not usually occur until adolescence or early adulthood, it is not yet fully understood how disruption of early brain development may ultimately lead to malfunction years later. In order to elucidate a possible role for neurodevelopmental factors in the pathogenesis of schizophrenia and to highlight potential new treatments, animal models are needed. Prepulse inhibition (PPI) is a model of sensorimotor gating mechanisms in the brain. It is disrupted in schizophrenia patients and the disruption can be reversed with atypical antipsychotics. It has been widely used in animal studies to explore central mechanisms possibly involved in schizophrenia. There has been a recent surge of behavioural and neurochemical animal studies on neurodevelopmental models, particularly on the effects of postweaning isolation, maternal separation and neonatal lesions of the hippocampus. In these models, long lasting alterations in behaviour and/or molecular changes in specific brain regions are observed, comparable to those seen in schizophrenia. The aim of this article is to critically review the available literature on such neurodevelopmental animal models with special focus on the effects on PPI and brain regions that are putatively involved in regulation of PPI.

Beyond survivorship? A discursive analysis of how people with pancreatic cancer negotiate identity transitions in their health

We explored how people negotiate, and respond to, identity transitions following a diagnosis of pancreatic cancer. Interviews with 19 people with pancreatic cancer were analysed using thematic discourse analysis. While discursively negotiating two transitions, “moving from healthy to ill” and “moving from active treatment to end-of-life care”, participants positioned themselves as “in control”, “optimistic” and managing their health and illness. In the absence of other discourses or “models” of life post-cancer, many people draw on the promise of survival. Moving away from “survivorship” may assist people with advanced cancer to make sense of their lives in a short timeframe.

Scoping study into wound management nurse practitioner models of practice

Objectives The primary objective of this research was to investigate wound management nurse practitioner (WMNP) models of service for the purposes of identifying parameters of practice and how patient outcomes are measured. Methods A scoping study was conducted with all authorised WMNPs in Australia from October to December 2012 using survey methodology. A questionnaire was developed to obtain data on the role and practice parameters of authorised WMNPs in Australia. The tool comprised seven sections and included a total of 59 questions. The questionnaire was distributed to all members of the WMNP Online Peer Review Group, to which it was anticipated the majority of WMNPs belonged. Results Twenty-one WMNPs responded (response rate 87%), with the results based on a subset of respondents who stated that, at the time of the questionnaire, they were employed as a WMNP, therefore yielding a response rate of 71% (n≤15). Most respondents (93%; n≤14) were employed in the public sector, with an average of 64 occasions of service per month. The typical length of a new case consultation was 60min, with 32min for follow ups. The most frequently performed activity was wound photography (83%; n≤12), patient, family or carer education (75%; n≤12), Doppler ankle-brachial pressure index assessment (58%; n≤12), conservative sharp wound debridement (58%; n≤12) and counselling (50%; n≤12). The most routinely prescribed medications were local anaesthetics (25%; n≤12) and oral antibiotics (25%; n≤12). Data were routinely collected by 91% of respondents on service-related and wound-related parameters to monitor patient outcomes, to justify and improve health services provided. Conclusion This study yielded important baseline information on this professional group, including data on patient problems managed, the types of interventions implemented, the resources used to accomplish outcomes and how outcomes are measured.

Murine, but not human, ephrin-B2 can be efficiently cleaved by the serine protease kallikrein-4: Implications for xenograft models of human prostate cancer

Background Ephrin-B2 is the sole physiologically-relevant ligand of the receptor tyrosine kinase EphB4, which is over-expressed in many epithelial cancers, including 66% of prostate cancers, and contributes to cancer cell survival, invasion and migration. Crucially, however, the cancer-promoting EphB4 signalling pathways are independent of interaction with its ligand ephrin-B2, as activation of ligand-dependent signalling causes tumour suppression. Ephrin-B2, however, is often found on the surface of endothelial cells of the tumour vasculature, where it can regulate angiogenesis to support tumour growth. Proteolytic cleavage of endothelial cell ephrin-B2 has previously been suggested as one mechanism whereby the interaction between tumour cell-expressed EphB4 and endothelial cell ephrin-B2 is regulated to support both cancer promotion and angiogenesis. Methods An in silico approach was used to search accessible surfaces of 3D protein models for cleavage sites for the key prostate cancer serine protease, KLK4, and this identified murine ephrin-B2 as a potential KLK4 substrate. Mouse ephrin-B2 was then confirmed as a KLK4 substrate by in vitro incubation of recombinant mouse ephrin-B2 with active recombinant human KLK4. Cleavage products were visualised by SDS-PAGE, silver staining and Western blot and confirmed by N-terminal sequencing. Results At low molar ratios, KLK4 cleaved murine ephrin-B2 but other prostate-specific KLK family members (KLK2 and KLK3/PSA) were less efficient, suggesting cleavage was KLK4-selective. The primary KLK4 cleavage site in murine ephrin-B2 was verified and shown to correspond to one of the in silico predicted sites between extracellular domain residues arginine 178 and asparagine 179. Surprisingly, the highly homologous human ephrin-B2 was poorly cleaved by KLK4 at these low molar ratios, likely due to the 3 amino acid differences at this primary cleavage site. Conclusion These data suggest that in in vivo mouse xenograft models, endogenous mouse ephrin-B2, but not human tumour ephrin-B2, may be a downstream target of cancer cell secreted human KLK4. This is a critical consideration when interpreting data from murine explants of human EphB4+/KLK4+ cancer cells, such as prostate cancer cells, where differential effects may be seen in mouse models as opposed to human clinical situations.

The importance of connexin hemichannels during chondroprogenitor cell differentiation in hydrogel versus microtissue culture models

Appropriate selection of scaffold architecture is a key challenge in cartilage tissue engineering. Gap junction-mediated intercellular contacts play important roles in precartilage condensation of mesenchymal cells. However, scaffold architecture could potentially restrict cell-cell communication and differentiation. This is particularly important when choosing the appropriate culture platform as well as scaffold-based strategy for clinical translation, that is, hydrogel or microtissues, for investigating differentiation of chondroprogenitor cells in cartilage tissue engineering. We, therefore, studied the influence of gap junction-mediated cell-cell communication on chondrogenesis of bone marrow-derived mesenchymal stromal cells (BM-MSCs) and articular chondrocytes. Expanded human chondrocytes and BM-MSCs were either (re-) differentiated in micromass cell pellets or encapsulated as isolated cells in alginate hydrogels. Samples were treated with and without the gap junction inhibitor 18-α glycyrrhetinic acid (18αGCA). DNA and glycosaminoglycan (GAG) content and gene expression levels (collagen I/II/X, aggrecan, and connexin 43) were quantified at various time points. Protein localization was determined using immunofluorescence, and adenosine-5'-triphosphate (ATP) was measured in conditioned media. While GAG/DNA was higher in alginate compared with pellets for chondrocytes, there were no differences in chondrogenic gene expression between culture models. Gap junction blocking reduced collagen II and extracellular ATP in all chondrocyte cultures and in BM-MSC hydrogels. However, differentiation capacity was not abolished completely by 18αGCA. Connexin 43 levels were high throughout chondrocyte cultures and peaked only later during BM-MSC differentiation, consistent with the delayed response of BM-MSCs to 18αGCA. Alginate hydrogels and microtissues are equally suited culture platforms for the chondrogenic (re-)differentiation of expanded human articular chondrocytes and BM-MSCs. Therefore, reducing direct cell-cell contacts does not affect in vitro chondrogenesis. However, blocking gap junctions compromises cell differentiation, pointing to a prominent role for hemichannel function in this process. Therefore, scaffold design strategies that promote an increasing distance between single chondroprogenitor cells do not restrict their differentiation potential in tissue-engineered constructs.

Mathematical models for collective cell spreading

Collective cell spreading is frequently observed in development, tissue repair and disease progression. Mathematical modelling used in conjunction with experimental investigation can provide key insights into the mechanisms driving the spread of cell populations. In this study, we investigated how experimental and modelling frameworks can be used to identify several key features underlying collective cell spreading. In particular, we were able to independently quantify the roles of cell motility and cell proliferation in a spreading cell population, and investigate how these roles are influenced by factors such as the initial cell density, type of cell population and the assay geometry.

Assessing testamentary and decision-making capacity: Approaches and models

The need for better and more accurate assessments of testamentary and decision-making capacity grows as Australian society ages and incidences of mentally disabling conditions increase. Capacity is a legal determination, but one on which medical opinion is increasingly being sought. The difficulties inherent within capacity assessments are exacerbated by the ad hoc approaches adopted by legal and medical professionals based on individual knowledge and skill, as well as the numerous assessment paradigms that exist. This can negatively affect the quality of assessments, and results in confusion as to the best way to assess capacity. This article begins by assessing the nature of capacity. The most common general assessment models used in Australia are then discussed, as are the practical challenges associated with capacity assessment. The article concludes by suggesting a way forward to satisfactorily assess legal capacity given the significant ramifications of getting it wrong.

Cultural adaptation and resilience: Controversies, issues and emerging models

What enables people to bounce back from stressful experiences? How do certain individuals maintain a sense of purpose and direction over the long term, even in the face of adversity? This is the first book to move beyond childhood and adolescence to explore resilience across the lifespan. Coverage ranges from genetic and physiological factors through personal, family, organizational, and community processes. Contributors examine how resilience contributes to health and well-being across the adult life cycle; why—and what happens when—resilience processes fail; ethnic and cultural dimensions of resilience; and ways to enhance adult resilience, including reviews of exemplary programs.

Resilience: A new integrative approach to health and mental health research

We know from anecdote and research, science and art, that human resilience is a powerful, seemingly ubiquitous force. What is needed is a better understanding of the properties, variations, and applications of that concept to health and well-being. In this paper we put forth two definitions of resilience: Sustainability of purpose in the face of stress, and recovery from adversity. We review current thinking in the social sciences on the nature of biological, psychological and socio-community processes that may confer resilience. In doing so, we encourage greater attention to aspects of biopsychosocial resourcefulness as a dimension of influence on health and mental health distinct from measures of risk found in standard models of public health inquiry. Multi-level, longitudinal, and intervention methods are advocated for research and applications of the concept with conceptual guidelines for the examination of laboratory, diary, and community indicator data on manifestations of resilience across the life span.

Integrating LGBTIQ health personnel in the workplace: A literature review

Aim Lesbian, Gay, Bisexual, Transgender (LGBTIQ) issues have attracted attention in the popular media. The purpose of this study was to explore the workplace acceptance and experiences of LGBTIQ health and medical practitioners. Methods A systematic search of academic databases and reference lists from selected papers were the sources of the data. Inclusion criteria were research papers published in English, which focused on workplace acceptance and experiences of LGBTIQ health personnel. Both authors abstracted data from all eligible papers. Results Thirty-three papers were included in this review. Evidence indicated that LGBTIQ health personnel experienced discrimination from their patients, heterosexual colleagues and within the LGBTIQ community. Positive contribution of LGBTIQ health personnel include improved patient care and role models for LGBTIQ peers. Inclusive policy is required for LGBTIQ health personnel workforce retention. Conclusions There has been improvement in the acceptance and experiences of LGBTIQ health personnel in recent times. An inclusive workplace policy of LGBTIQ embraces and celebrates the value of diversity.

N-ethyl-N-nitrosourea (ENU) induced mutations within the Klotho gene lead to ectopic calcification and reduced lifespan in mouse models

Ectopic calcification (EC), which is the pathological deposition of calcium and phosphate in extra-skeletal tissues, may be associated with hypercalcaemic and hyperphosphataemic disorders, or it may occur in the absence of metabolic abnormalities. In addition, EC may be inherited as part of several monogenic disorders and studies of these have provided valuable insights into the metabolic pathways regulating mineral metabolism. For example, studies of tumoural calcinosis, a disorder characterised by hyperphosphataemia and progressive EC, have revealed mutations of fibroblast growth factor 23 (FGF23), polypeptide N-acetyl galactosaminyltransferase 3 (GALNT3) and klotho (KL), which are all part of a phosphate-regulating pathway. However, such studies in humans are limited by the lack of available large families with EC, and to facilitate such studies we assessed the progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for EC. This identified two mutants with autosomal recessive forms of EC, and reduced lifespan, designated Ecalc1 and Ecalc2. Genetic mapping localized the Ecalc1 and Ecalc2 loci to a 11.0 Mb region on chromosome 5 that contained the klotho gene (Kl), and DNA sequence analysis identified nonsense (Gln203Stop) and missense (Ile604Asn) Kl mutations in Ecalc1 and Ecalc2 mice, respectively. The Gln203Stop mutation, located in KL1 domain, was severely hypomorphic and led to a 17-fold reduction of renal Kl expression. The Ile604Asn mutation, located in KL2 domain, was predicted to impair klotho protein stability and in vitro expression studies in COS-7 cells revealed endoplasmic reticulum retention of the Ile604Asn mutant. Further phenotype studies undertaken in Ecalc1 (kl203X/203X) mice demonstrated elevations in plasma concentrations of phosphate, FGF23 and 1,25-dihydroxyvitamin D. Thus, two allelic variants of Kl that develop EC and represent mouse models for tumoural calcinosis have been established. © 2015 Esapa et al.

Predicting surgical outcomes for paediatric spinal deformity patients using subject specific finite element models

INTRODUCTION Adolescent idiopathic scoliosis (AIS) is a spinal deformity, which may require surgical correction by attaching rods to the patient’s spine using screws inserted into the vertebrae. Complication rates for deformity correction surgery are unacceptably high. Determining an achievable correction without overloading the adjacent spinal tissues or implants requires an understanding of the mechanical interaction between these components. Our novel patient specific modelling software creates individualized finite element models (FEM) representing the thoracolumbar spine and ribcage of scoliosis patients. We have recently applied the model to investigate the influence of increasing magnitudes of surgically applied corrective force on predicted deformity correction...

Adjustable stiffness, external fixator for the rat femur osteotomy and segmental bone defect models

The mechanical environment around the healing of broken bone is very important as it determines the way the fracture will heal. Over the past decade there has been great clinical interest in improving bone healing by altering the mechanical environment through the fixation stability around the lesion. One constraint of preclinical animal research in this area is the lack of experimental control over the local mechanical environment within a large segmental defect as well as osteotomies as they heal. In this paper we report on the design and use of an external fixator to study the healing of large segmental bone defects or osteotomies. This device not only allows for controlled axial stiffness on the bone lesion as it heals, but it also enables the change of stiffness during the healing process in vivo. The conducted experiments have shown that the fixators were able to maintain a 5 mm femoral defect gap in rats in vivo during unrestricted cage activity for at least 8 weeks. Likewise, we observed no distortion or infections, including pin infections during the entire healing period. These results demonstrate that our newly developed external fixator was able to achieve reproducible and standardized stabilization, and the alteration of the mechanical environment of in vivo rat large bone defects and various size osteotomies. This confirms that the external fixation device is well suited for preclinical research investigations using a rat model in the field of bone regeneration and repair.