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.

Mimicking breast cancer-induced bone metastasis in vivo: Current transplantation models and advanced humanized strategies

Bone metastasis is a complication that occurs in 80 % of women with advanced breast cancer. Despite the prevalence of bone metastatic disease, the avenues for its clinical management are still restricted to palliative treatment options. In fact, the underlying mechanisms of breast cancer osteotropism have not yet been fully elucidated due to a lack of suitable in vivo models that are able to recapitulate the human disease. In this work, we review the current transplantation-based models to investigate breast cancer-induced bone metastasis and delineate the strengths and limitations of the use of different grafting techniques, tissue sources, and hosts. We further show that humanized xenograft models incorporating human cells or tissue grafts at the primary tumor site or the metastatic site mimic more closely the human disease. Tissue-engineered constructs are emerging as a reproducible alternative to recapitulate functional humanized tissues in these murine models. The development of advanced humanized animal models may provide better platforms to investigate the mutual interactions between human cancer cells and their microenvironment and ultimately improve the translation of preclinical drug trials to the clinic.

Mixture models of nucleotide sequence evolution that account for heterogeneity in the substitution process across sites and across lineages

Molecular phylogenetic studies of homologous sequences of nucleotides often assume that the underlying evolutionary process was globally stationary, reversible, and homogeneous (SRH), and that a model of evolution with one or more site-specific and time-reversible rate matrices (e.g., the GTR rate matrix) is enough to accurately model the evolution of data over the whole tree. However, an increasing body of data suggests that evolution under these conditions is an exception, rather than the norm. To address this issue, several non-SRH models of molecular evolution have been proposed, but they either ignore heterogeneity in the substitution process across sites (HAS) or assume it can be modeled accurately using the distribution. As an alternative to these models of evolution, we introduce a family of mixture models that approximate HAS without the assumption of an underlying predefined statistical distribution. This family of mixture models is combined with non-SRH models of evolution that account for heterogeneity in the substitution process across lineages (HAL). We also present two algorithms for searching model space and identifying an optimal model of evolution that is less likely to over- or underparameterize the data. The performance of the two new algorithms was evaluated using alignments of nucleotides with 10 000 sites simulated under complex non-SRH conditions on a 25-tipped tree. The algorithms were found to be very successful, identifying the correct HAL model with a 75% success rate (the average success rate for assigning rate matrices to the tree's 48 edges was 99.25%) and, for the correct HAL model, identifying the correct HAS model with a 98% success rate. Finally, parameter estimates obtained under the correct HAL-HAS model were found to be accurate and precise. The merits of our new algorithms were illustrated with an analysis of 42 337 second codon sites extracted from a concatenation of 106 alignments of orthologous genes encoded by the nuclear genomes of Saccharomyces cerevisiae, S. paradoxus, S. mikatae, S. kudriavzevii, S. castellii, S. kluyveri, S. bayanus, and Candida albicans. Our results show that second codon sites in the ancestral genome of these species contained 49.1% invariable sites, 39.6% variable sites belonging to one rate category (V1), and 11.3% variable sites belonging to a second rate category (V2). The ancestral nucleotide content was found to differ markedly across these three sets of sites, and the evolutionary processes operating at the variable sites were found to be non-SRH and best modeled by a combination of eight edge-specific rate matrices (four for V1 and four for V2). The number of substitutions per site at the variable sites also differed markedly, with sites belonging to V1 evolving slower than those belonging to V2 along the lineages separating the seven species of Saccharomyces. Finally, sites belonging to V1 appeared to have ceased evolving along the lineages separating S. cerevisiae, S. paradoxus, S. mikatae, S. kudriavzevii, and S. bayanus, implying that they might have become so selectively constrained that they could be considered invariable sites in these species.

Comparing multilevel and Bayesian spatial random effects survival models to assess geographical inequalities in colorectal cancer survival: a case study

Background Multilevel and spatial models are being increasingly used to obtain substantive information on area-level inequalities in cancer survival. Multilevel models assume independent geographical areas, whereas spatial models explicitly incorporate geographical correlation, often via a conditional autoregressive prior. However the relative merits of these methods for large population-based studies have not been explored. Using a case-study approach, we report on the implications of using multilevel and spatial survival models to study geographical inequalities in all-cause survival. Methods Multilevel discrete-time and Bayesian spatial survival models were used to study geographical inequalities in all-cause survival for a population-based colorectal cancer cohort of 22,727 cases aged 20–84 years diagnosed during 1997–2007 from Queensland, Australia. Results Both approaches were viable on this large dataset, and produced similar estimates of the fixed effects. After adding area-level covariates, the between-area variability in survival using multilevel discrete-time models was no longer significant. Spatial inequalities in survival were also markedly reduced after adjusting for aggregated area-level covariates. Only the multilevel approach however, provided an estimation of the contribution of geographical variation to the total variation in survival between individual patients. Conclusions With little difference observed between the two approaches in the estimation of fixed effects, multilevel models should be favored if there is a clear hierarchical data structure and measuring the independent impact of individual- and area-level effects on survival differences is of primary interest. Bayesian spatial analyses may be preferred if spatial correlation between areas is important and if the priority is to assess small-area variations in survival and map spatial patterns. Both approaches can be readily fitted to geographically enabled survival data from international settings

Factors associated with health risk behavior among school children in urban Vietnam

Background Health risk behavior among young people is a public health problem in Vietnam. In addition, road traffic injuries are the leading cause of death for those aged 15–29 years. The consequences can be devastating for adolescents and their families, and can create a significant economic burden on society. Objective: The aim of this study was to identify protective and risk factors that may influence three health risk behaviors among school children: suicidal thinking (ST), drinking alcohol (DA), and underage motorbike driving (MD). Methods A cross-sectional survey of 972 adolescents (aged 12–15 years) was conducted in two secondary schools in Hanoi, Vietnam. The schools were purposely selected, one each from the inner city and a suburban area, from which classes (grade 6 to 8) were randomly selected. All students attending classes on survey days took part in the survey. The anonymous, self-completed questionnaire included measures of risk behavior, school connectedness, parental bonding, and other factors. Multivariable regression models were used to examine associations between the independent variables and the three health risk behaviors controlling for confounding factors. Results Young people in the inner city school reported a higher prevalence of all three risk behaviors than those in the suburban area (ST: 16.1% [95% confidence interval, or CI, 12.9–19.3] versus 4.6% [95% CI 2.7–6.5], p<0.001; DA: 20.3% [95% CI 16.8–23.8] versus 8.3% [95% CI 5.8–10.8], p<0.001, and MD: 10.1% [95% CI 7.4–12.8] versus 5.7% [95% CI 3.6–7.8], p<0.01). School connectedness and mother and father care appeared to be significant protective factors. For males, bullying in school was associated with suicidal thoughts, whereas for both males and females, school connectedness may be protective against suicidal ideation. Conclusion This study supports findings from other nations regarding suicidal thoughts and alcohol use, and appears to be one of the first to examine risk and protective factors forMD. Health promotion within schools should be introduced to improve students’ feelings of connectedness in combination with communication and education campaigns focusing on parental care and engaging teachers for the promotion of safer, supportive school environments.

Convergence of regenerative medicine and synthetic biology to develop standardized and validated models of human diseases with clinical relevance

In order to progress beyond currently available medical devices and implants, the concept of tissue engineering has moved into the centre of biomedical research worldwide. The aim of this approach is not to replace damaged tissue with an implant or device but rather to prompt the patient's own tissue to enact a regenerative response by using a tissue-engineered construct to assemble new functional and healthy tissue. More recently, it has been suggested that the combination of Synthetic Biology and translational tissue-engineering techniques could enhance the field of personalized medicine, not only from a regenerative medicine perspective, but also to provide frontier technologies for building and transforming the research landscape in the field of in vitro and in vivo disease models.

Predictors of mental health in midlife and older Australian women: A multilevel investigation

The purpose of this article is to examine the factors associated with women's mental health. A random sample of 340 Australian women aged 40–55 completed surveys on menopausal and lifestyle factors and mental health at three time points. We used hierarchical models to show that decrements in mental health were associated with a corresponding increase in some midlife symptoms (p < .01), time (p < .01), and poor physical health (p < .01), but the effect was not permanent. In older women, mental health was associated with physical functioning, climacteric symptoms, and time, while individual variations in mental health score were largely explained by lifestyle factors.

Factors influencing sustainability of health service innovation: Emergency nurse practitioner services

Introduction: Emergency department nurse practitioner services are one of the most frequently implemented service delivery models in Australian hospitals. This research examined factors influencing sustainability of this innovative service delivery model and offers some recommendations for future service integration. Background Many health service innovations have been implemented in an attempt to meet the growing demand for efficient, cost effective health care however, sustainability of many of these innovations has not been evaluated and is poorly understood. Aim The aim of the research was to identify factors that influence sustainability of emergency department nurse practitioner services and to operationalise a theoretical framework for evaluating innovation sustainability. Methodology The research used case study methodology. The case was emergency nurse practitioner services, and units of analysis were emergency department staff, emergency nurse practitioners and documents relating to nurse practitioner services. The data collection methods included, survey, one-on-one interviews, document analysis and telephone survey. Results This research shows that emergency nurse practitioner services partially comply with the factors of sustainability as described in the Sustainability of Innovation theoretical framework: Political, Organisational, Workforce, Financial and Innovation specific factors. Where services do not entirely meet the factors the existing benefits of the service may outweigh the barriers and other means of working around shortfalls are also implemented by staff to ensure patient safety. Conclusion The rapidly expanding emergency nurse practitioner service has been examined using case study methodology to find that certain factors may be threatening the sustainability of this health service innovation. Potentially an innovation may be sustained when only some factors are met in the short term, however, long term sustainability may be challenged if factors are not addressed and supported.