Generalized binomial Tau-leap method for biochemical kinetics incorporating both delay and intrinsic noise

The delay stochastic simulation algorithm (DSSA) by Barrio et al. [Plos Comput. Biol.2, 117–E (2006)] was developed to simulate delayed processes in cell biology in the presence of intrinsic noise, that is, when there are small-to-moderate numbers of certain key molecules present in a chemical reaction system. These delayed processes can faithfully represent complex interactions and mechanisms that imply a number of spatiotemporal processes often not explicitly modeled such as transcription and translation, basic in the modeling of cell signaling pathways. However, for systems with widely varying reaction rate constants or large numbers of molecules, the simulation time steps of both the stochastic simulation algorithm (SSA) and the DSSA can become very small causing considerable computational overheads. In order to overcome the limit of small step sizes, various τ-leap strategies have been suggested for improving computational performance of the SSA. In this paper, we present a binomial τ- DSSA method that extends the τ-leap idea to the delay setting and avoids drawing insufficient numbers of reactions, a common shortcoming of existing binomial τ-leap methods that becomes evident when dealing with complex chemical interactions. The resulting inaccuracies are most evident in the delayed case, even when considering reaction products as potential reactants within the same time step in which they are produced. Moreover, we extend the framework to account for multicellular systems with different degrees of intercellular communication. We apply these ideas to two important genetic regulatory models, namely, the hes1 gene, implicated as a molecular clock, and a Her1/Her 7 model for coupled oscillating cells.

A phosphorylation-induced turn defines the Alzheimer's disease AT8 antibody epitope on the tau protein

Post mortem biochemical staging of Alzheimer’s disease is currently based on immunochemical analysis of brain slices with the AT8 antibody. The epitope of AT8 is described around the pSer202/pThr205 region of the hyperphosphorylated form of the neuronal protein tau. In this study, NMR spectroscopy was used to precisely map the AT8 epitope on phosphorylated tau, and derive its defining structural features by a combination of NMR analyses and molecular dynamics. A particular turn conformation is stabilized by a hydrogen bond of the phosphorylated Thr205 residue to the amide proton of Gly207, and is further stabilized by the two Arg residues opposing the pSer202/pThr205.

Molecular dynamics simulation of the phosphorylation-induced conformational changes of a tau peptide fragment

Aggregation of the microtubule associated protein tau (MAPT) within neurons of the brain is the leading cause of tauopathies such as Alzheimer's disease. MAPT is a phospho-protein that is selectively phosphorylated by a number of kinases in vivo to perform its biological function. However, it may become pathogenically hyperphosphorylated, causing aggregation into paired helical filaments and neurofibrillary tangles. The phosphorylation induced conformational change on a peptide of MAPT (htau225−250) was investigated by performing molecular dynamics simulations with different phosphorylation patterns of the peptide (pThr231 and/or pSer235) in different simulation conditions to determine the effect of ionic strength and phosphate charge. All phosphorylation patterns were found to disrupt a nascent terminal β-sheet pattern (226VAVVR230 and 244QTAPVP249), replacing it with a range of structures. The double pThr231/pSer235 phosphorylation pattern at experimental ionic strength resulted in the best agreement with NMR structural characterization, with the observation of a transient α-helix (239AKSRLQT245). PPII helical conformations were only found sporadically throughout the simulations. Proteins 2014; 82:1907–1923. © 2014 Wiley Periodicals, Inc.

Implicit difference approximation for the time fractional diffusion equation

In this paper, we consider a time fractional diffusion equation on a finite domain. The equation is obtained from the standard diffusion equation by replacing the first-order time derivative by a fractional derivative (of order $0<\alpha<1$ ). We propose a computationally effective implicit difference approximation to solve the time fractional diffusion equation. Stability and convergence of the method are discussed. We prove that the implicit difference approximation (IDA) is unconditionally stable, and the IDA is convergent with $O(\tau+h^2)$, where $\tau$ and $h$ are time and space steps, respectively. Some numerical examples are presented to show the application of the present technique.

Psychometric evaluation of the Chinese version of the diabetes coping measure scale

Purpose: To evaluate the psychometric properties of a Chinese version of the Diabetes Coping Measure (DCM-C) scale.----- Methods: A self-administered questionnaire was completed by 205 people with type 2 diabetes from the endocrine outpatient departments of three hospitals in Taiwan. Confirmatory factor analysis, criterion validity, and internal consistency reliability were conducted to evaluate the psychometric properties of the DCM-C.----- Findings: Confirmatory factor analysis confirmed a four-factor structure (χ2 /df ratio=1.351, GFI=.904, CFI=.902, RMSEA=.041). The DCM-C was significantly associated with HbA1c and diabetes self-care behaviors. Internal consistency reliability of the total DCM-C scale was .74. Cronbach’s alpha coefficients for each subscale of the DCM-C ranged from .37 (tackling spirit) to .66 (diabetes integration).----- Conclusions: The DCM-C demonstrated satisfactory reliability and validity to determine the use of diabetes coping strategies. The tackling spirit dimension needs further refinement when applies this scale to Chinese populations with diabetes.----- Clinical Relevance: Healthcare providers who deal with Chinese people with diabetes can use the DCM-C to implement an early determination of diabetes coping strategies.

Interventions for preventing and managing aggressive patients admitted to an acute hospital setting: A systematic review

Background: Violence in health care has been widely reported and health care workers, particularly nurses in acute care settings, are ill-equipped to manage patients who exhibit aggressive traits. Aim: The aim of this systematic review was to establish best practice in the prevention and management of aggressive behaviours in patients admitted to acute hospital settings. Data Sources: An extensive search of the major databases was conducted from 1990 to 2007. The search included published and unpublished studies and papers in English. Review Methods: This review considered any quantitative research study design that evaluated the effectiveness of interventions in the prevention and management of patients who exhibit aggressive behaviours in an acute hospital setting. Each included study was quality assessed by two independent reviewers and data were extracted using the relevant tools developed by the Joanna Briggs Institute. Results: Ten studies met the inclusion criteria and were included in the review. The evidence identified from the studies includes: the benefit of education and training of acute care nurses in aggression management techniques; use of “as required” medications is effective in minimising harm to patients and staff; and that specific interventions such as physical restraint may play a role in managing aggressive behaviours from patients in the acute care setting. Conclusions: This review makes several recommendations for the prevention and management of aggressive behaviours in acute hospital patients. However, due to the lack of high-quality studies conducted in the acute care setting there is huge scope for future research in this area.

Neuroprotective effects of low-dose lithium in individuals at ultra-high risk for psychosis. A longitudinal MRI/MRS study

Objectives: To investigate if low-dose lithium may counteract the microstructural and metabolic brain changes proposed to occur in individuals at ultra-high risk (UHR) for psychosis. Methods: Hippocampal T2 relaxation time (HT2RT) and proton magnetic resonance spectroscopy (1H-MRS) measurements were performed prior to initiation and following three months of treatment in 11 UHR patients receiving low-dose lithium and 10 UHR patients receiving treatment as usual (TAU). HT2RT and 1H-MRS percentage change scores between scans were compared using one-way ANOVA and correlated with behavioural change scores. Results: Low-dose lithium significantly reduced HT2RT compared to TAU (p=0.018). No significant group by time effects were seen for any brain metabolites as measured with 1H-MRS, although myo-inositol, creatine, choline-containing compounds and NAA increased in the group receiving low-dose lithium and decreased or remained unchanged in subjects receiving TAU. Conclusions: This pilot study suggests that low-dose lithium may protect the microstructure of the hippocampus in UHR states as reflected by significantly decreasing HT2RT. Larger scale replication studies in UHR states using T2 relaxation time as a proxy for emerging brain pathology seem a feasible mean to test neuroprotective strategies such as low-dose lithium as potential treatments to delay or even prevent the progression to full-blown disorder.

Anisotropy of articular cartilage reflects the ECM gradient architecture : Hough-Radon Transform Analysis

Tissue-specific extracellular matrix (ECM) is known to be an ideal bioscaffold to inspire the future of regenerative medicine. It holds the secret of how nature has developed such an organization of molecules into a unique functional complexity. This work exploited an innovative image processing algorithm and high resolution microscopy associated with mechanical analysis to establish a correlation between the gradient organization of cartiligous ECM and its anisotropic biomechanical response. This was hypothesized to be a reliable determinant that can elucidate how microarchitecture interrelates with biomechanical properties. Hough-Radon transform of the ECM cross-section images revealed its conformational variation from tangential interface down to subchondral region. As the orientation varied layer by layer, the anisotropic mechanical response deviated relatively. Although, results were in good agreement (Kendall's tau-b > 90%), there were evidences proposing that alignment of the fibrous network, specifically in middle zone, is not as random as it was previously thought.

Validation of scales measuring self-efficacy and outcome expectancy in evidence-based practice

Background: Evidence-based practice (EBP) is embraced internationally as an ideal approach to improve patient outcomes and provide cost-effective care. However, despite the support for and apparent benefits of evidence-based practice, it has been shown to be complex and difficult to incorporate into the clinical setting. Research exploring implementation of evidence-based practice has highlighted many internal and external barriers including clinicians’ lack of knowledge and confidence to integrate EBP into their day-to-day work. Nurses in particular often feel ill-equipped with little confidence to find, appraise and implement evidence. Aims: The following study aimed to undertake preliminary testing of the psychometric properties of tools that measure nurses’ self-efficacy and outcome expectancy in regard to evidence-based practice. Methods: A survey design was utilised in which nurses who had either completed an EBP unit or were randomly selected from a major tertiary referral hospital in Brisbane, Australia were sent two newly developed tools: 1) Self-efficacy in Evidence-Based Practice (SE-EBP) scale and 2) Outcome Expectancy for Evidence-Based Practice (OE-EBP) scale. Results: Principal Axis Factoring found three factors with eigenvalues above one for the SE-EBP explaining 73% of the variance and one factor for the OE-EBP scale explaining 82% of the variance. Cronbach’s alpha for SE-EBP, three SE-EBP factors and OE-EBP were all >.91 suggesting some item redundancy. The SE-EBP was able to distinguish between those with no prior exposure to EBP and those who completed an introductory EBP unit. Conclusions: While further investigation of the validity of these tools is needed, preliminary testing indicates that the SE-EBP and OE-EBP scales are valid and reliable instruments for measuring health professionals’ confidence in the process and the outcomes of basing their practice on evidence.

Enhancing and promoting Indigenous women's wellness

The term "Social and Emotional Wellbeing" (SEWB) was coined through the noted inability of conventional psychiatric terminology when addressing Indigenous holistic connections and opposes the Anglo-Saxon terminology that often boxes "mental health" as a diagnosis, disease or illness into separate origins from that of other personal holistic existence, which in turn directly objects to Indigenous thinking and perceptions of wellbeing. Purpose: This study's aim was to explore what Indigenous Women's Social and Emotional Wellbeing is, through Indigenous perceptions, beliefs and knowledge of Indigenous women's wellbeing experiences. Methods: Data was derived from semi-structured focus groups incorporating Indigenous specific Yarning, where Aboriginal and Torres Strait Islander women who have experienced or were at risk of developing social and emotional wellness problems came together. Results: The women identified many factors underpinning social and emotional wellness and what it means for Aboriginal and Torres Strait Islander women. The major themes centred around wellness and health, autonomy, Indigenous women being heard, historical factors, support and Indigenous women's group development and continuation. Conclusion: These issues where then explored and compared to the National Aboriginal and Torres Strait Islander Women's Health Strategy Action Areas.

Study protocol : Screening and treatment of alcohol-related trauma (START): a randomised controlled trial

Background: The incidence of mandibular fractures in the Northern Territory of Australia is very high, especially among Indigenous people. Alcohol intoxication is implicated in the majority of facial injuries, and substance use is therefore an important target for secondary prevention. The current study tests the efficacy of a brief therapy, Motivational Care Planning, in improving wellbeing and substance misuse in youth and adults hospitalised with alcohol-related facial trauma. Methods and design: The study is a randomised controlled trial with 6 months of follow-up, to examine the effectiveness of a brief and culturally adapted intervention in improving outcomes for trauma patients with at-risk drinking admitted to the Royal Darwin Hospital maxillofacial surgery unit. Potential participants are identified using AUDIT-C questionnaire. Eligible participants are randomised to either Motivational Care Planning (MCP) or Treatment as Usual (TAU). The outcome measures will include quantity and frequency of alcohol and other substance use by Timeline Followback. The recruitment target is 154 participants, which with 20% dropout, is hoped to provide 124 people receiving treatment and follow-up. Discussion: This project introduces screening and brief interventions for high-risk drinkers admitted to the hospital with facial trauma. It introduces a practical approach to integrating brief interventions in the hospital setting, and has potential to demonstrate significant benefits for at-risk drinkers with facial trauma.

Perceived barriers to healthy lifestyle activities in midlife and older Australian women with type 2 diabetes

Purpose: Type 2 diabetes is a leading cause of morbidity and mortality in midlife and older Australian women with known modifiable risk factors for type 2 diabetes including smoking, nutrition, physical activity and obesity. In Australia little research has been done to investigate the perceived barriers to healthy lifestyle activities in midlife and older women with type 2 diabetes. The primary aim of this study was to explore the level and type of perceived barriers to health promotion activities. The secondary aim was to explore the relationship of perceived barriers to smoking behaviour, fruit and vegetable intake, physical activity, and body mass index. Methods: The study was a cross sectional survey of women, aged over 45 with type 2 diabetes, attending metropolitan community health clinics (N = 41). Data was collected from self-report questionnaire and analysed using descriptive and inferential statistics. Results: Women in the study had average total barriers scores similar to those reported in the literature for women with a range of physical disabilities and illnesses. The leading barriers for this group of women were: lack of interest, concern about safety, too tired, lack of money and feeling what they do does not help. There was no association between total barriers scores and body mass index, physical activity, fruit and vegetable intake or socio-demographic variables. Conclusion: This study contributes to understanding the perceptions of midlife and older women with type 2 diabetes about the level and type of barriers to healthy lifestyle activities that they experience. Evidence from this study can be applied to inform health promotion for lifestyle risk factor reduction in women with type 2 diabetes.