Measuring older patients’ attitudes to general practice registrars: Exploratory factor analysis of a survey instrument

Introduction: Training general practice registrars (GPRs) to meet the challenges of an ageing population is hampered by their relatively reduced contact with older patients and a paucity of suitable research to inform training models. This paper describes an exploratory factor analysis of a survey instrument assessing the attitudes of older patients to GPRs, as part of a project to address these concerns. Methods: The instrument was developed on the basis of a qualitative study and a literature review and distributed to 500 patients aged 60 years and over from 10 training practices in regional Australia. Responses to 22 of the survey’s Likert scale items were examined, including inter-item correlations and internal consistency (Cronbach’s alpha). Exploratory factor analysis was performed to identify domains of patients’ attitudes. Results: The response rate was 39.2% (n=196). None of the items were redundant and the scale had appropriate levels of internal consistency (Cronbach’s alpha = 0.76). The exploratory factor analysis identified three factors. Factor one, labelled ‘interpersonal trust’, explained 26.2% of the variance. Factor two accounted for 11.4% of the variance and was labelled ‘system trust’. Factor three, labelled ‘interpersonal continuity’, explained 7.5% of the variance. Conclusion: The instrument demonstrated acceptable psychometric properties and three distinct factors reflecting older patients’ attitudes toward GPRs, with trust appearing to be particularly important. The instrument appears effective in obtaining valid data, which should assist in developing improved training models. These findings warrant confirmation with a larger sample and exploration of adaptations of the instrument to be used in other contexts. Keywords: general practice registrar; post-graduate training; patient attitude

A murine model of variant late infantile ceroid lipofuscinosis recapitulates behavioral and pathological phenotypes of human disease.

Neuronal ceroid lipofuscinoses (NCLs; also known collectively as Batten Disease) are a family of autosomal recessive lysosomal storage disorders. Mutations in as many as 13 genes give rise to ∼10 variants of NCL, all with overlapping clinical symptomatology including visual impairment, motor and cognitive dysfunction, seizures, and premature death. Mutations in CLN6 result in both a variant late infantile onset neuronal ceroid lipofuscinosis (vLINCL) as well as an adult-onset form of the disease called Type A Kufs. CLN6 is a non-glycosylated membrane protein of unknown function localized to the endoplasmic reticulum (ER). In this study, we perform a detailed characterization of a naturally occurring Cln6 mutant (Cln6(nclf)) mouse line to validate its utility for translational research. We demonstrate that this Cln6(nclf) mutation leads to deficits in motor coordination, vision, memory, and learning. Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes. As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation. Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6. Together, these findings highlight the behavioral and pathological similarities between the Cln6(nclf) mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics

Tropical cyclone perceptions, impacts and adaptation in the Southwest Pacific: an urban perspective from Fiji, Vanuatu and Tonga

The destruction caused by tropical cyclone (TC) Pam in March 2015 is considered one of the worst natural disasters in the history of Vanuatu. It has highlighted the need for a better understanding of TC impacts and adaptation in the Southwest Pacific (SWP) region. Therefore, the key aims of this study are to (i) understand local perceptions of TC activity, (ii) investigate impacts of TC activity and (iii) uncover adaptation strategies used to offset the impacts of TCs. To address these aims, a survey (with 130 participants from urban areas) was conducted across three SWP small island states (SISs): Fiji, Vanuatu and Tonga (FVT). It was found that respondents generally had a high level of risk perception and awareness of TCs and the associated physical impacts, but lacked an understanding of the underlying weather conditions. Responses highlighted that current methods of adaptation generally occur at the local level, immediately prior to a TC event (preparation of property, gathering of food, finding a safe place to shelter). However higher level adaptation measures (such as the modification to building structures) may reduce vulnerability further. Finally, we discuss the potential of utilising weather-related traditional knowledge and non-traditional knowledge of empirical and climate-model-based weather forecasts to improve TC outlooks, which would ultimately reduce vulnerability and increase adaptive capacity. Importantly, lessons learned from this study may result in the modification and/or development of existing adaptation strategies

Locally adaptive Bayesian birth-death model successfully detects slow and rapid rate shifts

Birth-death processes have given biologists a model-based framework to answer questions about changes in the birth and death rates of lineages in a phylogenetic tree. Therefore birth-death models are central to macroevolutionary as well as phylodynamic analyses. Early approaches to studying temporal variation in birth and death rates using birth-death models faced difficulties due to the restrictive choices of birth and death rate curves through time. Sufficiently flexible time-varying birth-death models are still lacking. We use a piecewise-constant birth-death model, combined with both Gaussian Markov random field (GMRF) and horseshoe Markov random field (HSMRF) prior distributions, to approximate arbitrary changes in birth rate through time. We implement these models in the widely used statistical phylogenetic software platform RevBayes, allowing us to jointly estimate birth-death process parameters, phylogeny, and nuisance parameters in a Bayesian framework. We test both GMRF-based and HSMRF-based models on a variety of simulated diversification scenarios, and then apply them to both a macroevolutionary and an epidemiological dataset. We find that both models are capable of inferring variable birth rates and correctly rejecting variable models in favor of effectively constant models. In general the HSMRF-based model has higher precision than its GMRF counterpart, with little to no loss of accuracy. Applied to a macroevolutionary dataset of the Australian gecko family Pygopodidae (where birth rates are interpretable as speciation rates), the GMRF-based model detects a slow decrease whereas the HSMRF-based model detects a rapid speciation-rate decrease in the last 12 million years. Applied to an infectious disease phylodynamic dataset of sequences from HIV subtype A in Russia and Ukraine (where birth rates are interpretable as the rate of accumulation of new infections), our models detect a strongly elevated rate of infection in the 1990s. Author summary Both the growth of groups of species and the spread of infectious diseases through populations can be modeled as birth-death processes. Birth events correspond either to speciation or infection, and death events to extinction or becoming noninfectious. The rates of birth and death may vary over time, and by examining this variation researchers can pinpoint important events in the history of life on Earth or in the course of an outbreak. Time-calibrated phylogenies track the relationships between a set of species (or infections) and the times of all speciation (or infection) events, and can thus be used to infer birth and death rates. We develop two phylogenetic birth-death models with the goal of discerning signal of rate variation from noise due to the stochastic nature of birth-death models. Using a variety of simulated datasets, we show that one of these models can accurately infer slow and rapid rate shifts without sacrificing precision. Using real data, we demonstrate that our new methodology can be used for simultaneous inference of phylogeny and rates through time

Area level socioeconomic disadvantage and diabetes control in the SIMLR Study cohort: Implications for health service planning

Abstract of a poster presentation at the 2015 PHC Research Conference, Adelaide, 29-31 July, 2015

Resting-state fMRI Activity Profile in Prodromal Alzheimer’s Disease and Older Adults with Cognitive Complaints

poster abstractBackground: Resting-state functional MRI (RS-fMRI) has been proposed to detect neurodegenerative disease-related network alterations before brain atrophy has emerged. Disrupted resting-state connectivity in the posterior cingulate cortex (PCC) and hippocampus has been reported in AD (Grecius, 2004), yet results in prodromal AD including MCI vary. Other methods have suggested the feasibility of earlier detection in euthymic older adults with marked cognitive complaints (CC) but normal neuropsychological test performance (Saykin, 2006). The current study was designed to assess RS-fMRI patterns in CC compared with MCI, AD and healthy controls (HC). Methods: To date, 13 CC, 9 HC, 4 MCI and 3 AD participants were scanned at rest with eyes closed on a Siemens 3T. RS-fMRI was analyzed using FSL, AFNI and SPM8. For each individual, the sum of amplitude of low frequency fluctuation (ALFF; 0.01–0.1 Hz) was calculated at each voxel (Biswal, 2010). Using PCC seed ROIs adapted from Fox et al (2005) voxel-wise cross-correlation maps were generated for each subject. Group comparisons and covariate analyses were performed using SPM8 with age as a covariate. Results: Compared to HC, MCI/AD showed decreased ALFF in the PCC (p CC > MCI/AD, p<0.05, effect size: 0.61), and ALFF of hippocampus (HC < CC < MCI/AD, p<0.01, effect size: 0.75). ALFF of PCC was positively correlated with neuropsychological performance (MMSE, DRS and CVLT; r=0.45 to 0.56, p<0.01), while hippocampal ALFF was negatively correlated with performance (r=-0.48 to -0.67, p<0.01). PCC seeded crosscorrelation maps showed decreased hippocampal connectivity in MCI/AD compared to HC or CC (p<0.01). Conclusions: RS-fMRI appears sensitive to early prodromal neurodegenerative changes in regions associated with AD, notably including pre-MCI individuals with CC. While there is decreased functional connectivity between PCC and hippocampus, regionally increased ALFF in hippocampus may indicate a compensatory mechanism in early prodromal AD

Immature B cells preferentially switch to IgE with increased direct Sμ to Sε recombination

Immunoglobulin heavy chain (IgH) class-switch recombination (CSR) replaces initially expressed Cμ (IgM) constant regions (C(H)) exons with downstream C(H) exons. Stimulation of B cells with anti-CD40 plus interleukin-4 induces CSR from Cμ to Cγ1 (IgG1) and Cε (IgE), the latter of which contributes to the pathogenesis of atopic diseases. Although Cε CSR can occur directly from Cμ, most mature peripheral B cells undergo CSR to Cε indirectly, namely from Cμ to Cγ1, and subsequently to Cε. Physiological mechanisms that influence CSR to Cγ1 versus Cε are incompletely understood. In this study, we report a role for B cell developmental maturity in IgE CSR. Based in part on a novel flow cytometric IgE CSR assay, we show that immature B cells preferentially switch to IgE versus IgG1 through a mechanism involving increased direct CSR from Cμ to Cε. Our findings suggest that IgE dysregulation in certain immunodeficiencies may be related to impaired B cell maturation

Activation of the innate immune receptor Dectin-1 upon formation of a 'phagocytic synapse'.

Innate immune cells must be able to distinguish between direct binding to microbes and detection of components shed from the surface of microbes located at a distance. Dectin-1 (also known as CLEC7A) is a pattern-recognition receptor expressed by myeloid phagocytes (macrophages, dendritic cells and neutrophils) that detects β-glucans in fungal cell walls and triggers direct cellular antimicrobial activity, including phagocytosis and production of reactive oxygen species (ROS). In contrast to inflammatory responses stimulated upon detection of soluble ligands by other pattern-recognition receptors, such as Toll-like receptors (TLRs), these responses are only useful when a cell comes into direct contact with a microbe and must not be spuriously activated by soluble stimuli. In this study we show that, despite its ability to bind both soluble and particulate β-glucan polymers, Dectin-1 signalling is only activated by particulate β-glucans, which cluster the receptor in synapse-like structures from which regulatory tyrosine phosphatases CD45 and CD148 (also known as PTPRC and PTPRJ, respectively) are excluded (Supplementary Fig. 1). The 'phagocytic synapse' now provides a model mechanism by which innate immune receptors can distinguish direct microbial contact from detection of microbes at a distance, thereby initiating direct cellular antimicrobial responses only when they are required

Association of polymorphisms in HCN4 with mood disorders and obsessive compulsive disorder

Hyperpolarization activated cyclic nucleotide-gated (HCN) potassium channels are implicated in the control of neuronal excitability and are expressed widely in the brain. HCN4 is expressed in brain regions relevant to mood and anxiety disorders including specific thalamic nuclei, the basolateral amygdala, and the midbrain dopamine system. We therefore examined the association of HCN4 with a group of mood and anxiety disorders. We genotyped nine tag SNPs in the HCN4 gene using Sequenom iPLEX Gold technology in 285 Caucasian patients with DSM-IV mood disorders and/or obsessive compulsive disorder and 384 Caucasian controls. HCN4 polymorphisms were analyzed using single marker and haplotype-based association methods. Three SNPs showed nominal association in our population (rs12905211, rs3859014, rs498005). SNP rs12905211 maintained significance after Bonferroni correction, with allele T and haplotype CTC overrepresented in cases. These findings suggest HCN4 as a genetic susceptibility factor for mood and anxiety disorders; however, these results will require replication using a larger sample

The Dawn of Open Access to Phylogenetic Data

The scientific enterprise depends critically on the preservation of and open access to published data. This basic tenet applies acutely to phylogenies (estimates of evolutionary relationships among species). Increasingly, phylogenies are estimated from increasingly large, genome-scale datasets using increasingly complex statistical methods that require increasing levels of expertise and computational investment. Moreover, the resulting phylogenetic data provide an explicit historical perspective that critically informs research in a vast and growing number of scientific disciplines. One such use is the study of changes in rates of lineage diversification (speciation - extinction) through time. As part of a meta-analysis in this area, we sought to collect phylogenetic data (comprising nucleotide sequence alignment and tree files) from 217 studies published in 46 journals over a 13-year period. We document our attempts to procure those data (from online archives and by direct request to corresponding authors), and report results of analyses (using Bayesian logistic regression) to assess the impact of various factors on the success of our efforts. Overall, complete phylogenetic data for ~60% of these studies are effectively lost to science. Our study indicates that phylogenetic data are more likely to be deposited in online archives and/or shared upon request when: (1) the publishing journal has a strong data-sharing policy; (2) the publishing journal has a higher impact factor, and; (3) the data are requested from faculty rather than students. Although the situation appears dire, our analyses suggest that it is far from hopeless: recent initiatives by the scientific community -- including policy changes by journals and funding agencies -- are improving the state of affairs