The unmet needs of Aboriginal Australians with musculoskeletal pain: A mixed method systematic review

Objective: Musculoskeletal pain (MSP) conditions are the biggest cause of disability and internationally, Indigenous peoples experience a higher burden. There are conflicting reports about Aboriginal Australians and MSP. We conducted a systematic review to describe the prevalence, associated factors, impacts, care access, health care experiences, and factors associated with MSP among Aboriginal Australians. Methods: A systematic search of quantitative and qualitative scientific and grey literature (PROSPERO number: CRD42016038342). Articles were appraised using the Mixed Methods Appraisal Tool. Due to study heterogeneity a narrative synthesis was conducted. Results: Of 536 articles identified, 18 were included (14 quantitative, 4 qualitative), of high (n=11), medium (n=2) and low (n=5) quality. Prevalences of MSP in Aboriginal populations were similar to or slightly higher than the non‐Aboriginal population (prevalence rate ratio 1.1 for back pain, 1.2‐1.5 for osteoarthritis (OA), 1.0‐2.0 for rheumatoid arthritis). Aboriginal people accessed primary care for knee or hip OA at around half the rate of non‐Aboriginal people, and were less than half as likely to have knee or hip replacement surgery. Communication difficulties with health practitioners were the main reason why Aboriginal people with MSP choose not to access care. No articles reported interventions. Conclusions: Findings provide preliminary evidence of an increased MSP burden amongst Aboriginal Australians and, particularly for OA, a mismatch between the disease burden and access to health care. To increase accessibility, health services should initially focus on improving Aboriginal patients’ experiences of care, in particular by improving patient‐practitioner communication. Implications for care and research are outlined

Transcriptomic Identification of Iron-Regulated and Iron-Independent Gene Copies within the Heavily Duplicated Trichomonas vaginalis Genome

Gene duplication is an important evolutionary mechanism and no eukaryote has more duplicated gene families than the parasitic protist Trichomonas vaginalis. Iron is an essential nutrient for Trichomonas and plays a pivotal role in the establishment of infection, proliferation, and virulence. To gain insight into the role of iron in T. vaginalis gene expression and genome evolution, we screened iron-regulated genes using an oligonucleotide microarray for T. vaginalis and by comparative EST (expressed sequence tag) sequencing of cDNA libraries derived from trichomonads cultivated under iron-rich (+Fe) and iron-restricted (−Fe) conditions. Among 19,000 ESTs from both libraries, we identified 336 iron-regulated genes, of which 165 were upregulated under +Fe conditions and 171 under −Fe conditions. The microarray analysis revealed that 195 of 4,950 unique genes were differentially expressed. Of these, 117 genes were upregulated under +Fe conditions and 78 were upregulated under −Fe conditions. The results of both methods were congruent concerning the regulatory trends and the representation of gene categories. Under +Fe conditions, the expression of proteins involved in carbohydrate metabolism, particularly in the energy metabolism of hydrogenosomes, and in methionine catabolism was increased. The iron–sulfur cluster assembly machinery and certain cysteine proteases are of particular importance among the proteins upregulated under −Fe conditions. A unique feature of the T. vaginalis genome is the retention during evolution of multiple paralogous copies for a majority of all genes. Although the origins and reasons for this gene expansion remain unclear, the retention of multiple gene copies could provide an opportunity to evolve differential expression during growth in variable environmental conditions. For genes whose expression was affected by iron, we found that iron influenced the expression of only some of the paralogous copies, whereas the expression of the other paralogs was iron independent. This finding indicates a very stringent regulation of the differentially expressed paralogous genes in response to changes in the availability of exogenous nutrients and provides insight into the evolutionary rationale underlying massive paralog retention in the Trichomonas genome

A Novel Two-Step Hierarchical Quantitative Structure–Activity Relationship Modeling Work Flow for Predicting Acute Toxicity of Chemicals in Rodents

BackgroundAccurate prediction of in vivo toxicity from in vitro testing is a challenging problem. Large public–private consortia have been formed with the goal of improving chemical safety assessment by the means of high-throughput screening.ObjectiveA wealth of available biological data requires new computational approaches to link chemical structure, in vitro data, and potential adverse health effects.Methods and resultsA database containing experimental cytotoxicity values for in vitro half-maximal inhibitory concentration (IC50) and in vivo rodent median lethal dose (LD50) for more than 300 chemicals was compiled by Zentralstelle zur Erfassung und Bewertung von Ersatz- und Ergaenzungsmethoden zum Tierversuch (ZEBET; National Center for Documentation and Evaluation of Alternative Methods to Animal Experiments). The application of conventional quantitative structure–activity relationship (QSAR) modeling approaches to predict mouse or rat acute LD50 values from chemical descriptors of ZEBET compounds yielded no statistically significant models. The analysis of these data showed no significant correlation between IC50 and LD50. However, a linear IC50 versus LD50 correlation could be established for a fraction of compounds. To capitalize on this observation, we developed a novel two-step modeling approach as follows. First, all chemicals are partitioned into two groups based on the relationship between IC50 and LD50 values: One group comprises compounds with linear IC50 versus LD50 relationships, and another group comprises the remaining compounds. Second, we built conventional binary classification QSAR models to predict the group affiliation based on chemical descriptors only. Third, we developed k-nearest neighbor continuous QSAR models for each subclass to predict LD50 values from chemical descriptors. All models were extensively validated using special protocols.ConclusionsThe novelty of this modeling approach is that it uses the relationships between in vivo and in vitro data only to inform the initial construction of the hierarchical two-step QSAR models. Models resulting from this approach employ chemical descriptors only for external prediction of acute rodent toxicity

The dynamics of root cap sloughing in Arabidopsis is regulated by peptide signalling

The root cap protects the stem cell niche of angiosperm roots from damage. In Arabidopsis, lateral root cap (LRC) cells covering the meristematic zone are regularly lost through programmed cell death, while the outermost layer of the root cap covering the tip is repeatedly sloughed. Efficient coordination with stem cells producing new layers is needed to maintain a constant size of the cap. We present a signalling pair, the peptide IDA-LIKE1 (IDL1) and its receptor HAESA-LIKE2 (HSL2), mediating such communication. Live imaging over several days characterized this process from initial fractures in LRC cell files to full separation of a layer. Enhanced expression of IDL1 in the separating root cap layers resulted in increased frequency of sloughing, balanced with generation of new layers in a HSL2-dependent manner. Transcriptome analyses linked IDL1-HSL2 signalling to the transcription factors BEARSKIN1/2 and genes associated with programmed cell death. Mutations in either IDL1 or HSL2 slowed down cell division, maturation and separation. Thus, IDL1-HSL2 signalling potentiates dynamic regulation of the homeostatic balance between stem cell division and sloughing activity

Dissecting the long-term emission behaviour of the BL Lac object Mrk 421

We report on long-term multiwavelengthmonitoring of blazar Mrk 421 by the GLAST-AGILE Support Program of the Whole Earth Blazar Telescope (GASP-WEBT) collaboration and Steward Observatory, and by the Swift and Fermi satellites. We study the source behaviour in the period 2007–2015, characterized by several extreme flares. The ratio between the optical, X-ray and γ -ray fluxes is very variable. The γ -ray flux variations show a fair correlation with the optical ones starting from 2012.We analyse spectropolarimetric data and find wavelengthdependence of the polarization degree (P), which is compatible with the presence of the host galaxy, and no wavelength dependence of the electric vector polarization angle (EVPA). Optical polarimetry shows a lack of simple correlation between P and flux and wide rotations of the EVPA.We build broad-band spectral energy distributions with simultaneous near-infrared and optical data from the GASP-WEBT and ultraviolet and X-ray data from the Swift satellite. They show strong variability in both flux and X-ray spectral shape and suggest a shift of the synchrotron peak up to a factor of ∼50 in frequency. The interpretation of the flux and spectral variability is compatible with jet models including at least two emitting regions that can change their orientation with respect to the line of sight.http://10.0.4.69/mnras/stx2185Accepted manuscrip

Using theory to improve low back pain care in Australian Aboriginal primary care: a mixed method single cohort pilot study

Background: Low back pain (LBP) care is frequently discordant with research evidence. This pilot study evaluated changes in LBP care following a systematic, theory informed intervention in a rural Australian Aboriginal Health Service. We aimed to improve three aspects of care; reduce inappropriate LBP radiological imaging referrals, increase psychosocial oriented patient assessment and, increase the provision of LBP self-management information to patients. Methods: Three interventions to improve care were developed using a four-step systematic implementation approach. A mixed methods pre/post cohort design evaluated changes in the three behaviours using a clinical audit of LBP care in a six month period prior to the intervention and then following implementation. In-depth interviews elicited the perspectives of involved General Practitioners (GPs). Qualitative analysis was guided by the theoretical domains framework. Results: The proportion of patients who received guideline inconsistent imaging referrals (GICI) improved from 4.1 GICI per 10 patients to 0.4 (95 % CI for decrease in rate: 1.6 to 5.6) amongst GPs involved in the intervention. Amongst non-participating GPs (locum/part-time GPs who commenced post-interventions) the rate of GICI increased from 1.5 to 4.4 GICI per 10 patients (95 % CI for increase in rate: .5 to 5.3). There was a modest increase in the number of patients who received LBP self-management information from participating GPs and no substantial changes to psychosocial oriented patient assessments by any participants; however GPs qualitatively reported that their behaviours had changed. Knowledge and beliefs about consequences were important behavioural domains related to changes. Environmental and resource factors including protocols for locum staff and clinical tools embedded in patient management software were future strategies identified. Conclusions: A systematic intervention model resulted in partial improvements in LBP care. Determinants of practice change amongst GPs were increased knowledge of clinical guidelines, education delivered by someone considered a trusted source of information, and awareness of the negative consequences of inappropriate practices, especially radiological imaging on patient outcomes. Inconsistent and non-evidence based practices amongst locum GPs was an issue that emerged and will be a significant future challenge. The systematic approach utilised is applicable to other services interested in improving LBP care

Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the R6/2 Mouse Model of HD

Huntington's disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6/2 mouse model of HD expresses a mutant version of exon 1 HTT and develops motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Despite the vast number of studies that have been performed on this model, the association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood. In an attempt to link these factors, we have performed longitudinal assessments of behavior (rotarod, open field, passive avoidance) and of regional brain abnormalities determined through magnetic resonance imaging (MRI) (whole brain, striatum, cortex, hippocampus, corpus callosum), as well as an end-stage histological assessment. Detailed correlative analyses of these three measures were then performed. We found a gender-dependent emergence of motor impairments that was associated with an age-related loss of regional brain volumes. MRI measurements further indicated that there was no striatal atrophy, but rather a lack of striatal growth beyond 8 weeks of age. T2 relaxivity further indicated tissue-level changes within brain regions. Despite these dramatic motor and neuroanatomical abnormalities, R6/2 mice did not exhibit neuronal loss in the striatum or motor cortex, although there was a significant increase in neuronal density due to tissue atrophy. The deposition of the mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the brain. End-stage histopathological assessments were not found to be as robustly correlated with the longitudinal measures of brain atrophy or motor impairments. In conclusion, modeling pre-manifest and early progression of the disease in more slowly progressing animal models will be key to establishing which changes are causally related. © 2013 Rattray et al

Implementing efficient concerted rotations using Mathematica and C code

In this article we demonstrate a general and efficient metaprogramming implementation of concerted rotations using Mathematica. Concerted rotations allow the movement of a fixed portion of a polymer backbone with fixed bending angles, like a protein, while maintaining the correct geometry of the backbone and the initial and final points of the portion fixed. Our implementation uses Mathematica to generate a C code which is then wrapped in a library by a Python script. The user can modify the Mathematica notebook to generate a set of concerted rotations suited for a particular backbone geometry, without having to write the C code himself. The resulting code is highly optimized, performing on the order of thousands of operations per second