Keeping it real: Virtual connection with SToP trial community navigators

Building trust and forging relationships with remote Aboriginal communities is an essential element of culturally informed, reciprocal research. Historically these relationships have been formed over-time where community members and researchers come together face to face to share their knowledge and yarn in both an informal and formal manner. Researchers from Telethon Kids Institute are partnering with local stakeholders and remote Aboriginal communities in the Kimberley, Western Australia (WA) to support healthy skin through the SToP (See, Treat, Prevent skin sores and scabies) Trial. The SToP trial, a collaboration between Telethon Kids Institute, Kimberley Aboriginal Medical Services (KAMS), Nirrumbuk Environmental Health Services and Western Australia Country Health Services (WACHS) – Kimberley is a clustered randomised trial with a stepped-wedge design. SToP trial consultation with stakeholders and communities commenced in 2016 to proceed consenting in 2018 and trial commencement in 2019. Since that time, the SToP trial team have been conducting intermittent fieldwork in nine remote Aboriginal communities in the Kimberley. However, due to the COVID-19 pandemic when Aboriginal health leaders recommended a cessation to research related travel in northern WA from March 11, 2020 to prevent the incursion of COVID-19 into Aboriginal communities with health vulnerabilities, crucial face-to-face yarning was no longer possible. At the time it appeared the existing relationships with communities involved in our research (the SToP trial) would be challenging to maintain without this ability to visit the communities. Fortunately, when tested, this assumption was erroneous. Here we report the successful use of technology to bridge the inability to visit communities in 2020 due to COVID-19. The Telethon Kulunga Aboriginal Unit (Kulunga) and SToP trial team members were able to connect virtually with Community Navigators from the Dampier Peninsula communities. The initial virtual meeting using Microsoft Teams technology involved four Community Navigators and their mentor, three Telethon Kids Institute and five Kulunga staff members. Community Navigators joined Microsoft Teams from their respective communities and Kulunga and Telethon Kids Institute staff joined from their homes. Not only was this an exciting new way of communicating, it enabled existing relationships to continue to be strengthened. Since the initial meeting, the teams have continued to meet virtually, and plan SToP trial health promotion activities including a community-driven, collaborative music video. While the significance of face-to-face yarning can never be overstated, having to adjust to a new way of yarning has reiterated the importance of connection, albeit virtually. Unfortunately, due to technical limitations, intermittent internet connectivity and various other challenges, there has been no opportunity to engage virtually with SToP trial communities in the East Kimberley. However, we continue to seek ways where virtual communication in these communities is possible

De novo mutations in regulatory elements in neurodevelopmental disorders

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this recordWe previously estimated that 42% of patients with severe developmental disorders carry pathogenic de novo mutations in coding sequences. The role of de novo mutations in regulatory elements affecting genes associated with developmental disorders, or other genes, has been essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 patients with developmental disorders. Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant twofold enrichment of recurrently mutated elements. We estimate that, genome-wide, 1-3% of patients without a diagnostic coding variant carry pathogenic de novo mutations in fetal brain-active regulatory elements and that only 0.15% of all possible mutations within highly conserved fetal brain-active elements cause neurodevelopmental disorders with a dominant mechanism. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasize the importance of combining functional and evolutionary evidence to identify regulatory causes of genetic disorders.Health Innovation Challenge FundWellcome TrustUK Department of HealthWellcome Trust Sanger Institut

Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data.

Mosaic genetic variants can have major clinical impact. We systematically analyse trio exome sequence data from 4,293 probands from the DDD Study with severe developmental disorders for pathogenic postzygotic mosaicism (PZM) in the child or a clinically-unaffected parent, and use ultrahigh-depth sequencing to validate candidate mosaic variants. We observe that levels of mosaicism for small genetic variants are usually equivalent in both saliva and blood and ~3% of causative de novo mutations exhibit PZM; this is an important observation, as the sibling recurrence risk is extremely low. We identify parental PZM in 21 trios (0.5% of trios), resulting in a substantially increased sibling recurrence risk in future pregnancies. Together, these forms of mosaicism account for 40 (1%) diagnoses in our cohort. Likely child-PZM mutations occur equally on both parental haplotypes, and the penetrance of detectable mosaic pathogenic variants overall is likely to be less than half that of constitutive variants

Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data.

Mosaic genetic variants can have major clinical impact. We systematically analyse trio exome sequence data from 4,293 probands from the DDD Study with severe developmental disorders for pathogenic postzygotic mosaicism (PZM) in the child or a clinically-unaffected parent, and use ultrahigh-depth sequencing to validate candidate mosaic variants. We observe that levels of mosaicism for small genetic variants are usually equivalent in both saliva and blood and ~3% of causative de novo mutations exhibit PZM; this is an important observation, as the sibling recurrence risk is extremely low. We identify parental PZM in 21 trios (0.5% of trios), resulting in a substantially increased sibling recurrence risk in future pregnancies. Together, these forms of mosaicism account for 40 (1%) diagnoses in our cohort. Likely child-PZM mutations occur equally on both parental haplotypes, and the penetrance of detectable mosaic pathogenic variants overall is likely to be less than half that of constitutive variants

Lady Gaga as (dis)simulacrum of monstrosity

Lady Gaga’s celebrity DNA revolves around the notion of monstrosity, an extensively researched concept in postmodern cultural studies. The analysis that is offered in this paper is largely informed by Deleuze and Guattari’s notion of monstrosity, as well as by their approach to the study of sign-systems that was deployed in A Thousand Plateaus. By drawing on biographical and archival visual data, with a focus on the relatively underexplored live show, an elucidation is afforded of what is really monstrous about Lady Gaga. The main argument put forward is that monstrosity as sign seeks to appropriate the horizon of unlimited semiosis as radical alterity and openness to signifying possibilities. In this context it is held that Gaga effectively delimits her unique semioscape; however, any claims to monstrosity are undercut by the inherent limits of a representationalist approach in sufficiently engulfing this concept. Gaga is monstrous for her community insofar as she demands of her fans to project their semiosic horizon onto her as a simulacrum of infinite semiosis. However, this simulacrum may only be evinced in a feigned manner as a (dis)simulacrum. The analysis of imagery from seminal live shows during 2011–2012 shows that Gaga’s presumed monstrosity is more akin to hyperdifferentiation as simultaneous employment of heterogeneous and potentially dissonant inter pares cultural representations. The article concludes with a problematisation of audience effects in the light of Gaga’s adoption of a schematic and post-representationalist strategy in the event of her strategy’s emulation by competitive artists

Inter-examiner reliability of the diagnosis of cervical pillar hyperplasia (CPH) and the correlation between CPH and spinal degenerative joint disease (DJD)

BACKGROUND: Cervical pillar hyperplasia (CPH) is a recently described phenomenon of unknown aetiology. Its clinical importance is poorly understood at the present time; therefore, the objective of this study was to determine (1) the inter-examiner reliability of detecting CPH and (2) if there is a clinically important correlation (r > 0.4) between the number of cervical spine levels showing signs of degenerative joint disease (DJD) and CPH. METHODS: The sample consisted of 320 radiographs of human male and female subjects who ranged from 40 to 79 years of age. The inter-examiner reliability of assessing the presence/absence of pillar hyperplasia was evaluated on 50 neutral lateral radiographs by two examiners using line drawings and it was quantified using the kappa coefficient of concordance. To determine the presence/absence of hyperplastic pillars as well as the presence/absence of DJD at each intervertebral disc and zygapophysial joint, 320 AP open mouth, AP lower cervical and neutral lateral radiographs were then examined. The unpaired t-test at the 5% level of significance was performed to test for a statistically significant difference between the number of levels affected by DJD in patients with and without hyperplasia. The Spearman's rho at the 5% level of significance was performed to quantify the correlation between DJD and age. RESULTS: The inter-examiner reliability of detecting cervical pillar hyperplasia was moderate with a kappa coefficient of 0.51. The unpaired t-test indicated that there was no statistically significant difference (p > 0.05) between the presence/absence of cervical pillar hyperplasia and the number of levels affected by DJD in an age-matched population, regardless of whether all elements were considered together, or the discs and facets were analyzed separately. A Spearman correlation rank of 0.67 (p < 0.05) suggested a moderately strong correlation between the number of elements (i.e. discs/facets) affected, and the age of the individual. CONCLUSION: Cervical pillar hyperplasia is a reasonable concept that requires further research. Its evaluation is easy to learn and acceptably reliable. Previous research has suggested that CPH may affect the cervical lordosis, and therefore, alter biomechanics which may result in premature DJD. This current study, however, indicates that, globally, CPH does not appear to be related to the development of DJD

A Geospatial Modelling Approach Integrating Archaeobotany and Genetics to Trace the Origin and Dispersal of Domesticated Plants

Background: The study of the prehistoric origins and dispersal routes of domesticated plants is often based on the analysis of either archaeobotanical or genetic data. As more data become available, spatially explicit models of crop dispersal can be used to combine different types of evidence. Methodology/Principal Findings: We present a model in which a crop disperses through a landscape that is represented by a conductance matrix. From this matrix, we derive least-cost distances from the geographical origin of the crop and use these to predict the age of archaeological crop remains and the heterozygosity of crop populations. We use measures of the overlap and divergence of dispersal trajectories to predict genetic similarity between crop populations. The conductance matrix is constructed from environmental variables using a number of parameters. Model parameters are determined with multiple-criteria optimization, simultaneously fitting the archaeobotanical and genetic data. The consilience reached by the model is the extent to which it converges around solutions optimal for both archaeobotanical and genetic data. We apply the modelling approach to the dispersal of maize in the Americas. Conclusions/Significance: The approach makes possible the integrative inference of crop dispersal processes, whil

Accuracy of Predicting the Genetic Risk of Disease Using a Genome-Wide Approach

Background - The prediction of the genetic disease risk of an individual is a powerful public health tool. While predicting risk has been successful in diseases which follow simple Mendelian inheritance, it has proven challenging in complex diseases for which a large number of loci contribute to the genetic variance. The large numbers of single nucleotide polymorphisms now available provide new opportunities for predicting genetic risk of complex diseases with high accuracy. Methodology/Principal Findings - We have derived simple deterministic formulae to predict the accuracy of predicted genetic risk from population or case control studies using a genome-wide approach and assuming a dichotomous disease phenotype with an underlying continuous liability. We show that the prediction equations are special cases of the more general problem of predicting the accuracy of estimates of genetic values of a continuous phenotype. Our predictive equations are responsive to all parameters that affect accuracy and they are independent of allele frequency and effect distributions. Deterministic prediction errors when tested by simulation were generally small. The common link among the expressions for accuracy is that they are best summarized as the product of the ratio of number of phenotypic records per number of risk loci and the observed heritability. Conclusions/Significance - This study advances the understanding of the relative power of case control and population studies of disease. The predictions represent an upper bound of accuracy which may be achievable with improved effect estimation methods. The formulae derived will help researchers determine an appropriate sample size to attain a certain accuracy when predicting genetic ris

Segment-specific association between cervical pillar hyperplasia (CPH) and degenerative joint disease (DJD)

BACKGROUND: Cervical pillar hyperplasia (CPH) is a recently described phenomenon of unknown etiology and clinical significance. Global assessment of pillar hyperplasia of the cervical spine as a unit has not shown a relationship with degenerative joint disease, but a more sensible explanation of the architectural influence of CPH on cervical spine biomechanics may be segment-specific. OBJECTIVE: The objective of this study was to determine the level of association between degenerative joint disease (DJD) and cervical pillar hyperplasia (CPH) in an age- and gender-matched sample on a [cervical spine] by-level basis. RESEARCH METHODS: Two-hundred and forty radiographs were collected from subjects ranging in age between 40 and 69 years. The two primary outcome measures used in the study were the segmental presence/absence of cervical pillar hyperplasia from C3 to C6, and segment-specific presence/absence of degenerative joint disease from C1 to C7. Contingency Coefficients, at the 5% level of significance, at each level, were used to determine the strength of the association between CPH and DJD. Odds Ratios (OR) with their 95% Confidence Intervals (95% CI) were also calculated at each level to assess the strength of the association. RESULTS: Our study suggests that an approximately two-to-one odds, or a weak-to-moderate correlation, exists at C4 and C5 CPH and adjacent level degenerative disc disease (DDD); with the strongest (overall) associations demonstrated between C4 CPH and C4–5 DDD and between C5 CPH and C5–6 DDD. Age-stratified results demonstrated a similar pattern of association, even reaching the initially hypothesized OR ≥ 5.0 (95% CI > 1.0) or "moderately-strong correlation of C ≥ .4 (p ≤ .05)" in some age categories, including the 40–44, 50–59, and 60–64 years of age subgroups; these ORs were as follows: OR = 5.5 (95% CI 1.39–21.59); OR = 6.7 (95% CI 1.65–27.34); and OR = 5.3 (95% CI 1.35–21.14), respectively. CONCLUSION: Our results suggest that CPH has around two-to-one odds, that is, only a weak-to-moderate association with the presence of DJD (DDD component) at specific cervical spine levels; therefore, CPH may be but one of several factors that contributes (to a clinically important degree) to the development of DJD at specific levels in the cervical spine