Indirect costs in the Australian for-purpose sector: Paying what it takes for Australian for-purpose organisations to create long-term impact

Indirect costs (or overhead) are a fraught topic in the not-for-profit world. Many people across philanthropy, government, the public and the media all expect them to be minimised, or not to pay for them at all. Yet they are essential to running a functioning, effective organisation. In the context of a struggling NFP sector, this is a crucial issue to ensure the long-term effectiveness of Australia’s charities. US research has shown that one of the key drivers of NFP vulnerability is insufficient funding of charity indirect costs. This is called the “non-profit starvation cycle”, in which funders having inaccurate expectations of how much overhead is needed to run a not-for-profit means that charities under report their costs to funders. This leads to a sector starved of the necessary core funding required to create resilient charities delivering long-term impact on complex social issues

Acute Kidney Injury Risk Prediction in Patients Undergoing Coronary Angiography in a National Veterans Health Administration Cohort with External Validation

Background: Acute kidney injury (AKI) occurs frequently after cardiac catheterization and percutaneous coronary intervention. Although a clinical risk model exists for percutaneous coronary intervention, no models exist for both procedures, nor do existing models account for risk factors prior to the index admission. We aimed to develop such a model for use in prospective automated surveillance programs in the Veterans Health Administration. Methods and Results: We collected data on all patients undergoing cardiac catheterization or percutaneous coronary intervention in the Veterans Health Administration from January 01, 2009 to September 30, 2013, excluding patients with chronic dialysis, end‐stage renal disease, renal transplant, and missing pre‐ and postprocedural creatinine measurement. We used 4 AKI definitions in model development and included risk factors from up to 1 year prior to the procedure and at presentation. We developed our prediction models for postprocedural AKI using the least absolute shrinkage and selection operator (LASSO) and internally validated using bootstrapping. We developed models using 115 633 angiogram procedures and externally validated using 27 905 procedures from a New England cohort. Models had cross‐validated C‐statistics of 0.74 (95% CI: 0.74–0.75) for AKI, 0.83 (95% CI: 0.82–0.84) for AKIN2, 0.74 (95% CI: 0.74–0.75) for contrast‐induced nephropathy, and 0.89 (95% CI: 0.87–0.90) for dialysis. Conclusions: We developed a robust, externally validated clinical prediction model for AKI following cardiac catheterization or percutaneous coronary intervention to automatically identify high‐risk patients before and immediately after a procedure in the Veterans Health Administration. Work is ongoing to incorporate these models into routine clinical practice

The Two Phases of Galaxy Formation

Cosmological simulations of galaxy formation appear to show a two-phase character with a rapid early phase at z>2 during which in-situ stars are formed within the galaxy from infalling cold gas followed by an extended phase since z<3 during which ex-situ stars are primarily accreted. In the latter phase massive systems grow considerably in mass and radius by accretion of smaller satellite stellar systems formed at quite early times (z>3) outside of the virial radius of the forming central galaxy. These tentative conclusions are obtained from high resolution re-simulations of 39 individual galaxies in a full cosmological context with present-day virial halo masses ranging from 7e11 M_sun h^-1 < M_vir < 2.7e13 M_sun h^-1 and central galaxy masses between 4.5e10 M_sun h^-1 < M_* < 3.6e11 M_sun h^-1. The simulations include the effects of a uniform UV background, radiative cooling, star formation and energetic feedback from SNII. The importance of stellar accretion increases with galaxy mass and towards lower redshift. In our simulations lower mass galaxies ($M_* < 9e10 M_sun h^-1) accrete about 60 per cent of their present-day stellar mass. High mass galaxy ($M_* > 1.7e11 M_sun h^-1) assembly is dominated by accretion and merging with about 80 per cent of the stars added by the present-day. In general the simulated galaxies approximately double their mass since z=1. For massive systems this mass growth is not accompanied by significant star formation. The majority of the in-situ created stars is formed at z>2, primarily out of cold gas flows. We recover the observational result of archaeological downsizing, where the most massive galaxies harbor the oldest stars. We find that this is not in contradiction with hierarchical structure formation. Most stars in the massive galaxies are formed early on in smaller structures, the galaxies themselves are assembled late.Comment: 13 pages, 13 figures, accepted for publication in Ap

Catching Element Formation In The Act

Gamma-ray astronomy explores the most energetic photons in nature to address some of the most pressing puzzles in contemporary astrophysics. It encompasses a wide range of objects and phenomena: stars, supernovae, novae, neutron stars, stellar-mass black holes, nucleosynthesis, the interstellar medium, cosmic rays and relativistic-particle acceleration, and the evolution of galaxies. MeV gamma-rays provide a unique probe of nuclear processes in astronomy, directly measuring radioactive decay, nuclear de-excitation, and positron annihilation. The substantial information carried by gamma-ray photons allows us to see deeper into these objects, the bulk of the power is often emitted at gamma-ray energies, and radioactivity provides a natural physical clock that adds unique information. New science will be driven by time-domain population studies at gamma-ray energies. This science is enabled by next-generation gamma-ray instruments with one to two orders of magnitude better sensitivity, larger sky coverage, and faster cadence than all previous gamma-ray instruments. This transformative capability permits: (a) the accurate identification of the gamma-ray emitting objects and correlations with observations taken at other wavelengths and with other messengers; (b) construction of new gamma-ray maps of the Milky Way and other nearby galaxies where extended regions are distinguished from point sources; and (c) considerable serendipitous science of scarce events -- nearby neutron star mergers, for example. Advances in technology push the performance of new gamma-ray instruments to address a wide set of astrophysical questions.Comment: 14 pages including 3 figure

Investigation of gene–environment interactions in relation to tic severity

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive–compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene–environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene–environment studies.This research was funded by National Institute of Mental Health (NIMH) grant R01MH092293 (to GAH and JAT) and NJCTS (New Jersey Center for Tourette Syndrome and Associated Disorders; to GAH and JAT). This work was also supported by grants from the Judah Foundation, the Tourette Association of America, National Institute of Health (NIH) Grants NS40024, NS016648, MH079489, MH073250, the American Recovery and Re-investment Act (ARRA) Grants NS040024-07S1; NS16648-29S1; NS040024-09S1; MH092289; MH092290; MH092291; MH092292; R01MH092293; MH092513; MH092516; MH092520; MH071507; MH079489; MH079487; MH079488; and MH079494. Dr. Mir has received grants from the Instituto de Salud Carlos III (PI10/01674, PI13/01461), the Consejería de Economía, Innovación, Ciencia y Empresa de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0741/2010, PI-0437-2012, PI-0471-2013), the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña and the Jaques and Gloria Gossweiler Foundation. Dr. Morer has received grants from the Fundacion Alicia Koplowitz and belongs to the research group of the Comissionat per Universitats i Recerca del Departmanent d’Innovacio (DIUE) 2009SGR1119. Dr. Münchau has received grants from the Deutsche Forschungsgemeinschaft (DFG: MU 1692/3-1, MU 1692/4-1 and FOR 2698). This study was also supported by a Grant from the National Institute for Environmental Health Science (R01 ES021462)

Selecting effective incentive structures in health care: A decision framework to support health care purchasers in finding the right incentives to drive performance

<p>Abstract</p> <p>Background</p> <p>The Ontario health care system is devolving planning and funding authority to community based organizations and moving from steering through rules and regulations to steering on performance. As part of this transformation, the Ontario Ministry of Health and Long-Term Care (MOHLTC) are interested in using incentives as a strategy to ensure alignment – that is, health service providers' goals are in accord with the goals of the health system. The objective of the study was to develop a decision framework to assist policymakers in choosing and designing effective incentive systems.</p> <p>Methods</p> <p>The first part of the study was an extensive review of the literature to identify incentives models that are used in the various health care systems and their effectiveness. The second part was the development of policy principles to ensure that the used incentive models are congruent with the values of the Ontario health care system. The principles were developed by reviewing the Ontario policy documents and through discussions with policymakers. The validation of the principles and the suggested incentive models for use in Ontario took place at two meetings. The first meeting was with experts from the research and policy community, the second with senior policymakers from the MOHLTC. Based on the outcome of those two meetings, the researchers built a decision framework for incentives. The framework was send to the participants of both meetings and four additional experts for validation.</p> <p>Results</p> <p>We identified several models that have proven, with a varying degree of evidence, to be effective in changing or enabling a health provider's performance. Overall, the literature suggests that there is no single best approach to create incentives yet and the ability of financial and non-financial incentives to achieve results depends on a number of contextual elements. After assessing the initial set of incentive models on their congruence with the four policy principles we defined nine incentive models to be appropriate for use in Ontario and potentially other health care systems that want to introduce incentives to improve performance. Subsequently, the models were incorporated in the resulting decision framework.</p> <p>Conclusion</p> <p>The design of an incentive must reflect the values and goals of the health care system, be well matched to the performance objectives and reflect a range of contextual factors that can influence the effectiveness of even well-designed incentives. As a consequence, a single policy recommendation around incentives is inappropriate. The decision framework provides health care policymakers and purchasers with a tool to support the selection of an incentive model that is the most appropriate to improve the targeted performance.</p

Synaptic processes and immune-related pathways implicated in Tourette syndrome

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS

Deletion of the Chd6 exon 12 affects motor coordination

Members of the CHD protein family play key roles in gene regulation through ATP-dependent chromatin remodeling. This is facilitated by chromodomains that bind histone tails, and by the SWI2/SNF2-like ATPase/helicase domain that remodels chromatin by moving histones. Chd6 is ubiquitously expressed in both mouse and human, with the highest levels of expression in the brain. The Chd6 gene contains 37 exons, of which exons 12-19 encode the highly conserved ATPase domain. To determine the biological role of Chd6, we generated mouse lines with a deletion of exon 12. Chd6 without exon 12 is expressed at normal levels in mice, and Chd6 Exon 12 −/− mice are viable, fertile, and exhibit no obvious morphological or pathological phenotype. Chd6 Exon 12 −/− mice lack coordination as revealed by sensorimotor analysis. Further behavioral testing revealed that the coordination impairment was not due to muscle weakness or bradykinesia. Histological analysis of brain morphology revealed no differences between Chd6 Exon 12 −/− mice and wild-type (WT) controls. The location of CHD6 on human chromosome 20q12 is overlapped by the linkage map regions of several human ataxias, including autosomal recessive infantile cerebellar ataxia (SCAR6), a nonprogressive cerebrospinal ataxia. The genomic location, expression pattern, and ataxic phenotype of Chd6 Exon 12 −/− mice indicate that mutations within CHD6 may be responsible for one of these ataxias

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.This work is supported by the UK Medical Research Council (MRC); Chinese Academy of Medical Sciences(CAMS) Innovation Fund for Medical Sciences (CIFMS), China; National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, and UK Researchand Innovation (UKRI)/NIHR through the UK Coro-navirus Immunology Consortium (UK-CIC). Sequencing of SARS-CoV-2 samples and collation of data wasundertaken by the COG-UK CONSORTIUM. COG-UK is supported by funding from the Medical ResearchCouncil (MRC) part of UK Research & Innovation (UKRI),the National Institute of Health Research (NIHR),and Genome Research Limited, operating as the Wellcome Sanger Institute. T.I.d.S. is supported by a Well-come Trust Intermediate Clinical Fellowship (110058/Z/15/Z). L.T. is supported by the Wellcome Trust(grant number 205228/Z/16/Z) and by theUniversity of Liverpool Centre for Excellence in Infectious DiseaseResearch (CEIDR). S.D. is funded by an NIHR GlobalResearch Professorship (NIHR300791). L.T. and S.C.M.are also supported by the U.S. Food and Drug Administration Medical Countermeasures Initiative contract75F40120C00085 and the National Institute for Health Research Health Protection Research Unit (HPRU) inEmerging and Zoonotic Infections (NIHR200907) at University of Liverpool inpartnership with Public HealthEngland (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.L.T. is based at the University of Liverpool. M.D.P. is funded by the NIHR Sheffield Biomedical ResearchCentre (BRC – IS-BRC-1215-20017). ISARIC4C is supported by the MRC (grant no MC_PC_19059). J.C.K.is a Wellcome Investigator (WT204969/Z/16/Z) and supported by NIHR Oxford Biomedical Research Centreand CIFMS. The views expressed are those of the authors and not necessarily those of the NIHR or MRC