No difference in effects of ‘PACE steps to success’ palliative care program for nursing home residents with and without dementia : a pre-planned subgroup analysis of the seven-country PACE trial

Background: 'PACE Steps to Success' is a multicomponent training program aiming to integrate generalist and non-disease-specific palliative care in nursing homes. This program did not improve residents' comfort in the last week of life, but it appeared to improve quality of care and dying in their last month of life. Because this program included only three dementia-specific elements, its effects might differ depending on the presence or stage of dementia. We aimed to investigate whether the program effects differ between residents with advanced, non-advanced, and no dementia. Methods: Pre-planned subgroup analysis of the PACE cluster-randomized controlled trial in 78 nursing homes in seven European countries. Participants included residents who died in the previous 4 months. The nursing home staff or general practitioner assessed the presence of dementia; severity was determined using two highly-discriminatory staff-reported instruments. Using after-death questionnaires, staff assessed comfort in the last week of life (Comfort Assessment in Dying-End-of-Life in Dementia-scale; primary outcome) and quality of care and dying in the last month of life (Quality of Dying in Long-Term Care scale; secondary outcome). Results: At baseline, we included 177 residents with advanced dementia, 126 with non-advanced dementia and 156 without dementia. Post-intervention, respectively in the control and the intervention group, we included 136 and 104 residents with advanced dementia, 167 and 110 with non-advanced dementia and 157 and 137 without dementia. We found no subgroup differences on comfort in the last week of life, comparing advanced versus without dementia (baseline-adjusted mean sub-group difference 2.1; p-value = 0.177), non-advanced versus without dementia (2.7; p = 0.092), and advanced versus non-advanced dementia (- 0.6; p = 0.698); or on quality of care and dying in the last month of life, comparing advanced and without dementia (- 0.6; p = 0.741), non-advanced and without dementia (- 1.5; p = 0.428), and advanced and non-advanced dementia (0.9; p = 0.632). Conclusions: The lack of subgroup difference suggests that while the program did not improve comfort in dying residents with or without dementia, it appeared to equally improve quality of care and dying in the last month of life for residents with dementia (regardless of the stage) and those without dementia. A generalist and non-disease-specific palliative care program, such as PACE Steps to Success, is a useful starting point for future palliative care improvement in nursing homes, but to effectively improve residents' comfort, this program needs further development

A systematic SNP selection approach to identify mechanisms underlying disease aetiology: Linking height to post-menopausal breast and colorectal cancer risk

Data from GWAS suggest that SNPs associated with complex diseases or traits tend to co-segregate in regions of low recombination, harbouring functionally linked gene clusters. This phenomenon allows for selecting a limited number of SNPs from GWAS repositories for large-scale studies investigating shared mechanisms between diseases. For example, we were interested in shared mechanisms between adult-attained height and post-menopausal breast cancer (BC) and colorectal cancer (CRC) risk, because height is a risk factor for these cancers, though likely not a causal factor. Using SNPs from public GWAS repositories at p-values < 1 × 10-5 and a genomic sliding window of 1 mega base pair, we identified SNP clusters including at least one SNP associated with height and one SNP associated with either post-menopausal BC or CRC risk (or both). SNPs were annotated to genes using HapMap and GRAIL and analysed for significantly overrepresented pathways using ConsensuspathDB. Twelve clusters including 56 SNPs annotated to 26 genes were prioritised because these included at least one height- and one BC risk- or CRC risk-associated SNP annotated to the same gene. Annotated genes were involved in Indian hedgehog signalling (p-value = 7.78 × 10-7) and several cancer site-specific pathways. This systematic approach identified a limited number of clustered SNPs, which pinpoint potential shared mechanisms linking together the complex phenotypes height, post-menopausal BC and CRC

Direct Visualization of Protease Action on Collagen Triple Helical Structure

Enzymatic processing of extracellular matrix (ECM) macromolecules by matrix metalloproteases (MMPs) is crucial in mediating physiological and pathological cell processes. However, the molecular mechanisms leading to effective physiological enzyme-ECM interactions remain elusive. Only scant information is available on the mode by which matrix proteases degrade ECM substrates. An example is the enzymatic degradation of triple helical collagen II fragments, generated by the collagenase MMP-8 cleavage, during the course of acute inflammatory conditions by gelatinase B/MMP-9. As is the case for many other matrix proteases, it is not clear how MMP-9 recognizes, binds and digests collagen in this important physiological process. We used single molecule imaging to directly visualize this protease during its interaction with collagen fragments. We show that the initial binding is mediated by the diffusion of the protease along the ordered helix on the collagen ¾ fragment, with preferential binding of the collagen tail. As the reaction progressed and prior to collagen degradation, gelatin-like morphologies resulting from the denaturation of the triple helical collagen were observed. Remarkably, this activity was independent of enzyme proteolysis and was accompanied by significant conformational changes of the working protease. Here we provide the first direct visualization of highly complex mechanisms of macromolecular interactions governing the enzymatic processing of ECM substrates by physiological protease

Influence of wiring cost on the large-scale architecture of human cortical connectivity

In the past two decades some fundamental properties of cortical connectivity have been discovered: small-world structure, pronounced hierarchical and modular organisation, and strong core and rich-club structures. A common assumption when interpreting results of this kind is that the observed structural properties are present to enable the brain's function. However, the brain is also embedded into the limited space of the skull and its wiring has associated developmental and metabolic costs. These basic physical and economic aspects place separate, often conflicting, constraints on the brain's connectivity, which must be characterized in order to understand the true relationship between brain structure and function. To address this challenge, here we ask which, and to what extent, aspects of the structural organisation of the brain are conserved if we preserve specific spatial and topological properties of the brain but otherwise randomise its connectivity. We perform a comparative analysis of a connectivity map of the cortical connectome both on high- and low-resolutions utilising three different types of surrogate networks: spatially unconstrained (‘random’), connection length preserving (‘spatial’), and connection length optimised (‘reduced’) surrogates. We find that unconstrained randomisation markedly diminishes all investigated architectural properties of cortical connectivity. By contrast, spatial and reduced surrogates largely preserve most properties and, interestingly, often more so in the reduced surrogates. Specifically, our results suggest that the cortical network is less tightly integrated than its spatial constraints would allow, but more strongly segregated than its spatial constraints would necessitate. We additionally find that hierarchical organisation and rich-club structure of the cortical connectivity are largely preserved in spatial and reduced surrogates and hence may be partially attributable to cortical wiring constraints. In contrast, the high modularity and strong s-core of the high-resolution cortical network are significantly stronger than in the surrogates, underlining their potential functional relevance in the brain

11β-hydroxysteroid dehydrogenase type 1 has no effect on survival during experimental malaria but affects parasitemia in a parasite strain-specific manner

status: publishe