Contamination in complex healthcare trials:the falls in care homes (FinCH) study experience

BACKGROUND: Trials are at risk of contamination bias which can occur when participants in the control group are inadvertently exposed to the intervention. This is a particular risk in rehabilitation studies where it is easy for trial interventions to be either intentionally or inadvertently adopted in control settings. The Falls in Care Homes (FinCH) trial is used in this paper as an example of a large randomised controlled trial of a complex intervention to explore the potential risks of contamination bias. We outline the FinCH trial design, present the potential risks from contamination bias, and the strategies used in the design of the trial to minimise or mitigate against this. The FinCH trial was a multi-centre randomised controlled trial, with embedded process evaluation, which evaluated whether systematic training in the use of the Guide to Action Tool for Care Homes reduced falls in care home residents. Data were collected from a number of sources to explore contamination in the FinCH trial. Where specific procedures were adopted to reduce risk of, or mitigate against, contamination, this was recorded. Data were collected from study e-mails, meetings with clinicians, research assistant and clinician network communications, and an embedded process evaluation in six intervention care homes. During the FinCH trial, there were six new falls prevention initiatives implemented outside the study which could have contaminated our intervention and findings. Methods used to minimise contamination were: cluster randomisation at the level of care home; engagement with the clinical community to highlight the risks of early adoption; establishing local collaborators in each site familiar with the local context; signing agreements with NHS falls specialists that they would maintain confidentiality regarding details of the intervention; opening additional research sites; and by raising awareness about the importance of contamination in research among participants. CONCLUSION: Complex rehabilitation trials are at risk of contamination bias. The potential for contamination bias in studies can be minimized by strengthening collaboration and dialogue with the clinical community. Researchers should recognise that clinicians may contaminate a study through lack of research expertise

“I was a full time proper smoker”: A qualitative exploration of smoking in the home after childbirth among women who relapse postpartum

Background: Many women stop smoking during pregnancy but relapse shortly afterwards, potentially putting their infants at risk of secondhand smoke (SHS) exposure. Women who were able to stop during pregnancy may be a motivated group, receptive to making behaviour changes postpartum to protect their infant from SHS exposure. Understanding more about their experiences of relapse, and if this influences home smoking behaviours and children’s exposure to SHS in the home may help to inform intervention development to prevent infant SHS exposure. Methods: Guided by interpretative phenomenological methodology we conducted and analysed nine semi-structured interviews with women who quit smoking during pregnancy, but relapsed ≤3 months postpartum. Findings: Central to mothers’ accounts of their smoking behaviours during pregnancy and postpartum was their desire to be a ‘responsible mother’. Mothers described using strategies to protect their infant from SHS exposure, and held strong negative attitudes towards other smoking parents. After relapsing, mothers appeared to reposition themselves as ‘social’ or ‘occasional’ smokers rather than ‘regular’ smokers Conclusions: Findings suggest that interventions to prevent/reduce infants' home SHS exposure should build on mothers' intentions to be responsible parents. As mothers who relapse principally view themselves as ‘social’ or ‘occasional’ smokers, interventions that are highlighted as relevant for women with these types of smoking patterns may be more likely to be responded to, and, ultimately, be effective

From planning to deployment - insights into installing publicly-accessible journey EV charging infrastructure

Deploying publicly accessible electric vehicle charging infrastructure involves engaging with multiple stakeholders from various organisations to ensure successful project delivery. When installing a fleet of charging points across a wide area, the number of stakeholders increases often resulting in a disjointed or non-standardised experience for EV infrastructure developers. Based on real-world learnings, this paper suggests several improvements that could be implemented by distribution network operators that would help streamline infrastructure deployment and help accelerate the uptake of zero-carbon transport solutions

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

OBJECTIVE: Src family kinases (SFK) have been implicated in regulating growth factor and integrin-induced proliferation, migration, and gene expression in multiple cell types. However, little is known about the role of these kinases in the growth, homing, and engraftment potential of hematopoietic stem and progenitor cells. RESULTS: Here we show that loss of hematopoietic-specific SFKs Hck, Fgr, and Lyn results in increased number of Sca-1(+)Lin(-) cells in the bone marrow, which respond differentially to cytokine-induced growth in vitro and manifest a significant defect in the long-term repopulating potential in vivo. Interestingly, a significant increase in expression of adhesion molecules, known to coincide with the homing potential of wild-type bone marrow cells is also observed on the surface of SFK(-/-) cells, although, this increase did not affect the homing potential of more primitive Lin(-)Sca-1(+) SFK(-/-) cells. The stem cell-repopulating defect observed in mice transplanted with SFK(-/-) bone marrow cells is due to the loss of Lyn Src kinase, because deficiency of Lyn, but not Hck or Fgr, recapitulated the long-term stem cell defect observed in mice transplanted with SFK(-/-) bone marrow cells. CONCLUSIONS: Taken together, our results demonstrate an essential role for Lyn kinase in positively regulating the long-term and multilineage engraftment of stem cells, which is distinct from its role in mature B cells and myeloid cells

The Yeast La Related Protein Slf1p Is a Key Activator of Translation during the Oxidative Stress Response

The mechanisms by which RNA-binding proteins control the translation of subsets of mRNAs are not yet clear. Slf1p and Sro9p are atypical-La motif containing proteins which are members of a superfamily of RNA-binding proteins conserved in eukaryotes. RIP-Seq analysis of these two yeast proteins identified overlapping and distinct sets of mRNA targets, including highly translated mRNAs such as those encoding ribosomal proteins. In paralell, transcriptome analysis of slf1Δ and sro9Δ mutant strains indicated altered gene expression in similar functional classes of mRNAs following loss of each factor. The loss of SLF1 had a greater impact on the transcriptome, and in particular, revealed changes in genes involved in the oxidative stress response. slf1Δ cells are more sensitive to oxidants and RIP-Seq analysis of oxidatively stressed cells enriched Slf1p targets encoding antioxidants and other proteins required for oxidant tolerance. To quantify these effects at the protein level, we used label-free mass spectrometry to compare the proteomes of wild-type and slf1Δ strains following oxidative stress. This analysis identified several proteins which are normally induced in response to hydrogen peroxide, but where this increase is attenuated in the slf1Δ mutant. Importantly, a significant number of the mRNAs encoding these targets were also identified as Slf1p-mRNA targets. We show that Slf1p remains associated with the few translating ribosomes following hydrogen peroxide stress and that Slf1p co-immunoprecipitates ribosomes and members of the eIF4E/eIF4G/Pab1p ‘closed loop’ complex suggesting that Slf1p interacts with actively translated mRNAs following stress. Finally, mutational analysis of SLF1 revealed a novel ribosome interacting domain in Slf1p, independent of its RNA binding La-motif. Together, our results indicate that Slf1p mediates a translational response to oxidative stress via mRNA-specific translational control

Convergence of marine megafauna movement patterns in coastal and open oceans

The extent of increasing anthropogenic impacts on large marine vertebrates partly depends on the animals’ movement patterns. Effective conservation requires identification of the key drivers of movement including intrinsic properties and extrinsic constraints associated with the dynamic nature of the environments the animals inhabit. However, the relative importance of intrinsic versus extrinsic factors remains elusive. We analyze a global dataset of ∼2.8 million locations from >2,600 tracked individuals across 50 marine vertebrates evolutionarily separated by millions of years and using different locomotion modes (fly, swim, walk/paddle). Strikingly, movement patterns show a remarkable convergence, being strongly conserved across species and independent of body length and mass, despite these traits ranging over 10 orders of magnitude among the species studied. This represents a fundamental difference between marine and terrestrial vertebrates not previously identified, likely linked to the reduced costs of locomotion in water. Movement patterns were primarily explained by the interaction between species-specific traits and the habitat(s) they move through, resulting in complex movement patterns when moving close to coasts compared with more predictable patterns when moving in open oceans. This distinct difference may be associated with greater complexity within coastal microhabitats, highlighting a critical role of preferred habitat in shaping marine vertebrate global movements. Efforts to develop understanding of the characteristics of vertebrate movement should consider the habitat(s) through which they move to identify how movement patterns will alter with forecasted severe ocean changes, such as reduced Arctic sea ice cover, sea level rise, and declining oxygen content

Dynamic changes in eIF4F-mRNA interactions revealed by global analyses of environmental stress responses

BACKGROUND: Translation factors eIF4E and eIF4G form eIF4F, which interacts with the messenger RNA (mRNA) 5' cap to promote ribosome recruitment and translation initiation. Variations in the association of eIF4F with individual mRNAs likely contribute to differences in translation initiation frequencies between mRNAs. As translation initiation is globally reprogrammed by environmental stresses, we were interested in determining whether eIF4F interactions with individual mRNAs are reprogrammed and how this may contribute to global environmental stress responses. RESULTS: Using a tagged-factor protein capture and RNA-sequencing (RNA-seq) approach, we have assessed how mRNA associations with eIF4E, eIF4G1 and eIF4G2 change globally in response to three defined stresses that each cause a rapid attenuation of protein synthesis: oxidative stress induced by hydrogen peroxide and nutrient stresses caused by amino acid or glucose withdrawal. We find that acute stress leads to dynamic and unexpected changes in eIF4F-mRNA interactions that are shared among each factor and across the stresses imposed. eIF4F-mRNA interactions stabilised by stress are predominantly associated with translational repression, while more actively initiating mRNAs become relatively depleted for eIF4F. Simultaneously, other mRNAs are insulated from these stress-induced changes in eIF4F association. CONCLUSION: Dynamic eIF4F-mRNA interaction changes are part of a coordinated early translational control response shared across environmental stresses. Our data are compatible with a model where multiple mRNA closed-loop complexes form with differing stability. Hence, unexpectedly, in the absence of other stabilising factors, rapid translation initiation on mRNAs correlates with less stable eIF4F interactions

Convergence of marine megafauna movement patterns in coastal and open oceans

Author Posting. © The Author(s), 2017. This is the author's version of the work. It is posted here for personal use, not for redistribution. The definitive version was published in Proceedings of the National Academy of Sciences of the United States of America 115 (2018): 3072-3077, doi:10.1073/pnas.1716137115.The extent of increasing anthropogenic impacts on large marine vertebrates partly depends on the animals’ movement patterns. Effective conservation requires identification of the key drivers of movement including intrinsic properties and extrinsic constraints associated with the dynamic nature of the environments the animals inhabit. However, the relative importance of intrinsic versus extrinsic factors remains elusive. We analyse a global dataset of 2.8 million locations from > 2,600 tracked individuals across 50 marine vertebrates evolutionarily separated by millions of years and using different locomotion modes (fly, swim, walk/paddle). Strikingly, movement patterns show a remarkable convergence, being strongly conserved across species and independent of body length and mass, despite these traits ranging over 10 orders of magnitude among the species studied. This represents a fundamental difference between marine and terrestrial vertebrates not previously identified, likely linked to the reduced costs of locomotion in water. Movement patterns were primarily explained by the interaction between species-specific traits and the habitat(s) they move through, resulting in complex movement patterns when moving close to coasts compared to more predictable patterns when moving in open oceans. This distinct difference may be associated with greater complexity within coastal micro-habitats, highlighting a critical role of preferred habitat in shaping marine vertebrate global movements. Efforts to develop understanding of the characteristics of vertebrate movement should consider the habitat(s) through which they move to identify how movement patterns will alter with forecasted severe ocean changes, such as reduced Arctic sea ice cover, sea level rise and declining oxygen content.Workshops funding granted by the UWA Oceans Institute, AIMS, and KAUST. AMMS was supported by an ARC Grant DE170100841 and an IOMRC (UWA, AIMS, CSIRO) fellowship; JPR by MEDC (FPU program, Spain); DWS by UK NERC and Save Our Seas Foundation; NQ by FCT (Portugal); MMCM by a CAPES fellowship (Ministry of Education)