High sensitivity of future global warming to land carbon cycle processes

Unknowns in future global warming are usually assumed to arise from uncertainties either in the amount of anthropogenic greenhouse gas emissions or in the sensitivity of the climate to changes in greenhouse gas concentrations. Characterizing the additional uncertainty in relating CO2 emissions to atmospheric concentrations has relied on either a small number of complex models with diversity in process representations, or simple models. To date, these models indicate that the relevant carbon cycle uncertainties are smaller than the uncertainties in physical climate feedbacks and emissions. Here, for a single emissions scenario, we use a full coupled climate–carbon cycle model and a systematic method to explore uncertainties in the land carbon cycle feedback. We find a plausible range of climate–carbon cycle feedbacks significantly larger than previously estimated. Indeed the range of CO2 concentrations arising from our single emissions scenario is greater than that previously estimated across the full range of IPCC SRES emissions scenarios with carbon cycle uncertainties ignored. The sensitivity of photosynthetic metabolism to temperature emerges as the most important uncertainty. This highlights an aspect of current land carbon modelling where there are open questions about the potential role of plant acclimation to increasing temperatures. There is an urgent need for better understanding of plant photosynthetic responses to high temperature, as these responses are shown here to be key contributors to the magnitude of future change

Effects of vitamin D supplementation on endothelial function:a systematic review and meta-analysis of randomised clinical trials

Background: In addition to regulating calcium homoeostasis and bone health, vitamin D influences vascular and metabolic processes including endothelial function (EF) and insulin signalling. This systematic review and meta-analysis of randomised clinical trials (RCTs) were conducted to investigate the effect of vitamin D supplementation on EF and to examine whether the effect size was modified by health status, study duration, dose, route of vitamin D administration, vitamin D status (baseline and post-intervention), body mass index (BMI), age and type of vitamin D.  Methods: We searched the Medline, Embase, Cochrane Library and Scopus databases from inception until March 2015 for studies meeting the following criteria: (1) RCT with adult participants, (2) vitamin D administration alone, (3) studies that quantified EF using commonly applied methods including ultrasound, plethysmography, applanation tonometry and laser Doppler.  Results: Sixteen articles reporting data for 1177 participants were included. Study duration ranged from 4 to 52 weeks. The effect of vitamin D on EF was not significant (SMD: 0.08, 95 % CI −0.06, 0.22, p = 0.28). Subgroup analysis showed a significant improvement of EF in diabetic subjects (SMD: 0.31, 95 % CI 0.05, 0.57, p = 0.02). A non-significant trend was found for diastolic blood pressure (β = 0.02; p = 0.07) and BMI (β = 0.05; p = 0.06).  Conclusions: Vitamin D supplementation did not improve EF. The significant effect of vitamin D in diabetics and a tendency for an association with BMI may indicate a role of excess adiposity and insulin resistance in modulating the effects of vitamin D on vascular function. This remains to be tested in future studies

Investigating Mass Reduction Capabilities of Additive Manufacturing through the Re-Design of a Space-Based Mirror

Additive manufacture (AM) involves creating a part layer by layer and is a rapidly evolving manufacturing process. It has multiple strengths that apply to space-based optics, such as the ability to consolidate multiple parts into one, reducing the number of interfaces. The process also allows for greater mass reduction, making parts more cost-effective to launch, achieved by optimising the shape for intended use or creating intricate geometries like lattices. However, previous studies have highlighted issues associated with the AM process. For example, when trying to achieve high-precision optical surfaces on AM parts, the latticing on the underside of mirrors can provide insufficient support during machining, resulting in the quilting effect. This paper builds on previous work and explores such challenges further. This will be implemented by investigating ways to apply AM to a deployable mirror from a CubeSat project called A-DOT. The reflective surface has a spherical radius of curvature of 682 mm and approximate external dimensions of 106 mm x 83 mm. The aim is to produce two mirrors that will take full advantage of AM design benefits and account for the challenges in printing and machining a near-net shape. The designs will have reduced mass by using selected internal lattice designs and topology-optimised connection points, resulting in two mirrors with mass reduction targets of 50% and 70%. Once printed in aluminium using laser powder bed fusion, the reflective surface will be created using single point diamond turning. Finally, an evaluation of the dimensional accuracy will be conducted, using interferometry, to quantify the performance of the reflective surface.Comment: 30 pages, 38 figures, submitted to SPIE Astronomical Telescopes & Instrumentation, Advances in Optical and Mechanical Technologies for Telescopes and Instrumentation VI (Conference 13100, Paper 140

Three major dimensions of human brain cortical ageing in relation to cognitive decline across the eighth decade of life

Different brain regions can be grouped together, based on cross-sectional correlations among their cortical characteristics; this patterning has been used to make inferences about ageing processes. However, cross-sectional brain data conflates information on ageing with patterns that are present throughout life. We characterised brain cortical ageing across the 8th decade of life in a longitudinal ageing cohort, at ages ~73, ~76, and ~79 years, with a total of 1,376 MRI scans. Volumetric changes among cortical regions of interest (ROIs) were more strongly correlated (average r = 0.805, SD = 0.252) than were cross-sectional volumes of the same ROIs (average r = 0.350, SD = 0.178). We identified a broad, cortex-wide, dimension of atrophy that explained 66% of the variance in longitudinal changes across the cortex. Our modelling also discovered more specific fronto-temporal and occipito-parietal dimensions, that were orthogonal to the general factor and together explained an additional 20% of the variance. The general factor was associated with declines in general cognitive ability (r = 0.431, p < 0.001) and in the domains of visuospatial ability (r = 0.415, p = 0.002), processing speed (r = 0.383, p < 0.001) and memory (r = 0.372, p < 0.001). Individual differences in brain cortical atrophy with ageing are manifest across three broad dimensions of the cerebral cortex, the most general of which is linked with cognitive declines across domains. Longitudinal approaches are invaluable for distinguishing lifelong patterns of brain-behaviour associations from patterns that are specific to aging

Impact of polygenic risk for Schizophrenia on cortical structure in UK Biobank

BACKGROUND: Schizophrenia is a neurodevelopmental disorder with many genetic variants of individually small effect contributing to phenotypic variation. Lower cortical thickness (CT), surface area, and cortical volume have been demonstrated in people with schizophrenia. Furthermore, a range of obstetric complications (e.g., lower birth weight) are consistently associated with an increased risk for schizophrenia. We investigated whether a high polygenic risk score for schizophrenia (PGRS-SCZ) is associated with CT, surface area, and cortical volume in UK Biobank, a population-based sample, and tested for interactions with birth weight.METHODS: Data were available for 2864 participants ( n male/ n female = 1382/1482; mean age = 62.35 years, SD = 7.40). Linear mixed models were used to test for associations among PGRS-SCZ and cortical volume, surface area, and CT and between PGRS-SCZ and birth weight. Interaction effects of these variables on cortical structure were also tested.RESULTS: We found a significant negative association between PGRS-SCZ and global CT; a higher PGRS-SCZ was associated with lower CT across the whole brain. We also report a significant negative association between PGRS-SCZ and insular lobe CT. PGRS-SCZ was not associated with birth weight and no PGRS-SCZ × birth weight interactions were found.CONCLUSIONS: These results suggest that individual differences in CT are partly influenced by genetic variants and are most likely not due to factors downstream of disease onset. This approach may help to elucidate the genetic pathophysiology of schizophrenia. Further investigation in case-control and high-risk samples could help identify any localized effects of PGRS-SCZ, and other potential schizophrenia risk factors, on CT as symptoms develop.</p

Epigenome-wide association study of global cortical volumes in Generation Scotland:Scottish Family Health Study

Funding This work was supported by the Wellcome Trust [104036/Z/14/Z]. Acknowledgements Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z). MCB is supported by a Guarantors of Brain Non-clinical Post-Doctoral Fellowship. AMM is supported by the Wellcome Trust (104036/Z/14/Z, 216767/Z/19/Z, 220857/Z/20/Z) and UKRI MRC (MC_PC_17209, MR/S035818/1). KLE is supported by the NARSAD Independent Investigator Award (Grant ID: 21956). JMW is supported by UK Dementia Research Institute which is funded by the MRC, Alzheimer’s Research UK and Alzheimer’s Society, by the Fondation Leducq (16 CVD 05), and the Row Fogo Centre for Research Into Ageing and the Brain (BRO- D.FID3668413). This work is part of a project that has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 847776.Peer reviewedPublisher PD

Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals

This project was funded by DPUK through MRC (grant no. MR/L023784/2) and the UK Medical Research Council Award to the University of Oxford (grant no. MC_PC_17215). L.S is funded by the Virtual Brain Cloud from European comission (grant no. H2020-SC1-DTH-2018-1). C.R.B is funded by National Institutes of Health (NIH) research grant R01AG054628. S.R.C is funded by National Institutes of Health (NIH) research grant (R01AG054628), Medical Research Council (MR/R024065/1), Age UK and Economic and Social Research Council. R.E.M. was supported by Alzheimer's Research UK major project grant ARUKPG2017B-10. C.H was supported by an MRC Human Genetics Unit programme grant “Quantitative traits in health and disease” (U.MC_UU_00007/10). H.C.W received funding from Wellcome Trust. J.W is funded by TauRx pharmaceuticals Ltd and received Educational grant from Biogen paid to Alzheimer Scotland/Brain Health Scotland. G.W received GRAMPIAN UNIVERSITY HOSPITALS NHS TRUST, Scottish Government—Chief Scientist Office, ROLAND SUTTON ACADEMIC TRUST, Medical Research Scotland, Sutton Academic Trust and ROLAND SUTTON ACADEMIC TRUST. J.M.W received Wellcome Trust Strategic Award, MRC UK Dementia Research Institute and MRC project grants, Fondation Leducq, Stroke Association, British Heart Foundation, Alzheimer Society, and the European Union H2020 PHC-03-15 SVDs@Target grant (666881). D.S received MRC (MR/S010351/1), MRC (MR/W002388/1) and MRC (MR/W002566/1). A.M is supported by the Wellcome Trust (104036/Z/14/Z, 216767/Z/19/Z, 220857/Z/20/Z) and UKRI MRC (MC_PC_17209, MR/S035818/1). This work is part of a project that has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847776. In addition, A.M has received grant support from The Sackler Trust, outside of the work presented. N.B received grant to institution from GSK as part of GSK/Oxford FxG initiative. A.N.H received John Black Charitable Fund-Rosetrees, H2020 funding from European Comission-Project Virtual Brain Cloud, AI for the Discovery of new therapies in Parkinson's (A2926), Rising Start Initiative—stage 2, Brain-Gut Microbiome (Call: PAR-18-296; Award ID: 1U19AG063744-01), Gut-liver-brain biochemical axis in Alzheimer's disease (5RF1AG057452-01), Virtual Brain Cloud (Call: H2020-SC1-DTH- 2018-1; Grant agreement ID: 826421). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006) and is currently supported by the Wellcome Trust (216767/Z/19/Z). Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” [STRADL] Reference 104036/Z/14/Z). We are grateful to all the families who took part; the general practitioners and the Scottish School of Primary Care for their help in recruiting them; and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, health-care assistants, and nurses.Peer reviewedPublisher PD

Safe inhalation pipe provision (SIPP): protocol for a mixed-method evaluation of an intervention to improve health outcomes and service engagement among people who use crack cocaine in England.

BACKGROUND: Over 180,000 people use crack cocaine in England, yet provision of smoking equipment to support safer crack use is prohibited under UK law. Pipes used for crack cocaine smoking are often homemade and/or in short supply, leading to pipe sharing and injuries from use of unsafe materials. This increases risk of viral infection and respiratory harm among a marginalised underserved population. International evaluations suggest crack pipe supply leads to sustained reductions in pipe sharing and use of homemade equipment; increased health risk awareness; improved service access; reduction in injecting and crack-related health problems. In this paper, we introduce the protocol for the NIHR-funded SIPP (Safe inhalation pipe provision) project and discuss implications for impact. METHODS: The SIPP study will develop, implement and evaluate a crack smoking equipment and training intervention to be distributed through peer networks and specialist drug services in England. Study components comprise: (1) peer-network capacity building and co-production; (2) a pre- and post-intervention survey at intervention and non-equivalent control sites; (3) a mixed-method process evaluation; and (4) an economic evaluation. Participant eligibility criteria are use of crack within the past 28 days, with a survey sample of ~ 740 for each impact evaluation survey point and ~ 40 for qualitative process evaluation interviews. Our primary outcome measure is pipe sharing within the past 28 days, with secondary outcomes pertaining to use of homemade pipes, service engagement, injecting practice and acute health harms. ANTICIPATED IMPACT: SIPP aims to reduce crack use risk practices and associated health harms; including through increasing crack harm reduction awareness among service providers and peers. Implementation has only been possible with local police approvals. Our goal is to generate an evidence base to inform review of the legislation prohibiting crack pipe supply in the UK. This holds potential to transform harm reduction service provision and engagement nationally. CONCLUSION: People who smoke crack cocaine in England currently have little reason to engage with harm reduction and drug services. Little is known about this growing population. This study will provide insight into population characteristics, unmet need and the case for legislative reform. TRIAL REGISTRATION: ISRCTN12541454  https://doi.org/10.1186/ISRCTN12541454

Mixed methods study protocol for combining stakeholder-led rapid evaluation with near real-time continuous registry data to facilitate evaluations of quality of care in intensive care units [version 1; peer review: awaiting peer review]

BACKGROUND: Improved access to healthcare in low- and middle-income countries (LMICs) has not equated to improved health outcomes. Absence or unsustained quality of care is partly to blame. Improving outcomes in intensive care units (ICUs) requires delivery of complex interventions by multiple specialties working in concert, and the simultaneous prevention of avoidable harms associated with the illness and the treatment interventions. Therefore, successful design and implementation of improvement interventions requires understanding of the behavioural, organisational, and external factors that determine care delivery and the likelihood of achieving sustained improvement. We aim to identify care processes that contribute to suboptimal clinical outcomes in ICUs located in LMICs and to establish barriers and enablers for improving the care processes. METHODS: Using rapid evaluation methods, we will use four data collection methods: 1) registry embedded indicators to assess quality of care processes and their associated outcomes; 2) process mapping to provide a preliminary framework to understand gaps between current and desired care practices; 3) structured observations of processes of interest identified from the process mapping and; 4) focus group discussions with stakeholders to identify barriers and enablers influencing the gap between current and desired care practices. We will also collect self-assessments of readiness for quality improvement. Data collection and analysis will be performed in parallel and through an iterative process across eight countries: Kenya, India, Malaysia, Nepal, Pakistan, South Africa, Uganda and Vietnam. CONCLUSIONS: The results of our study will provide essential information on where and how care processes can be improved to facilitate better quality of care to critically ill patients in LMICs; thus, reduce preventable mortality and morbidity in ICUs. Furthermore, understanding the rapid evaluation methods that will be used for this study will allow other researchers and healthcare professionals to carry out similar research in ICUs and other health services

Do little embryos make big decisions? How maternal dietary protein restriction can permanently change an embryo's potential, affecting adult health

Periconceptional environment may influence embryo development, ultimately affecting adult health. Here, we review the rodent model of maternal low-protein diet specifically during the preimplantation period (Emb-LPD) with normal nutrition during subsequent gestation and postnatally. This model, studied mainly in the mouse, leads to cardiovascular, metabolic and behavioural disease in adult offspring, with females more susceptible. We evaluate the sequence of events from diet administration that may lead to adult disease. Emb-LPD changes maternal serum and/or uterine fluid metabolite composition, notably with reduced insulin and branched-chain amino acids. This is sensed by blastocysts through reduced mammalian target of rapamycin complex 1 signalling. Embryos respond by permanently changing the pattern of development of their extra-embryonic lineages, trophectoderm and primitive endoderm, to enhance maternal nutrient retrieval during subsequent gestation. These compensatory changes include stimulation in proliferation, endocytosis and cellular motility, and epigenetic mechanisms underlying them are being identified. Collectively, these responses act to protect fetal growth and likely contribute to offspring competitive fitness. However, the resulting growth adversely affects long-term health because perinatal weight positively correlates with adult disease risk. We argue that periconception environmental responses reflect developmental plasticity and 'decisions' made by embryos to optimise their own development, but with lasting consequences