What are the impacts of within-field farmland management practices on the flux of greenhouse gases from arable cropland in temperate regions? A systematic map protocol

Background: Reducing greenhouse gas emissions is a vital step in limiting climate change and meeting the goals outlined in the COP 21 Paris Agreement of 2015. Studies have suggested that agriculture accounts for around 11% of total greenhouse gas emissions and the industry has a significant role in meeting international and national climate change reduction objectives. However, there is currently little consensus on the mechanisms that regulate the production and assimilation of greenhouse gases in arable land and the practical factors that affect the process. Practical advice for farmers is often overly general, and models based on the amount of nitrogen fertiliser applied, for example, are used despite a lack of knowledge of how local conditions affect the process, such as the importance of humus content and soil types. Here, we propose a systematic map of the evidence relating to the impact on greenhouse gas flux from the agricultural management of arable land in temperate regions. Methods: Using established methods for systematic mapping in environmental sciences we will search for, collate and catalogue research studies relating to the impacts of farming in temperate systems on greenhouse gas emissions. We will search 6 bibliographic databases using a tested search string, and will hand search a web-based search engine and a list of organisational web sites. Furthermore, evidence will be sought from key stakeholders. Search results will then be screened for relevance at title, abstract and full text levels according to a predefined set of eligibility criteria. Consistency checking will be employed to ensure the criteria are being applied accurately and consistently. Relevant studies will then be subjected to coding and meta-data extraction, which will be used to populate a systematic map database describing each relevant study's settings, methods and measured outcomes. The mapping process will help to identify knowledge gaps (subjects lacking in evidence warranting further primary research) and knowledge clusters (subjects with sufficient studies to allow a useful full systematic review), and will highlight best and suboptimal research methods

Standards of conduct and reporting in evidence syntheses that could inform environmental policy and management decisions

Accurate, unbiased and concise synthesis of available evidence following clear methodology and transparent report‑ ing is necessary to support effective environmental policy and management decisions. Without this, less reliable and/ or less objective reviews of evidence could inform decision making, leading to ineffective, resource wasteful inter‑ ventions with potential for unintended consequences. We evaluated the reliability of over 1000 evidence syntheses (reviews and overviews) published between 2018 and 2020 that provide evidence on the impacts of human activities or effectiveness of interventions relevant to environmental management. The syntheses are drawn from the Col‑ laboration for Environmental Evidence Database of Evidence Reviews (CEEDER), an online, freely available evidence service for evidence users that assesses the reliability of evidence syntheses using a series of published criteria. We found that the majority of syntheses have problems with transparency, replicability and potential for bias. Overall, our results suggest that most recently published evidence syntheses are of low reliability to inform decision making. Reviews that followed guidance and reporting standards for evidence synthesis had improved assessment ratings, but there remains substantial variation in the standard of reviews amongst even these. Furthermore, the term ‘system‑ atic review’, which implies conformity with a methodological standard, was frequently misused. A major objective of the CEEDER project is to improve the reliability of the global body of environmental evidence reviews. To this end we outline freely available online resources to help improve review conduct and reporting. We call on authors, editors and peer reviewers to use these resources to ensure more reliable syntheses in the future

Key Concepts for making informed Choices

Teach people to think critically about claims and comparisons — they will make better decisions

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

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

Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer\u27s disease: Associations with Aβ-PET, neurodegeneration, and cognition

Background: Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer\u27s disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. Methods: We evaluated plasma, serum, and cerebrospinal fluid (CSF) GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Results: Plasma GFAP elevations appear a decade before expected symptom onset, after amyloid beta (A ) accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished A -positive from A -negative ADAD participants and showed a stronger relationship with A load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Conclusion: Our findings support a role for plasma GFAP as a clinical biomarker of A -related astrocyte reactivity that is associated with cognitive decline and neurodegeneration. Highlights: Plasma glial fibrillary acidic protein (GFAP) elevations appear a decade before expected symptom onset in autosomal dominant Alzheimer\u27s disease (ADAD). Plasma GFAP was associated to amyloid positivity in asymptomatic ADAD. Plasma GFAP increased with clinical severity and predicted disease progression. Plasma and serum GFAP carried similar information in ADAD, while cerebrospinal fluid GFAP did not

CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice

Neuroinflammation and microglial activation are significant processes in Alzheimer's disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer's disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer's disease and other tau-mediated neurodegenerative diseases

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial

BACKGROUND: Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. METHODS: ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. FINDINGS: Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89–1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87–1·20], p=0·77). INTERPRETATION: In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. FUNDING: UK National Institute for Health and Care Research

Detection of High-Energy Gamma-Ray Emission from the Globular Cluster 47 Tucanae with Fermi

Gamma-Ray Pulsar Bonanza Most of the pulsars we know about were detected through their radio emission; a few are known to pulse gamma rays but were first detected at other wavelengths (see the Perspective by Halpern ). Using the Fermi Gamma-Ray Space Telescope, Abdo et al. (p. 840 , published online 2 July; see the cover) report the detection of 16 previously unknown pulsars based on their gamma-ray emission alone. Thirteen of these coincide with previously unidentified gamma-ray sources, solving the 30-year-old mystery of their identities. Pulsars are fast-rotating neutron stars. With time they slow down and cease to radiate; however, if they are in a binary system, they can have their spin rates increased by mass transfer from their companion stars, starting a new life as millisecond pulsars. In another study, Abdo et al. (p. 845 ) report the detection of gamma-ray emission from the globular cluster 47 Tucanae, which is coming from an ensemble of millisecond pulsars in the cluster's core. The data imply that there are up to 60 millisecond pulsars in 47 Tucanae, twice as many as predicted by radio observations. In a further companion study, Abdo et al. (p. 848 , published online 2 July) searched Fermi Large Area Telescope data for pulsations from all known millisecond pulsars outside of stellar clusters, finding gamma-ray pulsations for eight of them. Their properties resemble those of other gamma-ray pulsars, suggesting that they share the same basic emission mechanism. Indeed, both sets of pulsars favor emission models in which the gamma rays are produced in the outer magnetosphere of the neutron star

Inflammatory biomarkers in Alzheimer&apos;s disease plasma

Introduction: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a \u201cHoly Grail\u201d of AD research and intensively sought; however, there are no well-established plasma markers. Methods: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. Results: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APO\u3b54 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). Discussion: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation