An experiment of the impact of a neonicotinoid pesticide on honeybees : the value of a formal analysis of the data

This work received funding from the MASTS pooling initiative (The Marine Alliance for Science and Technology for Scotland) and their support is gratefully acknowledged. MASTS is funded by the Scottish Funding Council (Grant reference HR09011) and contributing institutions.Background: We assess the analysis of the data resulting from a field experiment conducted by Pilling et al. (2013) on the potential effects of thiamethoxam on honey bees. The experiment had low levels of replication, so Pilling et al. concluded that formal statistical analysis would be misleading. This would be true if such an analysis merely comprised tests of statistical significance and if the investigators concluded that lack of significance meant little or no effect. However, an analysis that includes estimation of the size of any effects—with confidence limits—allows one to reach conclusions that are not misleading and that produce useful insights. Main Body: For the data of Pilling et al. we use straightforward statistical analysis to show that the confidence limits are generally so wide that any effects of thiamethoxam could have been large without being statistically significant. Instead of formal analysis, Pilling et al. simply inspected the data and concluded that they provided no evidence of detrimental effects and from this that thiamethoxam poses a “low risk” to bees. Conclusions: Conclusions derived from inspection of the data were not just misleading in this case but are unacceptable in principle, for if data are inadequate for a formal analysis (or only good enough to provide estimates with wide confidence intervals) then they are bound to be inadequate as a basis for reaching any sound conclusions. Given that the data in this case are largely uninformative with respect to the treatment effect, any conclusions reached from such informal approaches can do little more than reflect the prior beliefs of those involved.Publisher PDFPeer reviewe

Preventing kidney transplant failure by screening for antibodies against human leucocyte antigens followed by optimised immunosuppression: OuTSMART RCT

Design: Investigator-led, prospective, open-labelled marker-based strategy (hybrid) randomised trial. Background: Allografts in 3% of kidney transplant patients fail annually. Development of antibodies against human leucocyte antigens is a validated predictive biomarker of allograft failure. Under immunosuppression is recognised to contribute, but whether increasing immunosuppression can prevent allograft failure in human leucocyte antigen Ab+ patients is unclear. Participants: Renal transplant recipients > 1 year post-transplantation attending 13 United Kingdom transplant clinics, without specific exclusion criteria. Interventions: Regular screening for human leucocyte antigen antibodies followed, in positive patients by interview and tailored optimisation of immunosuppression to tacrolimus, mycophenolate mofetil and prednisolone. Objective: To determine if optimisation of immunosuppression in human leucocyte antigen Ab+ patients can cost-effectively prevent kidney allograft failure. Outcome: Time to graft failure after 43 months follow-up in patients receiving the intervention, compared to controls, managed by standard of care. Costs and quality-adjusted life-years were used in the cost-effectiveness analysis. Randomisation and blinding: Random allocation (1 : 1) to unblinded biomarker-led care or double-blinded standard of care stratified by human leucocyte antigen antibodies status (positive/negative) and in positives, presence of donor-specific antibodies (human leucocyte antigen antibodies against donor human leucocyte antigen) or not (human leucocyte antigen antibodies against non-donor human leucocyte antigen), baseline immunosuppression and transplant centre. Biomaker-led care human leucocyte antigen Ab+ patients received intervention. Human leucocyte antigen Ab-negative patients were screened every 8 months. Recruitment Began September 2013 and for 37 months. The primary endpoint, scheduled for June 2020, was moved to March 2020 because of COVID-19. Numbers randomised: From 5519 screened, 2037 were randomised (1028 biomaker-led care, 1009 to standard of care) including 198 with human leucocyte antigen antibodies against donor human leucocyte antigen (106 biomaker-led care, 92 standard of care) and 818 with human leucocyte antigens antibodies against non-donor human leucocyte antigen (427 biomaker-led care, 391 standard of care). Numbers analysed: Two patients were randomised in error so 2035 were included in the intention-to-treat analysis. Outcome: The trial had 80% power to detect a hazard ratio of 0.49 in biomarker-led care DSA+ group, > 90% power to detect hazard ratio of 0.35 in biomarker-led care non-DSA+ group (with 5% type 1 error). Actual hazard ratios for graft failure in these biomarker-led care groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54 to 1.74), respectively. There was 90% power to demonstrate non-inferiority of overall biomarker-led care group with assumed hazard ratio of 1.4: This was not demonstrated as the upper confidence limit for graft failure exceeded 1.4: (1.02, 95% CI 0.72 to 1.44). The hazard ratio for biopsy-proven rejection in the overall biomarker-led care group was 0.5 [95% CI: 0.27 to 0.94: p = 0.03]. The screening approach was not cost-effective in terms of cost per quality-adjusted life-year. Harms: No significant differences in other secondary endpoints or adverse events. Limitations: Tailored interventions meant optimisation was not possible in some patients. We did not study pathology on protocol transplant biopsies in DSA+ patients. Conclusions: No evidence that optimised immunosuppression in human leucocyte antigen Ab+ patients delays renal transplant failure. Informing patients of their human leucocyte antigen antibodies status appears to reduce graft rejection. Future work: We need a better understanding of the pathophysiology of transplant failure to allow rational development of effective therapies. Trial registration: This trial is registered as EudraCT (2012-004308-36) and ISRCTN (46157828). Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (11/100/34) and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 5. See the NIHR Journals Library website for further project information

Neptunism and transformism:Robert Jameson and other evolutionary theorists in early nineteenth-century Scotland

This paper sheds new light on the prevalence of evolutionary ideas in Scotland in the early nineteenth century and establish what connections existed between the espousal of evolutionary theories and adherence to the directional history of the earth proposed by Abraham Gottlob Werner and his Scottish disciples. A possible connection between Wernerian geology and theories of the transmutation of species in Edinburgh in the period when Charles Darwin was a medical student in the city was suggested in an important 1991 paper by James Secord. This study aims to deepen our knowledge of this important episode in the history of evolutionary ideas and explore the relationship between these geological and evolutionary discourses. To do this it focuses on the circle of natural historians around Robert Jameson, Wernerian geologist and professor of natural history at the University of Edinburgh from 1804 to 1854. From the evidence gathered here there emerges a clear confirmation that the Wernerian model of geohistory facilitated the acceptance of evolutionary explanations of the history of life in early nineteenth-century Scotland. As Edinburgh was at this time the most important center of medical education in the English-speaking world, this almost certainly influenced the reception and development of evolutionary ideas in the decades that followed.</p

TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis

Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are critical for the clearance of myelin debris in areas of demyelination, a key step to allow remyelination. TREM2 is expressed by microglia and promotes microglial survival, proliferation, and phagocytic activity. Herein we demonstrate that TREM2 was highly expressed on myelin-laden phagocytes in active demyelinating lesions in the CNS of subjects with MS. In gene expression studies, macrophages from subjects with TREM2 genetic deficiency displayed a defect in phagocytic pathways. Treatment with a new TREM2 agonistic antibody promoted the clearance of myelin debris in the cuprizone model of CNS demyelination. Effects included enhancement of myelin uptake and degradation, resulting in accelerated myelin debris removal by microglia. Most importantly, antibody-dependent TREM2 activation on microglia increased density of oligodendrocyte precursors in areas of demyelination, as well as the formation of mature oligodendrocytes thus enhancing remyelination and axonal integrity. These results are relevant as they propose TREM2 on microglia as a potential new target to promote remyelination

Construction of an ~700-kb transcript map around the Familial Mediterranean Fever locus on human chromosome 16p13.3

We used a combination of cDNA selection, exon amplification, and computational prediction from genomic sequence to isolate transcribed sequences from genomic DNA surrounding the familial Mediterranean fever (FMF) locus. Eighty-seven kb of genomic DNA around D16S3370, a marker showing a high degree of linkage disequilibrium with FMF, was sequenced to completion, and the sequence annotated. A transcript map reflecting the minimal number of genes encoded within the ∼700 kb of genomic DNA surrounding the FMF locus was assembled. This map consists of 27 genes with discreet messages detectable on Northerns, in addition to three olfactory-receptor genes, a cluster of 18 tRNA genes, and two putative transcriptional units that have typical intron–exon splice junctions yet do not detect messages on Northerns. Four of the transcripts are identical to genes described previously, seven have been independently identified by the French FMF Consortium, and the others are novel. Six related zinc-finger genes, a cluster of tRNAs, and three olfactory receptors account for the majority of transcribed sequences isolated from a 315-kb FMF central region (betweenD16S468/D16S3070 and cosmid 377A12). Interspersed among them are several genes that may be important in inflammation. This transcript map not only has permitted the identification of the FMF gene (MEFV), but also has provided us an opportunity to probe the structural and functional features of this region of chromosome 16.Michael Centola, Xiaoguang Chen, Raman Sood, Zuoming Deng, Ivona Aksentijevich, Trevor Blake, Darrell O. Ricke, Xiang Chen, Geryl Wood, Nurit Zaks, Neil Richards, David Krizman, Elizabeth Mansfield, Sinoula Apostolou, Jingmei Liu, Neta Shafran, Anil Vedula, Melanie Hamon, Andrea Cercek, Tanaz Kahan, Deborah Gumucio, David F. Callen, Robert I. Richards, Robert K. Moyzis, Norman A. Doggett, Francis S. Collins, P. Paul Liu, Nathan Fischel-Ghodsian and Daniel L. Kastne

Fire and biodiversity in the Anthropocene

The workshop leading to this paper was funded by the Centre Tecnològic Forestal de Catalunya and the ARC Centre of Excellence for Environmental Decisions. L.T.K. was supported by a Victorian Postdoctoral Research Fellowship (Victorian Government), a Centenary Fellowship (University of Melbourne), and an Australian Research Council Linkage Project Grant (LP150100765). A.R. was supported by the Xunta de Galicia (Postdoctoral Fellowship ED481B2016/084-0) and the Foundation for Science and Technology under the FirESmart project (PCIF/MOG/0083/2017). A.L.S. was supported by a Marie Skłodowska-Curie Individual Fellowship (746191) under the European Union Horizon 2020 Programme for Research and Innovation. L.R. was supported by the Australian Government’s National Environmental Science Program through the Threatened Species Recovery Hub. L.B. was partially supported by the Spanish Government through the INMODES (CGL2014-59742-C2-2-R) and the ERANET-SUMFORESTS project FutureBioEcon (PCIN-2017-052). This research was supported in part by the U.S. Department of Agriculture, Forest Service, Pacific Southwest Research Station.BACKGROUND Fire has shaped the diversity of life on Earth for millions of years. Variation in fire regimes continues to be a source of biodiversity across the globe, and many plants, animals, and ecosystems depend on particular temporal and spatial patterns of fire. Although people have been using fire to modify environments for millennia, the combined effects of human activities are now changing patterns of fire at a global scale—to the detriment of human society, biodiversity, and ecosystems. These changes pose a global challenge for understanding how to sustain biodiversity in a new era of fire. We synthesize how changes in fire activity are threatening species with extinction across the globe, highlight forward-looking methods for predicting the combined effects of human drivers and fire on biodiversity, and foreshadow emerging actions and strategies that could revolutionize how society manages fire for biodiversity in the Anthropocene. ADVANCES Our synthesis shows that interactions with anthropogenic drivers such as global climate change, land use, and biotic invasions are transforming fire activity and its impacts on biodiversity. More than 4400 terrestrial and freshwater species from a wide range of taxa and habitats face threats associated with modified fire regimes. Many species are threatened by an increase in fire frequency or intensity, but exclusion of fire in ecosystems that need it can also be harmful. The prominent role of human activity in shaping global ecosystems is the hallmark of the Anthropocene and sets the context in which models and actions must be developed. Advances in predictive modeling deliver new opportunities to couple fire and biodiversity data and to link them with forecasts of multiple drivers including drought, invasive plants, and urban growth. Making these connections also provides an opportunity for new actions that could revolutionize how society manages fire. Emerging actions include reintroduction of mammals that reduce fuels, green fire breaks comprising low-flammability plants, strategically letting wildfires burn under the right conditions, managed evolution of populations aided by new genomics tools, and deployment of rapid response teams to protect biodiversity assets. Indigenous fire stewardship and reinstatement of cultural burning in a modern context will enhance biodiversity and human well-being in many regions of the world. At the same time, international efforts to reduce greenhouse gas emissions are crucial to reduce the risk of extreme fire events that contribute to declines in biodiversity. OUTLOOK Conservation of Earth’s biological diversity will be achieved only by recognition of and response to the critical role of fire in shaping ecosystems. Global changes in fire regimes will continue to amplify interactions between anthropogenic drivers and create difficult trade-offs between environmental and social objectives. Scientific input will be crucial for navigating major decisions about novel and changing ecosystems. Strategic collection of data on fire, biodiversity, and socioeconomic variables will be essential for developing models to capture the feedbacks, tipping points, and regime shifts characteristic of the Anthropocene. New partnerships are also needed to meet the challenges ahead. At the local and regional scale, getting more of the “right” type of fire in landscapes that need it requires new alliances and networks to build and apply knowledge. At the national and global scale, biodiversity conservation will benefit from greater integration of fire into national biodiversity strategies and action plans and in the implementation of international agreements and initiatives such as the UN Convention on Biological Diversity. Placing the increasingly important role of people at the forefront of efforts to understand and adapt to changes in fire regimes is central to these endeavors.PostprintPeer reviewe