Peat Moss–Like Vegetative Remains from Ordovician Carbonates

Premise of research. Climatically favorable conditions correspond with fossil evidence for dramatic Ordovician marine biodiversification, but coeval terrestrial biodiversity is less well understood. Although diverse Middle and Late Ordovician microfossils are interpreted as reproductive remains of early bryophyte-like land plants (consistent with molecular data indicating pre-Ordovician embryophyte origin), the vegetative structure of Ordovician plants remains mysterious, as do relationships to modern groups. Because distinctive fungal microfossils indicating land plant presence were previously reported from Ordovician carbonate deposits in Wisconsin, we examined another nearby outcrop for additional evidence of terrestrial biodiversification. Methodology. Replicate collections were made from well-understood 455–454 Ma Platteville Formation carbonates of relatively low porosity and hydraulic conductivity. We employed measures to avoid contamination, and organic remains extracted by acid maceration were characterized by light and scanning electron microscopy and energy-dispersive X-ray spectroscopy. Pivotal results. Multicellular organic fragments displayed distinctive cellular features shared with modern vegetative peat mosses but differed from modern materials, e.g., fossil presence of mineral coatings, absence of epibionts. Biometric features of mosslike microfossils isolated from carbonates collected and macerated 12 yr apart by separate investigators did not differ. Putative peat moss remains occurred with foraminifera similar in frequency and thermal maturity to types previously described from the same formation. No diatoms, pollen, or other indicators of post-Ordovician environments were observed. Conclusions. The peat moss–like fragments described here are the oldest-known vegetative remains of land plants and the oldest fossils having distinctive features linking them to a modern plant group. These findings are consistent with peat moss recalcitrance properties that foster fossilization and molecular evidence that the peat moss lineage is 460–607 Ma of age. The new findings suggest that moss-dominated peatlands—recognized for globally significant roles in modern terrestrial biodiversity and C and N cycling—were present hundreds of millions of years earlier than previously thought

PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons

Dipeptide repeat proteins are a major pathogenic feature of C9orf72 amyotrophic lateral sclerosis (C9ALS)/frontotemporal dementia (FTD) pathology, but their physiological impact has yet to be fully determined. Here we generated C9orf72 dipeptide repeat knock-in mouse models characterized by expression of 400 codon-optimized polyGR or polyPR repeats, and heterozygous C9orf72 reduction. (GR)400 and (PR)400 knock-in mice recapitulate key features of C9ALS/FTD, including cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction. Quantitative proteomics revealed an increase in extracellular matrix (ECM) proteins in (GR)400 and (PR)400 spinal cord, with the collagen COL6A1 the most increased protein. TGF-β1 was one of the top predicted regulators of this ECM signature and polyGR expression in human induced pluripotent stem cell neurons was sufficient to induce TGF-β1 followed by COL6A1. Knockdown of TGF-β1 or COL6A1 orthologues in polyGR model Drosophila exacerbated neurodegeneration, while expression of TGF-β1 or COL6A1 in induced pluripotent stem cell-derived motor neurons of patients with C9ALS/FTD protected against glutamate-induced cell death. Altogether, our findings reveal a neuroprotective and conserved ECM signature in C9ALS/FTD.</p

2017 Research & Innovation Day Program

A one day showcase of applied research, social innovation, scholarship projects and activities.https://first.fanshawec.ca/cri_cripublications/1004/thumbnail.jp

Phase II randomised discontinuation trial of brivanib in patients with advanced solid tumours

Background: Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]). Patients and methods: During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours. Results: A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p = 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4–4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3–1.6) for placebo (HR = 0.64, 95% CI: 0.38–1.07; p = 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6–4.2) months for brivanib and 2.0 months (95% CI: 1.2–2.7) for placebo (HR: 0.56, 95% CI: 0.26–1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6–4.2) and was 2.0 months (95% CI: 1.2–2.7) in those randomised to placebo (HR = 0.54, 95% CI: 0.25–1.17; p = 0.11). Conclusion: Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Methods: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. Findings: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96–1·28). Interpretation: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. Funding: National Institute for Health Research Health Services and Delivery Research Programme

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

BACKGROUND: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. METHODS: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. FINDINGS: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). INTERPRETATION: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. FUNDING: National Institute for Health Research Health Services and Delivery Research Programme

Research data supporting "Public opinion on sharing data from health services for clinical and research purposes without explicit consent: an anonymous online survey in the UK"

Anonymised data from a 2020 UK survey of public opinion about sharing NHS health data for clinical and research purposes. Study registration https://doi.org/10.1186/ISRCTN37444142 . Preprint at https://doi.org/10.1101/2021.07.19.21260635 . Final paper in BMJ Open at https://doi.org/bmjopen-2021-057579 .Supported by a UK Medical Research Council (MRC) Mental Health Data Pathfinder award (MC_PC_17213 to RNC), and MRC grant MR/W014386/1 (Health Data Research UK Mental Health Data Hub, DATAMIND). Recruitment was supported by the NIHR CRN and the REDCap installation was supported in part by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014); the views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care

Public opinion on sharing data from health services for clinical and research purposes without explicit consent: an anonymous online survey in the UK

Objectives: UK National Health Service/Health and Social Care (NHS/HSC) data are variably shared between healthcare organisations for direct care, and increasingly de-identified for research. Few large-scale studies have examined public opinion on sharing, including of mental health (MH) versus physical health (PH) data. We measured data sharing preferences. Design/setting/interventions/outcomes: Pre-registered anonymous online survey, measuring expressed preferences, recruiting February to September 2020. Participants were randomised to one of three framing statements regarding MH versus PH data. Participants: Open to all UK residents. Participants numbered 29 275; 40% had experienced an MH condition. Results: Most (76%) supported identifiable data sharing for direct clinical care without explicit consent, but 20% opposed this. Preference for clinical/identifiable sharing decreased with geographical distance and was slightly less for MH than PH data, with small framing effects. Preference for research/de-identified data sharing without explicit consent showed the same small PH/MH and framing effects, plus greater preference for sharing structured data than de-identified free text. There was net support for research sharing to the NHS, academic institutions, and national research charities, net ambivalence about sharing to profit-making companies researching treatments, and net opposition to sharing to other companies (similar to sharing publicly). De-identified linkage to non-health data was generally supported, except to data held by private companies. We report demographic influences on preference. A majority (89%) supported a single NHS mechanism to choose uses of their data. Support for data sharing increased during COVID-19. Conclusions: Support for healthcare data sharing for direct care without explicit consent is broad but not universal. There is net support for the sharing of de-identified data for research to the NHS, academia, and the charitable sector, but not the commercial sector. A single national NHS-hosted system for patients to control the use of their NHS data for clinical purposes and for research would have broad support. Trial registration number: ISRCTN37444142