Experimenting with ecosystem interaction networks in search of threshold potentials in real-world marine ecosystems

Thresholds profoundly affect our understanding and management of ecosystem dynamics, but we have yet to develop practical techniques to assess the risk that thresholds will be crossed. Combining ecological knowledge of critical system interdependencies with a large-scale experiment, we tested for breaks in the ecosystem interaction network to identify threshold potential in real-world ecosystem dynamics. Our experiment with the bivalves Macomona liliana and Austrovenus stutchburyi on marine sandflats in New Zealand demonstrated that reductions in incident sunlight changed the interaction network between sediment biogeochemical fluxes, productivity, and macrofauna. By demonstrating loss of positive feedbacks and changes in the architecture of the network, we provide mechanistic evidence that stressors lead to break points in dynamics, which theory predicts predispose a system to a critical transition

Genetic background may contribute to the latitude-dependent prevalence of dermatomyositis and anti-TIF1-γ autoantibodies in adult patients with myositis

Background: The prevalence of dermatomyositis (DM) versus DM and polymyositis (PM) combined has been shown to be negatively associated with latitude. This observation has been attributed to increasing exposure to ultraviolet (UV) light towards the equator. In this study, we investigated whether differing genetic background in populations could contribute to this distribution of DM. Methods: Case data derived from the MYOGEN (Myositis Genetics Consortium) Immunochip study (n = 1769) were used to model the association of DM prevalence and DM-specific autoantibodies with latitude. Control data (n = 9911) were used to model the relationship of human leucocyte antigen (HLA) associated with DM autoantibodies and DM or PM single-nucleotide polymorphisms (suggestive significance in the Immunochip project, P < 2.25 x 10(-5)) in healthy control subjects with latitude. All variables were analysed against latitude using ordered logistic regression, adjusted for sex. Results: The prevalence of DM, as a proportion of DM and PM combined, and the presence of anti-transcription intermediary factor 1 (anti-TIF1-gamma) autoantibodies were both significantly negatively associated with latitude (OR 0.96, 95% CI 0.95-0.98, P < 0.001; and OR 0.95, 95% CI 0.92-0.99, P = 0.004, respectively). HLA alleles significantly associated with anti-Mi-2 and anti-TIF1-gamma autoantibodies also were strongly negatively associated with latitude (OR 0.97, 95% CI 0.96-0.98, P < 0.001 and OR 0.98, 95% CI 0.97-0.99, P < 0.001, respectively). The frequency of five PM- or DM-associated SNPs showed a significant association with latitude (P < 0.05), and the direction of four of these associations was consistent with the latitude associations of the clinical phenotypes. Conclusions: These results lend some support to the hypothesis that genetic background, in addition to UV exposure, may contribute to the distribution of DM

Examination of a new mobile intermittent pneumatic compression device in healthy adults

Aim: Intermittent pneumatic compression (IPC) is an alternative method of compression treatment designed to compress the leg and mimic ambulatory pump action to actively promote venous return. This study explores the efficacy of a new portable IPC device on tissue oxygenation (StO2) in two sitting positions. Methods: Twenty-nine participants were screened and recruited using (PAR-Q, CA). All data conformed to the Declaration of Helsinki and ethical principles. Participants attended two separate one-hour sessions to evaluate StO2 in a chair-sitting and long-sitting position. StO2 was recorded for 20-minutes pre-, during and post- a 20-minute intervention of the IPC unit (VenaproTM, DJO Global, CA). Results: A significant difference was seen between the two seating positions (p=0.003) with long-sitting showing a 12% higher StO2 level than chair-sitting post intervention. A similar effect was seen in both seating positions when analysing data over three, time points (p=0.000). Post-hoc pairwise comparisons showed that significant improvements in StO2 (p≤0.000) were seen from baseline, throughout the intervention, continuing up to 15 minutes post intervention, indicating a continued effect of the device after a short intervention. Conclusion: Post-operative care poses huge demands and cost to health services worldwide, so promotion of portable rehabilitation tools that facilitate community rehabilitation affords immense potential. Increasing StO2 through short-intervention sessions with this portable device within various health and sports-based practices, improving tissue health, potentially reducing post-operative DVT risk or inflammation. Such devices lend themselves to wide self-management implementation

The thermal properties of the Mercia Mudstone Group

The Mercia Mudstone Group (MMG) crops-out extensively across England and Wales and its thermal properties are required for the design of infrastructure such as ground source heating and cooling schemes and electrical cable conduits. Data from the literature and new data from a borehole core have been compiled to generate an updated range of thermal conductivities related to rock type and the lithostratigraphy. These indicate a total range in saturated vertical thermal conductivity of 1.67–3.24 W m-1 K-1, comprising 1.67–2.81 W m-1 K-1 for mudstones, 2.12–2.41 W m-1 K-1 for siltstones and 2.3–3.24 W m-1 K-1 for sandstones. These data are all from measurements on samples and there will be uncertainty when considering the thermal properties of the rock mass due to micro and macro structural features. Geometric mean modelling of thermal conductivity based on mineralogy has overestimated the thermal conductivity. Correction factors for the modelled thermal conductivities have been calculated to enable a first estimate of MMG thermal conductivities when only mineralogical data are available. Measured thermal diffusivities from the borehole core were in the range of 0.63–3.07 x10-6 m2s-1 and are the first measured, thermal diffusivities to be reported for the MMG

Global Carbon Cycling on a Heterogeneous Seafloor

Diverse biological communities mediate the transformation, transport, and storage of elements fundamental to life on Earth, including carbon, nitrogen, and oxygen. However, global biogeochemical model outcomes can vary by orders of magnitude, compromising capacity to project realistic ecosystem responses to planetary changes, including ocean productivity and climate. Here, we compare global carbon turnover rates estimated using models grounded in biological versus geochemical theory and argue that the turnover estimates based on each perspective yield divergent outcomes. Importantly, empirical studies that include sedimentary biological activity vary less than those that ignore it. Improving the relevance of model projections and reducing uncertainty associated with the anticipated consequences of global change requires reconciliation of these perspectives, enabling better societal decisions on mitigation and adaptation.Peer reviewe

Maximising response to postal questionnaires – A systematic review of randomised trials in health research

Background Postal self-completion questionnaires offer one of the least expensive modes of collecting patient based outcomes in health care research. The purpose of this review is to assess the efficacy of methods of increasing response to postal questionnaires in health care studies on patient populations. Methods The following databases were searched: Medline, Embase, CENTRAL, CDSR, PsycINFO, NRR and ZETOC. Reference lists of relevant reviews and relevant journals were hand searched. Inclusion criteria were randomised trials of strategies to improve questionnaire response in health care research on patient populations. Response rate was defined as the percentage of questionnaires returned after all follow-up efforts. Study quality was assessed by two independent reviewers. The Mantel-Haenszel method was used to calculate the pooled odds ratios. Results Thirteen studies reporting fifteen trials were included. Implementation of reminder letters and telephone contact had the most significant effect on response rates (odds ratio 3.7, 95% confidence interval 2.30 to 5.97 p = <0.00001). Shorter questionnaires also improved response rates to a lesser degree (odds ratio 1.4, 95% confidence interval 1.19 to 1.54). No evidence was found that incentives, re-ordering of questions or including an information brochure with the questionnaire confer any additional advantage. Conclusion Implementing repeat mailing strategies and/or telephone reminders may improve response to postal questionnaires in health care research. Making the questionnaire shorter may also improve response rates. There is a lack of evidence to suggest that incentives are useful. In the context of health care research all strategies to improve response to postal questionnaires require further evaluation

A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)

The study was funded and the investigational drug NUC-3373 was supplied by NuCana plc. The centres that conducted this study are National Institute for Health and Care Research (NIHR) Biomedical Research Centres that also receive institutional funding as Cancer Research UK (CRUK) and Experimental Cancer Medicine Centres (ECMC). The Glasgow Experimental Cancer Medicine Centre (ECMC) is funded by Cancer Research UK and The Chief Scientist’s Office, Scotland (grant award A25174).Purpose 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU. Patients and methods NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity. Results Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival. Conclusion NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies. Trial registration Clinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240.Peer reviewe

The impact of non-alcoholic fatty liver disease and liver fibrosis on adverse clinical outcomes and mortality in patients with chronic kidney disease: a prospective cohort study using the UK Biobank

Abstract Background Chronic kidney disease (CKD) and non-alcoholic fatty liver disease (NAFLD) frequently co-exist. We assess the impact of having NAFLD on adverse clinical outcomes and all-cause mortality for people with CKD. Methods A total of 18,073 UK Biobank participants identified to have CKD (eGFR &lt; 60 ml/min/1.73 m2 or albuminuria &gt; 3 mg/mmol) were prospectively followed up by electronic linkage to hospital and death records. Cox-regression estimated the hazard ratios (HR) associated with having NAFLD (elevated hepatic steatosis index or ICD-code) and NAFLD fibrosis (elevated fibrosis-4 (FIB-4) score or NAFLD fibrosis score (NFS)) on cardiovascular events (CVE), progression to end-stage renal disease (ESRD) and all-cause mortality. Results 56.2% of individuals with CKD had NAFLD at baseline, and 3.0% and 7.7% had NAFLD fibrosis according to a FIB-4 &gt; 2.67 and NFS ≥ 0.676, respectively. The median follow-up was 13 years. In univariate analysis, NAFLD was associated with an increased risk of CVE (HR 1.49 [1.38–1.60]), all-cause mortality (HR 1.22 [1.14–1.31]) and ESRD (HR 1.26 [1.02–1.54]). Following multivariable adjustment, NAFLD remained an independent risk factor for CVE overall (HR 1.20 [1.11–1.30], p &lt; 0.0001), but not ACM or ESRD. In univariate analysis, elevated NFS and FIB-4 scores were associated with increased risk of CVE (HR 2.42 [2.09–2.80] and 1.64 [1.30–2.08]) and all-cause mortality (HR 2.82 [2.48–3.21] and 1.82 [1.47–2.24]); the NFS score was also associated with ESRD (HR 5.15 [3.52–7.52]). Following full adjustment, the NFS remained associated with an increased incidence of CVE (HR 1.19 [1.01–1.40]) and all-cause mortality (HR 1.31 [1.13–1.52]). Conclusions In people with CKD, NAFLD is associated with an increased risk of CVE, and the NAFLD fibrosis score is associated with an elevated risk of CVE and worse survival. </jats:sec