A Systematic Review of Biomarkers and Risk of Incident Type 2 Diabetes: An Overview of Epidemiological, Prediction and Aetiological Research Literature

$\textbf{BACKGROUND}$ Blood-based or urinary biomarkers may play a role in quantifying the future risk of type 2 diabetes (T2D) and in understanding possible aetiological pathways to disease. However, no systematic review has been conducted that has identified and provided an overview of available biomarkers for incident T2D. We aimed to systematically review the associations of biomarkers with risk of developing T2D and to highlight evidence gaps in the existing literature regarding the predictive and aetiological value of these biomarkers and to direct future research in this field. $\textbf{METHODS AND FINDINGS}$ We systematically searched PubMed MEDLINE (January 2000 until March 2015) and Embase (until January 2016) databases for observational studies of biomarkers and incident T2D according to the 2009 PRISMA guidelines. We also searched availability of meta-analyses, Mendelian randomisation and prediction research for the identified biomarkers. We reviewed 3910 titles (705 abstracts) and 164 full papers and included 139 papers from 69 cohort studies that described the prospective relationships between 167 blood-based or urinary biomarkers and incident T2D. Only 35 biomarkers were reported in large scale studies with more than 1000 T2D cases, and thus the evidence for association was inconclusive for the majority of biomarkers. Fourteen biomarkers have been investigated using Mendelian randomisation approaches. Only for one biomarker was there strong observational evidence of association and evidence from genetic association studies that was compatible with an underlying causal association. In additional search for T2D prediction, we found only half of biomarkers were examined with formal evidence of predictive value for a minority of these biomarkers. Most biomarkers did not enhance the strength of prediction, but the strongest evidence for prediction was for biomarkers that quantify measures of glycaemia. $\textbf{CONCLUSIONS}$ This study presents an extensive review of the current state of the literature to inform the strategy for future interrogation of existing and newly described biomarkers for T2D. Many biomarkers have been reported to be associated with the risk of developing T2D. The evidence of their value in adding to understanding of causal pathways to disease is very limited so far. The utility of most biomarkers remains largely unknown in clinical prediction. Future research should focus on providing good genetic instruments across consortia for possible biomarkers in Mendelian randomisation, prioritising biomarkers for measurement in large-scale cohort studies and examining predictive utility of biomarkers for a given context.This study was supported by the Medical Research Council UK (grant reference no. MC_UU_12015/1), http://gtr.rcuk.ac.uk/projects?ref=MC_UU_12015/1; Netherlands Organization for Scientific Research (NWO project number 825.13.004), http://www.nwo.nl/en/research-and-results/research-projects/i/85/10585.html; Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013), http://www.emif.eu/about. GSK provided support in the form of salaries for DW, DJN, AS. Pfizer provided support in the form of salary to JMB

A methodology for parameter estimation in seaweed productivity modelling

This paper presents a combined approach for parameter estimation in models of primary production. The focus is on gross primary production and nutrient assimilation by seaweeds. A database of productivity determinations, biomass and mortality measurements and nutrient uptake rates obtained over one year for Gelidium sesquipedale in the Atlantic Ocean off Portugal has been used. Annual productivity was estimated by harvesting methods, and empirical relationships using mortality/ wave energy and respiration rates have been derived to correct for losses and to convert the estimates to gross production. In situ determinations of productivity have been combined with data on the light climate (radiation periods, intensity, mean turbidity) to give daily and annual productivity estimates. The theoretical nutrient uptake calculated using a 'Redfield ratio' approach and determinations of in situ N and P consumption by the algae during incubation periods have also been compared. The results of the biomass difference and incubation approaches are discussed in order to assess the utility of coefficients determined in situ for parameter estimation in seaweed production models

LSD but not lisuride disrupts prepulse inhibition in rats by activating the 5-HT2A receptor

Compounds that activate the 5-HT2A receptor, such as lysergic acid diethylamide (LSD), act as hallucinogens in humans. One notable exception is the LSD congener lisuride, which does not have hallucinogenic effects in humans even though it is a potent 5-HT2A agonist. LSD and other hallucinogens have been shown to disrupt prepulse inhibition (PPI), an operational measure of sensorimotor gating, by activating 5-HT2A receptors in rats. We tested whether lisuride disrupts PPI in male Sprague–Dawley rats. Experiments were also conducted to identify the mechanism(s) responsible for the effect of lisuride on PPI and to compare the effects of lisuride to those of LSD. Confirming a previous report, LSD (0.05, 0.1, and 0.2 mg/kg, s.c.) reduced PPI, and the effect of LSD was blocked by pretreatment with the selective 5-HT2A antagonist MDL 11,939. Administration of lisuride (0.0375, 0.075, and 0.15 mg/kg, s.c.) also reduced PPI. However, the PPI disruption induced by lisuride (0.075 mg/kg) was not blocked by pretreatment with MDL 11,939 or the selective 5-HT1A antagonist WAY-100635 but was prevented by pretreatment with the selective dopamine D2/D3 receptor antagonist raclopride (0.1 mg/kg, s.c). The effect of LSD on PPI is mediated by the 5-HT2A receptor, whereas activation of the 5-HT2A receptor does not appear to contribute to the effect of lisuride on PPI. These findings demonstrate that lisuride and LSD disrupt PPI via distinct receptor mechanisms and provide additional support for the classification of lisuride as a non-hallucinogenic 5-HT2A agonist

Defining Chlorophyll-a Reference Conditions in European Lakes

The concept of “reference conditions” describes the benchmark against which current conditions are compared when assessing the status of water bodies. In this paper we focus on the establishment of reference conditions for European lakes according to a phytoplankton biomass indicator—the concentration of chlorophyll-a. A mostly spatial approach (selection of existing lakes with no or minor human impact) was used to set the reference conditions for chlorophyll-a values, supplemented by historical data, paleolimnological investigations and modelling. The work resulted in definition of reference conditions and the boundary between “high” and “good” status for 15 main lake types and five ecoregions of Europe: Alpine, Atlantic, Central/Baltic, Mediterranean, and Northern. Additionally, empirical models were developed for estimating site-specific reference chlorophyll-a concentrations from a set of potential predictor variables. The results were recently formulated into the EU legislation, marking the first attempt in international water policy to move from chemical quality standards to ecological quality targets

Global lake thermal regions shift under climate change

Water temperature is critical for the ecology of lakes. However, the ability to predict its spatial and seasonal variation is constrained by the lack of a thermal classification system. Here we define lake thermal regions using objective analysis of seasonal surface temperature dynamics from satellite observations. Nine lake thermal regions are identified that mapped largely contiguously globally, and robustly even for small lakes. The regions differed from other global patterns, and so provide unique information. Using a lake model forced by 21st century climate projections we found that 12, 27 and 66% of lakes will change to a lower latitude thermal region by 2080-2099 for low, medium and high greenhouse gas concentration trajectories (Representative Concentration Pathways 2.6, 6.0 and 8.5) respectively. Under the worst-case scenario, a 79% reduction in the number of lakes in the northernmost thermal region is projected. This thermal region framework will facilitate the global scaling of lake-research