Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium

Aims/hypothesis: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up). Methods: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at ~18 months (both cohorts) and at ~48 months (cohort 1) or ~36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe. Results: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean ± SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m2; fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m2; fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l. Conclusions/interpretation: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This work was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115317 (DIRECT), resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. RWK was funded by a STAR Award Novo Nordisk co-financed PhD fellowship. The work undertaken by PWF was supported in part by programme grants from the ERC-2015-CoG_NASCENT_681742 and the Swedish Research Council; strategic funding for Lund University Diabetes Centre, where some of the work described herein was performed, was provided by the Swedish Research Council, Strategic Research Area Exodiab, (Dnr 2009-1039), the Swedish Foundation for Strategic Research (IRC15-0067), the Swedish Research Council, Linnaeus grant (Dnr 349-2006-237). EP holds a Wellcome Trust Investigator award (grant reference 102820/Z/13/Z). Contributions to this work by SBru. were co-financed by the Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001).published version, accepted version (12 month embargo), submitted versio

Dietary metabolite profiling brings new insight into the relationship between nutrition and metabolic risk: An IMI DIRECT study

Background: Dietary advice remains the cornerstone of prevention and management of type 2 diabetes (T2D). However, understanding the efficacy of dietary interventions is confounded by the challenges inherent in assessing free living diet. Here we profiled dietary metabolites to investigate glycaemic deterioration and cardiometabolic risk in people at risk of or living with T2D. Methods: We analysed data from plasma collected at baseline and 18-month follow-up in individuals from the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohort 1 n = 403 individuals with normal or impaired glucose regulation (prediabetic) and cohort 2 n = 458 individuals with new onset of T2D. A dietary metabolite profile model (Tpred) was constructed using multivariable regression of 113 plasma metabolites obtained from targeted metabolomics assays. The continuous Tpred score was used to explore the relationships between diet, glycaemic deterioration and cardio-metabolic risk via multiple linear regression models. Findings: A higher Tpred score was associated with healthier diets high in wholegrain (β=3.36 g, 95% CI 0.31, 6.40 and β=2.82 g, 95% CI 0.06, 5.57) and lower energy intake (β=-75.53 kcal, 95% CI -144.71, -2.35 and β=-122.51 kcal, 95% CI -186.56, -38.46), and saturated fat (β=-0.92 g, 95% CI -1.56, -0.28 and β=-0.98 g, 95% CI -1.53, -0.42 g), respectively for cohort 1 and 2. In both cohorts a higher Tpred score was also associated with lower total body adiposity and favourable lipid profiles HDL-cholesterol (β=0.07 mmol/L, 95% CI 0.03, 0.1), (β=0.08 mmol/L, 95% CI 0.04, 0.1), and triglycerides (β=-0.1 mmol/L, 95% CI -0.2, -0.03), (β=-0.2 mmol/L, 95% CI -0.3, -0.09), respectively for cohort 1 and 2. In cohort 2, the Tpred score was negatively associated with liver fat (β=-0.74%, 95% CI -0.67, -0.81), and lower fasting concentrations of HbA1c (β=-0.9 mmol/mol, 95% CI -1.5, -0.1), glucose (β=-0.2 mmol/L, 95% CI -0.4, -0.05) and insulin (β=-11.0 pmol/mol, 95% CI -19.5, -2.6). Longitudinal analysis showed at 18-month follow up a higher Tpred score was also associated lower total body adiposity in both cohorts and lower fasting glucose (β=-0.2 mmol/L, 95% CI -0.3, -0.01) and insulin (β=-9.2 pmol/mol, 95% CI -17.9, -0.4) concentrations in cohort 2. Interpretation: Plasma dietary metabolite profiling provides objective measures of diet intake, showing a relationship to glycaemic deterioration and cardiometabolic health.This article is freely available to Open Access. Click on the Publisher URL to access it via the publisher's site.This work was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115,317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies.published version, submitted versio

Stability of urinary albumin and creatinine after 12 months storage at -20 °C and -80 °C.

Increasing albumin to creatinine ratio (ACR) within the normal range is a risk factor for cardiovascular disease in the general population. Clinical and epidemiological studies often store urine samples for long durations prior to ACR assessment. The stability of ACR at the lowest urinary albumin concentrations during prolonged storage has not been previously studied because routine clinical assays can't quantify very low concentrations of albumin.This article is freely available via Open Access. Click on the Publisher URL to access.Published (Open Access

Faster decline of pitch memory over time in congenital amusia

Congenital amusia (amusia, hereafter) is a developmental disorder that impacts negatively on the perception of music. Psychophysical testing suggests that individuals with amusia have above average thresholds for detection of pitch change and pitch direction discrimination; however, a low-level auditory perceptual problem cannot completely explain the disorder, since discrimination of melodies is also impaired when the constituent intervals are suprathreshold for perception. The aim of the present study was to test pitch memory as a function of (a) time and (b) tonal interference, in order to determine whether pitch traces are inherently weaker in amusic individuals. Memory for the pitch of single tones was compared using two versions of a paradigm developed by Deutsch (1970a). In both tasks, participants compared the pitch of a standard (S) versus a comparison (C) tone. In the time task, the S and C tones were presented, separated in time by 0, 1, 5, 10, and 15 s (blocked presentation). In the interference task, the S and C tones were presented with a fixed time interval (5 s) but with a variable number of irrelevant tones in between: 0, 2, 4, 6, and 8 tones (blocked presentation). In the time task, control performance remained high for all time in tervals, but amusics showed a performance decrement over time. In the interference task, controls and amusics showed a similar performance decrement with increasing number of irrelevant tones. Overall, the results suggest that the pitch representations of amusic individuals are less stable and more prone to decay than those of matched non-amusic individuals

Drivers of groundwater utilization in water-limited rice production systems in Nepal

Most rice farmers in Nepal’s Terai region do not fully utilize irrigation during breaks in monsoon rainfall. This leads to yield losses despite abundant groundwater resources and ongoing expansion of diesel pumps and tubewell infrastructure. We investigate this puzzle by characterizing delay factors governing tubewell irrigation across wealth and precipitation gradients. After the decision to irrigate, different factors delay irrigation by roughly one week. While more sustainable and inexpensive energy for pumping may eventually catalyze transformative change, we identify near-term interventions that may increase rice farmers’ resilience to water stress in smallholder-dominated farming communities based on prevailing types of irrigation infrastructure.</p

New ADS Functionality for the Curator

In this paper we provide an update concerning the operations of the NASA Astrophysics Data System (ADS), its services and user interface, and the content currently indexed in its database. As the primary information system used by researchers in Astronomy, the ADS aims to provide a comprehensive index of all scholarly resources appearing in the literature. With the current effort in our community to support data and software citations, we discuss what steps the ADS is taking to provide the needed infrastructure in collaboration with publishers and data providers. A new API provides access to the ADS search interface, metrics, and libraries allowing users to programmatically automate discovery and curation tasks. The new ADS interface supports a greater integration of content and services with a variety of partners, including ORCID claiming, indexing of SIMBAD objects, and article graphics from a variety of publishers. Finally, we highlight how librarians can facilitate the ingest of gray literature that they curate into our system.Comment: Submitted to the Proceedings of Library and Information Services in Astronomy VIII, Strasbourg, Franc

Decoherence, discord, and the quantum master equation for cosmological perturbations

We examine environmental decoherence of cosmological perturbations in order to study the quantum-to-classical transition and the impact of noise on entanglement during inflation. Given an explicit interaction between the system and environment, we derive a quantum master equation for the reduced density matrix of perturbations, drawing parallels with quantum Brownian motion, where we see the emergence of fluctuation and dissipation terms. Although the master equation is not in Lindblad form, we see how typical solutions exhibit positivity on super-horizon scales, leading to a physically meaningful density matrix. This allows us to write down a Langevin equation with stochastic noise for the classical trajectories which emerge from the quantum system on super-horizon scales. In particular, we find that environmental decoherence increases in strength as modes exit the horizon, with the growth driven essentially by white noise coming from local contribution to environmental correlations. Finally, we use our master equation to quantify the strength of quantum correlations as captured by discord. We show that environmental interactions have a tendency to decrease the size of the discord and that these effects are determined by the relative strength of the expansion rate and interaction rate of the environment. We interpret this in terms of the competing effects of particle creation versus environmental fluctuations, which tend to increase and decrease the discord respectively

The phenotype of type 1 diabetes in sub-Saharan Africa

The phenotype of type 1 diabetes in Africa, especially sub-Saharan Africa, is poorly understood. Most previously conducted studies have suggested that type 1 diabetes may have a different phenotype from the classical form of the disease described in western literature. Making an accurate diagnosis of type 1 diabetes in Africa is challenging, given the predominance of atypical diabetes forms and limited resources. The peak age of onset of type 1 diabetes in sub-Saharan Africa seems to occur after 18–20 years. Multiple studies have reported lower rates of islet autoantibodies ranging from 20 to 60% amongst people with type 1 diabetes in African populations, lower than that reported in other populations. Some studies have reported much higher levels of retained endogenous insulin secretion than in type 1 diabetes elsewhere, with lower rates of type 1 diabetes genetic susceptibility and HLA haplotypes. The HLA DR3 appears to be the most predominant HLA haplotype amongst people with type 1 diabetes in sub-Saharan Africa than the HLA DR4 haplotype. Some type 1 diabetes studies in sub-Saharan Africa have been limited by small sample sizes and diverse methods employed. Robust studies close to diabetes onset are sparse. Large prospective studies with well-standardized methodologies in people at or close to diabetes diagnosis in different population groups will be paramount to provide further insight into the phenotype of type 1 diabetes in sub-Saharan Africa