which marker is best for prediction? Pooled analysis of four German population-based cohort studies and comparison with a nationwide cohort study

Objective To compare the association between different anthropometric measurements and incident type 2 diabetes mellitus (T2DM) and to assess their predictive ability in different regions of Germany. Methods Data of 10 258 participants from 4 prospective population-based cohorts were pooled to assess the association of body weight, body mass index (BMI), waist circumference (WC), waist-to-hip-ratio (WHR) and waist-to-height-ratio (WHtR) with incident T2DM by calculating HRs of the crude, adjusted and standardised markers, as well as providing receiver operator characteristic (ROC) curves. Differences between HRs and ROCs for the different anthropometric markers were calculated to compare their predictive ability. In addition, data of 3105 participants from the nationwide survey were analysed separately using the same methods to provide a nationally representative comparison. Results Strong associations were found for each anthropometric marker and incidence of T2DM. Among the standardised anthropometric measures, we found the strongest effect on incident T2DM for WC and WHtR in the pooled sample (HR for 1 SD difference in WC 1.97, 95% CI 1.75 to 2.22, HR for WHtR 1.93, 95% CI 1.71 to 2.17 in women) and in female DEGS participants (HR for WC 2.24, 95% CI 1.91 to 2.63, HR for WHtR 2.10, 95% CI 1.81 to 2.44), whereas the strongest association in men was found for WHR among DEGS participants (HR 2.29, 95% CI 1.89 to 2.78). ROC analysis showed WHtR to be the strongest predictor for incident T2DM. Differences in HR and ROCs between the different markers confirmed WC and WHtR to be the best predictors of incident T2DM. Findings were consistent across study regions and age groups (<65 vs ≥65 years). Conclusions We found stronger associations between anthropometric markers that reflect abdominal obesity (ie, WC and WHtR) and incident T2DM than for BMI and weight. The use of these measurements in risk prediction should be encouraged

Anthropometric markers and their association with incident type 2 diabetes mellitus: which marker is best for prediction? Pooled analysis of four German population-based cohort studies and comparison with a nationwide cohort study

Objective: To compare the association between different anthropometric measurements and incident type 2 diabetes mellitus (T2DM) and to assess their predictive ability in different regions of Germany. Methods: Data of 10 258 participants from 4 prospective population-based cohorts were pooled to assess the association of body weight, body mass index (BMI), waist circumference (WC), waist-to-hip-ratio (WHR) and waist-to-height-ratio (WHtR) with incident T2DM by calculating HRs of the crude, adjusted and standardised markers, as well as providing receiver operator characteristic (ROC) curves. Differences between HRs and ROCs for the different anthropometric markers were calculated to compare their predictive ability. In addition, data of 3105 participants from the nationwide survey were analysed separately using the same methods to provide a nationally representative comparison. Results: Strong associations were found for each anthropometric marker and incidence of T2DM. Among the standardised anthropometric measures, we found the strongest effect on incident T2DM for WC and WHtR in the pooled sample (HR for 1 SD difference in WC 1.97, 95% CI 1.75 to 2.22, HR for WHtR 1.93, 95% CI 1.71 to 2.17 in women) and in female DEGS participants (HR for WC 2.24, 95% CI 1.91 to 2.63, HR for WHtR 2.10, 95% CI 1.81 to 2.44), whereas the strongest association in men was found for WHR among DEGS participants (HR 2.29, 95% CI 1.89 to 2.78). ROC analysis showed WHtR to be the strongest predictor for incident T2DM. Differences in HR and ROCs between the different markers confirmed WC and WHtR to be the best predictors of incident T2DM. Findings were consistent across study regions and age groups

Safety and tolerability of long-term treatment with darolutamide in patients with metastatic castration-resistant prostate cancer

Background In patients with metastatic castration-resistant prostate cancer, darolutamide was well tolerated for 25 months, but minimal long-term safety data are available. Methods Treatment-emergent adverse events (TEAEs) for patients receiving darolutamide for a median of 38 months (n = 13) are described in this pooled analysis of individual patient data from phase 1/2 studies. Results All patients reported TEAEs (mostly grade 1/2). The most common TEAEs were diarrhea, abdominal pain, and nausea. Serious TEAEs were reported in six patients (none related to darolutamide). All treatment-related TEAEs (n = 5) were grade 1. Conclusions Long-term darolutamide treatment was well tolerated; no new safety signals observed

Enhanced biological carbon consumption in a high CO2 ocean

The oceans have absorbed nearly half of the fossil-fuel carbon dioxide (CO2) emitted into the atmosphere since pre-industrial times1, causing a measurable reduction in seawater pH and carbonate saturation2. If CO2 emissions continue to rise at current rates, upper-ocean pH will decrease to levels lower than have existed for tens of millions of years and, critically, at a rate of change 100 times greater than at any time over this period3. Recent studies have shown effects of ocean acidification on a variety of marine life forms, in particular calcifying organisms4, 5, 6. Consequences at the community to ecosystem level, in contrast, are largely unknown. Here we show that dissolved inorganic carbon consumption of a natural plankton community maintained in mesocosm enclosures at initial CO2 partial pressures of 350, 700 and 1,050 μatm increases with rising CO2. The community consumed up to 39% more dissolved inorganic carbon at increased CO2 partial pressures compared to present levels, whereas nutrient uptake remained the same. The stoichiometry of carbon to nitrogen drawdown increased from 6.0 at low CO2 to 8.0 at high CO2, thus exceeding the Redfield carbon:nitrogen ratio of 6.6 in today’s ocean7. This excess carbon consumption was associated with higher loss of organic carbon from the upper layer of the stratified mesocosms. If applicable to the natural environment, the observed responses have implications for a variety of marine biological and biogeochemical processes, and underscore the importance of biologically driven feedbacks in the ocean to global change

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological systematic review of health technology assessments

Background: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Probing the redox environment of single human cancer cells using scanning electrochemical microscopy

Complex biological processes, such as the transport of molecules across cell membranes, are often difficult to understand or even to monitor using purely biological methodologies. Investigating these transport processes remains challenging, because biological objects exhibit highly complex chemical composition, target substances exist in small concentrations and studies require the analysis of living samples. Scanning electrochemical microscopy (SECM) is an electrochemical analytical technique, offering the detection of single molecules released from a single cell non-invasively. It does so by detecting electron transfer reactions at a biased microelectrode positioned in close proximity to a target cell.The presented dissertation investigates and quantifies the efflux of glutathione from human adenocarcinoma cervical cancer cells (HeLa) and a multidrug resistant variant (HeLa-R). Due to its ubiquitous antioxidant and regulatory redox properties, glutathione provides information about the overall cellular redox state. Herein, two methods are proposed to quantify the heterogeneous rate constant (kinetics) in HeLa and HeLa-R by means of SECM. First, the use of both, a cell permeable and a cell impermeable redox mediator during 3D live cell imaging and application of SECM theory leads to a direct comparison of HeLa and HeLa-R cell kinetics. Secondly, SECM line scan imaging at different scan velocities, supported by numerical simulations offers a rapid and convenient alternative solution for the quantitative determination of cellular glutathione efflux. Furthermore, issues related to a long experimental acquisition time during the mediator-based methodology could be resolved.To apply the SECM scan velocity based glutathione efflux quantification method to a biological relevant model as a proof of concept, the influence of Epigallocatechine gallate (EGCg), the most abundant catechin in tea, on HeLa cell kinetics is investigated. After exposure to EGCg the cells metabolic response is monitored electrochemically and biochemically over time. Finally, a direct comparison of the two proposed electroanalytical methods is conducted and discussed in the context of current literature. Suggestions are made for future studies and their impact in analytical and medical research is discussed.Les processus biologiques complexes, tels que le transport de molécules à travers les membranes cellulaires, sont souvent difficiles à comprendre ou même à observer en utilisant des méthodologies purement biologiques. Enquêter sur ces processus de transport reste difficile, parce que les corps biologiques présentent une composition chimique très complexe, les substances cibles existent en petites concentrations et les études nécessitent l'analyse d’échantillons vivants. La microscopie électrochimique à balayage (SECM) est une technique d'analyse électrochimique permettant la détection de molécules individuelles sécrétées par une seule cellule de façon non-invasive. Cette technique se base sur la détection de réactions de transfert d'électrons à une microélectrode polarisée positionnée à proximité immédiate de la cellule cible.La thèse présentée étudie et quantifie l'efflux de glutathion à partir de cellules humaines d'adénocarcinome du col de l'utérus (HeLa du cancer) et d'un variant présentant une résistance à de multiples médicaments (HeLa-R). En raison de ses propriétés antioxydantes omniprésentes et de propriétés régulatrices d’activités redox, le glutathion fournit des informations sur l'état redox général de la cellule. Ici, deux méthodes sont proposées pour quantifier la constante de vitesse hétérogène (cinétique) dans des cellules HeLa et HeLa-R au moyen de la SECM. Premièrement, l'imagerie 3D de cellules vivantes en utilisant deux médiateurs redox, un qui est perméable à la cellule et un qui ne l’est pas, et application de la théorie SECM conduit à une comparaison directe de la cinétique cellulaire d’HeLa et d’HeLa-R. Deuxièmement, l’imagerie SECM par balayage linéaire à différentes vitesses, soutenue par des simulations numériques, offre une solution de rechange rapide et pratique pour la détermination quantitative de l’efflux cellulaire du glutathion. En outre, les problèmes liés à une longue période d'acquisition au cours d’expériences impliquant des médiateurs pourraient être résolus.Pour prouver le concept, la méthode de quantification de l’efflux de glutathion par SECM a été appliquée à un système biologique modèle, soit les cellules HeLa. L'influence de l'épigallocatéchine gallate (EGCg), la catéchine la plus abondante dans le thé, sur la cinétique des cellules est étudiée. Après exposition à l’EGCg, la réponse métabolique des cellules est évaluée par voies électrochimique et biochimique au fil du temps. Enfin, une comparaison directe des deux méthodes électroanalytiques proposées est menée et discutée dans le contexte de la littérature actuelle. La thèse se conclut sur une discussion approfondie concernant les travaux futurs envisagés ainsi que leurs impacts potentiels dans les domaines de la chimie analytique et la recherche médicale

Landmarks in the Evolution of (t)-RNAs from the Origin of Life up to Their Present Role in Human Cognition

How could modern life have evolved? The answer to that question still remains unclear. However, evidence is growing that, since the origin of life, RNA could have played an important role throughout evolution, right up to the development of complex organisms and even highly sophisticated features such as human cognition. RNA mediated RNA-aminoacylation can be seen as a first landmark on the path from the RNA world to modern DNA- and protein-based life. Likewise, the generation of the RNA modifications that can be found in various RNA species today may already have started in the RNA world, where such modifications most likely entailed functional advantages. This association of modification patterns with functional features was apparently maintained throughout the further course of evolution, and particularly tRNAs can now be seen as paradigms for the developing interdependence between structure, modification and function. It is in this spirit that this review highlights important stepping stones of the development of (t)RNAs and their modifications (including aminoacylation) from the ancient RNA world up until their present role in the development and maintenance of human cognition. The latter can be seen as a high point of evolution at its present stage, and the susceptibility of cognitive features to even small alterations in the proper structure and functioning of tRNAs underscores the evolutionary relevance of this RNA species

Biological scanning electrochemical microscopy and its application to live cell studies

Peer reviewed: YesNRC publication: Ye