Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials

Background Change in albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lacking. We aimed to determine the association between treatment effects on early changes in albuminuria and treatment effects on clinical endpoints and surrograte endpoints, to inform the use of albuminuria as a surrogate endpoint in future randomised controlled trials. Methods In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including “chronic kidney disease”, “chronic renal insufficiency”, “albuminuria”, “proteinuria”, and “randomized controlled trial”; key inclusion criteria were quantifiable measurements of albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in albuminuria and the composite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1·73 m2, or doubling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on albuminuria to those on the clinical endpoint across studies and developed a prediction model for the treatment effect on the clinical endpoint on the basis of the treatment effect on albuminuria. Findings We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 participants (21 206 [71%] with diabetes). Over a median follow-up of 3·4 years (IQR 2·3–4·2), 3935 (13%) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0·89 (95% Bayesian credible interval [BCI] 0·13–1·70), each 30% decrease in geometric mean albuminuria by the treatment relative to the control was associated with an average 27% lower hazard for the clinical endpoint (95% BCI 5–45%; median R2 0·47, 95% BCI 0·02–0·96). The association strengthened after restricting analyses to patients with baseline albuminuria of more than 30 mg/g (ie, 3·4 mg/mmol; R2 0·72, 0·05–0·99]). For future trials, the model predicts that treatments that decrease the geometric mean albuminuria to 0·7 (ie, 30% decrease in albuminuria) relative to the control will provide an average hazard ratio (HR) for the clinical endpoint of 0·68, and 95% of sufficiently large studies would have HRs between 0·47 and 0·95. Interpretation Our results support a role for change in albuminuria as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria; for patients with low baseline levels of albuminuria this association is less certain

Brain Potentials Highlight Stronger Implicit Food Memory for Taste than Health and Context Associations

Increasingly consumption of healthy foods is advised to improve population health. Reasons people give for choosing one food over another suggest that non-sensory features like health aspects are appreciated as of lower importance than taste. However, many food choices are made in the absence of the actual perception of a food's sensory properties, and therefore highly rely on previous experiences of similar consumptions stored in memory. In this study we assessed the differential strength of food associations implicitly stored in memory, using an associative priming paradigm. Participants (N = 30) were exposed to a forced-choice picture-categorization task, in which the food or non-food target images were primed with either non-sensory or sensory related words. We observed a smaller N400 amplitude at the parietal electrodes when categorizing food as compared to non-food images. While this effect was enhanced by the presentation of a food-related word prime during food trials, the primes had no effect in the non-food trials. More specifically, we found that sensory associations are stronger implicitly represented in memory as compared to non-sensory associations. Thus, this study highlights the neuronal mechanisms underlying previous observations that sensory associations are important features of food memory, and therefore a primary motive in food choice.</p

Building connectomes using diffusion MRI: why, how and but

Why has diffusion MRI become a principal modality for mapping connectomes in vivo? How do different image acquisition parameters, fiber tracking algorithms and other methodological choices affect connectome estimation? What are the main factors that dictate the success and failure of connectome reconstruction? These are some of the key questions that we aim to address in this review. We provide an overview of the key methods that can be used to estimate the nodes and edges of macroscale connectomes, and we discuss open problems and inherent limitations. We argue that diffusion MRI-based connectome mapping methods are still in their infancy and caution against blind application of deep white matter tractography due to the challenges inherent to connectome reconstruction. We review a number of studies that provide evidence of useful microstructural and network properties that can be extracted in various independent and biologically-relevant contexts. Finally, we highlight some of the key deficiencies of current macroscale connectome mapping methodologies and motivate future developments

Visual Stability and the Motion Aftereffect: A Psychophysical Study Revealing Spatial Updating

Eye movements create an ever-changing image of the world on the retina. In particular, frequent saccades call for a compensatory mechanism to transform the changing visual information into a stable percept. To this end, the brain presumably uses internal copies of motor commands. Electrophysiological recordings of visual neurons in the primate lateral intraparietal cortex, the frontal eye fields, and the superior colliculus suggest that the receptive fields (RFs) of special neurons shift towards their post-saccadic positions before the onset of a saccade. However, the perceptual consequences of these shifts remain controversial. We wanted to test in humans whether a remapping of motion adaptation occurs in visual perception

Female Institutional Directors on Boards and Firm Value

The aim of this research is to examine what impact female institutional directors on boards have on corporate performance. Previous research shows that institutional female directors cannot be considered as a homogeneous group since they represent investors who may or may not maintain business relations with the companies on whose corporate boards they sit. Thus, it is not only the effect of female institutional directors as a whole on firm value that has been analysed, but also the impact of pressure-resistant female directors, who represent institutional investors (investment, pension and mutual funds) that only invest in the company, and do not maintain a business relation with the firm. We hypothesize that there is a non-linear association, specifically quadratic, between institutional and pressure-resistant female directors on boards and corporate performance. Our results report that female institutional directors on boards enhance corporate performance, but when they reach a certain threshold on boards (11.72 %), firm value decreases. In line with female institutional directors, pressure-resistant female directors on boards also increase firm value, but only up to a certain figure (12.71 % on boards), above which they have a negative impact on firm performance. These findings are consistent with an inverted U-shaped relationship between female institutional directors and pressure-resistant female directors and firm performance

The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours

Peptide receptor radionuclide therapy (PRRNT) is a molecularly targeted radiation therapy involving the systemic administration of a radiolabelled peptide designed to target with high affinity and specificity receptors overexpressed on tumours. PRRNT employing the radiotagged somatostatin receptor agonists (90)Y-DOTATOC ([(90)Y-DOTA(0),Tyr(3)]-octreotide) or (177)Lu-DOTATATE ([(177)Lu-DOTA(0),Tyr(3),Thr(8)]-octreotide or [(177)Lu-DOTA(0),Tyr(3)]-octreotate) have been successfully used for the past 15 years to target metastatic or inoperable neuroendocrine tumours expressing the somatostatin receptor subtype 2. Accumulated evidence from clinical experience indicates that these tumours can be subjected to a high absorbed dose which leads to partial or complete objective responses in up to 30 % of treated patients. Survival analyses indicate that patients presenting with high tumour receptor expression at study entry and receiving (177)Lu-DOTATATE or (90)Y-DOTATOC treatment show significantly higher objective responses, leading to longer survival and improved quality of life. Side effects of PRRNT are typically seen in the kidneys and bone marrow. These, however, are usually mild provided adequate protective measures are undertaken. Despite the large body of evidence regarding efficacy and clinical safety, PRRNT is still considered an investigational treatment and its implementation must comply with national legislation, and ethical guidelines concerning human therapeutic investigations. This guidance was formulated based on recent literature and leading experts’ opinions. It covers the rationale, indications and contraindications for PRRNT, assessment of treatment response and patient follow-up. This document is aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRNT and to deliver the treatment in a safe and effective manner. This document is largely based on the book published through a joint international effort under the auspices of the Nuclear Medicine Section of the International Atomic Energy Agency