Global Proteinuria Guidelines: Are We Nearly There Yet?

Assessment of albumin and/or protein excretion in the urine is a key step in the early detection and appropriate management of chronic kidney disease. The approach to testing for albuminuria/proteinuria in the community is variable and often suboptimal. It is hampered by: variation in laboratory measurement; lack of standard reference materials and testing procedures; variable definitions and units of reporting; conflicting recommendations and practices regarding who to test; and uncertainty over when and how testing is most appropriately done. This review discusses the current status of proteinuria guidelines around the world and the key clinical issues that need to be addressed before a unifying global guideline can be developed.     

Implementing quality by design for biotech products: Are regulators on track?

Quality by design (QbD) is an innovative approach to drug development that has started to be implemented into the regulatory framework, but currently mainly for chemical drugs. The recent marketing authorization of the first monoclonal antibody developed using extensive QbD concepts in the European Union paves the way for future further regulatory approvals of complex products employing this cutting-edge technological concept. In this paper, we report and comment on insights and lessons learnt from the non-public discussions in the European Medicines Agency''s Biologicals Working Party and Committee for Medicinal Products for Human Use on the key issues during evaluation related to the implementation of an extensive QbD approach for biotechnology-derived medicinal products. Sharing these insights could prove useful for future developments in QbD for biotech products in general and monoclonal antibodies in particular.     

Implementing quality by design for biotech products: Are regulators on track?

Quality by design (QbD) is an innovative approach to drug development that has started to be implemented into the regulatory framework, but currently mainly for chemical drugs. The recent marketing authorization of the first monoclonal antibody developed using extensive QbD concepts in the European Union paves the way for future further regulatory approvals of complex products employing this cutting-edge technological concept. In this paper, we report and comment on insights and lessons learnt from the non-public discussions in the European Medicines Agency's Biologicals Working Party and Committee for Medicinal Products for Human Use on the key issues during evaluation related to the implementation of an extensive QbD approach for biotechnology-derived medicinal products. Sharing these insights could prove useful for future developments in QbD for biotech products in general and monoclonal antibodies in particular.     

Are Treatments More Effective than Placebos? A Systematic Review and Meta-Analysis

BackgroundPlacebos are widely used in clinical practice in spite of ethical restrictions. Whether such use is justified depends in part on the relative benefit of placebos compared to ‘active’ treatments. A direct test for differences between placebo and ‘active’ treatment effects has not been conducted.ObjectivesWe aimed to test for differences between treatment and placebo effects within similar trial populations.ResultsIn trials with continuous outcomes (n = 115) we found no difference between treatment and placebo effects (MD = −0.29, 95% CI −0.62 to 0.05, P = 0.10). In trials with binary outcomes (n = 37) treatments were significantly more effective than placebos (RRR = 0.72, 95%CI = 0.61 to 0.86, P = 0.0003). Treatment and placebo effects were not different in 22 out of 28 predefined subgroup analyses. Of the six subgroups with differences treatments were more effective than placebos in five. However when all criteria for reducing bias were ruled out (continuous outcomes) placebos were more effective than treatments (MD = 1.59, 95% CI = 0.40 to 2.77, P = 0.009).

Conclusions and Implications

Placebos and treatments often have similar effect sizes. Placebos with comparatively powerful effects can benefit patients either alone or as part of a therapeutic regime, and trials involving such placebos must be adequately blinded.     

Body temperature and sleep: Are they controlled by the same mechanism?

Simultaneous changes in sleep and body temperature, produced either by lesion or by stimulation of the medial preoptic area (mPOA), have given reasons to suggest that thermoregulation and sleep regulation are controlled by the same set of neurons. The reasons for simultaneous changes in these parameters are discussed in the present paper with a view to explaining the relationship between thermoregulation and sleep regulation. Changes in body temperature and sleep on destruction of the preoptic area (POA) neurons and the sequence of these changes, suggest a separate control mechanism in the mPOA for regulation of sleep and body temperature. Evidence is put forward in the present paper to show that the mPOA is not involved in the downregulation or upregulation of changes in body temperature with alteration in the vigilance state. On the other hand, circadian modulation of body temperature is possibly involved in altering sleep propensity. A clear indication regarding separate control of sleep and body temperature came from the studies in which noradrenergic agents were applied into the mPOA of animals with and without lesion of the noradrenergic fibers projecting to the mPOA. Experiments in which sleep was analyzed after experimental manipulations of ambient temperature and body temperature, including peripheral, core and brain temperature, are presented here to show a close relationship between thermoregulation and sleep regulation. Various theories regarding the regulation of body temperature during slow wave sleep and rapid eye movement sleep are also discussed. The functional integrity of the mPOA may be essential not only for the regulation of body temperature and sleep-wakefulness but even for the homeostatic regulation of energy balance of the body in response to alterations in environmental temperature and sleep-wakefulness.

     

Are Tree Species Diversity and Genotypic Diversity Effects on Insect Herbivores Mediated by Ants?

Plant diversity can influence predators and omnivores and such effects may in turn influence herbivores and plants. However, evidence for these ecological feedbacks is rare. We evaluated if the effects of tree species (SD) and genotypic diversity (GD) on the abundance of different guilds of insect herbivores associated with big-leaf mahogany (Swietenia macrophylla) were contingent upon the protective effects of ants tending extra-floral nectaries of this species. This study was conducted within a larger experiment consisting of mahogany monocultures and species polycultures of four species and –within each of these two plot types– mahogany was represented by either one or four maternal families. We selected 24 plots spanning these treatment combinations, 10 mahogany plants/plot, and within each plot experimentally reduced ant abundance on half of the selected plants, and surveyed ant and herbivore abundance. There were positive effects of SD on generalist leaf-chewers and sap-feeders, but for the latter group this effect depended on the ant reduction treatment: SD positively influenced sap-feeders under ambient ant abundance but had no effect when ant abundance was reduced; at the same time, ants had negative effects on sap feeders in monoculture but no effect in polyculture. In contrast, SD did not influence specialist stem-borers or leaf-miners and this effect was not contingent upon ant reduction. Finally, GD did not influence any of the herbivore guilds studied, and such effects did not depend on the ant treatment. Overall, we show that tree species diversity influenced interactions between a focal plant species (mahogany) and ants, and that such effects in turn mediated plant diversity effects on some (sap-feeders) but not all the herbivores guilds studied. Our results suggest that the observed patterns are dependent on the combined effects of herbivore identity, diet breadth, and the source of plant diversity.     

Are Weeds Hitchhiking a Ride on Your Car? A Systematic Review of Seed Dispersal on Cars

When traveling in cars, we can unintentionally carry and disperse weed seed; but which species, and where are they a problem? To answer these questions, we systematically searched the scientific literature to identify all original research studies that assess seed transported by cars and listed the species with seed on/in cars. From the 13 studies that fit these criteria, we found 626 species from 75 families that have seed that can be dispersed by cars. Of these, 599 are listed as weeds in some part of the world, with 439 listed as invasive or naturalized alien species in one or more European countries, 248 are invasive/noxious weeds in North America, 370 are naturalized alien species in Australia, 167 are alien species in India, 77 are invasive species in China and 23 are declared weeds/invaders in South Africa. One hundred and one are classified as internationally important environmental weeds. Although most (487) were only recorded once, some species such as Chenopodium album, Poa pratensis and Trifolium repens were common among studies. Perennial graminoids seem to be favoured over annual graminoids while annual forbs are favoured over perennial forbs. Species characteristics including seed size and morphology and where the plants grew affected the probability that their seed was transported by cars. Seeds can be found in many different places on cars including under the chassis, front and rear bumpers, wheel wells and rims, front and back mudguards, wheel arches, tyres and on interior floor mats. With increasing numbers of cars and expanding road networks in many regions, these results highlight the importance of cars as a dispersal mechanism, and how it may favour invasions by some species over others. Strategies to reduce the risk of seed dispersal by cars include reducing seed on cars by mowing road verges and cleaning cars.     

Chytrid Blinders: What Other Disease Risks to Amphibians Are We Missing?

Amphibian declines are occurring on a global scale, and infectious disease has been implicated as a factor in some species. Batrachochytrium dendrobatidis (Bd) has been associated with amphibian declines and/or extinctions in many locations, however, few of the studies have actually performed detailed pathological investigations to link the emergence of the disease with mortality rates large enough to cause the declines. Many studies are based solely on the presence of infection, not disease, because of the reliance on molecular tests for Bd. The emphasis of the importance of Bd combined with easy molecular tests has resulted in poor investigations into amphibian mortality and declines in many areas. The line between infection and disease has been blurred, and a step back to basic pathological and biological investigations is needed as other disease risks to amphibians, such as ranaviruses, are likely being missed. In this article, starting points for proper investigative techniques for amphibian mortalities and declines are identified and areas that need to be improved, especially communication between biologist and veterinarians involved in amphibian disease research, are suggested. It is hoped that this will start a much needed discussion in the area and lead to some consensus building about methodologies used in amphibian disease research.     

Are pikas exposed to and affected by selenium deficiency?

Regional extirpations of pikas (Ochatona princeps) within the last few decades have been attributed to global warming. Other recent global alterations such as increased nitrogen (N) deposition and associated selenium (Se) deficiency may further stress pika populations. In 2003 and 2004, we live-trapped pikas from three populations in Wyoming and measured Se values in their hair. We also sampled hair and liver from museum specimens collected throughout the Northern Rocky Mountains in 1987 and 1988. Our results suggest that liver and hair values were related, and that pika hair reflected the Se concentrations of the geologic parent materials. We determined that animals residing in several remote areas in the Rocky Mountain region could be Se deficient and that increase in N deposition correlated with an increase rather than a decrease in Se values in pika hair. In addition, we found no relation between Se contents in hair and body condition index, suggesting that low Se levels may not have negative effects on individual pikas. Whether Se levels influence reproductive success of pikas is unknown and should be the focus of future studies.     

Iron Binding and Autoreduction by Citrate: Are These Involved in Signalling by Iron Regulatory Protein-l?

Ferric ions bind to citrate and undergo an autoreduction to form a ferrous-citrate complex, greatly increasing the redox activity of the iron complex. Ferrous ions and citrate are also essential for the enzymic activity of aconitase. Aconitase, with its iron-sulphur cluster has a versatile structure which allows it to act as an iron regulatory protein (IW-1). The purpose of this study was to see whether iron binding, and its autoreduction by citrate, could play a physiological signalling role in iron regulation. Significant amounts of ferrous ions were associated with citrate, when measured using ferrozine, however, these did not appear to activate iron-requiring aconitase.     

Guidelines for Guidelines: Are They Up to the Task? A Comparative Assessment of Clinical Practice Guideline Development Handbooks

Objectives

We conducted a comparative review of clinical practice guideline development handbooks. We aimed to identify the main guideline development tasks, assign weights to the importance of each task using expert opinions and identify the handbooks that provided a comprehensive coverage of the tasks.

Methods

We systematically searched and included handbooks published (in English language) by national, international or professional bodies responsible for evidenced-based guideline development. We reviewed the handbooks to identify the main guideline development tasks and scored each handbook for each task from 0 (the handbook did not mention the task) to 2 (the task suitably addressed and explained), and calculated a weighted score for each handbook. The tasks included in over 75% of the handbooks were considered as ‘necessary’ tasks.

Result

Nineteen guideline development handbooks and twenty seven main tasks were identified. The guideline handbooks’ weighted scores ranged from 100 to 220. Four handbooks scored over 80% of the maximum possible score, developed by the National Institute for Health and Clinical Excellence, Swiss Centre for International Health, Scottish Intercollegiate Guidelines Network and World Health Organization. Necessary tasks were: selecting the guideline topic, determining the guideline scope, identifying relevant existing guidelines, involving the consumers, forming guideline development group,, developing clinical questions, systematic search for evidence, selecting relevant evidence, appraising identifies research evidence, making group decision, grading available evidence, creating recommendations, final stakeholder consultation, guideline implementation strategies, updating recommendations and correcting potential errors.

Discussion

Adequate details for evidence based development of guidelines were still lacking from many handbooks. The tasks relevant to ethical issues and piloting were missing in most handbooks. The findings help decision makers in identifying the necessary tasks for guideline development, provide an updated comparative list of guideline development handbooks, and provide a checklist to assess the comprehensiveness of guideline development processes.     

Trust and Reciprocity: Are Effort and Money Equivalent?

Trust and reciprocity facilitate cooperation and are relevant to virtually all human interactions. They are typically studied using trust games: one subject gives (entrusts) money to another subject, which may return some of the proceeds (reciprocate). Currently, however, it is unclear whether trust and reciprocity in monetary transactions are similar in other settings, such as physical effort. Trust and reciprocity of physical effort are important as many everyday decisions imply an exchange of physical effort, and such exchange is central to labor relations. Here we studied a trust game based on physical effort and compared the results with those of a computationally equivalent monetary trust game. We found no significant difference between effort and money conditions in both the amount trusted and the quantity reciprocated. Moreover, there is a high positive correlation in subjects' behavior across conditions. This suggests that trust and reciprocity may be character traits: subjects that are trustful/trustworthy in monetary settings behave similarly during exchanges of physical effort. Our results validate the use of trust games to study exchanges in physical effort and to characterize inter-subject differences in trust and reciprocity, and also suggest a new behavioral paradigm to study these differences.