Randomization in clinical trials in orthodontics: its significance in research design and methods to achieve it

Randomization is a key step in reducing selection bias during the treatment allocation phase in randomized clinical trials. The process of randomization follows specific steps, which include generation of the randomization list, allocation concealment, and implementation of randomization. The phenomenon in the dental and orthodontic literature of characterizing treatment allocation as random is frequent; however, often the randomization procedures followed are not appropriate. Randomization methods assign, at random, treatment to the trial arms without foreknowledge of allocation by either the participants or the investigators thus reducing selection bias. Randomization entails generation of random allocation, allocation concealment, and the actual methodology of implementing treatment allocation randomly and unpredictably. Most popular randomization methods include some form of restricted and/or stratified randomization. This article introduces the reasons, which make randomization an integral part of solid clinical trial methodology, and presents the main randomization schemes applicable to clinical trials in orthodontics.

Tools for better SLM knowledge management and informed decision-making in addressing land degradation at different scales: the WOCAT–LADA–DESIRE methodology

Desertification research conventionally focuses on the problem – that is, degradation – while neglecting the appraisal of successful conservation practices. Based on the premise that Sustainable Land Management (SLM) experiences are not sufficiently or comprehensively documented, evaluated, and shared, the World Overview of Conservation Approaches and Technologies (WOCAT) initiative (www.wocat.net), in collaboration with FAO’s Land Degradation Assessment in Drylands (LADA) project (www.fao.org/nr/lada/) and the EU’s DESIRE project (http://www.desire-project.eu/), has developed standardised tools and methods for compiling and evaluating the biophysical and socio-economic knowledge available about SLM. The tools allow SLM specialists to share their knowledge and assess the impact of SLM at the local, national, and global levels. As a whole, the WOCAT–LADA–DESIRE methodology comprises tools for documenting, self-evaluating, and assessing the impact of SLM practices, as well as for knowledge sharing and decision support in the field, at the planning level, and in scaling up identified good practices. SLM depends on flexibility and responsiveness to changing complex ecological and socioeconomic causes of land degradation. The WOCAT tools are designed to reflect and capture this capacity of SLM. In order to take account of new challenges and meet emerging needs of WOCAT users, the tools are constantly further developed and adapted. Recent enhancements include tools for improved data analysis (impact and cost/benefit), cross-scale mapping, climate change adaptation and disaster risk management, and easier reporting on SLM best practices to UNCCD and other national and international partners. Moreover, WOCAT has begun to give land users a voice by backing conventional documentation with video clips straight from the field. To promote the scaling up of SLM, WOCAT works with key institutions and partners at the local and national level, for example advisory services and implementation projects. Keywords: Sustainable Land Management (SLM), knowledge management, decision-making, WOCAT–LADA–DESIRE methodology.

Quantitative multi-slice computed tomography assessment of the mitral valvular complex for transcatheter mitral valve interventions part 1: systematic measurement methodology and inter-observer variability

AIMS Transcatheter mitral valve replacement (TMVR) is an emerging technology with the potential to treat patients with severe mitral regurgitation at excessive risk for surgical mitral valve surgery. Multimodal imaging of the mitral valvular complex and surrounding structures will be an important component for patient selection for TMVR. Our aim was to describe and evaluate a systematic multi-slice computed tomography (MSCT) image analysis methodology that provides measurements relevant for transcatheter mitral valve replacement. METHODS AND RESULTS A systematic step-by-step measurement methodology is described for structures of the mitral valvular complex including: the mitral valve annulus, left ventricle, left atrium, papillary muscles and left ventricular outflow tract. To evaluate reproducibility, two observers applied this methodology to a retrospective series of 49 cardiac MSCT scans in patients with heart failure and significant mitral regurgitation. For each of 25 geometrical metrics, we evaluated inter-observer difference and intra-class correlation. The inter-observer difference was below 10% and the intra-class correlation was above 0.81 for measurements of critical importance in the sizing of TMVR devices: the mitral valve annulus diameters, area, perimeter, the inter-trigone distance, and the aorto-mitral angle. CONCLUSIONS MSCT can provide measurements that are important for patient selection and sizing of TMVR devices. These measurements have excellent inter-observer reproducibility in patients with functional mitral regurgitation.

[Implementation of a routine gradual psycho-diagnostic programme in somatic rehabilitation centres - results of a pilot study]

STUDY AIM: A pilot study was conducted to implement and evaluate a routine gradual psycho-diagnostic programme to improve diagnostics and treatment of mental disorders in somatic rehabilitation centres. First of all, implementation strategies were acquired in trainings together with psychologists and physicians. The psycho-diagnostic programme consists of a screening instrument (PHQ-9) designed to permit time-effective detection of comorbid mental disorders. Besides evaluation of the training, the aim of the study was to analyze the extent to which it is possible to implement the routine gradual psycho-diagnostic programme in practice. Additionally, it was intended to identify beneficial and obstructive conditions for implementation. METHODOLOGY: The pilot study was conducted in two orthopaedic and one cardiological rehabilitation centre. The training was evaluated directly after its completion using a questionnaire. Three months after its implementation, the introduction of the psycho-diagnostic programme was evaluated using interviews with n=11 physicians and psychologists. RESULTS: The training was rated positively by the participants . Implementation of the entire gradual psycho-diagnostic programme was possible in one centre and to some degree in the other two. Beneficial for implementation were a frank organisational climate, sufficient time resources, and physicians' biopsychosocial understanding of disease. A dismissive attitude towards psycho-diagnostics, little communication between staff members, little perceived advantage for one's own work and fear to stigmatise patients by psychiatric diagnoses were obstructive. CONCLUSION: Essential for a successful implementation are sufficient time and personal resources, a motivation for change in staff and centre management, and a positive attitude regarding psycho-diagnostics in clinic staff. Furthermore, flexibility in implementation strategies and the opportunity to participate in the implementation process are important.

The importance of allocation concealment and patient blinding in osteoarthritis trials: a meta-epidemiologic study

OBJECTIVE: To evaluate the association of adequate allocation concealment and patient blinding with estimates of treatment benefits in osteoarthritis trials. METHODS: We performed a meta-epidemiologic study of 16 meta-analyses with 175 trials that compared therapeutic interventions with placebo or nonintervention control in patients with hip or knee osteoarthritis. We calculated effect sizes from the differences in means of pain intensity between groups at the end of followup divided by the pooled SD and compared effect sizes between trials with and trials without adequate methodology. RESULTS: Effect sizes tended to be less beneficial in 46 trials with adequate allocation concealment compared with 112 trials with inadequate or unclear concealment of allocation (difference -0.15; 95% confidence interval [95% CI] -0.31, 0.02). Selection bias associated with inadequate or unclear concealment of allocation was most pronounced in meta-analyses with large estimated treatment benefits (P for interaction < 0.001), meta-analyses with high between-trial heterogeneity (P = 0.009), and meta-analyses of complementary medicine (P = 0.019). Effect sizes tended to be less beneficial in 64 trials with adequate blinding of patients compared with 58 trials without (difference -0.15; 95% CI -0.39, 0.09), but differences were less consistent and disappeared after accounting for allocation concealment. Detection bias associated with a lack of adequate patient blinding was most pronounced for nonpharmacologic interventions (P for interaction < 0.001). CONCLUSION: Results of osteoarthritis trials may be affected by selection and detection bias. Adequate concealment of allocation and attempts to blind patients will minimize these biases.

Appraising and selecting conservation measures to mitigate desertification and land degradation based on stakeholder participation and global best practices

Most desertification research focuses on degradation assessments without putting sufficient emphasis on prevention and mitigation strategies, although the concept of Sustainable Land Management (SLM) is increasingly being acknowledged. A variety of already applied conservation measures exist at the local level, but they are not adequately recognised, evaluated and shared, either by land users, technicians, researchers, or policy makers. Likewise, collaboration between research and implementation is often insufficient. The aim of this paper is to present a new methodology for a participatory process of appraising and selecting desertification mitigation strategies, and to present first experiences from its application in the EU-funded DESIRE project. The methodology combines a collective learning and decision approach with the use of evaluated global best practices. In three parts, it moves through a concise process, starting with identifying land degradation and locally applied solutions in a stakeholder workshop, leading to assessing local solutions with a standardised evaluation tool, and ending with jointly selecting promising strategies for implementation with the help of a decision support tool. The methodology is currently being applied in 16 study sites. Preliminary analysis from the application of the first part of the methodology shows that the initial stakeholder workshop results in a good basis for stakeholder cooperation, and in promising land conservation practices for further assessment. Study site research teams appreciated the valuable results, as burning issues and promising options emerged from joint reflection. The methodology is suitable to initiate mutual learning among different stakeholder groups and to integrate local and scientific knowledge.

Public health risks of enterobacterial isolates producing extended-spectrum β-lactamases or AmpC β-lactamases in food and food-producing animals: an EU perspective of epidemiology, analytical methods, risk factors, and control options

The blaESBL and blaAmpC genes in Enterobacteriaceae are spread by plasmid-mediated integrons, insertion sequences, and transposons, some of which are homologous in bacteria from food animals, foods, and humans. These genes have been frequently identified in Escherichia coli and Salmonella from food animals, the most common being blaCTX-M-1, blaCTX-M-14, and blaCMY-2. Identification of risk factors for their occurrence in food animals is complex. In addition to generic antimicrobial use, cephalosporin usage is an important risk factor for selection and spread of these genes. Extensive international trade of animals is a further risk factor. There are no data on the effectiveness of individual control options in reducing public health risks. A highly effective option would be to stop or restrict cephalosporin usage in food animals. Decreasing total antimicrobial use is also of high priority. Implementation of measures to limit strain dissemination (increasing farm biosecurity, controls in animal trade, and other general postharvest controls) are also important.

Language as a barrier and facilitator for women's career progress

Purpose When applying for leadership positions or acting as leaders, women are still perceived with a ‘lack of fit’, thus hired less likely and evaluated less favorably than their male counterparts. In many languages, different language forms can be used to refer to both women and men: masculine forms (e.g., CEO in German: ‘Geschäftsführer’) and alternative forms (e.g., feminine‐masculine word pairs, CEO in German ‘Geschäftsführerin/Geschäftsführer’). We assumed that the use of masculine forms endorses the ‘lack of fit’ for women in leadership, whereas alternative forms reduce it. Design/Methodology Two studies tested the hypotheses by manipulating language forms (masculine forms vs. alternative forms) and gender of the target to hire/evaluate (female vs. male). Results The results indicated as predicted that masculine forms lead to the ‘lack of fit’ for women in the leadership context, whereas alternative forms reduce it. Women were less likely to be employed for leadership positions (Study 1) and evaluated less favorably as leaders (Study 2) than their male counterparts with masculine forms. However, with alternative forms no differences in employment decisions and evaluations of women and men were found. Limitations These two studies were conducted with student‐samples. Further research is needed to replicate effects with relevant samples as HRmanagers and to investigate underlying mechanisms. Research/Practical Implications Organizations may use alternative forms instead of masculine forms in job advertisements for leadership positions to overcome barriers for women in leadership. Originality/Value These are the first studies in testing the effects of language forms in the leader selection and evaluation.

Frequency-Dependent Selection Predicts Patterns of Radiations and Biodiversity

Most empirical studies support a decline in speciation rates through time, although evidence for constant speciation rates also exists. Declining rates have been explained by invoking pre-existing niches, whereas constant rates have been attributed to non-adaptive processes such as sexual selection and mutation. Trends in speciation rate and the processes underlying it remain unclear, representing a critical information gap in understanding patterns of global diversity. Here we show that the temporal trend in the speciation rate can also be explained by frequency-dependent selection. We construct a frequency-dependent and DNA sequence-based model of speciation. We compare our model to empirical diversity patterns observed for cichlid fish and Darwin's finches, two classic systems for which speciation rates and richness data exist. Negative frequency-dependent selection predicts well both the declining speciation rate found in cichlid fish and explains their species richness. For groups like the Darwin's finches, in which speciation rates are constant and diversity is lower, speciation rate is better explained by a model without frequency-dependent selection. Our analysis shows that differences in diversity may be driven by incipient species abundance with frequency-dependent selection. Our results demonstrate that genetic-distance-based speciation and frequency-dependent selection are sufficient to explain the high diversity observed in natural systems and, importantly, predict decay through time in speciation rate in the absence of pre-existing niches.

Comparison of (31)P saturation and inversion magnetization transfer in human liver and skeletal muscle using a clinical MR system and surface coils.

(31)P MRS magnetization transfer ((31)P-MT) experiments allow the estimation of exchange rates of biochemical reactions, such as the creatine kinase equilibrium and adenosine triphosphate (ATP) synthesis. Although various (31)P-MT methods have been successfully used on isolated organs or animals, their application on humans in clinical scanners poses specific challenges. This study compared two major (31)P-MT methods on a clinical MR system using heteronuclear surface coils. Although saturation transfer (ST) is the most commonly used (31)P-MT method, sequences such as inversion transfer (IT) with short pulses might be better suited for the specific hardware and software limitations of a clinical scanner. In addition, small NMR-undetectable metabolite pools can transfer MT to NMR-visible pools during long saturation pulses, which is prevented with short pulses. (31)P-MT sequences were adapted for limited pulse length, for heteronuclear transmit-receive surface coils with inhomogeneous B1 , for the need for volume selection and for the inherently low signal-to-noise ratio (SNR) on a clinical 3-T MR system. The ST and IT sequences were applied to skeletal muscle and liver in 10 healthy volunteers. Monte-Carlo simulations were used to evaluate the behavior of the IT measurements with increasing imperfections. In skeletal muscle of the thigh, ATP synthesis resulted in forward reaction constants (k) of 0.074 ± 0.022 s(-1) (ST) and 0.137 ± 0.042 s(-1) (IT), whereas the creatine kinase reaction yielded 0.459 ± 0.089 s(-1) (IT). In the liver, ATP synthesis resulted in k = 0.267 ± 0.106 s(-1) (ST), whereas the IT experiment yielded no consistent results. ST results were close to literature values; however, the IT results were either much larger than the corresponding ST values and/or were widely scattered. To summarize, ST and IT experiments can both be implemented on a clinical body scanner with heteronuclear transmit-receive surface coils; however, ST results are much more robust against experimental imperfections than the current implementation of IT.

Continental-Scale Footprint of Balancing and Positive Selection in a Small Rodent (Microtus arvalis)

Genetic adaptation to different environmental conditions is expected to lead to large differences between populations at selected loci, thus providing a signature of positive selection. Whereas balancing selection can maintain polymorphisms over long evolutionary periods and even geographic scale, thus leads to low levels of divergence between populations at selected loci. However, little is known about the relative importance of these two selective forces in shaping genomic diversity, partly due to difficulties in recognizing balancing selection in species showing low levels of differentiation. Here we address this problem by studying genomic diversity in the European common vole (Microtus arvalis) presenting high levels of differentiation between populations (average FST = 0.31). We studied 3,839 Amplified Fragment Length Polymorphism (AFLP) markers genotyped in 444 individuals from 21 populations distributed across the European continent and hence over different environmental conditions. Our statistical approach to detect markers under selection is based on a Bayesian method specifically developed for AFLP markers, which treats AFLPs as a nearly codominant marker system, and therefore has increased power to detect selection. The high number of screened populations allowed us to detect the signature of balancing selection across a large geographic area. We detected 33 markers potentially under balancing selection, hence strong evidence of stabilizing selection in 21 populations across Europe. However, our analyses identified four-times more markers (138) being under positive selection, and geographical patterns suggest that some of these markers are probably associated with alpine regions, which seem to have environmental conditions that favour adaptation. We conclude that despite favourable conditions in this study for the detection of balancing selection, this evolutionary force seems to play a relatively minor role in shaping the genomic diversity of the common vole, which is more influenced by positive selection and neutral processes like drift and demographic history.

The Quiet Eye and Information Processing: Facilitation of Stimulus Identification and Response Selection

Background: A prerequisite for high performance in motor tasks is the acquisition of egocentric sensory information that must be translated into motor actions. A phenomenon that supports this process is the Quiet Eye (QE) defined as long final fixation before movement initiation. It is assumed that the QE facilitates information processing, particularly regarding movement parameterization. Aims: The question remains whether this facilitation also holds for the information-processing stage of response selection and – related to perception crucial – stage of stimulus identification. Method: In two experiments with sport science students, performance-enhancing effects of experimentally manipulated QE durations were tested as a function of target position predictability and target visibility, thereby selectively manipulating response selection and stimulus identification demands, respectively. Results: The results support the hypothesis of facilitated information processing through long QE durations since in both experiments performance-enhancing effects of long QE durations were found under increased processing demands only. In Experiment 1, QE duration affected performance only if the target position was not predictable and positional information had to be processed over the QE period. In Experiment 2, in a full vs. no target visibility comparison with saccades to the upcoming target position induced by flicker cues, the functionality of a long QE duration depended on the visual stimulus identification period as soon as the interval falls below a certain threshold. Conclusions: The results corroborate earlier findings that QE efficiency depends on demands put on the visuomotor system, thereby furthering the assumption that the phenomenon supports the processes of sensorimotor integration.

Bargaining for power and information : an experimental and theoretical analysis of the interaction between institutions, externalities and adverse selection

Bargaining is the building block of many economic interactions, ranging from bilateral to multilateral encounters and from situations in which the actors are individuals to negotiations between firms or countries. In all these settings, economists have been intrigued for a long time by the fact that some projects, trades or agreements are not realized even though they are mutually beneficial. On the one hand, this has been explained by incomplete information. A firm may not be willing to offer a wage that is acceptable to a qualified worker, because it knows that there are also unqualified workers and cannot distinguish between the two types. This phenomenon is known as adverse selection. On the other hand, it has been argued that even with complete information, the presence of externalities may impede efficient outcomes. To see this, consider the example of climate change. If a subset of countries agrees to curb emissions, non-participant regions benefit from the signatories’ efforts without incurring costs. These free riding opportunities give rise to incentives to strategically improve ones bargaining power that work against the formation of a global agreement. This thesis is concerned with extending our understanding of both factors, adverse selection and externalities. The findings are based on empirical evidence from original laboratory experiments as well as game theoretic modeling. On a very general note, it is demonstrated that the institutions through which agents interact matter to a large extent. Insights are provided about which institutions we should expect to perform better than others, at least in terms of aggregate welfare. Chapters 1 and 2 focus on the problem of adverse selection. Effective operation of markets and other institutions often depends on good information transmission properties. In terms of the example introduced above, a firm is only willing to offer high wages if it receives enough positive signals about the worker’s quality during the application and wage bargaining process. In Chapter 1, it will be shown that repeated interaction coupled with time costs facilitates information transmission. By making the wage bargaining process costly for the worker, the firm is able to obtain more accurate information about the worker’s type. The cost could be pure time cost from delaying agreement or cost of effort arising from a multi-step interviewing process. In Chapter 2, I abstract from time cost and show that communication can play a similar role. The simple fact that a worker states to be of high quality may be informative. In Chapter 3, the focus is on a different source of inefficiency. Agents strive for bargaining power and thus may be motivated by incentives that are at odds with the socially efficient outcome. I have already mentioned the example of climate change. Other examples are coalitions within committees that are formed to secure voting power to block outcomes or groups that commit to different technological standards although a single standard would be optimal (e.g. the format war between HD and BlueRay). It will be shown that such inefficiencies are directly linked to the presence of externalities and a certain degree of irreversibility in actions. I now discuss the three articles in more detail. In Chapter 1, Olivier Bochet and I study a simple bilateral bargaining institution that eliminates trade failures arising from incomplete information. In this setting, a buyer makes offers to a seller in order to acquire a good. Whenever an offer is rejected by the seller, the buyer may submit a further offer. Bargaining is costly, because both parties suffer a (small) time cost after any rejection. The difficulties arise, because the good can be of low or high quality and the quality of the good is only known to the seller. Indeed, without the possibility to make repeated offers, it is too risky for the buyer to offer prices that allow for trade of high quality goods. When allowing for repeated offers, however, at equilibrium both types of goods trade with probability one. We provide an experimental test of these predictions. Buyers gather information about sellers using specific price offers and rates of trade are high, much as the model’s qualitative predictions. We also observe a persistent over-delay before trade occurs, and this mitigates efficiency substantially. Possible channels for over-delay are identified in the form of two behavioral assumptions missing from the standard model, loss aversion (buyers) and haggling (sellers), which reconcile the data with the theoretical predictions. Chapter 2 also studies adverse selection, but interaction between buyers and sellers now takes place within a market rather than isolated pairs. Remarkably, in a market it suffices to let agents communicate in a very simple manner to mitigate trade failures. The key insight is that better informed agents (sellers) are willing to truthfully reveal their private information, because by doing so they are able to reduce search frictions and attract more buyers. Behavior observed in the experimental sessions closely follows the theoretical predictions. As a consequence, costless and non-binding communication (cheap talk) significantly raises rates of trade and welfare. Previous experiments have documented that cheap talk alleviates inefficiencies due to asymmetric information. These findings are explained by pro-social preferences and lie aversion. I use appropriate control treatments to show that such consideration play only a minor role in our market. Instead, the experiment highlights the ability to organize markets as a new channel through which communication can facilitate trade in the presence of private information. In Chapter 3, I theoretically explore coalition formation via multilateral bargaining under complete information. The environment studied is extremely rich in the sense that the model allows for all kinds of externalities. This is achieved by using so-called partition functions, which pin down a coalitional worth for each possible coalition in each possible coalition structure. It is found that although binding agreements can be written, efficiency is not guaranteed, because the negotiation process is inherently non-cooperative. The prospects of cooperation are shown to crucially depend on i) the degree to which players can renegotiate and gradually build up agreements and ii) the absence of a certain type of externalities that can loosely be described as incentives to free ride. Moreover, the willingness to concede bargaining power is identified as a novel reason for gradualism. Another key contribution of the study is that it identifies a strong connection between the Core, one of the most important concepts in cooperative game theory, and the set of environments for which efficiency is attained even without renegotiation.