The COVID-19 pandemic presents the worst public health crisis in recent history. The response to the COVID-19 pandemic has been challenged by many factors, including scientific uncertainties, scarcity of relevant research, proliferation of misinformation and fake news, poor access to actionable evidence, time constraints, and weak collaborations among relevant stakeholders. Knowledge translation (KT) platforms, composed of organisations, initiatives and networks supporting evidence-informed policy-making, can play an important role in providing relevant and timely evidence to inform pandemic responses and bridge the gap between science, policy, practice and politics. In this Commentary, we highlight the emerging roles of KT platforms in light of the COVID-19 pandemic. We also reflect on the lessons learned from the efforts of a KT platform in a middle-income country to inform decision-making and practice during the COVID-19 pandemic. The lessons learned can be integrated into strengthening the role, structures and mandates of KT platforms as hubs for trustworthy evidence that can inform policies and practice during public health crises and in promoting their integration and institutionalisation within the policy-making processes. The world is facing the worst public health crisis in recent history. The coronavirus disease COVID-19) pandemic has directly and indirectly affected more than four million people across the globe, disrupting health systems and economies 9 pandemi.Using the best available research evidence and data to guide public health and health systems decisions is integral to an effective and efficient response in public health emergencies –4. In crOrganisations, initiatives and networks that support evidence-informedpolicy-making can play an important role in providing relevant and timely evidence to inform pandemic responses and bridge the gap between science, policy and politics. An organised form of these aforementioned entities, known as knowledge translation (KT) platforms, brings decision-makers, researchers, practitioners, civil society groups and other stakeholders together to facilitate the process of translating evidence into policy and action by aligning research topics with policy priorities, responding to pressing issues through developing policy briefs, rapid responses and evidence summaries, and convening dialogues to guide policy formulation and implementation, taking into consideration local and political context –15.The role of KT platforms in pandemic responses is more important than ever, particularly in low- and middle-income countries, where public health and health systems are already overburdened and under-resourced, thus posing additional challenges to effective response. In this Commentary, we highlight the emerging roles of KT platforms in light of the COVID-19 pandemic. We also reflect on the lessons learned from a KT platform effort in a middle-income country to inform decision-making and practice during the COVID-19 pandemic. Lessons learned can be integrated into strengthening the role, structures and mandates of KT platforms as hubs for trustworthy evidence that can inform policies and practice during public health crises.KT platforms are uniquely positioned to help facilitate a rapid evidence-informed response during public health crises in different ways, as outlined below.A key starting point to inform decision-making processes is to identify policy- and practice-relevant priorities. Engaging decision-makers in priority-setting can increase the acceptability of evidence and foster its utilisation in the decision-making process . KT platWith the rapid spread of COVID-19 around the globe, decision-makers and practitioners are also required to mount a rapid response. This necessitates timely and relevant evidence to inform prevention, control and mitigation measures. Evidence includes not only findings from research but also other forms of knowledge such as local data, surveillance data, guidelines, national and international agency reports as well as media reports [Acknowledging the tension between rigor and speed, KT platforms can harness this large body of knowledge through synthesis to inform policy and practice. Specifically, they can filter current best available evidence from unsubstantiated or non-scientifically supervised sources and combine the results of multiple relevant studies while taking into consideration the quality of studies and biases in the existing evidence base. In doing so, they can provide decision-makers and practitioners with relevant, reliable and accessible evidence syntheses that address priority issues in a timely and transparent manner.The availability of evidence is a necessary but insufficient condition for evidence-informed response during public health crisis; evidence must reach people in policy and operational positions in an actionable form and with minimal time lag and, when used, should be applied effectively . Often, KT platforms recognise that a ‘one-size-fits-all’ approach for responding to public health crises may not be appropriate and, therefore, they provide context-specific and actionable evidence to enable countries to adapt global solutions to local needs and realities. Specifically, they can produce a range of KT products by combining insights from multiple sources  in a user-friendly format and plain language and tailoring the findings to local context. To further foster the use of evidence in policies and practice, they can leverage a range of uptake activities to disseminate the products to target audience and support the use of that evidence to its full potential. Additionally, they can maintain repositories of product pipelines that can serve as a ‘one-stop shop’ freely accessible by the different stakeholders to support evidence use in a timely manner.We’re not just fighting an epidemic; we’re fighting an infodemic” – Dr. Tedros Adhanom Ghebreyesus, WHO Director General, 15 February 2020.“While infodemics (or overflow of information) are not a novel phenomenon, the speed and reach of the COVID-19 infodemic and fake news has been unprecedented . This maThe scope and intensity of public health crisis means that no single agency can work alone to effectively control and mitigate its impact. Governments need to collaborate and shape the collective response through multi-sectoral actions that involve the public, private and civil society sectors .KT platforms can facilitate the coordinated and multi-disciplinary approach needed to inform policy and practice during a public health crisis. They can provide a platform  that brings together the different stakeholders  from different sectors  to shape policy problems, increase mutual understanding of challenges faced, deliberate about policy and practice solutions , and discuss implementation considerations. They can also serve as a neutral communication channel for real-time exchange of relevant information, ideas, concerns and best practices as the crisis unfolds. In doing so, they enable stakeholder group interaction, redistribution of power resources and evidence-informed deliberations alongside contextual factors, such as values, beliefs, interests or political goals, and the strategies of the different stakeholders . ImportaDuring the 2009 H1N1 influenza pandemic, evaluations of implemented response measures were hindered by the lack of planning for this activity, political sensitivities and legal issues. Additionally, little attention was paid to the recovery phase and to the transition to seasonal influenza . This poBelow, we reflect on the experience and lessons learned so far from the Knowledge to Policy (K2P) Center, a WHO Collaborating Centre for Evidence-Informed Policymaking and Practice. Established within a university setting in Lebanon (a middle-income country), K2P Center seeks to bridge the gap between science, policy and politics by making research evidence more accessible to a broader range of stakeholders, building institutional capacities for evidence-informedpolicy-making and seizing opportunities to advocate and influence policy outcomes. The Center’s response to COVID-19 builds on years of work in raising the awareness of policy-makers, stakeholders, civil society organisations and media on the importance of evidence in informing decision-making, developing their capacities in accessing and using evidence, raising demand for evidence, building trust and establishing critical linkages. With the pandemic still unfolding, new lessons will likely emerge, making this a learning platform and an evolving living experience.During a public health crisis, decision-makers are under tremendous pressure to respond urgently to demonstrate capability and meet public health needs. The time limitation is a critical barrier to evidence use during a crisis, thus necessitating the provision of evidence in a timely manner to decision-makers. In this regard, the rapid response service presents a key element in the response to the COVID-19 pandemic. It can respond to urgent requests from decision-makers and stakeholders by delivering relevant and high-quality evidence in short periods of time, ranging from 3 to 30 days. Rapid response products use systematic and transparent methods to search, synthesise and appraise the existing evidence base (giving precedence to existing systematic/rapid reviews when possible) while tailoring the implications to local context in order to support policy and systems decisions. They also utilise user-friendly formats and plain language to facilitate the uptake of evidence in decision-making.KT platforms should have the capability and flexibility to switch to rapid response mode during a crisis and tailor their suite of services to address the various aspects of the response. Operationalising the rapid response service is facilitated by the presence of Standard Operating Procedures and templates for preparing and disseminating rapid response products, the availability of a team with appropriate sets of skills and expertise, access to relevant databases, and flexibility in funding to re-orient human, financial and material resources to respond to the pandemic.At the time of crisis, KT platforms must rapidly position themselves as credible hubs that provide trustworthy evidence to policy-makers, stakeholders, citizens and media. This can be achieved by actively demonstrating the value of the platform early on rather than taking a back seat and waiting for people to turn to them for information. When the crisis hit Lebanon, the K2P Center launched the K2P COVID-19 Series Initiative and the first policy-relevant document produced in that series cemented and reinforced K2P’s role as a trusted reference centre for evidence and guidance related to COVID-19. At the downstream level, the K2P Center activated the ‘K2People’ initiative to educate and raise awareness of citizens and media about the virus and its mode of transmission as well as to address scepticisms and misconceptions through social media platforms. As part of the ‘K2People’ initiative, we sought to target vulnerable groups that are mostly affected by the COVID-19 pandemic such as smokers, cancer patients, elderly population, refugees and low socio-economic workers. We also tackled mental health problems affecting adults as well as children as a result of the COVID-19 pandemic. The abovementioned two initiatives also provided a clear portal for communicating COVID-19 information, which can be accessed for free by all relevant and interested stakeholders.Importantly, KT platforms must maintain their credibility throughout the crisis by demonstrating a high degree of responsiveness to priorities and needs, remaining objective, truthful and politically neutral, and ensuring transparency in the evidence and recommendations generated. This is particularly relevant for KT platforms established independently or within an academic institution where trust is a pre-requisite to interacting with such platforms.Decision-makers’ needs for evidence can vary, depending on the context, type of stakeholder, resource availability, or the specific phase of the pandemic cycle in a given country . To imprMoreover, given the high level of uncertainty associated with such a pandemic, there is a huge appetite for evidence to guide decision-making at all levels. This presents a critical opportunity for KT platforms to not only respond to decision-makers’ priorities and needs, but to also proactively shape the policy agenda by bringing important (often overlooked) issues to the attention of decision-makers. This requires KT platforms to remain vigilant of changes in the health system, closely monitor social media  and keep abreast of how the COVID-19 situation is unfolding at the international level. Anticipating the types of needed decisions can help KT platforms prioritise and prepare ahead of time in order to ensure a more timely response to emerging priorities.Furthermore, given the scale and breadth of COVID-19, a top-down approach will likely fail to achieve the desired impact; organisations, initiatives and networks that support evidence-informedpolicy-making can help balance top-down with bottom-up approaches by catering to the needs not only of governments and policy-makers but also of policy implementers, including municipalities, healthcare providers, civil society organisations and communities. For the latter groups, the lack of clarity on their roles and responsibilities may hinder their involvement in the pandemic response. To overcome this, the K2P Center produced a number of evidence-based guidance documents specifying the roles of the different actors and the link to the national pandemic response. These guidance documents played a role in empowering the different actors and prompted government to strengthen its stewardship function for a more effective and efficient response.During pandemics, evidence-informeddecision-making may be challenged by scientific uncertainties and scarcity of research, especially during the early phases of the crisis. Conventionally, systematic reviews and randomised controlled trials are considered the gold standards for informing decisions on what works. However, in crisis situations, evidence is needed to address a broad range of questions beyond what works. Moreover, the ‘best’ evidence, i.e. the most valid and reliable evidence, may not be available, yet decisions have to be made fast and under great uncertainty. In many instances, there may only be a single case study or an observational study available, rendering these the best available evidence. Furthermore, indirect evidence becomes particularly valuable during the early phases of the pandemic when there is limited research directly addressing COVID-19. Under such circumstances, turning to indirect evidence from closely related viruses like influenza, SARS (severe acute respiratory syndrome) or Ebola virus may be necessary to inform policy response. As such, KT platforms should aim for the best available evidence while acknowledging the tension between rigor and speed; waiting until more research and better data become available may risk decisions being made with no evidence at all due to time constraints.Unfortunately, evidence at time of crisis is scattered around different databases, journals, websites and in the grey literature . TherefoThe emergence of international initiatives like the COVID-19 Evidence Network to support Decision-making (COVID-END) partners, which are compiling COVID-related evidence from partners around the world in one repository, is a much needed step in addressing the fragmentation of the evidence base and reducing the duplication of efforts. Establishing similar initiatives at the country level is much warranted.The highly dynamic trajectory of the COVID-19 pandemic and the large number of intertwined health, social and economic factors associated with it mean that no single entity can provide all the needed support for a comprehensive response to the pandemic. Researchers, public health specialists, guideline developers, epidemiologists, data analysts and evaluation experts from both health and non-health sectors are all generating relevant and timely evidence to inform the various aspects of the pandemic — from controlling the spread of virus to assessing the effectiveness of public health and social interventions to evaluating the impact on health and the economy. Yet, the absence of a mechanism to bridge the different entities can result in ad hoc, fragmented and delayed engagement, which can undermine the efficiency and effectiveness of the pandemic response.The COVID-19 pandemic has exposed the deficiencies of siloed approaches to informing decision-making processes and re-enforced the need to build bridges to the organisations, institutions and networks working in complementary areas to inform decision-making related to different aspects of the pandemic. Moving forward, it is critical to establish mechanisms for coordinating and integrating research, data and expertise across stakeholders and sectors in transparent ways for a more effective policy response during pandemics.Dissemination of the evidence to target the right audience is crucial to achieve the desirable impact. In a time of pandemic, where conventional dissemination methods like policy dialogues may not be feasible, it is critical for KT platforms to innovate and leverage multiple dissemination channels suited to the context and audience at the right time.Social media is an increasingly important platform to disseminate evidence from research and knowledge translation products during pandemics . KT platThe response to the COVID-19 pandemic has been challenged by many factors, including scientific uncertainties, scarcity of relevant research, proliferation of misinformation and fake news, poor access to actionable evidence, time constraints, and weak collaboration among relevant stakeholders. This Commentary highlighted the emerging roles of KT platforms in light of the COVID-19 pandemic. The COVID-19 experience is an opportunity to amplify the roles of KT platforms and position them as the go-to hubs for trustworthy evidence that can inform policies and practice during public health crises. The lessons learned reflected in this Commentary can be integrated into strengthening the role, structures and mandates of KT platforms.In the post COVID-19 era, it is expected that much of the global and national efforts will focus on strengthening public health systems. Organisations, initiatives and networks supporting evidence-informedpolicy-making are an integral and indispensable component of strengthening public health systems and preparedness response; therefore, one of the best investments in the future is to invest in strengthening these entities to support a more proactive and swift response to public health crises that utilises the best available research evidence and data in a timely manner. This calls for countries, governments, science communities and funders to start investing in KT platforms in different regions through securing adequate resources and supporting capacity-building in KT through education and training programmes and, more importantly, promoting their integration and institutionalisation within the policy-making processes. This is particularly relevant in the context of low- and middle-income countries, where the utilisation of evidence in decision-making is still limited and challenged by the lack of importance given to evidence, the poor communication between researchers and decision-makers, corruption, insufficient training, institutional constraints and weak mechanisms to support evidence-informeddecision-making , 29.


Although the non-invasive measurement of visually evoked responses has been extensively studied, the structural basis of variabilities in latency in healthy humans is not well understood. We investigated how tissue properties of optic radiation could predict interindividual variability in the latency of the initial visually evoked component (C1), which may originate from the primary visual cortex (V1). We collected C1 peak latency data using magnetoencephalography (MEG) and checkerboard stimuli, and multiple structural magnetic resonance imaging (MRI) data from 20 healthy subjects. While we varied the contrast and position of the stimuli, the C1 measurement was most reliable when high-contrast stimuli were presented to the lower visual field (LVF). We then attempted to predict interindividual variability in C1 peak latency in this stimulus condition with a multiple regression model using MRI parameters along the optic radiation. We found that this model could predict >20% of variance in C1 latency, when the data were averaged across the hemispheres. The model using the corticospinal tract did not predict variability in C1 latency, suggesting that there is no evidence for generalization to a non-visual tract. In conclusion, our results suggest that the variability in neural latencies in the early visual cortex in healthy subjects can be partly explained by tissue properties along the optic radiation. We discuss the challenges of predicting neural latency using current structural neuroimaging methods and other factors that may explain interindividual variance in neural latency. Although the temporal properties of visually evoked responses has been studied extensively, the structural basis of variabilities in latency measured in healthy humans is not well understood. Here we tested how the properties of the optic radiation could predict interindividual variability in the latency of the initial visually evoked component (C1). We found that magnetic resonance imaging (MRI) measurements on the optic radiation could partly predict interindividual variability in C1 latency, while MRI measurements on the corticospinal tract did not. Overall, our work demonstrates that variability of neural latency in the early visual cortex of healthy humans can be partly explained by neuroimaging measurements of tissue properties along the optic radiation, although there are remaining challenges to explain latency variabilities from structural neuroimaging.Non-invasive measurement methods, such as electroencephalography (EEG) and magnetoencephalography (MEG), have been widely used to quantify the temporal properties of human cortical responses . One of Neurobiological studies suggested that the signal transmission efficiency (conduction velocity) along a long-range axon depends on the microstructural properties of white matter, such as the morphologic properties of the myelin sheaths or axons . We hypoRecent advances in non-invasive structural magnetic resonance imaging (MRI) and tractography have in part enabled us to measure the tissue properties of white matter and the trajectory of the major white matter pathways. Computational modeling of diffusion-weighted MRI (dMRI) signals provides a variety of structural measurements, ranging from those using a simpler diffusion tensor model  to thoseThe visual system is an excellent model system to test a hypothesis concerning microstructural measurements in white matter and functional measurements of neural latencies because both the anatomy of the white matter tract and the major evoked response components are relatively well understood. Moreover, recent advances in tractography algorithms have improved sensitivity for identifying the optic radiation, which carries signals from the lateral geniculate nucleus (LGN) to the V1, from a dMRI dataset . The optTo this end, we collected visually evoked response data using MEG and structural data for the optic radiation using dMRI and qT1 from 20 healthy subjects. We analyzed how measurements in the optic radiation may predict the interindividual variability of C1 latencies. The goal of this study was to test the extent to which MRI-based tissue measurements along the optic radiation could predict interindividual variability in C1 peak latency to understand the extent to which non-invasive structural measurements can explain variability in neural latency in the early visual cortex.Twenty healthy volunteers  participated in the study. All subjects had a normal or corrected-to-normal vision. dMRI, qT1, and MEG data were collected on different days. The study protocol was approved by the local ethics and safety committees at Center for Information and Neural Networks (CiNet), National Institute of Information and Communications Technology (NICT), and conducted in accordance with the ethical standards stated in the Declaration of Helsinki. Written informed consent was obtained from all study subjects.We collected T1-weighted MRI, dMRI and qT1 data from all subjects. We note that many parts of MRI acquisition method is common to those used in our previous works .https://surfer.nmr.mgh.harvard.edu/; We obtained T1-weighted magnetization-prepared rapid gradient-echo (MP-RAGE) images  from all subjects using a 3T SIEMENS Prisma/Trio scanner at CiNet, NICT to estimate the border between white matter and gray matter. The acquisition of T1-weighted MRI data took around 15 min for each subject. The tissue segmentation was performed using an automated procedure implemented in FreeSurfer software (3) implemented in a multiband accelerated EPI pulse sequence provided by the Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota (https://www.cmrr.umn.edu/multiband/). The diffusion weighting was isotropically distributed along six directions at b = 300 s/mm2, 30 directions at b = 1000 s/mm2, and 64 directions at b = 2000 s/mm2. Eight non-diffusion-weighted (b = 0) images were acquired per image set. To minimize EPI distortion, two image sets were acquired with reversed phase-encoding directions (anterior-posterior and posterior-anterior). The entire dMRI data acquisition took around 25 min for each subject.We measured dMRI data from all subjects. All dMRI data were acquired using the 3T Magnetom Prisma scanner (Siemens) with a 32-channel head coil at CiNet, NICT. The dMRI data were acquired using monopolar single-shot echo-planar imaging  with a 32-channel head coil at CiNet, NICT and the protocols described in previous publications . We acquIn a magnetically shielded room, we measured visually evoked responses from all subjects using a 360-channel whole-head MEG system  at CiNet, NICT. The MEG system consists of 204 planar gradiometers, 102 magnetometers, and 54 additional sensors for noise reduction. Magnetic signals were recorded at a sampling frequency of 1000 Hz. Both planar gradiometers and magnetometers were used for the analysis.https://github.com/hiroshiban/Mcalibrator2). The projector spanned 27.6 × 20.7° of the visual angle (1024 × 768 resolution) and had a 60-Hz refresh rate. The viewing distance was 61 cm. Subjects who used glasses wore plastic correction lenses during all MEG measurements. All stimuli were generated using the MATLAB programming environment (MathWorks) and the Psychophysics Toolbox 3 routines  on a translucent screen in a magnetically shielded room. Gamma correction on the LCD projector was performed using Mcalibrator2 software  changed. The change in the fixation color occurs randomly during each session, with no systematic relationship to stimulus onset or offset. On average, the fixation color changed 61.9 times during each session. The subjects were able to respond to a change in the fixation color within 1 s on 86.4% of occasions on average.We note that many parts of MRI data analysis pipeline are common to those used in our previous works .dMRI images were corrected for susceptibility-induced distortions using FSL TOPUP  based onhttp://www.mrtrix.org/; http://mig.cs.ucl.ac.uk/index.php?n=Tutorial.NODDImatlab) to obtain orientation dispersion index (ODI) and intracellular volume fraction (ICVF) maps.We fitted the diffusion tensor model to the dMRI data using iteratively reweighted linear least squares estimation  implemenWe identified the optic radiation using a dedicated method  in MATLAB to compute the qT1 map. In brief, qT1 maps were calculated based on variable flip angles which were corrected for B1 excite inhomogeneity based on the unbiased SEIR data  method  using MaWe used the single-ECD model to estimate the cortical origin of C1 from MEG signals, using the xfit tool (Elekta Neuromag Oy). We chose the single-ECD model because it is an adequate method for the localization of the magnetic field generated by a single localized source, such as in the context of early sensory or motor evoked responses , as compR) of C1 peak latency between the odd and even trials in four stimulus conditions . We estimated the 95% confidence intervals of the correlation coefficient by bootstrap resampling with 10,000 repetitions. Bootstrap analysis was conducted by using the MATLAB Statistics and Machine Learning Toolbox.We assessed C1 latency measurement’s test-retest reliability by separating MEG data in each stimulus condition into odd and even trials . We estimated the C1 dipole separately for odd and even trials using a single-ECD model and identified the C1 peak latency. The C1 latencies identified for left and right visual field presentations were averaged. Finally, we evaluated the degree of test-retest reliability by measuring the interindividual correlation  based on previously reported methods . Brieflyach node . We exclc):We fitted a multiple linear regression model in which C1 peak latency was predicted by the linear weighted sum of five MRI parameters  along the optic radiation with a constant  across the measured C1 latency and the C1 latency predicted from a multiple linear regression model.Leave-one-out cross-validation was used to evaluate how well the models predicted C1 peak latency. Specifically, we divided the data from all subjects into 19 training datasets and one test dataset to evaluate how much each model could predict C1 latency in a subject that was not included in the model fitting phase. We iterated this procedure 20 times by changing the selection of the test dataset. We evaluated the accuracy of the model by calculating a Pearson correlation coefficient . We then calculated the percentile of the original correlation coefficient with respect to the distribution of the correlations calculated over the 10,000 permutations. This percentile is reported as the p value, which is the likelihood of randomly acquiring the original correlation value.We also evaluated the statistical significance of the model prediction using a permutation test. We randomly shuffled the association between MRI measurements and C1 peak latency across all subjects 10,000 times. After each shuffle, we performed a model prediction from MRI measurements to C1 peak latency using a multiple linear regression model and leave-one-out cross-validation to obtain a correlation coefficient . The code was written in MATLAB and tested in MATLAB 2015a on Ubuntu 14.04 LTS.The code for reproducing figures and statistical analyses in this work is publicly available online via a public repository .First, we evaluated the extent to which the properties of C1 depend on the stimulus conditions used in our MEG experiment . F = 12.59, p = 0.0007), while the main effect of visual field (upper or lower) and the interaction between contrast and visual field were not  = 1.30, p = 0.26; interaction between contrast and visual field; F = 0.70, p = 0.41), suggesting that C1 latency was significantly delayed in the low-contrast condition.To evaluate how much C1 latency depends on the stimulus condition, we performed two-way ANOVA on the C1 peak latency data (with contrast and stimulus position as main effects). We found that the main effect of contrast was significant  = 48.17, p < 0.0001), while the main effect of contrast was only marginally significant  = 3.37, p = 0.07). The interaction between visual field and contrast was not statistically significant  = 0.77, p = 0.38). This result suggests that the amplitude of the C1 response was significantly larger for the stimuli presented at the LVF as compared with those presented at the UVF. A larger C1 response for LVF stimuli is consistent with previous reports  or low/high-contrast stimuli presented at the UVF  and identified the C1 peak latency in each condition. We observed the highest test-retest reliability of C1 latency when high-contrast stimuli were presented at the LVF  in interindividual variability of C1 latency . The result for this most reliable condition suggests that the interindividual variability of C1 peak latency can be at least partly explained by variability in tissue properties along the optic radiation. The prediction accuracy for other stimulus conditions was variable .In the main analysis, we used five MRI parameters to predict the variabilities in C1 latency. We sought to identify MRI parameters that contributed to predicting C1 latency in the LVF/high-contrast condition. To this end, we calculated n = 10) and slower (n = 10) C1 peak latencies. Group differences in each parameter were not significant (t(18) = 1.00, −0.19, −0.96, and −0.60; p = 0.33, 0.85, 0.35, and 0.56 for FA, MD, ODI, and ICVF), suggesting that individual parameters may not be sufficient for C1 peak latency prediction. Meanwhile, small group differences were found mostly in the middle to posterior part of the optic radiation (closer to V1), suggesting that voxels along the straight portion of the optic radiation may contribute to C1 peak latency prediction.To understand which part of the optic radiation contributed to the prediction of the C1 peak latency, we also calculated how much the spatial profile of MRI parameters depended on C1 peak latency. R = 0.48; R = 0.46), consistent with insignificant contribution of qT1 shown above. The full model outperformed the other models using a subset of parameters  or different scanning sequences (dMRI or qT1). We further tested how much variance in C1 peak latency under the LVF/high-contrast condition could be predicted by a subset of MRI parameters. We compared the performance of the full model using all five parameters with that of three reduced models using a subset of parameters A. The peR = 0.39) but did not outperform the full model used in the main analysis (R = 0.51). Therefore, while we did not find evidence that information on streamline length improves the prediction accuracy for C1 peak latency, there remains a possibility that some structural properties of the gray matter (V1) may provide further information relevant to predicting C1 latency.Finally, we compared the performance of the model when including either the tract length (mean optic radiation streamline length) or the CT of the V1 as an explanatory variable in addition to the MRI parameters . These results suggest that the prediction accuracy observed in the optic radiation cannot be generalized to a non-visual white matter tract.The corticospinal tract model did not significantly predict interindividual variability of C1 peak latency in the LVF/high-contrast condition  stimulation . A lacR = 0.51, 0.85, 0.54, 0.72 and 0.78 for FA, MD, ODI, ICVF, and qT1, respectively; R = 0.14; R = 0.91; left LVF/high-contrast, R = 0.94) such that the hemispheric differences in C1 peak latency are reproducible, rather than a product of unstable MEG measurements. These findings suggest that the lack of hemispheric specificity might be due to the fact that MRI measurements are correlated across hemispheres while MEG measurements are not. This may be a simple consequence of the fact that MRI measurements have insufficient sensitivity to be able to identify interhemispheric latency differences, since some estimates of MRI measurements in a single hemisphere may be noisy given a relatively lower interhemisphere correlations in FA and ODI or a larger confidence interval of interhemisphere correlation in ICVF  as an explanatory variable in the model but did not find any improvement in prediction accuracy (see Results). A potential limitation of this approach is that streamlines only approximate the trajectory of fiber bundles and are not true axons, so may not fully capture interindividual variability in length of the optic radiation fibers. Indeed, fibers in the optic radiation may change their position along the tract , and it Peak latency measured using MEG or EEG may reflect build-up process of local field potential but does not directly reflect the response latency of spiking activity in single-neuron electrophysiology. Such a response profile may involve multiple physiological factors, such as summation of local synaptic activity across neurons  or the dA number of anatomical, electrophysiological, and neuroimaging studies have demonstrated the existence of feedback signal from the extrastriate cortex to the V1 . A studyPrevious studies have demonstrated delayed visually evoked responses in patients with demyelinating diseases, such as multiple sclerosis . More reN = 20) used to elucidate interindividual variability, which may have limited the statistical power of the study. However, in addition to a limitation in statistical power, there are several existing challenges to current non-invasive MRI and MEG methods for establishing associations between structural measurements in white matter pathways and measurements of neural response latency in humans.This study did not provide evidence of generalization across all different stimulus conditions  and of hIn addition to the issues related to the signal qualities in the optic nerve and optic tract, as discussed above, dMRI measurements have limited spatial and angular resolution. Improved measurement methods may improve our ability to assess the properties of tissue in the visual white matter pathways without influence of a partial volume effect with other neighboring pathways or cerebrospinal fluid. Furthermore, improved dMRI data acquisition method may improve the accuracy of tractography on the optic radiation . There adMRI-based tractography is an excellent approach to identifying trajectories of major white matter pathways like the optic radiation . HoweverMEG measurements also pose challenges in terms of comparison with dMRI and qT1 data. For example, if we could obtain reliable peak latency measurements from the LGN, we could calculate the conduction velocity from the LGN to V1 for comparison with the tissue properties of the optic radiation. While a recent study has reported that the early peak of a visually evoked response can be localized to the LGN , it is dWe may also need to improve biophysical models to better understand the relationship between MRI measurements and underlying white matter microstructure. While microstructural modeling of MRI data for the corpus callosum has been successful , generalFinally, although peak latency is fairly reproducible and widely mentioned in the literature, the extent to which peak latency could represent the neuronal response latency in the visual system is debatable. For example, a limitation of peak latency is that it does not distinguish between a signal that starts early and rises slowly and a signal that starts late and rises rapidly . ModelinIn conclusion, we found that individual differences in latency of the early visually evoked response in humans can be partly explained by the differences in tissue along the optic radiation. Although the model using tissue properties of the optic radiation explained >20% of variance in C1 peak latency, other factors may need to be incorporated into the model to improve our understanding of the structural-functional relationship in the early visually evoked response in humans.


Wellbeing science is the scientific investigation of wellbeing, its’ antecedents and consequences. Alongside growth of wellbeing science is significant interest in wellbeing interventions at individual, organizational and population levels, including measurement of national accounts of wellbeing. In this concept paper, we propose the capability model of wellbeing literacy as a new model for wellbeing science and practice. Wellbeing literacy is defined as a capability to comprehend and compose wellbeing language, across contexts, with the intention of using such language to maintain or improve the wellbeing of oneself, others or the world. Wellbeing literacy is underpinned by a capability model , and is based on constructivist  and contextualist  epistemologies. The proposed capability model of wellbeing literacy adds to wellbeing science by providing a tangible way to assess mechanisms learned from wellbeing interventions. Moreover, it provides a framework for practitioners to understand and plan wellbeing communications. Workplaces and families as examples are discussed as relevant contexts for application of wellbeing literacy, and future directions for wellbeing literacy research are outlined.  Wellbeing science is the scientific investigation of wellbeing, its antecedents and consequences. Alongside the growth of wellbeing science has been significant interest in wellbeing interventions at individual, organizational and population levels, including measurement of national accounts of wellbeing. We assert that to achieve population-based wellbeing, a ubiquitous systemic lever is required, and that language use represents such a lever. The central focus of this article addresses how language can be intentionally used to cultivate and sustain wellbeing over time and across contexts. Intentional language use is one mechanism by which individuals learn, define and ultimately influence their own wellbeing. Dominant discourses affect private and public conceptions of wellbeing, leading to potential impacts on individual’s levels of thriving. In this context, the questions ‘how do people communicate about and for wellbeing?’ and ‘why does it matter?’ are central.Hence, we propose the concept of wellbeing literacy , definedLanguage provides insights into wellbeing experiences . Over reLanguage is also ubiquitous and therefore has broad, systemic effects on human social experiences. People actively construct meanings in their experiences through language ,15,16. TAs a communication system, language is a vehicle for transporting ideas and thoughts between people and processing information within one’s own head . HoweverThese ideas are consistent with Linguistic Relativity Theory (otherwise known as the Sapir–Whorf Hypotheses ), which In addition, studies have shown that individuals can intentionally change their experiences by using language in certain ways, showing that intentional use of language can improve wellbeing of the self . For example, Pennebaker and Seagal found that writing about important personal experiences using more positive emotion words improved mental and physical health . King deBroadening this idea further, it is important to pay attention to not only one’s own language, but also to the language that is used to generate discussion about important matters in society—otherwise known as dominant discourses. ‘Discourses’ here refers to ways in which social groups think about various aspects of society, and often come from social institutions, such as education, media and politics. Academics in social constructionism ,18 and cDiscourses arise within contexts and are often only relevant in that specific context. This is consistent with contextualist theories, which argue that behaviours and phenomenon are best understood in their relevant context ,31. ContThis discussion of contextualisation is directly applicable to learning for wellbeing. If ideas about wellbeing are taught and learnt too rigidly, there is the risk of people not knowing what to do when contexts change, or of applying information that is not useful for the new context. Contemporary literacy researchers have arrived at similar ideas about the relevance of context, power and meaning-making to the concept of literacy, with contemporary views of literacy recognising (a) the importance of multiple modes of communication  ; (b) theWhen narrowly defined, literacy has traditionally meant the “ability to read and write”  (p. 79).All people are capable of acquiring literacy.Literacy is a human right and is a fundamental part of the human experience.Literacy is not a trait that resides solely in the individual person. It requires and creates a connection (relationship) with others.Literacy includes communication, contact and the expectation that interaction is possible for all individuals; literacy has the potential to lead to empowerment.Literacy is the collective responsibility of every individual in the community; that is, to develop meaning making with all human modes of communication to transmit and receive information.The underlying principles of the more recent developments in literacy theory contribute to our work on wellbeing literacy. Keefe and Copeland summarised five core principles of literacy, which we follow in our conceptualising of wellbeing literacy :All peopThe concept of literacy is critical in many areas of life, such as families, communities, workplaces and healthcare settings. As such, its importance has been increasingly noticed by many non-literacy scholars  and in vA number of intellectual and disciplinary fields contribute to the concept of wellbeing literacy as depicted in We define wellbeing literacy as: “the capability of comprehending and composing wellbeing languages, across various contexts, that may be intentionally used to maintain or improve the wellbeing of oneself, others or the world”. By ‘language’ we mean ‘multimodal symbolic systems’, which may be alphabetic, pictorial, visual, aural or combinations of these. The symbolic systems often comprise of vocabulary, grammar and sentence structure, and this understanding of language is aligned with the theory of multiliteracies . By ‘useThere are five components to this definition, as shown and outlined in more detail in First, wellbeing literacy requires vocabulary, knowledge and language skills relevant to wellbeing. Individuals need some proficiency in wellbeing vocabulary  and wellbeing knowledge . Second, individuals need to be able to comprehend multimodal texts relevant to wellbeing including reading, listening and viewing . In contThird, wellbeing literacy requires composition of multimodal texts relevant to wellbeing, including writing, creating, and speaking . SimilarFourth, we discussed earlier the role of context in wellbeing. By ‘context’, we mean the who, where and when of the language use. Contemporary views frame literacy as a social construct; people develop ‘literacies’ in contexts outside of schools. These other contexts can be physical in nature  or digital in nature  . There aPeople with high wellbeing literacy are aware of differences across contexts and adapt their language to fit the situation in front of them. They recognise that how they communicate to a 12-year-old about and for their wellbeing, is going to be different to how they communicate to a 60-year old, and these would also be differ for each depending on the context . The meaning of words, for example, may also vary by context. Hence, the metacognitive skill of adjusting to context is part of being wellbeing literate.Finally, wellbeing literacy must involve some degree of intentionality—ongoing intention to improve and/or maintain the wellbeing of self, others or the wider world . This asA further way to understand intentionality is the idea of being mindful. Although a full analysis of mindfulness is beyond the scope of this paper, by ‘mindful’ we mean being aware of why language is used in certain ways, and intentionally adapting the use of language to meet the needs of certain contexts. Literacy is not only an autonomous and neutral skill , it is aTo summarise, five components interact to create wellbeing literacy as shown in capability [Importantly, wellbeing literacy is presented as a pability ,3,4 and The Capability Approach (CA) ,3,4 is a‘Functionings’ are capabilities realised—the endpoint of capabilities. Functionings are the things that people seek to ‘be and do’ that are valuable to them, and as such people have multiple functionings in their lives. Sometimes referred to as ‘achievements’, functionings can be elementary in nature  or more complex . According to the CA, the central feature of wellbeing is the opportunity to achieve valuable functionings. Being educated, riding a bike, eating lunch, are all examples of various ways that a person can value to ‘be or do’, in that they are observable expressions of wellbeing. A key strength of the Capability Approach is that unlike other economic models, it recognises the limitations of focusing on resources or achievements (functionings) as measures of a society’s wellbeing. For example, Alkire notes that:“the limits of focusing on achievements for assessing quality of life becomes obvious when considering cases where a low observed functioning  reflects a choice (as in the case of fasting), or where a high level of functioning reflects the choice of a benevolent dictator”  (p. 5). Similarly, the CA recognises that resources are a limited measure of wellbeing as they are only useful if they are able to be ‘converted’ into meaningful wellbeing achievements. In the CA, capabilities (opportunities) allow that conversion to take place. For example, Indira might be given access to a bike (resource), but in order to be able to ride that bike (functioning), Indira would need to have the capability to ride the bike. That capability would be affected by various factors—for example, safe roads to ride on, appropriate attire to ride the bike, and opportunity to safely leave the house. do with the environmental conditions that are available to them. In these terms, the capability is closely related to the concept of agency [The Capability Model of Wellbeing Literacy presents wellbeing literacy as a mediator (or moderator) in the wellbeing experience; a capability  that influences the experience of wellbeing. Wellbeing literacy allows individuals options of what to f agency . The higf agency . This isOur model also draws from the Engine of Wellbeing Model , which wthrifa, refers to ‘taking hold of the environment’. In this sense, the use of the capability is thriving, as it is taking hold of the internal or external environments, through language use, to achieve a wellbeing experience for self or others, or flourishing of a physical environment.The internal environmental conditions that will influence wellbeing literacy, and therefore also wellbeing, may include attributes of a person, for example, genetics, physiology and personality. External environmental conditions may include, but are not limited to, the social environment , economic and educational environments  and physical environments . The original notion of thriving, from To provide an example, John wants to experience love/connection with a person (wellbeing experience) because he feels this will be important to his wellbeing. He might be fortunate enough to have access to a community of people . However, his chances of experiencing love are reduced if he does not have wellbeing literacy capabilities around listening and communicating his needs. He may not have many relationship-building skills , and he also may not have access to different modes of communication  that would help him establish connections. Through the development of wellbeing literacy skills, combined with the environmental conditions of a good community, John can realise the capability resulting in wellbeing experiences related to loving connections. The capability model of wellbeing literacy, as per Various contexts, such as workplaces, families, schools , Wellbeing in the workplace has become of greater interest in recent years  and partFamilies can provide a natural and rich environment in which to develop and support wellbeing literacy. Gee suggests that primary ‘Discourses’ are developed early in life and within the family through our interactions with parents, siblings and those closest to us . Gee difUsing the Capability Model of Wellbeing Literacy, capability to family wellbeing  could be the capacity for a parent to actively listen. Listening is a generalised ‘wellbeing comprehension’ capability within the Capability Model of Wellbeing Literacy. There is ample evidence that listening builds deep positive relationships in families ,73,74 anHow do laypeople define and construct wellbeing through language ,82,83?How does wellbeing literacy relate to wellbeing now and over time?How do we increase wellbeing literacy ?Is wellbeing literacy a reactive approach, remedial approach, or a preventative approach, or a combination of these?What are the limits of wellbeing literacy?Is wellbeing literacy a mediator and/or moderator of wellbeing interventions .The research program of wellbeing literacy has examined both the concept, such as this paper, and how to measure wellbeing literacy . FurtherThe capability of language-use (literacy) about and for wellbeing has been introduced as wellbeing literacy. By combining literatures from wellbeing science, literacy, capability approaches, constructivism and contextualism, the multi-components of wellbeing literacy are proposed as the capability model of wellbeing literacy. This concept paper has outlined its formal elements to undergird and complement empirical and practice contributions.


This multidisciplinary consensus review summarizes the literature, and proposes recommendations for the perioperative care of patients undergoing total hip replacement and total knee replacement with an ERAS program.Background and purpose — There is a large volume of heterogeneous studies across all Enhanced Recovery After Surgery  over another will independently effect achievement of discharge criteria.® Society presents a comprehensive consensus review, for the perioperative care of patients undergoing total hip replacement and total knee replacement surgery within an ERAS® program. This unified protocol should now be further evaluated in order to refine the protocol and verify the strength of these recommendations.Interpretation — Based on the evidence available for each element of perioperative care pathways, the ERAS Over the last 15 years, the systematic implementation of an evidence-based perioperative care protocol (“fast-track” or “enhanced recovery pathway”), such as that developed by the Enhanced Recovery After Surgery (ERAS) Society, has shown that hospital length of stay and complications can be reduced for a number of surgical procedures  to present an updated and expanded consensus review of perioperative care for hip and knee replacement based on current evidence.This article represents the efforts of the ERAS Society , which includes Medline, CINAHL, Science Direct, PsycINFO, and Cochrane Database of Systematic Reviews databases. Whilst ERAS has evolved over the last 10–15 years, for completeness the peer-reviewed and English-language literature was systematically reviewed from January 1966 to October 2018. We appreciate that evidence from ERAS studies is evolving at a fast rate and so future studies may impact on findings; however, the recommendations presented are considered to reflect evidence at the time of writing (January 2019). Preoperative, surgical, anesthetic and analgesia, postoperative, and rehabilitation topics were searched. Reference lists of eligible articles were also reviewed for other relevant studies. Key words included “hip replacement,” “hip arthroplasty,” “knee replacement,” “knee arthroplasty,” “hip prosthesis,” “knee prosthesis,” and additional keywords were added depending on the topic.The authors screened titles and abstracts to identify potentially relevant articles, and reference lists of eligible articles were hand-searched for relevant studies. Systematic reviews, meta-analyses, randomized controlled trials, and non-randomized trials were considered for each topic, unless there were few papers identified, in which case all papers were screened. Qualitative studies were also considered in specific areas, where “hands on” experience of ERAS was described. We consider that although these do not qualify as high-level evidence, they provide valuable evidence on issues such as how patients perceive the ERAS pathway, and the role that nurses play. We carefully reviewed the final literature selected, and any discrepancies were resolved through group consensus. Studies in ERAS or fast-track set-ups showing improvements in the achievement of discharge criteria, or reducing length of stay, or having a positive effect on complications were targeted.The overall quality of evidence was assessed using criteria developed by the Centre for Evidence Based Medicine at Oxford, England. Possible levels of evidence included “high” , “moderate” , or “low” . In line with ERAS guidelines for other surgical procedures  the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system was used to evaluate the quality of evidence and recommendations . RecommePreoperative patient education has not been shown to independently affect postoperative outcomes, such as accelerating the achievement of discharge criteria, but it has been found to reduce preoperative anxiety across a number of systematic reviews . However, the association between current and former smoking and a substantially higher risk of postoperative complications and mortality post-surgery has level 1 evidence Singh . There iSummary/recommendation—4 weeks or more smoking cessation is recommended before hip and knee replacementEvidence level—HighRecommendation grade—StrongA large retrospective study found that hip and knee replacement patients who misused alcohol had a longer length of stay and were more likely to have medical and surgery related complications  has been proposed as an intervention to expedite discharge Recommendation grade—StrongRecent anesthetic guidelines indicate that the intake of clear fluids until 2 hours before surgery does not increase gastric content, reduce gastric fluid pH, or increase complication rates. Therefore, the intake of clear fluids until 2 hours before the induction of anesthesia as well as a 6-hour fast for solid food is recommended Recommendation grade—StrongSedative or anxiolytic drugs may be used to promote patient comfort and/or facilitate the successful completion of technical procedures such as spinal anesthesia. However, their use is not universal and side effects may include postoperative sedation. There are minimal data available (for or against) to support the preoperative use of sedative or anxiolytic medication to reduce anxiety and accelerate the achievement of discharge criteria .In general, large multi-center cohorts of exemplar ERAS hip and knee replacement pathways favor neuraxial techniques over general anesthesia, and this change in practice has been at the core of established ERAS pathways , moderate Recommendation grade—StrongThere has been considerable interest in the use of opioids as an addition to local anesthetic in spinal anesthesia for hip and knee replacement. Whilst spinal opioids have been shown to lower pain scores and analgesic use , moderate (negative safety and side-effect profile)Recommendation grade—StrongLocal infiltration analgesia (LIA) has an advantage over nerve blocks, because it produces no motor blockade. This can allow for earlier safe ambulation with a reduction in the side effects associated with both nerve blocks and epidural analgesia, where hypotension and urinary retention can cause additional problems.Concerns with LIA have been raised regarding potential risks of local anesthetic toxicity, wound healing, and infection  is distressing for patients and can lead to notable patient morbidity and an associated prolonged length of hospital stay. In general, female gender, a past history of motion sickness or PONV, and being a non-smoker are all risk factors for PONV  have been described for hip and knee replacement. Simple systemic techniques such as the addition of a high-dose preoperative glucocorticoid to multimodal regimes have been shown to be safe and effective in knee and hip replacement  use following hip and knee replacement Recommendation grade—StrongERAS programs emphasize the desire to minimize the use of opioids postoperatively and utilize alternative forms of analgesia. Nevertheless, their use when required is routinely reported in exemplar ERAS centers Husted . The effCurrently, opioid analgesics are used if needed within the immediate postoperative period. They can be used to enable a smooth transition from peripheral techniques  to non-opioid analgesia. The choice of opioid and method of delivery has been debated. Several studies investigated the use of controlled-release (CR) oxycodone following hip and knee replacement. Equivalency of analgesic effect has been demonstrated  recommends the pre-warming of patients and to maintain the active warming of all adults undergoing surgery throughout the intraoperative phase (NICE 2016). Multiple series suggest that normothermia should be targeted as part of the anesthetic care of hip and knee replacement patients. There are many methods described to conserve body temperature, including pre-warming and humidification of anesthetic gases, warming IV and irrigation fluids, and forced air-warming blankets and devices. However, the use of forced air-warming is not recommended as there is evidence that this is associated with an increased risk of infection  and pulmonary embolism (PE), which can lead to post-thrombotic syndrome (PTS) or death . Maintaining fluid balance is, therefore, a prominent component of general surgical ERAS pathways. However, due to limited intraoperative blood and fluid loss and the early intake of postoperative oral fluids, the term “effective fluid management” remains ambiguous in lower limb primary replacement. We are aware of only 1 study on fluid management on an ERAS pathway for total knee replacement .Care should be taken to detect and avoid electrolyte imbalance including hyponatremia Sah . IntraveSummary and recommendation—It is recommended that intravenous fluids should be used judiciously and postoperative intravenous fluids discouraged in favor of early oral intakeEvidence level—ModerateRecommendation grade—StrongUrinary catheters have been used routinely for longer surgical procedures to monitor urinary output and guide fluid resuscitation (Huang et al. Summary and recommendation—The routine use of urinary catheters is not recommended and when used they should be removed as soon as the patient is able to void, ideally within 24 hours after completion of surgery. A catheterization threshold of 800 mL should be used to reduce the need for postoperative urinary catheterizationEvidence level—ModerateRecommendation grade—StrongNo studies have investigated the direct association of early feeding or postoperative nutritional supplementation with the accelerated achievement of discharge criteria. However, return to normal food intake is considered an essential component of ERAS protocols in order to achieve return to normal behaviors. Early return to normal diet is a central component of all exemplar ERAS pathways, with units encouraging patients to eat and drink as soon as they feel able.Summary and recommendation—An early return to normal diet is recommended and should be promotedEvidence level—LowRecommendation grade—StrongPatients should be mobilized as soon as possible following surgery. Outpatient surgery is now established for 13–15% of unselected patients, and patients are routinely discharged on the first and second postoperative day (Gromov et al. Summary and recommendation—Patients should be mobilized as early as they are able to in order in order to facilitate early achievement of discharge criteriaEvidence level—StrongRecommendation grade—StrongA feature of exemplar hip and knee replacement ERAS pathways is that patients are discharged directly to their home and that objective discharge criteria are used. These criteria clearly define the requirements for going home from hospital, and are typified by including elements such as the ability to dress independently, the ability to get in and out of bed, the ability to sit and rise from a chair/toilet, the ability to be independent with personal care, and independent mobilization with walker/ crutches, and the ability to walk > 70 m with crutches (Husted et al. Summary and recommendation—Objective discharge criteria should be used to facilitate patient discharge directly to their homeEvidence level—LowRecommendation grade—StrongThe continual review of clinical practice and outcomes is a critical component of ongoing quality improvement in healthcare. Experience from other ERAS procedures indicates that the relative effectiveness of audit and feedback is likely to be greater when baseline adherence to recommended practice is low (Gustafsson et al. Summary and recommendation—Routine internal and/or external audit of process measures, clinical outcomes, cost-effectiveness, patient satisfaction/experience, and changes to the pathway is recommendedEvidence level—LowRecommendation grade—StrongThis document outlines the recommendations of the ERAS Society for the perioperative management of patients undergoing hip and knee replacement surgery, and summary details are provided in The aim is to provide a starting point for implementation for teams new to ERAS, and as a point of reflection for experienced ERAS teams to examine their current practice. These guidelines, and the testing of their implementation, as has been performed in other ERAS procedures, will hopefully allow us to consolidate consensus within the evidence base, and generate new evidence, through systematic prospective data collection and through clinical trials.Future work should focus on reaching the goal of the “pain and risk free” hip and knee replacement. In order to do this, we will need to better understand the pathophysiological mechanisms of recovery, and the potential to optimize post-discharge functional outcomes (Wainwright and Kehlet More specifically, work is still required in order to understand how to reduce the inflammatory response postoperatively; how to further reduce pain; how to reduce impairment of physical activity and improve function quicker postoperatively; how to better identify patients at high risk of complications owing to psychiatric disorders, chronic renal failure, and orthostatic intolerance; anemia and transfusion thresholds; postoperative urine retention and urinary bladder catheterization; and how to improve sleep (Wainwright and Kehlet TW—Consulting contracts with: Medtronic, ZimmerBiomet. Department/research funding from: ZimmerBiomet, Stryker, Lima Corporate.MG—No relevant conflicts of interest.DM—No relevant conflicts of interest.RM—Consulting contracts with: Stryker, ZimmerBiomet. Department/research funding from: ZimmerBiomet, Stryker, Lima Corporate.MR—Speakers’ Bureau: Heraeus, ZimmerBiomet, Stryker. Research funding: Heraeus Medical GMHB, ZimmerBiomet, 3M, Curetis GMHB, Vifor Pharma, Schuelke. Other financial/material support: Stryker, ZimmerBiomet, Heraeus, Biocomposites, Aquilant, Depuy, Smith & Nephew, Bone and Joint Infection Registry.OS—No relevant conflicts of interest.PY—Consulting contracts with: DepuySynthes, Zimmer, Global, Palacos, Corin, Matortho. Designer for: MatOrtho, Global Orthopaedics, Zimmer, Synthes, Corin. Department/research funding from: DepuySynthes, Zimmer, Global, Smith & Nephew, Stryker, Matortho.OL—Co-founder of and Chairman of the Executive Committee of the ERAS Society. Founder and shareholder in Encare AB, Advisor to Nutricia, NL; Advanced Medical Nutrition, Can. Speaker’s honoraria and travel support from Nutricia, Fresenius-kabi, BBraun, Merck, Medtronic, and Baxter.


Analysis of the thermal properties and tensile strength showed that the highest critical concentration of organoclay was 0.50 wt%.Poly (amic acid) s (PAAs) were synthesized using 4,4′-(hexafluoroisopropyl-idene) diphthalic anhydride (6FDA) and two types of diamines—bis(3-aminophenyl) sulfone (BAS) and bis(3-amino-4-hydroxyphenyl) sulfone (BAS-OH). Two series of transparent polyimide (PI) hybrid films were synthesized by solution intercalation polymerization and thermal imidization using various concentrations (from 0 to 1 wt%) of organically modified clay Cloisite 30B in PAA solution. The thermo-mechanical properties, morphology, and optical transparency of the hybrid films were observed. The transmission electronic microscopy (TEM) results showed that some of the clays were agglomerated, but most of them showed dispersed nanoscale clay. The effects of -OH groups on the properties of the two PI hybrids synthesized using BAS and BAS-OH monomers were compared. The BAS PI hybrids were superior to the BAS-OH PI hybrids in terms of thermal stability and optical transparency, but the BAS-OH PI hybrids exhibited higher glass transition temperatures ( Polyimide (PI), which has been used for a long time, was mainly studied for military purposes when it was first developed ,2. It haRecently, PI has been applied as an integrated material for semiconductor materials such as liquid crystal display (LCD) and plasma display panel (PDP) because of its low weight and its ability to improve electronic products. In addition, PI, which is lightweight and flexible, has been extensively studied for use in flexible plastic display substrates to overcome disadvantages such as heavy weight and tendency of shattering of glass substrates used in the field ,7,8.Although PI is a high-performance polymer material with excellent properties, including high thermal stability and good mechanical properties, chemical resistance, and electrical properties, it does not meet the basic requirements for display applications. Many synthesized PIs are insoluble and infusible and thus have poor processability. Therefore, efforts are now being made to improve these optical properties and the processability of PI. For example, PIs containing trifluoromethyl groups have been synthesized that show a high modulus, low thermal expansion coefficient, and good solubility in conventional organic solvents ,10,11. A2-) is required that can effectively introduce a bending structure which can interfere with the interaction between the PI main chains, thus aiding in the fabrication of a PI film with high transparency. For example, a -CF3 group, which is a strong electron-withdrawing group, is often used as a substituent, or bent monomer structures are used to prevent CT complexes from being formed in linear structures [PI is dark brown because electrons forming the double bonds in the benzene in the imide structure are transferred to the charge carriers of the π electrons generated by intermolecular bonding between the chain transfer complex (CT-complex) ,15. To rructures ,17.It is also possible to improve the processability of PI films by introducing couplers with small polarity and free rotation in the main chain or by introducing bulky substituents to reduce the crystallinity and molecular packing density ,19,20.Among various layered inorganic materials used as nanofillers, clay has a layered structure with ionic bonds and Van der Waals forces acting between the layers. Clay has platelets with a thickness of 1 nm and a width of 100–1000 nm ,22. In gIn this study, the diamine monomers—bis(3-aminophenyl) sulfone (BAS) and bis(3-amino-4-hydroxyphenyl) (BAS-OH)—were allowed to react with 4,4′-(hexafluoroisopropyl (6FDA)) as a dianhydride to synthesize two PIs. PI hybrids were prepared from the synthesized PIs and Cloisite 30B as an organoclay. Cloisite 30B is hydrophilic because it has -OH groups. Furthermore, it is expected that the affinity of this clay will increase if it is blended with PI containing -OH groups. BAS-OH containing a hydroxyl group can enhance the reactivity, dispersibility, and compatibility between the synthesized PI and clay.In this study, the thermo-mechanical properties, morphology, and optical transparency of the PI hybrids with various concentrations of organoclay (from 0 wt% to 1.00 wt%) were investigated, and their results were compared. We also described the effect of -OH groups in PI hybrids and compared the properties of the two PI hybrids synthesized using BAS and BAS-OH diamine monomers.Cloisite 30B was purchased from Southern Clay Product, Co. Most solvents used in this study were purchased from Daehan Chemical . 6FDA, BAS, and BAS-OH were purchased from TCI  and Aldrich Chemical Co. . DMAc was purified with 4Å molecular sieve and stored for water absorption treatment.−2 mol) and DMAc (30 mL) were placed in a flask and stirred at 0 °C for 1 h while supplying nitrogen. A solution of 6FDA  in DMAc (40 mL) was added to the BAS-OH/DMAc solution. This solution was stirred at a moderate speed at 25 °C for 14 h to synthesize a PAA solution having a solid content of 15.5 wt%. The inherent viscosities of the synthesized PAAs of BAS and BAS-OH were 1.02 and 0.94, respectively. The total 15.5 wt% PAA solution produced by this method was 77.62 g. When 0.39 g of Cloisite 30 B was added to the solution, the total solution weight was 78.01 g.Because the synthesis procedures of the two PAAs using BAS and BAS-OH diamine monomers are the same, only the method of fabricating BAS-OH PAA will be described here. BAS-OH  as a representative example will be described here. We first added 0.064 g of Cloisite 30 B, 13.0 g of PAA solution, and DMAc (20 mL) to a flask and vigorously stirred the mixture at room temperature for 3 h. The solution was also washed in an ultrasonic cleaner for 3 h, and the solvent was removed in a vacuum oven at 50 °C for 2 h. The obtained PAA film was dried in a vacuum oven at 80 °C for 1 h to completely remove the solvent.The PAA film was further imidized on the glass plate by sequential heating at 110 °C, 140 °C, and 170 °C for 30 min at each temperature, followed by 50 min at 195 °C and 220 °C each. Finally, the reaction was completed by heat treatment at 235 °C for 2 h.The thickness of the heat-treated film was approximately 67–70 µm. 13C chemical shifts for the BAS and BAS-OH were obtained using 13C cross-polarization/magic angle spinning nuclear magnetic resonance (CP/MAS NMR) at Larmor frequencies of ω0/2π = 100.61 MHz using Bruker AVANCE II+ 400 MHz NMR spectrometers  at the Korea Basic Science Institute, Western Seoul Center. The chemical shifts were referenced to tetramethylsilane (TMS). Powdered samples were placed in a 4-mm magic angle spinning (MAS) probe and the MAS rate was set to 10 kHz to minimize the spinning sideband overlap.The Differential scanning calorimeter (DSC) was measured using a NETZSCH DSC 200F3  instrument, and thermogravimetric analysis (Auto TGA 1000) was performed on a TA instrument  at a heating rate of 20 °C/min. Both DSC and TGA were operated under nitrogen conditions. The thermal expansion coefficient (CTE) of the film was obtained using a macroexpansion probe (TMA-2940) with a 0.1-N expansion force at a heating rate of 5 °C/min and a temperature range from 50 °C to 150 °C.Wide angle X-ray diffraction (XRD) values were obtained on a Rigaku  (D/Max-IIIB) X-ray diffractometer using Ni-filtered Cu-Kα radiation at room temperature. The scanning speed was 2°/min in the 2θ range = 2–12°. Transmission electron microscopy (TEM) photographs of ultra-thin sections of PI hybrid films containing various concentrations of Cloisite 30B were obtained using a Leo 912 OMEGA TEM  at an accelerating voltage of 120 kV. The yellow index (YI) value of the polymer film was measured using a Minolta spectrophotometer , and UV-Vis spectral results were obtained using Shimadzu UV-3600 .The tensile properties of the films were measured using an Instron  mechanical tester (Model 5564) with a crosshead speed of 20 mm/min at room temperature. Experimental errors of the obtained tensile strength and elastic modulus were within ± 1 MPa and ± 0.05 GPa, respectively. Average values of at least 20 samples were finally used for analysis.−1. C-N-C peaks indicating the imidization of the polymers were observed at 1377 cm−1. The spectrum of the BAS-OH monomer, the primary amine -NH2 was observed at 3374 cm−1, and the -OH peak was also observed at 3225 cm−1. In addition, C=C aromatic stretch. Peaks appeared at 1746, 1667, and, 1536 cm−1, respectively.−1. The -OH peaks in BAS-OH were smaller than typical hydroxyl peaks. The O-H stretching absorption of the hydroxyl group is sensitive to hydrogen bonding. Molecules with hydrogen donors and acceptors capable of intramolecular hydrogen bonding in the PI main chain show a broad O-H stretching absorption in the range from 3000 to 3500 cm−1. The spectrum of the BAS-OH polymer in −1 [In the BAS-OH polymer, the peak of O-H stretching was observed at 3324 cmer in −1 . These r13C CP/MAS NMR [13C chemical shifts of the BAS polymer were obtained at room temperature. The chemical shift for carbon in 4, 4′-hexafluoroisopropylidene (HFP) was present at 65.38 ppm, as shown in 3, and the chemical shift of C=O was 165.23 ppm. The resonance peak for the carbon in 4,4′-hexafluoroisopropylidene (HFP) had a smaller intensity. The spinning sidebands are marked with an asterisk. The chemical shifts for all carbons were consistent with the structure shown in Structural analyses of the BAS and BAS-OH polymers were carried out by solid state /MAS NMR . The 13C3. In addition, the 13C chemical shift at 157.74 and 165.94 ppm corresponding to C-OH and C = O, respectively, was consistent with the structure shown in On the other hand, the chemical shift for carbon in 4,4′-hexafluoroisopropylidene (HFP) in the BAS-OH polymer was present at 64.99 ppm, as shown in In both the hybrids, we found that clay was very uniformly distributed in the PI matrix regardless of the clay concentration. This denotes that the clay layers in the hybrid material are homogeneously dispersed in the PI matrix ,30.XRD is a useful technique for measuring d-spacing in dispersed clay layers of hybrids. In particular, studies using small-angle X-ray scattering can provide detailed information on composites. Schneider et al.  reportedDirect evidence regarding the formation of nano-sized composites can be confirmed via TEM of an ultra-microtomed section. TEM was used to more accurately measure the dispersion of clay layers in PI hybrids. Hydrophilic clay has good affinity with PI synthesized with BAS-OH monomers, which include an -OH group. Thus, good affinity of clay and PI can result in excellent dispersion. The TEM results of the BAS-OH hybrid are shown in gTs of PI hybrid films containing BAS monomer increased gradually from 227 °C to 245 °C as the clay content increased from 0 wt% to 0.50 wt%. This increase in gT is caused by the difficulty of movement of the inserted polymer chains in the clay layer, which results in difficulty in segmental motion [gT of the PI hybrid increased when organic clay content was increased to a certain critical concentration but decreased when the critical concentration was crossed. For example, when Cloisite 30 B was increased to 0.75 wt%, the gT of the PI hybrid decreased to 240 °C, and, when the organoclay content of PI reached 1.00 wt%, the gT further decreased to 236 °C.l motion ,35. HowegT increased from 259 °C to 270 °C. However, when the organoclay content was increased to 1.00 wt%, gT decreased to 257 °C. This reduction in gT was because of the agglomeration of excess clay above the critical concentration in the PI matrix. The trends exhibited by PI hybrids containing BAS-OH monomers were similar to those exhibited by PI hybrids containing BAS. When Cloisite 30B content was increased from 0 wt% to 0.50 wt%, gT is affected by various factors in addition to the critical concentration of the filler. That is, the gT of a polymer depends on the structural differences within the chain, chemical interactions such as hydrogen bonding and curing reaction, the chain flow according to the free volume, and the presence of additives [gT values of the PI hybrids—BAS and the BAS-OH— and those of the two monomers were compared, the gT value of the BAS-OH PI hybrids were found to be higher than those of the BAS PI hybrid, regardless of the concentration of organic clay. In addition, when the gT values of the hybrids with the same Cloisite 30 B concentrations were compared, the gT value of BAS-OH was found to be higher than that of BAS. These results show that the -OH groups of the BAS-OH monomers increase the dispersibility and compatibility of the monomers through hydrogen bonding with the -OH groups present in the clay, thereby increasing the gT values of the PI hybrids. Similar results have been obtained in previous studies [In general, dditives . When th studies ,38.TDi) of the PI hybrid film containing BAS monomer according to the concentration of the organoclay. As Cloisite 30 B content increased from 0 wt% to 0.50 wt%, the TDi value of the PI hybrids increased gradually from 456 °C to 533 °C  were almost the same regardless of the clay loading, as shown in R600wt was 79–84%. However, when the content of Cloisite was 0–1.00 wt%, the value of R600wt was almost constant at 60–62% for PI containing BAS-OH.3 °C see . This su6 °C see . The valTDi and R600wt values of the two different PIs containing BAS and BAS-OH monomers. The BAS hybrid showed an overall better thermal stability than the BAS-OH PI hybrid regardless of the concentration of Cloisite 30 B. These values conflicted with the gT results. This result can be explained by the weak thermal stability of the -OH group present in the main PI chain containing BAS-OH. In the curve of We compared the The CTE of the BAS PI hybrids decreased to the minimum at the critical content of 0.50% clay but then increased when the concentration of organoclay increased to 1.00% by weight. For example, the CTE of both PI hybrids decreased from 47.21 ppm/°C to 38.48 ppm/°C when the clay concentration increased from 0 wt% to 0.50 wt% but increased to 45.92 ppm/°C when the clay concentration increased to 1.00 wt%. The CTE values of the PI hybrids according to different organoclay concentrations are summarized in gT and TDi results previously described , and the obtained results are summarized in However, the initial modulus increased steadily with increasing organoclay concentration. As the concentration of Cloisite 30 B increased from 0 wt% to 1.00 wt%, the tensile modulus increased steadily from 2.24 GPa to 3.54 GPa for the BAS PI hybrid and from 2.80 GPa to 6.16 GPa for the BAS-OH PI hybrid. In contrast to the results of ultimate tensile strength, this improvement in the initial tensile modulus of the two hybrids was due to the high aspect ratio and orientation of the clay layer as well as the resistance of the clay itself to external forces ,48.We compared the mechanical properties of the two PI hybrids and those of the BAS and BAS-OH monomers. The mechanical properties of BAS-OH hybrids were better than those of the BAS hybrids regardless of the concentration of organoclay. This tendency was in contrast to the tendency of thermal stability and CTE. This result is attributed to the formation of a hybrid film with stronger bonds that can withstand external tensile forces because the hydroxyl groups between PI and organoclay form hydrogen bonds with each other. The elongation at break of the two hybrid films was almost constant regardless of the organoclay concentration. That is, when the organoclay content increased up to 1.00 wt%, the elongation at break varied from 2% to 4% see . This re0) using UV-Vis. absorption spectra, as shown in 0 increased steadily from 330 nm to 346 nm and from 344 nm to 350 nm, respectively. PI hybrids showed a small λ0 value because they have a -CF3 substituent and a kinked monomer structure that can reduce the interactions between the CT-complexes and the intermolecular interaction in the polymer main chain [The color intensity can be determined by measuring the cut-off wavelength , diamines (BAS and BAS-OH), and various concentrations of organoclay by solution intercalation. The PI hybrid films containing -CFgT and mechanical properties, BAS-OH hybrids showed better performance than BAS hybrids. However, BAS hybrids were superior to BAS-OH hybrids in terms of thermal stability, CTE, and optical transparency over the range of organoclay concentrations. The thermal properties and ultimate strengths of the two PI hybrid films were highest when the organic clay was 0.5 wt%.In this study, the PI hybrids synthesized using BAS and BAS-OH as diamines were compared with each other according to various Cloisite 30 B concentrations. In terms of In addition, these PI hybrid films are expected to be useful as high-performance polymer materials because of their excellent thermo-mechanical properties and optical transparencies as compared with general engineering plastics.


Before a medicine can be recommended for a marketing authorization research must be provided to regulators that convincingly supports the benefit‐risk of the product in the claimed indication. The established criteria for such research are usually expressed in terms of evidence from randomized controlled trials (RCT). If studies in real‐world data (RWD) are to be accepted as all or part of the package of evidence, it is necessary to understand the relationship between information from studies of RWD and that from RCTs. The aim of this review is to consider how the strength of such evidence can be quantified in a manner that relates to the decision‐making process, what research is currently available to further this understanding and what additional information will be required. Availability of large quantities of observational data from clinical practice and health insurance systems has prompted suggestions of a potential role in supporting regulatory assessment of drug effectiveness.In order to protect public health, regulators must understand the reliability of the evidence underlying their decisions.Analyses of observational data are prone to biases that necessitate empirical evaluation.Large‐scale experiments to measure errors in observational studies are already under way and will inform decisions on how the results of such studies can be used by regulators.Additional work will be required to ensure that the design of future studies conform to validated standards and that their conduct can be verified by regulators.1A responsibility of drug regulators is to check that evidence supports a favorable benefit‐risk profile throughout the product lifecycle. An early step in this process is to ensure that ineffective medicines never enter the market. The way that they do this is through evaluation of the research evidence supplied to them by the company wishing to market the product. This raises the question of what type of evidence is sufficient to allow the regulator to be confident of its decision. Regulators might like to require overwhelmingly convincing evidence but, as in all decision processes, there is a balance to be considered. If we demand extremely strong evidence the data will be difficult and very time‐consuming to collect and, consequently, the entry of good products into clinical practice may be delayed and their cost increased. Conversely, if we ask for too little evidence products with little clinical effect will slip through the net. These considerations highlight the fact that we need to be able to clearly define what we mean by “strength of evidence” and specify how it can be evaluated with respect to any chosen type of research.Most of us have an idea of what we mean by strength of evidence. Strong evidence is that which predisposes us to believe a fact firmly while weaker evidence leaves us with more doubt. However, such subjective notions are unsatisfactory for drug licensing: a formal decision‐making process that must apply equitable and verifiable standards across manufacturers and maintain the standards over time. One approach is to specify precisely the type and quantity of research that must be presented in support of a marketing authorization application and the nature of the results of that research that we would consider to support the conclusion that the drug is a useful medicine. Up till now this approach has proved to work for most drug licensing applications and, following much debate in the 1980s and 90s, the requirements have usually been phrased in terms of randomized controlled trials (RCT) which are formal experiments with dedicated data collection processes. However, other forms of study exist and some attention has lately been given to studies using observational data collected for purposes other than research, often in clinical practice or as part of the reimbursement process. These data are a subset of real‐world data (RWD). For regulatory definitions of RWD and a useful discussion of the strengths and challenges it is worth reading Beaulieu‐Jones.Fortunately, at the highest level, the characterization of strength of evidence is relatively simple. As discussed, practical decision processes are never perfect and their imperfections result in occasional incorrect decisions. In the case of drug authorization process, a proportion of drugs that do not have the intended clinical effect will be granted licenses—the false positive rate (FPR)—and a proportion of products that do work will be refused—the false negative rate (FNR). Thus, the problem of maintaining the same strength of evidence reduces to keeping the same FPR and FNR no matter what form of evidence is used. More details of these concepts can be found in the literature on statistical decision theory.2For a substantial majority of marketing applications pivotal RCTs are expected.Of course, studies using observational data are already occasionally accepted in clinical areas where RCTs are difficult. In this respect, Banzi3Although it is customary for more than one study to be submitted in support of any application to market a product, it is worth thinking first about single studies. Unfortunately, the error rates are not easily calculable in studies using observational data. Moreover, in contrast with RCTs, there is no way to reduce them to any chosen value. One reason for this difficulty is that patients who receive a treatment tend to differ from those who do not. Often this is because treatments in clinical practice are given preferentially to patients who appear to need them, and these patients are systematically different from untreated patients. When we see differences in outcome between treated patients and untreated patients, we ask whether the differences are due to the treatment or to natural differences between the patient groups. Of course, this has been known for many years and the fact that such bias complicates all observations in “real life” was exactly the reason that randomization has become the preferred approach to scientific research where the allocation of interventions can be controlled by the researcher.Although it is difficult to determine the strength of evidence from observational studies, there are good reasons to use such data in many areas of research and effort has been invested in developing methods to control the bias in study results. The existence of such methods and the reliance placed on this research in some important and difficult areas such as criminal justice, education, social work, road safety, environmental policy and not least, in drug safety, raises the question of whether this type of research could play a more important role in deciding which patients can be treated with a medical product for a given disease.4Some observational researchers acknowledge the doubt surrounding the question of strength of evidence and have attempted to address it using scientific methods. As a prelude, we should consider what has been observed with respect to past studies.Why most published research findings are false.In 2005, John Ioannidis published an essay called Can the methods when used according to best practice provide the required strength of evidence?Can regulatory guidelines be designed and enforced in a manner that assures adherence to best practice?Two questions arise in relation to use of new methods in drug development:The first of these questions is currently being studied by a number of researchers and we have selected two large projects, in particular, as important examples of ongoing effort.Following on from 21st Century Cures Act the U.S. FDAThe FPR is a matter of more immediate concern to regulators than the FNR. Licensing ineffective medicines could do substantial damage to patients as it might delay receipt of effective treatment or simply prolong suffering while unnecessarily exposing patients to potentially harmful effects. A major investigation of false positives in observation studies under highly standardized conditions—avoiding many of the problems discussed by Ioannidis—has been carried out using the ATLAS systemAre these results promising or not as regards reaching the desired strength of evidence for regulatory decision making? The answer is not straightforward. Schuemie's study suggests that some appreciable control of the FPR is possible. However, when differences between the three data sources and between outcomes are investigated significant systematic variation is detectable.As noted above, we also need to understand how the error rates from different studies can be combined into single values. The arguments are quite complex but, once again, theoretical methods are used for multiple RCTs that become more complex for observational studies because different studies of the same drug and outcome will tend to exhibit similar biases. These biases cannot be theoretically predicted but must be estimated from data. The recent development of very large and detailed repositories of clinical data make this a realistic, if not simple, proposition.5The methods discussed above to evaluate strength of evidence from observational studies could be applied to any study design. This article cannot go into detail about the possible types of study and the many fundamental design choices that must be made when implementing them. It suffices to say that much additional research effort is devoted to selection of methods that seem likely to reduce error probabilities. A promising idea is that designs should stay as close as possible to a notional RCT. Specific cases based on this ideaComplex study designs pose an interesting challenge for regulators. Generalization of empirical evaluations of error rates to future studies requires that the population of studies evaluated are substantively similar to new studies and this requires standardized and verifiable principles for study design. Further work is needed to standardize any chosen approach for regulatory purposes.6The variation in results, some of which may depend on choices made by the researcher, brings us back to the second regulatory concern. Can we ensure adherence to best practice? In addition to random assignment of treatments, formal trials frequently include a control treatment superficially indistinguishable to the test product, defined procedures for data collection and prespecified outcome measures, analysis plans, and success criteria. All these features have a role in avoiding unintentional and intentional bias in the results. The question of how and at what stage bias might enter an observational study will need to be thought through in equal detail and processes designed to ensure control of the bias.As an example, consider that most observational studies are run on data that have already been collected. In safety studies, this is a major advantage as the hypotheses have usually arisen recently and hence the data could not have been influenced by the hypothesis and a swift answer can be obtained as no further data collection is needed. By contrast, prospective indications for a medicine are often identified at an early stage of development. Thus, questions arise about whether knowledge of these planned indications affected collection of data in patients receiving the drug. This might sound unlikely, but it is a question frequently asked when safety problems have been known for some time; could this knowledge have differentially affected the recording of the event with the specific drug in comparison to alternative treatment. Regulatory control of this issue is difficult.Ioannidis points out that false positives in observational studies appear more common when vested interests are present. This raises the matter of how selection of outcome measures, analytic techniques, and data collection procedures may be protected from selection designed to enhance a desired result. The measures discussed above work well with RCTs but are often impossible in observational study. If data have already been collected, it is difficult to ensure that an analysis plan and outcome measures have been designed in ignorance of the data.Questions such as these will require careful thought and currently it is probably fair to say that the scientific evaluations such as those described above are somewhat in advance of the regulatory discussions and guideline production that will be necessary to support extension of the use of observational data to licensing decisions. However, this is probably justified when we are not yet at the stage of deciding that appropriate strength of evidence can be obtained even under ideal circumstances. In order to make this decision, we need to fully characterize the levels of FPR achievable and the factors that affect it, and then to work carefully through implications of various approaches to the research on the final decision processes. It may be a long road.7The preferred strength of evidence for routine licensing applications was vigorously debated in the 1980s and 1990s. Even so, it can be an uncomfortable area for open debate as it requires recognition that no decision process can ever guarantee perfect results. Even with current licensing practice, occasional recommendations for revocation for lack of efficacy occur, for example, Xigris in the European UnionThe authors declare no conflict of interest.The views expressed in this article are those of the authors and should not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.