The present increase of attention toward blockchain-based systems is currently reaching a tipping point with the corporate focus shifting from exploring the technology potential to creating Distributed Ledger Technology (DLT)-based systems. In light of a significant number of already existing blockchain applications driven by the Internet of Things (IoT) evolution, the developers are still facing a lack of tools and instruments for appropriate and efficient performance evaluation and behavior observation of different blockchain architectures. This paper aims at providing a systematic review of current blockchain evaluation approaches and at identifying the corresponding utilization challenges and limitations. First, we outline the main metrics related to the blockchain evaluation. Second, we propose the blockchain modeling and analysis classification based on the critical literature review. Third, we extend the review with publicly accessible industrial tools. Next, we analyze the selected results for each of the proposed classes and outline the corresponding limitations. Finally, we identify current challenges of the blockchain analysis from the system evaluation perspective, as well as provide future perspectives. Historically, blockchain systems were designed to support the data immutability among different decentralized nodes . This niDeloitte’s Global Blockchain Survey highlighted that the perception of the blockchain is presently reaching the point of no return, with the corporate focus shifting from exploring the technology potential to creating production business applications . As one Given the enormous interest in blockchain-based solutions, the number of startups is increasing yearly in both private and public sectors ,12. FromA recent survey of business leaders in Europe  showed tCryptocurrencies, and more specifically, Bitcoin, tend to be some of the first and central applications of the broadly known blockchain paradigm, receiving much more attention than other blockchain use cases. As of the third quarter of 2019, Bitcoin reached a high market capitalization of $205.4 billion U.S. dollars [As a result of the deep blockchain systems’ penetration into our everyday lives, the number of distributed node interactions is expected to increase significantly , bringinTo date, there is still a lack of unified tools and instruments for the performance evaluation and behavior observation of blockchains, while the number of related applications is already sky high . Blind dThe main research question highlighted in this paper is:This paper also aims at future prospects of blockchain simulation/modeling approaches, as well as at surveying existing solutions utilized for blockchain systems’ performance evaluation. It aims to provide an overview of existing strategies found in the literature, as well as in open access sources in order to provide the linkage between the approach and solved task or its general area.The rest of the paper is organized as follows. The next section provides the applied critical review methodology. In order to identify the key publications on the evaluation of blockchain technology, we performed a literature search in scientific databases following PRISMA guidelines  with minIn total, we gathered a set of 1432 potentially relevant publications, excluding grey literature and pre-prints. We removed potential duplicates and arrived at 960 resources. We then analyzed the titles, keywords, and abstracts of the publications to identify papers and articles that described at least one modeling or simulation approach for blockchain-based systems. In doing so, we selected a total of 44 publications. To further extend our literature sample, we analyzed the references of the selected publications for additional papers or articles relevant to our research. Following this process resulted in a total of 63 publications. Finally, we analyzed publicly-available solutions proposed by the actual blockchain developers and arrived at a total of 71 publications.Once the literature selection process was completed, we carefully read the selected sources to identify the described strategies and challenges. Next, we classified the extracted approaches into five general groups.This section elaborates on the identified approaches presently used for the blockchain evaluation from analytical, simulation, and emulation perspectives. The majority of modern software systems rely on numerous practical and theoretical approaches for their performance evaluation. Nonetheless, Software Development Life Cycle Models (SDLC) fall short in providing the necessary flexibility for describing blockchain systems still keeping the priority of the initial performance evaluation before the actual system deployment, as well as followed by continuous reevaluation and testing . Since tToday, simulations and analytical modeling are standard instruments for the behavior and performance evaluation of the majority of blockchain-based solutions . At the Simulation models could be either a pure but simplified simulation of the system behavior or, more often, could be considered as a subclass of mathematical models. In this case, the simulation would combine both mathematical and logical aspects of the system and try to replicate a real-life system behavior using computer software. Simulation tends to be used in cases when the analytical description cannot be formulated, or creating an analytical model is fundamentally impossible. Simulation attempts to approximate a system’s behavior and development over time by running a model . Those mMore broadly, computer simulation tries to approximate the system behavior and development over time by implementing and running a computer simulation model. By changing variables and conditions in the implemented simulation model, researchers can make predictions about the behavior of the simulated system without the need for the actual implementation of the entire system. A computer simulation is commonly used when it is a complicated task to accomplish the system emulation and for emulating the blockchain system as part of more complex environments .According to , the simBesides analysis and simulations, we can consider a standalone group of approaches used for the blockchain performance evaluation: the emulation of the entire or part of the system. It is the process of imitating the behavior that can be observed from the outside to match an existing target. The emulation mechanism’s internal state does not need to reflect the internal state of the emulated system accurately. On the other hand, simulation involves modeling the internal state of the analyzed system, i.e., the output of a good simulation is that the simulation model will emulate the simulated system. Emulators, therefore, require significant overhead to run the emulated interface and/or system’s functionality in real-time while providing the layers of virtualization needed to emulate a whole system. As a consequence, emulation seems to be more accurate in comparison with simulation but requires much computational resources to achieve it at the same time.Currently, the field of basic modeling theory of blockchain systems is still in its infancy, including but not limited to constructing mathematical models, providing security and performance analysis, and identifying potential optimization points. In order to identify the publications primarily addressing blockchain modeling, we performed a search on a range of scientific databases that cover the high-quality computer science journals and conferences. Based on the literature review, we divided blockchain evaluation approaches into the following classes see : queuingIn order to better understand the reasons behind the need for blockchain evaluation, this section outlines the main metrics of interest and evaluation strategies applied in this process. To date, the academic literature lacks explicit analysis of the strategies due to the nascent field of research.Generally, any blockchain-based system could be analyzed from various perspectives: usability, block analysis, functional testing, security analysis, integration, smart contracts, DApps, networks, and especially, performance evaluation, which is the main focus of this paper. Performance testing allows us to analyze the network size, and its ability to process transactions is critical, as it provides an opportunity to identify hardware and software bottlenecks in advance in addition to future Operational Expenses (OPEX). Performance-wise, the operation of a blockchain could be described by the set of the main metrics that could be classified into three main groups, as summarized in Most of the metrics have the lower/average/upper bounds defined by the system configuration, network, or hardware limitations. Thus, developers should carefully consider those during the system design phase, while the numbers usually found in the project descriptions may be somewhat speculative, e.g., tps could not be measured in an objective way since it will require analysis on all the blockchain nodes, which is mostly unfeasible in a real-life environment. Similar problems could be found at lower levels, i.e., being related to the distributed P2P network operation. The heterogeneity of the communication environment, as well as unpredictable node distribution, may have an extensive impact on the metrics of interest, including block delivery and transaction validation times. Notable for enterprise (mainly private) blockchains is the specific definition of system metrics, e.g., a developer might measure transaction latency on public blockchains as when a transaction is available on 80% of nodes. However, for widely used enterprise consensus mechanisms, the threshold will often be set to 100%.In truth, blockchain developers should consider the following metrics during the system design since the adjustments of already deployed distributed ones may be very challenging or even impossible.This section outlines the main academic activities related to the blockchain evaluation, while the industrial ones are given in A Queuing Model (QM) is a mathematical model allowing the prediction of the queue lengths and waiting time in the system. Some preliminary work on QM for a blockchain was carried out several years ago by Kasahara and Kawahara . This woLater on, Memon’s group developed a new simulation model of the mining process for blockchain systems using queuing theory in . The resSeveral recent studies utilized the fluid limit: a subsection in queuing theory describing deterministic processes, which aims at an approximation of the evolution of the analyzed stochastic process. For instance, the research group from the University of Amsterdam developed a Bitcoin-inspired infinite-server model with a random fluid limit . Moreoven and every a is a parameter of the model, c is a constant, and A Markov Process (MP) is a basic mathematical tool for performance evaluation of blockchain systems proposed more than 10 years ago in . It desc<t2<⋯<tn . From thSome preliminary work was carried out by Eyal and Sirer in . The autThe research group from Northeastern University developed a simple MP-based approach for analyzing the consistency properties of blockchain protocols . While pS is the finite set of states, A is the finite set of actions, a in state s moves to state s to state a.A Markov Decision Process (MDP) is a discrete time stochastic process, which is widely used as a mathematical framework for a sequential decision-making task with a fully observable environment described by a Markov transition model and additional rewards. MDP can be defined as a four-tuple In order to identify an optimal mining policy in blockchain systems, several studies utilized MDP as a mathematical modeling framework. For instance, several studies ,58,59 utA Random Walk (RW) is a stochastic mathematical model that describes a path that consists of random changes or steps on mathematical space at discrete points in time, widely utilized for various Information and Communications Technology (ICT) systems’ analysis ,64. GiveThe authors of  refined To summarize, most of the blockchain evaluation approaches based on analytical modeling and simulations are generally simplified abstractions of the actual systems aiming at a specific focus on particular aspects of the system operation, thus providing highly limited observations on the main blockchain evaluation metrics listed in Emulation (E) is the process of imitating the behavior that can be observed from the outside to match the selected target, which is mainly used by the actual blockchain developers having access to the actual system code. Most of the industry and integrators apply this approach to test the performance of their private or consortium blockchain-based solutions, while public ones obtain much less attention. The details on the main blockchain emulation examples are summarized in To start with, an industrial project titled Hyperledger  is one oAnother emulation tool is Blockbench , which iNext, VIBES , a publiBlockLite  is anothA particular niche of blockchain evaluation is related to private blockchains. Here, the developer may either develop his/her completely proprietary blockchain solution or base it on one of the open systems adopted for private use. One of the examples of the last group is Ethereum . Many deAnother toolbox utilized for private Ethereum-based blockchains’ evaluation is known as Truffle Suite . It is cA massive open-source environment called Corda Testing Tools provides a broad range of functionality, including unit tests and integration tests for both small projects and enterprises from the transaction perspective designed explicitly for R3 Corda project analysis . The maiOne more toolbox for private blockchain integration testing is Exonum Testkit . Its maiIt must be noted that there are some minor projects developed to analyze a particular part of the blockchain operation, but not for the actual blockchain evaluation, thus falling out of the scope of this paper. For example, Manticore  is a tooTo summarize, one of the critical aspects of constructing emulation models tends for the academic segment to be the computational resource limitations. Broadly utilized solutions for this issue are to simplify resource-competitive modules, utilize multi-threading programming in model implementation, and to deploy emulation models in the cloud. The impact of resource limitations for product developers and integrators is less critical; thus, most of their activities are targeted at the emulation environment. It allows users to obtain more detailed information on the system operation. Evidently, a unified solution for blockchain emulation does not exist, while this section listed the main aspects of existing projects in this field, providing the reader with an opportunity to select the tool of interest depending on the application from During the review, we identified that major analytical models are based on Markov processes, which are commonly utilized for examining the incentive-compatible property of blockchain systems, studying selfish mining attack strategies, and evaluating the consistency properties of blockchain protocols. At the same time, models based on Markov decision process are commonly used for obtaining relatively better results on examining selfish mining attack strategies. The majority of papers aiming at researching double spending attacks in blockchain systems are based on the random walks approach. Emulation approaches should be applied in cases when the detailed performance evaluation is required.The models listed in The first and the main social challenge is related to limited adoption of the technology. Adding to developers’ bad luck, many affiliate blockchains with cryptocurrency used for money laundering and tax fraud . It has One of the main challenges of today’s blockchain system developers is a lack of skills or experience in analyzing and developing blockchain applications. The steps from centralized to massively adopted distributed systems are only to be made in the coming years. Learning additional skills or understanding the best practices to implement blockchain applications is costly. It is essential to manifest the fact that blockchain technology has enormous potential for simplifying all the bureaucratic procedures for the state and making transactions transparent and more accessible, thus pushing the need for the systems’ evaluation to a higher priority.Based on the literature review, we can state that the evaluation of blockchain systems highly varies depending on the type, i.e., private, public, or consortium . GeneralEven if several articles focused on one problem ,57,58,59Following the previous challenge, historical data such as logs collected from monitoring nodes or general network statistics are commonly analyzed and utilized in simulation models. However, this approach suffers from several drawbacks. For instance, in the case of obtaining data from specific nodes, these data are under the analyzed blockchain system factors. As a consequence, it may not be representative to examine the blockchain system, which is under other network factors. Besides, these data are observed from logs of a limited amount of nodes, so they are not able to describe other nodes’ behavior . MoreoveEvent-based simulation models, e.g., ,96, perfWhile certain relations or even trade-offs between quantitative blockchain characteristics were deeply examined, e.g., the effect of the block-size limit to the transaction-confirmation time ,42, the In the case of modeling blockchain systems, running a simulation or an emulation may require significant computational resources in order to achieve relevant and accurate results. The basic approaches for reducing the need for computational power are to simplify resource-consumptive modules or procedures in the model implementation, or to utilize a certain central processing unit’s abilities such as multithreading, or to exclude some modules from the model. More advanced and combined approaches may be required to run the execution of a large-scale blockchain model on tens of thousands of nodes in the cloud .While Machine Learning (ML) solutions demonstrated an ability to perform successfully in system modeling tasks ,100,101,Based on the above, we can conclude that there exists a number of challenges to be addressed by the research and professional community pushed by the growing industrial and academic interest in blockchain modeling. Several issues, e.g., the development of a benchmark, the estimation of the influence of model abstractions, and the relations between blockchain characteristics, can be solved by researchers on their own, whereas some other challenges, e.g., access to representative historical data, could be overcome only by the whole blockchain-development community participating. At the same time, a few potential directions, such as machine learning techniques and cloud-based deployment, seem to be able to enforce the simulation accuracy and performance notably.In this paper, we executed a critical review, analyzed the state-of-the-art of blockchain evaluation approaches, and identified current challenges and future prospects of blockchain simulation and modeling.Firstly, we outlined the main motivation and background. Next, we listed the main perspectives and metrics that could be evaluated. Further on, we proposed a classification of blockchain modeling approaches into the following classes: Queuing Models, Markov Processes, Markov Decision processes, random walks, and emulations. We executed the literature review based on the PRISMA methodology extended by the industrial projects and reviewed selected papers for each of the proposed classes. Finally, we outlined current challenges and future perspectives in the area of blockchain evaluation.Based on the critical review, we concluded that analytical and simulation approaches based on queuing theory are mainly utilized for evaluating different blockchain architectures before deploying them over the blockchain network and designing the fluid limit of a random graph model for a shared ledger. Approaches based on Markov processes are commonly used for evaluating the consistency properties of blockchain protocols and studying various attack strategies. As an extension of the Markov processes, approaches based on Markov decision processes are commonly applied for obtaining relatively better results on examining selfish mining attacks. Approaches based on random walks are primarily used to examine double spending attacks in blockchain systems. Emulation is used when the computational and storage resources are not critical in contrast to previous ones. Those are mainly applied by actual developers and integrators when detailed system analysis is required for planning of private and enterprise blockchains.Finally, we identified current challenges and future prospects of blockchain simulation approaches, which include a lack of expertise, the need for developing a multi-task benchmark for reliable models’ comparison, gaining access to the representative historical data of blockchain systems, evaluating the influence of abstractions on the model accuracy, exploring relations between blockchain characteristics, reducing computational resources for simulation, and the usage of machine learning for better performance. We foresee that one of the main bottlenecks of blockchain evaluation adoption is the need for standardization activities, which is expected to be resolved in the oncoming years.


Patients who report suspected adverse drug reactions (ADRs) help minimize drug safety risks and bolster the pharmacovigilance system. The aim of this study was to examine the contribution of patients to pharmacovigilance and compare the tools used to promote patient reporting in European countries that implemented this reporting type in 2012–2013. A web-based questionnaire was sent to the national competent authorities (NCAs) of the European countries. The received answers were systematized and compared using statistical analysis. The performed statistical analysis demonstrated that changes in the number of received ADR reports increased significantly in each country during the analyzed period. These changes were significantly different in Ireland and Finland from those in the other reviewed countries. The common source of information on direct patient reporting was the country’s NCA website. Other sources used were social media pages, leaflets, and posters. This is the first study on patient reporting schemes implemented after the significant reform of the European regulatory system for pharmacovigilance. However, some countries did not actively promote their patient reporting schemes. Our findings indicate that countries with minimal experience in pharmacovigilance systems that include direct patient reporting should organize comprehensive campaigns on ADR reporting. The primary source of information about drug safety is health care professionals. However, studies have shown that doctors provide incomplete adverse drug reaction (ADR) reports or do not provide them at all . The faiIn several countries, the ADR reporting schemes for consumers have been promoted since the implementation of their pharmacovigilance systems or shortly after. For instance, the practice has been carried out in the US, New Zealand, the Netherlands, Denmark, and Sweden. After the introduction of new European pharmacovigilance legislation in 2012–2013, 15 countries in Europe implemented schemes for direct patient ADR reporting to competent authorities ,5. Some The aim of this study was to examine the contribution of patients to pharmacovigilance and compare tools used to promote patient reporting in European countries that implemented this type of reporting in 2012–2013. A web-based questionnaire and statistical analysis were used for achieving this aim.A questionnaire was emailed to the national competent authority (NCA) of each eligible country. A country was eligible to participate in the study if they first implemented their direct patient reporting of ADRs in 2012–2013 in response to the new European pharmacovigilance legislation. In total, 15 countries were eligible and were sent the study questionnaire: Austria, Belgium, Bulgaria, Estonia, Finland, Germany, Greece, Ireland, Latvia, Lithuania, Luxembourg, Poland, Portugal, Slovakia, and Spain. The questionnaire was designed to collect statistical data , methods for patients to report ADR, tools in use to promote patient reporting, and whether personalized feedback about the reported ADR was routinely given to the patient.A statistical analysis was performed to investigate the quantitative findings from different countries and provide a numerical estimate of significance of the change during the analyzed period in the interviewed countries. The analysis was performed on the number of patient-specific ADR reports submitted to competent authorities for the first year direct patient reporting was implemented and the most recent year (2017 or 2018). The comparison was completed using a random-effects model and fixed-effects model to evaluate the changes in the number of received ADR reports in participating countries during the analyzed period. Confidence intervals (95%) for each data set were calculated. MedCalc software  was used for data analysis. Heterogeneity was explored using the Cochran Q-test of heterogeneity. The significance was determined by reviewing the location of odds ratios. An odds ratio of one indicates no effect/no difference between interventions. Any line which crosses the line of null effect does not illustrate a statistically significant result. Countries with narrow confidence intervals  and crossing one  are inconclusive. Countries with narrow confidence intervals that do not cross one are judged statistically significant. If the odds ratios with confidence intervals fail to overlap, the differences between the two countries are statistically significant. If the results are similar between various countries, the data is homogeneous and statistically insignificant.Of the 15 countries that were contacted, 12 responded to the questionnaire. Follow-up emails were sent out to the nonresponsive NCAs—Luxembourg, Poland, and Bulgaria—but their responses were not received. The answers from 12 countries were representative of 80% of all eligible countries, which is a substantial portion for conducting a comprehensive study.In the participating countries, the primary methods used for ADR patient reporting were direct mail, email, phone call, fax, and online internet-based methods . These mPersonalized feedback was given to patients who reported ADRs in five (41.6%) countries: Estonia, Austria, Portugal, Spain, and Slovakia. In the other countries, feedback was provided with some exceptions. For example, in Belgium, feedback was given only if the patient’s report included questions. In Portugal, all reporters received a confirmation of submission. Additional information was requested from patients when necessary. Furthermore, causality was assessed in the case of serious ADRs in Spain and reported to patients. For the rest of the countries, patients who used the online reporting form received an automatic letter of confirmation upon submission.All participating NCAs had webpages where information about ADR reporting and standardized information could easily be found. Other methods used to promote patient reporting schemes are listed by country in Statistical analysis was performed for the comparison of received ADR reports during the period from the beginning of patient reporting schemes until the 2017–2018 period. Because the total number of received ADR reports was not provided by its NCA, Greece was excluded from the statistical analysis. The results of the statistical analysis and related forest plot are presented in The calculated results indicate that the number of direct patient reports changed significantly in each individual country during the analyzed period. Additionally, significant differences between some countries were observed. Furthermore, our findings indicate a relationship between a high number of different promoting tools used and increased patient ADR reporting. As shown in All the countries that participated in this study started patient ADR reporting in 2012 or 2013 after the major reform of the European regulatory system for pharmacovigilance was implemented in July 2012 ,12,13,14Based on the number of received ADR reports for the 12 participating countries, the problem of underreporting ADRs was seemingly present. However, it is not easy to establish an accurate measure of the level of underreporting in these countries. However, based on the findings of this study and existing research, the levels of underreporting are estimated to reach 90% or more . AlthougThe success of direct patient reporting depends on the adequate knowledge of pharmacovigilance systems and the tools used to inform society about using them . The metThe primary goal of the EU pharmacovigilance system is to deliver safer and faster decisions in medicine and health care. A systematic review showed that the median interval between the first reported ADR and the withdrawal of a drug launched after 1960 is three years, which is two times shorter than for drugs launched before 1960 . This shImportant data has shown in several studies that the active pharmacovigilance approach implemented in healthcare can significantly increase the number of ADRs ,23. ActiOur research has some limitations. First, not all invited competent authorities participated in the study or provided requested information. Secondly, the data does not show the changes that have taken place each year. The promoting tools were implemented by each NCA gradually. Statistical data was not collected for each year; therefore, the impact of separate tools on ADR reports cannot be measured. Despite these limitations, the information is still useful for policymakers and national authorities responsible for ADR report collection.This is the first study that summaries ADR reporting by patients in European countries that recently implemented patient reporting schemes. The number of ADR reports received from patients by competent authorities and the variety of methods used to promote direct patient reporting indicates a lack of adequate knowledge on the pharmacovigilance system and an insufficient level of health education among the public. Going forward, it is critical for health care practitioners, in collaboration with health care agencies, to establish concrete and reliable systems that can be used to help patients report ADRs. One formidable means of achieving this objective is to maximize public awareness of the importance of reporting ADRs to health care providers and its positive potential for improving the overall well-being of society.


Administrative data arising via the operation of public service delivery systems hold great benefits for citizens and society by enabling new research questions to be addressed, providing they can be made available in a safe, socially acceptable way. In recognition of this potential, the UK Administrative Data Research Network was established in 2013 to enable new research for public benefit. However, there are considerable challenges to be overcome for effective data use, and many of these are common to administrative data enterprises in general. Using this network as a practical case study, we set out to explore the issues and propose how to share the ‘good’, suggest solutions to the ‘bad’, and improve the ‘clunky’ issues, to lead to improvements in administrative data use.A qualitative survey representing the data use pathway was carried out across the network, followed by a workshop to discuss the summarised findings and make further suggestions. This led to a set of recommendations to inform the development of an action plan for implementation.The survey respondents (N=27) and workshop participants (N=95) comprised multi disciplinary staff from across the network. The responses were summarised by consensus of three researchers and grouped into six areas: A) Data acquisition pathway; B) Approval processes; C) Controls on access & disclosure; D) Data and metadata; E) Researcher support; and F) Data reuse & retention, leading to an embedded set of 18 recommendations. Key developments promoted by this study were the development of themed research partnerships to progress data acquisition, and a policy of data retention and reuse for research.The network has broken new ground in using administrative data for research. This study informed the development of an evidence-based action plan to address many challenges in the effective use of administrative data. It represents a practical worked example, and the learning is widely relevant to enterprises working with administrative data across the world. Administrative data can be defined as data arising via the operation of public service delivery systems, that is, information collected primarily for administrative (not research) purposes. These data are collected by a range of organisations such as government departments, local authorities, education establishments, social housing provision, and health & social care providers for the purposes of registration, transaction and record keeping, usually during the delivery of a service ,2. The sIn recognition of this imbalance, the UK Economic and Social Research Council (ESRC) commissioned an Administrative Data Taskforce (ADT) to advise on improving access to, and linkage, between government administrative data for research and policy purposes. The resulting report acknowledged the great untapped potential in UK administrative data, and this, supported by a positive UK government response, led to the establishment of the Administrative Data Research Network (ADRN) in 2013 ,5. The AFrom the outset, the aim of the ADRN was to enable new research using administrative data for public benefit and significant headway has been made. A range of datasets is available through the ADRCs, and a selection of almost 100 case studies have been published on the ADRN website to showcase the breadth of research that has been conducted. These include topics such as: special needs educational provision; the dynamics of disability benefits; developing measures of social capital; relationships between health and homelessness; anti-depressant prescribing; improving home energy efficiency; finding work on leaving prison; sociodemographic patterns in active commuting; and the effect of airport noise on mental health .Each ADRC operates a data repository model within its jurisdiction and makes data accessible for research in safe settings. Models of data access vary with the perceived sensitivity of the data. For example, ADRC-Wales is built upon the models in place for the Secure Anonymised Information Linkage (SAIL) Databank. SAIL is a national data safe haven of de identified person-based data about the population of Wales, with a rich array of datasets including, general practice, in patient and out-patient hospital data, screening services, cancer registry, education, and birth & death records ,9. TheseThe aim of this independent research study was to explore good practice, barriers and bottlenecks in the effective use of administrative data, and to propose how to share the ‘good’, solve the ‘bad’ and improve the ‘clunky’ issues, to lead to improvements in how administrative data are used for research. With its focus on the data use pathway across the ADRN, this study represents a partial evaluation of the implementation of the ADT report [However, there are still many challenges to address, much scope for improvement, and an appetite to move this forward. The ADRN is not unique in this regard, as highlighted in a recent report on data availability and use in Australia . Since tT report . BecauseThis paper is focused on developing a better understanding of the issues around effective administrative data use using the ADRN as a case study. As such, it does no’t explicitly cover the whole gamut of associated work areas, such as technology, infrastructure, communications and public engagement, etc., though they may be implicitly included. Information for the study was gathered from across the ADRN in two stages. The first was a qualitative on-line survey with a free-text response format and the second was a workshop to discuss the summarised findings and make further suggestions for addressing the identified challenges. The survey asked about the ADRN data use pathway, which is defined as the route from the identification of potential datasets through to data archiving. The 18 separate steps are shown in There was no obligation to comment on all topics and an additional ‘Other’ category was included to allow respondents to comment on any topics not included. The survey was produced in Google Forms and distributed across the ADRN by the main communications team, and it was open for a 3-week period between 21st April and 12th May 2017. As the survey was cascaded across the network, the response rate cannot be calculated. The responses (N=27) were reviewed, themed and summarised manually by consensus of three researchers.The processed responses to the survey were categorised into 6 areas to facilitate discussion in the workshop. These were:A)Data acquisition pathway(Qs 1-3)B)Approval processes(Qs 4-6)C)Controls on access & disclosure(Qs 7-9)D)Data and metadata(Qs 10-13)E)Researcher support(Qs 14-16)F)Data reuse & retention(Qs 17-18)stMay 2017 (N=95 in 10 groups of 9-10 people). It was facilitated by KHJ, with assistance from SH & KT. Summarised findings on each area were randomly provided to two separate groups of delegates for discussion, except for A) and F). This was because there were already dedicated ADRN workstreams on the data acquisition pathway (led by PJ) and data reuse & retention (led by CD). Each of these areas was allocated to a single group and the discussion facilitated by the respective workstream lead. The groups of delegates were asked to review the summaries and to choose one or more issues to discuss and provide feedback on how the ADRN could best progress in that area, by practical measures and influence. Each group wrote their comments on paper and gave verbal feedback in a plenary session at the end of the session. The written comments and notes  on the verbal feedback were transcribed and used to create a synthesis of main points and suggested actions by area (by KHJ), which were then reviewed for consensus by three researchers . The findings and recommendations were shared with the workstream leads for A) data acquisition pathway and F) data reuse & retention for feedback, and to include summary plans for these areas of work in the study report to the network directors. The report was provided to the directors in September 2017 and, following their deliberations, they produced an action plan for implementation. This was shared with the lead author (in January 2018) and the complete study was presented at the Administrative Data Research conference in June 2018 [The workshop was designed to further develop thinking on the issues emerging from the survey and was held at an ADRN general meeting in Edinburgh on 31une 2018 .All four ADRCs and the ADS were represented in the 27 responses to the survey: three from ADRC Northern Ireland; six from ADRC Scotland; two from ADRC Wales; five from ADRC England; five from the ADS; and six respondents didn’t give their affiliation. The job roles included were management, research and support, senior academics, researchers, directors, project managers, and staff involved in user services, teaching, public engagement, communications, office administration, data indexing, and data negotiation. At the workshop (N=95) there were 15 people associated with ADRC Northern Ireland, 33 from ADRC Scotland, 13 from ADRC Wales, 14 from ADRC England and 20 from the ADS. The roles profile was: 22 from management, 48 from research and 25 from support roles.The main ‘good, bad and clunky’ findings from the survey and the workshop discussions, along with actions suggested by the participants for sharing the good, solving the bad and improving the clunky issues, are summarise by area in The additional survey question (‘other topics’) allowed respondents to make further points. Where possible, these have been incorporated into the areas above. As noted, the aim of this study was on elucidating issues to lead to improvements in data use, but two important cross-cutting themes were identified. These were: the need for better, more regular, communications across the network; and to acknowledge that public engagement needs more attention, with a suggestion for more events with the public and wider stakeholders.Respondents said:‘Public opinion can be useful to the ADRN acquisition agenda if people could be convinced that de identified linked data could provide an advantage in the delivery of their services or in the efficiency of the economy.’‘Courting public opinion should always include a full and clear inclusion of the privacy safeguards which then builds trust’‘I think some of the bottlenecks are lack of awareness of or importance placed on public engagement’‘Need buy-in from leadership beyond recognising public engagement as crucial to the set-up of the ADRN and moving beyond low-level engagement like events and newsletters to thinking deeper about how public engagement can enhance research and research impact and placing a duty upon researchers to get involved.’The combined findings of the survey and workshop provided a rich source of viewpoints and ideas for improvement. They were used by the researchers  to develop a set of 18 recommendations across the six areas. These are shown below:Data acquisition pathway1) A regularly updated and well-signposted information resource on datasets, identifying the data custodian and providing metadata.2) A more streamlined data acquisition process, including a tracker on progress.3) A standardised process for data provider permissions, with greater clarity on who the decision makers are, shared protocols and agreed target timelines.Approval processes4) Greater transparency of regulatory approval processes and consistent advice to researchers, with more alignment between regulatory and network approval processes to avoid duplication.5) Proportionate peer-review, inclusive of wider stakeholders, with the network accepting the funder’s peer review where relevant.6) Clearer information on the circumstances where consent to link datasets is/is not needed, and on consent specificity, to inform discussions with data providers at the outset.Controls on access and disclosure7) Network approvals process to include cross-national UK studies, with greater use of remote access facilities and more safe rooms/pods.8) Greater clarity on what constitutes a disclosure risk and transparency on the Statistical Disclosure Control (SDC) measures applied to the data before being accessed for research.9) Harmonised training for those who check results for release, and opportunities for dialogue between checker and researcher.Data and metadata10) Recognising that data formats will vary, there is need for standardised documentation and versioning.11) Greater levels of communication with data providers to share data quality reports and gain information on data item provenance.12) Standardised data linkage quality reports and guidance for researchers.13) Consistency between metadata and dataset content through dialogue with data providers and a standardised metadata catalogue.Researcher support14) Consistent researcher support to be available across the network, and through the project life cycle, with agreed response times.15) More training for researchers on data manipulation and analysis to address the skills gap.16) Up-to-date tools and software provided in a timely way.Data reuse and retention17) Projects to be clustered into themes and all data to be reusable within a safe setting.18) Clearly defined stewardship of retained data, and an asset registration number for each dataset.The workstream leads for A) data acquisition pathway and F) data reuse and retention provided their feedback on the study, and a summary of the developing plans for these areas of work to be included in the report to the network directors. The study findings were received as a welcome contribution to the review and revision of ADRN policies, and it was noted that the results strongly reinforced the need, and provided practical evidence for the case, to move away from a create-and-destroy model to one where data are retained for reuse.During 2016-17 the ADRN had formed a task team to review network policy on data retention and destruction. The network had originally adopted the conservative position that linked data should only be available to single projects and then, when these projects had completed their work, the data destroyed. Whilst this was seen as a sensible initial position to take, the potential benefits of moving towards the reuse of data for suitability qualified research teams were becoming very apparent. The task team carried out a wide ranging review: analysing the legal considerations of a potential move to the reuse of data for research purposes; exploring the public’s views on data reuse through public panel meetings and reviews of the literature; reviewing practice in other countries; and exploring data reuse in the context of the ADRN core principles. The review established that there were no insurmountable barriers to a change in data reuse policy. As a result of the review and the findings of this study, and following discussions with senior UK government officials, network policy was changed to one of data reuse rather than create-and-destroy. These discussions were essential since much of the administrative data of interest is held in government departments. This change in policy will reduce duplication of effort and lead to greater data use for public benefit. It was acknowledged that that data reuse would be implemented at various different levels within the network depending on discussions with data controllers.In order to advance work on the data acquisition pathway, there has been a greater focus on research themes, with groupings of partners with an interest in each theme taking forward the creation of new linked datasets . These dThe ADRN directors developed an action plan for implementation, based on the recommendations of the report and in light of changes already in motion. In doing this they highlighted a key message in each of the six areas: A) to F), work underway and future actions. This is summarised in This unique study used the ADRN as a case study to uncover ‘good, bad and clunky’ points in using administrative data for research, and to suggest ways to highlight the good, solve the bad and improve on the clunky issues. As we were interested in improving data access and use for research, we chose to focus on topics along the data use pathway from data acquisition to data archiving. The establishment of the ADRN stemmed from the Administrative Data Taskforce report, and this study provides an in-practice evaluation of the adoption of the Taskforce recommendations for data use . It is aThis study has wide relevance since working with administrative data brings common challenges. These were highlighted in a recent review, namely, data generation, management, analysis, quality, access and linkage ,17; someau fait with the complexities of working with administrative data, support for researchers is much needed, and requires dedicated resource with expertise in the provenance, format and quality of datasets. All these lessons reinforce the importance of reusing datasets, rather than operating a create-and-destroy model, to avoid wasted time and effort in discarding hard won research resources. Data reuse, of course, must be properly governed with trustworthy data stewardship.With its practical focus, this study presents valuable lessons to be learned in working with administrative data. We share these lessons for others working in administrative data enterprises, or setting out to do so. For data acquisition, we found that government departments need a clear programme of work that clarifies potential benefits on a wide scale. The themed approach to data acquisition is showing promise as a better paradigm than merely requesting datasets, as it has revealed to government departments more about the possibilities of research using administrative data. It is not enough talk about the value of data per se; there need to be more compelling arguments for the potential outcomes, including the return on investment from data provision. Approvals processes need to be both robust and proportionate so that they protect data providers and citizens, but are not a hindrance to research . Where rAlthough our focus was not specifically on communications and public engagement, these are essential cross-cutting themes which we, and analogous enterprises, are wise to heed. At least for the ADRN, the development of research themes, and partnership groups to develop the associated datasets, have been key in implementing the action plan, and work is ongoing for further improvements. Good communication channels and on-going dialogue with the range of stakeholders, notably partnerships with data providers, are essential to avoid misunderstandings and duplication of effort. We highlight that effective communications and public engagement are essential for social licence in the use of person-based data . The ESRThere is also much further work to be done in relation to legal and ethical issues. Data from healthcare providers has long been legally provided to data centres by means of an NHS trusted third party to de identify the personal data: for example, the working arrangement between the NHS Wales Informatics Service and the SAIL Databank . The intThe main limitations of this study are that: some issues might have been missed since not everyone in the network completed the survey; response time was restricted to a three week window for practical reasons, so that the findings could be discussed at a pre-scheduled workshop; and the survey was only distributed to network staff and did not include wider views. Because survey respondents were not required to provide personal details, we cannot be sure that the views are representative of the whole network. However, the ADRCs operate on the same principal model, are subject to the same challenges, and we obtained responses from a range of job roles. As such, although not necessarily fully representative, we have no reason to believe the findings are invalid. Future work in due course, could be to evaluate progress since the implementation of the action plan, and to include wider stakeholders in the process. This study has not been able to address all the challenges and how they could be overcome. We propose there should be an evaluative research programme to guide investments in wider use of linked administrative for research by governments and by independent researchers.The ADRN has broken new ground in using administrative data for research in the UK. This innovative, practical study has revealed many good, bad and clunky issues along the data use pathway, has set out recommendations for evidence-based improvement, and shared the lessons learned. On reflection, the formation and development of the ADRN required new thinking and greater understanding of wider perspectives amongst the research community, data owners and the governance/oversight community. Consequently, we emphasise the central importance of effective stakeholder communications to enhance efficiency in data use. The conclusions reinforce many of the ADT recommendations, and inform others in the light of experience, to progress the effective use of administrative data. The findings and recommendations of this study are informing the work of the Administrative Data Research Partnership. Importantly, since many of the challenges are ubiquitous, this study is highly relevant generically, and as such, will be valuable to other enterprises working with a broad range of administrative data.


The maintenance of skeletal muscle mass plays a critical role in health and quality of life. One of the most potent regulators of skeletal muscle mass is mechanical loading, and numerous studies have led to a reasonably clear understanding of the macroscopic and microscopic changes that occur when the mechanical environment is altered. For instance, an increase in mechanical loading induces a growth response that is mediated, at least in part, by an increase in the cross-sectional area of the myofibers . However, very little is known about the ultrastructural adaptations that drive this response. Even the most basic questions, such as whether mechanical load-induced myofiber hypertrophy is mediated by an increase in the size of the pre-existing myofibrils and/or an increase in the number myofibrils, have not been resolved. In this review, we thoroughly summarize what is currently known about the macroscopic, microscopic and ultrastructural changes that drive mechanical load-induced growth and highlight the critical gaps in knowledge that need to be filled. Skeletal muscle comprises approximately 40% of body mass and plays a critical role in posture, breathing, motion, and metabolic regulation . As we aMechanical load-induced signals are one of the most widely recognized regulators of skeletal muscle mass. Indeed, historical evidence suggests that the growth-promoting effects of mechanical loading has been recognized since at least the 7th century BC . During Before considering the structural changes that drive mechanical load-induced growth, we want to ensure that the reader appreciates the basic structural design of skeletal muscle. One of the easiest ways to appreciate this design is to consider skeletal muscle as a hierarchy of contractile machinery that is visible at the macroscopic level (viewable without magnification), followed by the microscopic level (viewable with standard microscopy), and finally the ultrastructural level (viewable with high resolution microscopy). Below we will provide a brief overview of the primary components that are found at each of these levels. For excellent illustrations and more comprehensive discussions on this topic, the reader is referred to the following reviews ,25,26.At the macroscopic level, it can be noted that skeletal muscles are connected to bones via tendinous attachments and enact their contractile function by providing movement and articulation of the skeletal system. Moreover, as illustrated in At the microscopic level, a cross-section of skeletal muscle will reveal the presence of individual myofibers A,B. The The gelatinous sarcoplasm contains the primary ultrastructural elements of the myofiber, and as illustrated in When considering the structure of skeletal muscle, it is also essential to recognize that all myofibers are not created equal. For instance, some types of myofibers are heavily reliant on oxidative metabolism, exhibit a slow contractile speed and are resistant to fatigue. In contrast, other types of myofibers rely on anaerobic glycolytic metabolism, exhibit a fast contractile speed and rapidly fatigue when stimulated to contract . DiffereAt the whole muscle level, mechanical load-induced growth can be mediated by an increase in the length and/or an increase in the cross-sectional area (CSA) of the muscle. Growth resulting from an increase in length is referred to as longitudinal growth, and it can occur in response to a variety of different perturbations. For instance, during development, the length of muscles can more than double from birth to the termination of bone growth ,51,52. LAlthough skeletal muscle is capable of undergoing longitudinal growth, most models of mechanical loading do not lead to notable alterations in whole muscle length ,59. InstPrevious studies have shown that the initial mechanical load-induced increase in whole muscle CSA can be attributed, at least in part, to edema. However, the long-term changes are primarily caused by an expansion of the contractile elements ,73,74. FBased on the aforementioned point, mechanical load-induced changes in whole muscle CSA should be driven by changes that happen at the level of the muscle fascicles, and there are effectively two predominant ways in which this is thought to occur: (1) longitudinal growth of the fascicles or (2) radial growth of the fascicles. It is also possible that mechanical loading could lead to an increase in the number of fascicles per muscle, but we are not aware of any studies that have attempted to answer this technically difficult question.Upon first consideration, it can be challenging to appreciate how both longitudinal and radial growth of fascicles can lead to an increase in whole muscle CSA. Thus, to visualize these points, we have taken advantage of a geometric model that can be used to predict changes in the architectural properties of skeletal muscle ,76. SpecHaving illustrated how radial and longitudinal growth of fascicles can lead to an increase in whole muscle CSA, we will now consider the studies that have tested whether these types of adaptations occur. Specifically, we will first consider the studies that have examined whether mechanical load-induced alterations in whole muscle CSA are associated with changes in fascicle length, and fortunately, this has been a subject of extensive investigation ,83,84,85As mentioned above, the radial growth of fascicles could also lead to an increase in whole muscle CSA. Importantly, as detailed by the work of Maxwell et al. (1974), and as illustrated in As previously noted, mechanical load-induced alterations at each level of the skeletal muscle structure should be reflective of the changes that occurred at the preceding level within the hierarchy of the contractile machinery. Thus, having established that mechanical loading can lead to both longitudinal and/or radial growth of the fascicles, we will now consider how these changes can be mediated by alterations at the level of the myofibers.Fascicles are composed of bundles of myofibers, and the myofibers can either run the entire length of the fascicle, or only part of the length of the fascicle and exhibit an intrafascicular termination ,91,92. FAlthough a compelling body of evidence indicates that extreme models of mechanical loading can promote longitudinal growth of myofibers, only a handful of studies have directly addressed this topic within the confines of more physiologically relevant models. For instance, it has been shown that the eccentric contractions induced by downhill walking , and dowp < 0.01). Likewise, Goh et al. (2019) recently described a high intensity interval training (HIIT) for mice that leads to a 17% increase in the mass of the extensor digitorum longus muscle 185]. ColIn addition to his observations on longitudinal splitting, Dr Goldspink also noted that the thin myofilaments in sarcomeres do not run directly perpendicular to the Z-disc, but instead are offset at a slightly oblique angle (≈6–10°) . This waDr Goldspink’s model of myofibril splitting was developed over 40 years ago, and it has frequently served as the textbook explanation of how myofibril number could increase during the radial growth of myofibers ,190,191.If we assume that the basic concepts of the myofibril splitting model are correct, and that they can be applied to the radial growth of myofibers that occurs in response to increased mechanical loading, then the first part of the overall growth process would involve myofibril hypertrophy. This initial hypertrophic response would continue until the myofibrils reached the critical size that induces splitting. The splitting would result in the formation of daughter myofibrils that would then undergo hypertrophy until they split, and the cycle would repeat until the radial growth of the myofiber commenced. We will now examine the limited body of literature that surrounds this thesis.To the best of our knowledge, only one study has addressed whether mechanical load-induced myofiber hypertrophy is associated with myofibril hypertrophy . This stThe results of Ashmore and Summers (1981) provided support for the notion that mechanical loading can induce myofibril hypertrophy, and therefore raise questions about the processes that drive this response . When coAs illustrated in 3H-leucine to label newly synthesized proteins, and then electron microscope autoradiography was used to identify the location of the newly synthesized proteins [The work of Morkin (1970) is often cited as providing support for the notion that new myofilaments are added to the periphery of myofibrils . Specifiproteins . As showproteins . Howeverproteins ,194. ThiThe limitations of the resolution that can be obtained with electron microscope autoradiography have been thoroughly described by Caro (1962) and Salpeter et al. (1969) ,198. ImpAs mentioned in the previous section, the study by Ashmore and Summers (1981) provided support for the notion that the mechanical load-induced radial growth of myofibers is associated with myofibril hypertrophy, but unfortunately, the study did not address the concept of myofibril hyperplasia . In factAlthough we are not aware of any studies in skeletal muscle that have directly addressed whether mechanical load-induced myofiber hypertrophy is associated with myofibril hyperplasia, there are a few studies that have addressed this topic in the heart. For instance, Toffolo and Ianuzzo (1994) used aortic constriction to subject rat hearts to mechanical overload and found that after 30 days, the cardiomyocyte area had increased by ≈50% and this was associated with an ≈70% increase in the number of myofibrils per cardiomyocyte . An incrAs we have discussed, a substantial body of evidence indicates that the mechanical load-induced radial growth of myofibers is mediated by a proportional increase in the force-generating and non-force-generating elements. The force-generating elements are contained within the myofibrils, and the myofibrils account for ≈80% of the myofiber CSA. Thus, it can be argued that the bulk of the radial growth is driven by an expansion of the myofibrils. However, whether this expansion is due to hypertrophy of the individual myofibrils and/or myofibril hyperplasia remains to be established. Based on our collective view of the literature, we propose that both processes are involved, and can be explained by a model that we have defined as the “myofibril expansion cycle”. Specifically, as illustrated in Mechanical loads are one of the most potent regulators of muscle mass and the maintenance of muscle mass plays a critical role in health and quality of life. In As documented in this review, several of the adaptations that we consider as having weak supporting evidence have been engrained in the literature as “textbook” mechanisms . We hope that after reading this review, the reader appreciates how little we actually know about the structural adaptations that drive skeletal muscle growth, and the number of extremely fundamental gaps in knowledge that remain to be filled.


Rabies is a major and seriously neglected public health problem worldwide. A treatment consisting of supportive therapy with the use of drugs that show antiviral activity is called the Milwaukee Protocol. In Brazil, this protocol was adapted to the national reality and called the Recife Protocol. In this study, we compared the Milwaukee Protocol with the Recife Protocol, assessing the differences and how these differences may change the course of clinical management.  We searched electronic databases for the use of anti-rabies treatments. A total of 65 articles were published between 2004 and 2019.  The protocols have similarities in care related to rabies patients and are important for the treatment of patients in intensive care units. Both protocols indicate deep sedation, antiviral use, constant concern with electrolyte balance, and vasoconstriction related to the condition. Many differences were observed in this study. For the Milwaukee Protocol, sedation should be gradually removed after the eighth day, and on the twelfth day, the patient should be without sedation. In the Recife Protocol, in order to avoid immunomodulation, it is recommended to remove sedation according to the titers of neutralizing antibodies to the rabies virus in the cerebral spinal fluid.  In addition to the differences and similarities raised, our findings indicate that these protocols require a large center for rabies treatment, but the disease most often occurs in places where resources and hospital infrastructure are scarce. Lyssavirus, a member of the Rhabdoviridae family, which primarily infects mammals-Rabies is a disease caused by viruses of the genus The RABV incubation period is quite variable, and the first symptoms may occur from 20 to 90 days after exposureAlthough rabies has a high mortality rate, there are reports in the literature of patients who survived the disease. Approximately 20 cases are described as rabies survivors worldwideIn Brazil, the first case of a patient who survived rabies occurred in Recife in 2008Comparative analyses were performed between the Milwaukee Protocol, version 6.0, and the Recife Protocol that was administered in human rabies cases during the period of 2004-2019. A comprehensive search was conducted with the PubMed and Google Scholar databases using the following terms: “rabies survivor” and “rabies AND Milwaukee protocol”, and “rabies AND Recife protocol”. First, we identified 65 articles using these terms. After reading the abstract, 26 articles were excluded because they did not fit the aim of this paper, and two other articles were excluded because of duplication. Thus, a total of 37 articles describing 39 cases of human rabies submitted to the Milwaukee Protocol or to Recife Protocol were identified and included in this work.The information comparing the two protocols was tabulated using a Microsoft Excel spreadsheet, separated into two columns for the Milwaukee and Recife Protocols. The variables collected after reading the protocols were classified according to whether they were related to intensive care of the patient, recommended or not recommended medications, complementary exams that should be requested, and specific exams for rabies. The periodicity exams that should be requested were also tabulated in the data. When one of the protocols does not mention something that is cited in the other, this information has been left blank in the table. D1 was defined as the first day of the protocol, with subsequent days following numerical order. For glycemic control, the recommendation is insulin dripping or regular insulin use as needed, varying from protocol to protocol. For temperature control, the Celsius unit was used.All information gathered from case reports in which the Milwaukee Protocol was applied were sent to spreadsheets, detailing: the patient’s gender and age; the aggressor animal; dates of transmission; clinical presentation and protocol opening; outcomes; region of occurrence; use of ketamine, amantadine, and/or ribavirin, and sedation; and phylogenetic analysis of the virus related to the case. We excluded cases in which the transmission of the disease occurred after transplantation of organs from a patient with rabies.We observed differences between the protocols. Hyponatremia can also be a complication; the two most likely hypotheses are inappropriate antidiuretic hormone secretion syndrome (SSIHAD) or salt-losing brain syndrome (SCPS). When diagnosing SSIHAS, it is important to define normal fluid or hypervolemia, in which case, strict control of hydration becomes essential. It is important to collect uric acid to differentiate the diagnosis from SCPS; uric acid will be decreased in cases of SCPS. In SCPS, urinary sodium should be dosed, and the use of fludrocortisone or hydrocortisone should be considered.The Milwaukee and Recife Protocols have many similarities in care related to rabies patients and are important for the treatment and care of patients in intensive care units. Both protocols indicate deep sedation, antiviral use, constant concern with electrolyte balance, and vasoconstriction related to the condition.The Milwaukee Protocol highlights hyponatremia as a possible complication on the fifth day of hospitalization, and the use of prophylactic fludrocortisone may be indicated. The protocol points out that one of the causes of this disorder may be dehydration. This change may contribute to worsening brain injury, so recurrent sodium dosage is important. Both protocols recommend that serum sodium dosage should be performed twice a day.Cerebral vasospasm is also associated with complications in patients with rabies. Both protocols recommend daily transcranial Doppler for the evaluation of this complication. In the Milwaukee Protocol, the recommendation is to perform trans-orbital ultrasonography for cases of intracranial hypertension. As a preventive measure against cerebral vasospasm, sapropterin or biopterin is used. Vasospasm in rabies cases is due to tetrahydrobiopterin (BH4) deficiency, which is essential for the synthesis of neural nitrous oxide (23), an important cerebral vasodilator. The Recife Protocol states that biopterin should be used as soon as the diagnosis of rabies is suspected. The Milwaukee Protocol states that sapropterin should be prescribed from the fifth day of hospitalization because this period is characterized by a higher risk of vasospasm and related complications. In the Brazilian protocol, BH4 dosage is recommended to evaluate biopterin activity at two times the fifteenth day of hospitalization and 15 days after replacement at maximum dose.Another differing point in the protocols refers to sedation withdrawal. In the Milwaukee Protocol, sedation should be gradually removed after the eighth day, and on the twelfth day, the patient should be without sedation. In the Recife Protocol, in order to avoid immunomodulation, it is recommended to remove sedation according to the titers of neutralizing antibodies to the RABV in the cerebral spinal fluid. Specific rabies tests (serology and polymerase chain reaction [PCR]) are indicated repeatedly in both protocols. BH4 dosage is described in the Recife Protocol; this substance is associated with cerebral vasospasm in an angry patient. The Recife Protocol recommends the prophylactic use of biopterin, which must be maintained for four to six months, followed by a new dose of BH4 in the cerebrospinal fluid (CSF).The rabies cases that were submitted to Milwaukee and Recife Protocols are shown in We compared the Milwaukee Protocol with the Recife Protocol for the treatment of rabies. A total of 39 cases of rabies, in which the anti-rabies treatment was used, were included in this study. Unfortunately, many cases of rabies, especially when patients die, are not published in the literature, even though the Milwaukee Protocol was used.Vaccine and the use of immunoglobulin are contraindicated by both protocols. The development of antibodies against rabies in the central nervous system (CNS) is essential for curing the disease. Administration of immunoglobulin may delay thisAmantadine is a synthetic antiviral agent that can inhibit viral replication by binding to the NMDA antagonist receptorA severe immune response in the central nervous system can cause damage and dysfunction, contributing to the death of patients. The cells present in the microglia present T-cell viral antigens that activate and produce cytokines and migration of mononuclear cells. An exaggerated inflammatory reaction may cause CNS damage. This damage causes the release of NO, which may be a neurotoxinRibavirin, a nucleotide analog, has the ability to inhibit RABV replication in vitro but has not shown benefit when used in cases of human rabies,Since 2004, the year in which the Milwaukee Protocol was first applied, the protocol has been used in 38 published cases . The Rec,-Vaccination and immunoglobulin, contraindicated by the protocols, were used in some reports, most of them as prophylactic measures after exposure and prior to the onset of symptoms. Experimental studies with monkeys demonstrate that the administration of immunoglobulin, with or without rabies vaccine, induces a more rapid death, that is, an acceleration of the disease occurs in animals receiving immunoglobulin,,In the case reports of patients who survived rabies, it is noted that 3 casesPatients who contract rabies, a disease with a high mortality rate and treatment protocols that are widely questioned in the medical literature, may require effective antiviral treatment that is administered early in the clinical course of the disease. The phase in which the virus reaches the CNS, causing encephalitis, may be too late for effective administration of available therapy. The best option for the treatment of rabies is still immunoglobulin-associated vaccination, both applied early in relation to the contact with an animal carrying the virus. When this therapeutic approach is not performed, the available drugs are inefficient in blocking the evolution of the diseaseAmong the patients who survived the disease and acquired it after an incident with infected animals, excluding cases of patients who acquired the virus after transplantation, none were older than 18 years; all were younger patients, aged 4 years to 17 years.,-All patients who survived the rabies had a hospital stay longer than 30 days. This fact may be explained by the severity of the disease, requiring treatment in intensive care units and in-hospital rehabilitation care. Many patients still undergo a rehabilitation process at home or in specialized centers. There are reports of patients who remain bedridden and require home care due to disease sequelae-,Patients still died of rabies due to protocol complications such as vasospasm, diabetes insipidus, and electrolyte disturbances, leading to arrhythmias and cardiorespiratory arrest. Many patients after death have high CSF-neutralizing antibody titers,The incubation time of rabies in the presented cases ranged from four weeks to more than two years. This incubation period may be related to the viral inoculum, virus concentration in the aggressor animal's saliva, and the centripetal migration capacity of the virus until it reaches the nerve roots. Bite location as well as injury severity are important factors in the evolution of the diseaseIn these 39 cases, the dog was still the main rabies-related mammal, followed by the bat (21 dog accidents and 9 bat accidents). This information confirms the importance of prophylaxis in treating animals carrying the virus, which may eventually transmit it to humans. The average incubation period for dog incidents was 27.4 weeks and for bat incidents was 10.5 weeks. This fact may be related to the greater severity of bat incidents, deeper wounds with greater viral inoculum, facilitating migration of the virus through peripheral nerves.Most of the cases in which the main foundations of the Milwaukee Protocol were used occurred in developed countries. The country with the highest incidence of rabies in the world is India, with approximately 60,000 cases per year, but only 7 cases that occurred in India had publications on the use of the Milwaukee Protocol. A more accurate analysis of the effectiveness of this treatment needs to be evaluated in places where the incidence of rabies is high, such as India.,,,The Milwaukee Protocol has undergone several modifications from the first version to the current version (6.0), but the literature shows that further adjustment is neededThe causes of death presented in the case reports justify the concern about vascular complications (vasospasm) and electrolyte disturbances; therefore, repetitive electrolyte collection and transcranial Doppler are of fundamental importance in the treatment of this disease.The clinical presentation of rabies is very similar to that of other encephalitis; therefore, this disease may be more prevalent than it appears. Typical cases of the disease are unlikely to be confused with other conditions. The prolonged incubation period may make it more difficult for the physician to think about this diagnostic hypothesis. Many sites may have underdiagnosed cases of rabies, causing many patients to die without being properly diagnosed.Some of the patients died after infectious conditions; in the articles, we did not find information on the use of antibiotic therapy. Most probably, several patients used this medication. Although neither of the protocols (Recife or Milwaukee) discuss in depth the risk of secondary bacterial infection, this seems to be a concern that should be present in all patients undergoing ICU therapy.Of the patients who survived rabies, fewer than half were treated with amantadine, ketamine, or ribavirin. Of the surviving patients, 8 underwent induced coma as part of the rabies treatment. It is always worth remembering that treatment protocols cover a broad approach in patients, with care related to the most common complications and tests aimed at the early diagnosis of these complications and their correct treatment.Among the surviving patients, all were hospitalized longer than 30 days, and many of them required outpatient follow-up until stabilization of neurological sequelae. This information makes the cost of treatment high, and the use of the protocol is somewhat limited in countries with worse socioeconomic conditions.The last patient reported to have survived rabies occurred in Brazil in 2017. The patient had an accident with a bat, and two of his siblings, a boy and a girl, died of rabies. The patient came from a city located 399 km from the capital Manaus in the state of Amazonas, in the northern region of Brazil. The boy was admitted to the unit on December 2, 2018, and on December 9, showed signs of infection resolutionThe protocols presented in this article indicate care in intensive treatment units and recommend several tests and the use of medications that are often inaccessible in places where rabies is highly prevalent. Evaluation of the effectiveness of the protocols is impaired, as is their acceptance in clinical practice. Many concepts can be reviewed to adapt protocols to different realities. We observed that the Milwaukee Protocol requires a large center for rabies treatment, but the disease occurs in places where resources are scarce. The Brazilian protocol, in trying to adapt the Milwaukee protocol for the reality of Brazil, did not succeed. This information can be demonstrated by analyzing the low adherence to the Recife Protocol, which would be more appropriate for treating rabies in places where the disease is most prevalent.


Background: Recent decades have seen controversial discussions on the validity of dissection courses in medical education, with alternative programs tested for various reasons. On April 1, 2015 the classification of formaldehyde as a hazardous substance was upgraded by the EU, leding to some universities precluding the participation of pregnant and breastfeeding students in dissection course. However, the revision to the Maternity Protection Act, implemented in Germany on January 1, 2018, now protects student mothers from being disadvantaged in their studies as a consequence of their pregnancy or breastfeeding. Therefore, universities must offer alternatives to dissection courses using formaldehyde to these female students.Project description: As an alternative to regular dissection courses, which use the abovementioned chemical, the Centre for Anatomy at Charité has opted for developing dedicated courses for student mothers. These new courses use plastinated prosection material instead of formalin-treated cadavers of body donors. As the core of the anatomical education takes place during the third and fourth semester in the current curriculum of human medicine at Charité the alternative courses are limited to those two semesters. Additionally, alternative exams at the end of both semesters had to be developed. The alternative courses were designed to offer pregnant and breastfeeding students a study program as close as possible to the one in which their peers learn human anatomy.Results: For the new courses, plastinates had to be produced and further specimens are still needed. Additionally required sets of bones, models and radiological images were readily available at the Centre for Anatomy. The planning and conceptualization of the courses took half a year of intense preparation. The courses for the third and fourth semester were first running during summer semester 2017. There is a clear demand for courses among pregnant and breastfeeding students. At least 5 student participants per course were registered, corresponding to every fortieth female student in their semester cohorts. The highest number of student participants was 13 in one course so far. The performances of the participants in the anatomical examinations were matching that of students attending the regular courses.Discussion: The alternative macroscopic anatomy courses enable the implementation of the revised Maternity Protection Act. The targeted student group is highly satisfied with the offered alternative courses. Considering the number of participants and their examination performance so far, the Centre for Anatomy regards the efforts involved in planning and implementing the courses as justified. The courses allow pregnant and breastfeeding students to address the same anatomical themes at the same time as their fellow students. However, due to restricted flexibility of plastinates and because students cannot prepare specific anatomical structures independently the scope of topographic learning is limited. That being said, well-produced plastinates can display anatomical structures which often cannot be dissected in regular courses. The alternative macroscopic anatomy courses using plastinates constitute suitable alternatives to the regular dissection courses with formalin-treated cadavers for pregnant and breastfeeding students. In Europe, human cadavers have been used for about seven centuries  for the anatomical education of medical students , 2], , , 5], , , 8], , .Thorough knowledge of human anatomy is a fundamental requirement for medical practice, not only in surgery, radiology or physical examination, but also in explaining procedures to patients. Some authors claim that anatomical dissection courses are the most widespread and universal characteristic components of medical education .In recent decades, however, the share of practical anatomical teaching performed through dissection courses at medical faculties has decreased due to reorganizations of medical curricula in many countries , 5], , , 12]. I. I12]. IFor over 20 years, the apparent decline in the anatomical knowledge of medical students has been the focal point of international discussions in surgical specialties , 14]. A. A14]. ATwo recent legal changes with significant impact on medical education added further aspects to the historical discussion.The first of these changes pertains to the GHS classification  of formaldehyde (FA). On April 1, 2015, FA was classified as more hazardous and uprated to category 1B due to its carcinogenicity. Furthermore, as to its Mutagenicity, FA was classified into category 2, as it may also cause genetic defects . As a reThe second change was the revision to the Maternity Protection Act (Gesetz zur Neuregelung des Mutterschutzrechts)  that camOn the basis of these new regulations the Centre for Anatomy at Charité decided to develop and implement alternative macroscopic anatomical courses and examinations for pregnant and breastfeeding students in the third and fourth semester using FA-free plastinates that are acceptable to the female students and reasonable for the Centre for Anatomy.The revision of the Maternity Protection Act not only affects anatomical education at Charité. Pregnant and breastfeeding students are prevented from attending a number of courses in other fields, such as a practical training for the preparation of blood samples, some bedside teaching units, and part of the courses on pathology. All of these, however, are courses with a much lower amount of TUs, often single classes. The affected students may use their contingent of permissible absences. Establishing alternatives to these courses is therefore viewed as not purposeful and would constitute a disproportional additional effort. Therefore, until September 2019, there were no alternative courses in any other subject fields but anatomy at Charité.This article outlines the design of alternative macroscopic anatomical courses and presents a viable way of implementing the Maternity Protection Act. The implementation of these courses is discussed in the context of the abovementioned debates.The following pilot project for implementing the Maternity Protection Act was initially approved for 2 years by the Vice Dean for Learning and Teaching at Charité and was running from summer semester 2017 until winter semester 2018/2019. In this pilot project alternatives to formalin-fixed specimens were assessed and then course programs were designed and implemented subsequently. The aim was to develop alternative courses which offer pregnant and breastfeeding students a study program which enables them to acquire anatomical knowledge as efficiently as their fellow students without the opportunity of carrying out anatomical dissections themselves.The methods for preserving a body are limited. One method is to use a combination of phenol and ethanol , 22], w, w22], wToday, anatomical three-dimensional (3D) prints and computer programs are readily available from commercial providers. Virtual dissection tables are being used in anatomical education, as well as for specific surgical questions , 26], a, a26], aA further argument against using only these methods and/or materials, alone or in combination, as alternative to regular dissection is that medical faculties would also have to offer alternative examinations to these students. The exams have to be as similar as possible to the standard exams in their implementation and demand the same level of recognition from the students. However, the level of difficulty of a given question is considerably lower if a question is asked on a model rather than on human prosection material (unpublished results). There are similar findings for 3D prints  and the Another alternative to regular dissection courses is the use of plastinates for the alternative courses and exams. After the plastination process the tissue is suffused with silicone, free of FA and solid. The finished plastinates are safe , almost Topographical understanding is better supported by anatomical specimens compared to 3D models, which are in turn better than 2D illustrations , 34]. S. S34]. SAt the Centre for Anatomy at Charité a basic set of about 50 plastinates  was already available. As it was possible to produce further plastinated prosection material, offering and implementing the alternative macroscopic anatomy courses and exams utilizing primarily these FA-free plastinates was considered as the best solution.All organs for the production of the plastinates, as well as the cadavers for the dissection courses, are from body donors , who havIn implementing the pilot project, the curricula of the dissection courses in the third and fourth semester were analyzed and specific module manuals detailing the content covered each day of the courses were compiled. Based on these manuals, the demand for plastinates was identified and compared to the inventory of existing specimens. A list of plastinates still required was compiled and ranked by priority. For the production of larger plastinated dissections additional larger equipment was purchased. Additionally, four 3D printed models were bought  and models as well as teacher-centered direct instructions or lecturing, were identical to those in the regular dissection courses. Other strategies applied in the alternative courses included short student presentations on various topics, as a substitute for the students’ demonstration of their own dissection, as well as detailed discussions on the anatomical appearance, the topographical localization, and identification of structures during the dissection process. Apart from manual dissection skills, the alternative courses offer the students the same anatomical knowledge and skills as the regular dissection courses.As the regular dissection courses, the alternative courses are supplemented with additional visual aids, such as bones, models, radiological images and illustrations. These courses are offered parallel to the regular ones with the same frequency and duration, requiring the involvement of an additional lecturer at the curricular level. Maintaining the same schedule for two courses means that students can switch to the alternative courses at any time if necessary.The alternative exams, to be sat at the end of the third and fourth semester, were designed to be identical, as much as possible, to the regular exams as described above. The oral exams were performed by lecturers that did not teach in the alternative courses. Results achieved in the two exams by the participating students were provided by the Office of Student Affairs and anonymized for evaluation in this study. Admission to the alternative courses and examinations is strictly limited. Students have to prove their pregnancy or that they are breastfeeding by a medical certificate. All other students attend the regular dissection courses.To obtain feedback on the students’ experience in the various courses, Charité offers online feedback tools and requests the students to anonymously evaluate, for example, the dissection classes at the end of each curricular module.For the alternative courses the Curricular Evaluation Unit designed a questionnaire which included performed rating statements with scales of agreement, but also allowed for additional comments. In the comments sections the students were asked to give positive and negative feedback on the general curricular conditions, the workload, the teaching and learning success and on the course in general . The data from the regular and the alternative courses were analyzed by the Curricular Evaluation Unit and made anonymously available after the end of each semester.The conceptualization of the alternative courses for the third and fourth semester took half a year of intense planning, structuring and cataloguing.The compiled list of required plastinates was extensive, but mainly included speciments needed to supplement the existing collection and only a few others that were urgently needed. The list consisted of about 30 items, not including different stages of dissections , series of axial sections of the extremities and situs, as well as organ clusters. The most urgently needed plastinates were produced first. There was a range of plastinates already available to provide adequate visual aids for many topics covered in the course. Therefore, the alternative course could be implemented as early as in summer semester 2017.In adding necessary new plastinates that showed different stages of dissection, the opportunity arises to produce specimens illustrating anatomical variations, as well as pathologies found during dissection courses, which can be added to the inventory. These specimens will allow a better demonstration of the variability of anatomical structures and organs.Furthermore, the plastinated specimens specifically produced for the alternative courses can be use in other courses and lectures. For example, a set of specimens produced with distinct anatomical and pathological variations of the heart anatomy, can also be used in a practical course of the regular curriculum addressing coronary heart disorders to illustrate healthy and pathological conditions . The response rate in the alternative courses is markedly better, probably as a result of reminders to the students by the lecturer. Verbal feedback given directly to the lecturer has been only positive.The alternative courses offer a major advantage to the students by facilitating a seamless continuation of their studies, instead of completing the dissection courses and related exams at a substantially later date. The aim of this pilot project was to provide comparable conditions, as far as possible, for learning human anatomy to pregnant and breastfeeding students as experienced by their fellow students. Considering the feasibility of the implementation the results of the exams and evaluations, we believe that this aim has been achieved.The successful implementation of the Maternity Protection Act described here, may work less efficiently at smaller medical universities. With smaller student cohorts, fewer pregnant and breastfeeding students would be wishing to attend the courses. The financial burden would include the position of a lecturer, the costs for storaging the plastinates and if needed, the commercial acquisition of plastinates, estimated at about 500,000 € (based on quotes from a manufacturer). The interpretation of the law, as to when the introduction of a course for pregnant and breastfeeding students is considered to be unfeasible, is the universities’ responsibility and the disproportionate effort involved needs to be verifiably demonstrated. Individual circumstances will be the decisive factors. Transferring this concept of an alternative course to educational settings in other fields of medicine  is highly questionable as the circumstances and demands are too distinct. Additionally, the affected courses mostly involve much fewer teaching units. As other colleagues, we at the Centre for Anatomy at Charité agree that teaching human anatomy on human and flexible cadavers leads to the most sustainable learning results , 31]. A. A31]. AThe newly developed alternative macroscopic anatomy courses and exams for pregnant and breastfeeding students constitute adequate alternatives closely matching the regular dissection courses in the medical curriculum. This method is recommended to all institutes that have the appropriate resources and opportunities. The number of participants shows that there is enough demand to warrant the resources and efforts required to plan and implement such courses. The project at Charité was extended after the pilot phase and is running now as an integral part of the curriculum. The introduction of similar alternatives for anatomical courses in later semesters is in discussion.In view of the well established advantages of regular dissection courses and the limitations of their alternatives, we recommend dissection courses as the central elements in the anatomical education of medical students. At the same time, we recommend the here described alternative macroscopic anatomy courses which uses plastinates, as a valid and useful substitute program for pregnant and breastfeeding students.We want to thank our colleagues at the Office of Study Affairs for their support and for providing the anonymized exam results after the third and fourth semester and the team at the Curricular Evaluation Unit for designing the evaluation questionnaires and for providing the anonymized evaluation results. We also thank the Vice Deans for Teaching and Learning at Charité, Prof. A. Kuhlmey and Prof. J. Spranger, for their continued support in this project.Finally, a big thank you to all the dedicated people who decided to become body donors and support medical education.The authors declare that they have no competing interests.