West Virginia schools are consistently below the national average on the National Assessment of Educational Progress. Using Data Envelopment Analysis, we estimate the technical efficiency of West Virginia school districts. We find less variation in technical efficiency in West Virginia than in similar studies conducted in other states. This appears to be because of state policy imposing homogeneity of input usage. Due to the limited variation in technical efficiency across districts, we cannot analyze how non-school inputs such as socioeconomic factors affect technical efficiency across districts. Summary statistics organized by county economic status, however, suggest that socioeconomic status plays a role. Our results highlight an important limitation of DEA analysis on schools. Attending school raises the cognitive skill level of an individual, which positively correlates with economic growth . HanusheThere is a long literature on education production . In thisDEA is a mathematical programming approach that identifies the production frontier of a firm (such as a school district) based on existing data and assumptions about the production process . Doing sTo preview our results, we find very little variation in technical efficiency across West Virginia school districts. Further investigation highlighted that West Virginia school districts are constrained in terms of input usage by state policy. While this reduces the amount of technical inefficiency, these rules likely constrain districts on the frontier from shifting the education production frontier outward. Due to the limited variation in technical efficiency across districts, we were unable to analyze how non-school input factors affect technical efficiency by district. Summary statistics organized by county economic status, however, suggest that socioeconomic status likely play a role in explaining county-level variation in technical inefficiency.The remainder of the paper is as follows. Section 2The technical efficiency (TE) numbers drawn from our data envelopment analysis are based on the work done by m inputs used and n outputs produced by firm k. The technical efficiency can then be calculated by:λ is the parameter set, and γ is an indicator of the return of scale. In our research, we consider the Farrel's concept of technical efficiency, in which we assume that a more efficient production process is characterized by producing a certain level of output while utilizing the minimum resources required to do so.By changing the constraint (III), we can run a test to define whether the production process being analyzed operates at a decreasing or increasing returns to scale. We are able to run this test since the DEA is a non-parametric approach, which does not require us to define a specific production frontier. By solving the system above we are able to calculate a relative measure that represents the geometric distance of each school district's production function from the production possibility frontier (PPF); this generates a measurement bounded between zero and one and represents the technical efficiency of each county of the state. Therefore, we have a relative measure of efficiency.To calculate the technical efficiency measure, we used the “Benchmarking” package in R described by The choice of inputs and outputs is very important in the DEA set-up. We follow the education production function literature  to deterIn terms of discretionary inputs, the literature focuses on the resources available for the DMU. In this paper, we use expenditures, measured as staff and teachers salary per pupil, and resources available, measured by the number of teacher and staff per pupil. Unfortunately, we do not have data on physical resources such as computers, classrooms, among others. As for non-discretionary inputs, we use the population and real personal income which should account for socioeconomic and cyclical changes. For the non-discretionary variables we use data at the beginning of the school year.2.1West Virginia has 55 county public school districts. Data on discretionary inputs and output measures for each WV school district for the 2008/2009 to 2014/2015 school years were obtained from the West Virginia Department of Education (WVDOE). Data on the non-discretionary inputs come from the Bureau of Economic Analysis (BEA). One possible limitation from DEA analysis is the presence of outliers. If this is the case, one possible solution is the use of a super-efficiency analysis . Fig. 1 53To better understand school district efficiency in West Virginia we create two measures of technical efficiency by combining different inputs and outputs. For both measures of technical efficiency, we use the three listed variable as output, namely, 11th grade test scores in Math and English and graduation rates. For the first technical efficiency measure (TE1) we use only the discretionary variables, i.e., the number of staff members  and their respective average salaries. As for the technical efficiency measure (TE2), we add the discretionary and non-discretionary variables (income per capita and population). The average technical efficiency results for each West Virginia school district from 2008/2009 to 2014/2015 are presented in To get a good sense of the overall variation in our data, There are two things to note about the average technical efficiency numbers presented in Salaries are the largest cost of any school district, comprising 80% or more of current expenditures . That faGiven that DEA analysis is a relative measure of efficiency, the homogeneity of salaries mandated by West Virginia state law would seem to be leading to the high degree of efficiency in the state. This cost efficiency, however, may come with a downside that cannot be observed in our framework. To the extent that constraints on input usage such as restrictions on compensation, prevent school districts from shifting out the production frontier, West Virginia school districts could be technically efficient but at a lower level of output than could otherwise be achieved. These highlights and important limitation of DEA analyses in education – the legal and institutional environment in which schools operate often determined by state-level policy that affects all observations equally and thus does not directly appear in the analysis.The concept that imposing budget allocation constraints can limit the ability of school districts to perform well has also been highlighted by Typically what is done in technical efficiency studies is to regress non-school inputs, such as county demographics, on the measure of technical efficiency. This would be the second stage on a multi-stage DEA analysis. However, in this paper, we opted to use the non-discretionary variables as inputs in the production function, especially in light of the limited degree of demographic variation across school districts.6In Looking at the mean and the min column in Lastly, we calculate the scale efficiency (SE) for both technical efficiency measures. Scale Efficiency is defined as the ratio between the technical efficiency under CRS to VRS. According to Both 4The primary objective of this paper was to estimate the technical efficiency of West Virginia school districts in order to see if there were cost efficiencies that could be achieved. Our results show that, that the average West Virginia school district is operating at 93% efficiency, well above the average for similar studies. In addition, we see little variation between the level of efficiency among the school districts.Our findings have two implications for public policy in West Virginia. First, the high level of technical efficiency and the lack of variation reflects homogeneity across school districts. Some of this uniformity is undoubtedly due to the homogeneity in population characteristics across West Virginia counties compared to other settings. On the policy side, however, this uniformity is what appears to be desired policymakers in West Virginia given the requirement that salaries vary no more than 10% across school districts. Our results seem to support that the law is succeeding in leveling the playing field in West Virginia. Second, although the results suggest that education in West Virginia is doing well, this homogeneity might be resulting in a leveling down of education. This would be consistent with cross-state evidence from the National Assessment of Education Progress showing West Virginia schools as consistently being below average.More generally, our findings highlight an important limitation of DEA analysis. As a relative measure of efficiency, it is only useful to the extent that school districts have the ability to freely use available inputs to shift out the production frontier. However, if school districts or schools are severely constrained, as West Virginia law seems to do by severely restricting teacher salaries, then DEA analysis is of limited use. At a minimum, our results suggest that those utilizing DEA analysis need to carefully consider the legal and institutional context of a locality before interpreting their results.Given that WV has not shown any signs that this policy which imposes homogeneity in public schools will be modified, social policies are alternatives which could potentially improve students' outcomes as highlighted by Future work could explore the comparison between private and public school, an approach previously explored by Eduardo Minuci, Amir B. Ferreira Neto, Joshua Hall: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.The authors received no funding from an external source. Within West Virginia University, the authors would like to acknowledge travel funding from the Center for Free Enterprise.The authors declare the following conflict of interests: Minuci and Neto have no conflicts of interest. Hall has received grants and honoraria totaling more than $10,000 over the past decade from the Charles Koch Foundation, Institute for Humane Studies, Liberty Fund, Texas Tech University's Free Market Institute, Alliance for Market Solutions, and many smaller honoraria for public speaking at universities. A full list is available on his webpage.https://doi.org/10.1016/j.heliyon.2019.e01990.Supplementary content related to this article has been published online at No additional information is available for this paper.


Research ethics consultation is an advisory activity that differs from ethics committees, and its role is not yet widely known in Japan. Research ethics consultations were started in 2012 by members of the Clinical Trial Center of Tokushima University Hospital, a support section for clinical trials. We analyzed the research ethics consultation records from Tokushima University Hospital during the 5-year period of 2012–2016 to examine the Japanese context of research ethics consultation.During the study period, 125 research ethics consultations were carried out, 115 (91%) before starting studies. All but one request were from investigators at Tokushima University. The main issue was compatibility with guidance and regulations , such as ethical handling of human biological specimens and information utilized in research; only 6 (4.8%) requests involved research ethics issues that investigators face in their research. Therefore, it is necessary to expand the consultation function, with a nationwide system of consultant education and data sharing. Moreover, standardization of consultation should be considered. Attention to research ethics is a key element of biomedical research, and the role of research ethics committees is well established in many countries, including Japan . ResearcIn Japanese clinical research, the infrastructure for clinical trials for drug approval, also called registration trials, proceeded after the introduction of the good clinical practice (GCP) guidelines originally approved by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use in 1998. To provide infrastructure for registration trials and to comply with the GCP guidelines, organization and personnel training were pushed forward. However, in 2001–2003, ethics guidelines that apply to clinical studies other than registration trials were established by the government ministries [To provide infrastructure for registration trials and to comply with the GCP guidelines at Tokushima University Hospital, the Clinical Trial Center for Developmental Therapeutics (CTCDT) was established in April 1999. The original aim of the CTCDT was to manage and promote registration trials by liaising with clinical research coordinators (CRCs) . After tWe have been recording our research ethics consultations, including the following elements: client information, question, assessment and analysis, and recommendation. In the present study, we retrospectively analyzed these records. In a previous report of research ethics consultations from a Japanese institute, Kamisato et al.  divided The number and timing of research ethics consultations are shown in Table As shown in Table In biomedical research, research ethics is undoubtedly an important element. Apart from an ethical review by an ethics committee, research ethics consultation services have started to cope with issues in research ethics. As defined by Bescow et al. , the proIn Japan, few courses at the university are specialized in research ethics, but there are still a few faculty members of research ethics. The research ethics consultation providers at Tokushima University Hospital consist of one physician (the Director of the CTDCT) and two scientists in the clinical trial support section. This is in line with previous reports , 14. KamOur research ethics consultation providers were not ethics committee members. Ethics committee members may serve in research ethics consultation at some facilities, but we consider it desirable to build a system in which research ethics consultation acts independently from the ethics committee, clarifying the difference between advice and review. Currently, our research ethics consultation providers support the ethics committee with an annual survey of the ongoing state of approved studies, the maintenance of a web-based application system, and pre-checking application documents. However, separating practical support of the ethics committee from research ethics consultation could be desirable.The role of research ethics consultation is to advise on research ethics beyond simple guidance on compatibility, and this point makes research ethics consultation another activity rather than a simple response to inquiries from investigators. However, the situation is different in Japan. In Kamisato et al.’s  analysisIn research ethics consultation, it is necessary to expand the consultation function to research ethics issues that investigators face in their research; therefore, the quality of research ethics consultation providers is important. Under the present conditions, exchanging experiences among research ethics providers may be a method to consider. Moreover, it is necessary to have a nationwide system for advancing research ethics consultants, as well as facilities securing an employment system for these experts. In the CTSA consortium, a consultation group organizes and shares data on research ethics consultation, working towards the standardization of research ethics consultation . Porter We analyzed 125 research ethics consultations at Tokushima University Hospital and found that the main issue was consultation on the compatibility with guidance and regulations. It is necessary to expand the consultation function to the issues on research ethics that investigators face in their research. Establishment of a nationwide education system of consultants and data sharing with standardization of consultation is warranted.Several limitations should be considered in the present study. The present study was conducted in one university hospital in Japan. Although previous reports described similar situation in handling inquiry about issues in research ethics from investigators , 13, 14,


Health in All Policies (HiAP) has gained attention as a potential tool to address complex health and societal challenges at global, regional, national and subnational levels. In a recent article, Lawless et al propose an evaluation framework developed in the context of the South Australia HiAP initiative. Strategies, mediators, activities and impacts identified in the framework could potentially be useful for evaluating HiAP in other settings. Creating and sustaining political will, managing conflicts of interest and achieving financially, politically and conceptually sustainable HiAP initiatives are challenges that could be further strengthened in the current framework. Health in All Policies (HiAP) has gained attention as a potential tool to address complex health and societal challenges at global, regional, national and subnational levels. For the World Health Organization (WHO) Global Health Promotion Conference in 2013, WHO Regional Offices collected a wide range of case studies that used a HiAP approach.4 As the definition states, HiAP is not an objective by itself, but rather a tool to improve the quality of policy-making from the health and health equity point of view.HiAP has been defined as an “approach to public policies across sectors that systematically takes into account the health and health systems implications of decisions, seeks synergies, and avoids harmful health impacts, in order to improve population health and health equity.”12 The framework is based on program theory and departs from a linear understanding of policy-making. To account for the messy, “juggling” process of policy-making, the authors draw on Kingdon’s framework of three streams  and windows of opportunity arising after the convergence of these streams. The framework identifies the assumptions, context, strategies, activities – which includes actors, structures and processes involved in HiAP – that result in outputs and outcomes of HiAP in the State of South Australia.The ambitious task of developing a systematic framework for evaluating HiAP by Lawless et al is timely and highly welcomed.13The framework identifies three strategies worth commenting upon. Two strategies are devoted to building relational and governance systems that connect individuals and actors in an institutional context. Policy-making is, after all, made by people and connecting these people to create a culture of collaboration is essential to build a common ground for HiAP. The essential activities for these strategies include establishing structures, such as the dedicated HiAP unit, and processes  that allow bureaucrats and senior decision-makers to connect. A similar dedicated structure has been used in the California Health in All Policies Task Force.14 A broader conceptualization of structures and processes could strengthen the generalizability of Lawless et al framework. More importantly, dedicated structures and processes put HiAP at risk of transforming it in one more silo if not well balanced with a broad institutional vision of the importance of health in policy-making.15The authors denote these structures and processes in the way they have been implemented in South Australia. There are, however, several possible arrangements as documented carefully by McQueen and colleagues, with various degrees of success depending on contextual factors.intersectoral action for health). It could also prevent criticisms of “health imperialism.” For example, Ecuador has framed HiAP issues around the concept of wellbeing, as the agglutinating force of HiAP.1 In this view, all sectors contribute to the wellbeing of the population, placing the health sector as a contributor together with education, housing, social services, transport, economy, to name a few.A third strategy draws attention to the issue of framing, or how to articulate a common goal that provides policy gains not only for the health sector but to all sectors. A broad framing that includes the objectives of other  sectors can potentially provide better momentum to reach synergies and to gain greater political will than asking other sectors to contribute to a health issue , does not seem to have played a role in the South Australia experience. Recent research suggests, however, that conflicts of interest are a key factor preventing governments and subnational jurisdictions to promote cost-effective polities to curb NCDs. The experience of Mexico and Chile in the process of introducing and raising taxes on sugar-sweetened beverages remains as a cautionary tale of the power of the food industry to promote commercial interests over public health.One of the key challenges in all HiAP initiatives is sustainability. This includes financial sustainability to maintain the structures and processes, the political sustainability to keep the political will from the highest authority and the conceptual sustainability to systematically preserve HiAP in the context of competing agendas and frameworks. Changes in government can be particularly devastating when the HiAP initiatives are not administratively or legally grounded and can result in significant turnover of civil servants in the health and other sectors, as well as a change in routines and engagement mechanisms that proved successful in the past. They can, in turn, provide new windows of opportunity for policy change. The framework could be strengthened by taking sustainability more explicitly into account.All in all, the article by Lawless et al provides an excellent contribution to the evaluation of HiAP initiatives worldwide. Future research could provide more insights into how existing initiative have been able to create and sustain political will, address conflicts of interest and ensure sustainability over time.Not applicable.Author declares that he has no competing interests.SP is the single author of the paper.


The amplified warming of the Arctic in recent decades has been related to extreme weather events over the mid-latitudes, but its relative importance compared to other influences is not yet well understood. A Nature Research collection highlights evidence from theoretical and observational studies, as well as implications for future extreme events. As a consequence, amplified Arctic warming has direct economic and societal impacts for the societies in Europe, Asia and North America. However, although the existence of a link between the Arctic and mid-latitudes is now well established, there is a growing debate between scientists about the strength of the influence of Arctic warming versus that of other regions, like the Tropics, on the mid-latitudes. A new Nature Research collection from Nature Communications, Nature, Nature Geoscience and Nature Climate Change brings together Review articles and recent research on the relevance of Arctic warming for mid-latitude weather extremes.The Arctic is currently warming faster than most parts of the world as a consequence of human greenhouse gas emissions, resulting in extensive sea-ice and snow cover decline. Although these changes play a prominent role in the public debate on climate change, they are often perceived as remote, with little direct impact on humans. On the contrary, research has suggested that amplified Arctic warming can cause changes in the atmospheric circulation associated with an increasing frequency and intensity of extreme weather events over the mid-latitudes1. At the time, a possible Arctic influence on the mid-latitudes was not only argued for by concurrence of trends, but also by a theoretical understanding of how polar conditions can influence lower latitudes. A decline in sea-ice and snow cover is expected to change large scale patterns of sea level pressure that influence weather conditions over the Northern hemisphere, along with changes in the latitude and strength of the fast flowing air masses of the jet stream while promoting increasingly persistent weather patterns (Fig. When observational data showed an acceleration of Arctic warming and sea-ice loss from the 1990s onward, a correlation with increasing winter and summer extreme events in the mid-latitudes was noted2 and the economic cost of a single cold event in the US can be up to 3 billion Dollars3. Due to these vast societal impacts, scientific research on possible causes of single extreme weather events and their relationship to anthropogenic climate change has received significant media and public attention.Possible consequences from such changes include more frequent and severe cold spells, heavy rainfalls and heat waves. Events such as the Eurasian heat wave of 2010 and the increasing frequency of winter cold extremes over East Asia and North America have been attributed to the effects of Arctic warming. The heat wave of 2010 is estimated to have caused more than 50,000 deaths in Russia alone4. Furthermore, climate models, the main instruments to study causal relationships in the climate system, have shown a differing response of the atmospheric circulation to Arctic sea ice loss5. Such differing results could be explained by the short timeframe of observational data, with satellite measurements starting only in 1979, which is too short to detect significant trends. It is also possible that climate models may differ in representations of key processes that influence their response to sea ice variations5. These factors might play a role, but the conflicting evidence more likely reflects the multitude and complexity of influences on mid-latitude conditions from more than just the Arctic.While a potential linkage between Arctic warming and mid-latitude extreme events is now generally recognized, more research is still required to evaluate the strength of the Arctic influence. Some studies have reported effects which were predicted by Artic warming, for example a weakening of the jet stream, but some scientists debated the statistical significance of these changes4. For example, the atmosphere exhibits its strongest warming at different heights in the Arctic and the Tropics and as a consequence of this asymmetry, the jet stream is expected to shift southward in response to Arctic and northward in response to Tropical warming4. However, the competing effects of the regions do not necessarily cancel each other out, and therefore identifying which region is the strongest influence is crucial for unlocking how the mid-latitudinal weather changes due to global warming. Due to the complexity in reaching a consensus on how the mid-latitudes climate will change in the future, this demands collaborative research efforts, for example with systematic model comparison projects.This complexity has given rise to a tug-of-war between contrasting effects of the Arctic and Tropics on the mid-latitudes. It is well established that the Arctic is not the only region that changes atmospheric circulation, and that other regions, in particular the Tropics, can exert an influence over the mid-latitudes as well. Like the Arctic, the Tropics are also seeing dramatic changes due to anthropogenic greenhouse gas emissions. There is growing evidence to suggest that the Tropics could counter some of the effects a warming Arctic has on atmospheric circulationThe degree to which the consequences of anthropogenic warming in the Arctic and Tropics controls extreme weather events at the mid-latitudes will have significant implications for future climate risk assessment in these regions. Of course, the most efficient way to prevent catastrophic changes anywhere would be to reduce emissions that are driving the changes in the Arctic and the Tropics. If these efforts are not successful, however, a consistent and reliable estimation of expected extreme weather events is vital for governments to allow an effective adaptation to climate risks, as well as for stakeholders, such as the energy and insurance sectors.In addition to the direct political and economic interest, there are also societal implications of this research, as it has the potential to increase awareness of global climate change in those societies living in the high-population and high-emission regions of the mid-latitudes. Currently, some of the strongest effects of climate change are observed in the high- and low-latitudes and hence primarily affect societies around the Arctic Ocean or on Tropical Island states, which are often marginalized in the debates on climate change. The mechanisms discussed in the Nature Research Collection demonstrate once again that changes happening at distant locations cannot be viewed in isolation, but that the consequences of human greenhouse gas emissions affect all societies.


At present, the increasing trend of medical disputes has become a serious problem in the work of medical institutions, and directly affects the social stability and orderly development of the institutions. We searched the literature on medical disputes and crisis management in China and Australia within PubMed (2010–2019), China Knowledge Network , and Wanfang Data Knowledge Service Platform (2010–2019). There are several drawbacks in the management of hospital medical disputes in China: 1) the knowledge of crisis is unilateral and not systematic; 2) there are too much stereotype thoughts in crisis management; 3) the crisis attribution is too simple; the crisis impact assessment is insufficient. It is worth learning from Australia’s system, including the legal system, relevant non-governmental organizations, and doctor-patient communication. In view of the malpractice existing in China’s medical dispute management, Australia’s legal system for handling disputes, doctor-patient communication and other aspects are worthy of our reference. In particular, the construction of third-party supervision and mediation institutions and the prevention of doctor-patient disputes should be optimized. In recent decades, the number of global medical disputes has increased dramatically –2. In reFrom 1991 to 2005, 7.4% of doctors filed malpractice claims annually, and 1.6 percent received compensation for malpractice. Compared with that in 1991, the number of medical disputes has tripled in 2005 .This paper summarizes and analyzes the experience of doctor-patient crisis management in China and Australia, and puts forward the adjustment direction of medical dispute crisis management in China in the future.Since the beginning of the 21st century, the number of medical disputes in China has increased rapidly due to the contradiction between the supply and demand of medical services, as well as the enhancement of patients’ awareness of safeguarding their rights and the imperfection of the legal system. There were even “medical dispute profiteers” , 10. TheThe incidence of doctor-patient disputes is high according to the investigation report “The situation of violence in hospital places” by Chinese hospital association. The number of hospitals where doctors were injured jumped from 47.7% in 2008 to 63.7% in 2012. In 2008, there were 20.6 incidents of abuse and threats against medical staff in each hospital, and the number reached 27.3 in 2012 . AccordiMedical malpractice processing law of China, when civil liability disputes of compensation for medical malpractice occur, there are three ways to solve them: First, consultation between doctors and patients; Second, the parties apply for mediations in the administrative department of public health; Third, directly bring a civil lawsuit to the court  occur in tertiary and secondary hospitals . AlthougThird, the staff have limited ability to deal with medical disputes and cannot properly solve medical disputes in a timely manner, and the mass media exaggerated the doctor-patient disputes. After the occurrence of doctor-patient disputes, managers have no basic legal protection, and patients have no better channels to safeguard their own rights and interests. As a result, the problems between health workers and patients became more serious, and the crisis was not contained in the bud, which led to a larger crisis . Fourth,The research on crisis management in China lags behind compared with that in western countries. The research on medical dispute crisis management is in a beginning stage. After the outbreak of SARS in 2003, Chinese government and scholars began to pay attention to crisis management in the field of public health. According to the research results in the past decade, crisis management has been involved in various fields in China In 2011. Crisis management of medical disputes can help hospitals change medical disputes from “emergencies” to “pre-occurrence” events, grasp information in advance, and change their thinking from “post-emergency treatment” to “pre-occurrence control” The crisis before the outbreak, the risk assessment and crisis prevention work have been ignored, which make the hospital management department unable to predict the crisis timely, and unable to improve the quality of the management of the hospital medical disputes. It is not conducive to the hospital medical disputes on the solving the problem .Medical disputes in Chinese hospitals are mainly handled by the medical department, coordinated by the security department. They failed to found a joint management team with other relevant departments. To a certain extent, after the occurrence of medical and health disputes, the medical service department did not deal with medical disputes in a scientific manner according to the characteristics and specific circumstances of the crisis in time, which has an adverse effect on the handling the crisis. At the same time, the application of crisis management mode can easily lead to a solid thinking pattern of crisis management staff, which makes the hospital being the passive party in doctor-patient disputes and unable to truly solve the doctor-patient relationship.In dealing with medical disputes, it usually takes more time and energy to investigate the facts and analyze the causes, while ignoring the catalytic role of time cost and media in crisis events. As a hospital manager, it is often implied that disputes are caused by patients’ excessive expectations, while patients think that the high cost has not achieved the desired effect. Both sides always see the problem from different angles and get involved in long-term mediation or litigation, the cost is higher to protect their legitimate rights and interests than the cost of solving the problem. Crises are apt to lead to malignant events. The best solution to a crisis is “Symptomatic treatment” .In Australian, one of the departments is responsible for quality management, its purpose is to check the service quality of medical institutions. It also has a department responsible for drug supervision, it ensures that the drug use is implemented in accordance with national standards . It aimsThere are many non-governmental organizations or associations in Australia, many of which are public welfare organizations. The government may have many disadvantages in the implementation of medical risk management, and some organizations start to appear to help solve medical problems. Australia is very supportive to the work of such non-governmental organizations. The organization can work with health care providers to improve the quality of care. Australia has a special committee to certify these organizations. The NGOs after certification are generally professional, which could improve the service quality and reputation of medical institutions .In Australia, legal efforts were made to improve the medical level and service quality of the whole institution to a greater extent, so as to reduce the possibility of medical dispute crisis , 30.In Australia, the doctor cannot give a death notice within 24 hours for deaths due to a sudden accident, the death of a mental patient or death due to anesthetic drugs, etc. They must report this situation to the police station. After investigation, the health consultant identifies the death caused by special circumstances or a death caused by medical malpractice. Once confirmed, the court will make corresponding punishment or approval. The liability determination of medical disputes and accidents in Australia is also partly completed by the ethics committee within the hospital, and the other part is determined and arbitrated by the judicial system. The court has a special “health consultant”. Australian hospitals have at least one or two ethics committees. An ethics committee will surely be set up to determine and deal with the responsibilities of various medical malpractices and solve the contradictions therein. Australia’s relatively complete medical insurance and government compensation mechanism also allow doctors and patients to be relatively calm in handling accidents and disputes, and willing to trust the conclusions reached by relevant institutions.In Australia, every doctor will buy professional insurance, when the amount of compensation awarded by the court due to medical disputes exceeds 1 million Australian dollars, the government shall bear the excess. Because of occupational insurance and the government’s system of excessive compensation, medical disputes in Australia tend to be mild.The Australian experience can be referred. The third-party agencies, third party mediations are more neutral than administrative mediation, and more authoritative than bilateral negotiations. There are many reasons that may lead to medical disputes, such as the problems of doctors or patients themselves, communication problems and so on. Resolving medical disputes through litigation not only takes up a lot of judicial resources, but also has high cost, complicated procedure and strong antagonism. It is one of the effective ways to alleviate the contradiction between doctors and patients and solve medical disputes through mediation. With the enhancement of people’s awareness of safeguarding their rights, they are more and more eager to have a relatively neutral third-party organization to coordinate and handle conflicts and disputes, so as to ensure a more fair and just result of mediation. The Commission was born in this background.Although the individual interests of some patients and their families are legitimate, their behavior norms, methods and procedures should also be legal. As for the conflicts caused by medical disputes, the government departments should control the behaviors of both parties in the conflict within the scope permitted by law, support patients and their families to protect their legal rights, and stop illegal activities in time. There is no conflict in law between safeguarding social stability and punishing illegal rights and interests, When dealing with problems, only by strictly implementing laws and regulations can the law enforcement departments of the government fairly solve the problems, enable citizens and social organizations to revere the law and form a basic law-abiding mindset of abiding by the law in the whole society. If only the interests and risks of the departments are taken into consideration and laws, and regulations are ignored, the public will lose balance and the society will lose order, thus causing greater instability.It is necessary to improve the system of laws and regulations governing the handling of medical disputes between doctors and patients, and adjust existing laws and regulations that conflict with or are incompatible with the civil law and the law on tort liability. Given the implementation of compulsory medical liability insurance could achieve the purpose “to protect the damage of medical treatment accident victims get compensation according to law, to promote medical security”, based on the principles of legal reserve requirements, it is suggested that China should formulate a unified administrative “compulsory medical liability insurance regulations” .Let the public know that in the face of disease diagnosis and treatment and rescue, Medical institutions has accumulated much experience in human medical cognitive practice and diagnosis and treatment ability. The relevant laws of disease diagnosis and treatment and the relative certainty between different medical activities were also observed.In order to solve the disputes between doctors and patients, China has introduced various policies and improved various mechanisms in recent years. The relevant personage of the state health commission showed that China is speeding up the formation of a coordination mechanism formed by public security, protection and supervision, comprehensive governance, publicity and other departments. In 2015, the medical disturbance behavior was included in the criminal law regulation. Meanwhile, the medical liability insurance system has been established and improved, by the end of 2016, 110,000 medical institutions had participated in medical liability insurance. This is not only conducive to dispersing the economic and occupational risks of hospitals and medical staff, but also conducive to forming reasonable expectations of both parties.In addition, “hierarchical diagnosis and treatment” enables a “long-term contract” relationship between family doctors and patients, rather than the current “one-stop” relationship, which is also conducive to reducing the occurrence of disputes. Patients are guided by the family doctors “where to find a doctor and which doctors they should see”, instead of “blindly flocking to big hospitals”.In the judicial remedy, some simple disputes can be solved by judicial summary procedure. In the process of litigation, the damages caused by medical risks such as complications and medical accidents should be fully considered within the scope of compensation, to guide patients and their families through legal rights to obtain their compensation. The administrative relief realizes its function through the doctor-patient dispute mediation committee. The committee may be established through the bureau of justice, an insurance company or a political and legal commission. The members may be judges, medical personnel, supervisory commissions, government functionaries or members of the public. In mediation, the credibility can be enhanced by strengthening the mediation function, simplifying the mediation process, improving the procedure supervision, and highlighting the mediation effectiveness and execution. Social relief brings material help or spiritual relief to patients or their families through public power. It plays an important and irreplaceable role in correcting “market failure”, adjusting resource allocation, realizing social fairness, maintaining social stability and building a harmonious socialist society . It can In view of the malpractice existing in China’s medical dispute management, Australia’s legal system for handling disputes, doctor-patient communication and other aspects are worthy of our reference. In particular, the construction of third-party supervision and mediation institutions and the prevention of doctor-patient disputes should be optimized.Ethical issues  have been completely observed by the authors.


However, it is quite difficult to transform their discovery into practical use, because the viability of the studied material might require examination of all aspects of properties. In addition, for a material to become a product, a complete procedure involving a declaration, registration, and approval is necessary. This article introduces the technical indices that the investigators and reporters should provide in their declaration and registration data to meet the relevant standards in China. The indices include physical and chemical properties, biocompatibility, biosecurity, pre‐clinical animal model tests, sterilization and disinfection, product duration, and packaging. Full consideration of all possible indices is crucial to realize the transformation from a designed product to a commercial medical device, which requires effective interaction between clinicians and engineers.The use of bone‐filling material to repair bone defects and fix implanted bone grafts is a developing area in medicine. Investigators can evaluate bone‐filling materials through use of several indices to make comparisons and to determine suitability for application in humans For decades, orthopaedic studies have been investigating appropriate materials to fill defects in human bone. Use of bone‐filling material for repairing bone defects and fixing implanted bone grafts is a developing area of research. Researchers seek out special materials that not only have mechanical properties that resemble those of bone, but also have excellent biocompatibility to enable bone fusion.Despite a material having promising medical applications and excellent properties for bone filling it is difficult to reach the commercial stage. The main obstacles are the investigations into and the assessment of the viability of the material. This requires interaction between clinicians and engineers to transform the designed product into a commercial medical device. Certainly, the confirmatory experiments should be conducted according to the relevant national standards and announcements.GB/T 16886 Standard Series and ISO 10993 Standard Series list biological assessment methods for medical devices, providing an outline for structural procedures in biosecurity assessment. They also illustrate assessment methods for medical devices in regard to physical and chemical properties, biological properties, and risk assessments. Opinions on Deepening the Reform of the Evaluation and Approval Systems and Encouraging Innovation on Drugs and Medical Devices, issued by the General Office of the Communist Party of China (CPC) Central Committee and the General Office of the State Council, suggests essential strategies for clinical testing and administration of medical devices. The Announcement on Formations of Resource Requirements and Approval Demonstrative Files of Registering and Declaring Medical Devices (shortened as The Announcement) describes the procedures for approving and assessing organizations. The Investigation and Instruction on the registration of CaP/CaSi‐based bone filling materials (shortened as The Investigation) lists the data that should be submitted during the registration process, and the relevant experiments that should be conducted before registration to demonstrate the viability in regards to every tested property.This article aims to: (i) provide technical support for bone‐filling material registration and declaration; and (ii) discuss the potential experimental procedures to carry out for examination of product viability, to reasonably and efficaciously accomplish the declaration and registration of bone‐filling materials.Generally, the reporter should describe the chemical components, the processing methods, the sterilization types, and the expected uses. The source of control samples (including positive and sensitive control) used in the experiments and the reasons for applying them should be stated. The declared product should be set as the experimental group, and the same or similar type of listed products as the positive control group. A negative control group may also be required for conducting a control test of relevant properties.For each study and assessment report of the relevant property index, the reporter should illustrate in detail whether the product requires the study to be based on this index, and then state the reasons. For the property index studied, the experimental methods, results, discussions, and conclusions should be provided. For any quantitative or qualitative tests, the testing results should meet the requirements for data or criteria as stated in the national standards. For the properties indices that are not mentioned in the national standards but possibly required, the reporter should not only illustrate the experimental procedures, but also state the reasons for performing the experiments as well as whether the results meet the requirements of relevant articles or international standards quantitatively or qualitatively.The physical and chemical properties assessed for the product shall include, but not be restricted to, chemical composition, mechanical properties, density, porosity, and surficial features.in vitro toxicity should be recorded.For every single product, the reporter should indicate its chemical composition and the proportion of each componentWhen detecting its mechanical properties, the product should be closely connected with its material type and shape. For a solid product, the investigator should consider its compressive strengthV0 is the volume of the original product, V is the volume excluding pores, and ρ0 is the original density of the material. Each parameter could be measured several times and applied as the average. The results could be compared with the control sample product and natural bone product .As for the product with the same type of model, its density could be derived by the weight over volumeFor block‐shaped solid bone‐filling products, the surface roughness could be used to indicate its surficial featureThe Announcement, the safety indices for the material should include electrical safety, electromagnetic compatibility, and radiation safetyAccording to Other physical and chemical properties that might be detected in the experimental work include, but are not restricted to, crystallinity (by XRD)in vitro cellular toxicity, and degradationin vitro tests might be processed in a excessive strict condition compared to the practical conditionsin vitro test results sometimes do not represent the real results. Hence it is crucial to implement pre‐clinical animal model tests.Biocompatibility studies the properties of a product when it makes contact with the biological environment. The factors that should be considered include, but are not restrict to, cellular growth and proliferation, cellular adherence, This subsection investigates the ability of the bone‐related cells to grow and proliferate in the environment of the product as a scaffoldCellular adherence is not only a basic condition for stabilizing the tissue structure, but a regulatory factor for cell dynamics and cellular functions. It attaches great importance to the cellular proliferation and differentiationin vitro cellular toxicity testing, the reporter could indicate the components in the product that are possibly toxic, and that might influence cellular activity, based on the literaturein vitro cellular toxicity can be determined using either quantitative or qualitative methods. The quantitative method provides the ratio of deformed and damaged cells among all per unit areas, and extrapolates the cell activity in the related product. The qualitative method estimates the ratio of deformed and damaged cells and subjectively divides the results into gradient levels.Before 2+ and PO43−); and the decomposition of organic macro‐molecules into small particulates  or micro‐molecules  and the absorbance by related cells and tissues (such as the absorbance of bone morphogenetic protein in DBM)The degradation process for bone‐filling materials can be divided into two types: the ionization of the ceramic component in the product and the absorbance of ions by related cells and tissues  and filtered in 120 ± 1 h. The difference between the original sample weight and the residual weight of the particulate is then calculated to give the weight of the dissolved sample.The reporter should indicate whether the product components have potential degradation properties according to relevant literature, and discuss the necessity of the degradation test. According to GB/T 16886.9–2017Reports demonstrating the acquisition, processing, storage, and testing and treatment process of the product.The sources (including details of donators) or the inactivation process of virus, pathogen and substance with immune stimulation .A brief summary of technical verification.For products with biosecurity risk , relevant data demonstrating their biosecurity should be providedThe pre‐clinical test is necessary before the product is applied in the market. The test subjects should be common, healthy, adult mammals The investigation reveals that the bone graft fusion rate is a significant index to assess bone‐filling materials in pre‐clinical animal model tests, and qualitatively to assess the situation of fusion degree between the original bone and the applied product18.This part of the experiment should be conducted according to GB/T 16886.6–2015. The investigator should determine the position of the bone graft implantation and select appropriate animal species. The reporter should assure the least number of animals, periodic group division, and experimental conditions in each group. The local reaction results of the product could be observed by the naked eye and microscopy, and compared with the sample in the control group. Moreover, the reaction degree could be analyzed using a quantitative marking system and a half‐quantitative marking system, the indices of which can be derived from, for instance, the cellular morphology, new vascular formation ability, fibrosis, and fat immersionThis index assesses the possible hazards of the released chemical component from a bone‐filling product when it contacts a body partBecause various components from products might induce different toxic reactions during the pre‐clinical tests, the symptoms could be divided into acute, sub‐acute, sub‐chronic, and chronic, according to the degree of reactions. The study should determine the amount and frequency of the product dose to be injected and take into consideration that the dose amount should be related to the physical degradation ability of the productThe animal strain, source, age, gender, and environmental and food conditions.The experimental substance and sample, purity, stability, composition, and food intake.Experimental conditions such as food intake methods.Testing, extracting, detecting and confirming methods.The material recovery rate.The graph plotting of the results on each time point.The statement of corresponding quality standard and laboratory quality control criteria.Results, discussions, and explanations.This index is used to study absorption, distribution, metabolism, and excretion of the degradation outcomes after the implantation of bone‐filling material devices. The study should examine related dynamic parameters, including the absorption rate, the volume of distribution, half‐life, and clearanceAs mentioned above, the surface roughness of the material could be compared between the results before and after implantation. The change in roughness among all experimental and control groups could also be compared to examine the effect of various products. Because it might be affected by the mechanical properties of the product, the wear resistance behavior could be investigated during the pre‐clinical animal tests. The weight loss of the product could be measured by weighting the product before and after the pre‐clinical tests and calculating the difference. The wear resistance results could be presented as a detailed reportThe experimental assessment before declaration and registration attaches great importance to the properties and behavior of the bone‐filling product. The viability of the product should be fully examined and the requirements listed in the related standards should be satisfied. With the pre‐registration indices qualified, the interaction between clinicians and engineers could be more effective in the transformation of a bone‐filling material to a useful medical device in the market.


Frontiers in Psychiatry accepted to give us this opportunity . TheWe aimed at joining our competencies to provide a shared description of the methods to obtain an optimal therapeutic effect of baclofen in the treatment of AUD. We were aware that to obtain its therapeutic effect, the required dose of baclofen may largely vary among patients, certain patients requiring low doses and other high or very high doses. In other words, our experience showed that patients require “personalized doses” of baclofen that allow them to say “well, at this dose I have no more craving for alcohol, I do not experience craving when I see bottles or people who drink,” meaning that, following Olivier Ameisen’s words, the patient has reached a state of “indifference towards alcohol” .Our special issue had three goals. The first was to give a general view of baclofen use for AUD treatment in different countries. The second was to provide joined information on the methods to prescribe baclofen in the treatment of AUD. The third was to obtain recent data from different research teams involved in various aspects of baclofen use in the treatment of AUD. To achieve these goals, we solicited the participation of a large number of baclofen prescribers worldwide.Garbutt describes the use of baclofen in the US. According to this contribution, there is a limited use of baclofen to treat AUD in the US. However, Garbutt points out that there is, in general, a very low rate of medication use for the treatment of AUD in the US, largely due to a lack of knowledge of physicians and patients about the potential value of medications. Regarding baclofen, the results of meta-analyses showing that its efficacy is equivocal, the concerns of tolerability, and the fact that its prescription remains off label are all elements that may deter clinicians and patients. Garbutt nevertheless mentions that there are no accurate data on the use of baclofen in AUD in the US, making it difficult to know if clinicians prescribe it. These remarks probably apply to most other countries, except France, which is the only country where baclofen has an official approval from Health Authorities in the treatment of AUD, and where baclofen is more widely prescribed.For our first goal, Lancet Psychiatry in 2018 . In detail, we describe how, especially in experimental studies, baclofen is usually administered in fixed doses to evaluate the efficacy and safety of each specific dose whereas, in clinical practice, baclofen is usually administered in flexible doses. In other words, the dose is gradually increased until the patient achieves the desired effects or side effects that prevent a further increase in dose. In this article, other than this description of the methods adopted for baclofen administration, there is also an unprecedented exhaustive review of published studies, approved by 26 authors coming from seven different countries .For our second goal, we convened a large group of international experts, representative of researchers and physicians who contributed to the recent studies on baclofen and AUD. This group of experts achieved a consensus on the use of baclofen to treat AUD—“the Cagliari Statement”—published by  in 2018 . After tPinot et al.); a research report on the response to baclofen in patients receiving antidepressants ; reviews on the effects of baclofen in alcohol withdrawal syndrome (AWS) , on the adverse effects of baclofen , and on the management of self-poisoning with baclofen ; and reviews focused on comorbidities—with liver cirrhosis  and other mental disorders (Agabio and Leggio). In a 3-year retrospective study, Pinot et al. have followed 144 patients with AUD receiving tailored doses of baclofen , and the treatment was successful in 63.3% of the patients (according to the WHO classification criteria) , a percentage of success grossly similar to that reported in other previously published observational studies. Depression and antidepressant treatment are common features in patients with AUD, and it was important to search for a potential interaction between baclofen and antidepressants. Heng et al. show that in patients on long-term treatment with antidepressants prior to starting baclofen, a beneficial effect on drinking outcomes can be shown like in patients who are not using antidepressants. However, there was a trend to an interaction between the two that needs further investigations  . The effectiveness of baclofen in the treatment of AWS is controversial, and Cooney et al., in their review, confirm that the evidence does not support the use of baclofen as a first-line treatment of AWS. Adverse effects too often limit or circumvent baclofen treatment, and this issue must be seriously considered. Rolland et al. propose a thoughtful review on baclofen adverse effects, separating the common and benign ones  from the rare but potentially dangerous ones , and point that concurrent consumption of alcohol, benzodiazepines, and other sedatives may worsen many adverse effects. These considerations have consequences on baclofen treatment management in terms of prevention of adverse effects and obtaining an optimal response . Cases of intentional or non-intentional baclofen self-poisoning have increased in parallel with the increasing use of baclofen in AUD. These cases present with particular clinical features that clinicians must be aware of. Franchitto et al. review the literature on that subject and address the management of this condition. AUD is often associated with liver cirrhosis and/or mental illnesses. AUD is difficult to treat in patients with liver cirrhosis because approved AUD medications may impair liver function. Baclofen is attractive because it has no liver toxicity, and Mosoni et al. review the clinical trials investigating the effect of baclofen in patients with AUD associated with liver disease. The results show a very favorable effect of baclofen in these patients, although the most appropriate dose of the drug remains to be determined . Mental illness may alter the outcome in baclofen-treated patients. Agabio and Leggio address this issue by using a narrative analysis of all clinical and human laboratory studies of baclofen treatment in patients with AUD with or without mental illness. The most frequent psychiatric comorbidities are anxiety and depression. Further work is needed to determine if these comorbidities interfere with baclofen treatment outcome (Agabio and Leggio).For our third goal, several innovative reports dealing with baclofen prescription and use, pharmacokinetics, preclinical research, and clinical investigations aiming to understand its potential mechanisms of action in AUD are published in the special issue. Reports on baclofen prescription and use include a long-term retrospective study . The results show that baclofen has a linear pharmacokinetic profile, corresponding to a one-compartment model, with no influencing clinical or biological factor . In their second article, Simon et al. review the literature investigating the baclofen dose in relation to the pharmacokinetics of the drug. Indeed, the dose–response variability in baclofen-treated patients may be related to variability in pharmacokinetics. In particular, the effects of intestinal absorption, blood–brain barrier transport, and renal elimination are highlighted .Reports on baclofen pharmacokinetics include two studies by Simon et al. In their first article, Colombo and Gessa. Baclofen suppresses many alcohol-related behaviors in laboratory animals, including locomotor activity, alcohol drinking and self-administration, binge-like drinking, relapse drinking, alcohol seeking, and AWS symptoms. These effects of baclofen in animals provide interesting elements for the understanding of its mechanism of action in AUD (Colombo and Gessa). Two clinical studies also bring new data that could help the understanding of the mechanism of action of baclofen. Morley et al., using magnetic resonance spectroscopy, show that baclofen increases the concentrations of the antioxidants glutathione and N-acetyl aspartate in the brain of patients with AUD, and that higher glutathione levels predict favorable outcomes at follow-up. This supports the idea that the beneficial effects of baclofen in the treatment of AUD could be, at least in part, related to neuroprotective mechanisms . Durant et al. show that the effects of an acute administration of baclofen are very different in patients with AUD compared with healthy controls. The measured effects were growth hormone release and subjective experience . All these responses were blunted in patients with AUD while they were very marked in healthy controls. According to the authors, these results indicate a lower sensitivity to baclofen and, by extension, a general lower GABA-B receptor sensitivity in patients with AUD . Finally, the potential mechanisms of baclofen in AUD are reviewed in an article that concludes that baclofen may produce an indifference to alcohol by suppressing the Pavlovian association between alcohol cues and rewards through an action in a critical part of the dopaminergic network . This action of baclofen is made possible by the fact that baclofen and alcohol act on similar brain systems (in particular GABA-B systems) (de Beaurepaire).Preclinical research is reviewed by We really hope that this special issue will contribute to improve our knowledge and enhance debates and research on the use of baclofen in the treatment of AUD, a devastating illness that is dramatically undertreated.All authors equally contributed to this work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The reviewer GA declared a past co-authorship with one of the authors RA to the handling Editor.


Objective: This study investigated the impacts of the hierarchical medical system under the national health insurance program on residents’ healthcare-seeking behavior in Taiwan. Background: Healthcare authorities in Taiwan initiated an allowance reduction for outpatient visits at regional hospitals and higher hierarchical hospitals in 2018. The ultimate goal is to implement a hierarchical medical system to provide residents accessible as well as consistent medical services. Methods: This research was conducted through a questionnaire survey, and data were collected between August and December 2018 from the records of subjects who had recently sought medical attention. A total of 1340 valid questionnaires were returned. Results: A principal finding was that there were significant differences in the knowledge of new policies by age, marital status, annual income, education level, and occupation (p < 0.001). Regarding the effects on healthcare-seeking behavior, there were significant differences from persons aged 40–49 years (p < 0.1), in junior high school (p < 0.05), not aware of the policy (p < 0.001), and awareness of both the hierarchical medical system and the policy to reduce outpatient visits to large hospitals (p < 0.001). Conclusion: The health administration authorities should devote more effort into promoting knowledge of the policy in order to better inform the public about the hierarchical medical system. Taiwan’s current healthcare system is divided into four levels: Medical centers, regional hospitals, district hospitals, and clinics. After the implementation of the National Health Insurance (NHI) program in 1995, the convenience of seeking different healthcare facilities was based on the accessibility of healthcare services. The current NHI program discourages unnecessary healthcare-seeking behavior due to greater patient choice, easy access, and low medical cost burden . The perWhen the NHI program was introduced, the essence of the “medical referral system and hierarchical medical system” was included in the National Health Insurance Act. After the implementation of the NHI program, hospital crowding regardless of disease severity resulted in packed hospitals and overcrowded emergency rooms; meanwhile, district hospitals were shutting down ,5. AccorHence, the government of Taiwan has promoted a hierarchical medical system to enable medical centers and regional hospitals to refocus on the fundamental areas of teaching, research, and care for emergency cases and difficult diseases. Since 2017, the growth in the numbers of outpatient visits for minor ailment services at medical centers and regional hospitals has been limited; the number of outpatient visits could not exceed 90% of those in 2016 or the NHI program would not reimburse the costs. As a result, the upcoding of diagnosis for minor ailments by hospitals to reduce the number of patients under primary care was instituted to respond to the cuts in reimbursement. As these limits were not effective, in 2018, the Ministry of Health and Welfare established a hierarchical medical system and medical referral systems to promote reduced outpatient visits to large-scale hospitals to cut outpatient visits to medical centers and regional hospitals by 2% in 2018 and to reach the target of a 10% reduction within five years. Those facilities that fail to reach the target will not be reimbursed by the NHI program 7] discusSecond, significant effects were found on healthcare-seeking behavior among different age groups and various educational backgrounds, similar to the findings of Chang et al.  and of SFurthermore, low awareness of the hierarchical medical system and the policy to reduce outpatient visits to large hospitals have a significant impact on healthcare-seeking behavior. Similar to the findings of Chang , from thThe empirical results of this study also show that approximately three-fourths of the subjects were not aware or only party aware of the NHI policy. The main purpose of the hierarchical medical system is to lead to changes in healthcare-seeking behavior, improve efficiency, differentiate healthcare services, and promote the division of labor. The decision makers in the NHI must be informed about the re-structuring of the hierarchical medical system and policy to reduce hospital visits when deciding the promotion of policy. Thus, this study suggests that the competent authorities in health administration devote greater efforts to policy promotion to inform the public of the hierarchical medical system to help resolve the issue of healthcare-seeking upgrades.Over the past several years, a hierarchical medical system has been the goal of Taiwan’s healthcare policy. Since 2005, the National Health Insurance Administration began promoting a bi-directional medical transfer system in an attempt to increase the return visit rate of patients to local clinics and reduce outpatient visits of patients with minor ailments to large hospitals. In fact, the return visit rate to local clinics remains low. Based on their past visit experience and impressions of healthcare institutions, and especially when the patient–physician relationship is strong, the loyalty of patients toward their physicians will be reinforced . ReasonsThe healthcare system and background of each country have different impacts on social development. In Taiwan, although the medical transfer system and family doctors are available, medical resources are not integrated and there have been no coordinative measures. Family doctors fail to play the role of gatekeeper, the public often chooses outpatient visits to hospitals, and it is difficult to avoid treatment of minor ailments at large hospitals. Thus, it is especially important to restrict freedom of healthcare seeking to ensure the implementation of the hierarchical medical system.


The emergence of nanomedicine in the past decade has changed the landscape of disease diagnosis and treatment. Nanomedicine makes use of nanostructures for applications in different fields of medicine, including drug delivery, biosensors, neuro-electronic interfaces, in vivo imaging, and cell-specific molecular interactions. Despite its relative infancy, nanomedicine has generated a significant body of research as evidenced by peer reviewed literature and several patents. This proposed systematic review will focus specifically on drug delivery systems in which nanoparticles are used to enhance the pharmacological and therapeutic properties of drugs. The strength of nanoparticulate drug delivery systems is their ability to alter the pharmacokinetics and bio-distribution of drugs.Globally, the discourse on nanomedicine is dominated by research being done in the developed countries of Europe and in the United States of America. Less attention has been given to the applications of nanomedicine in developing countries, particularly Africa. There is dearth of information on the applications of nanomedicine in terms of drug delivery with particular reference to which diseases are being targeted generally in Africa. The review will describe the specific diseases that are being targeted and the progress being made in South Africa, with a view to determining whether the applications of nanomedicine are being appropriated to address the context-specific challenges in this country or if they mimic what is being done globally.Keywords related to nanomedicine and drug delivery will be combined to build a search strategy for each of the following databases: PubMed, Cochrane Library , Cochrane Database of Systematic Reviews, Cochrane Methodology Register), Google Scholar, NHS Health Technology Assessment Database and Web of Science. We will also check reference lists of included studies for other eligible reports and search unpublished data. To ensure that the search is comprehensive, grey literature will be searched extensively. Literature to be included will have nanomedicine in drug delivery as the primary application and report on the specific diseases that are targeted in South Africa. Two authors will independently screen the search output, select studies and extract data; discrepancies will be resolved by consensus and discussion. When no consensus is reached, the third author will be consultedThe systematic review will inform the government, policy-makers, investors, health professionals, scientists, and engineers about the applications of nanomedicine in drug delivery. In particular, it will identify the diseases targeted by the application of nanomedicine for drug delivery and the progress being made in South Africa as the disease burden of this country differs from that of developed countries where nanomedicine has been widely used for drug delivery.CRD42017057388PROSPERO The online version of this article (10.1186/s13643-018-0823-5) contains supplementary material, which is available to authorized users. Nanomedicine is defined in a variety of ways, but an all-encompassing definition includes the development of nanoparticles, nanostructured surfaces and nanoanalytical techniques for molecular diagnostics, treatment, follow-up and therapy of diseases . ResearcThe nano-scaled particles used in nanomedicine have revolutionised drug delivery, allowing therapeutic agents to be selectively targeted on organ, tissue and cell-specific levels, while minimising exposure of healthy tissues to drugs . The useThe ability of nanoparticles to interact with cells and tissues at a molecular level provides them with a distinct advantage over other polymeric or macromolecular substances . Nanopar. This can make in vivo delivery of drugs that pose serious delivery problems, a relatively easy task [New types of intelligent nanoparticles respond to an externally applied field, be it magnetic, focused heat, or light, in ways that make them ideal therapeutics or therapeutic delivery vehicles . The majasy task –19. Drugasy task .Developed countries have taken a leading role in the field of nanomedicine as they are investing large amounts of money into developments in the technology . For insWe will conduct a systematic review of studies pertaining to nanomedicine for drug delivery conducted by researchers in South Africa, with a focus on laboratory studies. This focus is motivated by the fact that nanomedicine is an emerging and specialised field in South Africa and much work is limited to fundamental laboratory-based research. All studies on nanomedicine for targeted drug delivery in South Africa will be eligible for inclusion. Primarily, nanomedicine studies include research from academic institutions, hospitals, research organisations, and pharmaceutical companies . The stuWhich diseases are being targeted for drug delivery using nanomedicine in South Africa?What methods of drug delivery using nanomedicine are being applied for the identified diseases?What progress has been made on the use of nanomedicine for drug delivery with reference to the identified disease areas?The systematic review proposes to address the following research questions:Identifying the applications of nanomedicine for drug delivery in South Africa.Synthesising information on the targeted diseases and the affiliations of the researchers in South Africa.Critically appraising the disease profiles of studies forming the evidence base for the applications of nanomedicine in drug delivery in South Africa.Document the diseases which are being targeted for drug delivery using nanomedicine in South Africa byExtracting quotes from included studies on the progress of the nanomedicine for drug delivery in South Africa.Coding, thematically grouping and iteratively analysing the data to characterise the progress in the use of nanomedicine for drug delivery.Provide a structured assessment of the progress of nanomedicine on drug delivery for the identified diseases in South Africa byIn line with the study questions above, the review seeks toThe population for this study consists of potential patients who could be recipients of drug delivery using nanomedicine. As nanomedicine is confined to laboratory studies as revealed by the preliminary literature search, and the focus of the proposed review is laboratory studies, included studies will not include real patients who will have been treated using the technology in South Africa. However, it is possible to infer the potential patients since nanomedicine studies target particular diseases and groups of people. For example, scientists at the Council for Scientific and Industrial Research in South Africa focus on encapsulating conventional tuberculosis drugs with nanoparticles to ensure targeted delivery for tuberculosis treatment. We can deduce from this example that the potential population consists of tuberculosis patients. This study, by virtue of being focused on the different applications of nanomedicine for drug delivery, will yield a heterogenous population consisting of patients with various disease profiles.Nanomedicine interventions to be included in the study should aim at drug delivery in South Africa for different diseases. The following nano-enabled drug delivery interventions and platforms will be considered for inclusion: liposome, polymeric drug, drug polymer conjugate, protein polymer conjugate, pegylated protein, nanoparticle, nanocapsule, nano-suspension, nanocrystal, gold nanoparticle, colloidal gold, silicate nanoparticle, calcium nanoparticle, biosilic, titanium dioxide nanoparticle, solid lipid nanoparticle, fullerene drug, dendrimer drug, nanoshell, phototherapy, hypothermal therapy and magnetic nanoparticle.Since nanomedicine is being applied to increase efficacy, safety, sensitivity and personalisation with the goal of improved therapy, the control for the study are traditional methods of drug delivery. Initial searches of literature on the applications of nanomedicine for drug delivery have shown that by default, use of nanomedicine for drug delivery is compared with existing practices.The outcomes of the systematic review will focus on frequency of publication and themes studied across retrieved literature. The diseases being targeted using nanomedicine for drug delivery in South Africa, the progress in nanomedicine for drug delivery based on thematic analysis and the contributing institutions will be presented, to describe the nanomedicine ecosystem in South Africa. The relationship between possible drug delivery platforms and diseases will be depicted in a map.We will identify relevant studies within the period starting in 1 January 2006 to date with language of publication limited to English. The start date has been selected as 1 January 2006, as this is the time when the South African nanotechnology strategy and an associated 10-year plan for nanotechnology were implemented. The databases to be searched include PubMed (NLM); Scopus; PsycINFO, EMBASE; Cochrane Library (Wiley) , Cochrane Database of Systematic Reviews, Cochrane Methodology Register, NHS Health Technology Assessment Database and Web of Science (Thomson Reuters). The studies to be included will be selected using predefined search terms adapted for the databases to be used. The terms comprise both free text word and medical subject heading (MeSH). We will use a Boolean search string, which includes keywords, namely, nanomedicine, drug delivery and South Africa. PubMed will be used as the primary database by virtue of being one of the largest archives of biomedical literature, and it conducts a review of the scientific quality of journals before indexing . The preNanomedicine is a specialised topic and as a result, to ensure that the search is comprehensive, the grey literature will be searched extensively. This includes searching relevant conference proceedings, the websites of scientific societies and pharmaceutical companies, the New York Academy of Literature and Open Grey. The reference lists of appropriate studies will be assessed. Full text articles of the studies extracted from the reference list will be obtained and reviewed for additional information. Unpublished studies will be identified, and the same eligibility criteria will be applied to select relevant studies.Once the search strategy has been developed and tested, the first author will retrieve all the relevant articles from the various databases. All the literature obtained will be saved in Endnote reference management software for further analysis. The titles and abstracts of studies identified in the literature search will be screened independently by two authors for eligibility. Prospective studies and studies retrospectively focusing on the applications of nanomedicine for drug delivery will be included. We acknowledge that nanomedicine is relatively new in South Africa, and we will focus on laboratory studies. The final assessment for inclusion will be made by consensus, based on the full text of articles. Discrepancies and disagreements will be resolved by a third author overseeing the review process. Clear reasons for exclusion will be documented by each reviewer. Figure Author/s and year of the studyType of facility/environmentAffiliation of authorType of participant/study population/demographic characteristicsType of nanomedicine drug delivery interventionType of targeted diseaseType of study (i.e. study design)Type of outcome measuredFindings/resultsA standardised form has been developed and will be piloted and revised if necessary to extract data from the eligible studies. Full texts of included abstracts will be retrieved and data extracted as per the pre-specified template  software, Version 5.3. . The first and second authors will verify the data entered, for missing or incorrect data. When deemed necessary, the authors of studies will be contacted for missing or incomplete data. Should there be no response from the authors, the limited data available will be included and the implications of missing/incomplete data will be discussed.The extracted data will be presented in an evidence table organised by targeted diseases, methods used for drug delivery, institutions and/or stakeholders involved, and milestones achieved in nanomedicine. We will review the use and progress of nanomedicine for drug delivery in South Africa by developing descriptive themes to answer each research question and synthesise extracted data through a narrative synthesis . The hetThe preliminary sketch depicted in Fig. The surge of applications of nanotechnology in developed countries has raised questions, with some scholars arguing that inequitable distribution of the benefits and profits will occur and accumulate in the north . NanomedWe acknowledge the limitation that our review is restricted to laboratory studies as clinical trial results are not yet available. Since there are few laboratories in South Africa that are designed to handle research on materials at nanoscale, we acknowledge that we may not be able to conduct a meta-analysis due to limited research activity. The initial scoping exercises which we conducted revealed that there are few, but dominant, research groups that engage in nanomedicine and it is more likely that the review will be limited to a few South African institutions and researchers. In addition, the reliance on published data may predispose the review to publication bias.Despite the limitations mentioned above, the proposed systematic review is of value both theoretically and practically. The study aims to provide an up to date account of the application of nanomedicine for drug delivery in South Africa. We seek to identify the diseases targeted for drug delivery using nanomedicine and synthesise information not only on the methods of intervention but also the progress made so far. The review will be essential to health professionals, policy-makers, funding organisations and the public at large in establishing the extent to which South Africa, a leading country in providing health care services and conducting biomedical research in sub-Saharan Africa, is exploiting the new opportunities provided by nanomedicine for the benefit of its health system.This systematic protocol has been registered with PROSPERO, the international prospective register of systematic reviews. The registration number is CRD42017057388. The authors acknowledge that it adheres to the PRISMA-P 2015 checklist as a condition for submission of systematic review protocols Additional file 2:PRISMA-P 2015 checklist. (DOCX 31 kb)