In developed countries around the world there is a trend to enhance the public-private collaboration in healthcare. In Spain, a decentralized country with a NHS funded with taxes and universal coverage, commissioning to for-profit private hospitals the production of healthcare services to specific patients that are publicly insured is a traditional practice. Around 43% of the for-profit private hospitals in Spain have a commissioning agreement with the NHS to diagnose or treat patients on public tariffs. These revenues represent 26% of the total revenues of private for-profit hospitals. The research question of this study is if commissioning with the NHS improves the financial performance of private-for-profit hospitals in Spain.With a long panel (2000–2017) of for-profit hospitals we estimate a model for the financial performance (return on assets) using commissioning as main explanatory variable and other variables as control . Specific models are estimated for subgroups of hospitals according to size and specialization. The models are estimated by panel regression with fixed effects and GMM as robustness.Private for-profit hospitals that have commissioning with NHS obtain higher financial performance than no-commissioning hospitals. This effect varies depending on hospital size and type , the advantage being more relevant for general hospitals and particularly for hospital with at least 50 beds.Commissioning with the NHS is a promising source of financial profitability for general acute private for-profit hospitals. The evidence provided by this study may orientate the NHS in the regulation and negotiation of commissioning contracts in healthcare.The online version contains supplementary material available at 10.1186/s13561-021-00304-4. New Public Management [commissioning, is traditionally the most common practice in the Spanish healthcare system.The public sector has adopted different management techniques from the private sector in the 1980’s, giving rise to what is now known as nagement , which inagement , 38. It In Spain, there are different public financing schemes for privately produced health services. They comprise global financing agreements and specific agreements for delimited and defined groups of patients, with payment for activity based on individual services. The latter type, which we will call commissioning, is the one we analyse in this paper. Although there are other types of public-private collaboration in Spain, in this study we focus on traditional commissioning arrangements, consisting in contracting out with private hospitals so that the public supplier (autonomous government) can send patients for specified healthcare services performed at a regulated fixed tariff. This kind of traditional commissioning has been defined as “supplementary network covering some diagnostic tests and procedures, elective surgery in the context of waiting list reduction programmes, palliative care, long-term care and non-acute mental health care” . We exclPrivate production represents 11.6% of public healthcare expenditures in Spain, including commissioning and other agreements. According to the National Catalog of Hospitals (CNH) around 43% of private for-profit hospitals were involved in public healthcare commissioning in 2018. Public funding (excluding the civil servants’ s vouchers) represented 26% of revenue for private-for-profit hospitals in 2016 .The empirical evidence on commissioning in the healthcare arena has focused on the impact of hiring or contracting public agents . Nevertheless, very few references in the literature analyze commissioning with a view from the private hospital and its impact on the financial and economic situation of the hospital.In this context, the aim of this study is to analyze if commissioning with the NHS improves the financial performance of private-for-profit hospitals in Spain by considering the possible moderating effect of hospital size and hospital type according to specialization in the commissioning-performance relationship. For-profit-private hospitals have not received much attention in the literature on healthcare economics, which suggest that the prevalence of for-profit ownership depends on the power of the market or the lower production costs for greater efficiency or improved access to capital .Our empirical analysis uses panel data during the period 2000–2017 and is taken from financial-economic and healthcare sources. Spain offers an appealing opportunity for studies of this nature because of the presence of universal coverage within the NHS and public financing . Even though the most of the healthcare services are provided by public centres with its own resources, there are nonetheless a significant number of commissioned hospitals. The main reason for this situation is that the Public Administration is unable to meet with its own resources the increasing demand for healthcare services resulting from universal healthcare for all of the public, which began in 1986. It should be noted that several important changes have occurred during the period of study: 1) Since 2002 all the 17 autonomous communities have full autonomyOur results reveal that private-for-profit hospitals, which are commissioned by the NHS, show better financial performance than those who do not do it, and that hospital size and typology are a mediating factor. General hospitals with more than 50 beds benefit the most.The rest of this paper is structured as follows. Section 2 offers a theoretical background about public-private collaboration and the impact of the commissioning on the financial performance of the private hospitals. The third section presents the data and reviews methodology. The next section offers a descriptive analysis and the results of the econometric study, while section 5 discusses the results, their limitations and the implications of the study. The paper ends with some conclusions.Studies in the literature concerning public-private collaboration in the healthcare arena have used several different approaches , 10, 39,Ex ante and Ex post. The first one refers to search costs and negotiation, while the second type includes the costs of controlling the contractual fulfilment by each part, and the costs of fulfilling contracts in case of disputes of an incomplete contractual specification. Stable/fixed contracts could lower both Ex ante and Ex post transaction costs.The theory of transaction costs defines transaction costs as the comparative costs of planning, adapting and controlling the completion of tasks, under the structures of alternative government . That isThe theory of transaction costs has been applied to private firms, and to explain decisions made in public service . Public Another perspective to solve the asymmetries of information and the incomplete contracts is related to reputation. In this sense, Atanasov et al.  assert tThe high amount of uncertainty in the healthcare arena leads to incomplete contracts and requires successive renewals, which is an explanation for their high costs . Given tOn the other hand, commissioning agreements allow the private sector an opportunity to increase potential demand, which could generate higher revenue and contribute to improved hospital performance, as long as they are able to contain costs and align public tariffs for commissioned services. Consequently, if commissioned private hospitals are able to reduce costs, even though at the cost of lowered quality of service, the commissioning arrangement would also have a positive effect on its financial performance. Participation in a commissioning arrangement must create value for the for-profit private hospitals, otherwise they would not continue with the arrangement. Along this line, the assumption of rational behaviour in organizations implies that those hospitals, which enter into the commissioning arrangement will be more profitable than if they do not.Hardly any references in the literature analyze how a commissioning arrangement for the delivery of healthcare services influences financial performance of a commissioned hospital. As previously mentioned, we expect that the effect of being a commissioned hospital is neutral (not significant) or positive for the ROA of a hospital. Nevertheless, it is plausible that the effect is heterogeneous according to hospital characteristics, specifically size and hospital specialization. Hospital size can play a moderating role on the relation between commissioning and financial performance. If the commissioning arrangement improves the expected profitability of large hospitals more than small ones is an empirical question, which we will explore in this study. Indeed, hospital size (beds and assets) approximates its negotiating stance .It is also reasonable to assume that both economies of scale and the actual profitability of the commissioning arrangement are heterogeneous according to hospital specialization because specialization is associated to transaction costs. Greater profits are obtained in technical services characterized by lower speciality and greater ease of measure, while lower profits are obtained for more complex services that require a higher level of speciality and are more difficult to measure. Consequently, we would expect that general hospitals would get higher profitability from the commissioning arrangement than other hospitals.A combination of healthcare, economic-financial and demographic databases has been used to create a panel of hospitals for the period 2000–2017. We start from the National Catalog of Hospitals (CNH) , annual The CNH base has been linked to the financial information of the hospitals, coming from the SABI database . SABI contains the information of the commercial register on the annual accounts of the companies. All companies are required to deliver their accounts, and SABI collects them. Therefore, SABI includes only hospitals with legal personality. In order to ensure the reliability of the information and its tracking throughout the entire period, the Tax Identification Number of each hospital has been previously located. In this way, cases of change of corporate name are detected, among other causes due to their incorporation into a hospital group. Once the companies are located in the SABI database and the existence of non-consolidated financial information has been confirmed, hospitals for which the necessary information is not available have been removed from the sample. Likewise, two forms of public-private collaboration, hospitals in the Catalan public utilization network and administrative concessions under the “Alzira model” have been eliminated.In addition, demographic data of the National Institute of Statistics (INE) have been used to obtain variables concerning the hospital environment (see below).Given the nature of the hospitals included in this study, it is assumed that they have as a financial objective the profitability. As in previous studies, in this work the financial performance of hospitals has been approximated through ROA or economic profitability e g, , 40, 43), 4340, 4The explanatory variable of interest is the dummy (commissioning) of the existence of a contract signed with the government of the autonomous community for the provision of specific health services to publicly insured patients, which are transferred to the private center.To approximate the size, the logarithm of the number of hospital beds installed has been used. As a robustness, the subsample of hospitals with at least 50 beds has been considered. Finally, the type of hospital has been considered in two subsamples: general and medium and long stay. The former includes maternal and pediatric and the latter integrates geriatric and psychiatric.First, a standardized index of technological endowment of the hospital has been created for general and surgical hospitals, with CNH data on the endowments of units of 10 types of high-tech diagnostic and therapeutic equipment. This index has been calculated using a principal component analysis of the number of available devices.Second, according to previous studies on hospital financial performance, the age, the level of indebtedness, the economic structure and the fixed effect of the year have been considered as control variables. The age is used in the financial literature as a proxy of experience. As companies gain more experience, they are able to add methods that improve their productivity. Organizational learning makes it possible to identify recurring problem-solving procedures, reducing the time and effort used . The ageLastly, it should be noted that some studies have considered control variables related to location , 31, 35,5yit is the ROA previously defined for hospital i in year t. Z includes the explanatory variables of interest, and specifically the existence of a commissioning contract. Although the agreement is quite stable over time , there is sufficient within-hospital variability, given the temporal length of the panel , we proTo analyze the possible mediating effect of hospital size and type on the effect of commissioning on financial performance, the model has been estimated for specific subsamples by purpose and size. Specifically, distinguishing general hospitals from the rest, and only for hospitals of minimum size 50 beds.The advantage of the fixed effects model is that by canceling the unobservable individual heterogeneity of the hospital (and of the year) by making the demeaning , the estimate of the commissioning effect would be consistent even if commissioning was not exogenous, but associated to intrinsic characteristics of the hospital. However, it could happen that commissioning is endogenous in the sense of presenting stochastic dependence with the time varying error. This would be so if some unobservable determinants of the ROA that vary temporarily and are part of the error are related to the agreement. Hospitals must meet certain requirements in order to be eligible for a commissioning agreement in Spain Some of these requirements, which vary among Autonomous Communities, are financial , but profitability is not one of them.To consider this possibility, and as proof of robustness, the model has been estimated by the Generalized Method of Moments (GMM) , which aAccording to the CNH, there were 305 for-profit hospitals in Spain in 2000, 336 in 2009 and 324 in 2017. The private sector represents between 41 and 44% of the total number of functioning hospitals during the period 2000–2017, although the number of beds is much less, not even reaching 20%. In 2017 the number of beds in the private- for-profit sector was 29,874 out of a total of 158,269, approximately 18.87%. These data clearly show that average bed size in public hospitals is double the number in private ones. Table There are 286 different hospitals that have been included for at least one year in the final SABI sample database. There are centres that were eliminated because of missing values. As regards hospital size, Table The distribution of observations  is nearly identical for the three groups, although the highest percentage of commissioned hospitals is found in the largest category, followed by the medium group and finally the small hospital group. General hospitals (including maternity-paediatrics) accumulate 64% of the panel observations, as opposed to surgical, at 9%, while psychiatric and geriatric together make up 22%. The percentage of commissioning arrangements in each type of hospital greater than 44%, except for psychiatric (27%), and for other specialities .Of the 286, 125 47.53%) were never classified as commissioned, 81 (30.80%) had always been for the observation period and the remaining 57 (21.67%) were commissioned for some years during the sampling period. Classification by typology and commissioning history is considered in Table % were neThere are significant differences in the prevalence of commissioned private for-profit hospitals by autonomous communities ; its variance is less than one because all of the non-general nor surgical centres have an index = 0 . Leverage (indebtedness level) is at 70% of assets in average and the tangibility  is 42%.The correlation displays low values for the explanatory variables and consequently there are no difficulties with respect to multicolinearity.Table Profitability of commissioned hospitals is greater than non-commissioned ones for small and medium-sized hospitals, although the opposite occurs for hospitals with more than 100 beds (a figure which is close to the sample mean). These figures suggest that the relationship between commissioned hospitals and profitability depends on hospital size.The relationship between profitability and size according to the commissioned status can be reflected by the differences in hospital size by hospital. In general, in acute care hospitals, as well as in other specialities, mean profitability of the commissioned hospitals is greater than the non-commissioned counterparts, while in long term care (psychiatric and geriatric) the difference is not significant, even though average profitability is greater for the non-commissioned hospitals. Geriatric hospitals and psychiatric ones are more profitable than the rest. However, in commissioned hospitals, the other monographic hospitals have the highest profitability.Table p < 0.01) in Models M1, M2 and M4 . In M3 and M5 commissioning is also significant at 5% . Regarding the size of the effect, coefficients range between 0.02 and 0.04. Commissioning increases the ROA between 2 and 4% for private hospitals.The commissioning variable is significant and positive in all models except in Model 6 (Medium & long stay whit at least 50 beds). Specifically, commissioning is highly significant , while the quadratic coefficient is negative and significant at 1%.Both leverage and tangibility are negative and highly significant in all of the models, with the exception of tangibility for those hospitals offering mid-term and long term care. Finally, fixed time effects  in Spain is much higher than for general and surgical ones. On the other hand, variability of ROA among hospitals in the study period is very high, as is the within-hospital variability of the ROA.Based on our modelling results, we can assert that a commissioning arrangement helps improve profitability of private for-profit hospitals, although this relationship is influenced by size and the type of healthcare provided by the hospital. Thus, the ROA could be around 2–4% higher for commissioned hospitals. This result is robust for general hospitals, as fixed effects within-group estimates and GMM estimates agree. On the contrary, for mid and long stay hospitals, the results of the fixed-effect models are not confirmed by the GMM estimation. The effect of commissioning on ROA is smaller for larger general hospitals than for the full sample of general hospitals.Control financial variables have the expected signs and are robust.Models M1-M6 show that profitability of for-profit Spanish hospitals worsened during the economic crisis, from 2010. Nevertheless, a change of effect during these years of economic crisis due to the commissioning agreement (interaction term) was not found significant (results not shown).Commissioning arrangements in Spain are stable, and many hospitals have entered this collaboration during the 18-year study period, while only 57 have joined to leave later during the study period. Stability reduces ex ante transaction costs . Ex post control costs are more limited for commissioned standardized procedures, as diagnostic tests, surgical interventions for elective surgery, or physical therapy sessions. In addition, as it is the public provider who refers patients specifically to the private commissioned center, the “capture of the regulator” is avoided. However, in practice the compatibility of the work of doctors in both networks, public and private, could cause deviations and generate commissioned activity not indicated clinically. This in turn might improve the financial performance of commissioned centers without providing therapeutic value, or only very marginally. A common practice in recent years is to hire facilities (operating rooms) and auxiliary staff of the private center but perform surgical interventions with surgeons of the public network under salary. In this case, the hypothetical conflict of interest problems would disappear.In the USA, panel data models showed that occupation rate, size, availability of technology and market power were significant predictors of hospital profitability . The datmarketisation, which does not necessarily lead to privatization [A review of commissioning in the case of England after the passing of the Health and Social Care Act 2012 reveals that it has been seen as a type of tization , as the The present work is novel on a topic which has been surprisingly ignored in the literature. A strong point of the study is the length of the panel data, which covers a time period from 2000 to 2017, allowing changes in size, technological structure, and financial variables of private for-profit hospitals to be seen. In addition, there have been changes in commissioning arrangements, signing of new contracts or finalizing current ones during the study. Another strength of the study is that the database used comes from the population register .Despite these advantages there are limitations in the study. The following two paragraphs address these limitations.As for the group of hospitals analyzed, although it is based on a population register (CNH), the effective criterion of inclusion in the sample is that the hospitals present the accounts in the commercial register, which excludes hospitals belonging to groups, when consolidated accounts are presented for the entire holding. Therefore, the study is limited to independent hospitals, which limits external validity for the entire NHS. It is not a serious limitation as it might seem because large groups of hospitals generally do not contract with the public system. The disappearance of individual hospitals from the database may be the effect not of their disappearance but of their absorption or purchase by a hospital group. In this sense, one might think that the model has attrition bias .Unfortunately, there is no information either on the type of outputs or inputs that are purchased at hospital level. Also, there is no available information on the fees, tariffs or payment strategy by the Autonomous Communities. There are variables explaining the profitability  that it has not been possible to consider due to lack of information, such as the length of the public waiting list (which will influence the level of commissioned activity more than the fact of opening new agreements), the productivity of the public sector, the specific morbidity associated with the services that are contracted and some of the organizational, management and structure variables that usually enter the models that explain the financial performance with longitudinal data from hospitals in the USA. Those variables might contribute to improve the explanatory capacity of the estimated models.Despite the aforementioned limitations, we have got robust estimates of the main effects we were analyzing regarding to the effect of commissioning on profitability.In conclusion when a general hospital (acute care), and particularly if it is above a 50 beds threshold, decides to be commissioned by the NHS, it would expect an improvement in its financial performance. There is no conclusive evidence that it will improve expected financial performance for hospitals that provide mid and long-term care.Additional file 1.Additional file 2.Additional file 3.


However, there are local environmental detrimental effects, and empirical evidence is not consistent as to the support of local communities. In the present paper, we analyse the antecedents of public generic perceptions of renewables grounded on objective location-related factors. Personal location-related factors can originate in the involvement of individuals with renewable energy sources. Regional location-related factors concern the importance of the renewable energy source in the district of residence and in relation to other renewables. We implement a questionnaire on public perceptions of renewable energy sources by the general population in mainland Portugal and complement respondent-level responses with renewable energy district information. Regression analysis shows that these objective location-related factors, both personal and regional, help explain public perceptions of renewables and thus we find empirical support for the proposed approach. These results can inform and guide policymakers in tackling future social acceptance issues of renewable energy policies towards lower carbon emissions and less polluting energy production.The public perception of renewable energy sources is generally positive, due to their role in air pollution and CO Renewable energy sources (RES) have been a fundamental part of climate change policies. The use of RES in electricity production has been proposed as a substitute for thermal electricity production powered by fossil fuels to lower carbon emissions and reduce air pollution and associated health problems . In addiThe substitution of fossil fuels by RES, such as wind, hydropower, solar and forest biomass, produces significant environmental and health benefits by reducing air pollution. However, the use of RES in electricity generation is not environmentally neutral: impacts on fauna, flora, soil fertility, landscape, cultural heritage, noise, and people displacement are some of the environmental and social adverse impacts associated with the operation of different renewables’ power plants e.g., ,4,5,6,7),5,6,74,5Also noteworthy is the fact that renewables’ adverse effects are mostly local in scope, affecting mainly the well-being and quality of life of those residing in the local communities next to renewables’ power plants, while the benefits accruing from the substitution of fossil fuels by RES are global, benefiting the entire population. This is clearly a situation of environmental and energy injustice  and y benign ,22,23), y benign ,25,26) ay benign ,27,28).Empirical studies on RES often find overall support for the use of renewables as opposed to traditional fossil fuels. However, when studies focus on specific RES projects, local opposition is observed, namely from the local communities living nearby ,29. ThisA direct interpretation of local opposition to RES facilities relates to the so-called not-in-my-backyard (NIMBY) phenomenon . NIMBY rNYMBYism is however not a straightforward concept in the literature, as some authors argue that local opposition depends on the symbolic interpretation of renewable energy facilities; as in one example in McLachlan  where a According to Wüstenhagen et al.  the concLocal support for local RES projects is clearly dependent on the experience with the actual projects. On the other hand, global support, which is a more abstract perception, may also be shaped by the context of the individual in terms of RES, namely familiarity with renewables and how RES shapes place identity. We argue that it is not only local support but global support for RES that depends on the specific RES context of the respondent. The literature does not suggest a straightforward relation between location-related factors and local or global support for renewables. On the one hand, place attachment encompasses different spatial ranges from the home to the neighbourhood or to the city and region ,39,40,41By contrast, community participation and empowerment at the planning stage help foster place attachment  and reduIn this research, we propose to study social acceptance for the case of different RES considering as antecedents objective location-related factors, either personal factors or regional factors. Particular attention is devoted to the regional intensity in terms of renewables, which will underlie the contact individuals have with RES. On the one hand, we argue that the more personal contact and self-involvement individuals have with RES , the more acceptable the RES is. Furthermore, a more general acquaintance with RES due to intensity in the district can also reinforce this acceptance. On the other hand, it is possible that negative experiences with local RES translate into negative perceptions, thus dampening support for RES.To test this approach, we use data from a case study in Portugal , where tPrevious studies in Portugal find positive public attitudes towards RES technologies  with surThe aim of this research was to explore whether the public acceptance of RES is influenced by objective location-related factors, either directly through personal factors or indirectly through regional characteristics related to renewables. We designed a questionnaire to be administered through personal interviews  (variable perception of friendliness of RES). So as not to force a response, this question included the possibility for respondents to state that they did not have an opinion, which allowed us to identify and exclude those individuals from the analysis, which would not have been possible if a forced opinion had been elicited.To capture the perception about RES, there was a question about the degree of friendliness of each renewable using a 5-point Likert scale .preponderance of wind/hydro/solar photovoltaic power); for example, the variable preponderance of solar photovoltaic power takes value 1 if solar photovoltaic was the source with highest installed capacity in the district, and was thus the most salient renewable in that particular district.Location-related factors can also originate from regional characteristics of the respondent’s district of residence. We aimed to account for the presence and importance of renewables, so we constructed two variables from statistical databases. One factor related to the importance of the specific renewable under appreciation in the region. A categorical variable was created which captured whether each RES individually was the renewable source with the highest installed capacity in the region .Additionally, we wanted to capture the importance of the region in the national context for each renewable. We thus constructed a variable for each renewable representing the fraction of installed capacity of each RES in each district relative to total capacity installed in Portugal , biomass (10.5%), photovoltaic (3.3%) and geothermal (0.7%). Observing the data by region, about 86% of the production took place in the North and Centre of the country, where the bulk of aerogenerators and most of the dams are located ,54.Regarding the geographical distribution of RES in mainland Portugal, there are regional differences in terms of installed capacity of RES. To better contextualize the case study at the time the data collection was carried out, During the first half of 2014, questionnaires were collected from a national sample using a face-to-face approach and personal interviews, through a specialized polling company that contacted participants following a stratification based on gender, age and district of residence. Upon contact by the polling company, participation was voluntary. For the purpose of this paper, we have a sample of 1678 questionnaires . The explanatory variables characterize the relation of the respondent to the RES . The variable visibility of RES is a dichotomous variable that captures whether the respondent sees an RES power facility either from home, work or during the daily commute. The variable involvement is a dichotomous variable to indicate if the respondent is directly or indirectly benefited from RES, namely whether the respondent, a family member or an acquaintance worked at the time of the questionnaire or in the past in the renewable energy sector. The remaining explanatory variables characterize the region in terms of RES  and are presented To model respondents’ opinions on RES environmental impacts as a function of location-related factors, a regression model is estimated and several covariates are considered, including two control variables for individual characteristics . When the primary renewable source in the district is hydropower, the perception of wind power is worse (preponderance of hydropower = 1); when SPV is the predominant renewable, the perception of wind power is better (preponderance of SPV = 1). These results suggest that perceptions of friendliness, in this case of wind power, depend on the relative importance of different renewables in the district of residence, with hydropower creating a negative spillover, and SPV a positive spillover on the perception of wind power.Analyzing the results for wind power (1), we observe that personal location-related factors, national contribution of region for hydropower). Being a resident in a district where the main power source installed is SPV (preponderance of SPV = 1) or wind (preponderance of wind = 1), positively affects respondents’ judgements on the environmental effects of hydropower.Regarding hydropower (2), the visibility of power plants has a negative impact on the perception of that RES, whereas the involvement variable does not have a statistically significant coefficient. As for the importance of RES, the fraction of hydropower installed in the district has no incremental effect on respondents’ evaluation of the environmental effects of hydropower (involvement). However, the regional contribution to the national production of SPV has not statistically significant impact. When respondents live in districts where either wind (preponderance of wind = 1) or hydric power (preponderance of hydropower = 1) are the predominant renewable source of energy, the perception of SPV is negatively impacted.Results for SPV (3) show that respondents directly or indirectly involved with the RES tend to positively evaluate the environmental effects of SPV  is 9.1%, 0.7% and 0.7%, respectively. Thus, hydropower is considered more environmentally detrimental than the other energy sources.2 emissions from the electricity production sector is a priority. As such, the increase in electricity production is increasingly demanding higher shares of renewable energy sources. The use of renewables contributes both to the use of endogenous sources of energy, and thus to energy security, and to the reduction in CO2 emissions, as long as they enter the energy mix in substitution of fossil fuels. However, the use of RES for electricity production is not environmentally impact free [Increasing national demand for energy requires either the expansion of own energy production, or the increase in imports. Moreover, in the context of climate change and air pollution, the challenge to reduce COact free . In addiact free , the queTo continue to promote RES for electricity generation in terms of expansion of existing projects and sources and development of new ones, policy-makers need to further the investment in renewables. For this, it is important to have citizen support in terms of public opinion and acceptability of new projects. Policy makers can devise communication strategies aimed at increasing the support of national citizens, but need to understand antecedents of perceptions towards renewables. Studies so far have taken two different views of public support. Generic perceptions of national residents have been analysed, while other studies have approached local residents and focused on very localized effects. Batel and Devine-Wright  argue thAs for regional characteristics of the RES under analysis, we also find statistically significant effects. Controlling for all other variables, the more wind power a district has in the national installed capacity, the less positively a respondent perceives wind power. We do not find an incremental effect of this variable for the other renewables.In terms of regional location-related factors, we also observe different effects on perceptions depending on the dominant renewable in the district of residence. We find, for example, than when respondents live in districts where hydropower is the dominant renewable, the perception of the other renewables is less positive. As for SPV, the spillover effect is positive for the perception of wind and hydropower .To promote the energy transition to less polluting and more sustainable energy production systems, renewables need to continue to be implemented and developed. However, electricity production through renewables is not impact-free and requires investment by public authorities, legitimized by public support. The opinion of national citizens depends on different factors, and on the energy mix of any country. Recently, empirical studies have attempted to move from abstract perceptions of renewables to situations that are more concrete, so as to bridge the so-called local-national gap in perceptions. The present study takes a complementary approach and attempts to explain individual perceptions as a function of location factors. Where the individual lives and works determines their experience, involvement and acquaintance with RES. We proposed to explain individual perceptions of friendliness through personal and regional variables, elicited either through a questionnaire or through RES databases. Understanding what antecedents condition perceptions in this manner can help policy makers create more effective communication strategies.For the specific case study in Portugal, we find that the generic perception of friendliness of renewables is indeed conditioned by the individual’s location-related factors. While the statistical relation we observe is related to the specific case study, the approach we apply can be used elsewhere to better understand public perceptions, by uncovering more objective antecedents of the social acceptance of RES. This approach can thus be another tool for policy makers when designing energy policy and communication strategies.


Objective: To analyze those factors contributing to the diagnostic delay in ALS.Methods: Consecutive ALS patients were categorized as those studied in departmental hospitals and those studied in a referral ALS center. Demographic and clinical variables, together with data of the diagnostic pathway were collected. Multivariable models were used to assess their effect in the time between symptoms onset and the first neurologist visit (time symptoms-neurologist), in the time between the first neurologist visit and the diagnosis (time neurologist-diagnosis) and in the diagnostic delay.Results: 166 ALS patients with a median diagnostic delay of 11.53 months  were included. The median diagnostic delay was 8.57 months  in the referral center vs. 12.08 months  in departmental centers. Bulbar onset, fast progression rate, upper motor neuron predominant phenotype and an early referral to the neurologist were associated with a shorter time between symptoms–neurologist. Being studied in a referral center was associated with a shorter time between neurologist–diagnosis. Comorbidities, familial ALS, bulbar onset, early referral to the neurologist and being studied in a referral center were associated with a shorter diagnostic delay. For patients studied in departmental hospitals, fast progression rate was also strongly associated with a shorter time between neurologist–diagnosis and diagnostic delay.Conclusion: Unmodifiable factors  as well as modifiable factors  have an independent effect in the diagnostic delay. The universalization of ALS Units is probably the most efficient measure to reduce the diagnostic delay. Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by a rapidly progressing upper and lower motor neuron (UMN and LMN) impairment that usually leads to death about 3 years after the onset of symptoms. Despite this fast progression, the diagnostic delay of ALS is ~12 months , which rThis diagnostic delay supposes several drawbacks for ALS patients and for the health system. Firstly, many unnecessary tests, consultations and treatments are often performed. For example, in a previous study in Spain, up to 50% of diagnostic tests were considered unnecessary  and, durSeveral studies have analyzed the diagnostic pathway of ALS and some factors related to the diagnostic delay  have been described –14. HoweTherefore, the objective of our study was to analyze which modifiable factors independently influence the diagnostic delay of ALS, in order to design appropriate tools that allow us to reduce it in the near future.Spain has a universal healthcare coverage structured in different health departments, with one hospital caring for a specific population area. In addition, some patients have a private insurance, so they can choose to be visited in a public or a private hospital. Regarding ALS, each hospital works in a self-sufficient way with its corresponding population but all of them are part of a network that differentiates between two healthcare levels: departmental centers and referral ones. The ALS Unit of La Fe Hospital acts as departmental center for its own surrounding population , but also works as the referral center for all the other public and private hospitals in the Valencian Community . Consequently, most patients in La Fe Hospital (about 85%) are referred from other centers for diagnosis, a second opinion or to participate in clinical trials.For this study, we reviewed the medical records of all patients with an initial clinical diagnosis of motor neuron disease, visiting, for the first time, the ALS Unit of La Fe Hospital between October 2013 and December 2017. Some of these patients had been evaluated and diagnosed in other centers, some had been evaluated in other sites and were finally diagnosed at La Fe Hospital and some others had been both evaluated and diagnosed at the referral center. Exclusion criteria were: patients in whom the ALS diagnosis was not confirmed after a minimum follow up of 2 years after the initial diagnosis, including, but not restricted to: those finally diagnosed with progressive muscular atrophy or primary lateral sclerosis as defined elsewhere ; patienthttps://ec.europa.eu/eurostat/web/nuts/local-administrative-units). For the purpose of this article, familial ALS was defined by the presence of first- or second-degree relatives with ALS. Comorbidities were considered all those pre-existent pathologies that could mask or whose symptoms could be mistaken with ALS during the diagnostic process. It is a wide concept that includes other pathologies that impair mobility, cause dysarthria, etc… According to the center of study, patients were categorized in private vs. public health care system and in referral  vs. departmental center . Not all variables were available in all patients. The whole data collection process was supervised by JFVC, who is responsible for the veracity of the data.All patients were evaluated by the same neurologist (JFVC) who prospectively recorded demographical and clinical data: age, sex, family history of ALS, referring hospital (including if it was public or private), date and site of symptoms onset , the phenotype, and the date, ALSFRS-R score, and Awaji category  at diagnP-values lower than 0.05 were considered statistically significant.Clinical data were summarized by mean (SD) and median  in the case of continuous variables and by relative and absolute frequencies in the case of categorical variables. All time variables and the progression rate were log transformed to obtain a normal distribution. Linear regression models were performed to study the associations between response variables and predictors. The diagnostic delay is composed by two main processes in which different factors intervene: the time symptoms-neurologist and the time neurologist-diagnosis. We first analyzed those factors which could influence the two latter times. Those factors being possibly associated, were included in the diagnostic delay model, together with other factors  previously associated with the diagnostic delay , 13, 14.A total of 217 patients with an initial diagnosis of motor neuron disease, were visited for the first time at the ALS Unit of La Fe Hospital between October 2013 and December 2017. Fifty-one patients were excluded based on the abovementioned criteria  and 166 We hypothesized that several variables dependent of the patient , of the health system  or of the disease  could influence the delay to see a neurologist. All these variables were fitted to an elastic net model and six of them were preselected by the model as candidates . Age and sex were added to the final linear regression model, based on previous reports in the literature of its influence in the diagnostic delay , 13, 14.0, i.e., for a progression rate of 1. This is represented in the We also hypothesized that several variables dependent of the patient (age and comorbidities), of the health system (experience of the center) or of the disease  could influence the time that the neurologist needed to make an ALS diagnosis. Moreover, we hypothesized that the progression rate would have a differential effect in this time, according to the experience of the center. Consequently, we introduced an interaction between the progression rate and the center. In the multivariable model , the pro0 or higher) had similar diagnostic delays in both departmental and referral centers . However, those progressing slower can suffer an additional diagnostic delay of several months if studied in an inexperienced center. For example, patients with a progression rate of e−1 (0.38) would suffer an additional delay of 3 months according to the For the diagnostic delay model, following variables were selected based on the results of previous models: comorbidities, first specialist, site of onset, progression rate, and experience of the center. Age, sex and familial ALS were added based on previous literature , 13, 14.The diagnostic delay in ALS is about 12 months, a figure that barely changes  amoGiven that the ALS diagnosis is clinical and highly based on the experience of the neurologist , we hypoMany studies have previously analyzed the influence of several factors in the diagnostic delay of ALS patients –14, but Previous studies performing multivariable analyses showed controversial results regarding the effect of age in the diagnostic delay. Some studies proposed that aged patients have longer diagnostic delays , 5, 13, Two studies have found an independent effect of male sex in shortening the diagnostic delay , 14, wheOnly one study addressed the impact of comorbidities in the diagnostic delay, although it focused only on neurologic comorbidities . That stPrevious studies have consistently shown longer diagnostic delay in spinal onset patients , 13, 14,A previous population study found considerable differences in the diagnostic delay according to the phenotype  and anotAlthough the progression rate is commonly seen as a major conditioning factor in the diagnostic delay , it has Only a previous study addressed this issue, finding a reduction in the diagnostic delay in familial ALS patients . Our stuA previous study failed to find statistically significant differences in the diagnostic delay according to the educational level, the distance from the hospital or the size of the population . Our stuThe fact that several studies in different countries with diverse health systems found comparable diagnostic pathways and delays, suggest that factors related with the structure and covering of the health system have little impact in the diagnostic delay, at least in developed countries. A previous study  found a Our study sheds some light on this complex matter, confirming that an early referral to a neurologist independently associates with a reduction in both, the time symptoms-neurologist and the diagnostic delay. More importantly, being studied in a referral center  resulted in a significant reduction in both the time neurologist-diagnosis and the diagnostic delay, in the latter having a greater effect than an early referral to the neurologist. This reduction, which can be of several months in the diagnostic delay, largely depends on its effect in normal or slow progressors, while fast progressors (progression rate > 1)  are diagAccording to these results, to effectively reduce the diagnostic delay in ALS, fast-track referral systems should be accompanied by educational plans targeting general practitioners and general neurologists. This could be a successful approach in a country such as Spain, with a universal healthcare coverage and a pyramidal structure: where general practitioners, at the base of the pyramid, perform the first symptoms' screening; while general neurologists, positioned in an intermediate level of assistance, are responsible of referring patients with suspected ALS to highly specialized centers.The main strength of our study is its design with a systematic collection of variables in a cohort of well-studied patients. To the best of our knowledge, our study is the most comprehensive one, with regards to the amount of variables collected. Moreover, the statistical approach allows an independent analysis of the effect of these variables in the different processes that result in the diagnostic delay. Our sample has the particularity that is composed by two sub-cohorts . This allowed us to analyze, for the first time, the effect of the study in different centers in the diagnostic delay. Moreover, although we studied a center-based cohort, this is probably representative of the general ALS population, since over 50% of ALS patients of the Valencian Community visit our center. Furthermore, the demographic and clinical characteristics of our series are comparable to population-based cohorts . In addiOur study shows that unmodifiable factors  as well as modifiable factors  have an independent effect on the diagnostic delay. Moreover, the evaluation in an ALS referral center would specifically reduce the diagnostic delay in normal and slow progressors, but probably not in fast progressors. Therefore, health care and educational plans should be designed and implemented with the aim to reduce the diagnostic delay, specifically targeting general practitioners and general neurologists. However, the establishment and reinforcement of ALS Units is probably the most efficient measure to reduce the diagnostic delay, while reassuring the best care for ALS patients.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethical Committee for biomedical research of La Fe Hospital. The patients/participants provided their written informed consent to participate in this study.MM-M participated in clinical data acquisition and interpretation and drafted the manuscript. HA-E, MP, MF, and VC participated in clinical data acquisition. TS critically revised the manuscript. DH participated in the design of the study and data analysis and interpretation. JV-C designed the study, participated in clinical data acquisition and interpretation, edited the manuscript, and had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors have approved the submitted version of the paper. All authors contributed to the article and approved the submitted version.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.


A great variety of functional foods, nutraceuticals, or foods with bioactive compounds are provided nowadays to consumers. Aware of the importance of the safety aspects, the food industry has to comply with different legal requirements around the world. In this review, the European regulatory framework for food-related bioactive compounds is summarized. The term ‘bioactive compound’ is not defined in the European regulations, however, since they can be part of food supplements, fortified foods, or novel food, they are included within the legal requirements of those corresponding types of foods or supplements. Lists of authorized compounds/foods appear in the correspondent regulations, however, when a new compound/food is going to be launched into the market, its safety assessment is essential. Although the responsibility for the safety of these compounds/foods lies with the food business operator placing the product on the market, the European Food Safety Authority (EFSA) carries out scientific evaluations to assess the risks for human health. To facilitate this procedure, different guidelines exist at the European level to explain the tier toxicity testing approach to be considered. This approach divides the evaluation into four areas: (a) toxicokinetics; (b) genotoxicity; (c) subchronic and chronic toxicity and carcinogenicity; and (d) reproductive and developmental toxicity. Over the last few decades, there has been a rapid increase in the knowledge of the biochemical and physiological cellular functions of human nutrients; in addition, the recommendations regarding macronutrients, micronutrients, and essential nutrients intake for a healthy status have increased. Moreover, the social perception of nutrition habits and physical activity, and their impact on the present and future health has rapidly evolved. Thus, the scientific knowledge and the consciousness of the importance of nutrition to prevent disease have increased the offer of foods with known healthy properties. A great variety of functional foods or foods with bioactive compounds or nutraceuticals can nowadays be easily found in the global market. In this global scenario, the food industry, which is aware of the importance of the safety aspects, has to comply with the legal requirements of regulatory frameworks that can be very different between countries.The objective of this article was to review the safety regulatory aspects in the European Union, and summarize the toxicity evaluation and safety assessment of bioactive compounds that can be found in food. First, clarification of the different terms used for food compounds that have a beneficial healthy effect is provided.“Bioactive compounds”, “nutraceuticals”, and “functional foods” are some of the terms widely used in the food context by both the industries and consumers, however, the boundaries between them all are not clear and are very often used interchangeably or with different nuances. Some of the definitions found in the recent literature are shown in The most basic definition of a bioactive compound found in many language dictionaries is “having or producing an effect on a living organism”. However, this broad definition is not precise enough for the current safety assessment framework and regulatory standards for human health. Indeed, it does not specify: (i) if the effect is beneficial or deleterious, (ii) in case of being beneficial, if the type of effect is pharmacological or nutritional, and (iii) the final form or vehicle in which the bioactive is present (in food or in a pre-formed presentation). The first point mentioned (i) points directly to safety evaluation issues, which is the cornerstone of EU legislation on food, while the type of effect (ii)  is a key point to differentiate between “pharmaceuticals” and “any bioactive compound present in food”, independently of the final form in which they are vehiculized (iii). Indeed, many bioactive compounds obtained from plants, fungi, or vegetables have been used as drugs for millennia, and many of them have become medicinal drugs, and so evaluated and commercialized as such. Therefore, at the European level, they are under the scope of Directive 2001/83/EC (and its amendments)  and are Another important aspect in the definitions proposed for bioactive compounds  is that Therefore, the specific aims of the present review are: (i) to compile the terms associated to food-related bioactive compounds  under the European regulatory framework , and ii. The preAt the European level, the general principles and requirements of food law, together with the establishment of the European Food Safety Authority (EFSA) and the basis for food safety, are laid down in the EU General Food Law (Regulation (EC) No. 178/2002) . This reAs previously mentioned, nutraceuticals, food/functional, or bioactive compounds are not regulated at the European level as such. However, any kind of bioactive compound susceptible for inclusion in food may fall under one (or more) regulation(s) as shown in At the EU level, one of the terms that appears specifically defined is food supplement and is defined under Directive 2002/46/EC  as: “fooDirective 2002/46/EC  represenFor instance, in relation to the fortification of foods, Regulation (EC) No. 1925/2006  harmonizAnother regulation that should be also taken into account is Regulation (EU) 609/2013  on FoodsFinally, Regulation (EU) No. 2015/2283  on NovelIt is worth mentioning that many of the bioactive compounds used in food  are naturally occurring substances called “botanicals or derived preparations”. These “botanical” products are becoming popular and widely available on the EU market  and are labelled as “natural”, together with many claims regarding their possible health effects. Many of these bioactive compounds have a long history of use, but this is not always the case, and some concerns might exist regarding their safety and quality . As foodFinally, other important legal frameworks, but out of the specific scope of the present review, also affect some of the foods previously mentioned. This is the case, for example, of any food containing additives or bioactive compounds with technological functions that shall comply with Regulation (EC) 1333/2008  on food Overall, at the EU level, bioactive compounds aimed to be used in food could fall under one  of the regulations affecting: (i) food supplements, (ii) substance for the fortification of food, (iii) food for specific groups, and (iv) novel foods. On the other hand, depending on the type of bioactive compound, they can be classified as (i) vitamins and minerals, (ii) other substances, or (iii) botanicals. It is important to note that the same bioactive ingredient  might fall in one or other regulation(s) depending on the final intention of use. In general, falling within the scope of one or other regulation(s) will depend on the final presentation (capsule/pill versus foodstuff), the functionality of the bioactive compound , and history of consumption of the food at the EU level (food consumed significantly prior to May 1997 versus new foods). However, it should also be noted that depending on the type of bioactive compound, the regulation is more or less developed. For example, within the food supplements framework, vitamins and minerals are more clearly regulated than the “other substances” or “plant extracts/botanicals”.As mentioned in the previous section, there are lists of bioactive compounds that have already been approved for use in foods. The Food Supplements Regulation provides lists of vitamins and minerals and vitamin and mineral substances that may be used in the production of food supplements (Directive 2002/46/EC) . The RegThe responsibility for the safety of food supplements, fortified foods, or novel foods lies with the food business operator placing the product on the market. In general, regulations mentioned in the previous section do not contain strategies or guidelines related to the toxicological evaluation; they only specify that the safety of each type of food launched into the market should be guaranteed. In this regard, the SCF and, later on, the EFSA, have published scientific opinions in the form of guidance to carry out the safety assessment of such substances. These guidelines assist the applicant in organizing the information in order to prepare a well-structured application to demonstrate the safety of the new compound/food. This will facilitate the EFSA to carry out its evaluation. In this section, the safety assessment process is explained, mainly focusing on the toxicological assessment according to the final use or characteristics of the bioactive compound: source of vitamins or minerals for food supplements and fortified food , novel fAs mentioned in the introduction, there are lists of vitamin and minerals and sources of vitamins and minerals permitted for used in food supplements and fortified food  No. 1925/2006) ,16. Regarding the nutrient itself, the SCF and EFSA performed an evaluation of the vitamins and minerals with the aim of establishing tolerable upper intake levels (ULs) for different groups of population; ULs being the highest dose in terms of chronic daily intake that is likely not to induce an adverse effect in humans. Like other chemical substances, vitamins and minerals may have adverse effects if consumed in excessive amounts, and thus the same principles of toxicological characterization apply to these micronutrients like other food chemicals. The specific principles for evaluation of the adverse effects of micronutrients in humans and for establishing upper levels of intake are explained in the SCF scientific opinion ”Guidelines of the scientific committee on food for the development of tolerable upper intake levels for vitamins and minerals” . One impIn relation to the source of these nutrients, when a company wants to launch a new source of vitamins or minerals on the market that is not included in the permitted lists, they have to submit an application to the European Commission, who may request that the EFSA perform the corresponding evaluation of the safety assessment. These safety assessments are published by the EFSA as scientific opinions. The EC reviews and updates the lists, taking into account the evaluations of the EFSA. The application includes a technical dossier that should be prepared following the corresponding EFSA guideline entitled “Guidance on safety evaluation of sources of nutrients and bioavailability of nutrient from the sources” . AccordiThe dissociation and the extent of dissociation of the source in the lumen of the human gastrointestinal tract is a key point in the evaluation of the safety assessment of a source of vitamins or minerals. Toxicological data should focus on the source and the relevant breakdown products. Existing toxicological evaluations of the resulting compounds should be included. If not available or not adequate, new data should be produced. In any case, the guidelines state that the tiered toxicity testing approach published as part of a scientific opinion entitled “Guidance for submission for food additive evaluations” should be considered  for the.. Some sThe guidelines regarding the safety assessment of the source of vitamins and minerals include a table in which different categories of substances that can be proposed as a source of vitamins or mineral are presented. This table also contains the additional data requirements for the safety assessment, depending on the category. Within the categories, the sources of botanical origin and sources related to novel foods are included. In this case, the information given in the following sections should also be considered. As mentioned previously, there is a list of novel foods authorized (Regulation (EC) No 2015/2283 and Implementing Regulation (EU) 2017/2470)) ,19. ThisIn 2016, the EFSA published the scientific opinion entitled “Guidance on the preparation and presentation of an application for authorization of a novel food in the context of Regulation (EU) 2015/2283” . In thisThe guidelines state that the tiered toxicity testing approach for food additives should also be applied  for the.. It is Botanicals can be novel foods as whole plants, compounds isolated from plants, or compounds produced from plants. In any case, the specific considerations provided by the EFSA for botanicals and botanical preparations should be taken into account see . It is important to mention that the EU does not have a centralized authorization procedure for the use of botanicals and botanical preparations in food. Business operators are responsible for the safety of these products and must comply with the general requirements set out in the general food law (Regulation (EC) No. 178/2002).In 2009, the EFSA published the Guideline entitled ‘Safety assessment of botanicals and botanical preparations intended for use as ingredients in food supplements’  to help The following data are required to perform the safety assessment of botanicals and botanical preparations: technical data as the identity and nature of the source material, manufacturing process, chemical composition, specifications , stability, proposed uses and use levels and information on existing assessments; data about exposure (extent and duration); and toxicological assessment.For the toxicological assessment of botanicals and botanical preparations, the EFSA has proposed an approach consisting of two levels: (1) safety assessment based on available knowledge (level A), and (2) safety assessment including newly generated data (level B). Regarding level A, available data from large population groups exposed to the ingredient (at a known level) can allow for conclusions regarding the absence of adverse effects. Actually, the EFSA has published the ‘Scientific Opinion on a Qualified Presumption of Safety (QPS) approach for the safety assessment of botanicals and botanical preparations’  to be usDue to the great amount of botanicals and their bioactivity (and toxicity), the EC has not produced a list of authorized ones. However, the EFSA has created a “Compendium of Botanicals” that have been reported to contain substances that may be of health concern when used in food or food supplements . These aFor botanical substances or botanical preparations going to be used as a source of nutrients or as a novel food, the corresponding process to put them on the market and perform the safety assessment should be followed see . The toxicity evaluation is a key point in all safety assessments. The EFSA guidelines produced to perform the safety assessment of the source of vitamins and minerals, novel foods, or botanicals suggest following the tier toxicity testing approach proposed for food additives in 2012  Table 3Table 3. Toxicokinetic evaluation provides data on the systemic exposure to the chemical and its metabolites as well as on the process involved in their absorption, distribution, metabolism, and excretion (ADME). It gives valuable information for the selection of the appropriate species and doses for toxicity testing and for the interpretation of the toxicity studies. Comparison of the animal internal dose to human exposure is very relevant for the safety assessment and both in vitro and in vivo techniques can be used.Genotoxicity studies the effect of chemicals on the DNA. It is known that genetic alterations are associated with serious health effects such as cancer and degenerative conditions. Moreover, genetic alteration in germ cells may induce abortions, infertility, or heritable damage. In genotoxicity testing, both the formation of point and chromosomal mutations, both structural and numerical, are evaluated using different in vitro and in vivo techniques. Toxicity studies are performed to assess changes in blood, urine, and clinical biochemistry parameters as well as gross and histopathological changes in organs and tissues following a prolonged exposure of animals to the test material. These studies may also provide information on neurofunctional and neurobehavioral effects. Subchronic toxicity studies  establish the main toxicological profile of the substance and provides information on the target organs and tissues affected, on the nature and severity of any effects, and on the dose-response relationships. Moreover, it allows the determination of very important toxicological parameters such as the non-observed adverse effect level (NOAEL), which is the highest dose at which adverse effects are not detected. Subchronic toxicity studies allow for the estimation of the dose to be used in chronic studies including carcinogenicity studies; the highest dose levels in these studies should induce some toxic effect. In carcinogenicity studies, animals are exposed to the test compound daily for two years and the endpoint is the formation of tumors.Reproductive toxicity and developmental toxicity studies are performed in animals in order to obtain information on the effects on the reproduction  and on prenatal development . Exposure can occur prenatally via the mother during the pregnancy and postnatally via maternal milk. Moreover the toxicity approach consists of three tiers: tier 1 testing includes the minimal data required for all compounds; tier 2 applies to the compounds that are absorbed or demonstrate toxicity or genotoxicity in tier 1; and tier 3 is performed on a case by case basis to study specific endpoints, depending on the results obtained in tier 2. Higher tier testing may be required in some cases. As can be observed in In in vivo studies, substances should normally be administered via the oral route and the highest dose should normally not exceed 5% of the diet in order to avoid nutritional imbalances. Deviation from the strategy or test proposed or protocols should be justified. All relevant knowledge on the novel foods should be considered in order to make decisions on whether and which toxicity studies are necessary. Human data from epidemiological studies, if available, should also be included for the evaluation. The ‘presumption of safety’ can be applied in some circumstances.Testing engineered nanomaterials (ENMs), which are also used as bioactive compounds or as carriers, may require the modification of some toxicity testing methods. According to the EFSA recommendation of the safety assessment of additives , the EFSThe scientific opinion regarding the preparation and presentation of an application for authorization of a novel food  also speAs it happens in the case of food additives, the study of the ADME of complex mixtures or whole foods should be performed with the toxicologically relevant constituents  ,33. HoweIt is worth mentioning that when a potential toxicological effect is identified, this should be discussed, taking into account the anticipated/calculated intake of the substance/food.Overall, the safety assessment of a bioactive compound  should be done by taking into account if it will be part of a food supplement or fortified food, or novel food. In all cases, the toxicity testing approach follows the general principles of toxicity characterization described for testing additives in food .


Introduction: Wrong site surgery (WSS) is a preventable error. When these events do occur, they are often devastating to the patient, nursing staff, surgeon, and facility where the surgery was performed. Despite the implementation of protocols and checklists to reduce the occurrence of WSS, the rates are estimated to be unchanged.Materials and Methods: An innovative technology was designed to prevent WSS through a systems-based approach. The StartBox Patient Safety System was utilized at six sites by 11 surgeons. The incidence of near misses and WSS was reviewed.Results: The StartBox System was utilized for 487 orthopedic procedures including Spine, Sports Medicine, Hand, and Joint Replacement. There were no occurrences of WSS events. Over the course of these procedures, medical staff recorded 17 near misses utilizing the StartBox System.Conclusions: StartBox successfully performed all tasks without technical errors and identified 17 near miss events. The use of this system resulted in the occurrence of zero wrong site surgeries. Wrong site surgery (WSS) continues to plague medical facilities across the globe despite implementation of initiatives, checklists, and protocols. WSS refers to surgery that is incorrectly performed on the wrong side, wrong spine level, wrong anatomy, wrong patient, or the wrong procedure. Estimates on the incidence of WSS vary widely, ranging from 0.09 to 4.5 per 10,000 procedures . This poWith the guidance of proper processes, checklists, and safeguards, the Joint Commission has declared that WSS is a preventable event that should never occur. In support of this expectation, the Joint Commission introduced a Universal Protocol in 2004 that provides guidelines for the fundamental elements of a WSS prevention protocol. The Universal Protocol includes requirements for marking of the surgical site, confirmation of patient identity, confirmation of the intended procedure, and review of these details among the surgical team during a time-out immediately prior to the start of surgery . While UThe StartBox Patient Safety System  is an innovative technology that was evaluated to assess its ability to prevent WSS. This evaluation was performed using cases performed by 11 surgeons at six sites with the StartBox System. The System collects procedure data including a description of the surgery, evaluation of any near misses or other safety benefits added to the case by StartBox, and postoperative evaluation of the occurrence of WSS events defined as any procedure performed at the wrong site including, incorrect procedures, and procedures performed on the wrong patient.Lavender, for Left; Rose, for Right; Neutral Gray, for No Laterality  and a data reporting tool. The software application of StartBox is an easy-to-implement, standardized platform that improves communication between the surgical team and the patient; between the surgeon's practice and surgical facility; and among care providers along the patient care continuum . The appterality . This cos injury . With thUpon completion of the procedure, the case data, including near misses, is stored and aggregated to generate predictive analytics related to future WSS prevention protocol improvements and training opportunities. Near misses related to WSS would include incorrectly booked surgery and improperly performed presurgical time-outs .The study was carried out with sequential series at each site using retrospective, deidentified data. The system is designed to protect the confidentiality, availability, and integrity of personal health information as required by HIPAA and satisfy the compliance requirements of institutional ethics committees.The StartBox System was utilized for 487 orthopedic procedures . The proNo Gos  No Gos were due to incorrect procedure information including site or description. Five (5) No Gos were due to laterality mismatch.Six (6) No Gos were recorded by the preop nurse at check-in on the day of surgery (9), followed by the circulating nurse in the OR (4) and the clinic scheduler (3). A surgeon recorded one No Go . The second was a spine case with a mismatched informed consent and dictated preoperative surgical plan . The patient identified the error after listening to the dictation at the hospital before being prepped for surgery and inquired with the nurse, who then confirmed with the surgeon. The informed consent was then corrected at preop. Both of these procedures were successfully completed with the StartBox System.Two final examples of Use of StartBox did not result in any reported impacts or use impedance to patient workflow at the clinic or hospital and there were no delays in surgery due to technical difficulties during the time-out or failure of the system to release a surgical blade after completion of the time-out.British psychologist James Reason suggested in his Swiss Cheese model of accident causation that catastrophic safety failures are almost never caused by isolated errors committed by individuals. Instead, most accidents result from multiple, smaller errors in environments (the holes in the cheese) with serious underlying system flaws. In this model, errors made by individuals result in disastrous consequences. Reason also emphasized that human error is inevitable, and that a systems approach can catch errors before they occur or block them from causing harm .The Hierarchy of Intervention Effectiveness, first introduced in 1999 by the Institute for Safe Medication Practices, presents a risk management theory that ranks intervention methods from least to most effective. Human-focused interventions such as education, training, rules, policies, and checklists are rated toward the bottom of its scale . While nConsidering this background, current measures fall short in two categories. First, WSS prevention protocols do not address potential sources of error, according to the Swiss Cheese model. Moreover, relying on a checklist without computerization or constraints is an inferior and generally acknowledged less-effective means of error prevention.With the end goal of improving WSS prevention protocols and ideally eliminating WSS altogether, the StartBox System was developed to enhance all three intervention methods. System-focused improvements include standardizing and streamlining workflows, as well as complementing existing electronic medical record systems. This system boosts human-oriented methods that contribute to effective communication, such as the huddle described in TeamSTEPPS (Team Strategies and Tools to Enhance Performance and Patient Safety)  as well The goal of this study is to report the early experience using this innovative system comprising the recording of the decision for surgery, verification of the procedure record for all the constituents in the patient care continuum, confirmation of procedure accuracy during the surgery time out, and the use of a physical forcing function before the surgical incision.In the clinical evaluation that is the focus of this report, StartBox was utilized with 487 procedures to standardize a process that is intended to prevent WSS. Users reported a good experience using the system, including the anecdotal feedback summarized in Near misses, sometimes referred to as close calls or potential adverse events, are defined as acts of commission or omission that could have harmed the patient but did not cause harm as a result of chance, prevention or mitigation . Near miAs a surrogate for WSS, analysis of near miss events may allow organizations to examine the effectiveness of complex systems designed to prevent WSS, without such an event ever occurring . A systeNo Go function of the StartBox System was triggered in 17 of 487 (3%) registered procedures. Quantifying near misses is an important step in understanding the risk of WSS and facilitating a longitudinal review of modified systems and protocols to prevent errors. These errors could have been mitigated by standard prevention protocols, but likely not tracked or reported. Near miss analysis is rare , requiring different room setup or approach to the spine after a midline incision. The StartBox System allowed for further precision to be communicated to the OR team by the surgeon, which was an improvement over previous processes. The system color-coding especially supported the awareness of procedure laterality (including room setup and approach) and contributed to the prevention of this frequent type of WSS.The number of patients in the study is small relative to the volume of surgical procedures at a given institution. The small number of patients limit an effective comparison between sites as well as perform any correlation analyses. Future studies with larger number of patients should provide better opportunity to do so. Additionally, the study at each site was conducted over a relatively short period of time, limiting the ability of the institution to perform in-depth analysis of the near misses and implement considerable systematic change or evaluate effectiveness of changes. Continued evaluation with an increasing number of patients over a longer period of time should help further the appreciation for the incidence of near misses and validate the StartBox System as a robust safety system for WSS prevention.StartBox is designed to prevent wrong site surgery and capture near misses through a real-time, data-driven approach. The system is designed to complement safety checklists, standardize and streamline workflows, integrate computerization, and provide a final constraint to prevent WSS.This evaluation included 487 surgical procedures during which StartBox successfully performed all tasks without technical errors and identified 17 near miss events that could have led to the occurrence of a wrong site surgery. Zero wrong site surgeries occurred in this study.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of Defense or the US government. DG is an employee of the US government. This work was prepared as part of their official duties and as such there is no copyright to be transferred.DG, BH, and DGS performed procedures that are its subject and wrote sections of the manuscript. All authors contributed conception and design of the research, contributed to manuscript revision, read, and approved the submitted version.BH, DGS, and JD have equity investment in StartBox, LLC. DS is a consultant for StartBox, LLC. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Professionalism is a core competency of medical residents in residency programs. Unprofessional behavior has a negative influence on patient safety, quality of care, and interpersonal relationships. The objective of this scoping review is to map the range of teaching methods of professionalism in medical residency programs . For doing so, all articles which are written in English in any country, regardless of their research design and regardless of the residents’ gender, year of study, and ethnic group will be reviewed.This proposed scoping review will be directed in agreement with the methodology of the Joanna Briggs Institute for scoping reviews. The six steps of Arksey and O’Malley methodological framework for conducting scoping reviews, updated by Levac et al. (Implement. Sci. 5(1): 69, 2010) will be followed. The findings from this study will be merged with those of the previous Best Evidence Medical Education (BEME) systematic review. All published and unpublished studies from 1980 until the end of 2019 will be reviewed, and the previous BEME review will be updated by the findings of the articles from the beginning of 2010 until the end of 2019. All research designs and all credible evidence will be included in this review.Conducting this scoping review will map the teaching methods of professionalism and will provide an inclusive evidence base to help the medical teachers in the choosing for proper teaching methods for use in their teaching practice.Not registered. Professionalism is “the habitual and judicious use of communication, knowledge, technical skills, clinical reasoning, emotions, values, and reflection in daily practice for the benefit of the individual and community being served” . It has Nowadays, teaching professionalism has been integrated into the mission statement of some medical schools. Professionalism is taught in some residency programs , 7. MediMedical residents are among the first to visit patients. Their interpersonal relationships, quality of care provided by them, and their patients’ safety are influenced by the training on professionalism . TherefoTeaching methods are the ways to deliver the content of education and facilitate the learning of students . TeachinThe importance of teaching professionalism is highlighted in a narrative review in 2014 . All teaWhile being important, teaching professionalism is challenging too. Many medical teachers are not trained enough to teach professionalism . They peSome studies (no systematic review) on teaching professionalism across surgery, orthopedic, and ophthalmology residency programs have been already conducted –19.In a systematic review by Berger and colleagues, professionalism curricula in postgraduate medical education (PGMED) are reviewed in 50 included interventional studies. The authors have searched only three databases, and reviewing the teaching methods of professionalism has been a small part of this review. Method of teaching professionalism has not been the subject of research in 17 out of 50 included studies in this review and some new methods of teaching professionalism such as teaching through social media or learning management systems are not included in the review. Except for teaching methods of professionalism, curricula duration, effectiveness, and assessment modalities are evaluated in this review too. As the authors of this review have concluded, finding best practices based on synthesizing previous findings, which were very heterogeneous, was difficult. It is also concluded that “even simple, short teaching sessions” would affect professionalism .Therefore, in order to help the medical teachers to keep themselves updated on methods of teaching professionalism, it was intended to conduct a scoping review focused on methods of teaching professionalism in medical residency programs, in all databases, regardless of the research design of the included studies. For this purpose, all published and unpublished studies from 1980 until the end of 2019 will be reviewed, and the previous BEME review will be updated by the findings of the articles from the beginning of 2010 until the end of 2019. The findings from this study will be merged with those of the previous BEME systematic review. As different medical specialties are of different nature, while reviewing teaching methods of professionalism, the methods will be systematically categorized by different specialty areas of residency training.Conducting this scoping review will map the teaching methods of professionalism, divided by specialty areas in PGME and will provide an inclusive evidence base to help the medical teachers in the choosing for proper teaching methods for use in their teaching practice and make even a little change on promoting professionalism in their own specialty area.This proposed scoping review will identify and map the available and emerging evidence on the topic of teaching professionalism in medical residency programs. It will be directed in agreement with the methodology of the Joanna Briggs Institute for scoping reviews . The six“What methods have been used to teach professionalism in each specialty area of medical residency programs?”What methods have been used to teach professionalism for medical residents in each culture?What methods have been used to teach professionalism for medical residents in each setting?How many medical residents have been trained about professionalism in one session, by each teaching method?What resources have been used to teach professionalism to medical residents, by each teaching method?What role(s) have teachers played in applying each method to teach professionalism to medical residents?What skills were applied to employ each method to teach professionalism for medical residents?This review will be guided by the following research questions:For this review, the following general keywords are identified: professionalism, medical ethics, professional role, teaching, education, hospitals, health care system, health system, primary care setting, secondary care setting, community care setting, teaching method, educational method, residency program, medical training, medical residents, and resident doctors. Specific keywords, which will be used during literature search, will be reported later in the final review.A broad search on teaching professionalism in postgraduate medical education will be conducted. All the articles and studies will be filtered, and only those related to medical residency programs will be selected for the next steps.The results will be merged with all related studies which were reviewed in BEME Guide Number 25 .Both published and unpublished studies (gray literature) will be considered in the search strategy. An initial search has been conducted in three main databases  until December 2019. A sample of our search strategy is added as Additional file After completing the search and loading all studies into EndNote X8, duplicates will be removed. In dealing with reviews that included duplicate original studies, if the original article is evaluated correctly in the review article, the review article will be used in the study instead of the original article. Moreover, secondary analyses related to a trial will not be included in the study. Secondly, assuming that a trial study may have been included in two different review studies, the occurrence of such a hypothetical case and not being able to delete that duplicate trial will be mentioned as a limitation of the study because we cannot disregard one of those two reviews because of the duplication of that trial. Inclusion and exclusion criteria for selecting articles are shown in Table The search results will be fully reported, and the final report will be shown in a Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram .Detail of data will be extracted in accordance with the JBI-recommended approach [20]. Data will be extracted by two independent extractors (blind to each other). A pilot form, with minimum requirements, is considered for data extraction. Based on the findings from the literature review, other necessary details will be added to the form. In order to standardize the form, consultation with experts in the field will be adopted. The data extraction tool for this protocol is presented in Table In this review, except for the data including the name of the first author, journal name, publication year, country of study, residents’ characteristics (PGY) including year of residency, objective of study, type of study, conclusions, and recommendations, qualitative data will be extracted, and the findings will be grouped into seven key variables: training discipline, culture, method of teaching professionalism, setting of teaching, number of participants in each educational session, the role of the teacher, necessary skills for teaching, resources used.All data on teaching methods of professionalism in medical residency programs will be charted and summarized in relation to the objective of the study.A total number of searched studies and selected ones will be reported. The decision process will be described. The flow of selection process will be reported using a PRISMA flow diagram . ResultsA narrative description of the main objective in teaching methods of professionalism to medical residents will be presented.The results will be classified under categories such as residents’ year of study and studying discipline and setting of training. Charts or tables will be used to present the results such as distribution of the teaching methods by residents’ year of study or etc. If quantitative synthesis was not possible, the results would be only described.Implications of the study finding for both practice and research will be identified.Primary findings will be used as a basis for consultation with both medical teachers and residents. By such a consultation, search strategies will be refined, and opportunities for knowledge transfer will be provided. The findings of this review will be shared at educational conventions and conferences. The report of the review as well as a peer-reviewed article will be published as well.Questions in this review do not relate to quality assessment debates. So, due to the nature of the aims of this review, risk of bias of the included evidence will not be evaluated as it is usual in most scoping reviews . MoreoveIn this scoping review, the available evidence and innovative practices on the topic of the methods to teach professionalism in medical residency programs will be identified and mapped. By synthesizing the evidence, research gaps in the existing literature will be recognized and the emerging research priorities will be consulted with stakeholders. Limitations of conducting this review, practical implications, and recommendations for future research will be reported in the discussion of the protocol’s article.Additional file 1. A sample of search in Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R)