Food safety is related to public health, social welfare, and human survival, all of which are important and pressing areas of concern all over the world. The government plays an increasingly important role in the supervision of food safety. The role of the government, however, is also controversial. Using provincial panel data of China from 2005 to 2015, the present study intends to shed light on the associations between government intervention and food safety performance under two scenarios of local government—competition and noncompetition. This will be accomplished through an exploratory spatial data analysis and a spatial econometric model. The results reveal negative associations between food safety performance and government intervention without considering local government competition. As was also observed, government intervention not only inhibits the improvement of food safety in the region, but also has a negative spatial spillover effect on food safety in neighboring provinces. This is the result after considering government competition, thus, showing the competitive strategic interaction of the “race to the bottom”. Further analysis reveals that, if geographically similar regions are selected as reference objects, the food safety performance of each province will have a stronger tendency to compete for the better. If regions with similar economic development levels are selected as reference objects, food safety performance will have a stronger tendency to compete for the worse. This work provides new evidence for the relationships between government intervention and food safety, and, also, proposes some insightful implications for policymakers for governing food safety. In the past few years, global food incidents have occurred frequently ,2, and tIn 2019, China ranked 35th out of 113 countries in food security, according to the Global Food Security Index (GFSI) . In the Although some countries, including China, have taken measures to strengthen the supervision of food safety, weak links in the implementation of these measures still exist . In the In the past few decades, many scholars have attempted to reveal the effects of government intervention on economic and social development. Government intervention measures mainly include the direct control of enterprises, as well as indirect economic regulation, such as tax subsidies, financial regulation, and labor mobility restrictions. Existing government intervention studies mostly focus on the impact of government intervention on various aspects of economic development, and different opinions have been expressed. Some scholars hold that government intervention is effective in achieving the stated goal. For example, Wang revealed the impact of government intervention on innovation performance in Hong Kong and Singapore . The stuThe history of human social progress has been accompanied by the solution and development of food safety problems. Consequently, numerous relevant scholars have also launched a significant number of discussions related to food safety. Xiong et al. evaluated the performance of the food safety management system (FSMS) of pork slaughter plants in China . The stuThe question must then be asked, has government intervention really improved food safety performance (FSP)? Some studies have shown that government intervention has strengthened the motivation of food production companies to provide safer food. Thus, government intervention has played an increasingly important role in the food supply system . Zhang eThe existing research on government intervention and food safety is relatively rich, but there are still some deficiencies. One is the lack of empirical research. Owing to the lack of data on food safety costs, benefits, and foodborne diseases, the number of empirical studies containing such information is limited . There iIn this study, the model was set up and the data was described firstly. Then, the spatial econometric analysis and the asymmetric response analysis were carried out. For the empirical analysis, the external commands in Stata software were used for model building and estimating. In order to better show the research process of this study, the research framework is presented in i at year t; the key explanatory variable  method was used to estimate regression. The Hausman test was used for fixed effect (FE) and random effect (RE). The test results were significant. Therefore, this paper used a two-way fixed effect model for estimation. The regression model for estimating was as follows:Due to development needs and performance evaluations, local governments will inevitably compete with each other. Government intervention—achieved by influencing market supervision—has become an important factor in the strategic food safety competition between local governments. In this research, the spatial relationship of each region was considered by the spatial weight matrix to test the associations between government intervention and food safety when considering local government competition. Since government intervention was an endogenous variable, this article drew on Lesage and Fischer  and intrOne can judge the strategy interaction mode of local government competition according to the sign and size of This paper focused on the associations between government intervention and food safety; the spatial spillover effect of government intervention and robustness of the results were also analyzed in detail. In addition, there are many factors that affect regional food safety, so, other control variables were introduced. The specific variable selection and calculation method are shown in The key dependent variable of this study was the food safety performance of each province. Owing to the limitation of data availability pertaining to positive indicators of food safety, this article, referring to Zhang et al., used the reciprocal of the number of food safety incidents in each province, every year, as the proxy variable of food safety performance . AccordiThe explanatory variable of this research was government intervention. This research was limited by the availability of data, as government intervention indicators cannot be obtained according to the corresponding specific policies; such indicators are also usually measured by constructing proxy variables ,16. Theri in each year, respectively. The length of schooling is set as 0, 6, 9, 12 and 16 years, respectively, and In order to control the impact of other factors on food safety, this research selected a series of control variables on the basis of combing relevant extant literature. Previous studies have found that both economic development level and urbanization level are important factors affecting food safety . Consequtization . In additization ,36. The i and j; A spatial econometric model is based on the spatial correlation between sample data. Therefore, a spatial autocorrelation test of the sample data is needed first. Based on the exploratory spatial data analysis (ESDA) method, this research investigates the global and local spatial correlations of different spatial unit observations of related variables. The following are the formulas used to calculate the global Moran’s I index.The local spatial autocorrelations are examined through the Moran scatter plots (MSP) by Geoda software . The plots indicate that most observations were located in Quadrants one and three. It can be concluded that the spatial agglomeration by FSP was evident. From 2005 to 2015, the distribution of observations tended to Quadrants one and three, showing that the feature of spatial clustering of FSP had enhanced with time.According to the above-designed Equation (1), a regression estimation is performed based on the OLS method. The control variables are added gradually from Column (1) to Column (5), and the upper and lower 1% winsorizing is adopted. The results are presented in As regards the control variables, it is noteworthy that economic development level, degree of marketization, technological innovation, and education level are positively associated with food safety. Moreover, the impact coefficients of openness degree and population growth rate on food safety are significantly negative. This shows that openness has restricted the improvement of food safety through the introduction of foreign capital and the strengthening of international competition. In addition, population growth has exacerbated the dual problems of supervision and the slow improvement of food safety. In addition, the influence coefficients of industrial structure and urbanization level on food safety are not significant. This finding shows that regional industrial structure and urbanization level had no significant association with food safety during the sample inspection period.Next, this study takes local government competition into consideration and conducts a spatial econometric analysis. Firstly, LR statistics are constructed to test whether the SDM can be simplified into a spatial lag model (SLM) and spatial error model (SEM). According to the results, the SDM should be selected for estimation under Ad-weight and Geo-weight. Then, FE and RE are selected according to the Hausman test and AIC principle. The fixed effect for estimation should be chosen based on the results.This research also analyzes the spatial spillover effect of government intervention on food safety performance. Referring to the research method of Lesage and Fischer , this stIn the estimation that does not consider local government competition , the spatial spillover effect is set to 0; the estimated coefficient of government intervention on food safety is −0.951. After considering local government competition, the direct effects of government intervention on food safety are −0.747 and −1.238 under Ad-weight and Geo-weight, respectively. By comparing the above two situations, one can find that the negative associations between government intervention and food safety are underestimated when spatial factors are not considered. When local government competition is not considered, local governments will adopt intervention strategies tailored to their local factor endowments and development situations, thereby reducing the effect of competition. After considering local government competition, based on target assessment and promotion incentives , various regions will inevitably compete with each other. This compels local governments to increase their levels of intervention, adopting the same, or even transcending, the strategies as used in neighboring provinces in order to maximize their interests. Finally, there is a “race to the bottom” strategic interaction among governments.In addition, it can be found from Columns (1) and (3) of In this research, the ratio of local government fiscal expenditure on general public services to GDP (Govern2), and the ratio of local government public health expenditures to GDP (Govern3), are used as alternatives to the core explanatory variable. The relevant data come from the CEIC. The Hausman test is employed to select both the FE and the RE. As can be concluded from the results, the former should choose the fixed effect model to estimate, while the latter should choose the random effect model to estimate under Ad-weight. The fixed effect model should be chosen to estimate under Geo-weight. The results are shown in Columns (1) to (4) of Since the strategic interaction between regions will not only consider neighboring provinces but, also, provinces with similar economic development levels, this article also establishes an economic distance weight matrix (Eco-weight). The matrix element is the reciprocal of the average difference of per capita GDP between each of the two provinces in the sample period. Based on Eco-weight, the Hausman test shows that the FE model should be selected for estimation. The results are presented in Column (5) of In this research, the SDM is used to solve endogeneity problems caused by measurement errors and missing variables. To test the robustness of endogenous problem solving, a spatial dynamic panel model is built. The model is based on the system generalized method of moments (SYS-GMM) method for re-estimation. Without introducing external instrumental variables (IV), SYS-GMM can select appropriate IV according to the time trend of variables, so as to solve the endogenous problem. The models have passed the Sargan test and Arellano–Bond test, indicating that both the model and the IV are reasonable and effective, and there is no over-identification problem. The results are shown in Column (6) of The estimated coefficients of Specifically, according to Columns (1) and (2) in The positive incentive for FSP is effectively embodied as a “reputation effect”; for example, the demonstration of China’s food safety cities and positive reports from the news media. In addition, the positive incentive also manifests as a kind of “peer effect” that competes with, and promotes, each other. The negative incentive is the need for more cost investment, the “risk effect” of supervision, and the fluke of being exempted from responsibility. Specifically, on the one hand, when geographically similar regions are taken as the reference objects, those regions’ food production, transportation, sales, and supervision are highly correlated. As such, the “yardstick competition” tendency is obviously greater than the “race to the bottom” tendency. On the other hand, when regions with similar economic development levels are taken as the reference objects, if they are among the more developed regions, the fluke mentality that they have already taken the lead will aggravate the motivation to compete for the worse. Owing to the distances involved, the connection between provinces is relatively sparse. Thus, motivation to compete for the better is relatively weak and is obviously less than motivation to compete for the worse. If the competition is between economically underdeveloped regions, the indicators of competition between the regions are generally manifested in the economic growth rate and the scale of investment promotion, while less attention is paid to food safety.Food safety issues usually stem from the asymmetry of information between consumers and suppliers, particularly with regard to the specific attributes of products, the asymmetry of costs and benefits, and the game of interest between related entities . In realFrom the government perspective, because a “regulatory trap” ,46 existFrom the perspective of market entities, government intervention may restrict the enthusiasm and initiative of relevant market entities to make the necessary efforts to improve food safety. On the one hand, government intervention highlights the functions of the government, but hinders the role of the market in resource allocation . CorruptFrom the consumer perspective, strengthening food safety supervision will lead to unrealistically high consumer expectations. This is not conducive to food safety governance ,54. WhenAccording to Waldo Tobler’s first law of geography, “Any geographical thing or attribute has a certain correlation in space, and the closer the distance is, the closer is the relationship” . In thisThis study finds that China’s food safety interests still face severe challenges. On the basis of an empirical analysis and discussion, this research puts forward some feasible suggestions regarding how to promote the improvement of food safety.Firstly, promote the reform of government regulation systems and enhance the effectiveness of government intervention. The spatial econometric estimation results show that there is a significantly negative association between government intervention and food safety. Therefore, on the one hand, an absolute requirement exists to improve food safety supervision and governance mechanisms, reasonably formulate food safety assurance plans, and clarify the division of responsibilities for supervisors. On the other hand, there is a need to establish the long-term guarantees mechanism of food safety, and to speed up the systems construction of food supply chain traceability and integrity.Secondly, strengthen regional cooperation and the exchange of experiences. Furthermore, improve the joint prevention and control mechanisms of food safety. The results of the asymmetric response analysis show that the FSP in neighboring provinces creates the interaction strategy of “yardstick competition”. Therefore, all regions are supposed to break through geographical boundaries; regional food safety joint guarantee organizations should be established to strengthen regional cooperation. In addition, food safety incidents should be increasingly exposed, with the help of the media; punishments for profit seeking behaviors that endanger food safety should be increased, and propaganda campaigns regarding food safety laws, regulations, and standards should be conducted.Thirdly, promote the participation of multiple entities in food safety maintenance, and promote the diversification of governance modes. Ensuring food safety is a systematic and complex social project, one which requires not only government intervention but also the cooperation of social forces. Governments should reasonably adjust their terms of reference so as to truly stimulate all market players’ sense of ownership. A government should not only pay attention to the supervision of food safety but should also ensure the effectiveness of the multidirectional information flow between different governance entities . The resThe results of this study show that, when local government competition is not considered, there is a negative association between government intervention and food safety performance; however, the degree of association is underestimated. This also confirms, to a certain extent, the existence of a “regulatory trap”. When local government competition is considered, government intervention not only has a negative association with food safety in the region, but, also, has a negative spatial spillover to neighboring regions, creating and showing the strategic characteristics of a “race to the bottom” strategy. After the decomposition of the spatial effect, it is found that the total effect, direct effect, and indirect effect of government intervention on food safety are significantly negative; there is also a negative feedback effect on food safety. Through the analysis of an asymmetric response model, it is found that, if geographically similar regions are selected as the reference objects, the food safety performance of each province has a stronger tendency to compete for the better. If the regions with similar economic development level are selected as the reference object, there is a stronger tendency for food safety performance to compete for the worse.Nevertheless, despite this paper’s meaningful findings, this research has some limitations, which could, in turn, be used as reference points for future studies. On the one hand, although this study successfully estimates the associations between government intervention and food safety performance in China, due to the imperfect (or missing) statistics on food-related data, the indicators selected in this study are representative but are not perfect. In follow-up work, further improvements can be made in terms of data collection and integration. On the other hand, the analysis in this study is aimed at China, a special developing country. Considering the differences of government intervention and food safety regulation in countries with different economic and cultural attributes, future studies could be conducted in other countries.


Background: Pediatric sedation and anesthesia techniques have plenty of difficulties and challenges. Data on the pharmacologic, electroencephalographic, and neurologic response to anesthesia at different brain development times are only partially known. New data in neuroscience, pharmacology, and intraoperative neuromonitoring will impact changing concepts and clinical practice. In this article, we develop a conversation to guide the debate and search for a view more attuned to the updated knowledge in neurodevelopment, electroencephalography, and clinical pharmacology for the anesthesiologic practice in the pediatric population. A retrospective study with data from 1996 to 2000 showed the impact of multiple surgeries and anesthesia on learning disabilities and the onset of ADHD in children under 3 years of age [The American Society of Anesthesia responded to these FDA claims by acknowledging that while there are data on anesthesia toxicity risks in developing brains , these aDuring the last few years, several studies have been developed in an attempt to clarify the undesirable effects of general anesthesia on children. Studies such as the GAS study, PANDA Project, and MASK study ,5,6 haveThe conceptualization of pediatric anesthesia, particularly the sedative component, as a pharmacological phenomenon associated principally with neocortical activity, presents many conceptual questions and a deficit of objective data in order to interpret whether the anesthetic action fulfills all the desired objectives. For this reason (and others), anesthetics are frequently performed with techniques, drugs, or concepts used in mature brains. For example, the full significance of recent electroencephalographic and functional imaging data obtained in children during anesthetic cortical depression is not yet fully understood, which has uncertain implications for our assessment of current clinical practice. The same applies to pharmacological data.For many years, it was assumed that young children, especially neonates, had no response to noxious aggression. Just as this concept has been demonstrated to be incorrect, similar concepts are being assumed about pediatric sedation. For example, the full significance of electroencephalographic and functional imaging data obtained in children exposed to anesthetic is not yet fully understood. In a recent study on infants <6 months of age, the relative percentages of density spectral array did not correlate with end-tidal sevoflurane, there being an absence of coherence in alpha and beta frequencies . This alNociceptive reactivity can be studied from 19 weeks of gestation age. At 20 weeks, the fetus already responds by releasing cortisol and beta-endorphins and noradrenaline, measured in the umbilical cord .Facial expressions of pain appear from a postconceptional age of 28 weeks, and cortical blood flow activity associated with the bilateral somatosensory cortex S2 has been measured between 25 and 45 weeks of gestation after venous puncture. However, this does not ensure that at that age it is possible to develop perceptive abilities, nor to interpret or memorize them as an explicit memory event. Many of these responses are pre-programmed responses of subcortical origin ,12.The concept of minimum alveolar concentration (MAC50) is frequently used in children to guide the anesthetic dosage using population statistical data. Difficulties in titrating inhaled drugs to well-defined pharmacodynamic targets are still major challenges. Generally, the use of MAC50 as a pharmacodynamic concept relies on the patient’s immobility as a clinical objective. This concept originates from the observation that much higher doses of an anesthetic agent are needed to inhibit spinal responses than the concentrations needed to achieve patient unconsciousness. However, this results in unnecessary depression of cortical activity to achieve “unconsciousness and immobility” .In pediatric practice, therefore, it is very unusual to titrate  the anesthetic requirement of the sedation/unconsciousness component. The drug dosages are usually guided by statistical tables, indirect markers such as hemodynamic response, or subcortical responses such as movement to surgical stimuli.Observing the differences at each stage of brain development in brain architecture, synaptogenesis, neuronal differentiation, neurochemical signals, and myelinization, we can intuit that it is not possible to apply the adult concepts to children at different ages of development .N-methyl-D-aspartate receptor (NMDA receptor) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor) subtypes of glutamate receptors peak in the neonatal period. Kainate receptor binding is initially low and gradually rises to adult levels by the fourth postnatal week [In human neonates, maturation of receptor activity has a critical period dependent on synaptogenesis and plasticity between birth and the age of two. Changes in the maturation of glutamate and gamma-amino butyric acid (GABA) receptors in the developing brain show that GABA activation generates significant depolarization, even months after birth. Inhibitory activity is gradually reached through development. Before full maturation of GABA-mediated inhibition, the tal week .If there is a high predominance of GABAergic activity in immature brains (preterm/newborns) and given its recognized role in epileptogenic activity at this age, we should question why the extensive use of GABAergic drugs such as propofol and sevoflurane continues to be promoted in this population, considering the risk of producing an as yet not well-defined excitatory condition. This excitatory GABA state produces a kind of disappearance of a minimal “state of consciousness” or perhaps simply the state of vigilance for these developing brains .Neuroapoptosis, or programmed cell death, is a physiological process of adjustment and occurs at an accelerated rate from 24 weeks of gestation until 4 weeks after birth. This process involves γ aminobutyric acid (GABA) and the glutamate neurotransmitter and receptor systems. This is a very important process for building the fetal brain connectome. In the absence of transmission and neuronal binding of GABA and glutamate, neurons produce neuroapoptosis in an unordered way. The majority of commonly used anesthetic and sedative agents bind to the GABA receptor or the N-methyl-D-aspartate receptor and affect neuroapoptosis very intensely . The binIn neonates, synaptogenesis has different densities in different brain areas. In prefrontal areas, the density is less abundant and reaches its peak only 12 months after birth . This maGlucose uptake in positron emission tomography (PET) studies also shows differences between different areas, with abundant and early activity in occipital zones at 3 months postnatal, while temporal activity begins at 6–8 months .Subplate neurons, the first neurons generated in the cerebral cortex, play a key role in brain development, and guide the formation of thalamocortical connections. The subplate cells form the first functional connections and are necessary for relaying early oscillatory activity in the developing brain .Neonates are affected by the inhibition of intrauterine wakefulness factors that disappear at birth. For example, norepinephrine reuptake is activated along with the activity of the locus coeruleus as a global amplifier center, stimulating arousal and wakefulness .This could justify the use of dexmedetomidine in the newborn by creating conditions like the intrauterine stage of lower connectivity to the environment.Baseline neuroapoptosis increased in neonatal rats exposed to isoflurane, but it was noted that it did not increase in neonatal rats exposed to dexmedetomidine alone. When dexmedetomidine was added to the isoflurane exposure group, they observed a dose-dependent reduction in neuroapoptosis to basal level with no effect on long-term cognitive outcome ,26.The recording of neural activities from use of dexmedetomidine show weak effects on the EEG; they appear to demonstrate incomplete elimination of synchronies such as phase–phase synchrony rhythms. However, from results in short-term studies, there were multiple strong correlations between the base state without the drug and the change of some basal feature value after the drug administration. This apparently indicates that dexmedetomidine did affect the cortical activity of the subjects, but probably indirectly .There are some limitations regarding the safe use of dexmedetomidine in children with congenital heart disease because sinus node and atrioventricular nodal function are both depressed ,29. HoweEEG and postnatal brain tractography show significant age differences in these patients. Synaptogenic arborization is also highly differentiable between neonates, young children, and adolescents .The development of the nervous system begins in the first weeks of gestation. In this phase of brain development, the neonatal cortical activity recorded with the EEG has unique characteristics that can be differentiated from that of an adult. In children before 37 weeks of gestational age, there is a discontinuity compared to the EEG of an adult, and the premature EEG is normally classified as continuous or discontinuous. An intermittent burst of activity in the presence of an otherwise discontinuous EEG is common in premature infants. These bursts of activity are called transient spontaneous activity (TSA) . They arFrom the point of view of consciousness, the fetus at birth is already aware of the body, perceiving pain and differentiating between touch and nontouch. It also presents facial expressions to certain stimuli, probably preprogrammed and of subcortical origin. It is capable of expressing emotions and shows signs of shared feelings. However, as described by Changeux, it is unthinking, present-oriented, and makes little reference to the concept of self . The absNewborns show characteristic features of what can be called basic consciousness, and still have to undergo considerable maturation to reach the level of adult consciousness, although as a premature infant they may open their eyes and make minimal eye contact with their mother, showing avoidance reactions to harmful stimuli.The immature brains of children under six months may be much more dependent on activating  activity than on intrinsic cortical activity, because the bank of experiential memory and the characteristics of connectivity are still extremely limited, preventing the emergence of what we define as explicit perceptual awareness.On the other hand, in adults, propofol induces a state of unconsciousness with an important alpha activity in the frontal spectrogram, resulting from the synchronic thalamo-cortical activity .This frontal delta spindle activity is not observed in children under 6 months. It appears only in children and adolescents where the overall activity (power) is much more intense than in adults. This is seen in the intensity of these alpha bands . In chilBrain monitoring during anesthesia with EEG-derived indices is used only to a limited extent in adults, rarely in children, and essentially not at all in infants. These EEG-derived indices, which have been developed in adults, can give inaccurate indications of anesthetic states in infants and younger children ,39.The current pediatric research has studied a limited set of anesthetics and has frequently used EEG montages with few electrodes. Different analysis methods have been used in different studies. Multielectrode recordings available in children have not been analyzed in relation to age. Dose-titration experiments commonly conducted in adult patients cannot be conducted in children for ethical reasons ,40.The EEG has characteristics that consistently change with arousal during anesthesia, but the relationship between arousal and the EEG is imprecise and drug dependent. This relationship is the basis for using the EEG to measure anesthesia and provides only an indirect measure of consciousness and memory formation in adult patients.Given the mentioned physiology in developing brains, the cortical activity is highly dependent on the activating ascending system  required to sustain an active level of consciousness, and it is minimally dependent on the contents of consciousness. In clinical pharmacologic terms, this means that drugs with subcortical predominant effect, such as opioids, alpha-2 agonists, or low doses of ketamine, are more fundamental than the use of GABAergic drugs to depress the level of consciousness, to simply reduce the arousal and put the cortex in a more synchronic rhythm.In older children, the problem is different. Data indicate that the brain is continually active and the EEG during loss of consciousness shows broad and very powerful alpha bands. The great challenge from the clinical point of view is the phenomenon of emergence delirium. To date, the causes have been poorly explained, but it is likely that this phenomenon is produced by a transitory alteration of the connectivity together with an overload of neuronal input coming from the surgical stimulation or from the postoperative environment. This data overload on a pharmacologically affected brain would generate an information-integration imbalance. Data demonstrating the excitation of the locus coeruleus by the effect of sevoflurane may explain this “overamplification” effect due to the norepinephrine released in this circumstance and eventually may explain emergence delirium in children . An imbaAvailable pharmacological data on children are also weak. The formulas describing distribution and elimination are complex, and weight as a covariable becomes insufficient to describe change over a wide range of ages and sizes. The concept of allometry has been incorporated into pharmacokinetics/pharmacodynamics (PK/PD) models to correct for the change in function and size across ages, particularly in relation to clearance. This approach  help to explain that weight has a different impact for each distributive phase or elimination clearance. It is not correct to use a single working weight to calculate the dose during all the anesthesia, but several, as the distributive process progresses ,43.Inhaled drugs have been the most widely used in neonatal population, but clinical data are primarily extrapolations from older children and based on the concept of immobility (MAC). To study the MAC awake  in this population is very questionable because of the lack of definition of consciousness in this population and absence of EEG correlates of these clinical states .In the case of dexmedetomidine the PK models with significant casuistry are only found in children over 2 years .In a recent study with 20 term infants, the most suitable model for dexmedetomidine was a mono-compartment model with an allometric clearance adjusted to postmenstrual age (PMA). PMA is defined as the time (in weeks) elapsed between the first day of the last menstrual period and birth  plus the time elapsed after birth . Currently there is no validated and approved target-controlled infusion technology available for clinical use to optimize the administration .A study with intensive care pediatric patients using four different data sets observed that the sedation concentration was similar to adults, but small children under 1 year of age with immature clearance required a dose adjustment . The studies of propofol, despite having managed to describe a broad spectrum of ages from infants to adolescents ,49,50, hIn our experience, the most appropriate model to use is Paedfusor  , becausePharmacodynamic models in children also have weaknesses. In PK/PD models, the unifying link between the dissociation of plasma concentrations and the appearance of the effect is called ke0. This ke0 is a constant of gradient proportionality that describes the time course of the effect and has been of great help in the possibility of titrating adult patients during inductions or moments of changes of anesthetic requirement. However, it needs to be refined in consideration of the phenomenon recently described as neuronal inertia. This protective phylogenetic phenomenon is necessary to maintain bistable states and is not represented in the reference studies of concentration–effect relationships used in current pharmacology ,54.As commented regarding the changes in the EEG, the biological markers that were used in children  monitor, spectral edge frequency (SEF50), or auditory evoked potential (AEP)) for the construction of these models, do not represent recent advancements in neuroscience. For example, in a Chilean study with children from 3 to 11 years of age, the mean ± standard deviation of the time to peak effect (TTpeak) of the BIS index was 65 ± 14 s and 201 ± 74 s with the Alaris AEP index. Validation of the effect model and its ke0 was only performed with the BIS monitor. In this case, the use of TTpeak is questionable because it is based on measurements made after a manual bolus where conditions of equilibrium between the plasma and the biophase cannot be ensured . For now, what is becoming clear is that children have faster equilibrium times than adults ,57.Another study with Chilean children and adults compared the calculated plasma concentrations (Cp) using the pharmacokinetic models of Kataria  and MarsHow the Brain Creates the Mind, 2010).The problem is even more significant in children under one year of age, for whom the PKPD data are even weaker. Questions arise here as to whether the use of GABAergic drugs in these brains that still have high excitatory GABA activity produces an anesthetic state, or perhaps just an epileptiform excitatory connectivity uncoupling. That is one of the reasons why the discussion of the potential synaptogenesis alterations that may impact late on cognitive performance is taking place. In fact, we could consider that in neonates up to 6 months, whose thalamo-cortical tracts are poorly developed, the emergence of experiential perceptual consciousness can even be discussed due to the difficulty of producing the phenomenon of “integration of information for complexity”  due to tCurrently, it is very uncommon to use any type of neuromonitoring in children, but there are studies that have reported that isoelectric EEG events were common in infants and young children undergoing sevoflurane or propofol anesthesia. The dosing, based frequently on patient hemodynamics and weak data coming from population pharmacokinetics, is often associated with unnecessarily deep anesthesia during surgery .In a recent study in children 0–37 months of age requiring general anesthesia for noncardiac or intracranial surgery using sevoflurane or propofol infusion, in 63% of the patients, an episode of isoelectricity was observed, more related to high ASA status patients .The true predictive value of the occurrence of burst suppression in pediatric anesthesia remains unknown. Still, it suggests that dosing based on population pharmacokinetics and patient hemodynamics is often associated with unnecessarily deep anesthesia during surgical procedures. There is a paucity of data on the incidence of overdose due to the low use of EEG monitoring in this population, but we suspect that overdose must be a common phenomenon due to the way in which the practice of sedation/unconsciousness titration in pediatric anesthesia is performed. There is widespread discussion on how to address all these challenges in a multifactorial way to reflect whether current anesthesia practice has a deleterious impact on pediatric patient outcomes .In summary, recent data in young children indicate that anesthetic drugs that act by GABAergic mechanisms and NMDA produce a greater risk of generating alterations in maturation. This would be more evident at repeated doses.The use of anesthetic concepts based on clinical and EEG definitions of how mature brains respond does not work for developing brains. Knowledge in these areas is still limited. In clinical practice, it is exceptional to finely titrate drugs based on well-defined objectives, precisely because they are weak; for example, the clinical definition of unconsciousness, or if cortical-thalamic-cortical uncoupling is required as in adults to obtain a neuronal depression that has the minimum impact on brain development.The deficit in drug modeling and not yet having automated administration technology available in target-controlled infusion (TCI) are complexities to be addressed.A better understanding of the EEG activity required to generate brain protection, avoiding isoelectric or convulsive phenomena, and identifying the EEG condition associated with a potential implicit memory of the surgical experience are now on the list of knowledge and concepts that must be progressed.


Single-use plastics have often replaced more sustainable materials in microbiology laboratories. Keeping in mind that one of the objectives of the United Nations Sustainable Development Goals is responsible consumption and production, we wanted to document how many single-use plastic items could be saved by taking reduction and reuse approaches in a microbiology laboratory. After taking 4 weeks to document the baseline levels of single-use plastic waste being generated in our laboratory and identifying ways to reduce our reliance on them, we implemented various reduction and reuse approaches and then documented our plastic use over a 7-week period. Reduction approaches included moving to sustainable materials, such as reusable wooden sticks for patch plating and metal loops for inoculation. Reuse approaches focused on reusing plastic tubes via a chemical decontamination station and autoclaving, facilitating the reduction of single-use plastics and a decrease in the amount of waste generated. By utilizing reduction and reuse strategies, which could be implemented in other microbiology laboratories, substantial single-use plastic savings were achieved. These savings had an impact on the amount of biohazard waste being autoclaved and incinerated, as well as generating substantial cost savings for the research institute. The reductions in waste documented in this study could act as a benchmark for others wanting to implement the changes described. Increasingly, the scientific community is discussing how researchers can develop more sustainable practices. Magazine articles have emphasized the essential role of science in achieving the United Nations Sustainable Development Goals and guidance has been provided by some members of the scientific community as to how to reduce research-related plastic waste. Here we provide a case report documenting, for the first time, the plastic use of a standard microbiology laboratory and the impact of reduction and reuse approaches on the number of plastic items used, as well as the weight of waste generated. This study highlights the large reductions in single-use plastic that can be achieved in research laboratories when a sustainable mindset is applied. Through the details provided in this case report, other research laboratories will be able to adopt the same or similar approaches in an effort to reduce single-use plastic consumption in science. A widespread adoption of such approaches could have significant impacts on the levels of plastic waste generated globally and allow scientific research to become a more responsible consumer of plastic.Blue Planet II and China limited the types of plastic being recycled from Europe and the USA [Public concern surrounding the levels of single-use plastic in our day-to-day lives has increased greatly since 2017, when the impact of plastic pollution in the sea was highlighted by the television series  the USA . Additio the USA . Such inSuch recycling schemes are important but do not reduce the amount of single-use plastic consumed by research laboratories. This is particularly concerning as it has been estimated that in 2014, 5.5 million tonnes of plastic waste were generated in research laboratories worldwide, the equivalent of 83 % of all plastic recycled in 2012 . CertainSimilar to other microbiology laboratories, our research covers a diverse range of disciplines, from molecular biology to immunology. Therefore, the equipment and consumable needs of each researcher can vary depending on the sterility and non-pyrogenic requirements. Overall, this means that our consumable needs, especially in terms of laboratory plastics, are quite representative of the needs of other laboratory disciplines. Despite this, we are aware that there are items on our consumables list, such as inoculation loops and Petri dishes for agar media, that are specific to microbiology research.At the Roslin Institute, University of Edinburgh, many plastic- and polystyrene-reducing measures have already been implemented . For insTo quantify the effects of new sustainability guidelines on our laboratory we started by monitoring its plastic use and waste. To establish a baseline, all plastic consumable items already in use were removed from the laboratory and tissue culture room and all waste bags were emptied. A digital weight scale was introduced close to the waste bin collection point, to allow all waste bags to be measured before disposal, and three white boards were introduced into the laboratory to allow all laboratory members to note the number of plastic items collected and used from the communal stock room. After every week, the values registered on the white boards were transferred to an excel spreadsheet and the white boards were cleaned to allow weekly measurements of plastic items collected.At the time, our research group was composed of two postdoctoral researchers, four PhD students and one master’s student working full time. The research projects involved activities related to bacterial isolation and cloning, protein purification and culture of primary cells and cell lines, all at biosafety category level 2. After four consecutive weeks, we had disposed of 97 kg of waste in biohazard waste bags and collected for use almost 2000 units of single-use microbiology plastic (loops and spreaders) and 2200 tubes .After an initial assessment of the major laboratory plastic items used in our research, we were able to identify practices that we believed could be replaced with more sustainable approaches without compromising work quality. We looked for guidance from the Roslin Institute Facilities team and recommendation guidelines from the University of Edinburgh Department of Social Responsibility and Sustainability . We seleAs in most laboratories, a large proportion of our plastic use is with tubes, from PCR tubes for small reactions to 50 ml Falcons. We already used glass containers to grow some of our bacterial cultures, but even in these cases, plastic tubes were often used for centrifugation or additional processing. Moreover, tissue culture protocols are required to be performed in a bacterial contaminant-free environment (non-pyrogenic conditions) that, so far, can only be achieved by using non-pyrogenic single-use plastic. Nevertheless, for most microbiology protocols, this condition does not need to be met, allowing for use of autoclave-sterile tubes. For that reason, and with the help of the institute’s central services team, we established a workflow to decontaminate and autoclave plastic tubes for reuse . The uniWe also implemented guidelines for the reuse of single-use plastic items, acquired new sustainable alternatives for some items, and engaged all research group members in training and sustainability awareness sessions . This trTo evaluate the effects of the new laboratory plastic-reducing guidelines, we measured the weight of the biohazard waste bags and monitored the use of single-use plastic items for 7 consecutive weeks after the implementation of the new measures. As expected, due to the varying work that is performed in our laboratory, variable quantities of waste and plastic items were used each week, both during the baseline and test periods . DespiteImportantly, we saw a dramatic reduction in the quantity of tubes and inoculation loops that we were using, but not in stripette use, which did not have a specific reduction strategy in place . The traWhen materials could not be easily replaced by more sustainable alternatives, we made efforts to reuse plastic. This was most successful with 15 and 50 ml Falcon tubes (Greiner Bio-one), which could be autoclaved for reuse. This approach has produced a dramatic reduction in the number of plastic tubes being used in our laboratory, which can be seen in Overall, these savings in terms of the number of plastic items led to a reduction of laboratory waste of 43 kg in a 4-week period (54 vs 97 kg in the 4-week baseline period) . This eqThis study is unique in documenting the impact of plastic reduction and reuse approaches in a research laboratory. By replacing plastic items and creating a procedure for decontaminating plastic, we observed major reductions in the number of single-use plastic items being required for use in the laboratory and in the amount of waste being sent for decontamination and ultimately incineration. As such, this work promotes the growing interest of research facilities and academic institutions in becoming more sustainable in the future.One such institution, University College London, has created a Laboratory Efficiency Assessment Framework (LEAF)  and a SuTo achieve even greater plastic reductions in our research laboratory, we are investigating the introduction of glass culture tubes, Petri dishes and stripettes to replace plastic versions. These glass items can be decontaminated by autoclaving and reused without the need for a chemical decontamination station. The reuse of plastic tips could also be implemented with machines such as those being marketed by Grenova . Even wiIt must also be made clear that the approaches highlighted in this study have drawbacks relating to efficiency and convenience of use. In order to avoid the use of plastic, we often reverted to more traditional microbiological techniques, such as the use of metal inoculation loops. These more traditional techniques are more time-consuming, as loops need to be decontaminated by flame and cooled between samples. This time cost, alongside the use of inoculation loops in a tissue culture hood, are the main reasons why plastic inoculation loops have not been eradicated from our laboratory . The decAs a concluding remark, we would like to encourage all microbiologists, and indeed all research scientists, to assess how they can reduce the number of single-use plastic items in their day-to-day research. Events such as #LabWasteDay, and certifications from My Green Lab and LEAF, are helping to identify our plastic problem . Let us


Lysosomal Storage Diseases (LSDs) are a group of Rare Diseases (RDs) caused by lysosomal enzyme deficiencies. Patients with LSDs suffer from a wide range of symptoms with a strong impact in their daily routines. In this study we aimed to explore the impact of the disease on the lives of patients with four LSDs, as well as how they experience Patient Journey from diagnosis to follow up. Unmet Needs (UNs) perceived by patients and clinicians were assessed to have a better understanding of which initiatives could improve LSDs management and especially those that could result in an improvement of patients’ quality of life.Qualitative research was the research methodology selected for the study. It provides plentiful and holistic insights into people’s views and actions. The study was conducted through in-depth face-to-face semi-structured interviews.In total, 20 patients and 25 Health Care Professionals (HCPs) from different Spanish regions were interviewed. Patients perceived that the highest impact of the LSDs was on their daily routines, specifically on their emotional side, their work/school environment, their family and their social life. Regarding the Patient Journey experience, the worst perceived stage was the pre-diagnosis, where patients only reported negative perceptions, being the delay in diagnosis and misdiagnosis the most commented issues. On the contrary, the follow-up stage was the one with less negative perceptions. Overall, patients and HCPs agreed on the priority UNs, such as accelerating diagnosis, reducing bureaucracy for the treatment access and a more coordinated attention for the patients, not only among different physicians but also with other professionals such as genetic counselors or social workers.Our data shows that there are still UNs to be addressed from the perspective of patients and HCPs. The main UN is accelerating diagnosis, which could be achieved by medical awareness and education, according to clinicians. A more comprehensive disease management was another main point to be worked on to improve LSD-patient experience and quality of life.The online version contains supplementary material available at 10.1186/s13023-021-02168-7. Rare diseases (RDs) are defined in the European Union (EU) as the ones that affect no more than 1 in 2000 people. This suggests an estimate of up to 36 million people affected in the EU given the RDs identified to date .Pinpointing the molecular defect underlying in a RD is not always easy. LSDs were among the first RDs in which the cause of the disease could be linked to an alteration in an enzyme , 5. A grQualitative research explores complex phenomena encountered by clinicians, health care providers, policy makers and consumers in health care. Interviews are widely used as a data collection tool in qualitative research . They arTherefore, qualitative research based in semi-structured interviews was the research vehicle selected for our project. Thus, we aimed to analyse the experience of patients with PD, MPSI, FD and GD during all their journey, from pre-diagnosis to diagnosis, follow-up, control of the disease and quality of life, and healthcare specialists’ perceptions.To set up this study, a group of internal medicine clinicians with broad experience in LSDs, organized into a Scientific Committee to decide the guidelines of the research and what qualitative research method was best to address the goals of the study. As such, the committee set the project guidelines, discussed the characteristics of patients and physicians needed to have a representative sample, and the specific elements of the Patient Journey to be studied more in depth.A Medical Agency (MA), Anima Strategic Consulting, with expertise in the matter, was also chosen. After several meetings around needs and goals, the study design, protocols, and materials  were set by the Scientific Committee and the MA.The Scientific Committee selected and invited to participate a group of clinicians based on the criteria described below. These clinicians were responsible for the selection of patients, based on the criteria also described below. As the objective of this qualitative study was to explore the impact of the disease on the lives of individuals with LSDs all along the Patient Journey, as well as to assess the UNs of patients and clinicians throughout the care process, in-depth interviews with both patients and HCPs were performed Fig. .Fig. 1DiTo recruit clinicians and patients, a non-probabilistic purposive sampling with pre-established inclusion criteria was used. To have different backgrounds and circumstances, the sample of patients had to include patients with and without specific treatment, from different geographical Spanish regions and from rural and urban areas. Five patients diagnosed with each one of the mentioned LSDs  were selected.In the case of the selected clinicians, they all had to have at least 5 years of professional experience as specialists and at least one year of LSDs-specific experience and be familiarized with all the stages of the Patient Journey. To include a variety of views, the sample had to include diversity on hospital size, HCPs from RDs-reference and non-reference centres as well as geographical dispersion across Spain.In the case of patients, the reflection was oriented towards their experience with the disease, from the moment they started experiencing symptoms to follow-up, including the moment they were diagnosed and began treatment. Perceived UNs were also commented.In the case of physicians, the reflection was oriented towards their priorities in managing people with lysosomal diseases, as well as the characteristics and needs of their patients.The qualitative research was carried out via semi-structured interviews from September 2018 to December 2018. Prior to the interview, pre-work assignment with questions regarding the most relevant aspects of the interview was provided to the interviewees to make them reflect on relevant aspects of the interview. Pre-work was a reflexive exercise, the individuals with LSDs and HCPs wrote their reflexions, and this material was analysed in detail during the interview. The questions addressed in the pre-work assignment are detailed in Additional file The in-depth interviews carried out were based on two semi-structured scripts -one for patients and one for HCPs-, with an approximate duration of 90 min. Semi-structured interviews allow the generation of rich, in-depth data, while using an interview guide to direct the content .All the interviews were carried out face-to-face. The location of the interview was chosen by the interviewees , which allowed to create a better environment for them. In the case of the clinicians, all the interviews took place in their offices. The two interviews with underaged patients in MPSI were conducted in the presence of their parents.The scripts were organized in five different sections, four of them common for patients and HCPs and one specific section for each. Diagnosis, treatment, follow-up, and ways of improving quality of life were the common sections, while professional profile was included only for HCPs and impact of the LSD on daily routines only for patients. A summary of the interview guides are detailed in Additional file Interviews were complemented with reflective/projective techniques to better capture insights. A Card Sorting technique was used as a complement. HCPs and patients were given a series of labelled cards, were asked to organise them into groups, and to sort them by the degree of importance. The number of cards determined the minimum and maximum prioritization score. The cards used in the card sorting exercise are detailed in Additional file The Consolidated Criteria for Reporting Qualitative research was used to ensure that our study meets the criteria for qualitative research .The interpretative description was the methodology guiding this study. Interpretative description does not require using a theoretical framework per se, but rather is a pragmatic methodology focused on generating findings that are useful for clinical practice .All semi-structured interviews were recorded and transcribed verbatim. The data was analysed using a constant comparative and iterative approach, reading, and comparing transcribed texts to determine if they reflected the same concept or theme. Transcriptions were analysed by three independent researchers by the MA. The researchers inductively and independently built categories according to the study aim. The three researchers read all the transcripts and hand-coded the data. These codes were discussed, revised, and compared collectively to refine the coding structure by adding codes as new insights were gained. These new themes were verified during subsequent interviews, asking more aspects in some questions introduced by the interviewer. This process helped to improve the rigor and validity of the analysis.The final coding was discussed with an additional researcher from the MA until reaching an agreement during a meeting that followed, to further discuss the main findings of the research and to reach a consensus in case of discrepancies.To classify the priorities using the card sorting technique , the analysis was performed by computing the average of each individual outcome. With all the obtained information, the Scientific Committee and the MA worked through the results to perform a deeper analysis.Overall, 20 patients and 25 HCPs scattered all around Spain were interviewed. The characteristics of the participants are described in Table Medical specialties were in accordance with the signs and symptoms of the given LSD. In the case of GD, all patients were affected with Type 1, in PD all patients were late-onset phenotype, and in MPSI, all patients had the mildest type: the Scheie Syndrome. Sixteen (80%) out of 20 patients were receiving treatment at the time of the study.We analysed the different perception of patients on the impact of the LSD on their daily routines. Patients would range the impact with labeled cards. A brief description of signs and symptoms, together with the course of each LSD is included in Table The greatest impact patients mentioned were related to their “emotional side”, their “work/school environment”, their “family”, and their “social life”. The results of this investigation are described in Table Their disease manifested in their day to day to different extents depending on the onset or severity of symptoms and not always on organic damage. Patients with FD or MPSI saw their quality of life more limited. On one hand, Fabry patients had suffered pain crisis, GI-symptoms and fatigue during their childhood that had very frequently conditioned their adult behaviours with insecurities at work or other social environments. On the other hand, patients with MPSI, with visible physical symptoms -mainly skeletal deformities-saw their quality of life limited, mainly due to mobility difficulties as the disease progressed. For most individuals with LSDs, the inability to carry out some activities at work or at school, sometimes limited the education and career opportunities. However, less limited patients could perform physical activities, sometimes following their doctors’ recommendations.Regarding the family impact, in some cases, they felt incomprehension from their close environment concerning some symptoms such as fatigue, which on many occasions changed to acceptance after diagnosis. Nevertheless, patients generally felt understood and supported by their closer family.The Patient Journey was elaborated based in the perceptions patients had. Individual perceptions are collected in Table The only stage in which patients only referred negative aspects was in the pre-diagnosis. The delay in diagnosis and misdiagnosis were the most mentioned issues. In MPSI patients, with a marked external phenotype since childhood, reaching diagnosis generally took only a few months in contrast to much longer diagnosis times in the other LSDs. Yet, a MPSI patient is the one with a greater diagnosis delay in our sample, although the reason for this delay was not identified.In general, once the diagnosis was reached, patients felt comfort in finally naming their condition and relief to know there was a treatment that attenuated the progression. Nevertheless, they also felt disappointment when they learnt their disease was progressive and incurable. The patients’ experiences differed depending on whether the diagnosis was reached as a child or as an adult. Those patients diagnosed as adults reported more negative aspects regarding pre-diagnosis and diagnosis stages, due to the diagnostic delay. One of the main concerns referred by patients was the possibility of transmitting the disease to their offspring, to the point that even guilt was present in parents of affected children.Regarding specific treatment and follow-up, both paths were parallel in patients who started with the first one. Some LSDs have oral or intravenous treatments with different degree of published evidence, while others have only an intravenous treatment. On addition, patients had to attend a close and multidisciplinary follow-up. Therefore, hospital dependency was elevated, and sometimes hospital visits interfered with personal life.Regarding treatment, most patients showed confidence in their specialists. Once the decision of starting treatment was made by the patient and the specialist, a long bureaucratic process started before approval, being the final decision taken by a committee. Patients expressed surprise, indignation, annoyance or understanding for not being examined directly by these committees.All patients felt empowered and satisfied when the treatment started, hoping their limitations would be reduced, but also faced uncertainty regarding their treatment response. The latter was more marked for many PD and MPSI patients since there is only one therapeutic option.The follow-up stage was the one in which there was fewer negative perceptions referrals. All patients had a close relationship with their LSD-specialist physician. A special mention needs to be made about the feelings of parents of LSD-patients and of those patients diagnosed at childhood. The moment of transition from the care of the Paediatrician to the follow-up by Internal Medicine specialists was anticipated by parents and experienced by patients with uncertainty and anguish. This was due to the fear of losing the bond with the Paediatricians after many years of building a strong relation with this specialist.sine qua non condition for early management of patients. For over 40% of clinicians, alleviating and controlling symptoms to delay organic damage was another of their priorities. Approximately around 40% also mentioned “maintaining the patient’s quality of life” as another of their priorities, “avoiding any type of irreversible complication” and “identifying other possible comorbidities”.Regardless of their specialty, background, and specific LSD with which they were involved, the first priority for physicians was early diagnosis of the LSD, as this was a Although main medical priorities were shared by HCPs independently of the specific LSD, there were priorities adapted to the course of the LSD. For example, in PD an early treatment allows preserving the motor and respiratory functionality, thus postponing or avoiding wheelchairs and mechanical ventilation. For these patients, that lacked evident symptoms initially, early treatment was precisely the main medical priority for HCPs. Table We analysed what patients and HCPs perceived as UNs. The UNs perceived by patients and HCPs were categorized in three groups: “Medical Attention” , “Treatment”  and “Disease Management” . Some individual perceptions are collected in Table Patients and specialists perceived early diagnosis as a very important UN. For HCPs, defining and standardising diagnosis criteria within clinical guidelines would be critical to ensure early diagnosis. Nevertheless, HCPs agreed on the fact that family testing, screening programmes as well and the development of Dried Blood Spot tests, had significantly improved early diagnosis. On the other hand, specialists emphasized on the need of patient-centricity, which implied coordination between the medical multidisciplinary team and social care experts.HCPs considered important to homogenize treatment-access-criteria among regions as well as reducing administrative procedures, which was also a strong UN for patients. On the other hand, for HCPs was very important promoting scientific research focused on expanding therapeutic options, especially in the diseases with a single treatment option (PD and MPSI). Clinicians had great expectations in gene therapy as a way of reaching a final cure. Additionally, the existence of industry-independent registries was perceived as a means of improving knowledge of long-term outcomes. For patients and physicians improving patient experience during infusions was also important, for HCPs this meant separating LSD-patients from other seriously ill patients, reducing waiting times, and journeys to the hospital by promoting home therapy.HCPs demanded a better promotion at national level of the existence of RDs-speciality centres/Units, as well as more resources and clearer boundaries at the political level of the capabilities and responsibilities of such structures. For both HCPs and patients, an UN was an easier access to genetic counselling and psychologists. Many patients also mentioned the need of social workers, as they often lacked information about the governmental benefits they were entitled to. Patients and HCPs also missed having reliable and verified sources of information adapted for patients. On the other hand, clinicians demanded forums where to debate on clinical cases with RD-specialists. The transition of paediatric patients from paediatricians to adult RDs-specialized HCPs was also an important UN for patients and parents. A better understanding by Society was also an important UN.To the best of our knowledge this is the first qualitative study to be published in a peer-review journal with LSD-patients in Spain. We decided to include a wide range of divergent characteristics of patients within the four LSDs to have different views and perspectives. There was a mixture of patient profiles which included phenotypical variation and geographical dispersion.This study has deepened in the way individuals with four LSDs experience their journey with the disease. Using qualitative research as the means to evaluate the relation these patients have within their “ecosystem” of self, family, medical attention and Society. These four LSDs share a common scientific background and the availability of a specific treatment for almost 20 years.The impact the LSD had on the lives of the patients in our study are common to the ones described in many other qualitative RD publications. Physical impairment, pain, fatigue, and psychological burden have a toll on day-to-day activities, on career opportunities and on family activities in RD patients –12. ConcMisdiagnosis was frequently mentioned in our study which is also described in the literature. As an example, different publications have explored wrong diagnosis given to Fabry in paediatric  and adulOne of the main issues and of the main priorities referred by all physicians and patients in our research was the importance of early diagnosis. In the literature, delays of up to five years in MPSI Scheie, ten in GD Type 1 and 16 for PD have been reported –19. A EuMedical suspicion and family testing are the most effective ways of early diagnosis, followed by screening programmes. Congruently, clinicians specifically prioritized medical education to improve early diagnosis, being primary care education especially important in their opinion. Medical unawareness has also been cited by patients and physicians as one of the causes leading to diagnosis delays and mistreatment in other qualitative RD studies , 13, 21.For the patients in this study, the diagnosis moment was a contradictory moment because of the sense of relief for finally naming their medical condition, yet it mixed with uncertainty feelings because of what could await ahead and because of the lack of enough reliable information. In the work by Esquivel-Sada , 2018, dAll patients in our study felt relief when they learnt there was a specific treatment for their condition, aware that this is not the case for most RDs. As reviewed by Lippe et al. , severalIn our research, all patients had a very good relationship with their specialist which is also common in many RD studies , 13 but Follow-up was burdensome for most of our patients, due to the multiorganic features of the selected LSDs. Multi-organic affection is shared by many RDs, and many patients complaint on the many different tests they must take periodically, and how coordination among HCPs is many times improvable , 21, 23.This study has some limitations and strengths that must be mentioned. A bias inherent to surveys and qualitative studies is the interviewee or acquiescence bias, in which respondents tend to select a positive response/connotation disproportionately more frequently . NeverthIn conclusion, our data reflect that there are still UNs to be addressed both in the view of people with LSDs and HCPs. For both patients and clinicians, accelerating diagnosis is crucial, being medical awareness and education the main paths to its achievement for clinicians. A comprehensive disease management was another main point to address patient’s quality of life that could improve LSDs-patients’ experience. Knowing first-hand the UNs of both patients and HCPs is essential to define new forms and initiatives that would help to respond to these needs and improve the satisfaction of all those in the ecosystem of the LSDs, especially the people with LSDs.Additional file 1. Table S1. Pre-Work assignment sent to patients and clinicians prior to the in-depth interview. Table S2. Card Sorting Technique used during the interview with patients. Table S3. Card Sorting Technique used during the interview with clinicians.Additional file 2. Appendix A. Patients’ Script Summary of patient’s in-depth interview: a full description of the questions usedfor the patient’s in-depth interview.Additional file 3. Appendix B. Physicians’ Script: Summary of clinician’s in-depth interview: a full description of the questionsused for the physicians’ in-depth interview.