We aim to determine a comprehensive set of requirements, perceptions, and expectations that people with spinal cord injury (SCI) and the clinicians in charge of their rehabilitation have regarding the use of wearable robots (WR) for gait rehabilitation.There are concerns due to the limited user acceptance of WR for gait rehabilitation. Developers need to emphasize understanding the needs and constraints of all stakeholders involved, including the real-life dynamics of rehabilitation centers.15 people with SCI, 9 without experience with WR and 6 with experience with these technologies, and 10 clinicians from 3 rehabilitation centers in Spain were interviewed. A directed content analysis approach was used.78 codes grouped into 9 categories  were expressed by at least 20% of the users interviewed, of whom 16 were not found in the literature. The agreement percentage between each group and subgroup included in the study, calculated as the number of codes that more than 20% of both groups expressed, divided over the total amount of codes any of those two groups agreed on (≥ 20%), showed limited agreement between patients and clinicians (50.00%) and between both types of patients (55.77%). The limited accessibility and availability of lower limb exoskeletons for gait rehabilitation arose in most of the interviews.The limited agreement percentage between patients and clinicians indicates that including both types of users in the design process of these technologies is important, given that their requirements are complementary. Engaging users with prior technology experience is recommended, as they often exhibit strong internal consensus and articulate well-defined requirements. This study adds up the knowledge available in the literature and the new codes found in our data, which enlighten important aspects that ought to be addressed in the field to develop technologies that respond to users’ needs, are usable and feasible to implement in their intended contexts.The set of criteria summarized in our study will be useful to guide the design, development, and evaluation of WR for gait rehabilitation to meet user’s needs and allow them to be implemented in their intended context of use.The online version contains supplementary material available at 10.1186/s12984-023-01264-y. During the last 30 years, we have witnessed an increase in the development and testing of robotic wearable (WR) exoskeletons for walking rehabilitation following spinal cord injury (SCI). The intended effect of these devices is to induce neuroplastic changes through intensive walking training , while aIn parallel, the scientific community is also becoming interested in the limitations related to users’ acceptance of WR and their interactions. Qualitative research allows exploring this phenomenon from the user’s point of view. Researchers have studied the perception of both patients and clinicians about the technologies after one session with a WR through face-to-face interviews , 7, usinTherefore, the limited clinical evidence regarding WR for gait rehabilitation, their lack of customization, and the constraints in user acceptance, arise doubts as to whether it is worth investing in these pricey technologies , since tA qualitative study using directed content analysis was conducted , followiThe initial codes and categories to implement the directed content analysis methodology were established based on a literature survey. An advanced search in the Scopus database was performed comprising the period until December 31st, 2020, using the query string “(exoskeleton) AND (user AND center* AND design) OR (perception) OR (experience) OR (perspective*)”, only research articles and reviews written in English were considered. Further selection was performed by reading the title and abstract, when necessary, to guarantee that the included articles assessed lower limb exoskeletons for gait rehabilitation in terms of the users’ perspective or experience.The National Hospital for Paraplegics (HNP) is the main monographic public hospital for intensive rehabilitation of SCI in Spain. Institute Guttmann (IG) is the main private foundation for rehabilitation of neurological injuries in the region of Catalonia. Both have vast experience in cooperating in research projects devoted to the development and evaluation of rehabilitation technologies, including lower limb exoskeletons. Spinal Cord Injury Foundation (FLM) is a private neurorehabilitation center located in Madrid, Spain, that provides integral rehabilitation, including therapy with lower limb WR, for people with SCI after their discharge from rehabilitation hospitals.Both people with SCI and clinicians were separately considered as end-users, as they might have different perspectives and requirements. In addition, and to better understand the impact of the technology on patient's expectancies, we split the SCI group within patients with and without previous experience with WR (e-SCI and n-SCI respectively). We aimed at assessing different perspectives: feedback about actual technologies and requirements that arose from experience (e-SCI and clinicians), expectations and unbiased requirements for the technologies (n-SCI), and expert advice on the requirements for the technologies to be effective as a gait rehabilitation tool (clinicians). The common exclusion criteria were inability to communicate in Spanish, inability to use to use crutches or a walker to walk with the WR, difficulties in comprehension and communication, and refusal to participate in the study. This research complied with the Declaration of Helsinki and was approved by the Institutional Review Board at the Ethics Committee of the Hospital Complex of Toledo, Spain . Informed consent was obtained from each participant.The sample size was determined following the estimates presented in , where iSimilarly, for the clinicians user group, physical medicine and rehabilitation physicians (PM&R) and physiotherapists (PT) involved with the rehabilitation of people with SCI and/or with experience in research with WR were recruited through convenience and snowball sampling techniques  between Individual, semi-structured interviews led by a theme-based interview guide with open-ended questions were used to obtain detailed descriptions of the themes previously identified in the literature , these were reviewed and corrected manually. Two authors analyzed each transcription performing deductive content analysis, following the directive content analysis approach [www.microsoft.com/microsoft-365/excel, Redmond, WA, USA). The whole codification process is shown in Fig. Verbatim transcriptions of all interviews were made using the semi-automated transcription software Amberscript , usability (17), psychology related codes (15), technical characteristics (14), activities (12), acquisition issues (4), context of use (3), development of the technologies (5), and clinical rehabilitation context (7). The full list is available in Additional file 1, usabilOur sample of primary users consisted of 15 adults with spinal cord injury 4 women, 26.67%), aged 45.5 ± 13.2 years (range 20 to 65 years), and with a median of 7.1 months since injury onset . All participants had a diagnosis of SCI with various degrees of impairment to walk, different etiologies of the injury , and a variety of injury classification : five PM&R and five PT. Average age was 41.8 ± 12.7 y.o. (range 26 to 62 years), and had on average 12.2 ± 10.6 years of experience working with SCI (range 2 to 30 years)  were not previously identified in the literature . This analysis showed that patients and clinicians agreed on 50.00% of the codes, n-SCI and e-SCI agreed on 55.77% of the codes, clinicians and e-SCI agreed on 45.83% of the codes and lastly, clinicians and n-SCI agreed on 45.45% of the codes.N). Some codes in the figures have a sign (*) at the end, representing that some users that talked about the same code but with a different perspective from the other users; these cases are detailed in the description of the corresponding figure.To visualize the codes expressed by at least 20% of clinicians or people with SCI, we use column charts showing the relative frequency of each group that referred to each code. Figures for each category are comprised within Figs. In this category, two out of the four new codes that emerged were related to negative aspects such as 40% of the patients having fears about using exoskeletons or 50% of the clinicians and 22.20% of n-SCI having reasons to reject their use. Examples of the fears are: falling, damaging the device, “doing it wrong”, and hurting one-self and affecting body parts that are currently healthy. Patients’ reason not to use the technologies is that for their recovery and independence it is better to do all the activities they can without the exoskeleton, and they need to know their capabilities at the end of their sub-acute rehabilitation to assess if an exoskeleton is needed. For clinicians the reasons include: the need to adapt to a new technology that could be complex to use, lack of trust towards technologies due to the fear that they will replace physiotherapists in their workplace, having to lift and move heavy devices, and believing that traditional therapy is better than robot-assisted therapy.Through qualitative research, we managed to determine a comprehensive set of requirements, perceptions, and expectations that people with spinal cord injury and the clinicians in charge of their rehabilitation have for the design of lower limb wearable exoskeletons for gait rehabilitation. To our knowledge, this is the first research comparing the expectations of people with SCI without experience in the use of exoskeletons versus the requirements of experienced users, and most importantly, the first study that aims to summarize a comprehensive list of criteria for the design of these technologies, encompassing the knowledge available in the literature and allowing new criteria to emerge from our own data. Both the criteria summarized in our study and the additional ones from literature , shows even though less clinicians than patients were interviewed, they agreed on more codes in interviews that were almost 1/3In relation to intergroup agreement rates, the agreement percentage among both types of patients (55.77%) demonstrates the contrast between the expectations from n-SCI and the “down-to-earth” requirements from e-SCI, and therefore, the complementarity of their requirements. Indeed, including both types of patients in this study and people with injuries of different severity was aimed at seeking requirements representative of the heterogeneous SCI population. Similarly, the intergroup agreement percentage of 50.0% between patients and clinicians indicates that including both type of users in the design process of these technologies is a must, given that their requirements are complementary. As shown in our results, both patients and clinicians agree on the importance of involving both types of users in the design and development of lower limb wearable exoskeletons, and they are motivated and willing to participate in these processes , 58. TheWith respect to the agreement intragroup see Fig. , cliniciThe new codes found in our data are one of the most important contributions of our paper. Considering the use of lower limb exoskeletons in rehabilitation settings, it is very important for PT that the devices have manageable weights and are easy to handle and move around, to not to increase the physical burden during therapy due to the manipulation of the device. All three groups agreed on the relevance of having devices that can be fit to different bodies and functionally adapted according to the patient needs, since these needs differ from user to user due to their specific impairment, and also evolve along therapy. Overall, there is a lack of scientific evidence to identify the specific population that can benefit from each technology depending on its features, as well as regarding the specific protocols that allow to optimize their use as rehabilitation devices .Mostly clinicians and some e-SCI demand an improvement in the interaction of the device with the surroundings through sensors that help the device to automatically adapt to different scenarios, and an improvement in the interaction of the device with the person wearing it by closing the control loop through biofeedback and intention detection to move the exoskeleton. The latter is key to enhance neuroplasticity in robotic-assisted gait rehabilitation . To thesIt is also very important to understand the fears that SCI people have regarding the use of these devices, because they ought to be addressed during the design of the technologies and when training the users, to allow them to trust the device and have a smooth interaction. Similarly, it is imperative to address clinicians’ concerns regarding the perceived threat of exoskeletons for walking rehabilitation through education. Exoskeletons for gait rehabilitation are not meant to replace physiotherapists, instead, they are meant to be a new tool to assist clinicians for physical therapy, exactly like the healthcare workers of our study expressed. Previous experiences with similar technologies, including for example the Lokomat, can show clinicians that these devices allow to provide intensive rehabilitation reducing the physical burden that PT have in traditional therapy, allowing them to (1) invest the time in more observation and evaluation of the progress of patients, (2) have more time available to design better therapy plans for patients and (3) have objective data regarding the patient movement and evolution, provided by the devices.All types of users interviewed in this study suggest an increase in funding for lower limb exoskeletons, mostly because they consider these technologies are still under development. Nonetheless, currently there are six (6) devices CE marked, and there are at least four times more devices in different development stages , most ofThe complete set of criteria summarized in our study, encompassing both the knowledge available in the literature and the new criteria that emerged from our own data, will be useful to guide developers of WR for gait rehabilitation in the design, development and evaluation of their technologies, to make sure the efforts invested in the field lead to technologies that respond to the needs and expectations of their end users and are feasible to implement in their intended context of use. Additionally, we emphasize the need to implement User-centered design and usability evaluation in the field, in line with the findings of this study.Qualitative research, due to its emphasis on in-depth understanding and context-specific insights, does not lend itself to statistical generalization of findings to the broader population . NeverthA potential limitation to the generalizability of the results is that the data collection was held in Spain, a country with a public health system. This could represent cultural differences in some of the expectations of users from other countries without a public health system, particularly those regarding the accessibility of the technologies and the constraints to effectively implement the technologies in clinical rehabilitation settings. Nevertheless, we consider user’s requirements in 6 out of the 9 categories presented in our study  are most likely preserved within people with a spinal cord injury regardless their country of residence, since their demands depend more on the functional limitations caused by the injury and the intrinsic condition of being humans interacting with a robotic device than by cultural expectations.Both the chronicity and injury severity differences between the subgroups of people with SCI are another limitation of this study, since they could have influenced the perspectives of the users interviewed. As indicated in the manuscript, the subjects were recruited through criterion and convenience sampling techniques, therefore, despite the research team sought for heterogeneity and managed to have both complete and incomplete SCI subjects in both patients’ subgroups, a more balanced sample was not feasible to be recruited for this study. Requirements of incomplete and complete SCI are indeed complementary instead of equivalent. The formers use WR for gait rehabilitation as tools to improve their ability to walk whereas the latter use them for gait rehabilitation mostly due to the physical and psychological benefits that these technologies represent, but not to improve their ability to walk. This is why it was imperative to gather insights in both subgroups and in the whole study from both types of subjects, to effectively summarize a comprehensive set of requirements from a heterogeneous sample of SCI subjects.Regarding the chronicity of the injury, the marked difference is due to the type of centers where each subgroup was recruited. One is meant for subacute inpatient rehabilitation while the other is for chronic rehabilitation after discharge from the first institution. The research team aimed to recruit both subgroups only from HNP but there were no experienced subjects in the institution, given that no active or recent research was ongoing with WR devices for gait rehabilitation due to the pandemic. Therefore, an alternative center with people with SCI with experience in the use of these technologies had to be included in the study, and due to proximity, cultural, and convenience reasons, the FLM was the institution reached to recruit the e-SCI sample. In spite of this limitation, the authors consider that the chronicity of the injury could possibly affect mostly the expectations expressed between the acute and the beginning of the subacute phase of the injury, with respect to the chronic phase, because SCI subjects are reaching the plateau of their gait rehabilitation by the end of the subacute period of their injury (6 months approximately), where the enhanced period of neuroplasticity is over. Taking this into account, the average time since injury of the n-SCI is by the end of the subacute period, and therefore, no massive differences are estimated between the expectations of these subjects and the ones expressed by the e-SCI. The time undergone in intensive rehabilitation is also essential to understand the rehabilitation goals of each subject with the specific characteristics of their injury and their maximum expected recovery. Therefore, while undergoing the subacute period, people with an SCI learn to understand their injury and adapt their lives while seeking the maximum possible rehabilitation, where the WR for gait rehabilitation could help.The research team was aware of these limitations regarding the differences in severity and chronicity of the injuries and decided to provide and analyze the overall requirements of SCI subjects as a whole and the subgroup statistics separately, to make both results available to developers and researchers in the field. In this way, this limitation does not affect the requirements summarized for the whole group of people with SCI.People with spinal cord injury and the clinicians in charge of their rehabilitation are stakeholders of exoskeletons with complimentary design requirements, thus, both must be involved in designing technologies that are usable, respond to users’ needs and that are feasible to implement in their intended contexts, because currently, there is limited accessibility and availability of lower limb exoskeletons for gait rehabilitation. This can be achieved through implementing User-centered design during the development of these technologies: users interviewed are motivated to participate in the developments and they agreed on the relevance of being involved. We provide a comprehensive set of requirements, perceptions, and expectations of these users for the design of lower limb wearable exoskeletons for gait rehabilitation that can serve as a starting point for developers.Additional file 1: Semi-structured interview guide.Additional file 2: Full list of codes found in the study and in the literature survey.


Randomized controlled trial (RCT) data have important implications in drug development. However, the feasibility and cost of conducting RCTs lower the motivation for drug development, especially for rare diseases. We investigated the potential factors associated with the need for RCTs in the clinical data package for new drug applications for rare diseases in the United States (US). This study focused on 233 drugs with orphan drug designations approved in the US between April 2001 and March 2021. Univariable and multivariable logistic regression analyses were conducted to investigate the association between the presence or absence of RCTs in the clinical data package for new drug applications.Multivariable logistic regression analysis showed that the severity of the disease outcome , type of drug usage , and type of primary endpoint  were associated with the presence or absence of RCTs.Our results indicated that the presence or absence of RCT data in the clinical data package for successful new drug application in the US was associated with three factors: severity of disease outcome, type of drug usage, and type of primary endpoint. These results highlight the importance of selecting target diseases and potential efficacy variables to optimize orphan drug development.The online version contains supplementary material available at 10.1186/s13023-023-02702-9. Because the market for drugs for rare diseases (orphan drugs) is fragmented, there is less competition among new drugs. Generic drugs are less likely to invade the market, even after the patent expires. Thus, it is possible to monopolize the market for a long time while maintaining a higher price . HoweverIn the United States (US), rare diseases are defined as “diseases with fewer than 200,000 patients in the US” . It is eDespite these efforts, the high cost of clinical trials, difficulty in patient recruitment, and strict regulatory requirements for new drug reviews have been highlighted as hurdles to developing orphan drugs. In many cases, patients are scattered across the country or region, specialized medical institutions are not always located nearby, and accurate diagnosis takes time, which makes conducting clinical trials difficult. Although consideration is given to such circumstances, guidance by regulatory authorities recommends generating as much high-quality evidence as possible –10.Pharmaceutical companies and regulatory authorities are constructing an optimal orphan drug development strategy that considers the required quality and quantity of evidence. The feasibility of clinical trials for rare diseases is also discussed on a case-by-case basis. Incorporating information outside clinical trials, such as natural history study data, research reports, and the use of real world data, to generate comprehensive evidence is also drawing attention due to the various biases considered –14. It hA randomized clinical trial (RCT) is still one of the most important elements in discussing high-quality evidence –19. ConvIn a previous study, we investigated the presence or absence of RCTs in the clinical data package for new drug applications in Japan and reported that the prevalence of the disease and type of primary endpoint was associated with the necessity of an RCT . Howeverhttps://www.accessdata.fda.gov/scripts/opdlisting/oopd/). Among them, drugs with missing patient prevalence data, drugs for diagnosis or surgery aid, and drugs that were approved without clinical trial data were excluded from the analysis.Newly approved drugs with an orphan drug designation (ODD) in the US between April 1, 2001, and March 31, 2021 were extracted from the approved drug list on the website of the US FDA , trial design , and the number of enrolled patients . The pivotal trial design was categorized as RCT or SAT. If several indications were approved in a single new drug application (NDA) based on different pivotal trials, each indication was treated as distinct approval. The following data were extracted for the selected drugs: approval year, prevalence of the target disease, modality, Anatomical Therapeutic Chemical (ATC) classification , target When assessing the potential association with the presence or absence of an RCT in the clinical data package as a response variable, the following factors were considered as explanatory variables: prevalence , severity of disease outcome , type of drug usage (monotherapy vs. combination therapy), therapeutic classification (oncology vs. non-oncology), target age segment (children with or without adult vs. adult only), and type of primary endpoint .https://www.orpha.net/consor/cgi-bin/index.php). Subsequently, some of the high-mortality diseases were changed to others, based on whether the mortality was manageable with alternative treatments, to reflect the impact of the available alternative treatments on the severity of disease outcome in the US.The severity of the disease outcome was categorized as high mortality or others  based on the information available on the review reports and the Orphanet website .The definitions and criteria of the other explanatory variables are summarized in P < 0.05. StatsDirect version 3.3.5 software was used for all the statistical analyses.The associations between the response variable and each of the explanatory variables were assessed using univariable and multivariable logistic regression analyses to calculate the crude odds ratio (OR) and 95% confidence interval (CI). In the multivariable logistic regression analysis, we removed therapeutic classification (oncology vs. non-oncology) from the explanatory variables because it showed a high association with the severity of the disease outcome (Cramer’s V > 0.5). Other explanatory variables did not show a strong association with each other and were included in the multivariable logistic regression analysis. Statistical significance was set at A total of 335 drugs with ODD containing new active substances approved in the US between April 1, 2001, and March 31, 2021 were identified. Among these, 233 drugs with ODD were selected for the analysis (Fig. The characteristics of the selected orphan drugs are summarized along with the design of the pivotal trial, RCT, or SAT Table . ApproxiTable In this study, we investigated the presence or absence of RCTs in the clinical data package of new drug applications with ODD in the US. We found that the severity of disease outcome, type of drug usage, and type of efficacy endpoint were associated with the presence or absence of RCTs. These results suggest the importance of understanding the target disease and its treatment environment.Disease severity, defined by high mortality, was positively associated with the absence of RCT in the package, implying that RCTs are more difficult to conduct in such disease areas. This result was expected because there is no authorized treatment available for most rare diseases , and it Second, the utilization of combination therapy for a test arm showed a positive association with the presence of RCT. From an ethical perspective, this is another expected result. When the test arm is a combination therapy in which an investigational drug is added to a standard therapy, a standard of care is warranted, which would lower ethical barriers and make it easier to justify conducting RCTs to pursue high-level evidence.Third, the use of clinical outcomes as an efficacy endpoint was positively associated with the presence of an RCT. This result is similar to that of our previous study using the Japanese data package . In geneIt was unexpected for no association to be found between the prevalence of the disease and the presence or absence of RCT. In general, an appropriate sample size is required to conduct an RCT. Thus, we assumed that a lower prevalence of the target disease would be associated with fewer RCTs due to decreased feasibility. In our previous study in Japan, a negative association was confirmed between RCTs and lower prevalence disease prevalence . AlthougThis study had several limitations. First, the study was conducted only for approved drugs, which could be regarded as a source of bias. The information available on negative results is less extensive than that available for approved drugs. Second, the data were collected only for drugs that had an ODD. There may be drugs that did not apply for ODD, although they met the ODD criteria. Third, the association between clinical equipoise or natural history data and the presence or absence of RCTs was not investigated. Clinical equipoise is an important ethical consideration for determining the feasibility of RCTs , and natOrphan drugs target various rare diseases with unmet medical needs. If drug development is conducted using SAT data based on sufficient research, discussion, and consideration, it will streamline the development timeline. Thus, patients with rare diseases and unmet medical needs may be afforded early access to these drugs. Conversely, RCTs may impact the feasibility and development period of drug development. However, they are recommended by various guidelines as the results obtained through RCTs are highly reliable and ultimately benefit patients. This argument is unavoidable in orphan drug development, emphasizing the importance of utilizing available evidence.Our results indicated the importance of selecting a target disease and potential efficacy variables to be used in the clinical trials to examine the need for RCT data for NDA. From a pharmaceutical company perspective, target disease selection is one of the initial steps in drug development. Preparation of a clinical development plan including pivotal study designs is initiated during this step, which significantly impacts the costs and timelines of drug development, consequently affecting corporate investment decisions. In addition, we believe that strategic collection of relevant information is necessary to establish efficacy variables for potential drug development. This can be achieved through collaboration among the industry, government, and academia, which will help facilitate orphan drug development.Our results indicated that the presence or absence of RCT data in the clinical data package for NDA in the US was associated with three factors: severity of disease outcome, type of drug usage, and type of primary endpoint. Due to the small population of rare diseases, discussion on the necessity of RCT data tends to focus on the feasibility of conducting the clinical trials. While it is an unavoidable nature of orphan drug development, our results indicated the importance of selecting a target disease and potential efficacy variables to be used in the clinical trials to examine the need for RCT data for NDA. We hope that the results of this study will contribute to improving the predictability of the need for RCT data, optimizing investment in new drug development, and enhancing strategic collection of relevant information to establish efficacy variables for potential orphan drug development.Below is the link to the electronic supplementary material.Supplementary Material 1


Background and objectives: Investigation into the impact of dental trauma on the results of orthodontic treatment is crucial because it can have a major influence on patient care. However, there has not yet been a thorough review or meta-analysis of the available data, which is inconsistent and scant. Therefore, the goal of this systematic review and meta-analysis is to investigate the impact of dental trauma on orthodontic parameters. Search methods and criterion of selection: Major online databases were searched (beginning from the year 2011) for relevant articles using a properly defined search strategy. Analysis protocol: Risk of bias (RoB) and the Cochrane risk of bias tool were utilized for the purposes of bias evaluation within the individual studies and within the review, respectively. Results: Out of the six clinical trials selected, a significant impact of trauma was observed in individuals in all but one paper. Gender predilection varied across studies and could not be conclusively determined. The follow-up period ranged from two months to two years in the trials. The odds ratio (OR) 0.38  and the risk ratio (RR) 0.52  indicated that both the odds as well as the relative risk of experiencing dental trauma were lower in the group with negligible impact compared to the group with noticeable impact. Conclusion and further implications: The findings show that dental trauma significantly affects orthodontic parameters, with lower risk and likelihood of suffering dental trauma in the group with negligible impact than in the group with noticeable impact. However, given the substantial heterogeneity among the studies, it is advised to exercise caution when extrapolating the findings to all populations. Registration and protocol: Registration in the PROSPERO database was carried out before initiating the investigation [CRD42023407218]. Dental trauma refers to any injury or damage to the teeth or surrounding tissues caused by physical impact or trauma . It is aThe impact of dental trauma can extend beyond the immediate physical damage to the teeth and surrounding tissues . Dental The different types of dental traumas include enamel fracture, enamel–dentin fracture, crown–root fracture, and root fracture . An enamThe damage caused by dental trauma can vary widely depending on the type and severity of the injury and the location of the trauma . In primDental trauma can have a significant impact on orthodontic treatment, which involves the correction of dental and skeletal abnormalities through the use of braces, aligners, and other appliances ,8. When The impact of dental trauma on orthodontic treatment outcomes is an important topic of research, as it can have significant implications for patient care. However, the current evidence on this topic is inconsistent and limited, with no systematic review or meta-analysis to date. Therefore, the aim of this systematic review and meta-analysis is to investigate the impact of dental trauma on orthodontic parameters. The review examined studies that assessed the impact of dental trauma on orthodontic treatment outcomes. Specifically, the review assessed the effect of dental trauma on orthodontic parameters such as tooth movement, occlusal relationships, and the impact on the patients who were undergoing treatment in the selected studies.The following PICOS strategy was adopted for our current investigation.Population (P): The population for this study included individuals who had experienced dental trauma and were undergoing orthodontic treatment.Intervention (I): The intervention of interest was the impact of dental trauma on orthodontic parameters, including tooth movement, occlusion, and arch development.Comparison (C): The comparison group for this study were individuals who had not experienced dental trauma and were undergoing similar orthodontic treatment .Outcome (O): The primary outcome of interest was the impact of dental trauma on orthodontic parameters, as measured by changes in tooth movement, occlusion, arch development, or pain perception. Secondary outcomes included the incidence and severity of dental trauma, as well as the effectiveness of orthodontic treatment in individuals who had experienced dental trauma.Study Design (S): This study was a systematic review and meta-analysis of clinical trials that examined the impact of dental trauma on orthodontic parameters. The study only included clinical trials published after 2011 to ensure that the most up-to-date evidence was included and subsequently reviewed in the analysis.By following this PICO strategy, the study was able to answer the research question in a systematic and comprehensive manner, and the results provide important insights into the impact of dental trauma on orthodontic treatment outcomes based on the most recent evidence available. On the basis of this PICOS strategy, the research question formulated was “What is the impact of dental trauma on orthodontic parameters, including tooth movement, occlusion, and how effective is orthodontic treatment in individuals who have experienced dental trauma?”.PubMed:  AND ) AND ;Web of Science: TS =  AND TS =  AND PT = ;Scopus: TITLE-ABS-KEY AND TITLE-ABS-KEY AND (DOCTYPE(ar) OR DOCTYPE(re));Google Scholar: allintitle: AND allintitle: AND .After identification of the relevant MeSH terms, we conducted a search across 4 major databases using Boolean operators. The strategy implemented is given as follows:The PRISMA guidelines  were useThe inclusion and exclusion criteria for this systematic review and meta-analysis were developed to ensure that only high-quality studies were included in the analysis. Inclusion criteria were studies that investigated the impact of dental trauma on orthodontic parameters, clinical trials published after 2011, studies that included a comparison group of individuals who did not experience dental trauma but underwent similar orthodontic treatment, studies that reported on outcomes related to changes in tooth movement, occlusion, and arch development, studies that reported on the incidence and severity of dental trauma, and studies that reported on the effectiveness of orthodontic treatment in individuals who have experienced dental trauma.On the other hand, exclusion criteria were studies that investigated the impact of dental trauma on orthodontic treatment outcomes but were not clinical trials, studies that were published before 2011, studies that did not include a comparison group of individuals who did not experience dental trauma but underwent similar orthodontic treatment, studies that did not report on outcomes related to changes in tooth movement, occlusion, and arch development, studies that did not report on the incidence and severity of dental trauma, and studies that did not report on the effectiveness of orthodontic treatment in individuals who have experienced dental trauma.By applying these inclusion and exclusion criteria, the systematic review was able to ensure that only relevant and high-quality studies were included in the analysis, which in turn would allow for a more accurate and reliable investigation into the impact of dental trauma on orthodontic parameters.The data selection protocol for this systematic review and meta-analysis involved a rigorous and systematic approach to study selection and data extraction. Two reviewers were brought in to independently assess each study for inclusion in the analysis based on the predefined inclusion and exclusion criteria. In case of any disagreement between the two reviewers regarding the inclusion or exclusion of a study, a third reviewer was consulted to help resolve the query. The data selection process was documented in detail, and all selected studies were obtained in full text for further analysis. Using a predefined data extraction form, the same two reviewers independently extracted data from each study. The extracted data was then cross-checked for accuracy and completeness by the two reviewers. Any discrepancies in the extracted data were resolved through discussion between the two reviewers or involving a third reviewer if necessary. Finally, the final data set was compiled and used for statistical analysis. By following this data selection protocol, the study aimed to ensure a rigorous and systematic approach to study selection and data extraction, minimizing the risk of bias and ensuring the reliability of the findings.Each included paper was assessed for risk of bias using the RoB-2 tool  13]. Th. Th13]. 2, Chi2, df, I2, and Z values, which were used to assess the degree of heterogeneity and the significance of the overall effect. The use of this tool allowed for a comprehensive and systematic analysis of the data, which provided important insights into the relationship between dental trauma and orthodontic parameters. The results of the meta-analysis can inform future research and clinical practice in this area and can help to improve patient outcomes by identifying the most effective treatment approaches.The RevMan 5 software (version 5.4.1) was used for the statistical analysis of our investigation. Both odds ratio (OR) and risk ratio (RR) were analyzed, assuming a 95% confidence interval (CI) and random effects (RE) model. The software was utilized to conduct a meta-analysis of the selected trials, which involved pooling data from multiple studies to estimate the overall effect size. The software was used to input the data from the selected trials and to calculate the OR and RR values for each trial. The software then calculated the overall effect size and provided a forest plot to visualize the results. The software also calculated the heterogeneity TauAs represented in The search strategy for this systematic review and meta-analysis involved searching four databases, including PubMed, Web of Science, Scopus, and Google Scholar. The initial search yielded 632 articles. After removing duplicates, 488 articles remained. These articles were then screened based on their titles and abstracts. Based on the inclusion and exclusion criteria, 65 articles were excluded, leaving 423 articles for full-text review. These articles were then assessed for eligibility based on the predetermined inclusion and exclusion criteria. Articles were excluded if they did not meet the criteria, were not randomized control trials (RCTs), or were published prior to 2011. After applying these criteria, 54 articles were excluded, leaving a total of 311 articles for further evaluation.At the end of this search protocol, a total of six RCTs were selected for inclusion in the investigation ,17,18,19Out of these six clinical trials, a significant impact of trauma was observed in individuals in all but one paper . Males w2 was found to be 0.53, with a Chi2 of 27.83 and df of 4 (p < 0.0001), indicating significant heterogeneity. The I2 value of 86% suggests a high degree of variability in the results across the RCTs. The test for overall effect yielded a Z value of 2.68 (p = 0.007), indicating a statistically significant difference between the two groups. Based on the analysis, it can be concluded that dental trauma has a noticeable impact on orthodontic parameters. The odds ratio of 0.38  indicates that the odds of experiencing a noticeable impact are 62% lower in the group with negligible impact compared to the group with a noticeable impact.For the meta-analysis, the study by Kalra et al.  was not 2 was found to be 0.26, with a Chi2 of 26.52 and df of 4 (p < 0.0001), indicating significant heterogeneity. The I2 value of 85% suggests a high degree of variability in the results across the trials. The test for overall effect yielded a Z value of 2.61 (p = 0.009), indicating a statistically significant difference between the groups. Based on the analysis, it can be concluded that dental trauma has a significant impact on orthodontic parameters. The risk ratio of 0.52  indicates that the risk of experiencing dental trauma is 48% lower in the group with negligible impact compared to the group with noticeable impact. However, the significant heterogeneity suggests that the results may not be generalizable to all populations, and further research is needed to confirm these findings. Overall, the statistical analysis provides important insights into the relationship between dental trauma and orthodontic parameters and can inform future research and clinical practice in this area.In The analysis of the selected RCTs revealed that dental trauma has a significant impact on orthodontic parameters. The study found that out of the six clinical trials analyzed, a significant impact of trauma was observed in individuals in all but one paper. This suggests that dental trauma has a noticeable impact on orthodontic parameters. The odds ratio and risk ratio both indicate that the odds and risk of experiencing a noticeable impact are significantly higher in individuals who have suffered dental trauma. However, the significant heterogeneity in the results suggests that the findings may not be generalizable to all populations, and further research is needed to confirm these findings. The I² value of 85–86% suggests a high degree of variability in the results across the RCTs. This variability could be due to differences in the populations, methodology, and other factors. Therefore, future studies should aim to address these limitations to obtain more reliable results. All in all, this study provides important insights into the relationship between dental trauma and orthodontic parameters. The findings can inform future research and clinical practice in this area. Dental practitioners and researchers can use these findings to develop effective strategies for preventing and managing dental trauma, which can help improve the quality of life for individuals who have experienced this type of injury.This study identified and synthesized the findings from several studies that have investigated the relationship between dental trauma and orthodontic parameters using different orthodontic appliances in a rather unique manner since selecting studies with varying interventions often generates heterogeneity. However, we believed this was important as different types of orthodontic appliances are used in clinical practice, and it is essential to understand the impact of dental trauma on orthodontic parameters in patients treated with different appliances. The present study included studies that used various orthodontic appliances such as Bionators and headgear, fixed appliances, mouthguards, and brackets. Despite the use of different appliances, the findings of the included studies showed that dental trauma can have a significant impact on orthodontic parameters. For instance, Chen et al.  reportedDental trauma can have a significant impact on orthodontic treatment, but with careful planning and a comprehensive approach, many patients are able to achieve successful outcomes and restore their oral health and function. Orthodontic treatment recommendations for individuals with a history of dental trauma vary not only across clinical contexts  but alsoBefore beginning orthodontic therapy, there is a high risk of further root breakdown in the apical area if there is apical root resorption . It is sAfter receiving orthodontic treatment, it is advised to follow up with dental trauma patients by having regular radiographic examinations and pulp vitality tests performed at regular intervals ,8,34. FuIn comparison, 44% of participants in a study felt that treating traumatized teeth with endodontic treatment should be conducted in the same manner as treating non-traumatized teeth . This obTo address the issues discussed in this review, orthodontic treatment plans for patients with dental trauma often involve a combination of restorative and corrective treatments. Restorative treatments such as fillings, crowns, and dental implants may be used to repair damaged teeth and restore their natural shape and function. Orthodontic treatments such as braces, aligners, and appliances may then be used to correct any misalignments and ensure that the teeth and jaws are properly aligned. In cases where the dental trauma is more severe, additional treatments such as oral surgery may be necessary to address any skeletal abnormalities or damage to the jawbone. It is important for patients with dental trauma to work closely with their dentist or orthodontist to develop an individualized treatment plan that considers their unique needs and concerns. The prognosis of a dental trauma case will deteriorate over time if there is a protracted delay in the replantation or unfavorable storage circumstances . This isDespite the significant findings of this study, there are several limitations that should be considered. Firstly, the search strategy was limited to four databases and did not include a hand search of reference lists, potentially leading to the exclusion of relevant studies. Secondly, the inclusion criteria were restricted to RCTs published after 2011, which may have excluded relevant studies conducted prior to this time period. Additionally, only studies published in English were included, which may have excluded studies conducted in other languages. Furthermore, the small number of RCTs included in the final analysis may limit the generalizability of the findings. Additionally, the heterogeneity among the studies was high, which suggests that the results may not be applicable to all populations. It is also important to note that the follow-up periods of the included studies varied, with some studies having shorter follow-up periods than others, which may have affected the results. Moreover, the exclusion of one study due to insufficient data may have impacted the accuracy of the meta-analysis. It is also important to acknowledge that the results of this study were limited to orthodontic patients and may not be applicable to the general population. Finally, it is important to consider the potential for publication bias, as studies with significant results may be more likely to be published. Overall, while the findings of this study provide valuable insights into the relationship between dental trauma and orthodontic parameters, further research is needed to confirm these findings and address these limitations.This systematic review and meta-analysis provide important insights into the impact of dental trauma on orthodontic parameters. The results indicate that dental trauma has a noticeable impact on orthodontic parameters, with lower risk and odds of experiencing dental trauma in the group with negligible impact compared to the group with a noticeable impact. However, the significant heterogeneity across the studies suggests that caution should be taken when generalizing the results to all populations. Furthermore, the limited number of studies included in the analysis and the small sample sizes of some studies are significant limitations. Despite these limitations, the findings of this study can inform future research and clinical practice in this area, emphasizing the importance of minimizing the impact of dental trauma on orthodontic outcomes.


The European Economic Area (EEA) provides a common market for goods, labour, services, and capital. Promoting integration between countries through the free movement of labour, or more generally persons, pre-dates the previous forms of the EEA. However, during the Southern and Eastern Expansions of the European Union, there have been transition agreements on persons, designed to restrict immigration. Opening up labour markets to the new member states with signifcantly lower GDP per capita than existing states, has been contentious. This is why the use of transition agreements have permitted periods which existing members can limit immigration. Not all existing member states impose restrictions, and during the Eastern Enlargements, the restrictions were imposed for varying lengths of time by different existing members up to a maximum of seven years. During the transition agreement, the economies of new members and existing members can converge, which is ultimately designed to limit the pull factor of migration. In this note, we provide a concise resource of the timeline of the expansion of full free movement of persons for countries in the EEA and Switzerland. In this research we answer: What year were citizens of the countries within the European Economic Area (EEA) able to move to another country in the EEA without any restrictions? Immigration is a controversial topic in most developed economies, but the EEA is a unique group of countries which offers its citizens the ability to live and work anywhere in its member countries. Political issues have risen when there are new members who have significantly lower GDP per capita than existing member states. To satisfy some of the existing members, they are able to limit migration from the new members for up to seven years. This research brings together many sources to detail when restrictions were lifted if this differed to the country joining the EU or EEA. Until 2020, the EU included the United Kingdom. The Single Market is for the free movement for goods, labour , services, and capital. However, joining the Single Market has not always been as simple as joining and assuming equivalent status as Existing Member States (EMS). This prime example of international co-operation and international integration can come with caveats. Transition agreements on free movement of labour have been implemented on the countries joining the EU in 1981, 1986, 2004 , 2007, and 2013. The transition agreements are in place to stop large shocks to the labour markets and population of EMS. The transition periods can last up to seven years, in which time it is probable that the economies of New Member States (NMS) have improved to be closer to EMS. As a result, there should be reduced incentive to migrate. The expansion, exit of the UK, candidate and potential candidate countries of the EU is shown inThe European Single Market includes the 27 countries of the European Union (EU) and the European Free Trade Association (EFTA) countries of Iceland, Liechtenstein, Norway, plus Switzerland.This paper provides a concise resource as to which years single market entry and freedom of movement was first obtained to enable researchers to easily access the information.The most suitable approach for this research is a multiple case study, as we are analysing the same question across 32 countries of the EU+ in 2019. Further, in the Eastern Expansions since 2004, there has been differing results across the EMS. The primary method used is document analysis the exact sources are detailed in the next sections. To formulate a timeline of freedom of movement, we proceed with two main questions: (i) what date did a country join the common market and (ii) was that country granted immediate freedom of movement for persons. If the answer for the second question is negative, we are required to explore further sources to find the years which full access was granted. Early research stages required creating a timeline of the evolution of the EEA  countries. Below we list the main treaties and evolution of the common (labour) market.European Coal and Steel Community (ECSC) The founder members were Belgium, France, Italy, Luxembourg, the Netherlands, and West Germany. The Treaty establishing the European Coal and Steel Community Treaty came into force on 23rd July 1952 (ly 1952 . This coEuropean Economic Community (EEC) The EEC succeeded the ECSC which aimed to establish a common market for the freedom of movement for goods, people, capital and services. This came into force 1st January 1958. Only by 1968 were any barriers to free movement of persons fully abolished, as preceding agreements still permitted countries to impose restrictions on foreign workers (Treaty of Accession (ToA) There were Treaties of Accession where new member countries joined the EU: 1972 for Denmark, Ireland and the United Kingdom, 1979 for Greece, 1985 for Spain and Portugal, and 1994 for Austria, Finland, and Sweden. The Treaties of Accession of 1979 and 1985 permitted transitional agreements which lasted until 1986 and 1992 respectively. There was not the expected large movements of people following during (or after) the transition period for Spain and Portugal, due to the improved economic  conditions   EEA includes the EU countries, Iceland, Liechtenstein, and Norway the agreement came into force on 1st January 1994. Austria, Finland and Sweden joined the EEA before subsequently joining the EU in 1995. The agreement brought the countries into the Single Market for the four freedoms. Not all of the EU policies were included in the agreement. EFTA today consists of Iceland, Liechtenstein, Norway, and Switzerland.Nordic Passport Union A membership of Denmark, Finland, Iceland, Norway and Sweden made in 1954 enabling free movement between the nations with members implementing it at different dates.Switzerland There are a number of safeguard agreements which applied to all countries when it came into force. Free movement in to Switzerland was suspended for a period under the safeguard agreement. The Eastern Expansion are subject to further delays on accessing the Swiss labour market beyond the seven years they are constrained to elsewhere in EU.Liechtenstein The small country in the centre of Europe is an anomaly. A member of the EFTA, and a population of less than 40,000. Working in the country is unrestricted for EEA and Swiss citizens but gaining a residence permit is more difficult due to the limitations allowed  expansions, transitional agreements on persons would likely be imposed. These agreements, designed to allow the closing of the gap of NMS to EMS, are likely to be minimal due to the existing GDP per capita gap that exists. The real GDP per capita of Montenegro, North Macedonia, Serbia, Bosnia and Herzegovina, and Kosovo for 2019 was less than 25% of that of the EU-15, with Turkey at 37%.Georgia, Moldova and Ukraine applied to join the EU following the invasion of Russia into Ukraine , which rIn addition, the fallout from Brexit within the United Kingdom cannot be ignored with support for independence in Scotland increasing, and the troubles associated with the Brexit agreement in Northern Ireland creating problems there. Scotland and Northern Ireland cannot be treated in the same way, with Northern Ireland’s requirements to satisfy the Good Friday agreement with the Republic of Ireland could see a reunified Ireland as one member of the EU, whereas Scotland would be an entirely separate state with no immediate right to be in the EU/EEA. From the perspective of a migrant, international migration is more challenging than domestic migration. The introduction of a common labour market has benefited millions of people, however, there are some issues that migrants encounter. One such struggle is a language barrier there are 24 official languages of the EU with more languages in use in the common labour market such as Icelandic, Norwegian, and regional ones. Having a poor command of the host country’s language can be a barrier to employment or fully integrating into the community. Where a country has a positive attitude towards migrants, they are more likely to integrate , conditions for using reciprocal measures etc. Whilst this version of the manuscript is mostly well-written and sound, I am of the opinion that there are still some minor issues which need to be addressed before this paper becomes the final version. These smaller interventions would improve the manuscript even further. - First, a note on this sentence from the intro: ‘’However, joining the Single Market has not always been as simple as joining and assuming equivalent status as Existing Member States (EMS)’’. From this sentence, it is not entirely clear whether the author considers all four freedoms in the single market to be equally difficult to access for new Member States (NMS) or does this only apply to free movement of labor. Please clarify accordingly. - in the first sentence of the methodology, the paper claims to conduct a multiple case study. I strongly advise against this claim because it does not reflect the reality and doesn’t do justice to what case study methodology and research look like. Multiple case studies are in-depth, qualitative investigations. I believe you can leave this claim out and refer to document analysis of all countries observed in this paper as a data collection method, and quantitative content analysis as the method of data analysis. - related to the previous point, it also seems to me from the description of the methodology and the presented results that the author actually conducted ‘quantitative content analysis’ instead of ‘qualitative content analysis’ as argued in the Analysis section. I suggest the author further looks into the differences between the two methodological approaches, and cites the relevant literature. Given the fact that this article observed documents and coded explicit dates in various documents , this approach differs from qualitative content analysis in which latent meanings are extracted from the text to generate categories. - the paragraph which discusses the Treaty of Accession leaves out (without an explanation why) a discussion of the 2007 and 2013 enlargement cycles. In the same paragraph, the author forgets to mention that Croatia also applied reciprocal restrictions, which is also evident from Table 2 and Table 3.https://www.admin.ch/gov/en/start/documentation/media-releases.msg-id-91561.html. Also, for a general overview:https://www.lexology.com/library/detail.aspx?g=958a571f-06a9-4322-a411-16024aeb0975 - Given how controversial the topic labor mobility has been in Swiss-EU relations, a broadening of that specific paragraph on p 7/11 is warranted. An explicit reference to the Agreement on the Free Movement of Persons from 2002 is needed. This agreement foresees a gradual opening of the Swiss labor market and a quota system. In the case of Croatia, the European Commission and Croatia repeatedly asked for restrictions to Croatian citizens to be lifted after Croatia’s entry into the EU in 2013, however a ban applied until 2021, only to be reapplied/reintroduced in 2023. Please see for Croatian case: - in Table 2 and Table 3, change acronym for Croatia from HRZ to either HRV, HR or CRO as the internationally recognised versions. - please clarify in the note or in the title of Table 2 and Table 3 whether they show the years in which the treaties/agreements foresaw a lifting of restriction, that is, the granting of free movement or do they reflect the actual years when the free movement was granted. Look at the case of Croatia – the table writes that Croatian citizens could access the Swiss labor market only from 2024 – which is inaccurate. Please see previous point for reference. Formally, the Swiss safeguard clause for Croatian nationals can be applied until 2024, however free movement was granted already in 2022. The fact that new quotas were reintroduces for Croatians starting 2023 does not deny the fact that restrictions were lifted at the end of 2021. Please clarify and if needed, include separate figures in brackets for cases where there is a discrepancy in the theoretical and actual revocation of mobility restrictions on the labor market. - Figure 1 should be updated to reflect the fact that Croatia entered the Eurozone starting 1 January 2023. Equally, the number of EA countries should be updated to 20. Related to this point, please also correct the numbers in the final section on ‘’Challenges of integration’’ – seven countries have not adopted the euro, and five are still to join (excluding Denmark and Sweden).If applicable, is the statistical analysis and its interpretation appropriate?Not applicableIs the study design appropriate and is the work technically sound?YesIs the work clearly and accurately presented and does it engage with the current literature?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesAre all the source data and materials underlying the results available?YesReviewer Expertise:European integration, Economic and Monetary Union, Social Europe, EU employment policy, Europeanisation of Public Policy, European Green DealI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. By providing a clear overview of the opening of labour markets to new (EEC/EU/EEA/EFTA) Member States, this article offers a useful addition to the literature on the history of free movement and will be a useful resource for scholarship on free movement and migration. I have three main points for improvement. - My main point is a lack of engagement with the  literature pointing at such phenomena as posted work and self-employed work. While workers are typically restricted from entering the labour markets of other Member States during transition agreements, there are typically no restrictions on the free movement of services and establishment. The famous Rush Portuguesa judgment is an example of this: while Portugal was still subjected to transition arrangements, Portuguese companies could already provide services and bring their Portuguese workers to other Member States for that purpose. Same goes for establishment: e.g., Polish citizens could set up a company and start economic activities as self-employed workers in other Member States. In other words: restrictions were merely imposed on the the free movement of workers and not all forms of migration itself (as suggested in the paper). For a comprehensive understanding of (the effects of) transition agreements, the difference between these forms of labour mobility seem pertinent to address.  - The discussion/conclusion does not seem to follow necessarily from the findings/results of this paper. One could arguably reflect on the prospect of free movement after (future) accession(s), but could one really reflect on the prospect of accession itself based on the findings? I am not saying that the discussion in its present form is not interesting, but how do your findings specifically add to the wider debate around accession? For one, the Russian war against Ukraine has accelerated the potential and the process of accession, of both Ukraine and other CC and PCCs. Additionally, I struggle to see the relevance of the final subsection on integration in light of the contribution of the article. This brings us to the main point: what is the added value of such a timeline? Perhaps this could be explicated better. - Stylistic: There are some typo's and informal use of language ("aren't"). Additionally, I would personally refrain from using abbreviations, especially since there are so many. The article is relatively short and the reader will not benefit from reading abbreviations like CC, PCC, ToA, NMS, EMS, etc.If applicable, is the statistical analysis and its interpretation appropriate?Not applicableIs the study design appropriate and is the work technically sound?YesIs the work clearly and accurately presented and does it engage with the current literature?PartlyAre the conclusions drawn adequately supported by the results?PartlyAre sufficient details of methods and analysis provided to allow replication by others?YesAre all the source data and materials underlying the results available?YesReviewer Expertise:EU citizenship, free movement of persons, internal market law.I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. In my view, the article “A timeline of freedom of movement in the European Economic Area” by Emily Barker provides a very useful support in the discussion and analysis of an indispensable plank of the Single Market: the freedom of mobility within the European Union but also across EFTA and the wider European Economic Area. On one hand, this might support further research into the actual transposition of EU/EEA legislation into national law and the adoption of national decrees to support freedom of movement. On the other hand, it might support research into actual labour mobility across EU/EEA member states. My prior is that freedom of movement might be higher among EU member states, but should still be significant among EEA states: this is an empirical question.Would be helpful to clearly distinguish between ratifications, adoption into national law, transposition with help of implementation decrees, enabling provision(s), and so on.Concerning Table 2, I am perplexed by the NA: keep blanks instead? Figure 1 is about the EMS (nice figure by the way). In the end implementation of the SM is a matter of degrees and modulation: what might subsequent empirical analysis show in terms of effective labor mobility?In the discussion: vague language when mentioning "...align their social, economic and political factors." Which factors? Minor points:The Single Market aims at/promotes....It should be “member states”.I am not sure that Liechtenstein would appreciate being labelled as an "anomaly", may be unique case?Please take out or redraft Footnote 7: not sure UK might appreciate.  Major points:If applicable, is the statistical analysis and its interpretation appropriate?PartlyIs the study design appropriate and is the work technically sound?YesIs the work clearly and accurately presented and does it engage with the current literature?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?PartlyAre all the source data and materials underlying the results available?YesReviewer Expertise:Economic integration and monetary policyI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


Transverse testicular ectopia (TTE) is a rare congenital malformation with a high rate of misdiagnosis and mistreatment before operation, which cannot be diagnosed even during operation due to lack of knowledge.Two patients with ectopic testes who were misdiagnosed as right inguinal hernia for the first time and underwent surgery. The “ovary” and “testicle” like structures was seen in the right inguinal region during the first operation. After being transferred to our hospital for laparoscopic surgery, it was found that the left spermatic cord and testis were transversely transverted to the right, the left testis was fixed at the right inner ring, and agglomerated soft tissue could be seen in the right inguinal canal, which was suspected to be Muller tube.Based on preoperative images and intraoperative findings, both cases were diagnosed with Transverse testicular ectopia (TTE). The postoperative pathology report for the second patient revealed the presence of an in situ spermatogenic cell tumor in the ectopic testis.Preperitoneal tension-free repair of right inguinal hernia and resection of left cryptorchidism were performed on the 2 patients.Postoperative pathology of the first patient confirmed that the resected specimens contained tubal-like and uterine-like structures. The postoperative pathology of the second patient showed that the resected tissue consists of immature testis, epididymis, uterus and seminal vesicle glands, in which an in situ spermatogenic tumor could be seen in the testicular tissue. Postoperative diagnosis: left transversal testicular ectopia and right indirect inguinal hernia.The clinical misdiagnosis and mistreatment rate of TTE is very high. Once the patients with cryptorchidism complicated with inguinal hernia are found in clinic, the possibility of the disease must be considered. For the patients whose cryptorchidism does not descend into the ipsilateral scrotum and it is difficult to diagnose, laparoscopy can be used for both diagnosis and treatment. If a patient has both inguinal hernia and cryptorchidism, it is crucial to rule out a diagnosis of TTE to prevent misdiagnosis and inappropriate treatment. Transverse testicular ectopia (TTE) is a special type of testicular ectopia that is often associated with Persistent Müllerian duct syndrome (PMDS). Both testicles may be located in the ipsilateral scrotal or inguinal region and are often associated with inguinal hernia and hydrocele of the testicular sheaths. Adult patients are usually characterized by inguinal hernia or infertility. Because the disease is rare and studies are limited, it can be challenging to detect it in its early stages, resulting in a high rate of misdiagnosis. Therefore, we recommend enhancing preoperative ultrasonography and magnetic resonance imaging for patients with cryptorchidism and inguinal hernia. For patients with difficulty in preoperative diagnosis, laparoscopy can help in diagnosis and treatment.In this paper, we introduce 2 patients with TTE who was misdiagnosed as unilateral inguinal hernia and during the first operation, “ovary” and “testicle” like structures was observed in the inguinal region. Then transferred to our hospital, reoperation confirmed that the patient had a transversed ectopic unilateral testis with a right indirect inguinal hernia and hydrocele. The disease is clinically rare, and the misdiagnosis and mistreatment rate is extremely high. The purpose of this paper is to explore the clinical experience and improve the understanding of the disease.A 45-year-old male patient was admitted to hospital because a reversible lump in the right inguinal region was found 2 months ago. Right inguinal hernia and left cryptorchidism were diagnosed, and surgical treatment of inguinal hernia repair was performed. During the operation, there was a 2cm × 2cm “ovary”-like structure in the hernia sac. The obstetricians and gynecologists were asked for consultation during the operation, but the diagnosis could not be confirmed. No hernia repair and other special treatments were performed after that. The incision was closed after exploration. The patient had an incision infection in the groin area after the operation, and was discharged after dressing change for about 1 month. The patient was treated in our hospital 2 months after the incision healed. There was no obvious abnormality in the patient history of past illness, personal and family history.At physical examination, the left testis was not found, and the left inguinal region did not touch the testis and epididymis. Normal testes are palpable within the right scrotum, and scars are present in the right inguinal region. The scar tissue was hyperplastic, and the palpation was unsatisfactory. The right inguinal region does not touch testis and epididymis. The 5cm-sized mass could be seen in the right scrotum in the standing position, and the mass in the supine position could be reduced but could not disappear completely Fig. . The scrLaparoscopic surgery was performed. During the operation, it was found that the left spermatic cord and testis crossed ectopic to the right side, the left testis was fixed at the right internal ring, and the right spermatic cord can move when pulling the right testicle. The defect of the right inner ring is about 2cm × 2cm, and the soft tissue can be seen in the inguinal canal, which is suspected to be Muller canal structure. In addition, hydrocele of testis can be seen Fig. . During Postoperative pathology confirmed that the resected specimen contained fallopian tube-like structure. The final diagnosis of the presented case was left transversal testicular ectopia and right indirect inguinal hernia, right testicular hydrocele, male pseudohermaphroditism. No postoperative complications was occurred. The patient was discharged on the fourth postoperative day. No recurrence of inguinal hernia was found in the follow-up for half a year.A 37-year-old male patient was admitted to hospital because a reversible lump in the right groin area was found 20 years ago. The patient was diagnosed with right inguinal hernia in a local hospital and underwent surgery 7 years ago. “Testicle” was found in the right hernia sac during surgery, and no hernia repair or other special treatment was performed. After exploration, the incision was closed. His younger brother had a right inguinal hernia and had a daughter. His past and personal history were unremarkable.Physical examination on admission was almost the same as that of the first patient, with normal penile development, a left scrotal void, and no testes and epididymis were palpated in the left inguinal region. A reduced-volume testis was palpable within the right scrotum, and a mass approximately 1.5cm in size was palpable in the right inguinal region, suspicious of an ectopic left testis. The 5cm-sized mass could be seen in the right scrotum of the patient in the standing position, and the mass in the supine position could be reduced but could not disappear completely. The scrotal light transmission test was positive Fig. . The patLaparoscopic surgical treatment was performed, and the intraoperative exploration findings were similar to those of the first patient, with the left spermatic cord and testis transversally ectopic to the right, except that the clear “uterus” structure was visible in the second patient Figs.  and 7. D in which the affected testis can be transferred to the contralateral side via the retroperitoneum or subcutaneously, and the bilateral testes can enter the ipsilateral scrotum or be fixed to the ipsilateral inguinal region or abdominal cavity. Patients may be complicated with permanent PMDS, inguinal hernia or hydrocele. Due to insufficient clinical understanding, they are often admitted to hospital with hydrocele, inguinal hernia or cryptorchidism. The rate of misdiagnosis and mistreatment is high. Most of the patients are infertile (neither of our 2 reported patients gave birth) , and the ectopic testicles of some patients can become malignant, which seriously affects the physical and mental health of the patients.TTE is a rare congenital testicular dysplasia, the incidence of this anomaly is one in 4 million in children, The third explanation is that the abnormal development of the ipsilateral testicular gubernaculum may lead to TTE. The mechanism of the descent of the testis due to the gubernaculum is unknown, but the gubernaculum growth secondary to the enlargement of the scrotum is a reasonable explanation. The fourth explanation is that the secondary inguinal ring exists below the classic external inguinal ring, and the ring-like structure below it is called the secondary inguinal ring. If the abnormal development of this position leads to obstruction or atresia, the descent of the ipsilateral testis is blocked, and the testis can be descended through other possible channels, resulting in a variety of testicular ectopia including testicular transversal ectopia. In addition, some scholars believe that the development of bilateral vas deferens is normal if they originate from the same side, and it will lead to unilateral testicular ectopia normal if they originate from different sides. Some scholars believe that the testes descend from the same position to the bilateral scrotum, if there is a persistent abnormal connection between the testis and the vas deferens, or between the vas deferens and muller duct, it can eventually lead to TTE.There are many explanations for the causes of ectopic testes. The first explanation is that normal male testicles originate from different genitel ridge, and if 2 testes originate from the same genitel ridge, it may lead to ectopic testes. The second explanation is that Mullerian duct degeneration is incomplete, and its mechanical effect limits the normal decline of the testis, which eventually leads to testicular ectopia.,9 Previous statistics show that the first type is the most common, accounting for about 50% of the total medical records. However, recent reports show that more and more patients are combined with PMDS, accounting for about 49.6% and 35.3%, which may be related to the improvement of detection technology and the increase in the application of laparoscopic technology.TTE was generally divided into 3 types. The first type is unilateral cryptorchidism with contralateral indirect inguinal hernia. The second type is complicated with PMDS, and the hernia contents include visible uterus, fallopian tube and other tissues. The third type is combined with other malformations except PMDS, such as hypospadias, ureteropelvic junction obstruction and other urinary malformations. Most of them are case reports. PMDS is a special type of pseudohermaphroditism. The genotype of the patient is  and the phenotype is male. In the early stage of embryonic development, both females and males have a pair of mesonephric ducts and a pair of Mullerian ducts. The mesonephric ducts are the primordia of the male reproductive system, and the Mullerian ducts are the primordia of the female reproductive system. In men, the androgen secreted by the Leydig cells promotes the development of the mesonephric duct into male reproductive duct, and the Mullerian duct inhibitor secreted by testicular Sertoli cells promotes the degeneration of Mullerian canal. In female, the mesonephric duct degenerates and mullerian duct develops into female reproductive duct. Mutations in AMH and AMHR2 genes may lead to deficiency of anti-mullerian hormone deficiency or reduced response of target organs to anti-mullerian hormone, resulting in the perpetuation of mullerian ducts and eventually lead to mullerian duct degenerative insufficiency syndrome.,13The 2 patients we reported belong to type II and postoperative pathological examination confirmed the existence of Miller canal tissue in the resected tissue. This type of disease is even rarer clinically, Fewer than 270 well documented cases of TTE were reported by 2019.PMDS can be divided into 3 types. The first type is unilateral indirect inguinal hernia, with the contents of uterus and ipsilateral fallopian tube. The second type, in addition to the first-type features, involves the passage of the contralateral testicles and fallopian tubes from extraperitoneal across the midline into the inguinal hernial sac, known as testicular transversality. The third type, called the female type, presents with bilateral testes not palpable to the scrotum, with the uterus in the pelvis and bilateral testes embedded in the broad ligaments of the uterus, similar to the position of the ovary. Most cases of TTE are diagnosed with inguinal hernia, hydrocele or infertility. Although the application of ultrasound CT and MRI in the diagnosis of TTE has improved the diagnosis rate, there is still a high rate of misdiagnosis and mistreatment.,16 Ultrasonography is the most commonly used in the preliminary diagnosis and differential diagnosis of TTE, and is of great significance in guiding clinical treatment. It is easy to make a diagnosis in patients with bilateral testicles descending to the ipsilateral scrotum. However, due to the changeable position of the testis across the ectopic testis, there is still a certain risk of missed diagnosis of the testis located in the abdominal cavity or the upper inguinal canal, especially when the ultrasound physician is inexperienced. For patients with multiple operations, the specificity of ultrasonic diagnosis is reduced. Kullendorff et al reported that in 5 of the 8 patients who underwent reoperation, the surgical results did not match the preoperative ultrasound diagnosis. Kattak et al counted 11 children with reoperation and reached a similar conclusion. The 2 patients we reported were also reoperated, and preoperative ultrasound did not find the location of cryptorchidism, failed to make the diagnosis of TTE. MRI has relatively high sensitivity and specificity in locating testis, especially for patients who have undergone reoperation or multiple operations, and it has advantages when the operation area is sticky and the anatomical structure is mixed.,20 However, because of the high cost of MRI and the need for longer examination time, TTE patients are mostly children, who can’t cooperate with the examination and often need to be sedated, so their use is limited. CT also plays an important role in the diagnosis of TTE, but it is not recommended in the diagnosis of TTE children because of its ionizing radiation. Laparoscopic technique can be used to diagnose and treat TTE, which is more and more widely used in clinic. It has a high accuracy in the diagnosis of TTE and cryptorchidism. For patients with difficulty in preoperative diagnosis, laparoscopic exploration can be performed during the operation to help further treatment.The preoperative diagnosis rate of TTE is low. Because of the poor effect of TTE on hormone therapy, surgical treatment is the only effective method. It is generally recommended that children aged from 6 to 18 months should complete the surgical treatment and fix the ectopic testis. For every 6 month increase in age at surgical treatment, the risk of malignant increased by 6%. So we recommended that surgical treatment should be performed promptly once diagnosed. Traditional surgical methods include fixation of ipsilateral testis after reduction, and fixation of testis across the scrotal mediastinum, etc. However, due to the rare occurrence and the common anatomic variations of the disease, the mullerian duct may be missed or the testicular blood supply may be damaged during the operation when the experience is insufficient. The application of laparoscopic technique can improve the therapeutic effect to some extent. During the operation, the type of TTE can be observed, whether PMDS is combined or not can be clarified, and the course of spermatic cord blood vessels on the affected side can be observed to guide the next surgical treatment.–29Testes of TTE patients are separated from the normal position and can be located in multiple positions such as the perineum or the abdominal cavity. The relatively high temperature can lead to infertility or even malignant. Statistics show that the rate of malignancy can be increased 5–10 times.,31 However, subsequent review by Farikullah et al showed that 11 cases of mullerian malignant tumor were found in about 200 cases, and the risk of mullerian malignant tumor for patients ranged from 3.1% to 8.4%. K Giri et al also reported a case in which mullerian duct tissue was preserved during surgery and advanced choriocarcinoma was diagnosed 25 years after surgery. Therefore, we believe that the course of the spermatic cord blood vessels should be clarified during the operation, so as to avoid damaging the testicular blood vessels and to resect the residual tissue of mullerian duct as much as possible.There is controversy about whether to resect mullerian duct during the operation. In the early reports, it was considered that there was no evidence for malignant transformation of the residual mullerian duct tissue, but instead the testicular blood vessels were damaged and the blood supply was affected during the resection. It was recommended that the resection be performed only when the mullerian duct tissue affected the testicular fixation.,34 For children over 10 years old and adults with TTE, orchiectomy on the affected side is generally advocated because the ectopic testis has been in high temperature environment for a long time and the risk of malignant transformation has increased significantly.,36 Both of the patients we reported are adults. In case 2, ectopic testis was found during the operation, but surgical treatment was not performed in time, the patient had testicular cancer when he underwent reoperation 7 years later.Most patients with TTE present as children, however, in some areas, many patients are adults, and they often see a doctor with infertility, inguinal hernia or malignant tumor instead of TTE.TTE is a rare hereditary disease. Due to insufficient understanding of this disease, the clinical misdiagnosis and mistreatment rate is extremely high. Once a patient with inguinal hernia complicated with cryptorchidism is found in clinical practice, the possibility of this disease must be considered. Preoperative ultrasound, magnetic resonance imaging and other examinations should be performed to confirm the diagnosis. For patients with cryptorchidism not descending into ipsilateral scrotum, preoperative diagnosis is difficult and laparoscopic has a certain advantage in the diagnosis and treatment.We sincerely thank the patient and his families for their participation and permission to publish this case report.Conceptualization: Bo Yang, Yin-Quan Wang.Data curation: Bo Yang, Chang-Hu Xie.Methodology: Bo Yang, Chang-Hu Xie, Yin-Quan Wang.Validation: Bo Yang, Yin-Quan Wang.Writing – original draft: Bo Yang.Writing – review & editing: Bo Yang, Yin-Quan Wang.


Spontaneous cases of pleural aspergillosis in healthy adults are rare, and the optimal therapeutic approach has not been established. Here we report a rare case of spontaneous pleural aspergillosis in an otherwise healthy young adult. Two-stage surgery with decortication and cavernostomy, followed by systemic antifungal therapy, finally resulted in a successful resolution of his empyema without any serious complications. In young patients with good pulmonary compliance, less invasive procedures, such as thoracoscopic decortication and/or carvernotomy, is a potential treatment option. VRCZvoriconazole1Pleural aspergillosis is defined as direct Aspergillus infection of the pleura or pleural space and is a rare entity among the spectrum of Aspergillus infections . PleuralThoracic fungal infections are associated with a high risk of mortality  and, mos2Aspergillus fumigatus, and serum Aspergillus antibodies were again positive. Other findings on CT included a very mildly infiltrated left upper lung parenchyma with intrapulmonary infection at the bottom of the cavity. The patient had no evidence of intrapulmonary infection on imaging or histology at the time of the initial surgery, suggesting that the fungus in the pleural and pneumoperitoneum had spread to the lungs after the previous surgery; hence, the patient was diagnosed with apical pleural aspergillosis because the main body of infection was located in the pleura and airspace.A 22-year-old male patient had been occasionally experiencing left chest pain and dyspnea for several years, but the symptoms had resolved spontaneously, and he had no history of medical examination. He presented to his home physician with persistent complaints of respiratory distress and high-grade fever for one month after the onset of left chest pain and dyspnea, and was found to have a pneumohydrothorax on chest radiography A. For thIt was determined that surgical intervention for the infection site in the pleura was necessary for curative treatment. Since the intrapulmonary infection was controlled with antifungal medication, lobectomy with extensive muscle filling was considered an excessive intervention. Because the dead space was confined to the apex of the lung, we decided to perform cavernostomy and minimal dead space filling as the first-line procedure.A 12-cm anterolateral incision was made in the third intercostal space, and cavernostomy was performed on the Aspergillus cavity, providing a clear view from apex to bottom . The thiPostoperatively, the thoracic drain was maintained for three weeks while the patient underwent intravenous voriconazole (VRCZ) therapy (4 mg/kg every 12 hours for 4 weeks), which was eventually transitioned to oral VRCZ (400 mg/day) for approximately a year. One year after the surgery, microbiological results remained negative for the organism. The patient had good lung reexpansion, with full extension into the bony thorax . With re3Pleural aspergillosis is a rare form of Aspergillus infection that is not always associated with pulmonary infection . CuriousSurgery for pleural aspergillosis follows the treatment principles of empyema. The key principles of surgery for chronic empyema are infection control by debridement, drainage, and closure of the fistula and cavity with dead space filling. In general, surgical treatment of empyema usually involves either decortication or thoracoplasty, which can be challenging in this population. For reference, the most recommended procedure for pulmonary aspergilloma is lobectomy and decortication to achieve complete resection of the lesion or control of the disease ,14. AddiReported cases of spontaneous pleural aspergillosis with pneumothorax were treated with relatively less invasive surgical procedures, such as surgical debridement  or right4In otherwise healthy patients with no underlying pulmonary disease, surgical procedures such as lobectomy and thoracoplasty for pleural aspergillosis can be overly invasive and can significantly compromise the patient's quality of life. Decortication and/or cavernostomy, less invasive surgical approaches, would be effective and sufficient as the definitive surgical procedures for such cases and may be emerging options that should be considered.This research did not receive any specific grant from funding agencies in the public, commercial, or non-profit sectors.All the authors contributed to the treatment of the patient.Informed consent was obtained from the patient.All medical procedures performed adhered to the tenets of the Declaration of Helsinki.The authors have no conflicts of interest to disclose.