Clostridium histolyticum  is an injectable, enzyme-based treatment indicated for the treatment of moderate to severe cellulite on the buttocks of adult women. The minimally invasive nature of the treatment makes it an attractive option for targeted disruption of the fibrous septae which give rise to the dimples characteristic of cellulite in buttocks and thighs.Collagenase The article provides an overview of cellulite treatment with CCH-aaes, including patient identification and education, treatment planning, CCH-aaes dilution, injection technique, safety, and early experience with mitigation of adverse events, including bruising.As part of a continuing medical education  event on developments in cellulite treatment, a panel of experts developed a course and roundtable, which included lectures on cellulite physiology, new developments in the field of cellulite treatment, demonstrations of injection technique for CCH-aaes, and a review of considerations for the use of CCH-aaes in real-world clinical practice.The practical guidance presented here is based upon real-world experience with CCH-aaes. The discussion includes strategies based on early experience for how to obtain the best results as well as suggestions on how to mitigate bruising.CCH-aaes has been a welcome addition to the armamentarium for the treatment of cellulite. With knowledge of proper patient evaluation and injection technique, thorough patient education, diligent photography, and developing research on bruising mitigation, CCH-aaes shows great promise as an effective and safe modality for the management of cellulite. Clostridium histolyticum  is a targeted, enzyme-based treatment approved by the FDA for the treatment of moderate to severe cellulite on the buttocks of adult women.1 Administered as a subcutaneous injection, CCH-aaes is composed of a 1:1 ratio of 2 collagenases: collagenase I  and collagenase II , which cleave type I and III collagen in a specific fashion.3 When injected into a cellulite dimple, CCH-aaes disrupts the fibrous septae tethered to the underside of the dermis, thereby alleviating the local tension thought to cause the skin topography characteristic of cellulite.4-6Collagenase 7 While a number of hypotheses exist as to the true underlying physiologic cause of the condition, the actual appearance of cellulite is thought to be a function of the type (thickness and organization) of fibrous septae, the capacity of the dermis to support the underlying tissues, and the architecture of both the deep and superficial fat layers.8 It is the loss of mechanical balance between these factors that dictates whether cellulite is apparent on the skin’s surface. Importantly, while laxity and adiposity contribute to the global appearance of the buttock and thigh area, they must be differentiated from true cellulite dimpling in order to assure appropriate treatment and optimal outcome. The central role of fibrous septae becomes apparent when assessing the relative efficacy and durability of alternate treatment modalities for the management of this condition. Treatments aimed exclusively at laxity  or adiposity  often have an inconsistent or temporary impact and may even exacerbate the underlying condition. Surgical subcision is a more effective treatment, as it directly addresses the fibrous septate, but is by definition an invasive therapy associated with discomfort and side effects that limit its widespread adoption.4 CCH-aaes represents both a targeted and minimally invasive option that allows for disruption of the fibrous septae and resolution of cellulite dimples in the buttocks and thighs (a cuttently off-label area). The familiarity of injection, minimal patient discomfort during the procedure, and short timeline to efficacy render CCH-aaes a welcome addition to the current collection of available treatments for managing this condition.Cellulite itself is a multifactorial condition, with skin laxity and/or thickness as well as patient body weight potentially exacerbating its appearance.As part of a continuing medical education (CME) event on developments in cellulite treatment , a panel of experts in the treatment of cellulite was convened. The panel included 3 plastic surgeons, 2 board-certified dermatologists , and 1 nurse practitioner injector. The faculty developed 3 hours of virtual webinars, including lectures on cellulite and new developments in the field, demonstrations of injection technique for CCH-aaes, and a review of proper patient selection. The meeting culminated in a 1-hour roundtable discussing the use of CCH-aaes in real-world clinical practice. The series was held at professional conferences and published online from September 2021 through March 2022. Through discussion, topics for this manuscript were identified by faculty, including patient identification and education, treatment planning and dilution, injection technique, safety, and mitigation of adverse events (AEs), including bruising. All patients discussed were treated in accordance with the principles outlined in the Declaration of Helsinki, and each patient consented to treatment and photography.The CME series was held at aesthetics-focused medical conferences and published online from September 2021 through March 2022. Through discussion, topics for this manuscript were identified by the faculty, including patient identification and education, treatment planning and dilution, injection technique, safety, and mitigation of AEs, including bruising. Together, the panelists have treated well over 350 patients with CCH-aaes both within the context of clinical trials and in clinical practice. While on-label use of CCH-aaes is currently restricted to cellulite on the buttocks, the discussion also included off-label treatment of the thighs. All patients discussed were treated in accordance with the principles outlined in the Declaration of Helsinki, and each patient consented to treatment and photography.Because injectables are widely recognized and accepted as both effective and minimally invasive, patients generally are comfortable with the idea of injections for cellulite, and interest in treatment in clinical practice has been high. While diligent patient selection is key to the success of all aesthetic treatments, an accurate diagnosis of cellulite and the relative contribution of laxity and skin quality issues to its appearance is critical. First, the treatment of cellulite will not mitigate unevenness in topography caused by laxity. Anecdotally, treatment of cellulite without proper management of contributing laxity may actually worsen overall appearance, as release of multiple points of tension removes local effects that may have held the skin somewhat taut. Furthermore, educating the patient on the difference between laxity  and cellulite, and the relative contribution of each to their global appearance, is essential for setting realistic patient expectations and and initiating any needed conversation around combination treatment with other modalities and why they may be needed for an optimal result. It is also crucial to obtain a detailed medical history, as contour irregularities may be secondary to previous procedures and interventions performed by other practitioners .While there is no age limit for the treatment of cellulite, the patients who respond best to CCH-aaes are generally younger with excellent skin elasticity and without compounding skin laxity. These patients often experience an excellent response regardless of the baseline severity of their condition. Importantly, however, even in patients with good skin quality, a very high BMI may make results difficult to appreciate given the independent contribution of localized adiposity to skin surface irregularity.Response to treatment in patients with excessive sun damage, which is common on the backs of the thighs, has not been as good, even in those with minimal additional laxity. The basis for this lack of response is not known, but one hypothesis is that the smoothing effect of CCH-aaes treatment is in part due to the induction of the healing response initiated by the cleaving of resident collagen and that this element of treatment response is not as robust in these patients.Most patients in clinical practice present with cellulite in both the buttocks and thighs. When treating these areas, several factors demand careful pretreatment planning. First, the patient must be evaluated in the standing position, in both a relaxed and clenched state, so that dimples can be identified and marked (Video 1). Once the patient is placed in the prone position for injection, dimples are difficult to identify. Second, the CCH-aaes dilution used to treat the buttock (0.23 mg/mL) is different from that used for the thigh . If treating both the buttocks and the thigh, the dimples must be identified ahead of time so that the proper dilution can be made. Of note, in one author’s practice, it is rare to split a vial between the buttock and the thighs. Rather, the buttock is treated with a dedicated vial and the thigh with a separate dedicated vial.The number of buttock dimples that can be treated is dependent upon the size of the vial. The calculations below assume some loss of volume during reconstitution and/or draw up of product: 9 While this calculation can be done ahead of time, a straightforward way to measure the remaining volume of QWO mid-treatment is to draw up the remaining product into a syringe to measure the volume, then multiply the remaining volume by 4 to obtain the volume of diluent needed.Once the number of desired buttock dimples has been identified, calculations are needed to determine the volume of diluent needed so that remainder of the vial can be properly prepared to treat the thighs. To treat the thighs, reconstituted CCH-aaes (0.23 mg/mL) should be diluted 1:5  to achieve the 0.046 mg/mL concentration needed for treatment.The following calculation can be used to determine the diluent needed to treat the thighs:orWith the volume of remaining CCH-aaes in hand, the volume of diluent needed to treat the thigh can be calculated:As the volume of diluent needed will likely be more than what can be accommodated by the vial, the CCH-aaes to be diluted may be added to a sterile container containing the desired volume of normal saline. The easiest way to accomplish this is to use a bottle of sterile saline (20 or 50 mL) with an appropriate volume removed. For example, if 16 mL of diluent is needed, then a 20-mL bottle of sterile saline can be used, with 4 mL removed before the addition of the CCH-aaes.The number of thigh dimples that can be treated is equal to the total volume of diluted CCH-aaes divided by the 1.5 mL needed to treat each dimple:10 For dilution, it is important to use normal saline rather than bacteriostatic saline. Laboratory data evaluating the activity, purity, and solubility of CCH-aaes have shown that bacteriostatic saline can cause up to a 40% loss in activity and aggregation of 5.3% of the protein, while normal saline does not have this effect.10When reconstituting CCH-aaes, it is important to use the solution that comes with the product, as it contains ions that are important for the function of the enzyme.11 Consistent background and lighting, distance from the camera , and clothing (a black G-string can be provided) facilitate comparison of the before and after images. In some instances, using the black and white mode for the camera can highlight shadowing caused by dimples, making them easier to see. Attention to lighting is particularly important as small changes in light direction and intensity can affect the appearance of shadows. For evaluating the impact of treatment, photographs can be taken before each treatment session with and without markings and in the relaxed and clenched positions. However, if the goal is to evaluate bruising, the trajectory of bruising demands more frequent photography with the patient returning for follow-up photography between treatments.Finally, pretreatment planning should involve standardized photography of the patient. Photographs should be taken from 0°, 22°, and 90° with the patient in the relaxed and clenched position. It is also important to take images of the patient before marking dimples to be treated and after the markings are made, so that the individual dimples injected are highlighted. While the highest standards of clinical photography for cellulite can involve advanced equipment and a high degree of technical expertise, for the practical purposes of documenting treatment effect for the patient, the most important aspect of photography is consistency.12 In the CCH-aaes phase 3 studies RELEASE-1 and RELEASE-2, a 37.1% and 47.6% composite response rate  was reported; however, subjects did not evaluate their cellulite in comparison to baseline photographs but instead were asked to base their score on their cellulite at the time of evaluation. On day 71 in RELEASE-1, 54.3% were “satisfied” or “very satisfied” with their treatment, and, in RELEASE-2, 46.8% of patients were at least satisfied.13 In clinical practice, the satisfaction of patients with treatment is generally higher. This is likely due, in part, to the personalized patient selection that occurs in real-world practice , but also because of the ability of patients to see their baseline photographs and compare them to photographs from posttreatment time points. While not fully quantified with real-world data, this disparity highlights the importance of both photography and patient selection.Clinical photography is especially important given the potential need for countering perceptual drift and recall bias over time.Anecdotally, one treatment effect that is not reported in studies but is apparent in clinical practice is a local smoothing effect in patients without significant laxity. Though the most efficient action of CCH-aaes is local, there can be a wider field of effect (3-5 cm from the site of injection in some patients), in particular in the thighs where dimples are oblong and less discrete. Whether this is related to small differences in the depth of injection and/or diffusion of the CCH-aaes enzyme itself or a secondary wound-healing effect is unclear, and the mechanism of this effect remains unknown. Further research in this area will likely define not only the field of effect but also the basis for the large surface area of bruising when it does occur.9 Of those, a 3-aliquot injection (three 0.1-mL injections of 0.23 mg/mL CCH-aaes) was identified as optimal for the buttock and later used in phase 3 pivotal studies  of patients.8 It stands to reason that disruption of these thicker septae could lead to bruising. Patients should be provided with before and after photographs that clearly show not just the treatment effect but also the severity and timeline for post-injection bruising.The authors note that bruising, nodularity, itching, and discomfort are the most consistently reported AEs by patients, but that they generally resolve without intervention. In clinical studies of CCH-aaes, a range of AEs were monitored. However, the most notable side effect of treatment is post-injection bruising. For a small subset of patients who bruise, hemosiderin staining or prolonged hyperpigmentation can occur. The mechanism of bruising with CCH-aaes is not entirely understood, but recent anatomical studies of cellulite have shown that septae that attach to the dermis may be thicker with origins in the deep fascia or thinner (and more numerous) with origins in the superficial fascia, and that these thicker septae are associated with neurovascular bundles.While bruising can vary widely in severity, the average trajectory of bruising is shown in During the discussion, the authors reviewed their personal experiences with various approaches for bruising mitigation. These measures are based on clinical experience alone and at the time of this writing have not been formally evaluated in clinical studies. For example, patients may be treated using the Radial Soundwave Technology  4 days after CCH-aaes injection to mitigate bruising and swelling and as a helpful adjunct for tightening skin and addressing any residual laxity. Residual bruising may also be treated with pulse dye laser treatment (PDL). Though these measures may be packaged as part of the CCH-aaes treatment, in some cases, education and reassurance for the patient that bruising is normal and will subside with time are sufficient. Formal controlled studies are needed to quantify any effect of these measures as well as whether their early use is able to reduce the risk of hemosiderin staining.While there are no studies to support the use of ice and/or compression, these may be recommended to reduce bruising and any swelling. Patients should also be advised to avoid exercise for 24-48 hours, as there is some anecdotal evidence that increased physical activity or treatment of the same area with high-intensity focused electromagnetic energy (HIFEM) on the day of treatment worsens bruising.16 While TXA can be injected or applied topically, oral treatment for melasma generally requires 250 mg twice daily for 4 to 6 months. In orthopedic and trauma surgery, TXA is used to reduce perioperative bleeding, in particular for patients with bleeding disorders or taking antithrombotic medications. For plastic surgery operative procedures, it has become increasingly common to administer 1 g IV TXA at the beginning of the case to minimize postoperative ecchymosis, and some surgeons now add TXA to their liposuction tumescent solution for the same reason. Due to some anecdotal success with topical site pretreatment with TXA by one of the authors, there is research ongoing to explore the potential efficacy of a range of concentrations for reduction of bruising following treatment of cellulite with CCH-aaes. Additionally, early evidence suggests that oral TXA (1300 mg twice daily × 8 days) starting 12 hours before injection has been beneficial. In the case study shown in 16For the authors, the overall lack of preventative options prompted the consideration of tranexamic acid (TXA) as a pretreatment adjunct. Preliminary experience with this agent is described below. TXA is an antifibrinolytic agent with anti-angiogenic and antimelanogenetic properties and an established history in dermatology for the treatment of melasma, among other conditions.As previously stated, the multifactorial contributions of cellulite along with laxity, skin quality, and localized adiposity suggest that combination therapies may yield the most optimal aesthetic results. There is no consensus on the optimal timing of skin tightening relative to CCH-aaes injections, and further research is warranted. Improving laxity before injection may permit a more precise location of actual dimples, which can improve the efficacy of injection. In contrast, if the patient desires volume augmentation, it may be more prudent to address the cellulite initially and then proceed with volumization in the form of injectable fillers or fat transfer. Skin tightening modalities can include hyperdilute biostimulatory fillers, radiofrequency, or ultrasound.4 While none of the panelists have routinely used CCH-aaes in areas outside of the buttocks or thighs, cellulite can occur in the abdomen as well as the anterior and inner thighs. In the small number of patients that some of the authors have treated in the anterior thighs, efficacy has been good and there are no signals of heightened bruising or other safety concerns. Additional research will be needed to inform optimal injection technique and the nature of response to CCH-aaes.While cellulite can occur anywhere there is subcutaneous adipose tissue, it is most common in the thighs and buttocks.Importantly, this manuscript is a reflection of the clinical experience of the authors. There is a need for evidence to further support our understanding of bruising mitigation. One shortcoming of this study is that CCH-aaes is so recently introduced to the market, that it is unclear which, if any of the presented strategies will be best for mitigation. Furthermore, additional real-world studies on outcomes for the thigh are needed, as are studies evaluating combination treatment with multiple modalities aimed at managing compounding issues such as laxity or adiposity.The introduction of CCH-aaes has been a welcome addition to the armamentarium for the treatment of cellulite. With knowledge of proper patient evaluation and injection technique, thorough patient education, diligent photography, and developing research on bruising mitigation, CCH-aaes is a minimally invasive treatment targeting septae, which shows promise as an effective and safe modality for the management of cellulite.


The aim of this study was to validate a three-class sentiment classification model for clinical trial abstracts combining adversarial learning and the BioBERT language processing model as a tool to assess trends in biomedical literature in a clearly reproducible manner. We then assessed the model's performance for this application and compared it to previous models used for this task.Using 108 expert-annotated clinical trial abstracts and 2,000 unlabeled abstracts this study develops a three-class sentiment classification algorithm for clinical trial abstracts. The model uses a semi-supervised model based on the Bidirectional Encoder Representation from Transformers (BERT) model, a much more advanced and accurate method compared to previously used models based upon traditional machine learning methods. The prediction performance was compared to those previous studies.The algorithm was found to have a classification accuracy of 91.3%, with a macro F1-Score of 0.92, significantly outperforming previous studies used to classify sentiment in clinical trial literature, while also making the sentiment classification finer grained with greater reproducibility.We demonstrate an easily applied sentiment classification model for clinical trial abstracts that significantly outperforms previous models with greater reproducibility and applicability to large-scale study of reporting trends. As a reThe current gold standard for systematic assessment of the qualitative interpretation of the findings has been rating systems performed by human raters. However, this method of assessment is time and resource intensive and has inherently poor reproducibility due to variability between the raters used –8. FortuIn recent years, several studies have explored the assessment of citation sentiment analysis in academic literature –12 with With the limitations of these previous studies in mind, this study's goal was to develop and validate a sentiment analysis model for clinical trial abstracts that can be practically applied to large-scale assessment of clinical literature using the more modern GAN-BERT architecture . This moThere are no publicly available annotated datasets specific to sentiment analysis of clinical trials, so for the purposes of this study an appropriate annotated dataset had to be created. Given that the best raters for the sentiment rating of clinical trials are trained clinician experts, creation of a fully annotated dataset for this study was determined to be particularly resource intensive, a problem inherent to clinically related natural language processing (NLP) tasks . As suchAll abstracts gathered for this study were from the National Library of Medicine's (NLM) PubMed database, filtered specifically to publications classified as clinical trials. The collection of these abstracts was automated using the NCBI's Entrez search and retrieval system with a data mining tool built by the authors using the BioPython toolkit . This toFor the creation of the labeled dataset, 12 abstracts each from clinical trials in the fields of Obstetrics & Gynecology, Orthopedics, Pediatrics, Anesthesiology, General Surgery, Internal Medicine, Thoracic Surgery, Critical Care, and Cardiology were randomly selected, for a total of 108 labeled abstracts. These abstracts were then stripped of all information other than the abstract text and provided to a panel of three clinicians with a range of 9–19 years of experience to independently label the abstracts as having positive, negative, or neutral sentiment, with examples shown in The conclusion sentences of the labeled and unlabeled abstracts to be used for training and validation were then extracted. This was done as it was found in previous study that using solely the concluding sentences led to an increase in classification accuracy , 16. UsiThe relative value of 0.125 was determined empirically in a previous study based on the analysis of 2,000 structured abstracts .Tokenization: Following extraction of the conclusion sentences, all sentences were tokenized using the BERT tokenizer available as part of the HuggingFace Transformers toolkit , which tGenerally, the GAN-BERT architecture consists of a generator function G based on the Semi-Supervised generalized adversarial network (GAN) architecture that generates fake samples F using a noise vector as input , the preBefore discussing the details of the algorithm used in this study it is key to first discuss the general BERT architecture. Bidirectional Encoder Representations from Transformers or BERT model is a method for language processing first described in 2018 by Devlin et al. that achieved state of the art performance on a variety of natural language processing tasks and has since become a heavily used tool in natural language processing research . BERT fuGiven the important role of the pretrained model in the BERT architecture, and the relative complexity of biomedical literature, general language models are likely to encounter lower accuracy when applied to a biomedical application such as the one in this study due to a change in the word distributions between general and biomedical corpora . As suchWhile BERT and its derivatives have been able to achieve state of the art performance on a variety of tasks, one major limitation of the model is that fully trained models typically require thousands of annotated examples to achieve these results . SignifiIn summary, in this study GAN-BioBERT takes the BERT architecture pretrained on biomedical text using BioBERT  and fineOf the 108 abstracts  labeled by the expert raters, 26 were classified as positive, 69 were classified as neutral, and 13 were classified as negative by the raters. As such, the negative samples were up-sampled, and the neutral samples were down-sampled so that each class contained 26 examples, for a final labeled dataset of 78 abstracts for training purposes. In order to have a test set with a distribution similar to what is present in application of the algorithm, 23 of the samples were held out as the test set for determining the performance of the algorithm prior to balancing of the training dataset.After completion of training, the final GAN-BioBERT algorithm was found to have an accuracy of 91.3%, and a macro F1-Score of 0.92. The training of the algorithm took 45 min using the Google Colaboratory Environment using 35 GB of RAM with TPU hardware acceleration. The confusion matrix associated with these results is shown in GAN-BERT using the base uncased BERT pretrained model was found to have an accuracy of 82.6% and a macro F1-score of 0.824. These results, alongside the results of the two previous studies investigating sentiment analysis of clinical trial abstracts, are summarized in From a technical perspective, these results show that GAN-BioBERT is a significant step forward for assessing the sentiment in clinical trial literature, with an 8.7% improvement in performance over GAN-BERT for the same classification task. This improvement in domain specific classification performance with creation of a domain specific algorithm is reasonable to expect but is important to assure the algorithms viability in an application where highly specific and technical language is commonplace. Beyond this, a reliable, rapid assessment method for clinical literature is a large step forward in the process of assessing trends in clinical literature as traditionally the assessment of clinical literature has been performed manually which creates significant resource and time restrictions on larger literature reviews. This also provides a reliable method of assessing potential biases in the literature by being able to operationalize some amount of subjective assessment of the literature using artificial intelligence.When technically compared to previous studies' attempts at classifying sentiment in clinical trial abstracts , 16, thiThis study presents GAN-BioBERT, a sentiment analysis classifier for the assessment of the sentiment expressed in clinical trial abstracts. GAN-BioBERT was shown to significantly outperform previous attempts to classify sentiment in clinical trial abstracts using sentiment analysis with regards to accuracy and number of sentiment classes. Considering this high multi-class accuracy, and the reproducible results GAN-BioBERT generates, this study posits GAN-BioBERT as a viable tool for large-scale assessment of the findings expressed in clinical trial literature in a way that was not previously possible, making a needed step forward in the methods used to address the important and patient-impacting issue of reporting bias in clinical literature. By using a tool such as GAN-BioBERT the large-scale assessment of qualitative reporting trends in clinical trial literature becomes significantly more feasible with more reproducible findings when compared to the past practice of manual assessment of reporting bias.https://doi.org/10.5281/zenodo.5699018.The model generated for this study can be found in the Zenodo repository at: JM, EK, and KS were responsible for conception and design. KS was responsible for administrative support. PM, KB, LK, and KS were responsible for provision of study materials. JM and EK were responsible for collection and assembly of data. JM was responsible for data analysis and interpretation. All authors were responsible for manuscript writing as well as final approval of the manuscript.This study was funded by the University of Wisconsin School of Medicine and Public Health's Shapiro Summer Research Program.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Psychosocial work factors are implicated in the development of stress and job satisfaction. This relationship has been scarcely studied in so-called singular activities, as is the case of professional drivers. This cross-sectional study of 601 professional drivers assesses psychosocial risks and job satisfaction using Copenhagen Psychosocial Questionnaire (COPSOQ) and Overall Job Satisfaction questionnaire models. The values of the psychosocial scales of professional drivers were compared with thresholds values of the Spanish working population. The relationships of the psychosocial scales with the level of job satisfaction were examined using logistic regression models, adjusted for age, gender, length of driving license and years of experience. In general, professional drivers have an unfavorable psychosocial environment compared to the average Spanish workers. The relationship between psychosocial scales and job satisfaction is observed, with the most influential variables being the meaning and development of work, integration in the company, social relations, esteem and level of psychological demands. Industrialized countries have to face major challenges related to psychosocial aspects of work as a result of the significant increase in workload and work stress . PsychosPsychosocial risk at work is defined as “those aspects of the design, organization and management of work, as well as its social and environmental context, which have the potential to cause physical, psychological or social harm to workers” . On the Previous studies have analyzed in depth the psychosocial burden in classic sectors such as teaching , healthcIn Spain about half a million people are professional drivers . In addiThe first aim of the present study was to analyze psychosocial factors in the usual work of professional drivers and to compare them with the general working population. A second objective was to relate psychosocial risk and job satisfaction of professional drivers.For the assessment of psychosocial factors at work we used the Copenhagen Psychosocial Questionnaire (COPSOQ). This tool was originally developed at the National Institute of Occupational Health in Denmark by Kristensen and Borg in 2000 , and wasCopenhagen Psychosocial Questionnaire covers the main areas of the psychosocial work environment: demands at work, work organization and interpersonal relations. The instrument includes 20 scales grouped in the following sections: Psychological demands at work; Control over work, influence, and development; Social support and quality of leadership; and Degree of compensation at work. The To measure job satisfaction, we used the “Overall Job Satisfaction Questionnaire” , which cp = q), a confidence level of 95% and a margin of error or precision of 5% (e = 5). Drivers taking training and refresher courses at 12 training centers in different Spanish provinces were invited to take part in the study. Informative talks were given beforehand with the drivers and the managers of the centers. Drivers agreed to take part, sending the questionnaires by post in sealed envelopes, guaranteeing confidentiality and anonymity at all times.This is a cross-sectional study in which the study population is professional drivers in Spain. The sample size, 385 surveys, was estimated for an infinite population, with a degree of heterogeneity or diversity of 50% (p < 0.05), point estimate of risk (OR) and 95% confidence interval (CI) were estimated. All analyses were performed in SPSS statistical software, ver. 25.0.The statistical analysis included a descriptive analysis and comparison of the mean values of the COPSOQ scale between the group of drivers and the Spanish population. A multivariate analysis was performed using a logistic regression model to explore which psychosocial aspects influenced the degree of job satisfaction, where the dichotomous dependent variable (level of job satisfaction) was assigned two values: 1 = good satisfaction (scores above the 75th percentile) and 0 = low job satisfaction (below the 75th percentile). Predictor or independent variables : salary, promotion possibilities in the company, level of attention and participation in the company, the way the company is managed, and the working hours .A way of expressing the magnitude of psychosocial risk has been proposed using the so-called ISTAS traffic light . The exaIn order to determine the weight of psychosocial factors on the degree of job satisfaction, a logistic regression model was performed, adjusting for age, gender, length of driving license and years of professional experience. The results are shown in Our study of 601 workers from 12 workplaces provides good support for the study of the relationships between job satisfaction and psychosocial risk factors of professional drivers. This study has used one of the recognized methods for assessing the psychosocial environment of workers (COPSOQ), proposed by the Danish National Institute for Occupational Health . The aimMultiple studies have evaluated the conditions of professional drivers and the factors of their activity that can bring serious consequences on the physical and psychological health of these workers .The average age of the drivers (43.9 years) was similar to the Spanish population (43.3 years) according to the latest provisional data from the National Institute of Statistics . There iWe observe that many psychosocial positive scales are below the lower tertile . This would indicate that, on average, professional drivers find themselves in a more unfavorable psychosocial environment than the average population of Spanish workers .Studies on healthcare workers showed many more favorable scales: group feeling, social relations, integration in the company, sense of work, development possibilities and influence at work  despite In relation to job satisfaction, professional drivers perform worse than other groups of workers. For example, workers in the administrative sector had a level of satisfaction close to 80% ; in the The association between job satisfaction and psychosocial work environment factors is maintained in multivariate models after adjusting for age, gender, and driving experience. In the multivariate analysis , it is oAlthough we use multivariate regression models to adjust for these factors, other residual confounders may still exist. However, it should be noted that some of these factors can be considered as mediators of the association.Our work has been limited to assessing psychosocial factors related to working conditions and the working environment. We are aware that other factors related to health status that could influence the degree of job satisfaction have not been assessed. In this sense, it is important to promote extensive multidisciplinary research that addresses all these aspects together.In conclusion, professional drivers carry out a work activity with specific characteristics which are difficult to assess and which have been linked to health problems, especially those arising from physical and ergonomic aspects. This study aims to provide evidence that this work activity is also influenced by psychosocial risk factors, which not only influence the degree of job satisfaction, but may also have a negative effect on the health of professional drivers.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.AG-R and EM-G: conceptualization, supervision, and writing—original draft. VH-R and MG-B: data curation and formal analysis. AG-R and MG-B: methodology. MG-B: validation. VH-R and EM-G: writing—review and editing. All authors contributed to the article and approved the submitted version.The APC was funded by Universidad de Málaga/CBUA.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Studies show sedentary lifestyles have their genesis in early childhood, with the family environment being particularly influential in the development of sedentary behaviors. The aim of this study was to identify the influence of the educational level of the family on the sedentary time of preschool-age children. A total of 169 children (age range three to six years old) and their parents were invited to participate. Their parents completed the Health Behavior in School-age Children questionnaire, which determines parental educational level  and the sedentary behavior of their children. Sedentary behavior time was also analyzed by fractions . As these tables reveal, approximately 70 percent of children aged from three to six years displayed high levels of sedentary behavior , mainly during the weekend. Children with parents of medium educational level dedicated more hours to other obligations per week , and reported more sedentary behavior during the week (mainly screen time). Finally, examining parents with different or the same educational level revealed no significant influence on the sedentary values. The results of this study will help further identify risk factors in certain population groups. Several studies show that social changes can have a considerable impact on healthy lifestyle behaviors ,2. From Sedentary lifestyle is generally associated with the development of cardiovascular diseases and higher rates of obesity and overweight status ,17,18. HClearly, investigating risk factors associated with sedentary lifestyles in young children is of critical importance. Children reporting greater sedentary time also report engaging in far less physical activity (PA) ,26, makiBagordo et al.  highlighTherefore, the objective of this study was to report on the sedentary times and behaviors of young Spanish children aged from three to six years, and analyze the influence of the educational level of the parents on the sedentary time and behavior, specifically, to identify the influence of this variable, and outlining specific areas in which to develop family orientation programs aimed at developing healthy habits.A cross-sectional observational study was carried out to compile data on children’s SB and its relationship with the educational level of the families.The sample was made up of 169 pupils in the second cycle of Early Childhood Education from the Spanish educational system, in Jaén, Spain . The inclusion criteria were: being pupils in the second cycle of Early Childhood Education and not having any disease that prevented them from practicing physical activity. Both the educational center and the parents and/or guardians were informed of the objectives of the study, presenting a written informed consent to participate in it. This work was approved by the Ethics Committee of the local institution .The parents and/or guardians of the students were summoned to a meeting where they were informed of the characteristics of the study and where they signed an informed consent for their children to participate. It was carried out in a week of common school routine in a spring period. The tests that were carried out included obtaining the educational level of parents/guardians and levels of sedentary behavior.Parents/guardians were asked about the highest level of education they had, using it as an indicator of their educational level. They were asked about the different levels of studies that cover Spanish education. The response options were categorized into three levels: (a) lower level: no graduation, primary/EGB, secondary/ESO; (b) middle level: vocational training I, medium-level training cycles, high school/BUP/COU, professional training II, higher-level training cycle; and, (c) higher level: university degree or technical engineering, Bachelor’s or higher engineering, graduate, master’s, doctorate. In turn, two more options were also considered: (a) father and mother with the same educational level and (b) father and mother with different educational level. This classification has been previously used by other authors ,42,43.Sedentary activities were determined using the Health Behavior in School-aged Children (HBSC) questionnaire , in 2019p < 0.05.The statistical package SPSS version 25.0 for Windows was used. A frequency analysis was performed, as well as a descriptive analysis of the data shown as mean and standard deviation. A non-parametric distribution was confirmed by means of the Kolmogorov-Smirnov Test. The Kruskal–Wallis test was used to observe the differences between the educational level , attending to the post-test. The post hoc test was adjusted to Bonferroni’s adjusted criterion for comparison by pairs. Through the U-Mann–Whitney test, the differences between equality or lack of equality in the educational level of the parents  were analyzed. Significance was set at p < 0.01). There is also a significant difference in the global time during the week with a sedentary behavior, where sedentary behavior is higher for parents of medium educational level (p < 0.05). Despite not being statistically significant, hours spent watching television stands out as the most sedentary behavior in the sample in general.Statistically significant differences are shown in the time spent on homework throughout the week, where more time is spent when the parents’ educational level is medium (It was observed that there were no statistically significant differences when the groups are compared in relation to whether or not the spouses have the same educational level. In turn, as in the total sample, there were nine cases of single-parents and, therefore, they are not included in the analysis.The aim of this study was to report on the level of sedentary behavior engaged in by young children, and to analyze the influence of parental education level on children’s sedentary behaviors. The results of this study showed that Spanish children aged 3–6 years old reportedly spend over eight and a half hours per week engaged in the examined sedentary behaviors; over four and a half hours watching television each week, and over one and a half hours using a tablet and completing homework, respectively. With regard to education level, children whose parents were categorized as possessing a medium education level were reported to spend more time engaged in homework per week and more total time engaged in sedentary behaviors per week. Whether parental education level was the same for both the mother and father was found to be of inconsequential influence on sedentary behaviors. Together, these findings suggest parental education level is only partially associated with the sedentary lifestyles of young children.The family is an influential factor in the sedentary lifestyle of their children ,48,49,50The study also coincides with others, finding that the most common sedentary behavior is engagement in screen time, specifically watching television ,58. InteIt is important to note that some work has shown an association between lower educational level with socioeconomic disadvantage ,61,62,63In relation to the performance of sedentary school tasks after school hours, the children of parents of medium or high educational levels dedicated more time to these tasks during the week. This time was also found to increase considerably during the weekend when compared with children of parents with a lower educational level. While some sedentary behaviors are crucial to education, such as after-school work, it is important that they are balanced with other sedentary behaviors and physical activity. Finally, there were no reported differences regarding sedentary lifestyle when comparing the equality or difference in the educational level of the father and mother.This study provides some evidence towards parental education level playing a role in childhood sedentary activity, suggesting an inverse relationship between educational level and sedentary activity ,27,48. TA very high percentage of the children aged three to six years observed show excessive levels of sedentary behavior, mainly during the weekend. When the parents’ educational level is medium, the volume of time spent performing homework during the week increases, as does sedentary behavior, compared to a low or high level of education for the parents. There are no statistically significant differences regarding the sedentary behavior of children from three to six years old, according to whether their parents have the same or different educational levels. These results confirm high sedentary behavior in children aged three to six years and the need to guide families, especially those with a lower educational level, on the need of avoiding sedentary behaviors in their children because of the impact on their development. They also allow holistic strategies to be developed between the educational center, the environment and families, with a view to creating life habits that can establish adherence in the future.


Cardiovascular diseases were the leading cause of death in the world prior to the COVID-19 pandemic. A wide range of risk factors may precipitate a cardiovascular disease and therefore multiple aspects of the patient's history may lend a hand in the diagnosis of the specific stage of cardiovascular disease that is presented by the patient. This article will give a general review of the knowledge and skillsets needed by a clinician to distinguish and at the same time correlate the different presenting symptoms and the potential cardiac issue associated with them. History taking is a very essential and critical clinical skill that is of paramount assistance in diagnosing and treating the patient with the right management therapies to find a cure for the disease. Basic approaches in the evaluation of the physical condition and cardiac assessment are important skills in healthcare that help decrease mortality in everyday life and therefore are needed to be learned efficiently. Lifestyle changes and modern standard of living especially in a developing country like India contribute majorly to the evolution of this disease in the population as well as the eating habits and addictions which play a vital role in the progression of the disease. The aim of this article is also to give an outline of various risk factors and recent etiological agents by analyzing the epidemiological variation and patterns that can be ruled out or considered associated with the cardiovascular related-symptomatology and relevant history of the patient to confirm a diagnosis by investigations which will direct the clinician towards specific treatments and recovery of the patient. A special topic of understanding would be the COVID-19-associated cardiovascular complications which have been recently discovered and studied as a result of the pandemic. Concerns and the quest to know about cardiovascular diseases (CVDs), which have been the main cause of mortality in industrialized nations, and the spread of the epidemic now to emerging countries have been seen from different perspectives by different researchers. The exact pathophysiology that is common to all is atheromatous vascular disease, which leads to peripheral vascular disease, cerebrovascular disease, coronary artery disease (CAD), and ultimately heart failure and cardiac arrhythmias. Long-term studies have identified several major risk factors for these disorders, including lack of physical exercise, regular tobacco consumption, metabolic disorders like diabetes mellitus, high blood pressure, central abdominal obesity, psychosocial factors, irregular timings of unhealthy meals, excessive alcohol consumption, and high levels of low-density lipoprotein or even hypercholesterolemia . A patieUnmodifiable risk factors are not changeable and include, heredity or genetic makeup, diabetes insipidus, and age. The deterioration of the body with age becomes a predisposing factor for the majority of chronic illnesses. The body is subjected to a variety of stresses as we age, including free radicals produced by the body, which promote the degeneration of organs and cell functioning. People who have a family history of coagulopathies and heart disease are more likely to acquire CVDs, according to epidemiological studies. Additionally, a person with type 1 (juvenile) diabetes experiences impairments in several bodily processes, most notably tolerance to glucose and metabolism of fats. The person is more prone to acquire CVDs as a result of such metabolic disorders. The increased prevalence of cardiovascular disease and stroke has also been attributed to risk factors such as severe migraines, abrupt anxiety, and hormonal contraceptive usage -5.When compared to inactivity, increased physical activity lowers the chance of having cardiovascular disease. Only people who are completely inactive or who have pre-existing health issues are at risk for acute cardiovascular events with abrupt, vigorous-intensity physical exercise, albeit there may be a threshold at which activity levels transmit higher risk. These dangers might be reduced by introducing the new activity and having a doctor check you out before starting an exercise program. Therefore, a personal history of physical fitness, duration, and intensity of exercise is as important as a history of a stationary lifestyle. It may also be influenced by the type of occupation of the person, i.e., desk-bound jobs, manually stressful jobs, etc .Diabetes mellitus has a lot of complications on the heart as increased oxidative stress, impaired protein kinase C signaling, and a rise in advanced glycation end-products cause inflammation and constriction of blood vessels, thrombus formation, and vascular dysfunction. These conditions are brought on by increased blood glucose levels, resistance to insulin, and an excess of fatty acids .An increase in cholesterol causes atherosclerosis of blood vessels and hypertension causes tearing of blood vessels due to excessive force of circulation and pumping of the heart triggered by different external and internal factors. Therefore, detailed history in consideration of all these will help in reaching the right diagnosis and treatment for the patient ,9.Clinical skills are acquired by assessing the risk factors, observing the signs presented and the history given by the patient in addition to reviewing the clinical investigations and coming to a provisional diagnosis, which may later be discussed among peers for a differential opinion, and finally coming to the most probable diagnosis. Accuracy and precision of the probable diagnosis need a wide range of knowledge of the various trends in the epidemiological distribution of the manifestations of cardiovascular diseases among different sections of the communities. These may be correctly deduced with the information provided by surveys and registered data about the disease prevalence and may be managed with different levels of treatment procedures and therapy.A clinician's approach to history taking and managementRapport Building with the Patients: A PerspectiveCommunication is the new age key to success and a very important part of the doctor-patient relationship. A good history comes with great communicative skills, established with the right amount of empathy, sympathy, and understanding the clinician builds with the patient. The main aim of the medical professional is to make the patient comfortable by creating the best environment possible so that there is trust built between them. The most effective way to extract the maximum and relevant information regarding the problems and the history is by communication in the vernacular language. This makes the patient feel the interest of the doctor, an association of being connected by the mother tongue which makes the patient talk about his/her problems transparently. Asking about the type of profession has also been proven to be effective by some researchers ,11.Airway, Breathing, Circulation, Disability, and Exposure (ABCDE) Approach to Emergency ManagementThis approach is very crucial along with the efficient assessment of the heart and history of the patient. It provides for the provision of a life-saving intervention and the division of challenging clinical problems into simpler parts. It creates a shared situational awareness among all healthcare professionals and allows time to determine a definitive diagnosis and course of action . ABCDE'sThe approach to recalling the eight elements of medical problems to ask the patient for obtaining a history of the presenting illness is shown in Table There is great relevance of the conversation-making skills of the clinician for good rapport building with the patient. It is also important for ethical decisions that the doctor needs to take after the diagnosis or while diagnosing the condition regarding the course of the treatment that needs to be taken while easing the patient throughout the process. Direct and indirect ways of asking diagnostically relevant questions to form a precise judgment and differential diagnosis based on the sharing level of the patient is an important communication skill that should be learned ,16.Symptomatology and Differential Diagnosis in a Cardiac Patient: An OutlookAcute coronary syndrome (ACS) is identified in 10% of individuals with acute chest discomfort. Many hospitals stay among low-risk patients might be avoided with the early, precise prediction of the probability of ACS in these individuals using the clinical examination, whilst high-risk patients could be treated right away -19.Dyspnea is the awareness of the shortness of breath and may be due to several respiratory and cardiac reasons. Orthopnea and paroxysmal nocturnal dyspnea are indications of left ventricular failure which occurs as breathlessness during the night while lying flat on the back ,21.Another important symptom is palpitations, which could be rapid or stationary. Dyspnea and palpitations both are associated with anxiety, physical exertion, and emotions ,23.Understanding the myocardial compromise brought on by myocardial necrosis, myocardial stunning, and mechanical consequences such as heart muscle bursting, ventricular septal defect, and ventricular free wall fissures are among the factors that contribute to the pathogenesis of heart failure development at the time of sudden myocardial infarction and admission to the hospital ,25.One percent of newborns are born with congenital heart disease (CHD), a type of birth abnormality. Although CHD can be induced by environmental exposures to teratogenic effects, the finding of a high-frequency risk and hereditary variants of the illness, and even the well-described link of CHD with chromosomal aberrations, strongly imply a genomic substrate for the condition ,27.Pregnant females who have indications of heart disease from routine hospital visits are also susceptible to suffering most commonly from cardiomyopathies and heart failures. The hormonal imbalances lead to overcompensation by the circulatory system with the same amount of blood in the body. This overloads the functioning of the heart leading to its failure or hypertrophy as a defense mechanism ,29.Psychiatric analysis and counseling should be recommended by doctors for patients with terminal or severe heart conditions, especially old people, who would need medical assistance in coping with grave situations like serious heart disease . Cardiovascular Diseases as a Sequel of COVID-19The most common symptoms and signs that a medical clinician should be keenly observant of in suspecting a cardiac condition are tachycardia, palpitations, chest pain, dyspnea on exertion, and intolerance to physical exercise. Studies, experiments, and case reports have led to a very basic understanding of the association between the virus and the cardiovascular system. In the COVID-19 era, acute myocarditis can show a wide range of clinical severity and provides considerable diagnostic difficulty. Chest discomfort, breathlessness, irregular heart rhythm, and acute left ventricular failure can all occur in COVID-19 patients -33. The The most obvious sign of COVID-19 infection might be acute cardiac failure. According to one study, less percentage of individuals who initially appear with COVID-19 may have acute heart failure than cardiomyopathy. With or without a history of hypertension or any cardiological dysfunction, this condition is seen to precipitate . Patients with COVID-19 infections have reported experiencing a wide variety of dysrhythmias. Such individuals typically have sinus tachycardia, which has several underlying factors such as feverishness, decreased perfusion, low oxygen delivery to the heart, and anxiety. According to one research, 44 percent of COVID-19 ICU patients and 17 percent of hospitalized patients both had dysrhythmias. Viral infection can lead to dysrhythmias because of hypoxia, inflammatory stress, and aberrant metabolism. In the differential diagnosis, the physician should take damage to the myocardium and acute myocarditis into account if dysrhythmias are linked to an increase in blood troponin. Over seven percent of individuals with COVID-19 may also present with palpitations in such conditions -39.Heart problems are the initial clinical sign of COVID-19 in some people who don't have normal symptoms like cough or fever. During COVID-19, myocardial damage is independently associated with an increased death rate. Furthermore, a condition resembling Kawasaki illness has been observed in children who may have COVID-19 -42.People diagnosed with COVID-19 having concomitant cardiovascular disorders are at risk for significant drug-disease interactions. We can better understand the possible processes behind COVID-19 by fusing our understanding of the mutating biological and structural compositions and characteristics of the virus and the host-virus interactions along with clinical results and we open the door to the accurate diagnosis and creation of prophylactic and therapeutic measures .With such viral complications affecting the functioning of the heart, the symptomatology and the signs perceived by the clinician may or may not be directed toward the exact cause of the disease, leading to misdiagnosis and mortality, especially in economically growing countries.In-depth knowledge of the manifestations of the numerous cardiovascular conditions and extensive observatory skills to look for the disease even with atypical presentations is the need of the hour and a significant area for learning. A proper sequence and protocol of standard clinical procedure compiled in this article may be of assistance in the hands-on practice of medicine where different patients showcase common or uncommon signs which need to be investigated thoroughly to narrow down the precipitating factor of causation of the disease. Awareness of the significance of various blood components, their irregular elevation and reduction, monitoring of electrocardiograms, and isolating of applicable etiology from the history of the patient is important and makes the process challenging with a wide window of inaccuracies. Being the leading cause of systemic death globally, cardiovascular diseases need to be screened, diagnosed, and treated with precision to be accountable for the pressing burden on the medical fraternity, clinicians, and medical assistants to this day. Diagnosis of a cardiovascular disease not only requires the appropriate clinical skillsets but also the knowledge of current epidemiological trends in the spread of diseases, its incidence in different population groups, and the ability to deduce the causative factor in order to treat the patients in the best possible way.


Cost containment is a major issue for health policy, in many countries. Policymakers have used various measures to deal with this problem. In Switzerland, the national parliament and subnational  governments have used moratoriums to limit the admission of specialist doctors and general practitioners.We analyze the impact of these regulations on the number of doctors billing in free practice and on the health costs created by medical practice based on records from the data pool of Swiss health insurers (SASIS) from 2007 to 2018 using interrupted time series and difference-in-differences models.We demonstrate that the removal of the national moratorium in 2012 increased the number of doctors, but did not augment significantly the direct health costs produced by independent doctors. Furthermore, the reintroduction of regulations at the cantonal level in 2013 and 2014 decreased the number of doctors billing in free practice but, again, did not affect direct health costs.Our findings suggest that regulating healthcare supply through a moratorium on doctors’ admissions does not directly contribute to limiting the increase in health expenditures.The online version contains supplementary material available at (10.1186/s12913-022-07735-7). A major challenge for policymakers around the world is to keep the cost of healthcare under control while maintaining the quality and affordability of services . In the This study contributes to the literature on regulatory adjustments for cost control in ambulatory healthcare by analysing the impact of a moratorium on new admissions of doctors in Switzerland. Similar to the United States and to other countries , 16, SwiIn this article, we deepen the analysis of the Swiss case by using time series data at the cantonal level as well as interrupted time series (ITS) and difference-in-differences (DID) models. Notably, we assess the net impact that the moratorium banning the admission of doctors has (a) on the number of doctors billing in free practice and (b) on direct health costs created by independent doctors, notably medical visits. We use original fine-grained monthly data to measure the development of doctors’ admissions and health expenditures to examine how the termination of the national moratorium and the reintroduction of moratoriums in some cantons have impacted the admission of specialist doctors (SP) and general practitioners (GP), as well as on the related health costs. Our analysis shows that the deregulation of admissions augments the number of newly admitted medical practitioners, however, it does not increase health expenditures from billings of individual doctors. Furthermore, the re-introduction of the moratorium at the cantonal level diminishes medical admissions but without reducing health cost increases. Our results are robust to alternative estimation strategies.These findings have important policy implications for and beyond Switzerland. Our results suggest that regulating the supply side of healthcare through the admission of doctors affects the number of newly admitted practitioners. Nevertheless, these measures do not reduce health expenditures from services billed by doctors. Yet, regulating the admission of new doctors neither increases such health costs. Thus, we conclude that regulating medical doctors’ admissions is an effective policy instrument to steer the number of healthcare professionals without creating additional health expenditures, however, the instrument does not contribute to reducing health costs.This article builds on two empirical findings in the literature. First, there is some evidence that regulating medical doctors’ admissions limits the number of providers –26. SecoAccording to the literature, there are different explanations for why regulating the admission of doctors might impact health expenditures, or, in other words, why the density of healthcare providers affects health costs –30. One Nevertheless, there are other explanations for the potential connection between a larger number of physicians and higher health expenditures. For example, the correlation between more doctors and higher health costs could be caused by a pre-existing unsatisfied demand for healthcare services and a higher number of doctors might reduce access costs for patients. Furthermore, causality could be reversed as newly admitted physicians select themselves into regions with already high levels of demand . ResearcEmpirical evidence has supported the correlation between higher numbers of healthcare providers and health expenditures and have shown that there is an effect on income for doctors. Nevertheless, the above-discussed alternative explanations cannot be completely excluded . ConsequThis study focuses on Switzerland. The Swiss health system is organized in a decentralized fashion . HistoriIn the Swiss health system, prices for services are fixed. Ambulatory healthcare services are paid for by the tariff system for ambulatory care whereas care in hospitals is reimbursed through a different payment system (SWISS DRG). Doctors are self-employed and use TARMED to bill the services they provide in their ambulatory practice. In addition, doctors – especially if they have a specialist qualification – can also practice in hospitals. Insurers and providers negotiate prices in the TARMED system. Since 2013, the federal government can adjust the prices in TARMED if health insurers and doctors fail to adjust prices . The fedSince the introduction of the KVG by the Federal Assembly , healthcTo deal with this problem, the Swiss Parliament decided to tackle increasing health expenditures by reducing the density of service providers . PreciseIn 2007, the Parliament created a moratorium reducing admissions of new doctors , 45. TheThe deregulation and re-regulation of doctors’ admissions in Switzerland provide an interesting case study to assess the impact of regulating healthcare providers through a moratorium on the admission of doctors. In the following, we are especially interested in the net effect of these policy changes on the number of doctors and the direct health costs created by these individual practitioners. The combination of deregulation and re-regulation events as well as the Swiss setting with 26 comparable cantonal health systems, which vary in their application of a moratorium, are an interesting case to test the impact of this regulation. Furthermore, the policy is interesting because it affected the migration of professionals to Switzerland. In particular, the removal of the admission ban for SP has increased the immigration of doctors from neighboring countries, whereas the reintroduction of the ban diminished the influx of practitioners .The background of the Swiss case also allows us to study whether there might be some evidence for supplier-induced demand. The population is fully insured, doctors are self-employed and the tariff system TARMED allows them to augment their income through increasing the amount of services provided. Furthermore, doctors can carry out their activities in different practices as well as in hospitals, which allows them to augment their income by providing more services , 34. ThiThe data for this study come from the database of Swiss insurers SASIS (see sasis.ch). We can observe the number of doctors billing in free practice and the health costs by specialty in each canton over the period 2007-2018 on a monthly basis (144 months). The records are based on registration numbers identifying independent practitioners and legal entities, which bill medical services to health insurers . Our data count the number of unique ZSR billings, in each month and canton by specialty. These data measure the medical claims billed by the ZSR under the KVG. Other healthcare services, such as pharmaceuticals and hospital services are billed using another identifier (see sasis.ch). The benefits paid by all health insurers in Switzerland are recorded by SASIS. Through the ZSR, our data inform about the number of independent SP and GP as well as the direct health costs they create over time. Our data show that the number of doctors billing in free practice and the related health costs have increased for both SP and GP . The seasonal effects appear since doctors tend to send their invoices to insurers at the end of each billing period.Nt, related to the aggregated number of ZSR by cantons, see also supplementary materials part A) and health costs (Ct) reported during a given month t. The independent variables are above all two binary variables identifying the policy change, i.e. the moratorium removal (Remt) as well as its later reintroduction (Reintt) in several cantons. They take the value of 0 before the change and 1 after that. We also account for a variable measuring the number of months since the policy change happened (Montht). Characterized by a unit increase, this variable takes the value of 1 at the first month of the new policy regulation; it is negative prior the change and positive after that. Finally, we analyze the temporal effect of a policy change by adding the interaction between the number of elapsed months and the policy change dummies (Montht×Remt respectively Montht×Reintt).From the raw data, we create a time-series cross-sectional data set at the level of months and cantons. To operationalize the impact of the moratorium, we define two response (dependent) variables, namely, the number of doctors billing in free practice . Concerning the reintroduction of the cantonal moratoriums, we base our study on 84 months of data from 01/2012 to 12/2018, i.e., from the removal date of the national moratorium to the last available record at the moment of data collection. This period includes all canton-specific reintroduction dates  andIn our case, possible concurrent events are the changes in the federal tariff for outpatient medical services, implemented by the federal government in 2014 and at the end of 2017. These events are not concurrent for the removal of the moratorium and for specialists and generalists. Nevertheless, the reform of 2014 increased income possibilities for physicians in outpatient care as of October 2014, in an attempt to shift health cost from the inpatient to the outpatient sector . Our resYt∈{Nt,Ct}  and policy intervention Xt∈{Remt,Reintt}  as follows: We consider the impact of the removal and reintroduction of the moratoriums on new doctors’ admissions and health costs. Stratified by cantons and type of specialty, we write our model for a response variable εt follows a negative binomial distribution when Yt=Nt and follows a log-normal distribution when Yt=Ct. In fact, the distributions chosen for both response variables are those that best fit the observations under the Akaike information criterion . While β0 represents the baseline level, β1 indicates the trend before the policy change −1”. For example, in GE, the annual increase in the number of doctors billing in free practice was 0.96% before the moratorium removal and 9.64% after that.The graphs (a) and (c) in Fig. The fit of the model mentclass2pt{minimIn the second part of Table % before the moratorium removal and 3.79% after that. This yields a difference of + 4.75 percentage points that can be compared with the 8.68 percentage points increase for SP (cf. above).The analysis of the removal of the moratorium for GP suggests similar findings . However, when comparing them to the results from SP, the observed changes in the rates of increase before and after the moratorium removal are slightly lower. For example, in GE, the annual change in the number of GP billing in free practice was − 0.96We now turn to the assessment of the reintroduction of cantonal moratoriums for SP, which happened in some but not all cantons. We do not consider the effect of the moratorium on GP since the reintroduction targeted SP only. Since only 18 cantons have re-introduced a moratorium, we have a control group available, which allows us to apply a difference-in-differences design. This research design compares the trends before and after moratorium re-introduction in those cantons that actually re-introduced the moratorium with those cantons that did not reintroduce the moratorium. In our analysis, we account for economic , demographic  and health-related  confounders . We alsoThe findings of the difference-in-differences models show that the reintroduction of the moratorium did not significantly increase the number of practitioners compared to the cantons where no moratorium was reintroduced Table . In otheTo further examine the re-introduction of the moratorium at the cantonal level, we turn again to ITS models. The results presented in Table We also examine the impact of the policy change on costs, which is shown in the right part of Table In the supplementary materials, we provide additional analyses, such as the effect of reintroduction by specialty. Furthermore, we present additional robustness tests, notably the analyses of health costs weighted by population size.Our results suggest that, overall, the removal and reintroduction of the moratorium impacted on the number of doctors billing in free practice, but not on the overall related health costs. These results are different from the findings by  who haveOur findings differ from the previous study because we compare the trends before and after moratorium removal using ITS and DID estimates and also focus on trends at the cantonal level. This method allows us to make more robust estimates that include a time trend variable in the models and analyze differences between cantons. Furthermore, we control for potential confounders over time, such as population growth, nominal GDP, household out-of-pocket payments for health care, unemployment rate, and long-term interest rates.Therefore, our findings provide robust descriptive evidence that there is neither a clear link between the removal of the moratorium and rising health costs, nor with its re-introduction and a clear decrease in health cost. Although we strengthen our analysis by estimating DID models, the causal implications of our findings need to be interpreted carefully, due to the following reasons.First, our operationalization measures the number of ZSR billings and not directly the number of doctors. Doctors may practice in several cantons and one doctor may bill services in different specialties. Practitioners receive their ZSR number from SASIS, a private organisation under the control of health insurers. The admission by the cantonal authorities is one of the conditions doctors must fulfill for obtaining a ZSR number. Some doctors obtain a cantonal authorization but apply only later for a ZSR number. Further, our data measure the place where a doctor practices and not the place of admission. Neither can we distinguish between part-time and full-time work. Finally, our data only include costs from independent practitioners and not bills from doctors practicing as employees in an institution . We cannot include such information as it is not available to us.3Second, we do not have information about doctors practicing in different cantons. In fact, once a practitioner obtains a ZSR number from a canton, the permission is valid everywhere in Switzerland. This permeability among cantons partly jeopardizes the containment effect of the heterogeneous reintroduction of cantonal moratoriums. Another potential issue is that patients can visit doctors in other cantons. This behavior is probably most relevant in small cantons; however, we do not have data available on the movement of patients between cantons. Furthermore, we find that the expansion of the number of doctors billing in free practice decreased also in cantons without moratorium reintroduction . This observation is puzzling. A possible explanation is that cantons adjusted their practice without formally adapting their policy. Such logic hints at a harmonization of implementation practices, even in the absence of harmonized formal policy changes. In addition, potential applicants, especially from abroad, may have perceived cantonal moratorium re-introductions as a national reintroduction and refrained from applying for positions in Switzerland.Third, despite the many control variables included in our analysis, we cannot account explicitly for all potentially confounding factors , in our These potential caveats do not invalidate the robust statistical evidence that there is no clear link between the moratorium and health cost. Nevertheless, our findings need to interpreted carefully regrading a causal link between taking off the moratorium and changes in health cost, especially regarding conclusions about the absence of supplier-induced demand.In this paper, we examine the impact of a moratorium regulating doctors’ admissions on the number of doctors billing in free practice and on health costs in Switzerland. Since the early 2000s, the national government and Federal Parliament have used this policy instrument to better control rising health expenditures by regulating the influx of doctors from other European countries. This regulation expired in 2010 for GP and in 2012 for SP. In mid-2013, some cantons reintroduced a moratorium on doctors’ admissions. We analyze the impact of this deregulation and re-regulation on the number of doctors billing in free practice and on the health costs resulting from free practice. In using original and fine-grained monthly data as well as interrupted time series regression models, we assess how the policy changes affect the number of doctors and health expenditures.Previous research on the topic has demonstrated that limiting doctors’ admissions through a moratorium reduces the number of practitioners. Concerning the impact of such moratoriums on health costs, the literature is unclear and has argued that a moratorium can either increase or decrease health expenditures. In the Swiss case, scholars have concluded that lifting the moratorium slightly increases cost . Our resOur research has important implications for policymakers. From a policy perspective, we suggest that regulatory measures limiting the admission of doctors do not necessarily result in reducing the cost growth and that decision-makers may revert to other instruments to achieve cost containment. Furthermore, particular care should be taken by defining homogeneous measures that apply to the whole country avoiding bias from permeability. From a political perspective, we speculate that the moratorium could be interpreted as a success. On the one hand, lifting the moratorium increased the number of GPs and specialists but it did not increase health expenditures. On the other hand, re-introducing the moratorium reduced the number of physicians but did not affect health expenditures. This link allows politicians to sell the moratorium as a successful instrument for steering the number of health professionals, for example in limiting immigration, without creating additional costs.Finally, further research should deepen the research on this topic. Specifically, scholars need to engage into further analyses dealing with the causal link between regulations of healthcare supply and health cost, for example by testing more explicitly the predictions from supply-sensitive care and supplier-induced demand theory. Regarding the Swiss health system, such analysis should also account for health costs other than payments to GPs and SP doctors . FurtherAdditional file 1 Supplementary materials.