To investigate the efficacy and safety of acupoint injection of Bacillus Calmette–Guerin polysaccharide nucleic acid (BCG-PSN) in the treatment of chronic urticaria (CU).The following databases will be searched from their inception: Medline, Embase, Pubmed, Web of Science, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure Database, China Biomedical Literature Database, China Science Journal Database, and Wanfang Database. All databases will be searched from the date of creation until October 2019. In addition, we will manually search the list of medical journals as a supplement. The scope of the search included randomized controlled clinical studies related to acupoint injection of BCG-PSN for CU. The primary outcome is the disease activity control. Secondary outcomes include response rate, adverse events, and recurrence rates. The Cochrane RevMan V5.3 Deviation Assessment Tool will be used to assess bias assessment risk, data integration risk, meta-analysis risk, and subgroup analysis risk (if conditions are met). The average difference, standard mean difference and binary data will be used to represent continuous results.This study will comprehensively review the existing evidence on the treatment of CU by acupoint injection of BCG-PSN.This systematic review will provide a judgment basis for the effectiveness and safety of acupoint injection of BCG-PSN in the treatment of CU.PROSPERO, CRD42019139885. The etiology of CU is still unknown, but many shreds of evidence suggest that it may be related to different biological systems, such as immunity, inflammation, and coagulation, which causes mast cells and basophils to degranulate and form wheal.–7 According to the survey, the global incidence of CU is close to 1%.–11 It can occur in any age group and has a higher incidence in women than men.,13–15 In most cases, symptoms in more than 70% of CU patients will last 2 to 5 years, 20% of them will last more than 5 years, If patients have hypertension, this can be as high as 74%.,16–18 1.8% of CU patients will never recover. Patients have a poor quality of life, with nearly 50% of them suffering from moderate to severe disease activity. CU patients are often accompanied by anxiety, depression, difficulty sleeping, social disorders, and so on, which have a significant impact on life of CU patients.,20–23Urticaria is defined as the sudden development of transient hives  and angioedema or both. A wheal is characterized by a circumscribed superficial edema of the skin, mostly surrounded by bright red erythema and associated with a strong itching or burning sensation. Chronic urticarial (CU) is defined as the presence of urticaria for a period exceeding 6 weeks, Attack twice a week or more.,25 and the guidelines,26,27 published between 2014 and 2018, Second-generation H1 antihistamines (sgAH) are the drugs of choice for initial therapy for CU. If unbearable symptoms appear after 2 to 4 weeks or earlier, the dose of the sgAH can be increased to 4 times the manufacturer's recommended dose (both unlicensed). Omalizumab should be added if it still does not improve significantly. If there is no satisfactory improvement within half a year, it is recommended to use cyclosporine and sgAH for treatment.,27,28 The sgAH can improve symptoms, but not reduce the total number of itching wheal episodes.,30 Studies have shown that long-term use of antihistamines can cause headaches, drowsiness, fatigue, dry mouth, allergies and other adverse reactions,–33 the median tolerance to h1-antihistamines in CU patients was 3 years, and 88.9% of patients had poor CU control. Omalizumab has been shown to be effective,–37 but its expensive cost cannot be ignored. Currently, there is no effective treatment for all patients, so it is necessary to explore and evaluate some other treatments to provide more options for the clinical treatment of CU.Based on the consensus1.2–41 Acupoint injection is 1 of the treatments of acupuncture which emerged in China during the 1950 s, and it is a modified acupuncture technique. it originated from intra-muscular injection in western medicine and was gradually integrated into traditional Chinese medicine.,44 Acupoint injection is an acupoint-stimulating technique in which a liquid agent is injected to prevent and/or treat diseases, The agents generally include Western medications, Chinese herbal extractions, vitamins, bee venom, and normal saline solution. It is widely used in China for CU,46,47 and had good curative effects.–50Acupuncture is an important part of complementary and alternative medicine, Studies have demonstrated its effectiveness and safety in treating CU. BCG-PSN is 1 of the Immunomodulators which participate in immunomodulatory actions, It is a mixture of nucleic acids and polysaccharides extracted from BCG immune-active substances. Some studies have shown that BCG-PSN can be used in allergic diseases.,52 At present, there are many studies on the treatment of CU by injecting BCG-PSN into acupoints in China, and the results were positive.–56 But 1 study has reported that BCG-PSN combined with antihistamine did not increase the effect of treating CU. So far, its clinical evidence is insufficient.Among then, Bacillus Calmette–Guerin polysaccharide nucleic acid (BCG–PSN) is the most commonly used 1 in China.From what has been discussed above, The efficacy and safety of acupoint injection of BCG-PSN in the treatment of CU have not been systematically evaluated. Therefore, it is necessary to make treatment recommendations based on the available evidence.22.1 and has been registered at PROSPERO (ID: CRD42019139885).This Study registration is designed in strict compliance with the preferred reporting items for systematic reviews and meta-analysis protocol.2.2The results of this systematic review are to evaluate the efficacy and safety of published randomized controlled clinical trial (RCT) about acupoint injections of BCG-PSN for CU to help clinicians and patients choose the appropriate treatment regimen. This review does not require ethical approval and will be reported in peer-reviewed journals.2.3We will use computers to search Medline, Embase, Pubmed, Web of Science and Cochrane Central Register of Controlled Trials and China's four databases: China National Knowledge Infrastructure Database, China Biomedical Literature Database, China Science Journal Database, and Wanfang Database. All databases will be searched from the date of creation until October 2019. The following search terms will be used: Urticaria, CU, Nettle-rash, Hives, Rubella, Wind cluster, Angioedema, acupoint injection, acupuncture point injection, acupoint-injection, hydro-acupuncture, point injection, acupoint block, BCG, Bacillus Calmette–Guerin, BCG-PSN, BCG polysaccharide nucleic acid, Bacillus Calmette–Guerin polysaccharide nucleic acid, Boolean operators ‘and’ and ‘or’ will be used within the search to combine the search terms. The example search strategy in Table 2.42.4.1This article only reviewed the RCT of acupoint injection as the main treatment. The control group included oral medication, non-acupoint, no treatment, placebo, diet and so on. In addition, both Chinese and English publications are subject to language restrictions. RCTs that are not subject to release status will be included, excluding the remaining types of documentation.2.4.2 or the Chinese guidelines for the diagnosis and treatment of urticaria version.Regardless of race, gender, age, and education, in our SR patients must comply with the European Academy of Allergology and Clinical Immunology, the Global Allergy and Asthma European Network, World Allergy Organization (EAACI/GA2LEN/EDF/ WAO) guidelines2.4.3Qualified interventions in the trial group were based on sterile syringes. Interventions include acupoint injection of BCG-PSN alone or in combination with other active therapies for CU. If combined with other methods, only the control group with the same intervention measures as the experimental group was included. The trial group such as Acupoint injection BCG-PSN combined with other traditional Chinese therapies , Acupoint injection BCG-PSN versus non-acupoint injection, will be excluded. The following processes will be compared:(1)Acupoint injection of BCG-PSN versus no treatment.(2)Acupoint injection of BCG-PSN versus other active therapies.(3)Acupoint injection of BCG-PSN plus active therapy versus the same active therapies.(4)Acupoint injection of BCG-PSN versus placebo or sham Acupoint injection.2.4.42.4.4.1The primary outcome was disease activity control, measured by the urticaria activity score (UAS), urticaria control test (UCT), or other validated symptom scores.2.4.4.2(1)Response rate.(2)Recurrence rate during the follow-up period.(3)Adverse events.2.52.5.1 The research flow chart is shown in Figure References from the search results will be added to the EndNote software (V.X8) document management software and duplicate content will be deleted. Two review authors (XX and LZ) will independently review and screen the titles, abstracts, and keywords of all retrieved studies to confirm eligible trials. The reviewer will receive a full report for further evaluation. Excluded explanations will be recorded in the excel data set. The disagreement between the reviewers (XX and LZ) is still unsolvable by discussion and is determined by a third party'S arbitration (YC).2.5.2The 2 review authors (YL and QZ) will extract data independently from the selected report or study and fill out the data extraction form. Extract the following information: general information, participants, methods, interventions, results, results, adverse events, main conclusions, conflicts of interest, ethical approval, etc. When the reported data is insufficient, we will contact the author for more information. In this process, any inconsistencies will be resolved through discussion between the 2 authors or judged by the third author (LW).2.6 This review uses L, U, and H as the key to these assessments, where L (low) indicates a lower risk of bias, U (unclear) indicates that the risk of bias is uncertain, and H (high) indicates a higher risk of bias. If inconsistent results appear, the final decisions will be made by the third author (SZ).The 2 authors (WC and QZ) will assess the study quality by using the checklist developed by the Cochrane Collaboration s bias risk assessment tool which evaluates the presence of potential selection bias , performance bias (blinding of investigators and participants), detection bias (blinding of outcome assessors), attrition bias (incomplete outcome data), reporting bias (selective reporting) and possible other sources of bias (funding bias).2.7For dichotomous data, risk ratio with 95% confidence interval (CIs) will be used to measure the treatment effect. For continuous data, mean difference (MD) and 95% CIs were used to measure treatment effectiveness.2.8We will handle missing data in accordance with the guideline stipulated in the Cochrane Handbook for SRs of Intervention. In particular, the following methods will be used:(1)Contact the corresponding author to request missing data.(2)Perform analysis of available cases.(3)Discuss the potential impact of missing data.2.9Q test statistic and quantified with the I2 value. If statistically significant, the cause will be discussed by narration and the use of subgroups and sensitivity analysis.Statistical heterogeneity will be assessed for significance with the Cochran 2.10We will evaluate publication bias using the Egger test and funnel plots.2.11We will use Review Manager 5.3 for all statistical analyses. The data will be pooled for the meta-analysis when the included studies are sufficiently homogeneous with respect to subjects, interventions, and outcomes. All similar studies will be pooled for a random-effects model to obtain the pooled intervention effect. The pooled intervention effect will be expressed in terms of the MD and 95% of CI if the outcome was reported as a continuous variable. If different scales were used to assess the outcome, the standard MD will be used. If the outcome was measured as a dichotomous variable, we will convert the OR into the standard MD as long as the underlying continuous measure followed an approximately normal distribution.2.12To resolve some potential problems, we will perform a subgroup analysis. First, we will compare the results of different drug injections at acupoints. Second, we will compare the results of acupoint injection alone with those combined with other active treatments.2.13To verify the robustness of the conclusions, sensitivity analyses will be performed to examine the impact of including low-quality studies in the meta-analysis and exclude studies with high or ambiguous bias risk.2.14We will judge the quality of evidence of the results by grading the methods of the recommendations, assessments, developments, and assessments of the working group. Risk of bias, consistency, directness, accuracy, publication bias and additional points were the areas we assessed. The assessment results will be divided into 4 levels: high, moderate, low, or very low.3 Acupoint injection of BCG-PSN is an important therapy of integrated Chinese and western medicine. Many studies at home and abroad have shown that it has a considerable effect on CU, and has the advantages of simple operation and low cost,–50 but its clinical evidence is insufficient and adverse reactions have been reported. As a drug commonly used in China to treat CU, BCG-PSN has been shown to be effective in many studies,,56 while some studies have not found the effectiveness of its combination. This SR will summarize the efficacy and safety of the current evidence and hope to provide convincing evidence for patients and clinicians during the decision-making process.CU is a disease with high incidence and seriously affects the quality of life and work of patients, but many patients are not satisfied with the current treatment.Conceptualization: Wei CaoData curation: Xianjun Xiao, Leixiao Zhang, Ying Liu, Lu Wang, Yue Cao, Qianhua Zheng,Formal analysis: Wei Cao, Siyuan Zhou.Investigation: Lu WangMethodology: Wei Cao, Xianjun Xiao.Project administration: Leixiao Zhang.Supervision: Ying Li.Writing – original draft: Wei Cao.Writing – review and editing: Chunxiao Li, Mingling Chen.


The COVID-19 pandemic caused a massive healthcare crisis. To investigate what makes healthcare system resilient and physicians better at coping during a crisis situation, our study investigated the role risk exposure, such as working at COVID-19 entry points, sleep, and perceived work safety played in reducing negative psychological functioning at work, as well as their effects on adverse and potentially fatal incidences of compromised safety and medical errors.Our study included a representative sample of 1,189 physicians, from all 12 Slovenian regions and all medical occupations, as registered by the Medical Chamber of Slovenia. For the purposes of this study, a Questionnaire of Sleep and Psychological Functioning at Work was developed in the form of an online retrospective self-report. Additionally, our study included items assessing physicians perceived work safety and frequency of negative outcomes  during the first month of the Covid-19 epidemic.Physicians working at COVID-19 entry points were more likely to experience night awakening, slept less than 5 h per night, experience nightmares, and had lower levels of psychological functioning in comparison to other physicians. Both hypothesized models showed adequate fit. A higher score on the sleep scale  has been shown to predict lower levels of negative psychological functioning at work and, indirectly, reduced incidences of compromised safety and medical errors. Contrary to our expectations, no significant direct effect of sleep on compromised safety and medical errors was found. When perceived work safety was added into the model, the model showed improved fit, with perceived work safety predicting better sleep, less negative psychological functioning at work, and less compromised safety.Sleep and safety both play an important role in reducing negative psychological functioning at work and, by doing so, decreasing the negative and potentially fatal incidents during the pandemic, such as compromised safety and medical errors. Further, research is needed to see how medical guidelines can be updated to ensure physicians sleep and that their safety is protected. The COVID-19 pandemic caused a massive healthcare crisis that many affected countries attempted to address with the national first-point-of-contact strategy for possible COVID-19 cases, as recommended by Understanding the sleep of physicians in relation to the COVID-19 response is important as: (1) Sleep deprivation increases the likelihood and subsequent adverse outcomes of infection . (2) SleResearch from Wuhan, China, during the first 2 months of the COVID-19 outbreak showed that sleep quality played an important role in self-efficacy and anxiety levels among healthcare professionals working with COVID-19-infected patients . Sleep aHypothesis 1). Negative psychological functioning at work will increase the incidences of compromised safety and medical errors (Hypothesis 2). Perceived work safety will be linked to better sleep, less negative psychological functioning, and lower levels of compromised safety (Hypothesis 3).Emerging research shows that healthcare workers, working directly with COVID-19-infected patients, were more likely to develop symptoms of depression, anxiety, and insomnia . Rangachn = 21). Based on the initial analysis and feedback provided by participants, the measures proposed in the questionnaire were adapted and improved. The items included in the survey were derived from theories, as well as following examples of pre-existing and pre-established measures assessing sleep, self-regulation, resilience, emotions, safety, and medical errors.On March 25, the Medical Chamber of Slovenia, in this case acting as the intermediary, sent the Questionnaire of Sleep and Psychological Functioning at Work to 9,727 registered physicians, of which 1,193 responded (12% response rate). The study was preregistered at the Department of Psychology at the University of Ljubljana, and the questionnaire was uploaded on 1ka.si (an online Slovenian platform used for research purposes). On the front page, physicians were informed about the purpose of the study, the right to withdraw, usage of the information, while anonymity of their responses was ensured. The study was conducted as a part of a larger survey designed to develop a measure assessing sleep and psychological functioning at work for physicians, including additional questions used in order to provide recommendations on how to improve emergency response to COVID-19. The questionnaire was presented on seven different pages with an average survey time of 10 min. After the participants submitted their responses, they were unable to return and change their submission. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Executive committee of the Medical Chamber of Slovenia. Before the survey was launched, a pilot study was conducted on a small sample of physicians  as well as COVID-19-related characteristics (working at a COVID-19 entry point and exposure to COVID-19).3–never, 2–less than once a week, 1–once or twice a week, 0–three or more times a week). Items referring to sleep quantity included sleep duration on workdays and non-workdays  and the occurrence of reduced sleep (<5 h sleep). Items referring to sleep quality included questions on the occurrence of insomnia symptoms and nightmares. Sleep latency included items of average sleep latency  and the occurrence of delayed sleep latency (> 30 min). Given that the items referring to frequency of reduced sleep (<5 h) and average sleep latency were scored on different continuums to the dimension of sleep quantity and quality, the scoring of the items was transformed to allow equal weights among indicators. The total score of sleep (0–30) is calculated as a sum of all the total scores on dimensions of sleep quantity (0–15), sleep latency (0–6), and sleep quality (0–16)  and four-factor structure (longer-version). Based upon psychometric analysis, items referring to sleep apnea, subjective sleep evaluation, and medicine taking were excluded from the measure. For the purpose of this study, a shorter version including nine items was used with three-dimensional factor structure . Scores on sleep scale are calculated as a sum of all dimensions  with the lowest score 0 and the highest score 30. Physicians reported the occurrence of sleeping problems on a four-point Likert scale (y (0–16) .never, 2—rarely, 3—sometimes, 4—often, 5—very often). The measure consists of seven items assessing self-regulatory failures , five items assessing negative affectivity , and five items referring to resilience . To allow for the comparability of different dimensions, we have averaged the score of specific dimensions and total score. The scale can be scored both on the negative as on the positive end of the continuum  were measured on a 4-point scale .Items referring to incidences of compromised safety and medical errors in the first month of COVID-19 epidemic  on statements referring to perceived work safety  based on a five-point Likert scale .—would never doze, 1—slight chance of dozing, 2—moderate chance of dozing, 3—high chance of dozing). Final scores are summed, and higher score indicates greater sleepiness, with score above 10 indicating excessive daytime sleepiness . The majority of physicians included in the sample was employed full-time , and 7.45% (80) of the subjects reported working part-time or being in a different contractual relationship (missing = 115). The sample predominantly consisted of female participants  and a smaller proportion of male participants , which is in line with the demographics of Slovenian physicians, as the SD = 11.56), with the youngest participant being 25 years of age and the oldest 84 years of age. As shown in Our study included a representative sample of physicians working in all 12 geographical regions of Slovenia. The number of physicians that participated in the study was the highest for the two regions with the largest population size . Surveys, 1,019, were completed; nevertheless, after the initial analysis, four participants were excluded from the analysis, as they have not met the criteria of being employed either full-time or part-time at the time of the study , p = 0.02, SRMR = 0.05. The total score showed good overall reliability  and adequate reliability of all three subdimensions referring to the parameters of sleep quantity , quality , and latency . Moderate positive correlations between all three dimensions of sleep indicate good multivariate outcome . Further on, we investigated the fit of the model for psychological functioning at work. Exploratory factor analysis indicated potentially three-dimensional factor structure, with high eigenvalue on first factor loading indicating potentially hierarchical factor structure. The model showed adequate fit for a hierarchical structure, and to improve the model fit, six indicators on latent dimensions were allowed to co-vary. Maximum likelihood χ2 = 619.02, df = 108, p < 0.001, χ2/df = 5.73, CFI = 0.95, TLI = 0.93, RMSEA = 0.06, 90% CI , p = 0.001, SRMR = 0.04. Reliability analysis of the questionnaire showed excellent reliability overall  and in the specific dimensions of negative affectivity , negative self-regulatory processes , and resilience .Confirmatory factor analysis showed an adequate fit of the proposed hierarchical model for sleep scale with Robust Maximum Likelihood statistics χr = −0.25, p < 0.001), as well as dimensions on sleep quantity , sleep quality , but with a very small, although significant, correlation with latency , indicating the validity of the measurement. Small to moderate significant positive association was found between all dimensions of sleep and the average score of psychological functioning of physicians at work . Negative moderate relationship was found between sleep and self-regulatory failures  as well as negative affectivity , while resilience has shown to be positively related to sleep . Psychological functioning of physicians at work was negatively associated to physicians’ total score on sleepiness . A lower score on sleep parameters and a higher score on daytime sleepiness was positively related to the incidence of physicians’ individual compromised safety at work ; similarly, a significant negative relationship was found between psychological functioning at work and incidences of compromised safety  as well as incidences of medical errors reported . The dimension of self-regulatory failures, specifically, was positively related to more compromised safety reported , with a significant positive moderate correlation between self-regulatory failures and medical errors committed due to exhaustion  and a small significant correlation to life-threatening medical errors . A significant negative relationship was found between resilience and compromised safety  and medical errors . A significant positive relationship was found between negative affectivity and compromised safety, which was higher for individual compromised safety , as well as for medical errors due to exhaustion . Furthermore, perceived work safety at the time of the COVID-19 epidemic was significantly related to lower psychological functioning at work , lower compromised safety , and lower number of life-threatening medical errors   .p < 0.001, R2 = 0.18, p < 0.001). When the total score on sleepiness was added, the model showed a small significant improvement (ΔR2 = 0.02). Physicians that experienced more daytime sleepiness showed a significant decrease in their psychological functioning at work , while positive perception of work safety at the time of the COVID-19 epidemic increased physicians’ psychological functioning at work  and provided improvement to the model .As can be seen in 2 = 1,142.06, df = 386, p = 0.000, χ2/df = 2.95, CFI = 0.93, TLI = 0.92, RMSEA = 0.04, p = 1, 90% CI , SRMR = 0.06, showed adequate fit to the hypothesized structure. Structural equation modeling showed that latent dimension of sleep significantly predicted a decrease in negative psychological functioning at work . However, contrary to the expectations, there were no significant direct effects of sleep on the incidences of compromised safety  and medical errors . Negative psychological functioning at work, on the other hand, increased the incidences of medical errors  and compromised safety . Sleep had indirectly, by decreasing negative psychological functioning at work, decreased incidences of medical errors  and compromised safety ]. Significant covariances were found between medical errors and compromised safety . This shows, partial support for the hypothesized model, with better sleep directly decreasing negative psychological functioning at work, and by doing so indirectly decreasing the incidences of compromised safety and medical errors , SRMR = 0.06, showing adequate fit to the data. Perceived work safety at the time of the Covid-19 epidemic has shown significant improvement in sleep , and reduction in negative psychological functioning at work  and incidences of compromised safety . Sleep predicted significantly less negative psychological functioning at work , while negative psychological functioning at work caused a significant increase in medical errors  and compromised safety . Significant co-variances were found between compromised safety and medical errors . In the same way, as in the previous model, sleep had indirectly, by decreasing negative psychological functioning at work, increased the likelihood of medical errors  and compromised safety . Different to the expectations, perceived work safety has shown a small, however significant, indirect effect by decreasing negative psychological functioning on the incidences of medical errors . The model supports the hypothesized model, showing perceived work safety as having important direct influence on improving sleep, reducing negative psychological functioning at work, compromised safety, and medical errors  = 5.99, p = 0.645, explaining 9.2% of total variance (Nagelkerke R2 = 0.92). Based on Wald statistics, physicians that worked at COVID-19 entry point were 1.26 times more likely to wake up during the night (p < 0.05), 1.25 times more likely to experience nightmares (p < 0.05), and 0.77 more likely to sleep less than 5 h per night (p < 0.01). Physicians working at COVID-19 entry points had significantly lower levels of psychological functioning at work (p < 0.001)  .To our knowledge, no prior studies have investigated how physicians’ sleep and perceived work safety during the first month of the COVID-19 epidemic could have impacted physician psychological functioning at work and the role they had in ensuring patient and physician safety. Physicians working at a COVID-19 entry points were more likely to wake up during the night, have nightmares, and sleep less than 5 h per night. This supports previous findings on medical staff from Wuhan, China, which showed that medical staff working in isolation unit had 1.71 times higher probability of reporting insomnia symptoms . SimilarOur results show that the majority of physicians slept less than what is recommended by the American Academy for Sleep Medicine and Sleep Research Society . PhysiciPhysicians that slept well in the first month of the COVID-19 epidemic experienced less self-regulatory failures at work, had lower negative affectivity, and were able to remain resilient while working. This provides support for previous findings linking sleep to better cognitive and emotional self-regulation , decreasOur study included a large sample of physicians and carries some important implications in terms of work settings and crisis management. Even though the Sleep and Psychological Functioning at Work Scale requires modifications, further validation and small sensitivity improvements, its psychometric properties, and established construct validity imply good potential for future research and monitoring purposes. By using retrospective self-reports, we were able to reach a large sample of physicians across Slovenia, which would have been otherwise very difficult to obtain due to quarantine restrictions imposed by the government such, as restriction of movement between municipalities and social distancing . It provBased upon our findings, training could be designed that would help physicians, identify and change potential outcomes of cognitive failures, regulate emotions, and remain resilient in difficult situations. Further research is needed, to see how crisis management during the first month of COVID-19 epidemic, could have impacted physicians’ sleep and psychological functioning at work differently, as it would have had in normal circumstances. In the future, special care should be taken to see how medical guidelines can be updated to better protect safety and sleep of physicians.Working at Covid-19 entry points increased the likelihood of sleep awakening during the night, nightmares, occurrences of sleep lower than 5 h, and lower psychological functioning at work. However, this can be problematic, as sleep and safety both play an important role in reducing negative psychological functioning at work and, by doing so, decreasing the likelihood that physicians will enact negative and potentially fatal incidents during the pandemic, such as compromised safety and medical errors. Further studies should be taken to see how medical guidelines can be adapted, to ensure physicians receive enough sleep and that their safety is protected.All datasets generated for this study are included in the article/The study was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments. The study was approved by the Executive committee of the Medical Chamber of Slovenia.All authors developed the study concept, contributed to the study design, data collection, and data analysis, interpreted the data, drafted the manuscript, and approved the final version for submission.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.


Three-dimensional (3D) mini plate systems are used in the treatment of mandibular fractures. The system is advantageous in comparison to conventional plates due to the stabilization of tension and compression areas, improved initial stability, and biomechanical behavior. The aim of this retrospective study was to evaluate the use of a 3D miniplate system for the treatment of patients with mandibular fractures. Patients with mandibular fractures treated with a 3D plate system at the Department of Oral and Maxillofacial Surgery, University Hospital Münster, during a period of 5 years, were included in this study. Mandibular fracture conditions and minor and major post-operative complications were reported. In total, 336 patients and 391 mandibular fractures were assessed. The most common fracture site was anterior mandible, and 155 cases involved a tooth-bearing area. Minor complications were seen in 8.03% of cases, whereas only 1.49% of patients suffered from major complications. The treatment of mandible fractures using 3D miniplates resulted in fracture reduction with a low complication rate. In the management of mandible fractures, it is essential to restore occlusion, temporomandibular function, and facial esthetics ,2. TreatTo ensure successful osteosynthesis with minimal invasive approach, three-dimensional (3D) miniplate systems can be used ,9,10,11.Simultaneous stabilization of tension and compression areas, improved initial stability, and biomechanical behavior are the main advantages of the 3D miniplate system in comparison to conventional plates ,11. In aPatients who had attended the Department of Oral and Maxillofacial Surgery at the University Hospital Münster over a period of five years were included in this study. Inclusion criteria were the presence of mandibular fractures treated with a 3D miniplate system . The system is adapted for craniofacial fractures and ensures the semi-rigid fixation of fractured bone. Exclusion criteria consisted of the use of alternative techniques, condylar fracture, or minimal fractures treated with conservative approaches.Patient data , surgical protocol, and radiographic exams were recorded. Fracture assessment was performed with panoramic radiograph, occlusal, and Clementschitsch view projections.Based on pre-operative panoramic radiographs, the localization of jaw fractures was classified as follows: (1) right and left mandibular angles, (2) right and left mandible body, (3) anterior mandible. The degree of displacement was classified as either major or minor. The presence of teeth at the fracture line, dental trauma, and additional soft-tissue injuries, as well as cranial, thoracic, and abdominal traumas were also assessed. In addition, the operation time was recorded.Surgical protocol was followed as briefly described: In order to access bone, an intra-oral vestibular incision was made and the mucoperiosteal flap was raised. After reducing bone fragments into their anatomical position, intermediate intermaxillary fixation (IMF) was performed using wire ligature or IMF screws to ensure adequate occlusion. Fracture osteosynthesis of the fracture was performed using the 3D locking miniplate system . Plates were adapted to the bone anatomy and fixed to the cortical bone using monocortical 2.0 mm screws . After ITreatment protocol, presence of multiple fractures, and the need for additional plate systems were assessed. Additionally, gaps between fractured segments and the presence of minor and major post-operative complications were recorded. Post-operative pain was assessed using the Visual Analogue Scale (VAS). Categories of pain were defined as follows: 1–3 = mild pain, 4–6 = moderate pain, and 7–10 = severe pain.Over five years, 582 cases of mandible fractures were surgically treated. Of these, 336 patients received a 3D miniplate . and were included in this study. Fifty-five patients showed a second fracture, totalizing 391 treated mandibular fractures.Participants consisted of male (73.5%) and female (26.5%) patients. At the time of the surgical osteosynthesis, most patients (46.72%) were between 21–40 years old. Among 70 patients that presented a comorbidity , 31.9% presented cardiovascular disease and a total of 22 patients required medication .The main fracture characteristics are reported in In addition, 107 patients received intermaxillary fixation to treat condylar fractures, and seven patients were treated with a head-chin bandage. Postoperative antibiotic therapy was prescribed for 320 patients (95.2%). In 87.79% of cases, there was a minor displacement of bone fragments, and the gap between fractured sites was less than 1 mm. Furthermore, in 89.3% of cases, no displacement was seen in the panoramic radiography.Post-operative minor complications were observed in 8.03% of the patients, which were treated with antibiotic therapy and local procedures. Only 1.48% of the patients presented major complications . No platEighty patients experienced no pain (23.8%), whereas 150 suffered only mild pain. Moderate and severe pain were reported by 96 (28.6%) and eight patients (2.4%), respectively.The present study shows a retrospective assessment of mandibular fractures treated with 3D miniplates. According to our results, post-operative complications occurred in 8.03% of cases, most of which were treated by antibiotic therapy and local management. This finding is consistent with previous studies evaluating 3D miniplates, in which the percentage of complications reached 6%.Sensibility disturbance was reported by a high number of patients. This may be related to the nerve injury during bone manipulation and plating, since only few of them reported sensibility disturbance after plate removal. Moreover, wound dehiscence, which tends to occur when the plate is placed close to the incision ,14, was Currently, the treatment of mandibular fractures is founded on two principles. The first one claims that the plate must provide sufficient rigidity to avoid displacement between fragments during functional movements. This is achieved by a rigid fixation using solid plates ,16. ConvThree-dimensional miniplates were introduced as a modification of Champy´s method, on which two plates are connected by interconnecting crossbars, and separated by a distance of 4–5 mm from each other. Due to their malleable format, they can be anatomically adapted without distortion. Thus, tensile and compressive forces are simultaneously neutralized, providing bone alignment and undisturbed healing. In addition, due to their shape and low profile, these plates allow reduced palpability and contouring in the fractured jaw area, decreasing the risk of paresthesia .A recent meta-analysis showed that 3D and conventional miniplates present a similar complication rate . In regaAnother advantage of miniplates is the easy handling, which contributes to the shortening of intra-operative time. The present study shows an acceptable mean operation time, which ranges from 12 to 630 min, according to the clinical condition and complexity of the case. Moreover, the treatment of anterior mandibular fracture using 3D miniplates reduced operative time . This miIn this study, most of the fractures treated with a 3D miniplate system showed a gap of less than 1 mm and no displacement between bone fragments. These factors play an important role in the final outcome, since one of the main purposes of the mandibular fracture treatment is to provide fixation and stabilization of the fractured bone . The optA previous systematic review showed a success rate of 88.9% for treatment of mandibular fractures with 3D miniplates. This result relies on the area of the fracture zone and fractured bone displacement. Regarding mandibular angle fractures, lower success rates have been reported . In thisIn regard to the patients’ data, our study provides further evidence for the higher prevalence of male patients as a result of brutality acts or accidents. In 155 cases, the fracture occurred in the tooth-bearing area, although only five required tooth removal. Further extractions involved dental trauma indications. According to the literature, indications for tooth extraction are related to the teeth’s condition, and the impossibility of reducing and fixating the fracture. Whereas fractured teeth, periodontal diseases, or caries are conditions that may require tooth extraction, the complication rate does not increase if a healthy tooth is maintained .Several treatment- and patient-related aspects can lead to complications, such as patient medical conditions, surgical managements, and patient compliance. These factors should be considered individually to provide a true relation between post-operative complications and the plate system. A limitation of the study is the bias related to the study design, since the choice to evaluate a 3D miniplate system for surgical treatment of mandibular fractures introduces selection bias. Furthermore, measurement of displacement is restricted to bidimensional images. For further studies, the authors recommend a 3D assessment of plating to obtain accurate results. Randomized trials comparing different plate systems and taking into consideration the case complexity should be performed to indicate the appropriate plate system according to individual situations.Within the limitations of this study, the treatment of mandible fractures using 3D miniplates resulted in fracture reduction with a low complication rate and an adequate surgical procedure time.


Health behavior was conducive to control the coronavirus disease (COVID-19) epidemic. This study aimed to determine the differences in health behaviors and related factors among rural and urban residents in China.From February 14 to 22, 2020, during the peak of the COVID-19 epidemic in China, a total of 2449 participants (1783 (72.81%) urban residents and 666 (27.19%) rural residents) were recruited by snowball sampling on WeChat and QQ social platforms, both owned by Tencent. Data were collected through the Web-questionnaire guided by an information–motivation–behavioral skills model. The multiple-group structural equation model was applied to analyze the factors.P = 0.042; total score was 40). Motivational, behavioral skills, and stress had direct positive and negative influences on health behaviors of urban and rural residents. Information and positive perception of interventions had direct effects on health behaviors in rural residents, but not in urban residents. All the factors were mediated by behavioral skills in rural and urban residents.Rural residents had lower health behavior scores than urban residents, even after adjusting demographic characteristics (33.86 vs 34.29, This study suggests that the government should pay attention to substantial rural and urban disparities and implement different COVID-19 prevention and intervention policies for health behaviors targeting rural and urban residents. The World Health Organization has raised the risk assessment of this disease as very high. As of May 13, 2020, 4 170 424 confirmed cases and 287 399 deaths were reported worldwide.In addition to policies that were implemented by the Chinese Government and other relevant departments, residents’ health behaviors, such as following management, taking corrective measures to wear masks, reducing outings, and maintaining a positive mentality, were also crucial for reducing the risk of infection and controlling the epidemic.3 Therefore, it can be expected that the health behaviors and their influencing factors may vary between urban and rural residents. It also is a very important consideration in determining comprehensive intervention strategies applicable to rural and urban areas.Even though the urban–rural gap in China is gradually decreasing, in comparison with urban areas, families who live in rural regions have lower levels of education, socioeconomic status, and medical resources.Therefore, based on the extended information–motivation–behavioral (IMB) skills model that included information, motivation, behavioral skills, perceived stress, positive perception of interventions and health behaviors and can be easily converted into intervention practice, this study accessed urban–rural disparities on the influencing factors of health behaviors during the COVID-19 outbreak in China, so as to give insight for targeted intervention measures and policies for other countries and regions.This cross-sectional online survey was conducted from February 14 to 22, 2020, the peak of the COVID-19 epidemic in China. Participants were recruited by snowball sampling on Tencent’s WeChat and QQ social platforms, using the online survey tool of questionnaire star to make structured questionnaires guided by the IMB model, and collecting data through the Web-questionnaire method in China. Each participant can become a seed and expand the sample by sharing the questionnaire to his or her social network. Participants had to read the informed consent and agree to participate before filling out the formal questionnaire. Inclusion criteria were (1) age ≥ 18 years old; (2) ability to use smart electronic devices ; and (3) agreeing to participate in the study. Exclusion criteria were (1) suffering from psychological diseases such as anxiety and depression and (2) response time of less than 1 minute or more than 30 minutes.In order to reduce bias, quality control had been carried out: (1) Each item in the questionnaire was set as a required question to ensure the integrity of the data; (2) each IP could be submitted only once to avoid repeated filling; and (3) real-time monitoring in the background and response time of participants were recorded.1. The higher the score in each construct, the higher the information, motivation, behavioral skills, positive perception of the government, the perceived stress, and the frequency of health behaviors during the COVID-19 epidemic. Especially, the correct answer of information would appear after submitting the questionnaires. Positive perception of interventions refers to residents’ perceptual evaluation of the government’s epidemic prevention and control measures, and the contents were the understanding, support, and evaluation of the interventions. The Chinese version of the Perceived Stress Scale was used in this study, with a total of 14 items, and the total scores were higher than 25, representing health risk stress.5The description of the questionnaire is shown in the Supplementary Table P-value < 0.05 was considered significant.Normal distribution variables were reported by mean and standard error (SE). The generalized linear regression model was used to test the differences between the urban and rural residents after adjusting for age, gender, education, marital status, personal monthly income, and occupation. Categorical variables were reported as numbers (n) and percent (%), and the chi-squared test was used to test the difference between the 2 groups. The confirmatory factor analysis (CFA) was used to test the relationship between latent variables and observable variables of the measurement model. Multiple-group structural equation modeling (MSEM) was used to test whether the relationship among constructs in the extended model was invariant between rural residents and urban residents in Amos 24.0. Statistical analysis was performed using SAS 9.4 . A P < 0.05; see P < 0.05; see P < 0.05; see P > 0.05; see P < 0.05; see This survey included 2449 valid participants  after excluding 104 participants. 1). Model fit indices results, χ2/df ratio = 1865.966/642 = 2.907, goodness-of-fit index (GFI) = 0.940, CFI = 0.937, IFI = 0.931, RMSEA = 0.029, indicated that the final model had a good fit with the data for both groups (P < 0.05).All measurement model had a good fit with incremental fit index (IFI) > 0.9, confirmatory fit index (CFI) > 0.9, and root mean square error of approximation (RMSEA) < 0.08 (Supplementary Table h groups . All patP < 0.05). Health risk stress had negative, indirect effects on health behaviors through information and behavioral skills, and positive perception of interventions had positive, indirect effects through motivation, behavioral skills, and health risk stress in all residents .P < 0.05), but significantly smaller path coefficients in “Behavioral Skills → Health Behaviors” . The total effect coefficients of information, motivation, behavioral skills, health risk stress, and positive perception of interventions on health behaviors were 0.14, 0.25, 0.53, -0.22, and 0.45 in urban residents, respectively, and these coefficients were 0.17, 0.31, 0.30, -0.19, and 0.47, respectively, in rural residents. Finally, the extended IMB model accounted for 46% of health behaviors for urban residents and 41% for rural residents . This study reveals that rural residents had lower health behavior scores than urban residents, even after adjusting demographic characteristics. There are differences in the factors affecting the health behaviors of urban and rural residents. First, information has direct effects on rural health behaviors, which means information is good for prevention, but not among urban residents. Information or knowledge about disease transmission and self-protection behavior is identified as one of the determinants of behavioral changes in most behavioral intervention models. However, this study indicated that residents had limited knowledge about COVID-19, especially residents in rural areas. The false knowledge may lead to ineffective preventive measures taken by residents and increase the risk of infection.6 and long-term prevention behaviors also depend on behavioral skills.7 Third, positive perception of interventions has a direct impact on health behavior in rural residents, but not in urban residents. This shows that, although urban and rural positive perceptions of intervention scores were similar, their effects on health behaviors were different.Second, the path coefficient of behavioral skills to health behaviors among urban residents was higher than that among rural residents (0.53 vs 0.31). This seems to imply that behavioral skills affect urban residents more deeply than rural residents. Behavioral skills are indispensable for improving health behaviors,8 Furthermore, positive perception of interventions had negative effects on health risk stress. This revealed that the prevention and control measures adopted by the Chinese Government and relevant organizations can reduce the fear and anxiety of residents and enhance health behaviors.Health risk stress had negative effects on health behaviors in urban and rural residents. Excessive stress may lead to negative coping styles, and only those who maintain a high level of awareness of danger and maintain a moderate level of stress are most likely to adopt appropriate health behaviors.This study had limitations: (1) The randomness of the samples was poor. We used a large sample to ensure that there was a certain number of individuals in all categories, to minimize bias; (2) results extrapolation was limited, to some extent. It mainly represented the regions of Chongqing and Sichuan or regions with similar epidemic severity. In view of the international nature of COVID-19 and its implications, future studies should include a broader sample.In general, information, motivation, behavioral skills, health risk stress, and positive perception of interventions were good explanatory variables of health behaviors, but their paths and coefficients on health behaviors were not consistent between rural and urban residents. This study provides possible evidence to support the need to implement different COVID-19 prevention and intervention policies for health behaviors targeting rural and urban residents.


Our results also revealed that emotional exhaustion is the only burnout dimension capable of explaining the variance of health while self-efficacy does regarding psychological capital. Conclusion: We conclude a significant reduction in self-perceived health and psychological capital during COVID-19 mandatory confinement, and that burnout acts as a predictor variable in both health and psychological capital variance.Background: Drawing on the impact of the COVID-19 global pandemic and its sanitary measures on coping strategies for preserving health, it is also necessary to add exposure to certain work stressors, such as burnout. The aim of the study was to assess the influence of the confinement situation caused by COVID-19 on the levels of self-perceived health and psychological capital in a sample of workers, as well as to analyze whether exposure to burnout before social isolation would help to explain the levels of health and psychological capital. Methods: Data were collected in a longitudinal design. Time 1 surveys (December 2019) were sent to a sample of 354 Spanish workers while in Time 2 (April 2020) the employees completed 235 questionnaires. Results: Our findings indicate a significant worsening of employees’ health perception (t = −4.13;  The 12 December 2019 marked, in the Chinese city of Wuhan, the appearance of a new human coronavirus with acute respiratory syndrome. Provisionally called 2019-nCoV or SARS-Cov2, it is the origin of a global pandemic, declared by the World Health Organization (WHO) on 11 March 2020. According to the latest data from the WHO . HencePsychological capital is one of the resources that could be framed in Conservation of Resources Theory ,11. It hEven though psychological capital could help in high-stress situations, some authors have emphasized that the continued use of individual resources (tangible and intangible) to achieve vital objectives and face stressful situations, could result in resource deterioration . When soDrawing on the impact of the COVID-19 global pandemic and its sanitary measures’ impact on health ,4,5 and Current literature supports the idea that burnout is a chronic work stressor, consisting of three symptoms: emotional exhaustion, cynicism, and low professional efficacy. Burnout syndrome is not an automatic process originated exclusively by work stressors, but the result of an interaction between personal characteristics and organizational features .Many studies have reported a positive association between burnout syndrome and worsening of workers’ health , alcoholFor explaining the association between burnout syndrome, self-perceived health, and psychological capital during COVID-19 social isolation, we apply the loss cycle put forward in Hobfoll’s Conservation of Resources Theory . In lineThe loss cycle hypothesis could be aligned with the idea that workers under high levels of stress perceive and create more work demands over time ,36. AppaAccording to the arguments exposed above, we hypothesize that:Hypothesis 1.The confinement situation caused by the spread of the COVID-19 virus will hurt the perception of health.Hypothesis 2.The confinement situation due to the spread of the COVID-19 virus will harm psychological capital levels.Hypothesis 3.Previous COVID-19 confinement burnout workers’ level will be able to predict their psychological capital (a) and self-perceived health (b) during COVID-19 social isolation measures.A longitudinal non probabilistic design was followed. Data were collected in two-time points. Burnout, psychological capital, and health were assessed at Time 1 (December 2019), whereas psychological capital and health were also assessed four months later at Time 2 (April 2020), during the social isolation confinement caused by COVID-19 in Spain. The study was carried out under the recommendations of the ethics committee of Universidad de Murcia. All subjects gave written informed consent following the Declaration of Helsinki. Participants received an email with a direct link to the questionnaire hosted on the Universidad de Murcia inquiry platform to ensure confidentiality and anonymity. The email also contained the research goal, the instructions for the correct completion of the questionnaire, and a reminder of voluntary participation in the study.Time 1 surveys were sent to a sample of 354 workers from different Spanish socioeconomic sectors. A total of 235 usable questionnaires were received, resulting in a response rate of 66.4%. About half of the respondent were men  with an average age of 36.62 years . In terms of education, 37.8% (N = 89) had university studies, 26.8% (N = 63) followed vocational training studies, 18.7% (N = 44) had primary studies, and 16.6% (N = 39) had completed high school. Regarding job position, 35.3% (N = 83) held positions as a qualified worker, 21.7% (N = 51) were technicians, 18.3% (N = 43) worked as an unskilled worker, 12.8% (30) were a middle manager, and 9.4% (22) executives. Most respondents were permanent employees . Lastly, the average professional experience was 9.37 years .Time 2 surveys were sent to a sample of 235 workers. A total of 198 usable questionnaires were received, resulting in a response rate of 84.3%. About half of the respondents were women  with an average age of 39.73 years . In terms of education, 48.6% (N = 95) had university studies, 22.8% (N = 46) followed vocational training studies, 18.6% (N = 37) had completed high school, and 10% (N = 20) had primary studies. Regarding job position, 36.8% (N = 73) held positions as a qualified worker, 23.5% (N = 47) were technicians, 11.8% (N = 23) worked as an unskilled worker, 16.2% (32) were a middle manager, and 11.8% (23) executives. Most respondents were permanent employees . Lastly, the average professional experience was 11.74 years .p < 0.001) for the exhaustion subscale, r = 0.34 (p < 0.001) for the cynicism subscale, and r = 0.37 (p < 0.001) for the efficacy subscale.We assessed Burnout by the Maslach Burnout Inventory-General Survey (MBI-GS), developed by Maslach, Jackson, Leiter and Schaufeli  in the Sp < 0.001).The OREA questionnaire developed by Meseguer-de Pedro, Soler, Fernández-Valera, and García-Izquierdo  was usedp < 0.001).As an indicator of the perception of psychological health, the GHQ-12 questionnaire by Goldberg and Williams  was usedt-test was used. Finally, to analyze the longitudinal relationships, different multiple-step hierarchical regression analyses were carried out.The statistical analyses were performed using the IBM SPSS Statistics Versión 24.0 computer program. Bearing in mind the longitudinal design of the study, we proceeded as follows: first, internal consistency and reliability analyses (test–retest) were performed, followed by descriptive and bivariate correlations. Subsequently, mean comparisons were made between the two measurement moments to check if there were changes in the socioeconomic and demographic variables and to test the temporal persistence of the main study variables. Finally, for testing means differences, Student’s We first inspected the descriptive statistics. p < 0.01) and in psychological capital  between Time 1 and Time 2, which resulted in a confirmation of self-perceived health and psychological capital deterioration during home confinement. In a more detailed analysis, the items that contribute the most to a worsening of self-perceived health are: item 2 “has felt overwhelmed and stressed?” , item 10 “Have you been able to enjoy your daily activities?” , and item 12 “do you feel reasonably happy?” . Similarly, in psychological capital, significant differences were found in the four psychological capital dimensions: optimism , resilience , hope , and self-efficacy .Secondly, we tested the existence of significant differences between self-perceived health and psychological capital in Time 1 and Time 2. For fulfilling this purpose, we applied the T Student proof. We found significant differences both in self-perceived health . We decided to introduce as input variables the three burnout dimensions  and age as a control variable, following the recommendations of previous health  and psychological capital research .The results show that age and emotional exhaustion explain 27% of self-perceived health total variance in Time 2 see . While, The uncommon scenario caused by COVID-19 has meant a great change in the way of life of the population. It is not surprising the negative impact that such a situation can have on mental health in the short and long term. The present study examined the influence of the confinement situation caused by COVID-19 on the levels of self-perceived health and psychological capital in a sample of workers, as well as to analyze whether exposure to burnout before social isolation would help to explain the levels of health and psychological capital behind it.Interestingly, the findings of this study provide support for the three proposed hypotheses: the first one stated that the confinement situation caused by the spread of the COVID-19 virus would have a negative influence on the perception of health; the second argued that the confinement situation caused by the spread of the COVID-19 virus would have a negative influence on psychological capital; finally, the third consisted of analyzing whether workers exposed to burnout before the confinement caused by COVID-19, would be more likely to enter a cycle of losses that would lead to a loss of their levels of self-perceived health and psychological capital.Regarding the first hypothesis, our findings indicate a significant worsening of employees’ health perception during mandatory confinement in Spain. These results strengthen the research carried out about the psychological impact of extreme emergencies on health , as wellRespecting the second hypothesis, our results have also revealed a significant reduction in employees’ psychological capital levels during mandatory confinement. One possible explanation could be the idea of resource depletion framed in Hobfoll’s Conservation of Resources Theory . AccordiConcerning the third hypothesis, our findings revealed, on the one hand, how age becomes a total variance predictor of both perceived health and psychological capital levels. What this seems to indicate is certain age-related changes affecting personal resources reserves would help to explain variations in physical health and psychological well-being . To illuOn the other hand, regarding burnout dimensions when explaining the variance of health and psychological capital levels, there is a significant and negative association between employees’ burnout in Time 1 with health and psychological capital in Time 2. These results corroborate previous research that has repeatedly shown the adverse burnout consequences on worker’s health ,25,26, aGiven the previous explanation, when analyzing our results in detail, it could be observed, first, that emotional exhaustion is the only burnout dimension capable of explaining the variance of health. In this regard, there is a consensus when it comes to affirming that emotional exhaustion is the central core of burnout, and as such the variable that would have the most influence on people’s health levels . TraditiFirstly, regarding the theoretical implications, the results of this study help to reinforce the application of the Conservation of Resources Theory for studying employee’s burnout and its consequent coping strategies. Secondly, two possible practical approaches emerge from this study: on the one hand, taking into account the substantial change in working conditions caused by COVID-19 and its influence on workers’ health, a jobs psychosocial risks reevaluation is needed both in face-to-face and teleworking modality. On the other hand, from the point of view of human resources management, it is necessary to build up employees’ personal psychological resources through training interventions, as well as to provide them with additional resources, such as social support from colleagues and supervisors.Several limitations of the present study should be acknowledged. First, the information was obtained through self-report questionnaires, which can produce response biases, exacerbating the common variance, and artificially increasing the correlations between variables .Second, the presence of social desirability in the responses to the questionnaire could be another limitation. To try to detect the effects of this phenomenon on the results, it would be beneficial to include additional measurement scales that estimate its presence in subsequent studies . An examFurther research is needed to focus on the prevalence of the disease in different settings. For example, future studies could examine if our results could differ according to the essential and nonessential workers distinction, between different labor market strata or even between labor layers.Overall, the results of this study have shown a significant reduction in self-perceived health and psychological capital between the two periods analyzed (before and during the COVID-19 mandatory confinement). Specifically, burnout together with age act as predictor variables in both health and psychological capital variance between the two times included in this study. However, not all dimensions of burnout contribute to the same extent. Thus, regarding health effects, emotional exhaustion explains 27% of the total variance, while, for psychological capital, the dimension that contributes the most is job self-efficacy, explaining 24% of its variance.


AKR1C genes which function as ketosteroid reductases in steroid hormone biosynthesis, including androgens and estrogens. Mutations in AKR1C genes are associated with human DSDs. Deletion boundaries, sequence properties and gene content were studied by PCR and whole genome sequencing of select deletion homozygotes and control animals. Deletion analysis by PCR in 940 horses, including 622 with DSDs and reproductive problems and 318 phenotypically normal controls, detected 67 deletion homozygotes of which 79% were developmentally or reproductively abnormal. Altogether, 8–9% of all abnormal horses were homozygous for the deletion, with the highest incidence (9.4%) among cryptorchids. The deletion was found in ~4% of our phenotypically normal cohort, ~1% of global warmblood horses and ponies, and ~7% of draught breeds of general horse population as retrieved from published data. Based on the abnormal phenotype of the carriers, the functionally relevant gene content, and the low incidence in general population, we consider the deletion in chromosome 29 as a risk factor for equine DSDs and reproductive disorders.Disorders of sex development (DSD) and reproduction are not uncommon among horses, though knowledge about their molecular causes is sparse. Here we characterized a ~200 kb homozygous deletion in chromosome 29 at 29.7–29.9 Mb. The region contains  Mammalian disorders of sex development (DSDs) encompass a broad range of complex congenital conditions that affect sex determination, sexual differentiation, and the development and function of gonads ,3,4,5,6.Sex development is a complex multi-step process controlled by many genes acting in networks ,5,11, whMultiple forms of XX and XY DSDs have also been described in horses ,13,14,15SRY-negative forms are associated with various Y chromosome deletions , th, thAKR1Crthologs . Nevertht viable ,49. AKR1C genes are necessary for normal sex development and reproduction and their mutations have consequences. Furthermore, in the CNV map of the human genome, the AKR1C genes are not among the ~100 “expendable” CNV genes which can be homozygously deleted with no deleterious effect [AKR1C family members is ambiguous , the cluster of AKR1C paralogs is located at chr29: 29.7–30.3 Mb, thus some members of the gene family may escape the deletion and compensate the loss of others. It is also possible that the size of the deletion differs between individual horses, but was not captured by PCR analysis of a short target region. However, perhaps the most plausible explanation for why not all animals with the deletion showed abnormal phenotypes, as well as why those with the deletion had a broad spectrum of abnormal phenotypes, stays in the very nature of the genetic regulation of steroid metabolism. It is well documented that among all CNV genes in humans and animals, the most abundant are G-protein coupled receptors, and immunity and steroid metabolism genes [The human and mouse data strongly suggest that s effect . This iss effect , and annmbiguous . The regch other . These fsm genes ,50,52,53sm genes . We therFurther, in the large cohort of 622 developmentally and reproductively abnormal horses, only 8%-9% carried the homozygous deletion and phenotypes of the carriers were diverse. Phenotypically, the most uniform group were cryptorchids of which 9.4% were homozygous for the deletion , though Nevertheless, based on the size and gene content of the deletion, the abnormal phenotype of the majority (79%) of deletion homozygotes, and the low frequency (~5%) of the homozygous deletion in general equine population, we consider this deletion as a possible causative, but definitely a risk factor, for some forms of equine DSDs, cryptorchidism, and reproductive disorders.AKR1C genes, which have been associated with DSDs in humans; ii) the frequency of the deletion was higher in abnormal horses (8–9%) compared to normal population (1–5%), and iii) the majority (79%) of horses with the homozygous deletion were phenotypically abnormal. Even though denoted as a risk factor because of difficulties to establish statistically sound causative genotype–phenotype relationship, the findings add to the currently very short list of genomic regions underlying equine disorders of sex development and reproduction  project (reviewed by [We characterized a homozygous ~200 kb deletion in ECA29 as a risk factor for equine DSDs and reproductive disorders. These conclusions were based on the following notions: i) the deletion eliminates functionally relevant iewed by ). A simpSRY gene . At the iewed by ) to iden


APOE, TREM2, and CD33) in tau pathology, and we discuss the role of extracellular soluble tau in neuroinflammation.Microglia are the cells that comprise the innate immune system in the brain. First described more than a century ago, these cells were initially assigned a secondary role in the central nervous system (CNS) with respect to the protagonists, neurons. However, the latest advances have revealed the complexity and importance of microglia in neurodegenerative conditions such as Alzheimer’s disease (AD), the most common form of dementia associated with aging. This pathology is characterized by the accumulation of amyloid-β peptide (Aβ), which forms senile plaques in the neocortex, as well as by the aggregation of hyperphosphorylated tau protein, a process that leads to the development of neurofibrillary tangles (NFTs). Over the past few years, efforts have been focused on studying the interaction between Aβ and microglia, together with the ability of the latter to decrease the levels of this peptide. Given that most clinical trials following this strategy have failed, current endeavors focus on deciphering the molecular mechanisms that trigger the tau-induced inflammatory response of microglia. In this review, we summarize the most recent studies on the physiological and pathological functions of tau protein and microglia. In addition, we analyze the impact of microglial AD-risk genes ( Alzheimer’s disease (AD) is recognized as the most common form of dementia associated with aging . It is tDescribed by Alois Alzheimer in 1906 ,5, AD isAlthough genetic evidence supports the amyloid hypothesis, Aβ accumulation is believed to be a necessary, but not sufficient, condition for AD progression. In this regard, several studies have established a greater relationship between NFTs and AD ,16,17,18MAPT on chromosome 17q21 [MAPT [Tau protein regulates the assembly and stabilization of microtubules . It is eme 17q21 . The adume 17q21 . Specifi21 [MAPT , the inh21 [MAPT , and the21 [MAPT  and RNA 21 [MAPT  are someThe subcellular localization of tau varies throughout development. In immature neurons, this protein is distributed in the soma and neurites. Later, when axons are generated and neurons acquire polarity, tau is found mostly in the axonal region . FurtherThe structure of tau is divided into the projection domain, which holds the N-terminal domains and is thought to regulate the space and crosslinking between microtubules ,43, and Tau protein is subject to numerous post-translational modifications: phosphorylation, glycosylation, glycation, isomerization, nitration, ubiquitination, SUMOylation, acetylation, and methylation . Of thesA large number of kinases have the capacity to phosphorylate tau . GlycogeTau aggregation is characteristic of several neurodegenerative diseases called tauopathies, including AD . These dThe different forms of tau presented below have been classified on the basis of their aggregation state . Tau monIn 1975, Weingarten et al. proposed that tau regulates microtubule assembly and stabilization . This fu−/−Mapt mouse has been widely used to study the aforementioned functions of tau. This model does not present a severe phenotype throughout its development thanks to compensation by other microtubule-stabilizing proteins [The proteins ,92. Duriproteins ,94. ThesSeveral in vitro  and in vExtracellular tau was once thought to originate from axonal degeneration and neuronal death ,102. HowOnce internalized, tau interacts with other tau molecules of the receptor neuron and induces their aberrant folding, thus propagating the pathology ,119. ProMore than a century ago, Iliá Méchnikov discovered that the introduction of rose thorns into starfish larvae caused the accumulation of mobile cells around these foreign bodies. This observation led him to conclude that these cells behaved as defense agents. On the basis of this discovery, he expounded the phagocytosis theory, and he tirelessly explored the role of this phenomenon in various diseases . Two decMicroglia are the resident macrophages of the CNS and the only cell type, along with endothelial cells, that do not have a neuroectodermal origin. The cells that give rise to microglia leave the yolk sac blood islands at E9.5 to colonize the neuroepithelium, just before the blood–brain barrier (BBB) is formed. Thereafter, this population proliferates and expands throughout the CNS ,139,140.Microglia make up 5–12% of CNS cells, and their distribution in the adult brain varies depending on the region, being more present in the hippocampus, basal ganglia, and substantia nigra compared to in the nervous tracts, cerebellum, and brain stem . MoreoveMicroglia contribute to the early stages of development by establishing the neural architecture of the CNS. To this end, microglia engulf neurons that have been over-generated . This phFurthermore, microglia shape neuronal circuits. In this regard, these cells can eliminate non-functional synapses, thus ensuring the establishment of efficient synaptic contacts . AdditioIn the adult brain, microglia show a basal motility characterized by continuous extension and retraction of their processes without movement of cell bodies. This motility allows microglia to quickly detect changes in their microenvironment and to rapidly phagocytose harmful substances ,163. To Alois Alzheimer was the first to recognize the involvement of glia in the disease that would bear his name . HoweverVirginia Lee’s group developed one of the most extensively used mouse models of tauopathy (P301S). They observed that treatment of this animal with an immunosuppressant inhibited microglial activation and attenuated tau pathology . Those aAging is the most important risk factor in AD . In thisε4 variant of APOE is the strongest genetic risk factor in AD [The hypothesis that activation of the innate immune system contributes to the pathogenesis of AD has been supported by genome-wide association studies, which have identified a set of genetic variants that are highly expressed in microglia. Among these, the or in AD ,189 and or in AD . In the or in AD ,28,191. or in AD ,193,194,or in AD .ε4 variant in the P301S mouse increases soluble tau levels, tau phosphorylation, microglial activation, and brain atrophy. However, the absence of ApoE is neuroprotective since it prevents neurodegeneration and inflammation [Although the interaction between ApoE and tau was described almost three decades ago , its conammation . Additioammation   is another molecule that interacts with ApoE ,203. KraThe R47H variant confers TREM2 loss-of-function and it is the second main genetic risk factor in AD in terms of the magnitude of its effects . ExpressTREM2 mutations [The contribution of TREM2 to tau pathology offers opposing results. One of the first reports showed that the absence of TREM2 increases tau hyperphosphorylation and aggregation , Extracellular signal-regulated kinase (ERK), p38, and GSK3β activation) and also induces microglial activation in the hTau mouse . Subsequutations . Nonetheutations .Some of the discrepancies found in these studies could be explained by the mouse model used, the differences between murine and human TREM2, and the stage of the disease. Regarding the latter, TREM2 appears to have a dual role throughout pathology, and its targeting might not be straightforward. In this regard, TREM2 function should be potentiated at early time points. However, its activity should be partially suppressed in advanced stages since complete abolishment could lead to Nasu–Hakola disease, which is characterized mainly by bone lesions  Figure .Additionally, soluble TREM2 (sTREM2) is one the of most reliable immune biomarkers in AD . Most sTCD33 is another AD risk gene [isk gene ,219,220 isk gene ,28. As aisk gene , CD33 reisk gene .CD33 expression is increased in AD, thereby causing a reduction in microglial activation and Aβ clearance. This reduction occurs due to the interaction of sialic acid residues of Aβ with CD33, leading to the inhibition of Aβ internalization. However, knockout of CD33 in the APP/PS1 mouse promoted Aβ uptake by microglia, thus reducing the amyloid plaque burden [e burden . This ree burden . Thus, CFurthermore, NFTs, along with other histopathological hallmarks that contain hyperphosphorylated tau, also present sialic acid residues ,226. In Of the cell–cell communicate strategies, the use of chemokines is one of the most highly regulated systems. Normally, a single cell type expresses the ligand for a receptor that is selectively found in another cell population, thereby conferring a high degree of specificity to the resulting signaling axis . This is−/−Cx3cr1 mouse, together with its crossing with other AD models, has greatly contributed to our understanding of the role of the CX3CL1–CX3CR1 axis in this pathology. Moreover, CX3CR1 deficiency decreases Aβ accumulation due to an increase in the phagocytic capacity of microglia [−/−Cx3cr1 microglia present a lower phagocytic and migratory capacity per se [−/−Cx3cr1 microglia of young animals are very similar to the wild type (WT) microglia of older animals [In addition to being essential in CNS development and connectivity , the CX3icroglia . Conversicroglia ,240. By icroglia . Subsequicroglia  . In this regard, previous reports showed that TNAP, whose expression and activity increases in AD, is capable of removing phosphorylated residues of tau present in the extracellular space. Afterward, tau acts as an agonist for muscarinic receptors, increasing the amount of Caack loop ,260,261.ack loop . HoweverAs we previously mentioned, tau also interacts with glia ,126,169.Therefore, these studies support the hypothesis that extracellular dephosphorylated tau has a toxic effect on surrounding cells such as microglia, whereas aggregated and/or hyperphosphorylated intracellular tau plays a key role in neuron functionality.+ T cells patrols the CNS [The aforementioned studies highlight that innate immune activation is a key factor in aging and AD progression. In this context, more research is needed to identify the role of other genetic risk factors, as well as the epigenetic changes that principally occur in microglia ,274,275. the CNS . These c the CNS . TherefoIn addition, the study of gut microbiota in neurodegenerative diseases has attracted the attention of the scientific community. Several reports indicate that microbiota govern the maturation and function of microglia  and, thuRegarding microglial malfunction during aging, it has been shown that microglial repopulation reverses synaptic alterations and improves cognitive function in aged mice . Further


To determine the incidence of keratoconus and to determine its possible association with common systemic diseases using a nationwide cohort.  This retrospective nationwide cohort study included 1,025,340 subjects from the Korean National Health Insurance Service-National Sample Cohort database from 2004 to 2013. Estimates for incidence rates of keratoconus were identified. After 1 : 5 matching using propensity scores, associations between keratoconus and certain systemic comorbidities were determined using multivariate logistic regression analysis. p < 0.001), asthma , atopic dermatitis , and diabetes mellitus (DM) .  The incidence during the same period was 15.1 cases per 100,000 person-years. Adjusted logistic regression analysis after propensity score matching revealed significant associations between keratoconus and allergic rhinitis (odds ratio (OR): 1.86; 95% confidence interval (CI): 1.63–2.13;  Estimates of the incidence of keratoconus may help in the planning of eye-care policies, and the results of this study determined the associations between allergic diseases and keratoconus. Conflicting results regarding the association between keratoconus and DM should be further evaluated. Keratoconus is a chronic, progressive, noninflammatory ectatic corneal condition that leads to decreased visual acuity because of increased myopia and irregular astigmatism. These conditions are known to affect patients 18–40 years of age. The severity of the disease varies from a subclinical stage to a severely progressive stage, resulting in corneal scarring, perforation, or even blindness . TreatmeThe previously reported annual incidence of keratoconus varied greatly from 1.3 to 32.3 cases per 100,000, according to the country where the study was conducted , 5.While the pathophysiology of keratoconus is currently not clearly known, a few previous studies investigated risk factors for keratoconus to clarify its pathophysiological mechanism . The repBased on these considerations, we evaluated the incidence of keratoconus and investigated associations between various systemic conditions and keratoconus using data from a nationwide sample of approximately 1 million residents from the National Health Insurance Service-National Sample Cohort 2002–2013 (NHIS-NSC 2002-2013).This study used data from the NHIS-NSC 2002–2013. The Korean National Health Insurance Service (KNHIS), which is a mandatory single medical insurer system, has been managing national health insurance in the Republic of Korea since 1989. All citizens are required to enroll in the system, and it provides nearly the entire healthcare coverage in the Republic of Korea. The KNHIS developed the NHIS-NSC for research purposes, which contains personal demographic records for all medical information related to insurance claims. The NHIS-NSC sampled 1,025,340 individuals from among 46,605,433 individuals in the NHID (2.2%) in 2002 and followed them until 2013 [To exclude chronic keratoconus patients, we excluded patients who were diagnosed with keratoconus in 2002 and 2003 and included patients who were diagnosed with keratoconus from 2004. The keratoconus cases were identified as patients who had the following Korean Classification of Diseases code as the main diagnosis code: H186 and H198, and had a keratometry measurement code (E6870).th, 41st–70th, and ≥71st percentiles), residential area , and year of enrollment.Control subjects were selected from individuals who did not have keratoconus diagnosis codes, each year, using propensity scores with nearest neighbor matching in a 1 : 5 ratio to keratoconus patients . PropensIn the matched populations, we compared the incidence of keratoconus. The earliest date of the keratoconus diagnosis was defined as the index date and the incident time, and the patient was considered an incident case in that corresponding year. Comorbid conditions included allergic rhinitis (codes), asthma (codes), atopic dermatitis (codes), aortic dissection (codes), sleep apnea (codes), collagen vascular diseases (codes), DM (codes E10–E14), mitral valve prolapse (codes), and Down syndrome (code) that were diagnosed between 2002 and 2008. Because the purpose of this study was to investigate associations between systemic diseases and keratoconus, and not necessarily to identify causative relationships between the conditions, we included cases and controls without considering the date when the diagnosis was made during the study period.Baseline characteristics are expressed as the mean and standard deviation or number and percentage. The chi square test was used to compare groups. Multivariate logistic regression analysis was performed to calculate odds ratio (OR) with a 95% confidence interval (CI) to evaluate the potential association between keratoconus and various systemic diseases. The variables included in multivariate analyses were age, sex, income, residential area, and systemic diseases of interest that were previously reported to be associated with keratoconus. All statistical analyses were conducted using SAS software, version 9.4 , and R 3.4.1 .The number of patients diagnosed with keratoconus from 2004 to 2013 came to 1,552, and 7,760 controls were included for comparison. The incident cases were 46 (4.5%), 30 (3.0%), 20 (2.0%), 40 (3.9%), 49 (4.9%), 76 (7.6%), 33 (3.3%), 48 (4.8%), 37 (3.7%), and 8 (0.8%) in 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, and 2013, respectively .p < 0.001), asthma (p < 0.001), and atopic dermatitis (p < 0.001) were more prevalent in the keratoconus group, while DM was more prevalent in the comparison group (p < 0.001). Other diseases, including aortic dissection, sleep apnea, and collagen vascular diseases, did not show any significant difference between groups. Mitral valve prolapse and Down syndrome were excluded for further analysis because the prevalence in both groups was not measurable or very low.p < 0.001), asthma , and atopic dermatitis , had significant associations with keratoconus after adjusting for confounding factors (p < 0.001). No significant association was found for demographic factors because they were used for propensity matching.Using multivariate logistic regression analysis, individuals with allergic diseases, including allergic rhinitis , which showed a high incidence rate compared to our study . The reaThe conclusions reached in our study showed a significant association between allergic diseases including allergic rhinitis, asthma, atopic dermatitis, and the presence of keratoconus. An earlier study also reported that atopic diseases including asthma, vernal keratoconjunctivitis, atopic keratoconjunctivitis, and seasonal or perennial allergic keratoconjunctivitis were associated with keratoconus, and their prevalence in keratoconus patients had a higher incidence than the control group . The mosImportantly, our study showed a positive association between keratoconus and DM. Regarding the association between keratoconus and DM, there are several studies that have reported patient groups with DM showing lower odds of having keratoconus, when compared to groups without diabetics, with reduced odds ranging from 20% to 78% , 25, 27.We also investigated the association between keratoconus and other systemic comorbidities, which were previously reported to be related with the disease. Previous studies have reported higher odds of keratoconus in patients with Down syndrome, mitral valve prolapse, collagen vascular disease, and sleep apnea –30. HoweThe present study, based on reliable and numerous population groups, supported the positive correlation of keratoconus and allergic diseases. This study is one of the few studies that has investigated the epidemiology of keratoconus in the Korean population. However, there were some limitations to our study. The prevalence of keratoconus was lower than expected in some diseases, especially in mitral valve prolapse and Down syndrome, so the necessity of better-designated control groups is indicated. Moreover, it suggests the need for further investigations regarding other parameters, such as eye rubbing or sleep positions.There are several limitations to consider when interpreting the results of our study. First, the diagnosis of keratoconus was entirely based on the KCD code system which may be inaccurate compared to the diagnosis made with a standardized diagnostic measurement. To overcome such limitations, we included those who had diagnostic code for keratoconus and underwent keratometry measurement, which may enhance the specificity of the keratoconus subjects included in this study. Second, it is possible that the OAG patients may have been underestimated because the data are based on hospital visits. The data do not include initial patients who did not experience symptoms and patients who do not visit the hospital for economic reasons. However, the degree of underestimation is limited due to the low cost and high accessibility of the Korean medical system, a government-run healthcare system including nearly the entire population of South Korea. Therefore, it is unlikely that inaccuracy and underestimation of the diagnosis affected the statistical results. Third, our data include only data for the Korean population, and there may be differences in other ethnic groups.In summary, statistical analysis showed a significant association between keratoconus and atopic diseases such as allergic rhinitis, asthma, and atopic dermatitis. Considering the incidence of keratoconus with the above comorbid conditions, studies investigating this association may help in the planning of eye-care policies. However, conflicting results regarding the possible association between keratoconus and DM should be further evaluated.