Mood profiling is a popular method of quantifying and classifying feeling states. Previous research has identified several novel mood profiles in predominantly Western English-speaking populations , and rep Retrieving the hypothesized mood profile clusters in a Singaporean sample will provide further support for the validity and generalizability of these mood profiles, demonstrating their cross-cultural replicability. Mood profiling as an applied technique has considerable potential for practitioners to examine relationships between mood and various outcomes of interest in clinical as well as non-clinical settings. Clarification of the distribution of mood profiles in relation to various demographic variables may provide insights into the design and implementation of potential interventions and programs to better serve various segments of the Singaporean population. Results from this study set the stage for further research in Singapore to explore the practical, clinical, and theoretical implications of mood profiling.n = 945) of respondents participated in sport either for leisure (n = 514) or competitively (n = 431). A total of 1,444 Singapore residents participated in the study . The ethnic distribution of participants was 80.5% Chinese, 8.2% Malay, 8.2% Indian, and 2.1% other, which approximates the ethnic distribution of Singapore as a whole . All parnot at all, 1 = a little, 2 = moderately, 3 = quite a bit, and 4 = extremely). The measure has six subscales  each with four items, with total subscale scores ranging from 0 to 16. No total mood disturbance scores were calculated, as the focus of the study was on the profiles generated from the six subscale scores. The BRUMS has been validated across diverse cultures  and completed a mood scale. Mood was assessed using the Brunel Mood Scale BRUMS; , 2003a, es e.g.,  and contes e.g., . Subscales e.g., . Cross-ces e.g., .Two methods of data collection were used to recruit English-speaking Singaporean participants. First, a link to an online version of the BRUMS, hosted on the university’s eResearch Survey System was distributed to a sample of Singapore residents using snowball sampling and assistance from the Singapore Sport Institute, which produced a sample of 695 respondents . A second group of participants was recruited at random from a range of organizations  who completed a paper-and-pencil version of the BRUMS. Participants were informed they were part of a research study aimed at validating a mood scale for use in Singapore, and their informed consent was sought prior to participation in the study. This study was conducted in accordance with the Australian Code for the Responsible Conduct of Research. The protocol was approved by the Human Research Ethics Committee at the University of Southern Queensland .p < 0.001. A case-by-case visual inspection suggested that response patterns were plausible. Given this, all outliers were retained, leaving a final sample of 1,444 respondents.A total of 13 cases with missing values for the BRUMS were excluded from the analysis. Data were screened for compliance with the assumptions of univariate and multivariate normality. Like previous samples , signifiThe results of this study are presented in three parts–cluster analysis, discriminant function analysis, and distribution of mood profiles by demographic variables.k-means clustering  was conducted to evaluate how well the clusters were classified. DFA predicts group membership in naturally occurring groups, based on predictor variables, and is not affected by unequal sample sizes  = 266.04 p < 0.001, partial η2 = 0.502. Using a Bonferroni-adjusted alpha level of 0.008, significant univariate effects were confirmed for all mood dimensions: tension, F = 352.14, p < 0.001, partial η2 = 0.550; depression, F = 609.78, p < 0.001, partial η2 = 0.680; anger, F = 444.98, p < 0.001, partial η2 = 0.607; vigor, F = 347.85, p < 0.001, partial η2 = 0.547; fatigue, F = 667.34, p < 0.001, partial η2 = 0.699; confusion, F = 539.79, p < 0.001, partial η2 = 0.652.To explore the clusters further, a le sizes . DFA is le sizes . A singlMood dimensions strongly associated with Function 1 were high depression, fatigue, confusion, anger, and tension. Function 2 identified high vigor and tension, and low fatigue. Function 3 identified low depression and anger, and high fatigue and vigor. Single-factor MANOVAs were used to provide an initial assessment of the influence of demographic variables on mood responses. Participants in the unspecified and “other” categories were excluded from these analyses. Significant multivariate variability was found for gender, age group, ethnicity, education level, and sport participation see  but not Chi-squared tests were used to assess the distribution of mood profile clusters according to the demographic variables of interest. Significant variations in distribution were evident see , for genThe distribution of the six mood profiles varied significantly by gender for all profiles. Males were over-represented in the iceberg, submerged, and surface profiles, whereas females were over-represented in the inverse Everest, inverse iceberg, and shark fin profiles, consistent with the findings of The distribution of inverse Everest, shark fin, and submerged profiles was independent of age group. Younger participants (≤25 years) were over-represented in the inverse iceberg and surface profiles and under-represented for the iceberg profile. Older participants (26+ years) were over-represented in the iceberg profile and under-represented in the inverse iceberg and surface profiles.The distribution of iceberg, shark fin, and surface profiles was independent of ethnicity. Chinese Singaporeans were over-represented in the submerged profile and under-represented in the inverse Everest and inverse iceberg profiles. Malay Singaporeans were over-represented in inverse Everest and inverse iceberg profiles and under-represented in the submerged profile.The distribution of the inverse Everest, inverse iceberg, and submerged profiles was independent of level of education. Participants with secondary school or below level of education were over-represented in the iceberg and surface profiles and under-represented in the shark fin profile. Participants with pre-university education (JC/IB/Poly/ITE) were over-represented in the surface profile, whereas those with a university education were over-represented in the shark fin profile and under-represented in the surface profile.The distribution for the shark fin profile was independent of sport participation. Those who participated in sport were over-represented in the iceberg and surface profiles and under-represented in the inverse Everest, inverse iceberg, and submerged profiles. Those who did not participate in sport were over-represented in the inverse Everest, inverse iceberg, and submerged profiles and under-represented in the iceberg and surface profiles.Six mood profile clusters previously identified by Support for the cross-cultural generalizability of these mood profiles makes a significant contribution to the literature on mood profiling and, more specifically, to the validation of the BRUMS as a tool for mood profiling in Singapore. The identification of associations between demographic variables and the incidence of mood profiles across multiple studies provides support for the use of mood profiling for various purposes, ranging from screening or monitoring of mental health to providing a tool to predict performance or other outcome variables of interest. Our findings enhance understanding of the association between demographic variables and mood profiles and may serve as a guide for practitioners and policy makers in the design of potential interventions to promote well-being among general as well as clinical populations.A noteworthy finding of our study was that men were over-represented in the more positive iceberg profile whereas females were over-represented in the more negative inverse Everest, inverse iceberg, and shark fin profiles. There are several possible explanations for this gender difference. First, it has been reported that men and women regulate mood differently. For example, women are more likely to ruminate that men, which may influence their reported mood . Second,Stress in America survey showed younger people report higher stress levels than older generations and also report that they do not manage it well  among Malay Singaporeans and a lower incidence among Chinese Singaporeans. Previous studies have found differences in health status as well as variations in the occurrence of mood disorders according to ethnicity . FurtherThere were few significant variations in the distribution of mood profiles related to level of education, although the relatively small number of participants in the primary/secondary and postgraduate education groups should be noted. Previous literature suggests that level of education and socioeconomic status may have an influence on the mental health of individuals  and therA significant finding from our study relates to the distribution of mood profile clusters in relation to participation in sport. Our findings showed a clear association between sport participation and mood responses. Those engaged in sport were over-represented in the positive iceberg mood profile and under-represented in the more negative inverse Everest, inverse iceberg, and submerged profiles. This association between sport participation and positive mood profiles might be related to the positive effects of sport on mood or the effects of mood on physical functioning , althougResearch has increasingly shown physical activity to be an effective intervention to promote physical and psychological benefits for both healthy and clinical populations  and our Despite our sample size of 1,444 participants, when participants were distributed across the six mood profiles the number of participants in some cells was very small see . We acknIn summary, when the previous validation of the BRUMS for use in a Singaporean context  is consiThe findings of the current study provide evidence that the mood profile clusters previously reported by The datasets generated for this study are available on request from the corresponding author.This study involving human participants was reviewed and approved by the Human Research Ethics Committee at the University of Southern Queensland . The participants provided informed consent to participate in this study.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Rheumatoid arthritis (RA) is associated with an increased risk for venous thromboembolism. However, so far, relatively few and small size-based studies have been conducted. We aimed to investigate the link between RA and venous thromboembolism utilizing a large sample of subjects originating from a large data base.The study was performed utilizing the medical database of Clalit Health Services, the largest healthcare provider in Israel. We enrolled all patients with RA and age- and gender-matched controls. Chi-square and t-tests were used for univariate analysis and a logistic regression model was used for a multivariate analysis. RA patients were compared to controls regarding the proportion of venous thromboembolic events . Multivariate logistic regression was employed to assess factors associated with thromboembolic events.The study included 11,782 patients with RA and 57,973 age- and gender-matched controls. RA patients had a higher rate of venous thromboembolism events compared with controls . RA and mean C-reactive protein levels were found to be independently associated with the proportion of thromboembolic events .RA and C-reactive protein levels are independently associated with venous thromboembolic events. Physicians should be aware of such findings and have a lower threshold for suspecting detecting such events in patients with RA, mainly those with mean high levels of C-reactive protein. All these factors converge to accelerated inflammation, in which the coagulation system also plays a role.4RA has many extra articular manifestations; cutaneous, salivary glands, ophthalmic, pulmonary and neurological manifestations are often reported.6 Mounting evidence suggests that the innate immune system and coagulation system share a common evolutionary origin, and extensive crosstalk exists between inflammatory cytokines and coagulation factors. Hence, the activation of the inflammatory cytokine networks may also induce prothrombotic conditions such as endothelial dysfunction, tissue factor (TF) overexpression, and inhibition of fibrinolysis and protein C.7Several studies have shown that the RA inflammatory state increases the concentration of different pro-coagulant and thrombolytic factors.Our goal in this study was to assess the association between RA and venous thromboembolic events (VTE), using the database of the largest healthcare provider in Israel.This study was approved by an institutional ethics committee in Soroka Hospital, Beer-Sheba, Israel. It was exempted by the ethics committee from signing informed consent forms.This study is one of a series of explorative and analytic studies based on the chronic disease registry of CHS , the largest healthcare provider in Israel that covers over 4.4 million enrollees, grossly half of the Israeli population.11CHS has a comprehensive computerized database with continuous real-time input from pharmaceutical, medical and administrative computerized operating systems. The database contains a chronic diseases registry, based on data from hospital discharge notes for inpatients and primary care and expert physicians’ reports for outpatients. The study was designed as a cross-sectional analysis. All RA patients in CHS’s database were included in the study, as well as five age- and gender-matched controls for each RA patient. Data for each patient included age, gender, socioeconomic status (SES), smoking status, body mass index (BMI), previous diagnosis of VTE , and previously documented levels of CRP. RA patients were defined as such when they had at least one documented diagnosis of RA, either by community physician or hospital discharge note. DVT/PE diagnosis was defined in a similar fashion. Due to the structure of the database, it was not possible to determine the etiology of each disorder. However, the validity of the diagnoses in the registry was found to be high in previous studies.CRP levels were represented by a mean value of all measured laboratory CRP levels for each participant in blood exams from 2002–2013 .We used student’s t-test to test difference between continuous variables and Chi-Square for categorical variables. Univariate analysis was conducted to assess the distribution of different study covariates between patients with and without VTE.A logistic regression model was used to test the association between RA and VTE while adjusting for age, gender, SES, smoking status and BMI. An additional model included all of the aforementioned variables, as well as CRP levels. Point estimates are presented with 95% confidence interval.Statistical analysis was preformed using R Statistical Software .Table 1). As expected by the epidemiology of RA disease, most of the patients in our cohort were females (about 77% in both groups). Of note, smoking was more frequent among RA patients in comparison with controls, as was high BMI.The study included 11,782 patients with RA, and 57,973 age- and gender-matched controls . of these events in the RA group, 704 were diagnosed with DVT (6%) and 160 with PE (1.4%).Table 2) has shown that RA patients who experienced VTE were older, more likely to be female and had a higher BMI and a higher mean CRP value. RA patients had a high risk of VTE . Surprisingly, smoking was not found to be associated with a history of VTE.Univariate analysis (Table 3 (model 1 and 2) demonstrates an independent association of VTE with increasing age and BMI, as well as female gender and RA. In model 2, it is shown that CRP levels were found to be linearly associated with the odds having VTE, regardless of RA.15 Studies on the role of RA and its systemic inflammation in VTE are not as common and are now emerging.Cardiovascular disorders are well documented to coexist in RA patients; this association is believed to be highly related with the degree of the inflammatory process. Studies to date have focused mainly on arterial atherosclerotic manifestations such as myocardial infarction and increased carotid artery stenosis, as targets for diagnosis and therapeutic interventions.16 have published a population-based ten-year-cohort study from Taiwan. Out of the 23.74 million people in their cohort, there were 29,238 RA patients , matched with 116,952 controls. The risk for developing DVT and PE in RA patients was increased by 3.36-fold and 2.07-fold respectively, compared to controls, after adjusting for age, gender and comorbidities. Other studies, based on hospitalized patients, also support the concept that RA patients have an increased risk for VTE.18 In the Copenhagen General Population Study, conducted between the years 2004 and 2012, researchers measured the concentration of immunoglobulin M (IgM) type RF (Rheumatoid factor) in patients without autoimmune rheumatic disease or VTE. The main outcome was the incidence of DVT. In a total of 368,381 person-years, 670 individuals developed DVT. An RF concentration higher than 110 IU/mL showed the strongest association with DVT with multivariable adjusted hazard ratios of 9.0 (95% CI 3.1–26) for 1-year follow-up, 4.3 (2.2–8.5) for 5-year follow-up, and 3.1 (1.7–5.6) for up to 32 years of follow-up.19Our data exhibited a significant association between RA and VTE, showing a twofold increase in the frequency of VTE among RA patients. Our results match those of other reports. Chung et al.20 These finding highlight even further the need for appropriate prophylaxis, as well as the need to add rheumatic conditions and RA in particular to different risk models assessing the chances of developing VTE during hospitalization.Our data, similarly to previous studies, may suggest that there should be a role for thromboprophylaxis in immune mediated diseases such as RA. From an economical aspect, VTE bears a great burden on the health system. Predicted costs of medical care were found to be 2.5-fold higher for patients with VTE related to current or recent hospitalizations for acute illness  when compared to hospitalized patients without VTE .21 The presented results may imply that the relative impact of a current inflammatory rheumatic condition should be assessed differently suggesting a more substantial contribution to the risk of VTE.The Padua Prediction Score was created to assess the risk for VTE in hospitalized patients, and determine their need for prophylaxis. Although the Padua Prediction Score identifies acute rheumatologic disorders as increased risk states for VTE, their importance in the scale is relatively low.24 Hypercoagulability could be induced by inflammation, for example via cytokine-induction of tissue factor (TF) expression, endothelial dysfunction, inhibition of the protein C system and inhibition of fibrinolysis.25 Inflammatory mediators, like CRP, tumour necrosis factor-alpha (TNFα), interleukin-6 (IL-6) as well as complement activation, can trigger TF synthesis in intravascular cells, such as monocytes and endothelial cells.26 As a result of inflammation, endothelial dysfunction and vascular injury may occur leading to rapid generation of thrombin at such sites by activating all the arms of the coagulation system.27To date, the underlying pathophysiologic pathway for the association between RA and the hypercoagulable state is not fully understood, however, several steps in the inflammatory process have been linked to hypercoagulability.28 Peters et al.29 reported that thrombin-activatable fibrinolysis inhibitor levels were significantly higher in RA patients with a high inflammatory state (CRP >10 mg/L) compared to those with lower CRP levels (CRP <10 mg/L). These reports are in line with our findings that demonstrated the higher probability for VTE in RA patients who have higher CRP levels.CRP is a hallmark of inflammation and serves as a surrogate marker for the inflammatory activity in many rheumatic disorders. Many disease activity formulas take in account the level of CRP as a contributor to the overall disease activity. Several observations even relate a direct pathogenic role to CRP in the process of joint erosions and bone destruction in RA. CRP was shown to be an inducer of the receptor activator of nuclear factor kappa-B ligand (RANKL). It has a direct effect on the differentiation of osteoclast precursors into mature osteoclasts. Therefore, lowering CRP levels is pertinent to the control and prevention of further joint damage in RA patients.In conclusion, our study has shown that RA is independently associated with VTE. CRP levels were also found to be directly related with an increased risk for VTE. Our results challenge the current understating of this linkage; suggesting that RA should be more commonly known as a risk factor for VTE. This may modify the current manner by which we calculate VTE risk and the need for thromboprophylaxis, as well as our VTE treatment regimens, with a possible effect on the intensity and length of therapy.


This study aimed to establish a deep learning system for detecting the active and inactive phases of thyroid-associated ophthalmopathy (TAO) using magnetic resonance imaging (MRI). This system could provide faster, more accurate, and more objective assessments across populations.A total of 160 MRI images of patients with TAO, who visited the Ophthalmology Clinic of the Ninth People’s Hospital, were retrospectively obtained for this study. Of these, 80% were used for training and validation, and 20% were used for testing. The deep learning system, based on deep convolutional neural network, was established to distinguish patients with active phase from those with inactive phase. The accuracy, precision, sensitivity, specificity, F1 score and area under the receiver operating characteristic curve were analyzed. Besides, visualization method was applied to explain the operation of the networks.Network A inherited from Visual Geometry Group network. The accuracy, specificity and sensitivity were 0.863±0.055, 0.896±0.042 and 0.750±0.136 respectively. Due to the recurring phenomenon of vanishing gradient during the training process of network A, we added parts of Residual Neural Network to build network B. After modification, network B improved the sensitivity (0.821±0.021) while maintaining a good accuracy (0.855±0.018) and a good specificity (0.865±0.021).The deep convolutional neural network could automatically detect the activity of TAO from MRI images with strong robustness, less subjective judgment, and less measurement error. This system could standardize the diagnostic process and speed up the treatment decision making for TAO. The study proposed a method based on deep convolutional neural network to detect the activity of thyroid-associated ophthalmopathy from orbital magnetic resonance imaging, with high accuracy, sensitivity and specificity.TAO, an autoimmune disease associated with thyroid disease, is the most common orbital disease in adults. TAO not only affects the appearance of patients but may also impair visual function seriously . Two phaMRI is another way to evaluate the activity of TAO. Orbital MRI can clearly reflect the structure and pathology of the orbit, with no ionizing radiation, high contrast of soft tissue, and multi-parameter imaging. The intraorbital signal intensity of patients with active TAO was significantly different from that of inactive patients in several MRI sequences, such as short TI inversion recovery sequence (STIR), diffusion tensor imaging, and dynamic enhancement techniques –8. PolitIn view of the shortcomings above, it is necessary to develop a sensitive and accurate method for activity staging of Asian patients, which is not limited to professional experience. Deep learning, an end-to-end machine learning method, is not limited by prior knowledge . As one In this study, a deep learning system based on DCNN was established to recognize orbital MRI for differentiating the active phase from the inactive phase in patients with TAO. In the rest of the paper we introduced the subject and the database, described the structure of the network we built and evaluated the performance through accuracy, precision, sensitivity, specificity, F1 score and area under the receiver operating characteristic curve.This study followed the tenets of the declaration of Helsinki and was approved by the ethics committee of Shanghai Ninth Peoples’ Hospital . Patients who came to the Ophthalmology Clinic of the Ninth People’s Hospital from May 01, 2018, to July 01, 2019, were retrospectively examined. The inclusion criteria were as follows: (1) age more than 18 years, (2) meeting the internationally recognized diagnostic criteria for TAO, and (3) intraorbital involvement confirmed by orbital MRI. European Group on Graves’ orbitopathy (EUGOGO) suggested that the severity of TAO could be divided into mild, moderate, and extremely severe according to the degree of eyelid retraction, exophthalmos, diplopia, and other indices [A total of 108 patients were included in this study. Among patients, there were 66 females and 42 males. Patients in active phase were treated with immunosuppressive therapy. One hundred sixty orbital MRIs were performed before and after treatment. Due to the lack of data and the significant change of MRI signal intensity before and after treatment, we regarded the data before and after treatment as independent data.MRI scanning was performed on a 3.0-T MRI system (Philips Ingenia 3.0 T). Throughout the scan, the patient’s head was stabilized in a supine position and kept stationary. The orbital MRI imaging protocol included T1-weighted turbo spin-echo (TSE), T2-weighted TSE spectral presaturation with inversion recovery (SPIR), and T2-weighted driven equilibrium radiofrequency reset pulse (DRIVE). Axial SPIR was chosen for the present study .The DCNN used in this study belongs to the supervised learning method. CAS is the most commonly used clinical staging index of TAO, whose assessment includes 7 clinical manifestations: spontaneous retrobulbar pain, pain on attempted upward or downward gaze, redness of eyelids, redness of conjunctiva, swelling of caruncle or plica, swelling of eyelids and swelling of eyelids. We used CAS to annotate the activity stage of orbital MRI . PatientThe dataset for testing was generated by a random split of 20% of the entire set, which didn’t participate in training process. A 32-image dataset was generated for testing, among which there were 7 MRI images of active phase and 25 MRI of inactive phase. K-fold cross-validation was employed to the remaining dataset (training set) for hyper-parameter tuning (k = 5). This algorithm divided the data into k folds randomly without replacement. During one cross-validation process, k-1 folds were used for training, and the remaining fold was used for validation. This process was then repeated k times to use each of the k folds once for validation. After finding the satisfactory hyper-parameters through K-fold cross-validation, A new model was trained from the whole training set.Intensity nonuniformity in MRI, also known as bias field, was caused by the location of patients, scanner parameters, and environment. This difference in signal intensity has nothing to do with anatomical and physiological factor, which may reduce the comparability of MRI images. N4 bias field correction was carried out to reduce this inconsistency . After cTo avoid overfitting, data enhancement techniques were used before each training, including random flipping and random crop, after which the size of the MRI became 128 × 128 × 5 pixels. Figure p=0.5). Softmax function, following fully connected layer, could convert the output to a probability distribution. Our proposed DCNNs inherited parts of Visual Geometry Group (VGG) network and Residual Neural Network (ResNet), structures of which are shown in Fig. The basic DCNN consisted of convolution layer, pooling layer and fully connected layer. Convolution layer could extract features by filters. In order to avoid the overfitting by the increase of features after several filters, pooling layer was proposed to subsample and to reduce the number of parameters. Besides, this layer could retain the relative invariance of space. After obtaining all the features, the fully connection layer was used to integrate them to complete the classification task. In addition to the basic structure of DCNN, we added nonlinear activation functions, batch normalization, dropout layer and softmax function to optimize the network. Rectified linear unit (ReLU) was applied as nonlinear activation function after every convolution layer and every fully connected layer, which could speed up the convergence by sparse activation. Between the convolution layer and the activation function, batch normalization was set up to normalize the distribution of each batch, which could effectively reduce the phenomenon of gradient disappearance . DropoutThe experiment was run four times to evaluate the stability of training. The convergence of loss value in training was achieved to evaluate the training process. The preprocessed image was input into the well-trained networks, the probability was calculated, and a decision was output. The average and standard deviation (SD) of accuracy, precision, sensitivity, specificity and F1 score of four runs on test set were calculated, the definitions of which were given by:F1 score is an index to measure the accuracy of binary classification model, which conveys the balance between precision and sensitivity. The effectiveness was also evaluated by drawing the receiver operating characteristic (ROC) curve and calculating the area under curve (AUC).In addition, it is difficult to tell how neural network works, so the occlusion testing, a kind of visualization method, was applied to reveal insights into the decisions of neural networks. We set gray occlusion region on the input image, and recorded the output probability while different regions were occluded. By converting these probability changes into heat map, the key parts of the input image for decision could be displayed.The experiment was run four times on both networks. The results of accuracy, precision, sensitivity, specificity and F1 score of each network were summarized in Table TAO is the most common orbital disease in adults. Its clinical staging is the main index to guide treatment. The existing CAS is entirely clinical, which makes it less sensitive to disease progression in subclinical patients and during treatment . OrbitalAt present, DCNN based on MRI is restricted to the brain, kidney, prostate and spine. The major technical problems include difficulty in three-dimensional reconstruction, overfitting caused by small datasets, and the “black box” problem . In ordeThe results shown in Table This study was novel in proposing a DCNN-based deep learning system to stage the activity of TAO. This deep learning system could avoid subjective error and explore in-depth information on intraorbital changes, which could assist ophthalmologists, who do not specialize in TAO, to evaluate the activity. Furthermore, the application of visualization methods may not only assist the staging of the disease, but also have educational significance for clinical beginners, such as indicating swelling and hyperemia of extraocular muscles and so on. However, this study had several limitations: (1) Manual interception of the orbital part was costly. This step will be further automated in the future. (2) Although regularization methods were applied, it was still difficult to completely avoid overfitting for such a small dataset. In further studies, the database should be expanded to increase the robustness of the system. (3) We only chose one MRI sequence for decision making, which may cause bias. Other MRI sequences should be added to look for new indicators and to further explain the role of MRI in clinical staging of TAO. Also, medical imaging data will be combined with treatment and prognosis to establish a sounder intelligent decision-making system. After finding a solution of data access and data protection, telemedicine platforms will be used to promote a new Predictive, Preventive, Personalized, and Participatory (4P) medical paradigm for the diagnosis and treatment of TAO.The orbital MRI contains the depth characteristics of TAO clinical staging. DCNN doesn’t rely on subjective judgment and could directly get these features from the orbital MRI to assist the clinical staging of TAO patients, with small measurement error and strong robustness. The networks established in this study performed well during evaluation process. In further studies, we will develop its potential for efficacy evaluation and prediction. Through telemedicine platforms, we could standardize the diagnosis and treatment of TAO and speed up the decision-making process in the future.


Chronic pharyngitis is a common disease with a dry throat, sore throat, pharyngeal itching, dry cough, and difficulty in swallowing, bringing inconvenience to patients’ daily life. Banxia-Houpo-Tang (BHT) has proven to be effective in the treatment of chronic pharyngitis, yet its real extent is not well understood. To prove this point, we will perform a protocol for a systematic review and meta-analysis of BHT for chronic pharyngitis.We will search for electronic databases both English and Chinese from inception to December 2019. Two experienced researchers select the qualified articles from: The Cochrane Library, EBM Reviews, OVID, Web of Science, PubMed, Chinese National Knowledge Infrastructure (CNKI), China Academic Journal Network Publishing Database (CAJD), China Biomedical Literature database (CBM), VIP Database for Chinese Technical Periodicals (VIP). Journal Integration Platform and WAN FANG Database. We select the appropriate searching language. The primary outcome was remission rate, and the secondary outcomes include clinical symptoms, clinical examination, adverse event. Data extraction and quality assessment will be conducted by 2 experienced researchers independently. Data analysis and the risk of bias assessment will be determined by RevMan 5.3 software.Based on the current proofs, we will get the exact evidence about the safety and effectiveness of BHT in the treatment of chronic pharyngitis.Our study is the first meta-analysis to evaluate the efficacy and safety of BHT in the treatment of chronic pharyngitis, and it will provide evidence for alternative treatment for the management of chronic pharyngitis.DOI 10.17605/OSF.IO/QNF6X Non-infectious diseases such as gastroesophageal reflux and recurrent acute pharyngitis also need to be considered. The main clinical manifestations of this disease include recurrent hoarseness, irritating cough, sore throat, and difficulty in swallowing. Sore throat, most of which are caused by a viral infection, lead to 5% children and 2% outpatient visited in clinical activities,–7 and puts enormous economic pressure on patients. Over 13 million visit the doctor annually in the United States related to this disease.,9 In the UK, the loss of productivity and doctors’ office visits due to pharyngeal pian was £400 million a year.,11Chronic pharyngitis is a common otolaryngology disease mainly caused by infectious etiologies such as viral, bacteria, Some chronic diseases with pharyngitis like tonsillitis threaten the health of patients especially children. In many countries, surgery of the tonsils is still the main treatment therapy for tonsillitis. However, because of the change of the disease indications and lack of evidence-based study, surgery for this disease needs further evidence.,14 And severe sore throat may still trouble patients after tonsillectomy. Although streptococcus pyogenes or group A β-haemolytic streptococcus (GABHS) is the major causative agent of acute pharyngitis, broad-spectrum antibiotics abusing without pathogen culture can be seen everywhere for pharyngitis. Pharyngitis was one of the diseases that account for one-third of all antibiotics prescribed in outpatient settings in American. But, the value of antibiotics is in reducing complications rather than treating them, so antibiotics are ineffective therapy in the treatment of sore throat, which (40%–80%) caused by viral infections. Recently studies indicate that insufficient evidence for antibiotics prevents sore throat. Antibiotic treatment is controversial in some high-income countries.–21 So, neither surgery nor antibiotics are effective treatments for pharyngitis. A reasonable choice with fewer side effects and few cost treatments are receiving increasing attention.At present, growing evidence reveals that antibiotic therapy and adenotonsillectomy surgical therapy are both effective measures in the treatment of the disease. but as a result of the inadequate presentation of the evidence, many effective and natural therapies cannot be recommended. Banxia-Houpo-Tang (BHT) is a prescription with thousands of years of clinical experience in China, and it is still widely used nowadays.–26 BHT is comprised of Banxia (Pinellia ternata), Houpo (Mangnolia), Fuling (Poria cocos), Shengjiang (Fresh ginger), Suye (Perilla leaf). However, no systematic review and meta-analysis aim to explain its efficacy and safety. To find natural medicine and further study, we provide a protocol to evaluate the safety and effectiveness of BHT for chronic pharyngitis.Some Chinese herbal medicine has been proven effective for treating sore throat,2To establish a systematic and comprehensive approach for locating the evidence, a review and meta-analysis will be used to whether the Banxia-Houpo-Tang is effective or can it ease the pressure of antibiotic abusing in the treatment of pharyngitis. Risk assessment and identify the most promising measures.33.1 guidelines.This study have been registered on the Open Science Framework (OSF) platform and the OSF registration number is DOI 10.17605/OSF.IO/QNF6X. The research process will be compliant with the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P)3.2We will search for electronic databases both English and Chinese from inception to December 2019. Two experienced researchers select the qualified articles from: The Cochrane Library, EBM Reviews, OVID, Web of Science, PubMed, Chinese National Knowledge Infrastructure (CNKI), China Academic Journal Network Publishing Database (CAJD), China Biomedical Literature database (CBM), VIP Database for Chinese Technical Periodicals (VIP). Journal Integration Platform and WAN FANG Database. Endnote 9.0 will be used to manage literature, export references, and pick articles after group discussion. Medical subject headings (Mesh) or (and) random words will be selected in electronic databases: Banxia-Houpo-Tang, Chinese herbal medicine, chronic pharyngitis, sore throat, dry throat, pharyngeal itching, dry cough, difficulty in swallowing. The literature search process of PubMed is performed in Table 3.33.3.1All the clinic trials of prospective, randomized, multi-center, double-blind, parallel-group, placebo-control studies about BHT (or Chinese patent medicine for BHT) will be included. Clinical observations without randomized, or placebo-control or follow-up will not be included.3.3.2 are as follow . The intervention in the control group included placebo or medicines that have proven effective at preventing chronic pharyngitis.3.3.4The primary outcome was remission rate. Remission was defined as all the uncomfortable symptoms such as dry throat, sore throat, pharyngeal itching, dry cough, difficulty in swallowing are not recurrence in 6 months. And pharyngeal mucosa without swollen, atrophic, hyperemic, and follicular hyperplasia in clinical signs. Secondary outcomes included: the recurrence rate  after treatment, remission rates of symptoms and signs , evaluation of adverse events.3.4https://www.endnote.com/). Two reviewers will screen the titles and abstracts of all studies to identify potential articles according to inclusion and exclusion criteria. If there was any disagreement, we will have a group discussion. After group discussion, all the articles passed are reviewed by a third author (XL). A flowchart to show the whole process of study selection , including the application of hidden, blind methods, information data for the generation, distribution of randomized control sequences, selective reports, and other possible problems. The risk of bias will be marked as high, uncertain and low: low risk of bias is defined as “existence bias does not affect the results of the study,” the risk of uncertainty bias is defined as “the bias of existence raises doubts about the results of the study,” the high risk of bias is defined as “the bias of existence seriously affects the credibility of the results.” Two investigators will use the Grading of Recommendations Assessment Development and Evaluation (GRADE) system for evidence evaluation. If there any questions, a third participator assessment will be used.According to the Cochrane Handbook for Systematic Reviews of Interventions,3.73.7.1Data statistics analysis will be performed using Review Manager 5.3 software  and Stata 14.0 . For dichotomous variables: adverse events, we will use the Relative Ratio (RR) value with 95% confidence intervals (CI) of the comparison, effective or not, will be described by using the OR value with 95% CI. For continuous variables, a combined statistical analysis will be performed by mean difference (SD) and standardized mean difference (SMD) with 95% CI.3.7.2I2 statistic will be figuring out to evaluate the results of the included studies. A high level of heterogeneity was referred to I2 ≥ 50, the random-effects model was recommended. A low level of heterogeneity was referred to I2 < 50, the fixed effects model was suggested.Heterogeneity analysis was used to test whether the results of each independent study were combinable or not. In this study, the 3.7.3If >10 standard-compliant studies are included, a funnel chart will be adopted to evaluate publication bias reports. If there is no publication bias, the data from these studies will present an inverted funnel shape and be symmetrically distributed. If an asymmetrical inverted funnel plot appears, the bias of the study samples will be presented. Egg and Begger tests will be used to detect the asymmetry of the funnel plot.3.7.4Subgroup analysis is used to find the reasons for heterogeneity. We will use the secondary data of the studies to build a meta-review model, screen out the influencing factors of heterogeneity, and conduct subgroup analysis for these influencing factors .3.7.5Sensitivity analysis is used to analyze the stability of the results, to exclude the study of abnormal results , and then to re-examine the meta-analysis to found if there is any change in the conclusions. Every time a study is excluded, analyze the stability of the results. If there is no essential difference between the results before and after the sensitivity analysis, it reveals that the results of this Meta-analysis were stable.3.8Our research without directly relates to individual patients and therefore the issue of ethical review does not exist.4 strictly, and the results will be published in peer-reviewed publications to provide a reference for the treatment of this disease.Currently, many patients are plagued by chronic pharyngitis, so drug abuse is widespread all over the world. To date, the attention of chronic pharyngitis is still insufficient, and there is not even a systematic evaluation of drug treatment for chronic pharyngitis. Traditional Chinese medicine resource is a treasure house that contains many effective methods that have not been proven by modern science. The purpose of this evaluation is to find safety and effective method for the treatment of chronic pharyngitis through existing published articles and provide some useful data support for the treatment of chronic pharyngitis and the development of later drugs. Therefore, we will systematically evaluate this study accordance with the requirements of the Cochrane Handbook for Systematic Reviews of Interventions4.1This project is funded by the National Natural Science Foundation of China (No. 81774279) and the Key Research and Development Project of Sichuan Province, Science and Technology Department of Sichuan (No. 2018SZ0068). The sponsors are not involved in design, execution, or writing the study.Conceptualization: Chenyi Xu, Rensong Yue.Methodology: Chenyi Xu, Rensong Yue.Supervision: Xuelian Lv, Yuan Chen, Tingchao Wu.Writing – original draft: Chenyi Xu, Xuelian Lv.Writing-review & editing: Yang Maoyi, Tingchao Wu.


Background: Early nutritional support of preterm infants is important because it influences long-term health and development. Body composition has an influence on cardiovascular disease, metabolic syndrome, and neurocognitive outcome in the long term.Objective: To assess body composition in preterm infants <32 weeks of gestation at term-equivalent age and to analyze the influence of an optimized nutritional approach.Methods: This is a prespecified secondary outcome analysis of a prospective observational study comparing the body composition in regard to gestational age. The preterm infants were classified according to gestational age as extremely preterm infants (<28 weeks gestation at birth) and very preterm infants (≥28 weeks gestation at birth) and according to weight percentile as appropriate for gestational age and small for gestational age. Body composition was determined by air displacement plethysmography using the PEA POD. The preterm infants obtained nutrition according to the ESPGHAN 2010 Guidelines.Results: Seventy-four preterm infants were analyzed. The mean (SD) gestational age was 28.7 (2.4) weeks, and birth weight was 1,162 (372) g. Fat mass percentage was significantly higher in extremely preterm infants in comparison to very preterm infants . There was no significant difference of fat mass percentage according to weight percentiles.Conclusions: Extremely preterm infants had a significantly higher fat mass percentage compared to very preterm infants at term-equivalent age. There was no significant difference of fat mass percentage according to weight percentiles. Adequate early nutritional support of preterm infants is essential for long-term health and development . EspeciaThe aim of the study was to assess FM and FFM in very preterm infants (VPI) born ≥28 weeks in comparison to extremely preterm infants (EPI) born <28 weeks of gestation at term-equivalent age. The second aim of the study was to analyze the relationship between FM and weight percentiles in neonates, who received nutrition according to the ESPGHAN 2010 Guidelines , 14.This study is a prespecified secondary outcome analysis of a prospective observational study conducted at the Division of Neonatology, Medical University of Graz, Austria . PretermThe present analysis and PEA POD measurements were a standard procedure during the period of that nutritional analysis study . The stuBody composition was performed by air displacement plethysmography, using the PEA POD, Infant Body Composition System , which is an accurate and reliable technique considered as the international gold standard for non-invasive evaluation of body composition in infants , 17. TheTo measure whole body volume, the device is equipped with two chambers of identical volume, the test chamber, and the reference chamber separated by a volume-perturbing diaphragm sensitive to pressure changes. First, the PEA POD calculates the body surface area using the Boyd formula, which is then used to obtain the surface area artifact. The surface area artifact and the thoracic gas volume, which is a predicted value, are needed to correct the raw body volume, measured by the PEA POD. With these variables, body volume can be calculated. Electronic scales are included in the PEA POD to measure the infants mass. By using body mass and volume, the whole body density can be calculated. Fat mass can easily be calculated by knowing the density of fat, which is accepted as a constant of 0.9007 g/ml. The density of FFM changes during growth and depends on age and sex. The PEA POD uses age- and sex-specific density of FFM values, which are available in literature , 19. FatAt birth, infants were weighed using electronic scales . At body composition measurement, infants were weighed using the integrated scales of the PEA POD device. All measurements of length were performed using the SECA 210 Mobile Measuring Mat for babies and toddlers  .The local feeding protocol of the included preterm infants has previously been described in detail by Khan et al. . The prehttp://ucalgary.ca/fenton). The data from the individual measurements were collected in a Microsoft Excel spreadsheet and edited. Mann–Whitney U-Test and Kruskal–Wallis test was used in intergroup comparisons of categorical variables, and categorical variables were expressed as numbers and percentages. Multivariable linear regression was used to examine the association between the FM and FFM and the study groups with adjustment for the covariates: sex  born <28 weeks gestation and very preterm infants (VPI group) born ≥28 weeks gestation. For the second analysis, preterm infants were stratified according to their weight percentile  at the time point of birth and measurement, making up four groups . The classification was based on a publication of the ESPGHAN and on a consensus paper of the Austrian Society for Pediatric and Adolescent Medicine (ÖGKJ) , 23. To tes: sex  and gesttes: sex . Estimatn = 11), death before body composition measurement (n = 7), genetic disorder (n = 1), insufficient quality of measurement (n = 2), and loss to follow-up (n = 5)  . A total (n = 5) .In regard to growth percentiles, the infants were assigned to the following groups: AGA/AGA: 58 infants (78%); group SGA/SGA: 3 infants (4%), and group AGA/SGA: 13 infants (18%). No infant could be assigned to group SGA/AGA . Pretermp < 0.001). Weight and length at measurement were significantly higher in the EPI group than those in the VPI group, and there was no significant difference in weight z-score between the groups . There was no significant difference in length at measurement between the three groups. Weight z-scores at measurement were significantly lower in the SGA groups in comparison to the AGA group, as expected  had a significantly lower weight at measurement in comparison to the AGA group . FM and In this study, we analyzed the body composition in the EPI in comparison to that in the VPI at term-equivalent age. FM percentage was significantly higher in the EPI compared to that in the VPI group. The groups according to weight percentiles  showed no significant differences in FM. Infants born <28 weeks at gestation in comparison to infants born ≥28 weeks of gestation were discharged later. They had a significantly higher percentage of FM% at measurement.Mean FM% in the whole study cohort (15.9 SD 3.7) corresponds well to published data by Roggero et al. where mean FM% was 14.8 (SD 4.4) in preterm infants <1,500 g at term corrected age . Simon eThe preterm infants in the present study obtained nutrition according to the ESPGHAN 2010 Guidelines , 14, usiRoggero et al. published two studies including preterm infants <1,500 g. In these studies, FM% was higher in AGA preterm infants compared to SGA preterm infants (measured at term corrected age) , 39. VilThe strength of the study is the inclusion of extremely preterm infants and the relatively large sample size. Furthermore, we think that the number of patients represent a typical 1 year's cohort for a tertiary neonatal intensive care unit. There are some limitations to the present study, too. First, it is a single center study, and the number of SGA infants is small. Second, single point measurements are difficult to interpret; therefore, longitudinal measurements are of major interest for further studies. Furthermore, the aim of the present study was to investigate the FM% of preterm infants according to gestational age, but at the moment, it is unclear whether this will be the ideal parameter for assessment of neonatal growth. Other parameters might be of equal or even of higher relevance in the future, such as FFM% for instance.Rochow et al. recently published a longitudinal observational study where the FM% of preterm infants <32 weeks of gestational age [stratified in EPI (<28 weeks) and VPI (28–31 weeks)] had an impact on the neurodevelopment outcome at the age of 18 months. Ninety-six preterm infants received a Bayley III assessment at 18 months corrected age, showing that infants with a higher fat mass during hospitalization had a higher Bayley score . In addiThe higher FM% in EPI might indicate a higher risk for the development of adiposity and cardiovascular disease in later life, but the optimal body composition of premature infants at term-equivalent age is still unknown; therefore, we can only speculate about that.In conclusion, EPI had a significantly higher FM% compared to VPI at term-equivalent age. Preterm infants weight percentile at birth and the course to discharge had no impact on body composition. The nutritional regimen in our cohort seems to be adequate as in comparison to reference charts the mean FM% of the present study population was within normal range.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.The studies involving human participants were reviewed and approved by Ethics Committee of the Medical University of Graz, Austria. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.MB and BU: conception and design. MB, NM, and BW: collection and assembly of data. MB, ZK, CB, NM, and BU: analyses and interpretation of data. MB, CB, and BU: drafting of the article. MB, ZK, CB, NM, BW, SH, and BU: critical revision, editing, and final approval of the article.ZK received a scholarship for her Doctoral Studies from the Higher Education Commission (HEC) Pakistan and OeAD. Urlesberger Berndt was a member of the Advisory Board of Milupa/Danone. The remaining 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.


Root canals were obturated with 35/0.04 gutta-percha (single-cone technique). The samples were obtained from apical, middle, and coronal thirds. Dentinal tubule penetration depth and percentage of penetration around the canal perimeter were measured. The statistical analysis was performed using Mann Whitney U test and Wilcoxon t-test . ES exhibited a significantly higher penetration than AHP in apical and middle thirds (p < 0.05), and in middle and coronal thirds relative to BR (p < 0.05). The percentage of penetration around the canal perimeter was significantly higher for ES compared to BR in all thirds, but only in the apical third for AHP (p < 0.05). The pre-mixed silicate-based sealer exhibited better penetration than the powder/liquid one.Dentinal tubule penetration influences root canal treatment sealing. The aim of this study was to compare dentinal penetration of two clinical presentations of silicate-based sealers using confocal laser. Sixty single-rooted human teeth from 50–70 year-old patients extracted for orthodontic/periodontal reasons were used. Canals were prepared using Mtwo system up to 35/0.04, with 5.25% NaOCl irrigation and final irrigation using 17% EDTA. Teeth were randomly assigned into study groups (n The objective of root canal obturation is to hermetically seal the canal system so that it is isolated, and thus prevent any leakage into or out of the root. The sealer applied in the process of obturation is responsible for dentin sealing, regardless of the technique used ,2. DiffeUnder the present criteria, endodontic sealers are expected not only to seal the root canal system, but also promote the healing of injured periapical tissues to produce a biological apical seal.Currently, new silicate-based sealers with a composition inspired by mineral trioxide aggregate (MTA) are available. These materials are formed, mainly, by calcium silicates and phosphates, and calcium hydroxide . They arEndoSequence BC Sealer  is a premixed silicate-based material presented in a ready-to-use format . BioRootSeveral studies have verified the excellent biocompatibility ,9 and biDentine tubular penetration represents a physical barrier for microorganisms and increases the retention of the sealer ,18, hencConfocal Laser Scanning Microscopy (CLSM) is a widely used technique for the study of tubular penetration of various materials. Several published studies in the field use this method to evaluate the penetration of sealing cements ,17,18,19Due to the increasing interest and clinical use of these endodontic biomaterials, there is a need to expand the existent information in this regard. The identification of significant differences in tubular penetration between the different presentation forms of the sealers could potentially lead to an increased clinical use of one form or another.Accordingly, the objective of the present in vitro study was to evaluate the dentinal tubular penetration of different endodontic sealers by comparing two silicate-based sealers, one premixed and the other in powder/liquid form with each other, and with a resin-based sealer; by means of an analysis with confocal laser scanning microscopy. The null hypothesis was that there is no difference between the tested materials in their tubular penetration.Universitat de València (ref. H1460624886119). Teeth with root resorptions, carious lesions , immature apices, fractures, or previous root canal treatments were excluded.Maxillary and mandibular single-rooted teeth extracted from 50–70 year-old patients due to periodontal or orthodontic reasons were selected (N = 60), all of which presented a type I canal configuration according to Weine’s classification , and an The selected teeth were decoronated at 15 mm from the apex to standardize sample lengths and they were prepared at a working length of 14 mm with the Mtwo rotary system  up to a 35/0.04 file, having previously achieved patency using K10 files . Irrigation during instrumentation was performed using 3 mL of 5.25% sodium hypochlorite , and final irrigation was carried out with 17% EDTA  during 1 min, followed by 5 mL saline solution.i = 20), according to the silicate-based sealers: group 1, EndoSequence BC Sealer (ES); group 2, BioRoot RCS (BR), and a control group (nc = 20) AH Plus (AHP). The sample size was established by comparison with similar studies in the field [Samples were randomly assigned to 2 study groups  to make them visible under confocal laser scanning microscopy (CLSM). One g of endodontic sealer was weighed on an analytic scale  with a precision of 0.0001 g. Next, 0.002 g of the Rhodamine B was weighed.Endodontic sealers were prepared following their manufacturers’ instructions, adding a fluorochrome  by means of the single-cone technique.During the storage period, before and after the instrumentation and obturation, the roots were kept in a 100% humidity environment. After a minimum of 72 h of storage, to ensure the complete setting of the materials, samples were obtained from the apical, middle, and coronal thirds at 3, 5, and 8 mm from the root apex, respectively, using a diamond disc to obtain a 1 mm section of each third. The obtained samples were fixed onto microscope slides and were polished using fine and superfine grain SoftLex discs . The samples were then stored in a light-free environment to avoid a previous exposure of the fluorochrome to light before it was viewed under CLSM.The equipment used for the microscopic study was CLSM Leica TCS SP2  with 543 nm and 578 nm excitation and emission wavelengths, respectively. Sample analysis was performed using 10× magnification. Images were registered and posteriorly analyzed via ImageJ v1.51 software . Dentinal tubule penetration depth (in μm) and the percentage of penetration around the canal perimeter was measured from the images obtained by CLSM .® SPSS V25.00 . Distribution was evaluated by the Kolmogorov Smirnov test, and it was determined that the variables did not present a normal distribution. Accordingly, values of penetration into dentinal tubules of the two silicate-based sealers were compared between them and with AH Plus sealer (control) in each root third  by U Mann Whitney test. Comparisons between thirds in each group was performed two by two by means of the Wilcoxon T-test. The confidence interval was established at 95%.Data obtained were statistically analyzed using IBMp < 0.05), and in the middle and coronal thirds relative to BR. The percentage of penetration around the canal perimeter was significantly higher for ES compared to BR in all thirds, but only in the apical third for AHP (p < 0.05).The quantitative results of the CLSM image analysis in terms of the tubular penetration depth and percentage of dentinal tubule perimeter penetration are presented in T-Test. Both in the silicate-based sealers and AHP groups, the penetration depth was significantly decreased from the coronal to the apical thirds (p < 0.05). In relation to the percentage of dentinal tubule perimeter penetrated by cement, ES group showed significant differences between the coronal and apical thirds (p < 0.01); BR group between the coronal and apical thirds, and between the coronal and middle thirds (p < 0.005); while AHP exhibited significant differences between all thirds (p < 0.05).Comparisons within each group, between thirds were performed two by two by means of the Wilcoxon p < 0.05).To the authors’ knowledge, the novelty of this paper resides in the fact that this is the first study to explore the differences in dentinal tubule penetration between silicate-based endodontic sealers in terms of their form of presentation (pre-mixed or powder/liquid).ES and BR are two pure silicate-based sealers. Although they present a similar composition, they differ in their presentation. While ES comes premixed, in a ready-to-use format, BR is available in powder/liquid form. This difference means that, despite the fact that both materials require water to start and complete their setting reaction, ES will only depend on the remaining humidity in the dentinal tubules, while BR starts its reaction when mixing it .Currently, no endodontic sealer meets all the ideal properties expected of them, such as dimensional stability, biocompatibility, and adhesion to root canal walls . HoweverCLSM is a widely used procedure for the study of tubular penetration ,26,27,28Techniques like scanning electron microscopy (SEM) have also been used for the study of tubular penetration ,31,32,33In relation to the results of the present study, ES showed a higher penetration compared to the other sealers although not significantly in all cases. This may be due, partially, to the size of the sealer particles (<1 μm) , which iEl Hachem et al.  and EymiThe median values showed by AHP are similar to those from various studies ,40,41. AThe assessment of the percentage of penetration around the canal perimeter has an important clinical relevance, acting as a representation of the sealing ability against microorganisms in the dentinal tubules, regardless of the depth of penetration of the sealer ,42. TherWang et al.  reportedDespite the fact that the tubular penetration of BR was not significantly different from that of AHP, the values obtained in our study were lower than ES. The difference in penetration between both silicate-based sealers may be due to their different forms of presentation. Even having followed the manufacturers’ instructions for the preparation of BR, small variations in the dosage during the mixing process may have been produced. Consequently, this may have acted as a limitation, potentially having an effect on the final results by varying the fluidity of the sealer, and thereby, influencing its tubular penetration. Since ES is presented in a premixed, ready-to-use format, its fluidity and consistency are not altered, so they are always optimal.Despite using human teeth extracted for different reasons , the tubular penetration pattern followed the same trend in all teeth. Both for the depth of penetration inside the dentinal tubule and for the percentage of tubular penetration, the apical third showed the lowest results, followed by the middle and coronal thirds; coinciding with other authors ,36,41,42The ready-to-use attribute from the premixed silicate-based sealers, together with their potentially higher dentinal tubule sealing exhibited in the present study, could act as supporting evidence for their clinical use versus powder/liquid sealers. However, the lack of similar studies regarding this comparison can act as a limitation for the applicability of the results of the present study. In order to extrapolate the results into the clinical setting, future studies comparing similar biomaterials under different conditions should be performed.ES exhibited the highest tubular penetration, while no significant differences were found between BR and AHP. Both the maximum depth of penetration inside the dentinal tubules and the percentage of penetration presented higher values in the coronal thirds for all the studied materials. Within the limitations of the present study, it can be concluded that tubular penetration was higher in the premixed endodontic sealer.


As for stroke recovery, rTMS was also better than the control condition . However, no significant difference was found for cognitive function recovery between the two groups . To explore the potential moderators for the primary outcome, a series of subgroup and sensitivity analyses were performed. The results implied that rTMS may be more effective in Asian samples than in North American samples (P=0.03). In conclusion, from the current evidence in this study, rTMS could be an effective treatment for patients with PSD. Further clinical studies with larger sample sizes and clearer subgroup definitions are needed to confirm these outcomes.We aimed to conduct a meta-analysis to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) in patients with post-stroke depression (PSD). Six relevant electronic databases  were searched. Randomized controlled trials (RCTs) that compared rTMS with control condition for PSD were included. The mean change in depression symptom scores was defined as the primary efficacy outcome. Secondary outcomes included the remission rate of depression, stroke recovery, and cognitive function recovery. In total, 7 RCTs with 351 participants were included. At post-treatment, rTMS was significantly more effective than the control condition, with a standardized mean difference (SMD) of -1.15 (95%CI: -1.62 to -0.69; P<0.001, I Stroke is one of the major public health concerns in the world, because of its high morbidity, mortality, and disability rates and serious financial burden . As one Several treatment options are now available for PSD, including medications, psychotherapy, and physiotherapy –7. AntiCompared to medication, physiotherapy have been demonstrated to be safer for elderly people. Among the techniques, repetitive transcranial magnetic stimulation (rTMS) is one of the most important means for PSD patients . rTMS usIn the past decades, rTMS has been widely used in the treatment of psychiatric disorders, especially for major depressive disorder (MDD) . A numbehttps://data.mendeley.com/datasets/kxcvx66s6g/1).Six relevant electronic databases  were searched from each database inception to December 2019, using different combinations of the following key words and their variants: “depression”, “stroke”, “vascular”, and “transcranial magnetic stimulation”. The detailed search strategy is provided in Supplementary Table S1. Additional articles were identified by scanning conference abstracts and reference lists of the articles obtained from the initial search and contacting the authors of the relevant RCTs for more information. The study protocol is available online (The following inclusion criteria were applied to the literature search: 1) Design: randomized controlled trials; 2) Participants: diagnosis of stroke (confirmed by computed tomography or nuclear magnetic resonance imaging) or have at least three cardiovascular risk factors; meet a diagnosis of depressive disorder according to a standardized diagnostic interview ), or present a current depressive status defined as scoring above a validated cut-off on a depressive rating scale ; 3) Intervention and control group: the efficacy of rTMS or combined therapy (rTMS plus antidepressants) was compared with that of a control condition, such as sham condition or usual treatment; and 4) Outcomes: the primary outcome was the mean change in scores from baseline to post-treatment in depressive rating scales. If there were more than one depressive rating scale used in a trial, we preferred the Hamilton Depression Scale (HAMD) as the first choice. Other scales, such as Montgomery Depression Rating Scale (MDRS) and Beck Depression Inventory (BDI), were also used as an alternative. The secondary outcomes included depression remission rate, stroke recovery, cognitive function recovery, and activities of daily living (ADL). The depression remission rate was defined as the proportion of patients whose validated depression rating score was below the determined threshold . Stroke recovery was assessed by the mean change in scores between baseline and post-treatment in stroke severity or functioning rating scales, such as National Institutes of Health Stroke Scale (NIHSS) , and ModTwo review authors (D.S. and Y.Z.) independently judged whether the study met the inclusion and exclusion criteria, evaluated the quality of the article, and completed a standardized data abstraction form. Any disagreements were resolved through discussion and sometimes with another reviewer (X.Z.) if necessary. For studies with incomplete data, a contact with the corresponding authors was attempted.http://www.training.cochrane.org/handbook) to evaluate the quality of included studies. The risk of bias was assessed and rated as “low risk”, “high risk”, or “unclear risk” according to the following domains: 1) sequence generation; 2) allocation sequence concealment; 3) blinding of participants and personnel; 4) blinding of outcomes assessment; 5) incomplete outcome data; 6) selective outcome reporting; and 7) other potential sources of bias. The criteria for rating the overall risk of bias of a study was as follows: high risk of bias (one or more domains were rated as “high risk”), low risk of bias , unclear . Any disagreements were resolved by consulting a third reviewer (X.Z.).We used the Risk of Bias Assessment Tool from the Cochrane Handbook for Systematic Reviews of Interventions (2). A P value <0.1 was deemed statistically significant, and I2 values of 25, 50, and 75% represented low, moderate, and high heterogeneity, respectively. A fixed-effects model was used to analyze the pooled data with low heterogeneity. For moderate or high heterogeneity, a random-effects model was used to analyze the pooled data  and Stata version 14.0 . We calculated the pooled estimates using standardized mean difference (SMD) for continuous outcomes and odds ratio (OR) for dichotomous outcomes. Heterogeneity was assessed using the chi-squared test and I-squared index ; 2) number of treatment sessions (≥10 vs <10); 3) augmentation with antidepressants (augmentation vs non-augmentation); 4) depression diagnosis criteria ; 5) control conditions (sham-rTMS controlled vs routine treatment controlled); and 6) region (North America vs Asia). In addition, we performed sensitivity analyses by omitting trials that were rated as high risk of bias, or trials of vascular depression. All the tests were bilateral tests, and statistical significance was defined as a probability value of P<0.05.Considering that different clinical characteristics and intervention parameters may significantly affect treatment outcomes, we performed the following subgroup analysis for the primary outcome: 1) stimulation pattern . After excluding duplicates, 384 studies remained. Of these, 358 were excluded based on their titles and abstracts because they did not meet the inclusion criteria. Two review authors independently read the full texts and excluded 19 studies for the following reasons: duplicate (n=4), ongoing trials (n=6), meeting abstract without available data (n=1), non-randomized design n=7), and no rTMS intervention (n=1). In total, seven trials were included in this meta-analysis , and no ,. FigureThe characteristics of the included trials are described in 2=71%; P=0.002). As for the remission rate of depression, patients receiving rTMS were more likely to acquire symptom remission than patients receiving control conditions , whereas the pooled estimate was not significantly changed .We conducted six different subgroup analyses to explore the potential moderators of the primary efficacy outcome. No significant differences were found between the different subgroups in stimulation pattern, number of treatment sessions, augmentation with antidepressants, depression diagnosis criteria, and the different control groups . In the Overall, the quality of the included studies in our meta-analysis was low to moderate. Two (28%) trials were rated as high risk of bias, and five (62%) were moderate . The risk of bias was rated as high concerning blinding of participants in two RCTs and masking of outcome assessors in one RCT . For the primary efficacy outcome, the funnel plot seemed asymmetric , suggesting a potential publication bias. We, therefore, performed a filled funnel plot using the trim-and-fill method. The adjusted SMD was -1.513 (95%CI: -2.056 to -0.971), indicating that rTMS groups were still significantly superior to the control conditions P<0.001, .In this study, we carried out a meta-analysis to pool the currently best clinical evidence of rTMS for the treatment of PSD. Our meta-analysis found that rTMS was an effective treatment for improving depressive symptoms in patients with PSD, compared with control conditions. Due to data limitations, our study only assessed the improvement of depressive symptoms at the end of treatment, while da Silva Júnior et al. reported that rTMS continued to relieve depressive symptoms until 1 month after the end of the treatment . The potWe conducted a series of subgroup analyses to further explore the potential moderators that may influence the result, which included the stimulation pattern, number of treatment sessions, augmentation with antidepressants, depression diagnosed criteria, different control conditions, and study region. The results showed that none but the study region significantly affected the primary outcome, and rTMS may be more effective in Asia than in North America (P=0.03). We considered that the non-blind design in some Asian studies may underestimate the placebo effect. Since the rTMS stimulation parameters such as frequency, intensity of RMT, and coil position vary among different studies, it is difficult to determine which specific parameter is best for clinical practice. For MDD, clinical consensus recommends high-frequency stimulation for the left dorsolateral prefrontal cortex (DLPFC) and low-frequency stimulation for the right DLPFC . The patOur study conducted three sensitivity analyses. The results of sensitivity analysis by omitting trials within high risk of bias suggested that the efficacy outcomes were robust. The sensitivity analysis after removing the trials focused on vascular depression suggested that adding data on vascular depression did not affect our findings. However, due to the small sample size of this data, this result requires further verification. In the sensitivity analysis by excluding each study one by one, we found that the study by Gu and Chang  was the 2=96%). Compared with our study, Shen et al. searched four Chinese databases and included more Chinese trials. The main reason for not including more Chinese studies was that most are unclear about the description of the clinical process, and after our verification, many of these studies had a case-control design; therefore, we did not search Chinese databases.Some studies have also explored the efficacy of rTMS in the treatment of PSD. Shen et al.  includedIn terms of secondary outcomes, our results showed that the remission rate of depression of the rTMS groups was statistically higher than that of the control groups. In terms of stroke recovery, better improvement was found in the rTMS groups than in the control groups. This positive result is consistent with the findings of many studies on the effect of rTMS on stroke patients without depression. In 2012, a multicenter RCT, which included 204 patients with hemiplegia after stroke, found that low-frequency rTMS could promote the recovery of limb function on the hemiplegic side, and there were no adverse reactions in all patients . Some stBased on our limited trial data, there was no significant difference in cognitive recovery between the two groups, but with a high degree of heterogeneity. We consider the high heterogeneity may due to two studies and too few participants included in our study. However, many previous studies have shown that rTMS is effective in improving cognitive function of patients without PSD. Anderkova et al. showed that rTMS improves cognitive function of patients with mild cognitive impairment and Alzheimer’s disease . Some stSafety is another important index for evaluating a treatment method. In the present study, there were two trials that described adverse events, including transient headaches, local discomfort at the site of the stimulation, and exacerbation of initial insomnia. Since the sample size was small, no statistical analysis was carried out. rTMS has been widely proven to be safe and tolerable. However, some studies have reported that it has side effects of inducing epilepsy in healthy people, and in depressed patients, tinnitus patients, and patients with chronic pain, all of which were case reports . In our Our research and previous studies have demonstrated the efficacy of rTMS in the treatment of PSD, but the detailed mechanism is still unclear. Studies have indicated that individuals with PSD may have altered brain network structures, as well as abnormal white matter function. rTMS may reduce depressive symptoms by increasing the fractional anisotropy value in patients with PSD. However, the stimulation target and specific parameters need to be optimized . In addiThere were some limitations of this meta-analysis. First, this study included a small sample size with a limited source of participants, which may affect the stability of the results. Second, some of the included studies did not clearly describe the allocation sequence concealment and sequence generation, which may be a potential risk of bias for the final results. Third, there was a potential publication bias in this article, and although we have made corrections, it may still have an impact on the results. Fourth, the evidence for PSD is very limited, given the small number of studies and the small number of participants included in each study. There was not enough data to explore the adequate parameters  of rTMS in treating PSD. Fifth, patients with vascular depression were also included in our study, and the clinical characteristics of these patients were different from those of patients with PSD. Although we have performed a sensitivity analysis and the primary result did not change significantly, the inclusion of such patients may still cause risk of bias in the results. Finally, due to the limitations of meta-analysis, individual data and basic clinical information cannot be directly analyzed.Repetitive TMS was effective in improving depressive symptoms and promoting stroke recovery. In addition, the side effects of rTMS treatment were minimal and controllable. More research with large sample sizes are needed to confirm the result.


Bisphenols (BPs) are commonly known plastifiers that are widely used in industry. The knowledge about the impact of BPs on thyroid function is scarce. Proper thyroid functioning is especially important for women of reproductive age, as hypothyroidism affects fertility, pregnancy outcomes and the offspring. There are no studies analyzing the influence of BPs on thyroid function and volume in non-pregnant young women. The aim of this cross-sectional study was to evaluate the relationship between bisphenol A and its 10 analogs  on thyroid function and volume in women of reproductive age. Inclusion criteria were: female sex, age 18–40 years. Exclusion criteria were history of any thyroid disease, pharmacotherapy influencing thyroid function, pregnancy or puerperium, and diagnosis of autoimmune thyroid disease during this study. Venous blood was drawn for measurement of thyrotropin (TSH), free thyroxine, thyroid peroxidase antibodies, thyroglobulin antibodies, BPs. Urine samples were analyzed for: ioduria and BPs. Ultrasound examination of thyroid gland was performed. One hundred eighty participants were included into the study. A negative correlation was found between urine BPC and the thyroid volume . Patients with detected urine BPC presented smaller thyroid glands than those with not-detected urine BPC (p = 0.0008). A positive correlation was found between TSH and urine BPC . Patients with detected urine BPC presented higher concentrations of TSH versus those with not-detected urine BPC (p = 0.003). There were no relationships between any of serum BPs as well as the other urine BPs and thyroid function and its volume. The only BP that demonstrated the relationship between thyroid function and its volume was BPC, probably because of its chemical structure that most resembles thyroxine. Exposure to this BP may result in the development of hypothyroidism that could have a negative impact on pregnancy and the offspring. Bisphenol A  was first developed in 1891 as a synthetic estrogen and in the 1930s has been shown to stimulate the female reproductive system in rats. Because of the ability to interfere with the action of hormones, BPA belongs to the class of endocrine disrupting chemicals (EDC) .The most studied bisphenol, BPA, shows numerous adverse development effects including estrogen dependent neoplasms –13; metaProper thyroid functioning is crucial for the maintenance of homeostasis in human organisms. For women of reproductive age, attaining euthyroidism is critically important since hypothyroidism affects fertility, pregnancy outcomes, and the health of the offspring. Pregnant women with overt or subclinical hypothyroidism have a higher risk of preeclampsia, premature delivery, premature abruption of placenta and miscarriage –22. Matein vitro  on thyroid function were performed in vitro , 25, 26 in vitro , 27–29, in vitro , 30–32. in vitro , while oin vitro , 27. HowTherefore, the aim of this cross-sectional study was to evaluate the potential relationship between BPA and its 10 analogs on the thyroid function and volume in women of reproductive age living in Warsaw, Poland. These 10 analogs include bisphenol S (BPS), bisphenol C (BPC), bisphenol E (BPE), bisphenol F (BPF), bisphenol G (BPG), bisphenol M (BPM), bisphenol P (BPP), bisphenol Z (BPZ), bisphenol FL (BPFL), and bisphenol BP (BPBP).a priori approval by the institution’s human research committee. The study was approved by the Committee on Bioethics at the Medical University of Warsaw (nr KB/104/2015). Written informed consent was obtained from all participants.This cross-sectional, clinical study was conducted in the Department of Internal Medicine and Endocrinology, Medical University of Warsaw in the period between October 2017 and May 2019. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in Inclusion criteria were female sex and age between 18 and 40 years. Exclusion criteria were as follows: (i) a documented history of no thyroid disease before the study ; (ii) pharmacotherapy influencing the thyroid function ; (iii) pregnancy or puerperium; and (iv) diagnosis of autoimmune thyroid disease during this study. Finally, 180 women were eligible for the study. All were students of Medical University of Warsaw. All of them were research volunteers. Detailed characteristics of the studied subjects are contained in Ultrasonography of the thyroid gland was performed by physician with a 5-year experience (JMB). All the ultrasound scans were performed using the Hitachi Avius Medical ultrasound technique system equipped with the 7.5–12 MHz high frequency linear array transducer. Thyroid ultrasound procedures were done on the basis of the Ultrasound Examination Standards of the Polish Ultrasound Society and American College of Radiology Guidelines , 34. TheAll procedures were performed with precautions intended to minimize the risk of sample contamination with BPs. Venous blood was drawn from all study participants, in the morning, after an overnight fasting (>8 h) into 7-ml glass tubes. After 30 min of incubation in the room temperature the blood samples were centrifuged for 15 min . Next, serum samples were collected into 1.5-ml glass vials with polytetrafluoroethylene caps using disposable transfer (Pasteur) pipette made of low-density polyethylene. Serum samples were frozen and stored vertically at −70°C for further analyses. Additionally, each study participant was asked to bring 100 ml of midstream morning urine sample for the evaluation of urinary iodine, creatinine and BPs. Urine samples were also collected into glass jars, then frozen and stored vertically at −70°C for further analyses.TSH, free thyroxine (fT4), thyroid peroxidase antibodies and thyroglobulin antibodies were measured in serum samples using an electrochemiluminescence immunoassay  on Cobas e411 Analyzer  in the Scientific Laboratory at the Department of Internal Medicine and Endocrinology, Medical University of Warsaw. Serum thyroid peroxidase antibodies and thyroglobulin antibodies above >34 and >115 IU/ml, respectively, were considered as “positive”.Urine iodine concentrations were measured by the catalytic arsenium-cerium method based on Sandell-Kolthoff reaction . UrinarySerum and urine concentrations of BPA and its 10 analogs  were measured using high performance liquid chromatography method with tandem mass spectrometry (HPLC-MS/MS) on the Shimadzu triple quadrupole LC-MS/MS system  equipped with an electrospray ionization source working in the negative multiple reaction mode, in the Department of Analytical Chemistry, Chemical Faculty, Gdańsk University of Technology. Detailed description of the whole method has been already published elsewhere . The limAll statistical analyses were performed with the usage of the computer program STATISTICA ver.13.0 for Windows. Distributions of the variables were evaluated with the Shapiro-Wilk test. Continuous variables are presented as arithmetic mean ± standard deviation (SD). Categorical data are presented as numbers and percentage values (%).The analysis of the results consisted of the following steps: First, correlations were performed between concentrations of selected BPs and thyroid volume, TSH and fT4 using the Spearman correlation test. Second, comparisons of thyroid volume, TSH and fT4 were performed in two independent groups of participants (with detected versus not-detected concentrations of studied BPs) using the Mann-Whitney U test.Because of the multiple comparisons, the Bonferroni correction was used and all results with p value < 0.0033 were considered statistically significant.Database analyzed in this study is available for interested researchers in DR as well as mean serum and urine concentrations for each of the studied BP are presented in All correlations between thyroid volume and concentrations of BPs, respectively in serum and urine, are given in All results from the comparison of thyroid volume according to the detection of the analyzed BPs (respectively in serum and urine) are presented in All correlations between TSH and fT4 with BPs concentrations in serum and urine are presented in The results from the comparison of TSH and fT4 levels according to the detection of selected BPs in serum and urine are shown in BPA analogs are widely used in many applications replacing BPA, but without proper understanding of their harmful potential. Human and wildlife observations point toward subtle, but significant effects of low-dose BPs exposure on the thyroid function. However, mechanistic and toxicological aspects as well as epidemiological design are necessary for the objective assessment of the impact of BPs on humans. Hence, this demands a great challenge for scientists who have to examine the possible toxicity of a selected molecule.DR of BPA in studies was mainly at over 90% , 38, 39.The difference in the level of DRs between studies is probably caused by living environment of the participants. Moreover, different methods of BPs detection were used . Also, the relatively high LOD for the method used could be another reason for lower DR of BPs in the current study. Furthermore, it is worth to emphasize the fact that in the studies there were examined conjugated, unconjugated or total BPs (mainly BPA). Also the stability of phenolic compounds differs according to the type of sample  and the method of samples storage .in vitro. In the study on 718 children of school-age living in China, Wang et al.  in fluids . To our g et al.  reportedin vitro. Moriyama et al. . To the best of our knowledge no studies on human or animals have considered the influence of exposure to BPC on thyroid function. The change of thyroid volume together with the increase of TSH with unaltered fT4 seems to happen only at subclinical level. We suggest that thyroids exposed to BPC secrete less amounts of thyroid hormones, but without statistical significance in fT4 levels. As a consequence, the level of TSH increases. In case of pregnancy overt hypothyroidism may be revealed that could contribute to an increased risk of neurodevelopmental disease, learning difficulties, language delay and IQ loss in offspring , tetrachlorobisphenol A (TCBPA), tetramethylbisphenol A (TMBPA), and 3,3’-dimethylbisphenol A. However, BPA and other analogs  did not show such action. These authors suggest that the 4-hydroxyl groups of the A phenyl ring and the B phenyl ring of BPA analogs are essential for these hormonal activities. Moreover, substituents at the 3,5-positions of the phenyl rings and the bridging alkyl moiety significantly modifies the thyroid hormonal activity. This could be the reason why in our study the only one BP that exhibited the relationship with thyroid functioning was BPC. The study presents strong relationship between thyroid and BPC, while the rest of the analyzed BPs did not show statistically significant trend for such relationships. Therefore, we suggest that the chemical structure of BPC most resembles T4 in that substituents of phenyl rings are as iodine ions in T4.Kitamura et al.  performein vitro study on the rat pituitary cell line (GH3) and the thyroid follicular cell line (FRTL-5) clearly indicated the down-regulation effect on tshβ, trα, trβ, dio1, and dio2 genes in GH3 cells caused by BPA and its selected derivatives. The analogs, such as BPF, BPM, and BPZ, presented even stronger potency compared to BPA. On the other hand, in FRTL-5 cells after exposure to BPA, BPAF, BPAP, BPM, or BPS, at least one gene responsible for either thyroid hormone synthesis  or their transcription factors (pax8 and nkx2.1) exhibited over 1.5-fold up-regulation. In contrast, BPC, BPF, BPP, and BPZ did not lead to transcriptional changes of >1.5-fold. The conclusion is that exposure to BPs could up-regulate or down-regulate gene transcription that depends on the cell line and the type of the BP.Hence, thyroid hormone disruption by BPs may not be solely explained by the interaction with the TR. Reports in the literature suggest other ways that BPs dysregulate thyroid hormone homeostasis at the transcriptional level. Lee et al.  in the iAn advantage of the present study is that it was conducted in the homogenous group of female participants at similar age. All were inhabitants of the same Mazovian district, thus eliminating the study bias reflecting the influence of the environmental factors. On the other hand, the small sample size and cross-sectional design are the limitations of this study. It would be interesting to examine women after follow-up as well as to conduct studies in other populations, such as pregnant women, children and men. Also, the study considering mixtures of thyroid EDCs and their synergies would be of a great value, as these are what we are most likely exposed to.In conclusion, to the best of our knowledge our study is the first to evaluate the potential effects of BPA and its 10 analogs on the thyroid function and volume in women of reproductive age. This cross-sectional study presents that BPC impacts on the thyroid function and volume that might have negative effects on fertility and pregnancy outcomes in young women , 44. It The database analyzed in this study is available for interested researchers in The studies involving human participants were reviewed and approved by Committee on Bioethics, Medical University of Warsaw, Warsaw, Poland. The patients/participants provided their written informed consent to participate in this study.Conceptualization: JM-B, PM, and TB. Methodology: JM-B, PM, KM-C, DR, and AW. Data collecting: JM-B and KM-C. Statistical analysis: JM-B. Writing—original draft preparation: JM-B and PM. Writing—review and editing: PM, TB, DR, AW, and KM-C. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.