Many clinicians are facing the dilemma about whether they should apply the active surveillance (AS) strategy for managing Clinically Node-negative (cN0) PTMC patients in daily clinical practice. This research plans to construct a dynamic nomogram based on network, connected with ultrasound characteristics and clinical data, to predict the risk of central lymph node metastasis (CLNM) in cN0 PTMC patients before surgery.A retrospective analysis of 659 patients with cN0 PTMC who had underwent thyroid surgery and central compartment neck dissection. Patients were randomly (2:1) divided into the development cohort (439 patients) and validation cohort (220 patients). The group least absolute shrinkage and selection operator (Group Lasso) regression method was used to select the ultrasonic features for CLNM prediction in the development cohort. These features and clinical data were screened by the multivariable regression analysis, and the CLNM prediction model and web-based calculator were established. Receiver operating characteristic, calibration curve, Clinical impact curve and decision curve analysis (DCA) were used to weigh the performance of the prediction model in the validation set.Multivariable regression analysis showed that age, tumor size, multifocality, the number of contact surface, and real-time elastography were risk factors that could predict CLNM. The area under the curve of the prediction model in the development and validation sets were 0.78 and 0.77, respectively, with good discrimination and calibration. A web-based dynamic calculator was built. DCA proved that the prediction model had excellent net benefits and clinical practicability.The web-based dynamic nomogram incorporating US and clinical features was able to forecast the risk of preoperative CLNM in cN0 PTMC patients, and has good predictive performance. As a new observational indicator, NCS can provide additional predictive information. The increase in the occurrence of thyroid cancer is mainly due to the increase in the incidence of papillary thyroid microcarcinoma (PTMC). Hence, PTMC dominates in the diagnosis and treatment of thyroid cancer. Since most tumors are not clinically obvious or palpable, most PTMCs are diagnosed by high-resolution ultrasound (US) or US-guided fine-needle aspiration. With these techniques becoming more common, an increasing number of cases were diagnosed as PTMC , leadingIn the recent years, the active surveillance (AS) strategy for low-risk PTMC has been gradually adopted worldwide to avoid over-treatment. However, AS is not suitable for all PTMC cases. Among them, central lymph node metastasis (CLNM) is the predominant influencing component. CLNM is more general in PTMC patients and the occurrence can be as high as 64.1% . PTMC paUS is the primary method to evaluate TNM staging of PTMC before surgery and AS, which is helpful for diagnosis and evaluation of PTMC that may relapse . The occIn the studies involving cN0 PTMC patients, the independent predictors of CLNM were not consistent –16. In aThe purpose of this study was to advance and validate a US-based dynamic nomogram to foresee the hazard of CLNM in cN0 PTMC patients.This research employed a single-center retrospective design, and all participated patients were anonymized. Hence, this research was permitted by the research ethics committee and the informed consent requirement was waved. Medical records from January 2018 to February 2020 were retrieved from our institution database. This research listed 659 patients totally with cN0 PTMC who met the demands. Inclusion criteria: (1) patients who underwent thyroidectomy and CCND for the first time and were diagnosed with PTMC with histopathology; (2) status of CLNM were confirmed by pathology; (3) preoperative imaging diagnosis was negative for CLNM; (4) patients who had undergone US examination in our department one month before surgery; (5) the tumors underwent real-time elastography (RTE); (6) there were complete medical data.Exclusion criteria: (1) patients who had thyroid carcinoma surgery or treatment before; (2) patients with other thyroid malignant tumors; (3) patients with distant metastasis or malignant tumors in other organs; (4) patients with few tumor foci or lymph node (LN) metastases, and pathological diagnosis of PTMC or CLNM metastasis could not be confirmed; (5) thyroid ablation was performed before surgery; (6) incomplete US image information, or poor image quality.During the study, all ultrasound examinations were performed by color Doppler diagnostic tools , with high frequency of 6-13 MHz linear array probe. All patients with thyroid nodules experienced preoperative US examination, and data were stored for follow-up analysis.Two independent radiologists with 11 and 16 years of thyroid imaging experience retrospectively analyzed these ultrasound pictures. In cases that the radiologists had different opinions, the third experts who have over 20 years of experience was involved in the discussion and a final decision was made. These three radiologists were not aware of patient’s medical data, and surgical and pathological results.The sonographic features of the tumor under ultrasound were observed and recorded, including tumor size, tumor position, multifocality, bilateral tumor , echogenicity, calcification patterns , number of contact surface , composition, shape, margin, taller-than-wide, chronic lymphocytic thyroiditis (CLT), internal color Doppler vascularity  for each nodule would be assigned different points  according to Asteria et al.  standardP <0.05, the difference is statistically significant. Continuous variables used Wilcoxon-Mann-Whitney U or test t-test. Pearson χ2 test or Fisher’s exact test was employed for categorical variables. Categorical variables used Fisher’s exact test or Pearson χ2 test. As there were many multi-categorical variables, the group least absolute shrinkage and selection operator (Group lasso) method using 10-fold cross-validation was applied to choose the most predictive US features in the development dataset. Multivariable logistic regression analysis was made on the above US risk factors and clinical data, and the risk predictors and regression coefficients were obtained, and the nomogram was generated. In the development and verification data set, the receiver operating characteristic (ROC) curve and calibration curve are derived to assess the performance of the web-based nomogram. In the validation set, decision curve analysis (DCA) and clinical impact curve were applied to assess the feasibility and application value of the optimization model in clinical practice  and R software  were used for statistical analysis.P =0.715). In addition, there were no significant differences in sex and age between the CLNM positive and the negative group, indicating the applicability of the development and validation data sets.The Group Lasso was used to select the non-zero coefficient features of the prediction model in the development dataset (P = 0.956), demonstrating that the model fitted well. The calibration curve shows that the predicted value is in good agreement with the actual value, and there is no deviation from the ideal model. The Hosmer-Lemeshow test of the predictive model in the validation set also did not show a significant difference (P=0.343). According to the calibration curve, when the prediction probability was between 22% and 50%, the development model slightly overestimated the prevalence (The AUC of the prediction model in the development set was 0.78 (95% CI: 0.735-0.825), and in the validation set was 0.77 (95% CI: 0.703-0.837) (https://predictclnminptc.shinyapps.io/DynNomapp3/) was generated to forecast the likelihood of CLNM in patients with cN0 PTMC. It is very convenient to input the risk prediction factors, such as patient’s age and US image features on the web page for real-time personalized prediction of patient’s CLNM probability. For example, the black line represents the probability (81.2%) and 95% CI (0.598-0.927) of CLNM in patients who are 30 years old, tumor diameter of 0.7 cm, multifocality, NCS ≥ 2, and ES of 3 , while other studies showed that the occurrence of CLNM in patients who had cN0 PTMC confirmed by histopathology was 31-60.9% 37/659, w. Most cNAccording to the multivariable regression analysis, our study found that young patients, maximum tumor diameter, multifocality, NCS, and RTE were independent risk factors that may predict CLNM. These predictors can be easily obtained before surgery. The model built in this study shows a high predictive value in the development and validation cohorts, and good consistency and recognition ability. Patients with more NCS and higher RTE scores may be, relatively, at higher risk of CLNM. Moreover, young patients with multifocality and larger tumor size should not be ignored, they are more likely to develop CLNM.P < 0.001. However, the multivariable analysis did not demonstrate a significant relationship between sex of cN0 PTMC patients and CLNM. The conclusion was consistent with the previous study  lesions; thus, it is often unable to find all lesions, which may underestimate the role of multifocality and bilateral tumors in predicting CLNM . FinallyIn conclusion, the web-based dynamic nomogram incorporating US and clinical features was able to forecast the risk of preoperative CLNM in cN0 PTMC patients, and has good predictive performance. As a new observational indicator, NCS can provide additional predictive information. The possibility of CLNM increased with an increase of NCS and ES.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by The Research Ethics Committee of Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences. Written informed consent from the participants’ legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.CH, SC, and BZ designed this study. SS, MW, HZ, SW, and XA collected the data. CH, BZ, SS, and ZL analyzed the data. All authors contributed to the article and approved the submitted version.This work was supported by the Guangzhou Municipal Science and Technology Planning Project (CN) , Medical Scientific Research Foundation of Guangdong Province (A2019080).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


P-values < 0.05 were considered statistically significant. The two-step cluster analysis determined three clusters: school adaptation group, school maladaptation group, and school over-adaptation group. The last group significantly exhibited the most mental health problems. Membership of this group was significantly associated with being female , being older , those who considered online education to be less beneficial , shorter sleep time on weekdays , longer sleep time on holidays , and worse restorative sleep . The results suggest that academic staff should understand distinctive features of school adaptation owing to the rapid transition of the educational system and should develop support systems to improve students' mental health. They should consider ways to incorporate online classes with their lectures to improve students' perceived benefits of online education. Additionally, educational guidance on lifestyle, such as sleep hygiene, may be necessary.This study aimed to clarify the adaptation features of University students exposed to fully online education during the novel coronavirus disease 2019 (COVID-19) pandemic and to identify accompanying mental health problems and predictors of school adaptation. The pandemic has forced many universities to transition rapidly to delivering online education. However, little is known about the impact of this drastic change on students' school adaptation. This cross-sectional study used an online questionnaire, including assessments of impressions of online education, study engagement, mental health, and lifestyle habits. In total, 1,259 students were assessed. The characteristics of school adaptation were analyzed by a two-step cluster analysis. The proportion of mental health problems was compared among different groups based on a cluster analysis. A logistic regression analysis was used to identify predictors of cluster membership.  With the onset of the novel coronavirus disease 2019 (COVID-19) pandemic, in 2020 –5. The mOn the one hand, the literature has revealed the following advantages of online education during the pandemic: remote learning, accessibility of programs, and asynchronous learning . On the This study aimed to clarify the features of school adaptation in University students exposed to a fully online education system during the COVID-19 pandemic and to identify the accompanying mental health problems and predictors of school adaptation.This study was conducted at Osaka University in Osaka Prefecture, Japan, from July 27, 2020 to August 10, 2020. Participants were regular affiliation students in their first year of undergraduate study who were currently enrolled at Osaka University, excluding those temporarily absent or studying abroad. In the Japanese education system, University students, with the exception of first year undergraduates, have few opportunities to attend common classes due to faculty-specific experiments or academic activities. As such, this study focuses on just the first year of undergraduate study to reveal the impact of sudden exposure to a fully online education system. Inclusion criteria were enrolment in all online-type lectures, which consisted of real-time classes, on-demand classes, and lecture material distribution classes. Students were excluded if they had any missing assessment data.This study was a part of the survey which sought to investigate the content and feature of online education provided to University students in the Osaka University during the COVID-19 pandemic, while also focusing on the characteristics of school adaptation and mental health for them. This study used a cross-sectional and observational design. The survey used an online questionnaire for all potential participants to assess their attendance status for online classes and mental health parameters. The study tool was distributed among participants by the online education support system of Osaka University and accessed by them using their own PC, tablet, or smartphone. In the online education support system, information about all students in Osaka University was registered. Students could not make multiple identifiers to answer the questionnaire. The questionnaire included a written explanation that completing the questionnaire implied informed consent; participation in the study was voluntary; and no negative consequences would occur if they chose not to participate.In total, 15,194 undergraduate students were registered at Osaka University. First year undergraduate students comprised 22.4% of the total number of students. The online questionnaire was sent to 3,294 students; 1,824 students responded (55.4%). Based on the eligibility criteria, 1,259 students (38.2%) were included in the analysis .The questionnaire employed in this study is presented in the The demographic data of the participants were obtained via the online education support system of Osaka University. The variables included their sex and age. The faculty of the respective classes that participants attended were also assessed since it was postulated that the degree or content of students' experience with online classes were likely to vary depending on the faculty member.Participants were asked to evaluate the level of subjective benefits of online education on a scale of 1 to 5  was used to assess study engagement . It consr = 0.66 (p < 0.01), respectively. As for the criterion-related validity, there were significant correlations among the UEWS-S-J, social support, resilience, and subjective happiness.The UWES-S-J has been reported to show good reliability and validity for the assessment of study engagement among Japanese students . The intParticipants were asked to evaluate the level of their current stress on a scale of 1 to 4, with 1 being a little stressed and 4 being very stressed. Fatigue, anxiety, and depression were each assessed as a binary variable, with 1 defined as yes and 0 as no.Participants were asked to report their total sleep time on both weekdays and holidays during the past month on the following scale: 1 = <5 h, 2 = 5–6 h, 3 = 6–7 h, 4 = 7–8 h, 5 = 8–9 h, and 6 = >9 h. These scores were replaced with approximate times: 4.5, 5.5, 6.5, 7.5, 8.5, and 9.5 h, respectively. Degree of restorative sleep in the past month was assessed on a scale of 1–4 .Regarding eating habits, the mean number of meals and snacks per day in the past month were assessed on the following scale: 1 = 0, 2 = 1, 3 = 2, 4 = 3, and 5 = ≥4. The score of 5 was replaced with 4 times per day in the statistical analysis.2 with ANOVA and Cramer's V with the chi-square test. Variables with a significant difference were subjected to post-hoc tests using the Games–Howell test, Dann–Bonferroni correction, and Bonferroni correction.Descriptive statistics were calculated for all variables. A two-step cluster analysis tested whether different groupings could be found based on the two indicators of study engagement and stress, which are important factors for maintaining better adaptation to college life , 17. Notpots-hoc test using the Bonferroni correction.To examine differences in the proportion of participants with mental health problems between different groups based on cluster analysis, Cramer's V with chi-square test was used to compare the presence of fatigue, anxiety, and depression. Items with a significant difference were subjected to To identify predictors of cluster membership, a logistic regression analysis was performed while controlling for potential confounders. The variables were category of cluster membership as a dependent variable. Two clusters with the highest and lowest mental health problems were regarded as the dependent variable. Sex , age, faculty (science vs. humanities), subjective benefits of online education (yes vs. no/not applicable), and lifestyle habit factors were the independent variables. Independent variables with the following two criteria were excluded to avoid multicollinearity: Pearson product-moment correlation coefficient among independent variables >0.70; and variance inflation factor >10. The sample size required for this logistic regression was over 90 participants in the smaller of the two outcome groups, in which the event per variable of 10 was calculated. The present study achieved this criterion.p-value of < 0.05 was considered statistically significant.All analyses were conducted using SPSS 27; a All procedures contributing to this work complied with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. All procedures involving human subjects were approved by the ethics committee at the Institute for Datability Science of Osaka University .Two-step cluster analysis based on the UWES-S-J score and the level of current stress determined three clusters. V = 0.392, 0.436, and 0.408, respectively).Participants in cluster 3 (school over-adaptation group) significantly evinced the most mental health problems, except for fatigue. Those in cluster 1 (school adaptation group) had the lowest mental health problems. Participants in Cluster 2  had significantly more fatigue, anxiety, and depression problems than those in cluster 1. The effect size for the comparison of fatigue, anxiety, and depression was medium to large . Sex, age, subjective benefits of online education, total sleep time on weekdays and on holidays, and degree of restorative sleep were significant predictors of cluster membership. Students who were female, older, considered online education to be less beneficial, had shorter total sleep time on weekdays, had longer total sleep time on holidays, and had worse restorative sleep were more likely to be classified into the school over-adaptation group.This study clarified characteristics of school adaptation in University students exposed to the drastic transition in the educational system from traditional face-to-face classes to fully online classes during the COVID-19 pandemic, while also exploring the accompanying mental health problems and factors associated with school adaptation. Two major findings emerged. First, after the participants were statistically classified into three groups based on study engagement and stress in the two-step cluster analysis , the school over-adaptation group was found to have the most mental health problems among the three groups. Second, participants who were female, older, considered online education to be less beneficial, and had shorter total sleep time on weekdays, longer total sleep time on holidays, and worse restorative sleep were more likely to belong to the school over-adaptation group.The two-step cluster analysis statistically linked the three school adaptation groups according to study engagement and stress. This implied that some students who suddenly experienced fully online education superficially adapted to the new school environment while exhibiting many mental health problems. The present results differ from a previous study that found three patterns of school success in a period with the usual education system: well-adjusted average academic achiever; average-adjusted high achiever, and low-adjusted low achiever , althougParticipants who were female, older, experienced poor subjective benefits of online education, and had shorter sleep time on weekdays, longer sleep time on holidays, and worse restorative sleep were more likely to be in the school over-adaptation group, based on the logistic regression analysis. To the best of our knowledge, limited data exist regarding the predictors of school over-adaptation for students undergoing fully online education during the COVID-19 pandemic. An interesting new finding is that students who did not recognize the advantages of online education were more likely to be classified in the school over-adaptation group. Thus, academic staff should consider how to utilize online classes with their lectures to improve students' ratings of subjective benefits of online education. The result concerning sleep problems is partly in line with other studies that have demonstrated an association between sleep difficulties and stress or mental health problems in University students, although these were not particular to the COVID-19 pandemic , 25. ConThis study has several limitations. First, the cross-sectional design precludes comparison of students' temporal changes with the transition from face-to-face to online programs. Pre-existing mental health problems have been predicted to affect students' current outcomes during the COVID-19 pandemic . Social This is the first study to reveal the characteristics of school adaptation in University students exposed to a fully online education system during the COVID-19 pandemic, and to identify the mental health characteristics and factors associated with school adaptation.The results suggest that academic staff members should provide extensive counseling to support students' mental health to prevent overlooking the existence of school over-adaptation and its risk factors, although providing online programs requires substantial resources. Future studies should identify temporal changes in students' mental health using comprehensive assessment tools. Students' perception of online education would play an important role in examining the effect of the rapid transition from traditional face-to-face teaching to online education.hadachi@psy.med.osaka-u.ac.jp.The datasets generated during the current study are not publicly available due to privacy considerations of the participants. Requests to access the datasets should be directed to Hiroyoshi Adachi, The studies involving human participants were reviewed and approved by the ethics committee at the Institute for Datability Science of Osaka University. The patients/participants provided their written informed consent to participate in this study.HA, HN, SS, and HT conceived the design and concept of this study. DI, HA, SS, and HT analyzed the data and DI wrote the first draft. NT, AM, TH, YY, and MI advised about the data analysis and interpretation. All authors contributed to the article and approved the submitted version.This work was partially supported by Innovation Platform for Society 5.0 of the Japan Ministry of Education, Culture, Sports, Science and Technology (Code: S004541). The funder of the study had no role in data collection, data analysis, data interpretation, writing of the report, or decision to submit the paper 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cardiac amyloidosis (CA) has been recently recognized as a condition frequently associated with aortic stenosis (AS). The aim of this study was to evaluate: the main characteristics of patients with AS with and without CA, the impact of CA on patients with AS mortality, and the effect of different treatment strategies on outcomes of patients with AS with concomitant CA.A detailed search related to CA in patients with AS and outcomes was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Seventeen studies enrolling 1,988 subjects  were included in the qualitative and quantitative analysis of main patients with AS characteristics with and without CA, difference in mortality, and treatment strategy.N-terminal pro-brain natriuretic peptide, and high-sensitivity troponin T were significantly associated with CA in patients with AS. Higher overall mortality in the 178 patients with AS + CA in comparison to 1,220 patients with AS alone was observed . Meta-regression analysis showed that younger age and diabetes were associated with overall mortality in patients with CS with CA . Finally, patients who underwent surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI) had a similar overall mortality risk, but lower than medication-treated only patients.The prevalence of CA resulted in a mean of 15.4% and it was even higher in patients with AS over 80 years old (18.2%). Patients with the dual diagnosis were more often males, had lower body mass index (BMI), were more prone to have low flow, low gradient with reduced left ventricular ejection fraction AS phenotype, had higher E/A and E/e', and greater interventricular septum hypertrophy. Lower Sokolow–Lyon index, higher QRS duration, higher prevalence of right bundle branch block, higher levels of Results from our meta-analysis suggest that several specific clinical, electrocardiographic, and echocardiographic features can be considered “red flags” of CA in patients with AS. CA negatively affects the outcome of patients with AS. Patients with concomitant CA and AS benefit from SAVR or TAVI. In the geriatric population, calcific aortic stenosis (AS) is one of the most prevalent cardiovascular diseases. It affects 3% of the general population older than 65 years . AS is aCardiac amyloidosis (CA) is characterized by extracellular amyloid infiltration into the heart, in most cases of light chain (AL) or transthyretin (TTR) types. Acquired TTR amyloidosis (ATTRwt) is also called “senile amyloidosis” and is highly prevalent in the elderly .The prevalence of CA in patients with AS is variable although consistent, ranging from 8  to 16%, N-terminal pro-brain natriuretic peptide (NT-proBNP), greater left ventricular (LV) hypertrophy, and advanced diastolic dysfunction  the prevalence of CA in patients with AS; (2) the “red flags” of CA in the context of AS; (3) the impact of CA on patients with AS outcome; (4) the impact of aortic valve replacement in patients with concomitant CA and AS; and (5) if there is a treatment of choice (SAVR or TAVI) in patients with concomitant CA and AS.To perform a complete search and analysis, a detailed protocol for this review was prospectively developed, specifying objectives, criteria for study selection, outcomes, and statistical methods.To identify all the available studies, a systematic search was evaluated in the electronic databases . A detailed search relating to CA in patients with AS and outcomes was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . FollowiAccording to the prespecified protocol, all the studies evaluating the prevalence and/or outcomes of concomitant CA and AS and the impact on cardiovascular risk factors were included. Case reports, case series not reporting data on prevalence and outcomes, reviews, and animal studies were excluded. We included in the analysis only studies on patients with AS with suspected or confirmed CA at echocardiography, cardiac magnetic resonance (CMR), and bone scintigraphy. In particular, we included two echocardiographic studies that identified patients with concomitant CA and severe AS with apical sparing pattern at LV strain analysis , 20. In Z scores and significance was set at p < 0.05. Statistical heterogeneity among studies was assessed with the chi-squared Cochran's Q-test and with I2 statistic, which measures the inconsistency across study results and describes the proportion of total variation in study estimates, that is due to heterogeneity rather than sampling error. In detail, I2 values of 0% indicate no heterogeneity, 25% low, 25–50% moderate, and 50% or more high heterogeneity . Differences among cases and controls in dichotomous variables were expressed as odds ratio (OR) with pertinent 95% CI and the differences in continuous variables were expressed as a standardized mean difference (SDM) and 95% CI. The overall effect was tested using ogeneity .p < 0.05 was considered as statistically significant. In order to be as conservative as possible, the random-effect method was used for all the analyses to consider the variability among the included studies  and the variables mentioned above as independent variables (x) were performed , and coronary artery disease presence], echocardiographic characteristics , electrocardiographic characteristics , and biochemical parameters. To assess the possible effect of such variables in explaining the different results observed across studies, meta-regression analyses after implementing a regression model with the mortality as dependent variables  and had lower BMI, SDM of −0.32 . Analysis of echocardiographic parameters found that patients with AS and CA were more prone to have low flow, low gradient with reduced LV ejection fraction (LVEF), OR of 2.26 , lower aortic valve mean gradient SDM of −0.33 , and higher E/A and E/e' ratios SDM of 2.26  and 0.48 , respectively. Interventricular septum (IVS) was thicker in patients with dual diagnosis , while stroke volume index (SVi) was higher in patients with AS alone . Electrocardiographic parameters significantly associated with AS and CA were: lower Sokolow–Lyon Index ; higher QRS duration ; and higher prevalence of right bundle branch block (RBBB) . Finally, higher levels of both the NT-proBNP and high-sensitivity troponin T (Hs-TnT) were significantly associated with AS and CA in comparison with the patients with AS alone, SDM of 0.76  and 0.93 , respectively. The heterogeneity of all the analyzed variables is given in Patients with concomitant CA and AS were more often males, 68 vs. 52%, with a corresponding odds ratio (OR) of 2.01 , with a moderate heterogeneity among studies , without low heterogeneity among studies (I2: 26% p = 0.219).Sensitivity analysis showed that, excluding the study of Ferreira et al. , due to Z-value: −3.0; p = 0.003, Z-value: 2.5; p = 0.013, For the evaluation of the impact of major clinical and demographic characteristics on the difference in overall mortality between patients with AS alone and with CA, meta-regression models were performed . Our resp = 0.002, vs. TAVI (p = 0.217).To evaluate the role of CA in patients with AS who underwent a different type of medical intervention, we analyzed data from ten studies , 27, 31,Funnel plots of effect size vs. SE for all the performed analyses were rather symmetrical and Egger's test showed the absence of publication bias .In the present systematic review and meta-analysis, we report that: (1) in elderly patients with AS, the prevalence of CA increases with age; (2) specific clinical, electrocardiographic, and echocardiographic features can be considered “red flags” of CA in patients with AS; (3) CA negatively affects the outcome of patients with AS; (4) patients with concomitant CA and AS benefit from aortic valve replacement; and (5) in patients with concomitant CA and AS, there is not a treatment of choice.The prevalence of CA in patients with AS is highly variable in literature. In the analyzed studies, it ranges from 8 to 16% . This vaAn important open question is whether CA should be considered an additive factor able to influence the choice of treatment modality (SAVR or TAVI) in a single patient. Conflicting evidence is reported in the literature on possible postprocedural complications in patients with both the CA and AS. Some authors suggest a high risk for TAVI because of operative and postoperative complications, including atrioventricular blocks with need for permanent pacemaker implantation and risk of LV rupture –35. JavaThis study has some potential limitations. In the analyzed publications, the diagnosis of CA was made by different imaging techniques; however, data were confirmed even without studies with uncertain CA diagnoses. Systemic red flags of CA, such as carpal tunnel syndrome, were not included in the analysis due to a lack of relevant data on concomitant carpal tunnel syndrome and CA in patients with AS. In articles evaluating outcomes, also patients with moderate AS were included, leading to an underestimation of overall mortality in particular of patients with AS referred to medical treatment. The small sample size in the different treatment strategies could explain the slightly decreased risk of overall mortality of patients with SAVR compared to pharmacologically treated ones. Finally, the results of this study were focused on overall mortality; however, the assessment of cardiovascular mortality, rehospitalization, and functional status could improve our understanding of CA role in AS context.The prevalence of CA in AS is consistent and increases with age. Patients with concomitant CA and AS are characterized by advanced age, male sex, lower BMI, and features of more advanced disease. The presence of CA confers a worse prognosis to patients with AS; however, the benefits of aortic valve replacement remain significant even in presence of both the diseases. Based on the analyzed studies, there is not a treatment of choice between SAVR and TAVI, but due to the low number of patients who undergo SAVR in clinical practice, randomized further studies are required to better define this issue. There are currently no data on the cumulative benefit of aortic valve replacement and tafamidis in patients with concomitant CA and AS.The original contributions presented in the study are included in the article/VM and MC conceived of the presented manuscript. VM, PP, and VP analyzed each article and performed the data extraction independently. VV, DM, and IM draft the method and result section with the input of VM and PP. LP and DL draft the introduction and discussion section with the input of MC and VP. All authors discussed the results and contributed to the final manuscript.This study was supported by the Italian Ministry of Health funds  and by the Fondazione Gigi e Pupa Ferrari ONLUS (FPF-14).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Among the growing number of patients with hematologic neoplasms hospitalized in the intensive care unit (ICU), the largest proportion of these patients are diagnosed with lymphoma. However, less attention has been paid in the past to identifying critically ill patients and assessing the prognosis of patients in ICU. Traditional critical care-related scores have shown limitations and inaccuracy in predicting mortality risk.Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) were searched for in the Marketplace for Information in Intensive Care Medicine III (MIMIC-III) database. We searched mortality within 28 days as the primary endpoint. Logistics regression was used to screen risk factors. A calibration curve was used for internal validation, and the ROC curve and AUC were used to compare the new model with traditional scores.405 patients with DLBCL are enrolled in the project. Multivariate analysis shows the patients with the level of lactate dehydrogenase (LDH) > 327 U/L had an increased risk of 28-day mortality in ICU than others . Notably, length of ICU stay, LDH, creatinine, white blood cell counts, and APS III score are independent prognostic factors for patients with DLBCL in the ICU. Then, all these independent prognostic factors are selected into our prediction model. The new model has good accuracy (C-index=0.863) and a calibration curve, which improves clinical status concerning established ratings such as IPI, NCCN-IPI score, SOFA, APS III, and LODS. The results of a multicenter external validation including 124 DLBCL patients also showed that the new model was more accurate than all other models.The elevated level of LDH indicates a poor prognosis of patients with DLBCL in the ICU. Our risk score with crossed validation based on the level of LDH shows a significant prognostic value and may be a valuable tool for assessing the critically ill as well. Diffuse large B-cell lymphoma is the most frequent type among invasive lymphoma, representing 30.0-40.0% of all non-Hodgkin’s lymphoma (NHL) , 2. It iLactate dehydrogenase is a tetrameric enzyme that catalyzes the reversible transformation of pyruvic acid to lactate in the terminal stage of the glycolytic enzymatic pathway, together with nicotinamide adenine dinucleotide dehydrogenase (NADH) oxidation to NAD+. The LDH has emerged as a meaningful prognostic biomarker in neoplastic diseases. The elevated level of LDH has shown a strong negative correlation with survival in both HL and NHL patients. In a recent investigation, Garcia et al. , 6 foundIn this study, our purpose is to demonstrate the association of elevated LDH levels with higher mortality. The value of LDH is established by multivariate logistics analysis. Then, we obtain a model to determine the predictive value of patients with DLBCL.st, to 2019 Jan 31st, 124 patients with DLBCL hospitalized in the ICU . Variables with normal distribution and skewness were expressed as mean ± standard deviation and median + IQR. Unpaired t-tests and Mann-Whitney U tests were used for comparisons between groups. The categorical variables were indicated as percentages and compared using the chi square test. Cumulative mortality was indicated by Kaplan-Meier curves and analyzed using the log-rank test. Multivariate and univariate survival analyses of overall survival (OS) were assessed using Cox regression models. The effect of covariates on prognosis was analyzed visually using forest plots. We included variables with p<0.015 in the prediction model and found that this as a criterion had the highest C-index and better accuracy.To build accurate predictive models, the contribution of each covariate was quantified and presented as a Nomogram plot with 2000 internal validations. The consistency of the developed models was assessed using a calibration method. Statistical analyses were performed using the ‘mice’, ‘rms,’ ‘surminer’, and ‘ggplot2’ packages of RStudio (R version 4.0.2).In total, 405 patients with DLBCL in ICU were selected for the investigation. The median age is 69 years (57-80 years), and 239 (59.0%) male patients were enrolled. The 28-day mortality rate and one-year mortality rate are 24.0% and 30.1%, respectively. The median duration of ICU stay is 2.97 days in all groups and 3.87 days in the 28-day death group (p=0.012). 150 (37%) patients were admitted to the ICU for respiratory failure, while 132 (33%) and 79 (20%) were for sepsis and cardiac insufficiency, respectively. The median LDH level is 327 U/L (interquartile range (IQR), 212-640) in all groups and 728 U/L  in the 28-day death group. We also calculate the IPI, SOFA, ASC III, and LODS scores, and the median scores are 4 , 44 , and 4 , respectively Table 1.By univariate analysis based on logistic regression, we realize that high LDH level may be a strong predictor of both 28-day and one-year mortality . In addition, length of ICU stay, bilirubin, creatinine, hemoglobin(HB), white bicarbonate, blood cell (WBC), platelet (PLT), partial thromboplastin time(PTT), International Normalized Ratio(INR), prothrombin time (PT), SOFA, APS III, and LODS score are negatively correlated both with 28-day and one-year mortality Table 2.28-day mortality is widely used in ICU treatment as an appropriate and meaningful endpoint. Predicting the 28-day mortality is important and meaningful for clinicians to adjust the therapeutic regimen to improve patient outcomes. Univariate analysis shows the length of ICU stay, bicarbonate, bilirubin, creatinine, WBC, HB, PLT, PTT, INR, PT, SOFA, APS III, and LODS scores are risk factors for 28-day mortality. We included variables that were significant  in the univariate analysis in the multifactorial analysis. The length of ICU stay, LDH, creatinine, WBC, and APS III score were independent variables of 28-day mortality in DLBCL Table 3.Our results show that the high level of LDH (>327 U/L) is a highly relevant predictor of increased mortality within 28 days in patients with DLBCL. When creating the new prediction model for the patients with DLBCL in ICU, the parameter, especially the level of LDH, is included, and the duration of ICU stays, WBC, creatinine, and ASP III score. We tested the accuracy with externally validated data and found that the prediction accuracy of the new model is above 80%. So, the validity and accuracy of this model were reasonable. Furthermore, the new model has a larger area under the AUC curve than traditional ICU scores such as SOFA, APS III, and LODS. For patients admitted to the ICU, death within 28 days is a very important clinical endpoint to judge the effectiveness of a patient’s treatment in the ICU. That is why we have adopted this clinical endpoint for lymphoma patients treated in the ICU. Our analysis also revealed that for non-ICU hospitalised lymphoma patients, the majority of patients do not die within 28 days. Therefore, the analysis of 28-day mortality in this group of patients is not meaningful or statistically significant.LDH is an adverse prognostic biomarker for several hematological diseases and solid tumors. In a recent meta-analysis, Petrelli et al. found that elevated LDH levels may predict poor prognosis in various solid tumors; this effect was most pronounced in prostate, lung, renal cell, nasopharyngeal, and gastric cancers . Also, eThe tumor microenvironment is widely implicated in tumorigenesis and interacts with surrounding cells through the network of extracellular matrix, soluble factors, and cells –21. LactIn conclusion, our results show that the elevated level of LDH predicted high 28-day mortality in patients with DLBCL treated in ICU. A cross-validated multivariate score shows a good agreement in predicting 28-day mortality in patients with DLBCL in ICU.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Informed consent was obtained from all patients or their immediate family members. All research programs are in line with the guidelines of the Ethics Committee of Soochow University and follow the Declaration of Helsinki.JQ designed and performed research studies, analyzed the data, and wrote the manuscript. CG and WW completed research studies and analyzed data. MX contributed to the data analysis and manuscript writing. JF and XC contributed to the research design, data analysis, manuscript writing, and study supervision. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China (Nos. 81873432 and 81670132), grants from the Jiangsu Province of China (Nos. ZDRCA2016047), Jiangsu Provincial Special Program of Social Development (No. SBE2016740635), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Hierarchical logistic regression between variables and anemia showed a significant association (p = 0.02) with households that improperly disposed of stool, children with minimum dietary diversity (p = 0.041), children in low age quartiles (p = < 0.001), and underweight children (p = 0.025). Maternal, household characteristics, and child factors were associated with childhood anemia in Zanzibar, Tanzania. Despite the significant decrease of anemia in Zanzibar, the overall prevalence rate is still a significant public health concern. Designing and strengthening comprehensive interventions to address anemia in the general population and different categories should be given special consideration.The aim of this study was to assess the prevalence of anemia and its determinants among children aged 6–59 months in Zanzibar, Tanzania, from 2005 to 2015. We used secondary data from the Tanzania Demographic and Health Surveys from three different periods: 2005, 2010, and 2015. A sample of 3502 child-mother pairs from three survey datasets was used to analyze the overall prevalence of anemia and reveal its determinants. Hierarchical logistic regression was used to demonstrate the prevalence odds ratio of factors, both from the mothers and children, for anemia prevalence. The study indicated a significant decrease in anemia prevalence from 76.1% in 2005 to 65.4% in 2015 ( Anemia is a global public health problem affecting one-third of the world’s population both in developed and developing countries, with significant consequences for human health as well as for social and economic development ,2. AnemiThough anemia affects people of all ages, pregnant women and children are more affected. It was estimated that 42% of children less than five years of age and 40% of pregnant women are anemic globally. It is a significant public health problem associated with increased morbidity and mortality in women and children ,7,8, pooAccording to the anemia regional disparities report, one-third of the Tanzanian population is anemic, and Zanzibar reported a slight reduction in childhood anemia prevalence of nearly 10% . Howeverwww.dhsprogram.com, access date: 16 January 2020). These national representative surveys employ cross-sectional study designs to measure levels, patterns and trends in demographic and health indicators and are conducted every five years in all regions of mainland Tanzania and Zanzibar, by the National Bureau of Statistics (NBS) in mainland Tanzania and the Office of the Chief Government Statistician (OCGS) in Zanzibar.The secondary data analysis utilized three Tanzania Demographic and Health Surveys (TDHS) conducted in 2005, 2010, and 2015, available from the online portal of demographic health programs  concentration in the blood. Blood samples were drawn from a drop of blood taken from a finger prick and collected in a micro cuvette. Hb level analysis was carried out on-site using a battery-operated portable Hemo-Cueanalyzer, and results were obtained on the spot. The cutoff points of anemia in TDHS were less than 110 g/L according to the cut off points for anemia recommended by WHO.Independent variables included child age in months, child’s sex, birth weight in grams, feeding practices of the children, diarrhea, fever, vitamin A supplementation, iron supplementation, deworming, and anthropometric indices . Other independent variables were the caregiver’s educational level, maternal anemia, number of children living in the house, maternal age, residence and wealth index, sex, and age of the head of the household. The anthropometric measurements were taken using a standard weighing scale and height board.Analysis of data was done using SPSS . Descriptive statistics were used to describe the characteristics of the study population. We used Pearson Chi-square tests to compare the prevalence of anemia between three years and between ages categories, where we used age quartiles to decrease the bias.p-value > 0.005, maternal factors as the second model, which had a p-value > 0.005, and child factors as the third model.A hierarchical regression model was used to determine factors associated with anemia. The association was measured using the recent survey dataset of 2015, aiming to avoid missing variables across the three surveys. Variables were categorized into three models: household factor as the first model, with a p < 0.05 with a 95% confidence interval.Association between dependent and independent variables was determined using odds ratios (OR) at p for tend = 0.004) and anemia also decreased with an increasing BMI of the mother respondents (p for tend = 0.01)...p-value < 0.001), almost 10%.As shown in The prevalence rate was high in the low age quartile across all surveys. Among 1147 individuals interviewed in 2005, the prevalence of anemia was high, 29.2% in the Q1 age group, and the least was 21.4% in the Q4 age group. In 2010, 30.9% of the anemic children were in the Q1 age group, while 20.1% were in the Q4 age group. In 2015, 33.4% of the anemic children were in the Q1 age group and the least, 18.1%, in the Q4 age group. The rate of anemia was revealed to be high in the Q1 age group across all surveys .p = 0.02), compared to households with a proper stool disposal system. No other household and maternal factors were revealed to have an association with childhood anemia.p < 0.001) and , and those children with minimum dietary diversity (MDD) were more likely to have anemia  compared to their counterparts. Underweight children were also at higher risk of having anemia .We finally analyzed the association of children’s characteristics with anemia . It was Childhood anemia is still a public health threat in Zanzibar. The findings showed that the overall prevalence of anemia is 65.4%, and the prevalence of anemia decreased significantly over 15 years, from 76.1% in 2005 to 65.4%. The prevalence rate was high in the low age quartile. There is a positive association between anemia and households with improperly disposed stool, children with minimum dietary diversity, children in low age quartiles, and underweight children.The reported prevalence is similar to the national reported prevalence of 65% . This prThe burden of child anemia has significantly declined for the past fifteen years from 74.1 to 65.0%. It was undoubtedly due to improved health care services and increased deworming coverage to over 90% in under-five children across all Zanzibar . HoweverThe analysis also revealed the disparities of prevalence rates in different age quartiles. The prevalence among young children was higher than that of all other age groups across all years. This situation was likely due to inappropriate feeding practices that lead to an insufficient daily intake of iron by children , as it wOur study revealed the association between anemia and households which dispose of stool improperly, children in the low age quartile, those with MDD, and those underweight. The likelihood of developing anemia was significantly associated with households that improperly disposed of stool, and this might be due to the exposure of helminth infections from stool that can contribute to the likelihood of anemia occurrence in children . It has The children’s age was significantly associated with anemia; younger children were more at risk than the older ones. The results showed that those in low-age quartiles had increased risk. The observed association may be due to poor feeding practices, early weaning, inadequate breastfeeding, and susceptibility to infection. A report that was written by Kinabo et al., in 2012, showed that there were problems of early weaning in children in Zanzibar, as the mean age of the weaning period was 4 months. There was also a lack of knowledge on the best complementary feeding practices in mothers . The repThe results showed a strong correlation between anemia and MDD, while MDD was associated with anemia in children due to inadequate food diversification. Although Zanzibar has a wide variety of local foods suitable for feeding children, in this study, only 18% had a MDD. In addition, mothers/caregivers lacked knowledge of how best to combine these foods to prepare energy- and nutrient-dense diets ,21. A nuAmong the analyzed variables related to children, low weight for age (underweight) remained associated positively with anemia. Many other factors contributed to the association of anthropometric indices and anemia, including poverty, water, and sanitation. As reported, there is a flawed centralized sewage system in Zanzibar and no sanitary policies and caring practices with food insecurity . This reThis study clarifies the prevalence of childhood anemia in Zanzibar, Tanzania, over 15 years, with some limitations to consider. The analysis of prevalence and trends included three surveys, and correlations were identified only from the most recent surveys and so older surveys may show different correlations compared to the most recent ones. However, the recent survey was used to avoid missing information on some variables that determine this association. Despite the above limitation, this study will provide insight into trends regarding anemia and will hopefully provide a clue on possible critical interventions for children in Zanzibar.Anemia in children aged 6–59 months decreased across the years, but this improvement was still not convincing, and the higher rate was found in lower age categories. Lower age, underweight, given MDD, and improper stool disposal were associated with childhood anemia in Zanzibar. Special interventions, such as improving the addition of iron-rich foods, vitamin C supplementation to children, supporting deworming programs, and community promotion on good feeding practices with food diversification should be given serious consideration to address this problem.


Obesity has been reported to be an important contributing factor for precocious puberty, especially in girls. The effect of green tea polyphenols on weight reduction in adult population has been shown, but few related studies have been conducted in children. This study was performed to examine the effectiveness and safety of decaffeinated green tea polyphenols (DGTP) on ameliorating obesity and early sexual development in girls with obesity.This is a double-blinded randomized controlled trial. Girls with obesity aged 6–10 years old were randomly assigned to receive 400 mg/day DGTP or isodose placebo orally for 12 weeks. During this period, all participants received the same instruction on diet and exercise from trained dietitians. Anthropometric measurements, secondary sexual characteristics, B-scan ultrasonography of uterus, ovaries and breast tissues, and related biochemical parameters were examined and assessed pre- and post-treatment.n = 31, control group n = 31) completed the intervention and were included in analysis. After the intervention, body mass index, waist circumference, and waist-to-hip ratio significantly decreased in both groups, but the percentage of body fat (PBF), serum uric acid (UA), and the volumes of ovaries decreased significantly only within the DGTP group. After controlling confounders, DGTP showed a significantly decreased effect on the change of PBF , serum UA , and ovarian volumes  in girls with obesity. No side effect was reported in both groups during the whole period.Between August 2018 and January 2020, 62 girls with obesity (DGTP group DGTP have shown beneficial effects of ameliorated obesity and postponed early sexual development in girls with obesity without any adverse effects. https://clinicaltrials.gov/ct2/show/NCT03628937], identifier [NCT03628937].[ Precocious puberty refers to the appearance of physical and hormonal signs of pubertal development at an age earlier than normal. Female precocious puberty is defined as the development of secondary sexual characteristics before the age of 8 or menarche before the age of 10 –4. In ChThe mechanisms of precocious puberty are complicated, which involve genetic, nutritional, psychosocial stress, and environmental toxin interactions , 10. SomGonadotropin-releasing hormone agonist therapy is well established as the standard treatment for central precocious puberty worldwide. In addition, some other clinical treatments like traditional Chinese medicine and acupuncture therapy were also used. Though clinically precocious puberty can be treated in some ways, it is important to find approaches to prevent or delay its development in children.Camellia sinensis and contains high quantities of polyphenols   , showing2; 7 years old, BMI ≥17.2 kg/m2; 8 years old, BMI ≥18.1 kg/m2; 9 years old, BMI ≥19.0 kg/m2; 10 years old, BMI ≥20.0 kg/m2). Participants with the following conditions were excluded: (1) menarche or central precocious puberty clearly diagnosed; (2) current treatment for obesity; (3) taking medications that would impact obesity, such as the stimulants and some psychotropic drugs; (4) severe systemic, liver, and renal disorders; and (5) judged to be ineligible by the study physician, such as mental disorders.We did a randomized, double-blinded, placebo-controlled trial that enrolled obese girls with a 12-week DGTP or placebo intervention period. This study was registered with a Clinical Trials.gov identifier NCT03628937 and was approved by the Ethics Committee of Xinhua Hospital . Participants were recruited from the Clinical Nutrition Department, Children Endocrinology Department, Children Health Care Department in Xinhua Hospital, and some primary schools near the hospital from August 2018 to January 2020. Flyers and posters with the study information were posted in the hospital, primary school campus, and also posted on the hospital and external websites . The inclusion criteria for this study were as follows: (1) girls with obesity aged 6–10 years old; (2) BMI reached or exceeded the overweight threshold of school-aged girls in China  to the DGTP group or the control group by computer-generated block randomization with block sizes of 4, conducted by the Clinical Research Unit of Shanghai Xinhua Hospital, China. The random results were sealed and given to a staff not involved in the trial investigation. For each new participant, the staff informed doctors the group of the participant orderly. The participants, guardians, outcome assessors, statisticians, conclusion drawers, as well as all doctors or dietitians were masked to the treatment allocation, except for the investigator who contacted DGTP capsule manufacturing companies and distributed the DGTP and placebo capsules to participants. Both DGTP and placebo were packed in the congruent opaque capsules for avoiding light and blinding. The two types of study capsules were assigned to transparent bottles of exactly the identical size and appearance, except for different label numbers on the bottles to distinguish their types. The randomization list and questionnaires were securely stored in a locker, and the data were stored in the researcher’s computer protected by a password.The DGTP were purchased from CHENGDU WAGOTT BIO-TECH CO., LTD , and the capsules, including the placebo capsules, were manufactured by LIAOCHENG AOJIAN BIO-TECH CO., LTD . The capsules were made from food additive gelatin with soybean oil and DGTP as filler, and all materials had certificates of safety testing and analysis.After the informed consent and randomization, participants in the DGTP group were asked to consume two capsules daily , while the control group was given indistinguishable capsules containing isodose soybean oil as a placebo treatment. The dosage of 400 mg daily DGTP (EGCG accounted for 50%) was verified to be safe for children in a previous study . The intAt baseline, participants were asked to complete demographic and lifestyle questionnaires, and bone age measurement. Other assessments were conducted at baseline and at the end of the 12-week intervention period, mainly including anthropometric measurements; body composition analysis; secondary sexual characteristics; B ultrasonic measurements in uterus, ovaries, and breast tissues; biochemical parameter measurements; and dietary assessments. The safety assessments were conducted during the whole study period. A timeline of the study is shown in The primary outcome was the effect of 12-week DGTP on percentage of body fat (PBF) change. The PBF of participants was measured using bioelectrical impedance analyses by whole-body impedance  pre- and post-treatment. The onset of menarche was reported to be closely related with the achievement of a certain PBF in girls. Secondary efficacy outcomes included the changes from baseline in BMI, fat-free mass (FFM), serum triglyceride, total cholesterol, and uric acid (UA); secondary sexual characteristics; volume of uterus, ovary, and breast; and sex hormones levels at week 12. The blood samples were collected in the morning with the participants in fasting state, and the serum was sent for laboratory test. Serum triglyceride, total cholesterol, and uric acid values were detected by uricase method using a Hitachi 7600 automatic biochemical analyzer , and sex hormone levels were measured with a chemiluminescence immuno-metric assay using a UniCell DXI 800 analyzer . Also, the average age of onset of menarche will be followed up and recorded in participants as a secondary outcome.Participants and their guardians were asked to record the number of capsules participants took every day and all adverse events occurred during the study. Side effects and adverse reactions on sleep or digestive tract were assessed at baseline, week 1, week 6, week 12, and 3 months follow-up after the intervention. Meanwhile, the serum trace elements, hepatic and renal function, and complete blood count of participants were also measured at baseline and week 12 to ensure safety. All participants were free to withdraw at any time during the study.t-test was performed for continuous variables and χ2 test for categorical variables. To compare differences between baseline and after 12-week intervention in the same groups, paired t-test was performed for continuous variables, and McNemar test was performed for matched categorical variables. In addition, the group differences in changes from week 0 to week 12 were calculated and analyzed using independent sample t-test and χ2 test as well.Data were analyzed using SPSS version 22.0 software . Continuous variables are presented as the mean ± SD, and categorical variables are presented as number and percentages. To compare differences between the DGTP group and the control group, independent sample p values were calculated based on two-sided test, and p < 0.05 was considered statistically significant.Multiple linear regression was employed to evaluate the effect of DGTP intake on the changes of obese and pubertal related outcomes after controlling confounding factors in girls with obesity. All After screening, 96 girls with obesity who met the inclusion criteria were invited to participate. Among them, eight girls refused to participate, while four others were excluded due to plans of moving out of town. The remaining 84 participants were enrolled and were randomly allocated into either the DGTP group or the placebo control group. During the study, 13 participants in the DGTP group and 9 in the control group withdrew or dropped out, and the dropout rate was 22/84 (26.2%). Specifically, in the 22 dropouts, 9 could not pay a punctual study visit due to the impact of the coronavirus disease 2019 (COVID-19) in early 2020, which was the period of the initial outbreak of this pandemic, and the original arrangements of follow-up in this study were unavoidably affected. Also, two girls in the DGTP group and one in the control group were diagnosed as precocious puberty and changed to gonadotropin-releasing hormone agonist therapy. Five participants in the DGTP group and five in the control group were considered non-adherent or discontinued the study due to personal reasons like too overload homework to cooperate with. Finally, 62 participants completed the study without any adverse events or side effects reported. The study flowchart is in vs. 10%; p < 0.05).2, Control group: ΔBMI: −0.7 ± 1.4 kg/m2; DGTP group: ΔWC: −2.8 ± 5.4 cm, Control group: ΔWC: −2.5 ± 4.9 cm; DGTP group: ΔWHR: −0.03 ± 0.05, Control group: ΔWHR: −0.03 ± 0.06; DGTP group: ΔWHtR: −0.03 ± 0.04, Control group: ΔWHtR: −0.03 ± 0.04; p < 0.05). No significant changes were found in weight, hip circumference, and blood pressure in either group . In addition, in the DGTP group, ovarian volumes on both sides significantly decreased  after 12 weeks, and the number of participants with diameter >4 mm follicles in the left ovary reduced by three (p < 0.05).As shown in As shown in The nutrient intake data are presented in β = 48.747, 95% confidence interval CI: 7.100 to 90.394, p = 0.02) in girls with obesity. In model 2, DGTP intake remained significantly associated with decreased ΔUA  and also associated with reduced Δright ovarian volume . Furthermore, in model 3, DGTP intake for 12 weeks was significantly associated with ΔPBF , ΔUA , Δright ovarian volume , and Δleft ovarian volume .After controlling various confounding factors, the association between DGTP intake and the changes of obesity- or sexual development-related parameters after intervention are presented in No participants withdrew from the study because of discomfort or adverse events related to the intervention. No adverse reactions and discomfort indigestion were noted and reported in the study period. The changes in their serum trace elements, hepatic and renal function and complete blood count showed no significant differences between the two groups and remained within the normal ranges (not shown in tables). Some participants reported that the size of the capsule was large, which was a little difficult to swallow for them.This study demonstrated that short-term DGTP daily consumption effectively ameliorated obesity and reduced the risk of hyperuricemia among girls with obesity. DGTP might also be effective in preventing early sexual development in girls with obesity. No adverse effects were reported. To our knowledge, this is the first randomized controlled trial study examining the effect of DGTP on obesity and precocious puberty in children, and these findings provided valuable evidence for DGTP clinical application.In our study, after the intervention, the BMI, WC, WHR, FFM, and PBF in the DGTP group decreased significantly, and DGTP could also reduce ΔPBF after controlling confounders. These findings suggested that DGTP could contribute to a decrease in obesity in children, which were similar with the results of some previous studies , 33–35 oin vitro and in vivo studies , and we considered our sample size would also be meaningful and, most importantly, provide effective evidence in this field. We also consulted some experts in epidemiology, pediatric endocrinology, and clinical nutrition about our study design and sample size, and they all agreed that this study could provide some preliminary implications if no previous literature helps to calculate the sample size, but small sample size was still one of the limitations. Third, human error may occur during testing and data collection. Participants all started at different times. The testing was done by different clinicians and thus the interpretation of results might be affected by their skills and experiences, e.g., the B-scan ultrasound imaging reports of uterus, ovaries, and breast tissues. Fourth, other parameters, such as sex hormone-binding globulin, could help to further explain the mechanisms between obesity and precocious puberty, but have not been measured in the present study. Finally, the 12-week 400 mg/day DGTP intervention period might not be sufficient to determine the final pubertal change of girls with obesity. This study is a preliminary explorer in this vacant field, and longer follow-up is also needed to determine whether their final age of menarche onset was delayed and the adult heights were as excepted.However, some limitations also existed in the current study. First, the dropout rate was 26.2% in this study, which was a little high in a RCT. As we described before, 9 of the 22 dropouts could not pay study visits on time due to the COVID-19 pandemic in early 2020 in China. The suddenly new outbreak of COVID-19 hit all the medical resources nationally and people were too scared and observed social distancing strictly, let alone went out to go to the hospital. Our study was unavoidably affected by the situation that the nine participants were way beyond their 12-week study visit when the pandemic alleviated after April 2020; thus, we did not take their post-treatment data into analysis due to the obvious bias. Referring to the study process before the pandemic, we suppose the dropout rate should be much lower without the impact of COVID-19. Second, as this is the first study to identify the effect of DGTP on precocious puberty in children, we have no reference to calculate our sample size. Therefore, referring to the only previous RCT about green tea catechins on children in Japan . Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.LX and XS conceptualized and designed the research, conducted the intervention to this study’s setting, contributed the data collection instruments, collected data, performed statistical analysis, wrote the paper, revised the manuscript, and had primary responsibility for final content. QT conceptualized and designed the study, coordinated and supervised data collection, supported training of data collection staff, and critically reviewed the manuscript for important intellectual content. DY, QG, HZ, and XW supported intervention to the setting and collected data. ZY helped with the initial manuscript and critically reviewed and revised the manuscript. All authors contributed to the article and approved the submitted version.This work is supported by the National Natural Science Foundation of China (No. 81773407).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Objective: The emergence of coronavirus in Serbia as well as in other European countries led to the declaration of a state of emergency, which, among other measures, included a switch to online education, the lockdown of public life and organized sports, and a curfew from 5 pm to 5 am. This study aimed to investigate the extent to which these measures affected children's daily routines. More specifically, it aimed to determine how children maintained their learning, physical activity, and screen time routines from the period before the state of emergency was declared.Methods: Response to an online parent-reported questionnaire was conducted (N = 450). The factorial validity of the scales was prepared using confirmatory factor analysis, with acceptable fit indices. Based on that, the authors tested the interrelations between dimensions using structural equation modeling in SPSS, AMOS 24.0.Results: The study results indicate a positive relationship between school achievement and study time (β = 0.25). They also indicate that children who were physically active before the pandemic continued their activities during the emergency state (β = 0.53). Physical activity impact during the COVID-19 emergency measures reduces children's behavior changes (β = 0.55). Finally, they highlight that children who spent more time with multimedia content had greater changes in anxiety, sensitivity, nervousness, and worry due to COVID-19 emergency measures (β = −0.38).Conclusions: Healthy lifestyle habits formed in childhood are suggested to be responsible for the greater “resistance to change” shown by the children from this study. As the pandemic Coronavirus Infectious Disease 2019 (COVID-19) has now been going on for a year, the results of numerous scientific studies suggest that the virus has left a major impact on the psychophysical health as well as on the social life of children and adults , namely,The first case of a COVID-19-positive patient in Serbia was reported on March 6, 2020. Following the example of other European countries and in the absence of other effective epidemiological measures, state authorities declared a state of emergency on March 15, 2020 to keep people at home, minimizing physical contact. These measures in Serbia included closing kindergartens, schools, and universities and switching to online teaching; recommending that the working population works from home; closing of parks, sports, and fitness centers to minimize physical contact. People over 65 years old were completely banned from leaving their homes, and for all other age groups, the curfew applied on March 16, 2020 was from 8 pm to 5 am and then on March 22, 2020 to April 30, 2020 from 5 pm to 5 am. According to official statistical data, by the end of May 2020, 11,275 positive cases for COVID-19 were registered in Serbia, with a total number of 240 deaths (vs. younger children (ages 5–8) perceived greater decreases in PA and greater increases in sedentary behavior in comparison to pre- to early-COVID-19 emergency measure (EM) periods  and free play outside houses and apartments. The results of previously published studies suggest that school-age children are at a higher risk after a long period without school commitments, especially in terms of nutrition, PA, motor skills, and, finally, general psychophysical health . More ne periods . A Slove periods . The abo periods . With thFor this purpose, we create a questionnaire on PA of children during the state of emergency caused by the COVID-19 pandemic. The survey was conducted in the Republic of Serbia, in the autonomous province of Vojvodina territory.Based on the new “externally imposed” framework of children's daily life, we decided to analyze several key parameters of their lives, namely, we conducted the analysis of interrelation of children's PA before and during the pandemic COVID-19 within the variables: school achievement, study time, and screen time. For the purpose of this study, we have chosen these “pillars” of children's daily lives because they are key parameters whose continuity could be maintained, reduced, or increased during EM. The above-mentioned literature review considered that children's time during the EM could influence their behavior changes. Thus, we expected that factors that describe part of the children's daily routines before COVID-19 EM (such as school achievement and PA) could influence their daily routine during EM . The examination of these interrelations was defined in hypotheses H1a, H1b, H1c, H2a, H2b, and H2c see . Furthervia schools, with the mediation of an association of physical education teachers who supervised the data collection. At the beginning of the online survey, all participants were informed about the research purpose. It lasted ~10 min, with protection of the anonymity of the respondents. The field research was conducted between May 29 to June 6, 2020.The online parent-reported questionnaire was conducted after the cancelation of the state of emergency in Serbia. According to a convenient way of collecting questionnaires that did not endanger the respondents' safety, the dissemination was conducted N = 450) from primary schools from the territory of Vojvodina, Serbia. The parent sample included 165 respondents (36.7%) whose children belong to younger school-age and 285 respondents (63.3%) with children of older school-age. By developing the research strategy, we decided that the online questionnaire should be completed by the parents, namely, we considered that the scale of parental assessment of the children's daily activities during COVID-19 EM would be more valid than the children's answers for two main reasons: this would prevent a possible misunderstanding of some questions at a younger age , and (3) children's involvement in any sports and recreational exercises in a sports club, outdoor sports, and exercise at home (in hours).Three items measured PA before COVID-19 EM: (1) children's previous participation in an organized way of PA (three times a week) as members of sports clubs (yes or no), (2) previous regular sports and recreational activity or a combination of several different recreational activities such as aerobics, jogging, dancing, gymnastics, basketball, swimming, via TV shows, and athletic training for children in sports clubs was via remote platforms (with a delay due to adaptation to the new circumstances).Physical activity during COVID-19 EM was measured with three items. The first item provides information about the children's PA at home (yes or no). Furthermore, this dimension includes items related to the amount of time the child spends in exercising at home (in minutes) and overall status of the children's physical form with exercise at home compared to the pre-quarantine period, with responses on five-point Likert scales . It should be emphasized that online school sports for children in primary school were performed Study time was measured with three items .Screen time was measured by including four items that summarize information about the time (in hours) the child spent in using various multimedia sources: (1) single or multiplayer computer games, (2) video and music, (3) TV, and (4) social networking.etc.).The positive effects of PA in COVID-19 EM were measured with three items related to the parents' opinions on the impact on their child's concentration, motivation, and good mood .Statistical procedures included structural equation modeling (SEM), conducted using SPSS, IBM, and AMOS 24.0, which tested the relationships of a hypothesized model of constructs. This method was applied as a multivariate, complex method that included factor and multiple regression analysis.α as proposed by Kline . An accepted value of 0.50 is suggested as a minimum threshold for AVE , 16. Thep < 0.001).In this model, school achievement and PA before COVID-19 EM were set as independent variables, three dimensions  were mediator variables, and changes in children's behavior were set as a dependent variable. Mediation analysis , 21 was The obtained results were divided into three segments: (1) descriptive statistics, (2) confirmatory factor analysis, and (3) structural equation modeling. According to the descriptive statistics  of schooAn evaluation of screen time showed that children spent more hours using different screen devices than the American Academy of Pediatrics' recommendations. These recommendations considered 1 up to 1.5 h per day for elementary school-aged children and up to 2 h per day for middle school-aged children .The positive effects of the PA were revealed on the concentration (65.1%), motivation (63.7%), and attention (55.6%) of children. Otherwise, every fourth child felt more sensitive, worried, and nervous than before COVID-19 EM.The validity and reliability measures are calculated in 2 = 2,130.6, df = 530, χ2/df = 4.02, CFI = 0.91, TLI = 091, NNFI = 0.90, and RMSEA = 0.05. Therefore, the values of CFI, TLI, and NNFI confirmed the acceptable fitting of the model suggested by Byrne  are significant, especially if we consider that the closure of schools, distance learning, and minimization of physical contact with other people is the first state of emergency in the lives of Vojvodina children.The variable screen time showed a negative direct impact on the variable changes in children's behavior, suggesting that children who spent more time with multimedia content showed greater changes in anxiety, worry, sensitivity, and nervousness to COVID-19 EM. The findings are consistent with previous research indicating a linear association between total screen time and less acceptable temperament dispositions, degraded socio-emotional relations, and decline of health-related indicators of quality of life .The variable study time showed a direct effect on changes in children's behavior, which means that more time focused the children's attention on learning materials, which contributed to reducing changes in the mentioned characteristics of children's behavior.This research represents a contribution to the study and understanding of school-age children's response and adaptation to the EM caused by the first wave of COVID-19 pandemic in Spring 2020. The research covered several “pillars” of children's daily lives: school achievement, study time, PA (before and during the pandemic), and screen time during the pandemic.A positive correlation between school achievement and study time was confirmed , which iThe results of the study show the continuation of PA routine at children who were physically active before the pandemic and consequently showed fewer negative behavioral changes such as anxiety, fear, quarrelsome behavior, indifference, and laziness developed due to COVID-19 EM in contrast to children who spent more time with multimedia content and were less physically active and sedentary. Although the recommendations for regular PA of children basically refer to living in “ordinary” social circumstances, the results of this research indicate that their importance became even more obvious during COVID-19 EM. The limited freedom of outdoor movement and the prolonged stay in the house/apartment are circumstances for development of risk of new inactive lifestyle habits.A negative direct impact of screen time on the variable changes in children's behavior suggests negative and greater changes in children who spent more time with multimedia content as shown in their anxiety, worry, sensitivity, and nervousness to COVID-19 EM. These results are consistent with previously conducted research , pointinThe research findings suggest that healthy lifestyle habits formed in childhood, emphasizing regular PA and study habits, are responsible for the greater “resistance to change” of the children from this study. Considering that this was the first epidemiological EM life experience for the studied population, the results' significance is more obvious. Additionally, this result is compatible with a similar research conducted on Italian adolescent samples . The resFinally, our results related to screen time are consistent with the findings of previous studies on children and youth populations –33. ScreA brief research report has study limitations, which can be marked as significant for directions in similar future research. There were independent variables selected in the theoretical model, school achievement, and PA as important indicators of the children's previous daily routines before COVID-19 EM. This model does not include the local community's effect on its pandemic strategies and actions on the ground. Regarding the pandemic situation, the environment for children's daily routine functioning and manifestation could be different. The sample included children from the whole administrative province of Vojvodina, where some pandemic measures were different during the pandemic period.etc.). Finally, it was cross-sectional research, which means that there is a lack of detailed monitoring of changes in children's behavior.Additionally, the model could be developed with more variables for examining children's active or passive lifestyle before the beginning of the pandemic. Therefore, this model can be tested in different contexts . Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.JV, RM, IM, and SP wrote the manuscript, performed analyses, and revised the manuscript. JV, RM, and DK collected the data. IM, RM, and NM overviewed previous studies and discussed the results. 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.


No association between leptin, resistin, and visfatin levels and the risk of RA was detected. In the cohort from the Medical Biobank of Northern Sweden, higher adiponectin was associated with an increased risk of RA only in participants with overweight/obesity , independently of other adipokines. Our results show that in individuals with overweight/obesity, higher circulating levels of adiponectin, but not leptin, resistin, or visfatin, were associated with an increased RA risk.We recently reported that increased serum adiponectin was associated with rheumatoid arthritis (RA) risk in subjects with obesity. We hereby aim to determine if other adipokines associate with RA risk and if the association between adiponectin and RA is independent of other adipokines. Two nested-case control studies were performed in two different cohorts: 82 participants of the Swedish Obese Subjects (SOS) study who developed RA during follow-up matched with 410 controls, and 88 matched pairs from the Medical Biobank of Northern Sweden. Baseline levels of circulating adipokines were measured using ELISA. In a multivariable analysis in the SOS cohort, higher adiponectin was associated with an increased risk of RA independently of other adipokines (OR for RA risk: 1.06, 95% CI: 1.01–1.12,  Adipose tissue is the largest endocrine organ in the human body, which produces large amounts of cell-signaling proteins, called adipokines . AdipokiSeveral adipokines have been found elevated in blood from patients with RA, a systemic inflammatory disease affecting mainly the joints . HoweverOther adipokines, such as leptin, resistin, and visfatin, have been associated with RA. Amongst those adipokines, leptin is the one with the most robust association with RA, as high circulating leptin levels correlate with RA disease activity and leptin is also able to stimulate RA fibroblast-like synoviocytes to produce pro-inflammatory cytokines ,16. CircBlood samples from patients who later developed RA show signs of inflammation several years before the disease onset. Autoantibodies, cytokines, and biomarkers of inflammation can be elevated up to 10 years before the first signs of RA ,24. We hThe objective of the current study was to determine if circulating adipokines other than adiponectin also associate with the future development of RA and if the association between circulating levels of adiponectin and higher risk of RA is independent of other adipokines. To answer these questions, we performed two nested-case control studies, one within the SOS study, which includes only patients with obesity, and the other one at a general population level within the Medical Biobank of Northern Sweden.Baseline characteristics of the 82 cases before the development of RA and the 410 matched controls are shown in p = 0.05; p = 0.02) independently of other adipokines as well as inflammation markers CRP and ESR. As previously shown in the same cohort [p = 0.01). ESR and serum levels of leptin, resistin, and visfatin did not show any significant association with the risk of RA.e cohort ,26, CRP p = 0.03) independently of other factors in the subgroup having BMI > 25 kg/m2 (n = 109) but not in the one having BMI ≤ 25 kg/m2 (n = 67), as shown in p = 0.13). Baseline clinical characteristics of the cohort from the Medical Biobank of Northern Sweden after stratification by BMI are shown in In the cohort from the Medical Biobank of Northern Sweden, no association between adipokines and risk of RA was detected in a multivariable analysis, including plasma adipokine levels and smoking A. SmokinBy performing two nested case-control studies in cohorts where blood samples and clinical information were available before the diagnosis of RA, we have observed no association between circulating levels of leptin, resistin, and visfatin and the future risk of RA. Only elevated circulating adiponectin levels were associated with an increased risk of developing RA in participants with overweight/obesity independently of other adipokines.This study confirms what we have shown in a recent publication where increased serum adiponectin levels were associated with the future incidence of RA in participants of the SOS, a longitudinal study including about 4000 subjects with obesity . This asIt is unclear why circulating adiponectin was associated with the future risk of RA exclusively in participants with overweight/obesity. A possible explanation is that a chronic pro-inflammatory state as seen in obesity is needed to expose the association between adiponectin levels and RA. Furthermore, as high BMI associates with low circulating adiponectin levels and at the same time with an increased risk of developing RA, it is possible to hypothesize that overweight and obesity uncover the link between adiponectin and risk of RA ,27. AccoThe finding that patients with RA have elevated circulating levels of adiponectin compared to controls is known for many years ,14. HoweCirculating levels of leptin, resistin, and visfatin have been previously shown to be elevated in patients with RA compared to controls ,15,17. MOur study has some limitations. We performed two nested case-control studies from two larger cohorts, and the low number of participants included might have affected the results. Specifically, the nested case-cohort study performed within the Medical Biobank of Northern Sweden is rather small. Based on the obtained ORs, this population does not have enough statistical power to allow detecting an association between circulating adipokines on the risk of developing RA at a general population level. Moreover, the two cohorts are very different in terms of baseline characteristics as well as the proportion of cases/controls. The limited number of participants with obesity in the Medical Biobank of Northern Sweden (10 RA cases and 8 matched controls having BMI > 30) did not allow us to stratify this cohort based on BMI equal to 30, and therefore we decided to use BMI equal to 25 (defining overweight) as a cut-off instead. Another limitation of the study is that it was not possible to measure visfatin in the cohort from the Medical Biobank of Northern Sweden due to the lack of plasma samples. Further studies in larger cohorts are warranted to determine if circulating levels of adipokines are able to predict the future development of RA at a general population level.https://clinicaltrials.gov/ (accessed on 22 June 2021) with the identifier NCT0147952. All patients gave informed consent to participate in the study.A nested case-control study was performed within the SOS study. Details about the SOS study, such as recruitment, inclusion criteria, and sample collection and storage, have been previously described ,34. BrieDiagnoses of RA were retrieved through the Swedish National Patient Register by looking for the following International Classification of Diseases (ICD) codes: 712.38, 712.39 (ICD-8), and 714.0-2 (ICD-9) and M05, M06.0, M06.8, and M06.9 (ICD-10) . SOS stuEleven patients had prevalent RA, and 343 had no available serum samples at baseline and were therefore excluded from the analyses A. Among A nested case-control study was performed in a group of individuals included in population surveys within the cohort from the Medical Biobank of Northern Sweden. Details about the recruitment, inclusion criteria, and sample collection and storage of the original study have been previously described . BrieflyOut of the 386 cases who later on developed RA, 88 participants had available plasma and were therefore included in the current report B. The prIn the SOS study, ESR was measured at the participants’ health care centers at the time of health examination visits. CRP levels at baseline were measured with an ultrasensitive immunoturbidimetric method  using the Architect c8200 analyzer  in Helsinki, Finland, between October 2010 and April 2011. Measurement of serum concentrations of adiponectin was performed at the German Diabetes Center, Duesseldorf, Germany, from November 2010 to April 2011 . Total aIn the cohort from the Medical Biobank of Northern Sweden, plasma adiponectin, leptin, and resistin were measured using the same ELISA kits as for the SOS study. All measurements were performed at the University of Gothenburg (Sweden) in August 2018. Two samples had leptin levels above the detection range, and their values were defined as the upper detection limit. The leptin level of one sample was below the detection range, and its value was defined as 0 ng/mL. Visfatin could not be measured in the cohort from the Medical Biobank of Northern Sweden due to a lack of plasma.p-values were two-sided, and p-values < 0.05 were considered statistically significant. Statistical analyses were performed with the Statistical Package for Social Science .Data are shown as mean ± SD for continuous variables or number (percentage) for categorical variables. Spearman’s test was used to assess the correlation among adipokines. Differences between group means were analyzed using analysis of covariance, whereas proportions were analyzed using a chi-squared or Fisher’s Exact test. Multivariable conditional logistic regression analysis was used to calculate adjusted odds ratios (OR) and corresponding 95% confidence intervals (CIs) for the risk of RA in the SOS cohort and in the cohort from the Medical Biobank of Northern Sweden. Odds ratio and corresponding 95% confidence intervals for the risk of RA in the cohort from the Medical Biobank of Northern Sweden after stratifying for BMI were calculated with binary logistic regression after adjustment for preselected risk factors. All This study shows that in subjects with overweight/obesity, increased circulating adiponectin levels were associated with a higher risk of developing RA independently of other adipokines. We were not able to detect any association between circulating levels of leptin, resistin, or visfatin and the risk of developing RA, regardless of weight.