This study aimed to examine the prevalence of adolescent active travel to school (ATS) across 31 countries and territories in Asia, overall and by age group, sex and body mass index (BMI) category.Cross-sectional study.31 Asian countries.152 368 adolescents aged 13–17 years with complete data for age, sex, measured weight and height and active travel to school from 31 Asian countries from the Global School-based student Health Survey (GSHS).Self-reported active travel to school categorised into passive (0 days) and active (1–7 days).Overall prevalence of adolescent ATS in Asia based on random-effect meta-analysis was 55%, ranging from 18% (UAE) to 84% (Myanmar). There was limited subregional variation: 47% in the Eastern Mediterranean (EM), 56% in the South East Asia and 64% in the Western Pacific. Summarised by random-effect meta-analysis, being an older adolescent aged 16 years and older  was positively associated with ATS. This association was strongest in EM countries. Summarised by random-effect meta-analysis, females  and adolescents with overweight/obesity  were less likely to use ATS. Association with sex was strongest in EM countries. Heterogeneity was considerable in all meta-analyses.The prevalence of adolescent ATS in Asia varies substantially. Overall, older and male adolescents, and adolescents with underweight and normal BMI category are more likely to actively travel to school. However, the main contributor to differences in ATS between and within regions remain unknown. Although there is substantial scope for improving ATS rates in Asia, any policy actions and interventions should be cognisant of local built, social and natural environmental contexts that may influence active travel behaviour. This study pooled comparable estimates on active travel to school from 152 368 adolescents from 31 countries in Asia.Data were collected using standardised sampling and data collection methods, enabling comparison across countries and subregions.Data were from low-income and middle-income countries; thus, the extent to which these findings are generalisable to other, particularly high-income, countries in Asia is unclear.Data collection was conducted in schools, and thus the conclusions drawn here are only relevant to adolescents in school.Globally, non-communicable diseases (NCDs), notably cancers, cardiovascular diseases, type 2 diabetes and chronic respiratory illness, are responsible for about 40 million deaths each year.5Studies have reported that health benefits gained from physical activity in adolescence, defined as age 10–19 years,Previous research in 63 low-income and middle-income countries (LMICs) showed that active travel to school is positively associated with adolescents’ physical activity,16 19 20Asia is the largest and most populous continent, with a population of 4.6 billion,A few studies have been conducted in limited East and Southeast Asian countries. However, these studies had relatively small sample sizes (between 330 and 1518 participants),26–30The goal of this study was to examine the prevalence of adolescent ATS across 31 countries and territories in Asia, overall and by age group, sex and BMI category.The reporting of this paper follows the Strengthening the Reporting of OBservational studies in Epidemiology guideline.31This study used data from the Global School-based Student Health Survey (GSHS), developed by WHO and the Center for Disease Control and Prevention (CDC) in collaboration with UNICEF, UNESCO and UNAIDS.34 35GSHS used a two-staged cluster sampling design to obtain a nationally representative sample of the adolescents. In the first stage, schools were randomly selected using the probability proportional to size sampling. In the second stage, classes were randomly selected in the selected schools, with varied number of classes depending on the school size. All students in the selected classes were eligible to participate in the survey, and the participation was anonymous and voluntary.https://wwwwhoint/teams/noncommunicable-diseases/surveillance/systems-tools/global-school-based-student-health-survey.The GSHS surveys have been conducted in 185 mostly LMICs globally from 2003 to 2017. The survey consists of 10 core modules on adolescent health behaviours including physical activity and nutrition and protective factors, along with other optional modules. Data on response rates from each survey and characteristics of non-respondents were not available. Data cleaning and management, or data edits, were performed on all GSHS datasets: out of range edits, multiple response edits, logical consistency edits, height and weight edits, variable edits and record-level edits, where when the responses did not meet the requirement, they were set to missing. Observations with missing data were kept in the datasets. All GSHS datasets are freely available on WHO’s website: This cross-sectional study used GSHS data from 31 Asian countries, as defined by the United Nations’ Statistics Division of geographic regions.Data management was done using RStudio V.1.4. Prior to WHO data publication, out of range edits, multiple response edits, logical consistency edits, height and weight edits, variable edits and record-level edits were performed on all GSHS datasets.passive (0 days) and active (1–7 days) travel. This categorisation was chosen based on the distribution of ATS across the dataset  and older (16 years old and over) adolescents. This cut-off point was as per standard GSHS reporting.male, and ‘2’ for female. Participants’ height and weight were measured by survey staff before survey administration. Measurements were written by staff on slips of paper and given to each participant to be entered into their GSHS answer sheet. BMI category was generated based on WHO categorisation of BMI-for-age among children aged 5–19s, and then categorised into: underweight and normal BMI or overweight and obesity.38Independent variables included age, sex and BMI category. Age (in years) and sex  were self-reported. For analysis, age was categorised into two groups: 2 was used to determine the importance of heterogeneity in each meta-analysis .All statistical analyses were conducted using RStudio V.1.4. Only participants with complete data were included in the analyses (ranging from 34.2% to 97.4% by country). The 31 countries were categorised into three subregions: Eastern Mediterranean (which mostly consists of Middle Eastern countries); South East Asia (which consists of countries in the South and some countries in the Southeast Asia region) and Western Pacific . This categorisation was based on cultural and climate similarities shared by these countries, as well as WHO regional offices.Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.Of the original 174 449 adolescents surveyed from the 31 countries, there were 152 368 (87.3%) adolescents aged 11–18 years with complete data included in the analysis. Participants were excluded due to missing values in one or more variables: n=893 for age, n=1518 for sex, n=19 996 for weight and height and n=2866 for travel to school. There was no significant difference between those included in this analysis, those excluded from this study and those excluded based on weight and height variables . Table 1The overall prevalence of adolescent ATS in Asia was 55%  . This as2) was considerable in all three meta-analyses   . Some rery: 51%) .This study showed that 55% of Asian adolescents walk or cycle to school at least once per week. This prevalence varied substantially by country, with estimates varying from 18% (UAE) to 84% (Myanmar). However, regional variation was limited with 47% ATS prevalence noted in the Eastern Mediterranean, 56% in the South East Asia and 64% in the Western Pacific. Overall, older adolescents, male adolescents and adolescents with underweight/normal weight were more likely to use active modes than their counterparts. However, these associations varied across countries, suggesting that there may be substantial country-level variation in determinants of ATS.The prevalence observed in the current study (55%) is broadly similar to that reported in previous studies from various countries and regions.Despite limited regional variation, the Eastern Mediterranean had the lowest prevalence of adolescent ATS, which might reflect the high prevalence of physical inactivity in the general adolescent population in Eastern Mediterranean countries.43–45Similar to our findings, a study in Hong Kong reported that older adolescents were more likely to actively travel to school.Findings from both our study and previous research using the GSHS and other global datasets demonstrated that female adolescents in Asia are less likely to actively travel to school than male adolescents.Although adolescents with overweight and obesity BMI category were less likely to actively travel to school, this association was not observed in the subregion stratified analyses. Strong associations were only present in Cambodia and Vietnam, which is similar to findings from a Dutch population study where BMI was found to negatively influence later levels of active travel.52This study pooled estimates from 152 368 adolescents from 31 countries in Asia. Subregion and age-specific, sex-specific and BMI-specific estimates were also analysed. Data were collected using standardised sampling and data collection methods, enabling comparison across countries and subregions. However, the prevalence of ATS was obtained from one single self-reported question on both walking and cycling to school. Participating countries in the GSHS were also mostly those categorised as LMICs in Asia. As a result, the extent to which these findings are generalisable to other, particularly high-income, countries in Asia is unclear. This study also dichotomised both dependent and independent variables for meta-analysis purposes, which may have contributed to biases in the results, such as loss of information about individual differences and loss of effect.This evidence shows that there is substantial scope for improving ATS prevalence in Asian countries, which less than half of adolescents using ATS in many countries. The prevalence of ATS varied between and within the three Asian subregions, as did the associations with individual factors . This suggests that targeted promotion to certain population subgroups may be useful. However, future research is needed to explore why these variations occur among these countries to inform future policies and practices on ATS. Noting the variation of ATS by age group among the countries, age of independent mobility, especially on Eastern Mediterranean countries, should be studied so that future interventions with focus of age groups are appropriately designed. Future interventions should also focus more on designing ATS interventions that target female adolescents in Eastern Mediterranean and South East Asia countries. Any policy actions or interventions will need to be contextually sensitive, cognisant of local built, social and natural environmental contexts that could influence ATS. Further studies are therefore needed to gather evidence on the roles that environmental factors, such as exposure to air pollution, high-density traffic, walkability and safety, play in influencing ATS across Asian countries.The overall prevalence of adolescent ATS in Asia was 55%. The prevalence was lowest in UAE and highest in Myanmar. Overall, older adolescents, male adolescents and adolescents with underweight and normal BMI were more likely to actively travel to school than their counterparts. Although age, sex and BMI status were associated with the prevalence of ATS to varying degrees in the Eastern Mediterranean, South East Asia and Western Pacific regions, the main driver of variation within and between Asian countries remains unknown. Further investigations to identify other potential factors which account for differences in adolescent ATS prevalence across Asian countries is therefore needed to inform policy and practice.10.1136/bmjopen-2021-057082.supp2Supplementary data


Grip strengths in the high-SMM groups of both genders were significantly higher than in low-SMM groups (p < 0.05), and blood glucose and hemoglobin A1c in high-FM groups were higher than in low-FM groups for both genders (p < 0.05). Conclusion: The models generated by XGBoost and ANN algorithms exhibited good accuracy for estimating SMM and FM, respectively. The prediction models take into account the actual clinical use since they included a small number of required features, and the features can be obtained in outpatients. SMM and FM predicted using the two models well represented the risk of low SMM and high fat in a clinical setting.Background: Skeletal muscle mass (SMM) and fat mass (FM) are essentially required for health and quality of life in older adults. Objective: To generate the best SMM and FM prediction models using machine learning models incorporating socioeconomic, lifestyle, and biochemical parameters and the urban hospital-based Ansan/Ansung cohort, and to determine relations between SMM and FM and metabolic syndrome and its components in this cohort. Methods: SMM and FM data measured using an Inbody 4.0 unit in 90% of Ansan/Ansung cohort participants were used to train seven machine learning algorithms. The ten most essential predictors from 1411 variables were selected by: (1) Manually filtering out 48 variables, (2) generating best models by random grid mode in a training set, and (3) comparing the accuracy of the models in a test set. The seven trained models’ accuracy was evaluated using mean-square errors (MSE), mean absolute errors (MAE), and R² values in 10% of the test set. SMM and FM of the 31,025 participants in the Ansan/Ansung cohort were predicted using the best prediction models . Metabolic syndrome and its components were compared between four groups categorized by 50 percentiles of predicted SMM and FM values in the cohort. Results: The best prediction models for SMM and FM were constructed using XGBoost (R2 = 0.82) and artificial neural network  algorithms, respectively; both models had a low MSE. Serum platelet concentrations and GFR were identified as new biomarkers of SMM, and serum platelet and bilirubin concentrations were found to predict FM. Predicted SMM and FM values were significantly and positively correlated with grip strength ( Societal aging is a global phenomenon, and in Korea, people aged over 65 years constituted 10.7% of the population in 2010, 12.7% in 2014, and 14.3% in 2020. Sarcopenia is characterized by a decline in skeletal muscle mass (SMM) and reduced age-related muscle strength [SMM loss increases the risk of falls, comorbidities, and premature death . MaintaiThe potential mechanisms responsible for SMM reduction involve changes in anabolic hormonal signaling, protein oxidation, oxidative stress, inflammation, metabolic stress, and neuromuscular junction degeneration, and these processes replace muscle fiber with fats ,10. SMM n = 8842) but not the city hospital cohort . However, since the Ansan/Ansung cohort was relatively small, it was unsuitable for investigations aimed at identifying novel risk regulators of SMM or FM using association methods. Nonetheless, best prediction algorithms based on integrating the relative importance of risk factors from the Ansan/Ansung cohort using a machine learning approach can be used to predict SMM and FM [SMM and FM can be estimated by bioelectric impedance (BIA), dual-energy X-Ray absorptiometry (DXA), magnetic resonance imaging (MRI), and computed tomography (CT). However, all of these techniques have limitations in measured SMM and FM accuracy . SMM andM and FM ,15. We hKoGES included the Ansan/Ansung cohort and the urban hospital-based cohort. Participants were aged 51.97 ± 8.85 and residents of Ansan City (a large city area) or Ansung City  from 2001 to 2007. In Ansan/Ansung cohort, body compositions, including SMM and FM, were measured using Inbody 4.0 . After excluding participants lacking SMM and FM data, 6657 participants (3216 men and 3441 women) were included in the present study, and 1411 variables were used to build predictive models of SMM and FM. Ansan/Ansung cohort was used to generate the best prediction model for SMM and FM using a machine learning approach.The urban hospital-based cohort is another KoGES cohort conducted from 2004 to 2013 and had 53,843 participants, and the predictive model was applied to predict SMM and FM of the participants in this cohort. However, body compositions, including SMM and FM, were not collected. After excluding participants with missing data for predictive model parameters, 31,025 participants  aged 52.23 ± 8.1 were included in the present study. The age distribution of Ansan/Ansung and urban hospital-based cohorts were similar .The study protocol was approved by the Institutional Review Board of the Korea Centers for Disease Control and Prevention (KBP-2015-055) and Hoseo University (1041231-150811-HR-034-01). Written informed consent was obtained from all participants.n = 666). We manually excluded participants with missing values and duplicates from the 1411 in the Ansan/Ansung cohort. Forty-eight variables were used to train a random forest algorithm to predict SMM and rated in order of importance. In order to reduce the number of variables required to predict SMM using the machine learning approach, we removed the variables one by one from low to high importance and iteratively trained the random forest model until the mean square errors (MSEs) of the model did not decrease significantly after eliminating one variable each. Finally, when the top 10 variables had been identified , XGBoost, decision tree, random forest, K-nearest neighbor (KNN), and artificial neural network (ANN). The best combination of variables was selected using a random grid search method for each algorithm, and each trained algorithm was used to calculate SMM and FM in the test set. The best algorithm was selected by comparing MSEs, mean absolute errors (MAEs), and R² values of SMM and FM predicted by each algorithm in the test set.The third step involved predicting the SMMs and FMs of participants in the urban hospital-based cohort using the selected best models for SMM and FM. Clinical characteristics of the participants with a high or low SMM or FM in a city hospital-based cohort are provided in Participants in the Ansan/Ansung cohort were randomly divided 90%:10% to a training set or a test set. The mean age in the SMM training set cohort was 51.38 ± 8.9, and the mean age in the test set cohort was 51.17 ± 8.9 . For FM,The trained models’ accuracies were evaluated using the remaining 10% of the Ansan/Ansung cohort as a test set by calculating mean-square errors (MSE), mean absolute errors (MAE), and R² values of the seven trained models. We also evaluated absolute errors in three SMM and FM ranges by quintiles  to check accuracy differences according to the ranges of SMMs and FMs. The optimal SMM prediction model was XGBoost, and its optimal hyperparameters were as follows—84 of trees and 2 of max depth. The optimal FM prediction model was ANN, and its optimal hyperparameter was as follows—10 artificial neurons in the input layer, six artificial neurons in a hidden layer, “relu” of the activation function, and one artificial neuron in the output layer.We used the two trained models by XGBoost and ANN algorithm to predict SMM and FM, respectively, in the urban hospital-based cohort and investigated the relationships between SMM and grip strength and between FM and BMI. We dichotomized subjects in the urban hospital-based cohort into 4 SMM/FM groups using SMM first quartile cutoffs of 48 kg for men and 35 kg for women and FM cutoffs of 25% for men and 30% FM for women. Accordingly, the four groups were: the HMLF group (high SSM and low FM); the HMHF group (high SSM and high FM), the LMLF group (low SSM and low FM), and the LMHF group (low SSM and high FM). Adjusted means and standard errors were determined for metabolic syndrome component and lifestyle variables after adjusting for age, gender, residence area, education, income, and BMI.p-values < 0.05. Results are presented as means ± standard deviations.The normality test of each continuous variable was determined, and the variables showed normal distribution. The significances of differences between variables for men and women were determined using the two-sample t-test in the Ansan/Ansung and urban hospital-based cohorts. Linear relationships were analyzed using Pearson’s correlation coefficients. Adjusted means and standard errors were calculated after adjusting for age, genders, residence area, education, income status, and BMI in the four groups (described above) of the urban hospital-based cohort. One-way ANOVA was used to determine the significances of intergroup differences. The analysis was performed using SPSS version 20 , and statistical significance was accepted for The mean subject age was ~51 in the Ansan/Ansung cohort and 54 in the urban hospital-based cohort . BMI andMetabolic parameters, including glucose and lipid levels, inflammation, and blood pressure, were better in the urban hospital-based cohort than in the Ansan/Ansung cohort, and with the exceptions of serum total cholesterol and platelet concentrations, which were better in women than men in both cohorts . Energy Random forest and XGBoost algorithms in the seven trained ones returned the importance of features A,B. Of tThe MSE and MAE values of the XGBoost SMM predictive models were the smallest, and R² was close to 1, indicating the model using the XGBoost algorithm exhibited strong relationships. The model’s MSE and MAE values for FM prediction using the ANN algorithm were the smallest, and its R² was also close to 1 .The random forest prediction model was applied to seven machine learning algorithms A,B. PredIn the FM predictive models provided by seven machine learning algorithms, the absolute error percentage in overall FM was ~10%, and it was bigger for FM than SMM. The prediction models generated by XGB, random forest, and ANN algorithm had the lowest absolute errors for FM prediction in all FM ranges. The absolute error was ~5% in the 20th–80th percentile range for the ANN model, and the prediction of FM in the > 80th percentile range exhibited a much higher absolute error value B.Since men and women had significantly different SMM and FM, SMM and FM cutoffs were defined separately for men and women . The cutIn men, serum glucose and HbA1c concentrations were higher in the high-fat groups, regardless of SMM. Serum triglyceride concentrations reduced in the order LMLF, HMLF, and HMHF = LMHF, whereas serum HDL concentrations increased in the order HMHF, LMHF = HMLF, and LMLF. GFR was higher for a low SMM and a high FM. SMM and waist and hip circumferences in women showed a similar trend to those observed in men. Grip strength was highest in the HMLF group and lowest in the LMHF group. In women, serum concentrations of glucose and HbAlc were higher in the HF than in the LF groups regardless of SMM. GFR exhibited different trends in men and women. In men, GFR was higher for low SMM and FM than for high SMM and FM, but in women, GFR was higher in high SMM and low-FM than for low SMM and high FM.p < 0.001, p < 0.001, Since grip strength is positively correlated with SMM and negatively associated with sarcopenia ,2, the XMachine learning has been attracted considerable attention during recent years, and machine learning data processing, clustering, classification, dimensionality reduction, regression, and other functions provide potent data mining tools. Unlike traditional computer algorithms that produce results when commands are executed, machine learning algorithms can construct and train algorithms to process data and obtain results in required forms . In the In the importance analysis, the random forest  and lineIn the present study, the FM prediction model using ANN included BMI, sex, hip circumference, waist circumference, total activity, and serum triglyceride, total cholesterol, total bilirubin, CRP, and platelet concentrations. Excessive fat accumulation is distributed in subcutaneous tissues related to disruption of lipid metabolism and inflammation in obese individuals to fatty liver and dyslipidemia . In the Plasma bilirubin concentration, an index of liver and gallbladder damage, is positively related to hepatic fat accumulation , and ourIn the present study, we compared the accuracies of regression models using machine learning algorithms and selected the best prediction models for SMM and FM. Of the seven machine algorithms examined, random forest, XGBoost, and ANN had the lowest MSEs for predicting SMM and FM in the Ansan/Ansung cohort test set. XGBoost and ANN have also been reported to achieve good accuracies, and XGBoost has been shown to enable the identification of biomarkers ,24. GripWe also divided anthropometric parameters into the HMLF, HMHF, LMLF, and LMHF groups to predict SMM and FM in men and women. Both male and female HM groups had higher grip strengths than their counterparts in the LM groups, which is consistent with the results of a previous study regarding the correlation between SMM and grip strength . Serum tWe trained multiple prediction models for SMM and FM using Ansan/Ansung data and eventually obtained SMM and FM predictions for urban hospital-based cohorts using the XGBoost and ANN models. The maximum R² values of the SMM and FM models were 0.82 and 0.89, respectively, which is in line with actual application indicators in the medical system. The results of the present study can be applied to clinical setting since the SMM and FM had specific characteristics as follows: (1) The prediction model of SMM and FM included relatively small number of variables, (2) variables included in the prediction algorithm was not fluctuated quickly in a short time, and (3) SMM and FM of the adults fell in the accurate ranges of prediction algorithm . TherefoHowever, the trained prediction models have several limitations. (1) Since they were trained using Korean data, our results may be unsuitable for applications in European or Hispanic populations. (2) Our study was performed on Koreans ≥40 years old and thus our findings may not be applicable in younger populations. (3) SMM and FM values determined in the Ansan/Ansung study were obtained using the Inbody machine, which is less accurate than DXA. However, we confirmed the applicability of the prediction models in a large urban hospital-based cohort, and the accuracy of predicted values was verified by linear relationships between grip strength and SMM and BMI and FM. (4) Regarding the feature importance analysis, we used simple XGBoost, random forest, and linear regression to explore important variables without knowing the impact of each variable. However, according to Lundberg’s research on SHapley Additive exPlanations (SHAP), the SHAP value can explain how each feature affects machine learning algorithms, providing a new interpretation method for the machine learning black box algorithms . In the The best prediction models, which included ten variables for SMM and FM, were generated using XGBoost and ANN algorithms, respectively, using the Ansan/Ansung cohort. The SMMs and FMs predicted by the models well represented the risk of low SMM and high FM in this hospital-based cohort. Adults with a low SMM and high FM are at risk of hyperglycemia, and the prediction models included potential biomarkers for SMM, such as serum platelet levels, triglyceride concentrations, and GFR. In contrast, those for FM included serum bilirubin and triglyceride concentrations. The prediction algorithm for SMM and FM can be considered to use in the clinical site since the variables in the algorithm are easy access. The prediction models are of practical significance in clinical settings and the predicted SMM and FM values can convince the patients to modulate their diet and physical exercise plans.


Background: This study describes patients with coronary artery disease (CAD) who are eligible for secondary prevention and assesses their healthcare consumption and costs from the perspective of the Italian National Health Service (INHS). Methods: From the Fondazione Ricerca e Salute’s database, which collects Italian healthcare administrative data, all patients aged ≥ 35, with ≥1 primary in-hospital CAD diagnosis and/or procedure on the coronary arteries, or with the specific disease exemption code, and who are suitable for long-term secondary prevention treatments, were identified in 2018 and analyzed. Demographics, comorbidities, one-year supplied drugs, hospitalizations, and costs were analyzed. Results: From >3 million inhabitants aged ≥ 35, 46,063 (1.3%) were identified . During a one-year follow-up, 96.4% were treated with ≥1 drug for secondary prevention (mainly antiplatelets and lipid lowering agents), 69.4% with ≥1 concomitant cardiovascular drug, and 95.8% with ≥1 concomitant non-cardiovascular therapy. Within one year, 30.6% of patients were hospitalized at least once, mostly due to non-cardiovascular events. Calculated by mean, the INHS paid EUR 6078 per patient. Conclusions: This analysis confirms the relevant burden of CAD for patients with many comorbidities and who are frequently hospitalized, and the burden on the INHS. A multidisciplinary healthcare approach is encouraged to improve patients’ outcomes and reduce costs for the INHS. Although the prevalence and mortality rates of coronary artery disease (CAD) had decreased by the early 1980s in Europe, they continue to remain high, with 9.2% of the European population affected by CAD and more than 1,700,000 patients dying every year . CAD morThis study of Italian healthcare administrative databases is aimed at describing patients with CAD and eligible for secondary CV prevention and assessing their healthcare resource consumption and costs from the perspective of the Italian National Health Service (INHS).This analysis was performed by means of healthcare administrative data from the Fondazione Ricerca e Salute (ReS) database, which has previously been used for several observational studies on various clinical questions in different clinical fields since 2018 ,15,16. FAll patients older than 35 in the ReS database in 2018, and with at least a healthcare resource consumption in the charge of the INHS since 2015, defined the starting population. Among them, subjects who were admitted to hospital at least once in 2018  and whose hospital discharge contained a primary/secondary diagnosis of CAD and/or a procedure on coronary arteries, or patients with a CAD-specific cost sharing exemption code, were selected for the analysis , the most relevant comorbidities were identified , ARBs (plain and their combinations (C09C/C09D), β-blockers (C07), lipid lowering agents (C10), and antiplatelet agents excluding heparin (B01AC).−Other CV drugs: at least a dispensation of pharmacological treatments belonging to ATC codes C and B01, different from those previously mentioned.−Non-CV drugs: at least a free, filled prescription of the drugs identified by ATC codes, different from those quoted in the above bullets.The analysis cohort was followed up 1 year after the index date in order to assess the consumption of drugs reimbursed by the INHS. These were analyzed after being split into:Pharmacological treatments were assessed by different ATC code levels in terms of the portion of patients treated and mean DDD (a standard measurement of the average daily consumption of the maintenance dosage) per treated subject.−Relevant CV diseases: acute coronary syndrome (ACS), angina pectoris, heart failure, haemorrhagic stroke/intracranial bleeding, ischemic stroke/transient ischemic attack (TIA).−Other CV diseases.−Non-CV diseases.Hospitalizations were analyzed by means of the information included in the hospital discharge form. They were analyzed in terms of the primary diagnoses of:Selection codes identifying all the aforementioned diagnoses are available in −Pharmaceutical costs extrapolated by the gross expenditure of local pharmacies’ sales and by the real hospital price  of hospital pharmacies’ supplies.−In-hospital expenses derived from DRG (Diagnosis-Related Group) tariffs. Each hospital discharge form was linked to a DRG code which synthetizes the entire healthcare provided at admission and throughout the in-hospital stay.−Outpatient specialist care costs derived from the current National system tariffs.Each healthcare administrative database also contained expenditure information. In particular, the healthcare costs analyzable by means of the ReS database were:Findings were provided as mean annual cost per capita of the single items  and of their integration .p values and have described nominal differences.Generally, when administrative data are analyzed, the number of patients/events is so large that even minimal differences will result in a conventional level of statistical significance, often without a corresponding and convincing level of clinical significance. For this reason, we have mostly avoided the use of detailed All analyses were performed by means of the Oracle SQL Developer, Italian version 18.1.0.095, California, United States.For more than five million inhabitants that were analyzable through the ReS database in 2018, 46,063 patients aged ≥ 35 (1.3%) were found to be affected by CAD and suitable for long-term secondary CV prevention treatments, according to the selection criteria described in the Males (72.1%) made up most of the CAD cohort, and the mean age (±SD) was 70 ± 12 . The preDuring the one-year follow-up, 96.4% of the cohort was treated with at least one drug for CV secondary prevention, with a mean consumption per patient of 1262 DDD .Exactly 30.6% of the cohort was hospitalized at least once during the one-year follow-up .In addition, 11.4% of patients were hospitalized due to relevant CV events. They were most frequently admitted due to ACS (5.2%) and heart failure (4.0%). Heart failure and haemorrhagic stroke/intracranial bleeding caused the longest in-hospital period of stay (approximately 11 days), as shown in On average, during the year following the index date, each patient with CAD and eligible for secondary CV preventive treatments cost the INHS EUR 6078 .The overall expenditure originated from the integration of all the health care charged to the INHS. Hospitalizations accounted for 69.9% of the overall expenditure. A substantial contribution was provided by non-CV causes . Pharmaceuticals accounted for 24.7% of the overall cost. Concomitant non-CV drugs, which also accounted for 11.7% of the overall expenditure per capita, determined approximately half of pharmaceutical costs.This study has assessed a population aged ≥35, affected by CAD, and eligible for secondary prevention, through Italian healthcare administrative data. The burden of CAD and the preventive strategies for further CAD risk reduction are, overall, not negligible, and increase with age ,19. Age Patients affected by CAD have several comorbidities (approximately 50% of them by three or more), which are also associated with the risk of further CV diseases. In this study, patients with CAD and eligible for secondary prevention were mostly affected by arterial hypertension, dyslipidaemia, and diabetes; this is in line with other real-world studies ,11,20. TDespite the prescription rate of preventive drugs having been on the increase for many years , and theThe prescription pattern of non-CV drugs reflects the clinical conditions of an elderly population, which is frequently treated with drugs for gastric disorders and anti-inflammatory or antibacterial agents, even in the absence of evidence-based recommendations.Different solutions have been proposed to favor the compliance to drug recommendations and improve the control of the CAD progression. Shimada and colleagues, by demonstrating that drugs are rarely prescribed by GPs after hospital discharge, have suggested that an improvement in prescriptions at discharge may be one of the most important interventions . SupportThe risk of recurrent admissions at one year after a CV event, especially for MI and stroke, has been found to be high, specifically for patients who did not follow guideline-recommended therapies ,11. The Exactly 9.1% of our cohort was hospitalized due to other CV events, however a relevant rate (17.5%) of patients was admitted due to non-CV causes, once again reflecting the elevated mean age of the target population and the burden of comorbidities. Moreover, 30.6% of our cohort was admitted to hospital at least once for any cause during the one-year follow-up. This rate of readmissions is close to that found by a German claims database analysis, which reported that from the third to the fifth quarter after MI, 40% of all patients were re-hospitalized due to any condition .The overall integrated cost charged to the INHS of a patient with CAD and eligible for secondary preventive treatments was elevated. The cost distributions of the overall expenditure clearly reflect the demographic and clinical conditions of this cohort, which was mostly elderly and affected by multiple comorbidities. Interestingly, the outpatient specialist services weighed a little. Causes could be the high utilization of the private outpatient specialist resources or the scarce frequency of controls and visits, especially for the cardiological ones. Interestingly, Ulrich and colleagues found that, one year after MI, only 22.8% of patients was visited by a cardiologist, only 34.1% received a laboratory investigation, and the reduction in visits to the cardiologist was particularly high in patients aged from 65 to 86 [Cost-effectiveness has been found to be strongly dependent on parameters such as the age of the target population, the overall population risk of CV diseases, and the interventions’ cost . Delate The perspective was only that of the INHS, both for the in-hospital and outpatient settings, therefore, the healthcare services not reimbursed by the INHS or that were privately provided  were not collected and analyzed in the administrative databases, leading to an inevitable underestimation. In particular, the Italian Medicine Agency reported that, in 2018, 23% of overall pharmaceutical expenditure was addressed to private purchase . NeverthThis is the most recent study on Italian healthcare administrative data, specifically designed for describing the epidemiology of patients with CAD, their public healthcare , including the specific pharmacological secondary prevention and costs covered by the INHS. Moreover, the present analysis can be considered complementary to clinical studies or registry studies since it provides updated information generalizable to the total population of subjects with this clinical condition. This analysis of the ReS database shows that patients with CAD determine a relevant burden for the INHS. The age of these patients is generally elevated, with very frequent comorbidities. This fact is particularly clear when non-CV reasons for hospital admission and the costs for non-CV drugs are considered. This study also shows that secondary prevention therapies remain insufficiently used in a real-world setting, highlighting a potential under-prescription of the guideline recommended drugs for effective CV risk factor control. Areas of improvement are various, and found at patient, physician, and population level. The healthcare of these patients, as well as the burden on the health system , would benefit from a collective and multidisciplinary effort on the part of all stakeholders involved in the care pathway.


Agriotes obscurus and A. lineatus, species that are pests in both Europe and North America. However, both blends appeared to reduce captures, even when combined with the pheromones of these species. Similarly, combining the pheromones of these two beetles into a single lure reduced captures of both species. Our results indicate that attractants for female click beetles may be highly species-specific, and that combining pheromones of closely related species with each other or with plant volatiles can reduce trapping efficacy. The development of attractants for females of key pest species would greatly advance our ability to monitor and manage these pests.Wireworms are the larval stage of click beetles, and are serious pests of multiple field crops worldwide. Pitfall traps for collecting the adult (beetle) stage of these pests are commonly used to determine the risk of crop injury, or to remove beetles from a field before they mate or lay eggs, but such traps are only effective when baited with an attractant. These attractants are typically sex pheromones produced by female beetles and attractive to males, but two blends of plant-derived compounds attract females of some species. We evaluated the attractiveness of these compounds to male and female Agriotes brevis and A. ustulatus, allowing the monitoring of both males and females of these species with lures containing both pheromones and plant volatiles. The attractiveness of these plant volatiles for two congeners, A. obscurus and A. lineatus, which are agricultural pests in Europe and North America, was evaluated in the current study. Both the four-component MINIM plant-derived lure for A. brevis, and the blend of (E)-anethol and (E)-cinnamaldehyde for A. ustulatus, were not attractive to A. obscurus and A. lineatus, and instead appeared to reduce captures—both when compared to blank controls, and when blended with and compared to the sex pheromones of these species. This was most pronounced in A. obscurus, where (E)-anethol and (E)-cinnamaldehyde reduced male captures by 43 and 37%, respectively. Combining the pheromones of A. obscurus and A. lineatus reduced captures of these species by 77 and 19%, respectively, compared to these pheromones singly. This suggests that attractants for female click beetles can be highly species-specific, and that the blending of pheromones of congeneric species with each other, or with plant volatiles, can reduce captures. Further research into developing such attractants for economic species is urgently needed.Sex pheromones are commonly used in traps to monitor populations and movements of male click beetles, but to date few attractants have been identified for females. Notable exceptions are plant-derived kairomones for female  Coleoptera: Elateridae), are increasingly important pests of cereals, corn, potato, vegetables and other field crops worldwide [Wireworms, the larval form of pestiferous click beetle species  and Lolium italicum (A. Br.) placed on plastic sheets on the soil, and subsequent analyses of volatile extracts and antennal responses of A. brevis to these extracts, led to the development of a four-component “MINIM” plant-derived lure attractive to female A. brevis in the field [A. ustulatus Schaller on traps deployed for western corn rootworm (Diabrotica v. virgifera Le Conte) and other insects led to the development of a blend of (E)-anethol and (E)-cinnamaldehyde, two floral compounds, which is attractive to both male and female A. ustulatus [A. sordidus (Illiger), A. brevis, and A. ustulatus, are attracted to their own pheromones [A. ustulatus resulted in higher catches than those baited with either compound alone [To date, very few attractants for female click beetles are known. Observations of female he field . Observastulatus . In addieromones ,19, thound alone .A. obscurus L. and A. lineatus L., two species of economic importance in both North America and Europe [A. brevis and A. ustulatus. Beetles were exposed to these blends singly, and in combination with their own or the heterospecific’s pheromone.The objective of the current study was to determine whether male and female d Europe , are attA. obscurus (AO), Vernon Beetle Traps [Z)-3-hexenyl acetate (300 mg), methyl benzoate (5 mg), (Z)-3-hexenol (30 mg), and methyl salicylate (30 mg), and AO pheromone lures  contained 175 μL of a blend of geranyl hexanoate and geranyl octanoate (1:1 ratio). The traps were placed during the peak swarming season (26 April) in three side-by-side 4 × 4 Latin square blocks with 8 m spacing between traps and 16 m between blocks, to effectively form a single 4-treatment, 12-replicate RCBD study. Care was taken to prevent cross-contamination between traps during trap checks , by using different gloves for different treatments during trap installation and checks. All beetles—AO, and incidental catches of co-occurring A. lineatus (AL)—were identified by species and their sexes were determined.Two studies were conducted. To determine the attractiveness of the MINIM lureand/or AO pheromone to male and female le Traps  were depE)-anethol and (E)-cinnamaldehyde (hereafter “plant volatiles”) to male and female AO and AL, Vernon Pitfall TrapsTM  [To determine the attractiveness of a blend of ( Canada)  were dep Canada) . All lur Canada) ,24. All p = 0.05.The numbers of male and female beetles collected in different treatments were analyzed per sex (in 2013) or combined (in 2021) using generalized linear models (GLM) , with a negative binomial distribution and log-link function. For the 2021 data, the proportions of female beetles in the subsamples sexed per trap were analyzed with a GLM with a binomial distribution and a logit-link function. For the 2021 data, the treatment replicate was nested within the landscape category. Where significant differences among treatments were observed, treatment means were separated using Tukey’s Standardized Range HSD test at Agriotes [Traps baited with AO pheromone collected significantly more male AO beetles than traps baited with MINIM lures or left unbaited on both collection dates, but traps with MINIM lures attracted numerically fewer male AO than control traps . BaitingAgriotes ,19, and Agriotes . As withA. lineatus in the 17 May but not in the 3 May collection , but this difference was only statistically significant for the 27 May and combined collections . For eacAs expected, the highest number of AO were collected in traps baited with AO pheromone . CombiniCombining the AO and AL pheromone into a single lure reduced captures of AO beetles by 94, 79, and 67% for the 12, 20, and 27 May collections, respectively , with the reduction statistically significant for each date . The relTraps baited with the plant volatiles collected fewer AL beetles than unbaited control traps overall (17%), but this reduction was only observed on the 12 May and in combined collections , and wasAs expected, the highest number of AL were collected in traps baited with AL pheromone . SimilarCombining the AO and AL pheromone into a single lure increased captures of AL beetles by 10% in the 12 May collection, but reduced captures by 23 and 36% for the 20 and 27 May collections, respectively ; none of these differences were statistically significant . This reHypnoidus bicolor (Eschscholtz) and Aeolus mellillus Say [Unlike in Europe, where pheromones for most of the economically important click beetle species have been identified and used in monitoring for some time ,31,32,33A. brevis and A. ustulatus [A. lineatus and various Limonius species in BC . When pheromone lures for AL and AO were combined, no difference was found in catches of AL in a preliminary study in Europe [Provided that the compounds are not repellent to either sex, click beetle pheromones and plant volatiles can potentially be combined to produce lures that are more attractive than those containing either compound singly, as demonstrated for stulatus ,20. Simin Europe , which ln Europe , and as Finally, the development of plant-derived or pheromone lures should also take into consideration that a species’ response to an attractant may vary with geographic region, possibly because of differences in pheromone composition  and in tAgriotes species, the plant-derived compound blends evaluated in these studies were not attractive to male or female AO and AL, but instead appeared to reduce captures. This suggests that the existence and nature of attractants for female click beetles will need to be determined per species, and that considerably more research is needed to determine whether pest species have preferred host plants for food sources and/or oviposition sites. AL beetles are attracted to the AO sex pheromone, but not vice versa, and combining the pheromones of these two species can reduce captures of both. While blending these pheromones in a single lure may allow the detection of both species in a field, it will reduce the effectiveness of traps baited with such lures for mass trapping.Although attractive to some


Lolium multiflorum and Trifolium subterraneum was conducted, with manipulation of species composition (five levels), and nitrogen (N)- and phosphorus (P)- fertilization (three levels). In the non-mycorrhizal state, interspecific competition did not play a major role. However, in the presence of AMF, Lolium was the strongest competitor, with this species being facilitated by Trifolium. While N-fertilization did not change the competitive balance, P-fertilization gave Lolium, a competitive advantage over Trifolium. The effect of AMF on the competitive outcome may be driven by differential C-P trade benefits, with Lolium modulating carbon investment in the mycorrhizal network and the arbuscule/vesicle ratio at the cost of Trifolium.Arbuscular mycorrhizal fungi (AMF) may affect competitive plant interactions, which are considered a prevalent force in shaping plant communities. Aiming at understanding the role of AMF in the competition between two pasture species and its dependence on soil nutritional status, a pot experiment with mycorrhizal and non-mycorrhizal  Rhizobium fix atmospheric nitrogen, making the system self-sufficient in nitrogen; yet an external input of phosphorus for optimal legume growth is necessary to sustain the positive effects of SBP  symbiosis. Although some studies showed AMF to be significant in enhancing plant nitrogen supply , AMF areTrifolium subterraneum and the grass, Lolium multiflorum. Both functional groups not only have different nutrient demands  and N- and P-fertilization (three levels). We hypothesized that (i) AMF would promote the competitive ability of the legume  over the grass , and that (ii) the influence of AMF on competitive outcome would be markedly modulated by N- and P-fertilization.Insights into mycorrhizal functioning and plant-fungal processes are important for understanding the competitive interactions between the grasses and legumes in SBP, and their potential role in the sustainability of these pastures. The predominant species used in the SBP mixture are the legume,  demands , but als demands  and rely demands . As AMF  demands , the higructures , which mT. subterraneum L. and the grass, L. multiflorum L. The species composition in the five competition treatments is depicted in Trifolium, competition 2 contains three Trifolium individuals and one Lolium individual, competition 3 contains two individuals of Trifolium and two individuals of Lolium, competition 4 contains one Trifolium individual and three Lolium individuals, and competition 5 is comprised of four individuals of Lolium. All competition treatments were subjected to three different fertilizer regimes with either standard nutrient solution (C), increased nitrogen (+N), or increased phosphorous (+P).A controlled pot experiment was conducted in a greenhouse at the University of Bielefeld, Germany. The experiment followed a randomized complete block design with three factors: with and without mycorrhizal inoculum (AM/NM), five competition treatments (competition 1–5), and three fertilizer regimes , with five replicates for each treatment, giving a total of 150 pots. In the competition treatments, we assessed the individual responses of two species typically dominant in the SBP seed mixtures: the legume, T. subterraneum L. and L. multiflorum L.  were surface-sterilized  and sown in boxes with sterilized (120°C for 1.5 h) sand. Three weeks after germination, the seedlings were transplanted to small pots (0.5 l) filled with sterilized sand. During transplanting, roots of AM treatment seedlings were inoculated using 20 g of an inoculum-sand-mixture containing dried Plantago lanceolata root fragments with at least 200,000 infective units of Rhizophagus irregularis per liter inoculum , while the NM treatment received 20 g of sterilized sand and 5 ml of a microbial wash, which was extracted from the inoculum by sieving the supernatant of a water-inoculum-mixture through a 20 μm sieve  at 90°C for 15 min  prior to further analysis. Subsequently, 2–4 mg of ground plant material was transferred to an elemental analyzer  and analyzed for total elemental C and N. Tissue P was measured using high-temperature oxidation and colorimetrical quantification according to 3– and NH4+ were extracted by shaking 15 g of soil with 30 ml of 0.1 M CaCl2 for 1 h.Soil NO43– was extracted using a modified calcium acetate–lactate (CAL) extraction method according to –1) was shaken for 90 min. Extracts of both mineral nitrogen and phosphorus were centrifuged at 3,000 rpm for 3 min and the supernatant was passed through a glass fiber filter (1 μm pore size) using a Luer syringe. Concentration of N and P in the extracts was determined by colorimetric analysis at 546 and 880 nm, respectively, using flow injection analysis .Soil POFor each species, at a given treatment, mycorrhizal growth dependency was calculated according to Eq. 1 :with AM corresponding to the total biomass of an individual mycorrhizal plant and corresponding to the mean total biomass of the equivalent non-mycorrhizal plants.For each species at a given treatment, mycorrhizal P-dependency was calculated according to Eq. 2 :P corresponding to the tissue P (%) of an individual mycorrhizal plant and corresponding to the mean tissue P (%) of the equivalent non-mycorrhizal plants.with AMTotal aboveground biomass was used to calculate the relative neighbor effect (RNE) according to Eq. 3 :control if B control > B mix and x being B mix if B control < B mix, where B mix is the aboveground biomass of a plant in interspecific competition  and B control is the aboveground biomass of an intraspecific control (competition 1 for Trifolium and competition 5 for Lolium).with x being B Tissue P (%) of plant material was used to calculate the relative neighbor effect for P-competition (RNE-P) according to Eq. 4 :control if P control > P mix and P mix if P control < P mix, where P mix is the tissue P (%) of a plant in interspecific competition  and P control is the tissue P (%) of an intraspecific control (competition 1 for Trifolium and competition 5 for Lolium).with x being P The relative performance ratio (PR) of the two species in the mixture at a given treatment is calculated according to Eq. 5:mix corresponding to the aboveground biomass per plant of the two species in interspecific competition .with B post hoc pairwise comparison was applied to determine the individual differences between means.Statistical analyses were performed using Statistica 6.0 . Data were tested for normal distribution (Kolmogorow-Smirnow test) and homogeneity of variances (Brown-Forsythe test). Data that did not satisfy the assumptions of normal distribution was log10 or arcsine square root transformed prior to analysis. Two-way ANOVA  was performed on the data of colonization level, MGD, MPD, and A:V ratio within each species. Three-way ANOVA  was performed on above- and belowground biomass, RNE, RNE-P, tissue N and P concentration of each species, soil N and P, and on PR. When appropriate, Tukey’s Trifolium, root colonization ranged from 89.2%  to 99.2% , with a significant effect of competition on Trifolium root colonization  as compared to the control and +N treatment .Mycorrhizal inoculation led to a high AMF root colonization in both species . In Trifnization . In LoliLolium than in Trifolium  was higher in rifolium . In Loli:V ratio . Values Trifolium  was not affected by competition or fertilization, while both factors did affect MGD in Lolium  as compared to Lolium (average of 11.5 ± 3.9).In n Lolium , althougn Lolium . Mycorrhn Lolium , with a   for both species was not affected by competition or mycorrhization . Fertililization . Howeverl plants , with TrCompetition did not affect soil inorganic P, although mycorrhization and fertilization did result in significant differences in soil P . In the Lolium  over the grass , as phosphorus uptake via the AMF pathway should be more efficient than via the direct root pathway  with relatively more nutrients .Slightly lower colonization in  species . Also, tLolium and mycorrhizal individuals of both species, this effect being more pronounced in the grass, which reached nearly double the biomass than in the other treatments.Phosphorous-fertilization on the other hand, had a positive growth effect on non-mycorrhizal Lolium with additional P, however, did not affect the competition with Trifolium in the non-mycorrhizal state. This was mainly caused by the Trifolium plants not being able to accumulate enough phosphorus to develop a biomass increase in the absence of mycorrhiza  and the prominent legume  in SBP with different N- and P-fertilization. Although the effects of competition on the studied parameters were generally weak, we showed clear and interesting trends of species composition in the pots on biomass, plant nutrient concentrations, and mycorrhizal investment.In this study, we addressed mycorrhizal effects on the competitive ability of the prominent grass (i.e., Lolium was clearly a better competitor for phosphorus than Trifolium and, in contrast to our hypothesis, was facilitated through the presence of mycorrhiza provided and sustained by the clover. Mycorrhizal Trifolium on the other hand, suffered from P-competition by the grass, showing a lower performance with increasing number of Lolium individuals in the pot. While N-fertilization in the mycorrhizal treatments did not change the competitive balance between mycorrhizal grass and clover, P-fertilization had a marked effect on both species with stronger biomass increases in Lolium as compared to Trifolium. Although the grass showed smaller mycorrhizal benefits, while clover did not, Lolium obtained a competitive advantage through mycorrhiza with extra P. This may be explained by the facultative mycotrophic Lolium being able to control the C–P trade of the AMF symbiosis by better adjustment of the A:V ratio than the highly responsive clover. The more plastic usage of the direct root uptake pathway over the mycorrhizal pathway for P-acquisition in Lolium than in Trifolium, and thereby ensuring a beneficial C–P trade in the common mycelial network, may thus be a key factor for the competitive success of the grass.From our results, we may conclude that in this study, in situ SBP?What are the implications of our results for the in situ, can be expected to be high, good management practices that encourage soil conditions (First, our results indicate that AMF were clearly beneficial for both species. As the majority of herbaceous plant species have AMF symbionts , and sinnditions  and graznditions  favorablTrifolium exhibiting lower biomass with higher Lolium count in the mixture and vice versa. As success and sustainability of SBP are dependent on a good legume performance, a higher legume: grass ratio in the seed mixtures for SBP is therefore advisable.Second, our results showed that competition between the two species was influenced by the available soil P with mycorrhizal in situ conditions is not totally straightforward. We used pre-inoculated plants, which does not reflect natural field conditions, where seedlings are usually inoculated via life hyphae from mycorrhizal networks already established by adult plants. However, in the studied Mediterranean system, this may not matter as much, as here, adult plants and life hyphae do not exist in large amounts after the summer drought and the system reestablishes from seedlings being inoculated by spores. In addition, in our study, the substrate only contained a single AMF isolate while in situ soils contain a large diversity of bacteria and fungi, and micro- and macrofauna, with the functional complementarity among species within an AMF community colonizing a single root system undoubtedly affecting mycorrhizal responsiveness (Extrapolation of our results to siveness . Neverthsiveness .Trifolium across all treatments and N-status of neither species depended on competition or fertilization, effects of nitrogen acquisition through rhizobial symbiosis probably played a minor role for the outcome of the experiment.Further, our study neither aims to assess the significance of rhizobial symbiosis, nor the effects of different fertilizer levels on this symbiosis, even though it is important for N-uptake in legumes . Differein situ situation, the main findings of this study are important for the SBP practice.Notwithstanding the limitations in the transferability of results from a pot study to the The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.SU, FMH, and KS designed the experiment. SU and MJ accomplished the data analysis, data interpretation and presentation, and wrote the manuscript. 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. The reviewer AN declared a shared affiliation with one of the authors MJ to the handling editor at the time of the review.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.


A clinical diagnosis of polycystic ovary syndrome (PCOS) can be tedious with many different required tests and examinations. Furthermore, women with PCOS have increased risks for several metabolic complications, which need long-term health management. Therefore, we attempted to establish an easily applicable model to identify such women at an early stage.To develop an easy-to-use tool for screening PCOS based on medical records from a large assisted reproductive technology (ART) center in China.A retrospective observational cohort from Peking University Third Hospital was used in the study. Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression with 10-fold cross-validation was applied to construct the model. The area under the receiver operating characteristic curve (AUC), sensitivity, and specificity values were used to evaluate and compare the models.This retrospective cohort study included 21,219 ovarian stimulation cycle records from January to December 2019 in Peking University Third Hospital.The main outcome was whether there was a clinical diagnosis of PCOS. The independent variables included were age, body mass index (BMI), upper limit of menstrual cycle length (UML), basal serum levels of anti-Müllerian hormone (AMH), testosterone androstenedione, antral follicle counts et al.http://121.43.113.123:8888/) has been developed to assist Chinese ART clinics.We have established a new mathematical model for diagnosing PCOS using serum AMH and androstenedione levels, UML, and BMI, with AUC values of 0.855 (0.838–0.870), 0.848 (0.791–0.891), 0.846 (0.812–0.875) in the training, validation, and testing sets, respectively. The contribution of each predictor to this model were: AMH 41.2%; UML 35.2%; BMI 4.3%; and androstenedione 3.7%. The top 10 groups of women most predicted to develop PCOS were demonstrated. An online tool (The models and online tool we established here might be helpful for screening and identifying women with undiagnosed PCOS in Asian populations and could assist in the long-term management of related metabolic disorders. Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic disorders in women of reproductive age, with a prevalence of 5.6% in the Chinese population . DespiteIn addition to androgen excess, insulin resistance is indicated to play an important role in pathophysiology of PCOS –5. For aThis was a retrospective observational cohort study in Peking University Third Hospital. In all, 21,219 ovarian stimulation cycle records were recovered from January to December 2019. We excluded the following: 3,289 cycles without menstrual cycle data; 150 without body mass index (BMI) information; 3,211 without one or more key hormone levels recorded; 2,546 without information on the antral follicle count (AFC); and 1303 multiple cycles of the same patient. The study flowchart is shown in Women with PCOS were diagnosed according to the 2003 Rotterdam criteria , which rHyperandrogenism was diagnosed by the presence of excessive acne, androgenic alopecia, or hirsutism; or chemically by high serum levels of total testosterone (TES) ≥ 2.5 nmol/L or androstenedione (AND) ≥ 11.5 nmol/L. Hirsutism was diagnosed as described . Briefly2) concentrations. Blood samples for measuring AMH were collected on any day of the menstrual cycle prior to ovarian stimulation. Samples were collected, immediately inverted five times and centrifuged at 1800g 10min for further endocrine assessments.Antral follicles measuring 2–10 mm in diameter in both ovaries were counted on menstrual cycle day 2 using transvaginal ultrasound scans. On the same day, intravenous blood was collected for measuring follicle stimulating hormone (FSH), luteinizing hormone (LH), TES, AND, and estradiol . The quality controls for FSH, LH, TES, AND, and E2 were supplied by Bio-RAD Laboratories . Serum AMH concentrations were measured using an ultrasensitive two-site enzyme-linked immunosorbent (ELISA) assay , using quality controls supplied with the ELISA kits. The coefficients of variation for the assays were <6% for AMH, FSH, and LH, and <10% for E2, AND, and TES.Serum levels of FSH, LH, TES, AND, and ELog L (β)) was used to evaluate the final model: the smaller the value of scaled –Log L (β) in the validation set the better the model fit. The logistic Least Absolute Shrinkage and Selection Operator (LASSO) model, a shrinkage method that can actively select from a large and potentially multicollinear set of variables and reduce the likelihood of overfitting, was applied to construct a predictive model. The logistic LASSO is a logistic regression analysis approach that penalizes the absolute size of the coefficients of a regression model based on the value of penalty term, λ. With larger penalties, the estimates of weaker factors shrink toward zero, so that only the strongest predictors remain in the model. The value of λ was determined with 10-fold cross validation, and the most predictive covariates—selected by the minimum value (λ min)—were used to construct the PCOS diagnostic models  of the data was selected randomly as a training set, which was used for model establishment, and the rest (30%) of the data was used as the testing set, which was used for model evaluation. Then a prediction model was constructed in the training set. The scaled negative loglikelihood (–c models . The perLog L (β) value in the validation set no longer decreased indicated in model building process of Model1 in The indicators in p values of each index are shown in The AUCs of Model 2 (without the AFC) in the training and validation data were 0.862 and 0.865, respectively, whereas the AUCs of Model 1 (with the AFC) in the training and validation data were 0.865 and 0.845, respectively. Inclusion of the AFC did not improve the performance of our models. The contribution of each variable is shown in The relationship between predicted probability and the prevalence of PCOS is shown in http://121.43.113.123:8888/). In this, the user inputs the required indicators, clicks ‘calculate’, and the results of specific probability of PCOS and risk group of a certain subject are displayed. The grouping criteria are as follows: a low-risk group, with a predicted probability of <10%; a medium-risk group, with a predicted probability of 10% to 50%; and high-risk group, with a predicted probability of >50%.Our algorithm for diagnosing PCOS has been developed into a website for Chinese ART clinics, . Similarly, combining the values of BMI <18.5 kg/m2 and AMH>10 ng/mL and UML of >90 days, the incidence of PCOS increased to 10/13 . These normal-weight or lean women still face fertility challenges, increased androgen levels and the resulting symptoms , and increased risk of diabetes and cardiovascular disease  for women with a BMI <18.5 kg/m disease . The diaIt has been demonstrated that serum AMH levels in oligomenorrheic girls without evidence of hyperandrogenism are similar to levels in adolescents and adults with PCOS but elevated compared with normal adolescents and adults . CombineFirst, although our sample size was large, our PCOS diagnostic models are still based on retrospective data, further prospective studies are needed to prove their applicability in ART practice. Second, the different AMH values obtained using diagnostic kits from different manufacturers might also affect the applicability of our models. Third, it has been acknowledged that the measurements of plasma or serum total TES levels in men have adequate sensitivity and clinical utility, but are relatively inaccurate for women because of poor accuracy and sensitivity, which severely limits their clinical utility . This mihttp://121.43.113.123:8888/). It can be used to early identify these women who have higher risk of having PCOS, so that they can be further diagnosed, thus contributing to their long-term health management. Moreover, it should be noted that our PCOS screening model is established based on data of reproductive aged women from infertility clinics, not adolescent girls, thus is not suitable for PCOS screening in adolescents.Women with PCOS are at increased risk of infertility and multiple metabolic symptoms, which need long-term health management. However, the clinical diagnosis of PCOS is complicated, requiring different tests and physical examinations. Currently, screening and diagnosis of PCOS is not an easy task for general gynecologists and primary physicians. Here, we establish an easy applicable PCOS screening model. By entering two serological indicators and the upper limit of the menstrual cycle length and BMI, the probability and the risk of having PCOS could be predicted ; the National Key Research and Development Program of China ; the Innovation & Transfer Fund of Peking University Third Hospital ; the Major National R&D Projects of China (Grant No. 2017ZX09304012-012); National Natural Science Foundation of China (Grant No. 81771650); the Capital Health Research and Development of Special Project (Grant No. 2018-1-4091).Author KA is employed by The Predict Health. Author YH is employed by Hangzhou Qingguo Medical Technology Co. Ltd.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Survival rates in patients with non-medullary thyroid carcinoma (NMTC) are high, increasing the possibility to develop a second malignant neoplasm (SMN). Many studies investigated the relationship between increased risk of SMN in NMTC patients treated with radioiodine, but few data are available about the impact of family history (FH) of thyroid cancer on SMN risk.To assess the risk of SMN in a large cohort of sporadic and familial NMTC using the standardized incidence ratio (SIR).We studied 918 NMTC patients  followed for a median follow-up of 9 years. In 798/918 (86.9%) patients, NMTC was sporadic, while the remaining 120 (13.1%) were familial NMTC (FNMTC).p = 0.01), primarily driven by families with more than two affected members. The risk of SMN was remarkably higher for breast cancer, especially in familial cases  compared to sporadic cases .We identified 119/918 (13%) patients with SMN in association with NMTC. NMTCs had an increased risk of SMN when compared to the general population . The rate of SMN for all sites was significantly higher in familial compared to sporadic NMTC (20% versus 11.9%, NMTC patients have a higher risk of SMN compared to the general population and this risk is much higher in patients with FNMTC. This observation raises the hypothesis that genetic risk factors for a first cancer may predispose to SMN, especially among individuals with familial clustering of the same or other tumors. Non-medullary thyroid carcinoma (NMTC), and in particular the papillary histotype (PTC), is the most common endocrine tumor, and it is responsible for 567,000 cases/year worldwide, ranking ninth for incidence . SurvivaFamilial non-medullary thyroid cancer (FNMTC), defined by the presence of the tumor in two or more first-degree relatives, in the absence of other predisposing hereditary causes, is reported in nearly 10% of NMTC patients . HoweverTherefore, this study was designed (1) to assess the risk of SMN in a large cohort of NMTC using the standardized incidence ratio (SIR) and (2) to verify the role of family history of thyroid cancer in the occurrence of SMN.An observational single-center study was conducted on 918 NMTC patients followed at the Section of Endocrinology, University of Siena , from 1995 to 2015. Patients with prior exposure to radiation and with anaplastic thyroid carcinoma, medullary thyroid carcinoma, malignant lymphoma, or other inherited familial cancer syndromes  were excluded. Surgical, pathological, and clinical data were retrieved from clinical records. Patients gave their informed consent to the use of their personal data for research purposes, and the study was approved by the local ethical committee.Initial treatment and follow-up strategy were based on the therapeutic protocols used before the introduction of the latest 2016 ATA guidelines. Almost all patients were submitted to near-total thyroidectomy followed by 131-I treatment. Lymphadenectomy was performed if suspicious lymph node metastases were found before surgery. Patients were followed every 6 months during the first year; subsequently, the frequency of the follow-up visits was based on the clinical course of the disease and the estimated risk of recurrence for each patient. At each control, basal or stimulated serum thyroglobulin (Tg), thyroglobulin antibodies (AbTg), and neck ultrasound were performed. Additional imaging procedures, such as 18FDG-PET/CT, RMN, computed tomography (CT) scan of the chest, and post-therapeutic 131-I whole body scan, were performed in selected patients to exclude the presence of distant metastases. Response to the initial therapy and the clinical status at each follow-up visit was defined according to the risk stratification system recommended by the 2016 ATA guidelines  was defined as any primary malignancy with histological confirmation occurring in an anatomical site other than the thyroid. According to the timing of SMN occurrence with respect to NMTC diagnosis, we divided the SMN group into pre-NMTC (not metachronous) and post-NMTC (metachronous), based on the tumor diagnosis made at least 12 months before or after NMTC, respectively. The SMNs diagnosed within this period were considered synchronous.R version 3.6.2. Data were presented as mean ± SD or median when needed or as absolute frequencies and percentages. The T test for independent data or the Mann–Whitney U test was performed for variables, normally or non-normally distributed , respectively. To evaluate significant differences in data frequency, the Chi-squared test, the Fisher exact test, or its approximation was performed, according to the dimension of contingency table and to the expected frequencies. The comparison between the Italian cancer risk and the risk of SMN in patients with thyroidal cancer diagnosed before and after NMTC was estimated using standardized incidence rate (SIR), which is a ratio of an observed to an expected number of patients with SMN. The expected number of SMN during the person‐years at risk was determined on the basis of gender, age, and calendar year specific incidence rates from the Italian Network of Cancer Registries (AIRTUM) data from 1976 and 2010, which includes 38 general cancer registries, covering almost 48% of the Italian population  and the As shown in As illustrated in As shown in p < 0.0001), were more frequently male (p = 0.0003), and had a higher rate of distant metastases at diagnosis (p = 0.001) when compared with patients without SMN. Patients with SMN showed the worst final outcome (p = 0.006) and had more frequently familial history of any type of cancer (p = 0.0004) and familial NMTC (p = 0.01). No differences were found about tumor histotype (p = 0.7), multicentricity (p = 0.6), bilaterality (p = 0.5), rate of lymph-node metastases (p = 0.8), tumor extension (p = 0.8), radioiodine treatment (p = 0.2), and follow-up length (p = 0.9).As reported in p = 0.01), 1.51 , 1.03 , and 1.75 , respectively. Moreover, patients with FNMTC had a significantly higher risk for SMN associated to thyroid cancer  of 1.54  and of 1.71 , respectively.To minimize potential selection bias due to higher age at diagnosis in the group of patients with SMN, we performed propensity score matching procedure, with a ratio of 1:1. After matching, only sex and FNMTC were significantly associated with the increased risk of SMN at multivariate analysis with a RR of 1.37  was found (p = 0.04] (p = 0.07] (≤45 vs. >45 years), the rate of a second primary cancer was significantly higher  (p = 0.7] (p = 0.8) in the site of SMN was observed between sporadic and familial NMTC patients (We identified 120 (13.1%) familial NMTC patients, of whom 98 (81.7%) belong to kindreds with two affected members (fNMTC-2) and 22 (18.3%) to kindreds with three or more affected members (fNMTC-3). A significantly higher rate of other primary cancers in the familial NMTC  compared to sporadic NMTC  than observed in familial NMTC . Among patients with familial NMTC, a higher SIR was observed in kindreds with three or more affected members , compared to FNMTC with only two affected members , but this difference was not statistically significant (p = 0.50). According to the site of the second primary neoplasm, a very high SIR was observed for breast cancer .Patients with NMTC showed a higher risk of SMN compared to the general population . Moreover, in familial NMTC, the rate of SMN correlated with the number of affected members and the risk of SMN was primarily driven by families with more than two members. Following our recent paper (p = 0.01). Our results show that patients with NMTC have a higher risk in developing SMN when compared with the general population and demonstrate, for the first time, that this risk was higher in familial than sporadic NMTCs . A possible explanation of the increased risk for FNMTC patients may be the effect of complex genetic and environmental factors or a greater genomic instability of the FNMTC patients compared to sporadic counterparts. To date, a prevalent polymorphism or germline mutations have not been identified yet in FNMTC, although several studies on different populations of NMTC patients identified common variants associated to NMTC risk with additive effects on cancer predisposition  in FNMTC patients  compared to sporadic patients and the general population. A recent meta-analysis suggested that the risk of developing thyroid cancer as a second primary malignancy in the context of BC and ther SMN . In our p = 0.01). Accordingly, a meta-analysis showed that male gender is an independent risk factor for the association with another cancer (The impact of familial NMTC in increasing the rate of SMN has also been confirmed by multivariate analysis in which family history of other tumors, male gender, and age at diagnosis, in addition to the familial form of NMTC, were independently associated with a higher risk of SMN. Family history of other tumors is a well-recognized risk factor for SMN in patients affected by different human cancers, even in individuals without well-established familial cancer syndromes . We founr cancer . Also, Nr cancer , 25, 33.The present study has strengths and limitations. The strengths include patients followed at the same institute with detailed information regarding NMTC diagnosis, treatment, and follow-up and occurrence of SMN before or after NMTC detection. In addition, the mean follow-up of 9 years is relatively long. A possible limitation is represented by the relatively small number of FNMTC patients with three or more affected members, but it is important to underline that this group is uncommon and accounts for less than 5% of major FNMTC series.In conclusion, we demonstrated that the risk of SMN was higher in FNMTC patients compared to sporadic NMTC patients. Our results suggest that a family history of thyroid cancer or other tumors, along with male gender and age at diagnosis of NMTC, increased the risk of SMN in NMTC patients. We can hypothesize that different cancers share common genetic factors and that FNMTC may represent a good model for exploring the potential role of genetic determinants that, probably in association with environmental factors, contribute to increase the relative risk for the same or other cancers beyond the nuclear family. Moreover, prospective studies in larger cohorts of patients with familial NMTC are needed in order to confirm our results and to translate this information in clinical practice. In light of our results, for example, the screening for a second cancer, and especially for breast cancer, might be suggested for patients with familial NMTC.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 Comitato Etico Regione Toscana – Area Vasta Sud Est. The patients/participants provided their written informed consent to participate in this study.MarcC was the main author and contributed to conception and design of the study. AS, NF, and SC organized the database. MariC contributed to interpretation of data for the work and manuscript revision. AC performed the statistical analysis. TP, FM, RF, and LB contributed to manuscript revision, read, and approved the submitted version. 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.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.


Ureteroscopy (URS) has been established as an effective treatment for stones in obese patients (OP). However, recent studies found that the efficacy of the procedure may be lower in patients with higher body mass index (BMI). In the current study, we aim to determine if obesity might influence the effectiveness and safety of URS.ClinicalTrials.gov to find eligible studies. Stone-free rate (SFR), operative time, length of stay, and complication rate were assessed utilizing RevMan 5.3.In May 2021, a comprehensive search was conducted in the PubMed, EMBASE, Web of Science, Cochrane Library, and OR): 1.09; 95% CI: 0.79, 1.52; p = 0.59], and between MOP and NWP . The operation time was similar between OP and NWP , and between MOP and NWP . In addition, no significant difference regarding length of stay existed between OP and NWP , and between MOP and NWP . Furthermore, we observed similar minor complication rate between OP and NWP , and between MOP and NWP . The differences concerning major complication rate between OP and NWP , and between MOP and NWP  were also not significant.Thirteen studies involving 4,583 normal-weight patients (NWP), 2,465 OP, and 291 morbidly OP (MOP) were included. Pooled results showed that statistically similar SFR existed between OP and NWP [odds ratio (Our study demonstrated that URS performed in MOP and OP appears to have the same efficacy and safety as well as in NWP group. ObesityOP (MOP) . RecentlOP (MOP) –8. PossiOP (MOP) , alteratOP (MOP) , insulinOP (MOP) .Obesity poses a management challenge in terms of imaging, anesthesia, and surgical methods to urologists . UsuallyAs for surgical options of the obese individuals with kidney stones, Extracorporeal Shock Wave Lithotripsy might not be a suitable procedure choice due to the farther skin-to-stone distance ; for anoClinicalTrials.gov was conducted to find eligible studies before May 2021, following Cochrane standards and PRISMA  guidelines  researches presenting the outcomes of URS in the OP for urolithiasis and (2) references of included researches were also assessed for eligibility.The exclusion criteria were: (1) data description was not clear enough; (2) non-English researches; and (3) studies published as review, case reports or comments.The following items were repeatedly extracted by two authors (WW and XSG): author, publication year, country, subgroup, age, number of patients, demographics, stone size, SFR , operation time, length of stay, complications based on modified Clavien–Dindo classification system . DisagreWW and XSG assessed all included studies independently for methodological quality and levels of evidence (LE), and the disagreements were solved by discussion. The Oxford Center for Evidence-Based Medicine  was usedOR) and 95% CI, and continuous data were extracted by weighted mean difference (MD) and 95% CI. The p-value was calculated from the Z-test, and a p ≤ 0.05 was deemed as statistically significant. We assessed the heterogeneity of the included studies by Q and I2 statistics. The p-value lower than 0.1 and I2 value higher than 50% were considered as high heterogeneity among studies, and the random-effects model was performed; if not, indicated low heterogeneity, and the fixed-effects model was conducted. Sensitivity analysis was performed to utilizing a single-item removal method. We utilized a funnel plot to assess publication bias.Analysis was performed to utilizing Review Manager Version 5.3 software. Dichotomous data were extracted to utilizing odds ratio  and stone location (p = 0.061) was observed in the three different populations. There were more category 1 patients of American Society of Anesthesiology (ASA) in the normal weight group relative to the overweight and obese groups (p < 0.0001). Predictably, there were more overweight and obese patients categorized as ASA 2 and ASA 3. Therefore, the ASA score is not similar between groups. Additionally, as shown in Thirteen studies –27 were p = 0.005, I2 = 59%) and between MOP and NWP , we used the random-effects model, which indicates no statistically significant difference exist between OP and NWP , and between MOP and NWP , and the random-effects model demonstrated that the operation time was similar between two groups .The three groups were compared concerning operative time. The heterogeneity was high between OP and NWP , and between MOP and NWP , and the fixed-effects model revealed no statistically significant difference regarding length of stay between OP and NWP , and between MOP and NWP , and fixed-effects model displayed that no statistically significant difference regarding the overall complication rate were observed between OP and NWP  and the major complications  and fixed-effect model revealed that the overall complication rate was similar between two groups  and the major complications . Similarly, Doizi et al. found that no significant differences regarding SFR for stones <10 mm existed between OP and NWP, and between MOP and NWP .Stone-free rate is a critical outcome variable to assess the effectiveness of endourological surgery. Chew et al. reported that MOP was associated with a relatively lower SFR compared with NWP . HoweverNo statistically differences existed in operation time and length of stay between OP and NWP, and between MOP and NWP groups in our study. Ishii et al. conducted a meta-analysis and demonstrated that the mean operation time for the OP and MOP was 68.5 and 68.9 min, respectively . In anotIn terms of post-operative morbidity, we assessed the complication rate between the different groups and no statistically significant difference was observed. In our analysis, the overall complication rate of MOP and OP was 8.3 and 5.1%, respectively. This is comparable to the complication rate of NWP (4.9%). Ishii et al. reported that the complication rate in the OP was 8.4%, which is consistent with our results. But they only observed 16 complications in MOP 17.6%) . They co.6% . TheLife style modification is the most important method for the prevention of recurrence of urolithiasis in OP . A diet A previous systematic review that included 7 studies involving 131 individuals found that URS could be conducted effectively and safely on OP, and SFR increased when stones size was <20 mm . HoweverAdditionally, several limitations need to be mentioned in the present analysis. First, all the eligible studies were retrospective, which are associated with methodology bias. Second, the definition of SFR was not standardized, several studies considered residual stones ranging from 0 to 4 mm as stone-free status , 19, 21,The URS procedure demonstrated similar results in MOP, OP, and NWP. Therefore, URS performed in MOP and OP appears to have the same efficacy and safety as well as in NWP group.The original contributions presented in the study are included in the article/WW and TJ collected and analyzed the data and prepared the manuscript. XG collected the data. LP analyzed the data and prepared a manuscript. All authors have read and approved the final manuscript.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.