Due to the growing global trend of obesity, it is necessary to study the diet quality as a modifiable factor to reduce the dangerous consequences of obesity. Therefore, the aim of this study was to evaluate the association between meal-based diet quality index-international (DQI-I) with obesity in adults.This cross-sectional study was performed on 850 men and women in Tehran (aged 20–59 y). Dietary intakes were assessed using three 24-h dietary recalls. Meal-based Diet quality was assessed based on the construction of DQI-I. The total DQI-I score ranged from 0 to 100, with higher scores denoting better diet quality. Multiple linear regression analysis was used to examine the association of DQI-I and BMI in each meal and Logistic regression analysis was used to examine the association of DQI-I and obesity in each meal.The mean (± SD) of age, body mass index (BMI), waist circumference (WC) and waist to hip ratio (WHR) were 42.35(± 10.90) years, 27.32(± 5.61) kg/m2, 89.09 (± 12.04) cm and 0.86 (± 0.11), respectively. In none of the meals, after adjusting for confounders, no significant difference in BMI was observed in the both women and men groups. After controlling of confounders, there was not any relationship between meal-based DQI-I and BMI resulted from multiple linear regression analysis also there was not any significant association between meal-based DQI-I and obesity resulted from Logistic regression analysis.In this study, we did not find any significant association between meal-specified DQI with obesity. To reach the better evaluation, more prospective studies with large sample size are needed. The global prevalence of obesity is increasing around the world and further increases are estimated in the future . The numDiet, sedentary lifestyle, genetic, environmental, neurological, physiological, biochemical, socio-cultural and psychological factors are elements that contributing to obesity . Diet asDietary Quality Indices (DQIs) are designed to examine the overall diet and categorize individuals based on the extent to which their eating behavior is healthy . The dieFew studies have done in relation to the association between the diet quality index-international with obesity and different results have been obtained, for example In Iran, Asghari et al. did not find a significant relationship between DQI and obesity , 17, butThe association of dietary patterns and diseases has been considered well so far, but little attention has been paid to meals . Foods an = 850) was divided by 40 to get the number of subjects in each health center. To be noted that we recruited people from the health centers of Tehran affiliated to the Health Bureau of the Municipality of Tehran. Indeed, Tehran is the Capital of Iran and has a multiethnic population, and in health research in Iran, population of Tehran are considered as a representative of Iran.A total of 850 healthy adult men and women, aged 18 to 59, who were willing to participate in this cross-sectional study, were recruited from health care centers of Tehran, via a two-stage cluster sampling using advertisement, spreading of flyers in common places and information sessions at health care centers about the goal and the benefit of the examination. First, the city was split into five regions north, east, south, west, and center. A list of all existing health care centers was provided and then eight health centers were randomly chosen from each region for a tally of forty health centers. Ultimately, the sample size , an error coefficient of d=0.04 and atα level of 0.05, a sample size of 546 people was calculated During the first visit, subjects completed a questionnaire designed to assess the participants' demographics including age (year), gender, body weight, height, waist circumference,body mass index (BMI), physical activity , educational level , marital status , job status , and smoking status .Body weight was measured using a standard body weight scale . Participant’s height was measured using a wall stadiometer with a precision of 1 cm . The BMI was calculated as weight in kilograms divided by the square of height in meters. Waist circumference was measured with a tape measure to the nearest 0.1 cm between the iliac crest and the lowest rib during exhalation. Hip circumference was recorded at maximal point, over light clothing, using a non-stretch tape measure and without exerting any pressure on body surface. Obesity was defined as BMI ≥ 30 kg/m2 .Dietary intakes of participants were assessed by using three 24-h dietary recalls. Trained dietitians completed the first 24-h dietary recall by face-to-face interview at the first visit at each health center. The other two 24-h dietary recalls were completed at random days including one weekend, by telephone interviews. All 24-h dietary recall interviews were carried out by same trained dietitians. For dietary analysis, daily intakes of all food items obtained from 24-h dietary recalls were computed and then were converted into grams by using household measures . The 3-dBreakfast was defined as a meal eaten between 05:00 and 11:00 .Lunch was predefined as a large meal eaten between 12:00 and 16:00 .Dinner was defined as a large meal eaten between 17:00 and 23:00 .Physical activity was assessed by using a validated short form of the International Physical Activity Questionnaire (IPAQ) . AccordiMeal-based Diet quality was assessed based on the DQI-I that included four major dietary components . The fir2) for categorical variables. We used analysis of covariance (ANCOVA) to compare adjusted means of BMI across the DQI-I tertiles. The multiple linear regression analysis was used to evaluate the association between DQI-I with BMI based on sex in each meal after adjusting for possible confounders. Furthermore, odds ratio (OR) and 95% confidence interval (CI) of obesity were estimated through binary logistic regression analysis in two models. Model I adjusted for age, physical activity, socioeconomic status, and smoking. Model II was adjusted for confounders in Model I plus energy intake. All statistical analyses were performed using the Statistical Package for the Social Sciences . P value less than 0.05 was considered statistically significant.Participants were categorized based on tertiles of DQI-I. Higher tertiles of DQI-I demonstrate higher diet quality compared to lower tertiles. The general characteristics and Dietary intakes of study subjects among tertiles of DQI-I were examined using analysis of variance (ANOVA) for continuous variables, and Chi-squared (χP < 0.001). Furthermore, in both breakfast and dinner meal, men had greater adherence to DQI than women (P < 0.001). Also, the education status was different across the DQI tertiles for breakfast (P < 0.001).Table P < 0.001), carbohydrate (P < 0.001), fat (P = 0.007), vitamin C (P < 0.001), calcium (P = 0.03) and iron (P < 0.001) and also associated with lower intake of SFA (P < 0.001) and MUFA(P = 0.04). Adherence to higher DQI for lunch was also associated with more intake of fat (P < 0.001), fiber (P < 0.001), vitamin C (P < 0.001), calcium (P < 0.001) and iron (P < 0.001) and correlated to lower consumption of cholesterol (P < 0.001), SFA (P < 0.001), PUFA (P < 0.001), MUFA (P < 0.001) and sodium (P < 0.001). Participants in the highest tertile of DQI for dinner consumed higher levels of energy (P < 0.001), carbohydrate (P < 0.001), fiber (P < 0.001), protein (P < 0.001), sodium (P = 0.01), vitamin C (P < 0.001), calcium (P < 0.001) and iron (P < 0.001) and they had a lower intake of, fat (P < 0.001), cholesterol (P < 0.001) SAFA (P < 0.001), PUFA (P < 0.001) and MUFA (P = 0.03).Table P = 0.90) and men (P = 0.83). Moreover, in the lunch meal, no significant difference was found regarding BMI across DQI categories in model 2 and both women (P = 0.54) and men (P = 0.66). In the dinner meal, we also found no significant differences in mean of BMI across tertiles of DQI in model 2 and both women (P = 0.22) and men (P = 0.81) population.The results of ANCOVA analysis shows the BMI differences across DQI tertiles in both male and female populations separately in Table P = 0.42) and dinner meal . A non-significant association was also found between DQI and BMI in breakfast , lunch  and dinner meal  in men.Results of multiple linear regression for the association between DQI-I and BMI based on sex in each meal are reported showed in Table Odds ratio (OR) and 95% confidence intervals (CIs) for obesity across the tertiles of DQI are indicated in Table This is the first study that used a meal specified to assess the potential association of the DQI, representing patterns of lifestyle and dietary intake, in a sample of Iranian adults, and obesity in adults. The main analysis of dietary intakes across the tertiles of DQI scores for each meal provided evidence that the overall diet quality of Iranian adults in this study has a relatively healthy pattern with lower consumption of cholesterol and SFA along with higher intake of micronutrients like vitamin C, calcium and iron. In the all three meals we found no significant differences for BMI across the DQI groups in adjusted models for both women and men. The chance of having obesity also was not different across DQI tertiles.Understanding the nutritional composition of meals and the ways in which different meal patterns make an impact on diet quality might help to elucidate important diet–disease relationships. The relationship between dietary patterns in adults with nutrient intake and diet quality is essential to determine if they represent the health and diversity of the entire diet. As a holistic view, these behaviors include several components that work synergistically on health and disease , 30. In In various countries including France , USA 3333–35, IrConflicting findings on the association between general obesity and diet quality indices can be explained by several reasons. Most of these dietary scores, which assessed adherence to dietary guidelines , were designed for the U.S. population. However, the population may not be able to assess the overall quality of the diet until more information is known about the consumption patterns. In addition, there are differences in the scoring models of indices, based on dietary guidelines. Simultaneously, measures of diet quality in developing countries are more complex to interpret; it is also complex in such countries to assess diet quality in terms of both micronutrient adequacy and prevention of overweight, indicating the need for better measures of diet quality specifically for these populations. The major issues in developing countries are both under- and over-nutrition . FurtherWe did not find gender-specific associations between DQI and BMI or obesity. However, gender differences in diet quality findings in other studies has been reported  that mayThe present study has important strengths. To the best of the authors’ knowledge, this is the first study to assess the relationship between DQI-I at meals and obesity in Iranian population. In this study, we had a sufficient sample size. Also, this sampling was done from different parts of health centers in Tehran. Then, results can be generalizable to all the Tehranian population and also as Tehran is the Capital of Iran and has a multiethnic population, and population of Tehran are considered as a representative of Iran. However, some limitations of the present study must be addressed. First, the cross-sectional design of the study also needs to be considered when interpreting the findings. Second, the use of 24-h dietary recall data may have been subjected to recall bias of self-reported measurement error due to within-subject variations. In addition, 24-h diet recall data is limited in its ability to capture dietary diversity. Finally, although we included a rich set of confounding variables in the models, some residual confounding may exist.In the present study, we failed to find any significant association between meal-specified DQI with obesity. Diet quality may be an integral component of a broader obesity intervention strategy. Although better diet quality may not lead to decreased BMI for all individuals, it is important for health promotion; other researchers have demonstrated substantial health benefits from consuming high-quality diets. To examine the exact relationships, more research is needed to better design and evaluate diet quality indices for each population.


There are few data to support accurate interpretation of spirometry data in South Asia, a major global region with a high reported burden of chronic respiratory disease.1) and FEV1/FVC ratio. Then, we used our data to derive (n=5589) and internally validate (n=1864) new prediction equations among South Asians, with further external validation among 339 healthy South Asians living in Singapore.We measured lung function in 7453 healthy men and women aged ≥18 years, from Bangladesh, North India, South India, Pakistan and Sri Lanka, as part of the South Asia Biobank study. First, we assessed the accuracy of existing equations for predicting normal forced vital capacity (FVC), forced expiratory volume in 1 s . Age, height and weight were strong predictors of lung function in our participants (p<0.001), and sex-specific reference equations using these three variables were highly accurate in both internal validation  and external validation . Further adjustment for study regions improves the model fit, with highest accuracy for estimation of region-specific lung function in South Asia.The Global Lung Initiative (GLI) and National Health and Nutrition Examination Survey consistently overestimated expiratory volumes (best fit GLI-African American, mean±We present improved equations for predicting lung function in South Asians. These offer the opportunity to enhance diagnosis and management of acute and chronic lung diseases in this major global population. Newly derived spirometry reference equations greatly improve prediction of normal lung function in South Asians, thus filling the long-standing gap of appropriate reference values for this ethnic group https://bit.ly/3H7ZGt5 Spirometry provides a simple noninvasive method for assessing pulmonary function, and is a key tool in the diagnosis of obstructive and restrictive lung diseases. Accurate interpretation of the results from spirometry testing requires knowledge of expected normal values in a healthy population. Since pulmonary function is influenced by physiological factors such as age, height, sex and weight, estimation of normal values is facilitated by reference equations that take into account an individual's relevant characteristics. Normative ranges for lung function also show striking differences between populations; with higher lung function among people of European ancestry, compared to African-American and Asian populations –4. In a The Global Lung Initiative (GLI 2012)  and the supplementary figure S1. In brief, we first evaluated the performance of the GLI 2012 and NHANES III spirometry equations using the data from 43 472 participants in the South Asia Biobank study. Next, we identified and evaluated reference equations reported for South Asians in available, published studies. Finally, we used our data to develop a South Asian specific spirometry equation, with both internal and external validation, including among people of South Asian ancestry who were born or living overseas.Our study design is summarised in Supplementary table S1 presents the number of subjects by exclusion criteria. 7453 subjects were included in the final analysis. The South Asia Biobank study was approved by the Imperial College London research ethics committee (18IC4698), and all participants provided informed consent.This is an ongoing prospective study comprising a representative, population-based cohort of >100 000 people aged ≥18 years, recruited from 118 surveillance sites that that were centred on local primary community healthcare units in five study regions: Bangladesh, South India, North India, Pakistan and Sri Lanka. Spirometry data were collected as a part of respiratory evaluation for environmental and smoking-related lung injury. Recruitment started in November 2018; the study method has been described previously . We used1) and forced vital capacity (FVC) of at least grade C were included. Only measurements that met these criteria were included, of which the largest FVC and FEV1 values were selected for analysis. All data were collected using a shared cloud-based database; spirometry data were captured at source by device integration.Data were collected using a single, standardised protocol at all study sites. An interviewer-administered questionnaire was used to collect sociodemographic data, information on smoking habit and respiratory and cardiovascular health. Height was measured using a portable stadiometer SECA213), and weight using electronic scales (OMRON BF-511). Lung function testing was performed according to ATS/ERS guidelines , and wei–16 and mwww.healthforlife.sg/). HELIOS  inclusion criteria specify Singaporean citizens or permanent residents aged 30–84 years. For the present external validity study, we identified 710 people of self-reported South Asian ancestry from among the 6400 people recruited into the HELIOS study prior to March 2020 (onset of the COVID-19 pandemic). From these, we selected 339 healthy never-smokers  with an age range of 30–81 years (supplementary figure S1). Sociodemographic, lifestyle and health information, including smoking habit, respiratory and cardiovascular health were collected by questionnaire. Lung function test was performed according to ATS/ERS guidelines [This is a longitudinal study of a multi-ethnic population in Singapore . All statistical analyses were conducted using STATA .All categorical data are presented as frequencies or proportion (%) and continuous variables are presented as mean±aleemet al. [hhabraet al. [asguptaet al. [esaiet al. [iswaset al. [garwalet al. [ooriyakanthanet al. [emonet al. [Supplementary tables S2 and S3 summarise the list of publications and their reference equations that were considered for inclusion in this study.Considering their wide usage in clinical laboratories and spirometer manufacturers, we first evaluated the performance of GLI 2012  and NHANmet al.  (SAL), Caet al. , Dasguptaet al. , Desaieiet al. , Biswasset al. , Agarwallet al. , Sooriyanet al.  and Memonet al. . Supplem1, FVC and FEV1/FVC ratio in each sex. We considered three modelling strategies that include age, height, weight and study regions as covariates. The first model (M1) included only age and height as the independent variables, to provide consistency with GLI 2012 and NHANES III equations. There was no evidence of nonlinear relationships and using μ-σ-λ analysis approaches did not materially improve the degree of fit for any of our analyses. For our second model (M2), we included weight in addition to age and height, as weight has been shown to be a potential predictor for lung function [We then used the data to derive new reference equations that might more accurately predict pulmonary function in healthy South Asians. We divided the South Asian Biobank study data at random (3:1) into development (n=5589) and internal validation (n=1864) datasets. With the development dataset, we use multiple linear regression to develop new predictive equations for FEVfunction . We then1, FVC and FEV1/FVC ratio for all participants, as well as the corresponding expected LLN, using each of the reference equations identified. We then determined the difference between observed and predicted, expressed as percentage predicted, z-score and the proportion of observed values falling below the predicted LLN using the following formula:To assess their predictive performance, we calculated predicted FEV% predicted=observed/predicted×100LLN=predicted – z-score=(observed – predicted)/residual standard deviation1/FVC<LLN and FVC≥LLN; restrictive: FEV1/FVC≥LLN and FVC<LLN; mixed: FEV1/FVC<LLN and FVC<LLN; and normal: FEV1/FVC≥LLN and FVC≥LLN) [To evaluate the possible misclassification of pulmonary function test results, we also classified individuals as showing obstructive, restrictive or mixed ventilatory defect based on accepted criteria (obstructive: FEVFVC≥LLN) .sd (range) age of 44.5±12.8 (18–85) years. Between countries, people from Pakistan were taller and heavier, while Sri Lankan subjects were older compared to those from other settings. FEV1 and FVC were highest in Bangladesh and lowest in India, while FEV1/FVC ratio was highest in Sri Lanka . Baseline characteristics of external HELIOS participants are summarised in supplementary table S5. They are on average older, taller and heavier than the South Asia Biobank participants, with higher FEV1 and FVC measurements.The characteristics of the 7453 healthy participants selected from among the South Asia Biobank study are summarised in 1 and FVC values in South Asians predicted by the GLI 2012 and NHANES III equations in men and women respectively. There is a shift for all reference values to lower z-scores (>−0.5) in men and women , which are considered clinically significant and correspond to ≥5–6% difference in the lung measurement [1 and FVC using Caucasian reference equations, and >17% were still below LLN using the African-American reference values, in both men and women  in both men and women, the differences between observed and expected were all statistically significant (p<0.01). 0.7–59.8% of our healthy subjects (both men and women) were categorised as below the LLN of FEV1 and FVC (supplementary table S7).We also found wide variation between observed and predicted values using published reference equations from South Asian countries. Although mean z-scores for FEVsupplementary table S8. There are no significant differences between the development and internal validation cohort. 2 for model M3 (supplementary table S9).The characteristics of participants used for development and internal validation for prediction of normal lung function in South Asians are shown in 1, FVC and FEV1/FVC. Among all participants, mean±sd z-scores for FEV1 were 0.03±0.98, 0.03±0.09 and 0.04±1.00 in females (supplementary table S10) and age group (supplementary figure S2), with mean z-scores between −0.5 and 0.5 and observed values that were within 5–6% predicted for all spirometry indices. Overall, M3 displayed better predictive accuracy for region-specific results (supplementary table S10).When we evaluated our prediction models among participants in our internal validation dataset (n=1864), models M1, M2 and M3 all showed high concordance between observed and predicted FEV females , and 0.0 females ; using m1 and FVC showed greater deviation from 0, indicating a poor fit to our study population. The results are similar when stratified by age group (supplementary figures S2 and S3). Among the internal validation samples, GLI 2012 and NHANES III continued to significantly overpredict FEV1 and FVC for both men and women, and the reported South Asian functions were consistently less accurate than our derived reference equation. The calculated LLN for these equations resulted in a high number of subjects being identified as below their LLN, which deviated from the expected 5% in a healthy population (supplementary table S11). This leads to a high fraction of healthy participants classified as having abnormal lung function with GLI 2012 and South Asian reference equations, compared to <10% with our derived reference values (supplementary table S12).Compared to our derived reference equations, GLI 2012, NHANES III and other published South Asian specific models had lower predictive accuracy. Their mean z-scores for FEVsd z-scores for M1 and M2 equations ranged from 0.13±0.99 to 0.34±0.96 for FEV1 and FVC. Similar to observations in the South Asia Biobank cohort, model fit was poor for FEV1 and FVC with GLI 2012 and NHANES III. In addition, models M1 and M2 predicted FEV1/FVC accurately in the HELIOS cohort, with z-scores ranging from −0.01±0.90 to 0.34±0.91, as did the GLI (South-East Asia) equations (mean z-score <|0.2|). Among our region-specific models, the M3 equation for Bangladesh and Sri Lanka had good fit for predicting FEV1, FVC and FEV1/FVC, compared to other study regions, with percentage below LLN close to 5% (supplementary table S13).We evaluated our M1 and M2 reference equations among our external validation set comprising 339 people of South Asian ancestry living in Singapore. International reference equations such as NHANES III and GLI 2012 are widely adopted as the preferred standard for prediction of normal lung function indices, and are commonly included in spirometry devices to enable rapid or automated interpretation of results. However, at the time these equations were developed, large-scale data were not available for South Asians, and the validity of these functions in this major ethnic group is unclear. Although there are locally derived reference equations for different subsets of South Asian population, their development has been limited to single-centre studies, without validation to assess generalisability .1 and FVC in men and women. The best-fitting ethnic reference group from GLI 2012 is African-Americans, but this still overestimates FEV1 and FVC, with ≥20% of our healthy subjects classified as having abnormal lung function. These findings are consistent with other studies conducted in South Asia [In our study, we find that both the GLI 2012 and NHANES III equations substantially overpredict FEVuth Asia –36. A siIt is well established that lung function varies between global regions and ethnic groups, in part reflecting anthropometric differences such as chest dimension and adiposity and lung size . SocioecTo advance beyond the status quo, we have developed new sex-specific risk functions for prediction of lung function in South Asians. Our simplest model includes just age and height, in keeping with international practice. Weight and study region were predictors of lung function independently of age and height, and including these variables into the prediction models improved the variance explained. Thus, we also present models that include weight and study region to enable the most accurate, region-specific estimation of lung function. While all three models showed good predictive accuracy, the M3 models were found to be the most accurate and are thus recommended for clinical purposes in people living in their respective South Asian regions.1 and FVC than other reported normative equations, including all available GLI models. FEV1/FVC was also predicted accurately by our M1 and M2 equations, although the GLI (South-East Asia) equation showed best overall fit. In addition, we explored our region-specific M3 equations in the HELIOS study population and show that Sri Lanka reference equations gave a better fit for predicting FEV1, FVC and FEV1/FVC than did the other study regions. This is consistent with the majority of the Singapore Indian ethnic group being descendants of Tamil settlers from South Asia. Thus, our normative reference equations are highly accurate in both internal and external validation, including among a cohort of South Asians born or living overseas, and whose lung function was measured with a different spirometer. These optimised reference equations offer the prospect of more accurate diagnosis and improved healthcare for South Asians, who represent 25% of the global population.We used data from the HELIOS study for external validation of our equations in South Asian people. We show that our generalised models that do not include region (M1 and M2) are more accurate for both FEVThe strengths of our study include large sample size with standardised protocol and spirometer devices being used across different countries, compared to the existing studies that were mostly derived from relatively small sample sizes with variations in instruments and exclusion criteria . Our stuThere are some limitations. Firstly, subjects from Pakistan were under-represented. Future studies with higher sampling of subjects from Pakistan will be helpful to improve the precision of our algorithms. Secondly, respiratory symptoms and comorbidities for exclusion criteria were based on survey questionnaires and might not have excluded all people with chronic diseases. Nevertheless, we adhered to common exclusion criteria that are applied in most spirometry studies and taking into consideration that individuals with certain comorbidities do exist in the general healthy population. Thirdly, countries such as Afghanistan, Bhutan, Nepal and Maldives were not included in the study, although they are part of the wider South Asia region. Further validation in these subpopulations will be useful to determine the generalisability and representation of our new equations in South Asia. Our study provides an updated spirometry reference values for the South Asian adult population. These newly derived reference equations will improve the accuracy of lung function predictions in the South Asian population, reducing misclassification and improving diagnosis and healthcare for this major global population.10.1183/13993003.02962-2021.Supp1Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.ERJ-02962-2021.SupplementSupplementary material 10.1183/13993003.02962-2021.Shareable1This one-page PDF can be shared freely online.ERJ-02962-2021.ShareableShareable PDF


P = 0.011), and median OS was 12.0 (6.0–30.0) versus 20.0 (10.0–39.0) months (P = 0.016), respectively. Median PFS and OS rates were highest in epidermal growth factor receptor (EGFR) (+) and EML (−) patients and lowest in EGFR (−) and EML (+) patients (P < 0.001). By multivariate cox regression analysis, PFS in overall patients with NSCLC was significantly associated with EML, EGFR mutation, performance status, and pleural effusion. NSCLC patients with EML had worse prognoses of PFS and OS than patients without EML.To evaluate the prognosis of non-small cell lung cancer (NSCLC) patients according to endobronchial metastatic lesion (EML), especially those not identified on positron emission tomography or computed tomography. We evaluated progression-free survival (PFS) and overall survival (OS) according to the presence of EML in patients with NSCLC who were diagnosed at a tertiary hospital between January 2010 and December 2019. A total of 364 patients were enrolled in this study. EML was found in 69 (19.0%) patients with NSCLC. In the patients with EML versus the patients without EML, median PFS was 7.0 (3.5–13.5) and 9.5 (5.5–17.5) months ( Non-small cell lung cancer (NSCLC) is the most common histologic type, with a 5-year survival rate of all stages approximately 15%, although 5-year survival rates are higher when diagnosed at very early stages1. When we refer to lung cancer, early diagnosis with the least-invasive method and acquisition of sufficient tissue sampling are very important2.Lung cancer is a leading health problem due to challenges in diagnosis and treatment, and, eventually results in poor prognosis3. Bronchoscopy is mainly used as a diagnostic tool for tissue biopsy to determine the histological type and it also has an extended role in developing therapeutic modalities4.Fibreoptic or flexible bronchoscopy plays an important role in the diagnosis and staging of lung cancer6. However, several limitations must be considered when interpreting PET/CT findings, even though PET/CT has been shown to be a promising modality for lung cancer staging. In particular, artifacts in CT or PET images can be misdiagnosed if the lesion is adjacent to the diaphragm or heart. Such a discrepancy can cause the micro-lesion to not be observed and result in false negatives8.Currently, positron emission tomography (PET)/computed tomography (CT) is known to be the most accurate diagnostic tool for lung cancer staging because it improves the detection of metastatic diseases, guides therapy, and predicts clinical outcomes9.An endobronchial metastatic lesion (EML) is considered present when infiltration of the bronchial epithelium by a malignant lesion is histologically consistent with the primary tumor. EML is an actually lesion that have metastasized to the central bronchi subsegmentally or more proximal to the extent of bronchoscopyIn particular, we have often diagnosed NSCLC with EML, especially those not identified on PET/CT. In this case, we had to modify the cancer stage according to the incidentally discovered EML that was histologically proven but not identified on PET/CT. However, there are few studies on EMLs not observed on PET/CT, and the treatment guidelines for these patients are still controversial.Therefore, we performed a cohort study of patients diagnosed with NSCLC at our institution and investigated the characteristics of NSCLC patients with histologically proven EML whether there was a difference in disease-free survival (DFS), progression-free survival (PFS) and overall survival (OS) according to EML.We reviewed patients with NSCLC who were diagnosed at a tertiary hospital in Korea between January 1, 2010, and December 31, 2019. Eligible patients in this study were: (1) patients with histologically confirmed NSCLC; (2) age ≥ 19 years; and (3) those who underwent complete staging work-up including bronchoscopic and radiologic evaluation such as PET/CT.10. Smoking status was defined as follows: never (< 100 lifetime cigarettes) or current (quit < 1 year before diagnosis).Baseline demographics, disease characteristics  performance status (PS)), and clinical outcomes  were retrospectively obtained from medical records. Pretreatment clinical tumor-node-metastasis (TNM) classification was defined using the American Joint Committee on Cancer Staging Manual, eighth editionExclusion criteria included: (1) previously diagnosed malignancy in addition to primary NSCLC, or previous or current illness thought likely to interfere with cancer treatment; (2) patients who did not complete the staging work-up including bronchoscopic and radiologic evaluation such as PET/CT; and (3) poor follow-up or follow-up performed in an outside institution. All patients gave their written informed consent for bronchoscopic evaluation, and Institutional Review Board of Yonsei University Wonju College of Medicine approved the analyses of the clinical and bronchoscopic data (IRB No. CR317051).11.All registered patients underwent a pretreatment evaluation comprising physical examination, hematology, and biochemistry profiles, as well as obtaining patients’ complete historical information. Initial clinical staging was based on chest and brain CT, whole-body bone scans with single-photon emission, and abdominal CT or ultrasonography. We performed PET/CT to determine the TNM stage, and to screen for metastases that might not be identified by CT alone12. Flexible bronchoscopy was done in a special procedure suite. Two expert pulmonologists  performed flexible bronchoscopy using a BF-260  to confirm endobronchial cancerous lesions and reduce complications. We assessed the baseline epidermal growth factor receptor (EGFR) mutation status in adenocarcinoma patients by a direct sequencing of DNA extracted from samples of tumor tissue gathered during biopsy or resection, usually in the form of formalin-fixed paraffin-embedded diagnostic blocks13. The treatment strategy was established by the patient’s histology, molecular pathology, age, PS, comorbidities, and patient's preferences. Systemic therapies were performed in advanced-stage NSCLC patients with a PS of 0–215.We performed flexible bronchoscopy for all patients with suspected lung cancer. As shown by Rivera, flexible bronchoscopy became the recommended procedure for all patients suspected of having lung cancerWe evaluated the characteristics of patients with NSCLC with histologically proven EML through bronchoscopy other than the primary cancer, especially those not identified on PET/CT, and evaluated DFS, PFS and OS according to the EML. We also compared PFS and OS according to EGFR status and EML in patients with lung cancer. Lastly, we investigated the prognostic factors associated with 1-year PFS and OS in patients with NSCLC according to EML. DFS was calculated from the length of time after primary treatment for a cancer ends that the patient survives without any signs or symptoms of that cancer. PFS was calculated from the start of the treatment until disease progression or death was confirmed. OS was defined as the duration from the date of diagnosis to the date of death or last follow-up.All statistical analyses were performed using SPSS for Windows software, ver. 26.0 . Descriptive statistics are expressed as median (interquartile range [IQR]) for continuous data and number (%) for categorical data. Wilcoxon rank-sum tests or t-tests were used to assess differences between NSCLC patients with and without EML, and between NSCLC patients with EML identified and not identified with PET/CT for continuous variables.P-values < 0.05 were defined as statistically significant.Pearson’s chi-square test or Fisher’s exact test was used to analyze categorical variables. Kaplan–Meier and log-rank tests were used to analyze DFS, PFS and OS between NSCLC patients with and without EML and between NSCLC patients with EML identified and not identified with PET/CT. Hazard ratios (HRs) and confidence intervals (CIs) were calculated using the Cox proportional hazard model. Univariate and multivariate analyses were performed to determine the prognostic factors associated with the 1-year PFS and OS in patients with NSCLC. Two-sided statistical tests were used, and This study was approved by the institutional review board of Yonsei University Wonju Severance Christian hospital (IRB No. CR317051).Informed consent to participate in the study was obtained from all participants.Of the 581 patients with NSCLC (343 patients with adenocarcinoma) diagnosed during the study period, 36 patients who were previously diagnosed with malignancy in addition to NSCLC and 128 patients  who did not complete staging work-up including bronchoscopy and radiologic evaluations such as PET/CT, were excluded. 53 patients dropped out because they were not satisfied with the follow-up. Therefore, 364 patients (172 with adenocarcinoma) were enrolled in this study  of the total NSCLC patients, but was not found in 295 (81.0%) patients. The histologic subtypes were as follows: 27 (39.1%) adenocarcinoma patients with EML versus (vs) 145 (49.2%) patients without EML, squamous cell carcinoma 38 (55.1%) versus 133 (45.1%); large cell carcinoma, 0 (0%) versus 7 (2.3%); and others, 4 (5.8%) versus 10 (3.4%). EGFR mutations were observed in 6 (8.7%) patients with EML and 44 (14.9%) patients without EML (Table 9.0% of tP = 0.912) , and median OS were 12.0 (6.0–30.0) and 20.0 (10.0–39.0) months , respectively. Median PFS and OS were significantly lower in patients with EML than in patients without EML  and median OS was 18.0 (11.0–36.0) versus 11.0 (5.5–26.0) months , respectively   and 32.0 (19.0–49.0) months and in patients with EML compared to patients without EML , and median OS was 15.5 (7.0–21.0) versus 34.0 (21.0–53.5) months , respectively , and the ratio of squamous cell carcinoma was higher in patients with EML not identified with PET/CT (P = 0.024)  were identified with PET/CT, but 18 26.1%) were not. When the characteristics of the patients were compared, there were no significant differences in age, sex, smoking status, and body mass index (BMI) between the two groups. However, ECOG showed better performance (6.1% were4) Table . SupplemP < 0.001). Median OS was also as follows; EGFR (−), EML (−) 17.0 (9.0–35.5); EGFR (+), EML (−) 34.0 (21.0–53.5); EGFR (−), EML (+) 12.0 (6.0–31.0); EGFR (+), EML (+) 15.5 (7.0–21.0) months, (P < 0.001). Both median PFS and OS were highest in the EGFR (+) and EML (−) groups. , EML (−) 11.0 5.0–24.5); EGFR (+), EML (−) 25.0 (12.5–39.5); EGFR (−), EML (+) 8.0 (4.0–16.0); EGFR (+), EML (+) 8.5 (3.0–14.0) months, , EGFR mutation , pleural effusion  and EML  were associated with 1-year PFS. One-year OS was associated with ECOG PS , EGFR mutation , and pleural effusion  (Table P = 0.060) was not associated with 1-year OS in multivariate analysis  and EML (−) patients had the highest median PFS and OS, whereas the EGFR (−) and EML (+) patients had the lowest (P < 0.001), as shown in Fig. EML can cause airway complications, which can worsen cancer-related quality of life. Moreover, we found that it is associated with poor clinical outcomes. The frequency of endobronchial metastasis varies from 2 to 50% of pulmonary metastases from extra-thoracic malignancies19. In this study, lung-to-lung or bone metastasis was more prevalent in patients with EML, but not statistically significant as other variables.When EGFR was positive, PFS and OS were significantly lower in patients with EML compared to patients without EML whereas there was no significant difference in EGFR-negative patients. This means that EML can have a significant impact on prognosis, especially in EGFR-positive patients. Although it is not clear why EML affects the prognosis of the EGFR-positive group, EGFR mutation was associated with more frequent distant relapse and short PFS rate after neoadjuvant chemoradiation therapy followed by surgery in locally advanced N2-positive NSCLCWhen we compared ipsilateral EML to contralateral EML, PFS and OS were significantly higher in ipsilateral EML group. Obviously, the group with ipsilateral EMLs showed statistically lower bone, spine, and pleural metastasis than the contralateral group. Therefore, when contralateral EMLs are observed, there is a possibility that metastasis to other organs is accompanied.20. Endobronchial metastases include (1) direct metastasis to the bronchus, (2) bronchial invasion by a parenchymal lesion, (3) mediastinal or hilar lymph node metastasis, and (4) the extension of a peripheral lesion along the proximal bronchus21. In the more advanced stages, the tumor tissue ulcerates through the epithelial layer, and the entire mucosal lining is gradually replaced by malignant tissue, resulting in bronchial stenosis20. Airway obstruction resulting in stenosis caused by endobronchial metastasis is a significant problem22, and as EML progresses, the chance of metastasis to other tissues becomes greater.Clinical presentations associated with EML include cough, shortness of breath, and hemoptysis23. However, there were no definite studies on how PET/CT could detect EMLs. In our study, we could identify that 73.9% of EMLs were identified using PET/CT.Although there was some disagreement between the CT findings and pathologic patterns of bronchial abnormality, a previous study demonstrated that chest CT helped detect superficial endobronchial lung cancer in 79% of cases24. Although PET is useful in cancer staging, it showed a false-positive rate of 15–20% and false-negative rate of 9–28%25. In general, lesion size ≤ 2 cm and histologic subtype of lung cancer were significant factors associated with negative findings on PET26. Endobronchial lesions are mostly confined to superficial lesions and are small in size, which makes them unlikely to be detected on PET, and our study showed that 26.1% of total EMLs were not identified on PET/CT. When we compared the prognosis of NSCLC patients with and without EML other than the primary cancer, the median PFS and OS were significantly lower in patients with EML. Based on this result, it will be necessary to confirm EML in patients with lung cancer, especially in advanced stages. However, when we compared NSCLC patients with EML identified and not identified on PET/CT, the median OS showed no significant differences between the two groups although median PFS was significantly higher in patients with EML not confirmed by PET/CT.Because of the increased reliance on PET/CT for cancer staging, it is vital that physicians be aware of pitfalls in PET/CT imaging to avoid misdiagnosis, over-staging, and unnecessary biopsies28 and our results also support this. For advanced NSCLC patients with EGFR mutations, especially exon 19 deletions, EGFR tyrosine kinase inhibitors were associated with better OS compared with conventional chemotherapy based on most studies including the phase III IPASS trial comparing gefitinib with doublet chemotherapy in the first-line setting30. Malignant pleural effusion is a common complication in patients with NSCLC and is associated with decreased survival in patients with distant metastases31.Regarding prognostic factors associated with 1-year PFS and OS in patients with NSCLC; ECOG PS, EGFR mutation, pleural effusion, and EML were associated with 1-year PFS and OS, except for 1-year OS for EML. The ECOG PS is a strong independent prognostic factor for survival of patients with advanced NSCLC and remains the gold standard prognostic measure32, which has been proposed to explain the development of multiple primary or locally recurrent cancers. In our study, many NSCLC patients with EML already showed advanced stages, such as lung-to-lung metastasis, which may have affected poor prognosis. This study is meaningful because it is the first to compare the prognosis of NSCLC patients with EML.In our study, EML with primary cancer, as well as ECOG PS and EGFR, were also significantly associated with poor prognosis in patients with NSCLC. Endobronchial metastasis originated from the primary cancer site via submucosal lymphatic or blood vessels rather than from carcinoma in situThis study had some limitations. First, we included patients with EML confirmed by histological examination; therefore, we excluded patients who had EML but were not proven histologically. Second, PET uptake for EML may have been different according to the patient’s condition at the time of diagnosis, and it could be seen as a false negative; however, the PET/CT scan protocol was uniform, and patients were required to fast for at least 6 h prior to imaging. Third, this was a single-center retrospective study, and 217 of the total 581 patients were excluded because they had a previous history of treatment for cancer or did not complete the staging work-up. This may have affected the outcome of the study due to selection bias. In addition, treatment methods are diverse depending on clinicopathological characteristics, therefore, there will be limitations in interpreting PFS and OS because the stage or patient characteristics are different. Therefore, a multi-center and prospective study is needed to minimize bias.In this study, NSCLC patients with EML showed worse prognosis, including median PFS and OS, than those without EML. EML, ECOG PS, EGFR, and malignant pleural effusion were also significantly associated with poor prognosis. Therefore, it is important to confirm the presence of EML through flexible bronchoscopy during lung cancer evaluation in patients with NSCLC.Patients with non-small cell lung cancer (NSCLC) are sometimes diagnosed with endobronchial metastatic lesions (EMLs), especially those not identified on positron emission tomography/computed tomography. The cancer stage has to be modified according to the incidentally discovered histologically proven EML. This study shows that the PSF and OS in patients with NSCLC were significantly lower in patients with EML than in those without EML. This study is the first study comparing the prognosis between NSCLC patients with EML confirmed using flexible bronchoscopy and NSCLC patients without EML. This study suggests that it is important to confirm the presence of EML through flexible bronchoscopy during lung cancer evaluation in patients with NSCLC.Supplementary Information.


Propofol-induced injection pain is a common adverse effect during the induction of general anesthesia. The purpose of this study is to investigate the effect of low-dose esketamine in preventing propofol injection pain.  In this double-blind, randomized, controlled trial, patients scheduled for elective ear surgery under general anesthesia received either normal saline (NS), or 40 mg lidocaine, or 0.15 mg/kg esketamine 30 seconds before manual injection of propofol. The primary outcome of this study was the incidence of propofol injection pain. The secondary outcomes included injection pain score, vital signs, total dosage of vasoactive drugs used within 5 minutes after induction, and adverse events related to drugs. P < 0.05); however, no significant difference was found between the esketamine and lidocaine groups. The median of injection pain score was significantly lower in the esketamine and lidocaine groups (both median (interquartile range) = 0 (0–1)) than that in the NS group (1 (0–2); P < 0.05). In addition, compared with the NS and lidocaine groups, preinjection esketamine provided more stable hemodynamic parameters within 5 minutes after induction (P < 0.05). No statistical difference was found in adverse events among the three groups.  A total of 105 patients were included. Compared with the NS group (67%), pretreatment with esketamine and lidocaine significantly reduced the incidence of injection pain to 29% and 33%, respectively . Pretreatment with a low-dose esketamine can not only reduce the incidence of propofol injection pain but also provide a more stable circulation in patients after anesthesia induction. This convenient, well-tolerated, and economic treatment appears as an option to be routinely applied in clinic practice.  Propofol is widely used in the induction of general anesthesia due to its rapid onset and early recovery without accumulation; however, pain is a common adverse effect during propofol injection . The incMany strategies have been adopted to prevent injection pain , 4–6. AmFrom a clinical point of view, pharmacological interventions, which only require drug injection as an adjunctive treatment prior to propofol, are more convenient and feasible to be implemented than the venous occlusion technique. Ketamine exerts its sedative and analgesic effects through activating N-methyl-D-aspartate (NMDA) receptor. Previous studies have reported that a small-dose intravenous ketamine could effectively reduce propofol injection pain in adults and children to different degrees –10; howeConsidering the advantages of pharmacological intervention in the clinical setting, we designed this trial to compare the effect of a low-dose esketamine with normal saline (NS) and lidocaine in preventing propofol injection pain.ChiCTR2100052742). The authors prepared this study in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines.This study was conducted as a randomized, double-blinded, controlled trial at Shanghai Eye and Ear, Nose, and Throat (ENT) Hospital of Fudan University. Ethical approval for this study  was provided by the Ethical Committee of Shanghai Eye and ENT Hospital of Fudan University  on December 22, 2020. The experiment was conducted with the patients' understanding and consents. The trial was registered with China Clinical Research Information Service  grade I or II, scheduled to undergo elective ear surgery were included. Patients were excluded if they were allergic to experimental drugs, had a serious risk of increased blood pressure (quiet blood pressure >170/100 mmHg) or intracranial pressure, had a history of hyperthyroidism, serious functional insufficiency of important organs, significant ischemic heart disease, sinus tachycardia, abuse of alcohol, analgesia, or sedative antidepressant.Eligible adult patients were randomly assigned into three groups with 35 patients in each group by computer-generated allocation. A specific anesthesia nurse who did not participate in this study generated a random allocation sequence and enrolled participants. The patients in group NS, group lidocaine, and group esketamine received pretreatment with NS, 40 mg lidocaine, and 0.15 mg/kg esketamine , respectively. The results of randomization were sealed in a closed envelope until the day of surgery. The patients and the participating anesthesiologists were both blinded to the results of randomization. The drugs were prepared in a 20 ml syringe with either 20 ml of NS or 40 mg lidocaine, or 0.15 mg/kg esketamine, by a specific anesthesia nurse who did not participate in this study.2). Subsequently, a 20 G intravenous cannula was inserted at the hand dorsum. After preoxygenation, the patients were pretreated with different agents intravenously 30 seconds before injection of 1% propofol medium-chain triglyceride (MCT) and long-chain triglyceride (LCT) emulsion . After pretreating the agents, propofol were manually injected 2 mg/kg (the dosage was based on lean body weight for obese patients) over 15 seconds. The patients were asked the degree of pain at 5 seconds after injection, and the researchers observed facial expressions and body movements and recorded pain scores. All of them were in deep sedation and unable to give a clear response. Then, the patients were injected with sufentanil 0.1 μg/kg and rocuronium 0.6 mg/kg for the induction of general anesthesia, followed by laryngeal mask (LMA) intubation. Dorasetron 0.35 mg/kg was administered 30 minutes before the end of surgery. After the operation, patients were transferred to the resuscitation room until fully recovered.On arrival in the operating room, the patients received routine monitoring, including electrocardiography, noninvasive blood pressure, and pulse oxygen saturation , a Bonferroni correction was used to adjust the type I error rate for multiple comparisons. Continuous variables were presented as median (25th and 75th percentiles) or mean ± standard deviation (SD). Categorical variables were presented as number of patients and percentages. All statistical tests are 2-tailed; the corrected differences were considered significant at P < 0.05.Continuous variables were analyzed by the one-way analysis of variance (ANOVA) test followed by the Dunnett test or Kruskal–Wallis test followed by the Mann–Whitney During the period from November 4, 2021, and February 4, 2022, a total of 105 patients were screened for eligibility and 101 patients were ultimately enrolled and analyzed . In the P < 0.05). However, the number of patients experiencing injection pain was not different between group esketamine and group lidocaine, suggesting that esketamine is just as effective as lidocaine.The incidences of propofol injection pain (pain score of 1 or more) are shown in P < 0.05) (The median of injection pain score in the esketamine and lidocaine groups was both 0 (0-1), which was significantly lower than that in the NS group (1 (0–2);  < 0.05) . The inc < 0.05) .P < 0.05), but had no significant effect on HR (P < 0.05), accompanied with a slight increase in T4, which may be due to the injection of vasoactive drugs (The hemodynamic data measured during 5 minutes within induction are shown in ct on HR . Compareve drugs . In addive drugs . Anestheve drugs .The cumulative dosage of phenylephrine during 5 minutes after induction was lower in the esketamine group compared with that in the NS and lidocaine groups; however, this did not reach a statistical significance .The distribution and incidence of adverse events in each group are given in In this study, we found that a low-dose esketamine at 0.15 mg/kg was as effective as lidocaine in attenuating propofol injection pain compared with NS. However, esketamine was more beneficial in providing a stable hemodynamic profile than lidocaine and NS during induction.A previous study reported that ketamine reduced propofol injection pain from 84.8% to 17% at a dosage of 0.3 mg/kg . ConsideThe major mechanism responsible for pretreatment with ketamine 30 seconds before propofol may be through peripheral local anesthetic action in the vascular endothelium, rather than a central analgesic effect . The exaPrevious studies have shown that a combination of propofol and ketamine is more beneficial for maintaining hemodynamic stability due to the cardiostimulant effects of ketamine balancing the cardiodepressant effects of propofol –16. ConsIt is well known that the use of ketamine as a single sedative agent has been limited by its psychotomimetic effects and other side effects . Our datIn our study, pretreatment with esketamine not only reduced the incidence of pain injection but also provided a stable hemodynamic profile after induction. From a clinical point of view, premedication with esketamine is easy and convenient to be implemented as well as economic wise in daily practice. The results of this study can be clinically applied in general.A limitation of our study is that the propofol injection cannot be eliminated completely. An optimal dosage of esketamine for propofol injection pain should be further examined. Furthermore, this study was only conducted at a single center. In the future, we will coordinate with different hospitals to evaluate the effects of esketamine on propofol-induced injection pain.The present study showed that pretreatment with low-dose esketamine at 0.15 mg/kg can relieve propofol-induced injection pain effectively and safely. Furthermore, 0.15 mg/kg esketamine can also provide more stable hemodynamic parameters during induction. Conclusively, pretreatment with a low-dose esketamine appears as a convenient, well-tolerated, and economical option used during the induction of anesthesia. The results of our study provide evidence for improving clinical practice with a positive impact on patient care.


Hypoalbuminemia is linked to the emergence of cardiovascular events. However, there is an unclear association between serum albumin (ALB) and gender in paroxysmal AF patients. This retrospective study aimed to explore the association between ALB levels and paroxysmal AF by gender in a Chinese population.This study included patients with paroxysmal AF who were hospitalized consecutively in China from January 2019 to September 2021. Controls with sinus rhythm and without paroxysmal AF were matched (2:1) to cases by gender and age. Pearson correlation analysis was used to study the correlation between ALB and blood lipid profiles, multivariate regression models were performed to investigate the association between ALB and paroxysmal AF.There were 305 patients with paroxysmal AF and 610 patients with controls included in this study. Low ALB in male with AF patients were significantly associated with paroxysmal AF . ALB was positively correlated with triglyceride (TG) , total cholesterol (TC) , low-density lipoprotein cholesterol (LDL-C) , and high-density lipoprotein cholesterol (HDL-C) .Low ALB in male patients is significantly associated with paroxysmal AF in a Chinese population. Monitoring for hypoalbuminemia in men might help reduce the incidence of paroxysmal AF. Atrial fibrillation (AF) with a lifetime risk of about 25% represents an increasing public health concern, the most common clinical arrhythmia encountered in clinical practice, currently affecting almost 33 million subjects worldwide accompanied by growing morbidity and mortality especially in developed countries , 2. StroSerum albumin (ALB) has many biochemical properties , includiHereby, in this case–control study, we aim to characterize the association between the ALB levels and paroxysmal AF by gender in 915 patients from China. We hypothesized that low serum ALB is associated with paroxysmal AF, the confirmation of this hypothesis has significant clinical value because serum ALB is adjustable.This study included patients with paroxysmal AF who were hospitalized consecutively from a single center in China between January 2019 and September 2021 in the electronic medical record system. The inclusion criteria for cases were as follows: (1) patients from the community who were hospitalized for less than 21 days, lived a healthy lifestyle through medical history, and a normal nutritional status through the subjective global assessment (SGA) questionnaire. (2) patients aged 28–80 years. (3) Paroxysmal AF was diagnosed by clinicians and clearly documented in the electronic medical record. The exclusion criteria were as follows: (1) cardiac surgery, valvular disease, and heart failure. (2) peripheral vascular disease, prior thromboembolism, and major bleeding. (3) severe hepatic or renal dysfunction on record. (4) malignancy, hyperthyroidism, or gout. (5) pregnant woman. (6) use of uric acid-lowering drugs. Controls were also routine hospital inpatients, most of whom lived in the communities. Controls with sinus rhythm and without paroxysmal AF were matched (2:1) to cases by gender and age. In the current study design, we initially included a total of 2000 patients, including 354 patients with paroxysmal AF, 27 patients were excluded due to abnormal nutritional status based on SGA assessment, and 22 patients met other exclusion criteria. Finally, we included 305 patients with paroxysmal AF and 610 age- and sex-matched controls. This study was based on the principles of the Helsinki Declaration and approved by the Medical Research Ethics Committee of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine. Because the data are anonymized, the Ethics Committee of Affiliated Hospital of Shandong University of Traditional Chinese Medicine (NO.20200512FA62) waived the need for informed consent.Demographic and clinical variables included gender, age, AF comorbidities (coronary heart disease (CHD), hypertension, and diabetes), and laboratory variables , total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (APOA1), serum apolipoprotein B (APOB), lipoprotein (a) [La(a)], serum creatinine (Scr), serum uric acid (SUA), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). These data were obtained during routine hospital procedures and then reviewed by us through the hospital's electronic medical record system. All disease diagnoses were made by professional cardiologists and all serum indicators were determined by hospital laboratories.According to the reported guidelines , paroxysThe serum ALB level conversion standard was as follows: 1 g/L = 0.1 g/dL. Levels of serum ALB were classified by tertiles. Serum ALB level in male patients was classified into 3 categories: < 37.9 mg/dL, 37.9–41.7 mg/dL, and > 41.7 mg/dL. Likewise, serum ALB level in female patients was classified into 3 categories: ALB level < 37.7 mg/dL, 37.7–41.1 mg/dL and > 41.1 mg/dL. As previously reported , ALB levAll analyses were conducted in SPSS software  and GraphPad Prism software (version 9.0.0). Continuous data were expressed as mean ± standard deviations (SD) or medians and interquartile ranges (IQR) where appropriate. Categorical data were presented as numbers and percentages. Baseline characteristics were compared between groups by Chi-squared tests for categorical variables and T-tests or Mann–Whitney U tests for continuous variables. Serum ALB was modeled as a continuous variable and was divided into tertiles based on sample distribution. The differences among the three groups of variables were analyzed by variance (ANOVA). Pearson correlation analyses were performed to analyze the correlation between ALB and blood lipid profiles. We used multivariable Binary Logistic Regression models to investigate the association between Serum ALB and AF. Model1 has not been adjusted. Model2 adjusted for CHD, hypertension, and diabetes. Model3 adjusted for TG, TC, LDL-C, HDL-C, APOA1, APOB, AST, SCr, and SUA. Model4 further adjusted for all these factors. A P value < 0.05 indicated significance, the tests were 2-sided.Table Figure Table Table Figure Table To our knowledge, this study is the first to evaluate the association between serum ALB and paroxysmal AF by gender in the Chinese population. Our current finding suggested that low serum low ALB levels in male patients were associated with paroxysmal AF; there was a positive correlation between ALB levels and blood lipid profiles in patients with paroxysmal AF. Nevertheless, further analyses didn’t support a significant difference in ALB levels among the comorbidities of paroxysmal AF. These findings imply that it would be interesting to monitor clinical hypoalbuminemia for clinicians to detect paroxysmal AF. We reported herein an association between low serum ALB levels and paroxysmal AF.A recent dose–response meta-analysis reported that low serum ALB level was related to an increased risk of AF . Liao etThe gender relationship between serum ALB and AF has not been fully explored. A prospective cohort design based on the Copenhagen City Heart Study reported that serum ALB levels only in females were inversely related to the risk of AF , which was inconsistent with our current results reporting that low serum low ALB levels in male patients were associated with paroxysmal AF. The main possible reason was the heterogeneity of the study population, it is clear that our study design relied on hospitalized patients in China, not the general population; more importantly, we also reliably differentiated paroxysmal AF from patients with AF; certainly, the influence of several potential unmeasured confounding factors can’t be ruled out. Admittedly, it would be interesting to perform a prospective cohort design to evaluate the association between serum ALB levels and paroxysmal AF in the future.According to a previous review , hypoalbIn the past, Annoura M et al.  reportedIt is well-known that hypertension, CHD, and diabetes are important risk factors for AF . In our Several potential study limitations warrant discussion. First, the small study population was recruited retrospectively from a single center in China, which was underrepresented and may have introduced selection bias. Therefore, further multicenter studies with large sample sizes are required. Second, the causal association between ALB levels and paroxysmal AF could not be determined due to the case–control design. Thus, further prospective cohort studies also are required. Third, low ALB, as an acute phase reactant, could be related to long-term inflammation . SeveralIn conclusion, our study indicates that low ALB levels in male patients are independently associated with paroxysmal AF. ALB levels are positively associated with TG, TC, HDL-C, and LDL-C. These findings imply that hypoproteinemia and low blood lipid profiles may act synergistically to involve in the pathological development of paroxysmal AF. Moreover, it would be essential to perform a prospective cohort design to investigate the causal relationships between these conditions.


Globally, the rapid increase of obesity is reaching alarming proportions. A new approach to reduce obesity and its comorbidities involves tackling the built environment. Environmental influences seem to play an important role, but the environmental influences in early life on adult body composition have not been thoroughly investigated. This study seeks to fill the research gap by examining early-life exposure to residential green spaces and traffic exposure in association with body composition among a population of young adult twins.As part of the East Flanders Prospective Twin Survey (EFPTS) cohort, this study included 332 twins. Residential addresses of the mothers at time of birth of the twins were geocoded to determine residential green spaces and traffic exposure. To capture body composition, body mass index, waist-to-hip ratio (WHR), waist circumference, skinfold thickness, leptin levels, and fat percentage were measured at adult age. Linear mixed modelling analyses were conducted to investigate early-life environmental exposures in association with body composition, while accounting for potential confounders. In addition, moderator effects of zygosity/chorionicity, sex and socio-economic status were tested.Each interquartile range (IQR) increase in distance to highway was found associated with an increase of 1.2% in WHR (95%CI 0.2–2.2%). For landcover of green spaces, each IQR increase was associated with 0.8% increase in WHR (95%CI 0.4–1.3%), 1.4% increase in waist circumference (95%CI 0.5–2.2%), and 2.3% increase in body fat (95%CI 0.2–4.4%). Stratified analyses by zygosity/chorionicity type indicated that in monozygotic monochorionic twins, each IQR increase in land cover of green spaces was associated with 1.3% increase in WHR (95%CI 0.5–2.1%). In monozygotic dichorionic twins, each IQR increase in land cover of green spaces was associated with 1.4% increase in waist-circumference (95%CI 0.6–2.2%).The built environment in which mothers reside during pregnancy might play a role on body composition among young adult twins. Our study revealed that based on zygosity/chorionicity type differential effects of prenatal exposure to green spaces on body composition at adult age might exist.The online version contains supplementary material available at 10.1186/s12940-023-00964-1. In many countries around the world, the rapid increase of obesity is reaching alarming proportions. Obesity is a serious public health issue which is linked to multiple adverse health conditions . It has According to the ‘Developmental Origins of Health and Disease’ hypothesis, being exposed to environmental influences in early life can have significant consequences on an individual’s risk for future chronic disease . PreviouTwin pregnancies are associated with a higher risk of adverse outcomes such as premature birth and low birth weight . TherefoTwin studies provide a unique opportunity to investigate prenatal environmental influences on the development of obesity as they allow us to distinguish and examine the environmental influences according to chorionicity. Whereas dizygotic  twins are always dichorionic, monozygotic  twins, can be further classified as monochorionic (MC) or dichorionic (DC) . VasculaThis study is part of a larger on-going prospective population based cohort: The East Flanders Prospective Twin Survey (EFPTS) . MultiplResidential addresses of the mothers at time of birth of the twins were geocoded. Residential green spaces and distance to roads were determined using Geographic Information System (GIS) functions. First, spatial analysis of the land cover was conducted in a 5000 m radius from the residential address using GIS and was based on data from CORINE (Coordination of Information of the Environment) Land Cover 1990 and 2000 (CLC1990 and CLC2000), published by the European Environment Agency. Green space included the classes of forest and semi natural areas, wetlands, water bodies and artificial vegetated areas and does not include agricultural areas. Second, GIS functions estimated traffic exposure through distances to nearest national road and distances to nearest highway. In addition, distance to nearest major road was defined by the two types of roads, whichever is nearest. All GIS analyses were performed using ArcGIS10 software .Two trained researchers examined anthropometric parameters and metabolic characteristics, as has been previously described in detail . In brieAt birth, the following variables were selected for this study: zygosity and chorionicity , gestational age (weeks), parity (primiparity vs. multiparity), birthweight (grams), and sex. Perinatal data about gestational age, parity, birthweight, and sex of the twins were captured from the obstetric records. At follow-up, additional information on maternal characteristics was collected via self-report questionnaires. Mothers were then asked to fill in a questionnaire including additional information on delivery mode (“spontaneous” versus “cesarean section”), maternal age during pregnancy, smoking status during pregnancy, maternal weight before pregnancy, maternal weight gain during pregnancy, maternal education . Neighborhood household income was used continuously and categorically. The categorical variable was categorized as “low-income household” (< lower quartile), “middle-income household” (> lower quartile and < higher quartile) and “high-income household” (> higher quartile). Moreover, information on twins’ age, physical activity by grading the current daily physical activity on a scale of 0 to 10 with 10 being the highest level of activity, and smoking status  were collected via self-report questionnaires filled in by each twin separately.p-value less than 0.05 was regarded as statistically significant unless otherwise specified.Statistical analyses were performed using the computing environment R, Version 3.5.1 . In thisMeans and standard deviations were used to summarize maternal height and birthweight, whereas medians and interquartile range (IQR) of the 25th percentile and the 75th percentile (p25-p75) were used to summarize the remaining variables with a non-normal distribution. Next, non-parametric Chi-Square tests of Independence and Kruskal-Wallis tests were performed to compare the distribution of the DZ, MZMC and MZDC groups. To detect the difference between groups, a Mann-Whitney U test was performed.Outcome variables were naturally log-transformed due to nonlinear distributed residuals. Linear mixed modelling with a random intercept to account for twins of the same mother was carried out. First, linear mixed modelling analyses were conducted to determine crude associations between one early-life environmental exposure  and body composition indices while accounting for the random effect of the twin-pair. Prior to analysis a directed acyclic graph (DAG) was made from literature review . The adjusted models with one exposure present were additionally adjusted for the other two exposures: distance to major road, distance to highway, and/or green spaces which ever appropriate. The multiplicative model was built of associations which were found significant by including three-way interaction terms between the three early-life environmental exposure variables. The other pre-selected modifiers sex, maternal education, and neighborhood household income were then also tested for effect modification, stratified by the level of the effect modifier when significant, additionally adjusted for the two other environmental exposures and a multiplicative model was built of associations which were found significant.Non-parametric Kendall’s Tau coefficients between the environmental exposures during early-life and adulthood were calculated. Then, the linear mixed modelling models assessing the effect of early-life green spaces and/or traffic exposure on body composition were additionally adjusted for the pre-identified intermediate factors. First environmental exposures during adulthood were included. Finally, these models were additionally adjusted for the pre-identified intermediates gestational age and birthweight.n = 168 mothers) and Table n = 332 individuals). No differences were found between the three types of twins, except in delivery mode, maternal education, and distance to nearest highway during adulthood. The median age of the mothers during pregnancy was 27 years (p25-p75 24.0–30.0). Groups of MZMC, MZDC, and DZ twins were fairly equally distributed. With a median BMI of 20.7 kg/m2 (p25-p75 19.3–22.7), the majority (77.1%) of our twin population were within normal BMI range (BMI 18.5–24.9 kg/m2). Higher values in distances to the nearest highway were reported among MZDC twins followed by MZMC twins and DZ twins, but this was not found significant.The characteristics of the study population are shown in Table After adjustment statistically significant associations were found between environmental factors during early life and body composition indices at adulthood. Each interquartile range (IQR) increase in distance to highway was found associated with an increase of 1.2% in WHR (95%CI 0.2–2.3%). For landcover of green spaces, each IQR increase was associated with 0.8% increase in WHR (95%CI 0.4–1.3%), 1.4% increase in waist-circumference (95 0.5–2.2%), and 2.3% increase in body fat (95%CI 0.2–4.4%)  was not a cause of concern. The Variance inflation factor (VIF) never exceeded 5 when investigating the additive co-effect.p = 0.054 vs p = 0.049). Each IQR increase in land cover of green spaces was associated with 1.0% increase in BMI (95% CI 0.0–2.0%) . Overall, in the additive model associations did not change substantially after additional adjustment for the two other environmental exposures. The association with BMI became statistically significant (Sex was not identified as a modifier. Neighborhood household income was identified as a modifier in the association on leptin (Supplementary Table p < 0.01), 0.689 (p < 0.01) and 0.630 (p < 0.01). Independent effects and co-effects of early-life exposure to traffic disappeared. The independent effects and co-effects of early-life exposure to green spaces on body composition remained after adjustment for environmental exposures at adult age  BMI, WHR and waist circumference of our study population to the internationally accepted cut-off values for overweight and obesity , 50, eveStudies have predominantly evaluated the association between early-life environmental exposures and body composition in the first years of life . PreviouMultiple studies have demonstrated positive birth outcomes when exposed to higher levels of green spaces during pregnancy , 58, 59.Our findings suggest that the association between early-life built environment and adult body composition is the same for the three twin types, except on the association between green spaces and waist-circumference. Previous EFPTS studies similarly investigated the influence of zygosity and chorionicity type on body composition and while they demonstrated that DZ twins significantly weigh more than MZ twins at birth , they alOne of the main strengths of this study is the longitudinal design. To our best knowledge, the EFPTS is the only large register that includes placental data that allows differentiation of DZ, MZMC, and MZDC twin groups with long-term follow-up. Secondly, study participants were randomly sampled for follow-up and those who participated did not differ compared to those who did not participate in gestational age, birthweight, and sex . AnotherUnfortunately, there are a number of limitations that remain. First, the possibility of exposure measurement error needs to be carefully considered. Data on residential location is available for the first and last residence and no information is available on moment of moving and frequency of moving in between inclusion and follow-up. Next, we included a twin population born from 1975 till 1982 but spatial data on green spaces was based on data from the CORINE land cover 1990 database, as no earlier satellite data were available. At adult age examination took place between 1997 and 2000 and CORINE land cover 2000 database was used. However strong correlations have been shown over time between periods of one decade . AlthougIn conclusion, the built environment in which mothers reside during pregnancy might play a role on body composition among slim and lean individuals at adult age. Even though our findings should be cautiously interpreted, they could contribute to the generation of new hypotheses to understand the influence of early-life environment on adult health within a population with lower measures of body composition. Our study suggests that based on zygosity and chorionicity type prenatal environmental exposures may have differential effects on adult body composition. To build upon our understanding, further exploration through larger prospective studies with inclusion of individuals from a wide range of body shapes and sizes, pre-selected confounders and personal exposure measurements is recommended.Additional file 1.


On the other hand, RR = 0.84  with insignificant heterogeneity of I2 = 20% and p = 0.28 was found for disease progression. Cochrane risk of bias (RoB) analysis revealed that three out of four articles were ranked as high-quality articles with low RoB. Based on the evidence grading, the overall certainty of evidences was moderate. In conclusion, baricitinib statistically significantly reduced mortality and disease progression in COVID-19 patients when the patients were treated with baricitinib at a dosage of 2 mg or 4 mg for a maximum duration of 14 days.Baricitinib is known to reduce mortality and disease progression in COVID-19 patients; however, the data are inconsistent. Therefore, it needs to be explored to further understand the clinical benefits of this drug in the management of COVID-19 patients. Does baricitinib statistically significantly reduce mortality and disease progression in COVID-19 patients? To answer these questions, three databases known as ScienceDirect, PubMed/MEDLINE, and Scopus and other sources, such as preprint (medRxiv) and reference lists, were thoroughly searched. Four randomised controlled trials (RCTs) were included. Based on the meta-analysis, baricitinib statistically significantly reduced mortality with the risk ratio (RR) of RR = 0.74 [95% CI: 0.58 to 0.94;  More than 6.3 million deaths were recorded, making COVID-19 as one of the deadly diseases in human history , but moderate high heterogeneity of I2 = 62% and p = 0.05 was found  and quantitative (MA) analyses . All seaas found . The hetp=0.005], but insignificant heterogeneity of I2 = 20% and p=0.28 was found  large sample size was included to derive concrete outcomes, (ii) only RCT studies were included, (iii) the focus for block disease progression was IMV, (iv) communication was established with one corresponding author to gather more data related to IMV, which was supplied by Lilly, the sponsor company, and (v) GradePro tool was used for grading the evidences, whereby this strategy was lacking in other MAs related to baricitinib. The limitation of the current study was that the result should be interpreted carefully since the heterogeneity was moderately high for mortality. Furthermore, due to the open-label study, performance bias was identified in a study by Horby et al. . This biIn conclusion, baricitinib statistically significantly reduced mortality and disease progression in COVID-19 patients when the patients were treated at the dosage of 2 mg or 4 mg for a maximum duration of 14 days.