The heart continuously transmits information to the cerebrum during each pulse, and influences information processing such as perception, cognition, and emotion, which are processed in the cerebrum. This is the basis for the theory of oriental medicine widely used in psychiatric medicine and clinical practice, so-called Simjushinji (heart and brain) theory, that the heart controls the mind. The present study aims to analyze the correlation between heart and brain function by 24-hour active electrocardiogram and quantitative electroencephalogram (EEG) measurement under meditation.t tests of both groups.This randomized, controlled, assessor-blinded, 2-armed, parallel, multicenter clinical trial will analyze a total of 50 subjects, including 25 each for the test group and the active control group. Subjects will be randomly allocated to the test group (performing resource mindfulness) and the control group (performing stress mindfulness) in a 1:1 ratio. The clinical trial consists of 3 stages. The first and third stages are stable states. The second stage is divided into the test and active comparator groups. Quantitative EEG (qEEG) measurements at stages 1 and 3 will be recorded for 10 minutes; measurements at stage 2 will be recorded for 20 minutes with the eyes closed. The 24-hour Holter Monitoring and heart rate variability will be evaluated at each stage. Before the beginning of stage 3, subjects will complete the questionnaires. The primary outcome will be analyzed by independent Scientific studies based on clinical epistemology are expected to serve as a basis for sustainable medical services in the field of psychiatric medicine in Korea. HRV, blood pressure index, and biometric index in qEEG, as determined by 24-hour Holter monitoring, will complement quantitative biomarkers and be useful in various fields. Physiologically, the heart continuously transmits information to the cerebrum during each heartbeat, which affects information processing such as perception, cognition, and emotion, which are managed in the cerebrum.,10 The vagus nerve in the heart controls the activation of the parasympathetic nervous system. The vagus nerve transmits information regarding the heart, such as heart rate, heart rhythm, and blood pressure, to the cerebrum through an afferent pathway. Thus, information regarding the heart, originating from the vagus nerve, is integrated in the nucleus solitarius of the brainstem through the afferent nerve pathway. In the nucleus solitarius, integrated afferent information is transmitted to the cerebral cortex via the limbic thalamus, hypothalamus, and amygdala. Information transmitted to the cerebral cortex is subjected to information processing in the brain, and then travels to the heart and major organs via the efferent pathway. Based on the information returning from the cerebrum, the heart regulates the sympathetic and parasympathetic nervous system of the autonomic nervous system to maintain the homeostasis of the human body, and is involved in human emotion, cognition, and behavioral responses.,15 Therefore, rather than separate interpretations of the brain and heart, the heart should be considered as an organ that interacts with the brain. In Donguibogam, the concept of “heart” is recognized as 3 things: mind, heart, and center.Brain and cardiovascular diseases contribute to the highest percentage of single-cause deaths (12.8%) worldwide. According to a 2017 report by the World Health Organization, 23.5 million people worldwide die of brain and cardiovascular diseases each year. In the West and in the Orient, a primary cause of these deaths was reported as mental stress. To do this, we will analyze the correlation between heart–brain function by using 24-hour active electrocardiogram (ECG) and quantitative electroencephalogram (EEG) during meditation. Specifically, subjects will be randomly assigned to 1 of 2 meditations recalling resources or stress situations, to observe the relationship between changes in 24-hour active ECG and quantified EEG. We will monitor the connectivity of the heart and brain by measuring the ECG and quantitative EEG (qEEG) through this study for 24-hour Holter monitoring during meditation, and will thus obtain regarding heart rate variability (HRV) and biomarkers for blood pressure and qEEG. In addition, clinical outcomes through mediation interventions can be used in various areas, including stress treatment, pain reduction, and cognitive awareness therapy for emotional instability. Furthermore, based on the epistemology, it is expected that the clear scientific identification of psycho-brain correlations will be the basis of sustainable medical services in the field of psychiatric medicine in Korea.This study is undertaken to scientifically clarify the theory of Shinju (mind and heart) (body's behavior), in which the “mind” (meaning heart) is involved in the “brain” (meaning cognition).2This study protocol followed the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist, which enhanced the quality of the clinical trial.2.1) function by measuring the qEEG and activity ECG for 24 hours under meditation.To scientifically identify the theory that the heart controls the mentality related with the brain, it is going to study on the correlation between the heart (mind and heart) and the brain , and a control group performing stress mindfulness (SM), at a 1:1 ratio. The clinical trial consists of 3 stages, 20 minutes each . The first and third stages are stable states. The second stage is divided into the test group and the active comparator group. The test group subjects will practice RM meditation and the active comparator group subjects will practice SM meditation. RM or SM meditation guide scripts will follow the M&L Psychotherapy Manual and the meditation guide will be directed by a professional practitioner trained by the M&L psychotherapist course. At stages 1 and 3, qEEG measurements will be taken for 10 minutes (5 minutes with eyes open and 5 minutes with eyes closed) from 5 minutes after the beginning of the stage. In the second stage, the qEEG measurements will be taken for 20 minutes, with eyes closed. The 24-hour Holter monitoring2.3Department of Neuropsychiatry of Korean Medicine & Inam Neuroscience Research Center, Wonkwang University Sanbon Hospital in Korea will recruit outpatients in the clinical practice setting. Clinical trial information will be posted on the bulletin board of each hospital and university, in online advertisements.2.41.Age: male and female individuals, age: 20 to 45 years2.Individuals who do not consume excessive amounts of tobacco, tea, and coffee; who eat regularly; and who have a normal sleep pattern3.Individuals who exhibit right-handedness4.Individuals who voluntarily participate in the study, as indicated by their written consent 2.51.Individuals who demonstrate arrhythmia on EKG, or whose pulse rate per minute is outside of the range of 50 to 1002.Individuals who have a severe physical illness or are medically unstable 3.Individuals who have a congenital illness, psychological illness, central nervous problem, peripheral nervous problem, endocrinal illness, immunological disease, basal heart disease, liver disease, or renal disease4.Individuals who have a neurological illness  or psychological history 5.Individuals with an intracardiac pacemaker inserted, or with a device that stimulates the brain, a ventricular peritoneal short circuit, or other artificial device inserted into the head6.Individuals who take medicines that may affect the autonomic nervous system within 1 week before enrollment in the clinical trial 7.Individuals who smoke, drink alcohol, or ingest caffeine-containing products, within less than 2 hours before the clinical trial 8.Individuals who are pregnant or breast feeding9.Individuals who participated in another clinical study within the prior 1 month or who are currently participating in other clinical studies10.Individuals who exhibit difficultly participating in this study, as judged by the investigator2.61.Violation of the inclusion criteria or fulfillment of the exclusion criteria2.Serious adverse events that impede trial continuation3.Withdrawal of consent by the subject or a legal representative4.Do not receive 3 consecutive mindfulness meditation sessions5.Violation of the clinical trial protocol by the investigator or the subject6.Use of medications or treatments that can affect the results for clinical trial7.Inappropriate progress as judged by the investigator2.7A randomization table will be created by an independent statistician using the balanced block.2.7.1The randomization number allocated according to the assigned tables generated will be managed by the clinical trial manager and sent to each hospital. Consent will be obtained by a Korean Medicine doctor. If the participant voluntarily signs informed consent and meets the inclusion criteria, the clinical research coordinator (CRC) will sequentially allocate the participant to the treatment or control group according to the random number and record the subject identification code on the case recording sheet and the assignment table.2.8Because of the study design, practitioners cannot be blinded. Only the participants will be blind. The assessor will be instructed to refrain from talking about the treatment to maintain blinding.2.92.9.1The study schedule is presented in Table 2.9.2At the screening phase, before conducting this clinical trial, the Korean oriental medical doctor (KMD) will explain to the subjects the contents of the “Instructions for obtaining subject consent” and confirm that the subject understands the contents, and that KMD must receive written permission that each subject is participating in the clinical trial of their own free will. And then, signing the informed consent form, the participants are selected as subjects by reviewing the selection criteria and exclusion criteria in accordance with the clinical trial plan. Selected subjects will fill in the demographic surveys, case medical history, physical examination, clinical pathology examination pregnancy test, single chest x-ray, ECG test, and will be assigned randomly into the test group or the active comparator group according to precompleted random templates, and after assigning a registration number, clinical trial will be conducted at the scheduled time. The subject identification codes will be recorded in the following manner:Provider Code: Wonkwang University Sanbon Hospital (WS)Agency Code – Test Year - Test Serial Number - Registered Order.2.9.3 hospital anxiety and depression scale, Korean sex role inventory-short form, five facet mindfulness questionnaire short scale, the Korean version of positive affect negative affect schedule, the core seven emotions inventory-short form, and Korea Sasang Constitutional Diagnostic Questionnaire-15.The clinical phases consist of 3 stages which prolong 20 minutes each . The first and third stages are stable state. The second stage is to practice resource or stress mindfulness meditation. Before the clinical trial, at first stage, subjects will fill in the Pre clinic Phase (=Mibyung) Questionnaire, psychosocial wellbeing index short form,At 1 and 3 stages, qEEG measurements were taken through 10 minutes (5 minutes with eyes open and 5 minutes with closed eyes) from 5 minutes after the beginning of the stage. In the second stage, the qEEG measurements were taken for 20 minutes with eyes closed. During 1, 2, and 3 stages, the 24-hour Holter monitoring was measured and HRV evaluated at each stage. The blood pressure and pulse were measured before and after the second stage. the Korean version of positive affect negative affect schedule (K-PANAS), the core seven emotions inventory-short form (CSEI-SF), and confirmation abnormal reaction.After the clinical trial, at third stage, subjects filled the Five Facet Mindfulness Questionnaire Short Scale (FFMQ-S),2.9.4,29 It is a method to increase inner strength by examining the uncritical and nonjudging aspects of thoughts that arise from “deep inside,” while remaining at the bottom of consciousness. The resource or stress mindfulness guideline script will follow the M&L Psychotherapy Manual, and the Meditation Guide will be directed by trained mentors trained by the M&L Psychotherapist course. It should be noted that the drug injections or physician treatment that affect EEG and heart during clinical trials are prohibited.Mindfulness is awareness training that observes what is happening in this moment as it is.2.9.5Resource mindfulness is to experience a safe and comfortable state by recalling the positive nourishment (resource) inside subject within the mindfulness state2.9.6Stress mindfulness is to experience emotions, feelings, memories, thoughts, and so on occurring within me when I recall a difficult situation inducing stress in the state of mindfulness.2.102.10.1 The reference electrode will be located between Fz and Cz; the amplifier will be a Mitsar-EEG 201 machine . Artifacts of the recorded EEG, modified automatically, will be manually removed by the qEEG expert for a reliability measurement of 0.9 or better. Spectral analysis, coherence, and Low Resolution Brain Electromagnetic Tomography analysis will be performed with WinEEG for records with artifact-free EEG segments >2 minutes and split-half reliability >95%. Spectral analysis will use linked-ears reference montage and local average (Laplacian) montage.,33 Linked-ears reference montage will be used as a general criterion; local average (Laplacian) montage can emphasize localized areas and minimize the overall effect of drugs on the brain. The absolute power and relative power will be calculated as delta (0.5–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), and beta (12–20 Hz), respectively, using the absolute power and relative power. Neuro-guide will be used as the basis for all analyses; EEG analysis will be conducted by BCN, an expert KMD. In addition, the EEG results will be analyzed by KMD and CP after mentoring by a neuro feedback supervisor (BCN) and biofeedback specialist on Applied Psychophysiology in the United States.The EEG of the subjects will be measured in a comfortable, quiet, cool room, wearing an electro-cap  with 21 surface electrodes placed in an international 10/20 system, for 5 minutes each in open-eye and closed-eye states. All electrode impedance will be less than 5 KΩ, based on the method of Ferree et al.2.10.2 This allows quantitative measurement of the activity of the autonomic nervous system, is easily applicable, and is noninvasive to the subjects. In addition, it can continuously monitor the electrical activity of the heart to understand the inter-relationship of rhythm disorders, such as dizziness, chest pain, syncope, palpitations, and tachycardia, and to evaluate the mechanisms of arrhythmia, abnormal blood dynamics, and rhythm disorders. Therefore, in clinical practice, 24-hour Holter monitoring is a widely used method. The spectral density value  is calculated for the low-frequency component (0.04–0.15 Hz) and the high-frequency component (0.15–0.4 Hz) in frequency domain analysis . Then, the low-to-high frequency ratio (LF/HF) of the low-frequency spectrum is analyzed; it is compared with mean NN , SDNN , pNN50 , and rMSSD  in the time-domain analysis. Low-frequency domain values among indicators in the frequency domain represent the activity of the sympathetic nervous system. High-frequency domain values represent the activity of parasympathetic nerves. SDNN, rMSSD, and pNN50 are indicators of time domain that are used as indicators of the vagus nerve dominance pattern in the heart. In addition, active blood pressure monitoring can observe changes in blood pressure by simultaneously observing systolic and diastolic blood pressures before and after intervention, such as meditation. Biochemical markers such as insulin, fasting blood glucose and lipid levels, and changes in insulin resistance and blood lipid levels can be used to assess the associations of cardiovascular risk factors with biomarkers. The measurement and flow chart is Fig. Heart rate variability is most commonly used to observe changes in the autonomic nervous system response.2.10.3 hospital anxiety and depression scale (HADS), psychosocial wellbeing index short form (PWI-SF), KSRI-F, FFMQ-S, K-PANAS, and CSEI-SF. For the clinical trial, within 10 minutes before the start of phase 3, the subjects will complete the FFMQ-S, K-PANAS, and CSEI-SF questionnaires, and Confirmation abnormal reaction.Before the clinical trial, the subjects will complete questionnaires such as the constitutional diagnosis questionnaire, Korea Sasang Constitutional Diagnostic Questionnaire-15 (KS-15),2.11 chest radiograph, electrocardiogram, clinical pathology , and infectious disease test by KMD and CP at the screening visit will be conducted by KMD or CP. physicians with ≥5 years of clinical experience will oversee the clinical evaluations.Physical examinations will be performed, and vital signs and adverse events will be checked at every visit. To examine the safety of meditation, the KS-15,During the clinical trial, any adverse event will be recorded and assessed in case report form (CRF). It will be calculated to the adverse event occurrence ratio. Adverse events associated with the meditation intervention will be monitored and appropriately handled by KMD and CP.2.12The CRC will collect data on a paper CRF. Records including medical records, questionnaires, consent forms, and other clinical trial relevant papers will be stored at each site in a locked cabinet or a password-protected computer that can be accessed only by an authorized individual and kept confidential, even when the results of the clinical trial are published. However, quester, monitor, and inspectors related to this clinical trial can view each subject's records for the purpose of monitoring and checking this clinical trial and management of the subject's progress. Additionally, all documents related to this clinical trial, such as case histories, will be recorded and distinguished by using each subject's identification code , but not by using any subject's name. After completion of the outcome report, the research will be kept for 5 years from the end of the clinical trial.2.13,38 using the G∗power program, the total effect size was set at 1.0, and the total number of samples in the 90% confidence interval (CI) was set at 46 subjects. Considering a dropout rate of 10%, 50 participants must be recruited to collect sufficient data for statistical analysis and interpretation.Based on the clinical trial study, the number of subjects was calculated as a minimum of 25 subjects each in the test and control groups, considering a 10% dropout rate. Based on previous studies,2.14 and Wilcoxon matched-pair signed-ranks tests will be performed, according to the test group (RM) and the control group (SM). Third, a verification of differences will be performed between qEEG, 24-hour Holter monitoring, FFMQ-S, CSEI-SF, and K-PANAS, according to the baseline test and control groups. Finally, a nonparametric Spearman correlation analysis will be conducted on the basis of the quantitative brain wave (qEEG), 24-hour Holter monitoring, FFMQ-S, CSEI-SF, and K-PANAS scales.To analyze the results of this clinical trial, the statistical software program SPSS 23.0 will be used to verify the homogeneity of each subject. The specific statistical analysis procedure is as follows. First, descriptive analysis  will be performed on the measured variables. Second, compared with baseline, nonparametric Wilcoxon sign2.15https://cris.nih.go.kr) The clinical trial registration number is KCT0003012. The final protocol version is 2.3 and dated July 21, 2018. A KMD in Wonkwang University Sanbon Hospital will ask participants who have decided to voluntarily enroll in the study to submit written consent. All data obtained from the subjects will be secured. Hard copies will be stored in double-locked locations in the laboratory of the hospital, and soft copies will be saved in memory devices not connected to the internet, also stored in double-locked locations. The corresponding author will have access to the final dataset. All subjects will be respected and protected, in accordance with the Declaration of Helsinki, and related laws and regulations. The results of this study will be published in a peer-reviewed journal.This study was approved by Wonkwang University Sanbon Hospital (WMCSB 201802-09). The protocol for this study has been registered at the Clinical Research Information Service (CRIS; 3This protocol was developed to analyze the relationship between brain and heart through RM and SM. There are some limitations to this present study. First, the participating institutions do not represent all clinical institutions in Korea, because this is limited to single institution. Second, because the participant age in this study is limited to the younger generation, it is not possible to generalize, with respect to age-related outcomes. Third, this study may exhibit difficulty in acquiring all of each subject's personal information because the measurement and intervention of the project is performed in 1 day.However, the data obtained in this study relating to the brain and heart can be used as basic data and reference data for future brain–heart research. In addition, we will expand the potential impact of oriental medical technology evaluation as evidence-based medicine, establish a scientific basis for clinical trials theory based on clinical data, generate a clinical model and quantitative index for the evaluation of meditation therapy, and identify effects of meditation therapy. Finally, this study will be the first to scientifically measure and analyze the brain–heart relationship in Korea. Therefore, the results of this study will help to gain information and build medical systems for enhanced medical intervention in all diseases that are related to brain and heart.3.1This trial is currently recruiting participants. Recruitment began on July 23, 2018. We expect the recruitment phase to be complete by October 31, 2018.Conceptualization: Moon Joo Cheong, Sung Eun Son, Hyung Won Kang, Kwang-Ho Bae, Yeonseok Kang.Data curation: Moon Joo Cheong, Hyung Won Kang.Formal analysis: Moon Joo Cheong, Hyung Won Kang.Funding acquisition: Hyung Won Kang.Investigation: Sung Eun Son, Youngseop Lee, Eun Mi Lee, Go-Eun Lee, Joo-Hee Seo, Hee-Wook Weon, Ji-Yoon Lee, Yeoung-Su Lyu.Methodology: Moon Joo Cheong, Sung Eun Son, Hyung Won Kang.Project administration: Hyung Won Kang.Resources: Youngseop Lee, Kwang-Ho Bae, Yeonseok Kang.Supervision: Hyung Won Kang.Writing – original draft: Moon Joo Cheong, Sung Eun Son, Hyung Won Kang.Writing – review & editing: Moon Joo Cheong, Hyung Won Kang.Hyung Won Kang orcid: 0000-0001-6497-0100.


High body mass index (BMI) is associated with development of hematological malignancies (HMs). However, although BMI is a well-established measurement of excess weight, it does not fully reflect body composition and can sometimes misclassify individuals. This study aimed at investigating what body composition measurements had highest association with development of HM. Body composition measurements on 27,557 individuals recorded by healthcare professionals as part of the Malmö Diet and Cancer study conducted in Sweden between 1991–1996 were matched with data from national registers on cancer incidence and causes of death. Cox regression models adjusted for age and sex were used to test the association between one standard deviation increments in body composition measurements and risk of HM. During a median follow-up of 20 years, 564 persons developed an HM. Several body composition measurements were associated with risk of developing an HM, but the strongest association was found for multiple myeloma (MM). Waist circumference  and waist-hip ratio  had higher risk estimates than BMI  for MM. In conclusion, our study shows that measurements of abdominal adiposity better predict the risk of developing HM, particularly MM, compared to BMI. Hematological malignancy (HM) is a common cause of morbidity and mortality, and includes neoplasia of both myeloid and lymphoid origin such as leukemia, lymphoma and plasma cell diseases. A slight incline in the incidence of several HMs, including non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), has been noted during the last decades. There iExcess body weight is popularly recorded as body mass index (BMI). Most of the previous evidence on the association between a high BMI and risk of HM comes from self-reported data on weight, height or BMI, which is known to be prone to recollection and misclassification biases, 11. AlsThe aim of this study was to investigate what body composition measurements that best predict development of HM, using a population-based cohort study where body measurements were objectively documented by health care professional and not self-reported by the study subjects. We also aimed at addressing the relationship between these measurements and specific HMs such as leukemia, lymphoma and MM.The present study is based on data from the EPIC cohort study, part ofth, 2014. The study followed the ethical guidelines in the Helsinki declaration. The ethics committee at Lund University approved the study (LU 51/90), and all participants provided informed consent.All Swedish citizens are assigned a personal identity number at birth. This alBMI was calculated as weight (kg) divided by the square of the height (m2). Waist circumference (WC) was defined as the circumference (cm) between the lowest rib margin and iliac crest, and hip circumference (cm) as the largest circumference between waist and thighs. Waist-hip ratio (WHR) was defined as the ratio of circumference of waist to hip. Waist-to-height ratio (WHtR) was defined as the WC divided by height, and waist-to-hip-to-height ratio (WHHR) was defined as the WHR divided by height. The A Body Shape Index (ABSI) was defined as WC/((BMI(2/3) x height(1/2)), myeloid malignancies  and lymphoid malignancies , or the corresponding ICD 7–9 codes . For subCox regression models were used to test the different anthropometric measurements as predictors of all HMs and separately for MM, myeloid and lymphoid malignancies. One crude and one adjusted model were calculated per anthropometric measurements. Covariates in the multivariate analysis were selected a priori, and included age and sex. Also, we evaluated a number of other covariates for inclusion in the multivariate model including alcohol consumption, smoking status, higher education and physical activity but as neither of these changed the estimates by more than 10%, giving no indication of confounding, these were not included in further analysis. In addition, a multivariate cubic regression spline model adjusted for age and sex with three degrees of freedom and an alpha-level of 0.05 was calculated per measure to test for linearity.2, between 18.5–25 kg/m2, between 25–30 kg/m2 and above 30 kg/m2. For WC results were categorized as above or below the defined cut-off stratified on sex (>94 cm for men and >80 cm for women). The cut-off for WHR was defined as 0.90 for men and 0.80 for women.Harrell’s C-statistics were useTime of follow-up began at recruitment and ended at the time of first diagnosis of HM, death, emigration or end of follow-up . Persons that died during the follow-up from other causes than HM were censored. Emigrants were considered lost to follow-up but contributed with follow-up time until the date of emigration. As a sensitivity analysis, we excluded all cases with a diagnosis of any HM within one year after baseline.2. The majority (88%) were born in Sweden and about one third (28.2%) were current smokers. Almost half (46.7%) of women and 62.4% of men were overweight as defined by BMI ≥25 kg/m2. Baseline data for the entire cohort stratified on sex  is presented in At baseline, there were 28,098 persons of whom 481 persons were excluded from the analyses because of missing data on body composition measurements or covariates. Of the 27,617 persons with complete data, 60 cases had been diagnosed with an HM prior to baseline and were therefore excluded. In the final cohort of 27,557 individuals, there were 16,750 women (60.8%) and 10,807 men (39.2%). Mean age was 58.1 years and mean BMI was 25.7 kg/mThe cohort was followed for a median time of 19.8 years , corresponding to 507,063 person-years. In total, 7,968 persons (29.2%) died and 249 persons (0.9%) emigrated. In all, 564 persons (2.1%) developed an HM, including 300 women (1.8%) and 264 men , and 11 persons developed two HMs. Of these in total 575 cases there were 107 cases of MM, 129 cases of myeloid malignancies  and 299 cases of non-Hodgkin lymphoma (NHL) (Hodgkin and T cell lymphoma were excluded) for subtype analysis . In addiIn multivariate analysis, the variables that best predicted development of any HM were WC and ABSI, both based on size of hazard ratio and on C-statistics . None of the other measurements evaluated in this study, including BMI, WHR, WHHR, WHtR, and BFP, showed significant associations with risk of developing HM. The results are presented in Next, we conducted a sub-analysis of all individuals with HM that could be grouped into myeloid malignancies, NHL or MM. This analysis revealed that the risk of developing MM was associated with waist measurements  , while n2 . However, when further dividing BMI into groups of those with BMI <18.5, 25–29.9 and >30 kg/m2 and compared that to the reference group with BMI of 18.5–24.9 kg/m2 we identified that individuals with BMI >30 kg/m2 had a statistically significant risk of developing MM  while persons with a BMI between 25–30 did not , standardized WHR was significantly associated with MM  while standardized BMI was not .In contrast to several previous reports, we did not observe a significantly increased risk of developing MM among individuals with BMI ≥25 kg/m did not . HoweverExcluding cases who received a diagnosis of any HM up to one year after baseline (n = 27) did not yield any significant differences in the estimates (Data not shown).High BMI has been linked to increased risk of cancer, including for most HMs, 25. How2 have higher risk than those with BMI of 25–29.9 kg/m2 [2).A plethora of published studies support a relationship between elevated BMI and risk of developing HMs. HoweverThe mechanism behind excess body weight and increased risk of cancer, including HMs, remains to be elucidated. Studies have linked increased glucose levels to higher risk of developing lymphoma and MM, 34 and Our study has several advantages over most studies published so far as body composition measurements in this study of 27,557 individuals followed for 20 years were recorded by health care professionals using standardized methods and calibrated instruments. Also, our study sample came from a population-based cohort, reducing selection bias. Moreover, as there are validated, population-based registers of high quality in Sweden and low rate of emigration, we were able to follow-up the absolute majority of individuals enrolled. Furthermore, the good health status of the Swedish population reduces the rate of potential risk factors that could bias our results. Hence, our cohort was homogenous with relatively few confounders and complete with only a few missing data points at the end of study. Nevertheless, it should be noted that this study, like for many other studies that assess body weight and risk of developing HM, is relatively small which potentially limits the power when analyzing HM subtypes. Despite this, we found an association between body composition measurements and risk of developing MM, while this was not found for the larger cohort of NHL. The latter may indicate that body composition measurements are stronger predictors for MM or that they are not relevant for the risk of developing NHL, but might also reflect that NHL is a heterogenous group of malignancies with different risk factors and that anthtropometric measurements might be related to some but not all NHLs.Changes in the respective body composition measurements may have occurred over the study period, which we did not have data on. These factors limited our ability to in detail investigate the association between body composition measurements and risk of developing HM. What time point in life and the duration an individual need to have excess body fat also remain unclear. Data from Maskarinec et al., where body weight at 21 years of age was shown to better predict the risk of developing NHL compared to weight at inclusion of a prospective study later in life, indicatBased on our data, we propose that measurements that take abdominal adiposity into account better predict the risk of developing an hematological malignancy, especially multiple myeloma compared to BMI.S1 FigFlow-chart on the total number of cases enrolled on the study and the number of, and reasons for, excluding enrolled cases from final analyses.(PDF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(a) Hazard ratios for development of any lymphoid malignancy in 27,557 Swedish men and women followed for a median time of 19.8 years. (b) Hazard ratios for development of any myeloid malignancy in 27,557 Swedish men and women followed for a median time of 19.8 years.(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.


To evaluate the clinical therapeutic efficacy and safety of modified Erzhi granules (MEG) in patients with menopause-related vulvovaginal atrophy (VVA).2), follicle stimulating hormone (FSH), pelvic ultrasound, breast ultrasound, and other safety parameters were measured, recording adverse events. This randomized, double-blind, placebo-controlled study comprised two groups, including the treatment and control groups. Patients receive MEG and placebo for 12 weeks, respectively. Vaginal health score (VHS), vaginitis score, vaginal maturation index (VMI), female sexual function index (FSFI), and modified Kupperman Index (modified KI) were used as efficacy endpoints and assessed at baseline, 4, 8, and 12 weeks during administration, and 4 weeks after drug withdrawal. At baseline and 12 weeks, serum estradiol (Ep>0.05). Serum E2 and FSH levels, endometrial thickness, and breast thickness in all patients were within the normal ranges before and after treatment, with no serious adverse reactions observed. At 12 weeks, VHS, percentage of superficial cells in the vaginal epithelium and FSFI were significantly increased, while vaginitis score, percentage of basal cells in the vaginal epithelium, and modified KI were significantly decreased in comparison with baseline and control group ; these differences persisted for up to 4 weeks after drug withdrawal. The placebo group showed no significant change during treatment compared with baseline values ( MEG significantly alleviates menopause-related vulvovaginal atrophy, with no overt adverse effects on the endometrium, breast, hepatic, and renal functions. Vulvovaginal atrophy (VVA), which often occurs 2-5 years after menopause , is a coAnother study in the United States found that VVA not only causes local discomfort in the vagina, but also significantly affects the patient's sexual function, sleep pattern, and personality . A survep=0.006) and adversely affects vaginal epithelial cells and flora [p=0.001), resulting in further aggravation of long-term symptoms [Hormone replacement is currently considered the most effective treatment . Meanwhind flora , 11. Morsymptoms . The effTraditional Chinese medicine suggests that the relationship between VVA occurrence and the kidney is the closest; the syndrome of Yin deficiency of kidney is mostly in the perimenopausal and early menopausal periods; with the prolongation of menopausal time, the innate essence is further exhausted, Yang cannot support Yin, and Yin impairment affects Yang, leading to kidney Yang debilitation. The main clinical manifestations are cold, declined sexual desire, soreness and weakness of waist and knees, vaginal dryness, and dysuria.Our previous studies , 14 foun Fructus Ligustri Lucidi, Eclipta, Herba Cistanches, Cynomorium Songaricum, and Cortex Phellodendri. A randomized, double-blind, placebo parallel control trial was conducted to assess the efficacy and safety of MEG on menopause-related VVA by observing changes in patient's VHS, vaginitis score, VMI, FSFI, and modified KI.The MEG is a compound preparation based on our previous clinical and pharmacological studies and includesChiCTR-IOR-16009312). All the patients included provided signed informed consent before enrolment.This study was approved by the ethics committee of the Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine and registered in the Chinese Clinical Trial Registry  of subjects 01 to 88 was obtained with the SPSS software, which generated a random coding table.This was two level of blind design. The first level was processing a code corresponding to the groups (group A or B); the second level was the drug corresponding to the processing code. All the drug encoding process was written in the form of a document (blind code record) by a code-blinded person, which was kept as one of the clinical trial documents. The contents included preparation of drugs, drug packaging, prescription, storage requirements, drug delivery method, generation of random processing, drug packaging box for each subject, emergency letter, preservation of treatment code, and regulation of unblinding. The two levels of treatment codes were sealed separately and conserved by the Experimental Center and Research Department of the Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine. There was an emergency letter corresponding to each coded trial drug for unblinding in case of emergency.The subjects were eligible patients treated from November 2016 to April 2017 at the gynecologic outpatient clinic of the Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine.2) ≤20 pg/ml; ⑤ signed informed content. Exclusion criteria were: ① a history of malignant tumor of the reproductive system or breast cancer; ② unexplained uterine bleeding; ③ combined with other severe primary diseases or severely impaired hepatic or renal function; ④ abnormal cervical smear; ⑤ endometrium thickness by vaginal ultrasound >5 mm; ⑥ a history of antidepressant drugs, antipsychotic drugs or drugs containing other components in the past 3 months.Inclusion criteria were ① age from 45 to 65 years, with menopause time ≥1 year; ② at least one of VVA symptoms, such as vaginal dryness, vaginal or genital itching, painful sexual intercourse and so on; ③ percentage of superficial cells in the vaginal epithelium ≤10% and vaginal pH>5; ④ follicle stimulating hormone (FSH) ≥40 mIU/ml and estradiol  for 12 consecutive weeks. The placebo group received placebo  as in the treatment group. All trial drugs, including treatment and placebo types, were provided by Huarun 39 medical Limited through Share Ltd. They were packaged according to the requirements of blinding and met quality requirements.(1) Efficacy Indexes. The primary efficacy measure in this trial was the VHS [ the VHS , which iSecondary efficacy parameters included vaginitis score, VMI, FSFI, and modified KI.Vaginitis score  was baseFor assessing the VMI , the vagThe FSFI  includedBased on the original Kupperman scale, two items were added to the modified KI , includi(2) Safety Parameters. Safety assessments included routine blood test, urine routine test, liver function test, renal function test, serum E2 and FSH level assessment, electrocardiography, breast ultrasound and pelvic ultrasound. Meanwhile, adverse events were recorded.Efficacy indexes were evaluated at baseline, and at 4, 8, and 12 weeks during drug administration, as well as 4 weeks after drug withdrawal. Safety parameters, including laboratory examination and ultrasound, were obtained before group assignment and at 12 weeks during drug administration. Adverse events were observed during the whole follow-up period.The SPSS 23.0 software was used for statistical analysis. Normality and homogeneity of variance were assessed for VHS, vaginitis score, VMI, and modified KI. Normally distributed data were assessed by independent two-sample t-test, with paired sample t-test used for within-group comparison before and after treatment. For nonnormally distributed parameters, the nonparametric test was used for comparing groups before and after treatment.A total of 88 patients were enrolled in this study, including 1 case of mistaken identity, 1 without medication record, 11 lost to follow up and 75 cases who completed treatment . All the enrolled patients met the set inclusion criteria. There was no statistical differences in baseline indexes, including demographic data  and efficacy indexes . The baseline parameters of the two groups were comparable .p<0.05). VHS in the placebo group after treatment and during the follow-up period were not statistically different from baseline values (p>0.05). During the medication period and at 4 weeks after drug withdrawal, VHS in the treatment group were markedly increased in comparison with those of the placebo group (p<0.05).All patients were followed up during the medication period and at 4 weeks after drug withdrawal. VHS in the treatment group were significantly increased in comparison with baseline values (p<0.05). After 4 weeks of treatment, the vaginal elasticity score in the treatment group was increased in comparison with the baseline value, but the difference was not statistically significant (p>0.05). After 8 and 12 weeks of treatment as well as at 4 weeks after drug withdrawal, vaginal elasticity scores in the treatment group were significantly increased in comparison with baseline values (p<0.05). During the medication period and follow-up, vaginal elasticity, moisture, pH, mucous, and discharge scores in the placebo group were not statistically different with those at baseline (p>0.05).During the medication period and at 4 weeks after drug withdrawal, vaginal moisture, pH, mucous, and discharge scores in the treatment group were significantly increased in comparison with baseline values (p<0.05). After 4 and 8 weeks of treatment, vaginal elasticity and vaginal pH in the treatment group were increased in comparison with those of the placebo group, but the differences were not statistically significant (p>0.05). After 12 weeks of treatment and at 4 weeks after drug withdrawal, vaginal elasticity and pH in the treatment group were significantly higher than those of the placebo group (p<0.05)  p<0.05). Vaginitis scores in the placebo group after medication and during the follow-up period were not statistically different from baseline values (p>0.05). Meanwhile, vaginitis scores in the treatment group during the medication period and 4 weeks after drug withdrawal were starkly decreased in comparison with those of the placebo group (p<0.05).During the medication period and 4 weeks after drug withdrawal, vaginitis scores in the treatment group were significantly decreased in comparison with baseline values ( p<0.05). After 4 and 8 weeks of treatment, painful sexual intercourse scores in the treatment group were decreased in comparison with baseline values, but the differences were not statistically significant (p>0.05); after 12 weeks of treatment and 4 weeks after drug withdrawal, painful sexual intercourse scores in the treatment group were significantly decreased in comparison with baseline values (p<0.05). Vaginal pain, painful sexual intercourse, vaginal itching, and burning scores in the placebo group in the medication period and during follow-up were not statistically different from those at baseline (p>0.05). In the medication period and 4 weeks after medicine withdrawal, vaginal pain and burning scores in the treatment group were markedly decreased in comparison with those of the placebo group (p>0.05). After 4 weeks of treatment, vaginal itching scores in the treatment group were decreased in comparison with those of the placebo group, but the difference was not statistically significant (p>0.05). After 8 and 12 weeks of treatment as well as 4 weeks after drug withdrawal, vaginal itching scores in the treatment group were significantly lower than those of the placebo group (p<0.05). After 4 and 8 weeks of treatment, respectively, painful sexual intercourse scores in the treatment group were decreased in comparison with those of the placebo group, but the differences were not statistically significant (p>0.05). After 12 weeks of treatment, painful sexual intercourse scores in the treatment group were significantly lower than those of the placebo group (p<0.05). At 4 weeks after drug withdrawal, there were no statistical differences in painful sexual intercourse scores between the treatment and placebo groups (p>0.05)  p<0.05). In the medication period and during follow-up, the percentages of superficial and basal cells in the vaginal epithelium were not statistically different from baseline values in the placebo group (p>0.05). However, 4 weeks after drug withdrawal, the percentages of basal cells in the vaginal epithelium in the placebo group were significantly increased in comparison with the baseline value (p<0.05). In the medication period and 4 weeks after drug withdrawal, the percentages of superficial cells in the vaginal epithelium in the treatment group were starkly increased while those of basal cells were significantly decreased, in comparison with those of the placebo group (p<0.05)  .p<0.05). FSFI in the placebo group in the medication period and during follow-up were not statistically different from those at baseline (p>0.05). In the medication period and 4 weeks after drug withdrawal, there was no significant difference in FSFI between the treatment and placebo groups (p<0.05).During the medication period and 4 weeks after drug withdrawal, the FSFI in the treatment group was significantly increased in comparison with the baseline value (p<0.05). Satisfaction scores in the treatment group were significantly increased in the medication period compared with baseline values (p<0.05) but not at 4 weeks after drug withdrawal (p>0.05). After 12 weeks of treatment and 4 weeks after drug withdrawal, painful sexual intercourse scores in the treatment group were starkly increased in comparison with baseline values (p<0.05). In the medication and follow-up periods, desire, subjective arousal ability and orgasm scores in the treatment group were not statistically different from baseline values (p>0.05). The six domains of the FSFI in the placebo group in the medication and follow-up periods were not statistically different from baseline values (p>0.05). In the medication period and during follow-up,no significant differences in the 6 domains of the FSFI between the treatment and placebo groups (p>0.05)  .p<0.05). Modified KI in the placebo group in the medication and follow-up periods were not statistically significant from baseline values (p>0.05). After 4 weeks of treatment, modified KI in the treatment group were decreased in comparison with those of the placebo group, but the difference was not statistically significant (p>0.05). After 8 and 12 weeks of treatment, as well as 4 weeks after drug withdrawal, modified KI in the treatment group were significantly decreased in comparison with those of the placebo group (p< 0.05).In the medication period and 4 weeks after drug withdrawal, modified KI in the treatment group were significantly decreased in comparison with baseline values (p<0.05). After 4 weeks of treatment, arthralgia and myalgia scores in the treatment group were decreased in comparison with baseline values, but the difference was not statistically significant (p>0.05). After 8 and 12 weeks of treatment, as well as 4 weeks after drug withdrawal, these scores were significantly decreased in the treatment group in comparison with baseline values (p<0.05). In the medication period, paresthesia, nervousness, melancholia, vertigo, headache, heart palpitation, sexual complaints scores in the treatment group were not statistically different from those at baseline (p>0.05). In the medication and follow-up period, modified KI in the placebo group were not statistically different from baseline values (p>0.05). In the medication period, scores for hot flashes, sweating, insomnia and fatigue in the treatment group were significantly decreased in comparison with those of the placebo group (p<0.05). At 4 weeks after drug withdrawal, fatigue scores in the treatment group remained significantly lower than those of the placebo group (p<0.05); however, no significant differences in scores for hot flashes, sweating and insomnia were found between the treatment and placebo groups (p>0.05). After 4 and 8 weeks of treatment, paresthesia scores in the treatment group were decreased in comparison with those of the placebo group, but the differences were not statistically significant (p>0.05). After 12 weeks of treatment and 4 weeks after drug withdrawal, paresthesia scores in the treatment group were significantly lower than those of the placebo group (p<0.05). After 4 weeks of treatment, bone and joint pain scores in the treatment group were decreased in comparison with those of the placebo group, but the difference was not statistically significant (p>0.05). After 8 and 12 weeks of treatment as well as 4 weeks after drug withdrawal, Arthralgia and myalgia scores in the treatment group were significantly lower than those of the placebo group (p<0.05). In the medication and follow-up periods, there was no statistical difference in modified KI between the treatment and placebo groups  and placebo  groups, respectively; both cases were mild, and symptoms were relieved by taking medicine after a meal. No vaginal bleeding was found in this study. There was no case of withdrawal due to adverse drug reactions .VVA is a common and frequently encountered disease in menopausal women. Unlike the symptoms of hot flashes, sweating, depression and anxiety, VVA is not relieved with time, and seriously affects the patients' quality of life.From the Chinese medicine perspective, menopausal symptoms are thought to be associated with a decline in kidney Yin or Yang or both. Kidney is the congenital life basis and closely related to reproduction physiological activities. TCM believes that the menstruation, pregnancy, delivery, and lactation in woman's life are all supported by kidney Yin. Excessive consumption of kidney Yin such as irregular periods, repeated pregnancy, and long time lactation will lead to kidney Yin deficiency. It is typically characterized by syndrome such as vaginal dryness, hot flushes and night sweats, dizziness, and insomnia. According to TCM theory, Yin and Yang grow together and nourish each other. It will be accompanied by kidney Yang deficiency as kidney Yin is further exhausted with stages of menopause. Women may present with symptoms such as vaginal burning and itching, aversion to cold, urine incontinence, and loose motions. Eclipta, Fructus Ligustri Lucidi, Cynomorium Songaricum, Herba Cistanches, and Cortex Phellodendri. The efficacy of Fructus Ligustri Lucidi and Eclipta is nourishing kidney Yin, so as to moisten the vagina. Herba Cistanches and Cynomorium Songaricum are often used for warming kidney Yang. Cortex Phellodendri has the function of clearing heat, relieving toxicity and diminishing inflammations, and it has antipruritic properties in patients with vulvovaginal atrophy. Therefore, the combination of these herbs is very effective for vulvovaginal atrophy due to deficiency of kidney Yin and Yang which is accompanied with systemic symptoms.MEG are composed of2 soft capsule (10 μg), vaginal dryness and itching scores decrease by 1.5 and 0.8 points, respectively; meanwhile, the percentages of superficial and basal cells in the vaginal epithelium increased by 17% and decreased by 44%, respectively [The current study showed that MEG obviously improved the symptoms of reduced vaginal discharge, pale mucous membrane and reduced vaginal elasticity, relieved vaginal pain, painful sexual intercourse, and vaginal itching and burning, while increasing the percentage of epithelial cells and decreasing that of basal cells in the vaginal epithelium. At 12 weeks of medication with MEG, vaginal dryness and itching scores were decreased by 1.18 and 1.01 points, respectively; the percentages of superficial and basal cells in the vaginal epithelium increased by 4.82% and decreased by 21.38%, respectively. Previous studies showed that 12 weeks after treatment with vaginal Eectively ; at 12 wectively . The abo Cynomorium Songaricum in rats can alleviate the effect of overexercise on serum testosterone and corticosterone, promote the synthesis of protein, inhibit breakdown of amino acid and protein, and increase hemoglobin content and glycogen stores. These effects may help improve insomnia, fatigue, and joint pain in postmenopausal women. Moreover, MEG did not affect serum E2 and FSH levels, and no damage to hepatic and renal function or serious adverse reactions occurred.Cases with VVA are often accompanied by other menopausal symptoms. A study showed that vaginal dryness is significantly related to the occurrence of hot flashes  . The durIn the present study, recurrence in patients was followed up 4 weeks after drug withdrawal, and local manifestations in the vagina , atrophy symptoms  and systemic symptoms  remained different from those of the placebo group. However, there are no reliable data about recurrence after withdrawal of other drugs such as Ospemifene, DHEA, and local estrogens. Fructus Ligustri Lucidi, Eclipta, Herba Cistanches, and Cynomorium Songaricum, have obvious estrogenic effects. There are terpenes, flavonoids, and coumaric esters in Fructus Ligustri Lucidi and Eclipta, with structures similar to that of estradiol [α, and ERβ amounts in vaginal tissues, and selectively upregulated ERβ in uterine tissues; moreover, Er Zhi Wan does not significantly affect ERα levels and serum estrogen content in ovariectomized rats. Wang [α and ERβ, increase the luciferase activity of ERE and play estrogenic roles. In addition, according to the upregulation of both components in the luciferase activity of ERE, selectivity of acteoside for ERα and ERβ is not significant, and echinacoside has higher affinity to ERβ. The regulatory effects of these selective estrogen receptors might be the molecular mechanism by which MEG effectively improved the symptoms of VVA, increasing VMI, and relieve the symptoms of hot flashes and sweating without endometrial thickening and changing serum hormone levels [Modern pharmacology found that the constituents of MEG, such asstradiol –31; theystradiol  found thts. Wang  found the levels .Here, a randomized, double-blind, placebo-controlled clinical trial was firstly conducted for the traditional Chinese medicine treating VVA. VHS, vaginitis score, and VMI are all commonly used parameters for VVA evaluation worldwide. Vaginal atrophy was comprehensively evaluated from the objective and subjective aspects; the FSFI has been the most frequently used female function scale in the past few decades, with good evaluation validity, credibility, and reliability . The modThere were limitations in this study. First, only related symptoms were assessed in patients 4 weeks after drug withdrawal, and the duration of curative effect was not determined. Therefore, the follow-up time should be increased to further characterize MEG. Secondly, the sample size was relatively small, and subgroup analysis was not performed on age and symptom severity; in addition, efficacy indexes, such as sexual function dimensions in some females, were not consistent with those of the placebo group and before medication. Therefore, sample size should be further expanded. Finally, this study did not include a positive drug group. Therefore, similar trials are underway in our group to further compare the clinical efficacy of MEG with that of local estrogens in the treatment of VVA.(1) Use of MEG for 4 weeks could obviously improve vaginal elasticity and vaginal moisture, increase vaginal discharge, decrease vaginal pH, obviously relieve vaginal pain, itching, and burning, and improve vaginal health in patients with menopause-related VVA. Moreover, the curative effects persisted 4 weeks after drug withdrawal.(2) Use of MEG for 8 weeks could obviously relieve painful sexual intercourse, and the curative effects were maintained after drug withdrawal; however, there was no obvious effect on sexual desire and subjective sexual arousal after administration of MEG.(3) With the prolongation of medication time, MEG could significantly increase the percentage of superficial cells in the vaginal epithelium, while decreasing that of basal cells, without significantly altering serum estrogen levels.(4) MEG could obviously improve menopause-related systemic symptoms such as hot flashes, sweating, insomnia, fatigue, and bone and joint pain.(5) No adverse effects on the endometrium, breast, liver, and kidney were observed with continuous use of MEG for 12 weeks.


Results were similar in strata of sex, age, and education, while the risk appeared somewhat lower in never-smokers and patients with pT1–pT4 bladder carcinomas. Among individual components of the MDS, we observed inverse associations for greater consumption of legumes, vegetables, and fish. In our study, which was carried out on an Italian population, the higher adherence to the Mediterranean diet was related to a lower risk of bladder cancer.Previous studies have reported that Mediterranean diet is inversely related to the risk of several neoplasms; however, limited epidemiological data are available for bladder cancer. Thus, we examined the association between Mediterranean diet and this neoplasm in an Italian multicentric case-control study consisting of 690 bladder cancer cases and 665 controls. We assessed the adherence to the Mediterranean diet via a Mediterranean Diet Score (MDS), which represents the major characteristics of the Mediterranean diet and ranges from 0 to 9 . We derived odds ratios (ORs) of bladder cancer according to the MDS score from multiple logistic regression models, allowing for major confounding factors. The ORs of bladder cancer were 0.72  for MDS of 4–5 and 0.66  for MDS of 6–9 ( Schistosoma haematobium and other chronic bladder infections, phenacetin-containing analgesics, history of metabolic syndrome, history of diabetes, and genetic predisposition [Bladder cancer is the ninth most common neoplasm in the world, particularly in high-income countries and among men . The besposition ,7,8,9,10Diet may influence bladder carcinogenesis, since many metabolites of foods are excreted through the urinary tract, such as chlorination byproducts and arsenic in drinking tap water . In addiThe so-called Mediterranean diet—defined as the dietary pattern of populations bordering the Mediterranean area—is a plant-centered diet that is rich in olive oil, fruits, vegetables, legumes, and whole grain cereals ,18. It hn = 642, 93%). According to the 2016 World Health Organization (WHO) grading system [n = 268) were noninvasive ; 27.8% were pT1 (n = 192) and 23.0% (n = 159) were muscle-invasive ; 44.5% of cases (n = 307) were moderately or well differentiated  and 45.2% (n = 312) were undifferentiated or poorly differentiated (G3–G4).The present analyses are based on a hospital-based case–control study carried out in four Italian areas—Milan, Pordenone, Naples, and Catania—in 2003–2014 . Cases cg system , 38.8% oControls consisted of 665 subjects (561 men and 104 women), identified among patients admitted to the same hospitals for various non-neoplastic acute diseases that were not associated to tobacco smoking or alcohol drinking and not related to long-term dietary changes . Among controls, 22.1% were admitted for nontraumatic orthopedic disorders, 28.9% for traumas, 39.3% for acute surgery, and 9.8% for various other illnesses.We submitted the study protocol to the Board of Ethics of the participating hospitals, which gave their approval, and all participants provided a written informed consent.Participants’ information were collected during the hospital stay by trained interviewers using a structured questionnaire. More than 95% of eligible cases and controls agreed to participate. In particular, data concerning sociodemographic characteristics, anthropometric parameters, lifetime tobacco and alcohol consumption, occupational exposure to specific chemical substances, and personal medical history of selected diseases were registered. Specifically, dietary habits in the two years preceding diagnosis for cases or interview for controls was evaluated using a valid and reproducible food frequency questionnaire (FFQ), including 80 foods and recipes as well as different types of alcoholic beverages ,29. SubjWe evaluated the adherence to the Mediterranean diet through the score proposed by Trichopoulou et al.  based on2 test. We derived the odd ratios (ORs)—and their 95% confidence intervals (CIs)—of bladder cancer according to the MDS  and according to its individual components fitting unconditional logistic regression models, adjusting for sex, age (5-years categories), year of interview (as a continuous variable), study center, years of schooling , body mass index , tobacco smoking , nonalcoholic energy intake (based on quartiles among controls), history of cystitis, history of diabetes, and family history of bladder cancer. We selected the adjustment variables included in the models on the basis of a priori knowledge. We also estimated the ORs for 1-point increment of the score in strata of sex, age, years of schooling, tobacco smoking, and tumor characteristics. We assessed the heterogeneity across strata using likelihood ratio tests.We assessed the differences between cases and controls in terms of categories of the main covariates using the χWe estimated the proportion of bladder cancer cases that would have been avoided if all subjects were in the highest category of adherence to the Mediterranean diet  using the population attributable fraction (PAF) according to the method proposed by Bruzzi et al. . We compp = 0.80), while cases were more frequently current smokers  and reported more often a history of cystitis (p = 0.04) and diabetes (p < 0.01) compared to controls. Moreover, family history of bladder cancer (p = 0.05) and alcohol drinking (p = 0.05) tended to be more frequent in cases than controls . The OR for 1-point increment of MDS was 0.89  for MDS = 4–5 and 0.66  for MDS = 6–9 compared to the lowest category  and among patients with pT1–pT4 tumors (p-heterogeneity = 0.09). No significant heterogeneity emerged for tumor grade (p-heterogeneity = 0.30). Moreover, we estimated similar ORs in sensitivity analyses that excluded subjects with history of diabetes  or cystitis .Bladder cancer risk did not show significant heterogeneity across strata of sex, age, and education . The invWhen considering high vs. low consumption of the individual components of the MDS, we observed significant inverse associations for the intake of legumes , vegetables  and fish ; this is shown in The findings from this Italian study indicate a favorable role of adherence to the Mediterranean diet on bladder cancer. Specifically, high adherence to such dietary pattern  was associated with an almost 35% reduced risk compared to low adherence , with approximately 13% of bladder cancer cases attributable to a scanty adherence. Consistent results were observed in strata of relevant covariates; the inverse association with MDS appeared slightly, though not significantly, stronger for never-smokers and patients with pT1–pT4.Only two other studies, both of which mainly based on non-Mediterranean populations, have previously investigated this dietary pattern on bladder cancer risk ,25.Findings from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort , which iAlthough the present findings are not entirely comparable with that of the two abovementioned studies—mainly in consideration of the different populations  and the different a priori scores used to assess the adherence to the dietary pattern—epidemiological data are suggestive of a favorable role of a high adherence to the Mediterranean diet against bladder cancer risk.The role of diet on bladder carcinogenesis may be mediated by many metabolites of foods, which are excreted through the urinary tract. Previous studies—although not all—on bladder cancer have shown a protective role of high intakes of fruit and vegetables and selected nutrients related to these foods ,37. A faThe lack of information on physical activity, a recognized protective factor for bladder cancer risk , is a poIn conclusion, our investigation from Italy showed that an elevated adherence to the Mediterranean diet reduces bladder cancer risk.


Polyomaviridae, Papillomaviridae, and Herpesviridae oncoviruses on the vaginal Community State Types (CSTs) and host immune response in reproductive-age women. In our cohort, only Polyomaviridae and Papillomaviridae were detected and were associated with changes in the resident bacteria of CST I and IV (p < 0.05). Lactobacilluscrispatus increased in CST I while Prevotella timonensis and Sneathia sanguinegens increased in CST IV. Conversely, CST II and III showed an alteration of the immune response, with the decrease of Eotaxin, MCP-1, IL-7, IL-9, and IL-15 (p < 0.05), leading to reduced antiviral efficacy. An efficient viral clearance was observed only in women from CST I, dominated by Lactobacillus crispatus. Our in vivo study begins to address the knowledge gap with respect to the role of vaginal bacteria and immune response in susceptibility to oncoviral infections.The picture of dynamic interaction between oncogenic viruses and the vaginal bacteria-immune host milieu is incomplete. We evaluated the impact of  The mutualism between the vaginal mucosa and its bacterial microbiome is a key point of the physiologic condition of the female reproductive tract .Cumulative pieces of evidence have shown that, alongside bacteria, viruses are a constitutive part of the vaginal microbiome and that the virome is composed by both eukaryotic and prokaryotic viruses. As the virome study methodologies improve, eukaryotic viruses causing latent or asymptomatic infections are being recognized as the more prominent members of the vaginal microbiome, suggesting an intimate relationship with both resident bacteria and host susceptibility and immune response to viral infections .Though to date, metagenomic studies on this complex interaction are far from reaching a complete understanding, the most intriguing aspect is whether and how bacterial community may promote or inhibit viral pathogenesis . A portiThe vaginal dysbiosis of the mucosa-associated microbiota seems to represent a risk factor acting as an enhancer of the tumorigenic potential through mechanisms including mucosal barrier failure and inflammation . These eSince a persistent infection enables virus-induced tumorigenesis, we can develop new approaches for preventing and treating malignancies by characterizing the host environment by which tumor viruses achieve infection.Lactobacillus dominating the vaginal microbiota might reduce HPV-related disease burden or increase the viral clearance [Wojciech Kwasniewski et al. hypothesized that a disturbed heterogeneity of the vaginal microbiome is associated with Human Papilloma Virus (HPV)-induced carcinogenesis, identifying the vaginal dysbiosis as a putative and potentially modifiable factor for HPV . Moreovelearance .Polyomaviridae and Herpesviridae families. Despite this possible finding, current knowledge on dynamic interaction with vaginal microbiome and host immune response is scarce [The “omics” technologies allowed us to discover that several divergent oncogenic viruses promote tumorigenesis through shared host cell targets and pathways modulating the surrounding microenvironment . During s scarce ,11.Papillomavirus, Polyomavirus, and Herpesvirus oncogenic viruses with the vaginal community state types (CSTs) and local immune environments before any clinical evidence of the cellular transformation is obtained.In this study, we integrated metagenomics and immune quantitative approaches to provide, to our knowledge, the first in vivo view of the interaction of During the first two months of 2018, 90 vaginal swabs from Caucasian immunocompetent women of reproductive age (20–40) who visited the gynecological ambulatory of the IRCCS Burlo Garofolo, Trieste, Italy, for urogenital complaints, were retrospectively selected on the basis of the following exclusion criteria: pregnancy, menopause, 5–7 days after menstruation, antibiotic/probiotic therapy, oral contraceptive use or hormonal replacement therapy, smoking, endocrine diseases, history of cancer, current laboratory detection of STIs pathogens, HIV, and cervical-vaginal lesions.n = 29).After 8 months from the laboratory diagnosis, following the indications of the clinical protocol, an additional vaginal swab was collected only from women who tested positive for viral infection . The swab was suspended in 1.5 mL of TE buffer for microbiome assessment and immune factors dosage, and stored at −80 °C. ® easyMAG® system , following the manufacturer’s instructions, starting from 500 µL of sample and with an elution volume of 50 µL. All DNA samples were stored at −80 °C prior to further processing.DNA was extracted from the swabs using the NucliSENSFirstly, a 500 base pair region of the V1-V3 portion of the 16S rRNA gene was amplified and subsequently the 200 base pair region of the V3 portion was amplified as well, as described elsewhere . The V3 Quality filtering was performed using the software QIIME , version 1.9.1 . SequencPolyomaviruses , and 10 Herpesviruses  [The identification of infectious agents was performed using a highly sensitive species-specific multiplex genotyping assay, combined with multiplex polymerase chain reaction (PCR), and a bead-based Luminex technology . Multiplex type-specific PCR  used primers specific to detect the presence of 21 mucosal HPV types , 13 nd HHV8) ,16, respnd HHV8) ,18. SubsThe concentrations of 48 cytokines, chemokines, and growth factors were analyzed by a quantitative cytokine assay by means of the Bioplex Pro™ human cytokine standard 27-plex and 21-plex panels based on xMAP technology . Data were collected and analyzed using a Bio-Rad BioPlex 200 instrument equipped with Bio-Plex Manager software version 6.0 . The immunoassay data were expressed in terms of mg protein/mL estimated from Bradford protein concentration in respective samples using Bio-Rad microtiter microassay kit  and human serum albumin , as recently published .Using QIIME 1.9.1, Chao1, Observed OTUs, and Phylogenetic diversity (PD) whole tree metrics were calculated to assess the alpha diversity and compared by means of a nonparametric T-test.To highlight the differences in the microbial composition we applied a nonparametric T-test for the pairwise comparisons.p-value was observed (p < 0.05), a multiple comparison test was used to determine which groups were different.To test the differences in the immune soluble factors, GraphPad Prism  was used. Specifically, the Kruskal-Wallis one-way analysis of variance was used for comparisons between groups. When a significant The dataset supporting the conclusions of this article has been uploaded to the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) under the project number SRP152778.Lactobacillus species. Four samples provided an exception since the microbiome was characterized by a massive colonization of Bifidobacteria, classified as B group for two of them, and the remaining two, classified as Mixed CST, showed two dominant Lactobacilli at equal amounts (in one sample L. crispatus and L. gasseri and in two samples L. crispatus and L. iners).Bacterial microbiome composition was evaluated in 90 vaginal swabs through sequencing of the barcoded V3 region of the 16S rRNA gene, and the swabs were clustered into four community state types (CSTs) based on the predominant We obtained a total of 5,683,658 reads  and a total number of observed OTUs of 11,168. For the analyses, we rarefied the otu_table.biom to a depth of 5000 reads/sample, excluding four samples. The two negative controls did not produce an output after the quality filtering.Lactobacillus crispatus was 72%, while in CST II, the average relative abundance of Lactobacillus gasseri was 58%. In CST III, Lactobacillus iners was 94%, while in CST IV, G. vaginalis was 10%. L. iners (40%) and B. breve (58%) were the dominant species in Mixed and B groups, respectively.Streptococcus spp. (12%) and by Gram-negative species such as Atopobium vaginae (7%) and Escherichia fergusonii (5%), compatible with a status of dysbiosis and biofilm production. Conversely, the CST III was the most homogeneous group, showing only the 6% of bacterial species that were different from L. iners (94%), underscoring its ability to colonize the vaginal epithelium both in eubiotic and dysbiotic conditions. Indeed, the alpha diversity showed a significant decrease only for samples from CST III (p < 0.005), showing the most homogeneous bacterial composition. When viral infected CSTs were compared with the corresponding negative ones, no statistical variation was observed  dominated by observed .Ureaplasma parvum has been detected only in the CST I and CST II where, in this last group, U. parvum showed the highest rate of colonization. Moreover, Gardnerella vaginalis has been detected in all samples, but with a relative amount inversely proportional to that of Lactobacilli spp.  samples, DNA of oncogenic viruses was identified. MCPyV was the Polyomavirus most frequently detected, while the HPV genotypes identified mostly belongs to the High-Risk HPV genotypes. The highest rate of infection of this series was measured in CST III  and in CST I  than in CST IV  and CST II . HPV DNA was more frequently associated with CST IV (5/6) followed by CST III (8/28) while regarding Polyomaviruses, the highest rate of infection was recovered in CST III (3/3) and CST I (5/7).The virome analysis highlighted that a small cluster of oncogenic viruses, including iven CST . We did Polyomaviruses, specifically of JCPyV and MCPyV, as unique or co-infections in all CST groups. In detail, in CST I, 2/7 samples were infected with HPV, 1/7 with HPV/JCPyV, 1/7 with JCPyV/MCPyV and 3/7 with MCPyV. Among CST II samples, 1/3 showed HPV/MCPyV and 2/3 MCPyV. Within the CST III, 6/12 were infected with HPV, 1/12 with HPV/JCPyV, 1/12 with HPV/MCPyV, 2/12 with JCPyV and MCPyV. In CST IV, 3/6 samples were infected with HPV, 1/6 with HPV/JCPyV, 1/6 HPV/MCPyV and 1/6 with MCPyV. The overall distribution highlighted the strong presence of Bifidobacteria indicated a positive sign positive for MCPyV. No viral infections were detected in the samples defined as mixed CST.One of the two remaining samples showing a massive presence of The effect of the oncogenic viral infections on the vaginal microbial composition and/or immune environment perturbations was analyzed for each CST group and described in p < 0.05). Specifically, L. crispatus increased in infected samples from CST I, showing a high rate infection with Polyomavirus, while Prevotella timonensis and Sneathia sanguinegens increased in infected samples from CST IV, characterized by a high rate of HPV infection.Considering oncogenic viruses as a variable, we observed a significant modulation only for dominant bacteria characterizing CST I and IV samples (p < 0.05). Conversely, infected samples from CST I and CST IV did not show a significant variation of the immune basal pattern.As detailed in Samples from women who tested positive for oncogenic viruses were recovered after eight months from laboratory diagnosis for additional gynecological and microbiological evaluations, as indicated by clinical protocol. Clinical examinations showed no sign of cervical lesions.L. crispatus (5/7 samples). Conversely, persistent infections due to HPV and Polyomavirus-HPV co-infections were confirmed in CST III (9/12) and CST IV (5/6) groups, which are considered to indicate a transitional state into a dysbiotic and a dysbiotic-BV like composition, respectively.Microbiological analysis showed no residual viral DNA in 15/29 (51.7%) of the samples. To note, clearance of the virus was more frequently observed in CST I group dominated by One of the most interesting aspects of the virome world is its interaction with resident bacteria, probably influencing viral infectivity and thus the infection outcome. These events, playing a central role in shaping innate and adaptive immune defenses, are exerted during the early phase of viral entry, clinically corresponding to the asymptomatic phase of infection ,20.Despite increased attention has been focused on the complexity of vaginal microbiome and its role in women’s health, the modality of interaction between oncogenic viruses and local microenvironment is still incomplete.A crucial point is the definition of the vaginal milieu that may influence the susceptibility and clearance of oncogenic viruses in women with an immune competent system, even if recent data suggest the vaginal dysbiosis as a risk factor for viral infections .Lactobacillus spp. in orchestrating the vaginal composition and immune defense has been exploited in our study [In order to optimize the complexity of the vaginal microbial profiles, the vaginal CSTs classification based on the central role of ur study . This stLactobacillus characterizing CSTs represent a key factor in influencing the modality of vaginal defense against viral infection through their direct involvement or by the modulation of the local immune response [L. crispatus, the increase of the relative abundance of this Lactobacillus, as the main controlling infection defense mechanism, did not modify the basal immune profile. The antiviral activity of L. crispatus has been very recently reported in mammalian cell lines to be preventing HSV entry to cells [L. crispatus as a first-line defense against HPV and MCPyV which share similar pathogenic mechanisms, even if MCPyV only very recently has been proposed as a sexually transmitted microorganism [We reinforced the concept that the species of response . In the to cells  and blocto cells . To corrorganism .L. gasseri and in CST III by L. iners, a different type of host response resulting in the modulation of immune profile leading to the simultaneous increase of pro-inflammatory cytokines and the decrease of anti-inflammatory and anti-tumoral factors has been observed. In the CST IV, depleted of Lactobacilli, the increase of Sneathia sanguinegens and Prevotella timonensis was observed in infected samples. Our in vivo study suggests the low antiviral efficacy of L. gasseri and L. iners, in contrast with recent in vitro data pointing to a protective anti-tumoral effect exerted by all Lactobacilli species colonizing the cervical epithelium [In contrast, in CST II dominated by ithelium .Sneathia spp. has been observed in HPV-positive women and associated with all stages of cervical carcinogenesis [S. sanguinegens to be more prevalent in women with high-grade dysplasia compared to women with a low-grade dysplasia [Prevotella spp. with symptomatic HPV infection [Previous studies have indicated the vaginal dysbiosis as a risk factor for HPV infection, although they cannot exclude reverse causation of HPV in altering the vaginal microbiome. A higher level of ogenesis . More reysplasia  while otnfection .We speculate that the composition of the vaginal microbiome “per se” is not a risk factor for the acquisition of viral infection but it seems to influence the viral clearance.Prevotella timonensis and Sneathia sanguinegens in women infected with HPV or Polyomavirus during the asymptomatic phase of infection, event probably facilitated by a steady state level of pro-inflammatory status characterizing the vaginal environment of these women. Thus, it seems that both HPV and Polyomaviruses may promote their active colonization of the mucosal microenvironment through immune evasion strategies, mainly directed towards down-regulating the pro-inflammatory response. Indeed, a decreased concentration of the pro-inflammatory IL-15, IL-7, and the anti-inflammatory IL-9 was observed. The down-regulation of these molecules, which are first-line immune components for fighting viruses, prevents basically the growth and the activity of monocytes and T cells and, most importantly, inhibits their immunostimulatory and immunomodulatory effects [In our cohort, we detected an increase of the relative abundance of  effects ,29,30. M effects . This fePolyomavirus as a sexually transmitted pathogen, although no significant association between MCPyV and cervical cancer has been already demonstrated. To note, HPV and MCPyV co-occurrence was detected mainly in samples with molecular signatures of mucosal inflammation, thereby indicating a similarity in the pathogenic pathway.Newly, the detection of MCPyV in the vaginal mucosa, as unique strain or in samples co-infected with HPV, reinforces a role for this oncogenic Lactobacilli load in the vagina is not an accurate parameter for asserting health status. Based on this observation, the introduction of CSTs has led to the comprehension that species of Lactobacilli differently exert a protective role in oncogenic viral infections. In addition, we highlighted that the microbiome heterogeneity is not predictive for HPV and Polyomavirus susceptibility, which, on the contrary, seems to benefit from the steady-state immune-bacterial crosstalk for establishing persistent infections. A main limitation of our study must be identified in the small study cohort. For this reason, we believe that further studies are needed to give more insights into the cross-talk between vaginal bacteriome and oncogenic virome.As already disclosed by several studies, the total


Previous studies have confirmed its effects on adverse birth outcomes, but few associated with premature small for gestational age (SGA). We report a retrospective cohort study conducted in Changzhou city to evaluate the association between air pollutants  in two- and three-pollutants models. In the whole gestation, a 10 μg/m3 increment in PM2.5 concentration in two- and three-pollutant models were related to premature SGA . The OR (95% CI) of premature SGA were increasing across quintiles of PM2.5, SO2, NO2 concentrations during the whole gestation period adjusting for confounders (Pfor trend < 0.001).We found that, in the third trimester, every 10 μg/m2.5, combined with other pollutants in the third trimester have a higher risk to deliver premature SGA babies, providing further evidence linking PM2.5 and pregnancy outcomes.These results indicated that pregnant women exposed to PM Another recent research [2.5 in the second trimester and exposure to PM10 in the late pregnancy had a strong effect on PTB. Le et al. [2 exceeding 6.8 ppb exposure in the first month. Although some studies had confirmed the significantly impacts of air pollutants on PTB and SGA, few studies had elucidated the relationship between air pollutants and premature SGA. However, whether they would affect the premature SGA is still unclear.With the rapid development of economy, air pollution has become a serious public health problem, and gained much global attention. A variety of studies have revealed the association of air pollution with many human diseases, such as respiratory infections , cardiovresearch  indicatee et al.  also fou2.5 components differ among different regions, local studies could not be replaced by those performed in other regions. In addition, the genetic variation of different populations is known to be associated with different responses to the environmental risks [Therefore, this study set to address this important question. It has been realized that the nature of the components in particulate matters mainly depend on local natural environment, industrial types and meteorological conditions, and that different composition would impose different effects . Given tal risks , so the In this study, we recruited only the premature birth and analyzed the associations between premature SGA and air pollutions in Changzhou city, and excluded other factors which may affect premature on SGA.<10th percentile of birth weight of gestational age. The first trimester of pregnancy was defined as gestational week 1 to 12, the second trimester as week 13 to 27 and the third trimester as from week 28 to birth.Our study subjects were obtained from a retrospective study of the premature infants and their mothers from Changzhou Maternity and Child Health Care Hospital affiliated to Nanjing Medical University during 2013–2016. Women below 37 weeks of gestational durations were enrolled in the birth registry. Birth records included the data of infant gender, date of birth, gestational age, birth weight, birth order, number of stillborn (if multiple births), maternal age at child’s birth, total number of live born and stillborn (ever). Maternal behaviors including smoking and alcohol consumption were not available. Small for gestational age (SGA) were defined as 2.5, SO2 and NO2) concentrations were simultaneously collected from seven fix-sited air pollution monitoring stations in Changzhou, including Chengjian school, Anjia, Wujin, Lucheng, Changgongyuan and Changzhou city from January 1, 2013 to December 31, 2016 in Changzhou Environment Protection Agency. The inverse distance weighting (IDW) method was performed by a geographic information system  according to the following procedures. First, the residential address of each pregnant women registered in the medical records was transferred into longitude and latitude using xGeocoding software. Researchers indicated the monitoring data could represent a good indicator of individual exposure if subjects resided less than 40 km from the nearest station. And the minimum and maximum distance from individuals’ residence addresses to the nearest monitoring station were measured at 0.04 and 29.44 km, respectively, in our study. Then, an appropriate spatial resolution (100 m) was used to divide study areas into 100 m × 100 m grid cells . Finally, we used the inverse squared distance (1/squared distance) to weight the monitoring data of the nearest station and the coordinates of subjects were applied to calculate the daily pollution levels. The gestational age and birth date were used to calculate trimester-specific and entire pregnancy periods. The air pollution measurements were integrated into monthly summaries.In this study, daily air pollutants , gestational age (continuous), parity , natural delivery or not, sex of infants , birth years (from 2013 to 2016). Birth seasons were classified into Spring: March – May; Summer: June – August; Fall: September – November; and Winter: December–February. Meteorological information, including mean temperature, relative humidity and air pressure, were obtained from the local department.Individual characteristics in the analyses included maternal age at delivery , median, percentiles and interquartile range (IQR) were calculated for air pollutants. The correlation among different air pollutants concentrations were assessed by Spearman correlation coefficient. Potential confounders of the relationships between air pollution exposure and premature SGA were described in terms of mean (quantitative variables) or percentages . In order to adjust for correlations within people belonging to the same city, a generalized estimating equations (GEE) models were used to examine the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for premature SGA and air pollutants in each exposure windows, adjusting for covariates including infant sex, gestational age, maternal age, parity, methods of delivery, season of birth, year of birth and meteorological information. Before running model, the linearity and independence of variants were checked by Durbin-Watson and scatter plots. The multi-collinearity was tested using variance inflation factor (VIF) which was less than five for all of the independent variables. The concentration-response curves were drawn using restricted cubic spline regression model. All statistical analyses were conducted using R3.3.1 .During the study period, there were 10,028 (2013), 12,198 (2014), 10,743 (2015), and 13,255 (2016) live births, in which 750 (2013), 856 (2014), 847 (2015), and 1078 (2016) preterm births were enrolled from the retrospective cohort study. There are 107 (2013), 130 (2014), 136 (2015), and 170 (2016) preterm SGA. The overall incidence of premature was 7.48, 7.02, 7.88, 7.83% and premature SGA was 14.2, 15.2, 16.1, 15.8%, both of which were increased with years . Table The concentrations of PM2.5 showed additional statistical significance when other pollutants were included in the models. There are positive associations with premature SGA for PM2.5  in the third trimester after adjusting confounders in two- (combined with exposure of SO2) and three-pollutant (combined with exposure of SO2 and NO2) models, in which the relative increment in risk incidence of premature SGA for each 10 μg/m3 increment in PM2.5 concentrations were 18 and 37%, respectively during the third trimester. While in other two pregnancy periods, no significant adverse effect results were observed. In the whole gestation, the relative increase of risk incidence of premature SGA in two- (combined with exposure of SO2) and three-pollutant (combined with exposure of SO2 and NO2) models were 53% (95% CI: 1.38–2.47) and 73% (95% CI:1.18–2.57) after adjustment for the potential confounders. Further, we examined the associations between PM2.5 concentrations and premature SGA in different exposure levels, as Table 2.5, SO2, NO2 concentrations during the whole gestation period adjusting for confounders (P for trend < 0.001). The restricted cubic spline regression model was used to evaluate the associations continuously , and this retrospective cohort study explored the adverse effects of maternal exposure on fetus outcomes in Changzhou, 2013–2016. The results indicate that increased PM2.5 levels were significantly associated with higher risks of premature SGA in multi-pollutants models in the third trimester and whole gestational period.To our knowledge, this is the first study to focus on the relationship between air pollution and premature SGA. The IDW model were applied to evaluate precisely the air pollutant concentrations  are higher in winter and lower in summer, which was in consistent with meteorology that higher temperature facilitates cyclone and is beneficiary for the pollutants to diffuse. And women with premature fetus were those who start pregnant in winter when the air pollutants concentrations were higher. It should be noted that the above difference was not significant in this study, which might be attribute to the sample size. Further studies on this would be warranted. Air pollutants were reported to induce premature under many molecular mechanisms, including causing maternal inflammation [We observed that both prevalence of SGA and the mean concentrations of pollutants , which was similar to the previous studies [2.5 might be the main risk factor for premature SGA, and we should set priority to low its concentration in the polluted air.Air pollutants were complex, and could have combinational toxic effects , pollutants could alter the chemical properties and enhance the toxicity of each other. For instance, PM studies . Our stuStrengths of the study included the retrospective cohort study and the accurate IDW exposure method based on the coordinate of monitoring stations and individual residential locations. However, the time spends in traffic, occupational activities and moving during pregnancy were unavailable. Although a series of potential confounders were controlled, maternal smoking and alcohol consumption, known risk factors for premature births, were excluded in this model. The main reason was that we focused on the pregnant consumption of tobacco and alcohol in every trimester pregnancy during the whole gestational period, and none was exposed. The maternal disease is also associated with premature, however, which was not adjusted for in our models since information on maternal diseases was missing for a large number of pregnant women. On the other hand, amount of important covariates was taken into account: delivery, gestational age, parity, natural delivery or not, sex of infants, birth years, birth season of birth. In addition, the positive association does not mean causality in a retrospective study.2.5 contributed more risk to the premature SGA than SO2 and NO2.In this retrospective study, we confirmed the association between premature SGA and air pollution in Changzhou city, and found that the third trimester was the window of susceptibility for the premature birth weight. We analyzed and identified the risk of several air pollutants, as well as their interactive effects, and indicated that PM