Constipation is a common nonmotor symptom of Parkinson disease (PD). Constipation can also impact patient's quality of life. Chinese herbal medicines have been used for the treatment of constipation in PD. This trial will evaluate the efficacy and safety of a Chinese herbal formula Bushen Yisui and Ziyin Jiangzhuo (BYZJ) for the treatment of constipation in PD.This randomized, double-blind, placebo-controlled, multicenter clinical trial will involve 4 hospitals in Beijing, China. The study will aim to recruit 90 PD patients with constipation between 30 and 80 years-of age with a score of 1 – 4 on the Hoehn and Yahr scale. Once recruited, Patients will be randomized into a BYZJ group or a placebo group in a 2:1 ratio. The trial will include a 1-week run-in period, a 4-week double-blind treatment period, a 4-week and a 12-week follow-up period. All patients will be educated about PD-related constipation during the run-in period. BYZJ granules and simulated granules will be administered twice daily for 4 weeks to the BYZJ group and the placebo group respectively. Assessments will be performed during run-in period, before the start of treatment , and at 4, 8, and 16 weeks. The primary outcome will be measured with the Constipation Severity Instrument, and secondary outcomes will be evaluated with the Patient Assessment of Constipation Quality of Life questionnaire, Bristol Stool Form Scale, Movement Disorders–Unified Parkinson Disease Rating Scale, Nonmotor Symptoms Scale, PD Sleep Scale, Parkinson Fatigue Scale-16. Laxative use (dose and frequency) will also be recorded. Intention-to-treat and per-protocol set analyses will be used to compare symptom improvement between the 2 groups. Any adverse events will be recorded.If found effective and safe, BYZJ formula will be one of Chinese herb to treat constipation and even other nonmotor or motor symptoms in PD patients. The results will sustain the broader use of BYZJ formula in PD. Long-term use of laxatives—especially of the irritant type—can lead to dependence and intestinal dysfunction, which aggravates constipation. A variety of medications for the treatment of PD can cause constipation such as levodopa; conversely, constipation affects intestinal absorption of levodopa, thereby reducing its efficacy and aggravating PD symptoms.Constipation is a common non-motor symptom (NMS) of Parkinson disease (PD).,7 However, there is a dearth of high-quality clinical studies on this subject.Chinese herbal medicines have long been used to treat PD. In recent years, traditional Chinese medicine (TCM) has focused more attention on the treatment of PD-related constipation, with many reports demonstrating that it can be alleviated by certain preparations.–9 Thus, strengthening Qi and Yin and nourishing the kidney and marrow is a potential treatment strategy.The Chinese herbal formulation Bushen Yisui and Ziyin Jiangzhuo (BYZJ) was developed based on practical experiences from TCM, It is used to regulate bowel movements and alleviate insomnia, fatigue, and anxiety, among other conditions. According to the dialectic principles underlying TCM, constipation in PD is caused by a deficiency in kidney and marrow essence .The objective of the present study is to assess the efficacy and safety of BYZJ in the treatment of constipation and other NMS as well as motor symptoms (MS) in PD patients.2This protocol is reported in accordance with the Standard Protocol Items: Recommendations for Interventional Trials guidelines.3BYZJ is effective and safe for the treatment of constipation, along with other NMS and MS, in patients with PD.4This will be a randomized, double-blind, and placebo-controlled multicenter trial. We aim to recruit 90 patients who will be assigned by stratified randomization in a 2:1 ratio) to intervention (BYZJ) and control (placebo) groups. The total study duration will be 9 weeks, with a 1-week run-in period, an intervention time of 4 weeks, and 4-week and 12-week washout follow-up periods. Efficacy and safety will be assessed at baseline (week 0) and at 4, 8, and 16 weeks ; patients who participated in other studies in the previous 2 weeks or are currently participating in other clinical trials, or have taken other TCM preparations in the previous 3 months; pregnant and lactating women; and patients or family members who are unwilling to cooperate or do not agree to sign the informed consent form.To be included in the trial, participants must meet the following criteria: diagnosed with idiopathic PD according to the 2015 Movement Disorder Society criteria7t test was estimated based on the results of a previous study involving the treatment of patients with PD-related constipation. Based on a 2:1 ratio of patients in the BYZJ and placebo groups, the minimum sample size was calculated with formula shown in Eq. (1).: The minimum sample size for statistical significance with a 2-sample 1-sided In Equation 1, n represents the sample size of each group, κ = nA/nB; μ represents the overall mean, μA represents the mean of group A, μB represents the mean of group B; σ represents the overall standard deviation, σA represents the standard deviation of group A, σB represents the standard deviation of group B; α represents type 1 errors; and β represents type 2 errors. Application of Eq. (1) showed that 52 are required for the BYZJ group and 26 cases are required for the placebo group. Considering a 15% dropout rate, we plan to recruit 60 and 30 cases for the BYZJ and placebo groups, respectively.8We plan to use the complete randomization function of SAS 9.13 statistical software  to create a table of random numbers that will be printed out and placed in a light-proof envelope and managed by a third party (not the investigators). Under a double-blind design, BYZJ granules and BYZJ simulated granules will be provided to patients in the BYZJ and placebo groups, respectively. Both formulations will be provided by the Dongzhimen Hospital pharmacy and labeled as constipation No. 1 and 2, respectively. In order to ensure blinding, both formulations will have identical packaging. The third party will be responsible for the implementation of blinding and its removal after the trial.In the event of a potential Suspected Unexpected Serious Adverse Reaction to the trial medication, unblinding will be undertaken by the sponsor in accordance with the regulatory requirements. Unblinding may also be performed at the request of a senior clinician responsible for the care of a trial participant but such requests are likely to occur only in the case of a serious adverse clinical event and are expected to be rare.99.1.1Subjects will receive health education with regards to constipation by specialist personnel during the 1-week run-in period. We also plan to develop a constipation instruction manual that includes dietary guidance, precautions, and the management of bowel habits.9.1.2Cistanche, Chinese wolfberry, Rehmannia glutinosa, dogwood, raw Rehmannia, Radix Ginseng, hemp kernel, raw Astragalus, Gastrodia elata, and raw licorice  throughout the trial. The amount of laxatives, and the frequency of their use, will be recorded for each patient.10 Typical drug types include levodopa, dopamine agonists, monoamine oxidase type B inhibitors, catechol-O-methyl transferase inhibitors, amantadine, and anticholinergics.The conventional medical treatment plan used by the subjects will need to meet the requirements of the European Federation of the Neurological Societies guideline for the Treatment of PD.11Any medication used for comorbidities will be recorded in detail, including the reason for their use, the name of the drug, the dose per administration, the total doses per day, the start date, the date of discontinuation, and the patient's status at the last visit.12We will collect a range of general information for each patient during the run-in period. The primary and secondary outcomes will be assessed at week 0 (baseline), and then again at weeks 4, 8, and 16. Safety and laboratory indicators will be assessed at week 0 (baseline), and then again at weeks 4 and 16 Fig. . The priWe will collect a range of demographic information, including name, sex, age, date of birth, height, weight, education, history of tobacco and alcohol use, family history of PD, occupation, home address, and contact telephone number. We will also record each patient's medical history, including current medical status and past medical history. Physiological data will include pulse, respiration, heart rate, standing blood pressure, and nervous system function. Safety indicators will include routine blood, urine, and stool parameters; liver and kidney function; and electrocardiography parameters. Any adverse events after the start of treatment will be recorded along with incident handling.13Before the start of the study, the investigators will receive standardized training relating to the data collection strategy and guidelines for the different scales that will be used to assess outcomes. During the trial, data will be collected by trained researchers to prevent bias. If the subjects experience the “on-off” phenomenon  and poor control (off) of their symptoms. The on-off phenomenon is often experienced in patients undergoing L-dopa therapy), the visit should be conducted during the “on” period.14An electronic data capture (EDC) system, that relies on the clinical research data platform of the Parkinson Medical Center at the Beijing Rehabilitation Hospital, will be used for all data entry and management. Data entry will be carried out by 1 data collector assigned to each center. Participant information will be stored in the EDC system; investigators will access this system using a password. The investigators will also check the case report forms to confirm that they are complete and also check for consistency between the code and the subject's screening entry list. Data will be validated after entry into the EDC system, and the original case will be reviewed again based on these results. Final data will be exported as an Excel  spreadsheet.15We have already established an independent Data and Safety Monitoring Board (DSMB) for this study that is independent of the sponsor, consisting of a TCM specialist, a Neurologist and a statistician. The DSMB will oversee whether the trial follows the study design and standard guidelines. The neurologist will assess, manage, and classify all adverse events. All serious adverse events will need to be reported to the main researchers, the Ethics Committees, and the DSMB, within 24 hours of occurrence. The DSMB and the main researchers will discuss such issues. The Ethics Committees and the DSMB will have the right to terminate the trial if they deem that such action is appropriate. The role of the statistician is to review the safety data.16t-test for between-group comparisons. Data that do not meet these criteria will be evaluated with a nonparametric test. Repeated measures analysis of variance will be used for within-group comparisons .SPSS v20.0 software  will be used for all data processing and analysis. Measurement data will be expressed as mean ± standard deviation. The normality and homogeneity of variance will be tested. Data with a normal distribution and uniform variance will be evaluated with the independent samples χ2 test. Intent-to-treat and compliance analyses will be performed to compare efficacy between the 2 groups. The last observation carry-forward method will be used for data processing. The significance level for each test will be set at P < .05.Numerical (count) data will be expressed as percentages. Between-group comparisons will be performed with the An intention-to-treat analysis will be adopted to deal with missing data, including all participants in the analysis based on the initial group allocation. A linear mixed model approach (a direct likelihood estimation method) will be applied to analyze all continuous variables as value is missing at random.17 and has been approved by the Ethics Committee of Beijing Rehabilitation Hospital, Capital Medical University. The trial will be conducted under the supervision of the Clinical Trials Center at the Rehabilitation Hospital, Capital Medical University. All participants must provide written, informed consent. All data will be anonymized. Participation is voluntary and patients may leave the study at any time. We will set up multiple communication channels to maintain close contact with participants. Those who are assigned to the placebo group will receive a 4-week supply of BYZJ granules as compensation after the trial has ended.The protocol adheres to the guidelines outlined by the Declaration of Helsinki Declaration and the Measures for Ethical Review of Biomedical Research involving Humans,18The personal information of all participants will remain private; only relevant codes will be used during statistical analysis. Participant information will be stored for 5 years in the EDC system at the Rehabilitation Hospital Affiliated with Capital Medical University, China. The final data set will be available to the principal investigator and the independent statistician. All participants will be asked if they would like to receive a copy of the outcomes of the study after the invention and an email address or telephone number will be collected to facilitate the distribution of any relevant publications. The participants will be informed of the result of this study after the intervention. The results of this study will be published in a peer-reviewed journal and presented at national and international conferences. We will follow all authorship eligibility guidelines and we do not intend to use professional writers.1919.1 Constipation is among the most common NMS of PD, with an incidence of 47% to 60%. Moreover, constipation may manifest years before a clinical diagnosis of PD,19 and may precede the appearance of typical MS.–24 The nonmotor symptoms scale and the autonomic NMS scores of PD patients with constipation are significantly higher than those of patients without constipation.,26 Furthermore, research has suggested that constipation is closely related to other NMS such as urinary urgency, nocturia, orthostatic hypotension, and attention deficit.Constipation is characterized by irregular bowel movements caused by dry feces or excretory difficulty even when feces are not dry. Clinically, patients are classified as having mild, moderate, and severe functional constipation according to the degree of constipation and the impact on quality of life.19.2 Defecation involves coordination between abdominal, internal anal sphincter, external anal sphincter, and puborectalis muscles; any dysregulation of this activity will reduce gastrointestinal motility, thereby obstructing defecation. Approximately 80% of patients with PD have delayed colonic transit, with a mean transit time of 43 hours to 168 hours compared to 12 hours in normal individuals. PD-related constipation is also a side effect of, or can be aggravated by, anti-Parkinson drugs. For example, levadopa slows gastrointestinal motility; the use of dopaminergic drugs has previously been shown to increase the frequency of constipation. A range of other factors are known to contribute to PD, including overall movement, reduced physical activity, eating habits, reduced water intake, mood, and intestinal dysbiosis.The pathogenesis of constipation in PD is thought to be related to several factors. Degenerative changes in the enteric nervous system such as the loss of intestinal interstitial dopaminergic neurons in patients with PD are known to affect the control of gastrointestinal motility, thereby weakening intestinal function and leading to constipation.19.3Western medical treatments for constipation include general-, drug-, and surgical-based treatments, and biofeedback therapy.19.3.1General treatment options include the replacement or discontinuation of drugs that induce constipation. Patients should also be encouraged to exercise, adopt reasonable eating habits, and increase their fluid and fibre intake. Collectively, these actions can result in regular bowel movements and relieve stress.19.3.2A range of drugs are commonly used to treat PD-related constipation, including laxatives, enemas, suppositories, drugs that promote gastrointestinal motility, and microecological preparations. The long-term intake of irritant laxatives, such as bisacodyl, can lead to colon hypofunction and is not recommended for routine use. Enemas  are administered through the anus but should be used cautiously to avoid dependence. Cisapride is no longer prescribed as this drug can increase the risk of cardiovascular disease. Lubiprostone is known to enhance intestinal secretion although this drug is associated with adverse effects such as nausea, diarrhea, and headache; moreover, the high cost of this treatment discourages adherence in many patients. Microbiological preparations, such as Bifidobacterium viable and triple-viable capsules, and Licheniformis viable capsules, promote bowel movement by reversing intestinal dysbiosis, although they have limited efficacy.19.3.3Biofeedback therapy is a treatment option for constipation caused by pelvic floor muscle dysfunction. This method aims to stimulate defecation through sounds and images; feedback to the brain triggers defecation by restoring the resting potential of the sphincter muscles. The efficacy of this treatment depends on the patient's compliance and the experience of the therapist.19.3.4 Moreover, surgical treatment has questionable efficacy; recurrence and complications often lead to poor outcomes.In rare cases, surgical intervention can represent an option for treating PD-related constipation, although there are strict indications and contraindications for its use.19.4Although laxative medicines can immediately relieve constipation, their effects may be short-lived, and their long-term use can lead to dependence and colonic melanosis. Furthermore, enema and pelvic floor biofeedback therapy can cause pain and are less effective than drugs. Surgical treatment for constipation remains in its infancy; in addition to its high cost, surgery may not provide long-term relief and patients may experience considerable pain and adverse events.19.5,35 Sluggish movement, involuntary tremor, rigidity, constipation, insomnia, and fatigue in PD are considered as manifestations of a lack of kidney essence . Thus, the management of PD-related constipation should be based on the principle of nourishing the kidney essence by strengthening Qi and Yin.TCM has certain advantages over Western medicine for the treatment of constipation in PD patients because it is based on dialectic therapy and the notion that constipation and PD have the same pathogenic origin. In TCM, kidney essence is fundamental to the body as it strengthens Qi, Yin, and cerebral function to promote agility, strengthen the spirit and bones, and allow smooth stool passage.,37 Chinese herbal formulations including Buzhong Yiqi decoction,39; Bushen Ziyin Runchang pills; and Zuogui pills and Zengye Chengqi decoction; can nourish the kidney essence,42 while Qi and Yin,39,43 can reduce turbidity. Collectively, these formulations have been shown to be effective in treating constipation in patients with PD. Stimulating ganglion cells of the intestinal nerve through acupuncture can also alleviate constipation by regulating intestinal function and enhancing peristalsis in the large intestine.–49Enhancing kidney and marrow function by strengthening Qi and Yin can alleviate NMS of PD such as constipation.Western medicines mostly target MS of PD, but do not improve NMS; they may even exacerbate the problem. These medicines are also associated with many adverse effects and poor long-term outcomes. In contrast, TCM has a good curative effect with regards to PD and address both the MS and NMS of PD when combined.19.6Cistanche, medlar, cooked Rehmannia, Dogwood, raw R glutinosa, black ginseng, hemp kernel, raw Astragalus, Gastrodia, and raw licorice. Our proposed randomized, double-blind, and placebo-controlled trial is expected to provide reliable evidence for the efficacy and safety of the BYZJ formulation for the treatment of constipation and other NMS symptoms in PD patients.The BYZJ formulation is derived from the Liuwei Dihuang Wan and Zengye decoction and has been pre-tested for the treatment of constipation, insomnia, and fatigue in patients with PD. Unlike other TCM treatments, BYZJ targets deficiencies in the kidneys, marrow, Qi, and Yin, through kidney tonification, Qi and Yin nourishiment, and turbidity reduction. The BYZJ formulation includes The authors thank all participants and researchers at each center for their contributions at each stage of this research.Conceptualization: Zhaohui Jin, Boyan Fang.Funding acquisition: Zhaohui Jin.Methodology: Boyan Fang.Project administration: Boyan Fang.Supervision: Boyan Fang.Writing – original draft: Zhaohui Jin.Writing – review & editing: Boyan Fang.


Parental separation is a very common childhood adversity. The association between other adverse childhood experiences and an increased risk of psychosis has been reported. However, the evidence on the risk of psychosis for children of separated parents is limited. In this systematic review, cohort, case–control, and cross-sectional studies, comparing the risk of psychotic disorders for people with and without separated parents, were searched, critically appraised, and summarized.Studies were searched in PubMed, EMBASE, PsycINFO, and the Web of Science, from database inception to September 2019. A meta-analysis, using random-effects models, was undertaken to obtain pooled estimates of the risk of psychosis among participants with separated parents.p < 0.001. The association remained significant when cohort, case–control, and cross-sectional studies were analyzed separately. The five cohort studies included in this review showed and increased risk of psychosis with odds ratio: 1.47 (95% CI: 1.26–1.69), p < 0.001.Twelve studies, with 305,652 participants from 22 countries, were included in the review. A significantly increased risk of psychosis for those with separated parents was observed, with a pooled odds ratio: 1.53 , Parental separation is a common childhood adversity associated with an increased risk of psychosis. Although the risk for an individual child of separated parents is still low, given the high proportion of couple that separate, the increased rates of psychosis may be substantial in the population. Further studies on the risk of psychosis in those with separated parents, and the explanatory factors for this association, are required. The dissolution of marriage is common, affecting 46% of married couples in the USA, 42% in Australia, and 43% in Europe –3. In maParental separation has consequences in children’s life, including exposure to conflict between parents, economic loss, reduced contact with one parent, and increased life stressors such as changing schools, childcare, or homes. Parental separation has become one of the most common adverse childhood experiences, second only to socioeconomic disadvantage ,7. Two sStrong evidence on the association between parental separation and psychosis could identify people at higher risk of having psychotic disorders and inform a proactive and multidisciplinary approach to them. This systematic review and meta-analysis present an up-to-date critical appraisal and summary of the available evidence on the risk of developing psychotic disorders in children of separated parents.The Meta-analysis of Observational Studies in Epidemiology criteria were used to undertake this review . ObservaThe bibliography lists of all papers fitting the inclusion criteria, and relevant reviews identified in the initial search, were checked for further articles. Papers citing all the included studies or relevant reviews were also searched in the Web of Science and considered for inclusion. There were no restrictions on the basis of language, sample size, or duration of follow-up.The following articles were not included: interventional studies; papers that presented only associations with specific domains or outcomes of psychosis; studies with composite outcome  unless separate results for psychosis were presented; those reporting outcome as a continuous variable ; articles presenting only subclinical psychosis or drug induced psychotic disorders; studies comparing participants with different mental health disorders instead of those with and without psychosis; papers in which the exposure was separation between parent and child but parental separation was not one of the reasons for this; those conducted in specific patient subpopulations ; studies reporting results only from univariate analysis; and ecological studies.One researcher (L.A.) conducted all searches of eligible studies. Eligibility was confirmed by two other researchers (M.P.-P. and S.A.). In some cases, the authors of the studies were contacted for any clarifications required including possible publication of two papers from the same sample. Where data from the same participants were presented in more than one paper, only data from the study with larger sample size were included in the analysis. Two researchers extracted the data from all the eligible studies (L.A. and S.A.) using a standardized data-collection form. The risk of bias and overall methodological quality of the studies fitting the inclusion criteria was assessed using the Quality Assessment Tools for Case–Control, Cohort and Cross-Sectional Studies of the National Institute of Health (USA) .p value ≤0.05 was used as a criterion for significance. The heterogeneity between studies was measured using I-squared index (I2), which represents inconsistency of the studies included and estimates the percentage of the total variation due to heterogeneity rather than chance [Pooled estimates of odds ratios (ORs) were obtained using random-effects models . ORs andn chance  All studn chance  and the n chance  were usen chance ,19. To an chance .The electronic search produced 2,210 references, 289 from PUBMED, 960 from EMBASE, 598 from PsychInfo, and 363 from Web of Science. Twelve reviews relevant to the topic, with a total of 1,126 references, and cited by 1,997 papers were also identified ,21–30. TTwelve papers including in total 305,652 participants were considered eligible ,17,31–40The meta-analysis showed that parental separation is significantly associated with psychosis, OR: 1.53 . Even so, all data were checked for accuracy on multiple occasions and all analyses were conducted several times and checked by a senior statistician (S.A.). Finally, some publications may have been miscoded or missed altogether.This study has strengths as well. The comprehensive search and critical assessment of studies conducted in this review allows estimation of the association between parental separation and psychosis obtained on a large number of participants assessed worldwide. The use of a random effect model, based on the assumption that studies were independently conducted and do not necessarily share a common effect size, allowing for more uncertainty of the final summary estimate, was a conservative choice. The overall estimate remained significant despite the increased width of the confidence intervals, providing support to the significance of the findings. The reasonably symmetrical funnel plot suggests provides no evidence of publication bias or small study effects .The risk of psychosis is higher for children exposed to other adversities such as sexual, emotional, physical abuse, or neglect (OR > 2) than for children of separated parents. However, the higher frequency of parental separation can result in a larger number of cases of psychosis associated with it in the population –3. ParenParental separation is associated with an increased risk of psychosis. This should be acknowledged by all professionals working with children of separated parents. Although the risk for an individual child of separated parents is still very low, given the high proportion of couple that separate, the increased rates of psychosis may be substantial in the population. Future studies addressing the possible mechanisms for this association are required.


Chronic hepatitis B virus (HBV) infections and colorectal cancer (CRC) are prevalent in Taiwan. We carried out a population-based case-control study to assess the association between HBV infection and CRC risk. Using the National Health Insurance Research Database of Taiwan, we identified 69,478 newly diagnosed patients with CRC from 2005 to 2011. We further randomly selected 69,478 age- and gender-matched controls without CRC from the same database. Odds ratios (ORs) were calculated to evaluate the association between chronic HBV infection and CRC using a logistic regression analysis. HBV infection was found to be associated with the risk of CRC  = 1.20–1.33). This relationship was similar in men and women. Age-specific analysis revealed that the CRC risk associated with HBV decreased with age. The adjusted ORs for patients aged <55, 55–64, and 65–74 years were 1.63 (95% CI = 1.48–1.79), 1.24 (95% CI = 1.13–1.37), and 1.02 (95% = 0.92–1.13), respectively. In conclusion, this study suggests that chronic HBV infection is significantly associated with an increased risk of CRC. Monitoring the risk of CRC development in young patients with HBV infection is crucial. Colorectal cancer (CRC) is one of the most common cancers and the third leading cause of cancer-related deaths in the world . The incHepatitis B virus (HBV) is considered to be a hepatotropic virus and is one of the major causes of hepatocellular carcinoma (HCC) worldwide . More thN = 15,355) had a hazard ratio (HR) of 1.42  for colorectal cancer compared with HBsAg seronegative [Furthermore, studies have indicated the existence of HBV in several extrahepatic organs and tissues, such as the kidneys, colon, stomach, lymph nodes, bone marrow, and pancreas ,10,11. Rnegative .The association between HBV infections and CRC Taiwanese patients has not been investigated in detail. Moreover, the role of HBV infection as a risk factor for CRC is unclear. Therefore, in the present study, we used the large insurance claims database in Taiwan to conduct a case-control study and assess the CRC risk in patients with HBV infection.This was a population-based case-control study using data obtained from the NHIRD in Taiwan. The database contained original data from the state-run NHI program, which was established in 1995 and provides national health care for 23 million Taiwanese residents. The coverage rate of this mandatory, single-payer insurance program was up to nearly 99% of the Taiwanese population by the end of 2004 [Patients newly diagnosed with CRC  from 2005 to 2011 were identified from the RCIP database. The RCIP is one of the patient care programs in Taiwan used to protect insured people with serious diseases and to reduce the financial burden. CRC is an NHI-defined catastrophic illness, and the NHI program covers the costs incurred during the treatment of this disease . The priThis study assessed the association between chronic HBV infection  and CRC risk. Patients with human immunodeficiency virus (HIV) were excluded . Additionally, patients with chronic HCV infection  were excluded. HBsAg and anti-HCV antibody were the diagnostic serum markers for HBV and HCV infections, respectively. Overall, after excluding 2370 patients , 69,478 CRC patients were enrolled in this study.Controls were randomly selected from the Longitudinal Health Insurance Database 2000 (LHID2000), which contains all claims data of one million randomly selected people in the NHIRD and updated registries from 2000 to 2011. The control group comprised randomly selected people, without a history of CRC, HCV, and/or HIV, who were matched to the CRC patients by age and gender at a ratio of 1:1. In this study, the age of each individual was calculated as the interval between the index date and the date of birth. Among the 880,409 people eligible as controls, 69,478 were enrolled in this study. The flowchart for the recruitment of the CRC patients from the RCIP database and the controls from the LHID2000 is illustrated in The chi-square test was used to compare the distributions of the demographic characteristics  and comorbidities between the CRC patients and controls. We selected 528 USD (USD: 1 USD as 30 new Taiwanese dollars) and 833 USD as the cutoff points for the monthly income. Associated comorbidities, such as diabetes mellitus, hypertension, hyperlipidemia, CAD, renal disease, COPD, obesity, and liver cirrhosis diagnosed during 2005–2011 were ascertained using diagnostic ICD-9-CM codes.p value <0.05 was considered statistically significant. Statistics were analyzed using SAS statistical software .A multivariable logistic regression analysis was applied to calculate the aORs and 95% CIs for variables significantly associated with CRC risk. Furthermore, the analyses of the association between chronic HBV infection and CRC risk were stratified by age and gender, and the odds and ORs of HBV infection were estimated. A two-sided N = 69,478) and controls . The disease was more common in men (57.2% in both groups) and in individuals aged >50 years (86.9%). The distributions of geographical region, occupation, urbanization level, and monthly income were significantly different between the CRC patients and the controls (p < 0.05). Diabetes mellitus and hypertension were more prevalent in the CRC patients than in the controls (p < 0.001), whereas coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD), and liver cirrhosis were more prevalent in the controls than in the CRC patients (p < 0.05).p < 0.001).The age-specific analysis revealed that the odds of HBV infection declined with an increase in age in both the CRC patients and controls . The difp = 0.569).We also performed a sensitivity analysis to evaluate how the chronic HBV infection was associated with risks of colon and rectal cancers. Colon cancer patients had the highest infection rates with an aOR of 1.32 (95% CI = 1.24–1.41), followed by rectal cancer with an aOR of 1.17  or, more rarely, the double-stranded linear DNA (dslDNA) genome of HBV is released into the cytoplasm and transported to the nucleus. The intra-nuclear dslDNA HBV genomes can then be integrated into the host cell genome at the site of double-stranded DNA breaks via DNA repair pathways . IntegraAs HBV DNA integrates in the host genome, HBx colocalizes in the mitochondrial cytoplasm and nucleus. In the cytoplasm, HBx regulates protein degradation, cellular transcription, apoptosis, and cell proliferation. HBx stimulates the replication of HBV in the nucleus . There ap = 0.04) [Mutagenic activity is an important factor in the development of malignancy. HBV has been identified in the colonic mucosa . However = 0.04) . A recen = 0.04) .Chronic inflammation, such as ulcerative colitis and Crohn’s disease, is one of the major risk factors for the development of CRC . ChronicOne study revealed that African Americans have a 20% higher incidence of colon cancer than Caucasians . Forde eThis study has several limitations. One is that some HBV-infected patients without obvious clinical symptoms might not receive medical services. As a result, some of these patients might be classified as non-HBV-infected. However, CRC diagnosis is unrelated to the HBV status. This nondifferential misclassification may lead to a bias of the estimated OR toward the null value. Second, patients with CRC, chronic HBV hepatitis, and comorbidities were identified using ICD-9-CM diagnosis codes, which are less accurate than clinical diagnoses. However, the National Health Insurance (NHI) administration randomly samples a fixed percentage of claims from every hospital. In addition, patients are randomly interviewed and charts are reviewed each year to verify the validity of the diagnoses and the quality of care. Patients with confirmed CRC diagnosis in Taiwan receive a catastrophic illness certificate, and the NHI program covers the treatment costs incurred by the disease. Therefore, these patients are representative of the CRC population in Taiwan. Third, information on some important factors that might be related to CRC  were not available in the NHI Research Database (NHIRD) and Registry for Catastrophic Illness Patient (RCIP) of Taiwan. To compensate for the lack of lifestyle-related data, the study accounted for related chronic diseases. COPD is correlated with the dose levels of cigarette smoking. Likewise, CAD, hypertension, and hyperlipidemia can be the results of poor diet and lifestyle. However, even with these adjustments, some of the potential confounding effects associated with these factors cannot be ruled out. Fourth, data of HBV DNA counts are not currently available in the NHIRD and RCIP of Taiwan; hence, comparisons of HBV viremia between case and control groups are not made. Finally, the vast majority of the residents in Taiwan are of Chinese ethnicity. Therefore, the ability to generalize the results to other racial/ethnic groups is unclear, given that the transmission route of HBV infection in the Chinese population might not be the same as that in other ethnic groups.In summary, this population-based case-control study suggests that chronic HBV infection is associated with the development of CRC, particularly at a young age. Further studies are required to apply our findings to other regions or races and to clarify the underlying pathophysiological mechanisms involved in the association between chronic HBV infection and CRC.


The concentration of the analyzed heavy metals was higher in SG. All the heavy metals showed a significant diagnostic value (p < 0.001). The highest value of area under the curve (AUC) was observed for manganese (Mn)  = 0.922–0.988), while the lowest value was found for zinc (Zn) . In one-dimensional models, high concentrations of each of the analyzed heavy metals significantly increased the chances of having MI from 7-fold (Cu) to 128-fold (Mn). All the models containing a particular metal showed a significant and high discrimination value for MI occurrence (AUC 0.72–0.92). Higher concentrations of Cu, Zn, Mn, Co, and Fe were found to considerably increase the chances of having MI. Considering the increasingly higher environmental exposure to heavy metals in recent times, their concentrations can be distinguished as a potential risk factor of CVDs.Cardiovascular diseases (CVDs) constitute the first cause of death among the population of developing and developed countries. Atherosclerosis, which is a disorder with multifactorial etiopathogenesis, underlies most CVDs. The available literature includes ample research studies on the influence of classic cardiovascular (CV) risk factors. However, environmental exposure to heavy metals, among other substances, is still an unappreciated risk factor of CVDs. This study aimed to assess the concentration of some heavy metals (copper (Cu), zinc (Zn), manganese (Mn), cobalt (Co), and iron (Fe)) in the blood serum of postmyocardial infarction (post-MI) patients and patients free from myocardial infarction (MI) as well as estimate the relationship between the occurrence of MI and increased concentration of heavy metals. The concentration of heavy metals  was assessed using the inductively coupled plasma mass spectrometry technique in a group of 146 respondents divided into two groups: post-MI group (study group (SG),  Cardiovascular diseases (CVDs) constitute the main health problems, and hence decreasing the mortality rate and the consequences of these diseases is one of the priority healthcare tasks in developed countries . Atheros3, such as Cu, Zn, Mn, Co, and Fe, are widespread in the Earth's crust, but they exist in low concentrations in living organisms. Even small traces of such metals in the atmosphere, soil, and water can cause serious health problems in the organisms. The main influence of heavy metals on people's health results primarily from occupational exposure, environmental pollution, or their accumulation in food [Heavy metals, frequently defined as those with a density higher than 5 g/cm in food . The mec in food . The pot in food . The pat in food .Scientific evidence indicates both positive and negative influences of heavy metal concentrations on the CV risk in humans , 16. Becp value of 0.05, based on the values given in a published article [The study was designed to have an 80% chance of detecting a 0.46 standardized mean difference in Cu concentration using a  article . To demo article . This crth day following their discharge from hospital after complete revascularization) and continued physiotherapy, diet therapy, and pharmacological therapy in the therapeutic unit “Uzdrowisko Nałęczów” S.A. in Nałęczów and the Railway Health Resort Hospital in Nałęczów (Eastern Poland). The research included patients from consecutive rehabilitation stays who were held every 21 or 28 days. All the SG patients had experienced MI once and were treated using percutaneous coronary intervention (PCI). The inclusion criteria were as follows: age between 40 and 65 years, post-MI condition, and written informed consent to take part in the study. The exclusion criteria were the following: a medical history of renal failure, neoplasm, lung disorder, or rheumatic disease, and age below 40 years or above 65 years. Another exclusion criterion encompassed the consumption of dietary supplements containing trace elements and vitamin complexes, which could affect the level of heavy metals in the blood serum.The SG constituted patients with a post-MI condition, who were hospitalized in the early period of cardiac rehabilitation (up to the 14The CG constituted adults who had never had cardiovascular event (CVE) and attended routine checkups with an occupational medicine physician during periodic examinations. The respondents were recruited from the Regional Preventive and Therapeutic Centre of Occupational Medicine in Lublin (Eastern Poland). The inclusion criteria were as follows: age between 40 and 65 years, absence of CVE in medical history, low 10-year CVE risk (SCORE < 5) , lack ofThe research project was approved by the Bioethics Commission at the Medical University of Lublin (KE-0254/197/2017) and was conducted in accordance with the Declaration of Helsinki. All the respondents were informed about the aim of the study and provided a written informed consent to participate in the research.Blood samples were collected from the ulnar vein of patients, while fasting in the morning (7–9 a.m.) after a full night's rest. The samples were taken in a tube coated with a clot activator and separating granules and then delivered within an hour to a laboratory. The tubes containing samples were stored at 4°C until delivered. Plasma was separated from the samples by centrifuging at a speed of 3 000 revolutions per minute for 10 minutes. The serum was centrifuged and directly placed in Eppendorf tubes and then stored at −80°C to check the concentrations of Cu, Zn, Mn, Co, and Fe.3) was purchased from Merck (Germany). Ultrapure water  was used for preparing 1% HNO3 and for diluting the samples. Additionally, the certified single-element standard solutions of Cu, Mn, Co, Zn, and Fe  were obtained from Agilent Technologies (USA). The certified reference material ClinChek® Plasma Control for Trace Elements, Level I (Germany), was prepared according to the manufacturer's instructions.Suprapur grade nitric acid . Wet mineralization was conducted by using a Mars 6 microwave mineralization system . After adding 2 ml of 65% HNO3 to samples, they were transferred to Teflon containers and digested at 180°C. Later, the samples were diluted by adding 5 ml of ultrapure water and analyzed to determine the concentration of the respective trace elements.Human plasma samples (0.2 ml each) were collected, and the organic matter was digested by adding 2 ml of 65% HNO3. The human plasma samples and quality control samples were analyzed in triplicate, and the average values were used as the final results.The concentrations of Cu, Mn, Co, Zn, and Fe in the diluted samples were determined using inductively coupled plasma mass spectrometry (ICP-MS) . The following parameters were used during the ICP-MS analysis: plasma gas flow 18 l/min, nebulizer gas flow 1 l/min, frequency power 1.37 kW, and auxiliary gas flow 1.70 l/min. To prepare the calibration curve (corresponding to the concentrations of trace elements in human plasma), the certified single-element standards were mixed and diluted in 1% HNO2) [The medical interview, physical examination, and sample collection were performed by a well-trained nurse. Sociodemographic data  were obtained using standard questionnaires. A respondent who had smoked at least one cigarette per month was considered as a smoker . All the2) .t-test or Mann–Whitney U test when considering quantitative variables and using Chi-square test when considering qualitative variables. The diagnostic usefulness of specific heavy metals for detecting MI was calculated using receiver operating characteristic (ROC) curves with area under the curve (AUC). A cut-off value corresponding to the highest accuracy rate was determined, and the related sensitivities and specificities were summarized in the Youden index. The multivariable logistic regression model was used to investigate the association between CVE and specific heavy metals . The results of the logistic regression model were presented as odds ratios (ORs) and 95% confidence intervals (CIs). The ROC curves were used to assess the discrimination of a fitted logistic model. Moreover, the AUC values for ROC curves with 95% CIs were calculated. All the analyses were performed in IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp. Statistical significance was defined as p < 0.05.The distribution of variables was presented as follows: numbers and percentages for categorical variables, means with standard deviations (SDs) for normally distributed continuous variables, and medians with interquartile ranges for continuous variables with skewed distribution. The Kolmogorov–Smirnov test was used to verify the normality of the data distribution. The SG and CG were compared using Student's p=0.13). The CG contained a higher percentage of individuals living in urban areas with higher education and a lower percentage of smokers than the SG. A significant difference was observed in the distribution of each heavy metal between the SG and the CG. The concentrations of the analyzed heavy metals were higher in the SG.p < 0.001). The highest value of AUC was observed for Mn , while the lowest value was observed for Zn . The cut-off values determined for heavy metals were slightly lower than their median values for the sample. The heavy metal Co displayed the highest percentage of distribution exceeding the cut-off value in 96 respondents (65.8%).In this cross-sectional study, concentrations of heavy metals  were compared in the SG and CG and the relationship between MI occurrence and higher concentrations of the metals was estimated. To recapitulate, the results indicated that concentrations of the analyzed heavy metals were significantly higher in the blood serum in the group of individuals who had MI in their medical history. Moreover, higher concentration of each heavy metal (determined using the ROC curves) was shown to considerably increase the probability of being diagnosed with MI. The highest discrimination value of the model determining the relationship between MI and the selected heavy metals was found for Mn. As far as known, the harmful influence of heavy metals on the CV system has not been studied thoroughly . The potthday from the incidence of MI. Similarly, Low and Ikram [th day, which shows that a low level of Zn in the blood serum can be an effect and not a cause of CVDs. However, research on the influence of Zn ions on the pathology of the CV system is still insufficient, and many key issues remain unexplained.As a strong prooxidant, Cu may play a role in the development of atherosclerosis, which underlies cardiovascular diseases . Similarnd Ikram  stated tMn exposure is associated with a higher risk of hypertension and mortality from CVD . In the Agarwal et al.  observed2+ secretory pathway—ATPase 1 (SPCA1) [The hemostasis of essential heavy metals is carefully regulated by a system of protein transporters involved in the uptake, distribution, storage, and excretion of metal ions in the body . In euka (SPCA1) , 50. Thein vivo and in vitro studies [Several potential mechanisms explain the relationship between heavy metal concentration and CVE occurrence. Copper works as a cofactor for different proteins and enzymes necessary for the maturity of cytoplasmic cuproproteins and production of enzymes in different organelles . Appropr studies . Formati studies . In addi studies , the hea studies . Lack of studies . Apart f studies  , and de studies . The met studies . Apart f studies . Mn can  studies . As Bae  studies  observed studies . In biol studies . Iron, i studies . Its act studies . Moreove studies  found th studies . However studies .Metal-binding proteins also play an important role in reducing oxidative stress, a factor that directly influences the formation of atherosclerotic lesions in blood vessels. For example, one of MT's important biological roles is protection against oxidative stress induced by various environmental stressors, including toxic metals. In mice studies, knockout mice lacking MT expression were shown to be more sensitive to Cd toxicity than mice in the control group . In geneThe strengths and limitations of this study are worth considering. An extensive analysis of the literature suggests that this is the first study where the ROC curves have been applied to define cut-off value for the analyzed heavy metals to diagnose MI. Another strength of this research is that the cut-off value obtained for the analyzed plasma metals were used in the models of logistic regression that enables the determination of significant predictors of MI. Additionally, for each heavy metal, the discriminating value of the model was given, which allows to compare the diagnostic usefulness of heavy metals among them. In this study, the MI diagnosis of the SG patients was confirmed in the medical documents and endorsed by a doctor during an angioplasty procedure. Furthermore, a complex clinical examination was performed on the CG participants to minimize the possibility of having undiagnosed and preclinical CVD.Nevertheless, this study has several limitations. Firstly, it is a cross-sectional study and thus does not show cause and effect or time and effect associations between the concentrations of heavy metals and the risk of MI. Secondly, only basic sociodemographic data were taken into account  along with two lifestyle variables that affect the level of heavy metals (smoking and obesity). A detailed analysis of heavy metal exposure, lifestyle behaviors, and other factors required to thoroughly assess the sources of exposure has not been performed. Thirdly, as each metal has its own placement in the organs and CV system, one specific approach for determining the general status of many metals has not been found. The assessment of plasma concentration cannot be the best way of showing the total concentration of some metals in the organism. However, Yuan et al.  analyzedThe findings of this study can have important political and scientific implications. The results highlight the significance of heavy metals in the current environment as an independent risk factor increasing the occurrence of MI, apart from traditional risk factors such as hypertension, low physical activity, and inappropriate diet. This might affect the prevention strategy used for no communicable diseases, which have so far focused on the factors determined by lifestyle, for instance, as indicated in the 2008 report of the World Health Organization (WHO) . The recAlthough the findings of this study require validation, they can have important implications for public health, taking into account the high rate of mortality due to CVDs. Further research is required to explain the mechanisms underlying the influence of heavy metals concentration on the risk of CVDs. Such research should be perspective and cohort-based, while taking into account a greater number of patients, and should involve long-term assessment of heavy metal exposure. Thus, future studies should perform repeated measurements of heavy metal concentration during the lifetime of an individual, as this can provide valuable information on the impact of long-term exposure to higher concentrations of heavy metals in the environment on the risk of CVDs. Moreover, this might allow understanding the regeneration of heavy metals. Secondly, future research should take into account the levels of metal-binding proteins, which indirectly reflect the levels of heavy metals in the human body.To summarize, this research revealed higher concentrations of Cu, Zn, Mn, Co, and Fe in the blood serum of post-MI patients in comparison with that of individuals free from CVE. Moreover, higher concentrations of the analyzed heavy metals were found to significantly increase the occurrence of MI. Considering the increasingly higher exposure to heavy metals in the environment, this study has numerous implications for public health.


Aim. Our objective is to explore the association between demographic variables and the knowledge of self-care practices in type 2 diabetes mellitus. Methods. We used observational cross-sectional descriptive study using a validated self-administered questionnaire in both Arabic and English languages as well. A descriptive correlation design analyzed the questionnaire completed by a convenience sample meeting the inclusion criteria. Results. A total of 100 patients met the inclusion criteria for the analysis out of 3251 patients who completed the questionnaire. The study population has low moderate knowledge in diabetes, moderate knowledge in self-care practices, and good knowledge about complications of nephropathy and cardiovascular disease. No significant association between demographic variables. However, better knowledge observed in male (p = 0.028) and self-care practices with female (p = 0.020). Further, educational status is significantly influencing the knowledge of diabetic patients. Conclusion. The study emphasizing irrespective of demographic variable and the importance of patient education to achieve well glycemic control.The chronic hyperglycemia in diabetes is associated with long-term damage, dysfunction, and failure of different organs. Lack of patient education and knowledge about these complications can worsen the quality of a patient's life. Hence, more efforts are needed to improve patient's education especially in rural areas.  Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder affecting about 425 million people worldwide in 2017, and, according to the International Diabetes Federation (IDF) report, is expected to affect up to 629 million people by 2045 . T2DM caPatients with T2DM were included in the study and given a predesigned questionnaire completed during face-to-face interviews. We randomly selected participants over the age of 18 years  at different locations in large primary care centers and private pharmacies in the Tabuk region. We excluded young people (younger than 18 years old) and lately diagnosed diabetic patients (before less than 5 years). Moreover, we excluded patients who had bad handwritings, who intended to hide information, who did not understand the questions even after explanation, who gave irrelevant information, who are mentally handicapped, who are with medical background , who had attended diabetes education programs in the last 6 months, who were on a hurry, and who did not complete the questionnaire. Subjects were consented to participate after they were given full details of the study and its intended aims. Moreover, we clarified their queries before obtaining the consent. Patients fulfilled the inclusion criteria ) and were included for the final analysis. The rationale for choosing the areas is to observe the transition of the disease as a consequence of changing lifestyles and the effect of the presence of both the university and diabetic center related to the ministry of health in Tabuk as well. Besides, these areas were included as 2.77% of the total population of Saudi live in such areas according to the 2019 national statistics .An observational cross-sectional descriptive study extended for one year from March 2018 to September 2019. We used a previously validated questionnaire for the knowledge, attitude, and practice for diabetes mellitus in both Arabic and English languages as well. The Arabic translation was done by a professional Arabic speaker and expert in both languages with good explaining ability for the meaning to the publics. The Arabic version then went through further revision and then back translated into English by another bilingual translator. This Arabic version of the final form was examined and approved by two diabetologists to assess content and construct validity. The questionnaire did not contain any questions which can reveal the identity of patients or their treating doctors. The first segment of the questionnaire included the socio-demographics of the participants. Data included gender, age, level of education, average income, and occupation. Participants were also asked whether their occupation and education were related to the medical field. Knowledge regarding T2DM was measured using eight main questions related to the risk factors, diagnosis, prevention, and complications of diabetes mellitus. The possible categorical answers were “Yes,” “Do not know,” and “No.” The diabetes attitude was assessed using seven questions related to compliance with the treatment of DM. The possible categorical answers were “Yes,” “Do not know,” and “No.” Patients' interviews were conducted at the outpatient departments (OPDs) of King Fahd Specialized Hospital in Tabuk and attended twelve different large private community pharmacies in Tabuk region. The sample size was calculated using alpha error 5% and study power 80%, a test value (%) of 11%, and expected sample value (%) of 14% giving a sample size of 100 with adding 10% for nonresponse rate a final sample of 100 was calculated. Participants were well informed about the study and also clarified their queries before obtaining the consent. Out of 325 participants with type 2 diabetes mellitus showed willingness to participate; however, only 100 participants fulfilled the inclusion criteria ) and were included in the study.t-test and ANOVA were used to test the equality of means between demographic variables.Before administering questionnaires, participants were orally informed about the purpose of the study, emphasizing that participation was voluntary and that their answers would be kept confidential. A structured and pretested data collection form to inquire about such as age, sex, residence, education, occupation, past-medical history, past medication history, and social. A questionnaire used to collect the information from the respondents is consisting four segments including the socio-demographic data, the knowledge of diabetes, self-care practices, and complications , 14. A pThe study protocol was approved by the Local Research Ethics Committee of the University of Tabuk under the number (UT-64-26-2018), including the use of oral consent for the collection of data. Meanwhile, the Institutional Review Board (IRB) of our institution exempted our study from review. The committee unconditionally approved the project and agreed to verbal consent to be used.During our study, 3786 males and 3831 females were subjected to the preliminary analysis. The percent of T2DM (4365 patients) from the totally analyzed patients was about 57.3%. 3251 patients, from those showed willingness to participate (74.48% response rate), were included in this study and were given a questionnaire using the purposive sampling method. Only 100 patients fulfilled the inclusion criteria ) and were included for the final analysis. In addition to KAP, we collected socio-demographic data that include gender, age, occupation, marital status, educational level, income, family history of diabetes, duration of diabetes, and medications. The details of patient demographics mentioned in t-test (Tables p = 0.028), awareness of self-monitoring of blood glucose level in diabetes (p = 0.020), and uncontrolled diabetes can cause stroke (p = 0.034). The analysis of ANOVA test results (Tables p ≤ 0.001) and awareness about HbA1c apart from blood glucose (p = 0.038).Student's t Tables  and 3 sh p = 0.03. The anas Tables  reflectsp = 0.036) and knowledge on uncontrolled diabetes can cause stroke (p = 0.026). Further, educational status has significant association with the importance of foot care in DM (p = 0.037).As shown in Saudi Arabia is ranked the second country in the Middle East and the seventh country worldwide for the rate of diabetes . This hip = 0.028 and 0.02, respectively). This result is more reliable than the previously published report [p = 0.02) higher in female [The studied population in the present study found to have a low to moderate knowledge about the disease factors, which is consistent with the recent systematic review published from Saudi Arabia and they addressed poor knowledge of health care professionals in this regard –21. The d report . A signin female . WillingModerate score on self-care practices observed with no significant influence on the demographic variables including age, gender, disease duration, and occupational status. The influence of socioeconomic factors in self-care practices of diabetes is already established by the previous investigators , 30. SocThis is a preliminary attempt to investigate the patient perceptions on knowledge, self-care practice, and complications of diabetes among the northwest population in Saudi Arabia. This study was also limited to diabetic patients who were interested to participate. We assessed their knowledge, attitude, and practice on disease, self-care practice, complications, and insulin use. Moreover, we used a well-documented questionnaire for the diabetic knowledge.The present study recommends the need of patient education to attain medication adherence; thus, it brings better glycemic control in order to protect this population from complications of diabetes mellitus. The pharmacist may play pivotal role in educating the diabetic population. The study showed moderate level of diabetes awareness and good level of positive attitudes towards self-care practice. There is a need to carry out large-scale awareness programs to spread the message to the general population.


Traditional Chinese medicine (TCM) has a long history of use in breast cancer, but lacking systematic evidence to support its clinical benefits. In this study, we evaluated the prophylactic and therapeutic effects of moxibustion combined with decoctions for treating chemotherapy-induced myelosuppression (CIM) in early-stage breast cancer patients.This is a randomized controlled clinical trial single-blinded for TCM decoction but not moxibustion. Patients are equally divided into the control group without decoction and moxibustion treatment (control), the decoction+moxibustion group (MD), and the placebo+moxibustion group (MP), according to the following stratification factors: age , chemotherapy regimen , and chemotherapy strategy (adjuvant and neoadjuvant). The TCM decoction is Wenshen Shengbai Decoction. The anticipated sample size is 462 cases (154 cases in each group). All participants are expected to treat with chemotherapy and recombinant human granulocyte colony-stimulating factor (rhG-CSF). The primary outcomes include the proportion of patients with relief of leukopenia and/or neutropenia, the myelosuppression-associated serious adverse event including grade 3–4 leukopenia and/or neutropenia, and febrile neutropenia, and the dose of rhG-CSF. The secondary outcomes include chemotherapy adherence, stratified analysis, adverse reactions, quality of life by EORTC Breast-Cancer-Specific Quality of Life Questionnaire including EORTC QLQ-C30 (V3.0) and QLQ-BR23, TCM Constitution, and 3-year disease-free survival and overall survival. Baseline information including age, surgical approach, chemotherapy regimen and strategy, pathological stage, and molecular subtype will be recorded.This will be the first randomized controlled trial to evaluate the efficacy of moxibustion combined with TCM decoction in treating CIM in early-stage breast cancer patients, aiming to standardize the TCM decoction and moxibustion method, thus providing evidence for its clinical benefit.ChiCTR-INR-16009557. Registered on 23 October 2016.chictr.org.cn  For patAt present, recombinant human granulocyte colony-stimulating factor (rhG-CSF) is commonly used in the prophylactic and therapeutic treatment of CIM –14. rhG-Nowadays, the value of traditional Chinese medicine (TCM) and moxibustion as a comprehensive treatment approach in breast cancer is getting well-recognized . A largeThe present study aims to evaluate the efficacy of moxibustion combined with TCM decoction in treating breast cancer patients with CIM, in a randomized controlled setting. Through this study, we intend to establish a standardized TCM regimen and moxibustion method and provide evidence for the clinical benefits of moxibustion combined with TCM decoction, in compliance with current clinical practice guidelines.This study is a randomized controlled clinical trial single-blinded for TCM decoction but not moxibustion. Patients will be divided into groups by stratified randomized grouping. The stratification factors involve age , chemotherapy regimen , and chemotherapy strategy (adjuvant and neoadjuvant). All eligible patients are equally divided into the control group with no TCM decoction/moxibustion treatment (control), the TCM decoction combined with moxibustion group (MD), and the placebo combined with moxibustion group (MP). All participants are expected to treat with standard chemotherapy and rhG-CSF regimen. The detailed study flow is illustrated in Fig. Patients will be recruited from Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine.Patients should meet both the TCM and the western diagnostic criteria. A pathological diagnosis is required for every recruited patient.Patients must be female.Aged 18 to 80 years old.Pathologically confirmed as primary invasive breast cancer.Expected to undergo chemotherapy according to the guidelines.Patients who agreed to, and are expected to, receive and complete a full course of chemotherapy.White blood cell (WBC) count and absolute neutrophil count (ANC) before chemotherapy must be higher than the upper limit of the normal value.Patients with good compliance in terms of language and willingness to follow-up.Signed written informed consent obtained.The inclusion criteria were as follows:For inclusion criteria 1, the clinical diagnosis is in accordance with the “Tumor of the Breast (Second Edition)” edited by Shao Zhimin. The pathological diagnosis is in accordance with the “WHO Classification of Tumours of the Breast ”. The diagnosis and staging are based on clinical examination and post-operative pathological results according to the cancer staging criteria described in American Cancer Joint Committee (AJCC) (7th Edition). For the TCM diagnostic standard, the diagnosis is in accordance with the “SHIYONG ZHONGYI WAIKEXUE ” edited by Lu Deming and “Guideline for Diagnosis and Treatment of Tumour in TCM (ZYYXH/T135-156-2008)” edited by the China Association of Chinese Medicine. Chemotherapy regimen is based on CACA Guidelines for Breast Cancer Diagnosis and Treatment (2015 Edition) and NCCN Clinical Practice Guidelines in Oncology: Breast Cancer (Version 3. 2015).Prior history of receiving systemic chemotherapy or radiotherapy.Severe liver and kidney dysfunctions .Severe heart dysfunction or other organ failures.Any previous or concurrent primary malignancy.Pregnant (serum β-HCG test) or lactating women.Participating in other clinical trials 3 months prior to enrolment.Cannot participant in the study due to any reasons such as language issues, geometrically unable to follow up, etc.Other conditions or diseases that may result in significant risk to the patients as determined by the investigator.The exclusion criteria were as follows:Written, informed consent to participate will be obtained from all participants through their responsible physicians. Participating in the study is voluntary. Participants may withdraw at any time without any given reason and the course of treatment will not be affected.On the consent form, participants will be asked if they agree to use their data in our ancillary study. Participants will also be asked for permission for the research team to share relevant data with people from the university taking part in the research or from regulatory authorities, where relevant.The control group is treated routinely without either TCM decoction or moxibustion. Both the MD and MP groups are treated with moxibustion. The MD group is additionally treated with TCM decoction, while TCM placebo is provided to the patients in the MP group.The TCM placebo which is made of excipients and flavouring agents is used as a comparator. The packaging, shape, weight, odour, and colour of the placebo are identical to that of the Wenshen Shengbai Decoction. The placebo is manufactured by Jiangyin Tianjiang Pharmaceutical Co., Ltd., and is stored and provided to the patients by the Central Pharmacy of Yueyang Hospital.Shenque (CV8), Qihai (CV6), Guanyuan (CV4), bilateral Zusanli (ST36), and bilateral Sanyinjiao (SP 6) acupoints were selected. The rationale for moxibustion acupoint selection, treatment course, and duration has been described in a previous review published by our team . ShenqueIn the Inner Canon of Huangdi, the relationship between breast and meridian was described. The Stomach Meridian of Foot-Yanming runs downward along the midclavicular line and cross Ruzhong. The Spleen Meridian of Foot-Taiyin arises from the stomach, ascends through the diaphragm, and enters the chest. The Liver Meridian of Foot-Jueyin ascends through the diaphragm, distributes in the costal and the hypochondriac regions, and curves around the nipple. The Kidney Meridian of Foot-Shaoyin runs into chest to meet with breast. The Ren meridian ascends along the anterior medial line to the Guanyuan and enters the chest. The Chong meridian runs along both sides of the umbilicus and spreads over the chest. Therefore, current doctors generally accept that women’s nipple belongs to liver, and breast belongs to stomach. Thus, breast disease has a close relationship with zang-fu of liver, kidney, spleen, and stomach, as well as meridians of Chong-Ren. Zusanli belongs to the Stomach Meridian of Foot-Yanming and plays a role in assisting digestion, regulating spleen and stomach, reinforcing weakness, and regulating Qi and blood. Sanyinjiao originating from the postnatal essence belongs to the Spleen Meridian of Foot-Taiyin. It is the main intercept of the liver, spleen, and kidney meridians, which can strengthen the spleen and blood and regulate the liver and kidney . ShenqueFully expose the acupoints with mild moxibustion method, that is, ignite the moxa sticks, and then apply them to the acupoints. Cut a 1.5-cm-long moxa stick (ensure that the size and density meet the required specifications). The ignited moxa sticks should remain about 2–3 cm away from the skin to allow the patient to feel warm, but not burning . The patient should be lying down, and the three acupoints including Shenque, Qihai, and Guanyuan should simultaneously apply moxibustion. Next, the patient should be sitting down, and Zusanli (both sides) followed by Sanyinjiao (both sides) should apply moxibustion. Each moxibustion lasts for 15 min. Gently massage the acupoints after moxibustion. The moxibustion should be performed once daily.Moxibustion starts from the 2nd day after chemotherapy and continued daily moxibustion until the day before the next cycle of chemotherapy. No moxibustion was given on the day of drug administration. The treatment course is completed 3 weeks after the end of the last chemotherapy. Daily self-moxibustion is carried out by the patient at home and is guided by Yueyang Hospital and Shanghai Acupuncture and Meridian Research Institute. Shanghai Research Institute of Acupuncture and Meridian will provide technical support for moxibustion.Astragalus, Codonopsis pilosula, Atractylodes macrocephala, Poria cocos, Adenophora tetraphylla, Lycium chinense,Epimedium, Cistanche deserticola, Morinda officinalis, Curcuma zedoaria, Salvia chinensis, Sophora flavescens, Rhizoma polygonati, Cornu cervi, and Psoralea corylifolia [Wenshen Shengbai Decoction consists of ylifolia . The herPost-operative CIM in breast cancer often causes fatigue, dizziness, and unwillingness to speak, palpitations, insomnia and dreaminess, spontaneous sweating and tachypnea, pale and enlarged tongue, weak pulses, etc. Although the concept of myelosuppression was not mentioned in ancient TCM, these clinical symptoms could be classified as a kind of “blood deficiency” and “consumptive diseases”. The treatment of CIM should, therefore, base on the concept of “tonifying the deficiencies” and “warming the consumptions”.Astragalus, Codonopsis pilosula, Atractylodes macrocephala, and Poria cocos in Wenshen Shengbai Decoction can tonify Spleen and support Qi and secure the postnatal condition, thus activating Qi and developing blood; Adenophora tetraphylla and Lycium chinense can nourish Yin and promote body fluid; Epimedium, Cistanche deserticola, and Morinda officinalis can tonify the kidney, regulate Chong Ren, and constrain the prenatal condition, thus enhancing the healthy Qi and resistance to pathogenic factors; Curcuma zedoaria and Salvia chinensis can promote blood circulation and detoxification and resolve phlegm; Sophora flavescens can clear away heat and dampness; Rhizoma polygonati, Cornu cervi, and Psoralea corylifolia can tonify kidney and fill the essence.The The rhG-CSF is performed according to the guidelines –14. PatiThe investigator is responsible to decide whether adjuvant chemotherapy or neoadjuvant chemotherapy is suitable for the patients according to the CACA Guidelines for Breast Cancer Diagnosis and Treatment (2015 Edition) and NCCN Clinical Practice Guidelines in Oncology: Breast Cancer (Version 3. 2015). Choices of chemotherapy regimens include anthracycline , taxanes , anthracycline combined taxanes , and others .Participants who show any adverse effects will be reported and followed up by their responsible physicians. A reduction in dose or discontinuation of treatment will be decided by the physician according to the CACA Guidelines for Breast Cancer Diagnosis and Treatment (2015 Edition) and NCCN Clinical Practice Guidelines in Oncology: Breast Cancer (Version 3. 2015), or upon participant request. Outcome data will be collected as usual according to the protocol for these participants.To improve the adherence and promote participant retention, the required amount of moxa sticks and TCM granule will be provided by the Central Pharmacy of Yueyang Hospital to the corresponding participants each time after receiving chemotherapy, for free. For participants who decide to discontinue the treatment and withdraw from the study, they will be asked to fill a questionnaire to simply explain the reason behind. After discontinuation, outcome data will not be collected for these participants.No specific concomitant care and interventions are permitted or prohibited during the trial.None.The proportion of patients with relief of leukopenia and/or neutropenia.The number and proportion of patients with relief of myelosuppression-associated SAE, defined as grade 3–4 leukopenia and/or neutropenia and FN.The median and mean duration time of relief of leukopenia and/or neutropenia.The dosing of rhG-CSF.Primary outcomes are as follows:9/L. Neutropenia is defined as an abnormal decrease in netrophils of less than LLN-1.5 × 109/L. The definition of FN is based on the IDSA guidelines (American Society of Infectious Diseases Guide 2010 edition), which is an absolute neutrophil count (ANC) of < 500 neutrophils/mcL or an anticipated decline to ≤ 500 in the next 48 h and progress to ≥ 38.3 °C orally or ≥ 38.0 °C for a duration over 1 h.The grading of adverse reactions is in accordance with the CTCAE 4.0.2 criteria. Leukopenia is defined as an abnormal decrease in white blood cells of less than LLN-3.0 × 10Chemotherapy adherence: The percentage of patients who completed the full-course chemotherapy in a standard dose. If only the full course of treatment is completed but the dose of chemotherapy is reduced, or the dose is unchanged but the course of treatment is shortened, the case will be treated as poor adherence.Stratified analysis: Subgroup analysis will be done according to age, chemotherapy regimen, and chemotherapy strategy.Adverse events: Any toxic side effects such as general condition, gastrointestinal reactions, liver and kidney function, skin reactions, burns, and heat syndrome will be recorded.ECOG PS: The performance status of the patients before and after the completion of the whole treatment cycle according to the Eastern Cooperative Oncology Group.Quality-of-life survey: EORTC QLQ-C30 (V3.0) and EORTC QLQ-BR23 will be used to assess the QoL of patients. QLQ-C30 is a scale developed by the European Organization for Research and Treatment of Cancer (EORTC) to measure the QoL of cancer patients. QLQ-BR23 is a QoL questionnaire designed for breast cancer patients, which is suitable for evaluating all breast cancer patients regardless of the type of treatments. Also, a TCM Constitution survey based on the judgement criteria recognized by the China Association of Chinese Medicine will be conducted . The TCMSurvival: The differences in 3-year DFS and OS between the treatment group and the control group will be analysed.Secondary outcomes are as follows:The time schedule of enrolment, interventions, and assessments is as shown in Table α = 0.05 and 1-β = 0.08, taking a 20% drop rate into account, the required total sample size is 462 cases and 154 cases in each group.In previous studies, the incidence rate of myelosuppression was 81.0% in the control group and 61.7% in the TCM decoction group . The curNone.The administrative staffs are responsible for generating the random allocation sequence using SPSS and providing the treatment allocation to the physicians in sealed envelopes.As mentioned above in {16a}.The physicians are responsible for patient enrollment and the assignment of participants to corresponding interventions according to the treatment allocation.Participants in the MD and MP groups are blinded to the use of TCM. The required amount of TCM granule or TCM placebo will be provided to the corresponding participants according to the grouping each time after chemotherapy. In consideration of the patient’s safety, outcome assessments are not blinded to the physicians.None.Paper-based case report forms are filled by the physicians and are securely delivered to the trial office by each corresponding physician as soon as possible. The filled data is double-checked by administrative staffs who are responsible for data entry and maintenance of the electronic database. Data will only be accessible to the physicians responsible for the data analysis after the completion of patient recruitment. The template of case report form is available upon request.Baseline information including age , surgical approach (breast-conserving and axillary conserving), chemotherapy regimen , chemotherapy strategy (adjuvant and neoadjuvant), pathological staging , and molecular subtype  will be recorded.Blood routine test: Monitoring WBC count and ANC once a week during every cycle of chemotherapy.TCM-related symptom: The investigators will evaluate the TCM-related symptoms based on the scoring method Table  describeAdverse effects: Grading on a scale of 0 to 4 according to CTCAE 4.0.2.Quality-of-life: EORTC QLQ-C30, QLQ-BR23, and TCM Constitution.All results are recorded in the case report form. Participants who show any adverse effects will be reported and followed up by their responsible physicians.Three-year, 5-year, and 10-year DFS and OS.Level 1: Safe—no adverse reactions; no abnormalities in safety indicators.Level 2: Comparatively safe—mild adverse reactions are observed; treatment can be continued without any intervention; no abnormality in safety indicators.Level 3: Safe issues arise—moderate adverse reactions or mild abnormalities in safety indicators are observed; treatment can be continued with suitable intervention.Level 4: Serious adverse reactions—study abortion due to serious adverse reactions; safety indicators are remarkably abnormal.Safety evaluation: Blood pressure, heart rate, heart rhythm, respiratory rate, blood routine test, and liver and kidney functions are assessed on a scale of four levels.All patients will undergo an 8-week follow-up on blood routine tests, liver and kidney functions, and adverse events. The detailed schedule of enrolment and assessment is listed in Table As mentioned above in {11c}.A data management team consisting of administrative staffs and physicians from the Yueyang Hospital is formed to monitor the study data.The patient’s names are de-identified in the database to protect the patients’ confidentiality.This trial involves collecting biological specimens for storage. Genetic analysis with the blood samples collected is planned in our ancillary study.P values < 0.05 considered as statistically significant.Data were analysed using SPSS 18.0  and Stata10.0 . Multivariate analysis was performed by multiple linear regression, COX regression, or logistic regression, where appropriate. All analyses are based on two-sided test, with H test and the Nemenyi test.If the data shows a normal distribution, the data will be expressed as the mean ± standard deviation. Differences between groups are analysed by one-way ANOVA. If the data does not show a normal distribution, the data will be expressed as the median, lower 25% quantile, and upper 75% quantile. Differences between groups are analysed by the Kruskal-Wallis The frequency, relative number, and rate of the data will be calculated. If the data is not in order, the chi-square test or Fisher’s exact test is used to compare the difference between groups. If the data is in order, the rank-sum test is used instead.The survival curve is plotted by the Kaplan-Meier Method. The log-rank test is used to compare the difference between groups.No interim analyses are planned in this study.None.Two datasets will be generated for subsequent analysis: the intent-to-treat (ITT) population which includes all eligible participants and the per-protocol (PP) population which includes only participants who completed the trial.None.As mentioned above in {19}.As mentioned above in {18a}, {19}, and {23}.As mentioned above in {11b}.The frequency and plans for auditing trial conduct are as shown in Table None.The final data of the study will be presented at national and international conferences. In addition, a manuscript will be written and submitted to open access peer-reviewed journals.Due to the huge population size of breast cancer patients in China, the society is now facing a heavy medical burden. Chemotherapy, as one of the routine systemic treatments for breast cancer, inevitably induced CIM which induces toxic side effects and increases the infection risk of patients, thus leading to chemotherapy discontinuation. As a result, the prevention and treatment of CIM is the key to treatment success. Although rhG-CSF is an effective treatment for myelosuppression, it is expensive and has numerous side effects that could impact the patients’ QoL.In many studies, TCM decoction is found effective to alleviate myelosuppression, which can act as a more economical alternative with fewer side effects and better adherence compared to the existing rhG-CSF treatment. Other than decoctions, moxibustion has also been widely used in preventing and treating diseases. Moxibustion has the function of warming meridians, eliminating phlegm and blood stasis, dispelling Yin and stagnation, replenishing Qi and Yang, rehabilitating and strengthening health, and preventing diseases. It also plays a role in reducing toxicity and improving the efficacy of cancer treatment . SeveralIn order to develop an evidence-based standardized regimen of TCM and moxibustion methodology, conclusive result from a comprehensive scientific study is essential. In this study, moxibustion, or both TCM decoction and moxibustion, is used in combination with rhG-CSF to treat CIM in early-stage breast cancer patients. We intend to create a novel standardized TCM-combined treatment and provide a clinically simple, convenient, and cost-effective intervention that can benefit breast cancer patients’ QoL. Our study integrates TCM and Western medicine to solve unmet medical needs. As a well-organized prospective study, we expect the results could facilitate the translation of TCM concepts into the modern clinical practice of cancer management. This study also aims to standardize a new combination of treatment strategy with integrative Chinese and Western medicine, ultimately forming related expert consensus and clinical guidelines.The trial started recruitment on 27 December 2017 . Until 8 December 2019, 218 patients were enrolled. The estimated date of recruitment completion is 31 December 2020.Additional file 1. SPIRIT 2013 checklist.Additional file 2. Figure S1. Clinical pathway of each participant


As relative LBM and ASM increased, the risk of MetS was more significantly reduced in the group with higher baseline BMI and body fat mass index (BFMI). In men, when the relative LBM increased , the risk of MetS was low despite increased BMI. Thus, our findings suggested that an increase in the relative LBM and ASM reduced the risk of MetS, whereas an increase in the relative BFMI increased the risk of MetS; this result was consistent in men despite an increase in BMI.In a cohort of 190,599 participants from The National Health Insurance Service-National Health Screening (NHIS-HEALS) study, we investigated the association of changes in the predicted body composition and metabolic profiles with the risk of metabolic syndrome (MetS) in the general population, which was hitherto incompletely elucidated. At baseline and follow-up examinations, the body composition, including lean body mass (LBM), body fat mass (BFM), and appendicular skeletal mass (ASM), were estimated using a prediction equation, and the risk of MetS was analyzed according to relative body composition changes. An increase in relative LBM and ASM decreased the risk of MetS in men and women (adjusted odds ratio (aOR), 0.78 and 0.80; 95% confidence interval (CI), 0.77–0.79 and 0.79–0.81, respectively; all  Metabolic syndrome (MetS) is a pathological condition characterized by abdominal obesity, impaired fasting glucose, dyslipidemia, and hypertension. It is estimated that approximately one-third of the US population, 15.5% of China’s population, and approximately one-quarter of the world population have MetS ,3, and cBody composition is related to various physiological and pathological states. Excessive body fat, which is characteristic of obesity, is a major health risk. Several organizations, such as the World Health Organization , the NatBody mass index (BMI), which is the preferred measure to assess general obesity, actually does not fully represent the adiposity of the body. The BMI does not distinguish the different body components of fat mass and muscle mass. Recently, the general clinical perception that the lack of muscle mass and excessive body fat are associated with metabolic diseases has increased . MoreoveIt is well-known that weight reduction can reduce the risk of MetS and improve metabolic profiles . HoweverThe Korean National Health Insurance Service (NHIS) database provides health insurance to >95% of Korean citizens  and bian2) were excluded from the analysis, as were 6137 participants with an estimated glomerular filtration rate of <30 mL/min/1.73 m2, consistent with chronic kidney disease stages IV and V. An additional 78,625 participants who already had MetS at baseline were excluded. Finally, 190,599 participants, including 101,536 men and 89,063 women, were enrolled. Of the 487,835 participants who underwent health examinations during the first (2010–2011) and the second (2012–2013) periods, 204,257 participants were excluded because of missing information on anthropometric profiles, metabolic profiles , physical activity, smoking status, alcohol habit, and serum creatinine levels. In total, 8217 underweight participants , BFMI (kg/m2), and ASMI (kg/m2) were calculated using the prediction equations presented in the The prediction equations were validated using the Bland–Altman plot and the intraclass correlation coefficient (ICC). The ICCs were all >0.9. Each of the prediction equations showed a high predictive power for each body composition  , percentage body fat mass (BFMI/BMI × 100), percentage appendicular skeletal muscle mass (ASMI/BMI × 100), relative lean body mass (relative LBM), relative body fat mass (relative BFM), and relative appendicular skeletal muscle mass (relative ASM). The relative LBM, BFM, and ASM were adopted in this study because these parameters could be adjusted for the body frame size. Additionally, the changes in relative body composition were the main focus of this study. The change in the relative LBM, termed ΔRelative LBM, was calculated from the difference between the first and second relative LBM, and the ΔRelative BFM and ΔRelative ASM were also calculated similarly.MetS was determined based on the NCEP-ATP III criteria that were modified for the Asian population . The parSmoking status, alcohol consumption, and physical activity were assessed by using a self-reported questionnaire. According to the previous study that described the characteristics of the NHIS-HEALS cohort database, the questionnaires for evaluating smoking status and alcohol use status were composed as follows : (1) smot-tests were used for the categorical variables and the continuous variables, respectively, to compare the general characteristics of the participants at baseline and follow-up. Linear regression analysis was performed to determine the linear relationship between body compositional changes  and changes in the metabolic profiles . A regression analysis was performed after adjusting for variables, such as age, household income, smoking status, alcohol consumption, physical activity, and the CCI. Logistic regression analysis was then performed to determine the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) of newly developed MetS and pathologies, including abdominal obesity, hyperglycemia, hypertension, hypertriglyceridemia, and low HDL-C, that were determined during follow-up based on the changes in the body composition (1% increments) between the baseline and follow-up examinations. Stratified analyses of the effects of changes in body composition on the risk of MetS were conducted according to the subgroup of the baseline BMI, baseline BFMI quartile, and the number of initial metabolic pathologies .The chi-squared and paired 2 during the two sequential health examinations), maintained BMI (changes in BMI between −2 kg/m2 and +2 kg/m2), and increased BMI (BMI increased by >2 kg/m2). We then performed a logistic regression analysis of the newly developed MetS cases according to the changes in their body composition . The covariates considered in the analysis included continuous variables, age and CCI, and categorical variables, such as household income , physical activity , smoking status , and alcohol consumption . Statistical significance was defined as p < 0.05 in a two-sided manner. All data collection and analyses were conducted using SAS version 9.4  and STATA version 13.0 .To evaluate the combined effects of the changes in BMI and body composition, stratified analysis was performed to evaluate the effect of changes in BMI during the two health examinations on the risk of MetS according to the changes in the body composition. We categorized the participants into three groups: decreased BMI (BMI decreased by >2 kg/mp < 0.001), 26.37 ± 6.57% from 26.29 ± 6.55% (p < 0.001), and 30.29 ± 3.81% from 30.25 ± 3.73% (p < 0.001), respectively.The association between the changes in the variable body composition and the changes in the metabolic profiles, WC, BP, FSG, serum TG, and serum HDL-C are shown in 2), overweight (BMI 23–24.9 kg/m2), and obese (BMI ≥ 25 kg/m2), baseline BFMI quartile , and the number of metabolic pathologies recorded during the baseline health examination . The effect of increased relative LBM and ASM on the risk of MetS was more prominent when the participants were more obese (p for trend < 0.001), and the effect increased when the initial BFMI was higher (p for trend < 0.001). The fewer the initial metabolic pathologies, the greater was the effect on the reduction in the risk of MetS (p for trend < 0.001). Contrary to the effect of relative LBM and ASM, an increased relative BFM increased the risk of MetS in all subgroups. In women, the results showed a similar association between changes in the relative body composition and the risk of MetS.The multivariable logistic regression analysis revealed an association between the risk of MetS and changes in body composition . In men,The findings of this large-scale population study suggested that an increase in relative muscle mass and a decrease in fat mass decreased the risk of MetS and improved the metabolic profiles. In particular, the same result was found in men even when BMI increased. This result suggests that, in agreement with our hypothesis, an increase in BMI may not necessarily be critical to an increase in the risk of MetS and that a change in body composition may be a more meaningful indicator for assessing the risk of MetS. In particular, the results were consistent with our hypothesis that a change in body composition, that is, an increase in relative muscle mass (LBM and ASM) or a decrease in relative BFM, lowered the risk of MetS regardless of the change in body weight.Recently, skeletal muscle has been considered an endocrine and paracrine organ. It is well established that skeletal muscle regulates glucose metabolism through interorgan crosstalk with the stomach, liver, kidney, and brain . MoreoveEven though several novel techniques and methods are now available for estimating body composition, BMI is still used as a surrogate marker and is assumed to be representative of adiposity. This situation is presumed to arise due to various difficulties in clinically applying new measurement methods to many subjects. A previous study showed that increased BMI is a major risk factor for MetS . In genep for trend < 0.001). In women, the maintained-BMI and the decreased-BMI groups showed similar results as in men. However, there was a difference in the increased-BMI group; the risk of MetS did not significantly decrease despite an increase in the relative muscle mass. In addition, the risk of MetS did not increase significantly with an increase in the relative BFM. A possible explanation for this result is that an increase in BMI and body weight is not achieved solely by an increase in BFM or muscle mass. If the relative muscle mass increased as the BMI decreased, it could be inferred that the BFM decreased relatively and absolutely. In addition, if the relative muscle mass increased while the BMI was maintained, we could infer that the relative fat mass decreased and the increase in the absolute fat mass was not noticeable.In men, the increase in the relative muscle mass reduced the risk of MetS among all BMI-change (increased/decreased BMI) groups. Even if the BMI increased, the increase in relative muscle mass reduced the risk of MetS. The increase in relative BFM increased the risk of MetS among all BMI-change groups. In particular, when the BMI was reduced, the harmful effect of increased relative BFM was most prominent among BMI-change groups . Third, the ethnicity of the study subjects was limited to Asians, which might limit the application of the results to all ethnic groups. Fourth, the follow-up period for observing changes in the body composition was relatively short (2 years), which may be insufficient to observe changes in the body composition and the risk of MetS. This study confirmed some degrees of changes in the risk of MetS according to the changes in the body composition, although a more remarkable result could have been confirmed if the follow-up period was longer.Our study has some limitations. First, the body composition was not measured by direct methods, such as dual-energy X-ray absorptiometry or bioelectrical impedance analysis. Consequently, there is a limitation that the subject’s body composition is a predicted value derived using a prediction equation rather than an actual measured value. Moreover, because of this limitation, it cannot be determined whether the change in the BFM was dominated by increased visceral fat or increased subcutaneous fat. Second, the prediction equation used in this study was not validated for patients with chronic kidney disease stage 4 and 5 with an estimated glomerular filtration rate of <30 mL/min/1.73 mIn conclusion, in Korean adults, a 1% increase in the relative LBM decreased the risk of MetS by 19–21%, and a 1% increase in the relative ASM reduced the risk of MetS by approximately 38%. Further, a 1% increase in the relative BFM increased the risk of MetS by 24–25%. This result was more prominent when the baseline BMI or BFMI was higher. In addition, in men, even if the BMI increased, the risk of MetS decreased as the relative muscle mass increased. The benefits and risks of increased relative muscle mass and BFM were attenuated when the BMI was increased in women. Based on our results, we recommend focusing on increasing the relative muscle mass and decreasing BFM rather than just decreasing BMI, especially in obese individuals. Further study is needed to evaluate the tradeoff between relative muscle mass gain and absolute body fat gain.