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Background: Many diabetic individuals use prescription and non-prescription opioids and opiates. We aimed to investigate the joint effect of diabetes and opiate use on all-cause and cause-specific mortality.Methods: Golestan Cohort study is a prospective population-based study in Iran. A total of 50 045 people-aged 40-75, 28 811 women, 8487 opiate users, 3548 diabetic patients-were followed during a median of 11.1 years, with over 99% success follow-up. Hazard ratio and 95% confidence intervals (HRs, 95% CIs), and preventable death attributable to each risk factor, were calculated.Results: After 533 309 person-years, 7060 deaths occurred: 4178 (10.8%) of non-diabetic non-opiate users, 757 (25.3%) diabetic non-users, 1906 (24.0%) non-diabetic opiate users and 219 (39.8%) diabetic opiate users. Compared with non-diabetic non-users, HRs (95% CIs) for all-cause mortality were 2.17 (2.00-2.35) in diabetic non-opiate users, 1.63 (1.53-1.74) in non-diabetic opiate users and 2.76 (2.40-3.17) in diabetic opiate users. Among those who both had diabetes and used opiates, 63.8% (95% CI: 58.3%-68.5%) of all deaths were attributable to these risk factors, compared with 53.9% (95% CI: 50%-57.4%) in people who only had diabetes and 38.7% (95% CI: 34.6%-42.5%) in non-diabetic opiate users. Diabetes was more strongly associated with cardiovascular than cancer mortality. The risk of early mortality in known cases of diabetes did not depend on whether they started opiate use before or after their diagnosis.Conclusions: Using opiates is detrimental to the health of diabetic patients. Public awareness about the health effects of opiates, and improvement of diabetes care especially among individuals with or at risk of opiate use, are necessary. [ABSTRACT FROM AUTHOR]

BACKGROUND Studies have indicated that branched amino acids play a crucial role in gene expression, protein metabolism, apoptosis, and restoration of hepatocytes and insulin resistance. This study aimed to compare the plasma levels of branched-chain amino acids in patients with esophageal cancer and normal individuals. METHODS Plasma levels of leucine and isoleucine of 37 patients with esophageal cancer and 37 healthy adults were investigated by high-pressure liquid chromatography. Data analysis was performed using SPSS (version 16) software, and t test was used to compare the plasma levels of branched-chain amino acids in the two groups. RESULTS In the patients group, the mean age ± SD was 63 ± 13.64 years, and 21 (56.8%) individuals were male. In the control group, the mean age ± SD was 64.24 ± 13.08 years, and 21 (54.1%) individuals were male. Plasma levels of leucine (37.68 ± 105) and isoleucine (22.43 ± 59.1) in patients with esophageal cancer were significantly reduced (p value of isoleucine:0.007, and leucine: 0.0001). CONCLUSION In the present study, the plasma levels of branched-chain amino acids in patients with esophageal cancer had changed. Evidence suggests that branched-chain amino acids are essential nutrients for cancer growth and are used by tumors in various biosynthetic pathways as energy sources. Thus, studies in this field can be useful in providing appropriate therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: A fixed-dose combination therapy (polypill strategy) has been proposed as an approach to reduce the burden of cardiovascular disease, especially in low-income and middle-income countries (LMICs). The PolyIran study aimed to assess the effectiveness and safety of a four-component polypill including aspirin, atorvastatin, hydrochlorothiazide, and either enalapril or valsartan for primary and secondary prevention of cardiovascular disease.Methods: The PolyIran study was a two-group, pragmatic, cluster-randomised trial nested within the Golestan Cohort Study (GCS), a cohort study with 50 045 participants aged 40-75 years from the Golestan province in Iran. Clusters (villages) were randomly allocated (1:1) to either a package of non-pharmacological preventive interventions alone (minimal care group) or together with a once-daily polypill tablet (polypill group). Randomisation was stratified by three districts (Gonbad, Aq-Qala, and Kalaleh), with the village as the unit of randomisation. We used a balanced randomisation algorithm, considering block sizes of 20 and balancing for cluster size or natural log of the cluster size (depending on the skewness within strata). Randomisation was done at a fixed point in time (Jan 18, 2011) by statisticians at the University of Birmingham (Birmingham, UK), independent of the local study team. The non-pharmacological preventive interventions (including educational training about healthy lifestyle-eg, healthy diet with low salt, sugar, and fat content, exercise, weight control, and abstinence from smoking and opium) were delivered by the PolyIran field visit team at months 3 and 6, and then every 6 months thereafter. Two formulations of polypill tablet were used in this study. Participants were first prescribed polypill one (hydrochlorothiazide 12·5 mg, aspirin 81 mg, atorvastatin 20 mg, and enalapril 5 mg). Participants who developed cough during follow-up were switched by a trained study physician to polypill two, which included valsartan 40 mg instead of enalapril 5 mg. Participants were followed up for 60 months. The primary outcome-occurrence of major cardiovascular events (including hospitalisation for acute coronary syndrome, fatal myocardial infarction, sudden death, heart failure, coronary artery revascularisation procedures, and non-fatal and fatal stroke)-was centrally assessed by the GCS follow-up team, who were masked to allocation status. We did intention-to-treat analyses by including all participants who met eligibility criteria in the two study groups. The trial was registered with ClinicalTrials.gov, number NCT01271985.Findings: Between Feb 22, 2011, and April 15, 2013, we enrolled 6838 individuals into the study-3417 (in 116 clusters) in the minimal care group and 3421 (in 120 clusters) in the polypill group. 1761 (51·5%) of 3421 participants in the polypill group were women, as were 1679 (49·1%) of 3417 participants in the minimal care group. Median adherence to polypill tablets was 80·5% (IQR 48·5-92·2). During follow-up, 301 (8·8%) of 3417 participants in the minimal care group had major cardiovascular events compared with 202 (5·9%) of 3421 participants in the polypill group (adjusted hazard ratio [HR] 0·66, 95% CI 0·55-0·80). We found no statistically significant interaction with the presence (HR 0·61, 95% CI 0·49-0·75) or absence of pre-existing cardiovascular disease (0·80; 0·51-1·12; pinteraction=0·19). When restricted to participants in the polypill group with high adherence, the reduction in the risk of major cardiovascular events was even greater compared with the minimal care group (adjusted HR 0·43, 95% CI 0·33-0·55). The frequency of adverse events was similar between the two study groups. 21 intracranial haemorrhages were reported during the 5 years of follow-up-ten participants in the polypill group and 11 participants in the minimal care group. There were 13 physician-confirmed diagnoses of upper gastrointestinal bleeding in the polypill group and nine in the minimal care group.Interpretation: Use of polypill was effective in preventing major cardiovascular events. Medication adherence was high and adverse event numbers were low. The polypill strategy could be considered as an additional effective component in controlling cardiovascular diseases, especially in LMICs.Funding: Tehran University of Medical Sciences, Barakat Foundation, and Alborz Darou. [ABSTRACT FROM AUTHOR]

Background and Objectives: The incidence rate of esophageal cancer (EC) is high in north and northeast of Iran. Taurine is a sulfur-containing amino acid with a wide range of vital biological functions. The aim of this study was to compare plasma levels of taurine between patients with EC and healthy controls. Methods: Plasma samples from 36 recently diagnosed cases of EC and 36 healthy adults were analyzed by high-pressure liquid chromatography. Data analysis was done using SPSS (version 16). The t-test was used to evaluate significant differences in the level of taurine between the two groups. P-values less than 0.05 were considered statistically significant. Results: Patients with EC had significantly higher levels of plasma taurine compared with the controls (P<0.05). Conclusion: Patients with EC have significantly higher levels of plasma taurine compared with healthy individuals. This finding suggests that the measurement of plasma taurine in patients with EC could be useful for the early diagnosis of the disease. [ABSTRACT FROM AUTHOR]

Objective: There are limited studies on the relationship between inflammatory marker such as IL-6 and lipid peroxidation and metabolic syndrome. The aim of present study was to assess IL-6 and lipid peroxidation in subjects with and without the metabolic syndrome and their association with metabolic syndrome components. Methodology: Age and gender matched 40 subjects with metabolic syndrome and 40 control groups took part in this study. Results: The mean malondialdehyde level was significantly higher in overweight and obese subjects with metabolic syndrome than control groups (P<0.05). The mean level of IL-6 in men and the mean level of malondialdehyde in women with metabolic syndrome was significantly higher than control groups (p < 0.05). There were significant positive correlation between malondialdehyde and fasting blood glucose, triglyceride and systolic blood pressure (p<0.05). Conclusion: Our results suggest that higher levels of IL-6 and malondialdehyde may cause insulin resistance and metabolic disorders in all subjects with metabolic syndrome. Malondialdehyde level shows strong association with some metabolic syndrome components. This means the greater risk of metabolic syndrome. [ABSTRACT FROM AUTHOR]

Background: Esophageal squamous cell carcinoma (ESCC) is a major health problem in many developing countries, including Iran. ESCC has a very poor prognosis, largely due to late diagnosis. As a first step in developing an early detection and treatment program, we conducted a population-based endoscopic screening for ESCC and its precursor lesion, esophageal squamous dysplasia (ESD), in asymptomatic adults from Golestan Province, northern Iran (a high-risk area for ESCC) to evaluate the feasibility of such a program and to document the prevalence and risk factor correlates of ESD. Methods: This cross-sectional study was conducted among participants of the Golestan Cohort Study (GCS), a population-based cohort of 50,000 adults in eastern Golestan Province. Randomly selected GCS participants were invited by telephone. Those who accepted were referred to a central endoscopy clinic. Eligible subjects who consented were asked to complete a brief questionnaire. Detailed information about selected risk factors was obtained from the GCS main database. Endoscopic examination with was performed with Lugol's iodine staining; biopsies were taken from unstained lesions as well as the normally stained mucosa of the esophagus, and the biopsies were diagnosed by expert pathologists according to previously described criteria. Results: In total, 1906 GCS subjects were invited, or whom only 302 (15.8%) were successfully enrolled. Esophagitis (29.5%) and ESD (6.0%) were the most common pathological diagnoses. Turkmen ethnicity (adjusted OR = 8.61; 95%CI: 2.48-29.83), being older than the median age (OR = 7.7; 95% CI: 1.99-29.87), and using deep frying cooking methods (OR = 4.65; 95%CI: 1.19-18.22) were the strongest predictors for ESD. There were significant relationships between esophagitis and smoking (p-value<0.001), drinking hot tea (P value = 0.02) and lack of education (P value = 0.004). Conclusion: We observed a low rate of participation in endoscopic screening. The overall prevalence of ESD was 6.0%. Developing nonendoscopic primary screening methods and screening individuals with one or more risk factors may improve these rates. [ABSTRACT FROM AUTHOR]

Background: Esophageal squamous cell carcinoma (ESCC) is a major health problem in many developing countries, including Iran. ESCC has a very poor prognosis, largely due to late diagnosis. As a first step in developing an early detection and treatment program, we conducted a population-based endoscopic screening for ESCC and its precursor lesion, esophageal squamous dysplasia (ESD), in asymptomatic adults from Golestan Province, northern Iran (a high-risk area for ESCC) to evaluate the feasibility of such a program and to document the prevalence and risk factor correlates of ESD. Methods: This cross-sectional study was conducted among participants of the Golestan Cohort Study (GCS), a population-based cohort of 50,000 adults in eastern Golestan Province. Randomly selected GCS participants were invited by telephone. Those who accepted were referred to a central endoscopy clinic. Eligible subjects who consented were asked to complete a brief questionnaire. Detailed information about selected risk factors was obtained from the GCS main database. Endoscopic examination with was performed with Lugol's iodine staining; biopsies were taken from unstained lesions as well as the normally stained mucosa of the esophagus, and the biopsies were diagnosed by expert pathologists according to previously described criteria. Results: In total, 1906 GCS subjects were invited, or whom only 302 (15.8%) were successfully enrolled. Esophagitis (29.5%) and ESD (6.0%) were the most common pathological diagnoses. Turkmen ethnicity (adjusted OR = 8.61; 95%CI: 2.48-29.83), being older than the median age (OR = 7.7; 95% CI: 1.99-29.87), and using deep frying cooking methods (OR = 4.65; 95%CI: 1.19-18.22) were the strongest predictors for ESD. There were significant relationships between esophagitis and smoking (p-value<0.001), drinking hot tea (P value = 0.02) and lack of education (P value = 0.004). Conclusion: We observed a low rate of participation in endoscopic screening. The overall prevalence of ESD was 6.0%. Developing nonendoscopic primary screening methods and screening individuals with one or more risk factors may improve these rates. [ABSTRACT FROM AUTHOR]

Division of Cancer Epidemiology and Genetics, NCI, NIH 9609 Medical Center Drive, Bethesda, MD 20892, USA. Corrigendum Corrigendumto:Jointeffectofdiabetesand opiateuseonall-causeandcause-specific mortality:theGolestancohortstudy MahdiNalini, 1,2† MasoudKhoshnia, 3† FarinKamangar, 4 MaryamSharafkhah, 1 HosseinPoustchi, 5 AkramPourshams, 1 GholamrezaRoshandel, 3 SamadGharavi, 1 MahdiZahedi, 6 AlirezaNorouzi, 3 MasoudSotoudeh, 1 ArashNikmanesh, 7,8 PaulBrennan, 9 PaoloBoffetta, 10,11 SanfordMDawsey, 12 ChristianCAbnet, 12 RezaMalekzadeh 1 and ArashEtemadi 1,12 * 1 Digestive Oncology Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran, 2 Cardiovascular Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran, 3 Golestan Research Center of Gastroenterology and Hepatology (GRCGH), Golestan University of Medical Sciences, Gorgan, Iran, 4 Department of Biology, School of Computer, Mathematical, and Natural Sciences, Morgan State University, Baltimore, MD, USA, 5 Liver and Pancreaticobilliary Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran, 6 Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran, 7 Digestive Disease Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran, 8 Sasan Alborz Research Center, Masoud Clinic, Tehran, Iran, 9 Section of Genetics, International Agency for Research on Cancer, Lyon, France, 10 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA, 11 Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy and 12 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA *Corresponding author. [Extracted from the article]

Background: Environmental risk factors are significant contributors to cancer mortality, which are neglected. Purpose: This study aimed to estimate the population attributable fraction of cancer mortality due to the environmental risk factors. Methods: Golestan cohort study is a population-base cohort on 50045 participants between 40–75 with about 18 years of follow up. We detected 2,196 cancer mortality and applied a multiple Cox model to compute the hazard ratio of environmental risk factor on all cancer and cancer-specific mortality. The population attributable fraction was calculated, accordingly. Results: Biomass fuels for cooking, as an indoor air pollution, increased the risk of colorectal, esophageal, gastric cancer, and all-cancer mortality by 84%, 66%, 37%, and 17% respectively. Using gas for cooking, particularly in rural areas, could save 6% [Population Attributable Fraction: 6.36(95%CI: 1.82, 10.70)] of esophageal cancer, 3% [Population Attributable Fraction: 3.43 (0, 7.33)] of gastric cancer, and 6% [Population Attributable Fraction: 6.25 (1.76, 13.63)] of colorectal cancer mortality. Using a healthy tap water source could save 5% [Population Attributable Fraction:5.50(0, 10.93)] of esophageal cancer mortality, particularly in rural areas. There was no significant association between indoor air pollution for heating purposes and animal contact with cancer mortality. Conclusion: Considering the results of this study, eliminating solid fuel for most daily usage, among the population with specific cancer types, is required to successfully reduce cancer related mortality. Adopting appropriate strategies and interventions by policymakers such as educating the population, allocating resources for improving the healthy environment of the community, and cancer screening policies among susceptible populations could reduce cancer related mortalities. [ABSTRACT FROM AUTHOR]

Background Studying carcinogens in tobacco and nontobacco sources may be key to understanding the pathogenesis and geographic distribution of esophageal cancer. Methods The Golestan Cohort Study has been conducted since 2004 in a region with high rates of esophageal squamous cell carcinoma. For this nested study, the cases comprised of all incident cases by January 1, 2018; controls were matched to the case by age, sex, residence, time in cohort, and tobacco use. We measured urinary concentrations of 33 exposure biomarkers of nicotine, polycyclic aromatic hydrocarbons, volatile organic compounds, and tobacco-specific nitrosamines. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals for associations between the 90th vs the 10th percentiles of the biomarker concentrations and incident esophageal squamous cell carcinoma. Results Among individuals who did not currently use tobacco (148 cases and 163 controls), 2 acrolein metabolites, 2 acrylonitrile metabolites, 1 propylene oxide metabolite, and one 1,3-butadiene metabolite were significantly associated with incident esophageal squamous cell carcinoma (adjusted odds ratios between 1.8 and 4.3). Among tobacco users (57 cases and 63 controls), metabolites of 2 other volatile organic compounds (styrene and xylene) were associated with esophageal squamous cell carcinoma (OR = 6.2 and 9.0, respectively). In tobacco users, 2 tobacco-specific nitrosamines (NNN and N' -Nitrosoanatabine) were also associated with esophageal squamous cell carcinoma. Suggestive associations were seen with some polycyclic aromatic hydrocarbons (especially 2-hydroxynaphthalene) in nonusers of tobacco products and other tobacco-specific nitrosamines in tobacco users. Conclusion These novel associations based on individual-level data and samples collected many years before cancer diagnosis, from a population without occupational exposure, have important public health implications. [ABSTRACT FROM AUTHOR]

Background: Poor oral health has been linked to various systemic diseases, including multiple cancer types, but studies of its association with lung cancer have been inconclusive. Methods: We examined the relationship between dental status and lung cancer incidence and mortality in the Golestan Cohort Study, a large, prospective cohort of 50,045 adults in northeastern Iran. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between three dental health measures (i.e., number of missing teeth; the sum of decayed, missing, or filled teeth (DMFT); and toothbrushing frequency) and lung cancer incidence or mortality with adjustment for multiple potential confounders, including cigarette smoking and opium use. We created tertiles of the number of lost teeth/DMFT score in excess of the loess adjusted, age- and sex-specific predicted numbers, with subjects with the expected number of lost teeth/DMFT or fewer as the reference group. Results: During a median follow-up of 14 years, there were 119 incident lung cancer cases and 98 lung cancer deaths. Higher DMFT scores were associated with a progressively increased risk of lung cancer (linear trend, p = 0.011). Compared with individuals with the expected DMFT score or less, the HRs were 1.27 (95% CI: 0.73, 2.22), 2.15 (95% CI: 1.34, 3.43), and 1.52 (95% CI: 0.81, 2.84) for the first to the third tertiles of DMFT, respectively. The highest tertile of tooth loss also had an increased risk of lung cancer, with a HR of 1.68 (95% CI: 1.04, 2.70) compared with subjects with the expected number of lost teeth or fewer (linear trend, p = 0.043). The results were similar for lung cancer mortality and did not change substantially when the analysis was restricted to never users of cigarettes or opium. We found no associations between toothbrushing frequency and lung cancer incidence or mortality. Conclusion: Poor dental health indicated by tooth loss or DMFT, but not lack of toothbrushing, was associated with increased lung cancer incidence and mortality in this rural Middle Eastern population. [ABSTRACT FROM AUTHOR]

Opiates can affect glucose metabolism and obesity, but no large prospective study (to our knowledge) has investigated the association between long-term opium use, body mass index (BMI; weight (kg)/height (m)2), and incident type 2 diabetes mellitus (T2DM). We analyzed prospective data from 50,045 Golestan Cohort Study participants in Iran (enrollment: 2004–2008). After excluding participants with preexisting diseases, including diabetes, we used adjusted Poisson regression models to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for T2DM in opium users compared with nonusers, using mediation analysis to assess the BMI-mediated association of opium use with incident T2DM. Of 40,083 included participants (mean age = 51.4 (standard deviation, 8.8) years; 56% female), 16% were opium users (median duration of use, 10 (interquartile range), 4–20) years). During follow-up (until January 2020), 5,342 incident T2DM cases were recorded, including 8.5% of opium users and 14.2% of nonusers. Opium use was associated with an overall decrease in incident T2DM (IRR = 0.83, 95% CI: 0.75, 0.92), with a significant dose-response association. Most (84.3%) of this association was mediated by low BMI or waist circumference, and opium use did not have a direct association with incident T2DM (IRR = 0.97, 95% CI: 0.87, 1.08). Long-term opium use was associated with lower incidence of T2DM, which was mediated by low body mass and adiposity. [ABSTRACT FROM AUTHOR]

Background: Recent evidence suggests overall diet quality, as assessed by dietary scores, may play a role in the development of upper gastrointestinal (UGI) cancers. However, the existing dietary scores are derived from high-income countries with different dietary habits than regions with the highest burden of UGI cancers, where limited data is available. This study aimed to investigate the association between overall diet quality and risk of esophageal and stomach cancers in a high-risk region for UGI cancers. Methods: We recruited 50 045 individuals aged 40-75 between 2004-2008 from northeastern Iran and followed them annually through July 2020. Data on demographics, diet, and various exposures were collected using validated questionnaires. Diet quality was assessed by calculating the Healthy Eating Index (HEI), Alternative Healthy Eating Index (AHEI), Alternative Mediterranean Diet (AMED), Dietary Approaches to Stop Hypertension (DASH), and World Cancer Research Fund--American Institute for Cancer Research (WCRF-AICR) scores. Results: During an average 12 years of follow-up, 359 participants developed esophageal cancer and 358 developed stomach cancer. After adjustments, each standard deviation increase in baseline dietary scores was associated with up to 12% reduction in esophageal cancer risk and up to 17% reduction in stomach cancer risk. Esophageal cancer showed stronger inverse associations with adherence to AMED (HRQ4-vs-Q1 = 0.69 (0.49-0.98), P-trend = 0.038). Stomach cancer showed stronger inverse correlation with WCRF-AICR (HRQ4-vs-Q1 = 0.58 (0.41-0.83), P-trend = 0.004), and DASH (HRC4-vs-C1 = 0.72 (0.54-0.96), P-trend = 0.041). These associations were comparable across different population subgroups. We did not observe significant associations between HEI and AHEI scores and UGI cancers in this population. Conclusion: Despite the differences in consuming individual food groups, adherence to the available dietary recommendations (derived from high-income countries) was associated with lower risk for subsequent esophageal and gastric cancers in this high-risk population. Educating the public to have a healthy eating pattern might be an effective strategy towards prevention of UGI cancers in high-risk regions. [ABSTRACT FROM AUTHOR]

Background and Objectives: Capparis spinosa has been used in traditional medicine for various applications including treatment of liver disorders and cancer. We studied the effects of this plant on cell proliferation and morphological characteristics of PLC/PRF/5 liver cancer cell line. Methods: After preparing ethanolic extract of the plant, the inhibitory effect of the extract was assessed using MTT assay, and morphological changes were assessed by an inverted microscope. Results: C. spinosa ethanolic extract exhibited anti-cancer effects in a concentrationdependent manner. Half-maximal inhibitory concentration of the extract was 1051±4.21 mg/mL. Morphological changes including cell shrinkage, reduction of cell volume and nuclear condensation confirmed the inhibitory effect of C. spinosa on PLC/PRF/5 cells. Conclusion: According to the results of this study, extract of C. spinosa seems to be suitable for prevention and treatment of liver cancer. Further studies on animal models could verify the efficiency of the extract against cancer cells. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to estimate the level and trend of plasma cholesterol and raised total cholesterol (TC > 200 mg/dl) prevalence at national and subnational level of Iran. Methods: Nine national surveys and 27 studies, encompassing 3,505 unique points on over 500,000 adults, aged > 25 years with a report of laboratory measurement of TC were found. Age-spatio-temporal model and Gaussian Process Regression were used to estimate mean TC for each sex, 5-year age groups, and 31 provinces from 1990 to 2016. Results: At national level, age-standardized prevalence of TC > 200 mg/dL has decreased from 57·2%(53·3–61·1) to 22·4%(20·5–24·3) in women and 53·2%(49·1–57·3) to 18·0%(16·4–19·6) in men. TC distribution presented a condensation between 170-200 mg/dL. At subnational level, decreasing and converging patterns of raised TC prevalence were detected. Conclusion: The decrease in raised TC is likely the result of statin widespread use, food industry improvements, and the expanded primary health care. [ABSTRACT FROM AUTHOR]

Background and Objective: Esophageal cancer is the third most common type of cancer in Iran. Studies on water, soil, grains, waste and sediments in Golestan Province have shown that the environmental concentrations of antimony and strontium are increased in areas with high incidence rate for cancer. The carcinogenic effects of strontium have been reported, but carcinogenicity of antimony is still unclear. Since there is not enough information regarding the relationship between the concentration of strontium and antimony and prevalence of esophageal cancer in the province, this study aimed to evaluate serum levels of these elements in patients with esophageal cancer using atomic absorption spectroscopy. Methods: This study was performed on 30 patients with esophageal squamous cell carcinoma and 30 healthy matched controls. After sampling, concentrations of strontium and antimony were measured using atomic absorption spectroscopy. Results: Half of the esophageal cancer patients and control participants were male. The mean age of patients and controls was 66 ± 13 and 64 ± 8 years, respectively. The mean serum concentration of strontium in patients and controls was 24.18 ± 1.62 and 24.08 ± 1.46 μg/L, respectively. The mean serum concentration of antimony in patients and controls was 18.61 ± 1.48 and 18.98 ± 1.93 μg/L, respectively. No statistically significant difference was observed between the serum concentrations of the two elements in patients and controls. Conclusion: There is no difference between serum levels of strontium and antimony in cancer patients and healthy controls, which could be due to tissue accumulation. [ABSTRACT FROM AUTHOR]

Background: Environmental exposures account for a growing proportion of global mortality. Large cohort studies are needed to characterize the independent impact of environmental exposures on mortality in low-income settings. Methods: We collected data on individual and environmental risk factors for a multiethnic cohort of 50,045 individuals in a low-income region in Iran. Environmental risk factors included: ambient fine particular matter air pollution; household fuel use and ventilation; proximity to traffic; distance to percutaneous coronary intervention (PCI) center; socioeconomic environment; population density; local land use; and nighttime light exposure. We developed a spatial survival model to estimate the independent associations between these environmental exposures and all-cause and cardiovascular mortality. Findings: Several environmental factors demonstrated associations with mortality after adjusting for individual risk factors. Ambient fine particulate matter air pollution predicted all-cause mortality (per μg/m3, HR 1.20, 95% CI 1.07, 1.36) and cardiovascular mortality (HR 1.17, 95% CI 0.98, 1.39). Biomass fuel use without chimney predicted all-cause mortality (reference = gas, HR 1.23, 95% CI 0.99, 1.53) and cardiovascular mortality (HR 1.36, 95% CI 0.99, 1.87). Kerosene fuel use without chimney predicted all-cause mortality (reference = gas, HR 1.09, 95% CI 0.97, 1.23) and cardiovascular mortality (HR 1.19, 95% CI 1.01, 1.41). Distance to PCI center predicted all-cause mortality (per 10km, HR 1.01, 95% CI 1.004, 1.022) and cardiovascular mortality (HR 1.02, 95% CI 1.004, 1.031). Additionally, proximity to traffic predicted all-cause mortality (HR 1.13, 95% CI 1.01, 1.27). In a separate validation cohort, the multivariable model effectively predicted both all-cause mortality (AUC 0.76) and cardiovascular mortality (AUC 0.81). Population attributable fractions demonstrated a high mortality burden attributable to environmental exposures. Interpretation: Several environmental factors predicted cardiovascular and all-cause mortality, independent of each other and of individual risk factors. Mortality attributable to environmental factors represents a critical opportunity for targeted policies and programs. [ABSTRACT FROM AUTHOR]

Backgrounds: Normal or elevated values of serum alanine aminotransferase level (ALT) vary in different studies mostly related to characteristics of reference population including age, gender, body mass index, nonalcoholic fatty liver disease (NAFLD), and metabolic syndrome prevalence. Objectives: To measure upper normal limit (UNL) for serum ALT in an apparently healthy Iranian old population (which we had not sufficient data before this study), and its modulating factors. Patients and Methods: All inhabitants (> 50 years old) of Kalaleh, Golestan, Iran (N = 1986) were invited to the study. ALT measurements were performed for all subjects using the same laboratory method. Upper limit of normal (ULN) ALT was calculated based on its 95th percentile in normal weight subjects. Modulating factors of ALT were determined by multivariate analysis. Results: A total of 1309 subjects, with the mean age of 61.5 ± 7.5 years were included. UNL of ALT was 18.8 U/L and 21.4 U/L in women and men, respectively. Based on univariate analysis, waist circumference (r = 0.124, P = 0.01), body mass index (r = 0.118, P = 0.01), triglyceride (r = 0.143, P = 0.01), and having metabolic syndrome (OR = 2.04) modulate ALT levels in men. Also triglyceride (r = 0.119, P = 0.01) modulates ALT levels in women. Conclusions: The calculated level for UNL of ALT is considerably far lower than previous accepted value. Age, gender, ethnicity, and metabolic factors should be accounted in future studies to determine normal ALT level. [ABSTRACT FROM AUTHOR]

Background: While hepatitis B virus (HBV) is the most prevalent cause of adult liver transplants in Iran, the mortality rates and leading causes of death in HBV patients are not well-understood. This study aimed to investigate all-cause and cause-specific mortality among HBsAg positive individuals in a large Iranian cohort. Methods: The Golestan Cohort Study includes 50 045 individuals aged 40-75 residing in Iran's Golestan province, enrolled during 2004-2008. HBsAg test was performed at baseline. For the present study, individuals with hepatitis C coinfection were excluded. All-cause mortality was considered as the primary outcome. The association between HBsAg and different mortality causes was evaluated using Cox proportional hazard models. P value < 0.05 was considered significant. Results: The current study included 49 667 participants. After 11.33 (median) follow-up years, there were 7,686 total deaths, with 635 deaths in the HBsAg positive group. In the multivariate Cox proportional hazard model, HBsAg positive individuals had higher all-cause (adjusted hazard ratio [aHR] = 1.15, 95% CI: 1.06-1.24) and liver-related mortality risk (aHR = 7.13; 5.19-9.79). Mortality from colorectal and pancreatic cancers was higher among male HBsAg positive participants (aHRs = 2.41 and 2.22, respectively). Nevertheless, cardiovascular diseases (CVDs) and extrahepatic malignancies were the leading causes of death among both HBsAg positive and negative individuals, and liver-related deaths contributed to an overall 10% of deaths in HBsAg positive patients. Conclusion: HBV is associated with significant mortality risk from different causes in Iranian adults. However, solely focusing on liver outcomes in Iranian HBV patients might result in overlooking non-liver events, especially CVD and extrahepatic cancers. [ABSTRACT FROM AUTHOR]

Molecular knowledge regarding the primary esophageal achalasia is essential for the early diagnosis and treatment of this neurodegenerative motility disorder. Therefore, there is a need to find the main microRNAs (miRNAs) contributing to the mechanisms of achalasia. This study was conducted to determine some patterns of deregulated miRNAs in achalasia. This case-control study was performed on 52 patients with achalasia and 50 nonachalasia controls. The miRNA expression profiling was conducted on the esophageal tissue samples using the next-generation sequencing (NGS). Differential expression of miRNAs was analyzed by the edgeR software. The selected dysregulated miRNAs were additionally confirmed using the quantitative reverse transcription polymerase chain reaction (qRTPCR). Fifteen miRNAs were identified that were significantly altered in the tissues of the patients with achalasia. Among them, three miRNAs including miR-133a-5p, miR-143-3p, and miR-6507-5p were upregulated. Also, six miRNAs including miR-215-5p, miR-216a-5p, miR-216b-5p, miR-217, miR-7641 and miR-194-5p were downregulated significantly. The predicted targets for the dysregulated miRNAs showed significant disease-associated pathways like neuronal cell apoptosis, neuromuscular balance, nerve growth factor signaling, and immune response regulation. Further analysis using qRT-PCR showed significant down-regulation of hsa-miR-217 (p-value = 0.004) in achalasia tissue. Our results may serve as a basis for more future functional studies to investigate the role of candidate miRNAs in the etiology of achalasia and their application in the diagnosis and probably treatment of the disease. [ABSTRACT FROM AUTHOR]

BACKGROUND: Three billion people burn nonclean fuels for household purposes. Limited evidence suggests a link between household fuel use and gastrointestinal (GI) cancers. OBJECTIVES: We investigated the relationship between indoor burning of biomass, kerosene, and natural gas with the subsequent risk of GI cancers. METHODS: During the period 2004–2008, a total of 50,045 Iranian individuals 40–75 years of age were recruited to this prospective population-based cohort. Upon enrollment, validated data were collected on demographics, lifestyle, and exposures, including detailed data on lifetime household use of different fuels and stoves. The participants were followed through August 2018 with <1% loss. RESULTS: During the follow-up, 962 participants developed GI cancers. In comparison with using predominantly gas in the recent 20-y period, using predominantly biomass was associated with higher risks of esophageal [hazard ratio (HR): 1.89; 95% confidence interval (CI): 1.02, 3.50], and gastric HR: 1.83; 95% CI: 1.01, 3.31) cancers, whereas using predominantly kerosene was associated with higher risk of esophageal cancer (HR: 1.84; 95% CI: 1.10, 3.10). Lifetime duration of biomass burning for both cooking and house heating (exclusive biomass usage) using heating-stoves without chimney was associated with higher risk of GI cancers combined (10-y HR: 1.14; 95% CI: 1.07, 1.21), esophageal (10-y HR: 1.19; 95% CI: 1.08, 1.30), gastric (10-y HR: 1.11; 95% CI: 1.00, 1.23), and colon (10-y HR: 1.26; 95% CI: 1.03, 1.54) cancers. The risks of GI cancers combined, esophageal cancer, and gastric cancer were lower when biomass was burned using chimney-equipped heating-stoves (strata difference 푝-values = 0:001, 0.003, and 0.094, respectively). Duration of exclusive kerosene burning using heating-stoves without chimney was associated with higher risk of GI cancers combined (10-y HR: 1.05; 95% CI: 1.00, 1.11), and esophageal cancer (10-y HR: 1.14; 95% CI: 1.04, 1.26). DISCUSSION: Household burning of biomass or kerosene, especially without a chimney, was associated with higher risk of some digestive cancers. Using chimney-equipped stoves and replacing these fuels with natural gas may be useful interventions to reduce the burden of GI cancers worldwide. [ABSTRACT FROM AUTHOR]

Background: We aimed to present the temporal and geographical trends in the incidence of stomach cancer in the Golestan province, a high-risk area in Northern Iran. Methods: This study was conducted on stomach cancer cases registered in the Golestan Population-based Cancer Registry (GPCR) during 2004-2016. Age-standardized incidence rates (ASRs) per 100000 person-years were calculated. The Joinpoint regression analysis was used to calculate the average annual percent changes (AAPC). We also calculated the contribution of population aging, population size and risk to the overall changes in incidence rates. Results: Overall, 2964 stomach cancer patients were registered. The ASR of stomach cancer was significantly higher in men (26.9) than women (12.2) (P<0.01). There was a significant decreasing trend in incidence of stomach cancer in men (AAPC=-1.80, 95% CI: -3.30 to-0.28; P=0.02). We found a higher ASR of stomach cancer in the rural (21.4) than urban (18.1) (P=0.04) population, as well as a significant decreasing trend in its rates (AAPC=-2.14, 95% CI: -3.10 to -1.17; P<0.01). The number of new cases of stomach cancer increased by 22.33% (from 215 in 2004 to 263 in 2016), of which 18.1%, 25.1% and -20.9% were due to population size, population aging and risk, respectively. Our findings suggest a higher rate for stomach cancer in eastern areas. Conclusion: We found high incidence rates as well as temporal and geographical diversities in ASR of stomach cancer in Golestan, Iran. Our results showed an increase in the number of new cases, mainly due to population size and aging. Further studies are warranted to determine the risk factors of this cancer in this high-risk population. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association between adherence to the Dietary Approaches to Stop Hypertension (DASH) diet and overall and cause-specific mortality in the Golestan Cohort Study (GCS).Methods: A total of 50 045 participants aged 40 years or older were recruited from Golestan Province, Iran, from 2004 to 2008 and followed for a mean of 10.64 years. The DASH diet score was calculated for each individual based on food groups. The primary outcome measure was death from any cause.Results: During 517 326 person-years of follow-up, 6763 deaths were reported. After adjustment for potential confounders, DASH diet score was inversely associated with risk of death from all causes and cancers [hazard ratio (HR): 0.86; 95% confidence interval (CI): 0.75, 0.98; and HR: 0.65; 95% CI: 0.47, 0.90, respectively]. A higher DASH diet score was associated with lower risk of gastrointestinal cancer mortality in men (HR: 0.55; 95% CI: 0.30, 0.99). A greater adherence to DASH diet was also associated with lower other-cancer mortality in women (HR: 0.50; 95% CI: 0.24, 0.99). No association between DASH diet score and cardiovascular disease mortality was observed, except that those dying of cardiovascular disease were younger than 50 years of age and smokers.Conclusions: Our findings suggest that maintaining a diet similar to the DASH diet is independently associated with reducing the risk of total death, cancers, and especially gastrointestinal cancers in men. [ABSTRACT FROM AUTHOR]

Background: The incidence and survival of breast cancer (BC) vary across countries. This study aimed to determine risk factors for BC and estimate the overall survival rate in BC patients of the Golestan Cohort Study (GCS). Methods: This case-control study was performed among participants of the GCS. Cases (N = 99) consisted of women who were diagnosed with BC and controls (n = 400) were selected out of women participating in the same cohort and had not developed any cancer during the follow-up period. Controls were frequency matched to case on both place of residency and 5-year categories of age. Results: Considering confounding variables, logistic regression analysis manifested a reverse association between parity and BC (OR [odds ratio] = 0.87, 95% CI: 0.80--0.95, P = 0.001). In addition, we found women who had family history of any cancer (OR = 1.63, 95% CI: 1.02--2.60, P = 0.04) and long term oral contraceptive (OCP) use (≥10 years) (OR = 3.17, 95% CI: 1.27--7.95, P = 0.01) were at higher risk of BC. Of the total patients, 23 (23.2%) were died due to BC after a mean follow-up of 102.4 ± 5.31 months. Using the Kaplan-Meier analysis, the 5-year survival in these patients was 74%. Conclusion: In the Golestan Cohort population, long term OCP use and family history of cancer were risk factors for BC, while parity was a protective factor. The 5-year survival of BC patients in the GCS is still lower relative to Europe and the United States. [ABSTRACT FROM AUTHOR]

Background: It is unclear which anthropometric obesity indicator best predicts adverse health outcomes. This study aimed to investigate the association of body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), waist-to-hip ratio (WHR), and hip-adjusted WC with all-cause and cardiovascular mortality. Methods: 50 045 people aged 40-75 (58% women, median BMI: 26.3 kg/m²) participated in the population-based Golestan Cohort Study. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI) for the association of obesity indicators with mortality. We also examined the association of these indicators with intermediate outcomes, including hypertension, blood glucose, dyslipidemia, carotid atherosclerosis, nonalcoholic fatty liver, and visceral abdominal fat. Results: After a median follow-up of 10.9 years (success rate: 99.1%), 6651 deaths (2778 cardiovascular) occurred. Comparing 5th to the 1st quintile, HRs (95% CIs) for all-cause and cardiovascular mortality were 1.12 (1.02-1.22) and 1.59 (1.39-1.83) for BMI, 1.16 (1.07-1.27) and 1.66 (1.44-1.90) for WC, 1.28 (1.17-1.40) and 1.88 (1.63-2.18) for WHtR, 1.44 (1.32-1.58) and 2.04 (1.76-2.36) for WHR, and 1.84 (1.62-2.09) and 2.72 (2.23-3.32) for hip-adjusted WC, respectively. Hip-adjusted WC had the strongest associations with the intermediate outcomes. Conclusion: Indicators of visceral adiposity (e.g., hip-adjusted WC) were much stronger predictors of overall and cardiovascular mortality than were indicators of general adiposity (e.g., BMI). The full-strength effect of visceral adiposity becomes apparent only when both WC, as a risk factor, and hip circumference, as a protective factor, are individually and simultaneously taken into consideration. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate the intra-familial transmission of chronic hepatitis B (CHB) in Golestan province, that has the highest prevalence of CHB in Iran. Methods: The Golestan Cohort Study (GCS) is a population-based prospective study of 50 045 individuals, 40 years or older, initially set-up to study upper GI cancers in Northern Iran. In 2008, a baseline measurement of hepatitis B surface antigen (HBsAg) on the stored serum of all GCS participants identified 3505 HBsAg+ individuals. In 2011, we assessed HBV serological markers in 2590 initially HBsAg+ individuals and their first-degree relatives including spouses (1454) and children (3934). Results: The median (IQR) age of spouses and children were 52 (12) and 25 (12) years respectively. Out of 5388 family members, 2393 (44.5%) had no HBV markers, indicating susceptibility to infection. Of these, 378 (15.8%) were fully-vaccinated children with no apparent response to primary immunization. HBsAg was positive in 2.2% (n = 33) of spouses and 8.2% (n = 325) of children (overall rate of 6.6%). HBcAb was positive in 761 (52.3%) and 914 (23%) spouses and children, respectively. The rate of spontaneous loss of HBsAg (HBsAg-, HBsAb+ and HbcAb+) was 41.3% and 13.9% in spouses and children, respectively. A higher rate of HBsAg+ children (10.2%) was found in families in which the mother was positive for HBsAg compared with families where the father was positive for HBsAg (6.3%) (P < 0.001). When both parents were positive for HBsAg, the rate of HBsAg positivity was high (23.5%, P < 0.001). Despite high virus exposure rates between spouses (52.6 %), the prevalence of HBsAg positivity among them was very low (2.3 %). Conclusion: Sexual and parent-to-child transmission are important routes of CHB spread in this population from northern Iran despite the fact that 24 years have passed since the beginning of hepatitis B vaccination in infants. Low percentage of HBsAg positivity in spouses is related to high HBsAg clearance rate among them. [ABSTRACT FROM AUTHOR]

Background: Nut consumption has been inversely associated with gastric cancer incidence in US-based studies, but not with oesophageal cancer. However, there is aetiologic heterogeneity, among oesophageal squamous cell carcinoma (ESCC) cases in low-risk vs. high-risk populations. The objective of this study was to evaluate the association between nut consumption and risk of ESCC in a high-risk population.Methods: The Golestan Cohort Study enroled 50,045 participants in Northeastern Iran, between 2004 and 2008. Intake of peanuts, walnuts and mixed nuts (including seeds) were assessed using a validated food frequency questionnaire at baseline. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals for subsequent ESCC adjusted for potential confounders. Non-consumers of nuts were used as the reference category and the consumers were categorised into tertiles.Results: We accrued 280 incident ESCC cases during 337,983 person-years of follow up. Individuals in the highest tertiles of total nut consumption, and mixed nut consumption were significantly associated with lower risk of developing ESCC compared to non-consumers (HR = 0.60, 95% CI = 0.39-0.93, p-trend = 0.02, and HR = 0.52, 95% CI = 0.32-0.84, p trend = 0.002, respectively).Conclusions: We found a statistically significant inverse association between total nut consumption and the risk of ESCC in this high-risk population. [ABSTRACT FROM AUTHOR]

BACKGROUND Achalasia, as an incurable disease is defined by the lack of normal esophageal peristalsis and loss of lower esophageal sphincter relaxation due to impaired myenteric neural plexus. The exact cause of myenteric neural cells degeneration in achalasia is still unknown. One hypothesis is that certain neurotropic viruses and autoimmune factors cause the inflammatory response in myenteric network, which consequently destroy neural cells. This study was designed to find the evidence of viral causes of achalasia. METHODS In this case-control study, 52 patients with achalasia and 50 controls referred to Shariati Hospital, were evaluated for the genome of neurotropic viruses, HPV, and adenovirus by polymerase chain reaction (PCR) and reverse transcription (RT) PCR techniques. RESULTS Genome assessment of neurotropic DNA viruses turned out negative in the patients, however, the genome of HSV-1 (Herpes simplex virus) was found in tissues of six controls. No neurotropic RNA viruses were observed in the tissue samples and whole blood of both the patients and controls. Among non-neurotropic viruses, adenovirus genome was positive in tissues of two out of 52 patients and three out of 50 controls. In addition, one out of 52 patients and two out of 50 controls were positive for HPV infection in tissues. CONCLUSION We could not detect any significant relationship between achalasia and HPV, adenovirus, and neurotropic viruses in the cases. Nevertheless, it does not exclude the hypothesis of either an alternate viral species or resolved viral infection as the etiology of achalasia. [ABSTRACT FROM AUTHOR]

Background: Previous studies have found associations between oral health and mortality, but the majority of previous studies have been conducted in high-income countries.Methods: We used data from the Golestan Cohort Study, a study of 50 045 people aged 40 to 75 years in north eastern Iran, recruited from January 2004 to June 2008. Tooth loss and decayed, missing and filled teeth (DMFT) were assessed by trained physicians. Frequency of tooth brushing and use of dentures were self-reported. Cause-specific mortality was ascertained through March 2014. We calculated hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the associations between the oral health variables, overall mortality and cause-specific mortality.Results: Participants with the greatest tooth loss had increased overall mortality (HR 1.43; 95% CI: 1.28, 1.61) compared with those with the least tooth loss; similar estimates were observed for DMFT score. For cause-specific mortality, an increased risk of death was found for tooth loss and mortality from cardiovascular disease (HR 1.33; 95% CI: 1.13, 1.56), cancer (HR 1.30; 95% CI: 1.03, 1.65) and injuries (HR 1.99; 95% CI: 1.28, 3.09). The associations between oral health and injury mortality were strongly attenuated after exclusion of participants with comorbid conditions at baseline. No statistical interaction was found between denture use and tooth loss or DMFT on mortality.Conclusions: Poor oral health appears to predict overall and cause-specific mortality in populations in economic transition. Investigation of the underlying mechanisms might provide an important contribution to reducing mortality. [ABSTRACT FROM AUTHOR]

Studies conducted in China linked selenium deficiency to higher risk of esophageal squamous cell carcinoma ( ESCC), but this has not been widely tested outside that selenium-deficient region. The aim of this study was to investigate the association between selenium and other mineral concentrations in toenails and risk of ESCC in a region with high incidence rates. In this nested case-control study, we identified 222 cases of ESCC from the Golestan Cohort Study, Iran, which has followed up 50,045 participants since enrollment (2004-2008). We randomly selected one control for each case matched by age and sex, using incidence density sampling. We used toenail samples collected at baseline to measure the concentration of selenium, zinc, chromium, mercury, and scandium using instrumental neutron activation analysis. Multivariate adjusted logistic regression models were used to estimate odds ratios ( OR) and 95% confidence intervals. Median nail selenium, zinc, chromium, and mercury levels were 1.01, 74.59, 0.77, and 0.018 μg/g in cases and 1.02, 75.71, 0.71, and 0.023 μg/g in controls, respectively. The adjusted odds ratios comparing each fourth quartile of mineral status versus the first quartile were as follows: selenium = 0.78 (95% CI, 0.41-1.49); zinc=0.80 (95% CI, 0.42-1.53); chromium = 0.91 (95% CI, 0.46-1.80); and mercury=0.61 (95% CI, 0.27-1.38), and all trend tests were non-significant. The nail selenium concentration in our controls reflects relatively high selenium status. No evidence of association between selenium or chromium concentrations in toenails and the risk of ESCC was detected in this population. [ABSTRACT FROM AUTHOR]

Background: The burden of chronic kidney disease (CKD) is increasing globally in particular in fast emerging economies such as Iran. Population-based studies on prevalence of CKD in Iran are scarce. The objective of the current study was to explore the prevalence and determinants of CKD in the setting of Golestan Cohort Study (GCS), the largest prospective cohort in the Middle East. Methods: In this observational study, 11,409 participants enrolled in the second phase of GCS were included. Sex, age, literacy, residence, anthropometric measurements, smoking, opium use, self-reported history of cardiovascular diseases (heart disease and/or stroke), hypertension, diabetes, and lipid profile were the predictors of interest. The outcomes of interest were eGFR and CKD defined as eGFR< 60 ml/min/1.73m2. Results: Mean (SD) of GFR was 70.0 ± 14.7 ml/min/1.73m2 among all participants, 68.2 ± 14.2 among women, and 72.0 ± 15.0 among men. Prevalence of CKD was 23.7% (26.6% in women, 20.6% in men). The prevalence of CKD stages 3a, 3b, 4, and 5 were 20.0%, 3.3%, 0.4% and 0.1%, respectively. Female sex, older age, urban residence, history of CVD, hypertension or diabetes, larger body mass and surrogates of body fat and opium use were all associated with CKD. Opium had a significant positive association with CKD in adjusted model. All anthropometric measurements had positive linear association with CKD. Being literate had inverse association. Sex had significant interaction with anthropometric indices, with higher odds ratios among men compared with women. A significantly high association was observed between the rate of change in waist circumference and systolic blood pressure with risk of CKD. Conclusion: One in four people in this cohort had low eGFR. Obesity and overweight, diabetes, hypertension, and dyslipidemia are major risk factors for CKD. Halting the increase in waist circumference and blood pressure may be as important as reducing the current levels. [ABSTRACT FROM AUTHOR]

We investigated the association between dairy product consumption and all-cause, cardiovascular disease (CVD), and cancer mortality in the Golestan Cohort Study, a prospective cohort study launched in January 2004 in Golestan Province, northeastern Iran. A total of 42,403 men and women participated in the study and completed a diet questionnaire at enrollment. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals. We documented 3,291 deaths (1,467 from CVD and 859 from cancer) during 11 years of follow-up (2004-2015). The highest quintile of total dairy product consumption (versus the lowest) was associated with 19% lower all-cause mortality risk (hazard ratio (HR) = 0.81, 95% confidence interval (CI): 0.72, 0.91; Ptrend = 0.006) and 28% lower CVD mortality risk (HR = 0.72, 95% CI: 0.60, 0.86; Ptrend = 0.005). High consumption of low-fat dairy food was associated with lower risk of all-cause (HR = 0.83, 95% CI: 0.73, 0.94; Ptrend = 0.002) and CVD (HR = 0.74, 95% CI: 0.61, 0.89; Ptrend = 0.001) mortality. We noted 11% lower all-cause mortality and 16% lower CVD mortality risk with high yogurt intake. Cheese intake was associated with 16% lower all-cause mortality and 26% lower CVD mortality risk. Higher intake of high-fat dairy food and milk was not associated with all-cause or CVD mortality. Neither intake of individual dairy products nor intake of total dairy products was significantly associated with overall cancer mortality. High consumption of dairy products, especially yogurt and cheese, may reduce the risk of overall and CVD mortality. [ABSTRACT FROM AUTHOR]

Introduction: Dietary protein comes from foods with greatly different compositions that may not relate equally with mortality risk. Few cohort studies from non-Western countries have examined the association between various dietary protein sources and cause-specific mortality. Therefore, the associations between dietary protein sources and all-cause, cardiovascular disease, and cancer mortality were evaluated in the Golestan Cohort Study in Iran.Methods: Among 42,403 men and women who completed a dietary questionnaire at baseline, 3,291 deaths were documented during 11 years of follow up (2004-2015). Cox proportional hazards models estimated age-adjusted and multivariate-adjusted hazard ratios (HRs) and 95% CIs for all-cause and disease-specific mortality in relation to dietary protein sources. Data were analyzed from 2015 to 2016.Results: Comparing the highest versus the lowest quartile, egg consumption was associated with lower all-cause mortality risk (HR=0.88, 95% CI=0.79, 0.97, ptrend=0.03). In multivariate analysis, the highest versus the lowest quartile of fish consumption was associated with reduced risk of total cancer (HR=0.79, 95% CI=0.64, 0.98, ptrend=0.03) and gastrointestinal cancer (HR=0.75, 95% CI=0.56, 1.00, ptrend=0.02) mortality. The highest versus the lowest quintile of legume consumption was associated with reduced total cancer (HR=0.72, 95% CI=0.58, 0.89, ptrend=0.004), gastrointestinal cancer (HR=0.76, 95% CI=0.58, 1.01, ptrend=0.05), and other cancer (HR=0.66, 95% CI=0.47, 0.93, ptrend=0.04) mortality. Significant associations between total red meat and poultry intake and all-cause, cardiovascular disease, or cancer mortality rate were not observed among all participants.Conclusions: These findings support an association of higher fish and legume consumption with lower cancer mortality, and higher egg consumption with lower all-cause mortality. [ABSTRACT FROM AUTHOR]

Background: Refined grains and white rice have been associated with elevated risk of type 2 diabetes mellitus (T2DM). In this study, we sought to quantify the effect of white rice intake on incident T2DM in two prospective population-based cohort studies from Iran, where white rice is one of the main staple.Methods: We used follow-up data from 9,182 participants from Golestan Cohort Study (GCS, 2004-2007, conducted mainly in rural areas) and 2,173 from Tehran Lipid and Glucose Study (TLGS, 2004-2006) who did not have T2DM and other chronic diseases at baseline. Diet was assessed using validated food frequency questionnaires. Multivariable logistic regression models were used to estimate adjusted odds ratios (ORs) for incident T2DM.Results: We documented 902 new cases of T2DM in GCS and 81 in TLGS. Age-standardized cumulative incidence of T2DM was 9.9% in Golestan and 8.0% in Tehran. Daily white rice intake was significantly higher among residents of Tehran compared to Golestan (median daily intake: 250 vs. 120 grams; P-value < 0.001). After adjustment for potential confounders, there was no significant association between daily white rice intake and incident T2DM in GCS. In TLGS, the adjusted OR (95% confidence interval (CI)) was 2.1 (1.1, 3.9) comparing participants with daily white rice intake of >250 grams/day to those with <250.Conclusions: We observed an increased lieklihood of T2DM associated with high white rice intake among residents of Tehran and no association in Golestan. Our findings, if further supported by other studies, have important public health implications especially for countries where white rice is a major staple and diabetes is increasing rapidly incidence is high. Further research is needed to investigate lack of an association between lower levels of white rice intake and T2DM. [ABSTRACT FROM AUTHOR]

Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor that is typically diagnosed only when the tumor has gained remarkable size, extended to peripheral tissues, and led to dysphagia. Five-year survival of advanced cancer is still very poor (19%), even with improved surgical techniques and adjuvant chemoradiation therapy. Therefore, early detection and prevention are the most important strategies to reduce the burden of ESCC. Our review will focus on the studies conducted in Golestan province, an area with a high prevalence of ESCC in northern Iran. We review three aspects of the research literature on ESCC: epidemiological features, environmental factors (including substance abuse, environmental contaminants, dietary factors, and human papilloma virus [HPV]), and molecular factors (including oncogenes, tumor suppressor genes, cell cycle regulatory proteins, and other relevant biomarkers). Epidemiological and experimental data suggest that some chemicals and lifestyle factors, including polycyclic aromatic hydrocarbons (PAHs), cigarette smoking, opium use, and hot tea drinking are associated with the development of ESCC in Golestan. HPV infects the esophageal epithelium, but so far, no firm evidence of its involvement in esophageal carcinogenesis has been provided. Some of these factors, notably hot tea drinking, may render the esophageal mucosa more susceptible to injury by other carcinogens. There are few studies at molecular level on ESCC in Golestan. Increasing awareness about the known risk factors of ESCC could potentially reduce the burden of ESCC in the region. Further studies on risk factors, identifying high risk populations, and early detection are needed. [ABSTRACT FROM AUTHOR]

Objective(s): Similar characteristics of molecular pathways between cellular reprogramming events and tumorigenesis have been accentuated in recent years. Reprogramming-related transcription factors, also known as Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC), are also well-known oncogenes promoting cancer initiation, progression, and cellular transformation into cancer stem cells. Long non-coding RNAs (lncRNAs) are a major class of RNA molecules with emerging roles in stem cell pluripotency, cellular reprogramming, cellular transformation, and tumorigenesis. The long intergenic non-coding RNA ROR (lincRNA-ROR, linc-ROR) acts as a regulator of cellular reprograming through sponging miR-145 that normally negatively regulates the expression of the stemness factors NANOG, OCT4, and SOX2. Materials and Methods: Here, we employed a real-time PCR approach to determine the expression patterns of linc-ROR and its two novel spliced variants (variants 2 and 4) in esophageal squamous cell carcinoma (ESCC). Results: The quantitative real-time RT-PCR results revealed a significant up-regulation of linc-ROR (P=0.0098) and its variants 2 (P=0.0250) and 4 (P=0.0002) in tumor samples of ESCC, compared to their matched non-tumor tissues obtained from the margin of same tumors. Our data also demonstrated a significant up-regulation of variant 4 in high-grade tumor samples, in comparison to the low-grade ones (P=0.04). Moreover, the ROC curve analysis demonstrated that the variant 4 of ROR has a potential to discriminate between tumor and non-tumor samples (AUC=0.66, P<0.05). Conclusion: Our data suggest a significant up-regulation of linc-ROR and its variants 2 and 4 in ESCC tissue samples. [ABSTRACT FROM AUTHOR]

BACKGROUND In the Golestan Cohort Study that was launched to investigate the causes of esophageal cancer, a complete biospecimen bank was established for storage of collected blood, urine, hair, and nail samples. The objective of this study was to evaluate the feasibility of nail samples as a biomarker of selected trace elements status. METHODS Thirty toenail samples were selected randomly from the participants of Golestan Cohort Study (GCS). The samples were cleaned and analyzed for selenium, mercury, chromium, iron, zinc, and scandium by instrumental neutron activation analysis at the University of Missouri Research Reactor Center. Pearson correlation coefficients were computed for selected trace elements concentration versus scandium concentration to assess terrestrial contamination. RESULTS The selenium, zinc, and mercury were not correlated with scandium, suggesting they were free from substantial contamination. The high correlations of scandium with iron and chromium suggest that the iron and chromium levels may be compromised by terrestrial contamination. The coefficients of variation for duplicate samples for selenium and zinc were 2.6% and 7.2%, respectively. CONCLUSION The nail samples from Golestan Cohort Study appears to be useable as a biomarker of selenium, zinc, and mercury and could be considered for use in future studies. [ABSTRACT FROM AUTHOR]

Introduction: Individuals with nonalcoholic steatohepatitis or elevated liver enzymes have increased cardiovascular mortality but are often excluded from prevention trials. We investigated the effectiveness of fixed-dose combination therapy in prevention of major cardiovascular events (MCVE) among individuals with and without presumed nonalcoholic steatohepatitis (pNASH). Methods: 2400 Participants over 50 were randomized into intervention and control. Consent was taken post randomization. Participants in the intervention group were given a combination pill containing aspirin, atorvastatin, hydrochlorothiazide, and valsartan (Polypill). Participants were followed for 5 years. pNASH was diagnosed by ultrasonography and elevated liver enzymes. The primary outcome was MCVE. Clinical Trials. gov ID: NCT01245608. Results: 892 participants did not consent or meet enrollment criteria and 1508 entered the study. During 5-years of follow-up, 63/787 (8. 0%) intervention group participants and 86/721 (11. 9%) controls had MCVE (adjusted RR 0. 61, 95%CI 0. 44 to 0. 83). Although the adjusted relative risk of MCVE in participants with pNASH (0. 35, 95%CI 0. 17 to 0. 74) was under half that for participants without pNASH (0. 73, 95%CI 0. 49 to 1. 00), the difference did not reach statistical significance. Outcomes were also evaluated for the pre-consent population. 138/1249 in the intervention group (11. 0%) and 137/1017 controls (13. 5%) had MCVE during the 5-year follow-up (unadjusted RR 0. 83, 95%CI 0. 66-1. 03). Participants with pNASH in the intervention group had a significant decrease in liver enzyme levels after 60 months of follow-up (intragroup -12. 0 IU/L, 95%CI -14. 2 to -9. 6). Conclusion: Fixed-dose combination therapy is safe and effective for prevention of MCVE even among participants with fatty liver and increased liver enzymes. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease (CVD) is among the most common causes of mortality in all populations. Nonalcoholic steatohepatitis is a common finding in patients with CVD. Prevention of CVD in individual patients typically requires periodic clinical evaluation, as well as diagnosis and management of risk factors such as hypertension and hyperlipidemia. However, this is resource consuming and hard to implement, especially in developing countries. We designed a study to investigate the effects of a simpler strategy: a fixed-dose combination pill consisting of aspirin, valsartan, atorvastatin and hydrochlorthiazide (PolyPill) in an unselected group of persons aged over 50 years. Design: The PolyIran-Liver study was performed in Gonbad city as an open label pragmatic randomized controlled trial nested within the Golestan Cohort Study. We randomly selected 2,400 cohort study participants aged above 50 years, randomly assigned them to intervention or usual care and invited them to participate in an additional measurement study (if they met the eligibility criteria) to measure liver related outcomes. Those agreeing and randomized to the intervention arm were offered a daily single dose of PolyPill. We will follow participants for 5 years. The primary outcome is major cardiovascular events, secondary outcomes include all-cause mortality and liver related outcomes: liver stiffness and liver enzyme levels. Cardiovascular outcomes and mortality will be determined from the cohort study and liver-related outcomes in those consenting to follow up. Analysis will be by allocated group. Trial status: Between October and December 2011, 1,320 intervention and 1,080 control participants were invited to participate in the additional measurement study. For all these participants, the major cardiovascular events will be determined using blind assessment of outcomes through the cohort study. In the intervention and control arms, 875 (66%) and 721 (67%) respectively, met the eligibility criteria and agreed to participate in the additional measurement study. Liver related outcomes will be measured in these participants. Of the 1,320 participants randomized to the intervention, 787 (60%) accepted the PolyPill. Conclusion: The PolyIran-liver urban study will provide us with important information on the effectiveness of PolyPill on major cardiovascular events, all-cause mortality and liver related outcomes. (ClinicalTrials.gov ID: NCT01245608). [ABSTRACT FROM AUTHOR]

BACKGROUND Only a few studies in Western countries have investigated the association between gastroesophageal reflux disease (GERD) and mortality at the general population level and they have shown mixed results. This study investigated the association between GERD symptoms and overall and cause-specific mortality in a large prospective population-based study in Golestan Province, Iran. METHODS Baseline data on frequency, onset time, and patient-perceived severity of GERD symptoms were available for 50001 participants in the Golestan Cohort Study (GCS). We identified 3107 deaths (including 1146 circulatory and 470 cancer-related) with an average follow-up of 6.4 years and calculated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for multiple potential confounders. RESULTS Severe daily symptoms (defined as symptoms interfering with daily work or causing nighttime awakenings on a daily bases, reported by 4.3% of participants) were associated with cancer mortality (HR 1.48, 95% CI: 1.04-2.05). This increase was too small to noticeably affect overall mortality. Mortality was not associated with onset time or frequency of GERD and was not increased with mild to moderate symptoms. CONCLUSION We have observed an association with GERD and increased cancer mortality in a small group of individuals that had severe symptoms. Most patients with mild to moderate GERD can be re-assured that their symptoms are not associated with increased mortality. [ABSTRACT FROM AUTHOR]

Background: Gastroesophageal reflux disease (GERD) is a common cause of discomfort and morbidity worldwide. However, information on determinants of GERD from large-scale studies in low- to medium-income countries is limited. We investigated the factors associated with different measures of GERD symptoms, including frequency, patient-perceived severity, and onset time. Methods: We performed a cross-sectional analysis of the baseline data from a population-based cohort study of ∼50,000 individuals in in Golestan Province, Iran. GERD symptoms in this study included regurgitation and/or heartburn. Results: Approximately 20% of participants reported at least weekly symptoms. Daily symptoms were less commonly reported by men, those of Turkmen ethnicity, and nass chewers. On the other hand, age, body mass index, alcohol drinking, cigarette smoking, opium use, lower socioeconomic status, and lower physical activity were associated with daily symptoms. Most of these factors showed similar associations with severe symptoms. Women with higher BMI and waist to hip ratio were more likely to report frequent and severe GERD symptoms. Hookah smoking (OR 1.34, 95% CI 1.02–1.75) and opium use (OR 1.70, 95% CI 1.55–1.87) were associated with severe symptoms, whereas nass chewing had an inverse association (OR 0.87, 95% CI 0.76–0.99). After exclusion of cigarette smokers, hookah smoking was still positively associated and nass chewing was inversely associated with GERD symptoms (all frequencies combined). Conclusion: GERD is common in this population. The associations of hookah and opium use and inverse association of nass use with GERD symptoms are reported for the first time. Further studies are required to investigate the nature of these associations. Other determinants of GERD were mostly comparable to those reported elsewhere. [ABSTRACT FROM AUTHOR]

Objectives:Opium use, particularly in low doses, is a common practice among adults in northeastern Iran. We aimed to investigate the association between opium use and subsequent mortality from disorders of the digestive tract.Methods:We used data from the Golestan Cohort Study, a prospective cohort study in northeastern Iran, with detailed, validated data on opium use and several other exposures. A total of 50,045 adults were enrolled during a 4-year period (2004-2008) and followed annually until December 2012, with a follow-up success rate of 99%. We used Cox proportional hazard regression models to evaluate the association between opium use and outcomes of interest.Results:In all, 8,487 (17%) participants reported opium use, with a mean duration of 12.7 years. During the follow-up period 474 deaths from digestive diseases were reported (387 due to gastrointestinal cancers and 87 due to nonmalignant etiologies). Opium use was associated with an increased risk of death from any digestive disease (adjusted hazard ratio (HR)=1.55, 95% confidence interval (CI)=1.24-1.93). The association was dose dependent, with a HR of 2.21 (1.57-3.31) for the highest quintile of cumulative opium use vs. no use (Ptrend=0.037). The HRs (95% CI) for the associations between opium use and malignant and nonmalignant causes of digestive mortality were 1.38 (1.07-1.76) and 2.60 (1.57-4.31), respectively. Increased risks were seen both for smoking opium and for ingestion of opium.Conclusions:Long-term opium use, even in low doses, is associated with increased risk of death from both malignant and nonmalignant digestive diseases. [ABSTRACT FROM AUTHOR]

Esophageal cancer (EC) is the eighth common cancer and the sixth most common cause of death from cancer worldwide. Esophageal squamous cell carcinoma (ESCC) remains the most common type of EC in the developing world and an important health problem in high-risk areas. Most of ESCC cases present in late stages, resulting in delayed diagnosis and poor prognosis. Prevention is the most effective strategy to control ESCC. Primary and secondary preventive methods may be considered for ESCC. In primary prevention, we try to avoid known risk factors. The aim of the secondary preventive method (ESCC screening programs) is to detect and eliminate premalignant precursor lesion of ESCC, preventing its progression into advanced stages. Similar to all population-based screening programs, any screening for early detection of ESCC must be cost-effective; otherwise, screening may not be indicated in that population. Endoscopy with iodine staining has been accepted as a population-level ESCC screening program in some high-risk areas including parts of China. This method may be too expensive and invasive in other high-risk communities. Nonendoscopic methods may be more applicable in these populations for population-based screenings. The limitations (questionable validity and costs) of new endoscopic imaging modalities, including narrow-band imaging (NBI), made them inappropriate to be used in population-level ESCC screening programs. Low-cost, less-invasive endoscopic imaging methods with acceptable diagnostic performance may make screening of ESCC in high-risk areas cost-effective. [ABSTRACT FROM AUTHOR]

Background: Esophageal cancer (EC) is the eighth common cancer worldwide. Esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAD) are the most common histologic types of EC. Many recent reports showed an increasing trend in EAD and a decreasing trend in ESCC in many Western countries. Golestan Province in northeastern Iran has been known as a high-risk area for EC. The aim of this study was to describe the time trend of EAD in this area between 2000-2009. Methods: Data on cancer cases were obtained from Golestan Population-based Cancer Registry. Analysis was done using Joinpoint software. To examine the incidence trends, the annual percent change was calculated. The possibilities of anatomic and histologic misclassification were considered by assessing the trend of ESCC and gastric adenocarcinoma. Results: A total number of 1186 histologically-confirmed EC cases were recruited. The incidence rate of EAD showed a significant increasing trend. There was no significant trend in the incidence of ESCC during the study period. A significant increase in the incidence rate of gastric adenocarcinoma was observed during the period of 2000-2005, followed by a plateau during the period of 2005-2009. Conclusions: We found a significant increasing trend in the incidence rate of EAD. We find no evidence to support an alternative explanation including anatomic and histologic misclassification. So, the observed rise in the incidence of EAD seems to be real. Therefore, designing and implementation of control programs, including control of preventable risk factors of EAD, should be considered in this high-risk area. [ABSTRACT FROM AUTHOR]

A pilot study to investigate the occurrence of 10 mycotoxins (deoxynivalenol, DON; 3-acetyldeoxynivalenol, 3-ADON; 15-acetyldeoxynivalenol, 15-ADON; fusarenon-X, FUS-X; diacetoxyscirpenol, DAS; nivalenol, NIV; neosolaniol, NEO; zearalenone, ZON; zearalanone, ZAN; T-2 toxin, T-2; and HT-2 toxin, HT-2) in esophageal cancer patients was performed with the urinary biomarkers approach in Golestan, Iran. Urine multimycotoxin analysis was performed by dispersive liquid–liquid microextraction and gas chromatography–tandem mass spectrometry (GC–MS/MS) analysis, and values were normalized with urinary creatinine (μg/g). Four mycotoxins, namely NEO (40%), HT-2 (17.6%), DON (10%), and HT-2 (5.8%), were detected in the analyzed urine samples. DON was only detected in the control group (5.09 μg/g creatinine), while T-2 (44.70 μg/g creatinine) was only present in the esophageal cancer group. NEO and HT-2 were quantified in both control and case groups, showing average of positive samples of 9.09 and 10.45 μg/g creatinine for NEO and 16.81 and 29.09 μg/g creatinine for HT-2, respectively. Mycotoxin co-occurrence was observed in three samples as binary (NEO/HT-2 and T-2/HT-2) and ternary (DON/NEO/HT-2) combinations, reaching total concentrations of 44.58, 79.13, and 30.04 µg/g creatinine, respectively. Further investigations are needed to explore a causal association between mycotoxin contamination and esophageal cancer. For this pilot study in Golestan, the low sample size was a very limiting factor. [ABSTRACT FROM AUTHOR]

Background and Objectives: Flavonoids are the most important group of polyphenols with well-known beneficial effects on health. However; the association of intake of total flavonoid or their subclasses with all-cause or cause-specific mortality is not fully understood. The present study aims to evaluate the association between intake of total flavonoid, flavonoid subclasses, and total and cause-specific mortality in a developing country.Methods: A total number of 49,173 participants from the Golestan cohort study, who completed a validated food frequency questionnaire at recruitment, were followed from 2004 till 2018. Phenol-Explorer database was applied to estimate dietary intakes of total flavonoid and different flavonoid subclasses. Associations were examined using adjusted Cox proportional hazards models.Results: During a mean follow-up of 10.63 years, 5104 deaths were reported. After adjusting for several potential confounders, the hazard ratios (HRs) of all-cause mortality for the highest versus the lowest quintile of dietary flavanones, flavones, isoflavonoids, and dihydrochalcones were 0.81 (95% confidence interval = 0.73-0.89), 0.83(0.76-0.92), 0.88(0.80-0.96) and 0.83(0.77-0.90), respectively. However, there was no association between total flavonoid intake or other flavonoid subclasses with all-cause mortality. In cause-specific mortality analyses, flavanones and flavones intakes were inversely associated with CVD mortality [HRs: 0.86(0.73-1.00) and 0.85(0.72-1.00)] and isoflavonoids and dihydrochalcones were the only flavonoid subclasses that showed a protective association against cancer mortality [HR: 0.82(0.68-0.98)].Conclusion: The results of our study suggest that certain subclasses of flavonoids can reduce all-cause mortality and mortality rate from CVD and cancer. [ABSTRACT FROM AUTHOR]

LINKED CONTENT This article is linked to the Al‐Ani et al papers. To view these articles, visit https://doi.org/10.1111/apt.15779 and https://doi.org/10.1111/apt.15954 [ABSTRACT FROM AUTHOR]