Obesity is associated with biliary tract cancer mortality and incidence: A pooled analysis of 21 cohort studies in the Asia Cohort Consortium.

Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population-based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m2 ); normal (18.5-22.9 kg/m2 ); overweight (23-24.9 kg/m2 ); and obese (25+ kg/m2 ). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 [CI 1.02-1.38] for males, HR 1.30 [1.14-1.49] for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis.

Diabetes is associated with increased liver cancer incidence and mortality in adults: A report from Asia Cohort Consortium.

There has been growing evidence suggesting that diabetes may be associated with increased liver cancer risk. However, studies conducted in Asian countries are limited. This project considered data of 968,738 adults pooled from 20 cohort studies of Asia Cohort Consortium to examine the association between baseline diabetes and liver cancer incidence and mortality. Cox proportional hazard model and competing risk approach was used for pooled data. Two-stage meta-analysis across studies was also done. There were 839,194 subjects with valid data regarding liver cancer incidence (5654 liver cancer cases [48.29/100,000 person-years]), follow-up time and baseline diabetes (44,781 with diabetes [5.3%]). There were 747,198 subjects with valid data regarding liver cancer mortality (5020 liver cancer deaths [44.03/100,000 person-years]), follow-up time and baseline diabetes (43,243 with diabetes [5.8%]). Hazard ratio (HR) (95% confidence interval [95%CI]) of liver cancer diagnosis in those with vs. without baseline diabetes was 1.97 (1.79, 2.16) (p < .0001) after adjusting for baseline age, gender, body mass index, tobacco smoking, alcohol use, and heterogeneity across studies (n = 586,072; events = 4620). Baseline diabetes was associated with increased cumulative incidence of death due to liver cancer (adjusted HR (95%CI) = 1.97 (1.79, 2.18); p < .0001) (n = 595,193; events = 4110). A two-stage meta-analytic approach showed similar results. This paper adds important population-based evidence to current literature regarding the increased incidence and mortality of liver cancer in adults with diabetes. The analysis of data pooled from 20 studies of different Asian countries and the meta-analysis across studies with large number of subjects makes the results robust.

Dental health and lung cancer risk in the Golestan Cohort Study.

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.

Population attributable proportion and number of cancer cases attributed to potentially modifiable risk factors in Iran in 2020.

In the current study, we aimed to calculate the fraction of cancer attributable to modifiable risk factors in Iran in 2020. Population attributable fractions (PAFs) were calculated for established cancer risk factors using three data sources: the national cancer incidence reports, relative risks extracted from global and national meta-analyses, and exposure prevalence from national/subnational population-based surveys. In addition to overall cancers, the PAFs were estimated separately for each cancer site among men and women. Overall, 32.6% of cancers in 2020 in Iran were attributable to known risk factors. The PAF in men (40.2%) was twice as high as in women (21.1%). Cigarette smoking (15.4%), being overweight (5.0%), opium use (3.9%) and H. pylori infection (3.8%) were the leading causes of cancers. For men, the highest PAFs belonged to cigarette smoking (26.3%), opium use (6.8%) and being overweight (3.1%), while for women, the highest PAFs belonged to being overweight (7.2%), H. pylori infection (2.7%) and cigarette smoking (2.7%). Among Iranian men and women, the PAFs of waterpipe smoking were 2% and 0.9%, respectively. A third of incident cancers in Iran are due to modifiable exposures, mainly cigarette smoking, being overweight, and H. pylori infection. Opium consumption and waterpipe smoking collectively accounted for 8.8% of cancer occurrence in men and 1.3% in women in Iran. These emerging risk factors should be taken into consideration in future PAF studies.

RNA-sequencing for transcriptional profiling of whole blood in early stage and metastatic pancreatic cancer patients.

We investigated the transcriptional profile of whole blood in early and metastatic stages of pancreatic cancer (PaC) patients to identify potential diagnostic factors for early diagnosis. Blood samples from 18 participants (6 healthy individuals, 6 patients in early stage (I/II) PaC, and 6 patients in metastatic PaC) were analyzed by RNA-sequencing. The expression levels of identified genes were subsequently compared with their expression in pancreatic tumor tissues based on TCGA data reported in UALCAN and GEPIA2 databases. Overall, 331 and 724 genes were identified as differentially expressed genes in early and metastatic stages, respectively. Of these, 146 genes were shared by early and metastatic stages. Upregulation of PTCD3 and UBA52 genes and downregulation of A2M and ARID1B genes in PaC patients were observed from early stage to metastasis. TCGA database showed increasing trend in expression levels of these genes from stage I to IV in pancreatic tumor tissue. Finally, we found that low expression of PTCD3, A2M, and ARID1B genes and high expression of UBA52 gene were positively correlated with PaC patients survival. We identified a four-gene set (PTCD3, UBA52, A2M, and ARID1B) expressed in peripheral blood of early stage and metastatic PaC patients that may be useful for PaC early diagnosis.

Smoke exposure associated with higher urinary benzene biomarker muconic acid (MUCA) in Golestan Cohort Study participants.

Background. Benzene is a known human carcinogen. Human exposure to benzene can be assessed by measuring trans, trans-muconic acid (MUCA) in urine. Golestan Province in northeastern Iran has been reported to have high incidence of esophageal cancer linked to the use of tobacco products. This manuscript evaluates the urinary MUCA concentrations among the participants of the Golestan Cohort Study (GCS).Methods. We analyzed MUCA concentration in 177 GCS participants' urine samples and performed nonparametric pairwise multiple comparisons to determine statistically significant difference among six different product use groups. Mixed effects model was fitted on 22 participants who exclusively smoked cigarette and 51 participants who were classified as nonusers. The urinary MUCA data were collected at the baseline and approximately five years later, and intraclass correlation coefficient (ICC) was calculated from the model.Results. Compared with nonusers, tobacco smoking was associated with higher urinary MUCA concentrations. Based on the nonparametric test of pairwise multiple comparisons, MUCA concentrations among participants who smoked combusted tobacco products were statistically significantly higher compared to nonusers. Urinary MUCA collected five years apart from the same individuals showed moderate reliability (ICC = 0.41), which was expected given the relatively short half-life (∼6 h) of MUCA.Conclusion. Our study revealed that tobacco smoke was positively associated with increased levels of urinary MUCA concentration, indicating that it is a significant source of benzene exposure among GCS participants.

The carcinogenicity of opium consumption: a systematic review and meta-analysis.

The carcinogenicity of opium consumption was recently evaluated by a Working Group convened by the International Agency for Research on Cancer (IARC). We supplement the recent IARC evaluation by conducting an extended systematic review as well as a quantitative meta-analytic assessment of the role of opium consumption and risk for selected cancers, evaluating in detail various aspects of study quality on meta-analytic findings. We searched the published literature to identify all relevant studies on opium consumption and risk of selected cancers in humans through 31 October, 2022. Meta-relative risks (mRRs) and associated 95% confidence intervals (CIs) were estimated using random-effects models for studies of cancer of the urinary bladder, larynx, lung, oesophagus, pancreas, and stomach. Heterogeneity among studies was assessed using the I2 statistic. We assessed study quality and conducted sensitivity analyses to evaluate the impact of potential reverse causation, protopathic bias, selection bias, information bias, and confounding. In total, 2 prospective cohort studies and 33 case-control studies were included. The overall pooled mRR estimated for 'ever or regular' versus 'never' use of opium ranged from 1.50 (95% CI 1.13-1.99, I2 = 0%, 6 studies) for oesophageal cancer to 7.97 (95% CI 4.79-13.3, I2 = 62%, 7 studies) for laryngeal cancer. Analyses of cumulative opium exposure suggested greater risk of cancer associated with higher opium consumption. Findings were robust in sensitivity analyses excluding studies prone to potential methodological sources of biases and confounding. Findings support an adverse association between opium consumption and cancers of the urinary bladder, larynx, lung, oesophagus, pancreas and stomach.

Higher intakes of fiber, total vegetables, and fruits may attenuate the risk of all-cause and cause-specific mortality: findings from a large prospective cohort study.

BACKGROUND: Although studies have reported an inverse association between fruits, vegetables, and fiber consumption and all-cause and cause-specific mortality, the issue remains incompletely defined in the Middle Eastern population. AIMS: The current study aimed to investigate the association between dietary fiber, fruit, and vegetable intake and all-cause and cause-specific mortality. METHODS: A total of 48632 participants (mean age = 52years), 57.5% (n = 27974) women and 42.5% (n = 20658) men, were recruited from an ongoing large-scale prospective cohort study (the Golestan Cohort Study (GCS)), in the north of Iran. Using a validated semi-quantitative 116-item food questionnaire, dietary intakes were collected. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) of all-cause and cause-specific mortality were reported. RESULTS: After approximately 14 years of follow-up, 10,774 deaths were recorded. In the fully adjusted model, compared to those in the lowest quintile of intake, those in the second and third quintiles of dietary fiber intake had a 7%-10% reduction in risk of all-cause mortality, and a 15%-17% reduction in the risk of mortality from other causes. Increasing consumption of fruits was also associated with a decreased risk of mortality for all-cause mortality by 9%-11%, and all cancer by 15-20%. Further, those in the third and fourth quintiles of vegetables intake had 11%-12% lower risk for CVD mortality. DISCUSSION: The results from the GCS further support the current recommendations on following a healthy diet containing proper amounts of fiber, vegetables, and fruits, as health-protective dietary items. CONCLUSIONS: Higher intake of dietary fiber, fruits, and vegetables has the potential to reduce both overall and cause-specific mortality rates. However, additional cohort studies with larger sample size and long-term follow-up durations are required to establish these findings.

Meat consumption and risk of esophageal and gastric cancer in the Golestan Cohort Study, Iran.

Red meat and processed meat are associated with some gastrointestinal cancers. Our study aims to investigate the association of different meat types with esophageal and gastric cancer (EC, GC) in a high-risk population. The Golestan Cohort Study (GCS) is a population-based cohort of 50 045 individuals aged 40 to 75 from northeast Iran. Detailed data on different exposures were collected using validated questionnaires. We considered quintiles of meat consumption, using grams and density (g/1000 kcal/day). We calculated intake of red, processed, organ and white meat, as well as total red meat, including the first three. We used proportional hazards regression models to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the association between meat types and cancer. During 12 years of follow-up, out of 49 585 participants (57.4% women), 369 developed EC (48.2% women) and 368 developed GC (27.5% women), including 309 esophageal squamous cell, 20 esophageal adenocarcinomas, 216 cardia and 95 non-cardia GC. No association was found for EC except for red meat among females (HR for one quintile increase 1.13, 95% CI = 1.00-1.27). The risk of GC increased for intake of total red meat (HR 1.08, 95% CI = 1.00-1.17) and red meat separately (HR 1.09, 95% CI = 1.00-1.18). The HR for red meat and non-cardia GC was 1.23 (95% CI = 1.02-1.48). No associations were observed for other types of meat. In conclusion, in this high-risk population red meat intake is associated with GC, but not EC, suggesting a substantial role of this modifiable factor in determining the burden of GC.

Dietary acid load and mortality from all causes, CVD and cancer: results from the Golestan Cohort Study.

Given the limited studies and controversial results on association between dietary acid load and mortality from CVD and cancers, we aimed to investigate this association in a large population cohort study in Middle East, with a wide range of dietary acid load. The study was conducted on the platform of the Golestan Cohort Study (GCS), which enrolled 50 045 participants in 2004-2008. Dietary intake was assessed using a validated FFQ. Dietary potential renal acid load (PRAL) score was calculated from nutrient intake. Death and its causes were identified and confirmed by two or three physicians. Cox proportional hazards regression was used to estimate hazard ratio (HR) and 95 % CI for total and cause-specific mortalities. Then, the associations were modelled using restricted cubic splines. PRAL range was -57·36 to +53·81 mEq/d for men and -76·70 to +49·08 for women. During 555 142 person-years of follow-up, we documented 6830 deaths, including 3070 cardiovascular deaths, 1502 cancer deaths and 2258 deaths from other causes. For overall deaths, in final model after adjustment for confounders, participants in the first and fifth quintiles of PRAL had a higher risk of mortality compared with the second quintile of PRAL (HR: 1·08; 95 % CI1·01, 1·16 and HR: 1·07; 95 % CI 1·01, 1·15, respectively); Pfor trend < 0·05). Participants in the first and fifth quintiles of PRAL had a 12 % higher risk of CVD mortality compared with the Q2 of PRAL (HR: 1·12; 95 % CI 1·01-1·25 and HR: 1·12; 95 % CI 1·01, 1·26, respectively; Pfor trend < 0·05). We found that all-cause and CVD mortality rates were higher in the lowest and highest PRAL values, in an approximately U-shaped relation (P-values for the overall association and the non-linear association of energy-adjusted PRAL with total mortality were < 0·001 and < 0·001, and with CVD mortality were 0·008 and 0·003, respectively). Our results highlight unfavourable associations of high acidity and alkalinity of diet with the increased total and CVD mortality risk. It may be important to consider a balanced acid-base diet as a protective strategy to prevent pre-mature death, especially from CVD.

Opium Use and Cancer Risk: A Comprehensive Systematic Review and Meta-Analysis of Observational Studies.

Background: Epidemiological studies have reported inconsistent associations between opium use and cancer risk. We therefore conducted a systematic review and meta-analysis to investigate the relationship between opium use and cancer risk. Methods: We searched PubMed, Scopus, ISI Web of Knowledge, and Google Scholar until February 2021 and references of retrieved relevant articles for observational studies that reported the risk of cancer in relation to opium use. Random-effects models were used to calculate pooled effect sizes (ESs) as well as 95% confidence intervals (CIs) for the association between opium use and cancer risk by considering opium doses and types, duration of consumption, and routes of opium use. Results: In total, 21 observational articles, with a total sample size of 64,412 individuals and 6,658 cases of cancer, were included in this systematic review and meta-analysis. Ever opium users, compared with never opium users, had 3.53 times greater risk of overall cancer (pooled ES: 3.53, 95% CI: 2.60-4.79, P ≤ 0.01). This positive association was also seen for some individual types of cancers except for esophageal and colon cancers. Also, we found that higher opium doses and higher duration of consumption were associated with an increased risk of overall and individual types of cancer. However, the associations between opium doses and the risk of head and neck and larynx cancers were not significant. In terms of the routes of opium use, both opium ingestion and smoking were positively associated with the risk of cancer. Regarding opium types, we found that using teriak, but not shireh, could increase the risk of cancer. Conclusions: Our findings showed that opium use, particularly in the form of teriak, is a risk factor for cancer.

The association of dietary intake and plasma fatty acid panel in pancreatic cancer patients: Results from Golestan cohort study.

BACKGROUND & AIMS: High mortality rate of pancreatic cancer (PC) as one of the most common cancers worldwide made it a center of attention for recent researches on its pathology, etiology, screening and early diagnosis. In previous researches, association of dietary intake and plasma levels of fatty acids with risk of pancreatic cancer was investigated. In this study we aimed to evaluate the correlation between dietary and plasma fatty acids in case and control groups. METHODS: From 50,045 adults between 40-75 years old participated in Golestan cohort study, fifty incident cases of PC were diagnosed and 150 controls matched by age, sex and residence place were randomly selected. Dietary intakes and plasma levels of fatty acids was evaluated by validated food-frequency questionnaire (FFQ) and Gas Chromatography - Flame Ionization Detector (GC-FID), respectively. Then, Spearman's correlation was used to measure the correlation between dietary and plasma levels of fatty acids in case and control groups. RESULTS: Among all the fatty acids, there was a significant association between plasma and dietary intake of a few fatty acids including trans fatty acids (TFA), polyunsaturated fatty acids (PUFA), 22:6n-3 and 14:0 only in control group. Only total PUFA intake modified plasma level of some fatty acids in case group. There was no difference between association of desaturase enzymes and fatty acids in case and controls. CONCLUSIONS: Since, plasma levels of fatty acids might be influenced by recent diet, we did not find any specific differences between the associations of plasma levels of fatty acids with dietary intake of fats in case and control groups.

Dietary quality using four dietary indices and lung cancer risk: the Golestan Cohort Study (GCS).

PURPOSE: The lung cancer incidence in Iran has increased almost ten times over the past three decades. In addition to the known causes such as smoking and certain occupational exposure, dietary quality has been suggested to play a role in lung cancer. We aim to explore the association between dietary pattern and lung cancer risk among a Middle East population. METHODS: Data came from Golestan Cohort Study which included 48,421 participants with 136 lung cancer cases diagnosed during a median follow-up of 12 years. Multivariable Cox proportional hazards regression models were used to calculate the HRs and 95% CI of lung cancer risk by tertile of the four dietary index scores-the Health Eating Index (HEI)-2015, the Alternative Health Eating Index (AHEI)-2010, the Alternative Mediterranean Diet (AMED), and the Dietary Approach to Stop Hypertension (DASH)-Fung. RESULTS: A higher DASH-Fung score was inversely associated with risk of lung cancer after adjusting for potential confounders (tertile three vs. tertile one: HR = 0.59 (0.38-0.93); p for trend = 0.07), and pinteraction with smoking was 0.46. Similar findings were observed among current smokers with the HEI-2015 score (tertile three vs. tertile one: HR = 0.22 (0.08-0.60): p for trend < 0.01), and pinteraction between smoking and the HEI-2015 score was 0.03. CONCLUSION: In the GCS, consuming a diet more closely aligned with the DASH diet was associated with a reduced risk of lung cancer, which appeared to be independent of smoking status. There was also an inverse link between the HEI-2015 score and lung cancer risk among current smokers. Our finding is particularly important for the Middle East population, as diet may play an important role in cancer prevention and overall health.

Dietary intake of fatty acids and risk of pancreatic cancer: Golestan cohort study.

BACKGROUND: As pancreatic cancer (PC) is a malignancy with poor prognosis, finding strategies for its prevention became a notable priority. Among all the factors influencing the risk of PC, dietary items especially fats are considered as the most modifiable risk factors.This study is designed to assess the associations of dietary intake of fatty acids with the risk of PC incidence. METHODS: A total of 50,045 adults between 40 and 75 years old participated in this cohort study in 2004-2008 and were followed up to the present. Intakes of fatty acids was evaluated by validated food-frequency questionnaire (FFQ). Cox proportional hazards regression model was used to estimate hazard ratio (HR) with 95 % confidence interval of differing levels of dietary intakes of fatty acids for incidence of PC. RESULTS: At the end of follow-up period, 76 cases of PC were identified and 46,904 participants without history of cancer, acute kidney disorders, fibrosis and cirrhosis were included in the study. Dietary total saturated fatty acids (SFAS) was associated with PC risk (HR = 1.05 (1.01-1.09), Ptrend=0.01), whereas dietary total monounsaturated fatty acids (MUFAS) was inversely associated with the risk of PC (HR = 0.92 (0.86-0.99), Ptrend=0.04). Dietary total polyunsaturated fatty acids (PUFAS) did show a protective but not significant association with the risk of PC (HR = 0.91(0.84-1.00), Ptrend=0.05). CONCLUSIONS: The amount of total fat intake is not a risk factor for PC in our study and focusing on the intake of specific fatty acids becomes more striking. Unsaturated fatty acids including PUFAS and especially MUFAS are considered as protective dietary factors in PC prevention. In contrast, total SFAS is positively associated with the increased risk of PC. However, very long chain and odd-chain saturated fatty acids intake may be protective against PC.

A prospective study of tea drinking temperature and risk of esophageal squamous cell carcinoma.

Previous studies have reported an association between hot tea drinking and risk of esophageal cancer, but no study has examined this association using prospectively and objectively measured tea drinking temperature. We examined the association of tea drinking temperature, measured both objectively and subjectively at study baseline, with future risk of esophageal squamous cell carcinoma (ESCC) in a prospective study. We measured tea drinking temperature using validated methods and collected data on several other tea drinking habits and potential confounders of interest at baseline in the Golestan Cohort Study, a population-based prospective study of 50,045 individuals aged 40-75 years, established in 2004-2008 in northeastern Iran. Study participants were followed-up for a median duration of 10.1 years (505,865 person-years). During 2004-2017, 317 new cases of ESCC were identified. The objectively measured tea temperature (HR 1.41, 95% CI 1.10-1.81; for ≥60°C vs. <60°C), reported preference for very hot tea drinking (HR 2.41, 95% CI 1.27-4.56; for "very hot" vs. "cold/lukewarm"), and reported shorter time from pouring tea to drinking (HR 1.51, 95% CI 1.01-2.26; for <2 vs. ≥6 min) were all associated with ESCC risk. In analysis of the combined effects of measured temperature and amount, compared to those who drank less than 700 ml of tea/day at <60°C, drinking 700 mL/day or more at a higher-temperature (≥60°C) was consistently associated with an about 90% increase in ESCC risk. Our results substantially strengthen the existing evidence supporting an association between hot beverage drinking and ESCC.

Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial.

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.

Individual and Combined Effects of Environmental Risk Factors for Esophageal Cancer Based on Results From the Golestan Cohort Study.

BACKGROUND & AIMS: Northeast Iran has one of the highest reported rates of esophageal squamous cell carcinoma (ESCC) worldwide. Decades of investigations in this region have identified some local habits and environmental exposures that increase risk. We analyzed data from the Golestan Cohort Study to determine the individual and combined effects of the major environmental risk factors of ESCC. METHODS: We performed a population-based cohort of 50,045 individuals, 40 to 75 years old, from urban and rural areas across Northeast Iran. Detailed data on demographics, diet, lifestyle, socioeconomic status, temperature of drinking beverages, and different exposures were collected using validated methods, questionnaires, and physical examinations, from 2004 through 2008. Participants were followed from the date of enrollment to the date of first diagnosis of esophageal cancer, date of death from other causes, or date of last follow-up, through December 31, 2017. Proportional hazards regression models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the association between different exposures and ESCC. RESULTS: During an average 10 years of follow-up, 317 participants developed ESCC. Opium smoking (HR 1.85; 95% CI 1.18-2.90), drinking hot tea (≥60°C) (HR 1.60; 95% CI 1.15-2.22), low intake of fruits (HR 1.48; 95% CI 1.07-2.05) and vegetables (HR 1.62; 95% CI 1.03-2.56), excessive tooth loss (HR 1.66; 95% CI 1.04-2.64), drinking unpiped water (HR 2.04; 95% CI 1.09-3.81), and exposure to indoor air pollution (HR 1.57; 95% CI 1.08-2.29) were significantly associated with increased risk of ESCC, in a dose-dependent manner. Combined exposure to these risk factors was associated with a stepwise increase in the risk of developing ESCC, reaching a more than 7-fold increase in risk in the highest category. Approximately 75% of the ESCC cases in this region can be attributed to a combination of the identified exposures. CONCLUSIONS: Analysis of data from the Golestan Cohort Study in Iran identified multiple risk factors for ESCC in this population. Our findings support the hypothesis that the high rates of ESCC are due to a combination of factors, including thermal injury (from hot tea), exposure to polycyclic aromatic hydrocarbons (from opium and indoor air pollution), and nutrient-deficient diets. We also associated ESCC risk with exposure to unpiped water and tooth loss.

Habitual dietary intake of flavonoids and all-cause and cause-specific mortality: Golestan cohort study.

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.

The application of six dietary scores to a Middle Eastern population: a comparative analysis of mortality in a prospective study.

Background The associations between dietary indices and mortality have not been evaluated in populations from the Middle East, which have different dietary patterns compared to the US and Europe. In this study, we evaluated the association between six dietary indices and mortality in the Golestan Cohort Study (GCS) in Iran, which is the largest prospective study in the Middle East with 50,045 participants. Methods The six dietary indices, namely the Healthy Eating Index (HEI-2015), Alternative Healthy Eating Index (AHEI-2010), Alternative Mediterranean Diet (AMED), Dietary Approach to Stop Hypertension created by Fung (DASH-Fung) and Mellen (DASH-Mellen), and the World Cancer Research Fund (WCRF/AICR) index, were applied to data from a food frequency questionnaire, computed and divided into quintiles. Adjusted Cox models were used to estimate hazards ratio (HR) and 95% confidence intervals (CI) for overall and cause-specific mortality, using the lowest quintile as a reference group. Results Among 42,373 participants included in the current analyses, 4424 subjects died during 10.6 years of follow-up. Participants with the highest quintile dietary scores, compared with the lowest quintile dietary scores, had significantly decreased overall mortality in the AHEI-2010, AMED, DASH-Fung, and WCRF/AICR indices (HR 0.88, 95% CI = 0.80-0.97; 0.80, 0.70-0.91; 0.77, 0.70-0.86; and 0.79, 0.70-0.90, respectively). A reduced cardiovascular mortality was found for high AHEI-2010 and DASH-Fung scores (17% and 23%, respectively), and a reduced cancer mortality for high HEI-2015, AMED, and DASH-Fung scores (21, 37 and 25%, respectively). Conclusion Various indices of dietary quality are inversely associated with overall mortality, and selectively with cancer and cardiovascular mortality in the GCS, which contribute to the generalizability and validity of dietary guidelines.

Nut consumption and the risk of oesophageal squamous cell carcinoma in the Golestan Cohort Study.

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.