Incident cancers attributable to using opium and smoking cigarettes in the Golestan cohort study.

Background: Opium consumption has recently been identified as a carcinogen, but the impact of opium use on cancer burden is unknown. We aimed to evaluate the fraction of cancers that could be attributed to opium use alone and in combination with cigarette smoking in a region where opium is widely used. Methods: 50,045 Iranian adults were recruited to this prospective cohort study between 2004 and 2008 and were followed through January 2022. We assessed the association between using opium and/or cigarette smoking and various cancers using proportional hazards regression models. We then calculated population attributable fractions (PAFs) for all cancers and for groups of cancers causally linked to opium and cigarette smoking. Findings: Of the total participants, 8% only used opium, 8.3% only smoked cigarettes, and 9% used both substances. During a median 14 years of follow-up, 2195 individuals were diagnosed with cancer, including 215 opium-related cancers (lung, larynx, and bladder) and 1609 tobacco-related cancers (20 types). Opium use alone was estimated to cause 35% (95% CI: 26%-45%) of opium-related cancers, while smoking cigarettes alone was estimated to cause 9% (6%-12%) of tobacco-related cancers in this population. Using opium and/or cigarettes was estimated to cause 13% (9%-16%) of all cancers, 58% (49%-66%) of opium-related cancers, and 15% (11%-18%) of tobacco-related cancers. Moreover, joint exposure to opium and cigarettes had the greatest impact on cancers of the larynx, pharynx, lung, and bladder, with PAFs ranging from 50% to 77%. Interpretation: Using opium and smoking cigarettes account for a large proportion of cancers in this population. To reduce the cancer burden, prevention policies should aim to decrease the use of both substances through public awareness campaigns and interventional efforts. Funding: The Golestan Cohort Study work was funded by the Tehran University of Medical Sciences, Cancer Research UK, U.S. National Cancer Institute, International Agency for Research on Cancer. The presented analysis was supported by the International HundredK+ Cohorts Consortium (IHCC).

Association Between Incident Type 2 Diabetes and Opium Use: Mediation by Body Mass and Adiposity.

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.

Diet Quality and Subsequent Incidence of Upper Gastrointestinal Cancers: Results from the Golestan Cohort Study.

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 50045 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.

Incidence, early case fatality and determinants of stroke in Iran: Golestan Cohort Study.

OBJECTIVES: While few studies investigated the incidence of stroke in Iran, no Iranian cohort has estimated the standardized-incidence rate and early fatality of first-ever-stroke subtypes along with associated factors. METHODS: Golestan Cohort Study is a prospective study launched in northeastern Iran in 2004, including 50,045 individuals aged 40-75 at baseline. Age-standardized incidence rate of first-ever-stroke was calculated per 100,000 person-years, according to World Standard Population. The 28-day case fatality was calculated by dividing the number of fatal first-ever-stroke during the first 28 days by total events. Cox proportional hazard models were conducted to assess incidence and fatality risk factors. We used Population Attributable Fractions to estimate the incidence and early fatality proportions reduced by ideal risk factor control. RESULTS: 1,135 first-ever-strokes were observed during 8.6 (median) years follow-up. First-ever-stroke standardized incidence rate was estimated 185.2 (95% CI: 173.2-197.2) per 100,000 person-years. The 28-day case fatality was 44.1% (95% CI: 40.4-48.2). Hypertension and pre-stroke physical activity were the strongest risk factors associated with first-ever-stroke incidence (Hazard ratio: 2.83; 2.47-3.23) and 28-day case fatality (Hazard ratio: 0.59; 0.44-0.78), respectively. Remarkably, opium consumption was strongly associated with hemorrhagic stroke incidence (Hazard ratio: 1.52; 1.04-2.23) and ischemic stroke fatality (Hazard ratio: 1.44; 1.01-2.09). Overall, modifiable risk factors contributed to 83% and 61% of first-ever-stroke incidence and early fatality, respectively. CONCLUSION: Efficient risk factor control can considerably reduce stroke occurrence and fatality in our study. Establishing awareness campaigns and 24-hour stroke units seem necessary for improving the stroke management in this area.

All-Cause and Cause-Specific Mortality in Middle-Aged Individuals with Positive HBsAg: Findings from a Prospective Cohort Study.

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 50045 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 49667 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.

Simultaneous disruption of circulating miR-21 and cytotoxic T lymphocytes (CTLs): Prospective diagnostic and prognostic markers for esophageal squamous cell carcinoma (ESCC).

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) as the most prominent type of esophageal cancer (EC) in developing countries encompasses a substantial contribution of cancer-related mortalities and morbidities. Cytotoxic T lymphocytes (CTLs) are the major subset of effector T cells against cancer. However, the microRNAs involved in the development and regulation of CTLs could be disrupted in cancers such as EC. METHODS: Here, we evaluated the population of IL-10, TGF-ß, IFN-γ, and IL-17a-producing CD3+CD8+ T cells, their association with the circulating levels of miR-21 and miR-29b, and their diagnostic and/or prognostic (after 160 weeks of follow-up) utilities in 34 ESCC patients (12 newly diagnosed: ND, 24 under-treatment: UT) and 34 matched healthy donors. RESULTS: The population of IL-10 and TGF-ß-producing CTLs (CD8+ Tregs) were considerably expanded, in addition to the overexpression of miR-21 in both groups (ND and UT) of ESCC patients, while the frequency of Tc17 and CD8+ Treg cells increased only in UT patients. The expression means of TGF-ß and IL-10 in CTLs were considered to be excellent biomarkers (1 ≥ area under the curve: AUC ≥0.9) in distinguishing ESCC patients and associated subgroups from healthy subjects. Moreover, the lower expressions of TGF-ß, IL-17a, IL-10, and IFN-γ in CTLs were associated with ESCC better prognosis. CONCLUSIONS: The association between the impaired function of CD3+ CD8+ T cell subsets and miR-21 expression could be introduced as novel therapeutic targets and powerful diagnostic and prognostic markers for ESCC.

Obesity and incident gastrointestinal cancers: overall body size or central obesity measures, which factor matters?

BMI does not reflect the location or amount of body fat. We aimed to investigate the role of general and central obesity measures in the prediction of incident gastrointestinal cancers. In this analysis of the Golestan Cohort Study, we included 47 586 cancer-free individuals followed for 12.3 years (IQR: 10.5-13.2). We investigated the association of obesity measures including BMI, waist circumference and waist-to-hip ratio (WHR) at enrollment and the incidence of esophageal, gastric, colorectal and pancreatic cancers. Cox proportional hazard models were used to estimate the association between covariates and gastrointestinal cancer risk. We observed no significant associations between obesity measures and incidence of the above-mentioned gastrointestinal cancers in men. In women, BMI, waist circumference and WHR were associated with significant reductions in the risk of esophageal squamous cell carcinoma (ESCC): hazard ratio (HR): 0.67 [95% confidence interval (CI): 0.56-0.81], HR: 0.71 (95% CI: 0.60-0.84) and HR: 0.80 (95% CI: 0.68- 0.94), respectively. In addition, WHR was associated with significantly increased risks for colorectal cancer (HR: 1.39, 95% CI: 1.08-1.78) and gastric cancer (HR: 1.24, 95% CI: 1.01-1.51) in women. In this study, statistically significant associations between obesity measures and incident esophageal, gastric and colorectal cancers were seen in women.

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.

Long-term opiate use and risk of cardiovascular mortality: results from the Golestan Cohort Study.

AIMS: Tens of millions of people worldwide use opiates but little is known about their potential role in causing cardiovascular diseases. We aimed to study the association of long-term opiate use with cardiovascular mortality and whether this association is independent of the known risk factors. METHODS AND RESULTS: In the population-based Golestan Cohort Study-50 045 Iranian participants, 40-75 years, 58% women-we used Cox regression to estimate hazard ratios and 95% confidence intervals (HRs, 95% CIs) for the association of opiate use (at least once a week for a period of 6 months) with cardiovascular mortality, adjusting for potential confounders-i.e. age, sex, education, wealth, residential place, marital status, ethnicity, and tobacco and alcohol use. To show independent association, the models were further adjusted for hypertension, diabetes, waist and hip circumferences, physical activity, fruit/vegetable intake, aspirin and statin use, and history of cardiovascular diseases and cancers. In total, 8487 participants (72.2% men) were opiate users for a median (IQR) of 10 (4-20) years. During 548 940 person-years-median of 11.3 years, >99% success follow-up-3079 cardiovascular deaths occurred, with substantially higher rates in opiate users than non-users (1005 vs. 478 deaths/100 000 person-years). Opiate use was associated with increased cardiovascular mortality, with adjusted HR (95% CI) of 1.63 (1.49-1.79). Overall 10.9% of cardiovascular deaths were attributable to opiate use. The association was independent of the traditional cardiovascular risk factors. CONCLUSION: Long-term opiate use was associated with an increased cardiovascular mortality independent of the traditional risk factors. Further research, particularly on mechanisms of action, is recommended.

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.

Household Fuel Use and the Risk of Gastrointestinal Cancers: The Golestan Cohort Study.

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 p-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. https://doi.org/10.1289/EHP5907.

Opium use and subsequent incidence of cancer: results from the Golestan Cohort Study.

BACKGROUND: Evidence is emerging for a role of opiates in various cancers. In this study, we aimed to investigate the association between regular opium use and cancer incidence. METHODS: This study was done in a population-based cohort of 50 045 individuals aged 40-75 years from northeast Iran. Data on participant demographics, diet, lifestyle, opium use, and different exposures were collected upon enrolment using validated questionnaires. We used proportional hazards regression models to estimate hazard ratios (HRs) and corresponding 95% CIs for the association between opium use and different cancer types. FINDINGS: During a median 10 years of follow-up, 1833 participants were diagnosed with cancer. Use of opium was associated with an increased risk of developing all cancers combined (HR 1·40, 95% CI 1·24-1·58), gastrointestinal cancers (1·31, 1·11-1·55), and respiratory cancers (2·28, 1·58-3·30) in a dose-dependent manner (ptrend<0·001). For site-specific cancers, use of opium was associated with an increased risk of developing oesophageal (1·38, 1·06-1·80), gastric (1·36, 1·03-1·79), lung (2·21, 1·44-3·39), bladder (2·86, 1·47-5·55), and laryngeal (2·53, 1·21-5·29) cancers in a dose-dependent manner (ptrend<0·05). Only high-dose opium use was associated with pancreatic cancer (2·66, 1·23-5·74). Ingestion of opium (but not smoking opium) was associated with brain (2·15, 1·00-4·63) and liver (2·46, 1·23-4·95) cancers in a dose-dependent manner (prend<0·01). We observed consistent associations among ever and never tobacco users, men and women, and individuals with lower and higher socioeconomic status. INTERPRETATION: Opium users have a significantly higher risk of developing cancers in different organs of the respiratory, digestive, and urinary systems and the CNS. The results of this analysis show that regular use of opiates might increase the risk of a range of cancer types. FUNDING: World Cancer Research Fund International, Cancer Research UK, Tehran University of Medical Sciences, US National Cancer Institute, International Agency for Research on Cancer.

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.

A Case-Control Study of Breast Cancer in Northeast of Iran: The Golestan Cohort Study.

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.

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.

Comparing Anthropometric Indicators of Visceral and General Adiposity as Determinants of Overall and Cardiovascular Mortality.

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: 50045 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.

Dysregulation of helper T lymphocytes in esophageal squamous cell carcinoma (ESCC) patients is highly associated with aberrant production of miR-21.

Dysregulation of helper T (Th) cell subsets has been contributed to the initiation and propagation of esophageal squamous cell carcinoma (ESCC). Different microRNAs (miRNAs) have been reported to control the development and functions of tumor-associated immune cells in ESCC. Here, we aimed to assess the IL-10, TGF-ß, IFN-γ, and IL-17a-producing CD3+CD8- T cells in association whit miR-21, miR-29b, miR-106a, and miR-155 expression in ESCC patients. A total of 34 ESCC patients including 12 newly diagnosed (ND) and 22 under-treatment (UT) cases and also 34 age-matched healthy donors were enrolled. Flow cytometric characterization of stimulated T cells was performed by staining of the cells with fluorescent conjugated specific anti-human CD3 and CD8 cell surface markers as well as IL-17a, IFN-γ, IL-10, and TGF-ß intracytoplasmic cytokines. Circulating RNA was extracted from the plasma, and qRT-PCR was used to evaluate the expression of microRNAs. TGF-ß plasma levels were also assessed by ELISA. Results showed that the frequency of Th cells was significantly reduced in patients. A significant increase in Treg as well as Th17 cells population in both patient subgroups was observed. ND patients showed elevated level of Th1 cells and IL-10. However the mean expression of IFN-γ was significantly decreased in Th cells. We also detected higher level of miR-21 in the ESCC patients which was significantly correlated with different subsets of Th cells. Our findings revealed that immune response related to the Th cells is highly impaired in ESCC patients. Association between miR-21 and Th subsets could be correlated with the impairment of anti-tumor immunity and ESCC pathogenesis, which could be potentially used as an important target for immunotherapeutic approaches.

Adherence to the Dietary Approaches to Stop Hypertension (DASH) diet and risk of total and cause-specific mortality: results from the Golestan Cohort Study.

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.

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.