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The incidence of esophageal squamous cell carcinoma (ESCC) is disproportionately high in the eastern corridor of Africa and parts of Asia. Emerging research has identified a potential association between poor oral health and ESCC. One possible link between poor oral health and ESCC involves the alteration of the microbiome. We performed an integrated analysis of four independent sequencing efforts of ESCC tumors from patients from high- and low-incidence regions of the world. Using whole genome sequencing (WGS) and RNA sequencing (RNAseq) of ESCC tumors from 61 patients in Tanzania, we identified a community of bacteria, including members of the genera Fusobacterium, Selenomonas, Prevotella, Streptococcus, Porphyromonas, Veillonella and Campylobacter, present at high abundance in ESCC tumors. We then characterized the microbiome of 238 ESCC tumor specimens collected in two additional independent sequencing efforts consisting of patients from other high-ESCC incidence regions (Tanzania, Malawi, Kenya, Iran, China). This analysis revealed similar ESCC-associated bacterial communities in these cancers. Because these genera are traditionally considered members of the oral microbiota, we next explored whether there was a relationship between the synchronous saliva and tumor microbiomes of ESCC patients in Tanzania. Comparative analyses revealed that paired saliva and tumor microbiomes were significantly similar with a specific enrichment of Fusobacterium and Prevotella in the tumor microbiome. Together, these data indicate that cancer-associated oral bacteria are associated with ESCC tumors at the time of diagnosis and support a model in which oral bacteria are present in high abundance in both saliva and tumors of some ESCC patients.

Background and objective: Two decades ago, an international initiative (GEMINI) was launched in a high-risk, low-resource region in Northeast Iran, aiming to investigate incidence, etiology, early detection, and treatment of esophageal squamous cell carcinoma (ESCC). An earlier report from this area, highlighted poor ESCC survival rates, with a 5-year survival probability of 3.3% and the median survival time of 7 months. Our study assesses whether ESCC survival has improved since the implementation of the GEMINI initiative in this region. Material and methods: 490 adult patients with histologically-confirmed ESCC were recruited from the Atrak clinic, Golestan, Iran, between 2007 and 2018. At recruitment, information on demographics and various exposures were collected. Active (telephone surveys) and passive (linkage to Golestan population-based cancer and death registries) follow-up methods were used to determine patients' vital status though March 2019. Survival estimates were obtained by Kaplan-Meier method and Cox proportional hazards regression models. Results: Over the study period 340 deaths were recorded. Five-year ESCC survival probability was 23% (95% Confidence Interval: 19% to 28%), and the median survival time was 19 months. Five-year survival probability was higher among individuals who were younger (35% in <60-year-olds vs. 12% for >70-year-olds, p<0.001), educated (34% vs. 21% for no formal education, p = 0.027), never used opium (28% vs. 15%, p = 0.0016), and received cancer treatment (37% vs. 4%, p<0.001). In the adjusted models, a higher hazard of death was associated with older age [HR for each 10-year increase = 1.36 (95% CI = 1.22 to 1.51)], Turkman ethnicity [HR = 1.35 (95%CI: 1.07 to 1.70)], opium use [HR = 1.53 (95%CI: 1.20 to 1.94)],and receiving no cancer treatment [HR = 5.81 (95%CI: 3.97 to 8.52)]. Conclusion: Over the last two decades, ESCC survival in this population has significantly improved, highlighting the potential of enhancing healthcare infrastructure and ensuring access to affordable medical care in resource-limited, high-risk regions. Older age at diagnosis, Turkman ethnicity, opium use, and untreated cases (indicative of advanced disease at diagnosis) were identified as the main ESCC prognostic factors in this population. [ABSTRACT FROM AUTHOR]

BackgroundThe 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.MethodsIn 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.ResultsMean (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.ConclusionOne 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.

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: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a rising global public health concern. It has been demonstrated that its prevalence and characteristics vary by region and racial/ethnicity. We aimed to investigate the prevalence of MAFLD and its characteristics among Turkmen and non-Turkmen ethnic groups in a multiethnic population region of Iran. Methods: In this cross-sectional study, we analyzed baseline data for 1614 participants, aged above 50 years, from the PolyIran- Liver trial who were randomly selected from Gonabad city and determined the prevalence of MAFLD and its demographic and metabolic disorders for both the Turkmen and non-Turkmen ethnic groups. Multivariate binary logistic regressions were applied to identify MAFLD-associated factors for men and women separately for the Turkmen and non-Turkmen populations. Results: The mean (SD) age of the participants was 59.1(6.7) years. Of the participants, 51.5% (n = 831) were men, and 52.9% (n = 854) were Turkmen. The prevalence of MAFLD among the overall study population was 39.8% (n = 614). It was more common among women (45.8% vs. 34.1% in men, P < 0.001), non-Turkmens (43.9% vs. 36.1% in Turkmens, P < 0.001), and at age 50-64 (41.5% vs.36.1% in age ≥ 65 P = 0.004). The fully adjusted multivariate analysis in sex strata exhibited an independent negative association between Turkmen ethnicity only among men but not among women. The increased waist circumference (WC) was the most common metabolic disorder, observed in more than 95.5% of patients with MAFLD (P < 0.001). Multivariate analysis in sex/ ethnic strata with adjustment for potential confounders revealed an independent association of MAFLD with increased WC, insulin resistance, impaired fasting glucose/diabetes type 2, and high alanine aminotransferase (ALT) among women in both ethnic groups while with elevated triglyceride (TG) only among Turkmen and high body mass index (BMI) only among non-Turkmen women. Increased WC had the strongest independent association with MAFLD among women and the highest odds ratio (OR) with MAFLD in Turkmen women (OR: 6.10; 95% CI 1.56-23.86 vs. 4.80 in non-Turkmen women). Among men, MAFLD was independently associated with insulin resistance, high BMI, and high ALT in both ethnic groups and elevated TG only in non-Turkmen men (all P < 0.001). Insulin resistance had the strongest independent OR with MAFLD among men with similar size in both ethnic groups (4.68 [95% CI 2.56-8.55]) in non-Turkmen men and 4.37 (95% CI 2.27-8.42 in Turkmen men). Conclusion: This study revealed the high prevalence of MAFLD with a sex and ethnic disparity in the middle-aged population of Gonabad city. Further research is needed to understand the factors contributing to the higher prevalence of MAFLD in this region, particularly in women. Furthermore, considering the diverse ethnic population of Iran, it is suggested that future investigations on the sex and ethnic aspects of MAFLD in the Iranian population be conducted to provide targeted prevention strategies better suited for the Iranian population. [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]

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]

Introduction. The role of progranulin in individuals with metabolic syndrome is not exactly clear.We aimed to assess the serum level of progranulin in type 2 diabetic patients with and without metabolic syndrome and compare them with healthy controls.

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 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, Introduction An estimated 3 billion people still cook and heat their homes using open fires or leaky stoves fueled by kerosene, biomass, or coal (WHO 2018). Combustion of these fuels [...]

Prior studies have conflicting findings regarding the association between gastroesophageal reflux disease (GERD) and esophageal squamous cell carcinoma (ESCC). We examined this relationship in a prospective cohort in a region of high ESCC incidence. Baseline exposure data were collected from 50 045 individuals using in‐person interviews at the time of cohort entry. Participants were followed until they developed cancer, died, or were lost to follow up. Participants with GERD symptoms were categorized into any GERD (heartburn or regurgitation), mixed symptoms, or heartburn alone. Multivariable Cox regression was used to assess the relationship between GERD symptom group and histologically confirmed ESCC. The model was adjusted for known risk factors for GERD and ESCC. 49 559 individuals were included in this study, of which 9005 had GERD symptoms. Over 13.0 years of median follow up, 290 individuals were diagnosed with ESCC. We found no association between any GERD and risk of ESCC (aHR 0.90, 95% CI: 0.66‐1.24, P =.54). Similar findings were observed for the GERD symptom subtypes. Significant interactions between any GERD and sex (P =.013) as well as tobacco smoking (P =.028) were observed. In post‐hoc analyses, GERD was associated with a decreased risk of ESCC in men (aHR 0.51, 95% CI: 0.27‐0.98 P =.04) and in smokers (aHR 0.26, 95% CI: 0.08‐0.83 P =.02). While there was little evidence for an overall association between GERD symptoms and ESCC risk, significant interactions with sex and smoking were observed. Men and smokers with GERD symptoms had a lower risk of ESCC development. [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]

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. [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]

Aims Individuals with non-alcoholic 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 for the prevention of major cardiovascular events (MCVE) among individuals with and without presumed non-alcoholic steatohepatitis (pNASH). Methods and results Two thousand four hundred participants over 50 were randomized into the intervention and control groups. Consent was obtained post-randomization. Consenting participants in the intervention group were given a pill containing aspirin, atorvastatin, hydrochlorothiazide, and valsartan (polypill). Participants were followed for 5 years. Presumed non-alcoholic steatohepatitis was diagnosed by ultrasonography and elevated liver enzymes. The primary outcome was MCVE. ClinicalTrials.gov: NCT01245608. Among the originally randomized population, 138 of 1249 in the intervention group (11.0%) and 137 of 1017 controls (13.5%) had MCVE during the 5-year follow-up [unadjusted risk ratio (RR) 0.83, 95% confidence interval (CI) 0.66–1.03]. Of the 1508 participants who consented to additional measurements and treatment, 63 of 787 (8.0%) intervention group participants and 86 of 721 (11.9%) controls had MCVE (adjusted RR 0.61, 95% CI 0.44–0.83). Although the adjusted relative risk of MCVE in participants with pNASH (0.35, 95% CI 0.17–0.74) was under half that for participants without pNASH (0.73, 95% CI 0.49–1.00), the difference did not reach statistical significance. There was no change in liver enzymes in participants taking polypill but among those with pNASH, there was a significant decrease after 60 months of follow-up (intragroup −12.0 IU/L, 95% CI −14.2 to −9.6). Conclusion Among patients consenting to receive fixed-dose combination therapy, polypill is safe and effective for the prevention of MCVE, even among participants with fatty liver and increased liver enzymes. [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: 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]

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. What's new? Previous studies have indicated that hot tea may increase the risk of esophageal cancer. In this large, prospective study, the authors found that drinking hot tea is indeed associated with an increased risk of esophageal squamous cell carcinoma (ESCC). Furthermore, a preference for "very hot" tea more than doubled this risk. It may thus be a reasonable public‐health measure to extrapolate these results to all types of beverages, and to advise the public to wait for beverages to cool to <60°C before consumption. [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: 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]

Objectives To examine the causes of premature mortality (<70 years) and associated risk factors in the Golestan Cohort Study. Design Prospective. Setting The Golestan Cohort Study in northeastern Iran. Participants 50 045 people aged 40 or more participated in this population-based study from baseline (2004-2008) to August 2017, with over 99% success follow-up rate. Main outcome measures The top causes of premature death, HR and their 95% CI and population attributable fraction (PAF) for risk factors. Results After 444 168 person-years of follow-up (median of 10 years), 6347 deaths were reported, of which 4018 (63.3%) occurred prematurely. Ischaemic heart disease (IHD) accounted for 33.9% of premature death, followed by stroke (14.0%), road injuries (4.7%), stomach cancer (4.6%) and oesophageal cancer (4.6%). Significant risk/ protective factors were: wealth score (HR for highest vs lowest quintile: 0.57, PAF for lowest four quintiles vs top quintile: 28%), physical activity (highest vs lowest tertile: 0.67, lowest two tertiles vs top tertile: 22%), hypertension (1.50, 19%), opium use (1.69, 14%), education (middle school or higher vs illiterate: 0.84, illiterate or primary vs middle school or higher: 13%), tobacco use (1.38, 11%), diabetes (2.39, 8%) and vegetable/fruit consumption (highest vs lowest tertile: 0.87, lowest two tertiles vs top tertile: 8%). Collectively, these factors accounted for 76% of PAF in men and 69% in women. Conclusion IHD and stroke are the leading causes of premature mortality in the Golestan Cohort Study. Enhancing socioeconomic status and physical activity, reducing opium and tobacco use, increasing vegetable/ fruit consumption and controlling hypertension and diabetes are recommended to reduce premature deaths. [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: We examined the association between opium consumption and pancreatic cancer incidence in a large-scale prospective cohort of the general population in northeastern Iran. Methods: A total of 50,045 adults were systematically followed up (median of 7.4 years), and incident cases of pancreatic cancer were identified. Self-reported data on opium consumption was collected at baseline. Cumulative use (-year) was defined as number of nokhods (a local unit, approximately 0.2 g) of opium consumed per day multiplied by number of years consuming. Adjusted HRs and 95% confidence intervals (CIs) for the association between opium consumption and pancreatic cancer were calculated using Cox proportional hazards regression models. Results: Overall, 54 confirmed cases of pancreatic cancer were identified. Opium use of more than 81 nokhod-years (high cumulative use), compared with never use, was strongly associated with pancreatic cancer even after adjustments for multiple potential confounding factors [HR = 3.01; 95% CI, 1.25-7.26]. High cumulative consumption of opium was significantly associated with risk of pancreatic cancer after adjusting for cumulative dose of cigarette smoking [HR = 3.56; 95% CI, 1.49-8.50]. In a sensitivity analysis, we excluded participants (including 2 pancreatic cancer cases) who were recruited within the first 5 years of starting opium consumption; high cumulative use of opium was still associated with pancreatic cancer risk [HR = 2.75; 95% CI, 1.14-6.64]. Conclusions: Our results showed a positive association between opium consumption and pancreatic cancer. Impact: This is the first prospective large-scale study to show the association of opium consumption with pancreatic cancer as a risk factor. [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 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]