Publications by authors named "Shahin Merat"

130 Publications

An intervention to increase hepatitis C virus diagnosis and treatment uptake among people in custody in Iran.

Int J Drug Policy 2021 May 12;95:103269. Epub 2021 May 12.

Digestive Oncology Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.

Background: Iran is among countries with high opioid agonist therapy (OAT) coverage in prisons, which provides an infrastructure to increase feasibility of HCV programs. We aimed to evaluate the impact of an intervention to improve HCV screening, diagnosis, and treatment, including alongside the provision of OAT, in an Iranian prison.

Methods: During July-December 2018, in the Gorgan prison, all incarcerated adults (>18 years) received HCV antibody rapid testing and, if positive, provided a venepuncture sample for HCV RNA testing. Participants with positive RNA received direct-acting antiviral (DAA) therapy [(Sofosbuvir/Daclatasvir) for 24 or 12 weeks, respectively, for those with and without cirrhosis]. Response to treatment was measured by the sustained virological response at 12 weeks post-treatment (SVR12).

Results: Among 2015 incarcerated people with a median age of 35 years (IQR:29-41), the majority were male (97%), had not finished high school (68%), and had a history of drug use (71%), of whom 15% had ever injected drugs. A third of participants were receiving OAT, including 54% of those who had ever injected. HCV antibody prevalence was 6.7%, and RNA was detected in 4.6% of all participants; this prevalence was 32.6% and 24.7% among those with a history of injection, respectively. Treatment uptake was 82% (75/92) and was similar among people on OAT and those with a history of injection (81%). The majority completed treatment in prison and were available for SVR12 assessment (71%, 53/75). Achieved SVR12 was 100% (53/53) based on the available case analysis; those who did not have available SVR12 were released either prior to treatment initiation or completion (n = 39).

Conclusion: The availability of OAT infrastructure should be considered as an opportunity for enhancing HCV care in prisons. Where resources are limited, the prison harm reduction network could be used to design targeted HCV programs among people who are at higher risk of infection.
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http://dx.doi.org/10.1016/j.drugpo.2021.103269DOI Listing
May 2021

Single-pill sofosbuvir and daclatasvir for treating hepatis C in patients co-infected with human immunodeficiency virus.

Int J Clin Pract 2021 Aug 17;75(8):e14304. Epub 2021 May 17.

Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Background: The current recommendation for treating hepatitis C virus (HCV) in HIV patients includes the combination of sofosbuvir (SOF) and daclatasvir (DCV). DCV should be used at different doses to compensate for interactions with antiretroviral therapy (ART). Up to three pills a day might be required which will significantly add to the pill burden of these patients. In this study, we have used a single-tablet approach to treating HCV-HIV coinfection.

Methods: Patients coinfected with HIV and HCV were prospectively enrolled from 10 centers throughout the country. Patients received a single once-daily fixed dose combination (FDC) pill containing 400 mg SOF and 30, 60 or 90 mg DCV depending on the type of ART they were receiving for 12 or 24 weeks. (ClinicalTrials.gov ID: NCT03369327).

Results: Two hundred thirty-three patients were enrolled from 10 centers. Twenty-three patients were lost to follow-up and two patients died from causes unrelated to treatment. Two hundred eight patients completed the treatment course of which 201 achieved SVR (96.6%).

Conclusion: Single-tablet combination of DCV and SOF is an effective and safe treatment for patients coinfected with HIV and HCV. The combination works well in patients on ART in which dose adjustment is required. Patients with cirrhosis, previous treatment failure and various genotypes respond identically. The expenses of genotyping can be saved.
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http://dx.doi.org/10.1111/ijcp.14304DOI Listing
August 2021

Effects of supplementation with main coffee components including caffeine and/or chlorogenic acid on hepatic, metabolic, and inflammatory indices in patients with non-alcoholic fatty liver disease and type 2 diabetes: a randomized, double-blind, placebo-controlled, clinical trial.

Nutr J 2021 04 10;20(1):35. Epub 2021 Apr 10.

Department of Clinical Nutrition & Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Non-alcoholic fatty liver disease (NAFLD) is much more frequent and more severe, including cirrhosis, hepatocellular carcinoma in patients with type 2 diabetes. Coffee is a complex beverage with hundreds of compounds whereas caffeine and chlorogenic acid are the most abundant bioactive compounds. The published epidemiological data demonstrating beneficial associations between all categories of coffee exposure and ranges of liver outcomes are rapidly growing; however, the main contributors and cause-effect relationships have not yet been elucidated. To address existing knowledge gaps, we sought to determine the efficacy and safety of 6 months chlorogenic acid and/or caffeine supplementation in patients with type 2 diabetes affected by NAFLD.

Methods: This trial was carried out at two Diabetes Centers to assess the effects of supplementation with daily doses of 200 mg chlorogenic acid, 200 mg caffeine, 200 mg chlorogenic acid plus 200 mg caffeine or placebo (starch) in patients with type 2 diabetes and NAFLD. The primary endpoint was reduction of hepatic fat and stiffness measured by FibroScan, and changes in serum hepatic enzymes and cytokeratin - 18 (CK-18) levels. Secondary endpoints were improvements in metabolic (including fasting glucose, homeostasis model assessment-estimated insulin resistance (HOMA-IR), hemoglobin A1c (HBA1C), C-peptide, insulin and lipid profiles) and inflammatory (including nuclear factor k-B (NF-KB), tumor necrosis factor (TNF-α), high sensitive- C reactive protein(hs-CRP)) parameters from baseline to the end of treatment.

Results: Neither chlorogenic acid nor caffeine was superior to placebo in attenuation of the hepatic fat and stiffness and other hepatic outcomes in patients with diabetes and NAFLD. Except for the lower level of total cholesterol in caffeine group (p = 0.04), and higher level of insulin in chlorogenic acid plus caffeine group (p = 0.01) compared with placebo, there were no significant differences among the treatment groups.

Conclusion: These findings do not recommend caffeine and/or chlorogenic acid to treat NAFLD in type 2 diabetes patients.

Trial Registration: IRCT201707024010N21 . Registered 14 September 2017.
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http://dx.doi.org/10.1186/s12937-021-00694-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037901PMC
April 2021

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

Eur J Cancer Prev 2021 May;30(3):267-274

Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

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.
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http://dx.doi.org/10.1097/CEJ.0000000000000657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015184PMC
May 2021

Mutational screening through comprehensive bioinformatics analysis to detect novel germline mutations in the APC gene in patients with familial adenomatous polyposis (FAP).

J Clin Lab Anal 2021 May 26;35(5):e23768. Epub 2021 Mar 26.

Department of Biology, Faculty of Science, Yazd University, Yazd, Iran.

Background: Familial adenomatous polyposis (FAP) as a colon cancer predisposition syndrome is an autosomal-dominant inherited condition and is diagnosed by the progress of hundreds or thousands of adenomatous colonic polyps in the colon. This study aims at the nature and effect of Adenomatous Polyposis Coli (APC) gene mutations in FAP tumorigenesis.

Methods: The genetic screening of 59 FAP Iranian patients in 10 families was performed by polymerase chain reactions and the direct sequencing of the entire coding exons of the APC gene. To do linkage haplotype analysis and multiplex PCR-based microsatellite examination, six short tandem repeat loci were selected in this gene. To evaluate and predict the potentially deleterious effects, comprehensive bioinformatics pathogenicity assays were used.

Results: A total of 12 germline heterozygous and homozygous nucleotide variations were identified. They included two missense mutations, four nonsense mutations, which would lead to the truncated and nonfunctional protein products, four synonymous or silent variations, and two nucleotide deletions of 1 to 5 bp or frameshift mutations. In addition, three novel heterozygous nonsense mutations were found in exons 10, 14, and 15 of the gene. There was also p.Arg653Met as a novel heterozygote mutation in exon 14 of the gene.

Conclusions: Bioinformatics analysis and three-dimensional structural modeling predicted that these missense and nonsense mutations generally are associated with the deleted or truncated domains of APC and have functional importance and mainly affected the APC protein. These findings may provide evidence for the progress of potential biomarkers and help to understand the role of the APC gene in FAP.
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http://dx.doi.org/10.1002/jcla.23768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128300PMC
May 2021

Red Meat Consumption and Risk of Nonalcoholic Fatty Liver Disease in a Population With Low Meat Consumption: The Golestan Cohort Study.

Am J Gastroenterol 2021 Mar 24. Epub 2021 Mar 24.

Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran; Departments of Biology, School of Art and Sciences, Utica College, Utica, New York, USA; Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Radiology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran; Department of Biology, School of Computer, Mathematical, and Natural Sciences, Morgan State University, Baltimore, Maryland, USA; Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA; Departments of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Genetic Epidemiology Group, Section of Genetics, International Agency for Research on Cancer, the World Health Organization, Lyon, France; Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

Introduction: Nonalcoholic fatty liver disease (NAFLD), as the most common liver disease in the world, can range from simple steatosis to steatohepatitis. We evaluated the association between meat consumption and risk of NAFLD in the Golestan Cohort Study (GCS).

Methods: The GCS enrolled 50,045 participants, aged 40-75 years in Iran. Dietary information was collected using a 116-item semiquantitative food frequency questionnaire at baseline (2004-2008). A random sample of 1,612 cohort members participated in a liver-focused study in 2011. NAFLD was ascertained through ultrasound. Total red meat consumption and total white meat consumption were categorized into quartiles based on the GCS population, with the first quartile as the referent group. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

Results: The median intake of total red meat was 17 and total white meat was 53 g/d. During follow-up, 505 individuals (37.7%) were diagnosed with NAFLD, and 124 of them (9.2%) had elevated alanine transaminase. High total red meat consumption (ORQ4 vs Q1 = 1.59, 95% CI = 1.06-2.38, P trend = 0.03) and organ meat consumption (ORQ4 vs Q1 = 1.70, 95% CI = 1.19-2.44, P trend = 0.003) were associated with NAFLD. Total white meat, chicken, or fish consumption did not show significant associations with NAFLD.

Discussion: In this population with low consumption of red meat, individuals in the highest group of red meat intake were at increased odds of NAFLD. Furthermore, this is the first study to show an association between organ meat consumption and NAFLD (see Visual Abstract, http://links.lww.com/AJG/B944).
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http://dx.doi.org/10.14309/ajg.0000000000001229DOI Listing
March 2021

Changes in liver fibrosis in patients with chronic hepatitis C after successful direct-acting antiviral therapy.

Int J Clin Pract 2021 Jun 21;75(6):e14145. Epub 2021 Mar 21.

Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Introduction And Objectives: After successful treatment of hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs), the stage of liver fibrosis decreases over time. Here, we aimed to assess the changes in the liver fibrosis stage using transient elastography (TE) after successful DAA therapy in HCV-infected cirrhotic patients who were referred to Shariati hospital from 2016 to 2017.

Material And Methods: In this observational cohort, all HCV-infected cirrhotic patients who were treated with a combination of sofosbuvir/daclatasvir, had sustained virologic response (SVR), and had undergone pre- and post-treatment TE, were enrolled. The primary outcome was the changes in TE parameters six months after the end of treatment compared with baseline.

Results: A total of 442 eligible subjects received DAA therapy. Overall, the SVR rate was 96.6%. Of these, 149 patients had completed the protocol and were enrolled. The mean age of patients was 56.1 ± 10.3 years and the predominant sex was male (77.9%). The median (Q -Q ) liver stiffness (LS) value at baseline was 26.3 kPa (18.1-38 kPa), which significantly decreased to 20.9 kPa (12-29.7 kPa) [z = -8.45, P-value < .001]. Also, the liver steatosis of patients with baseline CAP ≥ 220 dB/m had a significant response to treatment [z = -2.3, P-value = .023]. Based on multivariate analysis, a higher baseline liver fibrosis stage was the only determinant of LS values improvement in our study.

Conclusion: Successful HCV eradication in patients with liver fibrosis results in significant improvement in LS, even in cirrhotic patients.
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http://dx.doi.org/10.1111/ijcp.14145DOI Listing
June 2021

Correction: Effectiveness of Polypill for Prevention of Cardiovascular Disease (PolyPars): Protocol of a Randomized Controlled Trial.

Arch Iran Med 2021 02 1;24(2):166. Epub 2021 Feb 1.

Digestive Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Teheran, Iran.

This corrects the article "Effectiveness of polypill for prevention of cardiovascular disease (PolyPars): protocol of a randomized controlled trial" published on 2020: Volume 23, Issue 08, Pages 548-556. Correction to: Arch Iran Med. 2020;23(8):548-556. doi: 10.34172/aim.2020.58. In the original version of this article, the recruitment period was wrongly reported to last from December 2014 to December 2015 in abstract and methods sections of the article. This is corrected into "from December 2015 to December 2016" in the PDF and HTML versions of the article. Also the "PolyIran" is changed to "PolyPars" in the last paragraph of the discussion section in the PDF and HTML versions of the article.
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http://dx.doi.org/10.34172/aim.2021.26DOI Listing
February 2021

An updated systematic review and meta-analysis on efficacy of Sofosbuvir in treating hepatitis C-infected patients with advanced chronic kidney disease.

PLoS One 2021 10;16(2):e0246594. Epub 2021 Feb 10.

Digestive Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Sofosbuvir seems to be a revolutionary treatment for Hepatitis C-infected patients with advanced chronic kidney disease (CKD) but existing evidence is not quite adequate. The aim of this study was to evaluate the efficacy and safety of Sofosbuvir-based therapy without Ribavirin for all hepatitis C virus genotypes among patients with advanced CKD. We conducted an updated systematic literature search from the beginning of 2013 up to June 2020. Sustained virologic response (SVR) rate at 12 and/or 24 weeks after the end of treatment, and adverse events in HCV-infected patients with advanced CKD were pooled using random effects models. We included 27 published articles in our meta-analyses, totaling 1,464 HCV-infected patients with advanced CKD. We found a substantial heterogeneity based on the I2 index (P = 0.00, I2 = 56.1%). The pooled SVR rates at 12 and 24 weeks after the end of Sofosbuvir-based treatment were 97% (95% Confidence Interval: 95-99) and 95% (89-99) respectively. The pooled SVR12 rates were 98% (96-100) and 94% (90-97) in patients under 60 and over 60 years old respectively. The pooled incidence of severe adverse events was 0.11 (0.04-0.19). The pooled SVR12 rate after completion of the half dose regimen was as high as the full dose treatment but it was associated with less adverse events (0.06 versus 0.14). The pooled SVR12 rate was 98% (91-100) in cirrhotic patients and 100% (98-100) in non-cirrhotic patients. The endorsement of Sofosbuvir-based regimen can improve the treatment of hepatitis C virus infection in patients with advanced CKD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246594PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875415PMC
February 2021

Sofosbuvir and daclatasvir for the treatment of COVID-19 outpatients: a double-blind, randomized controlled trial.

J Antimicrob Chemother 2021 02;76(3):753-757

Gastrointestinal Cancer Research Center, Non-Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran.

Introduction: Effective treatments are urgently needed to tackle the novel coronavirus disease 2019 (COVID-19). This trial aims to evaluate sofosbuvir and daclatasvir versus standard care for outpatients with mild COVID-19 infection.

Methods: This was a randomized controlled clinical trial in outpatients with mild COVID-19. Patients were randomized into a treatment arm receiving sofosbuvir/daclatasvir plus hydroxychloroquine or a control arm receiving hydroxychloroquine alone. The primary endpoint of the trial was symptom alleviation after 7 days of follow-up. The secondary endpoint of the trial was hospital admission. Fatigue, dyspnoea and loss of appetite were investigated after 1 month of follow-up. This study is registered with the IRCT.ir under registration number IRCT20200403046926N1.

Results: Between 8 April 2020 and 19 May 2020, 55 patients were recruited and allocated to either the sofosbuvir/daclatasvir treatment arm (n = 27) or the control arm (n = 28). Baseline characteristics were similar across treatment arms. There was no significant difference in symptoms at Day 7. One patient was admitted to hospital in the sofosbuvir/daclatasvir arm and four in the control arm, but the difference was not significant. After 1 month of follow-up, two patients reported fatigue in the sofosbuvir/daclatasvir arm and 16 in the control arm; P < 0.001.

Conclusions: In this study, sofosbuvir/daclatasvir did not significantly alleviate symptoms after 7 days of treatment compared with control. Although fewer hospitalizations were observed in the sofosbuvir/daclatasvir arm, this was not statistically significant. Sofosbuvir/daclatasvir significantly reduced the number of patients with fatigue and dyspnoea after 1 month. Larger, well-designed trials are warranted.
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http://dx.doi.org/10.1093/jac/dkaa501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798988PMC
February 2021

Evaluation of miR-122 Serum Level and IFN-λ3 Genotypes in Patients with Chronic HCV and HCV-infected Liver Transplant Candidate.

Microrna 2020 Dec 16. Epub 2020 Dec 16.

Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran. Iran.

Background: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are the most common markers of liver damage, but serum level interpretation can be complicated. In hepatocytes, microRNA-122 (miR-122) is the most abundant miRs and its high expression in the serum is a characteristic of liver disease.

Objective: We aimed to compare the circulatory level of miR-122 in patients with chronic hepatitis C (CHC), hepatitis C virus (HCV) infected liver transplant candidates (LTC) and healthy controls to determine if miR-122 can be considered as an indicator in chronic and advanced stage of liver disease.

Method: MiR-122 serum level was measured in 170 interferon-naïve (IFN-naïve) CHC patients, 62 LTC patients, and 132 healthy individuals via TaqMan real-time PCR. Serum levels of miR-122 were normalized to the serum level of Let-7a and miR-221. Also, the ALT and AST levels were measured.

Results: ALT and AST activities and the expression of circulatory miR-122 were similar in the CHC and LTC groups, but it had significantly increased compared to healthy individuals (P<0.001 and P<0.001, respectively). Up-regulation of miR122 in the sample of patients with normal ALT and AST activities was also observed, indicating that miR-122 is a good marker with the high sensitivity and specificity for diagnosing liver damage.

Conclusion: miR-122 seemed to be more specific for liver diseases in comparison with the routine ALT and AST liver enzymes. Since the lower levels of circulating miR-122 were observed in the LTC group compared to CHC group, advanced liver damages might reduce the release of miR-122 from the hepatocytes, as a sign of liver function deficiency.
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http://dx.doi.org/10.2174/2211536609666201217101414DOI Listing
December 2020

Continuum of hepatitis C care cascade in prison and following release in the direct-acting antivirals era.

Harm Reduct J 2020 10 20;17(1):80. Epub 2020 Oct 20.

Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, N. Kargar St., 14117, Tehran, Iran.

Background: People with criminal justice involvement contribute remarkably to the rising hepatitis C virus (HCV) burden; however, the continuum of care is a major barrier to prison-based programs. We aimed to evaluate a comprehensive HCV care model in an Iranian provincial prison.

Methods: Between 2017-2018, in the Karaj Central Prison, newly admitted male inmates received HCV antibody testing and venipuncture for RNA testing (antibody-positive only). Participants with positive RNA underwent direct-acting antiviral (DAA) therapy (Sofosbuvir/Daclatasvir). Sustained virological response was evaluated at 12 weeks post-treatment (SVR12).

Results: Overall, from 3485 participants, 182 (5.2%) and 117 (3.4%) tested positive for HCV antibody and RNA, respectively. Among 116 patients who were eligible for treatment, 24% (n = 28) were released before treatment and 72% (n = 83) initiated DAA therapy, of whom 81% (n = 67/83) completed treatment in prison, and the rest were released. Of total released patients, 68% (n = 30/44) were linked to care in community, and 70% (n = 21/30) completed treatment, including 60% (n = 12/20) and 90% (n = 9/10) among those who were released before and during treatment, respectively. The overall HCV treatment uptake and completion were 89% (n = 103/116) and 85% (n = 88/103), respectively. From people who completed treatment, 43% (n = 38/88) attended for response assessment and all were cured (SVR12 = 100%).

Conclusions: Integrated HCV care models are highly effective and can be significantly strengthened by post-release interventions. The close collaboration of community and prison healthcare systems is crucial to promote high levels of treatment adherence. Future studies should investigate the predictors of engagement with HCV care following release.
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http://dx.doi.org/10.1186/s12954-020-00431-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576794PMC
October 2020

Sofosbuvir/daclatasvir regimens for the treatment of COVID-19: an individual patient data meta-analysis.

J Antimicrob Chemother 2021 01;76(2):286-291

Department of Translational Medicine, University of Liverpool, UK.

Background: The combination of sofosbuvir and daclatasvir has a well-established safety profile and improves clinical outcomes in HCV patients. In silico and in vitro studies suggest that sofosbuvir/daclatasvir may show antiviral activity against SARS-CoV-2.

Methods: Three clinical trials comparing sofosbuvir/daclatasvir-based regimens with a comparator in hospitalized COVID-19 patients were combined in a meta-analysis. The primary outcomes measured were clinical recovery within 14 days of randomization, time to clinical recovery and all-cause mortality. A two-step approach was used to analyse individual-level patient data. The individual trial statistics were pooled using the random-effects inverse-variance model.

Results: Our search identified eight studies of which three met the inclusion criteria (n = 176 patients); two studies were randomized and one was non-randomized. Baseline characteristics were similar across treatment arms. Clinical recovery within 14 days of randomization was higher in the sofosbuvir/daclatasvir arms compared with control arms [risk ratio = 1.34 (95% CI = 1.05-1.71), P = 0.020]. Sofosbuvir/daclatasvir improves time to clinical recovery [HR = 2.04 (95% CI = 1.25-3.32), P = 0.004]. The pooled risk of all-cause mortality was significantly lower in the sofosbuvir/daclatasvir arms compared with control arms [risk ratio = 0.31 (95% CI = 0.12-0.78), P = 0.013].

Conclusions: Available evidence suggests that sofosbuvir/daclatasvir improves survival and clinical recovery in patients with moderate to severe COVID-19. However, the sample size for analysis was relatively small, one of the trials was not randomized and the designs were not standardized. These results need to be confirmed in larger randomized controlled trials.
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http://dx.doi.org/10.1093/jac/dkaa418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665526PMC
January 2021

Upper Normal Limits of Serum Alanine Aminotransferase in Healthy Population: A Systematic Review.

Middle East J Dig Dis 2020 Jul;12(3):194-205

Digestive Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

BACKGROUND Measuring serum alanine aminotransferase (ALT) enzyme is a routine clinical test commonly used to evaluate abnormalities in the body in general, and in the liver function in particular. Higher ALT levels are associated with some metabolic disorders. The upper limit normal (ULN) is considered as a reliable threshold for the definition of high ALT.

Objectives: To assess the existing evidence on the ULN for ALT in the general population.

Data Source: PubMed (Medline), EMBASE, Scopus, and Web of Science (ISI) were searched using a specified search strategy.

Eligibility Criteria: We collected documents published from 1980 to 2018 in the English language, focusing on human samples at the population level and extracted the data after qualitative evaluation. METHODS We conducted this study in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. We used specific search terms and their combinations to find documents from relevant databases. We used a snowballing approach to find documents not captured in the main phase of the search. Two authors separately conducted the search, screened the articles, and selected documents that were qualified for data extraction based on the defined inclusion criteria. Finally, data extraction was conducted by two authors using PRISMA checklist. Reported ULNs for ALT and 95% confidence intervals (CIs) were documented in previously developed datasheets. RESULTS Out of 15242 studies, 47 articles were included for data extraction and analysis. Data were sparse and lacked the consistency to precisely estimate ULN for serum ALT. The ULN of ALT was significantly diverse across various geographical locations and sexes. The lowest value of ULN for ALT was 19 IU/L in Chinese children (age range: 7 to < 10 years), and the highest value of ULN for ALT was 55 IU/L in children from Ghana aged < 5 years.

Limitations: The main limitation of the current systematic review was the scarcity of the reported measures for ULN of ALT. CONCLUSION Based on the results of the current systematic review, it is suggested that the normal range of ALT be redefined, but this redefinition should be done according to the localized data. In order to redefine the ULN for ALT, regional differences, methods used in ALT measurements, and ULN determination should be considered.
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http://dx.doi.org/10.34172/mejdd.2020.182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548087PMC
July 2020

Effectiveness of Polypill for Prevention of Cardiovascular Disease (PolyPars): Protocol of a Randomized Controlled Trial.

Arch Iran Med 2020 08 1;23(8):548-556. Epub 2020 Aug 1.

Digestive Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Teheran, Iran.

Background: Cardiovascular diseases (CVDs) are the leading cause of death in Iran. A fixed-dose combination therapy (polypill) was proposed as a cost-effective strategy for CVD prevention, especially in lower-resource settings. We conducted the PolyPars trial to assess the effectiveness and safety of polypill for prevention of CVD.

Methods: The PolyPars trial is a pragmatic cluster randomized controlled trial nested within the Pars Cohort Study. Participants were randomized to an intervention arm and a control arm. Participants in the control arm received minimal non-pharmacological care, while those in the intervention arm received polypill in addition to minimal care. The polypill comprises hydrochlorothiazide 12.5 mg, aspirin 81 mg, atorvastatin 20 mg, and either enalapril 5 mg or valsartan 40 mg. The primary outcome of the study is defined as the first occurrence of acute coronary syndrome (non-fatal myocardial infarction and unstable angina), fatal myocardial infarction, sudden cardiac death, new-onset heart failure, coronary artery revascularization procedures, transient ischemic attack, cerebrovascular accidents (fatal or non-fatal), and hospitalization due to any of the mentioned conditions. The secondary outcomes of the study include adverse events, compliance, non-cardiovascular mortality, changes in blood pressure, fasting blood sugar, and lipids after five years of follow-up.

Results: From December 2014 to December 2015, 4415 participants (91 clusters) were recruited. Of those, 2200 were in the polypill arm and 2215 in the minimal care arm. The study is ongoing. This trial was registered with ClinicalTrials.gov number NCT03459560.

Conclusion: Polypill may be effective for primary prevention of CVDs in developing countries.
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http://dx.doi.org/10.34172/aim.2020.58DOI Listing
August 2020

Sofosbuvir and daclatasvir compared with standard of care in the treatment of patients admitted to hospital with moderate or severe coronavirus infection (COVID-19): a randomized controlled trial.

J Antimicrob Chemother 2020 11;75(11):3379-3385

Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Background: Currently no effective antiviral therapy has been found to treat COVID-19. The aim of this trial was to assess if the addition of sofosbuvir and daclatasvir improved clinical outcomes in patients with moderate or severe COVID-19.

Methods: This was an open-label, multicentre, randomized controlled clinical trial in adults with moderate or severe COVID-19 admitted to four university hospitals in Iran. Patients were randomized into a treatment arm receiving sofosbuvir and daclatasvir plus standard care, or a control arm receiving standard care alone. The primary endpoint was clinical recovery within 14 days of treatment. The study is registered with IRCT.ir under registration number IRCT20200128046294N2.

Results: Between 26 March and 26 April 2020, 66 patients were recruited and allocated to either the treatment arm (n = 33) or the control arm (n = 33). Clinical recovery within 14 days was achieved by 29/33 (88%) in the treatment arm and 22/33 (67%) in the control arm (P = 0.076). The treatment arm had a significantly shorter median duration of hospitalization [6 days (IQR 4-8)] than the control group [8 days (IQR 5-13)]; P = 0.029. Cumulative incidence of hospital discharge was significantly higher in the treatment arm versus the control (Gray's P = 0.041). Three patients died in the treatment arm and five in the control arm. No serious adverse events were reported.

Conclusions: The addition of sofosbuvir and daclatasvir to standard care significantly reduced the duration of hospital stay compared with standard care alone. Although fewer deaths were observed in the treatment arm, this was not statistically significant. Conducting larger scale trials seems prudent.
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http://dx.doi.org/10.1093/jac/dkaa334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454592PMC
November 2020

Evaluation of the efficacy of sofosbuvir plus daclatasvir in combination with ribavirin for hospitalized COVID-19 patients with moderate disease compared with standard care: a single-centre, randomized controlled trial.

J Antimicrob Chemother 2020 11;75(11):3373-3378

Gut and Liver Research Center, Mazandaran University of Medical Sciences, Sari, Iran.

Background: New therapeutic options are urgently needed to tackle the novel coronavirus disease 2019 (COVID-19). Repurposing existing pharmaceuticals provides an immediate treatment opportunity. We assessed the efficacy of sofosbuvir and daclatasvir with ribavirin for treating patients with COVID-19.

Methods: This was a single-centre, randomized controlled trial in adults with moderate COVID-19 admitted to the Ghaem Shahr Razi Hospital in Mazandaran Province, Iran. Patients were randomly assigned to 400 mg sofosbuvir, 60 mg daclatasvir and 1200 mg ribavirin (intervention group) or to standard care (control group). The primary endpoint of this study was length of hospital stay. This study is registered by IRCT.ir under the ID: IRCT20200328046886N1.

Results: Between 20 March 2020 and 8 April 2020, 48 patients were recruited; 24 patients were randomly assigned to the intervention group and 24 to the control group. The median duration of hospital stay was 6 days in both groups (P = 0.398). The number of ICU admissions in the sofosbuvir/daclatasvir/ribavirin group was not significantly lower than the control group (0 versus 4, P = 0.109). There was no difference in the number of deaths between the groups (0 versus 3, P = 0.234). The cumulative incidence of recovery was higher in the sofosbuvir/daclatasvir/ribavirin arm (Gray's P = 0.033).

Conclusions: This randomized trial was too small to make definitive conclusions. There were trends in favour of the sofosbuvir/daclatasvir/ribavirin arm for recovery and lower death rates. However, there was an imbalance in the baseline characteristics between the arms. Larger randomized trials should be conducted to investigate this treatment further.
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http://dx.doi.org/10.1093/jac/dkaa332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454669PMC
November 2020

A simple risk-based strategy for hepatitis C virus screening among incarcerated people in a low- to middle-income setting.

Harm Reduct J 2020 08 14;17(1):56. Epub 2020 Aug 14.

Digestive Oncology Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.

Background: Hepatitis C virus (HCV) is among the highest priority diseases in custodial settings; however, the diagnosis remains suboptimal among people in custody. This study aimed to validate a short survey for identifying people with HCV infection in a provincial prison in Iran.

Methods: Between July and December 2018, residents and newly admitted inmates of Gorgan central prison completed a questionnaire, including data on the history of HCV testing, drug use, injecting drug use, sharing injecting equipment, and imprisonment. Participants received rapid HCV antibody testing, followed by venipuncture for RNA testing (antibody-positive only). Each enrollment question (yes/no) was compared with the testing results (positive/negative).

Results: Overall, 1892 people completed the questionnaire, including 621 (34%) who were currently on opioid agonist therapy (OAT); 30% of participants had been tested for HCV previously. About 71% had a history of drug use, of whom 13% had ever injected drugs; 52% had ever shared injecting equipment. The prevalence of HCV antibody and RNA was 6.9% (n = 130) and 4.8% (n = 90), respectively. The antibody prevalence was higher among people on OAT compared to those with no history of OAT (11.4% vs. 4.0%). History of drug use was the most accurate predictor of having a positive HCV antibody (sensitivity: 95.2%, negative predictive value: 98.9%) and RNA testing (sensitivity: 96.7%, negative predictive value: 99.5%). The sensitivity of the drug use question was lowest among people with no OAT history and new inmates (87% and 89%, respectively). Among all participants, sensitivity and negative predictive value of the other questions were low and ranged from 34 to 54% and 94 to 97%, respectively.

Conclusions: In resource-limited settings, HCV screening based on having a history of drug use could replace universal screening in prisons to reduce costs. Developing tailored screening strategies together with further cost studies are crucial to address the current HCV epidemic in low- to middle-income countries.
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http://dx.doi.org/10.1186/s12954-020-00400-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427767PMC
August 2020

Impact of IL28 Genotypes and Modeling the Interactions of HCV Core Protein on Treatment of Hepatitis C.

Interdiscip Sci 2020 Dec 12;12(4):424-437. Epub 2020 Jul 12.

Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Background: Mutations in the core CVR region of hepatitis C virus (HCV) and polymorphisms of interleukin 28B (IL28B) are associated with progression toward liver disease and in response to therapy. In addition, interactions of the core protein with some cell interactors can be related to HCV liver damage.

Aim: This study aimed to evaluate the effect of core mutations as well as IL28B polymorphism on clinical features, sustained virological response (SVR) in 1a and 3a HCV genotypes amongst Iranian HCV infected patients, and the impact of mutations on core protein properties, antigenic properties, and interactions with HCV inhibitors, using several bioinformatics tools.

Methods: Seventy-nine Iranian patients infected with HCV genotypes 1a and 3a and diagnosed with chronic active hepatitis were examined. Plasma viral RNA was used to amplify and sequence the HCV Core gene; also, HCV viral load, molecular genotyping, and the liver enzymes were determined for all samples. The sequencing results were analyzed by several reliable bioinformatics tools to determine the physicochemical properties, B cell epitopes, post-modification changes, and secondary/tertiary structures; and evaluate the interactions with 4 drugs by docking method.

Result: There were some substitutions in core CVR related to ALT and AST enzymes that can lead to HCV advanced liver disease. The most prevalent mutation for 3a genotypes was a substitution in aa 162 (I to V) while we did not find any mutation in 1a responder group. Polymorphism of the rs8099917 showed that the majority of patients had TG heterozygous and carried CT genotype at the rs12979860. Analysis indicated several phosphorylation sits for core protein as well as two important disulfide bonds. Immunogenic prediction showed that core protein can strongly induce the immune system. Interaction analysis, using the docking method revealed two potential interactors (Vitronectin and SETD2).

Conclusion: Generally, mutations in all core CVR regions in all patients showed a relationship between such substitutions and higher liver enzymes that can result in advanced liver disease progression in HCV infected patients. Furthermore, immunoinformatics analysis determined the possible immunodominant regions to be considered in HCV vaccine designs. Furthermore, no association between SVR and IL28B polymorphism was shown. In silico analysis determined modification sites, structures, B-cell epitopes of core protein and interactions with several interactors can lead to persistent HCV infection in the cell and the progress of liver diseases.
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http://dx.doi.org/10.1007/s12539-020-00382-8DOI Listing
December 2020

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

Environ Health Perspect 2020 06 17;128(6):67002. Epub 2020 Jun 17.

Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

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 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 , 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.
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http://dx.doi.org/10.1289/EHP5907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299082PMC
June 2020

Effect of Storage Temperature and Time on Stability of Liver Enzymes in Blood Serum.

Arch Iran Med 2020 05 1;23(5):296-301. Epub 2020 May 1.

Digestive Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Background: It is increasingly common to collect and store specimens for future unspecified research. However, the effects of prolonged storage on the stability and quality of analytes in serum have not been well investigated. We aimed to determine whether the stability of liver enzymes extracted from frozen bio-samples stored at the baseline is affected by storage conditions.

Methods: A total of four liver enzymes in the sera of 400 patients were examined following storage. After deter-mining the baseline measurements, the serum of each patient was aliquoted and stored at -70°C for three and six months, as well as one, two, and five years after collecting the original sample. The percent change from baseline measurements was calculated both statistically and clinically. Linear models were also used to correct the results of the samples based on the time they were frozen.

Results: In almost all samples, liver enzymes were detectable until two years after the baseline, while in a signifi-cant proportion of samples, enzymes were not ultimately detectable five years after the baseline. Linear regression analysis on log-transformed levels of enzymes shows that the performance is acceptable until one year after the baseline. The performance of the prediction model declines substantially two and five years after the baseline, except for GGT.

Conclusion: Long-term storage of serum samples significantly decreases the concentration of the liver enzymes from the baseline, except for GGT. It is not recommended to store samples for more than two years, as liver en-zymes are not detectable afterwards.
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http://dx.doi.org/10.34172/aim.2020.18DOI Listing
May 2020

The combination of sofosbuvir and daclatasvir is effective and safe in treating patients with hepatitis C and severe renal impairment.

J Gastroenterol Hepatol 2020 Sep 5;35(9):1590-1594. Epub 2020 Feb 5.

Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Background And Aim: Many of the treatment regimens available for hepatitis C include sofosbuvir. Unfortunately, sofosbuvir has not been recommended for use in patients with severe renal impairment leaving these group of patients with very few options. Nevertheless, there are many reports in which these patients have been treated with sofosbuvir-containing regiments without important adverse events. This study aims at determining the safety and effectiveness of a sofosbuvir-based treatment in patients with severe renal impairment, including those on hemodialysis.

Method: We enrolled subjects with hepatitis C and estimated glomerular filtration rate under ml/min/1.73m from 13 centers in Iran. Patients were treated for 12 weeks with a single daily pill containing 400-mg sofosbuvir and 60-mg daclatasvir. Patients with cirrhosis were treated for 24 weeks. Response to treatment was evaluated 12 weeks after end of treatment (sustained viral response [SVR]). ClinicalTrials.gov identifier: NCT03063879.

Results: A total of 103 patients were enrolled from 13 centers. Seventy-five patients were on hemodialysis. Thirty-nine had cirrhosis and eight were decompensated. Fifty-three were Genotype 1, and 27 Genotype 3. Twenty-seven patients had history of previous failed interferon-based treatment. Three patients died in which cause of death was not related to treatment. Six patients were lost to follow-up. The remaining 94 patients all achieved SVR. No adverse events leading to discontinuation of medicine was observed.

Conclusions: The combination of sofosbuvir and daclatasvir is an effective and safe treatment for patients infected with all genotypes of hepatitis C who have severe renal impairment, including patients on hemodialysis.
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http://dx.doi.org/10.1111/jgh.14994DOI Listing
September 2020

Fecal Microbiota in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: A Systematic Review.

Arch Iran Med 2020 01 1;23(1):44-52. Epub 2020 Jan 1.

Digestive Disease Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Background: With the increasing prevalence of obesity, non-alcoholic fatty liver disease (NAFLD), has become a frequent cause of chronic liver disease, often leading to cirrhosis. In recent decades, gut microbiota have been evaluated as an effective factor in NAFLD pathogenesis, causing steatohepatitis by involving the host immune system. The aim of this study is to evaluate gut microbiota dysbiosis in NAFLD/NASH patients in comparison to healthy controls.

Methods: We conducted a systematic search of published studies that have examined the composition of gut microbiota in relation to NAFLD. PubMed, Scopus and ISI Web of Science were searched. After the exclusion of irrelevant studies, 15 eligible studies were included and summarized.

Results: Overall, some studies reported the composition of microbiota at the phyla level, while others reported them at smaller subgroups; the results of studies were contradictory in some cases.

Conclusion: Overall, study findings indicate a relationship between microbial composition and NAFLD. Study methods and sequencing techniques influenced these results.
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January 2020

Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017: A Systematic Analysis for the Global Burden of Disease Study.

JAMA Oncol 2019 12;5(12):1749-1768

Department of Family and Community Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.

Importance: Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data.

Objective: To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning.

Evidence Review: We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence.

Findings: In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572 000 deaths and 15.2 million DALYs), and stomach cancer (542 000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819 000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601 000 deaths and 17.4 million DALYs), TBL cancer (596 000 deaths and 12.6 million DALYs), and colorectal cancer (414 000 deaths and 8.3 million DALYs).

Conclusions And Relevance: The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care.
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http://dx.doi.org/10.1001/jamaoncol.2019.2996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777271PMC
December 2019

SD1000: High Sustained Viral Response Rate in 1361 Patients With Hepatitis C Genotypes 1, 2, 3, and 4 Using a Low-cost, Fixed-dose Combination Tablet of Generic Sofosbuvir and Daclatasvir: A Multicenter, Phase III Clinical Trial.

Authors:
Shahin Merat

Clin Infect Dis 2020 05;70(10):2206-2212

Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Shariati Hospital, Iran.

Background: The combination of sofosbuvir and daclatasvir is a potent, pangenotypic regimen suitable for mass-scale hepatitis C treatment, especially in resource-limited countries where newer, expensive combinations are not available. This combination has been widely tested on genotype 4. However, Phase III trials of this combination in other genotypes have been cost prohibitive. With the introduction of generic, low-cost sofosbuvir and daclatasvir, large-scale studies in resource-limited countries are now possible.

Methods: Sofosbuvir at 400 mg and daclatasvir at 60 mg were coformulated into a fixed-dose combination (FDC) tablet (Sovodak, Rojan Pharma, Tehran, Iran). Patients from 46 centers were dosed for 12 or 24 weeks with or without ribavirin, in line with existing guidelines. Responses to treatment were evaluated 12 weeks after the end of treatment (for a sustained virological response at Week 12; SVR12).

Results: There were 1361 patients recruited. Overall, the patients were 21% female, with a mean age of 50 years; 39% were cirrhotic; 22% were treatment-experienced; 47% were genotype 1, 41% were genotype 3, and 2% were other genotypes. The genotype was not known in 10% of the patients. The intention-to-treat and per-protocol SVR12 rates were 94.7% and 98.8%, respectively. The safety profile was unremarkable, treatment was well tolerated, and compliance with the single-tablet regimen was excellent.

Conclusions: The treatment with FDC of sofosbuvir and daclatasvir achieved high SVR12 rates, equivalent to those seen in Phase III trials of other pangenotypic options, and has been conducted at a similar scale in a representative, real-world population at a cost of under $100 per patient, which makes this combination suitable for elimination protocols in resource-limited countries.

Clinical Trials Registration: NCT03200184.
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http://dx.doi.org/10.1093/cid/ciz628DOI Listing
May 2020

Pharmacological prophylaxis versus pancreatic duct stenting plus pharmacological prophylaxis for prevention of post-ERCP pancreatitis in high risk patients: a randomized trial.

Endoscopy 2019 10 27;51(10):915-921. Epub 2019 Aug 27.

Liver and Pancreaticobiliary Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Background: Acute pancreatitis is a serious complication of endoscopic retrograde cholangiopancreatography (ERCP). The aim of this noninferiority study was to evaluate the effectiveness of pancreatic duct (PD) stenting plus pharmacological prophylaxis vs. pharmacological prophylaxis alone in the prevention of post-ERCP pancreatitis (PEP) in high risk patients.

Methods: In this randomized, controlled, double-blind, noninferiority trial, patients at high risk of developing PEP were randomly allocated to pharmacological prophylaxis (rectal indomethacin, sublingual isosorbide dinitrate, and intravenous hydration with Ringer's lactate) plus PD stenting (group A) or pharmacological prophylaxis alone (group B). The rate and severity of PEP, serum amylase levels, and length of hospital stay after ERCP were assessed.

Results: During 21 months, a total of 414 patients (mean age 55.5 ± 17.0 years; 60.2 % female) were enrolled (207 in each group). PEP occurred in 59 patients (14.3 %, 95 % confidence interval [CI] 11.1 % - 17.9 %: 26 patients [12.6 %, 95 %CI 8.6 % - 17.6 %] in group A and 33 [15.9 %, 95 %CI 11.4 % - 21.4 %] in group B). There was no significant difference between the two groups in PEP severity ( = 0.59), amylase levels after 2 hours ( = 0.31) or 24 hours ( = 0.08), and length of hospital stay ( = 0.07).

Conclusions: The study failed to demonstrate noninferiority or inferiority of pharmacological prophylaxis alone compared with PD stenting plus pharmacological prophylaxis in the prevention of PEP in high risk patients.
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http://dx.doi.org/10.1055/a-0977-3119DOI Listing
October 2019

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

Lancet 2019 08;394(10199):672-683

Digestive Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran; Digestive Oncology Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran; Liver and Pancreaticobiliary Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

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; p=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.
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http://dx.doi.org/10.1016/S0140-6736(19)31791-XDOI Listing
August 2019
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