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1.  Non-administration of thrombolytic agents in acute myocardial infarction patients in Hajar hospital, Shahrekord, Iran: prevalence rate and causes 
ARYA Atherosclerosis  2013;9(1):115-118.
BACKGROUND
Cardiovascular diseases are the major causes of mortality worldwide and acute myocardial infarction (AMI) is the leading cause of mortality among cardiovascular diseases. Thrombolytic therapies, especially during the first few hours after the disease onset, can significantly reduce AMI-related mortality.
METHODS
The current study aimed to determine the prevalence and causes of non-administration of thrombolytic therapy for AMI patients admitted to Hajar Hospital, Shahrekord, Iran, from May until November 2000. Non-probability convenient sampling method was used to select 106 subjects with Q-wave AMI. Data was collected by completing a questionnaire, reviewing medical records, and interviewing with patients. SPSS7.5 was for data analysis.
RESULTS
A total number of 106 AMI patients were studied among whom 62 (59%) individuals received thrombolytic therapy. Delayed referral to the hospital was the major cause of failure to provide thrombolytic therapy. The cause of non-treatment could not be identified in 15 (19.5%) subjects eligible to receive therapy.
CONCLUSION
Training general practitioners and individuals involved in this regard along with accelerating the process of patient referral to hospitals can reduce AMI-related mortality.
PMCID: PMC3653256  PMID: 23696767
Acute Myocardial Infarction; Thrombolytic; Therapy
2.  Primary percutaneous coronary intervention in the Isfahan province, Iran; A situation analysis and needs assessment 
ARYA Atherosclerosis  2013;9(1):38-44.
BACKGROUND
Primary percutaneous coronary intervention (PPCI) is considered as a choice of treatment in ST-elevation myocardial infarction (STEMI). PPCI has been performed in the Isfahan Province for several years. This study was performed to describe the situation, and determine in-hospital and early (30 days) clinical outcomes of the patients in order to provide sufficient evidence to evaluate and modify this treatment modality if necessary.
METHODS
All patients, who underwent PPCI for STEMI from July to December 2011 at Chamran and Saadi Hospitals (PPCI centers in the Isfahan Province), were included in this case series study. Premedication, angioplasty procedure, and post-procedural treatment were performed using standard protocols or techniques. All discharged patients were followed for 30 days by phone. Endpoints consisted of clinical success rate, and in-hospital and 30 day major adverse cardiac events (MACEs) (death, reinfarction, stroke, and target vessel revascularization).
RESULTS
93 patients (83 (89.2%) at Chamran Hospital and 10 (10.8%) patients at Saadi Hospital) had PPCI. Mean Age of the patients was 59.60 ± 11.10 and M/F ratio was 3.89. From the 181 involved vessels (involved vessels/patient ratio = 1.97 ± 0.70), the treatment of 105 lesions (lesions/patient ratio = 1.13 ± 0.368) was attempted. The clinical success rate was 72%. Pain-to-door and door-to-balloon times were, respectively, 255.1 ± 221.4 and 148.9 ± 168.5 min. The reason for failure was impaired flow (n = 17 (18.3%)), failure to cross with a guidewire (n = 2 (2.2%)), suboptimal angiographic results (n = 2 (2.2%)), and death in one patient. The in-hospital and 30 days MACE rates were, respectively, 8.6% and 3.2%.
CONCLUSION
Low success rate in our series could be due to prolonged pain-to-door and door-to-balloon times and lack of an established, definite protocol to regularly perform PPCI in a timely fashion. We should resolve these problems and improve our techniques in order to prevent and treat slow/no-reflow phenomenon.
PMCID: PMC3653265  PMID: 23696758
Acute Coronary Syndrome; Myocardial Infarction; Percutaneous Transluminal Coronary Angioplasty; Cardiogenic Shock; No-Reflow Phenomenon
3.  Effect of Hibiscus sabdariffa Calices on Dyslipidemia in Obese Adolescents: A Triple-masked Randomized Controlled Trial 
Materia Socio-Medica  2013;25(2):76-79.
Conflict of interest: none declared.
Objective
We aimed to evaluate the effects of Hibiscus sabdariffa (HS) calices on controlling dyslipidemia in obese adolescents.
Methodology
In this triple blind randomized placebo-controlled clinical trial which was registered in the Iranian registry for clinical trials (IRCT201109122306N2), 90 obese adolescents aged 12-18 years with documented dyslipidemia were randomly assigned in two groups of cases who received 2 grams of fine powdered calices of Hibiscus sabdariffa per day for one month and controls who received placebo powder with the same dietary and physical activity recommendations and duration of exposure. Full lipid profile and fasting blood sugar measured before and after the trial. Data were analyzed using multivariate general linear model.
Findings
Overall, 72 participants (mean age of 14.21±1.6, 35 boys) completed the trial. The two arms of the study (cases and controls) were not statistically different in terms of age, gender, weight, body mass index (BMI) and lipid profile before the trial. Serum total cholesterol, low density lipoprotein cholesterol and serum triglyceride showed a significant decrease in cases group but high density lipoprotein cholesterol level was not changed significantly.
Conclusion
It is concluded that Hibiscus sabdariffa calyces powder may have significant positive effects on lipid profile of adolescents which maybe attributed to its polyphenolic and antioxidant content. Further studies are needed on dose-response and formulation optimization.
doi:10.5455/msm.2013.25.76-79
PMCID: PMC3769081  PMID: 24082826
Hibiscus sabdariffa L.; Metabolic syndrome; hyperlipidemia; Adolescents
4.  The impact of a community trial on the pharmacological treatment in the individuals with the metabolic syndrome: findings from the Isfahan Healthy Heart Program, 2001-2007 
Archives of Medical Science : AMS  2012;8(6):1009-1017.
Introduction
Pharmacological therapy is a crucial step in the management of individuals with the metabolic syndrome, when lifestyle modifications alone cannot achieve the therapeutic goals. The present study aimed to evaluate the efficacy of comprehensive interventions with the pharmacological treatment in individuals with the metabolic syndrome.
Material and methods
A cross-sectional population-based survey examined a sample of adults before and after conducting a community trial. Physical examination and blood sampling, data regarding the demographic characteristics, medical status and history of medication use were obtained. Pharmacologic treatment related to metabolic syndrome's components was also determined.
Results
The most common pharmacologic agents consumed by individuals with metabolic syndrome were β-blockers (26.1% and 30.4% in 2001 and 2007, respectively), followed by lipid-lowering agents (5.4% and 14% in 2001 and 2007, respectively), with significant differences before and after intervention. The prevalence of metabolic syndrome was higher in women than in men both before (36.4% vs. 14%) and after the community trial (26.1% vs. 16%, respectively) in the intervention areas (p < 0.001).
Conclusions
We found a significant increase in medication use to control blood pressure and dyslipidemia among the individuals with the metabolic syndrome, notably in the intervention areas. In addition to the population approach, the high-risk approach should be considered in community trials for prevention and control of non-communicable diseases.
doi:10.5114/aoms.2012.32407
PMCID: PMC3542491  PMID: 23319975
metabolic syndrome; pharmacological treatment; community trial; Iran
5.  Hypertension control in industrial employees: findings from SHIMSCO study 
ARYA Atherosclerosis  2012;7(4):191-196.
BACKGROUND:
Hypertension prevention and control are among the most important public health priorities. We evaluated the impacts of a workplace intervention project “Stop Hypertension in Mobarakeh Steel Company” (SHIMSCO) on controlling hypertension in industrial workers.
METHODS:
The study was carried out in Mobarakeh Steel Company in Isfahan among 7286 male workers and employees. All individuals were evaluated for the presence of hypertension (HTN). According to examinations, 500 subjects with systolic blood pressure (SBP) ≥ 140 mmHg, and/or diastolic blood pressure (DBP) ≥ 90 mmHg, and/or those using antihypertensive medications were confirmed to have HTN and thus included in this study. They were questioned for sociodemographic characteristics, past medical history and medication use. They received an educational program including healthy lifestyle and self-care recommendations of HTN management and control as well as training for accurate blood pressure measurement and home monitoring for two years. SBP, DBP, weight, height and routine lab tests were measured for all hypertensive subjects before and after the interventions. Paired t-test, generalized estimation equation (GEE) and ordinary linear regression (OLR) were used for statistical analysis in SPSS.
RESULTS:
The comparison of SBP and DBP before and after the educational program showed significant reductions in both parameters (−7.97 ± 14.72 and −2.66 ± 9.96 mmHg, respectively). However, a greater decrease was detected in case of DBP. GEE showed SBP and DBP to decrease about −0.115 and −0.054 mmHg/month. OLR also revealed reductions of 4.88 and 2.57 mmHg respectively in SBP and DBP upon adding each antihypertensive drug.
CONCLUSION:
SHIMSCO, a 3-year interventional project in workplaces, was effective in reducing SBP and DBP among hypertensive employees and workers. We conclude that implementing simple educational programs in worksites can improve the management and control of hypertension and perhaps other chronic diseases.
PMCID: PMC3413089  PMID: 23205054
Hypertension; Worksite; Industrial; Blood Pressure; Control
6.  How does the impact of a community trial on cardio-metabolic risk factors differ in terms of gender and living area? Findings from the Isfahan healthy heart program 
Objective:
To assess the impact of gender and living area on cardiovascular risk factors in the context of a comprehensive lifestyle intervention program.
Design:
Data from independent sample surveys before (2000--2001) and after (2007) a community trial, entitled the Isfahan Healthy Heart Program (IHHP) were used to compare differences in the intervention area (IA) and reference area (RA) by gender and living area.
Setting:
The interventions targeted the population living in Isfahan and Najaf-Abad counties as IA and Arak as RA.
Participants:
Overall, 12 514 individuals who were more than 19 years of age were studied at baseline, and 9570 were studied in postintervention phase.
Interventions:
Multiple activities were conducted in connection with each of the four main strategies of healthy nutrition, increasing physical activity, tobacco control, and coping with stress.
Main Outcomes:
Comparing serum lipids levels, blood pressure, blood glucose and obesity indices changes between IA and RA based on sex and living areas during the study.
Results:
In IA, while the prevalence of hypertension declined in urban and rural females (P < 0.05). In IA, the prevalence of hypercholesterolemia and hypertriglyceridemia decreased in both females and males of urban and rural areas except for hypercholesterolemia in rural males (P < 0.01). In RA, the significant changes include both decrease in the hypercholesterolemia among rural males (P < 0.001) and hypertriglyceridemia in urban females (P < 0.01), while hypertriglyceridemia was significantly increased in rural females (P < 0.01).
Conclusions:
This comprehensive community trial was effective in controlling many risk factors in both sexes in urban and rural areas. These findings also reflect the transitional status of rural population in adopting urban lifestyle behaviors.
PMCID: PMC3687879  PMID: 23798939
Age; cardiovascular risk factor; community health program; health promotion; rural; sex; urban
7.  Role of Benzodiazepines in the management of agitation due to inappropriate use of naltrexone 
Background:
Agitation is an early symptom of the acute opioid withdrawal syndrome in addicts that may start by inappropriate use of naltrexone. The current drug interventions are not efficient or need critical care as well. This study compares the clinical role of midazolam and diazepam for the management of agitation due to inappropriate use of naltrexone.
Materials and Methods:
In this double-blind randomized controlled clinical trial, 44 agitated addicts, who did not use any type of benzodiazepine, not on systematic central nervous system depressant drugs, without any known hypersensitivity to diazepam, midazolam, or any other component of their formulation and had no evidence for the need of critical care, were enrolled. An i.v. stat dose of 0.1 mg/kg diazepam and 0.1 mg/kg stat dose of midazolam and a 0.1 mg/kg/h infusion of these drugs were administered for different groups of patients, respectively. Agitation scores were recorded at 30, 60, 120 min after the start of drug administration using Richmond Agitation Sedation Scale score.
Results:
A significant difference between the mean onset of agitation control in midazolam group (at 67 min) and diazepam group (at 81 min) was recorded. The difference of mean agitation score in the midazolam and diazepam group was only significant at 120 min. There was a negative correlation between agitation score and time elapsed from naltrexone administration to admission.
Conclusion:
Midazolam and diazepam may not be considered suitable and perfect pharmacologic agents for the initial controlling of agitation induced by naltrexone.
PMCID: PMC3703077  PMID: 23853649
Benzodiazepines; naltrexone; psychomotor agitation; substance withdrawal syndrome
8.  Risk factors of atherosclerosis in male smokers, passive smokers, and hypertensive nonsmokers in central Iran 
ARYA Atherosclerosis  2012;8(2):90-95.
BACKGROUND
Some studies showed that smoking follows an upward trend in Asian countries as compared with other countries. The purpose of this study was to examine the effect of cigarette smoking on cardiovascular diseases and risk factors of atherosclerosis in patients with hypertension.
METHODS
This study was conducted on 6123 men residing in central Iran (Isfahan and Markazi Provinces) that participated in Isfahan Healthy Heart Project (IHHP). Subjects were randomly selected using cluster sampling method. All the subjects were studied in terms of their history of cardiovascular disease, demographic characteristics, smoking, blood pressure, physical examination, pulse rate, respiratory rate, weight, height, waist circumference, and blood measurements including LDL-C, HDL-C, total cholesterol, triglyceride, fasting blood sugar and 2-hour post prandial test.
RESULTS
While 893 subjects suffered from hypertension, 5230 subjects were healthy. The hypertension prevalence was 2.5 times more in urban areas compared to rural areas that showed a significant difference as it increased to 3.5 times smoking factor was considered. The prevalence of risk factors of atherosclerosis and also cardiovascular complications in patients with hypertension were significantly higher than healthy people. Furthermore, they were higher in smokers with hypertension and those exposed to the cigarette smoke than nonsmokers.
CONCLUSION
Smoking and passive smoking had an increasing effect on the prevalence of risk factors of atherosclerosis and consequently the incidence of cardiovascular diseases in patients with hypertension.
PMCID: PMC3463995  PMID: 23056110
Hypertension; Cigarette Smoking; Cardiovascular Disease; Risk Factor
9.  Effect of different dosages of nitroglycerin infusion on arterial blood gas tensions in patients undergoing on- pump coronary artery bypass graft surgery 
Background:
On-pump coronary artery bypass graft (CABG) surgery impairs gas exchange in the early postoperative period. The main object on this study was evaluation of changes in arterial blood gas values in patients underwent on pump CABG surgery receiving different dose of intravenous nitroglycerin (NTG).
Materials and Methods:
sixty-seven consecutive patients undergoing elective on-pump CABG randomly enrolled into three groups receiving NTG 50 μg/min (Group N1, n =67), 100 μg/min (Group N2, n = 67), and 150 μg/min (Group N3, n = 67). Arterial blood gas (ABG) tensions were evaluated just before induction of anesthesia, during anesthesia, at the end of warming up period, and 6 h after admission to the intensive care unit.
Results:
Pao2 and PH had the highest value during surgery in Group N1, Group N2, and Group N3. No significant difference was noted in mean values of Pao2 and PH during surgery between three groups (P > 0.05). There was no significant difference in HCO3 values in different time intervals among three groups (P > 0.05).
Conclusion:
our results showed that infusing three different dosage of NTG (50, 100, and 150 μg/min) had no significant effect on ABG tensions in patients underwent on-pump CABG surgery.
PMCID: PMC3525027  PMID: 23264783
Blood gas analysis; coronary artery bypass; nitroglycerin
10.  Polymorphism of Apo lipoprotein E gene and the risk of multiple sclerosis 
BACKGROUND:
Apolipoprotein E (ApoE) gene encodes an important protein in reforming injuries of central nervous system (CNS). It is assumed that various ApoE alleles may be functionally different. The purpose of this study was to investigate the distribution of ApoE genotypes in multiple sclerosis (MS) patients in a small cohort of Iranians.
METHODS:
In this case-control study, blood samples of patients and healthy volunteers were collected (n = 40) from Neurology Clinic of Alzahra Medical Complex. The ApoE genotypes were determined using DNA extracted from the samples by polymerase chain reaction (PCR) techniques followed by digestion with HhaI restriction enzyme. The results were adjusted for age of MS onset, sex, expanded disability status scale (EDSS), and type of MS (primary or secondary progressive). Results were statistically analyzed using chi-square test.
RESULTS:
The ApoE3/E3 genotype was detected in the majority of MS patients and the control group. Frequency distribution of E4 allele did not differ significantly between the two groups. There was no difference between ApoE allele and age of disease onset, sex, expanded disability status, or type of multiple sclerosis.
CONCLUSIONS:
We found no significant differences in genotype frequency between patients with multiple sclerosis and the control group. Despite the fact that small sample size was a limitation for our study, it seems that ApoE polymorphism may not be useful as a marker for screening patients with multiple sclerosis.
PMCID: PMC3434891  PMID: 22973358
Apolipoprotein E; Allele; Multiple Sclerosis; Polymorphism; Gene
11.  Cytochrome P450 2C19 Polymorphism in Iranian Patients with Coronary Artery Disease 
ARYA Atherosclerosis  2011;7(3):106-110.
BACKGROUND
The polymorphisms of cytochrome P450 2C19 (CYP2C19) gene are major prognostic factors for the response to clopidogrel therapy in patients with coronary artery diseases (CAD). The CYP2C19*2 is the most important allele responsible for resistance to clopidogrel therapy. This study examined CYP2C19 gene polymorphism (CYP2C19*1 and *2) in Iranian patients.
METHODS
This cross-sectional study was performed on 43 Iranian patients with CAD who underwent percutaneous coronary intervention (PCI) and received drug-eluted stents (DES). CYP2C19 polymorphisms were assessed using real time PCR and frequency of CYP2C19*1 and CYP2C19*2 were determined, and then homo- or heterozygous state of genes was detected by Melt Curve Analysis method.
RESULTS
Forty three patients (mean age = 58.8 ± 10.0 years, 79.1% male) participated in this study. CYP2C19*1/CYP2C19*1 genotype was observed in 31 (72.1%) of participates, CYP2C19*1/CYP2C19*2 genotype in 10 (23.3%), and CYP2C19*2/CYP2C19*2 genotype in 2 patients (4.7%). The frequency of CYP2C19*2 allele in the sample was 27.9%.
CONCLUSION
This study demonstrated a high prevalence of CYP2C19*2 gene polymorphism in Iranian patients. Further studies with larger samples or longitudinal are required to determine the effects of this polymorphism on the prognosis of CAD patients in our population.
PMCID: PMC3347856  PMID: 22577456
CYP2C19; Polymorphism; Clopidogrel; Coronary Artery Disease; Iran
12.  The impact of a 6-year comprehensive community trial on the awareness, treatment and control rates of hypertension in Iran: experiences from the Isfahan healthy heart program 
Objectives
We aimed to evaluate the changes over time in the prevalence, awareness, treatment, and control rate of hypertension in intervention and reference areas of a comprehensive community trial with reference area.
Methods
Data from independent sample surveys before and after implementation of the program (2001 vs.2007) were used to compare differences in the intervention and references areas over time. Hypertension was defined as blood pressure ≥140/90 mmHg in non-diabetic patients and ≥130/80 mmHg in diabetic individuals and or taking antihypertensive medications. Interventional activities included educational strategies at population level as well as for hypertensive patients, their families and health professionals.
Results
The study population of the baseline survey included 6175 (48.7% males) in the interventional area and 6339 (51.3% male) in the reference area. The corresponding figures in the post-intervention phase was 4717 (49.3% male) in the interventional area and 4853 (50.7% male) individuals in the reference area. The prevalence of hypertension had a non-significant decrease from 20.5%to 19.6%, in the interventional area whereas in the reference area, it increased from 17.4% to 19.6% (P = 0.003). If we consider Bp ≥ 140/90 in diabetic and non-diabetic patients as hypertension definition, the prevalence of hypertension in the interventional areas had a non-significant decrease from 18.9% in 2001 to 17.8% in 2007, whereas in the reference area, it had a significant rise from 15.7% to 17.9% (P = 0.002) respectively. Awareness, treatment and control rates of hypertension had better improvement in urban and rural part of the interventional area compared to reference area. The awareness, treatment, and control rates of hypertension increased significantly in the age groups of more than 40 years, as well as in all groups of body mass index in interventional areas without significant change in the reference area. Mean systolic blood pressure of study population in the interventional area decreased from 116.13 ±19.37 to 112.92 ± 18.27 mmHg (P < 0.001) without significant change in reference area.
Conclusions
This comprehensive and integrated program of interventions was effective in tackling with the prevalence of hypertension, and may improve the awareness, treatment and control rates of this disorder in a developing country setting.
doi:10.1186/1471-2261-10-61
PMCID: PMC3023732  PMID: 21172033
13.  Gender Differences in Obesogenic Behaviour, Socioeconomic and Metabolic Factors in a Population-based Sample of Iranians: The IHHP Study 
This study investigated the gender differences in association of some behavioural and socioeconomic factors with obesity indices in a population-based sample of 12,514 Iranian adults. The mean body mass index (BMI), waist circumference (WC), and the waist-to-hip ratio (WHR) were significantly higher in women than in men. Current and passive smoking had an inverse association with BMI among males whereas current smoking, transportation by a private car, and longer duration of watching television (TV) had a positive association with BMI among females. Current and passive smoking, cycling, and Global Dietary Index (GDI) had an inverse association with WC among males. Higher consumption of fruits and vegetables, current and passive smoking, duration of daily sleep, and GDI had an inverse association with WC among females. Using a private car for transportation had a significant positive association with WHR among both males and females. Living in an urban area, being married, and having a higher education level increased the odds ratio of obesity among both the genders. Non-manual work also increased this risk among males whereas watching TV and current smoking increased this risk among females. Such gender differences should be considered for culturally-appropriate interventional strategies to be implemented at the population level for tackling obesity and associated cardiometabolic risk factors.
PMCID: PMC2995029  PMID: 21261206
Cardiovascular diseases; Cross-sectional studies; Lifestyle; Obesity; Risk factors; Socioeconomic factors; Iran
14.  How effective are strategies for non-communicable disease prevention and control in a high risk population in a developing country? Isfahan Healthy Heart Programme 
Introduction
The Isfahan Healthy Heart Programme (IHHP) is a community-based programme for non-communicable diseases prevention and control using both a population and high risk approach in Iran. This study demonstrated the efficacy of IHHP interventional strategies to improve lifestyle behaviours in a population at risk for developing cardiovascular diseases.
Material and methods
Healthy Lifestyle for NCDs High Risk Population is one of ten projects of IHHP. High risk individuals were defined as those who have at least one risk factor for developing coronary artery disease (CAD). Changes of behavioural indicators have been compared between two areas with a survey after 5 years of intervention.
Results
Among high risk individuals in the intervention and reference areas, 77.8% and 82.5% had at least one major risk factor for CAD. The prevalence of major risk factors for CAD (except cigarette smoking) was decreased in both intervention and reference areas during 5 years of intervention and the pattern of diet and physical activity was improved.
Conclusions
Interventional activities in IHHP targeting the high risk population seem to be effective in improving lifestyle behaviour, increasing awareness and control of risk factors of the high risk population.
doi:10.5114/aoms.2010.13503
PMCID: PMC3278939  PMID: 22371716
coronary artery disease; risk factor; healthy lifestyle; community interventions; developing country; Iran
15.  Association of Socioeconomic Status and Life-style Factors with Coping Strategies in Isfahan Healthy Heart Program, Iran 
Croatian Medical Journal  2009;50(4):380-386.
Aim
To investigate the association between life-style and socioeconomic factors and coping strategies in a community sample in Iran.
Method
As part of a community-based study called Isfahan Healthy Heart Program, we studied 17 593 individuals older than 19 living in the central part of Iran. Demographic and socioeconomic factors (age, sex, occupation status, marital status, and educational level) and lifestyle variables (smoking status, leisure time physical activity, and psychological distress), and coping strategy were recorded. Data were analyzed by Pearson correlation and multiple linear regression.
Results
Not smoking (women β = -11.293, P < 0.001; men β = -3.418, P = 0.007), having leisure time physical activity (women β = 0.017, P = 0.046; men β = 0.005, P = 0.043), and higher educational level (women β = 0.344, P = 0.015; men β = 0.406, P = 0.008) were predictors of adaptive coping strategies, while smoking (women β = 11.849, P < 0.001; men β = 9.336, P < 0.001), high stress level (women β = 1.588, P = 0.000; men β = 1.358, P < 0.001), and lower educational level (women β = -0.443, P = 0.013; men β = -0.427, P = 0.013) were predictors of maladaptive coping strategies in both sexes. Non-manual work was a positive predictor of adaptive (β = 4.983, P < 0.001) and negative predictor of maladaptive (β = -3.355, P = 0.023) coping skills in men.
Conclusion
Coping strategies of the population in central Iran were highly influenced by socioeconomic status and life-style factors. Programs aimed at improving healthy life-styles and increasing the socioeconomic status could increase adaptive coping skills and decrease maladaptive ones and consequently lead to a more healthy society.
doi:10.3325/cmj.2009.50.380
PMCID: PMC2728387  PMID: 19673038

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