Publications by authors named "Farzane Saeidifard"

15 Publications

  • Page 1 of 1

Treatment of Sleep Apnea with Positive Airway Pressure and Its Association with Diastolic Dysfunction: A Systematic Review and Meta-Analysis.

Respiration 2021 Dec 6:1-11. Epub 2021 Dec 6.

Cardiology Department, SUNY Downstate, Brooklyn, New York, USA.

Background: This meta-analysis assessed the effect of long-term (>6 weeks) noninvasive positive airway pressure (PAP) on diastolic function in patients with obstructive sleep apnea (OSA).

Methods: We searched the databases for randomized clinical trials including Ovid MEDLINE, Ovid Embase Scopus, Web of Science, Google Scholar, and EBSCO CINAHL from inception up to December 20, 2019. The search was not restricted to time, publication status, or language. Two independent investigators screened the studies and extracted the data, in duplicate. Risk of bias was assessed using Cochrane collaboration tools.

Results: A total of 2,753 abstracts were resulted from literature search. A total of 9 randomized clinical trials assessing the effect of long-term (>6 weeks) PAP on diastolic function in patients with OSA including 833 participants were included. The following echo parameters were found in treated patients: a decrease in deceleration time (-39.49 ms CI [-57.24, -21.74]; p = 0.000), isovolumic relaxation time (-9.32 ms CI [-17.08, -1.57]; p = 0.02), and the ratio of early mitral inflow velocity to mitral annular early diastolic velocity (-1.38 CI [-2.6, -0.16]; p = 0.03). However, changes in left-atrial volume index and the ratio of early to late mitral inflow velocities were not statistically different. The risk of bias was mild to moderate among the studies.

Conclusion: Our results suggest that chronic treatment of moderate to severe OSA with noninvasive PAP is associated with improvement in echocardiographic findings of diastolic dysfunction.
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http://dx.doi.org/10.1159/000519406DOI Listing
December 2021

Association of Bipolar Disorder With Major Adverse Cardiovascular Events: A Population-Based Historical Cohort Study.

Psychosom Med 2022 Jan;84(1):97-103

From the Department of Psychiatry and Psychology (Foroughi, Suarez, Prieto, Frye, Morgan), Mayo Clinic, Rochester, Minnesota; Department of Psychiatry and Behavioral Sciences (Foroughi), SUNY Downstate Health Sciences University, Brooklyn, New York; Division of Preventive Cardiology, Department of Cardiovascular Medicine (Medina Inojosa, Lopez-Jimenez, Saeidifard), Mayo Clinic, Rochester, Minnesota; Department of Medicine (Saeidifard), Northwell Health-Lenox Hill Hospital, New York, New York; International Clinical Research Center (Stokin), St. Anne's University Hospital, Brno, Czech Republic; Department of Psychiatry, Faculty of Medicine (Prieto), Universidad de los Andes; Mental Health Service (Prieto), Clínica Universidad de los Andes, Santiago, Chile; Division of Epidemiology, Department of Health Sciences Research and Department of Neurology (Rocca), Mayo Clinic, Rochester, Minnesota; and Center of Biomedical Research and Innovation (Prieto), Universidad de los Andes, Santiago. Chile.

Objective: This study aimed to assess the association of bipolar disorder (BD) with risk of major adverse cardiac events (MACEs) after adjusting for established cardiovascular disease (CVD) risk factors.

Methods: We conducted a population-based historical cohort study using the Rochester Epidemiology Project. Patients older than 30 years with a clinical encounter from 1998 to 2000 with no prior MACE, atrial fibrillation, or heart failure were followed up through March 1, 2016. BD diagnosis was validated by chart review. Cox proportional hazards regression models were adjusted for established CVD risk factors, alcohol use disorder, other substance use disorders (SUDs), and major depressive disorder (MDD).

Results: The cohort included 288 individuals with BD (0.81%) and 35,326 individuals without BD as the reference group (Ref). Median (interquartile range) follow-up was 16.5 (14.6-17.5) years. A total of 5636 MACE events occurred (BD, 59; Ref, 5577). Survival analysis showed an association between BD and MACE (median event-free-survival rates: BD, 0.80; Ref, 0.86; log-rank p = .018). Multivariate regression adjusting for age and sex also yielded an association between BD and MACE (hazard ratio [HR] = 1.93; 95% confidence interval [CI] = 1.43-2.52; p < .001). The association remained significant after further adjusting for smoking, diabetes mellitus, hypertension, high-density lipoprotein cholesterol, and body mass index (HR = 1.66; 95% CI = 1.17-2.28; p = .006), and for alcohol use disorder, SUD, and MDD (HR = 1.56; 95% CI = 1.09-2.14; p = .010).

Conclusions: In this study, BD was associated with an increased risk of MACE, which persisted after adjusting for established CVD risk factors, SUDs, and MDD. These results suggest that BD is an independent risk factor for major clinical cardiac disease outcomes.
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http://dx.doi.org/10.1097/PSY.0000000000001017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8678204PMC
January 2022

Multicomponent Cardiac Rehabilitation and Cardiovascular Outcomes in Patients With Stable Angina: A Systematic Review and Meta-analysis.

Mayo Clin Proc Innov Qual Outcomes 2021 Aug 24;5(4):727-741. Epub 2021 Jul 24.

Division of Preventive Cardiology, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN.

Objective: To carry out a systematic review of the effect of cardiac rehabilitation (CR) and its components on cardiovascular outcomes in patients with stable angina.

Methods: We searched the databases including Ovid MEDLINE, Ovid Embase, Scopus, Web of Science, Google Scholar, and EBSCO CINAHL from their inception up to November 1, 2017. The search was not restricted to time or publication status but was limited to the English language. Two independent investigators screened the identified studies and extracted the data in duplicate. We reviewed the included studies and, where possible, pooled their results and conducted meta-analyses. Risk of bias was assessed using Cochrane Collaboration tools.

Results: The search identified 7508 studies. Ten randomized trials including 4005 participants with the mean (SD) age of 59.6 (5.7) years were considered eligible for inclusion in our analyses. The results of meta-analyses of exercise-based CR for patients with stable angina revealed that CR improved exercise capacity (the difference between baseline and follow-up was 0.76 watt [0.49 to 1.02] higher in the CR group vs the non-CR group) and decreased angina frequency (standard mean difference, -0.27 [CI, -0.43 to 0.11]). No significant differences were noted in other outcomes, including quality of life. Mortality could not be adequately assessed because it was analyzed in only 1 exercise-based CR study.

Conclusion: Our systematic review, involving a relatively small number of studies with low to moderate risk of bias and with considerable heterogeneity, found a significant decrease in angina frequency and increase in exercise capacity in patients with stable angina who participated in an exercise-based CR program. Studies involving the impact of components of CR are limited and generally report beneficial outcomes. Additional studies are needed to clarify the possible role of CR in the management of patients with stable angina.
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http://dx.doi.org/10.1016/j.mayocpiqo.2021.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325103PMC
August 2021

The rationale behind systematic reviews in clinical medicine: a conceptual framework.

J Diabetes Metab Disord 2021 Jun 8;20(1):919-929. Epub 2021 Apr 8.

Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.

A systematic review (SR) is a type of review that uses a systematic method to provide a valid summary of existing literature addressing a clear and specific question. In clinical medicine (CM), the concept of SR is well recognized, especially after the introduction of evidence-based medicine; The SR of randomized clinical trials (RCTs) is considered the highest level of evidence on therapeutic effectiveness. Despite the popularity of the SRs and the increasing publication rate of SRs in CM and other healthcare literature, the concept has raised criticisms. Many of proper criticisms can be due to the deviation of some existing SRs from the original philosophy and well-established rationale behind the concept of SR. On the other hand, many criticisms are misconceptions about SRs which still exist even several decades after introducing the concept. This article presents a conceptual framework for clarifying the rationale behind SR in CM by providing the relevant concepts and their inter-relations, explaining how methodological standards of an SR and its rationale are connected, and discussing the rationale under the three-section: SR as a type of synthetic research, SR as a more informed and less biased review, and SR as an efficient scientific tool.
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http://dx.doi.org/10.1007/s40200-021-00773-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212290PMC
June 2021

Hypocalcemia in Covid-19: A Prognostic Marker for Severe Disease.

Iran J Pathol 2021 24;16(2):144-153. Epub 2020 Oct 24.

Molecular Pathology and Cytogenetic Ward, Pathology Department, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

Background & Objective: Previous studies have addressed the electrolyte abnormalities such as hypocalcemia in COVID-19 patients. We aimed to compare the laboratory findings especially the electrolyte levels among COVID-19 patients and healthy controls and evaluate their prognostic values.

Methods: This case-control study included 91 COVID-19 patients and 169 healthy individuals. Their laboratory parameters including electrolytes, albumin, liver enzymes, complete blood count, vitamin D, and parathyroid hormone (PTH) were compared. We also analyzed the association between these markers and the major outcomes including severity, mortality and hospitalization.

Results: Among patients with COVID-19, 59.3% of the patients had hypocalcemia on admission while in control group only 32.5% had low calcium level (OR=3.02, 95% CI: 1.79-5.13, <0.001). The rates of death and ICU admission were significantly higher among the patients in hypocalcemic group than those of eucalcemic group (85.7% vs 14.3% and 33.3% Vs 9.1%, respectively). However, there was no significant difference in the mean PTH and vitamin D levels between the two groups. In terms of the severity of the infection, 74.1% of patients in hypocalcemic group had a severe infection while 24.3% of the patients in eucalcemic group were diagnosed with severe infection (OR=8.89, 95% CI: 3.38-23.37, <0.001).

Conclusion: Patients with COVID-19 may present with considerable laboratory abnormalities including hypocalcemia. The hypocalcemia would be also associated with worse major clinical outcome and higher mortality risk.
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http://dx.doi.org/10.30699/IJP.2020.130491.2442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085287PMC
October 2020

The Effect of Replacing Sitting With Standing on Cardiovascular Risk Factors: A Systematic Review and Meta-analysis.

Mayo Clin Proc Innov Qual Outcomes 2020 Dec 1;4(6):611-626. Epub 2020 Dec 1.

Division of Preventive Cardiology, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN.

Objective: To investigate the effect of replacing sitting with standing on cardiovascular risk factors tested in clinical trials.

Methods: We searched databases from inception up to August 28, 2019, for studies examining the effect of replacing sitting with standing on fasting blood glucose, fasting insulin, and lipid levels; blood pressure; body fat mass; weight; and waist circumference in healthy adults. Differences in mean ± SD values were used for pooling the data and calculating the mean differences and CIs.

Results: The search found 3507 abstracts. Nine clinical trials (8 randomized and 1 nonrandomized) with 877 (64.4% [n=565] women) participants met all inclusion criteria. The mean ± SD age was 45.34±5.41 years; mean follow-up was 3.81 months, and mean difference in standing time between the intervention and control groups was 1.33 hours per day. The follow-up fasting blood glucose and body fat mass values were slightly but significantly lower than baseline records in the intervention groups compared with control groups (-2.53; 95% CI, -4.27 to -0.79 mg/dL; and -0.75; 95% CI, -0.91 to -0.59 kg). The analysis for fasting insulin levels, lipid levels, blood pressure, weight, and waist circumference revealed no significant differences.

Conclusion: Replacing sitting with standing can result in very small but statistically significant decreases in fasting blood glucose levels and body fat mass with no significant effect on lipid levels, blood pressure, weight, and waist circumference. Replacing sitting with standing can be used as an adjunctive intervention to decrease the burden of cardiovascular risk factors but cannot be used as an alternative to physical activity to decrease sedentary time.
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http://dx.doi.org/10.1016/j.mayocpiqo.2020.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749276PMC
December 2020

The association of resistance training with mortality: A systematic review and meta-analysis.

Eur J Prev Cardiol 2019 10 19;26(15):1647-1665. Epub 2019 May 19.

Division of Preventive Cardiology, Department of Cardiovascular Medicine, Mayo Clinic Rochester, USA.

Background: The benefits of aerobic exercise are well-studied; there is no consensus on the association between resistance training and major adverse cardiovascular outcomes. This systematic review and meta-analysis aimed to address this issue.

Design And Methods: We searched for randomized trials and cohort studies that evaluated the association between resistance training and mortality and cardiovascular events. Two investigators screened the identified abstracts and full-texts independently and in duplicate. Cochrane tools were used to assess the risk of bias. We calculated hazard ratios and 95% confidence intervals using random effect models.

Results: From the 1430 studies identified, 11 (one randomized trial and 10 cohort studies) met the inclusion criteria, totaling 370,256 participants with mean follow-up of 8.85 years. The meta-analysis showed that, compared with no exercise, resistance training was associated with 21% (hazard ratio (95% confidence interval (CI)), 0.79 (0.69-0.91)) and 40% (hazard ratio (95% CI), 0.60 (0.49-0.72)) lower all-cause mortality alone and when combined with aerobic exercise, respectively. Furthermore, resistance training had a borderline association with lower cardiovascular mortality (hazard ratio (95% CI), 0.83 (0.67-1.03)). In addition, resistance training showed no significant association with cancer mortality. Risk of bias was low to intermediate in the included studies. One cohort study looked at the effect of resistance training on coronary heart disease events in men and found a 23% risk reduction (risk ratio, 0.77, CI: 0.61-0.98).

Conclusion: Resistance training is associated with lower mortality and appears to have an additive effect when combined with aerobic exercise. There are insufficient data to determine the potential beneficial effect of resistance training on non-fatal events or the effect of substituting aerobic exercise with resistance training.
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http://dx.doi.org/10.1177/2047487319850718DOI Listing
October 2019

The impact of alcohol on breathing parameters during sleep: A systematic review and meta-analysis.

Sleep Med Rev 2018 Dec 11;42:59-67. Epub 2018 Jun 11.

Center for Sleep Medicine, Mayo Clinic, Rochester, MN, USA.

Alcohol, a muscle relaxant, can potentially worsen obstructive sleep apnea (OSA) but the literature on the effects of alcohol on OSA is conflicting. This systematic review and meta-analysis of randomized controlled trials examined the impact of alcohol on breathing parameters during sleep. Ovid Medline, Embase and PsycINFO databases were queried through November 1, 2017 for studies that reported objective measures of breathing during sleep, prior to and after alcohol administration. Weighted mean differences (WMD) and 95% confidence intervals (CI) were calculated for apnea-hypopnea index (AHI) and mean oxyhemoglobin saturation (SpO2). Secondary outcome measures were examined where available. The meta-analysis of 14 eligible studies (n = 422; 71.9% male) found that AHI increased significantly after alcohol administration (WMD = 2.33; 95% CI = 1.41 to 3.25, I = 62%) and mean SpO2 was significantly reduced (WMD = -0.60; 95% CI = -0.72 to -0.49, I = 0%). The increase in AHI was greater in snorers (WMD = 4.20; 95% CI = 1.19 to 6.50, I = 0%) and those with a diagnosis of OSA (WMD = 7.10; 95% CI = 3.59 to 10.61, I = 0%). Additionally, a significant increase in respiratory event duration (WMD = 0.86; 95% CI = 0.18 to 1.55, I = 19%) and decrease in nadir SpO2 (WMD = -1.25; 95% CI = -2.00 to -0.50, I = 25%) were noted. Alcohol is a modifiable risk factor that can result in the development or worsening of OSA.
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http://dx.doi.org/10.1016/j.smrv.2018.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520474PMC
December 2018

Differences of energy expenditure while sitting versus standing: A systematic review and meta-analysis.

Eur J Prev Cardiol 2018 03 31;25(5):522-538. Epub 2018 Jan 31.

1 Division of Preventive Cardiology, Department of Cardiovascular Medicine, Mayo Clinic, USA.

Background Replacing sitting with standing is one of several recommendations to decrease sedentary time and increase the daily energy expenditure, but the difference in energy expenditure between standing versus sitting has been controversial. This systematic review and meta-analysis aimed to determine this difference. Designs and methods We searched Ovid MEDLINE, Ovid Embase Scopus, Web of Science and Google Scholar for observational and experimental studies that compared the energy expenditure of standing versus sitting. We calculated mean differences and 95% confidence intervals using a random effects model. We conducted different predefined subgroup analyses based on characteristics of participants and study design. Results We identified 658 studies and included 46 studies with 1184 participants for the final analysis. The mean difference in energy expenditure between sitting and standing was 0.15 kcal/min (95% confidence interval (CI) 0.12-0.17). The difference among women was 0.1 kcal/min (95% CI 0.0-0.21), and was 0.19 kcal/min (95% CI 0.05-0.33) in men. Observational studies had a lower difference in energy expenditure (0.11 kcal/min, 95% CI 0.08-0.14) compared to randomised trials (0.2 kcal/min, 95% CI 0.12-0.28). By substituting sitting with standing for 6 hours/day, a 65 kg person will expend an additional 54 kcal/day. Assuming no increase in energy intake, this difference in energy expenditure would be translated into the energy content of about 2.5 kg of body fat mass in 1 year. Conclusions The substitution of sitting with standing could be a potential solution for a sedentary lifestyle to prevent weight gain in the long term. Future studies should aim to assess the effectiveness and feasibility of this strategy.
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http://dx.doi.org/10.1177/2047487317752186DOI Listing
March 2018

Immediate impact of positive airway pressure on atrial fibrillation.

Sleep Med 2017 11 9;39:84-86. Epub 2017 Sep 9.

Center for Sleep Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. Electronic address:

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http://dx.doi.org/10.1016/j.sleep.2017.08.009DOI Listing
November 2017

Correlation between clinicians-assigned weights to findings and their diagnostic odd ratio; case of congestive heart failure.

J Diabetes Metab Disord 2015 23;15:39. Epub 2016 Sep 23.

Radiology Department of Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.

Background: Incorrect estimation of pretest probability and misinterpretation of test results can change post-test probability in medical decision making. The aim of this study was to evaluate how physicians assess weight of findings of congestive heart failure (CHF) and how much their estimation is correlated with findings' Diagnostic Odd Ratio (DOR).

Methods: The participants were asked to answer a questionnaire based on a scenario of a patient having dyspnea. Eighteen findings in 3 categories including: history, examination and radiographic findings were inserted along a column and a row as a matrix. The respondents had to compare each finding in the column with all other findings in the row and insert a mark in boxes below the findings of the row that had greater weight compared to the finding in the column. The weight of each finding was considered as total number of "marked boxes" in front of that finding. DOR of findings was calculated using their positive and negative likelihood ratios (LRs) based on current best evidence. Findings ranked in the order of their DOR and were compared with the ranking in the order of participants-assigned weights. We examined correlation between average weights assigned by physicians and DOR of findings. In subgroup analysis correlations between average weights assigned by physicians and DOR of history, examination and radiographic findings were examined.

Results: Seventy five physicians completed the questionnaire. Correlation between ranking in the order of findings' DOR and ranking in the order of clinicians-assigned weights was significant (p-value = 0.005 r = 0.64). In contrast correlations between participants-assigned weights and DOR of history, examination and radiographic findings were positive but non- significant (r = 0.181, p-value = 0.7, r = 0.343, p-value = 0.506 and r = 0.219, p-value = 0.723 respectively).

Conclusion: Our result show that although correlation between clinicians-assigned weights and DOR of entire findings was significant, correlations between clinicians-assigned weights to the different categories of findings and their DOR were not significant. Reevaluating probabilistic reasoning by emphasis on using LRs can make pretest probability estimating and interpretation of test results more objective and would ultimate in more precise and homogenous post-test probabilities.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035489PMC
http://dx.doi.org/10.1186/s40200-016-0262-6DOI Listing
October 2016

Concept mapping as a method to teach an evidence-based educated medical topic: a comparative study in medical students.

J Diabetes Metab Disord 2014 1;13(1):86. Epub 2014 Nov 1.

Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.

Background: The objective of this study was to compare concept mapping with lecture-based method in teaching of evidence based educated topic to medical students.

Methods: This randomized controlled trial was carried out on medical students during sixth year of 7-year MD curriculum clerkship phase. Cluster randomization was used to divide students into intervention and control groups. Both groups, at the beginning, were taught "Diabetic Ketoacidosis" (DKA) using evidence-based tool named Critically Appraised Topics (CAT). Students of intervention group were taught construction of concept maps on DKA and in the control group students had a lecture and a group discussion about what they had been taught on DKA. In the end, all of the students had an exam that they had to answer to 7 questions following to two clinical scenarios. The questions addressed physiopathology, diagnosis and treatment of patients with DKA and were scored separately. Sum of these scores was considered as total score. Scores were compared between intervention and control groups.

Results: Seventy six medical students (28 male, 48 female) were participated in this study. Total score among intervention group was higher than control group (78.2% vs. 72.5%, p < 0.001). Subgroup analysis revealed significant differences between scores of students in the intervention group and scores of students in the control group in the diagnostic section of questions (81.0% vs. 71.5%, P < 0.001). The scores of students in the intervention group were also significantly higher than control group in physiopathology section of questions. No statistically significant difference was discovered between two groups in scores of answers to treatment section of questions (78.1 (7.3) vs. 72.5 (5.5) P = 0.03).

Conclusion: The results of the study showed that concept mapping method was more successful in education of evidence-based educated topic via CATs in comparison with lecture-based method. Interpretation of this finding would be the concept mapping method may develop meaningful learning among medical students.
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http://dx.doi.org/10.1186/s40200-014-0086-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241228PMC
November 2014

The risk of osteoporotic fractures and its associating risk factors according to the FRAX model in the Iranian patients: a follow-up cohort.

J Diabetes Metab Disord 2014 22;13(1):93. Epub 2014 Oct 22.

Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.

Background: The present study is designed to assess the incidence rate of osteoporotic fracture and its risk factors, particularly those used to predict the 10-year risk of osteoporotic fracture in FRAX based on the data gathered through a follow up cohort initiated in 2000.

Methods: The present retrospective cohort was conducted on men and women from 40 to 90 years of age enrolled in the IROSTEOPs study. A phone survey was conducted during 2013 and beginning of 2014 to assess the fractures (traumatic/osteoporotic) occurring at the time of inclusion until the date of the telephone survey, its type and mechanism, and the patient's age at the time of accident. Survival analysis using Kaplan-Meier product-limit method was performed with the time of fracture as the study outcome.

Results: Final study population consisted of 1233 individuals, translated in to 9133 person years. The incidence rate of osteoporotic fracture was reported to be 359.1 cases in every 10,000 person years. The 10-year Kaplan-Meier estimate of any kind of major osteoporotic fractures for all the subcohort population was 10.75%. Osteoporosis (HR = 0.75), Discordance between femoral neck and spine (HR = 1.45), Diabetes (HR = 1.81), IBD (HR = 1.84), immobility more than 90 days (HR = 2.19), and personal history of fracture (HR = 7.75) had a considerable effect on the 10-year risk of major osteoporotic fractures.

Conclusions: Adding new clinical risk factors to FRAX® may help improve fracture prediction in the Iranian population.
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http://dx.doi.org/10.1186/s40200-014-0093-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209052PMC
October 2014

AIs Scientific Production Problem-Oriented? Diabetes and Ramadan as an Example.

Oman Med J 2014 May;29(3):244

Endocrinology & Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.

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http://dx.doi.org/10.5001/omj.2014..62DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052387PMC
May 2014
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