Publications by authors named "Fatemeh Yazdi"

58 Publications

Effect of prevalent polychlorinated biphenyls (PCBs) food contaminant on the MCF7, LNCap and MDA-MB-231 cell lines viability and PON1 gene expression level: proposed model of binding.

Daru 2021 Jun 21;29(1):159-170. Epub 2021 Apr 21.

Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran.

Background: Polychlorinated biphenyls (PCBs) are a group of synthetic organic chlorine compounds known as an organic pollutant in food sources, which play important roles in malignancies. The present study aimed to investigate the direct effects of prevalent PCBs in food in hormone-responsive and non-responsive cell lines.

Methods: In the current study, MCF-7, LNCap, and MDA-MB231 cell lines were treated with serial concentrations (0.001-100 μM) of PCBs for 48 h and cell viability assessment was performed using MTT assay. The best concentration then applied and the expression level of PON1 was evaluated using real-time PCR. Besides, molecular docking was performed to determine the binding mechanism and predicted binding energies of PBCs compounds to the AhR receptor.

Results: Unlike MCF-7 and LNCap cells, the viability of MDA-MB231 cells did not significantly change by different concentrations of PCBs. Meanwhile, quantitative gene expression analysis showed that the PON1 was significantly more expressed in MCF-7 and LNCap lines treated with PCB28 and PCB101. However, the expression level of this gene in other groups and also MDA-MB231cells did not demonstrate any significantly change. Also, the results of molecular docking showed that PBCs had steric interaction with AhR receptor.

Conclusions: Current results showed that despite of hormone non-responsive cells the PCBs have a significant positive effect on hormone-responsive cell. Therefore, and regarding to the existence of PCBs contamination in food there should be serious concern about their impact on the prevalence of different malignancies which certainly should result in a standard limit for this material. This study aimed to investigate the direct effects of prevalent PCBs in food in hormone-responsive and non-responsive cell lines. Cell lines were treated with serial concentrations of PCBs and cell viability assessment was performed using MTT assay. The expression level of PON1 was evaluated using real-time PCR. Molecular docking was performed to determine the binding mechanism and predicted binding energies of PBCs compounds to the AhR receptor. PCBs contamination in food there should be serious concern about their impact on the prevalence of different malignancies which certainly should result in a standard limit for this material.
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http://dx.doi.org/10.1007/s40199-021-00394-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149541PMC
June 2021

Comparative Efficacy and Safety of Ultra-Long-Acting, Long-Acting, Intermediate-Acting, and Biosimilar Insulins for Type 1 Diabetes Mellitus: a Systematic Review and Network Meta-Analysis.

J Gen Intern Med 2021 08 19;36(8):2414-2426. Epub 2021 Mar 19.

Knowledge Translation Program, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.

Background: Increasing availability of competing biosimilar alternatives makes it challenging to make treatment decisions. The purpose of this review is to evaluate the comparative efficacy and safety of ultra-long-/long-/intermediate-acting insulin products and biosimilar insulin compared to human/animal insulin in adults with type 1 diabetes mellitus (T1DM).

Methods: MEDLINE, EMBASE, CENTRAL, and grey literature were searched from inception to March 27, 2019. Randomized controlled trials (RCTs), quasi-experimental studies, and cohort studies of adults with T1DM receiving ultra-long-/long-/intermediate-acting insulin, compared to each other, as well as biosimilar insulin compared to human/animal insulin were eligible for inclusion. Two reviewers independently screened studies, abstracted data, and appraised risk-of-bias. Pairwise meta-analyses and network meta-analyses (NMA) were conducted. Summary effect measures were mean differences (MD) and odds ratios (OR).

Results: We included 65 unique studies examining 14,200 patients with T1DM. Both ultra-long-acting and long-acting insulin were superior to intermediate-acting insulin in reducing A1c, FPG, weight gain, and the incidence of major, serious, or nocturnal hypoglycemia. For fasting blood glucose, long-acting once a day (od) was superior to long-acting twice a day (bid) (MD - 0.44, 95% CI: - 0.81 to - 0.06) and ultra-long-acting od was superior to long-acting bid (MD - 0.73, 95% CI - 1.36 to - 0.11). For weight change, long-acting od was inferior to long-acting bid (MD 0.58, 95% CI: 0.05 to 1.10) and long-acting bid was superior to long-action biosimilar od (MD - 0.90, 95% CI: - 1.67 to - 0.12).

Conclusions: Our results can be used to tailor insulin treatment according to the desired results of patients and clinicians and inform strategies to establish a competitive clinical market, address systemic barriers, expand the pool of potential suppliers, and favor insulin price reduction.

Prospero Registration: CRD42017077051.
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http://dx.doi.org/10.1007/s11606-021-06642-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342652PMC
August 2021

Prevalence, comorbidity and predictors of anxiety disorders among children and adolescents.

Asian J Psychiatr 2020 Oct 16;53:102059. Epub 2020 May 16.

Department of Pediatric Psychiatry, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran. Electronic address:

Childhood anxiety may lead to serious health consequences in later life. The present study provides the prevalence, comorbidity, and predictors of anxiety disorders among children and adolescents. This was a cross-sectional national project that was implemented on 28,698 children and adolescents in Iran. Participants entered the study by multistage cluster sampling with an equal number of each gender and three age groups (6-9, 10-14, and 15-18 years) within each cluster. The tools used in this research were the demographic questionnaire and K-SADS-PL. To analyze the data logistic regression and chi-square tests were used in SPSS (ver. 16). The prevalence of anxiety disorder in children and adolescents was 13.2 in boys and 15.1 in girls. Furthermore, gender, age, place of residence and history of psychiatric hospitalization of parents could predict anxiety disorders. Anxiety disorders had comorbidity with behavioral disorders, neurodevelopmental disorders, mood disorders, psychotic disorders, substance abuse disorders, and elimination disorders. According to our findings in this study, anxiety disorders affect the performance, health and life of children and adolescents, identifying the childhood anxiety, as well as finding diseases that are associated with anxiety disorders, can help in the prevention of the disorder.
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http://dx.doi.org/10.1016/j.ajp.2020.102059DOI Listing
October 2020

Drug induced pancreatitis: A systematic review of case reports to determine potential drug associations.

PLoS One 2020 17;15(4):e0231883. Epub 2020 Apr 17.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Objective: A current assessment of case reports of possible drug-induced pancreatitis is needed. We systematically reviewed the case report literature to identify drugs with potential associations with acute pancreatitis and the burden of evidence supporting these associations.

Methods: A protocol was developed a priori (PROSPERO CRD42017060473). We searched MEDLINE, Embase, the Cochrane Library, and additional sources to identify cases of drug-induced pancreatitis that met accepted diagnostic criteria of acute pancreatitis. Cases caused by multiple drugs or combination therapy were excluded. Established systematic review methods were used for screening and data extraction. A classification system for associated drugs was developed a priori based upon the number of cases, re-challenge, exclusion of non-drug causes of acute pancreatitis, and consistency of latency.

Results: Seven-hundred and thirteen cases of potential drug-induced pancreatitis were identified, implicating 213 unique drugs. The evidence base was poor: exclusion of non-drug causes of acute pancreatitis was incomplete or poorly reported in all cases, 47% had at least one underlying condition predisposing to acute pancreatitis, and causality assessment was not conducted in 81%. Forty-five drugs (21%) were classified as having the highest level of evidence regarding their association with acute pancreatitis; causality was deemed to be probable or definite for 19 of these drugs (42%). Fifty-seven drugs (27%) had the lowest level of evidence regarding an association with acute pancreatitis, being implicated in single case reports, without exclusion of other causes of acute pancreatitis.

Discussion: Much of the case report evidence upon which drug-induced pancreatitis associations are based is tenuous. A greater emphasis on exclusion of all non-drug causes of acute pancreatitis and on quality reporting would improve the evidence base. It should be recognized that reviews of case reports, are valuable scoping tools but have limited strength to establish drug-induced pancreatitis associations.

Registration: CRD42017060473.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231883PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164626PMC
July 2020

Methods for the early detection of drug-induced pancreatitis: a systematic review of the literature.

BMJ Open 2019 11 5;9(11):e027451. Epub 2019 Nov 5.

Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Objectives: We systematically reviewed the literature to identify evidence-informed recommendations regarding the detection of drug-induced pancreatitis (DIP) and, secondarily, to describe clinical processes for the diagnosis of DIP.

Design: Systematic review.

Data Sources: Ovid MEDLINE, including Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase Classic+Embase, the Cochrane Library.

Eligibility Criteria: We included clinical practice guidelines, systematic reviews, narrative reviews and observational studies with a focus of establishing incidence, prevalence or diagnostic approaches for DIP. Clinical trials that diagnosed DIP as an outcome were also included.

Data Extraction And Synthesis: Two reviewers screened citations and performed data extraction. A narrative synthesis of the evidence was prepared.

Results: Fifty-nine studies were included. Early published evidence suggested serial pancreatic ultrasound could detect subclinical pancreatitis; however, subsequent studies demonstrated no utility of serial ultrasound or serial monitoring of pancreatic enzymes in the early detection of DIP. Two small studies conducted in patients with a high baseline risk of acute pancreatitis concluded serial monitoring of pancreatic enzymes may be useful to guide early discontinuation of medications with known associations with pancreatitis. Early discontinuation of medication was not advised for lower-risk patients because some medications cause transient elevations of pancreatic enzymes that do not progress to acute pancreatitis. Eight of 52 studies (15%) reporting a clinical diagnostic process for DIP reported using currently accepted criteria for the diagnosis of acute pancreatitis. A variety of methods were used to assess drug-related causality.

Conclusions: There is minimal evidence to support the use of serial monitoring by ultrasound or pancreatic enzymes to detect cases of DIP. Serial monitoring may be useful to guide early discontinuation of DIP-associated drugs in high-risk patients, but not in lower-risk patients. Greater uptake of standardised diagnostic and causality criteria for DIP is needed.

Trial Registration Number: CRD42017060473.
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http://dx.doi.org/10.1136/bmjopen-2018-027451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858245PMC
November 2019

Characterization of functionalized chitosan-clinoptilolite nanocomposites for nitrate removal from aqueous media.

Int J Biol Macromol 2019 Jun 23;130:545-555. Epub 2019 Feb 23.

Environment Research Department, Energy and Environment Research Center, Niroo Research Institute, End of Dadman Blvd., Shahrak-e-Ghods., P.O. Box 14665-517, Tehran, Iran.

The nanochitosan/clinoptilolite (Nano-CS/Clino) composite, Nano-CS/Clino activated by hydrochloric acid (Nano-CS/[email protected]) and Nano-CS/Clino functionalization with pentaethylenehexamine (Nano-CS/[email protected]) has been used to removal of nitrate ions from aqueous media. The textural properties of the Nano-CS/Clino nanocomposites were studied by various characterization techniques. The Nano-CS was synthesized by ionic gelation technique that using tripolyphosphate as cross-linking agent. The BET specific surface area of chitosan and Nano-CS is 0.9774 and 52.8850 m/g. The effects of different parameters on the removal of nitrate were measured in detail. The prepared Nano-CS/[email protected] composite possess enhanced nitrate adsorption capacity of 277.77 mg/g than Nano-CS/[email protected] and Nano-CS/Clino were found to be 227.27 and 185.18 mg/g. The Dubinin-Radushkevich, Freundlich and Langmuir adsorption models were applied to describe the equilibrium isotherms. The experimental data were also analyzed by first- and second-order and intra particle diffusion. Thermodynamic parameters studies revealed that the nature of adsorption nitrate by nanocomposites synthesized is spontaneous and exothermic. The overall adsorption tendency of synthesized nanocomposites toward nitrate (NO) in the presence of CO, SO and Cl under competitive conditions, followed the order: NO > CO> Cl> SO. Desorption process was carried out with NaOH and proven it was an effective agent in the discharge of nitrate.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.02.127DOI Listing
June 2019

Evaluating comparative effectiveness of psychosocial interventions for persons receiving opioid agonist therapy for opioid use disorder: protocol for a systematic review.

BMJ Open 2018 10 18;8(10):e023902. Epub 2018 Oct 18.

Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Introduction: The opioid crisis has resulted in increasing rates of death caused by problematic opioid use. Current clinical guidelines recommend that individuals with persons with opioid use disorder (OUD) receive pharmacological (eg, opioid agonist therapy) and psychosocial (eg, cognitive behavioural therapy) therapy; however, the best combination of pharmacologic and psychosocial components is not known. Our objective of the planned study is to conduct a comprehensive systematic review to assess the relative benefits of psychosocial interventions as an adjunct to opioid agonist therapy among persons with OUD.

Methods And Analysis: A comprehensive search for randomised controlled trials published in English or French will be conducted from database inception to March 2018. The search will be conducted in MEDLINE and translated for Embase, PsycINFO and the Cochrane Central Register of Controlled Trials. Two independent reviewers will screen, extract and assess risk of bias of eligible articles. Primary outcomes of interest will be treatment retention and opioid use (based on urinalysis results). Secondary outcomes will include self-reported opioid use, abstinence from illicit drugs, adherence to psychosocial therapy and opioid agonist therapy, risk for sexually transmitted disease, risk for blood borne pathogens, changes in mental health symptoms (eg, depression), measures of craving and changes in patients' quality of life and relevant adverse events. If sufficient data and adequate homogeneity exists, network meta-analyses (NMA) will be performed.

Ethics And Dissemination: This will be the first systematic review to incorporate NMA to compare psychosocial treatments used as an adjunct to opioid agonist therapy for OUD. Results of this review will inform clinical management of persons with OUD.

Trial Registration Number: CRD42018090761.
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http://dx.doi.org/10.1136/bmjopen-2018-023902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196951PMC
October 2018

Incidence, causes, and consequences of preventable adverse drug reactions occurring in inpatients: A systematic review of systematic reviews.

PLoS One 2018 11;13(10):e0205426. Epub 2018 Oct 11.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Background: Preventable adverse drug reactions (PADRs) in inpatients are associated with harm, including increased length of stay and potential loss of life, and result in elevated costs of care. We conducted an overview of reviews (i.e., a systematic review of systematic reviews) to determine the incidence of PADRs experienced by inpatients. Secondary review objectives were related to assessment of the effects of patient age, setting, and clinical specialty on PADR incidence.

Methods: The protocol was registered in PROSPERO (CRD42016043220). We performed a search of Medline, Embase, and the Cochrane Library, limiting languages of publication to English and French. We included published systematic reviews that reported quantitative data on the incidence of PADRs in patients receiving acute or ambulatory care in a hospital setting. The full texts of all primary studies for which PADR data were reported in the included reviews were obtained and data relevant to review objectives were extracted. Quality of the included reviews was assessed using the AMSTAR-2 tool. Both narrative summaries of findings and meta-analyses of primary study data were undertaken.

Results: Thirteen systematic reviews encompassing 37 unique primary studies were included. Across primary studies, the PADR incidence was highly varied, ranging from 0.006 to 13.3 PADRs per 100 patients, with a pooled incidence estimate of 0.59 PADRs per 100 patients. Substantial heterogeneity was present across both reviews and primary studies with respect to review/study objectives, patient age, hospital setting, medical discipline, definitions and assessment tools used, event detection methods, endpoints of interest, and units of measure. Thirteen primary studies used prospective event detection methods and had a pooled PADR incidence of 3.13 (2.87-3.38) PADRs per 100 patients; however, extreme statistical heterogeneity (I2 = 97%) indicated this finding should be considered with caution. Subgroup meta-analyses demonstrated that PADR incidence varied significantly with event detection method (prospective > retrospective > voluntary reporting methods), hospital setting (ICU > wards), and medical discipline (medical > surgical). High statistical heterogeneity (I2 > 80%) was present across all analyses, indicating results should be interpreted with caution. Effects of patient age could not be assessed due to poor reporting of age groups used in primary studies.

Discussion: The method of event detection appeared to significantly influence PADR incidence, with prospective methods having the highest reported PADR rate. This finding is in agreement with the background literature. High methodological and statistical heterogeneity across primary studies evaluating adverse drug events reduces the validity of the overall PADR incidence derived from the meta-analyses of the pooled data. Data pooled from studies using only prospective methods of event detection should provide an overall estimate closest to the true PADR incidence; however, our estimate should be considered with caution due to the statistical heterogeneity found in this group of studies. Future studies should employ prospective methods of detection. This review demonstrates that the true overall incidence of PADRs is likely much greater than the overall pooled incidence estimate of 0.59 PADRs per 100 patients obtained when event detection method was not taken into consideration.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205426PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181371PMC
March 2019

Comparative safety of bowel cleansers: protocol for a systematic review and network meta-analysis.

BMJ Open 2018 06 27;8(6):e021892. Epub 2018 Jun 27.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Introduction: The US Food and Drug Administration has withdrawn the bowel cleansing kit HalfLytely (PEG 3500) with 10 mg bisacodyl tablets due to an increased risk of ischaemic colitis compared with the same kit with only 5 mg bisacodyl. This is of interest in Canada given that the bowel cleansing kit Bi-Peglyte (PEG 3500) with 15 mg bisacodyl is currently approved for use. The objective is to assess the comparative safety of various bowel cleansers with or without bisacodyl, with a primary interest inpolyethylene glycol (PEG)-based and sodium-picosulfate-based products.

Methods And Analysis: Given the existing volume of the literature, the review will be conducted in two stages. Stage 1 will consist of a scoping exercise by searching MEDLINE, Embase and the Cochrane Library (up to 21 November 2017) to identify randomised controlled trials, quasirandomised studies and non-randomised studies in which any bowel cleanser regimens were compared among persons undergoing colonoscopy. The outcomes will be mapped to establish a listing of the studies and their comparisons and outcomes currently available in the literature. From this, a data synthesis plan will be determined. In stage 2, a systematic review with meta-analyses will be pursued, focused on the bowel cleanser comparisons and outcomes of interest identified in stage 1. Two reviewers will screen, extract and quality assess the articles. Outcomes of interest include ischaemic colitis, electrolyte imbalances and their consequences, seizures, bowel perforation and patient tolerability. If sufficient data exist and studies are of sufficient homogeneity, network meta-analyses (NMAs) will be performed.

Ethics And Dissemination: Ethics approval was not necessary due to study design. Updating the safety profile of bowel cleansers among the generally healthy population undergoing colonoscopy is pertinent given recent approval changes. This will be the first NMA within this population. Policy considerations may be reconsidered to minimise risk during bowel cleanser use.

Prospero Registration Number: CRD42018084720.
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http://dx.doi.org/10.1136/bmjopen-2018-021892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020982PMC
June 2018

The prevalence of patient engagement in published trials: a systematic review.

Res Involv Engagem 2018 22;4:17. Epub 2018 May 22.

Ottawa Hospital Research Institute, Ottawa, ON Canada.

Plain English Summary: With the growing movement to engage patients in research, questions are being asked about who is engaging patients and how they are being engaged. Internationally, research groups are supporting and funding patient-oriented research studies that engage patients in the identification of research priorities and the design, conduct and uptake of research. As we move forward, we need to know what meaningful patient engagement looks like, how it benefits research and clinical practice, and what are the barriers to patient engagement?We conducted a review of the published literature looking for trials that report engaging patients in the research. We included both randomized controlled trials and non-randomized comparative trials. We looked at these trials for important study characteristics, including how patients were engaged, to better understand the practices used in trials. Importantly, we also discuss the number of trials reporting patient engagement practices relative to all published trials. We found that very few trials report any patient engagement activities even though it is widely supported by many major funding organizations. The findings of our work will advance patient-oriented research by showing how patients can be engaged and by stressing that patient engagement practices need to be better reported.

Abstract:

Background: Patient-Oriented Research (POR) is research informed by patients and is centred on what is of importance to them. A fundamental component of POR is that patients are included as an integral part of the research process from conception to dissemination and implementation, and by extension, across the research continuum from basic research to pragmatic trials [J Comp Eff Res 2012, 1:181-94, JAMA 2012, 307:1587-8]. Since POR's inception, questions have been raised as to how best to achieve this goal.We conducted a systematic review of randomized controlled trials and non-randomized comparative trials that report engaging patients in their research. Our main goal was to describe the characteristics of published trials engaging patients in research, and to identify the extent of patient engagement activities reported in these trials.

Methods: The MEDLINE®, EMBASE®, Cinahl, PsycINFO, Cochrane Methodology Registry, and Pubmed were searched from May 2011 to June 16th, 2016. Title, abstract and full text screening of all reports were conducted independently by two reviewers. Data were extracted from included trials by one reviewer and verified by a second. All trials that report patient engagement for the purposes of research were included.

Results: Of the 9490 citations retrieved, 2777 were reviewed at full text, of which 23 trials were included. Out of the 23 trials, 17 were randomized control trials, and six were non-randomized comparative trials. The majority of these trials (83%, 19/23) originated in the United States and United Kingdom. The trials engaged a range of 2-24 patients/ community representatives per study. Engagement of children and minorities occurred in 13% (3/23) and 26% (6/23) of trials; respectively. Engagement was identified in the development of the research question, the selection of study outcomes, and the dissemination and implementation of results.

Conclusions: The prevalence of patient engagement in patient-oriented interventional research is very poor with 23 trials reporting activities engaging patients. Research dedicated to determining the best practice for meaningful engagement is still needed, but adequate reporting measures also need to be defined.
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http://dx.doi.org/10.1186/s40900-018-0099-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963039PMC
May 2018

A systematic review of adverse events of rifapentine and isoniazid compared to other treatments for latent tuberculosis infection.

Pharmacoepidemiol Drug Saf 2018 06 23;27(6):557-566. Epub 2018 Mar 23.

Ottawa Hospital, Ottawa, Canada.

Purpose: Tuberculosis (TB) remains a common cause of death globally. A regimen of 12 doses of isoniazid (INH) and rifapentine given once weekly (INH/RPT-3) has recently been recommended by the World Health Organization for the treatment of latent TB infection (LTBI). We aimed to determine whether the INH/RPT-3 regimen had similar or lesser rates of adverse events compared to other LTBI regimens, namely INH for 9 months, INH for 6 months, rifampin for 3 to 4 months, and rifampin plus INH for 3 to 4 months.

Methods: We searched MEDLINE, Embase, CENTRAL, PubMed, ICTRP, clinicaltrials.gov, and Canadian Agency for Drugs and Technologies in Health's Gray Matters Light for randomized, postmarketing, and comparative nonrandomized studies of patients with confirmed LTBI that reported the frequency of at least 1 adverse event of relevance for a regimen of interest. The search included studies published until March 2017. The frequencies of adverse events were extracted and are presented descriptively.

Results: Data from 23 randomized and 55 nonrandomized studies were included. Although inconsistent event reporting and high heterogeneity limited comparisons, the adverse event profile of INH/RPT-3 appeared generally favorable. Flu-like reactions were reported with an increased frequency and hepatotoxicity with a lower frequency than standard treatment.

Conclusions: While INH/RPT-3 had an overall low frequency of adverse events compared to INH monotherapy, reporting of adverse events for many regimens was limited meaning results should be interpreted cautiously. Future studies of LTBI treatment would benefit from more complete collection and reporting of adverse events and more consistent definitions of hepatotoxicity.
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http://dx.doi.org/10.1002/pds.4423DOI Listing
June 2018

Flaws in the application and interpretation of statistical analyses in systematic reviews of therapeutic interventions were common: a cross-sectional analysis.

J Clin Epidemiol 2018 03 2;95:7-18. Epub 2017 Dec 2.

Centre for Journalology, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6, Canada; School of Epidemiology, Public Health and Preventive Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada.

Objectives: The objective of the study was to investigate the application and interpretation of statistical analyses in a cross-section of systematic reviews (SRs) of therapeutic interventions, without restriction by journal, clinical condition, or specialty.

Study Design And Setting: We evaluated a random sample of SRs assembled previously, which were indexed in MEDLINE® during February 2014, focused on a treatment or prevention question, and reported at least one meta-analysis. The reported statistical methods used in each SR were extracted from articles and online appendices by one author, with a 20% random sample extracted in duplicate.

Results: We evaluated 110 SRs; 78/110 (71%) were non-Cochrane SRs and 55/110 (50%) investigated a pharmacological intervention. The SRs presented a median of 13 (interquartile range: 5-27) meta-analytic effects. When considering the index (primary or first reported) meta-analysis of each SR, just over half (62/110 [56%]) used the random-effects model, but few (5/62 [8%]) interpreted the meta-analytic effect correctly (as the average of the intervention effects across all studies). A statistical test for funnel plot asymmetry was reported in 17/110 (15%) SRs; however, in only 4/17 (24%) did the test include the recommended number of at least 10 studies of varying size. Subgroup analyses accompanied 42/110 (38%) index meta-analyses, but findings were not interpreted with respect to a test for interaction in 29/42 (69%) cases, and the issue of potential confounding in the subgroup analyses was not raised in any SR.

Conclusions: There is scope for improvement in the application and interpretation of statistical analyses in SRs of therapeutic interventions. The involvement of statisticians on the SR team and establishment of partnerships between researchers with specialist expertise in SR methods and journal editors may help overcome these shortcomings.
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http://dx.doi.org/10.1016/j.jclinepi.2017.11.022DOI Listing
March 2018

Comparative Effectiveness and Safety of Cognitive Enhancers for Treating Alzheimer's Disease: Systematic Review and Network Metaanalysis.

J Am Geriatr Soc 2018 01 29;66(1):170-178. Epub 2017 Sep 29.

Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.

Background/objectives: To examine the comparative effectiveness and safety of cognitive enhancers for Alzheimer's disease (AD).

Design: Systematic review and Bayesian network metaanalysis (NMA).

Setting: MEDLINE, EMBASE, Cochrane Library, CINAHL, Ageline (inception-March 2016).

Participants: Individuals with AD in randomized controlled trials (RCTs), quasi-RCTs, and nonrandomized studies.

Intervention: Any combination of donepezil, rivastigmine, galantamine, or memantine.

Measurements: Two reviewers independently screened titles, abstracts, and full-texts; abstracted data; and appraised risk of bias.

Results: Twenty thousand three hundred forty-three citations were screened, and 142 studies were included (110 RCTs, 21 non-RCTs, 11 cohort studies). NMA found that donepezil (Mini-Mental State Examination: mean difference (MD) = 1.39, 95% credible interval (CrI) = 0.53-2.24), donepezil+memantine (2.59, 95% CrI = 0.12-4.98), and transdermal rivastigmine (2.02, 95% CrI = 0.02-4.08) improved cognition more than placebo. NMA found that donepezil (Alzheimer's Disease Assessment Scale-cognitive: MD = -3.29, 95% CrI = -4.57 to -1.99) and galantamine (MD = -2.13, 95% CrI = -3.91 to -0.27) improved cognition more than placebo. NMA found that donepezil+memantine (MD = -5.23, 95% CrI = -8.72 to -1.56) improved behavior more than placebo. NMA found that donepezil (MD = -0.32, 95% CrI = -0.46 to -0.19), donepezil+memantine (MD = -0.57, 95% CrI = -0.95 to -0.21), oral rivastigmine (MD = -0.38, 95% CrI = -0.56 to -0.17), and galantamine (MD = -3.79, 95% CrI = -6.98 to -0.59) improved global status more than placebo. NMA found that galantamine decreased the odds of mortality (odds ratio = 0.56, 95% CrI = 0.36-0.87). No agent increased risk of serious adverse events, falls, or bradycardia. Some increased risk of headache (oral rivastigmine), diarrhea (oral rivastigmine, donepezil), nausea (oral rivastigmine, donepezil, galantamine), and vomiting (oral rivastigmine, donepezil, galantamine).

Conclusion: An exhaustive review of the literature involving 142 studies demonstrated that cognitive enhancers in general have minimal effects on cognition according to minimal clinically important difference and global ratings. The drugs appear safe, but this must be interpreted cautiously because trial participants may have less comorbidity and fewer adverse effects than those treated with these drugs in clinical practice.
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http://dx.doi.org/10.1111/jgs.15069DOI Listing
January 2018

Reproducible research practices are underused in systematic reviews of biomedical interventions.

J Clin Epidemiol 2018 02 4;94:8-18. Epub 2017 Nov 4.

Centre for Journalology, Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada; School of Epidemiology, Public Health and Preventive Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada.

Objectives: To evaluate how often reproducible research practices, which allow others to recreate the findings of studies, given the original data, are used in systematic reviews (SRs) of biomedical research.

Study Design And Setting: We evaluated a random sample of SRs indexed in MEDLINE during February 2014, which focused on a therapeutic intervention and reported at least one meta-analysis. Data on reproducible research practices in each SR were extracted using a 26-item form by one author, with a 20% random sample extracted in duplicate. We explored whether the use of reproducible research practices was associated with an SR being a Cochrane review, as well as with the reported use of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.

Results: We evaluated 110 SRs of therapeutic interventions, 78 (71%) of which were non-Cochrane SRs. Across the SRs, there were 2,139 meta-analytic effects (including subgroup meta-analytic effects and sensitivity analyses), 1,551 (73%) of which were reported in sufficient detail to recreate them. Systematic reviewers reported the data needed to recreate all meta-analytic effects in 72 (65%) SRs only. This percentage was higher in Cochrane than in non-Cochrane SRs (30/32 [94%] vs. 42/78 [54%]; risk ratio 1.74, 95% confidence interval 1.39-2.18). Systematic reviewers who reported imputing, algebraically manipulating, or obtaining some data from the study author/sponsor infrequently stated which specific data were handled in this way. Only 33 (30%) SRs mentioned access to data sets and statistical code used to perform analyses.

Conclusion: Reproducible research practices are underused in SRs of biomedical interventions. Adoption of such practices facilitates identification of errors and allows the SR data to be reanalyzed.
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http://dx.doi.org/10.1016/j.jclinepi.2017.10.017DOI Listing
February 2018

Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breast feeding: a systematic review and network meta-analysis.

BMJ Open 2017 Jul 20;7(7):e017248. Epub 2017 Jul 20.

Li Ka Shing Knowledge Institute,St. Michael's Hospital, Toronto, Canada.

Objectives: Compare the safety of antiepileptic drugs (AEDs) on neurodevelopment of infants/children exposed in utero or during breast feeding.

Design And Setting: Systematic review and Bayesian random-effects network meta-analysis (NMA). MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched until 27 April 2017. Screening, data abstraction and quality appraisal were completed in duplicate by independent reviewers.

Participants: 29 cohort studies including 5100 infants/children.

Interventions: Monotherapy and polytherapy AEDs including first-generation (carbamazepine, clobazam, clonazepam, ethosuximide, phenobarbital, phenytoin, primidone, valproate) and newer-generation (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, vigabatrin) AEDs. Epileptic women who did not receive AEDs during pregnancy or breast feeding served as the control group.

Primary And Secondary Outcome Measures: Cognitive developmental delay and autism/dyspraxia were primary outcomes. Attention-deficit hyperactivity disorder, language delay, neonatal seizures, psychomotor developmental delay and social impairment were secondary outcomes.

Results: The NMA on cognitive developmental delay (11 cohort studies, 933 children, 18 treatments) suggested that among all AEDs only valproate was statistically significantly associated with more children experiencing cognitive developmental delay compared with control (OR=7.40, 95% credible interval (CrI) 3.00 to 18.46). The NMA on autism (5 cohort studies, 2551 children, 12 treatments) suggested that oxcarbazepine (OR 13.51, CrI 1.28 to 221.40), valproate (OR 17.29, 95% CrI 2.40 to 217.60), lamotrigine (OR 8.88, CrI 1.28 to 112.00) and lamotrigine+valproate (OR 132.70, CrI 7.41 to 3851.00) were associated with significantly greater odds of developing autism compared with control. The NMA on psychomotor developmental delay (11 cohort studies, 1145 children, 18 treatments) found that valproate (OR 4.16, CrI 2.04 to 8.75) and carbamazepine+phenobarbital+valproate (OR 19.12, CrI 1.49 to 337.50) were associated with significantly greater odds of psychomotor delay compared with control.

Conclusions: Valproate alone or combined with another AED is associated with the greatest odds of adverse neurodevelopmental outcomes compared with control. Oxcarbazepine and lamotrigine were associated with increased occurrence of autism. Counselling is advised for women considering pregnancy to tailor the safest regimen.

Trial Registration Number: PROSPERO database (CRD42014008925).
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http://dx.doi.org/10.1136/bmjopen-2017-017248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642793PMC
July 2017

Effectiveness of different compression-to-ventilation methods for cardiopulmonary resuscitation: A systematic review.

Resuscitation 2017 09 2;118:112-125. Epub 2017 Jun 2.

Li Ka Shing Knowledge Institute, St. Michael's Hospital, 209 Victoria Street, Toronto, Ontario, M5B 1W8, Canada; Epidemiology Division, Dalla Lana School of Public Health, University of Toronto, Health Sciences Building, 155 College Street, 6th floor, Toronto, Ontario, M5T 3M7, Canada. Electronic address:

Aim: To compare the effectiveness of different compression-to-ventilation methods during cardiopulmonary resuscitation (CPR) in patients with cardiac arrest.

Methods: We searched MEDLINE and Cochrane Central Register of Controlled Trials from inception until January 2016. We included experimental, quasi-experimental, and observational studies that compared different chest compression-to-ventilation ratios during CPR for all patients and assessed at least one of the following outcomes: favourable neurological outcomes, survival, return of spontaneous circulation (ROSC), and quality of life. Two reviewers independently screened literature search results, abstracted data, and appraised the risk of bias. Random-effects meta-analyses were conducted separately for randomised and non-randomised studies, as well as study characteristics, such as CPR provider.

Results: After screening 5703 titles and abstracts and 229 full-text articles, we included 41 studies, of which 13 were companion reports. For adults receiving bystander or dispatcher-instructed CPR, no significant differences were observed across all comparisons and outcomes. Significantly less adults receiving bystander-initiated or plus dispatcher-instructed compression-only CPR experienced favourable neurological outcomes, survival, and ROSC compared to CPR 30:2 (compression-to-ventilation) in un-adjusted analyses in a large cohort study. Evidence from emergency medical service (EMS) CPR providers showed significantly more adults receiving CPR 30:2 experiencing improved favourable neurological outcomes and survival versus those receiving CPR 15:2. Significantly more children receiving CPR 15:2 or 30:2 experienced favourable neurological outcomes, survival, and greater ROSC compared to compression-only CPR. However, for children <1 years of age, no significant differences were observed between CPR 15:2 or 30:2 and compression-only CPR.

Conclusions: Our results demonstrated that for adults, CPR 30:2 is associated with better survival and favourable neurological outcomes when compared to CPR 15:2. For children, more patients receiving CPR with either 15:2 or 30:2 compression-to ventilation ratio experienced favourable neurological function, survival, and ROSC when compared to CO-CPR for children of all ages, but for children <1years of age, no statistically significant differences were observed.
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http://dx.doi.org/10.1016/j.resuscitation.2017.05.032DOI Listing
September 2017

Comparative safety of anti-epileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomes.

BMC Med 2017 05 5;15(1):95. Epub 2017 May 5.

Knowledge Translation Program, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 209 Victoria Street, East Building, Toronto, Ontario, M5B 1W8, Canada.

Background: Pregnant women with epilepsy frequently experience seizures related to pregnancy complications and are often prescribed anti-epileptic drugs (AEDs) to manage their symptoms. However, less is known about the comparative safety of AED exposure in utero. We aimed to compare the risk of congenital malformations (CMs) and prenatal outcomes of AEDs in infants/children who were exposed to AEDs in utero through a systematic review and Bayesian random-effects network meta-analysis.

Methods: MEDLINE, EMBASE, and Cochrane CENTRAL were searched from inception to December 15, 2015. Two reviewers independently screened titles/abstracts and full-text papers for experimental and observational studies comparing mono- or poly-therapy AEDs versus control (no AED exposure) or other AEDs, then abstracted data and appraised the risk of bias. The primary outcome was incidence of major CMs, overall and by specific type (cardiac malformations, hypospadias, cleft lip and/or palate, club foot, inguinal hernia, and undescended testes).

Results: After screening 5305 titles and abstracts, 642 potentially relevant full-text articles, and 17 studies from scanning reference lists, 96 studies were eligible (n = 58,461 patients). Across all major CMs, many AEDs were associated with higher risk compared to control. For major CMs, ethosuximide (OR, 3.04; 95% CrI, 1.23-7.07), valproate (OR, 2.93; 95% CrI, 2.36-3.69), topiramate (OR, 1.90; 95% CrI, 1.17-2.97), phenobarbital (OR, 1.83; 95% CrI, 1.35-2.47), phenytoin (OR, 1.67; 95% CrI, 1.30-2.17), carbamazepine (OR, 1.37; 95% CrI, 1.10-1.71), and 11 polytherapies were significantly more harmful than control, but lamotrigine (OR, 0.96; 95% CrI, 0.72-1.25) and levetiracetam (OR, 0.72; 95% CrI, 0.43-1.16) were not.

Conclusion: The newer generation AEDs, lamotrigine and levetiracetam, were not associated with significant increased risks of CMs compared to control, and were significantly less likely to be associated with children experiencing cardiac malformations than control. However, this does not mean that these agents are not harmful to infants/children exposed in utero. Counselling is advised concerning teratogenic risks when the prescription is written for a woman of childbearing age and before women continue with these agents when considering pregnancy, such as switching from polytherapy to monotherapy with evidence of lower risk and avoiding AEDs, such as valproate, that are consistently associated with CMs. These decisions must be balanced against the need for seizure control.

Systematic Review Registration: PROSPERO CRD42014008925.
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http://dx.doi.org/10.1186/s12916-017-0845-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418725PMC
May 2017

Efficacy and completion rates of rifapentine and isoniazid (3HP) compared to other treatment regimens for latent tuberculosis infection: a systematic review with network meta-analyses.

BMC Infect Dis 2017 04 11;17(1):265. Epub 2017 Apr 11.

Department of Medicine, The Ottawa Hospital, Ottawa, Canada.

Background: We conducted a systematic review and network meta-analysis (NMA) to examine the efficacy and completion rates of treatments for latent tuberculosis infection (LTBI). While a previous review found newer, short-duration regimens to be effective, several included studies did not confirm LTBI, and analyses did not account for variable follow-up or assess completion.

Methods: We searched MEDLINE, Embase, CENTRAL, PubMed, and additional sources to identify RCTs in patients with confirmed LTBI that involved a regimen of interest and reported on efficacy or completion. Regimens of interest included isoniazid (INH) with rifapentine once weekly for 12 weeks (INH/RPT-3), 6 and 9 months of daily INH (INH-6; INH-9), 3-4 months daily INH plus rifampicin (INH/RFMP 3-4), and 4 months daily rifampicin alone (RFMP-4). NMAs were performed to compare regimens for both endpoints.

Results: Sixteen RCTs (n = 44,149) and 14 RCTs (n = 44,128) were included in analyses of efficacy and completion. Studies were published between 1968 and 2015, and there was diversity in patient age and comorbidities. All regimens of interest except INH-9 showed significant benefits in preventing active TB compared to placebo. Comparisons between active regimens did not reveal significant differences. While definitions of regimen completion varied across studies, regimens of 3-4 months were associated with a greater likelihood of adequate completion.

Conclusions: Most of the active regimens showed an ability to reduce the risk of active TB relative to no treatment, however important differences between active regimens were not found. Shorter rifamycin-based regimens may offer comparable benefits to longer INH regimens. Regimens of 3-4 months duration are more likely to be completed than longer regimens.
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http://dx.doi.org/10.1186/s12879-017-2377-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387294PMC
April 2017

Intra-accumbal Orexin-1 Receptors are Involved in Antinociception Induced by Stimulation of the Lateral Hypothalamus in the Formalin Test as an Animal Model of Persistent Inflammatory Pain.

Iran J Pharm Res 2016 ;15(4):851-859

Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, PO Box 19615-1178, Tehran, Iran.

Orexin, mainly produced by orexin-expressing neurons in the lateral hypothalamus (LH), plays an important role in pain modulation. Moreover, it is shown that the nucleus accumbens (NAc) is one of the important areas involved in this modulation. Orexin-1 (OX1) and orexin-2 (OX2) receptors are densely distributed in the NAc. The study investigated the involvement of OX1 receptors in the NAc on antinociception induced by intra-LH administration of carbachol in formalin test. Rats were unilaterally implanted by two separate cannulae into the LH and NAc. Different doses of SB334867, as an OX1 receptor antagonist, were microinjected into the NAc (1, 3 and 10 nM/0.5 µL DMSO) prior to intra-LH carbachol injection (250 nM/0.5 µL saline). Formalin test was applied as an animal model of persistent inflammatory pain. The animals received a subcutaneous injection of formalin into the hind paw, 5 min after SB334867 administration. Pain scores were calculated at 5-min blocks for a 60-min test period. Results showed that the administration of SB334867 into the NAc decreased LH chemical stimulation-induced antinociception dose-dependently in early and second phase of formalin test. Our findings showed that OX1 receptors in the NAc may be involved in modulation of inflammatory pain.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316264PMC
January 2016

Correction: Summary of Glaucoma Diagnostic Testing Accuracy: An Evidence-Based Meta-Analysis.

J Clin Med Res 2017 Mar 25;9(3):231. Epub 2017 Jan 25.

Ivey Eye Institute, University of Western Ontario, London, ON, Canada; Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada.

[This corrects the article DOI: 10.14740/jocmr2643w.].
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http://dx.doi.org/10.14740/jocmr2643wc1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289146PMC
March 2017

Incidence, causes, and consequences of preventable adverse drug events: protocol for an overview of reviews.

Syst Rev 2016 12 5;5(1):209. Epub 2016 Dec 5.

Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.

Background: Medication errors represent a noteworthy source of harm to patients. In recent years, several systematic reviews have assessed the frequency and causes of these events, as well as other factors such as commonly associated drugs, their incidence in different specialties, and their consequences to patients. Despite this past literature, there remains a need to study discrepancies between these reviews and establish the current state of the evidence. The planned review will bring together, compare, and contract existing evidence related to the occurrence of medication errors in acute and continuing/long-term care settings.

Methods: A systematic review of reviews will be performed. A literature search designed by an experienced information specialist will be carried out in Medline, Embase, and the Cochrane Library. We will seek systematic reviews and meta-analyses of primary research studies that evaluate one or more of the following aspects of the occurrence of preventable adverse drug events in hospitals and long-term care centers: the incidence of preventable adverse drug events, either overall or within subgroups of interest related to setting; drug or patient characteristics; cited consequences of these events to patients, including death, emergency room visits, or other outcomes; and established causes of the preventable adverse drug events. Two researchers will independently screen all abstracts and full texts for study selection and subsequently perform data extraction from all included studies. Quality of the reviews will be assessed using the assessing the methodological quality of systematic reviews (AMSTAR) tool. Where objectives from two or more reviews overlap, we will employ the Jadad framework to assess the causes of any noted discrepancies between reviews. An overall summary of results will be performed using tabular and graphical approaches and will be supplemented by narrative description.

Discussion: This overview will help synthesize the broad degree of information available on this important topic. This review is being performed by members of the Drug Safety and Effectiveness Network along with collaboration from Health Canada, and its findings will be published in a peer-reviewed journal. The results may also inform future research in this area.

Systematic Review Registration: PROSPERO CRD42016043220.
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http://dx.doi.org/10.1186/s13643-016-0392-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5139092PMC
December 2016

Inhibition of pseudoperoxiadse activity of human red blood cell hemoglobin by methocarbamol.

Int J Biol Macromol 2017 Jan 16;94(Pt B):788-792. Epub 2016 Sep 16.

Faculty of Science, York University, Toronto, Canada.

After red blood cells lysis, hemoglobin is released to blood circulation. Hemoglobin is carried in blood by binding to haptoglobin. In normal individuals, no free hemoglobin is observed in the blood, because most of the hemoglobin is in the form of haptoglobin complex. In some diseases that are accompanied by hemolysis, the amount of released hemoglobin is higher than its complementary haptoglobin. As a result, free hemoglobin appears in the blood, which is a toxic compound for these patients and may cause renal failure, hypertensive response and risk of atherogenesis. Free hemoglobin has been determined to have peroxidase activity and considered a pseudoenzyme. In this study, the effect of methocarbamol on the peroxidase activity of human hemoglobin was investigated. Our results showed that the drug inhibited the pseudoenzyme by un-competitive inhibition. Both K and V decreased by increasing the drug concentration. K and IC values were determined as 6 and 10mM, respectively. Docking results demonstrated that methocarbamol did not attach to heme group directly. A hydrogen bond linked NH of carbamate group of methocarbamol to the carboxyl group of Asp126 side chain. Two other hydrogen bonds could be also observed between hydroxyl group of the drug and Ser102 and Ser133 residues of the pseudoenzyme.
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http://dx.doi.org/10.1016/j.ijbiomac.2016.09.049DOI Listing
January 2017

Summary of Glaucoma Diagnostic Testing Accuracy: An Evidence-Based Meta-Analysis.

J Clin Med Res 2016 Sep 30;8(9):641-9. Epub 2016 Jul 30.

Ivey Eye Institute, University of Western Ontario, London, ON, Canada; Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada.

Background: New glaucoma diagnostic technologies are penetrating clinical care and are changing rapidly. Having a systematic review of these technologies will help clinicians and decision makers and help identify gaps that need to be addressed. This systematic review studied five glaucoma technologies compared to the gold standard of white on white perimetry for glaucoma detection.

Methods: OVID(®) interface: MEDLINE(®) (In-Process & Other Non-Indexed Citations), EMBASE(®), BIOSIS Previews(®), CINAHL(®), PubMed, and the Cochrane Library were searched. A gray literature search was also performed. A technical expert panel, information specialists, systematic review method experts and biostatisticians were used. A PRISMA flow diagram was created and a random effect meta-analysis was performed.

Results: A total of 2,474 articles were screened. The greatest accuracy was found with frequency doubling technology (FDT) (diagnostic odds ratio (DOR): 57.7) followed by blue on yellow perimetry (DOR: 46.7), optical coherence tomography (OCT) (DOR: 41.8), GDx (DOR: 32.4) and Heidelberg retina tomography (HRT) (DOR: 17.8). Of greatest concern is that tests for heterogeneity were all above 50%, indicating that cutoffs used in these newer technologies were all very varied and not uniform across studies.

Conclusions: Glaucoma content experts need to establish uniform cutoffs for these newer technologies, so that studies that compare these technologies can be interpreted more uniformly. Nevertheless, synthesized data at this time demonstrate that amongst the newest technologies, OCT has the highest glaucoma diagnostic accuracy followed by GDx and then HRT.
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http://dx.doi.org/10.14740/jocmr2643wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974833PMC
September 2016

Role of orexin-2 receptors in the nucleus accumbens in antinociception induced by carbachol stimulation of the lateral hypothalamus in formalin test.

Behav Pharmacol 2016 08;27(5):431-8

aNeuroscience Research Center, Shahid Beheshti University of Medical Sciences bDepartment of Toxicology & Pharmacology, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University (IAUPS), Tehran, Iran.

Orexins, which are mainly produced by orexin-expressing neurons in the lateral hypothalamus (LH), play an important role in pain modulation. Previously, it has been established that the nucleus accumbens (NAc) is involved in the modulation of formalin-induced nociceptive responses, a model of tonic pain. In this study, the role of intra-accumbal orexin-2 receptors (OX2rs) in the mediation of formalin-induced pain was investigated. A volume of 0.5 μl of 10, 20, and 40 nmol/l solutions of TCS OX2 29, an OX2r antagonist, were unilaterally microinjected into the NAc 5 min before an intra-LH carbachol microinjection (0.5 μl of 250 nmol/l solution). After 5 min, animals received a subcutaneous injection of formalin 2.5% (50 μl) into the hind paw. Pain-related behaviors were assessed at 5 min intervals during a 60-min test period. The findings showed that TCS OX2 29 administration dose dependently blocked carbachol-induced antinociception during both phases of formalin-induced pain. The antianalgesic effect of TCS OX2 29 was greater during the late phase compared with the early phase. These observations suggest that the NAc, as a part of a descending pain-modulatory circuitry, partially mediates LH-induced analgesia in the formalin test through recruitment of OX2rs. This makes the orexinergic system a good potential therapeutic target in the control of persistent inflammatory pain.
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http://dx.doi.org/10.1097/FBP.0000000000000216DOI Listing
August 2016

Reply.

Pain 2016 Feb;157(2):505-506

Department of Anesthesiology, The Ottawa Hospital Knowledge Synthesis Group, Centre for Practice-Changing Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada School of Epidemiology, Public Health and Preventive Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.

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http://dx.doi.org/10.1097/j.pain.0000000000000395DOI Listing
February 2016

Binding of Cimetidine to Balb/C Mouse Liver Catalase; Kinetics and Conformational Studies.

Curr Clin Pharmacol 2016 ;11(1):21-7

BioResearch Lab, Faculty of Biological Sciences, Shahid Beheshti University, GC, Tehran, Iran.

Catalase is responsible for converting hydrogen peroxide (H2O2) into water and oxygen in cells. This enzyme has high affinity for hydrogen peroxide and can protect the cells from oxidative stress damage. Catalase is a tetramer protein and each monomer contains a heme group. Cimetidine is a histamine H2 receptor blocker which inhibits acid release from stomach and is used for gasterointestinal diseases. In this research, effect of cimetidine on the activity of liver catalase was studied and the kinetic parameters of this enzyme and its conformational changes were investigated. Cell free extract of mouse liver was used for the catalase assay. The activity of the catalase was detected in the absence and presence of cimetidine by monitoring hydrogen peroxide reduction absorbance at 240 nm. The purified enzyme was used for conformational studies by Fluorescence spectrophotometry. The data showed that cimetidine could inhibit the enzyme in a non-competitive manner. Ki and IC50 values of the drug were determined to be about 0.75 and 0.85 uM, respectively. The Arrhenius plot showed that activation energy was 6.68 and 4.77 kJ/mol in the presence and absence of the drug, respectively. Fluorescence spectrophotometry revealed that the binding of cimetidine to the purified enzyme induced hyperchromicity and red shift which determined the conformational change on the enzyme. Cimetidine could non-competitively inhibit the liver catalase with high affinity. Binding of cimetidine to the enzyme induced conformational alteration in the enzyme.
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http://dx.doi.org/10.2174/1574884711666160122093020DOI Listing
December 2016

Differential roles of orexin receptors within the dentate gyrus in stress- and drug priming-induced reinstatement of conditioned place preference in rats.

Behav Neurosci 2016 Feb 21;130(1):91-102. Epub 2015 Dec 21.

Neuroscience Research Center, Shahid Beheshti University of Medical Sciences.

Orexins are hypothalamic peptides involved in the modulation of the feeding, arousal, reward function, learning, and memory; nevertheless, the role of orexins in stress and relapse are largely unclear. Therefore, in the present study, the reinstatement model were used to examine the effects of intradentate gyrus (DG) administration of SB334867 as an orexin-1 receptor antagonist and TCS OX2 29, as an orexin-2 receptor antagonist on drug priming- and forced swim stress (FSS)-induced reinstatement of morphine. One-hundred and 44 adult male albino Wistar rats weighing 200 g-280 g were bilaterally implanted by cannulas into the DG. For induction of conditioned place preference (CPP), subcutaneous (sc) injection of morphine (5 mg/kg) was used daily during a 3-day conditioning phase. Then, the conditioning score (conditional stimulus [CS]) was calculated. After a 24 hr "off" period following achievement of extinction criterion, rats were tested for drug priming-induced reinstatement by priming dose of morphine (1 mg/kg, sc) and for FSS-induced reinstatement 10 min after FSS. In the next experiments, animals received different doses of intra-DG administration of SB334867 and TCS OX2 29 (3, 10, and 30 μg/0.5 μl 12% DMSO per side), bilaterally and were subsequently tested for morphine priming- and FSS-induced reinstatement. Our findings indicated that the FSS-induced the reinstatement of seeking behaviors. Furthermore, intra-DG administration of orexin-1 and orexin-2 receptor antagonists attenuated drug priming-induced reinstatement dose-dependently. However, they have trivial role in FSS-induced reinstatement. It is concluded that drug priming-induced reinstatement may be mediated, at least in part, by stimulation of orexin receptors in the DG.
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http://dx.doi.org/10.1037/bne0000112DOI Listing
February 2016

Comparative safety and effectiveness of long-acting inhaled agents for treating chronic obstructive pulmonary disease: a systematic review and network meta-analysis.

BMJ Open 2015 Oct 26;5(10):e009183. Epub 2015 Oct 26.

Knowledge Translation Program, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada Department of Geriatric Medicine, University of Toronto, 27 Kings College Circle, Toronto, Ontario, Canada.

Objective: To compare the safety and effectiveness of long-acting β-antagonists (LABA), long-acting antimuscarinic agents (LAMA) and inhaled corticosteroids (ICS) for managing chronic obstructive pulmonary disease (COPD).

Setting: Systematic review and network meta-analysis (NMA).

Participants: 208 randomised clinical trials (RCTs) including 134,692 adults with COPD.

Interventions: LABA, LAMA and/or ICS, alone or in combination, versus each other or placebo.

Primary And Secondary Outcomes: The proportion of patients with moderate-to-severe exacerbations. The number of patients experiencing mortality, pneumonia, serious arrhythmia and cardiovascular-related mortality (CVM) were secondary outcomes.

Results: NMA was conducted including 20 RCTs for moderate-to-severe exacerbations for 26,141 patients with an exacerbation in the past year. 32 treatments were effective versus placebo including: tiotropium, budesonide/formoterol, salmeterol, indacaterol, fluticasone/salmeterol, indacaterol/glycopyrronium, tiotropium/fluticasone/salmeterol and tiotropium/budesonide/formoterol. Tiotropium/budesonide/formoterol was most effective (99.2% probability of being the most effective according to the Surface Under the Cumulative RAnking (SUCRA) curve). NMA was conducted on mortality (88 RCTs, 97 526 patients); fluticasone/salmeterol was more effective in reducing mortality than placebo, formoterol and fluticasone alone, and was the most effective (SUCRA=71%). NMA was conducted on CVM (37 RCTs, 55,156 patients) and the following were safest: salmeterol versus each OF placebo, tiotropium and tiotropium (Soft Mist Inhaler (SMR)); fluticasone versus tiotropium (SMR); and salmeterol/fluticasone versus tiotropium and tiotropium (SMR). Triamcinolone acetonide was the most harmful (SUCRA=81%). NMA was conducted on pneumonia occurrence (54 RCTs, 61 551 patients). 24 treatments were more harmful, including 2 that increased risk of pneumonia versus placebo; fluticasone and fluticasone/salmeterol. The most harmful agent was fluticasone/salmeterol (SUCRA=89%). NMA was conducted for arrhythmia; no statistically significant differences between agents were identified.

Conclusions: Many inhaled agents are available for COPD, some are safer and more effective than others. Our results can be used by patients and physicians to tailor administration of these agents.

Protocol Registration Number: PROSPERO # CRD42013006725.
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http://dx.doi.org/10.1136/bmjopen-2015-009183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636655PMC
October 2015

Functional interaction between OX2 and CB1 receptors in the ventral tegmental area and the nucleus accumbens in response to place preference induced by chemical stimulation of the lateral hypothalamus.

Pharmacol Biochem Behav 2015 Dec 19;139(Pt A):39-46. Epub 2015 Oct 19.

Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Orexinergic projections derived from the lateral hypothalamus (LH) to the ventral tegmental area (VTA) and the nucleus accumbens (NAc), play a key role in the acquisition of conditioned place preference (CPP) induced by LH stimulation. On the other hand, there are several studies which support the idea of the existence of a cross-talk between the orexinergic and cannabinoid systems. Nevertheless, the function and how both systems interact in the reward circuit remain unknown. In this study, the authors tried to clarify the role of orexin-2 receptor (OX2r) within the VTA and NAc in the development of reward-related behaviors after chemical stimulation of the LH and also find out the involvement of CB1 cannabinoid receptors in this phenomenon. Animals were implanted by two separate cannulae into the LH and VTA or NAc, unilaterally. The CPP paradigm was done; and conditioning scores were recorded. The results showed that administration of TCS OX2 29 as a selective OX2r antagonist (1, 3 and 10 nM/rat) into the VTA or NAc just 5 min before microinjection of carbachol (250 nM/0.5 μl saline), a cholinergic agonist, into the LH during the 3-day conditioning phase, could dose-dependently inhibit the development of LH stimulation-induced CPP. Furthermore, concurrent injection of ineffective doses of TCS OX2 29 and AM251, as a CB1 receptor antagonist, into the NAc could reduce conditioning scores. The findings of this study showed that the OX2 receptor has a critical role in modulating reward circuit in the VTA and NAc, when the LH was stimulated by carbachol. Moreover, we suggest the existence of an interaction between orexinergic and cannabinoid systems within the VTA and NAc in place preference induced by LH stimulation.
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http://dx.doi.org/10.1016/j.pbb.2015.10.012DOI Listing
December 2015
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