Publications by authors named "Ani Orchanian-Cheff"

25 Publications

  • Page 1 of 1

A review of respiratory manifestations and their management in Ehlers-Danlos syndromes and hypermobility spectrum disorders.

Chron Respir Dis 2021 Jan-Dec;18:14799731211025313

Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Background: Ehlers-Danlos Syndromes (EDS) and Hypermobility Spectrum Disorders (HSD) are a heterogeneous group of heritable genetic connective tissue disorders with multiple characteristics including joint hypermobility, tissue fragility, and multiple organ dysfunction. Respiratory manifestations have been described in EDS patients, but have not been systematically characterized. A narrative review was undertaken to describe the respiratory presentations and management strategies of individuals with EDS and HSD.

Methods: A broad literature search of Medline, Embase, Cochrane Database of Systematic Reviews, and Cochrane CENTRAL was undertaken from inception to November 2020 of all study types, evaluating EDS/ HSD and pulmonary conditions. This narrative review was limited to adult patients and publications in English.

Results: Respiratory manifestations have generally been described in hypermobile EDS (hEDS), classical and vascular EDS subtypes. Depending on EDS subtype, they may include but are not limited to dyspnea, dysphonia, asthma, sleep apnea, and reduced respiratory muscle function, with hemothorax and pneumothorax often observed with vascular EDS. Respiratory manifestations in HSD have been less frequently characterized in the literature, but exertional dyspnea is the more common symptom described. Respiratory symptoms in EDS can have an adverse impact on quality of life. The respiratory management of EDS patients has followed standard approaches with thoracotomy tubes and pleurodesis for pleural manifestations, vocal cord strengthening exercises, continuous positive pressure support for sleep apnea, and exercise training. Reduced respiratory muscle function in hEDS patients responds to inspiratory muscle training.

Conclusion: Respiratory symptoms and manifestations are described in EDS and HSD, and have generally been managed using conservative non-surgical strategies. Research into the prevalence, incidence and specific respiratory management strategies in EDS and HSD is needed to mitigate some of the associated morbidity.
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http://dx.doi.org/10.1177/14799731211025313DOI Listing
July 2021

Prognostic value of natriuretic peptides in heart failure: systematic review and meta-analysis.

Heart Fail Rev 2021 Jul 5. Epub 2021 Jul 5.

Ted Rogers Center for Heart Research, University Health Network, Toronto, ON, Canada.

Risk models, informing optimal long-term medical management, seldom use natriuretic peptides (NP) in ascertaining the absolute risk of outcomes for HF patients. Individual studies evaluating the prognostic value of NPs in HF patients have reported varying effects, arriving at best estimates requires a systematic review. We systematically summarized the best evidence regarding the prognostic value of brain natriuretic peptide (BNP) and NT-proBNP in predicting mortality and hospitalizations in ambulatory heart failure (HF) patients. We searched bibliographic databases from 2005 to 2018 and included studies evaluating the association of BNP or NT-proBNP with mortality or hospitalization using multivariable Cox proportional hazard models. We pooled hazard ratios using random-effect models, explored heterogeneity using pre-specified subgroup analyses, and evaluated the certainty of evidence using the Grading of Recommendations and Development Evaluation framework. We identified 67 eligible studies reporting on 76,178 ambulatory HF patients with a median BNP of 407 pg/mL (261-574 pg/mL). Moderate to high-quality evidence showed that a 100-pg/mL increase in BNP was associated with a 14% increased hazard of mortality (HR 1.14, 95% CI 1.06-1.22); a 1-log-unit increase was associated with a 51% increased hazard of mortality (HR 1.51, 95% CI 1.41-1.61) and 48% increased hazard of mortality or hospitalization (HR 1.48, 95% CI 1.29-1.69). With moderate to high certainty, we observed a 14% independent relative increase in mortality, translating to a clinically meaningful increase in absolute risk even for low-risk patients. The observed associations may help in developing more accurate risk models that incorporate NPs and accurately prognosticate HF patients.
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http://dx.doi.org/10.1007/s10741-021-10136-3DOI Listing
July 2021

Systematic review and meta-analysis of post-transplant diabetes mellitus in liver transplant recipients.

Clin Transplant 2021 07 13;35(7):e14340. Epub 2021 Jun 13.

Multi Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, ON, Canada.

Post-transplant diabetes mellitus (PTDM) compromises long-term survival in liver transplant (LT) recipients. The aim of this study was to determine incidence of PTDM after LT and risk factors associated with it. A literature search was conducted, and prospective studies that reported on the incidence of PTDM in LT adult patients on tacrolimus, sirolimus, or cyclosporine were included. We performed random effects meta-analyses for the incidence of PTDM stratified by immunosuppressant and time period. Of 9817 articles identified, 26 studies were included in the qualitative analysis and 21 studies were eligible for the quantitative analysis representing 79 559 LT recipients in 32 separate treatment arms. The proportion of patients who developed PTDM by two-three years was 0.15 (95% CI: 0.10-0.24) for cyclosporine, 0.23 (95% CI: 0.14-0.36) for tacrolimus, and 0.27 (95% CI: 0.23-0.30) for sirolimus. CONCLUSION: Our results showed that sirolimus-based immunosuppression was associated with a higher incidence of PTDM than tacrolimus or cyclosporine at two-three years. However, there were only two studies that compared all three drugs which is a limitation of the study and requires more studies with patients on sirolimus. Recipient factors increasing the risk of PTDM are older age, male sex, and high BMI.
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http://dx.doi.org/10.1111/ctr.14340DOI Listing
July 2021

Barriers to Accessing Kidney Transplantation Among Populations Marginalized by Race and Ethnicity in Canada: A Scoping Review Part 1-Indigenous Communities in Canada.

Can J Kidney Health Dis 2021 3;8:2054358121996835. Epub 2021 Mar 3.

Division of Nephrology, Ajmera Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada.

Background: Kidney transplantation (KT), a treatment option for end-stage kidney disease (ESKD), is associated with longer survival and improved quality of life compared with dialysis. Inequities in access to KT, and specifically, living donor kidney transplantation (LDKT), have been documented in Canada along various demographic dimensions. In this article, we review existing evidence about inequitable access and barriers to KT and LDKT for patients from Indigenous communities in Canada.

Objective: To characterize the current state of literature on access to KT and LDKT among Indigenous communities in Canada and to answer the research question, "what factors may influence inequitable access to KT among Indigenous communities in Canada."

Eligibility Criteria: Databases and gray literature were searched in June and November 2020 for full-text original research articles or gray literature resources addressing KT access or barriers in Indigenous communities in Canada. A total of 26 articles were analyzed thematically.

Sources Of Evidence: Gray literature and CINAHL, OVID Medline, OVID Embase, and Cochrane databases.

Charting Methods: Literature characteristics were recorded and findings which described rates of and factors that influence access to KT were summarized in a narrative account. Key themes were subsequently identified and synthesized thematically in the review.

Results: Indigenous communities in Canada experience various barriers in accessing culturally safe medical information and care, resulting in inequitable access to KT. Barriers include insufficient incorporation of Indigenous ways of knowing and being in information dissemination and care for ESKD and KT, spiritual concerns, health beliefs, logistical hurdles to accessing care, and systemic mistrust resulting from colonialism and systemic racism.

Limitations: This review included studies that used various methodologies and did not assess study quality. Data on Indigenous status were not reported or defined in a standardized manner. Indigenous communities are not homogeneous and views on organ donation and KT vary by individual.

Conclusions: Our scoping review has identified potential barriers that Indigenous communities may face in accessing KT and LDKT. Further research is urgently needed to better understand barriers and support needs and to develop strategies to improve equitable access to KT and LDKT for Indigenous populations in Canada.
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http://dx.doi.org/10.1177/2054358121996835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934025PMC
March 2021

Barriers to Accessing Kidney Transplantation Among Populations Marginalized by Race and Ethnicity in Canada: A Scoping Review Part 2-East Asian, South Asian, and African, Caribbean, and Black Canadians.

Can J Kidney Health Dis 2021 3;8:2054358121996834. Epub 2021 Mar 3.

Ajmera Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada.

Background: Kidney transplantation (KT), a treatment option for end-stage kidney disease (ESKD), is associated with longer survival and improved quality of life compared with dialysis. Inequities in access to KT, and specifically, living donor kidney transplantation (LDKT), have been documented in Canada, along various demographic dimensions. In this article, we review existing evidence about inequitable access to KT and LDKT for patients from communities marginalized by race and ethnicity in Canada.

Objective: To characterize the currently published data on rates of KT and LDKT among East Asian, South Asian, and African, Caribbean, and Black (ACB) Canadian communities and to answer the research question, "what factors may influence inequitable access to KT among East Asian, South Asian, and ACB Canadian communities?."

Eligibility Criteria: Databases and gray literature were searched in June and November 2020 for full-text original research articles or gray literature resources addressing KT access or barriers in East Asian, South Asian, and ACB Canadian communities. A total of 25 articles were analyzed thematically.

Sources Of Evidence: Gray literature and CINAHL, OVID Medline, OVID Embase, and Cochrane databases.

Charting Methods: Literature characteristics were recorded and findings which described rates of and factors that influence access to KT were summarized in a narrative account. Key themes were subsequently identified and synthesized thematically in the review.

Results: East Asian, South Asian, and ACB communities in Canada face barriers in accessing culturally appropriate medical knowledge and care and experience inequitable access to KT. Potential barriers include gaps in knowledge about ESKD and KT, religious and spiritual concerns, stigma of ESKD and KT, health beliefs, social determinants of health, and experiences of systemic racism in health care.

Limitations: This review included literature that used various methodologies and did not assess study quality. Data on ethnicity and race were not reported or defined in a standardized manner. The communities examined in this review are not homogeneous and views on organ donation and KT vary by individual.

Conclusions: Our review has identified potential barriers for communities marginalized by race and ethnicity in accessing KT and LDKT. Further research is urgently needed to better understand the barriers and support needs of these communities, and to develop strategies to improve equitable access to LDKT for the growingly diverse population in Canada.
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http://dx.doi.org/10.1177/2054358121996834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934034PMC
March 2021

Emergency department interventions for homelessness: a systematic review.

CJEM 2021 01 10;23(1):111-122. Epub 2020 Dec 10.

Department of Medicine, University of Toronto, 1901 Elizabeth Street, R Fraser Elliot Building, 3-805, Toronto, ON, M5G 2C4, Canada.

Background: The social determinants of health are economic and social conditions that contribute to health. Access to housing is a major social determinant of health and homeless patients often rely on emergency departments (EDs) for their healthcare. These patients are frequently discharged back to the street which further perpetuates the cycle of homelessness and negatively affects their health. Previous work has described the financial and systems implications of ED-housed interventions for homeless patients; this review summarizes ED-based interventions that seek to improve the social determinants of health of homeless patients.

Methods: We conducted a search of multiple databases and gray literature for studies investigating interventions for homelessness that were initiated in the ED. Studies had to use a control group or use a pre/post-intervention design and measure outcomes that demonstrate an effect on health or the social determinants of health.

Results: Thirteen studies were identified that met the inclusion criteria. Two studies were housing first interventions and were effective in providing housing and improving health. Seven studies used variations of case management and were able to address many of the social needs of people who are homeless.

Conclusion: This review demonstrated that ED interventions can be effective in improving the social determinants of health of homeless individuals and can be the place to initiate housing interventions. ED providers must advocate for the resources necessary to properly address the social needs of this marginalized population. Equipped with the proper resources, EDs can be one place where the cycle of homelessness is broken.
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http://dx.doi.org/10.1007/s43678-020-00008-4DOI Listing
January 2021

Muscle and cerebral oxygenation during cycling in chronic obstructive pulmonary disease: A scoping review.

Chron Respir Dis 2021 Jan-Dec;18:1479973121993494

Department of Medicine, Division of Respirology, 7938University of Toronto, University Health Network, Toronto, Ontario, Canada.

To synthesize evidence for prefrontal cortex (PFC), quadriceps, and respiratory muscle oxygenation using near-infrared spectroscopy (NIRS) during cycling in individuals with chronic obstructive pulmonary disease (COPD). A scoping review was performed searching databases (inception-August 2020): Ovid MEDLINE, EMBASE, Cochrane Systematic Reviews, Cochrane Central Register of Controlled Clinical Trials, CINAHL, SPORTDiscus and Pedro. The search focused on COPD, cycling, and NIRS outcomes. 29 studies (541 COPD participants) were included. Compared to healthy individuals (8 studies), COPD patients at lower cycling workloads had more rapid increases in vastus lateralis (VL) deoxygenated hemoglobin (HHb); lower increases in VL total hemoglobin (tHb) and blood flow; and lower muscle tissue saturation (StO). Heliox and bronchodilators were associated with smaller and slower increases in VL HHb. Heliox increased VL and intercostal blood flow compared to room air and supplemental oxygen in COPD patients (1 study). PFC oxygenated hemoglobin (OHb) increased in COPD individuals during cycling in 5 of 8 studies. Individuals with COPD and heart failure demonstrated worse VL and PFC NIRS outcomes compared to patients with only COPD-higher or more rapid increase in VL HHb and no change or decrease in PFC OHb. Individuals with COPD present with a mismatch between muscle oxygen delivery and utilization, characterized by more rapid increase in VL HHb, lower muscle OHb and lower muscle StO. PFC OHb increases or tends to increase in individuals with COPD during exercise, but this relationship warrants further investigation. NIRS can be used to identify key deoxygenation thresholds during exercise to inform PFC and muscle oxygenation.
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http://dx.doi.org/10.1177/1479973121993494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897842PMC
February 2021

Barrier enclosure use during aerosol-generating medical procedures: A scoping review.

Am J Emerg Med 2021 Mar 6;41:209-218. Epub 2020 Nov 6.

Division of Emergency Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Toronto General Hospital - Emergency Department, University Health Network, Toronto, ON, Canada. Electronic address:

Introduction: Barrier enclosure devices were introduced to protect against infectious disease transmission during aerosol generating medical procedures (AGMP). Recent discussion in the medical community has led to new designs and adoption despite limited evidence. A scoping review was conducted to characterize devices being used and their performance.

Methods: We conducted a scoping review of formal databases (MEDLINE, Embase, Cochrane Database of Systematic Reviews, CENTRAL, Scopus), grey literature, and hand-searched relevant journals. Forward and reverse citation searching was completed on included articles. Article/full-text screening and data extraction was performed by two independent reviewers. Studies were categorized by publication type, device category, intended medical use, and outcomes (efficacy - ability to contain particles; efficiency - time to complete AGMP; and usability - user experience).

Results: Searches identified 6489 studies and 123 met criteria for inclusion (k = 0.81 title/abstract, k = 0.77 full-text). Most articles were published in 2020 (98%, n = 120) as letters/commentaries (58%, n = 71). Box systems represented 42% (n = 52) of systems described, while plastic sheet systems accounted for 54% (n = 66). The majority were used for airway management (67%, n = 83). Only half of articles described outcome measures (54%, n = 67); 82% (n = 55) reporting efficacy, 39% (n = 26) on usability, and 15% (n = 10) on efficiency. Efficacy of devices in containing aerosols was limited and frequently dependent on use of suction devices.

Conclusions: While use of various barrier enclosure devices has become widespread during this pandemic, objective data of efficacy, efficiency, and usability is limited. Further controlled studies are required before adoption into routine clinical practice.
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http://dx.doi.org/10.1016/j.ajem.2020.10.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837026PMC
March 2021

Resting Heart Rate as an Important Predictor of Mortality and Morbidity in Ambulatory Patients With Heart Failure: A Systematic Review and Meta-Analysis.

J Card Fail 2021 Mar 7;27(3):349-363. Epub 2020 Nov 7.

Ted Rogers Centre for Heart Research, University Health Network, Toronto, Ontario, Canada. Electronic address:

Background: Resting heart rate is a risk factor of adverse heart failure outcomes; however, studies have shown controversial results. This meta-analysis evaluates the association of resting heart rate with mortality and hospitalization and identifies factors influencing its effect.

Methods And Results: We systematically searched electronic databases in February 2019 for studies published in 2005 or before that evaluated the resting heart rate as a primary predictor or covariate of multivariable models of mortality and/or hospitalization in adult ambulatory patients with heart failure. Random effects inverse variance meta-analyses were performed to calculate pooled hazard ratios. The Grading of Recommendations, Assessment, Development and Evaluation approach was used to assess evidence quality. Sixty-two studies on 163,445 patients proved eligible. Median population heart rate was 74 bpm (interquartile range 72-76 bpm). A 10-bpm increase was significantly associated with increased risk of all-cause mortality (hazard ratio 1.10, 95% confidence interval 1.08-1.13, high quality). Overall, subgroup analyses related to patient characteristics showed no changes to the effect estimate; however, there was a strongly positive interaction with age showing increasing risk of all-cause mortality per 10 bpm increase in heart rate.

Conclusions: High-quality evidence demonstrates increasing resting heart rate is a significant predictor of all-cause mortality in ambulatory patients with heart failure on optimal medical therapy, with consistent effect across most patient factors and an increased risk trending with older age.
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http://dx.doi.org/10.1016/j.cardfail.2020.11.003DOI Listing
March 2021

Predicting the Risk of Right Ventricular Failure in Patients Undergoing Left Ventricular Assist Device Implantation: A Systematic Review.

Circ Heart Fail 2020 10 28;13(10):e006994. Epub 2020 Sep 28.

Heart Failure and Transplant Program, Peter Munk Cardiac Centre (M.M., J.K.K.V.-N., F.F., F.B., A.C.A.), University Health Network, Toronto, Canada.

Background: Right ventricular failure (RVF) is a cause of major morbidity and mortality after left ventricular assist device (LVAD) implantation. It is, therefore, integral to identify patients who may benefit from biventricular support early post-LVAD implantation. Our objective was to explore the performance of risk prediction models for RVF in adult patients undergoing LVAD implantation.

Methods: A systematic search was performed on Medline, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews from inception until August 2019 for all relevant studies. Performance was assessed by discrimination (via C statistic) and calibration if reported. Study quality was assessed using the Prediction Model Risk of Bias Assessment Tool criteria.

Results: After reviewing 3878 citations, 25 studies were included, featuring 20 distinctly derived models. Five models were derived from large multicenter cohorts: the European Registry for Patients With Mechanical Circulatory Support, Interagency Registry for Mechanically Assisted Circulatory Support, Kormos, Pittsburgh Bayesian, and Mechanical Circulatory Support Research Network RVF models. Seventeen studies (68%) were conducted in cohorts implanted with continuous-flow LVADs exclusively. The definition of RVF as an outcome was heterogenous among models. Seven derived models (28%) were validated in at least 2 cohorts, reporting limited discrimination (C-statistic range, 0.53-0.65). Calibration was reported in only 3 studies and was variable.

Conclusions: Existing RVF prediction models exhibit heterogeneous derivation and validation methodologies, varying definitions of RVF, and are mostly derived from single centers. Validation studies of these prediction models demonstrate poor-to-modest discrimination. Newer models are derived in cohorts implanted with continuous-flow LVADs exclusively and exhibit modest discrimination. Derivation of enhanced discriminatory models and their validations in multicenter cohorts is needed.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.006994DOI Listing
October 2020

Clinical outcomes associated with computed tomography-based body composition measures in lung transplantation: a systematic review.

Transpl Int 2020 12 14;33(12):1610-1625. Epub 2020 Oct 14.

Department of Physical Therapy, University of Toronto, Toronto, ON, Canada.

Computed tomography (CT) is gaining increased recognition in the assessment of body composition in lung transplant (LTx) candidates as a prognostic marker of post-transplant outcomes. This systematic review was conducted to describe the methodology of CT measures of body composition used in LTx patients and its association with post-transplant outcomes. Six databases were searched (inception-April 2020) for studies of adult LTx patients with thoracic or abdominal CT measures [muscle cross-sectional area (CSA) and/or adiposity]. Thirteen articles were included with 1911 LTx candidates, 58% males, mean age range (48-61 years) and body mass index of 21.0-26.1 kg/m . Several methods were utilized using thoracic or abdominal CT scans to assess skeletal muscle (n = 11) and adiposity (n = 4) at various anatomic locations (carina, thoracic, and lumbar vertebrae), differing muscle groups, and adipose tissue compartments. Low muscle mass was associated with adverse outcomes in 6/11 studies, including longer mechanical ventilation days (n = 2), intensive care (n = 2) and hospital stay (n = 2), and mortality (n = 4). Greater subcutaneous and mediastinal fat were associated with increased risk of primary graft dysfunction (n = 2), but implications of adiposity on survival were variable across four studies. Further standardization of CT body composition assessments is needed to assess the prognostic utility of these measures on LTx outcomes.
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http://dx.doi.org/10.1111/tri.13749DOI Listing
December 2020

Quality Assurance Processes Ensuring Appropriate Follow-up of Test Results Pending at Discharge in Emergency Departments: A Systematic Review.

Ann Emerg Med 2020 11 25;76(5):659-674. Epub 2020 Aug 25.

Department of Medicine, Division of Emergency Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Emergency Medicine, University Health Network, Toronto, Ontario, Canada.

Study Objective: In many cases, emergency department (ED) care leads to investigations for which there are not final results at patient disposition. The follow-up for these test results pending at discharge, most commonly final diagnostic imaging reports and microbiology cultures, is a significant safety concern for patients and a medicolegal risk for ED practitioners. Our objective is to perform a systematic review of the literature and report on the structure and outcomes of existing ED quality assurance processes to address these test results pending at discharge.

Methods: We searched for studies that reported processes to ensure follow-up of test results pending at discharge for patients discharged from ED settings in 6 relevant databases, from inception to June 11, 2019. We appraised the quality of each study and extracted characteristics of the quality assurance process being discussed, as well as its influence and outcomes, cost, and feasibility.

Results: We identified 17,862 studies, and 17 met our criteria for inclusion. Four major processes were identified to improve the follow-up of test results pending at discharge: only nurses or clerks involved, physician-driven process, direct patient contact, and pharmacist-led process. The 5 recommendations generated by our literature review included dedicating staff to the quality assurance process, protecting their quality assurance time from clinical duties, ensuring electronic medical record integration, encouraging collaboration among health care disciplines, and engaging patients.

Conclusion: A variety of quality assurance processes have been described to follow up on ED test results pending at discharge, and we provided recommendations to improve patient care. All ED leaders should consider implementing these according to their local context.
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http://dx.doi.org/10.1016/j.annemergmed.2020.07.024DOI Listing
November 2020

Artificial intelligence, diagnostic imaging and neglected tropical diseases: ethical implications.

Bull World Health Organ 2020 Apr 3;98(4):288-289. Epub 2020 Mar 3.

Division Infectious Diseases, Toronto General Hospital, University of Toronto, 14EN 209, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.

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http://dx.doi.org/10.2471/BLT.19.237560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133484PMC
April 2020

Organ donation and transplant: The Islamic perspective.

Clin Transplant 2020 04 11;34(4):e13832. Epub 2020 Mar 11.

Division of Nephrology, Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada.

Islam is the second most practiced religion globally, and the number of Muslims in Western countries has been increasing due to recent trends in migration. Studies have shown that Muslims in the Western world have more negative attitudes toward organ donation and transplantation compared with individuals from other religious backgrounds. Multiple barriers have been postulated that may prevent Muslims from exploring organ donation or transplantation. We conducted a literature review with the goal of summarizing the opinions of major Sunni and Shia scholars and Islamic bodies about organ donation and transplantation, including their opinions and rulings on the neurological determination of death to inform healthcare professionals, community members, and leaders. We also identified factors and attitudes that may prevent members of the Muslim community from achieving equitable access to transplantation or from consenting to donate organs during life or after death. Key factors or concerns identified included: lack of information regarding organ donation, mistrust of the healthcare system, family opinions, sacredness of the body, lack of clear understanding of religious rulings, and opinions of religious leaders. Studies have suggested that partnering with religious leaders to address these concerns may help foster positive attitudes toward organ donation and transplantation.
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http://dx.doi.org/10.1111/ctr.13832DOI Listing
April 2020

Ethical issues associated with solid organ transplantation and substance use: a scoping review.

Monash Bioeth Rev 2019 Dec;37(3-4):111-135

Joint Centre for Bioethics, University of Toronto, 155 College Street, Suite 754, Toronto, ON, M5T 1P8, Canada.

While solid organ transplantation for patients with substance use issues has attracted ethical discussion, a typology of the ethics themes has not been articulated in the literature. We conducted a scoping review of peer-reviewed literature on solid organ transplantation and substance use published between January 1997 and April 2016. We aimed to identify and develop a typology of the main ethical themes discussed in this literature and to identify gaps worthy of future research. Seventy articles met inclusion criteria and underwent inductive content analysis. Four main ethical themes were identified: (1) personal responsibility; (2) utility; (3) moral character; and (4) fairness. Each theme had multiple sub-themes and there was substantial overlap between themes. This scoping review identified a disproportionate emphasis in the literature regarding personal responsibility, which was referenced by each of the other themes, and a narrow focus on alcohol and liver. We recommend future research further investigate these connections between ethical themes and focus on ethical issues associated with transplants from organ groups other than liver for patients who use substances other than alcohol.
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http://dx.doi.org/10.1007/s40592-019-00100-1DOI Listing
December 2019

Risk prediction models for survival after heart transplantation: A systematic review.

Am J Transplant 2020 04 16;20(4):1137-1151. Epub 2019 Dec 16.

Peter Munk Cardiac Centre, Toronto General Hospital-University Health Network, Toronto, Canada.

Risk prediction scores have been developed to predict survival following heart transplantation (HT). Our objective was to systematically review the model characteristics and performance for all available scores that predict survival after HT. Ovid Medline and Epub Ahead of Print and In-Process & Other Non-Indexed Citations, Ovid Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Clinical Trials were searched to December 2018. Eligible articles reported a score to predict mortality following HT. Of the 5392 studies screened, 21 studies were included that derived and/or validated 16 scores. Seven (44%) scores were validated in external cohorts and 8 (50%) assessed model performance. Overall model discrimination ranged from poor to moderate (C-statistic/area under the receiver operating characteristics 0.54-0.77). The IMPACT score was the most widely validated, was well calibrated in two large registries, and was best at discriminating 3-month survival (C-statistic 0.76). Most scores did not perform particularly well in any cohort in which they were assessed. This review shows that there are insufficient data to recommend the use of one model over the others for prediction of post-HT outcomes.
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http://dx.doi.org/10.1111/ajt.15708DOI Listing
April 2020

Ambiguous identities of drugs and people: A scoping review of opioid-related stigma.

Int J Drug Policy 2019 12 28;74:205-215. Epub 2019 Oct 28.

Toronto Western Hospital, University Health Network, 399 Bathurst Street, 8th Floor, McLaughlin Pavilion, Room 443, Toronto, ON M5T 2S8, Canada; University of Toronto Joint Centre for Bioethics, Canada; Dalla Lana School of Public Health, University of Toronto, Canada. Electronic address:

Background: Human beings have long consumed opiates and opioids for pleasure and as a treatment for numerous ailments, most notably pain. North America is currently in the grips of a crisis of opioid-related overdoses, and stigma is considered a major driver of the harms. While it is well established that substance use in general is highly stigmatized, stigma is a complex concept and opioid-related stigma is not well understood. A lack of clarity on opioid-related stigma has practice and policy implications in terms of understanding the sources of opioid stigma, how it manifests in various contexts, its impact on affected groups, and the development of effective strategies to redress it.

Methods: We performed a scoping review of the academic literature to develop a typology of opioid-related stigma. A charting process identified the type, agent, and recipient of stigma as well as the methodology and substances considered.

Results: Our search yielded 8,543 articles, from which 49 were included in the analysis. Based on the findings, we developed a typology of four main themes: (1) interpersonal and structural stigma toward people accessing opioid agonist therapy (OAT); (2) stigma related to opioids for the treatment of chronic pain; (3) stigma in healthcare settings; and (4) self-stigma.

Conclusion: How opioid-stigma is (re)produced depends on the context of opioid use, the social identity and networks of the person who is consuming the opioid, and what type of opioid is being consumed, including medically-sanctioned forms of treatment. Opioid-related stigma permeates intrapersonal, interpersonal, structural, and societal levels, and people who consume opioids are marginalized at all levels. Our review describes our typology of stigma and illuminates multi-level considerations for reducing opioid-related stigma in healthcare settings.
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http://dx.doi.org/10.1016/j.drugpo.2019.10.005DOI Listing
December 2019

Risk Factors for 1-Year Graft Loss After Kidney Transplantation: Systematic Review and Meta-Analysis.

Clin J Am Soc Nephrol 2019 11 20;14(11):1642-1650. Epub 2019 Sep 20.

Department of Health Research Methods, Evidence, and Impact and.

Background And Objectives: With expansion of the pool of kidney grafts, through the use of higher-risk donors, and increased attention to donor management strategies, the 1-year graft survival rate is subject to change. It is, therefore, useful to elucidate 1-year graft survival rates by dissecting the characteristics of the low-risk and high-risk kidney transplant cases. The objective of our study was to evaluate factors purported to influence the risk of 1-year graft loss in kidney transplant recipients.

Design, Setting, Participants, & Measurements: We searched bibliographic databases from 2000 to 2017 and included observational studies that measured the association between donor, recipient, the transplant operation, or early postoperative complications, and 1-year death-censored graft loss.

Results: We identified 35 eligible primary studies, with 20 risk factors amenable to meta-analysis. Six factors were associated with graft loss, with moderate to high degree of certainty: donor age (hazard ratio [HR], 1.11 per 10-year increase; 95% confidence interval [95% CI], 1.04 to 1.18), extended criteria donors (HR, 1.35; 95% CI, 1.28 to 1.42), deceased donors (HR, 1.54; 95% CI, 1.32 to 1.82), number of HLA mismatches (HR, 1.08 per one mismatch increase; 95% CI, 1.07 to 1.09), recipient age (HR, 1.17 per 10-year increase; 95% CI, 1.09 to 1.25), and delayed graft function (HR, 1.89; 95% CI, 1.46 to 2.47) as risk factors for 1-year graft loss. Pooled analyses also excluded, with a high degree of certainty, any associations of cold ischemia time, recipient race, pretransplant body mass index, diabetes, and hypertension with 1-year graft loss.

Conclusions: Recipient age, donor age, standard versus extended criteria donor, living versus deceased donor, HLA mismatch, and delayed graft function all predicted 1-year graft survival. The effect of each risk factor is small.
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http://dx.doi.org/10.2215/CJN.05560519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832056PMC
November 2019

Pre-transplant factors associated with mortality after lung transplantation in cystic fibrosis: A systematic review and meta-analysis.

J Cyst Fibros 2019 05 25;18(3):407-415. Epub 2018 Oct 25.

Division of Respirology, Adult Cystic Fibrosis Centre, St. Michael's Hospital, Toronto, ON, Canada.

Background: Mortality risk stratification is essential in lung transplantation (LTx) to allow listing, prioritization and mitigating strategies. In cystic fibrosis (CF) patients, predictors of post-LTx mortality are not established.

Methods: For this systematic review and meta-analysis, seven databases were searched until January 3, 2018 to identify predictors of post-LTx mortality in CF. We excluded studies of multi-organ transplantation, re-transplantation and graft survival. For multiple studies assessing the same population during overlapping time-periods, the largest one was analyzed. Risk of bias was assessed with the Newcastle-Ottawa scale (NOS). Pooled hazard ratios were calculated using random-effects models.

Results: Fifty-four studies were included in the systematic review and 11 studies in the meta-analyses (low-to-moderate bias risk, NOS score ≥ 5). Among 10 factors assessed in the meta-analysis, B. cepacia complex (BCC) (N = 1451, unadjusted HR = 2.35, 95%CI:1.80-3.06; I = 20.4% and adjusted HR = 2.49, 95%CI:1.74-3.57; I = 46.2%) and ascending chronological year of LTx (N = 4207, unadjusted HR = 0.98, 95%CI:0.97-0.98, I = 4.8%) were predictors of post-LTx mortality. Male gender (N = 2903, adjusted HR = 1.12, 95%CI:1.0-1.26, I = 0%) and age in adults (N = 3677, unadjusted HR = 0.99, 95%CI:0.97-1.00; I = 64.1% and N = 2605, adjusted HR = 0.98, 95%CI:0.97-0.99; I = 34.3%) had borderline significant associations with post-LTx mortality. P. aeruginosa colonization, forced expiratory volume in one second (FEV), pulmonary hypertension, body mass index (BMI), pancreatic insufficiency and CF-related diabetes (CFRD) were not predictors of mortality.

Conclusions: BCC was associated with a higher post-LTx mortality whereas FEV, pulmonary hypertension, BMI, CFRD and female gender were not associated with post-LTx mortality. These findings indicate that CF-specific risk estimates of post-LTx mortality should be considered.
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http://dx.doi.org/10.1016/j.jcf.2018.10.013DOI Listing
May 2019

The Impact of High-Flow Nasal Oxygen in the Immunocompromised Critically Ill: A Systematic Review and Meta-Analysis.

Respir Care 2018 Dec;63(12):1555-1566

Interdepartmental Division of Critical Care Medicine, Sinai Health System/University Health Network, University of Toronto, Ontario, Canada.

Background: High-flow nasal-cannula (HFNC) may be an oxygen modality useful for preventing invasive mechanical ventilation and mortality; however, its role in acute hypoxemic respiratory failure is not clearly defined. We sought to evaluate the impact of HFNC on mortality across immunocompromised subjects compared to alternative noninvasive oxygen therapies, namely conventional oxygen therapy and noninvasive ventilation (NIV).

Methods: We systematically searched the major databases to identify randomized, controlled trials (RCTs) or observational studies (until May 2018). We included studies reporting the use of HFNC in immunocompromised subjects and evaluated its impact on mortality and invasive mechanical ventilation.

Results: Upon review of 6,506 titles, 13 studies (1,956 subjects) fulfilled our inclusion criteria (4 RCTs, 9 observational studies). The predominant cause of immunocompromised status was cancer. Bacterial pneumonia was the most common cause of acute hypoxemic respiratory failure with a median P/F of 145 mm Hg (interquartile range 115-175). HFNC was used as the first oxygen strategy in 474 subjects compared to NIV (242 subjects) and conventional O therapy (703 subjects). There was a 46% rate of invasive mechanical ventilation and 36% mortality. Mortality at the longest available follow-up was lower with HFNC compared to the oxygen therapy controls (NIV or conventional O therapy) in 7 studies (1,429 subjects; relative risk 0.72, 95% CI 0.56-0.93, = .01). There was a lower rate of invasive mechanical ventilation with HFNC compared to the oxygen therapy controls across 8 studies (1,529 subjects, relative risk 0.81, 95% CI 0.67-0.96, = .02). These results were robust across a series of sensitivity analyses.

Conclusions: There exists a need to develop a greater evidence base evaluating the utility of HFNC in immunocompromised subjects. In our exploratory analysis, HFNC was found to decrease mortality and use of invasive mechanical ventilation compared to alternative noninvasive oxygen controls. These results are meant to be exploratory. Higher-quality studies evaluating a more homogeneous population are needed to further elucidate its benefit.
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http://dx.doi.org/10.4187/respcare.05962DOI Listing
December 2018

Mediation analysis with a time-to-event outcome: a review of use and reporting in healthcare research.

BMC Med Res Methodol 2018 10 29;18(1):118. Epub 2018 Oct 29.

Department of Medicine, University of Toronto, Toronto, Canada.

Background: Mediation analysis tests whether the relationship between two variables is explained by a third intermediate variable. We sought to describe the usage and reporting of mediation analysis with time-to-event outcomes in published healthcare research.

Methods: A systematic search of Medline, Embase, and Web of Science was executed in December 2016 to identify applications of mediation analysis to healthcare research involving a clinically relevant time-to-event outcome. We summarized usage over time and reporting of important methodological characteristics.

Results: We included 149 primary studies, published from 1997 to 2016. Most studies were published after 2011 (n = 110, 74%), and the annual number of studies nearly doubled in the last year (from n = 21 to n = 40). A traditional approach (causal steps or change in coefficient) was most commonly taken (n = 87, 58%), and the majority of studies (n = 114, 77%) used a Cox Proportional Hazards regression for the outcome. Few studies (n = 52, 35%) mentioned any of the assumptions or limitations fundamental to a causal interpretation of mediation analysis.

Conclusion: There is increasing use of mediation analysis with time-to-event outcomes. Current usage is limited by reliance on traditional methods and the Cox Proportional Hazards model, as well as low rates of reporting of underlying assumptions. There is a need for formal criteria to aid authors, reviewers, and readers reporting or appraising such studies.
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http://dx.doi.org/10.1186/s12874-018-0578-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206666PMC
October 2018

Acute Cellular Rejection: Is It Still Relevant?

Semin Respir Crit Care Med 2018 04 26;39(2):181-198. Epub 2018 Mar 26.

Division of Respirology and Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.

Despite significant progress in the field of transplant immunology, acute cellular rejection (ACR) remains a very frequent complication after lung transplantation (LTx), with almost 30% of LTx recipients experiencing at least one episode of treated ACR during the first year of follow-up. Most episodes respond to the first-line immunosuppressive treatment and are rarely a direct cause of death. However, the association of ACR with later adverse outcomes, such as chronic lung allograft dysfunction, bronchial stricture, and infectious complications associated with the intensification of immunosuppression, negatively impacts long-term survival. The burden imposed on patients and health-care resources is even higher in cases of refractory or recurrent ACR, which accelerates lung function decline. Although important laboratory and clinical research conducted over the last two decades has improved our understanding of the mechanisms underlying ACR, there are still many uncertainties about the risk factors for ACR, the optimal monitoring strategies, and the prediction of long-term outcomes. These knowledge gaps contribute to the large variability in clinical practice among LTx centers, which renders multicenter studies of ACR challenging. In this review, we summarize current evidence on the epidemiology, pathogenesis, and risk factors of ACR. We describe diagnostic and therapeutic approaches that are currently used in the clinical practice and also review promising diagnostic tools that are under investigation. Associations between ACR and other adverse outcomes of LTx are examined. Finally, within each topic of discussion, we highlight the main areas of controversy and opportunities for future research.
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http://dx.doi.org/10.1055/s-0037-1617424DOI Listing
April 2018

Use of Viral Load as a Surrogate Marker in Clinical Studies of Cytomegalovirus in Solid Organ Transplantation: A Systematic Review and Meta-analysis.

Clin Infect Dis 2018 02;66(4):617-631

Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.

Symptomatic cytomegalovirus (CMV) disease has been the standard endpoint for clinical trials in organ transplant recipients. Viral load may be a more relevant endpoint due to low frequency of disease. We performed a meta-analysis and systematic review of the literature. We found several lines of evidence to support the validity of viral load as an appropriate surrogate end-point, including the following: (1) viral loads in CMV disease are significantly greater than in asymptomatic viremia (odds ratio, 9.3 95% confidence interval, 4.6-19.3); (2) kinetics of viral replication are strongly associated with progression to disease; (3) pooled incidence of CMV viremia and disease is significantly lower during prophylaxis compared with the full patient follow-up period (viremia incidence: 3.2% vs 34.3%; P < .001) (disease incidence: 1.1% vs 13.0%; P < .001); (4) treatment of viremia prevented disease; and (5) viral load decline correlated with symptom resolution. Based on the analysis, we conclude that CMV load is an appropriate surrogate endpoint for CMV trials in organ transplant recipients.
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http://dx.doi.org/10.1093/cid/cix793DOI Listing
February 2018

Utilization of non-invasive imaging tools for assessment of peripheral skeletal muscle size and composition in chronic lung disease: A systematic review.

Respir Med 2017 10 11;131:125-134. Epub 2017 Aug 11.

Dept. of Physical Therapy, University of Toronto, Canada. Electronic address:

Objectives: Non-invasive imaging modalities allow for detailed assessment of peripheral skeletal muscle wasting, which is associated with increased morbidity and mortality in chronic lung disease. Given the increased utilization of imaging tools, a systematic review was conducted using PRISMA guidelines to describe the modalities and acquisition techniques used to evaluate skeletal muscle in chronic lung disease and assess the relationships of muscle size and composition with strength, physical performance, structural alterations and clinical outcomes.

Methods: Six electronic databases were searched (inception-May 2017) to identify prospective studies measuring peripheral skeletal muscle size or composition using computed tomography (CT), magnetic resonance imaging/spectroscopy (MRI/MRS), or ultrasound (US) in adult chronic lung disease patients.

Results: Fifty-eight articles were included, which utilized: CT (n = 26), MRI/MRS (n = 16) and US (n = 16) in 2254 participants. All studies measured muscle size, predominantly of the lower extremity (n = 53), and only nine assessed muscle composition (i.e. fat infiltration) mainly with CT or MRI/MRS (n = 7). Thigh muscle size had a significant association with strength (r = 0.43-0.83, n = 13/14 studies), 6-min walk distance (r = 0.60-0.62, n = 3/6) and physical activity (r = 0.30-0.82, n = 3). Thigh muscle atrophy was independently associated with increased re-hospitalization (n = 1) and mortality (n = 3). Increased muscle fat infiltration had a moderate association with reduced physical performance partly related to increased anaerobic metabolism, but its prognostic utility was not assessed.

Conclusion: Imaging modalities are valuable tools for the characterization of skeletal muscle dysfunction in chronic lung disease in clinical and research settings. The use of muscle imaging as a prognostic marker is promising and requires further study.
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http://dx.doi.org/10.1016/j.rmed.2017.08.007DOI Listing
October 2017

Internet search engines.

Aust Fam Physician 2008 Jan-Feb;37(1-2)

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March 2008
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