Living donor liver transplantation can address disparities in transplant access for patients with primary sclerosing cholangitis.

BACKGROUND: Liver transplantation (LT) is frequently lifesaving for people living with primary sclerosing cholangitis (PSC). However, patients are waitlisted for LT according to the model for end-stage liver disease-sodium (MELD-Na) score, which may not accurately reflect the burden of living with PSC. We sought to describe and analyze the clinical trajectory for patients with PSC referred for LT, in a mixed deceased donor/living donor transplant program. METHODS: This was a retrospective cohort study from November 2012 to December 2019, including all patients with PSC referred for assessment at the University Health Network Liver Transplant Clinic. Patients who required multiorgan transplant or retransplantation were excluded. Liver symptoms, hepatobiliary malignancy, MELD-Na progression, and death were abstracted from chart review. Competing risk analysis was used for timing of LT, transplant type, and death. RESULTS: Of 172 PSC patients assessed, 84% (n = 144) were listed of whom 74% were transplanted. Mean age was 47.6 years, and 66% were male. Overall mortality was 18.2% at 2 years. During the follow-up, 16% (n = 23) were removed from the waitlist for infection, clinical deterioration, liver-related mortality or new cancer; 3 had clinical improvement. At listing, 82% (n = 118) had a potential living donor (pLD). Patients with pLD had significantly lower waitlist and liver-related waitlist mortality (HR 0.20, p<0.001 and HR 0.17, p<0.001, respectively), and higher rates of transplantation (HR 1.83, p = 0.05). Exception points were granted to 13/172 (7.5%) patients. CONCLUSIONS: In a high-volume North American LT center, most patients with PSC assessed for transplant were listed and subsequently transplanted. However, this was a consequence of patients engaging in living donor transplantation. Our findings support the concern from patients with PSC that MELD-Na allocation does not adequately address their needs.

A longitudinal analysis of early lung function trajectory in survivors of childhood Hodgkin lymphoma.

BACKGROUND: Childhood Hodgkin lymphoma survivors suffer from long-term effects decades after treatment completion with a prevalence of pulmonary dysfunction of up to 65.2%. AIMS: This study explored the early trajectory of pulmonary function in pediatric cancer patients with Hodgkin lymphoma who received pulmonary toxic therapy. METHODS AND RESULTS: In this single-center, 20-year retrospective cohort study, we included patients who were <18 years old at diagnosis of Hodgkin lymphoma between January 1994 and December 2014, and received bleomycin or thoracic radiation. We measured pulmonary function and reported on percent predicted values for forced expiratory volume in 1 s, total lung capacity, and diffusing capacity of the lungs. We used linear mixed models to identify the association of clinical factors with longitudinal changes in lung function at time points before and after treatment completion. Of 80 children who met inclusion criteria, all were treated with bleomycin, and 83.8% received thoracic radiation. More than half (51.2%) of patients had any abnormalities in lung function measures during the study observation period which averaged 24.2 months (±31.1SD). Females, younger age at diagnosis and treatment with radiation were associated with lower lung function measurements at various time points. While the majority of children experienced a recovery of their lung function within 1-2 years after treatment completion, some children with these risk factors did not. CONCLUSION: Pulmonary function abnormalities begin early in children treated for Hodgkin lymphoma. While the majority of children demonstrate a slow and continuous improvement in lung function back to baseline over time, we recommend routine asymptomatic screening of pulmonary function in certain childhood cancer survivors, particularly females, those diagnosed young and patients who received radiation therapy.

Economic feasibility of a novel tool to assist extubation decision-making: an early health economic modeling.

OBJECTIVES: To estimate the minimum percent change in failed extubation to make a tool designed to reduce extubation failure (Extubation Advisor [EA]) economically viable. METHODS: We conducted an early return on investment (ROI) analysis using data from intubated intensive care unit (ICU) patients at a large Canadian tertiary care hospital. We obtained input parameters from the hospital database and published literature. We ran generalized linear models to estimate the attributable length of stay, total hospital cost, and time to subsequent extubation attempt following failure. We developed a Markov model to estimate the expected ROI and performed probabilistic sensitivity analyses to assess the robustness of findings. Costs were presented in 2020 Canadian dollars (C$). RESULTS: The model estimated a 1 percent reduction in failed extubation could save the hospital C$289 per intubated patient (95 percent CI: 197, 459). A large center seeing 2,500 intubated ICU patients per year could save C$723,124/year/percent reduction in failed extubation. At the current annual price of C$164,221, the EA tool must reduce extubation failure by at least 0.24 percent (95 percent CI: .14, .41) to make the tool cost-effective at our site. CONCLUSIONS: Clinical decision-support tools like the EA may play an important role in reducing healthcare costs by reducing the rate of extubation failure, a costly event in the ICU.

Healthcare Professionals' Understandings of the Definition and Determination of Death: A Scoping Review.

Background: During the 1950s, advances in critical care, and organ transplantation altered the relationship between organ failure and death. There has since been a shift away from traditional cardiocirculatory based to brain-based criteria of death, with resulting academic controversy, despite the practice being largely accepted worldwide. Our objective is to develop a comprehensive description of the current understandings of healthcare professionals regarding the meaning, definition, and determination of death. Methods: Online databases were used to identify papers published from 2003 to 2020. Additional sources were searched for conference proceedings and theses. Two reviewers screened papers using predefined inclusion and exclusion criteria. Complementary searches and review of reference lists complemented the final study selection. A data extraction instrument was developed to iteratively chart the results of the review. A qualitative approach was conducted to thematically analyze the data. Results: Seven thousand four hundred twenty-eight references were identified. In total, 75 papers met the inclusion criteria. Fourteen additional papers were added from complementary searches. Most were narratives (35%), quantitative investigations (21%), and reviews (18%). Identified themes included: (1) the historical evolution of brain death (BD), (2) persistent controversies about BD and death determination, (3) wide variability in healthcare professionals' knowledge and attitudes, (4) critical need for BD determination revision. Conclusions: We concluded that although BD is widely accepted, there exists variation in healthcare providers' understanding of its conceptual basis. Death determination remains a divisive issue among scholars. This review identified a need for increased opportunities for formal training on BD among healthcare providers.

Public Understandings of the Definition and Determination of Death: A Scoping Review.

Background: Advances in medicine and technology that have made it possible to support, repair, or replace failing organs challenge commonly held notions of life and death. The objective of this review is to develop a comprehensive description of the current understandings of the public regarding the meaning/definition and determination of death. Methods: This scoping review was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist. Online databases were used to identify articles published from 2003 to 2021. Two reviewers (S.S. and K.Z.) screened the articles using predefined inclusion and exclusion criteria, extracted data for specific content variables, and performed descriptive examination. Complementary searches of reference lists complemented the final study selection. A search strategy using vocabulary of the respective databases was created, and criteria for the inclusion and exclusion of the articles were established. Results: Seven thousand four hundred twenty-eight references were identified. Sixty were retained for analysis, with 4 additional references added from complementary searches. A data extraction instrument was developed to iteratively chart the results. A qualitative approach was conducted to thematically analyze the data. Themes included public understanding/attitudes toward death and determination of death (neurological determination and cardiocirculatory determination of death), death and organ donation, public trust and legal variability, and media impacts. Conclusions: This review provides a current and comprehensive overview of the literature related to the general public's understanding and attitudes toward death and death determination and serves to highlight the gaps in this topic.

Feasibility of implementing Extubation Advisor, a clinical decision support tool to improve extubation decision-making in the ICU: a mixed-methods observational study.

OBJECTIVES: Although spontaneous breathing trials (SBTs) are standard of care to extubation readiness, no tool exists that optimises prediction and standardises assessment. In this study, we evaluated the feasibility and clinical impressions of Extubation Advisor (EA), a comprehensive clinical extubation decision support (CDS) tool. DESIGN: Phase I mixed-methods observational study. SETTING: Two Canadian intensive care units (ICUs). PARTICIPANTS: We included patients on mechanical ventilation for ≥24 hours and clinicians (respiratory therapists and intensivists) responsible for extubation decisions. INTERVENTIONS: Components included a predictive model assessment, feasibility evaluation, questionnaires and interviews with clinicians. RESULTS: We enrolled 117 patients, totalling 151 SBTs and 80 extubations. The incidence of extubation failure was 11% in low-risk patients and 21% in high-risk patients stratified by the predictive model; 38% failed extubation when both the model and clinical impression were at high risk. The tool was well rated: 94% and 75% rated the data entry and EA report as average or better, respectively. Interviews (n=15) revealed favourable impressions regarding its user interface and functionality, but unexpectedly, also concerns regarding EA's potential impact on respiratory therapists' job security. CONCLUSIONS: EA implementation was feasible, and users perceived it to have potential to support extubation decision-making. This study helps to understand bedside implementation of CDS tools in a multidisciplinary ICU. TRIAL REGISTRATION NUMBER: NCT02988167.

Implementation and evaluation of "I-Guide," a pilot near-peer Internal Medicine mentorship program.

An Internal Medicine (IM) specific, near-peer mentorship program was initiated at the University of Ottawa (uOttawa) in 2017. Medical students were paired with IM resident mentors to improve career decision-making through student-oriented discussion topics. Program evaluation was completed using data from three participant cohorts and showed that the program had a positive impact on students' career decision-making. Given the program's flexible nature and ease of implementation, it is well suited for adaptation at other institutions.

Un programme de mentorat par les quasi-pairs spécifique à la médecine interne (MI), a été lancé à l'Université d'Ottawa en 2017. Les étudiants en médecine ont été jumelés avec des mentors résidents en MI afin d'aider les premiers à prendre des décisions concernant leur carrière par le biais de discussions sur des sujets d'intérêt pour eux. L'évaluation du programme, réalisée sur la base des données de trois cohortes de participants, a montré qu'il a eu un impact positif sur la prise de décisions des étudiants à propos de leur carrière. Étant donné la nature souple du programme et sa mise en œuvre facile, il peut être adapté sans difficulté au contexte d'autres établissements.

Impact of physician's sex/gender on processes of care, and clinical outcomes in cardiac operative care: a systematic review.

OBJECTIVES: This systematic review aimed to assess the role of physician's sex and gender in relation to processes of care and/or clinical outcomes within the context of cardiac operative care. DESIGN: A systematic review. DATA SOURCES: Searches were conducted in PsycINFO, Embase and Medline from inception to 6 September 2018. The reference lists of relevant systematic reviews and included studies were also searched. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Quantitative studies of any design were included if they were published in English or French, involved patients of any age undergoing a cardiac surgical procedure and specifically assessed differences in processes of care or clinical patient outcomes by physician's sex or gender. Studies were screened in duplicate by two pairs of independent reviewers. OUTCOME MEASURES: Processes of care, patient morbidity and patient mortality. RESULTS: The search yielded 2095 publications after duplicate removal, of which two were ultimately included. These studies involved various types of surgery, including cardiac. One study found that patients treated by female surgeons compared with male surgeons had a lower 30-day mortality. The other study, however, found no differences in patient outcomes by surgeon's sex. There were no studies that investigated anaesthesiologist's sex/gender. There were also no studies investing physician's sex or gender exclusively in the cardiac operating room. CONCLUSIONS: The limited data surrounding the impact of physician's sex/gender on the outcomes of cardiac surgery inhibits drawing a robust conclusion at this time. Results highlight the need for primary research to determine how these factors may influence cardiac operative practice, in order to optimise provider's performance and improve outcomes in this high-risk patient group.

A Scoping Review of Registered Clinical Trials of Convalescent Plasma for COVID-19 and a Framework for Accelerated Synthesis of Trial Evidence (FAST Evidence).

Many parallel studies of convalescent plasma with modest enrolment projections have been launched for the treatment of COVID-19. By pooling data from multiple parallel studies that are similar, we can increase the effective sample size and achieve enough statistical power to determine effectiveness more quickly through meta-analysis. A scoping review of registered clinical trials of convalescent plasma for COVID-19 was conducted to assess the feasibility of performing a rapid and timely meta-analysis that will support accelerated review for approval and implementation. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched April 23, 2020. Trials were included if they utilized convalescent plasma to treat or prevent COVID-19. Forty-eight registered trials (projected to enroll more than 5000 subjects) of convalescent plasma were identified and included for analysis. The majority of studies (33 studies with 4440 projected enrolment) will address the treatment of severe and/or critical cases of COVID-19. Twenty-nine studies are controlled and 17 of these are reported as actively recruiting. The combined enrolment of patients from similar studies should be sufficient to determine meaningful improvements in mortality, rates of admission to intensive care and need for mechanical ventilation by the end of 2020-sooner than any individual study could determine effectiveness. Accessing supplemental outcome data from investigators may be needed; however, to align reporting of some outcomes from these studies. Heterogeneity in product potency due to different antibody titers is anticipated and studies using conventional treatment as controls instead of placebo may complicate our understanding of efficacy. Convalescent plasma is being tested in ongoing controlled studies, largely to treat severe and/or critical cases of COVID-19. Sufficient combined power to detect clinically important reductions in multiple outcomes, including mortality, is expected by September 2020. Regulatory approval, funding and implementation by blood operators could be accelerated by planned meta-analysis as study results become available.

A Scoping Review of Registered Clinical Trials of Cellular Therapy for COVID-19 and a Framework for Accelerated Synthesis of Trial Evidence-FAST Evidence.

The urgent need for safe and effective treatments for COVID-19 has fueled the launch of many parallel complex studies of cellular therapies with small to modest enrolment projections. By pooling data from multiple studies that are similar, we can increase the ability to achieve sufficient power to determine effectiveness more quickly through meta-analysis. A scoping review of registered clinical trials using cell-based interventions for COVID-19 was conducted to identify candidate studies for meta-analysis that could support an accelerated regulatory review. ClinicalTrials.gov and WHO International Clinical Trials Registry Platform were searched April 23, 2020. Trials were included if they utilized cell or cell-derived products to treat or prevent COVID-19. Fifty-four registered cellular therapy trials were identified and included for analysis. Studies of mesenchymal stromal cells (MSCs; 41 studies; 1129 subjects projected to receive cells) and natural killer (NK) cells (5 studies; 135 projected to received cells) were observed most commonly. A subset of studies are controlled (34 studies, or 63%), including 27 studies of MSCs and 3 of NK cells. While heterogeneity in study design exists, the cumulative projected enrolment of patients from similar studies appears sufficient to allow the detection of meaningful differences in clinically important outcomes such as mortality, admission to intensive care and need for mechanical ventilation by September 2020-sooner than any individual study could determine effectiveness. MSCs are the predominant cell type in registered trials for severe or critical COVID-19 and represent the most promising candidates for future meta-analysis. Sufficient pooled sample size to detect clinically important reductions in multiple outcomes, including mortality, is anticipated by September 2020, but may require accessing supplementary data to align outcome reporting. Regulatory approval, funding and implementation by cell manufacturing partners will be accelerated by our framework for rapid meta-analysis.

Human endothelial colony-forming cells in regenerative therapy: A systematic review of controlled preclinical animal studies.

Endothelial colony-forming cells (ECFCs) hold significant promise as candidates for regenerative therapy of vascular injury. Existing studies remain largely preclinical and exhibit marked design heterogeneity. A systematic review of controlled preclinical trials of human ECFCs is needed to guide future study design and to accelerate clinical translation. A systematic search of Medline and EMBASE on 1 April 2019 returned 3131 unique entries of which 66 fulfilled the inclusion criteria. Most studies used ECFCs derived from umbilical cord or adult peripheral blood. Studies used genetically modified immunodeficient mice (n = 52) and/or rats (n = 16). ECFC phenotypes were inconsistently characterized. While >90% of studies used CD31+ and CD45-, CD14- was demonstrated in 73% of studies, CD146+ in 42%, and CD10+ in 35%. Most disease models invoked ischemia. Peripheral vascular ischemia (n = 29), central nervous system ischemia (n = 14), connective tissue injury (n = 10), and cardiovascular ischemia and reperfusion injury (n = 7) were studied most commonly. Studies showed predominantly positive results; only 13 studies reported ≥1 outcome with null results, three reported only null results, and one reported harm. Quality assessment with SYRCLE revealed potential sources of bias in most studies. Preclinical ECFC studies are associated with benefit across several ischemic conditions in animal models, although combining results is limited by marked heterogeneity in study design. In particular, characterization of ECFCs varied and aspects of reporting introduced risk of bias in most studies. More studies with greater focus on standardized cell characterization and consistency of the disease model are needed.

Patient-centred and family-centred care of critically ill patients who are potential organ donors: a qualitative study protocol of family member perspectives.

INTRODUCTION: In a patient-centred and family-centred approach to organ donation, compassion is paramount. Recent guidelines have called for more research, interventions and approaches aimed at improving and supporting the families of critically ill patients. The objective of this study is to help translate patient-centred and family-centred care into practice in deceased organ donation. METHODS AND ANALYSIS: This will be a national, qualitative study of family members of deceased organ donors in Canada. We will include family members who had been approached regarding an organ donation decision, including those who agreed and declined, at least 2 months and no later than 3 years after the patients' death. Data collection and analysis is ongoing and will continue until September 2020 to include approximately 250 participants. Family members will be identified and recruited from provincial organ donation organisation databases. Four experienced qualitative researchers will conduct telephone interviews in English or French with audio-recording for subsequent transcription. The research team will develop a codebook iteratively through this process using inductive methods, thus generating themes directly from the dataset. ETHICS AND DISSEMINATION: Local research ethics boards (REB) at all participating sites across Canada have approved this protocol. The main REB involved is the Ottawa Health Science Network REB. Data collection began in August 2018. Publication of results is anticipated in 2021. Study findings will help improve healthcare provider competency in caring for potential organ donors and their families and improve organ donation consent rates. Findings will also help with the development of educational materials for a competency-based curriculum for critical care residents.

Impressions of Early Mobilization of Critically Ill Children-Clinician, Patient, and Family Perspectives.

OBJECTIVES: To understand patient, family caregiver, and clinician impressions of early mobilization, the perceived barriers and facilitators to its implementation, and the use of in-bed cycling as a method of mobilization. DESIGN: A qualitative study, conducted as part of the Early Exercise in Critically ill Youth and Children, a preliminary Evaluation (wEECYCLE) Pilot randomized controlled trial. SETTING: McMaster Children's Hospital PICU, Hamilton, ON, Canada. PARTICIPANTS: Clinicians (i.e., physicians, nurses, and physiotherapists), family caregivers, and capable patients age greater than or equal to 8 years old who were enrolled in a clinical trial of early mobilization in critically ill children (wEECYCLE). INTERVENTION: Semistructured, face-to-face interviews using a customized interview guide for clinicians, caregivers, and patients respectively, conducted after exposure to the early mobilization intervention. MEASUREMENTS AND MAIN RESULTS: Thirty-seven participants were interviewed (19 family caregivers, four patients, and 14 clinicians). Family caregivers and clinicians described similar interrelated themes representing barriers to mobilization, namely low prioritization of mobilization by the medical team, safety concerns, the lack of physiotherapy resources, and low patient motivation. Key facilitators were family trust in the healthcare team, team engagement, an a priori belief that physical activity is important, and participation in research. Increased familiarity and specific features such as the virtual reality component and ability to execute passive and or active mobilization helped to engage critically ill children in in-bed cycling. CONCLUSIONS: Clinicians, patients, and families were highly supportive of mobilization in critically ill children; however, concerns were identified with respect to how and when to execute this practice. Understanding key stakeholder perspectives enables the development of strategies to facilitate the implementation of early mobilization and in-bed cycling, not just in the context of a clinical trial but also within the culture of practice in a PICU.

Early Exercise in Critically Ill Youth and Children, a Preliminary Evaluation: The wEECYCLE Pilot Trial.

OBJECTIVES: To determine the feasibility of conducting a full trial evaluating the efficacy of early mobilization using in-bed cycling as an adjunct to physiotherapy, on functional outcomes in critically ill children. DESIGN: Single center, pilot, randomized controlled trial. SETTING: Twelve-bed tertiary care, medical-surgical PICU at McMaster Children's Hospital, Hamilton, ON, Canada. PATIENTS: Children 3-17 years old who were limited to bed-rest with an expected PICU stay of at least 48 hours. Patients were excluded if they were at their baseline level of function, already mobilizing out of bed or expected to do so within 24 hours. INTERVENTIONS: Patients were randomized in a 2:1 ratio to early mobilization using in-bed cycling in addition to usual care physiotherapy (cycling arm) or to usual care physiotherapy alone (control). Usual care was according to institutional practice guidelines. The primary outcome was feasibility and safety. MEASUREMENTS AND MAIN RESULTS: Thirty patients were enrolled (20 to the cycling and 10 to control) over a 12-month period, at a 93.7% consent rate. The median (interquartile range) time from PICU admission to mobilization was 1.5 days (1-3) in the cycling arm and 2.5 days (2-7) in the control arm. Total duration of mobilization therapy in PICU was 210 (152-380) and 136 minutes (42-314 min) in cycling and control arms, respectively. Total number of PICU days mobilized was 5.0 (3-6) with cycling and 2.5 (2-4.8) with usual care. No adverse events occurred in either arm. The main threat to feasibility of mobilization was the availability of physiotherapists or research personnel. CONCLUSIONS: Early mobilization is safe and feasible in the PICU. In-bed cycling may facilitate greater duration and intensity of mobilization, in critically ill children. A full-scale randomized controlled trial is warranted to evaluate the efficacy of this intervention on PICU-acquired morbidities and functional outcomes in this population.