Publications by authors named "Kevin E Thorpe"

123 Publications

Adherence at 2 years with distribution of essential medicines at no charge: The CLEAN Meds randomized clinical trial.

PLoS Med 2021 May 21;18(5):e1003590. Epub 2021 May 21.

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

Background: Adherence to medicines is low for a variety of reasons, including the cost borne by patients. Some jurisdictions publicly fund medicines for the general population, but many jurisdictions do not, and such policies are contentious. To our knowledge, no trials studying free access to a wide range of medicines have been conducted.

Methods And Findings: We randomly assigned 786 primary care patients who reported not taking medicines due to cost between June 1, 2016 and April 28, 2017 to either free distribution of essential medicines (n = 395) or to usual medicine access (n = 391). The trial was conducted in Ontario, Canada, where hospital care and physician services are publicly funded for the general population but medicines are not. The trial population was mostly female (56%), younger than 65 years (83%), white (66%), and had a low income from wages as the primary source (56%). The primary outcome was medicine adherence after 2 years. Secondary outcomes included control of diabetes, blood pressure, and low-density lipoprotein (LDL) cholesterol in patients taking relevant treatments and healthcare costs over 2 years. Adherence to all appropriate prescribed medicines was 38.7% in the free distribution group and 28.6% in the usual access group after 2 years (absolute difference 10.1%; 95% confidence interval (CI) 3.3 to 16.9, p = 0.004). There were no statistically significant differences in control of diabetes (hemoglobin A1c 0.27; 95% CI -0.25 to 0.79, p = 0.302), systolic blood pressure (-3.9; 95% CI -9.9 to 2.2, p = 0.210), or LDL cholesterol (0.26; 95% CI -0.08 to 0.60, p = 0.130) based on available data. Total healthcare costs over 2 years were lower with free distribution (difference in median CAN$1,117; 95% CI CAN$445 to CAN$1,778, p = 0.006). In the free distribution group, 51 participants experienced a serious adverse event, while 68 participants in the usual access group experienced a serious adverse event (p = 0.091). Participants were not blinded, and some outcomes depended on participant reports.

Conclusions: In this study, we observed that free distribution of essential medicines to patients with cost-related nonadherence substantially increased adherence, did not affect surrogate health outcomes, and reduced total healthcare costs over 2 years.

Trial Registration: ClinicalTrials.gov NCT02744963.
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http://dx.doi.org/10.1371/journal.pmed.1003590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139488PMC
May 2021

Short-term intensive insulin as induction and maintenance therapy for the preservation of beta-cell function in early type 2 diabetes (RESET-IT Main): A 2-year randomized controlled trial.

Diabetes Obes Metab 2021 May 6. Epub 2021 May 6.

Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada.

Aim: To test the hypothesis that the addition of periodic courses of short-term intensive insulin therapy (IIT) could enhance the effect of metformin (MET) maintenance therapy on preservation of beta-cell function following induction IIT.

Methods: In this multicentre, randomized controlled trial, 108 adults with type 2 diabetes (median 1.3 years' duration; HbA1c 6.6% ± 0.6%) were randomized to 3 weeks of induction IIT (glargine, lispro) followed by MET maintenance, either with or without periodic 2-week courses of IIT every 3 months for 2 years. Beta-cell function was assessed by the Insulin Secretion Sensitivity Index-2 (ISSI-2) at an oral glucose tolerance test every 3 months.

Results: In both arms, induction IIT increased ISSI-2, improved whole-body insulin sensitivity and reduced hepatic insulin resistance (all P ≤ .0004). The primary outcome of baseline-adjusted ISSI-2 at 2 years was not improved by the addition of intermittent IIT (MET + IIT) and was slightly higher in the MET arm (baseline-adjusted difference -35 [95% CI: -66, -3]), with three additional beta-cell measures showing no significant differences. Baseline-adjusted HbA1c at 2 years did not differ between MET and MET + IIT (6.3% ± 0.1% vs. 6.4% ± 0.1%, P = .46), with 32.6% of participants in each arm maintaining HbA1c of 6.0% or less at 2 years.

Conclusion: Although initial induction IIT induces metabolic improvement, subsequent repeat courses of IIT every 3 months do not further enhance the effect of MET maintenance therapy on beta-cell function.
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http://dx.doi.org/10.1111/dom.14421DOI Listing
May 2021

Swallowing, Oral Motor, Motor Speech, and Language Impairments Following Acute Pediatric Ischemic Stroke.

Stroke 2021 Apr 1;52(4):1309-1318. Epub 2021 Mar 1.

Pediatric Stroke Program, Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada (V.S., I.B., G.D., N.D., D.M., E.P., M.M.).

Background And Purpose: Following adult stroke, dysphagia, dysarthria, and aphasia are common sequelae. Little is known about these impairments in pediatric stroke. We assessed frequencies, co-occurrence and associations of dysphagia, oral motor, motor speech, language impairment, and caregiver burden in pediatric stroke.

Methods: Consecutive acute patients from term birth-18 years, hospitalized for arterial ischemic stroke (AIS), and cerebral sinovenous thrombosis, from January 2013 to November 2018 were included. Two raters reviewed patient charts to detect documentation of in-hospital dysphagia, oral motor dysfunction, motor speech and language impairment, and caregiver burden, using a priori operational definitions for notation and assessment findings. Other variables abstracted included demographics, preexisting conditions, stroke characteristics, and discharge disposition. Impairment frequencies were obtained by univariate and bivariate analysis and associations by simple logistic regression.

Results: A total of 173 patients were stratified into neonates (N=67, mean age 2.9 days, 54 AIS, 15 cerebral sinovenous thrombosis) and children (N=106, mean age 6.5 years, 73 AIS, 35 cerebral sinovenous thrombosis). Derived frequencies of impairments included dysphagia (39% neonates, 41% children); oral motor (6% neonates, 41% children); motor speech (37% children); and language (31% children). Common overlapping impairments included oral motor and motor speech (24%) and dysphagia and motor speech (23%) in children. Associations were found only in children between stroke type (AIS over cerebral sinovenous thrombosis) and AIS severity (more severe deficit at presentation) for all impairments except feeding impairment alone. Caregiver burden was present in 58% patients.

Conclusions: For the first time, we systematically report the frequencies and associations of dysphagia, oral motor, motor speech, and language impairment during acute presentation of pediatric stroke, ranging from 30% to 40% for each impairment. Further research is needed to determine long-term effects of these impairments and to design standardized age-specific assessment protocols for early recognition following stroke.
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http://dx.doi.org/10.1161/STROKEAHA.120.031893DOI Listing
April 2021

Randomized Trial of Oral Iron and Diet Advice versus Diet Advice Alone in Young Children with Nonanemic Iron Deficiency.

J Pediatr 2021 Jun 4;233:233-240.e1. Epub 2021 Feb 4.

Applied Health Research Centre of the Li Ka Shing Knowledge Institute, Toronto, Ontario, Canada.

Objective: To compare the effects of 2 treatment options on neurodevelopmental and laboratory outcomes in young children with nonanemic iron deficiency.

Study Design: A blinded, placebo-controlled, randomized trial of children 1-3 years with nonanemic iron deficiency (hemoglobin ≥110 g/L, serum ferritin <14 μg/L) was conducted in 8 primary care practices in Toronto, Canada. Interventions included ferrous sulfate or placebo for 4 months; all parents received diet advice. The primary outcome was the Early Learning Composite (ELC) using the Mullen Scales of Early Learning (mean 100, SD 15). Secondary outcomes included serum ferritin. Measurements were obtained at baseline and 4 and 12 months. Sample size was calculated to detect a between-group difference of 6-7 points in ELC.

Results: At enrollment (n = 60), mean age was 24.2 (SD 7.4) months and mean serum ferritin was 10.0 (SD 2.4) μg/L. For ELC, the mean between-group difference at 4 months was 1.1 (95% CI -4.2 to 6.5) and at 12 months was 4.1 (95% CI -1.9 to 10.1). For serum ferritin, at 4 months, the mean between-group difference was 16.9 μg/L (95% CI 6.5 to 27.2), and no child randomized to ferrous sulfate had a serum ferritin <14 μg/L (0% vs 31%, P = .003).

Conclusions: For young children with nonanemic iron deficiency, treatment options include oral iron and/or diet advice. We remain uncertain about which option is superior with respect to cognitive outcomes; however, adding ferrous sulfate to diet advice resulted in superior serum ferritin outcomes after 4 months. Shared decision-making between practitioners and parents may be considered when selecting either option.

Trial Registration: Clinicaltrials.gov: NCT01481766.
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http://dx.doi.org/10.1016/j.jpeds.2021.01.073DOI Listing
June 2021

Empagliflozin Reduces Myocardial Extracellular Volume in Patients With Type 2 Diabetes and Coronary Artery Disease.

JACC Cardiovasc Imaging 2021 Jun 13;14(6):1164-1173. Epub 2021 Jan 13.

Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Division of Cardiology, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada. Electronic address:

Objectives: This study sought to evaluate the effects of empagliflozin on extracellular volume (ECV) in individuals with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD).

Background: Empagliflozin has been shown to reduce left ventricular mass index (LVMi) in patients with T2DM and CAD. The effects on myocardial ECV are unknown.

Methods: This was a prespecified substudy of the EMPA-HEART (Effects of Empagliflozin on Cardiac Structure in Patients with Type 2 Diabetes) CardioLink-6 trial in which 97 participants were randomized to receive empagliflozin 10 mg daily or placebo for 6 months. Data from 74 participants were included: 39 from the empagliflozin group and 35 from the placebo group. The main outcome was change in left ventricular ECV from baseline to 6 months determined by cardiac magnetic resonance (CMR). Other outcomes included change in LVMi, indexed intracellular compartment volume (iICV) and indexed extracellular compartment volume (iECV), and the fibrosis biomarkers soluble suppressor of tumorgenicity (sST2) and matrix metalloproteinase (MMP)-2.

Results: Baseline ECV was elevated in the empagliflozin group (29.6 ± 4.6%) and placebo group (30.6 ± 4.8%). Six months of empagliflozin therapy reduced ECV compared with placebo (adjusted difference: -1.40%; 95% confidence interval [CI]: -2.60 to -0.14%; p = 0.03). Empagliflozin therapy reduced iECV (adjusted difference: -1.5 ml/m; 95% CI: -2.6 to -0.5 ml/m; p = 0.006), with a trend toward reduction in iICV (adjusted difference: -1.7 ml/m; 95% CI: -3.8 to 0.3 ml/m; p = 0.09). Empagliflozin had no impact on MMP-2 or sST2.

Conclusions: In individuals with T2DM and CAD, 6 months of empagliflozin reduced ECV, iECV, and LVMi. No changes in MMP-2 and sST2 were seen. Further investigation into the mechanisms by which empagliflozin causes reverse remodeling is required. (Effects of Empagliflozin on Cardiac Structure in Patients With Type 2 Diabetes [EMPA-HEART]; NCT02998970).
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http://dx.doi.org/10.1016/j.jcmg.2020.10.017DOI Listing
June 2021

Impact of a tuberculosis treatment adherence intervention versus usual care on treatment completion rates: results of a pragmatic cluster randomized controlled trial.

Implement Sci 2020 12 11;15(1):107. Epub 2020 Dec 11.

Dignitas International, Zomba, Malawi.

Background: With the global shortage of skilled health workers estimated at 7.2 million, outpatient tuberculosis (TB) care is commonly task-shifted to lay health workers (LHWs) in many low- and middle-income countries where the shortages are greatest. While shown to improve access to care and some health outcomes including TB treatment outcomes, lack of training and supervision limit the effectiveness of LHW programs. Our objective was to refine and evaluate an intervention designed to address common causes of non-adherence to TB treatment and LHW knowledge and skills training needs.

Methods: We employed a pragmatic cluster randomized controlled trial. Participants included 103 health centres (HCs) providing TB care in four districts in Malawi, randomized 1:1 stratified by district and HC funding (Ministry of Health, non-Ministry funded). At intervention HCs, a TB treatment adherence intervention was implemented using educational outreach, a point-of-care reminder tool, and a peer support network. Clusters in the control arm provided usual care. The primary outcome was the proportion of patients with successful TB treatment (i.e., cure or treatment completion). We used a generalized linear mixed model, with district as a fixed effect and HC as a random effect, to compare proportions of patients with treatment success, among the trial arms, with adjustment for baseline differences.

Results: We randomized 51 HCs to the intervention group and 52 HCs to the control group. Four intervention and six control HCs accrued no eligible patients, and 371 of 1169 patients had missing outcome, HC, or demographic data, which left 74 HCs and 798 patients for analysis. Randomization group was not related to missing outcome, however, district, age, and TB type were significantly related and included in the primary analysis model. Among the 1153 patients with HC and demographic data, 297/605 (49%) and 348/548 (64%) in the intervention and control arms, respectively, had treatment success. The intervention had no significant effect on treatment success (adjusted odds ratio 1.35 [95% confidence interval 0.93-1.98]).

Conclusion: We found no significant effect of the intervention on TB treatment outcomes with high variability in implementation quality, highlighting important challenges to both scale-up and sustainability.

Trial Registration: ClinicalTrials.gov NCT02533089 . Registered August 20, 2015.
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http://dx.doi.org/10.1186/s13012-020-01067-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731739PMC
December 2020

Effets du climat et des interventions de santé publique sur la pandémie de COVID-19 : une étude de cohorte prospective.

CMAJ 2020 11;192(44):E1374-E1382

Centre de recherche en santé appliquée (Jüni, Rothenbühler, Bobos, Thorpe, da Costa, Slutsky) Institut du savoir Li Ka Shing, Hôpital St. Michael; Département de médecine et Institut des politiques, de la gestion et de l'évaluation de la santé (Jüni), Université de Toronto, Toronto, Ont.; Ava AG (Rothenbühler), Zürich, Suisse; Département des sciences de la santé et de la réadaptation (Bobos), Université Western, London, Ont.; École Dalla Lana de santé publique (Thorpe, Fisman, Gesink), Université de Toronto, Toronto, Ont.; Institut des soins de santé primaires (da Costa), Université de Berne, Suisse; Division interdépartmentale de médecine de soins intensifs (Slutsky), Université de Toronto, Toronto, Ont.

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http://dx.doi.org/10.1503/cmaj.200920-fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647477PMC
November 2020

Impact of MyDiabetesPlan, a Web-Based Patient Decision Aid on Decisional Conflict, Diabetes Distress, Quality of Life, and Chronic Illness Care in Patients With Diabetes: Cluster Randomized Controlled Trial.

J Med Internet Res 2020 09 30;22(9):e16984. Epub 2020 Sep 30.

South East Toronto Family Health Team (Toronto East Health Network), Toronto, ON, Canada.

Background: Person-centered care is critical for delivering high-quality diabetes care. Shared decision making (SDM) is central to person-centered care, and in diabetes care, it can improve decision quality, patient knowledge, and patient risk perception. Delivery of person-centered care can be facilitated with the use of patient decision aids (PtDAs). We developed MyDiabetesPlan, an interactive SDM and goal-setting PtDA designed to help individualize care priorities and support an interprofessional approach to SDM.

Objective: This study aims to assess the impact of MyDiabetesPlan on decisional conflict, diabetes distress, health-related quality of life, and patient assessment of chronic illness care at the individual patient level.

Methods: A two-step, parallel, 10-site cluster randomized controlled trial (first step: provider-directed implementation only; second step: both provider- and patient-directed implementation 6 months later) was conducted. Participants were adults 18 years and older with diabetes and 2 other comorbidities at 10 family health teams (FHTs) in Southwestern Ontario. FHTs were randomly assigned to MyDiabetesPlan (n=5) or control (n=5) through a computer-generated algorithm. MyDiabetesPlan was integrated into intervention practices, and clinicians (first step) followed by patients (second step) were trained on its use. Control participants received static generic Diabetes Canada resources. Patients were not blinded. Participants completed validated questionnaires at baseline, 6 months, and 12 months. The primary outcome at the individual patient level was decisional conflict; secondary outcomes were diabetes distress, health-related quality of life, chronic illness care, and clinician intention to practice interprofessional SDM. Multilevel hierarchical regression models were used.

Results: At the end of the study, the intervention group (5 clusters, n=111) had a modest reduction in total decisional conflicts compared with the control group (5 clusters, n=102; -3.5, 95% CI -7.4 to 0.42). Although there was no difference in diabetes distress or health-related quality of life, there was an increase in patient assessment of chronic illness care (0.7, 95% CI 0.4 to 1.0).

Conclusions: Use of goal-setting decision aids modestly improved decision quality and chronic illness care but not quality of life. Our findings may be due to a gap between goal setting and attainment, suggesting a role for optimizing patient engagement and behavioral support. The next steps include clarifying the mechanisms by which decision aids impact outcomes and revising MyDiabetesPlan and its delivery.

Trial Registration: ClinicalTrials.gov NCT02379078; https://clinicaltrials.gov/ct2/show/NCT02379078.
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http://dx.doi.org/10.2196/16984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557444PMC
September 2020

Impact of a Web-Based Clinical Decision Support System to Assist Practitioners in Addressing Physical Activity and/or Healthy Eating for Smoking Cessation Treatment: Protocol for a Hybrid Type I Randomized Controlled Trial.

JMIR Res Protoc 2020 Sep 29;9(9):e19157. Epub 2020 Sep 29.

Nicotine Dependence Services, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Background: Modifiable risk factors such as tobacco use, physical inactivity, and poor diet account for a significant proportion of the preventable deaths in Canada. These factors are also known to cluster together, thereby compounding the risks of morbidity and mortality. Given this association, smoking cessation programs appear to be well-suited for integration of health promotion activities for other modifiable risk factors. The Smoking Treatment for Ontario Patients (STOP) program is a province-wide smoking cessation program that currently encourages practitioners to deliver Screening, Brief Intervention, and Referral to treatment for patients who are experiencing depressive symptoms or consume excessive amounts of alcohol via a web-enabled clinical decision support system. However, there is no available clinical decision support system for physical inactivity and poor diet, which are among the leading modifiable risk factors for chronic diseases.

Objective: The aim of this study is to assess whether adding a computerized/web-enabled clinical decision support system for physical activity and diet to a smoking cessation program affects smoking cessation outcomes.

Methods: This study is designed as a hybrid type 1 effectiveness/implementation randomized controlled trial to evaluate a web-enabled clinical decision support system for supporting practitioners in addressing patients' physical activity and diet as part of smoking cessation treatment in a primary care setting. This design was chosen as it allows for simultaneous testing of the intervention, its delivery in target settings, and the potential for implementation in real-world situations. Intervention effectiveness will be measured using a two-arm randomized controlled trial. Health care practitioners will be unblinded to their patients' treatment allocation; however, patients will be blinded to whether their practitioner receives the clinical decision support system for physical activity and/or fruit/vegetable consumption. The evaluation of implementation will be guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework.

Results: Recruitment for the primary outcome of this study is ongoing and will be completed in November 2020. Results will be reported in March 2021.

Conclusions: The findings of the study will provide much needed insight into whether adding a computerized/web-enabled clinical decision support system for physical activity and diet to a smoking cessation program affects smoking cessation outcome. Furthermore, the implementation evaluation would provide insight into the feasibility of online-based interventions for physical activity and diet in a smoking cessation program. Addressing these risk factors simultaneously could have significant positive effects on chronic disease and cancer prevention.

Trial Registration: ClinicalTrials.gov NCT04223336; https://clinicaltrials.gov/ct2/show/NCT04223336.

International Registered Report Identifier (irrid): DERR1-10.2196/19157.
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http://dx.doi.org/10.2196/19157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556369PMC
September 2020

Efficacy of dexamethasone treatment for patients with the acute respiratory distress syndrome caused by COVID-19: study protocol for a randomized controlled superiority trial.

Trials 2020 Aug 16;21(1):717. Epub 2020 Aug 16.

Keenan Research Center for Biomedical Science at the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Canada.

Background: There are no specific generally accepted therapies for the coronavirus disease 2019 (COVID-19). The full spectrum of COVID-19 ranges from asymptomatic disease to mild respiratory tract illness to severe pneumonia, acute respiratory distress syndrome (ARDS), multisystem organ failure, and death. The efficacy of corticosteroids in viral ARDS remains unknown. We postulated that adjunctive treatment of established ARDS caused by COVID-19 with intravenous dexamethasone might change the pulmonary and systemic inflammatory response and thereby reduce morbidity, leading to a decrease in duration of mechanical ventilation and in mortality.

Methods/design: This is a multicenter, randomized, controlled, parallel, open-label, superiority trial testing dexamethasone in 200 mechanically ventilated adult patients with established moderate-to-severe ARDS caused by confirmed SARS-CoV-2 infection. Established ARDS is defined as maintaining a PaO/FiO ≤ 200 mmHg on PEEP ≥ 10 cmHO and FiO ≥ 0.5 after 12 ± 3 h of routine intensive care. Eligible patients will be randomly assigned to receive either dexamethasone plus standard intensive care or standard intensive care alone. Patients in the dexamethasone group will receive an intravenous dose of 20 mg once daily from day 1 to day 5, followed by 10 mg once daily from day 6 to day 10. The primary outcome is 60-day mortality. The secondary outcome is the number of ventilator-free days, defined as days alive and free from mechanical ventilation at day 28 after randomization. All analyses will be done according to the intention-to-treat principle.

Discussion: This study will assess the role of dexamethasone in patients with established moderate-to-severe ARDS caused by SARS-CoV-2.

Trial Registration: ClinicalTrials.gov NCT04325061 . Registered on 25 March 2020 as DEXA-COVID19.
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http://dx.doi.org/10.1186/s13063-020-04643-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429135PMC
August 2020

Timing of Initiation of Renal-Replacement Therapy in Acute Kidney Injury.

N Engl J Med 2020 07;383(3):240-251

From the Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta and Alberta Health Services, Edmonton (S.M.B.), the Division of Nephrology (R.W.), St. Michael's Hospital and the University of Toronto, Li Ka Shing Knowledge Institute (R.W., B.R.C., O.M.S., K.E.T.), Department of Medicine (R.W., O.M.S.), and Applied Health Research Centre (B.R.C., K.E.T.), St. Michael's Hospital, the Dalla Lana School of Public Health (K.E.T.), the Institute of Health Policy, Management, and Evaluation (R.W., B.R.C.), University of Toronto, and the Department of Critical Care Medicine, Sunnybrook Health Sciences Centre and the University of Toronto (N.K.J.A.), Toronto, the Department of Medicine, Université de Sherbrooke and Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Sherbrooke, Sherbrooke, QC (F.L.), the Division of Critical Care, Juravinski Hospital, McMaster University, Hamilton, ON (B.R.), and the Division of Nephrology, London Health Sciences Centre, London, ON (M.W.) - all in Canada; the Department of Intensive Care, Austin Hospital and Royal Melbourne Hospital, School of Medicine, University of Melbourne, Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University (R.B., A.D.N.), Melbourne, VIC, and the George Institute for Global Health, Concord Clinical School, Faculty of Medicine, University of Sydney, Sydney (M.P.G., A.Y.W.) - both in Australia; the Institute of Primary Health Care, University of Bern, Bern (B.R.C.), and the Department of Critical Care Medicine, CHU Vaudois, Lausanne (A.G.S.) - both in Switzerland; Hôpital Louis Mourier (D.D.) and Université Léonard de Vinci (S.G.), INSERM Unité UMR S1155, Sorbonne Université and Université de Paris, Paris, Hôpital Avicenne, Bobigny (S.G.), and Hôpital Universitaire François Mitterrand, Lipness Team, INSERM Research Center Lipids, Nutrition, Cancer-Unité Mixte de Recherche 1231 and Laboratoire d'Excellence LipSTIC, Centre d'Investigation Clinique-Epidemiologie Clinique, CHU Dijon-Bourgogne, and INSERM Centre d'Investigation Clinique 1432, Université de Bourgogne, Dijon (J.-P.Q.) - all in France; the Department of Critical Care Medicine, Peking Union Medical College Hospital, Beijing (B.D.), and the Department of Critical Care Medicine, Zhongda Hospital Southeast University, Nanjing (H.Q.) - both in China; the Department of Intensive Care, University of Ghent, Ghent, Belgium (E.A.H.); the Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, Medical University Innsbruck, Innsbruck, Austria (M.J.); Vita Salute San Raffaele University and IRCCS San Raffaele Scientific Institute, Milan (G.L.); the Divisions of Nephrology and Critical Care Medicine, University of California, San Francisco, San Francisco (K.D.L.); the Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, and the Regional Intensive Care Unit, Royal Victoria Hospital, Belfast (D.F.M.), and King's College London, Guy's and St. Thomas' Hospital, London (M.O.) - both in the United Kingdom; the Cardiothoracic and Vascular Intensive Care Unit, Auckland City Hospital, Auckland (S.P.M.), and the Medical Research Institute of New Zealand (S.P.M.) and the Intensive Care Unit, Wellington Regional Hospital and Medical Research Institute of New Zealand (P.Y.), Wellington - both in New Zealand; the Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington (J.A.N.); University College Dublin Clinical Research Centre at St. Vincent's University Hospital, Dublin (A.D.N.); the Division of Nephrology, University of Pittsburgh, and Veterans Affairs Pittsburgh Healthcare System, Pittsburgh (P.M.P.); the Department of Intensive Care, University of Helsinki, and Helsinki University Hospital, Helsinki (V.P., S.V.); Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil (F.T.); and the Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany (A.Z.).

Background: Acute kidney injury is common in critically ill patients, many of whom receive renal-replacement therapy. However, the most effective timing for the initiation of such therapy remains uncertain.

Methods: We conducted a multinational, randomized, controlled trial involving critically ill patients with severe acute kidney injury. Patients were randomly assigned to receive an accelerated strategy of renal-replacement therapy (in which therapy was initiated within 12 hours after the patient had met eligibility criteria) or a standard strategy (in which renal-replacement therapy was discouraged unless conventional indications developed or acute kidney injury persisted for >72 hours). The primary outcome was death from any cause at 90 days.

Results: Of the 3019 patients who had undergone randomization, 2927 (97.0%) were included in the modified intention-to-treat analysis (1465 in the accelerated-strategy group and 1462 in the standard-strategy group). Of these patients, renal-replacement therapy was performed in 1418 (96.8%) in the accelerated-strategy group and in 903 (61.8%) in the standard-strategy group. At 90 days, death had occurred in 643 patients (43.9%) in the accelerated-strategy group and in 639 (43.7%) in the standard-strategy group (relative risk, 1.00; 95% confidence interval [CI], 0.93 to 1.09; P = 0.92). Among survivors at 90 days, continued dependence on renal-replacement therapy was confirmed in 85 of 814 patients (10.4%) in the accelerated-strategy group and in 49 of 815 patients (6.0%) in the standard-strategy group (relative risk, 1.74; 95% CI, 1.24 to 2.43). Adverse events occurred in 346 of 1503 patients (23.0%) in the accelerated-strategy group and in 245 of 1489 patients (16.5%) in the standard-strategy group (P<0.001).

Conclusions: Among critically ill patients with acute kidney injury, an accelerated renal-replacement strategy was not associated with a lower risk of death at 90 days than a standard strategy. (Funded by the Canadian Institutes of Health Research and others; STARRT-AKI ClinicalTrials.gov number, NCT02568722.).
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http://dx.doi.org/10.1056/NEJMoa2000741DOI Listing
July 2020

Personalized dosing of nicotine replacement therapy versus standard dosing for the treatment of individuals with tobacco dependence: study protocol for a randomized placebo-controlled trial.

Trials 2020 Jun 29;21(1):592. Epub 2020 Jun 29.

Nicotine Dependence Services, Centre for Addiction and Mental Health, 175 College St, Toronto, Ontario, M5T 1P7, Canada.

Background: Medications for smoking cessation are currently only effective in helping a minority of smokers quit. Drug development is slow and expensive; as such, there is much interest in optimizing the effectiveness of existing treatments and medications. Current standard doses of nicotine replacement therapy are not effective for many smokers, and in many cases, the amount of nicotine provided is much less than when a smoker is smoking their usual number of cigarettes. The proposed study will test if titrating the dose of the nicotine patch (up to 84 mg) will improve quitting success compared to those receiving a 21-mg nicotine patch with increasing doses of placebo patch.

Methods: This is a multicenter, pragmatic, two-arm, placebo-controlled, block randomized controlled trial. We will recruit participants who smoke at least 10 cigarettes daily and are interested in making a quit attempt. After 2 weeks of usual treatment with a 21-mg patch, participants who fail to quit smoking (target n = 400) will be randomized to receive escalating doses of a nicotine patch vs matching placebo patches for an additional 10 weeks or up to a maximum dose of 84 mg per day. Those who stop smoking during the first 2 weeks of usual treatment will continue with 21 mg patch treatment for 10 weeks and will form an additional comparison arm. In addition to the medication, participants will receive brief behavioral counseling at each study visit. The primary outcome will be biochemically confirmed continuous abstinence from smoking during the last 4 weeks of treatment (weeks 9 to 12).

Discussion: Research evidence supporting the effectiveness of personalized doses of nicotine replacement therapy could change current practice in a variety of healthcare settings. Given the evidence that quitting smoking at any age diminishes the risk of tobacco-related morbidity and mortality, even small increases in absolute quit rates can have a substantial population-level impact on reducing smoking-related disease, mortality rates, and associated healthcare costs.

Trial Registration: ClinicalTrials.gov, NCT03000387 . Registered on 22 December 2016.
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http://dx.doi.org/10.1186/s13063-020-04532-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325031PMC
June 2020

Design and Rationale of the PACt-MD Randomized Clinical Trial: Prevention of Alzheimer's dementia with Cognitive remediation plus transcranial direct current stimulation in Mild cognitive impairment and Depression.

J Alzheimers Dis 2020 ;76(2):733-751

Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Background: By the time Alzheimer's disease and related disorders (ADRD) are diagnosed, efficacy of treatments is limited. Preventive interventions are urgently needed.

Objective: To design a randomized controlled trial to assess a novel intervention that aims to prevent ADRD in high-risk groups.

Methods: We report on the rationale and describe the design of a multisite randomized controlled trial that aims to prevent ADRD in older persons with: (1) mild cognitive impairment (MCI); (2) remitted major depressive disorder (MDD) without MCI; or (3) remitted MDD with MCI.

Results: PACt-MD (Prevention of Alzheimer's dementia with Cognitive remediation plus transcranial direct current stimulation in Mild cognitive impairment and Depression) is a trial that randomized 375 older participants with MCI, MDD, or MCI + MDD to cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) or sham-CR + sham-tDCS for 5 days/week for 8 weeks followed by boosters for 5 days/week once every 6 months until participants progress to MCI or ADRD, or the end of the study. Between boosters, participants are asked to train on CR daily. At baseline, end of 8 weeks, and yearly from baseline, participants undergo clinical, cognitive, and functional assessments. The primary aims are to compare the efficacy of CR + tDCS versus sham + sham in preventing: 1) long-term cognitive decline; and 2) incidence of ADRD or MCI. The secondary aim is to assess for cognitive improvement after the 8-week course. We will also explore the moderating and mediating effects of several biomarkers collected from the participants.

Conclusion: PACt-MD is unique in combining brain stimulation and a psychosocial intervention to prevent ADRD. PACt-MD is also a platform for studying multi-domain biomarkers that will advance our understanding of the relationships among MCI, MDD, and ADRD.
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http://dx.doi.org/10.3233/JAD-200141DOI Listing
May 2021

Vision-Related Functioning in Patients Undergoing Pneumatic Retinopexy vs Vitrectomy for Primary Rhegmatogenous Retinal Detachment: A Post Hoc Exploratory Analysis of the PIVOT Randomized Clinical Trial.

JAMA Ophthalmol 2020 08;138(8):826-833

Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, England.

Importance: Although rhegmatogenous retinal detachment (RRD) repair techniques have high anatomical reattachment rates, there may be differences in various aspects of postoperative vision-related quality of life (VRQoL).

Objective: To explore the differences in various aspects of VRQoL between pneumatic retinopexy (PnR) and pars plana vitrectomy (PPV) following RRD repair.

Design, Setting, And Participants: Post hoc exploratory analysis of the the Pneumatic Retinopexy vs Vitrectomy for the Management of Primary Rhegmatogenous Retinal Detachment Outcomes randomized clinical trial conducted between August 2012 and May 2017 at St Michael's Hospital, Toronto, Ontario, Canada. Patients with RRD with a single break or multiple breaks within 1 clock hour of detached retina in the superior 8 clock hours of the retina with any number, location, and size of retinal breaks or lattice degeneration in attached retina.

Main Outcomes And Measures: Differences in the 25-Item National Eye Institute Visual Function Questionnaire 12 subscale scores between the PnR and PPV groups at 6 months following RRD repair.

Results: A total of 160 patients were included in this analysis, with 81 patients (92%) and 79 patients (90%) in the PnR and PPV groups, respectively. The PnR group consisted of 32% women with a mean (SD) age of 60.9 (9.3) years, while the PPV group consisted of 38% women with a mean (SD) age of 60.3 (7.6) years. For the 152 patients with 6-month follow-up (75 patients in PnR [85%] and 77 patients in PPV [88%]), there was evidence for an association of PnR with superior vision-related functioning compared with PPV for several subscales. There were no differences between groups at 1 year. After adjusting for age, sex, baseline macular status, visual acuity in the nonstudy eye, and lens status, patients who underwent PnR had higher scores for distance activities (mean [SD] PnR, 88.7 [13.4]; PPV, 82.8 [17.1]; adjusted difference, 6.5; 95% CI, 1.6-11.4; P = .01), mental health (mean [SD] PnR, 84.3 [17.4]; PPV, 78.7 [21.1]; adjusted difference, 6.7; 95% CI, 0.4-13; P = .04), dependency (mean [SD] PnR, 96.1 [10.1]; PPV, 91.1 [18.6]; adjusted difference, 5.7; 95% CI, 0.6-10.8; P = .03), and peripheral vision (mean [SD] PnR, 91.6 [16.2]; PPV, 81.2 [24.4]; adjusted difference, 10.8; 95% CI, 4.3-17.4; P = .001) at 6 months.

Conclusions And Relevance: These findings demonstrate that patients undergoing PnR for RRD report higher mental health scores and superior vision-related functioning scores in several subscales of the 25-Item National Eye Institute Visual Function Questionnaire during the first 6 months postoperatively compared with PPV.

Trial Registration: ClinicalTrials.gov Identifier: NCT01639209.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.2007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303897PMC
August 2020

Association of preoperative spirometry with cardiopulmonary fitness and postoperative outcomes in surgical patients: .

EClinicalMedicine 2020 Jun 6;23:100396. Epub 2020 Jun 6.

Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada.

Background: Preoperative spirometry and cardiopulmonary exercise testing (CPET) may stratify risk for respiratory complications. This secondary analysis of the Measurement of Exercise Tolerance before Surgery (METS) study examined whether CPET performance (i.e., cardiopulmonary fitness) confounds associations of spirometry with outcomes.

Methods: The analysis included 1200 participants having major non-cardiac surgery at 25 hospitals in Canada, Australia, New Zealand and UK. Forced expiratory volume in 1 s (FEV), and ratio of FEV to forced vital capacity (FVC) were measured during preoperative spirometry, and peak oxygen consumption and ventilatory efficiency during preoperative CPET. Outcomes were respiratory morbidity (Postoperative Morbidity Survey) and pulmonary complications (pneumonia or respiratory failure). We used multivariable logistic regression models to estimate associations of FEV with outcomes after adjustment for risk factors and either peak oxygen consumption or ventilatory efficiency.

Findings: 128 participants (11%) developed respiratory morbidity, and 48 (4%) developed pulmonary complications. There was no strong evidence that FEV predicted respiratory morbidity after adjustment for peak oxygen consumption ( = 0·80) or ventilatory efficiency ( = 0·76), or FEV predicted pulmonary complications after adjustment for ventilatory efficiency ( = 0·37). Peak oxygen consumption (odds ratio 0·66 per 5 mL/kg/min increase; 95% CI, 0·54-0·82) was associated with respiratory morbidity. Ventilatory efficiency was associated with respiratory morbidity ( = 0·04) and pulmonary complications ( = 0·02). Peak oxygen consumption also confounded the association between FEV and respiratory morbidity.

Interpretation: After accounting for fitness and clinical factors, FEV was not strongly predictive of respiratory complications. Prior associations between FEV and respiratory morbidity may be explained by confounding by peak oxygen consumption.

Funding: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research, Innovation and Science, UK National Institute of Academic Anaesthesia, UK Clinical Research Collaboration, Australian and New Zealand College of Anaesthetists, and Monash University.
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http://dx.doi.org/10.1016/j.eclinm.2020.100396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280772PMC
June 2020

Impact of climate and public health interventions on the COVID-19 pandemic: a prospective cohort study.

CMAJ 2020 05 8;192(21):E566-E573. Epub 2020 May 8.

Applied Health Research Centre (Jüni, Rothenbühler, Bobos, Thorpe, da Costa, Slutsky) Li Ka Shing Knowledge Institute of St. Michael's Hospital; Department of Medicine and Institute of Health Policy, Management and Evaluation (Jüni), University of Toronto, Toronto, Ont.; Ava AG (Rothenbühler), Zürich, Switzerland; Department of Health and Rehabilitation Sciences (Bobos), Western University, London, Ont.; Dalla Lana School of Public Health (Thorpe, Fisman, Gesink), University of Toronto, Toronto, Ont.; Institute of Primary Health Care (da Costa), University of Bern, Switzerland; Interdepartmental Division of Critical Care Medicine (Slutsky), University of Toronto, Toronto, Ont.

Background: It is unclear whether seasonal changes, school closures or other public health interventions will result in a slowdown of the current coronavirus disease 2019 (COVID-19) pandemic. We aimed to determine whether epidemic growth is globally associated with climate or public health interventions intended to reduce transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Methods: We performed a prospective cohort study of all 144 geopolitical areas worldwide (375 609 cases) with at least 10 COVID-19 cases and local transmission by Mar. 20, 2020, excluding China, South Korea, Iran and Italy. Using weighted random-effects regression, we determined the association between epidemic growth (expressed as ratios of rate ratios [RRR] comparing cumulative counts of COVID-19 cases on Mar. 27, 2020, with cumulative counts on Mar. 20, 2020) and latitude, temperature, humidity, school closures, restrictions of mass gatherings, and measures of social distancing during an exposure period 14 days previously (Mar. 7 to 13, 2020).

Results: In univariate analyses, there were no associations of epidemic growth with latitude and temperature, but weak negative associations with relative humidity (RRR per 10% 0.91, 95% confidence interval [CI] 0.85-0.96) and absolute humidity (RRR per 5 g/m 0.92, 95% CI 0.85-0.99). Strong associations were found for restrictions of mass gatherings (RRR 0.65, 95% CI 0.53-0.79), school closures (RRR 0.63, 95% CI 0.52-0.78) and measures of social distancing (RRR 0.62, 95% CI 0.45-0.85). In a multivariable model, there was a strong association with the number of implemented public health interventions ( for trend = 0.001), whereas the association with absolute humidity was no longer significant.

Interpretation: Epidemic growth of COVID-19 was not associated with latitude and temperature, but may be associated weakly with relative or absolute humidity. Conversely, public health interventions were strongly associated with reduced epidemic growth.
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http://dx.doi.org/10.1503/cmaj.200920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259972PMC
May 2020

Predictors of remission after repetitive transcranial magnetic stimulation for the treatment of major depressive disorder: An analysis from the randomised non-inferiority THREE-D trial.

EClinicalMedicine 2020 May 30;22:100349. Epub 2020 Apr 30.

Temerty Centre for Therapeutic Brain Intervention and Campbell Family Research Institute, Centre for Addiction and Mental Health, 1001 Queen St. W., Unit 4-115, Toronto, ON M6J1H4, Canada.

Background: Although repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depressive disorder (MDD), treatment selection is still mainly a process of trial-and-error. The present study aimed to identify clinical predictors of remission after a course of rTMS delivered to the left DLPFC to improve patient selection.

Methods: Data from a large randomised non-inferiority trial comparing standard 10 Hz and intermittent theta burst stimulation (iTBS) for the treatment of MDD were used for the exploratory analyses. Individual variables were assessed for their association with remission and then included in a logistic regression model to determine odds ratios (OR) and corresponding 95% confidence intervals. Model discrimination (internal validation) was carried out to assess model optimism using the c-index. ClinicalTrials.gov identifier: NCT01887782.

Findings: 388 subjects were included in the analysis (199-iTBS and 189-10 Hz, respectively). Higher baseline severity of both depressive and anxiety symptoms were associated with a lower chance of achieving remission (OR=0.64, 95% CI 0.46-0.88; and 0.78, 95% CI 0·60-0.98, respectively). Current employment was a positive predictor for remission (OR=1.69, 95% CI 1.06-2.7), while greater number of treatment failures was associated with lower odds of achieving remission (OR=0.51, 95% CI 0.27-0.98). A non-linear effect of age and remission was observed. An analysis to allow an estimate of the probability of remission using all variables was assessed. The c-index for the fitted model was 0.687.

Interpretation: Our results suggest that measuring depression symptom severity, employment status, and refractoriness are important in prognosticating outcome to a course of rTMS in MDD.

Funding: Canadian Institutes of Health Research MOP-136801.
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http://dx.doi.org/10.1016/j.eclinm.2020.100349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200243PMC
May 2020

Subomohyoid Anterior Suprascapular Block versus Interscalene Block for Arthroscopic Shoulder Surgery: A Multicenter Randomized Trial.

Anesthesiology 2020 04;132(4):839-853

From the Department of Anesthesiology and Pain Medicine, and the Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada (F.W.A.) the Department of Anesthesia (F.W.A., D.N.W., R.B., A.M., V.W.S.C.) the Institute of Health Policy, Management, and Evaluation (D.N.W., A.L.) the Department of Medicine (A.L.) the Dalla Lana School of Public Health (K.E.T.), University of Toronto, Toronto, Canada the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Canada (F.W.A., D.N.W., A.L.) the Department of Anesthesia (D.N.W.) the Department of Medicine (A.L.), St. Michael's Hospital, Toronto, Canada the Department of Anesthesia and Pain Management, University Health Network, Toronto, Canada (D.N.W., V.W.S.C.) the Department of Anesthesia, Women's College Hospital, Toronto, Canada (R.B.) the Department of Anesthesia, North York General Hospital, Toronto, Canada (A.M.) the Department of Anesthesia, Wexner Medical Center, Ohio State University, Columbus, Ohio (N.H.) the Applied Health Research Centre, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Canada (K.E.T.).

Background: Interscalene brachial plexus block, the pain relief standard for shoulder surgery, is an invasive technique associated with important complications. The subomohyoid anterior suprascapular block is a potential alternative, but evidence of its comparative analgesic effect is sparse. The authors tested the hypothesis that anterior suprascapular block is noninferior to interscalene block for improving pain control after shoulder surgery. As a secondary objective, the authors evaluated the success of superior trunk (C5-C6 dermatomes) block with suprascapular block.

Methods: In this multicenter double-blind noninferiority randomized trial, 140 patients undergoing shoulder surgery were randomized to either interscalene or anterior suprascapular block with 15 ml of ropivacaine 0.5% and epinephrine. The primary outcome was area under the curve of postoperative visual analog scale pain scores during the first 24 h postoperatively. The 90% CI for the difference (interscalene-suprascapular) was compared against a -4.4-U noninferiority margin. Secondary outcomes included presence of superior trunk blockade, pain scores at individual time points, opioid consumption, time to first analgesic request, opioid-related side-effects, and quality of recovery.

Results: A total of 136 patients were included in the analysis. The mean difference (90% CI) in area under the curve of pain scores for the (interscalene-suprascapular) comparison was -0.3 U (-0.8 to 0.12), exceeding the noninferiority margin of -4.4 U and demonstrating noninferiority of suprascapular block. The risk ratio (95% CI) of combined superior trunk (C5-C6 dermatomes) blockade was 0.98 (0.92 to 1.01), excluding any meaningful difference in superior trunk block success rates between the two groups. When differences in other analgesic outcomes existed, they were not clinically important.

Conclusions: The suprascapular block was noninferior to interscalene block with respect to improvement of postoperative pain control, and also for blockade of the superior trunk. These findings suggest that the suprascapular block consistently blocks the superior trunk and qualify it as an effective interscalene block alternative.
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http://dx.doi.org/10.1097/ALN.0000000000003132DOI Listing
April 2020

Effectiveness of Intrapleural Tissue Plasminogen Activator and Dornase Alfa vs Tissue Plasminogen Activator Alone in Children with Pleural Empyema: A Randomized Clinical Trial.

JAMA Pediatr 2020 04;174(4):332-340

Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

Importance: Clinical guidelines recommend that children with pleural empyema be treated with chest tube insertion and intrapleural fibrinolytics. The addition of dornase alfa (DNase) has been reported to improve outcomes in adults but remains unproven in children.

Objective: To determine if intrapleural tissue plasminogen activator (tPA) and DNase is more effective than tPA and placebo at reducing hospital length of stay in children with pleural empyema.

Design, Setting, And Participants: This multicenter, parallel-group, placebo-controlled, superiority randomized clinical trial included children diagnosed as having pleural empyema requiring drainage aged 6 months to 18 years treated at 6 tertiary Canadian children's hospitals. A total of 379 children were assessed for eligibility; 281 were excluded and 98 were randomized. One child was excluded after randomization for not meeting the inclusion criteria. Data were collected from March 4, 2013, to December 13, 2017.

Interventions: Participants underwent chest tube insertion and 3 daily administrations of intrapleural tPA, 4 mg, followed by DNase, 5 mg (intervention group), or 5 mL of normal saline (placebo; control group). Participants, families, clinical staff, and members of the study team were blinded to allocation.

Main Outcomes And Measures: The primary outcome was hospital length of stay from chest tube insertion to discharge. Secondary outcomes included time to meeting discharge criteria, time to chest tube removal, mean fever duration, additional pleural drainage procedures, hospital readmissions, and total health care cost.

Results: Of the 97 analyzed children with pleural empyema, 52 (54%) were male, and the mean (SD) age was 5.1 (3.6) years. A total of 49 children were randomized to tPA and DNase and 48 were randomized to tPA and placebo. Treatment with tPA and DNase was not associated with decreased hospital length of stay compared with tPA and placebo (mean [SD] length of stay, 9.0 [4.9] vs 9.1 [5.3] days; mean difference, -0.1 days; 95% CI, -2.0 to 2.1; P = .96). Similarly, no significant differences were observed for any of the secondary outcomes. Of the 14 adverse events in the tPA and DNase group, 6 (43%) were serious; of the 21 adverse events in the tPA and placebo group, 8 (38%) were serious. There were no deaths.

Conclusions And Relevance: The addition of DNase to intrapleural tPA for children with pleural empyema had no effect on hospital length of stay or other outcomes compared with tPA with placebo. Clinical practice guidelines should continue to support the use of chest tube insertion and intrapleural fibrinolytics alone as first-line treatment for pediatric empyema.

Trial Registration: ClinicalTrials.gov identifier: NCT01717742.
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http://dx.doi.org/10.1001/jamapediatrics.2019.5863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042898PMC
April 2020

Whole milk compared with reduced-fat milk and childhood overweight: a systematic review and meta-analysis.

Am J Clin Nutr 2020 02;111(2):266-279

Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.

Background: The majority of children in North America consume cow-milk daily. Children aged >2 y are recommended to consume reduced-fat (0.1-2%) cow-milk to lower the risk of obesity.

Objectives: To evaluate the relation between cow-milk fat consumption and adiposity in children aged 1-18 y.

Methods: Embase (Excerpta Medica Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), MEDLINE, Scopus, and Cochrane Library databases from inception to August 2019 were used. The search included observational and interventional studies of healthy children aged 1-18 y that described the association between cow-milk fat consumption and adiposity. Two reviewers extracted data, using the Newcastle-Ottawa Scale to assess risk of bias. Meta-analysis was conducted using random effects to evaluate the relation between cow-milk fat and risk of overweight or obesity. Adiposity was assessed using BMI z-score (zBMI).

Results: Of 5862 reports identified by the search, 28 met the inclusion criteria: 20 were cross-sectional and 8 were prospective cohort. No clinical trials were identified. In 18 studies, higher cow-milk fat consumption was associated with lower child adiposity, and 10 studies did not identify an association. Meta-analysis included 14 of the 28 studies (n = 20,897) that measured the proportion of children who consumed whole milk compared with reduced-fat milk and direct measures of overweight or obesity. Among children who consumed whole (3.25% fat) compared with reduced-fat (0.1-2%) milk, the OR of overweight or obesity was 0.61 (95% CI: 0.52, 0.72; P < 0.0001), but heterogeneity between studies was high (I2 = 73.8%).

Conclusions: Observational research suggests that higher cow-milk fat intake is associated with lower childhood adiposity. International guidelines that recommend reduced-fat milk for children might not lower the risk of childhood obesity. Randomized trials are needed to determine which cow-milk fat minimizes risk of excess adiposity. This systematic review and meta-analysis was registered with PROSPERO (registration number: CRD42018085075).
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http://dx.doi.org/10.1093/ajcn/nqz276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997094PMC
February 2020

Effectiveness of the Genomics ADvISER decision aid for the selection of secondary findings from genomic sequencing: a randomized clinical trial.

Genet Med 2020 04 11;22(4):727-735. Epub 2019 Dec 11.

Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.

Purpose: To evaluate the effectiveness of the Genomics ADvISER (www.genomicsadviser.com) decision aid (DA) for selection of secondary findings (SF), compared with genetic counseling alone.

Methods: A randomized controlled trial (RCT) was conducted to evaluate whether the Genomics ADvISER is superior to genetic counseling when hypothetically selecting SF. Participants were randomized to use the DA followed by discussion with a genetic counselor, or to genetic counseling alone. Surveys were administered at baseline and post-intervention. Primary outcome was decisional conflict. Secondary outcomes were knowledge, preparation for, and satisfaction with decision-making, anxiety, and length of counseling session.

Results: Participants (n = 133) were predominantly White/European (74%), female (90%), and ≥50 years old (60%). Decisional conflict (mean difference 0.05; P = 0.60), preparation for decision-making (0.17; P = 0.95), satisfaction with decision (-2.18; P = 0.06), anxiety (0.72; P = 0.56), and knowledge of sequencing limitations (0.14; P = 0.70) did not significantly differ between groups. However, intervention participants had significantly higher knowledge of SF (0.39; P < 0.001) and sequencing benefits (0.97; P = 0.01), and significantly shorter counseling time (24.40 minutes less; P < 0.001) CONCLUSIONS: The Genomics ADvISER did not decrease decisional conflict but reduced counseling time and improved knowledge. This decision aid could serve as an educational tool, reducing in-clinic time and potentially health care costs.
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http://dx.doi.org/10.1038/s41436-019-0702-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425118PMC
April 2020

Association between Serum Ferritin and Cognitive Function in Early Childhood.

J Pediatr 2020 02 2;217:189-191.e2. Epub 2019 Nov 2.

Applied Health Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

In infants 1-3 years of age, we found higher serum ferritin values associated with higher cognitive function, as measured by the Mullen Scales of Early Learning (P = .02 for the nonlinear relationship). A serum ferritin of 17 μg/L corresponded to the maximum level of cognition, beyond which there was no meaningful improvement. TRIAL REGISTRATION: Clinicaltrials.gov NCT01481766 and NCT01869530.
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http://dx.doi.org/10.1016/j.jpeds.2019.09.051DOI Listing
February 2020

The Avoiding Diabetes After Pregnancy Trial in Moms Program: Feasibility of a Diabetes Prevention Program for Women With Recent Gestational Diabetes Mellitus.

Can J Diabetes 2019 Dec 25;43(8):613-620. Epub 2019 Sep 25.

Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada; Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, Ontario, Canada.

Objective: Our aim in this study was to evaluate the feasibility of a home-based diabetes prevention program, delivered by interdisciplinary certified diabetes educators (CDEs), and customized for postpartum women with recent gestational diabetes mellitus (GDM).

Methods: This pilot randomized trial recruited women with GDM from 24 to 40 weeks gestation from 4 centres, and trained 10 CDEs in behaviour coaching, physical activity (PA) and low glycemic index education. Women were randomized after 3 months postpartum to standard care (1 visit) or 1 of 3 24-week coaching interventions (1 visit and 12 telephone calls): i) PA and diet, ii) PA only or iii) diet only. Feasibility outcomes included recruitment, retention, adherence and satisfaction.

Results: Of 1,342 eligible patients, 392 were actively invited (29.3%) and 227 (16.9%) consented. Of these, 149 (65.6%) were randomized postpartum, of whom 131 (87.9%) started the program and 105 (70.5%) attended the final assessment. Intervention arm participants completed a median 75% (interquartile range, 50% to 92%) of telephone calls. Visit and call duration were a mean 71.4 (standard deviation, 13.8) and 18.1 (standard deviation, 6.5) minutes, respectively. Participants reported excellent/very good satisfaction 73% of the time, and 87% would recommend the program to others.

Conclusions: A home-based diabetes prevention program customized for postpartum women with GDM can be feasibly delivered by CDEs, and it is associated with >70% retention, adherence and satisfaction.
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http://dx.doi.org/10.1016/j.jcjd.2019.08.019DOI Listing
December 2019

Health outcomes, utility and costs of returning incidental results from genomic sequencing in a Canadian cancer population: protocol for a mixed-methods randomised controlled trial.

BMJ Open 2019 10 7;9(10):e031092. Epub 2019 Oct 7.

Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada

Introduction: Genomic sequencing has rapidly transitioned into clinical practice, improving diagnosis and treatment options for patients with hereditary disorders. However, large-scale implementation of genomic sequencing faces challenges, especially with regard to the return of incidental results, which refer to genetic variants uncovered during testing that are unrelated to the primary disease under investigation, but of potential clinical significance. High-quality evidence evaluating health outcomes and costs of receiving incidental results is critical for the adoption of genomic sequencing into clinical care and to understand the unintended consequences of adoption of genomic sequencing. We aim to evaluate the health outcomes and costs of receiving incidental results for patients undergoing genomic sequencing.

Methods And Analysis: We will compare health outcomes and costs of receiving, versus not receiving, incidental results for adult patients with cancer undergoing genomic sequencing in a mixed-methods randomised controlled trial. Two hundred and sixty patients who have previously undergone first or second-tier genetic testing for cancer and received uninformative results will be recruited from familial cancer clinics in Toronto, Ontario. Participants in both arms will receive cancer-related results. Participants in the intervention arm have the option to receive incidental results. Our primary outcome is psychological distress at 2 weeks following return of results. Secondary outcomes include behavioural consequences, clinical and personal utility assessed over the 12 months after results are returned and health service use and costs at 12 months and 5 years. A subset of participants and providers will complete qualitative interviews about utility of incidental results.

Ethics And Dissemination: This study has been approved by Clinical Trials Ontario Streamlined Research Ethics Review System that provides ethical review and oversight for multiple sites participating in the same clinical trial in Ontario.Results from the trial will be shared through stakeholder workshops, national and international conferences, and peer-reviewed journals.

Trial Registration Number: NCT03597165.
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http://dx.doi.org/10.1136/bmjopen-2019-031092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797333PMC
October 2019

Effect on Treatment Adherence of Distributing Essential Medicines at No Charge: The CLEAN Meds Randomized Clinical Trial.

JAMA Intern Med 2019 Oct 7. Epub 2019 Oct 7.

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

Importance: Nonadherence to treatment with medicines is common globally, even for life-saving treatments. Cost is one important barrier to access, and only some jurisdictions provide medicines at no charge to patients.

Objective: To determine whether providing essential medicines at no charge to outpatients who reported not being able to afford medicines improves adherence.

Design, Setting, And Participants: A multicenter, unblinded, parallel, 2-group, superiority, outcomes assessor-blinded, individually randomized clinical trial conducted at 9 primary care sites in Ontario, Canada, enrolled 786 patients between June 1, 2016, and April 28, 2017, who reported cost-related nonadherence. Follow-up occurred at 12 months. The primary analysis was performed using an intention-to-treat principle.

Interventions: Patients were randomly allocated to receive free medicines on a list of essential medicines in addition to otherwise usual care (n = 395) or usual medicine access and usual care (n = 391).

Main Outcomes And Measures: The primary outcome was adherence to treatment with all medicines that were appropriately prescribed for 1 year. Secondary outcomes were hemoglobin A1c level, blood pressure, and low-density lipoprotein cholesterol levels 1 year after randomization in participants taking corresponding medicines.

Results: Among the 786 participants analyzed (439 women and 347 men; mean [SD] age, 51.7 [14.3] years), 764 completed the trial. Adherence to treatment with all medicines was higher in those randomized to receive free distribution (151 of 395 [38.2%]) compared with usual access (104 of 391 [26.6%]; difference, 11.6%; 95% CI, 4.9%-18.4%). Control of type 1 and 2 diabetes was not significantly improved by free distribution (hemoglobin A1c, -0.38%; 95% CI, -0.76% to 0.00%), systolic blood pressure was reduced (-7.2 mm Hg; 95% CI, -11.7 to -2.8 mm Hg), and low-density lipoprotein cholesterol levels were not affected (-2.3 mg/dL; 95% CI, -14.7 to 10.0 mg/dL).

Conclusions And Relevance: The distribution of essential medicines at no charge for 1 year increased adherence to treatment with medicines and improved some, but not other, disease-specific surrogate health outcomes. These findings could help inform changes to medicine access policies such as publicly funding essential medicines.

Trial Registration: ClinicalTrials.gov identifier: NCT02744963.
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http://dx.doi.org/10.1001/jamainternmed.2019.4472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784757PMC
October 2019

A qualitative study to understand parent and physician perspectives about cow's milk fat for children.

Public Health Nutr 2019 11 2;22(16):3017-3024. Epub 2019 Sep 2.

Department of Nutritional Sciences, University of Toronto, Toronto,Canada.

Objective: Consensus guidelines recommend that children consume reduced-fat (0·1-2 %) cow's milk at age 2 years to reduce the risk of obesity. Behaviours and perspectives of parents and physicians about cow's milk fat for children are unknown. Objectives were to: (i) understand what cow's milk fat recommendations physicians provide to 2-year-old children; (ii) assess the acceptability of reduced-fat v. whole cow's milk in children's diets by parents and physicians; and (iii) explore attitudes and perceptions about cow's milk fat for children.

Design: Online questionnaires and individual interviews were conducted. Questionnaire data were analysed using descriptive statistics. Interview transcripts were analysed using a general inductive approach and thematic analysis.

Setting: The TARGet Kids! practice-based research network in Toronto, Canada.

Participants: Questionnaire respondents included fifty parents and fifteen physicians; individual interviews were conducted with with fourteen parents and twelve physicians.

Results: Physicians provided various milk fat recommendations for 2-year-old children. Parents also provided different cow's milks: eighteen (36 %) provided whole milk and twenty-nine (58 %) provided reduced-fat milk. Analysis of qualitative interviews revealed three themes: (i) healthy eating behaviours, (ii) trustworthy nutrition information and (iii) importance of dietary fat for children.

Conclusions: Parents provide, and physicians recommend, a variety of cow's milks for children and hold mixed interpretations of the role of cow's milk fat in children's diets. Clarity about its effect on child adiposity is needed to help make informed decisions about cow's milk fat for children.
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http://dx.doi.org/10.1017/S136898001900243XDOI Listing
November 2019

Effect of Recombinant Activated Coagulation Factor VII on Hemorrhage Expansion Among Patients With Spot Sign-Positive Acute Intracerebral Hemorrhage: The SPOTLIGHT and STOP-IT Randomized Clinical Trials.

JAMA Neurol 2019 12;76(12):1493-1501

Department of Neurology, University of Cincinnati Academic Health Center, Cincinnati, Ohio.

Importance: Intracerebral hemorrhage (ICH) is a devastating stroke type that lacks effective treatments. An imaging biomarker of ICH expansion-the computed tomography (CT) angiography spot sign-may identify a subgroup that could benefit from hemostatic therapy.

Objective: To investigate whether recombinant activated coagulation factor VII (rFVIIa) reduces hemorrhage expansion among patients with spot sign-positive ICH.

Design, Setting, And Participants: In parallel investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trials in Canada ("Spot Sign" Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy [SPOTLIGHT]) and the United States (The Spot Sign for Predicting and Treating ICH Growth Study [STOP-IT]) with harmonized protocols and a preplanned individual patient-level pooled analysis, patients presenting to the emergency department with an acute primary spontaneous ICH and a spot sign on CT angiography were recruited. Data were collected from November 2010 to May 2016. Data were analyzed from November 2016 to May 2017.

Interventions: Eligible patients were randomly assigned 80 μg/kg of intravenous rFVIIa or placebo as soon as possible within 6.5 hours of stroke onset.

Main Outcomes And Measures: Head CT at 24 hours assessed parenchymal ICH volume expansion from baseline (primary outcome) and total (ie, parenchymal plus intraventricular) hemorrhage volume expansion (secondary outcome). The pooled analysis compared hemorrhage expansion between groups by analyzing 24-hour volumes in a linear regression model adjusted for baseline volumes, time from stroke onset to treatment, and trial.

Results: Of the 69 included patients, 35 (51%) were male, and the median (interquartile range [IQR]) age was 70 (59-80) years. Baseline median (IQR) ICH volumes were 16.3 (9.6-39.2) mL in the rFVIIa group and 20.4 (8.6-32.6) mL in the placebo group. Median (IQR) time from CT to treatment was 71 (57-96) minutes, and the median (IQR) time from stroke onset to treatment was 178 (138-197) minutes. The median (IQR) increase in ICH volume from baseline to 24 hours was small in both the rFVIIa group (2.5 [0-10.2] mL) and placebo group (2.6 [0-6.6] mL). After adjustment, there was no difference between groups on measures of ICH or total hemorrhage expansion. At 90 days, 9 of 30 patients in the rFVIIa group and 13 of 34 in the placebo group had died or were severely disabled (P = .60).

Conclusions And Relevance: Among patients with spot sign-positive ICH treated a median of about 3 hours from stroke onset, rFVIIa did not significantly improve radiographic or clinical outcomes.

Trial Registration: ClinicalTrials.gov identifier: NCT01359202 and NCT00810888.
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http://dx.doi.org/10.1001/jamaneurol.2019.2636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704754PMC
December 2019

Agreement between a health claims algorithm and parent-reported asthma in young children.

Pediatr Pulmonol 2019 10 22;54(10):1547-1556. Epub 2019 Jul 22.

Child Health Evaluative Sciences, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.

Introduction: Asthma prevalence is commonly measured in national surveys by questionnaire. The Ontario Asthma Surveillance Information System (OASIS) developed a validated health claims diagnosis algorithm to estimate asthma prevalence. The primary objective was to assess the agreement between two approaches of measuring asthma in young children. Secondary objectives were to identify concordant and discordant pairs, and to identify factors associated with disagreement.

Study Design And Setting: A measurement study to evaluate the agreement between the OASIS algorithm and parent-reported asthma (criterion standard). Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. Multivariable logistic regression was used to determine factors associated with disagreement.

Results: Healthy children aged 1 to 5 years (n =3642) participating in the TARGet Kids! practice based research network 2008-2013 in Toronto, Canada were included. Prevalence of asthma was 14% and 6% by the OASIS algorithm and parent-reported asthma, respectively. The Kappa statistic was 0.43, sensitivity 81%, specificity 90%, PPV 34%, and NPV 99%. There were 3249 concordant and 393 discordant pairs. Statistically significant factors associated with asthma identified by OASIS but not parent report included: male sex, higher zBMI, and parent history of asthma. Males were less likely to have asthma identified by parent report but not OASIS.

Conclusion: The OASIS algorithm identified more asthma cases in young children than parent-reported asthma. The OASIS algorithm had high sensitivity, specificity, and NPV but low PPV relative to parent-reported asthma. These findings need replication in other populations.
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http://dx.doi.org/10.1002/ppul.24432DOI Listing
October 2019