Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. Although it has been theorized that sodium-glucose cotransporter 2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine whether sodium-glucose cotransporter 2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure. METHODS: Between April 2021 and January 2022, 169 individuals, 40 to 80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomly assigned to empagliflozin (10 mg/d; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and LV end-systolic volumes indexed to baseline body surface area and LV ejection fraction. RESULTS: Among the 169 participants (141 men [83%]; mean age, 59.3±10.5 years), baseline LVMi was 63.2±17.9 g/m2 and 63.8±14.0 g/m2 for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group versus placebo group adjusted for baseline LVMi was -0.30 g/m2 (-2.1 to 1.5 g/m2; P=0.74). Median baseline (interquartile range) NT-proBNP (N-terminal-pro B-type natriuretic peptide) was 51 pg/mL (20-105 pg/mL) and 55 pg/mL (21-132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin versus placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were -1.3 mm Hg (-5.2 to 2.6 mm Hg; P=0.52), 0.69 mm Hg (-1.9 to 3.3 mm Hg; P=0.60), and -6.1 pg/mL (-37.0 to 24.8 pg/mL; P=0.70) for systolic blood pressure, diastolic blood pressure, and NT-proBNP, respectively. No clinically meaningful between-group differences in LV volumes (diastolic and systolic indexed to baseline body surface area) or ejection fraction were observed. No difference in adverse events was noted between the groups. CONCLUSIONS: Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, sodium-glucose cotransporter 2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04461041.

A randomized sham-controlled trial of high-dosage accelerated intermittent theta burst rTMS in major depression: study protocol.

BACKGROUND: Intermittent theta burst stimulation (iTBS), a novel form of repetitive transcranial magnetic stimulation (rTMS), can be administered in 1/10th of the time of standard rTMS (~ 3 min vs. 37.5 min) yet achieves similar outcomes in depression. The brief nature of the iTBS protocol allows for the administration of multiple iTBS sessions per day, thus reducing the overall course length to days rather than weeks. This study aims to compare the efficacy and tolerability of active versus sham iTBS using an accelerated regimen in patients with treatment-resistant depression (TRD). As a secondary objective, we aim to assess the safety, tolerability, and treatment response to open-label low-frequency right-sided (1 Hz) stimulation using an accelerated regimen in those who do not respond to the initial week of treatment. METHODS: Over three years, approximately 230 outpatients at the Centre for Addiction and Mental Health and University of British Columbia Hospital, meeting diagnostic criteria for unipolar MDD, will be recruited and randomized to a triple blind sham-controlled trial. Patients will receive five consecutive days of active or sham iTBS, administered eight times daily at 1-hour intervals, with each session delivering 600 pulses of iTBS. Those who have not achieved response by the week four follow-up visit will be offered a second course of treatment, regardless of whether they initially received active or sham stimulation. DISCUSSION: Broader implementation of conventional iTBS is limited by the logistical demands of the current standard course consisting of 4-6 weeks of daily treatment. If our proposed accelerated iTBS protocol enables patients to achieve remission more rapidly, this would offer major benefits in terms of cost and capacity as well as the time required to achieve clinical response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04255784.

Time Course of Early Hematoma Expansion in Acute Spot-Sign Positive Intracerebral Hemorrhage: Prespecified Analysis of the SPOTLIGHT Randomized Clinical Trial.

BACKGROUND: In the SPOTLIGHT trial (Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy), patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral hemorrhage were randomized to rFVIIa (recombinant activated factor VIIa; 80 µg/kg) or placebo within 6 hours of onset, aiming to limit hematoma expansion. Administration of rFVIIa did not significantly reduce hematoma expansion. In this prespecified analysis, we aimed to investigate the impact of delays from baseline imaging to study drug administration on hematoma expansion. METHODS: Hematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total hematoma volume (intracerebral hemorrhage+intraventricular hemorrhage) change between the 3 scans was calculated as an estimate of how much hematoma expansion occurred before and after studying drug administration. RESULTS: Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2-2.6). Median time from baseline CT to study drug was 62.5 (55-80) minutes, and from study drug to early post-dose CT was 19 (14.5-30) minutes. Median (interquartile range) total hematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (-0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8-8.3) in the placebo arm (P=0.96). Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (-2.6 to 8.3) in the rFVIIa arm and 0.7 mL (-1.6 to 2.1) in the placebo arm (P=0.98). Total hematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted hematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI, 0.71-1.43]; P=0.99). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI, 0.994-1.003]; P=0.50; Table 3). CONCLUSIONS: In the SPOTLIGHT trial, the adjusted hematoma volume growth was not associated with Factor VIIa treatment. Most hematoma expansion occurred between the baseline CT and the early post-dose CT, limiting any potential treatment effect of hemostatic therapy. Future hemostatic trials must treat intracerebral hemorrhage patients earlier from onset, with minimal delay between baseline CT and drug administration. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01359202.

Great expectations: patients' preferences for clinically significant results from genomic sequencing.

We aimed to describe patient preferences for a broad range of secondary findings (SF) from genomic sequencing (GS) and factors driving preferences. We assessed preference data within a trial of the Genomics ADvISER, (SF decision aid) among adult cancer patients. Participants could choose from five categories of SF: (1) medically actionable; (2) polygenic risks; (3) rare diseases; (4) early-onset neurological diseases; and (5) carrier status. We analyzed preferences using descriptive statistics and drivers of preferences using multivariable logistic regression models. The 133 participants were predominantly European (74%) or East Asian or mixed ancestry (13%), female (90%), and aged > 50 years old (60%). The majority chose to receive SF. 97% (129/133) chose actionable findings with 36% (48/133) choosing all 5 categories. Despite the lack of medical actionability, participants were interested in receiving SF of polygenic risks (74%), carrier status (75%), rare diseases (59%), and early-onset neurologic diseases (53%). Older participants were more likely to be interested in receiving results for early-onset neurological diseases, while those exhibiting lower decisional conflict were more likely to select all categories. Our results highlight a disconnect between cancer patient preferences and professional guidelines on SF, such as ACMG's recommendations to only return medically actionable secondary findings. In addition to clinical evidence, future guidelines should incorporate patient preferences.

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

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.).

How do members of the public expect to use variants of uncertain significance in their health care? A population-based survey.

PURPOSE: Genomic sequencing can generate complex results, including variants of uncertain significance (VUS). In general, VUS should not inform clinical decision-making. This study aimed to assess the public's expected management of VUS. METHODS: An online, hypothetical survey was conducted among members of the Canadian public preceded by an educational video. Participants were randomized to 1 of 2 arms, VUS or pathogenic variant in a colorectal cancer gene, and asked which types of health services they expected to use for this result. Expected health service use was compared between randomization arms, and associations between participants' sociodemographic characteristics, attitudes, and medical history were explored. RESULTS: Among 1003 respondents (completion rate 60%), more participants expected to use each type of health service for a pathogenic variant than for a VUS. However, a considerable proportion of participants expected to request monitoring (73.4%) and consult health care providers (60.9%) for a VUS. There was evidence to support associations between expectation to use health services for a VUS with family history of genetic disease, family history of cancer, education, and attitudes toward health care and technology. CONCLUSION: Many participants expected to use health services for a VUS in a colorectal cancer predisposition gene, suggesting a potential disconnect between patients' expectations for VUS management and guideline-recommended care.

School-based health care: improving academic outcomes for inner-city children-a prospective cohort quasi-experimental study.

BACKGROUND: We examined whether a school-based health center model improved academic achievement compared to usual care. METHODS: This was a quasi-experimental prospective cohort study. The primary outcome was an academic achievement. In addition, we analyzed sociodemographic characteristics and their relationship to academic achievement, and the wait time for a developmental assessment. RESULTS: The differences in change of grades over time (from 2016/2017 to 2018/2019) were small for reading (-0.83, 95% CI -3.48, 1.82, p = 0.51), writing (-1.11, 95% CI -3.25, 1.03, p = 0.28), and math (0.06, 95% CI -3.08, 2.94, p = 0.98). The experimental arm's average wait time for developmental assessment was 3.4 months. CONCLUSION: In this small, quasi-experimental prospective cohort study, we did not find evidence that our SBHC model improved academic achievement; however, the wait time at the SBHCs was considerably less than the provincial wait time for a developmental assessment. TRIAL REGISTRATION: NCT04540003. IMPACT: This study describes a unique and innovative school-based health center model. Our findings support the benefits of school-based health centers in diagnosing and treating children with developmental and mental health disorders for disadvantaged communities. This study did not find an improvement in academic achievement for school-based health center users. This study found that the wait time to developmental assessment was shorter for school-based health center users compared to the wait time reported in the community. Pandemic-associated school disruptions have highlighted the importance of accessible school-based health services for children requiring mental health and developmental assessments and care.

Strengthening oropharyngeal muscles as an approach to treat post-stroke obstructive sleep apnea: A feasibility randomised controlled trial.

This study aimed to determine the feasibility of a randomised controlled trial (RCT) evaluating oropharyngeal exercise (OPE) intervention as an alternative therapy for obstructive sleep apnea (OSA) in patients with stroke or transient ischaemic attack (TIA). Despite the high prevalence of OSA in this population, the standard therapy, continuous positive airway pressure (CPAP), is often poorly tolerated. Thirty stroke/TIA patients with OSA unable to tolerate CPAP were randomly assigned to an oropharyngeal exercise or sham exercise protocol. They performed exercises for 6 weeks, 5 days per week, 30 minutes twice per day. Feasibility was ascertained by the proportion of enrolled patients who completed more than 80% of the OPE regimen. Isometric tongue pressures, apnea-hypopnea index (AHI), oxygen desaturation index (ODI), daytime sleepiness, and quality of life (QOL) outcomes were collected at baseline, post-training (6-week follow-up), and retention (10-week follow-up) to document preliminary efficacy. Adherence to study exercises was excellent, with 83% of participants completing more than 80% of the exercises. The isometric tongue pressures were observed to improve in the oropharyngeal exercise group (compared with the sham group), along with a decrease in OSA severity (measured by the AHI and ODI), reduced daytime sleepiness, and enhanced quality of life outcomes following the exercise programme. Only the effects on posterior isometric tongue pressure and daytime sleepiness remained significantly different between groups at the retention session. In conclusion, an RCT evaluating the efficacy of oropharyngeal exercises on post-stroke/TIA OSA is feasible and our preliminary results suggest a clinically meaningful effect.

Survival and health care costs after inpatient elective surgery: comparison of patients with and without chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is common among surgical patients, and patients with COPD have higher risk for complications and death within 30 days after surgery. We sought to describe the longer-term postoperative survival and costs of patients with COPD compared with those without COPD within 1 year after inpatient elective surgery. METHODS: In this retrospective population-based cohort study, we used linked health administrative databases to identify all patients undergoing inpatient elective surgery in Ontario, Canada, from 2005 to 2019. We ascertained COPD status using validated definitions. We followed participants for 1 year after surgery to evaluate survival and costs to the health system. We quantified the association of COPD with survival (Cox proportional hazards models) and costs (linear regression model with log-transformed costs) with partial adjustment (for sociodemographic factors and procedure type) and full adjustment (also adjusting for comorbidities). We assessed for effect modification by frailty, cancer and procedure type. RESULTS: We included 932 616 patients, of whom 170 482 (18%) had COPD. With respect to association with risk of death, COPD had a partially adjusted hazard ratio (HR) of 1.61 (95% confidence interval [CI] 1.58-1.64), and a fully adjusted HR of 1.26 (95% CI 1.24-1.29). With respect to impact on health system costs, COPD was associated with a partially adjusted relative increase of 13.1% (95% CI 12.7%-13.4%), and an increase of 4.6% (95% CI 4.3%-5.0%) with full adjustment. Frailty, cancer and procedure type (such as orthopedic and lower abdominal surgery) modified the association between COPD and outcomes. INTERPRETATION: Patients with COPD have decreased survival and increased costs in the year after surgery. Frailty, cancer and the type of surgical procedure modified associations between COPD and outcomes, and must be considered when risk-stratifying surgical patients with COPD.

Association between preoperative cardiac risk assessment and health care costs in major noncardiac surgery: a multicentre health economic analysis.

PURPOSE: Patients with impaired functional capacity who undergo major surgery are at increased risk of postoperative morbidity including complications and increased length of stay. These outcomes have been associated with increased hospital and health system costs. We aimed to assess whether common preoperative risk indices are associated with postoperative cost. METHODS: We conducted a health economic analysis focused on the subset of Measurement of Exercise Tolerance before Surgery (METS) study participants in Ontario, Canada. Participants were scheduled for major elective noncardiac surgery and underwent several preoperative assessments of cardiac risk, including physicians' subjective assessment, Duke Activity Status Index (DASI) questionnaire, peak oxygen consumption, and N-terminal pro-B-type natriuretic peptide concentration. Using linked health administrative data, postoperative costs were calculated for both one year and in-hospital. Using multiple regression models, we tested for association between the preoperative measures of cardiac risk and postoperative costs. RESULTS: Our study included 487 patients (mean [standard deviation] age 68 [11] yr and 47.0% female) who underwent noncardiac surgery between 13 June 2013 and 8 March 2016. Overall, the median [interquartile range] cost incurred within one year postoperatively was CAD 27,587 [13,902-32,590], of which CAD 12,928 [10,253-12,810] were incurred in-hospital and CAD 14,497 [10,917-15,017] were incurred by 30 days. None of the four preoperative measures of cardiac risk assessment were associated with costs incurred in hospital or at one year postoperatively. This lack of strong association persisted in sensitivity analyses considering type of surgical procedure, burden of preoperative cost, and when costs were categorized as quantiles. CONCLUSION: In patients undergoing major noncardiac surgery, common measures of functional capacity are not consistently associated with total postoperative cost. Until further data exist that differ from this analysis, clinicians and health care funders should not assume that preoperative measures of cardiac risk are associated with annual health care or hospital costs for such surgeries.

RéSUMé: OBJECTIF: La patientèle présentant une capacité fonctionnelle dégradée qui bénéficie d'une intervention chirurgicale majeure court un risque accru de morbidité postopératoire, y compris de complications et de prolongation de la durée de séjour. Ces issues ont été associées à une augmentation des coûts hospitaliers et du système de santé. Notre objectif était d'évaluer si des indices de risque préopératoires communs étaient associés aux coûts postopératoires. MéTHODE: Nous avons effectué une analyse de l'économie de la santé axée sur le sous-ensemble des participant·es à l'étude METS (Measurement of Exercise Tolerance before Surgery) en Ontario, au Canada. Les participant·es devaient bénéficier d'une chirurgie non cardiaque et non urgente majeure et ont complété plusieurs évaluations préopératoires du risque cardiaque, notamment l'évaluation subjective des médecins, le questionnaire DASI (Duke Activity Status Index), la consommation maximale d'oxygène et la concentration de prohormone N-terminale du peptide natriurétique de type B (cérébral) (NT-proBNP). À l'aide de données administratives couplées de santé, les coûts postopératoires ont été calculés à la fois pour une année et à l'hôpital. À l'aide de modèles de régression multiples, nous avons testé l'association entre les mesures préopératoires du risque cardiaque et les coûts postopératoires. RéSULTATS: Notre étude a inclus 487 personnes (âge moyen [écart type] 68 [11] ans et 47,0 % de femmes) ayant bénéficié d'une chirurgie non cardiaque entre le 13 juin 2013 et le 8 mars 2016. Dans l'ensemble, le coût médian [écart interquartile] engagé dans l'année qui a suivi l'opération était de 27 587 CAD [13 902­32 590], dont 12 928 CAD [10 253­12 810] ont été encourus à l'hôpital et 14 497 CAD [10 917­15 017] ont été encourus dans les premiers 30 jours. Aucune des quatre mesures préopératoires de l'évaluation du risque cardiaque n'était associée aux coûts engagés à l'hôpital ou un an après l'opération. Cette absence d'association forte persistait dans les analyses de sensibilité tenant compte du type d'intervention chirurgicale, du fardeau des coûts préopératoires et lorsque les coûts étaient classés en quantiles. CONCLUSION: Chez la patientèle bénéficiant d'une chirurgie non cardiaque majeure, les mesures courantes de la capacité fonctionnelle ne sont pas systématiquement associées au coût postopératoire total. Jusqu'à ce qu'il existe d'autres données qui diffèrent de cette analyse, les cliniciens et cliniciennes et les organismes finançant les soins de santé ne devraient pas présumer que les mesures préopératoires du risque cardiaque sont associées aux coûts annuels des soins de santé ou des hôpitaux pour de telles chirurgies.

Generating Items for a Novel Bedside Dysphagia Screening Tool Post Acute Pediatric Stroke.

Bedside dysphagia assessment protocols are not well developed in acute pediatric stroke unlike adults. The objective of this study was to identify items deemed relevant and feasible by expert consensus to inform the development of a bedside dysphagia screening tool for acute pediatric stroke. A two-phase study was conducted: (1) literature review and expert consultation generated a comprehensive list of dysphagia assessment items; (2) items were formatted in an online survey asking respondents opinion of relevance to acute pediatric stroke and feasibility for bedside administration by a trained health professional. The Dillman Tailored Design approach optimized response rate. Respondents were identified using the snowball method. Speech-language pathologists with > 2 years in pediatric dysphagia were invited to complete the survey. Demographic and practice variables were compared using univariate statistics. Item relevance and feasibility were made using binary or ordinal responses, combined to derive item-content validity indices (I-CVI) to guide item reduction. Items with I-CVI > 0.78 (excellent content validity) were moved forward to tool development. Of the 71 invited respondents, 57(80.3%) responded, of which 34(59.6%) were from North America. Sixty-one items were generated of which 4(6.6%) items were rated 'to keep'. These were face symmetry (I-CVI:0.89), salivary control (I-CVI:0.95), alertness (I-CVI:0.89) and choking (I-CVI:0.84). Of all respondents, 31(54.4%) endorsed swallowing trials, of which 25(80.6%) endorsed thin liquid by teaspoon (n = 17, 68%) or open cup (n = 20, 80%). We identified candidate items for bedside dysphagia screening with excellent content validity for acute pediatric stroke patients. Next steps include assessment of the psychometric value of each item in identifying dysphagia in children in the acute stage of recovery from stroke.

SLEAP SMART (Sleep Apnea Screening Using Mobile Ambulatory Recorders After TIA/Stroke): A Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Poststroke/transient ischemic attack obstructive sleep apnea (OSA) is prevalent, linked with numerous unfavorable health consequences, but remains underdiagnosed. Reasons include patient inconvenience and costs associated with use of in-laboratory polysomnography (iPSG), the current standard tool. Fortunately, home sleep apnea testing (HSAT) can accurately diagnose OSA and is potentially more convenient and cost-effective compared with iPSG. Our objective was to assess whether screening for OSA in patients with stroke/transient ischemic attack using HSAT, compared with standard of care using iPSG, increased diagnosis and treatment of OSA, improved clinical outcomes and patient experiences with sleep testing, and was a cost-effective approach. METHODS: We consecutively recruited 250 patients who had sustained a stroke/transient ischemic attack within the past 6 months. Patients were randomized (1:1) to use of (1) HSAT versus (2) iPSG. Patients completed assessments and questionnaires at baseline and 6-month follow-up appointments. Patients diagnosed with OSA were offered continuous positive airway pressure. The primary outcome was compared between study arms via an intention-to-treat analysis. RESULTS: At 6 months, 94 patients completed HSAT and 71 patients completed iPSG. A significantly greater proportion of patients in the HSAT arm were diagnosed with OSA (48.8% versus 35.2%, P=0.04) compared with the iPSG arm. Furthermore, patients assigned to HSAT, compared with iPSG, were more likely to be prescribed continuous positive airway pressure (40.0% versus 27.2%), report significantly reduced sleepiness, and a greater ability to perform daily activities. Moreover, a significantly greater proportion of patients reported a positive experience with sleep testing in the HSAT arm compared with the iPSG arm (89.4% versus 31.1%). Finally, a cost-effectiveness analysis revealed that HSAT was economically attractive for the detection of OSA compared with iPSG. CONCLUSIONS: In patients with stroke/transient ischemic attack, use of HSAT compared with iPSG increases the rate of OSA diagnosis and treatment, reduces daytime sleepiness, improves functional outcomes and experiences with sleep testing, and could be an economically attractive approach. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02454023.

Restrictive versus liberal transfusion in patients with diabetes undergoing cardiac surgery: An open-label, randomized, blinded outcome evaluation trial.

AIM: To characterize the association between diabetes and transfusion and clinical outcomes in cardiac surgery, and to evaluate whether restrictive transfusion thresholds are harmful in these patients. MATERIALS AND METHODS: The multinational, open-label, randomized controlled TRICS-III trial assessed a restrictive transfusion strategy (haemoglobin [Hb] transfusion threshold <75 g/L) compared with a liberal strategy (Hb <95 g/L for operating room or intensive care unit; or <85 g/L for ward) in patients undergoing cardiac surgery on cardiopulmonary bypass with a moderate-to-high risk of death (EuroSCORE ≥6). Diabetes status was collected preoperatively. The primary composite outcome was all-cause death, stroke, myocardial infarction, and new-onset renal failure requiring dialysis at 6 months. Secondary outcomes included components of the composite outcome at 6 months, and transfusion and clinical outcomes at 28 days. RESULTS: Of the 5092 patients analysed, 1396 (27.4%) had diabetes (restrictive, n = 679; liberal, n = 717). Patients with diabetes had more cardiovascular disease than patients without diabetes. Neither the presence of diabetes (OR [95% CI] 1.10 [0.93-1.31]) nor the restrictive strategy increased the risk for the primary composite outcome (diabetes OR [95% CI] 1.04 [0.68-1.59] vs. no diabetes OR 1.02 [0.85-1.22]; Pinteraction  = .92). In patients with versus without diabetes, a restrictive transfusion strategy was more effective at reducing red blood cell transfusion (diabetes OR [95% CI] 0.28 [0.21-0.36]; no diabetes OR [95% CI] 0.40 [0.35-0.47]; Pinteraction  = .04). CONCLUSIONS: The presence of diabetes did not modify the effect of a restrictive transfusion strategy on the primary composite outcome, but improved its efficacy on red cell transfusion. Restrictive transfusion triggers are safe and effective in patients with diabetes undergoing cardiac surgery.

The PROMIZING trial enrollment algorithm for early identification of patients ready for unassisted breathing.

BACKGROUND: Liberating patients from mechanical ventilation (MV) requires a systematic approach. In the context of a clinical trial, we developed a simple algorithm to identify patients who tolerate assisted ventilation but still require ongoing MV to be randomized. We report on the use of this algorithm to screen potential trial participants for enrollment and subsequent randomization in the Proportional Assist Ventilation for Minimizing the Duration of MV (PROMIZING) study. METHODS: The algorithm included five steps: enrollment criteria, pressure support ventilation (PSV) tolerance trial, weaning criteria, continuous positive airway pressure (CPAP) tolerance trial (0 cmH2O during 2 min) and spontaneous breathing trial (SBT): on fraction of inspired oxygen (FiO2) 40% for 30-120 min. Patients who failed the weaning criteria, CPAP Zero trial, or SBT were randomized. We describe the characteristics of patients who were initially enrolled, but passed all steps in the algorithm and consequently were not randomized. RESULTS: Among the 374 enrolled patients, 93 (25%) patients passed all five steps. At time of enrollment, most patients were on PSV (87%) with a mean (± standard deviation) FiO2 of 34 (± 6) %, PSV of 8.7 (± 2.9) cmH2O, and positive end-expiratory pressure of 6.1 (± 1.6) cmH2O. Minute ventilation was 9.0 (± 3.1) L/min with a respiratory rate of 17.4 (± 4.4) breaths/min. Patients were liberated from MV with a median [interquartile range] delay between initial screening and extubation of 5 [1-49] hours. Only 7 (8%) patients required reintubation. CONCLUSION: The trial algorithm permitted identification of 93 (25%) patients who were ready to extubate, while their clinicians predicted a duration of ventilation higher than 24 h.

Prolonged mechanical ventilation after cardiac surgery: substudy of the Transfusion Requirements in Cardiac Surgery III trial.

PURPOSE: Prolonged mechanical ventilation (MV) is a major complication following cardiac surgery. We conducted a secondary analysis of the Transfusion Requirements in Cardiac Surgery (TRICTS) III trial to describe MV duration, identify factors associated with prolonged MV, and examine associations of prolonged MV with mortality and complications. METHODS: Four thousand, eight hundred and nine participants undergoing cardiac surgery at 71 hospitals worldwide were included. Prolonged MV was defined based on the Society of Thoracic Surgeons definition as MV lasting 24 hr or longer. Adjusted associations of patient and surgical factors with prolonged MV were examined using multivariable logistic regression. Associations of prolonged MV with complications were assessed using odds ratios, and adjusted associations between prolonged MV and mortality were evaluated using multinomial regression. Associations of shorter durations of MV with survival and complications were explored. RESULTS: Prolonged MV occurred in 15% (725/4,809) of participants. Prolonged MV was associated with surgical factors indicative of complexity, such as previous cardiac surgery, cardiopulmonary bypass duration, and separation attempts; and patient factors such as critical preoperative state, left ventricular impairment, renal failure, and pulmonary hypertension. Prolonged MV was associated with perioperative but not long-term complications. After risk adjustment, prolonged MV was associated with perioperative mortality; its association with long-term mortality among survivors was weaker. Shorter durations of MV were not associated with increased risk of mortality or complications. CONCLUSION: In this substudy of the TRICS III trial, prolonged MV was common after cardiac surgery and was associated with patient and surgical risk factors. Although prolonged MV showed strong associations with perioperative complications and mortality, it was not associated with long-term complications and had weaker association with long-term mortality among survivors. STUDY REGISTRATION: www. CLINICALTRIALS: gov (NCT02042898); registered 23 January 2014. This is a substudy of the Transfusion Requirements in Cardiac Surgery (TRICS) III trial.

RéSUMé: OBJET: La ventilation mécanique (VM) prolongée est une complication majeure après chirurgie cardiaque. Nous avons effectué une analyze secondaire de l'étude TRICS III sur les besoins de transfusion au cours de la chirurgie cardiaque pour décrire la durée de la VM, identifier les facteurs associés à une VM prolongée et examiner les associations de la VM prolongée avec la mortalité et les complications. MéTHODES: Quatre mille huit cent neuf participants subissant une chirurgie cardiaque dans 71 hôpitaux à travers le monde ont été inclus. La VM prolongée a été définie à partir de la définition de la Society of Thoracic Surgeons comme un événement durant 24 heures ou plus. Des associations ajustées de facteurs liés aux patients et à la chirurgie avec la VM prolongée ont été examinées en utilisant une régression logistique multifactorielle. Des associations de la VM prolongée avec des complications ont été évaluées en utilisant des rapports de cotes; les associations ajustées entre VM prolongée et mortalité ont été évaluées au moyen d'une régression multinominale. Les associations d'une VM de plus courte durée avec la survie et des complications ont été explorées. RéSULTATS: La VM prolongée est survenue chez 15 % (725/4 809) des participants. Une VM prolongée a été associée à des facteurs chirurgicaux indicateurs de complexité (comme une chirurgie cardiaque antérieure, la durée de la circulation extracorporelle et les tentatives de débranchement) et à des facteurs liés au patient (comme un état préopératoire critique, une défaillance ventriculaire gauche, une insuffisance rénale et une hypertension pulmonaire). La VM prolongée a été associée à des complications périopératoires, mais pas à des complications à long terme. Après ajustement pour le risque, la VM prolongée a été associée à la mortalité périopératoire; son association avec la mortalité à long terme des survivants a été plus faible. Les durées plus courtes de VM n'ont pas été associées à une augmentation du risque de mortalité ou à des complications. CONCLUSION: Dans cette étude auxiliaire de l'essai TRICS III, la VM prolongée a été fréquente après chirurgie cardiaque et a été associée à des facteurs de risque liés au patient et à la chirurgie. Bien que la VM prolongée ait présenté de fortes associations avec les complications périopératoires et la mortalité, elle n'a pas été associée avec des complications à long terme et était plus faiblement associée à la mortalité à long terme parmi les survivants. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT02042898); enregistrée le 23 janvier 2014. Il s'agit d'une étude auxiliaire de l'étude TRICS III sur les besoins de transfusion en chirurgie cardiaque.

The Impact of a Clinical Decision Support System for Addressing Physical Activity and Healthy Eating During Smoking Cessation Treatment: Hybrid Type I Randomized Controlled Trial.

BACKGROUND: People who smoke have other risk factors for chronic diseases, such as low levels of physical activity and poor diet. Clinical decision support systems (CDSSs) might help health care practitioners integrate interventions for diet and physical activity into their smoking cessation programming but could worsen quit rates. OBJECTIVE: The aims of this study are to assess the effects of the addition of a CDSS for physical activity and diet on smoking cessation outcomes and to assess the implementation of the study. METHODS: We conducted a pragmatic hybrid type I effectiveness-implementation trial with 232 team-based primary care practices in Ontario, Canada, from November 2019 to May 2021. We used a 2-arm randomized controlled trial comparing a CDSS addressing physical activity and diet to treatment as usual and used the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework to measure implementation outcomes. The primary outcome was self-reported 7-day tobacco abstinence at 6 months. RESULTS: We enrolled 5331 participants in the study. Of these, 2732 (51.2%) were randomized to the intervention group and 2599 (48.8%) to the control group. At the 6-month follow-up, 29.7% (634/2137) of respondents in the intervention arm and 27.3% (552/2020) in the control arm reported abstinence from tobacco. After multiple imputation, the absolute group difference was 2.1% (95% CI -0.5 to 4.6; F1,1000.42=2.43; P=.12). Mean exercise minutes changed from 32 (SD 44.7) to 110 (SD 196.1) in the intervention arm and from 32 (SD 45.1) to 113 (SD 195.1) in the control arm (group effect: B=-3.7 minutes; 95% CI -17.8 to 10.4; P=.61). Servings of fruit and vegetables changed from 2.64 servings to 2.42 servings in the intervention group and from 2.52 servings to 2.45 servings in the control group (incidence rate ratio for intervention group=0.98; 95% CI 0.93-1.02; P=.35). CONCLUSIONS: A CDSS for physical activity and diet may be added to a smoking cessation program without affecting the outcomes. Further research is needed to improve the impact of integrated health promotion interventions in primary care smoking cessation programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04223336 https://www.clinicaltrials.gov/ct2/show/NCT04223336. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/19157.

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

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.

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

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.

Patient and public preferences for being recontacted with updated genomic results: a mixed methods study.

Variants of uncertain significance (VUS) are frequently reclassified but recontacting patients with updated results poses significant resource challenges. We aimed to characterize public and patient preferences for being recontacted with updated results. A discrete choice experiment (DCE) was administered to representative samples of the Canadian public and cancer patients. DCE attributes were uncertainty, cost, recontact modality, choice of results, and actionability. DCE data were analyzed using a mixed logit model and by calculating willingness to pay (WTP) for types of recontact. Qualitative interviews exploring recontact preferences were analyzed thematically. DCE response rate was 60% (n = 1003, 50% cancer patient participants). 31 participants were interviewed (11 cancer patients). Interviews revealed that participants expected to be recontacted. Quantitatively, preferences for how to be recontacted varied based on certainty of results. For certain results, WTP was highest for being recontacted by a doctor with updates ($1075, 95% CI: $845, $1305) and for contacting a doctor to request updates ($1038, 95% CI: $820, $1256). For VUS results, WTP was highest for an online database ($1735, 95% CI: $1224, $2247) and for contacting a doctor ($1705, 95% CI: $1102, $2307). Qualitative data revealed that preferences for provider-mediated recontact were influenced by trust in healthcare providers. Preferences for a database were influenced by lack of trust in providers and desire for control. Patients and public participants support an online database (e.g. patient portal) to recontact for VUS, improving feasibility, and provider-mediated recontact for certain results, consistent with usual care.

Six-Month Outcomes after Restrictive or Liberal Transfusion for Cardiac Surgery.

BACKGROUND: We reported previously that, in patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive transfusion strategy was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis by hospital discharge or 28 days after surgery, whichever came first. We now report the clinical outcomes at 6 months after surgery. METHODS: We randomly assigned 5243 adults undergoing cardiac surgery to a restrictive red-cell transfusion strategy (transfusion if the hemoglobin concentration was <7.5 g per deciliter intraoperatively or postoperatively) or a liberal red-cell transfusion strategy (transfusion if the hemoglobin concentration was <9.5 g per deciliter intraoperatively or postoperatively when the patient was in the intensive care unit [ICU] or was <8.5 g per deciliter when the patient was in the non-ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis occurring within 6 months after the initial surgery. An expanded secondary composite outcome included all the components of the primary outcome as well as emergency department visit, hospital readmission, or coronary revascularization occurring within 6 months after the index surgery. The secondary outcomes included the individual components of the two composite outcomes. RESULTS: At 6 months after surgery, the primary composite outcome had occurred in 402 of 2317 patients (17.4%) in the restrictive-threshold group and in 402 of 2347 patients (17.1%) in the liberal-threshold group (absolute risk difference before rounding, 0.22 percentage points; 95% confidence interval [CI], -1.95 to 2.39; odds ratio, 1.02; 95% CI, 0.87 to 1.18; P=0.006 for noninferiority). Mortality was 6.2% in the restrictive-threshold group and 6.4% in the liberal-threshold group (odds ratio, 0.95; 95% CI, 0.75 to 1.21). There were no significant between-group differences in the secondary outcomes. CONCLUSIONS: In patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive strategy for red-cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis at 6 months after surgery. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898 .).