Integration of variant annotations using deep set networks boosts rare variant association testing.

Rare genetic variants can have strong effects on phenotypes, yet accounting for rare variants in genetic analyses is statistically challenging due to the limited number of allele carriers and the burden of multiple testing. While rich variant annotations promise to enable well-powered rare variant association tests, methods integrating variant annotations in a data-driven manner are lacking. Here we propose deep rare variant association testing (DeepRVAT), a model based on set neural networks that learns a trait-agnostic gene impairment score from rare variant annotations and phenotypes, enabling both gene discovery and trait prediction. On 34 quantitative and 63 binary traits, using whole-exome-sequencing data from UK Biobank, we find that DeepRVAT yields substantial gains in gene discoveries and improved detection of individuals at high genetic risk. Finally, we demonstrate how DeepRVAT enables calibrated and computationally efficient rare variant tests at biobank scale, aiding the discovery of genetic risk factors for human disease traits.

International Society for Heart and Lung Transplantation Guidelines for the Evaluation and Care of Cardiac Transplant Candidates-2024.

The "International Society for Heart and Lung Transplantation Guidelines for the Evaluation and Care of Cardiac Transplant Candidates-2024" updates and replaces the "Listing Criteria for Heart Transplantation: International Society for Heart and Lung Transplantation Guidelines for the Care of Cardiac Transplant Candidates-2006" and the "2016 International Society for Heart Lung Transplantation Listing Criteria for Heart Transplantation: A 10-year Update." The document aims to provide tools to help integrate the numerous variables involved in evaluating patients for transplantation, emphasizing updating the collaborative treatment while waiting for a transplant. There have been significant practice-changing developments in the care of heart transplant recipients since the publication of the International Society for Heart and Lung Transplantation (ISHLT) guidelines in 2006 and the 10-year update in 2016. The changes pertain to 3 aspects of heart transplantation: (1) patient selection criteria, (2) care of selected patient populations, and (3) durable mechanical support. To address these issues, 3 task forces were assembled. Each task force was cochaired by a pediatric heart transplant physician with the specific mandate to highlight issues unique to the pediatric heart transplant population and ensure their adequate representation. This guideline was harmonized with other ISHLT guidelines published through November 2023. The 2024 ISHLT guidelines for the evaluation and care of cardiac transplant candidates provide recommendations based on contemporary scientific evidence and patient management flow diagrams. The American College of Cardiology and American Heart Association modular knowledge chunk format has been implemented, allowing guideline information to be grouped into discrete packages (or modules) of information on a disease-specific topic or management issue. Aiming to improve the quality of care for heart transplant candidates, the recommendations present an evidence-based approach.

Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial.

BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059). INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis. FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

Prevention of infections and fever to improve outcome in older patients with acute stroke (PRECIOUS): a randomised, open, phase III, multifactorial, clinical trial with blinded outcome assessment.

Background: Infections and fever after stroke are associated with poor functional outcome or death. We assessed whether prophylactic treatment with anti-emetic, antibiotic, or antipyretic medication would improve functional outcome in older patients with acute stroke. Methods: We conducted an international, 2∗2∗2-factorial, randomised, controlled, open-label trial with blinded outcome assessment in patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and a score on the National Institutes of Health Stroke Scale ≥ 6. Patients were randomly allocated (1:1) to metoclopramide (oral, rectal, or intravenous; 10 mg thrice daily) vs. no metoclopramide, ceftriaxone (intravenous; 2000 mg once daily) vs. no ceftriaxone, and paracetamol (oral, rectal, or intravenous; 1000 mg four times daily) vs. no paracetamol, started within 24 h after symptom onset and continued for four days. All participants received standard of care. The target sample size was 3800 patients. The primary outcome was the score on the modified Rankin Scale (mRS) at 90 days analysed with ordinal logistic regression and reported as an adjusted common odds ratio (an acOR < 1 suggests benefit and an acOR > 1 harm). This trial is registered (ISRCTN82217627). Findings: From April 2016 through June 2022, 1493 patients from 67 European sites were randomised to metoclopramide (n = 704) or no metoclopramide (n = 709), ceftriaxone (n = 594) or no ceftriaxone (n = 482), and paracetamol (n = 706) or no paracetamol (n = 739), of whom 1471 were included in the intention-to-treat analysis. Prophylactic use of study medication did not significantly alter the primary outcome at 90 days: metoclopramide vs. no metoclopramide (adjusted common odds ratio [acOR], 1.01; 95% CI 0.81-1.25), ceftriaxone vs. no ceftriaxone (acOR 0.99; 95% CI 0.77-1.27), paracetamol vs. no paracetamol (acOR 1.19; 95% CI 0.96-1.47). The study drugs were safe and not associated with an increased incidence of serious adverse events. Interpretation: We observed no sign of benefit of prophylactic use of metoclopramide, ceftriaxone, or paracetamol during four days in older patients with a moderately severe to severe acute stroke. Funding: This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No: 634809.

Testing the cognitive effects of tadalafil. Neuropsychological secondary outcomes from the PASTIS trial.

Cerebral small vessel disease (SVD) is a major cause of cognitive impairment in older people. As secondary endpoints in a phase-2 randomised clinical trial, we tested the effects of single administration of a widely-used PDE5 inhibitor, tadalafil, on cognitive performance in older people with SVD. In a double-blinded, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥ 7 days apart (randomised to order of treatment). The Montreal Cognitive Assessment (MOCA) was administered at baseline, alongside a measure to estimate optimal intellectual ability (Test of Premorbid Function). Then, before and after treatment, a battery of neuropsychological tests was administered, assessing aspects of attention, information processing speed, working memory and executive function. Sixty-five participants were recruited and 55 completed the protocol (N = 55, age: 66.8 (8.6) years, range 52-87; 15/40 female/male). Median MOCA score was 26 (IQR: 23, 27], range 15-30). No significant treatment effects were seen in any of the neuropsychological tests. There was a trend towards improved performance on Digit Span Forward (treatment effect 0.37, C.I. 0.01, 0.72; P = 0.0521). We did not identify significant treatment effects of single-administration tadalafil on neuropsychological performance in older people with SVD. The trend observed on Digit Span Forward may help to inform future studies. Clinical trial registration: http://www.clinicaltrials.gov. Unique identifier: NCT00123456, https://eudract.ema.europa.eu. Unique identifier: 2015-001,235-20NCT00123456.

Phase II randomised, placebo-controlled, clinical trial of interleukin-1 receptor antagonist in intracerebral haemorrhage: BLOcking the Cytokine IL-1 in ICH (BLOC-ICH).

PURPOSE: Recombinant human interleukin-1 receptor antagonist (anakinra) is an anti-inflammatory with efficacy in animal models of stroke. We tested the effect of anakinra on perihaematomal oedema in acute intracerebral haemorrhage (ICH) and explored effects on inflammatory markers. METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled trial in patients with acute, spontaneous, supratentorial ICH between May 2019 and February 2021. Patients were randomised to 100 mg subcutaneous anakinra within 8 h of onset, followed by five, 12-hourly, 100 mg subcutaneous injections, or matched placebo. Primary outcome was oedema extension distance (OED) on a 72 h CT scan. Secondary outcomes included plasma C-reactive protein (CRP) and interleukin-6 (IL-6). FINDINGS: 25 patients (target = 80) were recruited, 14 randomised to anakinra, 11 to placebo. Mean age was 67 and 52% were male. The anakinra group had higher median baseline ICH volume (12.6 ml, interquartile range[IQR]:4.8-17.9) versus placebo (5.5 ml, IQR:2.1-10.9). Adjusting for baseline, 72 h OED was not significantly different between groups (mean difference OED anakinra vs placebo -0.05 cm, 95% confidence interval [CI]: -0.17-0.06, p = 0.336). There was no significant difference in area-under-the-curve to Day 4 for IL-6 and CRP, but a post-hoc analysis demonstrated IL-6 was 56% (95% CI: 2%-80%) lower at Day 2 with anakinra. There were 10 and 2 serious adverse events in anakinra and placebo groups, respectively, none attributed to anakinra. CONCLUSION: We describe feasibility for delivering anakinra in acute ICH and provide preliminary safety data. We lacked power to test for effects on oedema thus further trials will be required.

Possible nirmatrelvir/ritonavir-induced bradycardia in a patient with asymptomatic COVID-19.

COVID-19 emerged in 2019 and was declared a pandemic by the World Health Organization in March 2020. COVID-19 is highly transmissible and can lead to bilateral pneumonia with severe respiratory failure. COVID-19 has led to more than 6.5 million deaths worldwide. The significant morbidity and mortality due to COVID-19 have resulted in the development of treatment modalities, such as novel antivirals, to reduce hospitalizations and progression of disease. In 2021, the US Food and Drug Administration authorized nirmatrelvir/ritonavir for emergency use in nonhospitalized patients with COVID-19. Nirmatrelvir is a newly developed protease inhibitor and is combined with a commonly used pharmacokinetic boosting agent, ritonavir. Given the novelty of nirmatrelvir/ritonavir, potential adverse effects remain uncertain. In this case, we describe a patient who was initiated on a course of nirmatrelvir/ritonavir and developed symptomatic bradycardia.

Ambulatory Pulmonary Artery Pressure Monitoring Reduces Costs and Improves Outcomes in Symptomatic Heart Failure: A Single-Centre Canadian Experience.

Background: Pulmonary artery pressure (PAP) monitoring reduces heart failure (HF) hospitalizations (HFHs) and improves quality of life in New York Heart Association (NYHA) class III HF. We evaluated the impact of PAP monitoring on outcomes and health spending in a Canadian ambulatory HF cohort. Methods: Twenty NYHA III HF patients underwent wireless PAP implantation at Foothills Medical Centre, Calgary, Alberta. Baseline, and 3-, 6-, 9-, and 12-month assessments of laboratory parameters, hemodynamics, 6-minute walk text and Kansas City Cardiomyopathy Questionnaire scores were collected. Healthcare costs 1 year pre- and post-implantation were collected from administrative databases. Results: Mean age was 70.6 years; 45% were female. Results were as follows: an 88% reduction in emergency room visits (P = 0.0009); an 87% reduction in HFHs (P < 0.0003); a 29% reduction in heart function clinic visits (P = 0.033), and a 178% increase in nurse calls (P < 0.0002). Questionnaire and 6-minute walk test scores at baseline vs last follow-up were 45.4 vs 48.4 (P = 0.48) and 364.4 vs 402.8 m (P = 0.58), respectively. Mean PAP at baseline vs follow-up was 31.5 vs 24.8 mm Hg (P = 0.005). NYHA class improved by at least one class in 85% of patients. Mean measurable HF-related spending preimplantation was CAD$29,814 per patient per year and postimplantation was CAD$25,642 per patient per year (including device cost). Conclusions: PAP monitoring demonstrated reductions in HFHs, and emergency room and heart function clinic visits, with improvements in NYHA class. Although further economic evaluation is needed, these results support the use of PAP monitoring as an effective and cost-neutral tool in HF management in appropriately selected patients in a publicly funded healthcare system.

Contexte: La surveillance de la pression artérielle pulmonaire (PAP) réduit les hospitalisations liées à l'insuffisance cardiaque (HIC) et améliore la qualité de vie des patients atteints d'insuffisance cardiaque (IC) de classe III de la New York Heart Association (NYHA). Nous avons évalué l'effet de la surveillance de la PAP sur les résultats et les dépenses en santé dans une cohorte de patients ambulatoires atteints d'IC au Canada. Méthodologie: Vingt patients atteints d'IC de classe III de la NYHA se sont fait implanter un dispositif sans fil de surveillance de la PAP au Foothills Medical Centre, à Calgary, en Alberta. Nous avons évalué les patients au départ et aux mois 3, 6, 9 et 12 en fonction des paramètres de laboratoire, de l'hémodynamique, des scores au test de marche de 6 minutes et au questionnaire de cardiomyopathie de Kansas City. Les coûts liés aux soins de santé un an avant et après l'implantation du dispositif ont été extraits de bases de données administratives. Résultats: L'âge moyen des patients est de 70,6 ans et 45 % sont des femmes. Les résultats vont comme suit : une réduction de 88 % des visites à l'urgence (p = 0,0009); une réduction de 87 % des HIC (p < 0,0003); une réduction de 29 % des visites à une clinique de fonction cardiaque (p = 0,033) et une augmentation de 178 % des appels du personnel infirmier (p < 0,0002). Les scores initiaux au questionnaire et au test de marche de 6 minutes par rapport à ceux du dernier suivi sont respectivement de 45,4 contre 48,4 (p = 0,48) et de 364,4 contre 402,8 m (p = 0,58). La PAP moyenne au départ par rapport au suivi est de 31,5 contre 24,8 mmHg (p = 0,005). La classe de l'IC selon la NYHA s'est améliorée d'au moins une position chez 85 % des patients. Les dépenses mesurables moyennes liées à l'IC avant l'implantation sont de 29 814 $ CA par patient par année et de 25 642 $ CA par patient par année après l'implantation (incluent le coût du dispositif). Conclusions: La surveillance de la PAP entraîne une réduction des HIC ainsi que des visites à l'urgence et à la clinique de fonction cardiaque, et une amélioration de la classe de l'IC selon la NYHA. Bien qu'une évaluation économique plus approfondie soit nécessaire, ces résultats militent en faveur de la surveillance de la PAP comme outil de prise en charge de l'IC sans incidence sur les coûts chez les patients adéquatement choisis dans un système de soins de santé financé par les fonds publics.

The COVID-19 Pandemic and Adult Cardiac Transplantation: Impact, Interventions, and Implications.

In this review, we provide a comprehensive overview of the impact of the COVID-19 pandemic on adult heart transplantation. We highlight the decline in the number of adult transplantations performed throughout the pandemic as a consequence of restrictions imposed on individual programs and hospitals. There were challenges to maintaining cardiac transplant activity at multiple levels, including organ donation in intensive care units, logistical difficulties with organ procurement, and rapidly changing resource considerations at health system and jurisdictional levels. We also review the impact of COVID-19 on cardiac transplant recipients. Despite the high rates of morbidity and mortality observed during the initial phases of the pandemic among heart transplant patients infected with COVID-19, the availability of effective vaccines, pre-exposure prophylaxis, and specific antiviral therapies have drastically improved outcomes over time. Vaccines have proven to be safe and effective in reducing infections and illness severity, but specific considerations in the immunocompromised solid organ transplant population apply, including the need for additional booster doses to achieve sufficient immunisation. We further outline the strong rationale for vaccination before transplantation wherever possible. Finally, the COVID-19 response created a number of barriers to safe and efficient post-transplantation care. Given the need for frequent evaluation and monitoring, especially in the first several months after cardiac transplantation, the pandemic provided the impetus to improve virtual care delivery and explore noninvasive rejection surveillance through gene expression profiling. We hope that lessons learned will allow us to prepare and pivot effectively during future pandemics and health care emergencies.

Ethics of Technology Practice: Beliefs and Behaviors of Certified Rehabilitation Counselors During the COVID-19 Pandemic.

The coronavirus (COVID-19) pandemic represented a critical moment for technology use within rehabilitation counseling. This study explored trends in the beliefs and behaviors of certified rehabilitation counselors (CRCs) regarding the ethical use of technology before and during the pandemic. Specifically, this study compared two groups of CRCs regarding the degree to which they engaged in 59 technology behaviors and whether they viewed each behavior to be ethical. Overall, group comparisons suggested an increased use of telephone, videoconferencing, and email to deliver counseling, assessment, and supervision services during the pandemic. Furthermore, supervision via videoconferencing and email in the pandemic were rated as more ethically appropriate than before the pandemic. As a general trend, synchronous modes of communication such as the telephone and video conferencing were rated as more ethically appropriate than asynchronous modes such as social networking and text messaging. Indicating a high degree of congruence between beliefs and behaviors, the technology practices viewed as most ethical were used the most often. Implications address the revisions to the Code of Professional Ethics for Rehabilitation Counselors regarding the ethical use of technology in rehabilitation counseling.

Sternum-Sparing Left Ventricular Assist Device Insertion Reduces Perioperative Transfusions and Blood Loss: A Single-Centre Canadian Experience.

Background: Left ventricular assist devices (LVADs) improve survival and quality of life, as either destination therapy or a bridge to transplantation. Although less-invasive hemisternotomy approaches for LVAD implantation are well studied, only a paucity of data is available in the literature on sternum-sparing bilateral minithoracotomy (BMT). Our centre has one of Canada's most extensive experiences with the BMT approach. Herein, we compared LVAD implantation via BMT with patients who received full median sternotomy or hemisternotomy. Methods: A single-centre retrospective review of data from Foothills Medical Centre (Calgary, Canada) was performed. Patients underwent LVAD insertion from 2012 to 2019, receiving either BMT (n = 11) or sternotomy (full median sternotomy or upper hemisternotomy with left minithoracotomy; n = 38). Intraoperative and early postoperative outcomes were assessed. Results: Patients who received BMT had significantly fewer transfusions of red blood cells, fresh frozen plasma, and platelets. The BMT group had lower chest-tube output in the first 12 hours. No significant differences occurred in ventilation time, intensive care unit length of stay, mortality, stroke, or reoperation for bleeding. Conclusions: Outcomes suggest that sternum-sparing LVAD implantation is a feasible alternative to sternotomy, leading to less postoperative blood loss and transfusion in the early postoperative period. Less transfusion is particularly valuable in this patient population, to reduce antigen-related sensitization prior to transplantation. Additional study is needed to assess potential benefits related to right heart function, postoperative mobility, and re-entry for transplantation.

Introduction: Les dispositifs d'assistance ventriculaire gauche (DAVG) contribuent à améliorer la survie et la qualité de vie, soit en traitement définitif ou en attente d'une transplantation. Bien que des approches d'hémisternotomie moins invasives lors de l'implantation d'un DAVG font l'objet d'un bon nombre d'études, seules de rares données sont disponibles dans la littérature sur la minithoracotomie bilatérale (MTB) sans ouverture du sternum. Notre centre possède l'une des expériences les plus approfondies au Canada de l'approche par MTB. Dans le présent article, nous avons comparé l'implantation du DAVG par MTB chez les patients qui avaient subi une sternotomie médiane complète ou une hémisternotomie. Méthodes: Nous avons réalisé une revue rétrospective unicentrique des données du Foothills Medical Centre (Calgary, Canada). Les patients avaient subi l'insertion d'un DAVG de 2012 à 2019, soit par MTB (n = 11) ou par sternotomie (sternotomie médiane complète ou hémisternotomie supérieure associée à une minithoracotomie gauche ; n = 38). Nous avons évalué les résultats peropératoires et postopératoires précoces. Résultats: Les patients qui avaient subi une MTB avaient eu significativement moins de transfusions de globules rouges, de plasma frais congelé et de plaquettes. Le groupe de MTB avait un plus faible débit du drain thoracique dans les 12 premières heures. Aucune différence significative dans la durée de ventilation, la durée du séjour aux soins intensifs, la mortalité, l'accident vasculaire cérébral ou la réopération en raison d'un saignement n'a été observée. Conclusions: Les résultats montrent que l'implantation de DAVG sans ouverture du sternum est une alternative à la sternotomie, qui entraîne moins de pertes de sang postopératoires et de transfusions en phase postopératoire précoce. Un moins grand nombre de transfusions est particulièrement important au sein de cette population de patients afin de réduire la sensibilisation aux antigènes avant la transplantation. D'autres études sont nécessaires pour évaluer les avantages potentiels liés à la fonction du cœur droit, la mobilité après l'opération et la réadmission pour une transplantation.

The PASTIS trial: Testing tadalafil for possible use in vascular cognitive impairment.

INTRODUCTION: There are few randomized clinical trials in vascular cognitive impairment (VCI). This trial tested the hypothesis that the PDE5 inhibitor tadalafil, a widely used vasodilator, increases cerebral blood flow (CBF) in older people with symptomatic small vessel disease, the main cause of VCI. METHODS: In a double-blind, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥7 days apart (randomized to order of treatment). The primary endpoint, change in subcortical CBF, was measured by arterial spin labelling. RESULTS: Tadalafil increased CBF non-significantly in all subcortical areas (N = 55, age: 66.8 (8.6) years) with greatest treatment effect within white matter hyperintensities (+9.8%, P = .0960). There were incidental treatment effects on systolic and diastolic blood pressure (-7.8, -4.9 mmHg; P < .001). No serious adverse events were observed. DISCUSSION: This trial did not identify a significant treatment effect of single-administration tadalafil on subcortical CBF. To detect treatment effects may require different dosing regimens.

Test-retest reliability of arterial spin labelling for cerebral blood flow in older adults with small vessel disease.

Cerebral small vessel disease (SVD) is common in older people and is associated with lacunar stroke, white matter hyperintensities (WMH) and vascular cognitive impairment. Cerebral blood flow (CBF) is reduced in SVD, particularly within white matter.Here we quantified test-retest reliability in CBF measurements using pseudo-continuous arterial spin labelling (pCASL) in older adults with clinical and radiological evidence of SVD (N=54, mean (SD): 66.9 (8.7) years, 15 females/39 males). We generated whole-brain CBF maps on two visits at least 7 days apart (mean (SD): 20 (19), range 7-117 days).Test-retest reliability for CBF was high in all tissue types, with intra-class correlation coefficient [95%CI]: 0.758 [0.616, 0.852] for whole brain, 0.842 [0.743, 0.905] for total grey matter, 0.771 [0.636, 0.861] for deep grey matter (caudate-putamen and thalamus), 0.872 [0.790, 0.923] for normal-appearing white matter (NAWM) and 0.780 [0.650, 0.866] for WMH (all p<0.001). ANCOVA models indicated significant decline in CBF in total grey matter, deep grey matter and NAWM with increasing age and diastolic blood pressure (all p<0.001). CBF was lower in males relative to females (p=0.013 for total grey matter, p=0.004 for NAWM).We conclude that pCASL has high test-retest reliability as a quantitative measure of CBF in older adults with SVD. These findings support the use of pCASL in routine clinical imaging and as a clinical trial endpoint.All data come from the PASTIS trial, prospectively registered at: https://eudract.ema.europa.eu (2015-001235-20, registered 13/05/2015), http://www.clinicaltrials.gov (NCT02450253, registered 21/05/2015).

Donor and Recipient Size Matching in Heart Transplantation With Predicted Heart and Lean Body Mass.

Donor and recipient size matching during heart transplant can be assessed using weight or predicted heart mass (PHM) ratios. We developed sex-specific allomteric equations for PHM and predicted lean body mass (PLBM) using the United Kingdom Biobank (UKB) and evaluated their predictive value in the United Network of Organ Sharing database. Donor and recipient size matching was based on weight, PHM and PLBM ratios. PHM was calculated using the Multiethnic Study of Atherosclerosis and UKB equations. PLBM was calculated using the UKB and National Health and Nutrition Examination Survey equations. Relative prognostic utility was compared using multivariable Cox analysis, adjusted for predictors of 1-year survival in the Scientific Registry of Transplant Recipients model. Of 53,648 adult patients in the United Network of Organ Sharing database between 1996 and 2016, 6528 (12.2%) died within the first year. In multivariable analysis, undersized matches by any metric were associated with increased 1-year mortality (all P < 0.01). Oversized matches were at increased risk using PHM or PLBM (all P < 0.01), but not weight ratio. There were significant differences in classification of size matching by weight or PHM in sex-mismatched donor-recipient pairs. A significant interaction was observed between pulmonary hypertension and donor undersizing (hazard ratio 1.15, P = 0.026) suggesting increased risk of undersizing in pulmonary hypertension. Donor and recipient size matching with simplified PHM and PLBM offered an advantage over total body weight and may be more important for sex-mismatched donor-recipient pairs. Donor undersizing is associated with worse outcomes in patients with pulmonary hypertension.

Retrospective Characterization of Initial Peste des petits ruminants Outbreaks (2008-2012) in the Democratic Republic of the Congo.

Peste des petits ruminants (PPR) is an acute, contagious viral disease of small ruminants, goats and sheep. The Democratic Republic of the Congo (DRC) was a PPR-free country until 2007, although in 2006, scare alerts were received from the east and the southwest of the country, reporting repeated mortalities, specifically in goats. In 2008, PPR outbreaks were seen in several villages in the west, leading to structured veterinary field operations. Blood, swabs and pathological specimens consisting of tissues from lungs, spleens, lymph nodes, kidneys, livers and hearts were ethically collected from clinically infected and/or dead animals, as appropriate, in 35 districts. Epidemiological information relating to major risk factors and socio-economic impact was progressively collected, revealing the deaths of 744,527 goats, which converted to a trade value of USD 35,674,600. Samples from infected and dead animals were routinely analyzed by the Central Veterinary Laboratory at Kinshasa for diagnosis, and after official declaration of PPR outbreaks by the FAO in July 2012, selected tissue samples were sent to The Pirbright Institute, United Kingdom, for genotyping. As a result of surveys undertaken between 2008 and 2012, PPR virus (PPRV)-specific antibodies were detected in 25 locations out of 33 tested (75.7%); PPRV nucleic acid was detected in 25 locations out of 35 (71.4%); and a typical clinical picture of PPR was observed in 23 locations out of 35 (65.7%). Analysis of the partial and full genome sequences of PPR viruses (PPRVs) obtained from lymphoid tissues of dead goats collected in Tshela in the DRC in 2012 confirmed the circulation of lineage IV PPRV, showing the highest homology (99.6-100%) with the viruses circulating in the neighboring countries of Gabon, in the Aboumi outbreak in 2011, and Nigeria (99.3% homology) in 2013, although recent outbreaks in 2016 and 2018 in the western part of the DRC that borders with East Africa demonstrated circulation of lineage II and lineage III PPRV.

Clinical Outcomes after Intravenous Alteplase in Elderly Patients with Acute Ischaemic Stroke: A Retrospective Analysis of Patients Treated at a Tertiary Neurology Centre in England from 2013 to 2018.

Intravenous thrombolysis with alteplase within 4.5 hours from symptom onset is a well-established treatment of acute ischaemic stroke (AIS). The aim was to compare alteplase for AIS between patients aged >80 and ≤80 years in our registry data, from 2013 to 2018. Mechanical thrombectomy cases were excluded. We assessed clinical outcomes over the six-year period and between patients aged over 80 and ≤80 years, using measures including the discharge modified Rankin Scale (mRS), 24-hour National Institutes of Health Stroke Scale (NIHSS) improvement, and symptomatic intracerebral haemorrhage (sICH) rate. Of a total of 805 AIS patients who received intravenous alteplase, 278 (34.5%) were over 80 years old, and 527 (65%) were younger. 616 (76.5%) received thrombolysis ≤ 3 hours after symptom onset and 189 (23.5%) within 3-4.5 hours. Median baseline mRS and NIHSS of the elderly cohort were 1 (IQR 0-5) and 13 (IQR 2-37), respectively, compared to the younger cohort 0 (IQR 0-5) and 9 (IQR 0-29). The sICH rate was 7.2% in the elderly and 4.6% in those ≤80 years, p = 0.05. NIHSS improved within 24 hours in 34% of the elderly cohort compared to 35% in the younger cohort. At hospital discharge, the mortality rate was 9% in the elderly cohort compared to the 6% in the younger cohort, p = 0.154. 25% of patients aged >80 years had mRS ≤ 2 compared to 47% in the younger patients (p < 0.0001). In conclusion, thrombolysis in elderly patients results in clinical improvement comparable to younger patients.

Characteristics of Clinicians Are Associated With Their Beliefs About ICD Deactivation: Insight From the DECIDE-HF Study.

BACKGROUND: Discussing goals of care with heart failure patients is recommended but is not done systematically, due to factors such as time and personal beliefs. A recent survey showed that one-fifth of clinicians believe that implantable cardioverter defibrillator deactivation (ICDD) is unethical or constitutes physician-assisted suicide. We investigated whether individuals' characteristics are associated with these beliefs. METHODS: The Decision-Making About Goals of Care for Hospitalized Patients With Heart Failure (DECIDE-HF) survey was given to healthcare providers at 9 hospitals to assess their perceived barriers to goals-of-care discussions. The association between respondent characteristics and their beliefs was examined using 2 adjusted logistic regression models. RESULTS: We included 760 clinicians (459 nurses, 94 fellows, and 207 cardiologists). The responses varied among professions, with the belief that ICDD is unethical considered to be important barrier by nurses (24%), fellows (10%), and staff (7%); P < 0.001). After adjusting for site, spirituality being more important in life (odds ratio [OR]: 2.21; 95% confidence interval [CI]:1.37-3.56; P = 0.001, compared to less important), region of training (Asia [OR: 5.88; 95% CI: 2.12-16.31; P = 0.001] and Middle East [OR: 5.55; 95% CI:1.57-19.63; P = 0.008] compared to Canada), and years in practice (OR: 1.32; 95% CI: 1.07-1.63; P = 0.01 per decade) influenced beliefs about ICDD being unethical, with similar results for the belief that ICDD represents physician-assisted suicide. CONCLUSIONS: Sociocultural factors, region of training, and profession influence clinicians' beliefs about ICDD being unethical and representing physician-assisted suicide. These factors and beliefs must be acknowledged when facing the delicate issue of end-of-life discussion.

CONTEXTE: Une discussion sur les objectifs de soins avec les patients atteints d'insuffisance cardiaque est recommandée, mais elle n'est pas systématiquement menée en raison de facteurs tels que les contraintes de temps et les croyances personnelles. Selon une enquête récente, un cinquième des cliniciens croient qu'une désactivation d'un défibrillateur cardioverteur implantable (DDCI) est contraire à l'éthique ou représente un suicide assisté par le médecin. Nous avons vérifié si des caractéristiques individuelles sont associées à ces croyances. MÉTHODOLOGIE: L'enquête DECIDE-HF ( Deci sion-Making About Goals of Care for Hospitalize d Pati e nts With H eart F ailure) a été réalisée chez des professionnels de la santé de neuf hôpitaux dans le but d'évaluer les obstacles qu'ils percevaient face à la discussion sur les objectifs de soins. Le lien entre les caractéristiques des répondants et leurs croyances a été analysé à l'aide de deux modèles ajustés de régression logistique. RÉSULTATS: Nous avons interrogé 760 cliniciens (459 infirmières, 94 médecins associés et 207 cardiologues). Les réponses ont varié d'une profession à l'autre, la croyance qu'une DDCI est contraire à l'éthique étant considérée comme un obstacle important par 24 % des infirmières, 10 % des médecins associés et 7 % des membres du personnel (p < 0,001). Après ajustement selon l'établissement, l'importance de la spiritualité dans la vie (très important [rapport de cotes {RC}] = 2,21; intervalle de confiance [IC] à 95 % : 1,37-3,56; p = 0,001 comparativement à moins important), la région d'obtention du diplôme (Asie [RC = 5,88; IC à 95 % : 2,12-16,31; p = 0,001] et Moyen-Orient [RC = 5,55; IC à 95 % : 1,57-19,63; p = 0,008] comparativement au Canada) et le nombre d'années d'exercice (RC = 1,32; IC à 95 % : 1,07-1,63; p = 0,01 par tranche de 10 ans) ont influencé les croyances voulant qu'une DDCI soit contraire à l'éthique, et les résultats ont été similaires pour la croyance selon laquelle une DDCI représente un suicide assisté par le médecin. CONCLUSIONS: Des facteurs socioculturels, la région de formation et la profession influencent les croyances des cliniciens sur la DDCI et le fait qu'ils la considèrent comme étant une démarche contraire à l'éthique ou un suicide assisté par un médecin. Ces facteurs et croyances doivent être reconnus lorsque vient le temps d'aborder la délicate question de la discussion sur la fin de vie.

Myocarditis and Pericarditis After COVID-19 mRNA Vaccination: Practical Considerations for Care Providers.

The mRNA vaccines against COVID-19 infection have been effective in reducing the number of symptomatic cases worldwide. With widespread uptake, case series of vaccine-related myocarditis/pericarditis have been reported, particularly in adolescents and young adults. Men tend to be affected with greater frequency, and symptom onset is usually within 1 week after vaccination. Clinical course appears to be mild in most cases. On the basis of the available evidence, we highlight a clinical framework to guide providers on how to assess, investigate, diagnose, and report suspected and confirmed cases. In any patient with highly suggestive symptoms temporally related to COVID-19 mRNA vaccination, standardized workup includes serum troponin measurement and polymerase chain reaction testing for COVID-19 infection, routine additional lab work, and a 12-lead electrocardiogram. Echocardiography is recommended as the imaging modality of choice for patients with unexplained troponin elevation and/or pathologic electrocardiogram changes. Cardiovascular specialist consultation and hospitalization should be considered on the basis of the results of standard investigations. Treatment is largely supportive, and myocarditis/pericarditis that is diagnosed according to defined clinical criteria should be reported to public health authorities in every jurisdiction. Finally, we recommend COVID-19 vaccination in all individuals in accordance with the Health Canada and National Advisory Committee on Immunization guidelines. In patients with suspected myocarditis/pericarditis after the first dose of an mRNA vaccine, deferral of a second dose is recommended until additional reports become available.

Long COVID-19: A Primer for Cardiovascular Health Professionals, on Behalf of the CCS Rapid Response Team.

It is now widely recognized that COVID-19 illness can be associated with significant intermediate and potentially longer-term physical limitations. The term, "long COVID-19" is used to define any patient with persistent symptoms after acute COVID-19 infection (ie, after 4 weeks). It is postulated that cardiac injury might be linked to symptoms that persist after resolution of acute infection, as part of this syndrome. The Canadian Cardiovascular Society Rapid Response Team has generated this document to provide guidance to health care providers on the optimal management of patients with suspected cardiac complications of long COVID-19.