Induction therapy in heart transplantation: A systematic review and network meta-analysis for developing evidence-based recommendations.

INTRODUCTION: Induction therapy (IT) utility in heart transplantation (HT) remains contested. Commissioned by a clinical-practice guidelines panel to evaluate the effectiveness and safety of IT in adult HT patients, we conducted this systematic review and network meta-analysis (NMA). METHODS: We searched for studies from January 2000 to October 2022, reporting on the use of any IT agent in adult HT patients. Based on patient-important outcomes, we performed frequentist NMAs separately for RCTs and observational studies with adjusted analyses, and assessed the certainty of evidence using the GRADE framework. RESULTS: From 5156 publications identified, we included 7 RCTs and 12 observational studies, and report on two contemporarily-used IT agents-basiliximab and rATG. The RCTs provide only very low certainty evidence and was uninformative of the effect of the two agents versus no IT or one another. With low certainty in the evidence from observational studies, basiliximab may increase 30-day (OR 1.13; 95% CI 1.06-1.20) and 1-year (OR 1.11; 95% CI 1.02-1.22) mortality compared to no IT. With low certainty from observational studies, rATG may decrease 5-year cardiac allograft vasculopathy (OR .82; 95% CI .74-.90) compared to no IT, as well as 30-day (OR .85; 95% CI .80-.92), 1-year (OR .87; 95% CI .79-.96), and overall (HR .84; 95% CI .76-.93) mortality compared to basiliximab. CONCLUSION: With low and very low certainty in the synthetized evidence, these NMAs suggest possible superiority of rATG compared to basiliximab, but do not provide compelling evidence for the routine use of these agents in HT recipients.

Heart failure clinic inclusion and exclusion criteria: cross-sectional study of clinic's and referring provider's perspectives.

OBJECTIVES: There are substantial variations in entry criteria for heart failure (HF) clinics, leading to variations in whom providers refer for these life-saving services. This study investigated actual versus ideal HF clinic inclusion or exclusion criteria and how that related to referring providers' perspectives of ideal criteria. DESIGN, SETTING AND PARTICIPANTS: Two cross-sectional surveys were administered via research electronic data capture to clinic providers and referrers (eg, cardiologists, family physicians and nurse practitioners) across Canada. MEASURES: Twenty-seven criteria selected based on the literature and HF guidelines were tested. Respondents were asked to list any additional criteria. The degree of agreement was assessed (eg, Kappa). RESULTS: Responses were received from providers at 48 clinics (37.5% response rate). The most common actual inclusion criteria were newly diagnosed HF with reduced or preserved ejection fraction, New York Heart Association class IIIB/IV and recent hospitalisation (each endorsed by >74% of respondents). Exclusion criteria included congenital aetiology, intravenous inotropes, a lack of specialists, some non-cardiac comorbidities and logistical factors (eg, rurality and technology access). There was the greatest discordance between actual and ideal criteria for the following: inpatient at the same institution (κ=0.14), congenital heart disease, pulmonary hypertension or genetic cardiomyopathies (all κ=0.36). One-third (n=16) of clinics had changed criteria, often for non-clinical reasons. Seventy-three referring providers completed the survey. Criteria endorsed more by referrers than clinics included low blood pressure with a high heart rate, recurrent defibrillator shocks and intravenous inotropes-criteria also consistent with guidelines. CONCLUSIONS: There is considerable agreement on the main clinic entry criteria, but given some discordance, two levels of clinics may be warranted. Publicising evidence-based criteria and applying them systematically at referral sources could support improved HF patient care journeys and outcomes.

Use of induction therapy post-heart transplantation: Clinical practice recommendations based on systematic review and network meta-analysis of evidence.

BACKGROUND: The use of induction therapy (IT) agents in the early post-heart transplant period remains controversial. The following recommendations aim to provide guidance on the use of IT agents, including Basiliximab and Thymoglobulin, as part of routine care in heart transplantation (HTx). METHODS: We recruited an international, multidisciplinary panel of 15 stakeholders, including patient partners, transplant cardiologists and surgeons, nurse practitioners, pharmacists, and methodologists. We commissioned a systematic review on benefits and harms of IT on patient-important outcomes, and another on patients' values and preferences to inform our recommendations. We used the GRADE framework to summarize our findings, rate certainty in the evidence, and develop recommendations. The panel considered the balance between benefits and harms, certainty in the evidence, and patient's values and preferences, to make recommendations for or against the routine post-operative use of Thymoglobulin or Basiliximab. RESULTS: The panel made recommendations on three major clinical problems in HTx: (1) We suggest against the routine post-operative use of Basiliximab compared to no IT, (2) we suggest against the routine use of Thymoglobulin compared to no IT, and (3) for those patients for whom IT is deemed desirable, we suggest for the use of Thymoglobulin as compared to Basiliximab. CONCLUSION: This report highlights gaps in current knowledge and provides directions for clinical research in the future to better understand the clinical utility of IT agents in the early post heart transplant period, leading to improved management and care.

Longitudinal outcomes of COVID-19 in solid organ transplant recipients from 2020 to 2023.

Data regarding coronavirus disease 2019 (COVID-19) outcomes in solid organ transplant recipients (SOTr) across severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) waves, including the impact of different measures, are lacking. This cohort study, conducted from March 2020 to May 2023 in Toronto, Canada, aimed to analyze COVID-19 outcomes in 1975 SOTr across various SARS-CoV-2 waves and assess the impact of preventive and treatment measures. The primary outcome was severe COVID-19, defined as requiring supplemental oxygen, with secondary outcomes including hospitalization, length of stay, intensive care unit (ICU) admission, and 30-day and 1-year all-cause mortality. SARS-CoV-2 waves were categorized as Wildtype/Alpha/Delta (318 cases, 16.1%), Omicron BA.1 (268, 26.2%), Omicron BA.2 (268, 13.6%), Omicron BA.5 (561, 28.4%), Omicron BQ.1.1 (188, 9.5%), and Omicron XBB.1.5 (123, 6.2%). Severe COVID-19 rate was highest during the Wildtype/Alpha/Delta wave (44.6%), and lower in Omicron waves (5.7%-16.1%). Lung transplantation was associated with severe COVID-19 (OR: 4.62, 95% CI: 2.71-7.89), along with rituximab treatment (OR: 4.24, 95% CI: 1.04-17.3), long-term corticosteroid use (OR: 3.11, 95% CI: 1.46-6.62), older age (OR: 1.51, 95% CI: 1.30-1.76), chronic lung disease (OR: 2.11, 95% CI: 1.36-3.30), chronic kidney disease (OR: 2.18, 95% CI: 1.17-4.07), and diabetes (OR: 1.97, 95% CI: 1.37-2.83). Early treatment and ≥3 vaccine doses were associated with reduced severity (OR: 0.29, 95% CI: 0.19-0.46, and 0.35, 95% CI: 0.21-0.60, respectively). Tixagevimab/cilgavimab and bivalent boosters did not show a significant impact. The study concludes that COVID-19 severity decreased across different variants in SOTr. Lung transplantation was associated with worse outcomes and may benefit more from preventive and early therapeutic interventions.

Utilization of Shock Team and Veno-Arterial Extracorporeal Membrane Oxygenation (VA-ECMO) in the Management of Cardiogenic Shock in Northern Ontario.

Background: Despite advancements in critical care and coronary revascularization, cardiogenic shock (CS) outcomes remain poor. Implementing a shock team and use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) have been associated with improved CS outcomes, but its feasibility in remote and rural areas remains unknown. Methods: This retrospective study included patients with CS who required mechanical circulatory support (MCS) at Health Sciences North, Sudbury, Ontario. The analysis aimed to accomplish 2 objectives: first, to review the outcomes associated with use of Impella (Abiomed, Danvers, MA) and, second, to assess the feasibility of establishing a shock team to facilitate the local implementation of VA-ECMO. The primary endpoint was in-hospital mortality. Results: The outcomes of 15 patients with CS who received Impella between 2015 and 2021 were reviewed. Their average age was 65 years (standard deviation [SD]: 13), and 8 patients (53%) were female. CS was ischemic in 12 patients (80%). Transfemoral Impella CP (cardiac power) was the most frequently used (93%). Thirteen patients (87%) died during the index hospital stay post-Impella because of progressive circulatory failure. The shock team was established following consultations with several Canadian MCS centres, leading to the development of a protocol to guide use of MCS. There have been 4 cases in which percutaneous VA-ECMO using Cardiohelp (Getinge/Maquet, Wayne, NJ) has been used; 3 (75%) survived beyond the index hospitalization. Conclusions: This analysis demonstrated the feasibility of implementing a shock team in remote Northern Ontario, enabling the use of VA-ECMO with success in a centre with a sizeable rural catchment area. This initiative helps address the gap in cardiac care outcomes between rural and urban areas in Ontario.

Introduction: En dépit des avancées des soins aux patients en phase critique et de la revascularisation coronarienne, les résultats du choc cardiogénique (CC) semblent mauvais. La mise en place d'une équipe de choc et l'utilisation de l'oxygénation extracorporelle (ECMO, de l'anglais extracorporeal membrane oxygenation) par voie veino-artérielle (VA) (VA-ECMO) ont été associées à de meilleurs résultats du CC, mais on ignore sa faisabilité dans les régions éloignées et rurales. Méthodes: La présente étude rétrospective portait sur des patients en CC qui ont eu besoin d'une assistance circulatoire mécanique (ACM) à Horizon Santé-Nord, à Sudbury, en Ontario. L'analyse visait 2 objectifs : le premier objectif était de passer en revue les résultats associés à l'utilisation de Impella (Abiomed, Danvers, MA) et, le deuxième était d'évaluer la faisabilité de la mise en place d'une équipe de choc pour faciliter la mise en œuvre locale de la VA-ECMO. Le principal critère d'évaluation était la mortalité intrahospitalière. Résultats: Nous avons passé en revue les résultats cliniques de 15 patients ayant subi un CC qui avaient reçu une Impella entre 2015 et 2021. L'âge moyen était de 65 ans (écart type [ET] : 13), et 8 patients (53 %) étaient des femmes. Le CC était d'origine ischémique chez 12 patients (80 %). L'Impella CP (cardiac power, soit la pompe cardiaque) par voie transfémorale était la plus fréquemment utilisée (93 %). Treize patients (87 %) sont morts durant le séjour de référence à l'hôpital après l'utilisation de l'Impella en raison d'insuffisance circulatoire progressive. La mise en place de l'équipe de choc à la suite des consultations dans plusieurs centres canadiens d'ACM a mené à l'élaboration d'un protocole d'utilisation de l'ACM. Il y a eu 4 cas chez lesquels la VA-ECMO par voie percutanée à l'aide de Cardiohelp (Getinge/Maquet, Wayne, New Jersey, É.-U.) a été utilisée ; 3 (75 %) ont survécu après l'hospitalisation de référence. Conclusions: Cette analyse a démontré la faisabilité de la mise en place d'une équipe de choc dans les régions éloignées du nord de l'Ontario, qui a permis d'utiliser efficacement la VA-ECMO dans un centre d'une circonscription hospitalière rurale non négligeable. Cette initiative aide à remédier à l'écart des résultats en soins cardiaques entre les régions rurales et urbaines de l'Ontario.

Sperm exposure to accessory gland secretions alters the transcriptomic response of the endometrium in cattle.

In cattle, mating to intact, but not vasectomised, bulls has been shown to modify the endometrial transcriptome, suggesting an important role of sperm in the modulation of the uterine environment in this species. However, it is not clear whether these changes are driven by intrinsic sperm factors, or by factors of accessory gland (AG) origin that bind to sperm at ejaculation. Therefore, the aim of the present study was to determine whether ejaculated sperm, which are suspended in the secretions of the AGs, elicit a different endometrial transcriptomic response than epididymal sperm, which have never been exposed to AG factors. To this end, bovine endometrial explants collected from heifers in oestrus were (co-)incubated for 6 h alone (control), or with epididymal sperm or ejaculated sperm, following which transcriptomic changes in the endometrium were evaluated. Epididymal sperm elicited a more dramatic endometrial response than ejaculated sperm, in terms of the number of differentially expressed genes (DEGs). Indeed, RNA-sequencing data analysis revealed 1912 DEGs in endometrial explants exposed to epididymal sperm compared with control explants, whereas 115 DEGs were detected between endometrial explants exposed to ejaculated sperm in comparison to control explants. The top pathways associated with genes upregulated by epididymal sperm included T cell regulation and TNF, NF-KB and IL17 signalling. Interestingly, ejaculated sperm induced downregulation of genes associated with T cell immunity and Th17 differentiation, and upregulation of genes involved in NF-KB signalling, in comparison to epididymal sperm. These data indicate that factors of AG origin modulate the interaction between sperm and the endometrium in cattle.

Horizontal gene transfer facilitates the molecular reverse-evolution of antibiotic sensitivity in experimental populations of H. pylori.

Reversing the evolution of traits harmful to humans, such as antimicrobial resistance, is a key ambition of applied evolutionary biology. A major impediment to reverse evolution is the relatively low spontaneous mutation rates that revert evolved genotypes back to their ancestral state. However, the repeated re-introduction of ancestral alleles by horizontal gene transfer (HGT) could make reverse evolution likely. Here we evolve populations of an antibiotic-resistant strain of Helicobacter pylori in growth conditions without antibiotics while introducing an ancestral antibiotic-sensitive allele by HGT. We evaluate reverse evolution using DNA sequencing and find that HGT facilitates the molecular reverse evolution of the antibiotic resistance allele, and that selection for high rates of HGT drives the evolution of increased HGT rates in low-HGT treatment populations. Finally, we use a theoretical model and carry out simulations to infer how the fitness costs of antibiotic resistance, rates of HGT and effects of genetic drift interact to determine the probability and predictability of reverse evolution.

The Turnout Gap in Surveys: Explanations and Solutions.

Postelection surveys regularly overestimate voter turnout by 10 points or more. This article provides the first comprehensive documentation of the turnout gap in three major ongoing surveys (the General Social Survey, Current Population Survey, and American National Election Studies), evaluates explanations for it, interprets its significance, and suggests means to continue evaluating and improving survey measurements of turnout. Accuracy was greater in face-to-face than telephone interviews, consistent with the notion that the former mode engages more respondent effort with less social desirability bias. Accuracy was greater when respondents were asked about the most recent election, consistent with the hypothesis that forgetting creates errors. Question wordings designed to minimize source confusion and social desirability bias improved accuracy. Rates of reported turnout were lower with proxy reports than with self-reports, which may suggest greater accuracy of proxy reports. People who do not vote are less likely to participate in surveys than voters are.

Successful management of stuttering priapism using home self-injections of the alpha-agonist metaraminol

Low-flow priapism can result in impotence if treatment is delayed, yet patients with recurrent priapism often suffer delay before therapy. We describe management of recurrent priapism using self-administered injections of intracavernosal metaraminol (AramineÖ, Merck), a long-acting vasoconstricting amine that is considered safer than epinephrine. The patient injects as often as once daily using 5-10 mg of drug. Our patient reports rapid detumescence and has not required emergency room visits since starting injections. He denies complications. Treatment of priapism using metaraminol has been suggested in the hospital setting; however, this is the first report of successful home self-administration of the drug.