A Markov analysis of azacitidine and venetoclax vs induction chemotherapy for medically fit patients with AML.

ABSTRACT: Although induction chemotherapy (IC) is the standard of care in medically fit patients with newly diagnosed acute myeloid leukemia (AML), limited retrospective data indicate that patients at adverse-risk may benefit from azacytidine and venetoclax (aza-ven). Our goal was to perform a Markov decision analysis to determine whether IC or aza-ven is the optimal induction regimen in this population. Using the TreeAge software, Markov models were created for adverse-risk and intermediate-risk cohorts. A systematic review of the literature informed the transition probabilities and utilities included in the analyses. Our primary outcome was quality-adjusted life years (QALYs) gained over 5 years after diagnosis. Overall, patients at adverse risk treated with IC gained 1.4 QALYs, compared with 2.0 QALYs in patients treated with aza-ven. Patients at adverse risk treated with IC and allogeneic stem cell transplantation (allo-SCT), IC, aza-ven and allo-SCT, or aza-ven gained 2.1, 1.5, 3.0, and 1.9 QALYs, respectively. Meanwhile, patients at intermediate risk treated with IC gained 2.0 QALY, compared with 1.7 QALY in patients treated with aza-ven. Patients at intermediate risk treated with IC and allo-SCT, IC, aza-ven and allo-SCT, and aza-ven gained 2.7, 2.3, 2.6, and 1.8 QALYs, respectively. We have demonstrated that medically fit patients with newly diagnosed adverse-risk AML may benefit from treatment with aza-ven over those treated with IC, whereas IC remains the preferred approach for patients at intermediate risk. Our work challenges the use of the European LeukemiaNet risk classification for patients treated with aza-ven and highlights the need for prospective investigation into aza-ven as induction therapy for medically fit patients.

Social Deprivation and Post-TAVR Outcomes in Ontario, Canada: A Population-Based Study.

Background Transcatheter aortic valve replacement (TAVR)/intervention has become the standard of care for treatment of severe aortic stenosis across the spectrum of risk. There are socioeconomic disparities in access to TAVR. The impact of these disparities on postprocedural outcomes remains unknown. Our objective was to examine the association between neighborhood-level social deprivation and post-TAVR mortality and hospital readmission. Methods and Results We conducted a population-based retrospective cohort study of all 4145 patients in Ontario, Canada, who received TAVR from April 1, 2017, to March 31, 2020. Our co-primary outcomes were 1-year postprocedure mortality and 1-year postprocedure readmission. Using Cox proportional hazards models for mortality and cause-specific competing risk hazard models for readmission, we evaluated the relationship between neighborhood-level measures of residential instability, material deprivation, and concentration of racial and ethnic groups with post-TAVR outcomes. After multivariable adjustment, we found a statistically significant relationship between residential instability and postprocedural 1-year mortality, ranging from a hazard ratio of 1.64 to a hazard ratio of 2.05. There was a significant association between the highest degree of residential instability and 1-year readmission (hazard ratio, 1.23 [95% CI, 1.01-1.49]). There was no association between material deprivation and concentration of racial and ethnic groups with post-TAVR outcomes. Conclusions Residential instability was associated with increased risk for post-TAVR mortality, and the highest quintile of residential instability was associated with increased post-TAVR readmission. To reduce health disparities and promote an equitable health care system, further research and policy interventions will be required to identify and support economically and socially minoritized patients undergoing TAVR.

Risk Factors for Hospital Readmission Post-Transcatheter Aortic Valve Implantation in the Contemporary Era: A Systematic Review.

Background: Despite transcatheter aortic valve implantation (TAVI) becoming a widely accepted therapeutic option for the management of aortic stenosis, post-procedure readmission rates remain high. Rehospitalization is associated with negative patient outcomes, as well as increased healthcare costs, and has therefore been identified as an important target for quality improvement. Strategies to reduce the post-TAVI readmission rate are needed but require the identification of patients at high risk for rehospitalization. Our systematic review aims to identify predictors of post-procedure readmission in patients eligible for TAVI. Methods: We conducted a comprehensive search of the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases for the time period from 2015 to the present for articles evaluating risk factors for rehospitalization post-TAVI with a follow-up period of at least 30 days in adults age ≥ 70 years with aortic stenosis. The quality of included studies was evaluated using the Newcastle-Ottawa Scale. We present the results as a qualitative narrative review. Results: We identified 49 studies involving 828,528 patients. Post-TAVI readmission is frequent, and rates vary (14.9% to 54.3% at 1 year). The most-frequent predictors identified for both 30-day and 1-year post-TAVI readmission are atrial fibrillation, lung disease, renal disease, diabetes mellitus, in-hospital life-threatening bleeding, and non-femoral access. Conclusions: This systematic review identifies the most-common predictors for 30-day and 1-year readmission post-TAVI, including comorbidities and potentially modifiable procedural approaches and complications. These predictors can be used to identify patients at high-risk for readmission who are most likely to benefit from increased support and follow-up post-TAVI.

Contexte: Bien que l'implantation valvulaire aortique par cathéter (IVAC) soit maintenant une option thérapeutique largement acceptée pour la prise en charge de la sténose aortique, les taux de réadmission des patients après cette intervention demeurent élevés. La réhospitalisation est associée à des résultats de santé défavorables pour les patients ainsi qu'à des coûts de soins de santé plus élevés, ce qui en fait une cible importante pour l'amélioration de la qualité des soins. Des stratégies de réduction des taux de réadmission après l'IVAC sont nécessaires, mais elles exigent de repérer les patients qui présentent des risques de réhospitalisation plus élevés. Notre revue systématique vise à cerner les facteurs prédictifs de réhospitalisation après l'intervention chez les patients admissibles à une IVAC. Méthodologie: Nous avons effectué une recherche exhaustive dans les bases de données MEDLINE, Embase et Cochrane Central Register of Controlled Trials (CENTRAL) pour trouver les articles publiés entre 2015 et aujourd'hui qui rapportent les facteurs de risque de réhospitalisation suite à une IVAC chez les adultes âgés de 70 ans et plus atteints de sténose aortique, avec une période de suivi d'au moins 30 jours. La qualité des études retenues a été évaluée à l'aide de l'échelle Newscastle-Ottawa. Les résultats sont présentés sous forme d'une revue narrative qualitative. Résultats: Nous avons retenu 49 études, réalisées auprès de 828 528 patients. La réhospitalisation après l'IVAC était fréquente, et les taux étaient variables (de 14,9 % à 54,3 % après un an). Les facteurs prédictifs de réhospitalisation les plus fréquents, déterminés 30 jours et un an après l'IVAC, étaient la fibrillation auriculaire, la maladie pulmonaire, la maladie rénale, le diabète, l'hémorragie menaçant le pronostic vital lors du séjour à l'hôpital, et l'approche par une voie non fémorale. Conclusions: La présente revue systématique nous a permis de caractériser les facteurs prédictifs les plus fréquents de réhospitalisation, 30 jours et un an après une IVAC, dont certaines affections concomitantes et certains facteurs potentiellement modifiables liés aux approches d'intervention et aux complications. Ces facteurs pourraient permettre de cibler les patients à risque élevé de réhospitalisation, qui seraient les plus susceptibles de bénéficier d'un soutien et d'un suivi accrus après une IVAC.

A rapid review of the pathoetiology, presentation, and management of delirium in adults with COVID-19.

Background COVID-19 causes significant morbidity and mortality. Despite the high prevalence of delirium and delirium-related symptoms in COVID-19 patients, data and evidence-based recommendations on the pathophysiology and management of delirium are limited. Objective We conducted a rapid review of COVID-19-related delirium literature to provide a synthesis of literature on the prevalence, pathoetiology, and management of delirium in these patients. Methods Systematic searches of Medline, Embase, PsycInfo, LitCovid, WHO-COVID-19, and Web of Science electronic databases were conducted. Grey literature was also reviewed, including preprint servers, archives, and websites of relevant organizations. Search results were limited to the English language. We included literature focused on adults with COVID-19 and delirium. Papers were excluded if they did not mention signs or symptoms of delirium. Results 229 studies described prevalence, pathoetiology, and/or management of delirium in adults with COVID-19. Delirium was rarely assessed with validated tools. Delirium affected >50% of all patients with COVID-19 admitted to the ICU. The etiology of COVID-19 delirium is likely multifactorial, with some evidence of direct brain effect. Prevention remains the cornerstone of management in these patients. To date, there is no evidence to suggest specific pharmacological strategies. Discussion Delirium is common in COVID-19 and may manifest from both indirect and direct effects on the central nervous system. Further research is required to investigate contributing mechanisms. As there is limited empirical literature on delirium management in COVID-19, management with non-pharmacological measures and judicious use of pharmacotherapy is suggested.

Predictors of Long-term Cardiovascular Versus Non-cardiovascular Mortality and Repeat Intervention in Patients Having Transcatheter Aortic Valve Implantation.

There is a paucity of literature characterizing the risk of long-term mortality and reintervention after transcatheter aortic valve implantation (TAVI). Addressing this gap has become increasingly relevant with the inclusion of intermediate and low surgical risk patients and the need for data to inform their long-term management. We sought to investigate the long-term trends and predictors of cardiovascular versus noncardiovascular mortality as well as reintervention in post-TAVI patients. Our cohort consisted of 5,406 patients who underwent TAVI in Ontario, Canada from 2011 to 2018. We used Kaplan-Meier analysis to estimate 7-year all-cause mortality and a Cox proportional hazard model to identify demographic, co-morbid, and procedural predictors. Similarly, cumulative incidence functions were used to estimate cardiovascular versus noncardiovascular mortality at 5 years, with predictors identified through Fine-Gray models. The Kaplan-Meier estimate for 7-year all-cause mortality in our cohort was 67%; this was driven by a number of co-morbidities including congestive heart failure and liver disease. We found that cardiovascular death was more likely for approximately the first 2 years post-TAVI whereas noncardiovascular death was more likely from this point to the end of the study. We identified a number of factors that uniquely modified the risk of either cardiovascular or noncardiovascular mortality. Only 1.6% of patients who underwent repeat intervention. The distinct factors associated with cardiovascular versus noncardiovascular death suggest different approaches to short-term and long-term surveillance of patients post-TAVI by both the heart team and primary care providers.

Impact of procedural capacity on transcatheter aortic valve replacement wait times and outcomes: a study of regional variation in Ontario, Canada.

BACKGROUND: There has been rapid growth in the demand for transcatheter aortic valve replacement (TAVR), which has the potential to overwhelm current capacity. This imbalance between demand and capacity may lead to prolonged wait times, and subsequent adverse outcomes while patients are on the waitlist. We sought to understand the relationship between regional differences in capacity, TAVR wait times and morbidity/mortality on the waitlist. METHODS AND RESULTS: We modelled the effect of TAVR capacity, defined as the number of TAVR procedures per million residents/region, on the hazard of having a TAVR in Ontario from April 2012 to March 2017. Our primary outcome was the time from referral to a TAVR procedure or other off-list reasons on the waitlist/end of the observation period as measured in days. Clinical outcomes of interest were all-cause mortality, all-cause hospitalisations or heart failure-related hospitalisations while on the waitlist for TAVR. There was an almost fourfold difference in TAVR capacity across the 14 regions in Ontario, ranging from 31.5 to 119.5 TAVR procedures per million residents. The relationship between TAVR capacity and wait times was complex and non-linear. In general, increased capacity was associated with shorter wait times (p<0.001), reduced mortality (HR 0.94; p=0.08) and all-cause hospitalisations (p=0.009). CONCLUSIONS: The results of the present study have important policy implications, suggesting that there is a need to improve TAVR capacity, as well as develop wait-time strategies to triage patients, in order to decrease wait times and mitigate the hazard of adverse patient outcomes while on the waitlist.

Comparing and Contrasting MERS, SARS-CoV, and SARS-CoV-2: Prevention, Transmission, Management, and Vaccine Development.

The COVID-19 pandemic is responsible for an unprecedented disruption to the healthcare systems and economies of countries around the world. Developing novel therapeutics and a vaccine against SARS-CoV-2 requires an understanding of the similarities and differences between the various human coronaviruses with regards to their phylogenic relationships, transmission, and management. Phylogenetic analysis indicates that humans were first infected with SARS-CoV-2 in late 2019 and the virus rapidly spread from the outbreak epicenter in Wuhan, China to various parts of the world. Multiple variants of SARS-CoV-2 have now been identified in particular regions. It is apparent that MERS, SARS-CoV, and SARS-CoV-2 present with several common symptoms including fever, cough, and dyspnea in mild cases, but can also progress to pneumonia and acute respiratory distress syndrome. Understanding the molecular steps leading to SARS-CoV-2 entry into cells and the viral replication cycle can illuminate crucial targets for testing several potential therapeutics. Genomic and structural details of SARS-CoV-2 and previous attempts to generate vaccines against SARS-CoV and MERS have provided vaccine targets to manage future outbreaks more effectively. The coordinated global response against this emerging infectious disease is unique and has helped address the need for urgent therapeutics and vaccines in a remarkably short time.

Neutrophil Extracellular Trap Formation: Physiology, Pathology, and Pharmacology.

Neutrophil extracellular traps (NETs), a unique DNA framework decorated with antimicrobial peptides, have been in the scientific limelight for their role in a variety of pathologies ranging from cystic fibrosis to cancer. The formation of NETs, as well as relevant regulatory mechanisms, physiological factors, and pharmacological agents have not been systematically discussed in the context of their beneficial and pathological aspects. Novel forms of NET formation including vital NET formation continue to be uncovered, however, there remain fundamental questions around established mechanisms such as NADPH-oxidase (Nox)-dependent and Nox-independent NET formation. Whether NET formation takes place in the tissue versus the bloodstream, internal factors (e.g. reactive oxygen species (ROS) production and transcription factor activation), and external factors (e.g. alkaline pH and hypertonic conditions), have all been demonstrated to influence specific NET pathways. Elements of neutrophil biology such as transcription and mitochondria, which were previously of unknown significance, have been identified as critical mediators of NET formation through facilitating chromatin decondensation and generating ROS, respectively. While promising therapeutics inhibiting ROS, transcription, and gasdermin D are being investigated, neutrophil phagocytosis plays a critical role in host defense and any therapies targeting NET formation must avoid impairing the physiological functions of these cells. This review summarizes what is known in the many domains of NET research, highlights the most relevant challenges in the field, and inspires new questions that can bring us closer to a unified model of NET formation.