Restrictive vs Liberal Blood Transfusions for Patients with Acute Myocardial Infarction and Anaemia by Heart Failure Status: An RCT Subgroup Analysis.

BACKGROUND: Red blood cell transfusion can cause fluid overload. We evaluated the interaction between heart failure (HF) at baseline and transfusion strategy on outcomes in acute myocardial infarction (AMI). METHODS: We used data from the randomized REALITY trial (https://www. CLINICALTRIALS: gov/study/NCT02648113), comparing restrictive versus liberal transfusion strategies in patients with AMI and anaemia. HF was defined as history of HF or Killip class > 1 at randomization. Primary outcome was major adverse cardiovascular events (MACE: composite of all-cause death, non-recurrent AMI, stroke, or emergency revascularization prompted by ischaemia) at 30 days. RESULTS: Among 658 randomized patients, 311 (47.3%) had HF. HF patients had higher rates of MACE at 30 days and 1 year, and higher rates of non-fatal new-onset HF. There was no interaction between HF and effect of randomized assignment on the primary outcome or non-fatal new-onset HF. A liberal transfusion strategy was associated with increased all-cause death at 30 days and at 1 year in HF patients (Pinteraction = 0.009 and P = 0.049, respectively). The main numerical difference in cause of death between restrictive and liberal strategies was death by HF at 30 days (4 vs 11). CONCLUSIONS: HF is frequent in AMI patients with anaemia and is associated with higher risk of MACE (including all-cause death) and non-fatal new-onset HF. While there was no interaction of HF with effect of transfusion strategy on MACE, a liberal transfusion strategy was associated with higher all-cause death that appears driven by a higher risk of early death due to HF.

Academic challenges on advanced therapy medicinal products' development: a regulatory perspective.

Advanced therapy medicinal products (ATMPs) are becoming the new kid on the block for the treatment of a variety of indications with promising results. Despite the academic contribution to the basic and clinical research of ATMPs, undertaking a full product development process is extraordinarily challenging and demanding for academic institutions. Meeting regulatory requirements is probably the most challenging aspect of academic development, considering the limited experience and resources compared with pharmaceutical companies. This review aims to outline the key aspects to be considered when developing novel ATMPs from an academic perspective, based on the results of our own experience and interaction with the Spanish Agency of Medicines and Medical Devices (AEMPS) and European Medicine Agency (EMA) related to a number of academic ATMP initiatives carried out at our center during the last 5 years. Emphasis is placed on understanding the regulatory requirements during the early phases of the drug development process, particularly for the preparation of a Clinical Trial Application. Academic centers usually lack expertise in product-related documentation (such as the Investigational Medicinal Product Dossier), and therefore, early interaction with regulators is crucial to understand their requirements and receive guidance to comply with them. Insights are shared on managing quality, nonclinical, clinical, and risk and benefit documentation, based on our own experience and challenges. This review aims to empower academic and clinical settings by providing crucial regulatory knowledge to smooth the regulatory journey of ATMPs.

[Questions and Answers in Tobacco Smoking]. / Preguntas y respuestas en tabaquismo.

Smoking is an addictive, chronic and relapsing disease that, due to its high prevalence, morbidity and mortality, has become one of the main public health problems worldwide, affecting both smokers and rest of population involuntarily exposed to smoke tobacco.To overcome this pandemic, it is essential that all health professionals intervene on the problem in a manner adapted to their level of care, from giving brief advice for stop smoking to proposing intensive cognitive-behavioral and pharmacological treatment.Smoking cessation treatments have proven to be safe and effective, but unfortunately, the personal and economic resources dedicated to smoker care are not proportional to the magnitude of the problem, with few specialized consultations and lack of funding for pharmacological treatments.In addition, we must confront the arguments of the tobacco industry that interferes in the fight against smoking with new products that they pretend to offer as «harm reduction strategies¼ when really it is their way of attracting new addicts to tobacco products.

Economic evaluation of restrictive vs. liberal transfusion strategy following acute myocardial infarction (REALITY): trial-based cost-effectiveness and cost-utility analyses.

AIMS: To estimate the cost-effectiveness and cost-utility ratios of a restrictive vs. liberal transfusion strategy in acute myocardial infarction (AMI) patients with anaemia. METHODS AND RESULTS: Patients (n = 666) with AMI and haemoglobin between 7-8 and 10 g/dL recruited in 35 hospitals in France and Spain were randomly assigned to a restrictive (n = 342) or a liberal (n = 324) transfusion strategy with 1-year prospective collection of resource utilization and quality of life using the EQ5D3L questionnaire. The economic evaluation was based on 648 patients from the per-protocol population. The outcomes were 30-day and 1-year cost-effectiveness, with major adverse cardiovascular events (MACEs) averted as the effectiveness outcome. and a 1-year cost-utility ratio.The 30-day incremental cost-effectiveness ratio was €33 065 saved per additional MACE averted with the restrictive vs. liberal strategy, with an 84% probability for the restrictive strategy to be cost-saving and MACE-reducing (i.e. dominant). At 1 year, the point estimate of the cost-utility ratio was €191 500 saved per quality-adjusted life year gained; however, the cumulated MACE was outside the pre-specified non-inferiority margin, resulting in a decremental cost-effectiveness ratio with a point estimate of €72 000 saved per additional MACE with the restrictive strategy. CONCLUSION: In patients with AMI and anaemia, the restrictive transfusion strategy was dominant (cost-saving and outcome-improving) at 30 days. At 1 year, the restrictive strategy remained cost-saving, but clinical non-inferiority on MACE was no longer maintained. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02648113. ONE SENTENCE SUMMARY: The use of a restrictive transfusion strategy in patients with acute myocardial infarction is associated with lower healthcare costs, but more evidence is needed to ascertain its long-term clinical impact.

Tolerability and Reactogenicity Profile of mRNA SARS-Cov-2 Vaccines from a Mass Vaccination Campaign in a Tertiary Hospital: Between-Vaccine and Between-Population Prospective Observational Study (VigilVacCOVID Study).

BACKGROUND: The comparative safety profile of SARS-Cov2 vaccines requires further characterization in real-world settings. OBJECTIVES: The aim of the VigilVacCOVID study was to assess the short-term safety of BNT162b2 and mRNA-1273 during the vaccination campaign of healthcare professionals (HCPs) and solid-organ transplant recipients (SOTRs) at a hospital clinic. METHODS: We conducted an observational, prospective, single-center, post-authorization study to characterize short-term adverse reactions (ARs) after vaccination. The primary endpoint was to assess between-vaccine differences (HCPs receiving BNT162b2 or mRNA-1273) and between-population differences (HCPs and SOTRs, both receiving mRNA-1273) in the risk of any ARs. Propensity score and covariate-adjusted multivariate models were used. The key secondary endpoint was to provide a descriptive assessment of the frequencies and intensity distribution of ARs. RESULTS: We included 5088 HCPs and 1289 patients. mRNA-1273 showed greater reactogenicity than BNT162b2, with an odds ratio (OR) for any AR of 3.04 (95% confidence interval (CI) 2.48-3.73; p value: < 0.001) and a higher frequency and intensity of reported ARs. Compared with HCPs vaccinated with mRNA-1273, SOTRs showed a lower risk of ARs (OR = 0.36; 95% CI 0.25-0.50), with fewer and less severe ARs. Age, sex, and previous SARS-CoV-2 infection were statistically significant covariates for the risk of any AR. A history of drug allergy was significant in the comparison between vaccines (BNT162b2 vs. mRNA-1273), but not in that between SOTRs and HCPs. CONCLUSIONS: Our study shows that mRNA-1273 had greater reactogenicity than BNT162b2. Overall, both vaccines had an adequate tolerability profile. mRNA-1273 vaccination caused fewer ARs with milder severity in SOTRs.

The hospital exemption pathway for the approval of advanced therapy medicinal products: an underused opportunity? The case of the CAR-T ARI-0001.

In February 2021, the 'Advanced Therapy Medicinal Product' (ATMP) ARI-0001 (CART19-BE-01), developed at Hospital Clínic de Barcelona (Spain), received authorization from the Spanish Agency of Medicines and Medical Devices (AEMPS) under the 'hospital exemption' (HE) approval pathway for the treatment of patients aged >25 years with relapsed/refractory (RR) acute lymphoblastic leukemia (ALL). The HE pathway foreseen by the European Regulation establishing the legal framework for ATMPs intended to be placed on the market in the EU, allows access to ATMPs prepared on a non-routine basis, according to quality standards, like a custom-made product for an individual patient. Its use is limited to the same Member State where it was developed, in a hospital under the responsibility of a medical practitioner. HE-ATMPs must comply with national traceability and pharmacovigilance requirements and specific quality standards. HE offers an opportunity to develop ATMPs in close contact with clinical practice, with the quality and rapid access needed by patients and at a lower cost compared to regular market authorization. However, many barriers need to be overcome. Here we discuss relevant aspects of the development and authorization of ARI-0001 in the context of the heterogeneous frame of the European Regulation implementation across the Member States.

First report of CART treatment in AL amyloidosis and relapsed/refractory multiple myeloma.

Multiple myeloma (MM) remains incurable despite the number of novel therapies that have become available in recent years. Occasionally, a patient with MM will develop an amyloid light-chain (AL) amyloidosis with organ dysfunction. Chimeric antigen receptor T-cell (CART) therapy has become a promising approach in treating hematological malignancies. Our institution has developed a second-generation B-cell maturation antigen (BCMA)-CART which is currently being tested in a clinical trial for relapsed/refractory MM.We present the first reported case, to our knowledge, of a patient with AL amyloidosis and renal involvement in the course of an MM, successfully treated with CART therapy targeting BCMA. The patient received a fractioned dose of 3×106/kg BCMA-CARTs after lymphodepletion. At 3 months from infusion, the patient had already obtained a deep hematological response with negative measurable residual disease by flow cytometry in the bone marrow. After 12 months, the patient remains in hematological stringent complete remission and has achieved an organ renal response with a decrease of 70% of proteinuria.This case suggests that concomitant AL amyloidosis in the setting of MM can benefit from CART therapy, even in patients in which predominant symptoms at the time of treating are caused by AL amyloidosis.

Candida spp. co-infection in COVID-19 patients with severe pneumonia: Prevalence study and associated risk factors.

BACKGROUND: Invasive fungal infections (IFI) are increasing in prevalence in recent years. In the last few months, the rise of COVID-19 patients has generated a new escalation in patients presenting opportunistic mycoses, mainly by Aspergillus. Candida infections are not being reported yet. OBJECTIVES: We aimed to determine the prevalence of systemic candidiasis in patients admitted to ICUs due to severe pneumonia secondary to SARS-CoV-2 infection and the existence of possible associated risk factors that led these patients to develop candidiasis. PATIENTS/METHODS: We designed a study including patients with a confirmed diagnosis of COVID-19. RESULTS: The prevalence of systemic candidiasis was 14.4%, and the main isolated species were C. albicans and C. parapsilosis. All patients that were tested positive for Candida spp. stayed longer in the ICU in comparison to patients who tested negative. Patients with candidiasis had higher MuLBSTA score and mortality rates and a worse radiological involvement. In our study, Candida spp. isolates were found in patients that were submitted to: tocilizumab, tocilizumab plus systemic steroids, interferon type 1ß and Lopinavir-Ritonavir. CONCLUSIONS: Results suggested a high prevalence of systemic candidiasis in severe COVID-19-associated pneumonia patients. Patients with Candidiasis had the worst clinical outcomes. Treatment with tocilizumab could potentialize the risk to develop systemic candidiasis.

Is Hospital Exemption an Alternative or a Bridge to European Medicines Agency for Developing Academic Chimeric Antigen Receptor T-Cell in Europe? Our Experience with ARI-0001.

The hospital exemption (HE) allows for the use of advanced therapy medicinal products (ATMPs) next to marketing authorization (MA), but under special conditions. The HE is only applicable to individual patients treated in the hospital setting and it is limited to member states of the European Union (EU); HE is mainly conceded to the academic centers that developed the ATMP, being granted by the national competent authority (NCA), which, in the case of Spain, is the Spanish Agency of Medicines and Medical Devices (AEMPS). The HE follows strict standards of traceability, pharmacovigilance, and quality. In February 2021, our ATMP ARI-0001, a new autologous chimeric antigen receptor (CAR) targeting CD19, was approved by AEMPS under HE for patients >25 years with relapsed or refractory CD19+ acute lymphoblastic leukemia. This authorization was a first step in the development of, and access to, academic CAR T cell products in the EU. The fact that HE is limited to a specific country and hospital, the need of continuous evaluation by the NCA, and the potential future overlap with other centrally approved ATMPs, suggest that the HE could be used as an intermediate step before obtaining a centralized MA by the European Medicines Agency.

European survey on national harmonization in clinical research.

BACKGROUND: Clinical trials remain key to the development of evidence-based medical practice. However, they are becoming increasingly complex, mainly in a multinational setting. To address these challenges, the European Union (EU) adopted the Clinical Trial Regulation EU No. 536/2014 (CTR). Once in force, the CTR will lead to more consistent rules and simplification of procedures for conducting clinical trials throughout the EU. Existing harmonization initiatives and "research infrastructures" for clinical trials may facilitate this process. This publication offers a snapshot of the current level of harmonization activities in academic clinical research in Europe. METHODS: A survey was performed among the member and observer countries of the European Clinical Research Infrastructure Network (ECRIN), using a standardized questionnaire. Three rounds of data collection were performed to maximize completeness and comparability of the received answers. The survey aimed to describe the harmonization of academic clinical research processes at national level, to facilitate the exchange of expertise and experience among countries, and to identify new fields of action. RESULTS: Most scientific partners already have in place various working groups and harmonization activities at national level. Furthermore, they are involved in and open to sharing their know-how and documents. Since harmonization was mainly a bottom-up approach up until now, the extent and topics dealt with are diverse and there is only little cross-networking and cross-country exchange so far. CONCLUSIONS: Currently, the ECRIN member countries offer a very solid base and collaborative spirit for further aligning processes and exchanging best practices for clinical research in Europe. They can support a smooth implementation of the EU CTR and may act as single contact with consolidated expertise in a country.

Trichosporon asahii as Cause of Nosocomial Pneumonia in Patient With COVID-19: A Triple Co-infection / Neumonía nosocomial por Trichosporon asahii en un paciente con covid-19: una coinfección triple

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Effect of a Restrictive vs Liberal Blood Transfusion Strategy on Major Cardiovascular Events Among Patients With Acute Myocardial Infarction and Anemia: The REALITY Randomized Clinical Trial.

Importance: The optimal transfusion strategy in patients with acute myocardial infarction and anemia is unclear. Objective: To determine whether a restrictive transfusion strategy would be clinically noninferior to a liberal strategy. Design, Setting, and Participants: Open-label, noninferiority, randomized trial conducted in 35 hospitals in France and Spain including 668 patients with myocardial infarction and hemoglobin level between 7 and 10 g/dL. Enrollment could be considered at any time during the index admission for myocardial infarction. The first participant was enrolled in March 2016 and the last was enrolled in September 2019. The final 30-day follow-up was accrued in November 2019. Interventions: Patients were randomly assigned to undergo a restrictive (transfusion triggered by hemoglobin ≤8; n = 342) or a liberal (transfusion triggered by hemoglobin ≤10 g/dL; n = 324) transfusion strategy. Main Outcomes and Measures: The primary clinical outcome was major adverse cardiovascular events (MACE; composite of all-cause death, stroke, recurrent myocardial infarction, or emergency revascularization prompted by ischemia) at 30 days. Noninferiority required that the upper bound of the 1-sided 97.5% CI for the relative risk of the primary outcome be less than 1.25. The secondary outcomes included the individual components of the primary outcome. Results: Among 668 patients who were randomized, 666 patients (median [interquartile range] age, 77 [69-84] years; 281 [42.2%] women) completed the 30-day follow-up, including 342 in the restrictive transfusion group (122 [35.7%] received transfusion; 342 total units of packed red blood cells transfused) and 324 in the liberal transfusion group (323 [99.7%] received transfusion; 758 total units transfused). At 30 days, MACE occurred in 36 patients (11.0% [95% CI, 7.5%-14.6%]) in the restrictive group and in 45 patients (14.0% [95% CI, 10.0%-17.9%]) in the liberal group (difference, -3.0% [95% CI, -8.4% to 2.4%]). The relative risk of the primary outcome was 0.79 (1-sided 97.5% CI, 0.00-1.19), meeting the prespecified noninferiority criterion. In the restrictive vs liberal group, all-cause death occurred in 5.6% vs 7.7% of patients, recurrent myocardial infarction occurred in 2.1% vs 3.1%, emergency revascularization prompted by ischemia occurred in 1.5% vs 1.9%, and nonfatal ischemic stroke occurred in 0.6% of patients in both groups. Conclusions and Relevance: Among patients with acute myocardial infarction and anemia, a restrictive compared with a liberal transfusion strategy resulted in a noninferior rate of MACE after 30 days. However, the CI included what may be a clinically important harm. Trial Registration: ClinicalTrials.gov Identifier: NCT02648113.

Diferencias de género en las publicaciones originales de Archivos de Bronconeumología en el periodo 2001-2018 / Gender Differences in Original Archivos de Bronconeumología Publications, 2001-2018

INTRODUCCIÓN: La desigualdad de género existe en las publicaciones científicas. El objetivo del estudio fue determinar la evolución histórica de las diferencias de género y factores asociados a las posiciones de las autorías de los trabajos originales de Archivos de Bronconeumología (AB). MÉTODOS: Estudio bibliométrico de AB en el periodo 2001-2018. Se analizó el género de las autorías en cuatro escenarios: primera firma, última firma, autorías intermedias y mentorizadas. Se realizaron comparaciones por especialidad firmante, financiación recibida, carácter multicéntirico y área temática, entre otras. Se crearon modelos multivariantes ajustados por el porcentaje de médicas colegiadas en el sistema sanitario español para predecir el género femenino de la primera, intermedia y última firma. RESULTADOS: Se analizaron 828 publicaciones, donde las mujeres figuraron como primeras autoras en 286 (34,5%) y como últimas en 169 (20,4%). Se observó un incremento gradual de mujeres como primeras autoras (p = 0,0001), pero no como últimas firmantes (p = 0,570). En general, la media de autoras mujeres aumentó con el tiempo (1,6 ± 1,4 en 2001-2005 a 3,3 ± 2,3 en 2016-2018, p = 0,0001), sin apreciarse diferencias en las medias de hombres. Los modelos multivariantes ajustados reflejaron una relación bidireccional positiva entre la primera autoría y las intermedias, y una asociación negativa entre que el primer autor haya sido español con una última autoría femenina (OR 0,57; IC95% 0,36-0,88, p = 0,012). CONCLUSIONES: Se encontraron diferencias de género en varios aspectos de las autorías de AB, resumidas en una mayor participación de las mujeres como primeras firmantes e intermedias, pero no como últimas autoras

INTRODUCTION: Gender inequality exists in scientific publications. The aim of this study was to determine changing patterns in gender differences and factors associated with the positioning of authors' names in original articles published in Archivos de Bronconeumología (AB). METHODS: We performed a bibliometric study of articles published in AB between 2001 and 2018. Author gender was analysed in four scenarios: first author, last author, middle authors, and mentee authors. Comparisons were made by authors' specialties, funding received, multicentre studies, specialist areas, and others. Multivariate models adjusted for the percentage of registered physicians in the Spanish health system were created to predict the female gender of the first, middle, and last author. RESULTS: A total of 828 publications were analysed in which women appeared as first authors in 286 (34.5%) and last authors in 169 (20.4%). A gradual increase in women as first authors was observed (P = .0001), but not as last authors (P = .570). Overall, the average number of female authors increased over time (from 1.6 ± 1.4 in 2001-2005 to 3.3 ± 2.3 in 2016-2018, P = .0001), with no differences in male averages. The adjusted multivariate models reflected a positive bi-directional relationship between the first author and the middle authors, and a negative association between the first author being Spanish and the last author being female (OR 0.57; 95% CI 0.36-0.88, P = .012). CONCLUSIONS: Gender differences were found in various aspects of authorship in AB, summarized by a greater participation of women as first and intermediate authors, but not as last authors

Errare humanum est, ¡pero afortunado error / Errare Humanum Est, Though a Lucky Mistake, Indeed

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Restrictive vs liberal red blood cell transfusion strategies in patients with acute myocardial infarction and anemia: Rationale and design of the REALITY trial.

BACKGROUND: Anemia is common in patients with acute myocardial infarction (AMI), and is an independent predictor of mortality. The optimal transfusion strategy in these patients is unclear. HYPOTHESIS: We hypothesized that a "restrictive" transfusion strategy (triggered by hemoglobin ≤8 g/dL) is clinically noninferior to a "liberal" transfusion strategy (triggered by hemoglobin ≤10 g/dL), but is less costly. METHODS: REALITY is an international, randomized, multicenter, open-label trial comparing a restrictive vs a liberal transfusion strategy in patients with AMI and anemia. The primary outcome is the incremental cost-effectiveness ratio (ICER) at 30 days, using the primary composite clinical outcome of major adverse cardiovascular events (MACE; comprising all-cause death, nonfatal stroke, nonfatal recurrent myocardial infarction, or emergency revascularization prompted by ischemia) as the effectiveness criterion. Secondary outcomes include the ICER at 1 year, and MACE (and its components) at 30 days and at 1 year. RESULTS: The trial aimed to enroll 630 patients. Based on estimated event rates of 11% in the restrictive group and 15% in the liberal group, this number will provide 80% power to demonstrate clinical noninferiority of the restrictive group, with a noninferiority margin corresponding to a relative risk equal to 1.25. The sample size will also provide 80% power to show the cost-effectiveness of the restrictive strategy at a threshold of €50 000 per quality-adjusted life year. CONCLUSIONS: REALITY will provide important guidance on the management of patients with AMI and anemia.