Geographic EBV variants confound disease-specific variant interpretation and predict variable immune therapy responses.

ABSTRACT: Epstein-Barr virus (EBV) is a potent carcinogen linked to hematologic and solid malignancies and causes significant global morbidity and mortality. Therapy using allogeneic EBV-specific lymphocytes shows promise in certain populations, but the impact of EBV genome variation on these strategies remains unexplored. To address this, we sequenced 217 EBV genomes, including hematologic malignancies from Guatemala, Peru, Malawi, and Taiwan, and analyzed them alongside 1307 publicly available EBV genomes from cancer, nonmalignant diseases, and healthy individuals across Africa, Asia, Europe, North America, and South America. These included, to our knowledge, the first natural killer (NK)/T-cell lymphoma (NKTCL) EBV genomes reported outside of East Asia. Our findings indicate that previously proposed EBV genome variants specific to certain cancer types are more closely tied to geographic origin than to cancer histology. This included variants previously reported to be specific to NKTCL but were prevalent in EBV genomes from other cancer types and healthy individuals in East Asia. After controlling for geographic region, we did identify multiple NKTCL-specific variants associated with a 7.8-fold to 21.9-fold increased risk. We also observed frequent variations in EBV genomes that affected peptide sequences previously reported to bind common major histocompatibility complex alleles. Finally, we found several nonsynonymous variants spanning the coding sequences of current vaccine targets BALF4, BKRF2, BLLF1, BXLF2, BZLF1, and BZLF2. These results highlight the need to consider geographic variation in EBV genomes when devising strategies for exploiting adaptive immune responses against EBV-related cancers, ensuring greater global effectiveness and equity in prevention and treatment.

HLA-DRB1 and HLA-DQB1 genes in patients diagnosed with systemic lupus erythematosus in Guatemala.

Systemic lupus erythematosus (SLE) is an autoimmune disorder that impacts connective tissue and can affect various organs and systems within the body. One important aspect of this disease is the role of the human leukocyte antigen (HLA) system, a protein complex that plays a role in the immune response. Specifically, the HLA-DRB1 and HLA-DQB1 genes have been implicated in the development of SLE. In order to better understand this relationship in the Guatemalan population, a study was conducted with the objective of characterizing the allelic and haplotype profiles of the HLA-DQB1 and HLA-DRB1 loci in 50 patients diagnosed with SLE who were receiving treatment at a hospital in Guatemala. Allele and haplotype frequencies were determined and compared to 127 healthy Guatemalan subjects as a control group. The results of the analysis showed a reduction in the frequencies of HLA-DQB1*03 and HLA-DRB1*14 in SLE patients, which could suggest a protective effect on the development of the disease. In contrast, a risk association was found between HLA-DRB1*07, HLA-DRB1*08, HLA-DQB1*02 and HLA-DQB1*06 in SLE patients. Finally, we observed an additional protective associated of haplotype HLA-DRB1*04∼DQB1*03 with SLE patients, while haplotypes HLA-DRB1*07∼DQB1*02 and DRB1*08-DQB1*06 showed a risk association.

The efficacy of cryotherapy in reducing edema and ecchymosis in patients who underwent rhinoplasty: A narrative review.

OBJECTIVE: The aim of this article was to showcase current literature on the efficacy of different postoperative and intraoperative cryotherapy techniques in reducing edema, ecchymosis, and pain in patients who have undergone rhinoplasty. BACKGROUND: Rhinoplasty has some unfavorable postoperative temporary side effects, such as edema, ecchymosis, and pain, which hinder the patients' daily activities. Several interventions have been proposed in the literature, including cryotherapy, which refers to cold application to the desired facial area in patients who have undergone rhinoplasty. METHODS: Specific keywords were used, and PubMed, Scopus, and Embase databases were searched. Two extensive selection rounds were performed to finally include 27 articles; the first round was based on the title and abstract, while the second was based on the full article. DISCUSSION: The articles were split into postoperative and intraoperative categories based on the time cryotherapy was administered during the surgery. They were then subdivided depending on the specific cryotherapy technique used, and a detailed description of the method of application and improvement in patients' edema, ecchymosis, and pain was noted. Articles that compared different cryotherapy techniques were also compared with articles that discussed previously used techniques. CONCLUSION: Cryotherapy has shown promising outcomes in reducing edema, ecchymosis, and pain after rhinoplasty and bleeding. It is crucial to build further studies upon these outcomes and develop guidelines for surgeons to effectively use these cryotherapy techniques in their practice.

Short- and long-term survival of children treated with ventricular assist devices in Spain, based on 15 years' experience.

OBJECTIVES: To describe the use of ventricular assist devices (VAD) in children in Spain and to identify variables related to survival. METHODS: This is an observational cohort study of all children younger than 18 years of age who underwent an initial implantation of a VAD at any of the 6 paediatric heart transplant centres from May 2006 to December 2020. Subjects were identified retrospectively from each hospital's database. RESULTS: Paracorporeal VADs were implanted in 118 children [pulsatile (63%), continuous (30.5%) or both types (5.9%)]. Small children (<0.7 m2 of body surface area) comprised the majority of this cohort (63.3%). Overall, 67% survived to VAD explantation, and 64.9% survived to hospital discharge. Non-central nervous system haemorrhage (39%) and stroke (38.1%) were the most common complications. Body weight <5 kg, congenital heart disease, pre-implantation bilirubin >34 µmol/l and bridge to decision strategy were associated with a higher mortality at hospital discharge and in the long-term. Interagency registry for mechanically assisted circulatory support (INTERMACS) status 1 and cardiac arrest prior to VAD implantation were related to long-term mortality, whereas pre-implantation renal replacement therapy and extracorporeal membrane oxygenation were not related to mortality. CONCLUSIONS: In Spain, 67% of the VAD-supported children have been bridged to heart transplantation or to recovery. Body weight lower than 5 kg, congenital heart disease diagnosis, cholestatic liver dysfunction, bridge to decision as VAD strategy, INTERMACS-1 status and cardiac arrest were pre-implantation variables related to mortality, whereas pre-implantation renal replacement therapy and extracorporeal membrane oxygenation were not.

Understanding Mendelian errors in SNP arrays data using a Gochu Asturcelta pig pedigree: genomic alterations, family size and calling errors.

Up to 478 Gochu Asturcelta pig parents-offspring trios (61 different families) were genotyped using the Axiom_PigHDv1 Array to identify the causes of Mendelian errors (ME). Up to 545,364 SNPs were retained. Up to 40,540 SNPs gathering 292,297 allelic mismatches were identified and were overlapped with SINEs and LINEs (Sscrofa genome 11.1). Copy number variations (CNV) were called using PennCNV. ME were classified into eight different classes according to the trio member ("Trio" meaning no assignment) and the allele on which ME was identified: TrioA/B, FatherA/B, MotherA/B, OffspringA/B. Most ME occurred due to systematic causes: (a) those assigned to the Father, Mother or Offspring occurred by null or partial null alleles characterized by heterozygote deficiency, varied with family size, involved a low number of loci (6506), and gathered most mismatches (228,145); (b) TrioB errors varied with family size, covaried with SINEs, LINEs and CNV, and involved most ME loci (33,483) and mismatches (65,682); and (c) TrioA errors were non-systematic ME with no sampling bias involving 1.2% of mismatches only and a low number of loci (1939). The influence of TrioB errors on the overall genotyping quality may be low and, since CNV vary among populations, their removal should be considered in each particular dataset. ME assignable to the Father, Mother or Offspring may be consistent within technological platforms and may bias severely linkage or association studies. Most ME caused by null or partial null alleles can be removed using heterozygote deficiency without affecting the size of the datasets.

Anti-SARS-CoV-2 IgG antibodies pre- and post-vaccination behavior in health workers from a Guatemalan cancer center.

INTRODUCTION: The study of anti-SARS-CoV-2 IgG antibodies allows asymptomatic individuals with COVID-19 to be identified, and post-infection and post-vaccination immunity status to be evaluated. OBJECTIVE: To know the behavior of anti-SARS-CoV-2 IgG antibodies before and after vaccination in workers of a cancer center. METHODS: Prior to the application of the vaccine, the presence of anti-SARS-CoV-2 IgG antibodies (n = 171) was analyzed by evaluating anti-N IgG antibodies; post-vaccination, after receiving the second dose, anti-S IgG antibodies were evaluated (n = 60). RESULTS: Prior to vaccination, IgG antibodies were present in 18.71% of participants; they were detected in 65.22% of those with prior history of COVID-19 diagnosis and in 11.49% of those without it. The positions with the highest prevalence were nurses (28.26%), paramedics (27.59%) and administrative workers (27.78%), p < 0.01. Anosmia, ageusia and chest tightness were associated with the presence of IgG (p < 0.05). Post-vaccination, all participants developed IgG antibodies; people with a previous COVID-19 diagnosis had higher titers: 10,277 vs. 6,819 AU/mL, p < 0.001. CONCLUSIONS: The study of anti-SARS-CoV-2 IgG antibodies allowed asymptomatic health workers to be identified. A high percentage of participants with prior COVID-19 diagnosis had antibodies. All participants developed IgG antibodies after vaccination, with higher titers being identified in those with previous infection.

INTRODUCCIÓN: El estudio de anticuerpos IgG anti-SARS-CoV-2 permite identificar individuos asintomáticos con COVID-19 y evaluar la inmunidad posinfección y posvacunación. OBJETIVO: Conocer el comportamiento de los anticuerpos IgG anti-SARS-CoV-2 pre y posvacunación en trabajadores de un centro oncológico. MÉTODOS: Antes de aplicar la vacuna se analizaron los anticuerpos IgG anti-SARS-CoV-2 (n = 171) con la evaluación de IgG anti-N; después de la segunda dosis se evaluó IgG anti-S (n = 60). RESULTADOS: Prevacunación, los anticuerpos IgG estaban presentes en 18.71 % de los participantes; se detectaron en 65.22 % de aquellos con antecedente de diagnóstico de COVID-19 y en 11.49 % de aquellos sin antecedentes. Los profesiones con mayor prevalencia fueron enfermeros (28.26 %), paramédicos (27.59 %) y administrativos (27.78 %), p < 0.01. La anosmia, ageusia y opresión en el pecho se asociaron a la presencia de IgG (p < 0.05). Posvacunación, todos los participantes desarrollaron IgG; las personas con diagnóstico previo de COVID-19 presentaron mayores títulos: 10 277 versus 6819 UA/mL, p < 0.001. CONCLUSIONES: El estudio de anticuerpos IgG anti-SARS-CoV-2 permitió identificar a trabajadores de salud asintomáticos. Un alto porcentaje de los participantes con diagnóstico previo de COVID-19 presentó anticuerpos. Todos los participantes desarrollaron anticuerpos IgG posvacunación; las personas con infección previa presentaron una cuantificación más alta de títulos.

Identificación y evaluación de lesiones gástricas premalignas asociadas a la infección por Helicobacter pylori / Identification and evaluation of premalignant gastric lesions associated with Helicobacter pylori infection

Introducción: La infección por Helicobacter pylori es la causa principal de enfermedades gastroduodenales (gastritis crónica, úlceras pépticas y cáncer gástrico). En Guatemala existen pocos estudios sobre la prevalencia de H. pylori y su relación con enfermedades gastrointestinales, particularmente con cáncer. Objetivos: Identificar la presencia de lesiones premalignas (atrofia gástrica, metaplasia intestinal y displasia) y su relación con la infección por H. pylori en pacientes de consulta externa en unidades de gastroenterología de dos hospitales nacionales de la ciudad de Guatemala. Métodos: El diagnóstico histopatológico y bacteriológico se realizó por medio de las tinciones de H & E y Giemsa, cultivo e identificación bioquímica, detección de anticuerpos específicos mediante la prueba ELISA, diagnóstico molecular por la amplificación del gen glmM y genotipificación por PCR para identificar los genes VacA y CagA. Se analizaron datos clínico-epidemiológicos de los pacientes, la prevalencia de la infección por H. pylori y la genotipificación de la bacteria. Resultados: En 293 de los pacientes estudiados (83 por ciento) se encontró algún tipo de lesión premaligna; las más frecuentes fueron la atrofia gástrica (70 por ciento), metaplasia intestinal (11 por ciento) y displasia gástrica (2 por ciento). El 17 por ciento de los pacientes no presentó lesiones premalignas. Se halló una prevalencia de infección por H. pylori del 58 por ciento, y el gen cagA se detectó en 118 (57 por ciento) de los pacientes infectados. Conclusiones: La mayoría de los pacientes presentó atrofia gástrica (70 por ciento) y el 43,5 por ciento estaba infectado por H. pylori, principalmente con cepas CagA positivo. Este hecho confirma la importancia del estudio de H. pylori y su relación con cáncer gástrico(AU)

Introduction: Helicobacter pylori infection is the main cause of gastroduodenal diseases (chronic gastritis, peptic ulcer and gastric cancer). In Guatemala few studies have been carried out on the prevalence of H. pylori and its relationship with gastrointestinal diseases, particularly with cancer. Objective: To identify the presence of premalignant lesions (gastric atrophy, intestinal metaplasia and dysplasia) and their relationship with H. pylori infection in outpatients in gastroenterology units in two national hospitals in Guatemala City. Methods: Histopathological and bacteriological diagnostic testings were performed by H & E and Giemsa stain, culture and biochemical identification, detection of specific antibodies by ELISA, molecular diagnosis by glmM gene amplification, and genotypification by PCR to identify vacA and cagA genes. Clinical and epidemiological data from patients, prevalence of H. pylori infection, and bacterium genotypification were analyzed. Results: Among the studied patients, 293 (83 percent) presented some type of premalignant lesion. The most prevalent were gastric atrophy (70 percent), intestinal metaplasia (11 percent), and gastric dysplasia (2 percent). Seventeen percent of the patients did not have any premalignant lesions. The prevalence of H. pylori infection was 58 percent, and cagA gene was identified in 118 (57 percent) of the infected patients. Conclusions: The majority of the patients presented gastric atrophy (70 percent), and 43.5 percent were infected by H. pylori, mainly with positive cagA strains. This finding confirms the importance of studying H. pylori and its relationship with gastric cancer(AU)

Comportamiento de anticuerpos IgG anti-SARS-CoV-2 en trabajadores de salud pre y posvacunación en un centro oncológico de Guatemala / Anti-SARS-CoV-2 IgG antibodies pre- and post-vaccination behavior in health workers from a Guatemalan cancer center

Resumen Introducción: El estudio de anticuerpos IgG anti-SARS-CoV-2 permite identificar individuos asintomáticos con COVID-19 y evaluar la inmunidad posinfección y posvacunación. Objetivo: Conocer el comportamiento de los anticuerpos IgG anti-SARS-CoV-2 pre y posvacunación en trabajadores de un centro oncológico. Métodos: Antes de aplicar la vacuna se analizaron los anticuerpos IgG anti-SARS-CoV-2 (n = 171) con la evaluación de IgG anti-N; después de la segunda dosis se evaluó IgG anti-S (n = 60). Resultados: Prevacunación, los anticuerpos IgG estaban presentes en 18.71 % de los participantes; se detectaron en 65.22 % de aquellos con antecedente de diagnóstico de COVID-19 y en 11.49 % de aquellos sin antecedentes. Los profesiones con mayor prevalencia fueron enfermeros (28.26 %), paramédicos (27.59 %) y administrativos (27.78 %), p < 0.01. La anosmia, ageusia y opresión en el pecho se asociaron a la presencia de IgG (p < 0.05). Posvacunación, todos los participantes desarrollaron IgG; las personas con diagnóstico previo de COVID-19 presentaron mayores títulos: 10 277 versus 6819 UA/mL, p < 0.001. Conclusiones: El estudio de anticuerpos IgG anti-SARS-CoV-2 permitió identificar a trabajadores de salud asintomáticos. Un alto porcentaje de los participantes con diagnóstico previo de COVID-19 presentó anticuerpos. Todos los participantes desarrollaron anticuerpos IgG posvacunación; las personas con infección previa presentaron una cuantificación más alta de títulos.

Abstract Introduction: The study of anti-SARS-CoV-2 IgG antibodies allows asymptomatic individuals with COVID-19 to be identified, and post-infection and post-vaccination immunity status to be evaluated. Objective: To know the behavior of anti-SARS-CoV-2 IgG antibodies before and after vaccination in workers of a cancer center. Methods: Prior to the application of the vaccine, the presence of anti-SARS-CoV-2 IgG antibodies (n = 171) was analyzed by evaluating anti-N IgG antibodies; post-vaccination, after receiving the second dose, anti-S IgG antibodies were evaluated (n = 60). Results: Prior to vaccination, IgG antibodies were present in 18.71% of participants; they were detected in 65.22% of those with prior history of COVID-19 diagnosis and in 11.49% of those without it. The positions with the highest prevalence were nurses (28.26%), paramedics (27.59%) and administrative workers (27.78%), p < 0.01. Anosmia, ageusia and chest tightness were associated with the presence of IgG (p < 0.05). Post-vaccination, all participants developed IgG antibodies; people with a previous COVID-19 diagnosis had higher titers: 10,277 vs. 6,819 AU/mL, p < 0.001. Conclusions: The study of anti-SARS-CoV-2 IgG allowed asymptomatic health workers to be identified. A high percentage of participants with prior COVID-19 diagnosis had antibodies. All participants developed IgG after vaccination, with higher titers being identified in those with previous infection.

Large-scale study on virological and serological prevalence of SARS-CoV-2 in cats and dogs in Spain.

The disease produced by the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is currently one of the primary concerns worldwide. Knowing the zoonotic origin of the disease and that several animal species, including dogs and cats, are susceptible to viral infection, it is critical to assess the relevance of pets in this pandemic. Here, we performed a large-scale study on SARS-CoV-2 serological and viral prevalence in cats and dogs in Spain in order to elucidate their role and susceptibility. Samples from animals in contact with COVID-19 positive people and/or compatible symptoms (n = 492), as well as from random animals (n = 1024), were taken. Despite the large number of animals analyzed, only 12 animals (eight dogs and four cats), which represents 0.79% of the total analyzed animals (n = 1516), were positive for viral SARS-CoV-2 RNA detection by reverse transcription quantitative PCR (RT-qPCR) in which viral isolation was possible in four animals. We detected neutralizing antibodies in 34 animals, four of them were also positive for PCR. This study evidences that pets are susceptible to SARS-CoV-2 infection in natural conditions but at a low level, as evidenced by the low percentage of positive animals detected, being infected humans the main source of infection. However, the inclusion of animals in the surveillance of COVID-19 is still recommended.

Pathological Study of Facial Eczema (Pithomycotoxicosis) in Sheep.

Facial eczema (FE) is a secondary photosensitization disease of farm ruminants caused by the sporidesmin A, produced in the spores of the saprophytic fungus Pithomyces chartarum. This study communicates an outbreak of ovine FE in Asturias (Spain) and characterizes the serum biochemical pattern and the immune response that may contribute to liver damage, favoring cholestasis and the progression to fibrosis and cirrhosis. Animals showed clinical signs of photosensitivity, with decrease of daily weight gain and loss of wool and crusting for at least 6 months after the FE outbreak. Serum activity of γ-glutamyltransferase and alkaline phosphatase were significantly increased in sheep with skin lesions. In the acute phase, edematous skin lesions in the head, hepatocytic and canalicular cholestasis in centrilobular regions, presence of neutrophils in small clumps surrounding deposits of bile pigment, ductular proliferation, as well as cholemic nephrosis, were observed. Macrophages, stained positively for MAC387, were found in areas of canalicular cholestasis. In the chronic phase, areas of alopecia and crusting were seen in the head, and the liver was atrophic with large regeneration nodules and gallstones. Fibrosis around dilated bile ducts, "typical" and "atypical" ductular reaction and an inflammatory infiltrate composed of lymphocytes and pigmented macrophages, with iron deposits and lipofuscin, were found. The surviving parenchyma persisted with a jigsaw pattern characteristic of biliary cirrhosis. Concentric and eccentric myointimal proliferation was found in arteries near damaged bile ducts. In cirrhotic livers, stellated cells, ductular reaction, ectatic bile ducts and presence of M2 macrophages and lymphocytes, were observed in areas of bile ductular reaction.

Wristbands use to identify adult patients with difficult airway: a scoping review.

BACKGROUND: Difficult airway is a clinical situation in which a trained anesthesiologist experiences trouble with facemask ventilation and/or laryngoscopy and/or intubation. Poor identification of at-risk patients has been identified as one of the causes of difficult airway management. OBJECTIVES: We aimed to review the literature regarding the use of wristbands to identify adult patients with known or predicted difficult airway in hospitals. METHODS: We searched Web of Science (WoS), Scopus, MEDLINE and OVID following the stages described by the PRISMA Extension for Scoping Reviews (PRISMA-ScR). We used a combination of MeSH terms and non-controlled vocabulary regarding the use of difficult airway wristbands in adults. Three researchers independently reviewed the full texts and selected the papers to be included based on the inclusion criteria. RESULTS: Our search generated 334 articles after removing duplicates. After reviewing full text articles, only seven studies were included. Here we found that most were from the United States, in which the authors report the use of in-patients' wristbands in adults. According to the authors, the use of wristbands is being implemented as a measure of improved quality and safety of in-patients with difficult airway either known or suspected. CONCLUSIONS: The identification with wristbands of a difficult airway at an appropriate time is an identification strategy can have a low cost but a high impact on morbidity. It is pertinent to develop a methodology such as the use of wristbands, that allows a good classification and identification of patients with difficult airway in hospitals from Latin America.

Sensory Features Introduced by Brewery Spent Grain with Impact on Consumers' Motivations and Emotions for Fibre-Enriched Products.

The aim of this work was both to formulate three different fibre-enriched products by the addition of Brewery Spent Grain (BSG), and to evaluate the impact of this fibre enrichment on sensory quality, acceptability, and purchase intention under blind conditions. BSG was incorporated into bread, pasta, and chocolate milk at levels of 8.3%, 2.8%, and 0.35% (w/w), respectively. The fibre-enriched products and their regular counterparts were evaluated together by consumers through a CATA questionnaire, the EsSense 25 Profile, an overall acceptability rating, and a purchase intention ranking. Although fibre-enriched bread and chocolate milk ranked lower in overall acceptability compared with their counterparts, no significant difference was found for fibre-enriched pasta (p > 0.05). Purchase intention did not differ significantly for both bread and pasta (p > 0.05), yet the reasons for purchasing them differed significantly (p < 0.05). Consumers recognised the fibre enrichment in these two products and, therefore, were willing to partially compromise on sensory attributes. The fibre-enriched chocolate milk, nonetheless, scored significantly (p < 0.05) lower in purchase intention than the control. This work demonstrates that the effect of BSG addition is product-specific, and that fibre perception makes consumers feel more confident.

A rare HCN4 variant with combined sinus bradycardia, left atrial dilatation, and hypertrabeculation/left ventricular noncompaction phenotype.

INTRODUCTION AND OBJECTIVES: HCN4 variants have been reported to cause combined sick sinus syndrome (SSS) and left ventricular noncompaction (LVNC) cardiomyopathy. This relationship has been proven in few cases and no previous patients have associated left atrial dilatation (LAD). Our objective was to study a familial disorder characterized by SSS, LAD, and hypertrabeculation/LVNC and to identify the underlying genetic and electrophysiological characteristics. METHODS: A family with SSS and LVNC underwent a clinical, genetic, and electrophysiological assessment. They were studied via electrocardiography, Holter recording, echocardiography, and exercise stress tests; cardiac magnetic resonance imaging was additionally performed in affected individuals. Genetic testing was undertaken with targeted next-generation sequencing, as well as a functional study of the candidate variant in Chinese hamster ovary cells. RESULTS: Twelve members of the family had sinus bradycardia, associated with complete criteria of LVNC in 4 members and hypertrabeculation in 6 others, as well as LAD in 9 members. A HCN4 c.1123C>T;(p.R375C) variant was present in heterozygosis in all affected patients and absent in unaffected individuals. Electrophysiological analyses showed that the amplitude and densities of the HCN4 currents (IHCN4) generated by mutant p.R375C HCN4 channels were significantly lower than those generated by wild-type channels. CONCLUSIONS: The combined phenotype of SSS, LAD, and LVNC is associated with the heritable HCN4 c.1123C>T;(p.R375C) variant. HCN4 variants should be included in the genetic diagnosis of LVNC cardiomyopathy and of patients with familial forms of SSS, as well as of individuals with sinus bradycardia and LAD.

Ivabradine for chronic heart rate control in persistent atrial fibrillation. Design of the BRAKE-AF project.

INTRODUCTION AND OBJECTIVES: Ivabradine is an inhibitor of the If channel, the main determinant of the pacemaker function of the sinus node. The drug has been approved for the treatment of angina and heart failure. There is some evidence of its role as an inhibitor of atrial-ventricular node (AVN) conduction. The aim of the BRAKE-AF project is to assess ivabradine use for rate control in atrial fibrillation (AF). METHODS: A multicenter, randomized, parallel, open-label, noninferiority phase III clinical trial will be conducted to compare ivabradine vs digoxin in 232 patients with uncontrolled permanent AF despite beta-blockers or calcium channel blockers. The primary efficacy endpoint is the reduction in daytime heart rate measured by 24-hour Holter monitoring at 3 months. This clinical trial will be supported by an electrophysiological study of the effect of ivabradine on the action potential of the human AVN. To do this, an experimental model will be used with Chinese hamster ovarium cells transfected with the DNA encoding the expression of the t channels involved in this action potential and recording of the ionic currents with patch clamp techniques. RESULTS: New data will be obtained on the effect of ivabradine on the human AVN and its safety and efficacy in patients with permanent AF. CONCLUSIONS: The results of the BRAKE-AF project might allow inclusion of ivabradine within the limited arsenal of drugs currently available for rate control in AF. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Identifier: NCT03718273.