QT interval and short-term outcome in acute heart failure

Acute heart failure; Electrocardiogram; Emergency departmentInsuficiencia cardiaca aguda; Electrocardiograma; EmergenciasInsuficiència cardíaca aguda; Electrocardiograma; Servei d'urgènciesObjective: To investigate the association of corrected QT (QTc) interval duration and short-term outcomes in patients with acute heart failure (AHF). Methods: We analyzed AHF patients enrolled in 11 Spanish emergency departments (ED) for whom an ECG with QTc measurement was available. Patients with pace-maker rhythm were excluded. Primary outcome was 30-day all-cause mortality and secondary outcomes were need of hospitalization, in-hospital mortality and prolonged hospitalization (> 7 days). Association between QTc and outcomes was explored by restricted cubic spline (RCS) curves. Results were expressed as odds ratios (OR) and 95%CI adjusted by patients baseline and decompensation characteristics, using a QTc = 450 ms as reference. Results: Of 1800 patients meeting entry criteria (median age 84 years (IQR = 77-89), 56% female), their median QTc was 453 ms (IQR = 422-483). The 30-day mortality was 9.7%, while need of hospitalization, in-hospital mortality and prolonged hospitalization were 77.8%, 9.0% and 50.0%, respectively. RCS curves found longer QTc was associated with 30-day mortality if > 561 ms, OR = 1.86 (1.00-3.45), and increased up to OR = 10.5 (2.25-49.1), for QTc = 674 ms. A similar pattern was observed for in-hospital mortality; OR = 2.64 (1.04-6.69), for QTc = 588 ms, and increasing up to OR = 8.02 (1.30-49.3), for QTc = 674 ms. Conversely, the need of hospitalization had a U-shaped relationship: being increased in patients with shorter QTc [OR = 1.45 (1.00-2.09) for QTc = 381 ms, OR = 5.88 (1.25-27.6) for the shortest QTc of 200 ms], and also increasing for prolonged QTc [OR = 1.06 (1.00-1.13), for QTc = 459 ms, and reaching OR = 2.15 (1.00-4.62) for QTc = 588 ms]. QTc was not associated with prolonged hospitalization.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature

Expanding the clinical and genetic spectra of primary immunodeficiency-related disorders with clinical exome sequencing: expected and unexpected findings

Inmunodeficiencias primarias; Secuenciación de próxima generación; Secuenciación clínica del exomaImmunodeficiències primàries; Seqüenciació de propera generació; Seqüenciació clínica d’exomesPrimary immunodeficiencies; Next generation sequencing; Clinical exome sequencingPrimary immunodeficiencies (PIDs) refer to a clinically, immunologically, and genetically heterogeneous group of over 350 disorders affecting development or function of the immune system. The increasing use of next-generation sequencing (NGS) technology has greatly facilitated identification of genetic defects in PID patients in daily clinical practice. Several NGS approaches are available, from the unbiased whole exome sequencing (WES) to specific gene panels. Here, we report on a 3-year experience with clinical exome sequencing (CES) for genetic diagnosis of PIDs. We used the TruSight One sequencing panel, which includes 4,813 disease-associated genes, in 61 unrelated patients (pediatric and adults). The analysis was done in 2 steps: first, we focused on a virtual PID panel and then, we expanded the analysis to the remaining genes. A molecular diagnosis was achieved in 19 (31%) patients: 12 (20%) with mutations in genes included in the virtual PID panel and 7 (11%) with mutations in other genes. These latter cases provided interesting and somewhat unexpected findings that expand the clinical and genetic spectra of PID-related disorders, and are useful to consider in the differential diagnosis. We also discuss 5 patients (8%) with incomplete genotypes or variants of uncertain significance. Finally, we address the limitations of CES exemplified by 7 patients (11%) with negative results on CES who were later diagnosed by other approaches (more specific PID panels, WES, and comparative genomic hybridization array). In summary, the genetic diagnosis rate using CES was 31% (including a description of 12 novel mutations), which rose to 42% after including diagnoses achieved by later use of other techniques. The description of patients with mutations in genes not included in the PID classification illustrates the heterogeneity and complexity of PID-related disorders.This study was funded by Instituto de Salud Carlos III, grants PI14/00405 and PI17/00660, cofinanced by the European Regional Development Fund (ERDF)

Alteracions electrocardiogràfiques en insuficiència cardíaca aguda: prevalença i impacte en el pronòstic

La insuficiència cardíaca (IC) és una patologia crònica amb una elevada prevalença en la població de més de 65 anys i la morbimortalitat a causa de les seves descompensacions en forma d’insuficiència cardíaca aguda (ICA) continua incrementant-se. Això comporta consultes als serveis d’urgències i ingressos hospitalaris en nombroses ocasions. La cerca de models predictius i variables que permetin estratificar el risc i les possibles complicacions, constitueix una eina que permet millorar l’abordatge d’aquesta patologia per part dels professionals sanitaris. L’associació entre ICA i fibril·lació auricular ja ha estat àmpliament estudiada, però les alteracions de la conducció intraventricular, com els blocatges de branca, l’eixamplament del QRS i les alteracions de l’interval QT, han estat menys explorades. Els resultats de la tesi confirmen que aquestes alteracions són freqüents en els pacients amb ICA i la seva presència s’associa a un modest increment de la mortalitat per qualsevol causa i del risc d’hospitalització.Heart failure (HF) is highly prevalent in people over the age of 65 years, and morbidity and mortality associated with decompensations (Acute heart failure [AHF]) increases further. This often leads to emergency department consultations and hospital admissions. The search for predictive and variable models that allow risk and possible complications to be stratified is a tool that allows healthcare professionals to improve the approach to this pathology. The association between AHF and atrial fibrillation has already been widely studied, but intraventricular conduction disturbances, such as bundle branch blocks, wide QRS, and QT interval disturbances, have been less explored. The results of this doctoral thesis, confirm that these conduction disturbances are common in patients with AHF and their presence is associated with a modest increase in all-cause mortality and risk of hospitalization.Medicina i Ciències Biomèdique

Case Report : X-Linked SASH3 Deficiency Presenting as a Common Variable Immunodeficiency

SASH3 is a lymphoid-specific adaptor protein. In a recent study, SASH3 deficiency was described as a novel X-linked combined immunodeficiency with immune dysregulation, associated with impaired TCR signaling and thymocyte survival in humans. The small number of patients reported to date showed recurrent sinopulmonary, cutaneous and mucosal infections, and autoimmune cytopenia. Here we describe an adult patient previously diagnosed with common variable immunodeficiency (CVID) due to low IgG and IgM levels and recurrent upper tract infections. Two separate, severe viral infections drew our attention and pointed to an underlying T cell defect: severe varicella zoster virus (VZV) infection at the age of 4 years and bilateral pneumonia due type A influenza infection at the age of 38. Genetic testing using an NGS-based custom-targeted gene panel revealed a novel hemizygous loss-of-function variant in the SASH3 gene (c.505C>T/p.Gln169*). The patient's immunological phenotype included marked B cell lymphopenia with reduced pre-switch and switch memory B cells, decreased CD4 + and CD8 + naïve T cells, elevated CD4 + and CD8 + T cells, and abnormal T cell activation and proliferation. The patient showed a suboptimal response to Streptococcus pneumoniae (polysaccharide) vaccine, and a normal response to Haemophilus influenzae type B (conjugate) vaccine and SARS-CoV-2 (RNA) vaccine. In summary, our patient has a combined immunodeficiency, although he presented with a phenotype resembling CVID. Two severe episodes of viral infection alerted us to a possible T-cell defect, and genetic testing led to SASH3 deficiency. Our patient displays a milder phenotype than has been reported previously in these patients, thus expanding the clinical spectrum of this recently identified inborn error of immunity

Comparación de costes de tres tratamientos del cáncer de próstata localizado en España: prostatectomía radical, braquiterapia prostática y radioterapia conformacional externa 3D Cost comparison of three treatments for localized prostate cancer in Spain: radical prostatectomy, prostate brachytherapy and external 3D conformal radiotherapy

Objetivo: Comparar los costes de los tratamientos más establecidos para el cáncer de próstata localizado según grupos de riesgo, edad y comorbilidad, desde la perspectiva del proveedor asistencial. Métodos: Comparación de costes en pacientes reclutados consecutivamente entre 2003 y 2005 en una unidad funcional de tratamiento del cáncer de próstata. La utilización de servicios hasta 6 meses después del inicio del tratamiento se obtuvo de las bases de datos hospitalarias, y los costes directos se estimaron mediante cálculo microcoste. La información sobre las características clínicas de los pacientes y los tratamientos recogió prospectivamente. Los costes se compararon mediante tests no paramétricos de comparación de medianas (Kruskall-Wallis) y un modelo semilogarítmico de regresión múltiple. Resultados: La diferencia de costes fue estadísticamente significativa: medianas de 3229.10 &euro;, 5369.00 &euro; y 6265.60 &euro; para los pacientes tratados con radioterapia conformacional externa 3D, braquiterapia, y prostatectomía radical retropública, respectivamente (pObjective: To compare the initial costs of the three most established treatments for clinically localized prostate cancer according to risk, age and comorbidity groups, from the healthcare provider's perspective. Methods: We carried out a cost comparison study in a sample of patients consecutively recruited between 2003 and 2005 from a functional unit for prostate cancer treatment in Catalonia (Spain). The use of services up to 6 months after the treatment start date was obtained from hospital databases and direct costs were estimated by micro-cost calculation. Information on the clinical characteristics of patients and treatments was collected prospectively. Costs were compared by using nonparametric tests comparing medians (Kruskall-Wallis) and a semi-logarithmic multiple regression model. Results: Among the 398 patients included, the cost difference among treatments was statistically significant: medians were &euro;3,229.10, &euro;5,369.00 and &euro;6,265.60, respectively, for the groups of patients treated with external 3D conformal radiotherapy, brachytherapy and radical retropublic prostatectomy, (p<0.001). In the multivariate analysis (adjusted R²=0.8), the average costs of brachytherapy and external radiotherapy were significantly lower than that of prostatectomy (coefficient -0.212 and -0.729, respectively). Conclusions: Radical prostatectomy proved to be the most expensive treatment option. Overall, the estimated costs in our study were lower than those published elsewhere. Most of the costs were explained by the therapeutic option and neither comorbidity nor risk groups showed an effect on total costs independent of treatment

Uncovering Low-Level Maternal Gonosomal Mosaicism in X-Linked Agammaglobulinemia : Implications for Genetic Counseling

X-linked agammaglobulinemia (XLA) is a clinically and genetically well-defined immunodeficiency and the most common form of agammaglobulinemia. It is characterized by susceptibility to recurrent bacterial infections, profound hypogammaglobulinemia, and few or no circulating B cells. XLA is caused by mutations in the BTK gene, which encodes Bruton's tyrosine kinase (BTK). Because of its X-linked recessive inheritance pattern, XLA virtually only affects males, and the mother is the carrier of the mutation in 80-85% of the males with this condition. In the remaining 15-20% of the cases, the affected male is considered to have a de novo mutation. Here, we present the case of a child with a diagnosis of XLA caused by a missense mutation in the BTK gene (c.494G>A/p.C165Y). Apparently, his mother was wild type for this gene, which implied that the mutation was de novo, but careful analysis of Sanger electropherograms and the use of high-coverage massive parallel sequencing revealed low-level maternal gonosomal mosaicism. The mutation was detected in various samples from the mother (blood, urine, buccal swab, and vaginal swab) at a low frequency of 2-5%, and the status of the patient's mutation changed from de novo to inherited. This study underscores the importance of accurately establishing the parents' status on detection of an apparently de novo mutation in a patient, as inadvertent low-level mosaicism may lead to misinterpretation of the risk of recurrence, vital for genetic counselin

Expanding the Clinical and Genetic Spectra of Primary Immunodeficiency-Related Disorders With Clinical Exome Sequencing : Expected and Unexpected Findings

We are deeply grateful to the affected individuals who participated in this study and their families. We thank the Barcelona PID Foundation for patient support and for funding MG-P. We acknowledge Celine Cavallo for English language support. Funding. This study was funded by Instituto de Salud Carlos III, grants PI14/00405 and PI17/00660, cofinanced by the European Regional Development Fund (ERDF).Primary immunodeficiencies (PIDs) refer to a clinically, immunologically, and genetically heterogeneous group of over 350 disorders affecting development or function of the immune system. The increasing use of next-generation sequencing (NGS) technology has greatly facilitated identification of genetic defects in PID patients in daily clinical practice. Several NGS approaches are available, from the unbiased whole exome sequencing (WES) to specific gene panels. Here, we report on a 3-year experience with clinical exome sequencing (CES) for genetic diagnosis of PIDs. We used the TruSight One sequencing panel, which includes 4,813 disease-associated genes, in 61 unrelated patients (pediatric and adults). The analysis was done in 2 steps: first, we focused on a virtual PID panel and then, we expanded the analysis to the remaining genes. A molecular diagnosis was achieved in 19 (31%) patients: 12 (20%) with mutations in genes included in the virtual PID panel and 7 (11%) with mutations in other genes. These latter cases provided interesting and somewhat unexpected findings that expand the clinical and genetic spectra of PID-related disorders, and are useful to consider in the differential diagnosis. We also discuss 5 patients (8%) with incomplete genotypes or variants of uncertain significance. Finally, we address the limitations of CES exemplified by 7 patients (11%) with negative results on CES who were later diagnosed by other approaches (more specific PID panels, WES, and comparative genomic hybridization array). In summary, the genetic diagnosis rate using CES was 31% (including a description of 12 novel mutations), which rose to 42% after including diagnoses achieved by later use of other techniques. The description of patients with mutations in genes not included in the PID classification illustrates the heterogeneity and complexity of PID-related disorders

Detection and evolutionary dynamics of somatic FAS variants in autoimmune lymphoproliferative syndrome : Diagnostic implications

Autoimmune lymphoproliferative syndrome (ALPS) is a rare primary immune disorder characterized by impaired apoptotic homeostasis. The clinical characteristics include lymphoproliferation, autoimmunity (mainly cytopenia), and an increased risk of lymphoma. A distinctive biological feature is accumulation (>2.5%) of an abnormal cell subset composed of TCRαβ + CD4 - CD8 - T cells (DNTs). The most common genetic causes of ALPS are monoallelic pathogenic variants in the FAS gene followed by somatic FAS variants, mainly restricted to DNTs. Identification of somatic FAS variants has been typically addressed by Sanger sequencing in isolated DNTs. However, this approach can be costly and technically challenging, and may not be successful in patients with normal DNT counts receiving immunosuppressive treatment. In this study, we identified a novel somatic mutation in FAS (c.718_719insGTCG) by Sanger sequencing on purified CD3 + cells. We then followed the evolutionary dynamics of the variant along time with an NGS-based approach involving deep amplicon sequencing (DAS) at high coverage (20,000-30,000x). Over five years of clinical follow-up, we obtained six blood samples for molecular study from the pre-treatment (DNTs>7%) and treatment (DNTs400 variants called. In summary, our study illustrates the evolutionary dynamics of a somatic FAS mutation before and during immunosuppressive treatment. The results show that pathogenic somatic FAS variants can be identified with the use of DAS in whole blood of ALPS patients regardless of their DNT count

Prevalence, Related Factors and Association of Left Bundle Branch Block With Prognosis in Patients With Acute Heart Failure: a Simultaneous Analysis in 3 Independent Cohorts

To determine the prevalence, characteristics and association with prognosis of left bundle branch block (LBBB) in 3 different cohorts of patients with acute heart failure (AHF).; We retrospectively analyzed 12,950 patients with AHF who were included in the EAHFE (Epidemiology Acute Heart Failure Emergency), RICA (National Heart Failure Registry of the Spanish Internal Medicine Society), and BASEL-V (Basics in Acute Shortness of Breath Evaluation of Switzerland) registries. We independently analyzed the relationship between baseline and clinical characteristics and the presence of LBBB and the potential association of LBBB with 1-year all-cause mortality and a 90-day postdischarge combined endpoint (Emergency Department reconsultation, hospitalization or death). The prevalence of LBBB was 13.5% (95% confidence interval: 12.9%-14.0%). In all registries, patients with LBBB more commonly had coronary artery disease and previous episodes of AHF, were taking chronic spironolactone treatment, had lower left ventricular ejection fraction and systolic blood pressure values and higher NT-proBNP levels. There were no differences in risk for patients with LBBB in any cohort, with adjusted hazard ratios (95% confidence interval) for 1-year mortality in EAHFE/RICA/BASEL-V cohorts of 1.02 (0.89-1.17), 1.15 (0.95-1.38) and 1.32 (0.94-1.86), respectively, and for 90-day postdischarge combined endpoint of 1.00 (0.88-1.14), 1.14 (0.92-1.40) and 1.26 (0.84-1.89). These results were consistent in sensitivity analyses.; Less than 20% of patients with AHF present LBBB, which is consistently associated with cardiovascular comorbidities, reduced left ventricular ejection fraction and more severe decompensations. Nonetheless, after taking these factors into account, LBBB in patients with AHF is not associated with worse outcomes