Search

(1) Background: C-reactive protein (CRP) and albumin are inflammatory markers. We analyzed the prognostic capacity of serum albumin (SA) and CRP for an outcome comprising mortality, length of stay, ICU admission, and non-invasive mechanical ventilation in hospitalized COVID-19 patients. (2) Methods: We conducted a retrospective cohort study based on the Spanish national SEMI-COVID-19 Registry. Two multivariate logistic models were adjusted for SA, CRP, and their combination. Training and testing samples were used to validate the models. (3) Results: The outcome was present in 41.1% of the 3471 participants, who had lower SA (mean [SD], 3.5 [0.6] g/dL vs. 3.8 [0.5] g/dL; p < 0.001) and higher CRP (108.9 [96.5] mg/L vs. 70.6 [70.3] mg/L; p < 0.001). In the adjusted multivariate model, both were associated with poorer evolution: SA, OR 0.674 (95% CI, 0.551–0.826; p < 0.001); CRP, OR 1.002 (95% CI, 1.001–1.004; p = 0.003). The CRP/SA model had a similar predictive capacity (honest AUC, 0.8135 [0.7865–0.8405]), with a continuously increasing risk and cutoff value of 25 showing the highest predictive capacity (OR, 1.470; 95% CI, 1.188–1.819; p < 0.001). (4) Conclusions: SA and CRP are good independent predictors of patients hospitalized with COVID-19. For the CRP/SA ratio value, 25 is the cutoff for poor clinical course.

Background Advanced age is a well-known risk factor for poor prognosis in COVID-19. However, few studies have specifically focused on very old inpatients with COVID-19. This study aims to describe the clinical characteristics of very old inpatients with COVID-19 and identify risk factors for in-hospital mortality at admission. Methods We conducted a nationwide, multicenter, retrospective, observational study in patients ≥ 80 years hospitalized with COVID-19 in 150 Spanish hospitals (SEMI-COVID-19) Registry (March 1–May 29, 2020). The primary outcome was in-hospital mortality. A uni- and multivariate logistic regression was performed to assess predictors of mortality at admission. Results A total of 2772 consecutive patients (49.4% men, median age 86.3 years) were analyzed. Rates of atherosclerotic cardiovascular disease, diabetes mellitus, dementia, and Barthel Index < 60 were 30.8%, 25.6%, 30.5%, and 21.0%, respectively. The overall case-fatality rate was 46.9% (n: 1301) and increased with age (80–84 years: 41.6%; 85–90 years: 47.3%; 90–94 years: 52.7%; ≥95 years: 54.2%). After analysis, male sex and moderate-to-severe dependence were independently associated with in-hospital mortality; comorbidities were not predictive. At admission, independent risk factors for death were: oxygen saturation < 90%; temperature ≥ 37.8°C; quick sequential organ failure assessment (qSOFA) score ≥ 2; and unilateral–bilateral infiltrates on chest x-rays. Some analytical findings were independent risk factors for death, including estimated glomerular filtration rate < 45 mL/min/1.73 m2; lactate dehydrogenase ≥ 500 U/L; C-reactive protein ≥ 80 mg/L; neutrophils ≥ 7.5 × 103/μL; lymphocytes < 0.8 × 103/μL; and monocytes < 0.5 × 103/μL. Conclusions This first large, multicenter cohort of very old inpatients with COVID-19 shows that age, male sex, and poor preadmission functional status—not comorbidities—are independently associated with in-hospital mortality. Severe COVID-19 at admission is related to poor prognosis.

(1) Background: This work aims to analyze clinical outcomes according to ethnic groups in patients hospitalized for COVID-19 in Spain. (2) Methods: This nationwide, retrospective, multicenter, observational study analyzed hospitalized patients with confirmed COVID-19 in 150 Spanish hospitals (SEMI-COVID-19 Registry) from 1 March 2020 to 31 December 2021. Clinical outcomes were assessed according to ethnicity (Latin Americans, Sub-Saharan Africans, Asians, North Africans, Europeans). The outcomes were in-hospital mortality (IHM), intensive care unit (ICU) admission, and the use of invasive mechanical ventilation (IMV). Associations between ethnic groups and clinical outcomes adjusted for patient characteristics and baseline Charlson Comorbidity Index values and wave were evaluated using logistic regression. (3) Results: Of 23,953 patients (median age 69.5 years, 42.9% women), 7.0% were Latin American, 1.2% were North African, 0.5% were Asian, 0.5% were Sub-Saharan African, and 89.7% were European. Ethnic minority patients were significantly younger than European patients (median (IQR) age 49.1 (40.5–58.9) to 57.1 (44.1–67.1) vs. 71.5 (59.5–81.4) years, p < 0.001). The unadjusted IHM was higher in European (21.6%) versus North African (11.4%), Asian (10.9%), Latin American (7.1%), and Sub-Saharan African (3.2%) patients. After further adjustment, the IHM was lower in Sub-Saharan African (OR 0.28 (0.10–0.79), p = 0.017) versus European patients, while ICU admission rates were higher in Latin American and North African versus European patients (OR (95%CI) 1.37 (1.17–1.60), p < 0.001) and (OR (95%CI) 1.74 (1.26–2.41), p < 0.001). Moreover, Latin American patients were 39% more likely than European patients to use IMV (OR (95%CI) 1.43 (1.21–1.71), p < 0.001). (4) Conclusion: The adjusted IHM was similar in all groups except for Sub-Saharan Africans, who had lower IHM. Latin American patients were admitted to the ICU and required IMV more often.

Background: The WHO ordinal severity scale has been used to predict mortality and guide trials in COVID-19. However, it has its limitations. Objective The present study aims to compare three classificatory and predictive models: the WHO ordinal severity scale, the model based on inflammation grades, and the hybrid model. Design Retrospective cohort study with patient data collected and followed up from March 1, 2020, to May 1, 2021, from the nationwide SEMI-COVID-19 Registry. The primary study outcome was in-hospital mortality. As this was a hospital-based study, the patients included corresponded to categories 3 to 7 of the WHO ordinal scale. Categories 6 and 7 were grouped in the same category. Key Results A total of 17,225 patients were included in the study. Patients classified as high risk in each of the WHO categories according to the degree of inflammation were as follows: 63.8% vs. 79.9% vs. 90.2% vs. 95.1% (p

Objective To describe the impact of different doses of corticosteroids on the evolution of patients with COVID-19 pneumonia, based on the potential benefit of the non-genomic mechanism of these drugs at higher doses. Methods Observational study using data collected from the SEMI-COVID-19 Registry. We evaluated the epidemiological, radiological and analytical scenario between patients treated with megadoses therapy of corticosteroids vs low-dose of corticosteroids and the development of complications. The primary endpoint was all-cause in-hospital mortality according to use of corticosteroids megadoses. Results Of a total of 14,921 patients, corticosteroids were used in 5,262 (35.3%). Of them, 2,216 (46%) specifically received megadoses. Age was a factor that differed between those who received megadoses therapy versus those who did not in a significant manner (69 years [IQR 59–79] vs 73 years [IQR 61–83]; p < .001). Radiological and analytical findings showed a higher use of megadoses therapy among patients with an interstitial infiltrate and elevated inflammatory markers associated with COVID-19. In the univariate study it appears that steroid use is associated with increased mortality (OR 2.07 95% CI 1.91–2.24 p < .001) and megadose use with increased survival (OR 0.84 95% CI 0.75–0.96, p 0.011), but when adjusting for possible confounding factors, it is observed that the use of megadoses is also associated with higher mortality (OR 1.54, 95% CI 1.32–1.80; p < .001). There is no difference between megadoses and low-dose (p .298). Although, there are differences in the use of megadoses versus low-dose in terms of complications, mainly infectious, with fewer pneumonias and sepsis in the megadoses group (OR 0.82 95% CI 0.71–0.95; p < .001 and OR 0.80 95% CI 0.65–0.97; p < .001) respectively. Conclusion There is no difference in mortality with megadoses versus low-dose, but there is a lower incidence of infectious complications with glucocorticoid megadoses.

Our main aim was to describe the effect on the severity of ACEI (angiotensin-converting enzyme inhibitor) and ARB (angiotensin II receptor blocker) during COVID-19 hospitalization. A retrospective, observational, multicenter study evaluating hospitalized patients with COVID-19 treated with ACEI/ARB. The primary endpoint was the incidence of the composite outcome of prognosis (IMV (invasive mechanical ventilation), NIMV (non-invasive mechanical ventilation), ICU admission (intensive care unit), and/or all-cause mortality). We evaluated both outcomes in patients whose treatment with ACEI/ARB was continued or withdrawn. Between February and June 2020, 11,205 patients were included, mean age 67 years (SD = 16.3) and 43.1% female, 2162 patients received ACEI/ARB treatment. ACEI/ARB treatment showed lower all-cause mortality (p &lt, 0.0001). Hypertensive patients in the ACEI/ARB group had better results in IMV, ICU admission, and the composite outcome of prognosis (p &lt, 0.0001 for all). No differences were found in the incidence of major adverse cardiovascular events. Patients previously treated with ACEI/ARB continuing treatment during hospitalization had a lower incidence of the composite outcome of prognosis than those whose treatment was withdrawn (RR 0.67, 95%CI 0.63–0.76). ARB was associated with better survival than ACEI (HR 0.77, 95%CI 0.62–0.96). ACEI/ARB treatment during COVID-19 hospitalization was associated with protection on mortality. The benefits were greater in hypertensive, those who continued treatment, and those taking ARB.

There is some evidence that male gender could have a negative impact on the prognosis and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The aim of the present study was to compare the characteristics of coronavirus disease 2019 (COVID-19) between hospitalized men and women with confirmed SARS-CoV-2 infection. This multicenter, retrospective, observational study is based on the SEMI-COVID-19 Registry. We analyzed the differences between men and women for a wide variety of demographic, clinical, and treatment variables, and the sex distribution of the reported COVID-19 deaths, as well as intensive care unit (ICU) admission by age subgroups. This work analyzed 12,063 patients (56.8% men). The women in our study were older than the men, on average (67.9 vs. 65.7 years; p < 001). Bilateral condensation was more frequent among men than women (31.8% vs. 29.9%; p = 0.007). The men needed non-invasive and invasive mechanical ventilation more frequently (5.6% vs. 3.6%, p < 0.001, and 7.9% vs. 4.8%, p < 0.001, respectively). The most prevalent complication was acute respiratory distress syndrome, with severe cases in 19.9% of men (p < 0.001). In men, intensive care unit admission was more frequent (10% vs. 6.1%; p < 0.001) and the mortality rate was higher (23.1% vs. 18.9%; p < 0.001). Regarding mortality, the differences by gender were statistically significant in the age groups from 55 years to 89 years of age. A multivariate analysis showed that female sex was significantly and independently associated with a lower risk of mortality in our study. Male sex appears to be related to worse progress in COVID-19 patients and is an independent prognostic factor for mortality. In order to fully understand its prognostic impact, other factors associated with sex must be considered.

Background Most patients with COVID-19 receive antibiotics despite the fact that bacterial co-infections are rare. This can lead to increased complications, including antibacterial resistance. We aim to analyze risk factors for inappropriate antibiotic prescription in these patients and describe possible complications arising from their use. Methods The SEMI-COVID-19 Registry is a multicenter, retrospective patient cohort. Patients with antibiotic were divided into two groups according to appropriate or inappropriate prescription, depending on whether the patient fulfill any criteria for its use. Comparison was made by means of multilevel logistic regression analysis. Possible complications of antibiotic use were also identified. Results Out of 13,932 patients, 3047 (21.6%) were prescribed no antibiotics, 6116 (43.9%) were appropriately prescribed antibiotics, and 4769 (34.2%) were inappropriately prescribed antibiotics. The following were independent factors of inappropriate prescription: February-March 2020 admission (OR 1.54, 95%CI 1.18–2.00), age (OR 0.98, 95%CI 0.97–0.99), absence of comorbidity (OR 1.43, 95%CI 1.05–1.94), dry cough (OR 2.51, 95%CI 1.94–3.26), fever (OR 1.33, 95%CI 1.13–1.56), dyspnea (OR 1.31, 95%CI 1.04–1.69), flu-like symptoms (OR 2.70, 95%CI 1.75–4.17), and elevated C-reactive protein levels (OR 1.01 for each mg/L increase, 95% CI 1.00–1.01). Adverse drug reactions were more frequent in patients who received ANTIBIOTIC (4.9% vs 2.7%, p < .001). Conclusion The inappropriate use of antibiotics was very frequent in COVID-19 patients and entailed an increased risk of adverse reactions. It is crucial to define criteria for their use in these patients. Knowledge of the factors associated with inappropriate prescribing can be helpful.

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Farmacología. Fecha de lectura: 28-06-2019, Esta tesis tiene embargado el acceso al texto completo hasta el 28-12-2020

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Farmacología y Terapéutica. Fecha de lectura: 20-09-2017, Esta tesis tiene embargado el acceso al texto completo hasta el 20-03-2019, El receptor nicotínico para la acetilcolina del subtipo 7 (7-nAChR) está ampliamente distribuido en células del sistema nervioso central (SNC), tanto neuronas como células gliales. Mientras que el receptor expresado por las neuronas modula la liberación de ciertos neurotransmisores (glutamato, dopamina y serotonina), el expresado por la microglía controla el exceso de inflamación cerebral en respuesta a un estímulo lesivo. En el genoma humano se ha identificado un nuevo gen híbrido (CHRFAM7A) resultante de la combinación del gen CHRNA7, que codifica para la subunidad nicotínica 7, y del gen FAM. Durante mucho tiempo fue desconocida la función de la subunidad nicotínica codificada por el gen híbrido, dup7. En 2011, nuestro grupo demostró, por primera vez, que el dup7 se comportaba como un dominante negativo de la actividad del 7-nAChR en un modelo de expresión heteróloga, los ovocitos de Xenopus. Este hallazgo fue corroborado en estudios posteriores realizados por otros grupos. Hasta la fecha, se desconoce cuál puede ser el papel fisiopatológico de dup7 en células de mamíferos, así como el mecanismo por el que se produce la interacción 7/dup7 o las consecuencias fisiopatológicas de dicha interacción. Polimorfismos del gen CHRFAM7A han sido asociados a ciertas enfermedades neuropsiquiátricas, como la depresión, la esquizofrenia, el Alzheimer o la demencia por cuerpos de Lewy. En la etiopatogenia de la depresión han sido propuestas varias teorías, una de las cuales propugna la existencia de una inflamación basal en el paciente con elevación de los niveles de citoquinas proinflamatorias. En base a todo lo anterior, el objetivo central de este trabajo ha sido evaluar si dup7 interacciona físicamente con la subunidad 7 formando un receptor pentamérico mixto, en líneas celulares de mamíferos de tipo neuroendocrino (GH4C1), inmune (RAW 264.7) y neuronal (SHSY5Y), así como dilucidar el papel fisiopatológico de dicha interacción en la neurotransmisión. Para el estudio funcional, se procedió a la obtención de clones con sobreexpresión estable de dup7 de células SH-SY5Y. Los principales hallazgos del presente trabajo demuestran que células de mamíferos, de diversa naturaleza, son capaces de formar un receptor nicotínico mixto con la subunidad 7 (7dup7-nAChR) en detrimento de la formación de 7- nAChR homoméricos. La consecuencia fisiológica de la incorporación de dup7 a la estructura pentamérica del nAChR es la reducción de la señal de [Ca2+]i y la neurosecreción mediada por el 7-nAChR. Dado el papel modulador de 7-nAChR en la liberación de neurotransmisores y su actividad antiinflamatoria, nos propusimos averiguar si los niveles de expresión de 7 y dup7 ARNm de células de sangre periférica de pacientes depresivos correlacionaban con la gravedad de la enfermedad y la respuesta al tratamiento farmacológico. Los resultados arrojaron una perfecta correlación inversa entre ambos marcadores, indicando que la expresión de 7 ARNm puede ser un buen marcador del curso evolutivo de la depresión. Más aún, nos preguntamos si fármacos antidepresivos con diferentes mecanismos de acción, podrían ejercer su efecto terapéutico a través de la regulación de la expresión de las diferentes subunidades nicotínicas, modulando de este modo, la neurosecreción y la neuroinflamación. Nuestros resultados revelan que determinados fármacos aumentan la expresión 7 ARNm en neuronas y/o microglía conduciendo a una mayor liberación de neurotransmisores y una disminución de la neuroinflamación, lo cual puede contribuir a la acción antidepresiva de dichos fármacos.

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Farmacología y Terapéutica. Fecha de lectura: 5-09-2017, Esta tesis tiene embargado el acceso al texto completo hasta el 05-03-2019, El receptor nicotínico para la acetilcolina del subtipo α7 (α7 nAChR) presenta una amplia distribución en el organismo. Este subtipo de receptor ha sido identificado en queratinocitos, adipocitos, células inmunes, endoteliales, bronquiales y tumorales, desempeñando importantes funciones en cada una de estas localizaciones. En base a lo anterior, no es extraño que una deficiente actividad del α7 nAChR, o una reducción del número de receptores, hayan sido implicados en la etiopatogenia de diversos procesos patológicos neuropsiquiátricos (esquizofrenia, trastorno bipolar, Alzheimer, Parkinson), así como en enfermedades inflamatorias y neoplásicas. En el año 1998, Gault y cols identificaron en el cromosoma 15 del genoma humano un nuevo gen híbrido, el CHRFAM7A. El híbrido resulta de la combinación de un duplicado parcial del gen CHRNA7, que codifica para la subunidad α7 del nAChR, con el gen FAM7A. Nuestro grupo logró, por primera vez, identificar la función del transcrito del gen duplicado, el dupα7, el cual se comporta como un modulador endógeno de la actividad del α7 nAChR en ovocitos (de Lucas Cerrillo y col., 2011). Dada la implicación del α7 nAChR en múltiples procesos patológicos humanos, en este trabajo de Tesis nos planteamos estudiar la actividad de este receptor, y su posible modulación por dupα7, en enfermedades de gran importancia clínica como la sepsis, un prototipo de enfermedad inflamatoria extrema, y el carcinoma de pulmón de células no pequeñas (NSCLC). Se ha recurrido a utilizar una combinación de técnicas, incluyendo las de biología celular y molecular, bioquímica, microscopía confocal y técnicas específicas para el estudio de la actividad tumorogénica in vitro e in vivo de líneas celulares tumorales. Nuestros resultados derivados del estudio piloto realizado en pacientes sépticos revelan que los que presentan niveles de expresión altos de α7 ARNm y bajos de dupα7 en CMSP muestran un mejor control de la inflamación y mejor pronóstico. Por otro lado, nuestros resultados in vitro e in vivo con líneas celulares de NSCLC muestran que la sobreexpresión de dupα7 bloquea la progresión tumoral secundaria a la activación del α7 nAChR por nicotina y NNK. Adicionalmente, los datos obtenidos en biopsias pareadas tumorales y no tumorales de pacientes con NSCLC indican la sobreexpresión del α7 ARNm y la disminución del dupα7 en las muestras tumorales respecto a las no tumorales, lo que refuerza el papel decisivo del α7 nAChR en el desarrollo tumoral, así como la capacidad moduladora negativa de dupα7 en este proceso.

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 22-06-2017, Esta tesis tiene embargado el acceso al texto completo hasta el 22-12-2018

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 23-05-2016, Esta tesis tiene embargado el acceso al texto completo hasta el 23-11-2017

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Farmacología. Fecha de Lectura: 02-12-2022, Varios ensayos clínicos han demostrado peor evolución clínica y menor respuesta a la quimioterapia (quimiorresistencia), incluyendo a los derivados del platino, de los pacientes con cáncer de pulmón de células no pequeñas (NSCLC) fumadores frente a no fumadores. Datos preliminares in vitro de nuestro laboratorio han revelado que la nicotina del tabaco, y su nitrosamina derivada NNK, a través de la activación de receptores nicotínicos para la acetilcolina del subtipo α7 (α7-nAChRs) expresados en las células epiteliales y tumorales de pulmón, están implicadas en la anterior quimiorresistencia al interferir con el efecto citotóxico de cisplatino a nivel de la apoptosis. Sin embargo, se desconocen los mecanismos moleculares puestos en marcha por el α7-nAChR para interferir con el efecto proapoptótico de cisplatino, o si dicha resistencia a cisplatino mediada por el anterior subtipo de receptor se reproduce in vivo. También permanece por dilucidar si otros subtipos del nAChR, distintos al α7-nAChR, contribuyen a la anterior quimiorresistencia, así como si los hallazgos in vitro e in vivo relativos al mecanismo molecular implicado en la quimiorresistencia pueden ser corroborados en la clínica. En base a lo anterior, esta Tesis Doctoral tiene como OBJETIVO GENERAL tratar de resolver las cuatro incógnitas planteadas. Con este propósito hemos realizado experimentos in vitro utilizando diversas variantes de la línea celular humana de adenocarcinoma de pulmón A549 [salvaje, o con distintas subunidades del nAChR (α3, α5, β4, α7) silenciadas con siRNAs específicos (knockdown) o mediante CRISPR-Cas9 (knockout)], junto a experimentos in vivo en un modelo xenográfico murino de NSCLC, combinados con experimentos en tumores primarios de 107 pacientes con NSCLC, tanto fumadores (n = 59) como no fumadores (n = 48). En los experimentos in vitro e in vivo se ha empleado cisplatino como agente quimioterápico, y en el conjunto de la Tesis una combinación de técnicas que incluyen la PCR cuantitativa, citometría de flujo, microarrays proteicos, inmunoblot, inmunohistoquímica y ensayos de tumorogenicidad. Nuestros principales hallazgos son los siguientes: (i) se identifican las proteínas quinasas y factores de transcripción cuya actividad es desregulada por nicotina, a través del α7-nAChR, promoviendo la supervivencia celular y, por tanto, contrarrestando el efecto citotóxico de cisplatino; (ii) se corrobora in vivo el papel determinante del α7-nAChR en la resistencia a cisplatino inducida por nicotina en el tumor xenográfico NSCLC del ratón; (iii) se constata, también in vivo, que en la resistencia a cisplatino inducida por nicotina subyace un aumento de expresión de proteínas antiapoptóticas y disminución de las proapoptóticas en el tumor xenográfico; (iv) la anterior alteración del patrón de expresión génica de proteínas reguladoras de apoptosis inducida por nicotina in vivo es corroborada en tumores primarios NSCLC de fumadores frente a no fumadores; (v) se demuestra que otros subtipos de nAChRs, además del α7-nAChR, contribuyen a la anterior quimiorresistencia. En conjunto, nuestros resultados in vitro, in vivo y en tumores primarios de pacientes con NSCLC revelan el mecanismo molecular que subyace en la resistencia a la quimioterapia inducida por el consumo de tabaco en este tipo de tumor. A través de este mecanismo, los componentes del tabaco nicotina/NNK, activando α7-nAChRs y otros subtipos de nAChRs, alterarían la capacidad apoptótica celular generando un “estado antiapoptótico” en el tumor que lo haría refractario al efecto citotóxico de la quimioterapia. En base a nuestros hallazgos, la presente Tesis aporta argumentos científicos sólidos para concienciar a médicos, pacientes, y población en general, acerca de que el consumo de tabaco no solo es la principal causa prevenible de cáncer y muerte por cáncer, sino también del previsible fracaso terapéutico y peor evolución que este hábito puede ocasionaren en los pacientes con NSCLC y otros tumores asociados al tabaquismo, La presente Tesis Doctoral ha sido financiada por el Ministerio de Ciencia e Innovación de España bajo el proyecto SAF2017SAF2017-8268982689-R