Allelic Frequency of DPYD Genetic Variants in Patients With Cancer in Spain: The PhotoDPYD Study

Genetic variants; Cancer; SpainVariants genètiques; Càncer; EspanyaVariantes genéticas; Cáncer; EspañaIntroduction Identifying polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene is gaining importance to be able to predict fluoropyrimidine-associated toxicity. The aim of this project was to describe the frequency of the DPYD variants DPYD*2A (rs3918290); c.1679T>G (rs55886062); c.2846A>T (rs67376798) and c.1129-5923C>G (rs75017182; HapB3) in the Spanish oncological patients. Material and Methods Cross-sectional and multicentric study (PhotoDPYD study) conducted in hospitals located in Spain designed to register the frequency of the most relevant DPYD genetic variants in oncological patients. All oncological patients with DPYD genotype were recruited in the participant hospitals. The measures determined where the presence or not of the 4 DPYD previously described variants. Results Blood samples from 8054 patients with cancer from 40 different hospitals were used to determine the prevalence of the 4 variants located in the DPYD gene. The frequency of carriers of one defective DPYD variant was 4.9%. The most frequently identified variant was c.1129-5923C>G (rs75017182) (HapB3), in 2.9%, followed by c.2846A>T (rs67376798) in 1.4%, c.1905 + 1G>A (rs3918290, DPYD*2A) in 0.7% and c.1679T>G (rs55886062) in 0.2% of the patients. Only 7 patients (0.08%) were carrying the c.1129-5923C>G (rs75017182) (HapB3) variant, 3 (0.04%) the c.1905 + 1G>A (rs3918290, DPYD*2A) and one (0.01%) the DPYD c.2846A>T (rs67376798, p.D949V) variant in homozygosis. Moreover, 0.07% were compound heterozygous patients, 3 carrying the DPYD variants DPYD*2A + c.2846A>T, 2 the DPYD c.1129-5923C>G + c.2846A>T and one the DPYD*2A + c.1129-5923C>G variants. Conclusions Our results demonstrate the relatively high frequency of DPYD genetic variants in the Spanish patient with cancer population, which highlights the relevance of their determination before initiating a fluoropirimidine-containing regimen

Efficacy and safety of high doses of irinotecan in patients with metastatic colorectal cancer treated with the FOLFIRI regimen based on the UGT1A1 genotype: A systematic review

Efficacy; Metastatic colorectal cancerEficacia; Cáncer colorrectal metastásicoEficàcia; Càncer colorectal metastàticObjetivo: El objetivo de la presente revisión sistemática es analizar los datos publicados sobre la eficacia y seguridad de las dosis superiores a los 180 mg/m2 de irinotecán recomendadas en la ficha técnica en pacientes con cáncer colorrectal metastásico tratados con el esquema FOLFIRI y con genotipo UGT1A1*1/*1 y *1/*28. Método: Se realizó una revisión sistemática mediante una búsqueda bibliográfica en Medline y Embase de los artículos publicados hasta diciembre de 2021. Los métodos utilizados se basaron en los recomendados según Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA). Los criterios para la inclusión de los estudios se definieron previamente en base a los dos objetivos secundarios que aborda esta revisión: 1) Analizar la magnitud de la diferencia de la respuesta clínica y 2) estudiar la magnitud de la diferencia de los efectos adversos a irinotecán a dosis altas, en comparación con las dosis descritas en la ficha técnica para el esquema FOLFIRI en pacientes con cáncer colorrectal metastásico con el genotipo UGT1A1*1/*1 o *1/*28. Resultados: La estrategia de búsqueda reportó un total de 98 referencias, de las que 13 fueron seleccionadas para el análisis, 7 (53,8%) evaluando tanto eficacia como seguridad y 6 (46,2%) únicamente seguridad. En relación con los estudios que evaluaron eficacia y seguridad, 6 (85,7%) se mostraron favorables al aumento de dosis en términos de tasa de respuesta objetiva y supervivencia libre de progresión e, incluso, en 2 de ellos en supervivencia global. Los estudios que evaluaron seguridad apuntan a que dosis de irinotecán superiores a 180 mg/m2 son toleradas por la mayor parte de los pacientes UGT1A1*1/*1 y *1/*28. Conclusiones: La presente revisión sistemática muestra la conveniencia de valorar el ajuste de dosis de irinotecán dentro del esquema FOLFIRI en función de los polimorfismos del gen UGT1A1, con un potencial aumento de las probabilidades de una adecuada respuesta clínica.Objective: The purpose of this systematic review is to analyze the published data on the efficacy and safety of doses higher than 180 mg/m2 of irinotecan recommended in the drug’s summary of product characteristics in metastatic colorectal cancer patients with genotypes UGT1A1*1/*1 or *1/*28 who are treated with the FOLFIRI regimen. Method: A systematic review of the literature was carried out in Medline and Embase searching for articles published up to December 2021. The methods used were based on the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The criteria for the inclusion of studies were previously defined based on the two secondary goals addressed in this review: 1) To analyze the magnitude of the differences in clinical responses and 2) To study the magnitude of the differences in adverse effects of irinotecan at high doses, as compared to the doses described in the summary of product characteristics corresponding to the FOLFIRI regimen in patients with metastatic colorectal cancer with genotypes UGT1A1*1/* 1 or *1/*28. Results: The search yielded a total of 985 references, of which 13 were selected for analysis. Seven evaluated both efficacy and safety and six only safety. With regard to the studies that evaluated both efficacy and safety, six out of seven (85.7%) were in favor of increasing irinotecan dose according to the objective response rate and progression-free survival. Two of them even recommended dose increases based on overall survival. Irinotecan safety studies suggest that doses higher than 180 mg/m2 are tolerated by most UGT1A1*1/*1 and *1/*28 patients. Conclusions: The present systematic review shows the advisability of considering adjusting the dose of irinotecan when used as part of the FOLFIRI regimen based on the polymorphisms of the UGT1A1 gene as this may increase the likelihood of an adequate clinical response

Safety of Drugs Used during the First Wave of COVID-19: A Hospital-Registry-Based Study

COVID-19; Adverse drug reactions; HydroxychloroquineCOVID-19; Reaccions adverses als medicaments; HidroxicloroquinaCOVID-19; Reacciones adversas a los medicamentos; HidroxicloroquinaThe emergency of the coronavirus disease 2019 (COVID-19) pandemic led to the off-label use of drugs without data on their toxicity profiles in patients with COVID-19, or on their concomitant use. Patients included in the COVID-19 Patient Registry of a tertiary hospital during the first wave were analyzed to evaluate the adverse drug reactions (ADRs) with the selected treatments. Twenty-one percent of patients (197 out of 933) had at least one ADR, with a total of 240 ADRs. Patients with ADRs were more commonly treated with multiple drugs for COVID-19 infection than patients without ADRs (p < 0.001). They were younger (median 62 years vs. 70.1 years; p < 0.001) and took less medication regularly (69.5% vs. 75.7%; p = 0.031). The most frequent ADRs were gastrointestinal (67.1%), hepatobiliary (10.8%), and cardiac disorders (3.3%). Drugs more frequently involved included lopinavir/ritonavir (82.2%), hydroxychloroquine (72.1%), and azithromycin (66.5%). Although most ADRs recovered without sequelae, fatal cases were described, even though the role of the disease could not be completely ruled out. In similar situations, efforts should be made to use the drugs in the context of clinical trials, and to limit off-label use to those drugs with a better benefit/risk profile in specific situations and for patients at high risk of poor disease prognosis

COVID-19 Clinical Profile in Latin American Migrants Living in Spain: Does the Geographical Origin Matter?

COVID-19; Latin America; SeverityCOVID-19; Amèrica Llatina; GravetatCOVID-19; América Latina; GravedadThe aim of this study was to describe and compare the clinical characteristics of hospitalized patients with COVID-19 pneumonia according to their geographical origin. This is a retrospective case-control study of hospitalized patients with confirmed COVID-19 pneumonia treated at Vall d’Hebron University Hospital (Barcelona) during the first wave of the pandemic. Cases were defined as patients born in Latin America and controls were randomly selected among Spanish patients matched by age and gender. Demographic and clinical variables were collected, including comorbidities, symptoms, vital signs and analytical parameters, intensive care unit admission and outcome at 28 days after admission. Overall, 1080 hospitalized patients were registered: 774 (71.6%) from Spain, 142 (13.1%) from Latin America and the rest from other countries. Patients from Latin America were considered as cases and 558 Spanish patients were randomly selected as controls. Latin American patients had a higher proportion of anosmia, rhinorrhea and odynophagia, as well as higher mean levels of platelets and lower mean levels of ferritin than Spanish patients. No differences were found in oxygen requirement and mortality at 28 days after admission, but there was a higher proportion of ICU admissions (28.2% vs. 20.2%, p = 0.0310). An increased proportion of ICU admissions were found in patients from Latin America compared with native Spanish patients when adjusted by age and gender, with no significant differences in in-hospital mortality.Isabel Campos-Varela’s research activity is funded by grant PI19/00330 from Instituto de Salud Carlos III. CIBERehd is supported by Instituto de Salud Carlos III. The work was independent of all funding. This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors

Mecanismos farmacológicos implicados en la función deglutoria

El objetivo de esta Tesis Doctoral ha sido estudiar de forma integrada diferentes aspectos relacionados con los fármacos y la disfagia orofaríngea (DO) en el paciente adulto. La Tesis se ha centrado en el estudio de diferentes mecanismos farmacológicos implicados en la deglución. El objetivo del primer estudio fue conocer qué fármacos pueden asociarse a un efecto perjudicial y cuáles a un efecto beneficioso en la DO. Para este objetivo, se estudiaron retrospectivamente 966 pacientes ancianos ingresados en una Unidad Geriátrica de Agudos (UGA) en los que se realizó sistemáticamente el método clínico de volumen-viscosidad (MECV-V) para diagnosticar la presencia de DO y se revisó su tratamiento farmacológico, clasificando los fármacos según el nivel 4 (clasificación farmacológica y terapéutica) del sistema de clasificación anatómica, terapéutica y química (ATC). Los resultados sugirieron que los antipsicóticos (código ATC N06A), los antidepresivos (código ATC N02B) y los fármacos contra la demencia (código ATC N06D) se asociaban a un empeoramiento de la función deglutoria. No obstante, ninguno de ellos mostró una significación estadística cuando se ajustaron por patología (incluyendo la demencia y la depresión, respectivamente). En cuanto a los efectos beneficiosos, se observó un efecto favorable de los agentes que actúan en el sistema de renina-angiotensina (código ATC C08C), los antidiabéticos orales (código ATC A10B), los antagonistas del calcio (código ATC C08C), los antiinflamatorios y productos antireumáticos, no esteroidales (código ATC M01A) y los beta-bloqueantes (código ATC C07A). Aunque únicamente se mantuvo la significación estadística una vez realizado el análisis multivariado con este último grupo de fármacos. El objetivo del segundo estudio y el del anexo fue ampliar el conocimiento del efecto de los antipsicóticos en la DO. El estudio del anexo consistió en una revisión sistemática de la evidencia publicada hasta el momento basada en estudios clínicos que relacionaban la DO con los antipsicóticos, que concluyó que los pacientes en tratamiento con antipsicóticos pueden desarrollar disfagia, pero es difícil diferenciar si este efecto es debido al fármaco o a la enfermedad en sí. Por este motivo, el segundo estudio se realizó en pacientes con demencia y se compararon los parámetros deglutorios evaluados mediante la videofluoroscopia (VFS) de los pacientes con demencia en tratamiento con antipsicóticos para los síntomas conductuales de la demencia con pacientes también con demencia pero sin tratamiento con antipsicóticos. Asimismo, se comparó la fisiopatología de la deglución de los pacientes con demencia con pacientes sin demencia, encontrando diferencias en estos dos grupos, pero no se encontraron diferencias significativas en los pacientes con demencia que estaban en tratamiento con antipsicóticos respecto a los que no, únicamente se observó un retraso en el tiempo de apertura del esfínter esofágico inferior que no fue clínicamente significativo. En los pacientes con demencia, encontramos aumentado el tiempo de respuesta motora orofaríngea (RMO) y una mayor prevalencia de alteraciones de la seguridad de la deglución en comparación con los pacientes sin demencia. Finalmente, el objetivo del tercer estudio fue explorar las concentraciones de SP en sangre y en saliva en pacientes que estaban en tratamiento con beta-bloqueantes utilizando un ensayo por inmunoabsorción ligado a enzimas (ELISA), y conocer la relación de los niveles de SP con la DO. A partir de este estudio pudimos obtener 3 conclusiones: (i) las concentraciones de SP en sangre y en saliva de los pacientes en tratamiento con beta-bloqueantes fueron significativamente superiores en comparación con las de los pacientes que no estaban en tratamiento con beta-bloqueantes; (ii) la prevalencia de DO fue significativamente menor en los pacientes en tratamiento con beta-bloqueantes; y (iii) los pacientes con DO presentaban significativamente menores concentraciones de SP en saliva que los pacientes sin DO.The objective of this Doctoral Thesis has been to study, in an integrated way, different aspects related to drugs and oropharyngeal dysphagia (OD) in the adult patient. The Thesis has focused on the study of different pharmacological mechanisms involved in swallowing. The objective of the first study was to know which drugs can be associated with a detrimental effect and which ones in a beneficial effect in OD. For this purpose, we retrospectively studied 966 elderly patients admitted to an Acute Geriatric Unit (AGU), in which we systematically performed the volume-viscosity swallow test (V-VST) to assess the presence of OD, and reviewed their pharmacological treatment. We classified the drugs according to the level 4 (pharmacological and therapeutic classification) of the Anatomical, Therapeutics, Chemical (ATC) system. The results of this study suggested that antipsychotics (ATC code N06A), antidepressants (ATC code N02B) and anti-dementia drugs (ATC code N06D) were associated with a worsening of the swallowing function. However, none of them showed statistical significance when adjusted for pathology (including dementia and depression). Regarding the beneficial effects, we found that agents acting in the renin-angiotensin system (ATC code C08C), oral antidiabetics (ATC code A10B), calcium antagonists (ATC code C08C), anti-inflammatories and antirheumatic products, nonsteroidal (ATC code M01A) and beta-blockers (ATC code C07A) could have a protective effect on OD. However, only beta-blockers were statistically associated with OD after the multivariate analysis. The objective of the second study and the one included in the annex was to increase the knowledge of the effect of antipsychotics in OD. The study in the annex consisted of a systematic review of the evidence based on clinical studies that related OD with antipsychotics. We concluded that patients on antipsychotic treatment may develop dysphagia, but it is difficult to differentiate whether this effect is due to the drug or the disease itself. For this reason, the second study was conducted in patients with dementia. In this study, we compared swallowing parameters, evaluated by a videofluoroscopy (VFS) study, of patients with dementia in treatment with antipsychotics for behavioral symptoms of dementia with patients also with dementia but without treatment with antipsychotics. Similarly, the pathophysiology of swallowing of patients with dementia was compared with patients without dementia, finding differences in these two groups, but we did not found significant differences in patients with dementia with treatment with antipsychotics in comparison to those without treatment with antipsychotics. We only found a delay in the upper esophageal sphinchter time, but it was not clinically significant. Otherwise, we found an increase of the oropharyngeal motor response time in patients with dementia and a higher prevalence of swallowing safety alterations compared with patients without dementia. Finally, the objective of the third study was to explore the serum and saliva SP in patients who were in treatment with beta-blockers using an enzyme-linked immunosorbent assay (ELISA), and to know the relationship of SP levels with OD. From this study, we were able to obtain 3 conclusions: (i) SP serum and saliva levels of patients treated with beta-blockers were significantly higher in comparison with those patients who were not in treatment with beta-blockers; (ii) the prevalence of OD was significantly lower in patients taking beta-blockers; and (iii) patients with OD had significantly lower SP concentrations in saliva than patients without OD

Mecanismos farmacológicos implicados en la función deglutoria

El objetivo de esta Tesis Doctoral ha sido estudiar de forma integrada diferentes aspectos relacionados con los fármacos y la disfagia orofaríngea (DO) en el paciente adulto. La Tesis se ha centrado en el estudio de diferentes mecanismos farmacológicos implicados en la deglución. El objetivo del primer estudio fue conocer qué fármacos pueden asociarse a un efecto perjudicial y cuáles a un efecto beneficioso en la DO. Para este objetivo, se estudiaron retrospectivamente 966 pacientes ancianos ingresados en una Unidad Geriátrica de Agudos (UGA) en los que se realizó sistemáticamente el método clínico de volumen-viscosidad (MECV-V) para diagnosticar la presencia de DO y se revisó su tratamiento farmacológico, clasificando los fármacos según el nivel 4 (clasificación farmacológica y terapéutica) del sistema de clasificación anatómica, terapéutica y química (ATC). Los resultados sugirieron que los antipsicóticos (código ATC N06A), los antidepresivos (código ATC N02B) y los fármacos contra la demencia (código ATC N06D) se asociaban a un empeoramiento de la función deglutoria. No obstante, ninguno de ellos mostró una significación estadística cuando se ajustaron por patología (incluyendo la demencia y la depresión, respectivamente). En cuanto a los efectos beneficiosos, se observó un efecto favorable de los agentes que actúan en el sistema de renina-angiotensina (código ATC C08C), los antidiabéticos orales (código ATC A10B), los antagonistas del calcio (código ATC C08C), los antiinflamatorios y productos antireumáticos, no esteroidales (código ATC M01A) y los beta-bloqueantes (código ATC C07A). Aunque únicamente se mantuvo la significación estadística una vez realizado el análisis multivariado con este último grupo de fármacos. El objetivo del segundo estudio y el del anexo fue ampliar el conocimiento del efecto de los antipsicóticos en la DO. El estudio del anexo consistió en una revisión sistemática de la evidencia publicada hasta el momento basada en estudios clínicos que relacionaban la DO con los antipsicóticos, que concluyó que los pacientes en tratamiento con antipsicóticos pueden desarrollar disfagia, pero es difícil diferenciar si este efecto es debido al fármaco o a la enfermedad en sí. Por este motivo, el segundo estudio se realizó en pacientes con demencia y se compararon los parámetros deglutorios evaluados mediante la videofluoroscopia (VFS) de los pacientes con demencia en tratamiento con antipsicóticos para los síntomas conductuales de la demencia con pacientes también con demencia pero sin tratamiento con antipsicóticos. Asimismo, se comparó la fisiopatología de la deglución de los pacientes con demencia con pacientes sin demencia, encontrando diferencias en estos dos grupos, pero no se encontraron diferencias significativas en los pacientes con demencia que estaban en tratamiento con antipsicóticos respecto a los que no, únicamente se observó un retraso en el tiempo de apertura del esfínter esofágico inferior que no fue clínicamente significativo. En los pacientes con demencia, encontramos aumentado el tiempo de respuesta motora orofaríngea (RMO) y una mayor prevalencia de alteraciones de la seguridad de la deglución en comparación con los pacientes sin demencia. Finalmente, el objetivo del tercer estudio fue explorar las concentraciones de SP en sangre y en saliva en pacientes que estaban en tratamiento con beta-bloqueantes utilizando un ensayo por inmunoabsorción ligado a enzimas (ELISA), y conocer la relación de los niveles de SP con la DO. A partir de este estudio pudimos obtener 3 conclusiones: (i) las concentraciones de SP en sangre y en saliva de los pacientes en tratamiento con beta-bloqueantes fueron significativamente superiores en comparación con las de los pacientes que no estaban en tratamiento con beta-bloqueantes; (ii) la prevalencia de DO fue significativamente menor en los pacientes en tratamiento con beta-bloqueantes; y (iii) los pacientes con DO presentaban significativamente menores concentraciones de SP en saliva que los pacientes sin DO.The objective of this Doctoral Thesis has been to study, in an integrated way, different aspects related to drugs and oropharyngeal dysphagia (OD) in the adult patient. The Thesis has focused on the study of different pharmacological mechanisms involved in swallowing. The objective of the first study was to know which drugs can be associated with a detrimental effect and which ones in a beneficial effect in OD. For this purpose, we retrospectively studied 966 elderly patients admitted to an Acute Geriatric Unit (AGU), in which we systematically performed the volume-viscosity swallow test (V-VST) to assess the presence of OD, and reviewed their pharmacological treatment. We classified the drugs according to the level 4 (pharmacological and therapeutic classification) of the Anatomical, Therapeutics, Chemical (ATC) system. The results of this study suggested that antipsychotics (ATC code N06A), antidepressants (ATC code N02B) and anti-dementia drugs (ATC code N06D) were associated with a worsening of the swallowing function. However, none of them showed statistical significance when adjusted for pathology (including dementia and depression). Regarding the beneficial effects, we found that agents acting in the renin-angiotensin system (ATC code C08C), oral antidiabetics (ATC code A10B), calcium antagonists (ATC code C08C), anti-inflammatories and antirheumatic products, nonsteroidal (ATC code M01A) and beta-blockers (ATC code C07A) could have a protective effect on OD. However, only beta-blockers were statistically associated with OD after the multivariate analysis. The objective of the second study and the one included in the annex was to increase the knowledge of the effect of antipsychotics in OD. The study in the annex consisted of a systematic review of the evidence based on clinical studies that related OD with antipsychotics. We concluded that patients on antipsychotic treatment may develop dysphagia, but it is difficult to differentiate whether this effect is due to the drug or the disease itself. For this reason, the second study was conducted in patients with dementia. In this study, we compared swallowing parameters, evaluated by a videofluoroscopy (VFS) study, of patients with dementia in treatment with antipsychotics for behavioral symptoms of dementia with patients also with dementia but without treatment with antipsychotics. Similarly, the pathophysiology of swallowing of patients with dementia was compared with patients without dementia, finding differences in these two groups, but we did not found significant differences in patients with dementia with treatment with antipsychotics in comparison to those without treatment with antipsychotics. We only found a delay in the upper esophageal sphinchter time, but it was not clinically significant. Otherwise, we found an increase of the oropharyngeal motor response time in patients with dementia and a higher prevalence of swallowing safety alterations compared with patients without dementia. Finally, the objective of the third study was to explore the serum and saliva SP in patients who were in treatment with beta-blockers using an enzyme-linked immunosorbent assay (ELISA), and to know the relationship of SP levels with OD. From this study, we were able to obtain 3 conclusions: (i) SP serum and saliva levels of patients treated with beta-blockers were significantly higher in comparison with those patients who were not in treatment with beta-blockers; (ii) the prevalence of OD was significantly lower in patients taking beta-blockers; and (iii) patients with OD had significantly lower SP concentrations in saliva than patients without OD

Implantació de la digestió anaeròbia a la EDAR de Castell-Platja d’Aro

Estudi de la viabilitat tècnica i econòmica de la implantació de la digestió anaeròbia a l’EDAR de Castell-Platja d’Aro per tal de portar a terme un sistema de cogeneració. S’ha estudiant el funcionament actual amb digestió aeròbia i s’ha valorat mitjançant balanços de matèria, energia i econòmics els avantatges i desavantatges de substituir la digestió aeròbia per anaeròbi

Mecanismos farmacológicos implicados en la función deglutoria /

Premi Extraordinari de Doctorat concedit pels programes de doctorat de la UAB per curs acadèmic 2017-2018El objetivo de esta Tesis Doctoral ha sido estudiar de forma integrada diferentes aspectos relacionados con los fármacos y la disfagia orofaríngea (DO) en el paciente adulto. La Tesis se ha centrado en el estudio de diferentes mecanismos farmacológicos implicados en la deglución. El objetivo del primer estudio fue conocer qué fármacos pueden asociarse a un efecto perjudicial y cuáles a un efecto beneficioso en la DO. Para este objetivo, se estudiaron retrospectivamente 966 pacientes ancianos ingresados en una Unidad Geriátrica de Agudos (UGA) en los que se realizó sistemáticamente el método clínico de volumen-viscosidad (MECV-V) para diagnosticar la presencia de DO y se revisó su tratamiento farmacológico, clasificando los fármacos según el nivel 4 (clasificación farmacológica y terapéutica) del sistema de clasificación anatómica, terapéutica y química (ATC). Los resultados sugirieron que los antipsicóticos (código ATC N06A), los antidepresivos (código ATC N02B) y los fármacos contra la demencia (código ATC N06D) se asociaban a un empeoramiento de la función deglutoria. No obstante, ninguno de ellos mostró una significación estadística cuando se ajustaron por patología (incluyendo la demencia y la depresión, respectivamente). En cuanto a los efectos beneficiosos, se observó un efecto favorable de los agentes que actúan en el sistema de renina-angiotensina (código ATC C08C), los antidiabéticos orales (código ATC A10B), los antagonistas del calcio (código ATC C08C), los antiinflamatorios y productos antireumáticos, no esteroidales (código ATC M01A) y los beta-bloqueantes (código ATC C07A). Aunque únicamente se mantuvo la significación estadística una vez realizado el análisis multivariado con este último grupo de fármacos. El objetivo del segundo estudio y el del anexo fue ampliar el conocimiento del efecto de los antipsicóticos en la DO. El estudio del anexo consistió en una revisión sistemática de la evidencia publicada hasta el momento basada en estudios clínicos que relacionaban la DO con los antipsicóticos, que concluyó que los pacientes en tratamiento con antipsicóticos pueden desarrollar disfagia, pero es difícil diferenciar si este efecto es debido al fármaco o a la enfermedad en sí. Por este motivo, el segundo estudio se realizó en pacientes con demencia y se compararon los parámetros deglutorios evaluados mediante la videofluoroscopia (VFS) de los pacientes con demencia en tratamiento con antipsicóticos para los síntomas conductuales de la demencia con pacientes también con demencia pero sin tratamiento con antipsicóticos. Asimismo, se comparó la fisiopatología de la deglución de los pacientes con demencia con pacientes sin demencia, encontrando diferencias en estos dos grupos, pero no se encontraron diferencias significativas en los pacientes con demencia que estaban en tratamiento con antipsicóticos respecto a los que no, únicamente se observó un retraso en el tiempo de apertura del esfínter esofágico inferior que no fue clínicamente significativo. En los pacientes con demencia, encontramos aumentado el tiempo de respuesta motora orofaríngea (RMO) y una mayor prevalencia de alteraciones de la seguridad de la deglución en comparación con los pacientes sin demencia. Finalmente, el objetivo del tercer estudio fue explorar las concentraciones de SP en sangre y en saliva en pacientes que estaban en tratamiento con beta-bloqueantes utilizando un ensayo por inmunoabsorción ligado a enzimas (ELISA), y conocer la relación de los niveles de SP con la DO. A partir de este estudio pudimos obtener 3 conclusiones: (i) las concentraciones de SP en sangre y en saliva de los pacientes en tratamiento con beta-bloqueantes fueron significativamente superiores en comparación con las de los pacientes que no estaban en tratamiento con beta-bloqueantes; (ii) la prevalencia de DO fue significativamente menor en los pacientes en tratamiento con beta-bloqueantes; y (iii) los pacientes con DO presentaban significativamente menores concentraciones de SP en saliva que los pacientes sin DO.The objective of this Doctoral Thesis has been to study, in an integrated way, different aspects related to drugs and oropharyngeal dysphagia (OD) in the adult patient. The Thesis has focused on the study of different pharmacological mechanisms involved in swallowing. The objective of the first study was to know which drugs can be associated with a detrimental effect and which ones in a beneficial effect in OD. For this purpose, we retrospectively studied 966 elderly patients admitted to an Acute Geriatric Unit (AGU), in which we systematically performed the volume-viscosity swallow test (V-VST) to assess the presence of OD, and reviewed their pharmacological treatment. We classified the drugs according to the level 4 (pharmacological and therapeutic classification) of the Anatomical, Therapeutics, Chemical (ATC) system. The results of this study suggested that antipsychotics (ATC code N06A), antidepressants (ATC code N02B) and anti-dementia drugs (ATC code N06D) were associated with a worsening of the swallowing function. However, none of them showed statistical significance when adjusted for pathology (including dementia and depression). Regarding the beneficial effects, we found that agents acting in the renin-angiotensin system (ATC code C08C), oral antidiabetics (ATC code A10B), calcium antagonists (ATC code C08C), anti-inflammatories and antirheumatic products, nonsteroidal (ATC code M01A) and beta-blockers (ATC code C07A) could have a protective effect on OD. However, only beta-blockers were statistically associated with OD after the multivariate analysis. The objective of the second study and the one included in the annex was to increase the knowledge of the effect of antipsychotics in OD. The study in the annex consisted of a systematic review of the evidence based on clinical studies that related OD with antipsychotics. We concluded that patients on antipsychotic treatment may develop dysphagia, but it is difficult to differentiate whether this effect is due to the drug or the disease itself. For this reason, the second study was conducted in patients with dementia. In this study, we compared swallowing parameters, evaluated by a videofluoroscopy (VFS) study, of patients with dementia in treatment with antipsychotics for behavioral symptoms of dementia with patients also with dementia but without treatment with antipsychotics. Similarly, the pathophysiology of swallowing of patients with dementia was compared with patients without dementia, finding differences in these two groups, but we did not found significant differences in patients with dementia with treatment with antipsychotics in comparison to those without treatment with antipsychotics. We only found a delay in the upper esophageal sphinchter time, but it was not clinically significant. Otherwise, we found an increase of the oropharyngeal motor response time in patients with dementia and a higher prevalence of swallowing safety alterations compared with patients without dementia. Finally, the objective of the third study was to explore the serum and saliva SP in patients who were in treatment with beta-blockers using an enzyme-linked immunosorbent assay (ELISA), and to know the relationship of SP levels with OD. From this study, we were able to obtain 3 conclusions: (i) SP serum and saliva levels of patients treated with beta-blockers were significantly higher in comparison with those patients who were not in treatment with beta-blockers; (ii) the prevalence of OD was significantly lower in patients taking beta-blockers; and (iii) patients with OD had significantly lower SP concentrations in saliva than patients without OD

Rapid and accurate method for quantifying busulfan in plasma samples by isocratic liquid chromatography-tandem mass spectrometry (LC-MS/MS)

Objectives: Administration of busulfan is extending rapidly as a part of a conditioning regimen in patients undergoing hematopoietic stem cell transplantation (HSCT). Monitoring blood plasma levels of busulfan is recommended for identifying the optimal dose in patients and for minimizing toxicity. The aim of this research was to validate a simple, rapid, and cost-effective analytical tool for measuring busulfan in human plasma that would be suitable for routine clinical use. This novel tool was based on liquid chromatography coupled to mass spectrometry. Methods: Human plasma samples were prepared using a one-step protein precipitation protocol. These samples were then resolved by isocratic elution in a C18 column. The mobile phase consisted 2 mM ammonium acetate and 0.1% formic acid dissolved in a 30:70 ratio of methanol/water. Busulfan-d8 was used as the internal standard. Results: The run time was optimized at 1.6 min. Standard curves were linear from 0.03 to 5 mg/L. The coefficient of variation (%CV) was less than 8%. The accuracy of this method had an acceptable bias that fell within 85-115% range. No interference between busulfan and the interfering compound hemoglobin, lipemia, or bilirubin not even at the highest concentrations of compound was tested. Neither carryover nor matrix effects were observed using this method. The area under the plasma drug concentration-time curves obtained for 15 pediatric patients who received busulfan therapy prior to HSCT were analyzed and correlated properly with the administered doses. Conclusions: This method was successfully validated and was found to be robust enough for therapeutic drug monitoring in a clinical setting

COVID-19 Clinical Profile in Latin American Migrants Living in Spain : Does the Geographical Origin Matter?

The aim of this study was to describe and compare the clinical characteristics of hospitalized patients with COVID-19 pneumonia according to their geographical origin. This is a retrospective case-control study of hospitalized patients with confirmed COVID-19 pneumonia treated at Vall d'Hebron University Hospital (Barcelona) during the first wave of the pandemic. Cases were defined as patients born in Latin America and controls were randomly selected among Spanish patients matched by age and gender. Demographic and clinical variables were collected, including comorbidities, symptoms, vital signs and analytical parameters, intensive care unit admission and outcome at 28 days after admission. Overall, 1080 hospitalized patients were registered: 774 (71.6%) from Spain, 142 (13.1%) from Latin America and the rest from other countries. Patients from Latin America were considered as cases and 558 Spanish patients were randomly selected as controls. Latin American patients had a higher proportion of anosmia, rhinorrhea and odynophagia, as well as higher mean levels of platelets and lower mean levels of ferritin than Spanish patients. No differences were found in oxygen requirement and mortality at 28 days after admission, but there was a higher proportion of ICU admissions (28.2% vs. 20.2%, p = 0.0310). An increased proportion of ICU admissions were found in patients from Latin America compared with native Spanish patients when adjusted by age and gender, with no significant differences in in-hospital mortality