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Inhibidores de la calcineurina; Vacunación antigripal; Trasplante de riñón Calcineurin inhibitors; Influenza vaccination; Kidney transplantation Inhibidors de la calcineurina; Vacunació antigripal; Trasplantament de ronyó Emerging data suggest that costimulation blockade with belatacept effectively controls humoral alloimmune responses. However, whether this effect may be deleterious for protective anti-infectious immunity remains poorly understood. We performed a mechanistic exploratory study in 23 kidney transplant recipients receiving either the calcineurin-inhibitor tacrolimus (Tac, n=14) or belatacept (n=9) evaluating different cellular immune responses after influenza vaccination such as activated T follicular Helper (Tfh), plasmablasts and H1N1 hemagglutinin (HA)-specific memory B cells (HA+mBC) by flow-cytometry, and anti-influenza antibodies by hemagglutination inhibition test (HI), at baseline and days 10, 30 and 90 post-vaccination. The proportion of CD4+CD54RA-CXCR5+ Tfh was lower in belatacept than Tac patients at baseline (1.86%[1.25-3.03] vs 4.88%[2.40-8.27], p=0.01) and remained stable post-vaccination. At M3, HA+mBc were significantly higher in Tac-treated patients (0.56%[0.32-1.49] vs 0.27%[0.13-0.44], p=0.04) and correlated with activated Tfh numbers. When stratifying patients according to baseline HA+mBc frequencies, belatacept patients with low HA+mBC displayed significantly lower HA+mBc increases after vaccination than Tac patients (1.28[0.94-2.4] vs 2.54[1.73-5.70], p=0.04). Also, belatacept patients displayed significantly lower seroprotection rates against H1N1 at baseline than Tac-treated patients (44.4% vs 84.6%) as well as lower seroconversion rates at days 10, 30 and 90 after vaccination (50% vs 0%, 63.6% vs 0%, and 63.6% vs 0%, respectively). We show the efficacy of belatacept inhibiting T-dependent antigen-specific humoral immune responses, active immunization should be highly encouraged before starting belatacept therapy. This work was supported by the Instituto de Salud Carlos III (ISCIII) (grant numbers ICI14/00242 and PI16/01321, PI19/01710) and by the European Union’s Horizon 2020 Research and innovation program (grant agreement 754995). Also, this work was partly supported by the SLT002/16/00183 grant, from the Department of Health of the Generalitat de Catalunya by the call “Accioí instrumental de programes derecerca orientats en l’àmbit de la recerca i la innovacioí en salut.” The authors thank the Research Centers of Catalonia (CERCA) Programme/Generalitat de Catalunya for institutional support. OB was awarded with an intensification grant from the “Instituto de Salud Carlos III” [INT19/00051].

[eng] The present Thesis is divided in three chapters: 1. Design and synthesis of new soluble epoxide hydrolase inhibitors (sEHI) The synthesis of new soluble epoxide hydrolase inhibitors based on ureas as the main pharmacophore, a benzohomoadamantane unit and different arylpiperidine groups. The aim was to broaden the spectrum of inhibitors previously developed by the group, taking as starting point the Astellas pharmaceutical product AS2586114. Twelve new urea-based sEHIs were synthesized and evaluated. Two of them were selected for further in vitro studies. The synthesis of new sEHI derived from the substitution of the urea group by and amide group, in order to extend the Markush formula of a patent that the group filled in two years ago and, on the other hand, to improve the solubility of the urea-containing sEHI. Twelve novel amide-based sEHI were synthesized and evaluated. One of them was selected for further in vitro studies demonstrating potent anti-inflammatory properties. 2. Design and synthesis of new anti-influenza virus molecules. The development of new antiviral molecules against the influenza A virus H1/N1 subtype targeting the hemagglutinin of the virus, continuing previous research by our group. This part of the Thesis greatly improved and completed previous SAR studies on this kind of hemagglutinin inhibitors. 3. Design and synthesis of new anti-coronavirus molecules. The development of new antiviral molecules against coronavirus 229E, continuing group’s research in the field carrying out a more complete SAR study. Guanidine-bearing molecules were endowed with a great potency against 229E subtype. The most active compound was selected for further mechanistic studies in order to identify the targeted protein. Unfortunately, the compounds were not active against the SARS-2 coronavirus.

Resumen: Introducción: La información existente sobre el impacto de la gripe en la población infantil española es escasa. El presente trabajo pretende aumentar este conocimiento estudiando aspectos clave como la incidencia de hospitalización, clínica, comorbilidades y el estado vacunal en los niños hospitalizados. Métodos: Estudio retrospectivo, observacional, por revisión de historias clínicas, en menores de 15 años hospitalizados por gripe adquirida en la comunidad, confirmada microbiológicamente, durante 2 temporadas gripales (2014-2015 y 2015-2016). El estudio se realizó en 10 hospitales de 6 ciudades, que atienden aproximadamente al 12% de la población infantil española. Resultados: Fueron hospitalizados 907 niños con diagnóstico principal de gripe (447 50%) de los casos. Una gran parte de las formas graves de gripe en población infantil podrían ser evitada si se cumplieran las indicaciones actuales de vacunación. Abstract: Introduction: There are only a limited number of studies on the impact of influenza in the Spanish child population. The present work intends to increase this knowledge by studying some key aspects, such as the incidence of hospital admissions, clinic variables, comorbidities, and the vaccination status in the hospitalised children. Methods: A retrospective, observational study was conducted by reviewing the medical records of children under 15 years and hospitalised due to community acquired influenza confirmed microbiologically, during 2 ́flu seasons (2014-2015 and 2015-2016). The study was carried out in 10 hospitals of 6 cities, which represent approximately 12% of the Spanish child population. Results: A total of 907 children were admitted to hospital with main diagnosis of influenza infection (447 10 years. Admission to the PICU was required in 10% (92) of the cases, mainly due to acute respiratory failure. Conclusion: Influenza continues to be an important cause of hospitalisation in the Spanish child population. Children 50%) of the cases. Many of the severe forms of childhood influenza that occur today could be avoided if current vaccination guidelines were met.

Influenza A virus is one of the most outstanding human viruses. The major treatments against influenza are small analogues, monoclonal antibodies and vaccines, however, due to the fast mutation of the seasonal influenza strain, these methods are easily outdated, so vaccine production and antiviral development need to be in continuous growth and study to improve immunity and fight against influenza disease. The characterization of the viral structure and the identification of the mechanisms of action of newly synthesized antivirals are crucial to develop fast and powerful treatments, nonetheless, due to the small size of viruses, conventional fluorescence techniques are lacking the resolution power to resolve individual viral structures. In this context, super-resolution microscopy has positioned in the last decade as a powerful technique to characterize viral constructs by achieving resolutions up to 10 nm. Here, we have optimized and established a type of super-resolution microscopy technique entitled single-molecule localization microscopy (SMLM) to study viral structures at single-particle level by characterizing several viral structures, antivirals and vaccines. Firstly, we could characterize the filament formation of influenza virus and described how monoclonal antibodies disturbed the development of those filaments, deforming them. Further, we could relate this malformation with an inhibition of the infectivity, suggesting the crucial role of filament formation in the infectivity of influenza. Moreover, we optimized and implemented a novel SMLM called DNA-PAINT in the study of the target distribution and quantification in the nanoscale, validating this method using commercial nanoparticles for its further implementation in the study of the expression of recombinant proteins of influenza and the corresponding virus-like particle produced. In addition, we studied and identified several other viral structures and antivirals interactions using SMLM such as the distribution of Hepatitis B and Hepatitis Delta on paraffin tissues, the interaction of analogues of sialic acid on four strains of influenza and the uptake of nanovaccines from antigen-presenting cells, obtaining features on how these viruses and antivirals interact in order to produce a smart design of antivirals and vaccines, corroborating how SMLM could increase the knowledge of the mechanism of action of viruses.

Resumen: Objetivo: Conocer la efectividad de la vacuna de la gripe de la temporada 2018/2019 para la prevención de casos graves de gripe en un hospital terciario. Método: Estudio de casos y controles. Se incluyeron todos los pacientes hospitalizados con gripe confirmada por laboratorio durante la temporada 2018/2019. Los que cumplieron criterios de caso grave de gripe (neumonía, fallo multiorgánico, shock séptico, ingreso en la unidad de cuidados intensivos o muerte) se consideraron caso. Los que no cumplían criterios de gravedad se consideraron controles. Se calculó la efectividad de la vacuna (EV) cruda y ajustada (para prevenir casos graves de gripe), así como su intervalo de confianza del 95%, mediante la fórmula EV = (1 − odds ratio) × 100. Resultados: La efectividad ajustada por grupo de edad y comorbilidad fue del 60,7% (20,5-80,5). En el análisis ajustado y restringido a cada sexo, grupo de edad y presencia de comorbilidad, la vacuna de la gripe tuvo un efecto positivo en todos los grupos y categorías, siendo la efectividad del 55,0% (2,6-79,2) en el grupo de edad de 65 años o más. Conclusiones: La vacunación antigripal redujo la gravedad de la gripe en los pacientes hospitalizados. Estos hallazgos deberían tenerse en cuenta para mejorar las estrategias de vacunación y alcanzar mejores coberturas vacunales en la población de riesgo, con la finalidad no solo de disminuir los casos de gripe, sino también su gravedad. Abstract: Objective: To know the effectiveness of the 2018/2019 flu vaccine for the prevention of severe cases of flu in a tertiary hospital. Method: Case-control study. We included all patients hospitalized with influenza confirmed by laboratory during 2018/2019 season. Those who met the criteria of severe case of influenza (pneumonia, multiorgan failure, septic shock, ICU admission or death) were considered as cases. Non severe cases of influenza were included in the control group. We calculated the effectiveness of the raw and adjusted vaccine (to prevent severe cases of influenza) and its 95% confidence interval using formula VE = (1 − odds ratio) × 100. Results: Effectiveness of flu vaccine adjusted by age group and comorbidities was 60.7% (20.5-80.5). In the analysis adjusted and restricted to each sex, age group and presence of comorbidities, the influenza vaccine had a positive effect in all groups and categories, with effectiveness in the age group 65 years or more being 55.0% (2.6-79.2). Conclusions: Flu vaccination reduced the severity of influenza in hospitalized patients. These findings should be taken into account to improve vaccination strategies and achieve better vaccination coverage in the high-risk population in order not only to decrease flu cases, but also their severity.

OBJECTIVE: To know the effectiveness of the 2018/2019 flu vaccine for the prevention of severe cases of flu in a tertiary hospital. METHOD: Case-control study. We included all patients hospitalized with influenza confirmed by laboratory during 2018/2019 season. Those who met the criteria of severe case of influenza (pneumonia, multiorgan failure, septic shock, ICU admission or death) were considered as cases. Non severe cases of influenza were included in the control group. We calculated the effectiveness of the raw and adjusted vaccine (to prevent severe cases of influenza) and its 95% confidence interval using formula VE=(1-odds ratio)×100. RESULTS: Effectiveness of flu vaccine adjusted by age group and comorbidities was 60.7% (20.5-80.5). In the analysis adjusted and restricted to each sex, age group and presence of comorbidities, the influenza vaccine had a positive effect in all groups and categories, with effectiveness in the age group 65 years or more being 55.0% (2.6-79.2). CONCLUSIONS: Flu vaccination reduced the severity of influenza in hospitalized patients. These findings should be taken into account to improve vaccination strategies and achieve better vaccination coverage in the high-risk population in order not only to decrease flu cases, but also their severity.

Treball Final de Grau en Medicina. Codi: MD1158. Curs acadèmic: 2018/2019. OBJECTIVE: In Europe, despite the effectiveness of influenza vaccine, there is an unacceptable rate of vaccination in children with risk factors for complications of influenza. The objective of this work is to find out the reasons why this group of children does not reach higher vaccination rates, and incorporate strategies to increase them. METHOD: A case-control study is carried out in which the population to be analyzed consists of children between 6 months and 14 years with obesity as a risk factor for complications of the flu; currently assigned to the Illes Columbretes Health Center (Castellón de la Plana). The different causes of non-vaccination and the influence of the means of transmitting the information in the vaccination decision will be evaluated. RESULTS: 75% of the vaccinated and 20% of the unvaccinated admits having received information through the S. Sanitario; while, 50% of the vaccinated and 40% of the unvaccinated say they have received it through other means other than healthcare. The Chisquare analysis (p = 0.052 for information from S. Sanitario and p = 0.733 for other routes) and the Odds Ratio (0.083 for S. Sanitario and 0.667 for other routes) determine that there is no statistically significant relationship between the variables " Information "and" Vaccination ". CONCLUSION: The information deficit constitutes the main cause of non-vaccination of obese pediatric patients of C.S. Illes Columbretes. However, there does not appear to be a statistically significant relationship between the information received by the family members and the vaccination status of their children. OBJETIVO: En Europa, a pesar de la eficacia de la vacuna antigripal, existe una inaceptable tasa de vacunación en los niños con factores de riesgo de padecer complicaciones de la gripe. El objetivo de este trabajo es averiguar los motivos por los que este grupo de niños no alcanza tasas de vacunación más elevadas, e incorporar estrategias para aumentarlas. MÉTODO: Se realiza un estudio de casos y controles en el que la población a analizar la constituyen niños entre 6 meses y 14 años con obesidad como factor de riesgo de complicaciones de la gripe; adscritos actualmente al Centro de Salud Illes Columbretes (Castellón de la Plana). Se evaluarán las distintas causas de no vacunación y la influencia de las vías de trasmisión de la información en la decisión de vacunación. RESULTADOS: Un 75% de vacunados y un 20% de no vacunados admite haber recibido información por medio del S. Sanitario; mientras que, un 50% de los vacunados y un 40% de los no vacunados dicen haberla recibido por otras vías diferentes a la sanidad. El análisis Chicuadrado (p= 0,052 para información desde S. Sanitario y p=0,733 para otras vías) y de la Odds Ratio (0,083 para S. Sanitario y 0,667 para otras vías) determinan que no existe relación estadísticamente significativa entre las variables “Información” y “Vacunación”. CONCLUSIÓN: El déficit de información constituye la principal causa de no vacunación a los pacientes pediátricos obesos del C.S Illes Columbretes. Sin embargo, no resulta haber una relación estadísticamente significativa entre la información recibida por los familiares y el estado de vacunación de sus hijos.

Introduction: There are only a limited number of studies on the impact of influenza in the Spanish child population. The present work intends to increase this knowledge by studying some key aspects, such as the incidence of hospital admissions, clinic variables, comorbidities, and the vaccination status in the hospitalised children. Methods: A retrospective, observational study was conducted by reviewing the medical records of children under 15 years and hospitalised due to community acquired influenza confirmed microbiologically, during 2 ́flu seasons (2014-2015 and 2015-2016). The study was carried out in 10 hospitals of 6 cities, which represent approximately 12% of the Spanish child population. Results: A total of 907 children were admitted to hospital with main diagnosis of influenza infection (447 < 2 years), estimating an average annual rate of hospitalisation incidence of 0.51 cases / 1,000 children (95% CI; 0.48-0.55). Just under half (45%) of the cases had an underlying disease considered a risk factor for severe influenza, and most (74%) had not been vaccinated. The percentage of children with underlying diseases increased with age, from 26% in children < 6 months to 74% in children >10 years. Admission to the PICU was required in 10% (92) of the cases, mainly due to acute respiratory failure. Conclusion: Influenza continues to be an important cause of hospitalisation in the Spanish child population. Children < 6 months of age and children with underlying diseases make up the majority (> 50%) of the cases. Many of the severe forms of childhood influenza that occur today could be avoided if current vaccination guidelines were met.

Introduction: There are only a limited number of studies on the impact of influenza in the Spanish child population. The present work intends to increase this knowledge by studying some key aspects, such as the incidence of hospital admissions, clinic variables, comorbidities, and the vaccination status in the hospitalised children. Methods: A retrospective, observational study was conducted by reviewing the medical records of children under 15 years and hospitalised due to community acquired influenza confirmed microbiologically, during 2 ́flu seasons (2014-2015 and 2015-2016). The study was carried out in 10 hospitals of 6 cities, which represent approximately 12% of the Spanish child population. Results: A total of 907 children were admitted to hospital with main diagnosis of influenza infection (447 < 2 years), estimating an average annual rate of hospitalisation incidence of 0.51 cases / 1,000 children (95% CI; 0.48-0.55). Just under half (45%) of the cases had an underlying disease considered a risk factor for severe influenza, and most (74%) had not been vaccinated. The percentage of children with underlying diseases increased with age, from 26% in children < 6 months to 74% in children >10 years. Admission to the PICU was required in 10% (92) of the cases, mainly due to acute respiratory failure. Conclusion: Influenza continues to be an important cause of hospitalisation in the Spanish child population. Children < 6 months of age and children with underlying diseases make up the majority (> 50%) of the cases. Many of the severe forms of childhood influenza that occur today could be avoided if current vaccination guidelines were met.

There are only a limited number of studies on the impact of influenza in the Spanish child population. The present work intends to increase this knowledge by studying some key aspects, such as the incidence of hospital admissions, clinic variables, comorbidities, and the vaccination status in the hospitalised children. A retrospective, observational study was conducted by reviewing the medical records of children under 15 years and hospitalised due to community acquired influenza confirmed microbiologically, during 2́flu seasons (2014-2015 and 2015-2016). The study was carried out in 10 hospitals of 6cities, which represent approximately 12% of the Spanish child population. A total of 907 children were admitted to hospital with main diagnosis of influenza infection (447 10 years. Admission to the PICU was required in 10% (92) of the cases, mainly due to acute respiratory failure. Influenza continues to be an important cause of hospitalisation in the Spanish child population. Children 50%) of the cases. Many of the severe forms of childhood influenza that occur today could be avoided if current vaccination guidelines were met.

[cat] Aquest estudi va tenir com a objectiu analitzar l'existència d'una associació entre la classe social (categoritzats per tipus d'ocupació) i per analitzar les relacions entre l'exposició ocupacional i la infecció de la grip i l'hospitalització durant l'onada de pandèmia de 2009 a 2010 i l'epidèmia de grip de temporada 2010-2011 a Espanya. Aquest estudi multicèntric va comparar casos confirmats de manera ambulatòria de la grip A (H1N1) pmd09 mitjançant controls ambulatoris per mesurar el risc d'infecció, i amb casos confirmats de pacients hospitalitzats.. Les variables d'estudi van ser: edat, estat civil, tabac i alcohol, embaràs, malaltia pulmonar obstructiva crònica, insuficiència respiratòria crònica, malaltia cardiovascular, diabetis, malaltia hepàtica crònica, índex de massa corporal> 40, el tractament mitjançant corticosteroides i l’estat vacunal dels pacients. Es van registrar els casos de manera literal i es van agrupar segons la classe social i l’ocupació en el cas dels treballadors manuals i no manuals. Els llocs de treball es van classificar també pel que feia al seu alt, mitjà o baix risc d'exposició a la grip. Es va realitzar una anàlisi de regressió logística condicional. Hi havia 720 casos hospitalitzats de grip confirmada per transcripció inversa de la polimerasa-reacció en cadena (RT-PCR), 996 casos ambulatoris i 1062 controls ambulatoris inclosos en l'estudi. No s'ha trobat relació entre la classe social ocupacional i A (H1N1), la infecció pmd09 [quocient de probabilitats ajustat (ORA) 0 · 97, 95% interval de confiança (CI) 0,74-1,27], sinó una associació (ORA 1,53, IC del 95% 1.01- es va observar 2,31) entre la classe ocupacional i hospitalització per a pmd09 (H1N1). El grup d'alt risc d'exposició ocupacional es compon exclusivament de treballadors de la salut. Després d'ajustar per edat, sexe, estat de vacunació i les variables de predicció d'infecció per grip, els pacients amb un alt risc d'exposició ocupacional tenien un AOR de 2,14 (IC del 95%: 1,25-3,66) de ser un cas de grip ambulatòria i un AOR de 0,43 ( IC del 95%: 0,20 fins a 0,95) de ser un cas de la grip per a pacients hospitalitzats, en comparació amb aquells amb un baix risc. La vacunació contra la grip era un factor de protecció per a A (H1N1), la infecció pmd09 (ORA 0 · CI 41, 95% 0 · 23-0 · 73) però no per a l'hospitalització. Arribem a la conclusió que els treballadors manuals tenen el major risc d'hospitalització quan estan infectades per la grip que altres ocupacions, però que no tenen una probabilitat diferent d'estar infectats per la grip. Un alt risc d'exposició ocupacional és un factor de risc per a la infecció per influença, però no per a l'hospitalització. L'efectivitat ajustada de vacunació contra la grip va ser del 59% (IC del 95%: 27% -77%) quan es comparen els casos de grip ambulatòria amb els pacients ambulatoris sense símptomes de la grip i va aconseguir el 74% (IC 95%: 42% -88%) quan es consideren els riscos laborals., [eng] This study aimed to analyze the existence of an association between social class (categorized by type of occupation) and to analyze relationships between occupational exposure and influenza infection and hospitalization during the 2009-2010 pandemic wave and the 2010-2011 influenza seasonal epidemic in Spain. This multicentre study compared ambulatory A(H1N1)pmd09 confirmed cases with ambulatory controls to measure risk of infection, and with hospitalized A(H1N1)pmd09 confirmed cases to asses hospitalization risk. Study variables were: age, marital status, tobacco and alcohol use, pregnancy, chronic obstructive pulmonary disease, chronic respiratory failure, cardiovascular disease, diabetes, chronic liver disease, body mass index >40, systemic corticosteroid treatment and influenza vaccination status. Occupation was registered literally and coded into manual and non-manual worker occupational social class groups. Occupations were classified also as high, medium or low risk of influenza exposure. A conditional logistic regression analysis was performed. There were 720 hospitalized cases of influenza confirmed by reverse-transcription polymerase-chain-reaction (RT-PCR), 996 ambulatory cases and 1062 ambulatory controls included in the study. No relationship between occupational social class and A(H1N1)pmd09 infection was found [adjusted odds ratio (aOR) 0·97, 95% confidence interval (CI) 0.74–1.27], but an association (aOR 1.53, 95% CI 1.01–2.31) between occupational class and hospitalization for A(H1N1)pmd09 was observed. The high risk of occupational exposure group was composed only of health care workers. After adjustment for age, sex, vaccination status and predictive variables of influenza infection, patients with a high risk of occupational exposure had an aOR of 2.14 (95%CI: 1.25-3.66) of being an outpatient influenza case and an aOR of 0.43 (95%CI: 0.20-0.95) of being an inpatient influenza case, compared with those with a low risk. Influenza vaccination was a protective factor for A(H1N1)pmd09 infection (aOR 0·41, 95% CI 0·23–0·73) but not for hospitalization. We conclude that manual workers have the highest risk of hospitalization when infected by influenza than other occupations but they do not have a different probability of being infected by influenza. A high risk of occupational exposure is a risk factor for influenza infection but not for hospitalisation. The adjusted effectivity of influenza vaccination was 59% (95% CI: 27%-77%) when comparing outpatient influenza cases with outpatients without influenza symptoms and reached 74% (IC 95%: 42%-88%) when considering occupational risk.

Resumen La infección respiratoria aguda es la enfermedad más frecuente a lo largo de toda la vida del ser humano, con una variación en cuanto a su etiología condicionada, fundamentalmente, por la edad, las circunstancias medioambientales, el ámbito asistencial y la enfermedad de base. Se han identificado más de 200 virus diferentes distribuidos en seis familias implicados en la patogenia de las infecciones del tracto respiratorio. Estos hechos generan una demanda diagnóstica, cuya incorporación al ámbito asistencial no debe ser retrasada. Consciente de ello la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica ha redactado un procedimiento sobre diagnóstico microbiológico de las infecciones virales respiratorias. En éste se efectúa una puesta al día de las infecciones debidas, en primer término, a los virus de la gripe y, en segundo lugar, a otros virus respiratorios convencionales y emergentes. En todos los casos se revisan los métodos de diagnóstico virológico directo (cultivo celular, detección de antígenos y de ácido nucleico), con particular referencia a las técnicas de detección molecular y de caracterización genética.

Revisiones [ES] Objetivos: Conocer la evidencia científica existente en relación al comportamiento de los profesionales de la salud en situaciones de pandemia. Identificar puntos de mejora para el fortalecimiento de los profesionales sanitarios antes situaciones de pandemia. Objetivos secundarios: Identificar el impacto psicosocial, adopción y adhesión a medidas preventivas y a programas de vacunación. Métodos: Revisión sistemática de la literatura científica recogida en las bases de datos MEDLINE (Pubmed), SCOPUS y Cochrane Library Plus hasta Diciembre de 2014. Los términos más utilizados como descriptores fueron: «Disease outbreaks», «Coronavirus, sars», «Severe Acute Respiratory Syndrome», «Influenza a virus, h1n2 subtype», «Health occupations», «Emergencies,Infectious disease transmission», «patient-to professional», «Infectious disease transmission, professional-to-patient». Resultados: Se recuperaron 181 referencias que tras la eliminación de duplicados y aplicación de los criterios de inclusión y exclusión y análisis de calidad mediante los criterios STROBE, resultó una colección final de 17 artículos. El nivel de evidencia encontrado según los Criterios Sign es tres ya que se trata en todos los casos de estudios transversales. Once autores hacen referencia a efectos psicosociales, 3 a la vacunación y 12 a adhesión a medidas preventivas. En general las medidas preventivas en las dos pandemias fueron bien valoradas y seguidas por los profesionales. Se genera una importante carga de estrés por el miedo a enfermarse, contagiar a sus familias y la elevada carga laboral. Baja adherencia a programas de vacunación y a la utilización de literatura científica.Conclusiones: Sería recomendable mejorar la comunicación sobre las medidas preventivas en periodos de pandemia para aumentar su adherencia así como dar apoyo psicológico al personal sanitario. [EN] Objectives: To explore the scientific evidence regarding the behavior of health professionals in pandemic situations. Identify areas of improvement for the strengthening of health professionals before pandemic situations. Secondary Objectives: To identify the psychosocial impact, adoption and adherence to preventive measures and vaccination programs. Methods: Systematic review of the scientific literature collected in the MEDLINE (PubMed), Scopus and Cochrane Library Plus data until December 2014.The terms used as descriptors were: «Disease Outbreaks», «Coronavirus, sars», «Severe acute Respiratory Syndrome», «Influenza virus, subtype H1N2», «Health occupations», «Emergencies, Infectious disease transmission», «patient-to-professional», «Infectious disease transmission, professional-to-patient». Results: 181 references after the elimination of duplicates and application of the criteria for inclusion and exclusion and analysis of quality using the STROBE criteria, was a final collection of 17 articles were retrieved.The level of evidence found according to Sign Criteria is three as it is in all cases of cross-sectional studies. 11 Authors refer to psychosocial effects, 3-vaccination and 12 to adherence to preventive measures. In general preventive measures in the two pandemics were well appreciated and followed by professionals. A significant burden of stress for fear of getting sick is generated; infect their families and high workload. Low adherence to vaccination programs and use of scientific literature. Conclusions: It would be advisable to improve communication about preventive measures in times of pandemic to increase adherence and psychological support to health workers. No

[cat] La grip presenta un greu problema arreu del món, com les pandèmies del segle XX han demostrat. S’han pres algunes mesures per lluitar-hi que han realment disminuït els efectes devastadors de la malaltia, com son la hospitalització moderna, la vacunació i les noves medicines. Tot i així, l’amenaça d’un virus recombinant mutant que pugui afectar a milions de persones i la recentment descoberta resistència d’algunes soques del virus als tractaments actuals, han provocat que la necessitat per a noves maneres de lluitar contra la grip A sigui urgent. En la present Tesi, hem pres amantadina com a model, un medicament antiviral actualment en desús degut a l’aparició de soques resistents, que té com a diana un canal de protons del virus anomenat M2. Així doncs, hem sintetitzat i avaluat diverses amines policícliques com a potencials blocadors del canal salvatge M2 i mutants resistents a amantadine, com el V27A, també. Hem tingut èxit en l’obtenció de potents inhibidors del canal salvatge i del V27A i lo més destacable és que alguns han mostrat una activitat dual en ambos canals M2. Cap remarcar que, entre els compostos preparats,una guanidina policíclica va presentar l’activitat més alta mai enregistrada contra el mutant V27A. Seguint amb les molècules policícliques però des d’un punt de vista més teòric, el monomer, dimer i dihidrodimer de un alqué altament piramidalitzat van ser sintetitzats i completament caracteritzats. Cal subratllar que, el dimer posseïa quatre ciclohexans en conformació bot congelat i mostrava interaccions entre els hidrògens flagpole que eren rellevants per als químics orgànics teòrics, [eng] Influenza is a major health problem worldwide, as the periodic pandemics of the 20th century have highlighted. Some countermeasures have been developed and have indeed diminish the devastating effects of the disease, such as modern health care, vaccination and novel medicines. Yet, the threat of a recombinant mutant virus that could affect millions of people and the recently discovered resistance of some virus strains to the current available treatments, render the need for new ways of fighting influenza A virus urgent. In the present dissertation we have taken amantadine as a model, an antiviral drug in disuse at the moment due to the appearance of resistant strains, that targets a viral proton channel named M2. Thus, we have synthesized and evaluated several polycyclic amines as potential wild-type M2 channel blockers and amantadine-resistant mutants, like V27A, as well. We have succeeded in the obtention of highly potent wild-type and V27A inhibitors and most remarkable, some of them exhibited a dual activity on both M2 channels. Noteworthy, among the prepared compounds, a polycyclic guanidine presented the higher activity ever recorded against the V27A mutant. Again working with polycyclic molecules but from a more theoretical point of view, the monomer, dimer and dihydrodimer of a highly strained pyramidalized alkene were synthesized and fully characterized. Importantly, the dimer featured four cyclohexanes in a frozen boat conformation and possessed hydrogen flagpole interactions that were relevant to theoretical organic chemists.

Research for new antivirals to treat Influenza A virus infections has gained importance during this last decade due to the imminent danger of an Influenza pandemic. For some years, several new strains of this virus have appeared worldwide causing small outbreaks with a notable relevance, for example the ‘avian flu’ (H5N1 in 2007; H7N9 in 2012) and ‘swine flu’ (H1N1 in 2009), that have triggered the assumption that a new pandemic is coming. There are several strategies to treat an Influenza A virus infection targeting some of its surface proteins. In this Thesis, several compounds inhibiting the M2 channel of the virus are designed, synthesized and evaluated. Our approach is based on the synthesis of amantadine’s analogues by ring expansion, contraction and rearrangement. Amantadine is a drug already approved by the FDA for the treatment of Influenza A virus and it is known to target the M2 channel. Although it is no longer in use, because the FDA has recommended against its use, due to the appearance of resistance, it possessed good activity and an acceptable pharmacological behaviour. Our main goal was to synthesize an analogue of amantadine that was able to overcome the resistant virus and provide a new therapeutic alternative to the already marketed neuraminidase inhibitors such as Oseltamivir and Zanamivir. Importantly, we took advantage of the wide expertise of our research group in synthesizing polycyclic compounds to start a new research field that was based on the application of these optimized synthetic routes to the Medicinal chemistry. We established some external collaboration in order to set up the milestones and to build the rationale of the current project. These new collaborations are the following: - Prof. Lieve Naesens research group in the Rega Institute for Medical Research in Leuven, Belgium. This group of virologist made the plaque reduction assays and the study of the mutants to establish the mechanism of action of the tested compounds. - Lawrence H. Pinto research group of the Northwestern University, Evanston, Illinois, USA. This group of biochemist made the patch clamp assay to check if our compounds targeted the M2 channel. - Prof. Javier Luque of Universitat de Barcelona, Barcelona, España. This group made the docking and molecular dynamics of our compounds. In the following figures, the general structures of the compounds synthesized in the current Thesis are shown. Several of them showing an outstanding activity that allowed us to publish in the most important journals of the Medicinal Chemistry field: It it worth to mention that, several compounds have shown better activity than the reference compound, Amantadine. The most distinguished compounds are the following: Compound 1, 2 and 3 showed a superior activity against H1N1 strain in the cell culture assay while being almost inactive in the patch clamp assay. Prof. Lieve Naesen’s research group tried to identify the mechanism of action of these compounds selecting the mutants of hemagglutinin under the pressure of our compounds, revealing that this protein was the target of the first cluster of molecules. Compound 4 and 5 showed an outstanding activity against the wild-type and V27A M2 channels of influenza A virus. Taken together, all of these results show that tuning the polycyclic scaffold of amantadine could be the way to overcome the already stated resistance. A second part of this current Thesis consisted in a collection of compounds that have activity against vaccinia virus. These compounds are analogues of Tecovirimat®, a compound that it is currently in phase III clinical trials. When we started this project, we wanted to explore the impact in the EC50 of changing the polycyclic scaffold of the Tecovirimat® molecule, a common tool used in Medicinal Chemistry. We synthesized nearly 40 compounds and we obtained activities similar to Tecovirimat®, although none of our molecules was better than the reference compound.

[cat] INTRODUCCIÓ L’abril de 2009 s’identifica un nou virus de la grip, l’A (H1N1) pdm09, en humans. El juny del mateix any, l’Organització Mundial de la Salut declara l’estat de pandèmia a nivell mundial. La malaltia pel nou virus va afectar centenars de nens al nostre medi durant la temporada 2009-2010. OBJECTIUS - Descriure l'espectre de malaltia per grip A (H1N1) pdm09 moderat i greu (aquells casos que requeriren ingrés en un hospital pediàtric de tercer nivell) en la població pediàtrica en el nostre medi. - Descriure la malaltia per grip A (H1N1) pdm09 en pacients pediàtrics en tractament per leucèmia limfàtica aguda, tant els ingressats com els que es va optar per tractar i seguir ambulatòriament. - Descriure els valors de càrrega viral de grip A (H1N1) pdm09 al moment del diagnòstic en relació amb variables epidemiològiques i clíniques en els pacients ingressats amb clínica respiratòria. PACIENTS I MÈTODES - Es dissenyen tres estudis amb recollida prospectiva de dades epidemiològiques, clíniques, analítiques i microbiològiques de nens amb malaltia confirmada amb detecció del material genètic del virus de la grip A (H1N1) pdm09 en aspirat nasofaringi. Els tres estudis es realitzen en un hospital pediàtric de tercer nivell (Hospital Sant Joan de Déu, Universitat de Barcelona) i els resultats es presenten en la memòria d’aquesta tesi. La recollida de dades es porta a terme durant la temporada pandèmica 2009-2010. S'efectuen els procediments estadístics pertinents per al tractament de dades. RESULTATS - El perfil del nen ingressat amb malaltia per grip A (H1N1) pdm09 és el d'un nen prèviament sa preescolar o bé el d'un nen d'edat escolar amb malaltia de base. La dificultat respiratòria i la hipoxèmia són el motiu principal d'ingrés, encara que també s'observen manifestacions extrapulmonars (neurològiques i cardíaques principalment). Les malalties cròniques pulmonars i neurològiques són els grups més importants de pacients que tenen malaltia de base i que requereixen ingrés. D'entre ells, els pacients amb malalties neurològiques suposen el principal grup de malalties cròniques d'entre els que requereixen ingrés a la Unitat de Cures Intensives Pediàtriques (UCIP). En els pacients que requereixen ingrés en UCIP trobem un major temps d'evolució de la malaltia abans d'iniciar el tractament amb oseltamivir i aquest retard en l'inici del tractament antiviral es relaciona amb una major risc d'ingrés en UCIP en el model multivariant. - Els nens amb leucèmia limfàtica aguda en fases de tractament més intensiu presenten una malaltia per grip més greu (broncopneumònia). Els nens en tractament de manteniment no presenten cap complicació amb tractament amb oseltamivir. - Els valors de càrrega viral al diagnòstic es correlacionen negativament amb el temps de durada de la clínica en el moment de fer la recollida de la mostra. Tenir una càrrega viral alta havent passat 5 o més dies des de l'inici de la clínica es relaciona amb un major risc de malaltia greu per grip A (H1N1) pdm09 (necessitat de tractament amb ventilació mecànica invasiva o no invasiva)., [eng] “INFLUENZA A(H1N1)PDM09: MODERATE AND SEVERE DISEASE IN THE PEDIATRIC PATIENT. VIRAL LOAD AT DIAGNOSIS AS A BIOMARKER OF SEVERITY.” TEXT: INTRODUCTION A new influenza virus was identified in April 2009 in humans. The influenza A (H1N1) pdm09 disease affected hundreds of children in our country during the pandemic season (2009-2010). OBJECTIVES - To describe the moderate and severe influenza A (H1N1) pdm09 disease (cases requiring for admission in a tertiary pediatric hospital) in children of our setting. - To describe the influenza A (H1N1) pdm09 disease in pediatric patients with acute lymphatic leukemia. - To describe the influenza A (H1N1) pdm09 viral load values at diagnosis in hospitalized children with respiratory symptoms and their relations with epidemiological and clinical variables. PATIENTS AND METHODS - Three different studies were designed and their results are presented. The studies were performed in a tertiary pediatric hospital (Hospital Sant Joan de Déu, University of Barcelona). Data collection was carried out during the pandemic season (2009-2010) in children with confirmed infection with a real-time RT-PCR. RESULTS - A previously healthy infant or a school-aged patient with underlying disease was the profile of the hospitalized child with influenza A (H1N1) pdm09 infection. Respiratory distress and hypoxemia were the main reasons for admission, although extrapulmonary manifestations were also observed (mainly neurological and cardiac). Children with chronic pulmonary diseases or with neurological disorders were the most important groups of patients with an underlying disease of those who required hospitalization. Patients with neurological chronic diseases more often required admission to the Pediatric Intensive Care Unit (PICU). Delays in starting treatment with oseltamivir were associated with an increased risk of admission to PICU in a multivariate model. - Children with acute lymphatic leukemia in intensive treatment phases developed a more severe influenza disease. Children in maintenance treatment phase had not complications. All of them were treated with oseltamivir. - The values of viral load at diagnosis were correlated negatively with the duration of the symptoms at the moment of sampling. To have a high viral load after 5 or more days of the onset of clinical symptoms was associated with an increased risk of severe illness (requiring for mechanical ventilation) due to influenza A (H1N1) pdm09 infection.

La pandemia de gripe de 1918-19 es actualmente una de las más nombradas debido a las fuertes repercusiones que tuvo en todo el mundo, ocasionando millones de muertes, de las cuales Colombia no fue la excepción. En Colombia las zonas más afectadas fueron las de gran altitud, debido a los cambios bruscos y poco usuales de clima, los cuales hicieron de esta pandemia algo desastroso y de poca duración, que dejó perplejos a los encargados de la Higiene pública de la época en dichas regiones y, que ha sido tema satélite para el posterior desarrollo de este artículo tomando como base el proyecto: “Impacto de la pandemia de gripa de 1918-1919 en Boyacá”, propuesto por el Grupo de investigación Historia de la Salud en Boyacá de la UPTC. Tras la búsqueda en fuentes primarias y secundarias de la época y actuales, se ha hallado la relación entre fenómenos climáticos, tales como el fenómeno del niño o fenómeno ENOS y su contraparte la niña con la pandemia de 1918.

Infections by intracellular pathogens such as viruses, some bacteria and many parasites, are cleared in most cases after activation of specific T cellular immune responses that recognize foreign antigens and eliminate infected cells. Vaccines against those infectious organisms have been traditionally developed by administration of whole live attenuated or inactivated microorganisms. Nowadays, research is focused on the development of subunit vaccines, containing the most immunogenic antigens from the particular pathogen. However, when purified subunit vaccines are administered using traditional immunization protocols, the levels of cellular immunity induced are mostly low and not capable of eliciting complete protection against diseases caused by intracellular microbes. In this review, we present a promising alternative to those traditional protocols, which is the use of recombinant viruses encoding subunit vaccines as immunization tools. Recombinant viruses have several interesting features that make them extremely efficient at inducing immune responses mediated by T-lymphocytes. This cellular immunity has recently been demonstrated to be of key importance for protection against malaria and AIDS, both of which are major targets of the World Health Organization for vaccine development. Thus, this review will focus in particular on the development of new vaccination protocols against these diseases. Las infecciones por patógenos intracelulares como virus, algunas bacterias y numerosos parásitos son neutralizadas en la mayoría de los casos tras la activación de respuestas inmunitarias específicas mediadas por linfocitos T, que reconocen los antígenos extraños y eliminan las células infectadas. Las vacunas contra estos organismos infecciosos se han basado tradicionalmente en la administración de organismos enteros atenuados o inactivados. Actualmente la investigación se centra en el desarrollo de vacunas compuestas por subunidades que contengan los antígenos más inmunogénicos para cada patógeno particular. No obstante, si se administran vacunas de subunidades purificadas mediante los protocolos tradicionales de inmunización, los niveles inducidos de inmunidad celular son en su mayoría bajos e incapaces de generar una protección completa contra las enfermedades causadas por los microorganismos intracelulares. En esta revisión presentamos una prometedora alternativa a estos métodos tradicionales mediante el uso de virus recombinantes cuyo genoma codifica las subunidades de vacuna. Los virus recombinantes reúnen varias características que los hacen muy eficientes para inducir las respuestas inmunitarias mediadas por los linfocitos T. Recientemente se ha demostrado que la inmunidad celular es crucial en la protección contra la malaria y el SIDA, que son un objetivo prioritario de la Organización Mundial de la Salud en cuanto al desarrollo de vacunas. Por lo tanto, esta revisión se centra especialmente en el desarrollo de nuevos protocolos de vacunación contra estas dos enfermedades. As infecções causadas por patógenos intracelulares como os vírus, algumas bactérias e muitos parasitas terminam, em muitos casos, após ativação de respostas imunes de células T específicas, as quais reconhecem os antígenos estranhos e eliminam as células infectadas. As vacinas contra esses microorganismos infecciosos foram tradicionalmente desenvolvidas através da administração dos micróbios completos vivos ou atenuados. Hoje em dia, a pesquisa em vacinas de subunidade contendo os antígenos mais imunogênicos desses patógenos é a principal escolha para as doenças contra as quais não existem vacinas. Porém, quando as vacinas de subunidade são administradas seguindo os protocolos tradicionais de imunização, os níveis de imunidade celular induzidos são comumente baixos e incapazes de gerar proteção completa contra as doenças causadas pelos microorganismos intracelulares. Nesta revisão apresentamos uma alternativa promissora aos protocolos tradicionais, que é o uso como ferramentas de vacinação de vetores virais recombinantes que codificam vacinas de subunidade. Os vírus recombinantes têm várias características interessantes que os tornam extremamente eficientes na indução de respostas imunes mediadas por linfócitos T. Durante os últimos anos, observou-se que esta imunidade celular tem importância fundamental para a proteção contra duas doenças que são objetivos primordiais da Organização Mundial da Saúde: a malária e a AIDS. Por esses motivos esta revisão focaliza especialmente o desenvolvimento de novos protocolos de vacinação contra estas duas doenças.