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BACKGROUND: Pollen allergy poses a significant health and economic burden in Europe. Disease patterns are relatively homogeneous within Central and Northern European countries. However, no study broadly assessed the features of seasonal allergic rhinitis (SAR) across different Southern European countries with a standardized approach. OBJECTIVE: To describe sensitization profiles and clinical phenotypes of pollen allergic patients in nine Southern European cities with a uniform methodological approach. METHODS: Within the @IT.2020 multicenter observational study, pediatric and adult patients suffering from SAR were recruited in nine urban study centers located in seven countries. Clinical questionnaires, skin prick tests (SPT) and specific IgE (sIgE) tests with a customized multiplex assay (Euroimmun Labordiagnostika, Lübeck, Germany) were performed. RESULTS: Three hundred forty-eight children (mean age 13.1 years, SD: 2.4 years) and 467 adults (mean age 35.7 years SD: 10.0 years) with a predominantly moderate to severe, persistent phenotype of SAR were recruited. Grass pollen major allergenic molecules (Phl p 1 and/or Phl p 5) ranged among the top three sensitizers in all study centers. Sensitization profiles were very heterogeneous, considering that patients in Rome were highly poly-sensitized (sIgE to 3.8 major allergenic molecules per patient), while mono-sensitization was prominent and heterogeneous in other cities, such as Marseille (sIgE to Cup a 1: n = 55/80, 68.8%) and Messina (sIgE to Par j 2: n = 47/82, 57.3%). Co-sensitization to perennial allergens, as well as allergic comorbidities also broadly varied between study centers. CONCLUSIONS: In Southern European countries, pollen allergy is heterogeneous in terms of sensitization profiles and clinical manifestations. Despite the complexity, a unique molecular, multiplex, and customized in-vitro IgE test detected relevant sensitization in all study centers. Nevertheless, this geographical diversity in pollen allergic patients imposes localized clinical guidelines and study protocols for clinical trials of SAR in this climatically complex region.
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Hipersensibilidad , Rinitis Alérgica Estacional , Adulto , Humanos , Niño , Adolescente , Rinitis Alérgica Estacional/diagnóstico , Rinitis Alérgica Estacional/epidemiología , Inmunoglobulina E , Alérgenos , Polen , Pruebas Cutáneas , FenotipoRESUMEN
BACKGROUND: The epidemiological surveillance of contact dermatitis is one of the objectives of the Spanish Registry of Research in Contact Dermatitis and Cutaneous Allergy. Knowing whether the prevalence of positive tests to the different allergens changes over time is important for this monitoring process. OBJECTIVES: To describe the various temporary trends in allergen positivity in the GEIDAC standard series from 2018 through December 31, 2022. METHODS: This was a multicenter, observational trial of consecutive patients analyzed via patch tests as part of the study of possible allergic contact dermatitises collected prospectively within the Spanish Registry of Research in Contact Dermatitis and Cutaneous Allergy. The data was analyzed using 2 statistical tests: one homogeneity test (to describe the changes seen over time) and one trend test (to see whether the changes described followed a linear trend). RESULTS: A total of 11327 patients were included in the study. Overall, the allergens associated with a highest sensitization were nickel sulfate, methylisothiazolinone, cobalt chloride, methylchloroisothiazolinone/methylisothiazolinone, and fragrance mix i. A statistically significant decrease was found in the percentage of methylisothiazolinone positive tests across the study years with an orderly trend. CONCLUSIONS: Although various changes were seen in the sensitizations trends to several allergens of the standard testing, it became obvious that a high sensitization to nickel, methylchloroisothiazolinone/methylisothiazolinone and fragrances mix i remained. Only a significant downward trend was seen for methylisothiazolinone.
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Dermatitis Alérgica por Contacto , Dermatitis Atópica , Humanos , Tiazoles , Dermatitis Alérgica por Contacto/diagnóstico , Dermatitis Alérgica por Contacto/epidemiología , Dermatitis Alérgica por Contacto/etiología , Alérgenos/efectos adversos , Pruebas del Parche , Estudios RetrospectivosRESUMEN
OBJECTIVES: To assess the degree of consensus among a multidisciplinary expert panel on the transition of adolescents with severe asthma from pediatric to adult care. METHODS: A 61-item survey was developed based on guidelines for other chronic diseases, covering transition planning, preparation, effective transfer, and follow-up. A 2-round Delphi process assessed the degree of consensus among 98 experts (49 pediatricians, 24 allergists, and 25 pulmonologists). Consensus was established with ≥70% agreement. RESULTS: Consensus was reached for 42 items (70%). Panelists were unable to agree on an age range for initiation of transition. The main goal during the transition identified by the experts is for adolescents to gain autonomy in managing severe asthma and prescribed treatments. The panelists agreed on the importance of developing an individualized plan, promoting patient autonomy, and identifying factors associated with the home environment. They agreed that the adult health care team should have expertise in severe asthma, biologics, and management of adolescent patients. Pediatric and adult health care teams should share clinical information, agree on the criteria for maintaining biological therapy, and have an on-site joint visit with the patient before the effective transfer. Adult health care professionals should closely follow the patient after the effective transfer to ensure correct inhaler technique, adherence, and attendance at health care appointments. CONCLUSION: This consensus document provides the first roadmap for Spanish pediatric and adult teams to ensure that key aspects of the transition process in severe asthma are covered. The implementation of these recommendations will improve the quality of care offered to the patient.
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Asma , Transición a la Atención de Adultos , Humanos , Adolescente , Adulto , Niño , Consenso , España , Asma/tratamiento farmacológico , Terapia BiológicaRESUMEN
BACKGROUND: Fatal anaphylaxis is very rare, with an incidence ranging from 0.5 to 1 deaths per million person-years. OBJECTIVE: Based on a systematic review, we aimed to explain differences in the reported incidence of fatal anaphylaxis based on the methodological and demographic factors addressed in the various studies. METHODS: We searched PubMed/MEDLINE, EMBASE, and the Web of Science for relevant retrospective and prospective cohort studies and registry studies that had assessed the anaphylaxis mortality rate for the population of a country or for an administrative region. The research strategy was based on combining the term "anaphylaxis" with "death", "study design", and "main outcomes" (incidence). RESULTS: A total of 46 studies met the study criteria and included 16,541 deaths. The range of the anaphylaxis mortality rate for all causes of anaphylaxis was 0.002-2.51 deaths per million person-years. Fatal anaphylaxis due to food (range 0.002-0.29) was rarer than deaths due to drugs (range 0.004-0.56) or Hymenoptera venom (range 0.02-0.61). The frequency of deaths due to anaphylaxis by drugs increased during the study period (IRR per year, 1.02; 95%CI, 1.00-1.04). We detected considerable heterogeneity in almost all of the meta-analyses carried out. CONCLUSION: The incidence of fatal anaphylaxis is very low and differs according to the various subgroups analyzed. The studies were very heterogeneous. Fatal anaphylaxis due to food seems to be less common than fatal anaphylaxis due to drugs or Hymenoptera venom.
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Anafilaxia , Venenos de Artrópodos , Alérgenos , Anafilaxia/epidemiología , Anafilaxia/etiología , Humanos , Incidencia , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Dalbavancin is a lipoglycopeptide with potent activity against Gram-positive microorganisms, a long half-life, a favorable safety profile, and a high concentration in bone, which makes it an interesting alternative for treatment of osteoarticular infections. We performed a multicentric retrospective study of all patients with an osteoarticular infection (septic arthritis, spondylodiscitis, osteomyelitis, or orthopedic implant-related infection) treated with at least one dose of dalbavancin between 2016 and 2017 in 30 institutions in Spain. In order to evaluate the response, patients with or without an orthopedic implant were separated. A total of 64 patients were included. Staphylococcus epidermidis and Staphylococcus aureus were the most frequent microorganisms. The reasons for switching to dalbavancin were simplification (53.1%), adverse events (25%), or failure (21.9%). There were 7 adverse events, and no patient had to discontinue dalbavancin. In 45 cases, infection was related to an orthopedic implant. The implant material was retained in 23 cases, including that in 15 (65.2%) patients that were classified as cured and 8 (34.8%) that presented improvement. In 21 cases, the implants were removed, including those in 16 (76.2%) cases that were considered successes, 4 (19%) cases were considered improved, and 1 (4.8%) case that was considered a failure. Among the 19 cases without implants, 14 (73.7%) were considered cured, 3 (15.8%) were considered improved, and 2 (10.5%) were considered failures. The results show that dalbavancin is a well-tolerated antibiotic, even when >2 doses are administered, and is associated with a high cure rate. These are preliminary data with a short follow-up; therefore, it is necessary to gain more experience and, in the future, to establish the most appropriate dose and frequency.
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Huesos/microbiología , Articulaciones/microbiología , Osteomielitis/microbiología , Teicoplanina/análogos & derivados , Anciano , Femenino , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/patogenicidad , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Osteomielitis/tratamiento farmacológico , Staphylococcus aureus , Staphylococcus epidermidis/efectos de los fármacos , Staphylococcus epidermidis/patogenicidad , Teicoplanina/uso terapéuticoRESUMEN
BACKGROUND: Food allergy can have a major impact on quality of life of children and their parents. Questionnaires have been developed to measure the impact of this disorder. We aimed to validate the EuroPrevall questionnaire on Food Allergy-Quality of Life Questionnaire, Parent Form (FAQLQ-PF) and the Food Allergy Independent Measure (FAIM), translated into Spanish. METHODS: The internal consistency of the FAQLQ-PF and the FAIM, translated into Spanish (Spain) and completed by the parents of 74 children with IgE-mediated food allergy, were evaluated with Cronbach's alpha. To test construct validity of the FAQLQ-PF, its correlation with the FAIM was also calculated. To assess their discriminant validity, we compared the values of both depending on the number of offending foods and for children with and without anaphylaxis. RESULTS: The values of Cronbach's alpha for the three domains in the FAQLQ-PF were over 0.9. The value of alpha for FAIM questions was below 0.6, which was attributed to the wording of one question. When this question was removed, alpha increased to over 0.70. There was a significant correlation between the FAQLQ-PF score and the FAIM. There were significantly poorer FAQLQ-PF scores in children with more food allergies and worse FAIM in those who had had anaphylaxis. CONCLUSIONS: The Spanish version of the FAQLQ-PF had a good internal consistency, good construct validity and validity to discriminate patients with more food allergies and anaphylaxis. It can be used as a tool to evaluate and monitor the quality of life in families with food allergic children.
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Anafilaxia/epidemiología , Hipersensibilidad a los Alimentos/epidemiología , Lenguaje , Calidad de Vida , Encuestas y Cuestionarios/normas , Anafilaxia/diagnóstico , Niño , Preescolar , Estudios Transversales , Diagnóstico Diferencial , Femenino , Hipersensibilidad a los Alimentos/diagnóstico , Humanos , Lactante , Recién Nacido , Masculino , México/epidemiología , Padres , Reproducibilidad de los ResultadosRESUMEN
A new generation of biologics targeting the interleukin-23-T helper 17 pathway has been developed. This study aimed to assess the short-term effectiveness and safety of these new agents using a network meta-analysis. Twenty-seven randomized clinical trials (10 629 patients) were identified by a comprehensive systematic literature review (PROSPERO 2015: CRD42015025472). Quality of evidence was assessed following Cochrane-compliant rules and the Grading of Recommendations, Assessment, Development and Evaluations approach. Efficacy and safety outcomes at weeks 10-16 were compared using a random-effects network meta-analysis within a frequentist framework to estimate pooled odds ratios (ORs) of direct and indirect comparisons among the therapeutic options. There were six direct drug-to-drug comparisons in the network, with a high degree of consistency between the direct and indirect evidence. From the available evidence, infliximab 5 mg kg-1 every 8 weeks [OR 118·89, 95% confidence interval (CI) 60·91-232·04] and secukinumab 300 mg every 4 weeks (OR 87·07, 95% CI 55·01-137·82) are shown to be among the most effective short-term treatments, but are ranked as the biologics most likely to produce any adverse event or an infectious adverse event, respectively. Ustekinumab 90 mg every 12 weeks, the third most efficacious treatment (OR 73·67, 95% CI 46·97-115·56), was the only agent that did not show increased risk of adverse events compared with placebo. Treatment recommendations should also consider long-term outcomes and costs.
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Factores Biológicos/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Interleucina-23/metabolismo , Psoriasis/tratamiento farmacológico , Células Th17/efectos de los fármacos , Adulto , Factores Biológicos/efectos adversos , Enfermedad Crónica , Fármacos Dermatológicos/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Seguridad del Paciente , Resultado del TratamientoRESUMEN
BACKGROUND: The quality of systematic reviews and meta-analyses on psoriasis, a chronic inflammatory skin disease that severely impairs quality of life and is associated with high costs, remains unknown. OBJECTIVES: To assess the methodological quality of systematic reviews published on psoriasis. METHODS: After a comprehensive search in MEDLINE, Embase and the Cochrane Database (PROSPERO: CDR42016041611), the quality of studies was assessed by two raters using the Assessment of Multiple Systematic Reviews (AMSTAR) tool. Article metadata and journal-related bibliometric indices were also obtained. Systematic reviews were classified as low (0-4), moderate (5-8) or high (9-11) quality. A prediction model for methodological quality was fitted using principal component and multivariate ordinal logistic regression analyses. RESULTS: We classified 220 studies as high (17·2%), moderate (55·0%) or low (27·8%) quality. Lower compliance rates were found for AMSTAR question (Q)5 (list of studies provided, 11·4%), Q10 (publication bias assessed, 27·7%), Q4 (status of publication included, 39·5%) and Q1 (a priori design provided, 40·9%). Factors such as meta-analysis inclusion [odds ratio (OR) 6·22; 95% confidence interval (CI) 2·78-14·86], funding by academic institutions (OR 2·90, 95% CI 1·11-7·89), Article Influence score (OR 2·14, 95% CI 1·05-6·67), 5-year impact factor (OR 1·34, 95% CI 1·02-1·40) and article page count (OR 1·08, 95% CI 1·02-1·15) significantly predicted higher quality. A high number of authors with a conflict of interest (OR 0·90, 95% CI 0·82-0·99) was significantly associated with lower quality. CONCLUSIONS: The methodological quality of systematic reviews published about psoriasis remains suboptimal. The type of funding sources and author conflicts may compromise study quality, increasing the risk of bias.
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Metaanálisis como Asunto , Psoriasis , Literatura de Revisión como Asunto , Autoria , Conflicto de Intereses , Dermatología/estadística & datos numéricos , Ética en Investigación , Humanos , Factor de Impacto de la Revista , Publicaciones Periódicas como Asunto/ética , Publicaciones Periódicas como Asunto/normas , Sesgo de Publicación , Apoyo a la Investigación como AsuntoRESUMEN
BACKGROUND AND OBJECTIVE: Studies assessing the severity of anaphylaxis lack a comprehensive approach to collecting data on comorbidities that may worsen prognosis. Objective: Using the Elixhauser score (a systematic index associated with longer stay, hospital charges, and mortality), we determined which comorbidities were associated with more severe anaphylaxis. METHODS: We based our study on the Spanish Ministry of Health database of hospital discharges in Spain between 1997 and 2011. We constructed logistic regression models in which the dependent variables were outcomes related to greater severity (death, cardiac arrest, need for invasive mechanical ventilation or vasopressor drugs, admission to the intensive care unit, and length of stay) and the independent variables were the 30 comorbidities that comprise the Elixhauser score, age, sex, and main causes of anaphylaxis. RESULTS: We found that a higher risk of severe anaphylaxis was associated (3 or more logistic regressions) with age >50 years or having experienced cardiac arrhythmia, coagulation disorder, associated fluid-electrolyte imbalance, chronic pulmonary disease, or Echinococcus anaphylaxis. Likewise, in the adjusted analysis, a higher Elixhauser score was associated with most of the outcomes analyzed for severity of anaphylaxis. CONCLUSIONS: Cardiovascular and respiratory diseases increase the severity of anaphylaxis, and the resulting poor health status (represented as a higher Elixhauser score) is associated with more severe anaphylaxis.
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Anafilaxia/epidemiología , Enfermedades Cardiovasculares/epidemiología , Hospitalización , Enfermedades Respiratorias/epidemiología , Adolescente , Adulto , Factores de Edad , Anciano , Anafilaxia/diagnóstico , Anafilaxia/mortalidad , Anafilaxia/terapia , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/mortalidad , Niño , Preescolar , Comorbilidad , Bases de Datos Factuales , Femenino , Estado de Salud , Mortalidad Hospitalaria , Humanos , Lactante , Recién Nacido , Tiempo de Internación , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Alta del Paciente , Enfermedades Respiratorias/diagnóstico , Enfermedades Respiratorias/mortalidad , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , España/epidemiología , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: Dementia is characterised by cognitive deterioration and the manifestation of psychological and behavioural symptoms, especially changes in perception, thought content, mood, and conduct. In addition to drug therapy, non-pharmacological treatments are used to manage these symptoms, and one of these latter treatments is music therapy. Since this novel technique in non-verbal, it can be used to treat patients with dementia at any stage, even when cognitive deterioration is very severe. Patients' responses to music are conserved even in the most advanced stages of the disease DEVELOPMENT: A literature research was carried out using the following databases: Academic Search Complete, PubMed, Science Direct y Dialnet. The period of publication was 2003 to 2013 and the search keywords were 'Music Therapy, Dementia, Behaviour, Behaviour Disorders y Behavioural Disturbances'. Out of the 2188 studies that were identified, 11 studies met inclusion criteria for the systematic review. CONCLUSIONS: Music therapy is beneficial and improves behavior disorders, anxiety and agitation in subjects diagnosed with dementia.
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Demencia/terapia , Musicoterapia/métodos , Agitación Psicomotora/psicología , Ansiedad/psicología , Demencia/psicología , HumanosRESUMEN
Paravalvular leak (PVL) is a serious complication after surgical valve replacement or after transcatheter aortic valve replacement. Approximately 1-5% of PVLs can lead to serious clinical consequences, including congestive heart failure and/or haemolytic anaemia. For years, surgical re-intervention has been considered the treatment of choice for symptomatic patients with PVLs. However, surgical re-intervention is associated with a high risk of morbidity and mortality. Transcatheter PVL (TPVL) closure is a less invasive alternative to surgical re-intervention. The safety and feasibility of TPVL closure has been confirmed in several registries and a meta-analysis.In this review, we discuss the clinical implications and diagnosis of PVLs, technical considerations for TPVL, execution of the procedure and assessment of the results.
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The objective was to evaluate the efficacy of MP-AzeFlu (Dymista(®) ) vs fluticasone propionate (FP), (both 1 spray/nostril bid), in children with allergic rhinitis (AR). MP-AzeFlu combines azelastine hydrochloride, FP and a novel formulation in a single spray. Children were randomized in a 3 : 1 ratio to MP-AzeFlu or FP in this open-label, 3-month study. Efficacy was assessed in children aged ≥ 6 to <12 years (MP-AzeFlu: n = 264; FP: n = 89), using a 4-point symptom severity rating scale from 0 to 3 (0 = no symptoms; 3 = severe symptoms). Over the 3-month period, MP-AzeFlu-treated children experienced significantly greater symptom relief than FP-treated children (Diff: -0.14; 95% CI: -0.28, -0.01; P = 0.04), noted from the first day (particularly the first 7 days) and sustained for 90 days. More MP-AzeFlu children achieved symptom-free or mild symptom severity status, and did so up to 16 days faster than FP. MP-AzeFlu provides significantly greater, more rapid and clinically relevant symptom relief than FP in children with AR.
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Antialérgicos/uso terapéutico , Fluticasona/uso terapéutico , Rinitis Alérgica/tratamiento farmacológico , Antialérgicos/administración & dosificación , Antialérgicos/efectos adversos , Niño , Preescolar , Combinación de Medicamentos , Femenino , Fluticasona/administración & dosificación , Fluticasona/efectos adversos , Antagonistas de los Receptores Histamínicos/administración & dosificación , Antagonistas de los Receptores Histamínicos/uso terapéutico , Humanos , Masculino , Rinitis Alérgica/diagnóstico , Evaluación de Síntomas , Resultado del TratamientoAsunto(s)
Antígenos de Plantas/metabolismo , Toma de Decisiones Clínicas/métodos , Material Particulado/metabolismo , Polen/metabolismo , Rinitis Alérgica Estacional/diagnóstico , Adulto , Alérgenos/inmunología , Antígenos de Plantas/inmunología , Fagales , Femenino , Humanos , Masculino , Región Mediterránea/epidemiología , Material Particulado/inmunología , Pinales , Poaceae , Polen/inmunología , Rinitis Alérgica Estacional/epidemiología , Estaciones del AñoRESUMEN
This cross-sectional study analyzes factors associated with the development of CMV-specific CD8+ response, measured by IFNg production after cytomegalovirus (CMV) peptide stimulation, in CMV-seropositive solid organ transplantation candidates. A total of 114 candidates were enrolled, of whom 22.8% (26/114) were nonreactive (IFNγ < 0.2 IU/mL). Multivariate logistic regression analysis showed that age, HLA alleles and organ to be transplanted were associated with developing CMV-specific CD8+ immunity (reactive; IFNγ ≥ 0.2 IU/mL). The probability of being reactive was higher in candidates over 50 than in those under 50 (OR 6.33, 95%CI 1.93-20.74). Candidates with HLA-A1 and/or HLA-A2 alleles had a higher probability of being reactive than those with non-HLA-A1/non-HLA-A2 alleles (OR 10.97, 95%CI 3.36-35.83). Renal candidates had a higher probability of being reactive than lung (adjusted OR 8.85, 95%CI 2.24-34.92) and liver candidates (OR 4.87, 95%CI 1.12-21.19). The AUC of this model was 0.84 (p < 0.001). Positive and negative predictive values were 84.8% and 76.9%, respectively. In renal candidates longer dialysis was associated with an increased frequency of reactive individuals (p = 0.040). Therefore, although the assessment of CMV-specific CD8+ response is recommended in all R+ candidates, it is essential in those with a lower probability of being reactive, such as non-renal candidates, candidates under 50 or those with non-HLA-A1/non-HLA-A2 alleles.
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Linfocitos T CD8-positivos/inmunología , Citomegalovirus/inmunología , Trasplante de Órganos , Adulto , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Influenza epidemics affect all age groups, although children, the elderly and those with underlying medical conditions are the most severely affected. Whereas co-morbidities are present in 50% of fatal cases, 25-50% of deaths are in apparently healthy individuals. This suggests underlying genetic determinants that govern infection severity. Although some viral factors that contribute to influenza disease are known, the role of host genetic factors remains undetermined. Data for small cohorts of influenza-infected patients are contradictory regarding the potential role of chemokine receptor 5 deficiency (CCR5-Δ32 mutation, a 32 bp deletion in the CCR5 gene) in the outcome of influenza virus infection. We tested 171 respiratory samples from influenza patients (2009 pandemic) for CCR5-Δ32 and evaluated its correlation with patient mortality. CCR5-Δ32 patients (17.4%) showed a higher mortality rate than WT individuals (4.7%; P = 0.021), which indicates that CCR5-Δ32 patients are at higher risk than the normal population of a fatal outcome in influenza infection.
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Subtipo H1N1 del Virus de la Influenza A/fisiología , Gripe Humana/genética , Gripe Humana/mortalidad , Receptores CCR5/deficiencia , Adolescente , Adulto , Anciano , Niño , Femenino , Eliminación de Gen , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Subtipo H1N1 del Virus de la Influenza A/genética , Gripe Humana/metabolismo , Gripe Humana/virología , Masculino , Persona de Mediana Edad , Receptores CCR5/genética , Adulto JovenRESUMEN
BACKGROUND: We investigated the association of BRCA1 and XPG mutations with response rate (RR), progression-free survival (PFS) and overall survival (OS) in a subset of patients from a phase 3 clinical trial comparing the efficacy and safety of trabectedin + pegylated liposomal doxorubicin (PLD) versus PLD alone in patients with recurrent ovarian cancer. PATIENTS AND METHODS: A candidate array was designed based on the Breast Cancer Information Core database for BRCA mutation analyses. An exploratory analysis of BRCA1/XPG mutation status was conducted using a two-sided log-rank test and 0.05 significance in germline DNA samples from 264 women with failed first-line platinum-based chemotherapy, randomized (1 : 1) to trabectedin + PLD or PLD alone. RESULTS: Overall, 41 (16%) of the 264 women had BRCA1(mut) (trabectedin + PLD: n = 24/135, 18%; PLD: n = 17/129; 13%) and 17 (6%) had XPG(mut) (trabectedin + PLD: n = 8/135, 6%; PLD: n = 9/129, 7%). A higher RR was observed in BRCA1(mut) patients (20/41; 49%) versus BRCA1(wt) patients (62/223; 28%). Within the BRCA1(mut) group, trabectedin + PLD-treated patients had longer PFS and longer OS than PLD-treated patients (median PFS 13.5 versus 5.5 months, P = 0.0002; median OS 23.8 versus 12.5 months, P = 0.0086), whereas in BRCA1(wt) patients, OS was not significantly different (median OS: 19.1 versus 19.3 months; P = 0.9377). There were no differences in OS or PFS of patients with XPG(mut) between the two treatment arms. However, trabectedin + PLD-treated patients with XPG(mut) had a trend toward shorter PFS (median PFS: 1.9 versus 7.5 months; P = 0.1666) and OS (median OS: 14.5 versus 20.7 months; P = 0.1774) than those with XPG(wt). CONCLUSIONS: In this exploratory analysis, patients with recurrent ovarian cancer carrying the BRCA1(mut) had improved outcomes with trabectedin + PLD treatment compared with PLD alone. Prospective evaluation of BRCA status is likely an important evaluation for DNA-damaging agents and may significantly impact interpretation of clinical studies. XPG may be a biomarker of poor outcome in these patients.
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Antibióticos Antineoplásicos/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteína BRCA1/genética , Proteínas de Unión al ADN/genética , Dioxoles/uso terapéutico , Doxorrubicina/análogos & derivados , Endonucleasas/genética , Mutación , Proteínas Nucleares/genética , Neoplasias Ováricas/tratamiento farmacológico , Tetrahidroisoquinolinas/uso terapéutico , Factores de Transcripción/genética , Anciano , Antibióticos Antineoplásicos/efectos adversos , Antineoplásicos Alquilantes/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dioxoles/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neoplasias Ováricas/genética , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Farmacogenética , Polietilenglicoles/efectos adversos , Polietilenglicoles/uso terapéutico , Tetrahidroisoquinolinas/efectos adversos , Factores de Tiempo , Trabectedina , Resultado del TratamientoRESUMEN
UNLABELLED: Influenza virus transcription requires functional coupling with cellular transcription for the cap-snatching process. Despite this fact, RNA polymerase II (RNAP II) is degraded during infection in a process triggered by the viral polymerase. Reassortant viruses from the A/PR/8/34 (PR8) strain that induce (hvPR8) or do not induce (lvPR8) RNAP II degradation led to the identification of PA and PB2 subunits as responsible for the degradation process. Three changes in the PB2 sequence (I105M, N456D, and I504V) and two in PA (Q193H and I550L) differentiate PA and PB2 of lvPR8 from those of hvPR8. Using recombinant viruses, we observed that changes at position 504 of PB2, together with 550 of PA, confer the ability on lvPR8 for RNAP II degradation and, conversely, abolish hvPR8 degradation capacity. Since hvPR8 is more pathogenic than lvPR8 in mice, we tested the potential contribution of RNAP II degradation in a distant viral strain, the 2009 pandemic A/California/04/09 (CAL) virus, whose PA and PB2 subunits are of avian origin. As in the hvPR8 virus, mutations at positions 504 of PB2 and 550 of PA in CAL virus abolished its RNAP II degradation capacity. Moreover, in an in vivo model, the CAL-infected mice lost more body weight, and 75% lethality was observed in this situation compared with 100% survival in mutant-CAL- or mock-infected animals. These results confirm the involvement of specific PB2 and PA residues in RNAP II degradation, which correlates with pathogenicity in mice of viruses containing human or avian polymerase PB2 and PA subunits. IMPORTANCE: The influenza virus polymerase induces the degradation of RNAP II, which probably cooperates to avoid the antiviral response. Here, we have characterized two specific residues located in the PA and PB2 polymerase subunits that mediate this degradation in different influenza viruses. Moreover, a clear correlation between RNAP II degradation and in vivo pathogenicity in mice was observed, indicating that the degradative process constitutes a viral pathogenicity factor.
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Virus de la Influenza A/enzimología , Virus de la Influenza A/patogenicidad , Gripe Humana/enzimología , ARN Polimerasa II/metabolismo , ARN Polimerasa Dependiente del ARN/química , ARN Polimerasa Dependiente del ARN/metabolismo , Proteínas Virales/química , Proteínas Virales/metabolismo , Secuencias de Aminoácidos , Animales , Femenino , Humanos , Virus de la Influenza A/química , Virus de la Influenza A/genética , Gripe Humana/genética , Gripe Humana/virología , Ratones , Ratones Endogámicos BALB C , Proteolisis , ARN Polimerasa II/genética , ARN Polimerasa Dependiente del ARN/genética , Proteínas Virales/genética , VirulenciaRESUMEN
BACKGROUND: We analyzed the role of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) on the microscopic component of the disease in patients with a first recurrence of platinum-sensitive ovarian cancer after complete cytoreduction (CCR). PATIENTS AND METHODS: We analyzed the data of 54 patients who were operated on between January 2001 and July 2012 with the diagnosis of platinum-sensitive recurrent ovarian cancer. In all patients, it was possible to achieve a CCR. Patients were divided into two groups: group I (cytoreduction alone) consisted of 22 surgical patients and group II (cytoreduction and HIPEC) consisted of 32 patients. RESULTS: There were no significant differences in any of the preoperative variables studied. After a multivariate analysis of factors identified in the univariate analysis, only the presence of tumors with undifferentiated histology (hazard ratio 2.57; 95% CI 1.21-5.46; p < 0.05) was an independent factor associated with a reduced disease-free survival. The 1- and 3-year disease-free survival was 77 and 23% in patients from group I and 77 and 45% in patients from group II, respectively, with a tendency, but no significant differences (p = 0.078). There was no significant difference in postoperative morbidity between the two groups. CONCLUSIONS: The administration of HIPEC in patients in whom it is possible to achieve a CCR of the disease has not increased postoperative morbidity and mortality rates in our center. HIPEC with paclitaxel is effective in the treatment of microscopic disease in platinum-sensitive recurrent epithelial ovarian cancer patients with microscopic residual disease after cytoreduction, although with no statistically significant difference.