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Abstract Background Tumor mutational burden (TMB) has been demonstrated to predict the response to immune checkpoint inhibitors (ICIs) in various cancers. However, the role of TMB in head and neck squamous cell carcinoma (HNSCC) has not yet been specifically addressed. Since HNSCC patients exhibit a rather limited response to ICIs, there is an unmet need to develop predictive biomarkers to improve patient selection criteria and the clinical benefit of ICI treatment. Methods We conducted a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. HNSCC cohort studies were selected when TMB prior to ICI treatment was evaluated, TMB cutoff value was available, and the prognostic value of TMB was evaluated by time-to-event survival analysis. A total of 11 out of 1960 articles were analyzed, including 1200 HNSCC patients. Results The results showed that those patients harboring high TMB exhibited a significantly superior overall response rate (OR = 2.62; 95% CI 1.74–3.94; p

Modern science is frequently based on the exploitation of large volumes of information storage in datasets and involving complex computational architectures. The statistical analyses of these datasets have to cope with specific challenges and frequently involve making informed but arbitrary decisions. Epidemiological papers have to be concise and focused on the underlying clinical or epidemiological results, not reporting the details behind relevant methodological decisions. In this work, we used an analysis of the cardiovascular-related measures tracked in 4–8-year-old children, using data from the INMA-Asturias cohort for illustrating how the decision-making process was performed and its potential impact on the obtained results. We focused on two particular aspects of the problem: how to deal with missing data and which regression model to use to evaluate tracking when there are no defined thresholds to categorize variables into risk groups. As a spoiler, we analyzed the impact on our results of using multiple imputation and the advantage of using quantile regression models in this context.

BackgroundData about long-term prognosis after hospitalisation of elderly multimorbid patients remains scarce.ObjectivesEvaluate medium and long-term prognosis in hospitalised patients older than 75 years of age with multimorbidity. Explore the impact of gender, age, frailty, physical dependence, and chronic diseases on mortality over a seven-year period.MethodsWe included prospectively all patients hospitalised for medical reasons over 75 years of age with two or more chronic illnesses in a specialised ward. Data on chronic diseases were collected using the Charlson comorbidity index and a questionnaire for disorders not included in this index. Demographic characteristics, Clinical Frailty Scale, Barthel index, and complications during hospitalisation were collected.Results514 patients (46% males) with a mean age of 85 (± 5) years were included. The median follow-up was 755 days (interquartile range 25-75%: 76-1,342). Mortality ranged from 44% to 68%, 82% and 91% at one, three, five, and seven years. At inclusion, men were slightly younger and with lower levels of physical impairment. Nevertheless, in the multivariate analysis, men had higher mortality (pConclusionsIn our cohort, individual diseases had a limited predictive prognostic capacity, while the combination of chronic illness, frailty, and physical dependence were independent predictors of survival.

The comet assay in Drosophila has been used in the last few years to study DNA damage responses (DDR) in different repair-mutant strains and to compare them to analyze DNA repair. We have used this approach to study interactions between DNA repair pathways in vivo. Additionally, we have implemented an ex vivo comet assay, in which nucleoids from treated and untreated cells were incubated ex vivo with cell-free protein extracts from individuals with distinct repair capacities. Four strains were used: wild-type OregonK (OK), nucleotide excision repair mutant mus201, dmPolQ protein mutant mus308, and the double mutant mus201;mus308. Methyl methanesulfonate (MMS) was used as a genotoxic agent. Both approaches were performed with neuroblasts from third-instar larvae; they detected the effects of the NER and dmPolQ pathways on the DDR to MMS and that they act additively in this response. Additionally, the ex vivo approach quantified that mus201, mus308, and the double mutant mus201;mus308 strains presented, respectively, 21.5%, 52.9%, and 14.8% of OK strain activity over MMS-induced damage. Considering the homology between mammals and Drosophila in repair pathways, the detected additive effect might be extrapolated even to humans, demonstrating that Drosophila might be an excellent model to study interactions between repair pathways.

Resumen: Introducción: En el ámbito de los cuidados intensivos, existen numerosas escalas para cuantificar la gravedad de los pacientes. La mayoría de ellas son muy útiles, aunque en ocasiones laboriosas de completar, por lo que su implantación en la práctica habitual es escasa. Una de ellas es la escala de puntuación de intervenciones terapéuticas (TISS 76), que ha sido validada en unidades de adultos y pediátricas. Su versión simplificada y actualizada, la escala simplificada de puntuación de intervenciones terapéuticas (TISS 28), no ha sido validada en unidades pediátricas, siendo este el objetivo del estudio, con idea de disponer de una escala sencilla y rápida. Material y método: Estudio observacional prospectivo sin intervención, en la Unidad de Cuidados Intensivos Pediátricos (UCIP) de un hospital universitario. Se recogieron datos de 935 pacientes ingresados consecutivamente en la UCIP durante un periodo de 3 años, incluyendo los valores de TISS 76 y TISS 28 de todos durante los 4 primeros días de ingreso y la posterior evolución de los pacientes. Resultados: Los valores medios de TISS 76 y TISS 28 para el primer día de ingreso fueron de 18,27 y de 18,02, respectivamente, siendo más elevados en los pacientes con secuelas o que fallecían. Se encontró muy buena correlación entre la TISS 76 y la 28, con coeficiente de correlación de Pearson y de correlación intraclase > 0,9 (excepto para el segundo día). La ecuación de correlación para los 4 días fue: TISS76 = –1,74 + 1,05 × TISS28. La TISS 28 fue capaz de explicar el 82,4% de la variabilidad de la TISS 76. El área bajo la curva con un intervalo de confianza del 95% para el primer día fue de 0,80 para la TISS 76 y de 0,76 para la TISS 28. Conclusiones: Con los resultados obtenidos, la TISS 28 puede reemplazar a la TISS 26 en nuestra UCIP, sin empeorar la información proporcionada. Siendo una escala fiable y más sencilla de aplicar, podría ser útil su aplicación práctica. Abstract: Introduction: There are numerous scales in intensive care units that are used to quantify the severity of patients. Most of them are very useful, although sometimes laborious to complete, thus limiting their use in usual practice. One of these scales, the Therapeutic Intervention Scoring System (TISS 76), has been validated in adult and paediatric units. Its simplified and updated version, the Simplified Therapeutic Intervention Scoring System (TISS 28), has not yet been validated in paediatric units. The aim of this study is to validate TISS 28, in order to have a simple and rapid scale. Material and method: A prospective non-interventional observational study was conducted in a Paediatric Intensive Care Unit (PICU) of a university hospital. Data were collected from 935 consecutive patients admitted to the PICU over a 3-year period. These included the values of TISS 76 and TISS 28 during the first 4 days of admission and the subsequent outcome of the patients. Results: The mean values of TISS 76 and TISS 28 for the first day of admission were 18.27 and 18.02, respectively. Values were higher in patients who had sequelae or died (17.58 versus 27.23 and 37.44, respectively for TISS 76 (P 0.9 (except for the 2 nd day). The correlation equation for the overall 4 days was: TISS76 = - 1.74 + 1.05 × TISS28. TISS 28 was able to explain 82.4% of variability of TISS 76. The area under the curve with a confidence interval (CI) of 95% for the first day was 0.80 (0.73-0.87) for TISS 76, and 0.76 (0.67-0.84) for TISS 28. Conclusions: On observing the results obtained, TISS 28 can replace TISS 26 in our PICU, without worsening the information provided. Being a reliable scale and easier to apply, its practical application could be useful.

Introduction: There are numerous scales in intensive care units that are used to quantify the severity of patients. Most of them are very useful, although sometimes laborious to complete, thus limiting their use in usual practice. One of these scales, the Therapeutic Intervention Scoring System (TISS-76), has been validated in adult and paediatric units. Its simplified and updated version, the Simplified Therapeutic Intervention Scoring System (TISS-28), has not yet been validated in paediatric units. The aim of this study is to validate TISS-28, in order to have a simple and rapid scale. Material and method: A prospective non-interventional observational study was conducted in a Paediatric Intensive Care Unit (PICU) of a university hospital. Data were collected from 935 consecutive patients admitted to the PICU over a 3-year period. These included the values of TISS-76 and TISS-28 during the first 4 days of admission and the subsequent outcome of the patients. Results: The mean values of TISS-76 and TISS-28 for the first day of admission were 18.27 and 18.02, respectively. Values were higher in patients who had sequelae or died (17.58 versus 27.23 and 37.44, respectively for TISS-76 (p 0.9 (except for the 2nd day). The correlation equation for the overall 4 days was: TISS-76 = −1.74 + 1.05 × TISS-28. TISS-28 was able to explain 82.4% of variability of TISS-76. The area under the curve with a confidence interval (CI) of 95% for the first day was 0.80 (0.73–0.87) for TISS-76, and 0.76 (0.67–0.84) for TISS-28. Conclusions: On observing the results obtained, TISS-28 can replace TISS-76 in our PICU, without worsening the information provided. Being a reliable scale and easier to apply, its practical application could be useful. Resumen: Introducción: En el ámbito de los cuidados intensivos, existen numerosas escalas para cuantificar la gravedad de los pacientes. La mayoría de ellas son muy útiles, aunque en ocasiones laboriosas de completar, por lo que su implantación en la práctica habitual es escasa. Una de ellas es la escala de puntuación de intervenciones terapéuticas (TISS 76), que ha sido validada en unidades de adultos y pediátricas. Su versión simplificada y actualizada, la escala simplificada de puntuación de intervenciones terapéuticas (TISS 28), no ha sido validada en unidades pediátricas, siendo este el objetivo del estudio, con idea de disponer de una escala sencilla y rápida. Material y método: Estudio observacional prospectivo sin intervención, en la Unidad de Cuidados Intensivos Pediátricos (UCIP) de un hospital universitario. Se recogieron datos de 935 pacientes ingresados consecutivamente en la UCIP durante un periodo de 3 años, incluyendo los valores de TISS 76 y TISS 28 de todos durante los 4 primeros días de ingreso y la posterior evolución de los pacientes. Resultados: Los valores medios de TISS 76 y TISS 28 para el primer día de ingreso fueron de 18,27 y de 18,02, respectivamente, siendo más elevados en los pacientes con secuelas o que fallecían. Se encontró muy buena correlación entre la TISS 76 y la 28, con coeficiente de correlación de Pearson y de correlación intraclase >0,9 (excepto para el segundo día). La ecuación de correlación para los 4 días fue: TISS76 = −1,74 + 1,05 × TISS28. La TISS 28 fue capaz de explicar el 82,4% de la variabilidad de la TISS 76. El área bajo la curva con un intervalo de confianza del 95% para el primer día fue de 0,80 para la TISS 76 y de 0,76 para la TISS 28. Conclusiones: Con los resultados obtenidos, la TISS 28 puede reemplazar a la TISS 76 en nuestra UCIP, sin empeorar la información proporcionada. Siendo una escala fiable y más sencilla de aplicar, podría ser útil su aplicación práctica.

Background: The effect of resistance training on gut microbiota composition has not been explored, despite the evidence about endurance exercise. The aim of this study was to compare the effect of resistance and endurance training on gut microbiota composition in mice.Methods: Cecal samples were collected from 26 C57BL/6N mice, divided into three groups: sedentary (CTL), endurance training on a treadmill (END), and resistance training on a vertical ladder (RES). After 2 weeks of adaption, mice were trained for 4 weeks, 5 days/week. Maximal endurance and resistance capacity test were performed before and after training. Genomic DNA was extracted and 16S Ribosomal RNA sequenced for metagenomics analysis. The percentages for each phylum, class, order, family, or genus/species were obtained using an open-source bioinformatics pipeline.Results: END showed higher diversity and evenness. Significant differences among groups in microbiota composition were only observed at genera and species level. END showed a significantly higher relative abundance of Desulfovibrio and Desulfovibrio sp., while Clostridium and C. cocleatum where higher for RES. Trained mice showed significantly lower relative abundance of Ruminococcus gnavus and higher of the genus Parabacteroides compared to CTL. We explored the relationship between relative taxa abundance and maximal endurance and resistance capacities after the training period. Lachnospiraceae and Lactobacillaceae families were negatively associated with endurance performance, while several taxa, including Prevotellaceae family, Prevotella genus, and Akkermansia muciniphila, were positively correlated. About resistance performance, Desulfovibrio sp. was negatively correlated, while Alistipes showed a positive correlation.Conclusion: Resistance and endurance training differentially modify gut microbiota composition in mice, under a high-controlled environment. Interestingly, taxa associated with anti- and proinflammatory responses presented the same pattern after both models of exercise. Furthermore, the abundance of several taxa was differently related to maximal endurance or resistance performance, most of them did not respond to training.

In 2019, The Global Initiative for Chronic Obstructive Lung Disease (GOLD) modified the grading system for patients with COPD, creating 16 subgroups (1A–4D). As part of the COPD Cohorts Collaborative International Assessment (3CIA) initiative, we aim to compare the mortality prediction of the 2015 and 2019 COPD GOLD staging systems. We studied 17 139 COPD patients from the 3CIA study, selecting those with complete data. Patients were classified by the 2015 and 2019 GOLD ABCD systems, and we compared the predictive ability for 5-year mortality of both classifications. In total, 17 139 patients with COPD were enrolled in 22 cohorts from 11 countries between 2003 and 2017; 8823 of them had complete data and were analysed. Mean±sd age was 63.9±9.8 years and 62.9% were male. GOLD 2019 classified the patients in milder degrees of COPD. For both classifications, group D had higher mortality. 5-year mortality did not differ between groups B and C in GOLD 2015; in GOLD 2019, mortality was greater for group B than C. Patients classified as group A and B had better sensitivity and positive predictive value with the GOLD 2019 classification than GOLD 2015. GOLD 2015 had better sensitivity for group C and D than GOLD 2019. The area under the curve values for 5-year mortality were only 0.67 (95% CI 0.66–0.68) for GOLD 2015 and 0.65 (95% CI 0.63–0.66) for GOLD 2019. The new GOLD 2019 classification does not predict mortality better than the previous GOLD 2015 system.

Resumen: La infección peritoneal es un problema frecuente que afecta negativamente a la supervivencia del paciente y de la técnica. El inicio rápido del tratamiento de la infección peritoneal reduce las complicaciones.Se busca diseñar un índice multicomponente (MUL+DO) para el diagnóstico rápido y eficiente de infección peritoneal.Con ese objetivo, se crea una cohorte de construcción con muestras de efluente peritoneal que se analizaron con tiras Multistix ® 10 SG Siemens para la detección de leucocitos. Después, se examinó cada muestra según el patrón oro: número de leucocitos, porcentaje de polimorfonucleares y cultivo microbiológico. Se construyó MUL+DO sumándole un punto a la escala cromática modificada MULTISTIX [0-1-2-3] si el paciente reporta dolor. MUL+DO toma valores de 0 a 4. Posteriormente, se creó una cohorte de validación del modelo. MUL+DO se aplicó a cada muestra, determinándose también leucocitos y porcentaje de polimorfonucleares.La cohorte de construcción incluyó 134 muestras, 34 tenían infección (25,4% [17,6-33,1]). Las muestras con un valor MUL+DO >1, presentaron una sensibilidad y especificidad del 100%. La cohorte de validación incluyó 100 muestras con 16 infecciones (16% [8,3-23,7]).En la cohorte de validación asumiendo como positiva una muestra con un valor MUL+DO > 1, se obtuvo una sensibilidad del 100% y una especificidad del 95,2%.MUL+DO aplicado en la cohorte de construcción, mostró una separación perfecta de las poblaciones positiva y negativa. Todos los pacientes positivos presentaron una puntuación ≥2. En la cohorte de validación, el índice MUL+DO presentó una sensibilidad del 100% y una especificidad del 95,2%. Abstract: Peritoneal infection is a common problem that has a negative impact on the survival of patients and the technique. The early administration of peritoneal infection treatment reduces complications.The goal of this study is to propose a multicomponent index (MUL+DO) for the quick and efficient diagnosis of peritoneal infection.We selected a training cohort of peritoneal effluent samples which were analysed by Multistix ® 10 SG Siemens test strips for leukocyte detection. Then, each sample was examined according to the gold standard: number of leukocytes, polymorphonuclear percentage and microbiological culture. We constructed the MUL+DO index by adding one point to the MULTISTIX [0-1-2-3] modified chromatic scale if the patient reported pain. The MUL+DO index ranged from 0 to 4. A model validation cohort was then created. MUL+DO was applied to each sample and leukocytes and polymorphonuclear percentage were also assessed.The training cohort ultimately included 134 samples, 34 of which with infection (25.4% [17.6-33.1]). Samples with a MUL+DO value greater than 1 presented a sensitivity and specificity of 100%. The validation cohort included 100 samples with 16 infections (16% [8.3-23.7]).Assuming a sample with a MUL+DO value greater than 1 to be positive, we obtained a sensitivity of 100% and a specificity of 95.2%.The MUL+DO index applied to the training cohort showed a perfect separation of the positive and negative populations. All positive patients presented a score ≥2. In the validation cohort, the MUL+DO reported a sensitivity of 100% and a specificity of 95.2%. Palabras clave: Diálisis peritoneal, Peritonitis, Tiras test de orina, Diagnóstico, Keywords: Peritoneal dialysis, Peritonitis, Urine test strip, Diagnosis

Peritoneal infection is a common problem that has a negative impact on the survival of patients and the technique. The early administration of peritoneal infection treatment reduces complications.The goal of this study is to propose a multicomponent index (MUL+DO) for the quick and efficient diagnosis of peritoneal infection.We selected a training cohort of peritoneal effluent samples which were analyzed by Multistix® 10 SG Siemens test strips for leukocyte detection. Then, each sample was examined according to the gold standard: number of leukocytes, polymorphonuclear percentage and microbiological culture. We constructed the MUL+DO index by adding one point to the MULTISTIX [0-1-2-3] modified chromatic scale if the patient reported pain. The MUL+DO index ranged from 0 to 4. A model validation cohort was then created. MUL+DO was applied to each sample and leukocytes and polymorphonuclear percentage were also assessed.The training cohort ultimately included 134 samples, 34 of which with infection (25.4% [17.6–33.1]). Samples with a MUL+DO value greater than 1 presented a sensitivity and specificity of 100%. The validation cohort included 100 samples with 16 infections (16% [8.3–23.7]).Assuming a sample with a MUL+DO value greater than 1 to be positive, we obtained a sensitivity of 100% and a specificity of 95.2%.The MUL+DO index applied to the training cohort showed a perfect separation of the positive and negative populations. All positive patients presented a score ≥2. In the validation cohort, the MUL+DO reported a sensitivity of 100% and a specificity of 95.2%. Resumen: La infección peritoneal es un problema frecuente que afecta negativamente a la supervivencia del paciente y de la técnica. El inicio rápido del tratamiento de la infección peritoneal reduce las complicaciones.Se busca diseñar un índice multicomponente (MUL+DO) para el diagnóstico rápido y eficiente de infección peritoneal.Con ese objetivo, se crea una cohorte de construcción con muestras de efluente peritoneal que se analizaron con tiras Multistix ® 10 SG Siemens para la detección de leucocitos. Después, se examinó cada muestra según el patrón oro: número de leucocitos, porcentaje de polimorfonucleares y cultivo microbiológico. Se construyó MUL+DO sumándole un punto a la escala cromática modificada MULTISTIX [0-1-2-3] si el paciente reporta dolor. MUL+DO toma valores de 0 a 4. Posteriormente, se creó una cohorte de validación del modelo. MUL+DO se aplicó a cada muestra, determinándose también leucocitos y porcentaje de polimorfonucleares.La cohorte de construcción incluyó 134 muestras, 34 tenían infección (25,4% [17,6–33,1]). Las muestras con un valor MUL+DO >1, presentaron una sensibilidad y especificidad del 100%. La cohorte de validación incluyó 100 muestras con 16 infecciones (16% [8,3-23,7]).En la cohorte de validación asumiendo como positiva una muestra con un valor MUL+DO > 1, se obtuvo una sensibilidad del 100% y una especificidad del 95,2%.MUL+DO aplicado en la cohorte de construcción, mostró una separación perfecta de las poblaciones positiva y negativa. Todos los pacientes positivos presentaron una puntuación ≥2. En la cohorte de validación, el índice MUL+DO presentó una sensibilidad del 100% y una especificidad del 95,2%. Keywords: Peritoneal dialysis, Peritonitis, Urine test strip, Diagnosis, Palabras clave: Diálisis peritoneal, Peritonitis, Tiras test de orina, Diagnóstico

The early life gut microbiota has been reported to be involved in neonatal weight gain and later infant growth. Therefore, this early microbiota may constitute a target for the promotion of healthy neonatal growth and development with potential consequences for later life. Unfortunately, we are still far from understanding the association between neonatal microbiota and weight gain and growth. In this context, we evaluated the relationship between early microbiota and weight in a cohort of full-term infants. The absolute levels of specific fecal microorganisms were determined in 88 vaginally delivered and 36 C-section-delivered full-term newborns at 1 month of age and their growth up to 12 months of age. We observed statistically significant associations between the levels of some early life gut microbes and infant weight gain during the first year of life. Classifying the infants into tertiles according to their Staphylococcus levels at 1 month of age allowed us to observe a significantly lower weight at 12 months of life in the C-section-delivered infants from the highest tertile. Univariate and multivariate models pointed out associations between the levels of some fecal microorganisms at 1 month of age and weight gain at 6 and 12 months. Interestingly, these associations were different in vaginally and C-section-delivered babies. A significant direct association between Staphylococcus and weight gain at 1 month of life was observed in vaginally delivered babies, whereas in C-section-delivered infants, lower Bacteroides levels at 1 month were associated with higher later weight gain (at 6 and 12 months). Our results indicate an association between the gut microbiota and weight gain in early life and highlight potential microbial predictors for later weight gain.

Anti-CMV (cytomegalovirus) antibody titers are related to immune alterations and increased risk of mortality. To test whether they represent a marker of infection history, we analyzed the effect of viral reactivations on the production of specific antibodies in kidney transplant patients. We quantified CMV-DNAemia and antibody titers in 58 kidney transplant patients before transplantation and during a follow-up of 315 days (standard deviation, SD: 134.5 days). In order to calculate the intensity of the infection, we plotted the follow-up time of the infection on the x-axis and the number of DNA-CMV copies on the y-axis and calculated the area under the curve (CMV-AUC). The degree of T-lymphocyte differentiation was analyzed with flow cytometry, the cells were labelled with different monoclonal antibodies in order to distinguish their differentiation state, from naive T-cells to senescent T-cells. Peak viremia was significantly higher in patients experiencing a primary infection (VI) compared to patients experiencing viral reactivation (VR). Our data indicate that the overall CMV viral load over the course of a primary infection is significantly higher than in a reactivation of a previously established infection. Whereas patients who experienced an episode of CMV reactivation during the course of our observation showed increased levels of CMV-specific antibodies, patients who did not experience CMV reactivation (WVR) showed a drop in CMV antibody levels that corresponds to an overall drop in antibody levels, probably due to the continuing immunosuppression after the renal transplant. We found a positive correlation between the CMV viremia over the course of the infection or reactivation and the CMV-specific antibody titers in the examined patients. We also observed a positive correlation between anti-CMV titers and T-cell differentiation. In conclusion, our data show that anti-CMV antibody titers are related to the course of CMV infection in kidney transplant patients.

Objectives: Dientamoeba fragilis is a pathogenic protozoan of the human gastrointestinal tract with a worldwide distribution, which has emerged as an important and misdiagnosed cause of chronic gastrointestinal illnesses such as diarrhea and ‘irritable-bowel-like’ gastrointestinal disease. Very little research has been conducted on the use of suitable antimicrobial compounds. Furthermore, higher rates of co-infection with Enterobius vermicularis have been described, suggesting that E. vermicularis could influence the treatment of D. fragilis-infected patients. To study this, the treatment of E. vermicularis and D. fragilis co-infected patients was evaluated. Methods: Forty-nine patients with a D. fragilis infection, including 25 (51.0%) patients co-infected with E. vermicularis, were studied. All of them were treated with metronidazole. Patients with E. vermicularis co-infection and/or an E. vermicularis-positive case in the family were treated with mebendazole. Results: Metronidazole treatment failure was significantly more frequent in patients with E. vermicularis co-infection and in patients with children in the family. Conclusions: Co-infection with E. vermicularis may act as a factor favoring D. fragilis infection by preventing eradication measures. This suggests that both parasites should be treated simultaneously.

The Cramér-von Mises criterion is employed to compare whether the marginal distribution functions of a k-dimensional random variable are equal or not. The well-known Donsker invariance principle and the Karhunen-Loéve expansion is used in order to derive its asymptotic distribution. Two different resampling plans (one based on permutations and the other one based on the general bootstrap algorithm, gBA) are also considered to approximate its distribution. The practical behaviour of the proposed test is studied from a Monte Carlo simulation study. The statistical power of the test based on the Cramér-von Mises criterion is competitive when the underlying distributions are different in location and is clearly better than the Friedman one when the sole difference among the involved distributions is the spread or the shape. Both resampling plans lead to similar results although the gBA avoids the usual required interchangeability assumption. Finally, the method is applied on the study of the evolution inequality incomes distribution between some European countries along the years 2000 and 2011.

OBJECTIVE: to assess whether 25hydroxivitaminD or 25(OH)vitD deficiency has a high prevalence at pediatric intensive care unit (PICU) admission, and whether it is associated with increased prediction of mortality risk scores. METHOD: prospective observational study comparing 25(OH)vitD levels measured in 156 patients during the 12 hours after critical care admission with the 25(OH)vitD levels of 289 healthy children. 25(OH)vitD levels were also compared between PICU patients with pediatric risk of mortality III (PRISM III) or pediatric index of mortality 2 (PIM 2) > p75 [(group A; n = 33) vs. the others (group B; n = 123)]. Vitamin D deficiency was defined as < 20 ng/mL levels. RESULTS: median (p25-p75) 25(OH)vitD level was 26.0 ng/mL (19.2-35.8) in PICU patients vs. 30.5 ng/mL (23.2-38.6) in healthy children (p = 0.007). The prevalence of 25(OH)vitD < 20 ng/mL was 29.5% (95% CI: 22.0-37.0) vs. 15.6% (95% CI: 12.2-20.0) (p = 0.01). Pediatric intensive care patients presented an odds ratio (OR) for hypovitaminosis D of 2.26 (CI 95%: 1.41-3.61). 25(OH)vitD levels were 25.4 ng/mL (CI 95%: 15.5-36.0) in group A vs. 26.6 ng/mL (CI 95%: 19.3-35.5) in group B (p = 0.800). CONCLUSIONS: hypovitaminosis D incidence was high in PICU patients. Hypovitaminosis D was not associated with higher prediction of risk mortality scores.

Probably, one of the most useful criterions in order to compare distribution functions is the one introduced by the researchers Harald Cramér and Richard Edler von Mises which is known as Cramérvon Mises criterion $(C_M)$. It has been applied on a vast variety of problems. In this work, the theory of empirical processes is applied in order to obtain the asymptotic distribution for the generalization to the k-sample problem of $(C_M)$ proposed by Kiefer. The quality of this approximation is also studied and some indications about how to obtain an approximation to the final P-value are also included.

Objective: To estimate the incidence and 28-day and 5-year survival rates after a first acute myocardial infarction (AMI) in relation to socioeconomic status in the Basque Country (Spain) between 1999 and 2000. Methods: Data from a population-based registry of AMI were used. The study included 3,619 patients to calculate age-standardized incidence by the direct method and 2,003 patients (out-of-hospital deaths were excluded) to calculate observed and relative survival using the Kaplan-Meier and Hakulinen methods, respectively. Socioeconomic status was quantified using a deprivation index ecologically assigned to each patient according to the census tract of residence at diagnosis of AMI and was categorized into quintiles. Results: Among men, the risk of AMI was higher in the lowest socioeconomic group than in the highest socioeconomic group (RR=1.17; 95%CI: 1.02-1.34). In men, a higher risk of death was observed in the middle (Q3; HR=1.60; 95%CI: 1.02-2.51) and low (Q5; HR=1.65; 95%CI: 1.02-2.69) quintiles compared with the least deprived group for age-adjusted survival during the acute phase. In the fully adjusted model, this effect was attenuated and no significant differences were observed in long-term survival. Among women, no significant differences were observed either in incidence or in short- and long-term survival. Conclusions: Socioeconomic inequalities were only observed in men in incidence and in survival during the acute phase after an AMI.Objetivo: Estimar la incidencia y la supervivencia a 28 días y 5 años tras un primer infarto agudo de miocardio (IAM) según la posición socioeconómica en el País Vasco entre 1999 y 2000. Métodos: Utilizando datos de un registro poblacional de IAM se incluyeron 3.619 pacientes para estimar la incidencia ajustada por edad por el método directo, y 2003 (excluidas las muertes extrahopitalarias) para la supervivencia observada y relativa con el método de Kaplan-Meier y el de Hakulinen, respectivamente. El nivel socioeconómico se definió por un índice de privación ecológicamente asignado a cada paciente según la sección censal de residencia al diagnóstico del IAM, y se categorizó en quintiles. Resultados: Los hombres del nivel socioeconómico más bajo tuvieron un mayor riesgo de IAM que los del más alto (RR=1,17; IC95%: 1,02-1,34). En la supervivencia en la fase aguda ajustada por edad, los hombres de los quintiles medio (Q3; HR=1,60; IC95%: 1,02-2,51) y bajo (Q5; HR=1,65; IC95%: 1,02-2,69) presentaron un mayor riesgo de muerte en comparación con el grupo más favorecido. Este efecto se vio atenuado en los modelos completamente ajustados, y no hubo diferencias significativas en la supervivencia a largo plazo. En la mujeres no se hallaron diferencias significativas en la incidencia ni en la supervivencia a corto y largo plazo. Conclusiones: Sólo se han observado desigualdades socioeconómicas en los hombres en la incidencia y la supervivencia durante la fase aguda.

The study of diagnostic tests is a hot topic which has direct applications in biomedical sciences. Despite of the relevance, in a diagnostic process, of the threshold (or cutoff point) employed on the decision taken by the physician, the study and comparison of the accuracy among different diagnostic criterions has been the main field of study. In this paper, the authors are interested in the study of the involved cutoff point estimation in diagnostic tests with weighted errors. With this goal, a nonparametric smoothed utility function estimator is considered. The bootstrap and the asymptotic distributions for the related M-estimator are derived. Finally, the obtained results are applied to study the Procalcitonin level which determines whether a child within the Pediatric Intensive Care Unit (UCIP) has a virical sepsis.El estudio de tests diagnósticos es un tema candente con aplicaciones directas en las ciencias biomédicas. Aunque en la práctica, a la hora de tomar una decisión, los clínicos deben fijar un valor umbral (o punto de corte) a pesar de la relevancia que este valor tiene, el estudio y la comparación de la calidad entre diferentes criterios diagnósticos ha sido el principal campo de estudio. En este trabajo, los autores están interesados en el estudio de la estimación del punto de corte involucrado en un test diagnóstico con errores ponderados. Con este objetivo, se considera un estimador suavizado para una función de utilidad. Se estudian las distribuciones bootstrap y asintóticas del M-estimador resultante. Finalmente, los resultados obtenidos son aplicados al estudio de los niveles de Procalcitonina que determinan si un niño ingresado en la Unidad de Cuidados Intensivos Pediátricos (UCIP) tiene infección vírica.

In this paper, an algorithm for the automatic selection of an ad- equate test for the survival curves comparison is developed. The introduced procedure is an adaptation of the double minimum algo- rithm for the bandwidth selection in the smoothed nonparametric k-sample tests. The simulation study which was carried out, sug- gests us that the proposed method, although never is as good as the best one of the considered tests, is the most regular of them.

In this paper we deal with the distribution of the Gini Concentration Index (G). We derive its exact sample distribution which is useful only for small sample sizes and basing on the classic results for L-statistics of Egorov and Nevronov we prove the asymptotic normality for G from an original and probabilistic way. Keywords: Gini Index, Exact Distribution, L-Statistics.

Objetivo: Analizar el tiempo de supervivencia libre de enfermedad y la supervivencia relativa en mujeres diagnosticadas de cáncer de mama en la provincia de Gipuzkoa en un contexto de riesgos competitivos, valorando las diferencias encontradas entre el uso directo del estimador de Kaplan-Meier y el método de decrementos múltiples por un lado y la supervivencia relativa por otro. Métodos: Se consideraron todos los casos de cáncer de mama registrados en la provincia de Gipuzkoa durante los años 1995 y 1996 en estadio distinto del IV, y se hizo un seguimiento de 8 años para la recidiva y de 10 años para la supervivencia. Se analizó el tiempo de supervivencia libre de enfermedad mediante el método de decrementos múltiples. Asimismo, también se analizó el tiempo de supervivencia observado y corregido por la mortalidad esperada de la población, conocido como supervivencia relativa. Resultados: La estimación de la probabilidad de recidiva a los 8 años por el método de decrementos múltiples es un 8,8% inferior a la obtenida por el método de Kaplan-Meier. La diferencia entre la supervivencia observada y la relativa a los 10 años es del 10,8%. Ambos resultados indican que, en este caso, el método de Kaplan-Meier sobrestima tanto la probabilidad de recaída como la de muerte por la enfermedad. Conclusiones: Dos cuestiones que muchas veces se obvian al realizar un análisis de supervivencia son, por un lado, que la no independencia entre el tiempo de supervivencia y el tiempo de censura hacen no interpretables los resultados obtenidos por el estimador de Kaplan-Meier, y por otro el hecho, hasta hora incuestionable, de que de una manera u otra todos causamos fallo y, desde este planteamiento, en el estudio del tiempo de supervivencia hay que tener presente la probabilidad de fallo en la población general de referencia. En los resultados obtenidos se observa que utilizar de manera superficial el estimador de Kaplan-Meier comporta una sobrestimación tanto de la probabilidad de recidiva como de la mortalidad debida a la enfermedad.Objective: To analyze time of disease-free survival and relative survival in women diagnosed with breast cancer in the province of Gipuzkoa within the context of competing risks by assessing differences between the direct use of the Kaplan-Meier estimator and the multiple decrement method on the one hand, and relative survival on the other. Methods: All registered breast cancer cases in Gipuzkoa in 1995 and 1996 with stages other than stage IV were included. An 8-year follow-up for recurrence and a 10-year follow-up for survival were performed. Time of disease-free survival was studied by the multiple decrement model. Observed survival and survival corrected by the expected mortality in the population (relative survival) were also studied. Results: Estimation of the probability of recurrence at 8 years with the multiple decrement method was 8.8% lower than that obtained with the Kaplan-Meier method. The difference between the observed and relative survival rates at 10 years was 10.8%. Both results show how, in this case, the Kaplan-Meier estimator overestimates both the probability of recurrence and that of mortality from the disease. Conclusions: Two issues are often overlooked when performing survival analyses: firstly, because of the lack of independence between survival time and censoring time, the results obtained by the Kaplan-Meier estimator are uninterpretable; secondly, it is an incontrovertible fact that one way or another, everyone causes failures. In this approach, survival analyses must take into account the probability of failure in the general population of reference. The results obtained in this study show that superficial use of the Kaplan Meier estimator overestimates both the probability of recurrence and that of mortality caused by the disease.

In this paper a Chernoff type theorem for the L1 distance between kernel estimators from two independent and identically distributed random samples is developed. The harmonic mean is used to correct the distance for inequal sample sizes case. Moreover, the proved result is used to compute the Bahadur slope of a test based on L1 distance and to compare it with the classical nonparametric Mann-Whitney test by using the Bahadur relative efficiency.En este trabajo se desarrolla un teorema de tipo Chernoff para la distancia L1 entre estimadores núcleo procedentes de muestras aleatorias independientes e idénticamente distribuidas. Se usa la media armónica para corregir esta distancia en el caso de muestras de distintos tamaños. Además, se usa el resultado demostrado para el cálculo de la pendiente de Bahadur de un test para la comparación de densidades basado en la distancia L1 y se compara con el clásico test de Mann-Whitney a partir de la eficiencia relativa de Bahadur.

Una de las principales limitaciones de las técnicas de suavizamiento es la necesidad de elegir un parámetro de suavizado o ventana. La influencia de este parámetro sobre los resultados obtenidos obliga a que el uso de estos métodos en inferencia sea delicado, ya que la decisión final puede verse determinada por la elección del parámetro. El objetivo principal de este trabajo es el estudio de algunos algoritmos para el cálculo automático del parámetro ventana en problemas de contrastes de hipótesis para la igualdad de k poblaciones independientes.

Este trabajo estudia las ventajas y limitaciones de un test para contrastar la igualdad de las distribuciones de origen de k-muestras independientes. El estadístico propuesto, denominado LGk, está basado en una medida que generaliza la norma L1 entre funciones de densidad y que permite comparar simultáneamente k densidades. Desde esta medida y a partir de la estimación kernel, se desarrolla un test para contrastes de igualdad entre k poblaciones independientes (LGk). A partir de un "amplio" estudio de simulación, se estudia la potencia del test propuesto y se compara con algunos de los test no paramétricos ya existentes, considerando ocho estadísticos diferentes. También se analiza el tema de la elección del tamaño del parámetro ventana y se realizan algunas propuestas relativas a este problema.

Se aborda el problema de comparar el poder de clasificación de métodos diferentes a partir de la curva ROC. Por un lado, se propone un método de comparación basado en la medida del supremo y, por otro, una solución al problema de comparar más de dos pruebas diagnósticas a través del área bajo la curva ROC (AUC) a partir de sus propiedades asintóticas. También se comprueba la validez de los estimadores propuestos para muestras pequeñas a partir del método bootstrap. Finalmente, se aplican los métodos propuestos en la predicción de diagnósticos sépticos (infecciosos) en pacientes admitidos en la Unidad de Cuidados Intensivos Pediátricos (UCIP) del Hospital Central de Asturias.

The Hungarian Construction (Komlós et al. 1975) is used for getting a proof of asymptotic normality of S-Gini coefficient; this method is very interesting because it can be used to check asymptotic normality of other income inequality measures as Theil coefficient. Besides, explicit expressions of asymptotic means and variances are given for S-Gini and Theil estimators. Finally, to illustrate the performance of obtained results, we carry out a simulation study comparing the asymptotic and Smoothed Bootstrap approximations.Se usa el Proceso Húngaro (Komlós et al. 1975) para derivar la normalidad asintótica del S-Gini; Este método es muy interesante ya que puede ser usado para demostrar la normalidad asintótica de otros coeficientes usados para medir la desigualdad de ingresos como el de Theil. Se consiguen expresiones explícitas para la media y la varianza del S-Gini y del coeficiente de Theil. Finalmente, se realiza un estudio de simulación, en el que se compara el rendimiento de la aproximación asintótica propuesta y del método Bootstrap Suavizado.

Co-signaling molecules are responsible for full T-cell activation after solid organ transplantation. Their increased expression can lead to the release of a soluble form that can modulate the immune response post-transplantation. We analyzed the presence of co-signaling molecules (sCD30, sCD40, sCD137, sCTLA-4, sCD80, sCD28, sCD40L, sPD-1, and sPD-L1) in serum from kidney-transplanted patients (n = 59) obtained at different times (before transplantation, and 15 days, 3 months and 1 year post-transplantation) and their contribution to graft outcome was evaluated using principal component analysis. Before transplantation, high levels of soluble co-signaling molecules (mainly sCD30, sCD137 and sCD40) were detected in all patients. These molecules were modulated soon after receiving an allograft but never attained similar levels to those of healthy controls. A signature based on the determination of six soluble co-stimulatory (sCD30, sCD40, sCD137 and sCD40L) and co-inhibitory (sPD-1 and sPD-L1) molecules at 3 months post-transplantation allowed a group of patients to be identified (27.12%) with a worse long-term graft outcome. Patients with high levels of soluble molecules showed a progressive and gradual deterioration of kidney function (increased creatinine and proteinuria levels and decreased estimated glomerular filtration rate) over time and a higher risk of graft loss at 6 years post-transplantation than patients with low levels of these molecules (62.55% versus 5.14%, p

The aim of this study was to analyse the distribution of KIR haplotypes and the KIR2DL2/3 alleles in chronic HCV-infected patients in order to establish the influence on the response to pegylated interferon plus ribavirin classical treatment. The alleles study of previously associated KIR2DL2/3 showed that KIR2DL2*001 was more frequent in non-SVR (NSVR) (42.2% vs. 27.5%, p

Epigenetic deregulation is considered a common hallmark of cancer. Nevertheless, recent publications have demonstrated its association with a large array of human diseases. Here, we explore the DNA methylation dynamics in blood samples during hematopoietic cell transplant and how they are affected by pathophysiological events during transplant evolution. We analyzed global DNA methylation in a cohort of 47 patients with allogenic transplant up to 12 months post-transplant. Recipients stably maintained the donor's global methylation levels after transplant. Nonetheless, global methylation is affected by chimerism status. Methylation analysis of promoters revealed that methylation in more than 200 genes is altered 1 month post-transplant when compared with non-pathological methylation levels in the donor. This number decreased by 6 months post-transplant. Finally, we analyzed methylation in IFN-γ, FASL, IL-10, and PRF1 and found association with the severity of the acute graft-versus-host disease. Our results provide strong evidence that methylation changes in blood are linked to underlying physiological events and demonstrate that DNA methylation analysis is a viable strategy for the study of transplantation and for development of biomarkers.

Considering that hyperhomocysteinemia is an independent risk factor for cardiovascular disease, the purpose of this study was to determine the kinetics of serum homocysteine (tHcy) and the vitamins involved in its metabolism (folates, B(12), and B(6)) in response to acute exercise at different intensities. Eight sedentary males (18-27 yr) took part in the study. Subjects were required to complete two isocaloric (400 kcal) acute exercise trials on separate occasions at 40% (low intensity, LI) and 80% VO(2peak) (high intensity, HI). Blood samples were drawn at different points before (pre4 and pre0 h), during (exer10, exer20, exer30, exer45, and exer60 min), and after exercise (post0, post3, and post19 h). Dietary, genetic, and lifestyle factors were controlled. Maximum tHcy occurred during exercise, both at LI (8.6 (8.0-10.1) µmol/L, 9.3% increase from pre0) and HI (9.4 (8.2-10.6) µmol/L, 25.7% increase from pre0), coinciding with an accumulated energy expenditure independent of the exercise intensity. From this point onwards tHcy declined until the cessation of exercise and continued descending. At post19, tHcy was not different from pre-exercise values. No values of hyperhomocysteinemia were observed at any sampling point and intensity. In conclusion, acute exercise in sedentary individuals, even at HI, shows no negative effect on tHcy when at least 400 kcal are spent during exercise and the nutritional status for folate, B(12), and B(6) is adequate, since no hyperhomocysteinemia has been observed and basal concentrations were recovered in less than 24 h. This could be relevant for further informing healthy exercise recommendations.

Aims: To determine risk factors for active tuberculosis in patients with inflammatory bowel diseases. Methods: Retrospective, case-control study at 4 referral hospitals in Spain. Cases developed tuberculosis after a diagnosis of inflammatory bowel disease. Controls were inflammatory bowel disease patients who did not develop tuberculosis. For each case, we randomly selected 3 controls matched for sex, age (within 5 years) and time of inflammatory bowel disease diagnosis (within 3 years). Inflammatory bowel disease characteristics, candidate risk factors for tuberculosis and information about the tuberculosis episode were recorded. Multivariate analysis and a Chi-squared automatic interaction detector were used. Results: Thirty-four cases and 102 controls were included. Nine of the 34 cases developed active tuberculosis between 1989 and 1999, and 25 became ill between 2000 and 2012. Multivariate regression showed an association between active tuberculosis and anti-TNF (tumor necrosis factor) therapy in the previous 12 months (OR 7.45; 95% CI, 2.39-23.12; p = 0.001); hospitalization in the previous 6 months (OR 4.38; 95% CI, 1.18-16.20; p = 0.027); and albumin levels (OR 0.88; 95% CI, 0.81-0.95; p = 0.001). The median time between the start of biologic therapy and the onset of active tuberculosis was 13 (interquartile range, 1-58) months. Tuberculosis developed after a year of anti-TNF therapy in 53%, and late reactivation occurred in at least 3 of 8 patients. Conclusions: The main risks factors for developing tuberculosis were anti-TNF therapy and hospitalization. Over half the cases related to anti-TNF treatment occurred after a year.