Asthma Exacerbations: The Genes Behind the Scenes.

The clinical and socioeconomic burden of asthma exacerbations (AEs) constitutes a major public health problem. In the last 4 years, there has been an increase in ethnic diversity in candidate-gene and genome-wide association studies of AEs, which in the latter case led to the identification of novel genes and underlying pathobiological processes. Pharmacogenomics, admixture mapping analyses, and the combination of multiple "omics" layers have helped to prioritize genomic regions of interest and/or facilitated our understanding of the functional consequences of genetic variation. Nevertheless, the field still lags behind the genomics of asthma, where a vast compendium of genetic approaches has been used (eg, gene-environment nteractions, next-generation sequencing, and polygenic risk scores). Furthermore, the roles of the DNA methylome and histone modifications in AEs have received little attention, and microRNA findings remain to be validated in independent studies. Likewise, the most recent transcriptomic studies highlight the importance of the host-airway microbiome interaction in the modulation of risk of AEs. Leveraging -omics and deep-phenotyping data from subtypes or homogenous subgroups of patients will be crucial if we are to overcome the inherent heterogeneity of AEs, boost the identification of potential therapeutic targets, and implement precision medicine approaches to AEs in clinical practice.

Asthma Exacerbations: The Genes Behind the Scenes

The clinical and socioeconomic burden of asthma exacerbations (AEs) constitutes a major public health problem. In the last 4 years, there has been an increase in ethnic diversity in candidate-gene and genome-wide association studies of AEs, which in the latter case led to the identification of novel genes and underlying pathobiological processes. Pharmacogenomics, admixture mapping analyses, and the combination of multiple “omics” layers have helped to prioritize genomic regions of interest and/or facilitated our understanding of the functional consequences of genetic variation. Nevertheless, the field still lags behind the genomics of asthma, where a vast compendium of genetic approaches has been used (eg, gene–environment interactions, next-generation sequencing, and polygenic risk scores). Furthermore, the roles of the DNA methylome and histone modifications in AEs have received little attention, and microRNA findings remain to be validated in independent studies. Likewise, the most recent transcriptomic studies highlight the importance of the host–airway microbiome interaction in the modulation of risk of AEs. Leveraging -omics and deep-phenotyping data from subtypes or homogenous subgroups of patients will be crucial if we are to overcome the inherent heterogeneity of AEs, boost the identification of potential therapeutic targets, and implement precision medicine approaches to AEs in clinical practice (AU)

La carga clínica y socioeconómica de las exacerbaciones asmáticas (EA) representa un importante problema de salud pública. En los últimos cuatro años, ha aumentado la diversidad étnica en los estudios de asociación de genes candidatos y del genoma completo (GWAS) de las EA, lo que, en este último caso, ha llevado a la identificación de nuevos genes y procesos fisiopatológicos subyacentes. La farmacogenómica, los análisis de mapeo por mezcla y la combinación de múltiples capas "ómicas" han contribuido a priorizar regiones genómicas de interés y/o comprender las consecuencias funcionales de la variación genética. A pesar de esto, el campo todavía está en desarrollo en comparación con la genómica del asma, donde se ha utilizado un amplio compendio de enfoques genéticos (por ejemplo: interacciones gen-ambiente, secuenciación de nueva generación o puntuaciones de riesgo poligénico). Además, el papel de la metilación del ADN y las modificaciones de las histonas en las EA se ha explorado escasamente, y los hallazgos relacionados con los microARNs aún no se han validado en estudios independientes. Asimismo, los estudios transcriptómicos más recientes destacan la importancia de la interacción entre el microbioma de las vías respiratorias y el huésped en la modulación del riesgo de las EA. La integración de datos ómicos y de fenotipado profundo de subtipos o subgrupos homogéneos de pacientes será crucial para superar la heterogeneidad inherente de las EA e impulsar la identificación de dianas terapéuticas potenciales y la implementación de la medicina de precisión para las EA en la práctica clínica (AU)

Health-related quality of life of X-linked hypophosphatemia in Spain.

BACKGROUND: Health-related quality of life (HRQoL) of patients with X-linked hypophosphatemia (XLH) is lower than that of both the general population and the patients with other chronic diseases, mainly due to diagnostic delay, treatment difficulties, poor psychosocial support, and problems with social integration. Early diagnosis and optimal treatment are paramount to control the disease in patients with XLH, avoid complications, and maintain or improve their HRQoL. We, therefore, analyzed the HRQoL of pediatric and adult patients with XLH treated with conventional therapy in Spain. RESULTS: We used several versions of the EuroQol-5 dimensions (EQ-5D) instrument according to the age of patients with XLH. Then we compared the HRQoL of patients to that of the general Spanish population. Children with XLH (n = 21) had moderate problems in walking about (61.9%), washing or dressing themselves (9.52%), and performing their usual activities (33.33%). They also felt moderate pain or discomfort (61.9%) and were moderately anxious or depressed (23.81%). Adults with XLH (n = 29) had lower HRQoL, with problems in walking (93%, with 3.45% unable to walk independently), some level of pain (86%, with 3.45% experiencing extreme pain), problems with their usual activities (80%) and self-care (> 50%), and reported symptoms of anxiety and/or depression (65%). There were important differences with the general Spanish population. CONCLUSIONS: XLH impacts negatively on physical functioning and HRQoL of patients. In Spanish patients with XLH, the HRQoL was reduced despite conventional treatment, clearly indicating the need to improve the therapeutic approach to this disorder.

X-linked hypophosphatemia (XLH) is a severe inherited disease. It is caused by loss of phosphorus by kidneys. As a result, blood level of phosphorus is low, affectingX-linked hypophosphatemia (XLH) is a severe inherited disease. It is caused by loss of phosphorus by kidneys. As a result, blood level of phosphorus is low, affecting bones and muscles. Patients can have growth retardation, short stature, rickets, limb deformities, pain and other health problems despite traditional treatment. Consequently, their quality of life can be very bad. However, a recently available new treatment (burosumab) can improve this quality of life. We studied the quality of life of children and adults with XLH treated with traditional treatment in Spain. Results showed that children had moderate problems, but adults reported moderate-to-severe problems in walking and performing their usual activities and self-care. Pain and anxiety and/or depression were very frequent. There were important differences with the general Spanish population. Moreover, we also found that XLH is associated to high healthcare cost and even higher socioeconomic cost. Our results highlight the need of improving the treatment of XLH.bones and muscles. Patients can have growth retardation, short stature, rickets, limb deformities, pain and other health problems despite traditional treatment. Consequently, their quality of life can be very bad. However, a recently available new treatment (burosumab) can improve this quality of life. We studied the quality of life of children and adults with XLH treated with traditional treatment in Spain. Results showed that children had moderate problems, but adults reported moderate-to-severe problems in walking and performing their usual activities and self-care. Pain and anxiety and/or depression were very frequent. There were important differences with the general Spanish population. Moreover, we also found that XLH is associated to high healthcare cost and even higher socioeconomic cost. Our results highlight the need of improving the treatment of XLH.

Survival after antireflux surgery versus medication in patients with reflux oesophagitis or Barrett's oesophagus: multinational cohort study.

BACKGROUND: The aim was to examine the hypothesis that antireflux surgery with fundoplication improves long-term survival compared with antireflux medication in patients with reflux oesophagitis or Barrett's oesophagus. METHOD: Individuals aged between 18 and 70 years with reflux oesophagitis or Barrett's oesophagus (intestinal metaplasia) documented from in-hospital and specialized outpatient care were selected from national patient registries in Denmark, Finland, Iceland, and Sweden from 1980 to 2014. The study investigated all-cause mortality and disease-specific mortality, comparing patients who had undergone open or laparoscopic antireflux surgery with fundoplication versus those using antireflux medication. Multivariable Cox regression analysis was used to estimate hazard ratios (HRs) with 95 per cent confidence intervals for all-cause mortality and disease-specific mortality, adjusted for sex, age, calendar period, country, and co-morbidity. RESULTS: Some 240 226 patients with reflux oesophagitis or Barrett's oesophagus were included, of whom 33 904 (14.1 per cent) underwent antireflux surgery. The risk of all-cause mortality was lower after antireflux surgery than with use of medication (HR 0.61, 95 per cent c.i. 0.58 to 0.63), and lower after laparoscopic (HR 0.56, 0.52 to 0.60) than open (HR 0.80, 0.70 to 0.91) surgery. After antireflux surgery, mortality was decreased from cardiovascular disease (HR 0.58, 0.55 to 0.61), respiratory disease (HR 0.62, 0.57 to 0.66), laryngeal or pharyngeal cancer (HR 0.35, 0.19 to 0.65), and lung cancer (HR 0.67, 0.58 to 0.80), but not from oesophageal cancer (HR 1.05, 0.87 to 1.28), compared with medication, The decreased mortality rates generally remained over time. CONCLUSION: In patients with reflux oesophagitis or Barrett's oesophagus, antireflux surgery is associated with lower mortality from all causes, cardiovascular disease, respiratory disease, laryngeal or pharyngeal cancer, and lung cancer, but not from oesophageal cancer, compared with antireflux medication.

Usefulness of basic renal function tests in the management of hydronephrosis. / Utilidad de las pruebas básicas de función renal en el manejo de la hidronefrosis.

OBJECTIVE: Nowadays, the algorithms for the study of hydronephrosis in children include voiding cystourethrogram (VCUG) and diuretic renogram (DR) in all patients. Both are invasive, distressing, and associated with radiation risk. However, basic renal function tests (bRFTs) are not included. This study was designed to determine whether bRFTs may help avoid VCUG and/or DR in some children. METHODS: Retrospective review of hydronephrosis (≥20 mm renal pelvis) patient records over one year (n = 38) (pyeloureteral stenosis (PUS) n = 12; high-grade vesicoureteral reflux (VUR) n = 8; non-obstructive hydronephrosis (NOH) n = 18. Data from the three protocolized bRFTs (maximum urine osmolality after DDAVP (UOsm), albumin/creatinine ratio (Alb/Cr), and NAG/creatinine ratio (NAG/Cr), together with VCUG and DR, were analyzed. RESULTS: 38 hydronephrosis patients (pyeloureteral stenosis (PUS) n = 12; high grade vesicoureteral reflux (VUR) n = 8; non-obstructive hydronephrosis (NOH) n = 18. UOsm was decreased in 100% of VUR patients, 75% of PUS patients, and 16.7% of NOH patients. Alb/Cr ratio was increased in 62.5% of VUR patients, 8.3% of PUS patients, and 11.1% of NOH patients. NAG/Cr ratio was increased in 42.8% of VUR patients, 25% of PUS patients, and 6.7% of NOH patients. UOsm was decreased in most patients who required surgery (100% of VUR patients and 74% of PUS patients), but only in 11.1% of patients who did not (NOH group). CONCLUSIONS: These results suggest that bRFTs may be useful in delaying or avoiding VCUG in some hydronephrosis cases. UOsm is the most sensitive test. No child with (high grade) VUR had a normal UOsm. VCUG could have been avoided in 43% of our patients -with a normal UOsm- without missing any high grade VUR.

OBJETIVO: Actualmente, los algoritmos para estudiar hidronefrosis en niños, incluyen realizar cistografía miccional (CUMS) y renograma diurético (RD) a todos. Ambos son invasivos, molestos, y con riesgo de radiación. Contrariamente, las pruebas básicas de función renal (PFRb), no están incluidas. Este estudio se realizó para saber si las PFRb, pueden ayudarnos a evitar alguna CUMS y/o RD. METODOS: Análisis retrospectivo de todas las historias de niños con hidronefrosis (pelvis renal ≥20 mm) atendidos durante un año (n=38), [estenosis pieloureteral (EPU) n = 12; reflujo vesicoureteral (RVU) de alto grado n = 8; hidronefrosis no obstructiva (HNO) n = 18]. Analizamos las tres PFRb protocolizadas [osmolalidad urinaria máxima tras DDAVP (UOsm), albúmina/creatinina (Alb/Cr) y NAG/creatinina (NAG/Cr)], junto con CUMS y RD. RESULTADOS: UOsm estaba disminuida en 100% RVU, 75% EPU, 16,7% HNO. Alb/Cr estaba aumentado en 62,5% RVU, 8,3% EPU, 11,1% HNO. NAG/Cr estaba aumentado en 42,8% RVU, 25% EPU, 6,7% HNO. En relación a la necesidad de cirugía, UOsm estaba disminuida en la mayoría de pacientes intervenidos (100% con RVU y 74% con EPU), mientras solo en el 11% de pacientes sin cirugía (HNO). CONCLUSION: Estos resultados sugieren que las PFRb pueden ser útiles para retrasar o evitar CUMS en algunos niños con hidronefrosis. La UOsm es la PFRb más sensible. Ningún niño con RVU (de alto grado) mostró una UOsm normal. Se podrían haber evitado CUMS en el 43% de nuestros pacientes, con UOsm normal, sin haber perdido ningún diagnóstico de VUR (de alto grado).

Risk of cardiovascular involvement in pediatric patients with X-linked hypophosphatemia.

OBJECTIVE: To find out if cardiovascular alterations are present in pediatric patients with X-linked hypophosphatemia (XLH). STUDY DESIGN: Multicentre prospective clinical study on pediatric patients included in the RenalTube database ( www.renaltube.com ) with genetically confirmed diagnosis of XLH by mutations in the PHEX gene. The study's protocol consisted of biochemical work-up, 24-h ambulatory blood pressure monitoring (ABPM), carotid ultrasonography, and echocardiogram. All patients were on chronic treatment with phosphate supplements and 1-hydroxy vitamin D metabolites. RESULTS: Twenty-four patients (17 females, from 1 to 17 years of age) were studied. Serum concentrations (X ± SD) of phosphate and intact parathyroid hormone were 2.66 ± 0.60 mg/dl and 58.3 ± 26.8 pg/ml, respectively. Serum fibroblast growth factor 23 (FGF23) concentration was 278.18 ± 294.45 pg/ml (normal < 60 pg/ml). Abnormally high carotid intima media thickness was found in one patient, who was obese and hypertensive as revealed by ABPM, which disclosed arterial hypertension in two other patients. Z scores for echocardiographic interventricular septum end diastole and left ventricular posterior wall end diastole were + 0.77 ± 0.77 and + 0.94 ± 0.86, respectively. Left ventricular mass index (LVMI) was 44.93 ± 19.18 g/m2.7, and four patients, in addition to the obese one, had values greater than 51 g/m2.7, indicative of left ventricular hypertrophy. There was no correlation between these echocardiographic parameters and serum FGF23 concentrations. CONCLUSIONS: XLH pediatric patients receiving conventional treatment have echocardiographic measurements of ventricular mass within normal reference values, but above the mean, and 18% have LVMI suggestive of left ventricular hypertrophy without correlation with serum FGF23 concentrations. This might indicate an increased risk of cardiovascular involvement in XLH.

Bariatric surgery as a risk factor in the development of dental caries: a systematic review.

OBJECTIVES: Obesity is one of the most prevalent chronic pathologies in the world and has become a public health problem. At the present time, bariatric surgery (BS) is considered the best option and the only effective method of treatment, but it can occasionally result in a series of alterations at the oral level. This study aims to review the current literature to establish the possible association of patients who have undergone BS and a greater risk of dental caries. STUDY DESIGN: This study is a systematic review of the literature. METHODS: A search was made in the database of Medline (via PubMed), over the last 10 years, using the keywords 'bariatric surgery' OR 'gastrectomy' OR 'obesity surgery,' combined independently with the terms 'saliva' and 'dental caries' by means of the connector 'AND.' The criteria used were those described in the PRISMA® Declaration for performing systematic reviews. Inclusion criteria and study selection: (a) studies done with humans; (b) articles published in English and Spanish; (c) series of cases; and (d) clinical trials. The risk of bias was assessed independently by two authors. In both data extraction and risk of bias assessment, disagreements were resolved through discussion with a third author. RESULTS: Two independent reviewers read the titles and summaries of the 79 articles found. Finally, nine of them were included in the study. In the various articles, the parameters that had clinical relevance to the risk of dental caries were evaluated. CONCLUSIONS: Within the limitations of this study, it is plausible to think that patients who have undergone BS have a greater risk of dental caries. The oral complications associated with BS could be prevented or minimized by including in the multidisciplinary treatment of these patients a team of odontologists who would be responsible for prevention and oral assessment.

A pathway-based association study reveals variants from Wnt signalling genes contributing to asthma susceptibility.

BACKGROUND: Genetic susceptibility to asthma is currently linked to a handful of genes which have a limited ability to predict the overall disease risk, suggesting the existence of many other genes involved in disease development. Accumulated evidence from association studies in genes related by biological pathways could reveal novel asthma genes. OBJECTIVE: To reveal novel asthma susceptibility genes by means of a pathway-based association study. METHODS: Based on summary data from a previous a genomewide association study (GWAS) of asthma, we first identified significant biological pathways using a gene-set enrichment analysis. We then mapped all tested single nucleotide polymorphisms (SNPs) on the genes contributing to significant pathways and prioritized those with a disproportionate number of nominal significant associations for further studies. For those prioritized genes, association studies were performed for selected SNPs in independent case-control samples (n = 1765) using logistic regression models, and results were meta-analysed with those from the GWAS. RESULTS: Two biological processes were significantly enriched: the cytokine-cytokine receptor interaction (P = 0.002) and the Wnt signalling (P = 0.012). From the 417 genes interacting in these two pathways, 10 showed an excess of nominal associations, including a known asthma susceptibility locus (encoding SMAD family member 3) and other novel candidate genes. From the latter, association studies of 14 selected SNPs evidenced replication in a locus near the frizzled class receptor 6 (FZD6) gene (P = 9.90 × 10-4 ), which had a consistent direction of effects with the GWAS findings (meta-analysed odds ratio = 1.49; P = 5.87 × 10-6 ) and was in high linkage disequilibrium with expression quantitative trait loci in lung tissues. CONCLUSIONS AND CLINICAL RELEVANCE: This study revealed the importance of two biological pathways in asthma pathogenesis and identified a novel susceptibility locus near Wnt signalling genes.

Novel genetic risk factors for asthma in African American children: Precision Medicine and the SAGE II Study.

Asthma, an inflammatory disorder of the airways, is the most common chronic disease of children worldwide. There are significant racial/ethnic disparities in asthma prevalence, morbidity, and mortality among US children. This trend is mirrored in obesity, which may share genetic and environmental risk factors with asthma. The majority of asthma biomedical research has been performed in populations of European decent. We sought to identify genetic risk factors for asthma in African American children. We also assessed the generalizability of genetic variants associated with asthma in European and Asian populations to African American children. Our study population consisted of 1227 (812 asthma cases, 415 controls) African American children with genome-wide single nucleotide polymorphism (SNP) data. Logistic regression was used to identify associations between SNP genotype and asthma status. We identified a novel variant in the PTCHD3 gene that is significantly associated with asthma (rs660498, p = 2.2 × 10(-7)) independent of obesity status. Approximately 5 % of previously reported asthma genetic associations identified in European populations replicated in African Americans. Our identification of novel variants associated with asthma in African American children, coupled with our inability to replicate the majority of findings reported in European Americans, underscores the necessity for including diverse populations in biomedical studies of asthma.

Mortality from laparoscopic antireflux surgery in a nationwide cohort of the working-age population.

BACKGROUND: Both medication and surgery are effective treatments for severe gastro-oesophageal reflux disease (GORD). Postoperative risks have contributed to decreased use of antireflux surgery. The aim of this study was to assess short-term mortality following primary laparoscopic fundoplication. METHODS: This was a population-based nationwide cohort study including all Swedish hospitals that performed laparoscopic fundoplication between 1997 and 2013. All patients aged 18-65 years with GORD who underwent primary laparoscopic fundoplication during the study interval were included. The primary outcome was absolute all-cause and surgery-related 90- and 30-day mortality. Secondary outcomes were reoperation and length of hospital stay. Logistic regression was used to calculate odds ratios with 95 per cent confidence intervals of reoperation within 90 days and prolonged hospital stay (4 days or more). RESULTS: Of 8947 included patients, 5306 (59·3 per cent) were men and 551 (6·2 per cent) had significant co-morbidity (Charlson score above 0). Median age at surgery was 48 years, and median hospital stay was 2 days. The annual rate of laparoscopic fundoplication decreased from 15·3 to 2·4 patients per 100 000 population during the study period, whereas the proportion of patients with co-morbidity increased more than twofold. All-cause 90- and 30-day mortality rates were 0·08 per cent (7 patients) and 0·03 per cent (3 patients) respectively. Only one death (0·01 per cent) was directly surgery-related. The 90-day reoperation rate was 0·4 per cent (39 patients). Co-morbidity and older age were associated with an increased risk of prolonged hospital stay, but not reoperation. CONCLUSION: This population-based study revealed very low mortality and reoperation rates following primary laparoscopic fundoplication in the working-age population. The findings may influence clinical decision-making in the treatment of severe GORD.

Water renal management is altered more frequently than albuminuria in children in the G1 stage of the 2012 KDIGO Guideline / El manejo renal del agua se ve alterado con más frecuencia que la albuminuria en niños en el estadio G1 de la Guía KDIGO de 2012

Background: The G1 stage of chronic kidney disease (CKD) is defined in the 2012 KDIGO Guideline as kidney damage characterized by structural or functional kidney abnormalities without deterioration of glomerular filtration rate. Albuminuria and electrolyte abnormalities due to tubular disorders are considered functional markers of kidney damage. Changes in renal water handling are not explicitly cited in these guidelines. A large sample of children with abnormal dimercaptosuccinic acid (DMSA) scan located in the G1 stage was used in this study. Methods: Ambispective, cross-sectional study to evaluate the clinical histories of 116 pediatric patients. 100 patients were included in the first group (G1 stage) and 16 patients in the G2-G5 stages according to the classification of CKD Guideline KDIGO. All the patients had a renal pathologic DMSA scan. GFR, maximum urine osmolality and albumin/creatinine and NAG/creatinine ratios were determined. Results: The patients with normal GFR, in relation to those with reduced GFR, had significantly higher values of maximum urine osmolality and significantly reduced values of urine volume and albumin/creatinine and NAG/creatinine ratios. The most frequently observed alterations in children in the KDIGO G1 stage were those involving the water renal management such as urinary concentrating ability defect (29%) and increased urinary volume (20%). The frequency of children with increased urinary elimination of albumin (12%) and NAG (3%) was more lower. All children in KDIGO G2-G5 stages had alterations in water renal management. Conclusions: The parameters related with the water renal management are affected more frequently than albumin urinary excretion in children who have loss of parenchyma and normal GFR (AU)

Antecedentes: El estadio G1 de la enfermedad renal crónica (ERC) se define en la Guía KDIGO de 2012 como el daño renal caracterizado por anomalías estructurales o funcionales del riñón y sin deterioro del filtrado glomerular. Tanto la albuminuria como las anomalías que afectan a los electrolitos debido a trastornos tubulares se consideran marcadores de daños funcionales. No obstante, en esta guía no se explicitan cuáles son los cambios que se producen en el manejo renal del agua. En este estudio, se utilizó una muestra grande de niños en estadio G1 con gammagrafías con ácido dimercaptosuccínico (DMSA) anormales. Métodos: Llevamos a cabo un estudio transversal ambispectivo para evaluar las historias clínicas de 116 pacientes pediátricos. En el primer grupo, se incluyó a 100 pacientes en estadio G1 y a 16 pacientes en los estadios G2-G5 de la ERC de la clasificación de la Guía KDIGO. Las gammagrafías con DMSA de todos los pacientes revelaban patologías renales. Se calcularon las TFG, la osmolalidad urinaria máxima y los cocientes de albúmina/creatinina y de NAG/creatinina. Resultados: En comparación con los pacientes con TFG reducidas, los pacientes con TFG normales presentaron valores de osmolalidad urinaria máxima significativamente superiores, así como volúmenes urinarios y cocientes de albúmina/creatinina y de NAG/creatinina significativamente inferiores. Las alteraciones que se observaron con mayor frecuencia en los niños en estadio G1 de la Guía KDIGO afectaban al manejo renal del agua. Entre ellas, se encontraban fallos en la capacidad de concentración de la orina (29%) y un aumento del volumen urinario (20%). Sin embargo, se observó que la frecuencia de niños en los que aumentó la eliminación a través de la orina de albúmina (12%) y NAG (3%) era mucho menor. Por su parte, todos los niños en los estadios G2-G5 de la Guía KDIGO presentaban alteraciones en el manejo renal del agua. Conclusiones: Aquellos parámetros relacionados con el manejo renal del agua se ven afectados con más frecuencia que la albuminuria en niños con pérdidas de parénquima renal y TFG normales (AU)

ST13 polymorphisms and their effect on exacerbations in steroid-treated asthmatic children and young adults.

BACKGROUND: The clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS. METHODS: We performed a meta-analysis of three cohort studies: Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory effects (n = 357, age: 4-12 years, the Netherlands), BREATHE (n = 820, age: 3-22 years, UK) and Paediatric Asthma Gene Environment Study (n = 391, age: 2-16 years, UK). Seventeen genes were selected based on a role in the glucocorticoid signalling pathway or a reported association with asthma. Two outcome parameters were used to reflect exacerbations: hospital visits and oral corticosteroid (OCS) use in the previous year. The most significant associations were tested in three independent validation cohorts; the Childhood Asthma Management Programme (clinical trial, n = 172, age: 5-12 years, USA), the Genes- environment and Mixture in Latino Americans II- study (n = 745, age: 8-21, USA) and the Pharmacogenetics of adrenal suppression cohort (n = 391, age: 5-18, UK) to test the robustness of the findings. Finally, all results were meta-analysed. RESULTS: Two SNPs in ST13 (rs138335 and rs138337), but not in the other genes, were associated at a nominal level with an increased risk of exacerbations in asthmatics using ICS in the three cohorts studied. In a meta-analysis of all six studies, ST13 rs138335 remained associated with an increased risk of asthma-related hospital visits and OCS use in the previous year; OR = 1.22 (P = 0.013) and OR = 1.22 (P = 0.0017), respectively. CONCLUSION AND CLINICAL RELEVANCE: A novel susceptibility gene, ST13, coding for a cochaperone of the glucocorticoid receptor, is associated with exacerbations in asthmatic children and young adults despite their ICS use. Genetic variation in the glucocorticoid signalling pathway may contribute to the interindividual variability in clinical response to ICS treatment in children and young adults.

Water renal management is altered more frequently than albuminuria in children in the G1 stage of the 2012 KDIGO Guideline.

BACKGROUND: The G1 stage of chronic kidney disease (CKD) is defined in the 2012 KDIGO Guideline as kidney damage characterized by structural or functional kidney abnormalities without deterioration of glomerular filtration rate. Albuminuria and electrolyte abnormalities due to tubular disorders are considered functional markers of kidney damage. Changes in renal water handling are not explicitly cited in these guidelines. A large sample of children with abnormal dimercaptosuccinic acid (DMSA) scan located in the G1 stage was used in this study. METHODS: Ambispective, cross-sectional study to evaluate the clinical histories of 116 pediatric patients. 100 patients were included in the first group (G1 stage) and 16 patients in the G2-G5 stages according to the classification of CKD Guideline KDIGO. All the patients had a renal pathologic DMSA scan. GFR, maximum urine osmolality and albumin/creatinine and NAG/creatinine ratios were determined. RESULTS: The patients with normal GFR, in relation to those with reduced GFR, had significantly higher values of maximum urine osmolality and significantly reduced values of urine volume and albumin/creatinine and NAG/creatinine ratios. The most frequently observed alterations in children in the KDIGO G1 stage were those involving the water renal management such as urinary concentrating ability defect (29%) and increased urinary volume (20%). The frequency of children with increased urinary elimination of albumin (12%) and NAG (3%) was more lower. All children in KDIGO G2-G5 stages had alterations in water renal management. CONCLUSIONS: The parameters related with the water renal management are affected more frequently than albumin urinary excretion in children who have loss of parenchyma and normal GFR.

Whole-body MRI with diffusion-weighted sequences compared with 18 FDG PET-CT, CT and superficial lymph node ultrasonography in the staging of advanced cutaneous melanoma: a prospective study.

OBJECTIVES: The aim of our study was to compare the diagnostic performances of non-radiating whole-body magnetic resonance imaging (wbMRI), either volumetric, with Volumetric interpolated breath-hold examination (VIBE) or metabolic, with diffusion-weighted sequences (wbMRI), with classical irradiating techniques such as PET-CT, CT and with lymph node ultrasonography (US) for the staging of advanced melanoma. PATIENTS AND METHODS: Thirty-seven melanoma AJCC stage IV patients were prospectively included. All images were independently interpreted without prior knowledge of the results of studies performed with concurrent techniques, and all imaging techniques were scheduled within a mean interval of 7 days. The overall and site-specific diagnosis performances of each imaging modality were studied, as well as the interest of combined MRI VIBE and diffusion sequences. RESULTS: The number of visceral or lymph node metastases spotted was, respectively, 218, with 125 metastases for wbMRI, 191/103 for PET-CT, 209/115 for CT and 33/13 for lymph node US. No statistically significant difference (P < 0.05) of overall diagnostic performances between wbMRI (Se 84%, Sp 87.1%, PPV 89.8%, NPV 80.2%) and PET-CT (Se 79.8%, Sp 93.1%, PPV 93.2%, NPV 79.4%) was observed. No statistically significant difference was found between wbMRI and PET-CT with two channels for CT with respect to different metastatic sites. Compared with the CT, wbMRI had significantly better overall specificity (P = 0.0011) and PPV (P = 0.02). For lung exploration, sensitivity of wbMRI (51.6%) was inferior to CT (71.4%). To detect superficial metastatic lymph nodes, wbMRI and US both showed high diagnostic accuracy with no statistically significant difference. Intra-observer agreement was almost perfect for all imaging modalities considering the overall staging. Inter-observer agreement for wbMRI and diffusion alone was almost perfect except for bone and lymphatic sites. Overall diagnostic performance of diffusion alone was significantly inferior to those of combined VIBE and diffusion sequences. CONCLUSIONS: Whole-body MRI, using diffusion weighted sequences, was a reliable non-radiating imaging for staging of melanoma and offers the same diagnostic performances than combined CT, PET-CT and lymph node US.