Iodine status in children with intestinal failure.

OBJECTIVES: Children on long-term parenteral nutrition (PN) are at high risk of iodine deficiency (ID). However, most available information comes from cross-sectional studies. We investigated the iodine status, associated factors, and prevalence of hypothyroidism in children with intestinal failure (IF) who were followed up longitudinally. METHODS: This was a cohort study of children with IF monitored for urine iodine concentration (UIC), iodine intake, serum selenium concentration, and thyroid function in an intestinal rehabilitation program. The outcome variable ID was defined as a UIC value < 100 µg/L. Adjusted generalized estimating equations were used to assess the effects of the exposure variables on the UIC. RESULTS: Twenty-four patients aged 62.7 (39.1; 79.7) months who received PN for 46.5 (21.5) months were included. The average energy supply was 81.2 kcal/kg/day, 77.6% of which was provided by PN. An average of 5.2 UIC measurements per patient were performed. ID prevalence decreased from baseline (83.3%) to the last assessment (45.8%). Three patients had hypothyroidism secondary to iodine and selenium combined severe deficiency. Iodine intake from enteral or oral nutritional formulas was positively associated with UIC (ß = 0.71 [0.35, 1.07]; p < 0.001). Meeting approximately 80% of the estimated average requirement for iodine from nutritional formulas resulted in a greater probability of normal UIC values. CONCLUSION: ID is highly prevalent in children with IF who receive long-term PN and its frequency decreases with iodine intake from nutritional formulas. Severe combined iodine and selenium deficiencies are associated with the development of hypothyroidism in these patients.

Encouraging outcomes of using a small-donor single graft in pediatric kidney transplantation.

BACKGROUND: The use of small pediatric kidneys as single grafts for transplantation is controversial, due to the potential risk for graft thrombosis and insufficient nephron mass. METHODS: Aiming to test the benefits of transplanting these kidneys, 375 children who underwent kidney transplantation in a single center were evaluated: 49 (13.1%) received a single graft from a small pediatric donor (≤ 15 kg, SPD group), 244 (65.1%) from a bigger pediatric donor (> 15 kg, BPD group), and 82 (21.9%) from adult living donors (group ALD). RESULTS: Groups had similar baseline main characteristics. After 5 years of follow-up, children from the SPD group were comparable to children from BPD and ALD in patient survival (94%, 96%, and 98%, respectively, p = 0.423); graft survival (89%, 88%, and 93%, respectively, p = 0.426); the frequency of acute rejection (p = 0.998); the incidence of post-transplant lymphoproliferative disease (p = 0.671); the odds ratio for severely increased proteinuria (p = 0.357); the rates of vascular thrombosis (p = 0.846); and the necessity for post-transplant surgical intervention prior to discharge (p = 0.905). The longitudinal evolution of eGFR was not uniform among groups. The three groups presented a decrease in eGFR, but the slope of the curve was steeper in ALD children. At 5 years, the eGFR of the ALD group was 10 ml/min/1.73m2 inferior to the others. At that time, the eGFR from the SPD group was statistically similar to the BPD group (p = 0.952). CONCLUSION: In a specialized transplant center, the use of a single small pediatric donor kidney for transplantation is as successful as bigger pediatric or adult living donors, after 5 years of follow-up. A higher resolution version of the Graphical abstract is available as Supplementary information.

Access to treatment for chronic kidney disease by children and adolescents in Brazil.

BACKGROUND: This study aimed to identify main factors associated with child and adolescent access to chronic kidney disease (CKD) treatment in Brazil. METHODS: Multi-center cross-sectional study conducted in eight pediatric nephrology centers across all Brazilian geographic regions. Information was collected on characteristics associated with referral and treatment of patients with CKD. The following outcomes were analyzed as follows: (1) age at first consultation, and (2) time elapsed between referral and treatment at the specialized service. RESULTS: Three hundred thirty-five children were assessed. Variables associated with age at first consultation were as follows: CAKUT (HR=1.7; 95%CI 1.3-2.2, p<0.01); private health plan (HR=1.54; 95%CI 1.06-2.23, p=0.02); modified Medical Outcomes Study Social Support Survey mMOS-SS score (HR=1.02; 95%CI 1.00-1.03, p=0.024); maternal age (HR=0.96; 95%CI 0.95-0.97, p<0.01); and number of siblings in the household (HR=0.86; 95%CI 0.79-0.83, p<0.01). Significant variables associated with time elapsed between referral and treatment at the specialized service were as follows: each additional occupant sharing the household (HR=0.94; 95%CI:0.89-0.99, p=0.02), residing in the Northeast (HR=0.81; 95%CI:0.67-0.98, p=0.03) and having someone to take them to the physician (HR=1.36; 95%CI 1.07-1.74, p=0.01). The median time interval between patient referral and treatment by the service was 11 days (IQR 10-31). CONCLUSION: There are potentially modifiable factors hampering access of children with CKD to specialized treatment. The importance of the role of social support for the two outcomes should serve as an alert for health managers and professionals to consider this aspect throughout all steps of the care process of children with CKD.

Collaborative Brazilian pediatric renal transplant registry (CoBrazPed-RTx): A report from 2004 to 2018.

The Brazilian collaborative registry for pediatric renal transplantation began in 2004 as a multicenter initiative aimed at analyzing, reporting, and disseminating the results of pediatric renal transplantation in Brazil. Data from all pediatric renal transplants performed from January 2004 to May 2018 at the 13 participating centers were analyzed. A total of 2744 pediatric renal transplants were performed in the thirteen participating centers. The median age at transplantation was 12.2 years, with the majority being male recipients (56%). The main underlying diseases were CAKUT (40.5%) and glomerulopathy (28%). 1981 (72%) of the grafts were from deceased donors (DD). Graft survival at one year (censored by death) was 94% in the live donor group (LD) and 91% in the DD group (log-rank test P < 0.01). The patient's survival at one and 5 years was 97% and 95% for the LD group and 96% and 93% for the DD group (log-rank test P = 0.02). The graft loss rate was 19% (n = 517), more frequently caused by vascular thrombosis (n = 102) and chronic graft nephropathy (n = 90). DD recipients had 1.6 (1.0-2.2) times greater chance of death and 1.5 (1.2-1.8) times greater chance of graft loss compared to LD recipients. The mortality rate was 5.4% (n = 148), mainly due to infection (n = 69) and cardiovascular disease (n = 28). The results of this collaborative pediatric renal transplant record are comparable to other international registries, although we still have a high infection rate as a cause of death.

Vascular anastomosis for paediatric renal transplantation and new strategy in low-weight children.

The technical aspects of RT in low-weight children should be specific, particularly with regard to VA. This retrospective study assesses the main VA options in paediatric RTs and proposes a new strategy for renal artery trajectory when using the Ao and the right iVC. The sample included 81 patients and was categorized into a group of children weighing <16 kg and the other group of children weighing 16 kg or more. The smaller children received the graft predominantly on the Ao and iVC (63%); however, the VA options varied in children weighing more than 16 kg, with anastomoses predominantly to the common iliac vessels (46%). In the first group, when the Ao was the selected vessel for anastomosis on the right side, the trajectory adopted for the transplanted kidney artery was posterior to the iVC. This strategy may reduce the risk of compression of the iVC by the renal artery of the donor kidney and may reconstitute the normal anatomy of the renal artery. Moreover, it did not represent a risk factor for graft loss in this sample.

Growth of children with end-stage renal disease undergoing daily hemodialysis.

BACKGROUND: The aim of this report is to describe the effect of daily hemodialysis on the growth of children with end-stage renal disease (ESRD). METHODS: We performed a prospective, observational study on 24 children with ESRD undergoing daily hemodialysis (DHD). The control group comprised 26 children on concurrent conventional hemodialysis (CHD), and the follow-up for both groups was 9.3 ± 3.0 months. No patient received growth hormone (GH) therapy. RESULTS: At the onset of the study, the height-for-age Z-score was -2.12 ± 1.54 in the CHD group and -2.84 ± 2.27 in the DHD group (p = 0.313). Assuming an increase of 0.5 standard deviation scores (SDS) of the height-for-age parameter as an improvement of growth, there were 33 % of patients in the DHD group and 8 % in the CHD group (p = 0.035). The cumulative probability of gain in height for age at 12 months was 40 % in the DHD group versus 15 % in the CHD group (p = 0.047). Also, 98 % of patients in the DHD group had an adequate total caloric intake, whereas 38 % in the CHD group reached this goal (p < 0.001). No patient left the study due to intensification of the dialysis modality. CONCLUSIONS: Our data show that the DHD favored a 0.5 SDS height gain in a third of patients without GH treatment. Dialysis intensification was not a cause for treatment dropouts, and DHD should be considered as a treatment for selected cases, especially small children.

Copper Deficiency in Children With Intestinal Failure: Risk Factors and Influence on Hematological Cytopenias.

BACKGROUND: We investigated to what extent serum copper influences hemoglobin (Hb), neutrophil, and platelet counts and the factors associated with serum copper in children with intestinal failure (IF) who have their micronutrient status monitored according to a standard protocol. METHODS: Children with IF admitted to a pediatric intestinal rehabilitation program and receiving home parenteral nutrition (PN) were followed up prospectively. Patients received vitamins and multi-trace elements (TEs) as part of the PN. Copper, iron, zinc, vitamin A, and cobalamin serum levels were routinely monitored at 3-month intervals or monthly when a deficiency was detected. Complete blood counts were performed biweekly. Repeated-measures analyses were used to estimate the effect of explanatory variables on the outcomes. RESULTS: Thirteen children with a median time receiving PN of 16.6 months were included. An average of 7 copper measurements per patient were performed; 53.8% of patients had a low serum level at least twice during the follow-up. Eight patients with cholestasis had TEs of PN discontinued. In the multivariable analysis, copper was not associated with Hb levels; an increase of 10 µg/dL in serum copper resulted in an increase of 240/mm3 (95% confidence interval [CI], 18.0-30.1) neutrophils and of 8429/mm3 (95% CI, 466-1219) platelets (P < .001). Time of PN without copper, direct bilirubin levels, and ostomy were associated with lower serum copper. CONCLUSION: The increase in serum copper was associated with significant increases in neutrophil and platelet counts. Time without copper in PN, cholestasis, and having an ostomy negatively influenced copper status.

EMOTIONAL REPERCUSSIONS AND QUALITY OF LIFE IN CHILDREN AND ADOLESCENTS UNDERGOING HEMODIALYSIS OR AFTER KIDNEY TRANSPLANTATION.

OBJECTIVE: To investigate the emotional repercussions and quality of life (QOL) associated with end-stage kidney disease (ESKD) in children and adolescents undergoing hemodialysis or a kidney transplant (TX). METHODS: We conducted a quantitative-qualitative study. 48 children and adolescents with ESKD were interviewed; half of them underwent hemodialysis treatment, and the other half had a kidney transplantation. Their respective 48 caregivers also participated in the study. The questionnaire involved both the Pediatric Quality of Life Inventory and a thematic story-drawing tool. An analysis of the QOL questionnaire's results was done by comparing the sum of points between groups and the theme-based story-drawing consisted of interpreting the data contained in the material using Freudian and Lacanian theories. RESULTS: In the QOL questionnaires, the total score was higher in the transplanted patients and in their caregivers, suggesting a perception of better QOL after kidney transplantation. In the specific aspects of the questionnaire, physical capacity was considered superior by children who underwent transplants and their caregivers. There were no differences between the groups in the emotional, social and school aspects. However, the caregivers of the patients who had a transplant perceived a significant difference in QOL in the school aspect. In the thematic story-drawings, emotional suffering in the two analyzed groups was evidenced regardless of the treatment. CONCLUSIONS: Despite the questionnaire results suggesting that transplantation does improve some aspects of QOL, there were no differences observed between kidney replacement therapies regarding the emotional repercussion of chronic kidney disease.

Is Preoperative Preparation Time a Barrier to Small Children Being Ready for Kidney Transplantation?

BACKGROUND: Small children are less frequently transplanted when compared with older. The objective of the present study was to compare the preparation time for transplantation in children of different weights and to identify factors associated with a delay in the workup of small children. METHODS: We report on a retrospective cohort comprising all children referred for renal transplantation (RTx) workup between 2009 and 2017. The main outcome was transplantation workup time, defined as the time elapsed between the first consultation and when the child became ready for the surgery. RESULTS: A total of 389 children (63.5% males) were selected, with a median weight of 18 kg (interquartile range, 11-32). Patients were categorized into 2 groups: group A (study group): ≤15 kg (n = 165) and group B (control group): >15 kg (n = 224). The probability of being ready for RTx was comparable between groups A and B. The cumulative incidence rate difference between groups is -0.05 (95% confidence interval, -0.03 to 0.02). The median time for RTx workup was 5.4 (2.4-9.4) in group A and 4.3 (2.2-9.0) months in group B (P = 0.451). Moreover, the presence of urinary tract malformation was associated with the need for longer transplantation workup time (P < 0.001). CONCLUSIONS: In children >7 kg, the workup time for transplantation is not related to body weight. In a specialized center, children weighing 7-15 kg became ready within the same timeframe as children weighing >15 kg, despite the smaller children had greater difficulty being nourished, dialyzed, and a greater need for surgical correction of the urinary tract pretransplant.

The transition between a poroma and a porocarcinoma evidenced by the dermoscopy.

Eccrine porocarcinoma (EPC) is a rare malignant skin tumor. The dermoscopy of invasive EPC reveals focal presence of whitish-pink, structureless areas surrounded by pinkish-white halos. In an eccrine poroma (EP), such areas present diffuse distribution in the "frog- eggs" pattern. We reported an EPC in situ that presents a transitional dermoscopy pattern between EP and invasive EPC. We found a diffuse distribution; whitish-pink, structureless areas surrounded by pinkish-white halos; a central exulceration and a polymorphic vascular pattern.

Cost analysis of substitutive renal therapies in children.

OBJECTIVE: End-stage renal disease is a health problem that consumes public and private resources. This study aimed to identify the cost of hemodialysis (either daily or conventional hemodialysis) and transplantation in children and adolescents. METHODS: This was a retrospective cohort of pediatric patients with End-stage renal disease who underwent hemodialysis followed by kidney transplant. All costs incurred in the treatment were collected and the monthly total cost was calculated per patient and for each renal therapy. Subsequently, a dynamic panel data model was estimated. RESULTS: The study included 30 children who underwent hemodialysis (16 conventional/14 daily hemodialysis) followed by renal transplantation. The mean monthly outlay for hemodialysis was USD 3500 and USD 1900 for transplant. Hemodialysis costs added up to over USD 87,000 in 40 months for conventional dialysis patients and USD 131,000 in 50 months for daily dialysis patients. In turn, transplant costs in 50 months reached USD 48,000 and USD 70,000, for conventional and daily dialysis patients, respectively. For conventional dialysis patients, transplant is less costly when therapy exceeds 16 months, whereas for daily dialysis patients, the threshold is around 13 months. CONCLUSION: Transplantation is less expensive than dialysis in children, and the estimated thresholds indicate that renal transplant should be the preferred treatment for pediatric patients.

Publisher Correction: PTEN regulates glioblastoma oncogenesis through chromatin-associated complexes of DAXX and histone H3.3.

This corrects the article DOI: 10.1038/ncomms15223.

Humor in Life Scale (EHV): Development and Evidence of Validity and Reliability in Spanish Speakers / Escala de Humor ante la Vida (EHV): Desarrollo, Evidencias de Validez y Confiabilidad en Hispanohablantes

Abstract Despite the growing attention given to the study of humor, a measure in the Spanish language of people's experience and enjoyment of humor in everyday life is still missing. The present study describes the development and validation of the EHV (from the Spanish Escala de Humor ante la Vida, Humor in Life Scale). In phase I, the items were developed using focus groups and interviews; their content validity was assessed through expert judgment. In phase II, the EHV was answered by two Mexican samples (N=1380), women and men, from 18 to 66 years; it was administered together with the Numeric Rating Scale of Humor and the Positive and Negative Affect Schedule, in both printed and electronic formats. The exploratory factor analysis supported the single factor structure and the confirmatory factor analysis showed adequate fit indices for the final eight-item scale; the factor structure was partially invariant between sexes. Reliability indices were satisfactory. Convergent and discriminant validity tests showed that the EHV is related to a global measure of humor and positive and negative affect. In sum, the results indicate that the EHV is a brief, valid and reliable measure to assess humor in life in Spanish speakers.

Resumen A pesar de la creciente atención que se ha otorgado al estudio del sentido del humor, no se contaba con un instrumento en español que evaluara la experiencia y el disfrute del humor en la vida diaria. La investigación constó de dos fases. En la primera, a partir de grupos focales y entrevistas, se elaboraron 30 reactivos potenciales. Para evaluar su validez de contenido, se obtuvieron índices V de Aiken de los juicios de cuatro expertos. Los 14 reactivos que alcanzaron el criterio fueron sometidos a un piloteo, después del cual la escala quedó conformada por 11 reactivos, con siete opciones de respuesta. En la segunda fase, la EHV se aplicó, junto con la Escala de Evaluación Numérica del Humor (una medida global de humor) y la Escala de Afecto Positivo y Negativo (PANAS), a dos muestras de población general (n1=1380 y n1=550), hombres y mujeres con edades de 18 a 66 años. La aplicación de la batería se efectuó tanto en línea como en formato impreso en diversos lugares públicos. El análisis factorial exploratorio mostró una estructura unidimensional que explicó el 55.97% de la varianza total; dos reactivos fueron eliminados. Se obtuvieron índices de ajuste adecuados al someter a análisis factorial confirmatorio a la EHV, los cuales mejoraron con la eliminación de un reactivo, por lo que la escala quedó finalmente conformada por ocho reactivos. El AVE fue >.50 y los índices de confiabilidad alfa y omega resultaron >.91. Al evaluar la invarianza de la estructura factorial de la EHV por sexo, ésta resultó parcial, ya que se obtuvieron índices dentro de los criterios señalados para el modelo métrico y para el fuerte, pero no todos para el estricto. La correlación entre la EHV y la Escala de Evaluación Numérica del Humor resultó, como se esperaba, alta y positiva, así como con el factor de afecto positivo del PANAS, en tanto que lo opuesto se observó con el factor de afecto negativo. Tener creencias espirituales o religiosas y tener una pareja no mostraron relación con los puntajes de la EHV. Estos resultaron apoyaron la validez convergente y discriminante de la EHV. En conclusión, la EHV es un instrumento breve y unidimensional, con evidencias de validez y confiabilidad, que evalúa la experiencia y disfrute del humor en la vida cotidiana en personas de habla hispana.

Targeted Next-Generation Sequencing in Brazilian Children With Nephrotic Syndrome Submitted to Renal Transplant.

BACKGROUND: The aims of this study were to identify the genetic mutations profile in Brazilian children with nephrotic syndrome (NS) and to determine a genotype-phenotype correlation in this disease. METHODS: Next-generation sequencing and mutation analysis were performed on 24 genes related to NS in a cross-sectional study involving 95 children who underwent kidney transplantation due to NS, excluding congenital cases. RESULTS: A total of 149 variants were identified in 22 of 24 sequenced genes. The mutations were classified as pathogenic, likely pathogenic, likely benign and benign per the chance of causing the disease. NPHS2 was the most common mutated gene. We identified 8 (8.4%) patients with hereditary NS and 5 (5%) patients with probably genetically caused NS. COL4A3-5 variants were found as well, but it is not clear whether they should be considered isolated FSGS or simply a misdiagnosed type of the Alport spectrum. Considering the clinical results, hereditary NS patients presented a tendency to early disease onset when compared with the other groups (P = 0.06) and time to end stage renal disease (ESRD) was longer in this group (P = 0.03). No patients from hereditary NS group had NS recurrence after transplantation. CONCLUSIONS: This is the first study in children with steroid-resistant NS who underwent kidney transplantation using next-generation sequencing. Considering our results, we believe this study has shed some light to the uncertainties of genotype-phenotype correlation in NS, where several genes cooperate to produce or even to modify the course of the disease.

PTEN regulates glioblastoma oncogenesis through chromatin-associated complexes of DAXX and histone H3.3.

Glioblastoma (GBM) is the most lethal type of human brain cancer, where deletions and mutations in the tumour suppressor gene PTEN (phosphatase and tensin homolog) are frequent events and are associated with therapeutic resistance. Herein, we report a novel chromatin-associated function of PTEN in complex with the histone chaperone DAXX and the histone variant H3.3. We show that PTEN interacts with DAXX and, in turn PTEN directly regulates oncogene expression by modulating DAXX-H3.3 association on the chromatin, independently of PTEN enzymatic activity. Furthermore, DAXX inhibition specifically suppresses tumour growth and improves the survival of orthotopically engrafted mice implanted with human PTEN-deficient glioma samples, associated with global H3.3 genomic distribution changes leading to upregulation of tumour suppressor genes and downregulation of oncogenes. Moreover, DAXX expression anti-correlates with PTEN expression in GBM patient samples. Since loss of chromosome 10 and PTEN are common events in cancer, this synthetic growth defect mediated by DAXX suppression represents a therapeutic opportunity to inhibit tumorigenesis specifically in the context of PTEN deletion.

Pediatric Chronic Dialysis in Brazil: Epidemiology and Regional Inequalities.

INTRODUCTION: There are few reports in the literature estimating the epidemiologic characteristics of pediatric chronic dialysis. These patients have impaired physical growth, high number of comorbidities and great need for continuous attention of specialized services with high demand for complex and costly procedures. OBJECTIVE: The aim of this study was to estimate the incidence and prevalence rates and describe the characteristics of children and adolescents undergoing chronic dialysis treatment in a Brazilian demographic health survey. MATERIALS AND METHODS: A cross-sectional study was performed in a representative sample of dialysis centers (nc = 239) that was established from the 2011 Brazilian Nephrology Society Census (Nc = 708). We collected data encompassing the five Brazilian macro-regions. We analyzed the data from all patients under 19 years of age. The sample population consisted of 643 children and adolescents who were on chronic dialysis program anytime in 2012. Data collection was carried out in the dialysis services by means of patients' records reviews and personal interviews with the centers' leaders. RESULTS: We estimated that there were a total of 1,283 pediatric patients on chronic dialysis treatment in Brazil, resulting in a prevalence of 20.0 cases per million age-related population (pmarp) (95% CI: 14.8-25.3) and an incidence of 6.6 cases pmarp in 2012 (95% CI: 4.8-8.4). The South region had the highest prevalence and incidence rates of patients under dialysis therapy, 27.7 (95% CI: 7.3-48.1) and 11.0 (95% CI: 2.8-19.3) cases pmarp, respectively; the lowest prevalence and incidence rates were found in the North-Midwest region, 13.8 (95% CI: 6.2-21.4), and in the Northeast region, 3.8 (95% CI: 1.4-6.3) cases pmarp, respectively. CONCLUSION: Brazil has an overall low prevalence of children on chronic dialysis treatment, figuring near the rates from others countries with same socioeconomic profile. There are substantial differences among regions related to pediatric chronic dialysis treatment. Joint strategies aiming to reduce inequities and improving access to treatment and adequacy of services across the Brazilian regions are necessary to provide an appropriate care setting for this population group.

Kinase-independent role for CRAF-driving tumour radioresistance via CHK2.

Although oncology therapy regimens commonly include radiation and genotoxic drugs, tumour cells typically develop resistance to these interventions. Here we report that treatment of tumours with ionizing radiation or genotoxic drugs drives p21-activated kinase 1 (PAK1)-mediated phosphorylation of CRAF on Serine 338 (pS338) triggering a kinase-independent mechanism of DNA repair and therapeutic resistance. CRAF pS338 recruits CHK2, a cell cycle checkpoint kinase involved in DNA repair, and promotes CHK2 phosphorylation/activation to enhance the tumour cell DNA damage response. Accordingly, a phospho-mimetic mutant of CRAF (S338D) is sufficient to induce the CRAF/CHK2 association enhancing tumour radioresistance, while an allosteric CRAF inhibitor sensitizes tumour cells to ionizing radiation or genotoxic drugs. Our findings establish a role for CRAF in the DNA damage response that is independent from its canonical function as a kinase.

Long-segment thoracoabdominal aortic coarctation in a child with Down syndrome.

Midaortic syndrome is a rare vascular anomaly characterized by coarctation of the descending thoracic and abdominal aorta. Down syndrome is associated with multiple congenital cardiac malformations but is rarely associated with developmental vascular anomalies. Midaortic syndrome may result in severe renovascular hypertension that requires early intervention to prevent life-threatening complications. We report a child with Down syndrome who presented with occlusion of the aorta and was treated with aortic bypass. More than 4 years after the procedure, the patient's renal function remains normal, and there is no evidence of recurrent hypertension. Long-term follow-up is important to assess the benefits of surgical repair.