The orchestration of gene expression and the editing role of microRNA.

In this short educational communication the ESPU Research Committee presents the role of non-coding RNA and how these can affect gene expression. In particular we discuss the role of microRNA on post transcriptional changes and how these may cause pathological conditions within Pediatric Urology and how microRNA could be useful in future clinical practice.

COVID-19 and research in pediatric urology.

COVID-19 began in December 2019 then spread worldwide. Providers, including pediatric urologists, had to adapt their clinical processes, and many non-covid research activities were suspended. COVID-19 impacts how research is financed, performed, and published, and is itself the subject of intense research. We present current research and publications specifically related to the urinary tract and the pediatric population.

Evidence Based Medicine IV: how to find an evidence-based answer to a clinical question? Make a critically appraised topic!

This manuscript is the fourth in a five part series related to evidence based medicine (EBM) provided by the European society of pediatric urology (ESPU) research committee. It will present a way to come to a quick and critical appraisal of available evidence on a specific topic: a CAT (critically appraised topic). The way how to write a cat is described for interventions to be compared to a control group, and for other, more generalized clinical questions. While systematic reviews provide a throughout overview of all evidence available, a CAT provides a shorter way to come to quick insights based on EBM.

Evidence-based medicine III: level of evidence.

The present article is the third installment in a five-part series related to evidence-based medicine (EBM) provided by the European Society for Paediatric Urology Research Committee. It will present the different levels of evidence (i.e. systematic review, randomized controlled trial, cohort study) available to clinicians and researchers and describe the strengths of each study type. While EBM provides a valuable construct to aid in medical decision-making, it remains imperative that this information be interpreted and applied in the clinical context with a good dose of common sense.

EBM II: How to perform a literature search.

The present article is a second part related to evidence based medicine (EBM) in a series of five by the European society for paediatric urology (ESPU) research committee. It will present the different databases/search engines available to clinicians and researchers and describe strategies to focus the search to one's particular needs. Indeed, databases/search engines used and search strategy should vary according to the goal of the research. If the aim is to address a clinical problem, the search should allow to identify a small number of most pertinent articles (high specificity); if the search is for research purposes, instead, it should ensure no meaningful articles are overlooked (high sensitivity).

Evidence-based medicine 1: Background.

The Research Committee of the European Society of Pediatric Urology will present a series of short educational communications related to evidence-based medicine. The aim of the series is to emphasize the importance of grading evidence, thereby determining the best clinical practice for patients. The goal of this series is to guide the clinician in using tools for setting up a clinical question, finding appropriate information, searching appropriate databases, and evaluating the results in relation to the patient in mind. This first part will serve as an introduction or background. Following publications will cover the topics of hierarchy of evidence, information acquisition, clinical appraisal tools, and applications in clinical practice [3].

What about my daughter's future? Parental concerns when considering female genital restoration surgery in girls with congenital adrenal hyperplasia.

PURPOSE: The parental decision-making process regarding female genital restoration surgery (FGRS) for girls with congenital adrenal hyperplasia (CAH) is controversial and poorly understood. The aim of the study aim was to evaluate parental concerns related to their child's future and parental plans about disclosure prior to FGRS. MATERIALS AND METHODS: The authors performed an online survey of consecutive parents presenting at a tertiary referral center for consultation regarding FGRS for their daughter with CAH before 3 years of age (2016-2018). Twenty issues initially identified by three families and six clinicians were rated on a 6-point Likert scale of importance ('not at all' to 'extremely'). RESULTS: Sixteen consecutive families participated (Prader 3/4/5: 43.8%/43.8%/12.5%). Fourteen girls (87.5%) subsequently underwent FGRS at a median age of 8 months. Most issues (19/20, 95.0%) were ranked 'quite a bit' to 'extremely' important (Table). Top issues were not surgical: Normal physical/mental development, adrenal crisis and side-effects of medications. Surgery-related and self-image concerns followed in importance. Least prioritized issues were multiple genital exams ('quite a bit' important) and the child not being involved in the decision to proceed with FGRS ('somewhat' important). On average, no issues were considered 'not at all' or 'a little' important. Disclosure of FGRS to their daughter was the 15th prioritized issues. Almost all families (93.8%, 1 unsure) planned to disclose the surgery to their daughter, although many were unsure when and how to do it (33.3% and 37.5%, respectively). COMMENT: Initial efforts to understand the complex process of parental decision-making regarding FGRS in the context of CAH, a complex, multifactorial disease, are presented. Parents of infant girls with CAH simultaneously weigh multiple life-threatening concerns with a decision about FGRS. While issues of genital ambiguity and surgery are important, they are not overriding concerns for parents of girls with CAH. Parents report significant uncertainty about appropriate timing and approach to disclosing FGRS to their daughters. Unfortunately, best practice guidelines for this process are lacking. The findings are not based on actual history of disclosure but on parents' anticipated behavior. Further data are need from parents, children, and women with CAH about successful disclosure. Being a single-center series, these data may not correspond to the wider CAH community. CONCLUSIONS: Parental decision-making regarding FGRS is multifactorial. Even when considering FGRS, parents' largest concerns remain focused on the life-threatening and developmental effects of CAH and side-effects of its medical treatment. The disclosure process deserves further attention.

A case of base rate bias, or are adolescents at a higher risk of developing complications after catheterizable urinary channel surgery?

OBJECTIVE: Adolescents are considered to be at high risk of developing complications after lower genitourinary tract reconstruction. This perception may be due to base rate bias, where clinicians favor specific information (adolescents with complications), while ignoring more general information (number of total adolescents being followed). The goal of this study was to assess whether age was a true risk factor for subfascial and stomal revisions after continent catheterizable urinary (CCU) channel procedures. MATERIALS AND METHODS: Consecutive patients aged <21 years and who underwent appendicovesicostomy and Monti surgery at the present institution were retrospectively reviewed; demographic and surgical data were collected. Time to subfascial or stomal revision was stratified by age at initial surgery (child: <8, preteen: 8-12, adolescent: 13-17, adult: ≥18 years old) and analyzed with Cox proportional-hazards regression. Secondary analyses included: different age categories at initial surgery (<8, 8-11, 12-15, 16-19, ≥20 years), analyzing age as a continuous and a time-varying covariate. RESULTS: Of the 510 patients with CCU channels (median age at surgery: 7.9 years), 63 (12.4%) had subfascial and 53 (10.4%) had stomal revision (median follow-up: 6.8 years). Median age at subfascial and stomal revision was 11.3 and 10.3 years, respectively. Preteens contributed 33.0% and adolescents contributed 29.3% of the total follow-up time (3263.9 person-years). Over 80% of revisions occurred within 5 years of surgery, regardless of age at initial surgery (P ≥ 0.57) (Summary table). On multivariate analysis, age at initial surgery was not associated with undergoing subfascial (P ≥ 0.62) or stomal revisions (P ≥ 0.69). Montis were 2.1 times more likely than appendicovesicostomies to undergo a subfascial revision (P = 0.03). No other variables were associated with the risk of subfascial or stomal revision (P ≥ 0.11). Secondary analyses provided similar results. DISCUSSION: Since the median age at surgery was 8 years old and most complications occurred within the first 5 years of follow-up, it is not surprising that most revisions occurred in 8-13 year olds. Pediatric urologists appear to base their impression of adolescents being "high risk" on specific information (adolescents having complications), while subconsciously ignoring more general information (adolescents represent a large proportion of patients in follow-up). This study had several limitations: channel complications treated non-surgically (e.g. prolonged catheterization) were not included. The findings may not be generalizable to other genitourinary reconstructive procedures or clinical settings. CONCLUSIONS: While complications were twice as high in Monti channels than appendicovesicostomies, no single age group was at increased risk. The impression that adolescents are a high-risk group appears to represent a base rate bias.

Ambulatory patients with spina bifida are 50% more likely to be fecally continent than non-ambulatory patients, particularly after a MACE procedure.

INTRODUCTION: While fecal incontinence (FI) affects many patients with spina bifida (SB), it is unclear if it is associated with ambulatory status. OBJECTIVE: To determine if ambulatory status is associated with FI, and a potential confounding variable, in patients with and without a Malone antegrade continence enema (MACE). STUDY DESIGN: This study retrospectively reviewed of patients aged ≥8 years with SB who were enrolled in an international quality of life study at outpatient visits (January 2013 to September 2015). Patients reported FI over the last 4 weeks (strict criteria: any FI/accidents vs no FI). Patients unable to self-report FI due to developmental delay were excluded. Those who were ambulating outdoors with/without braces/crutches were considered community ambulators. Non-parametric tests and logistic regression were used for analysis. RESULTS: A total of 115 patients with a MACE and 57 without a MACE were similar in gender (P = 0.99), ventriculoperitoneal status (P = 0.15) and age (16.0 vs 15.4 years, P = 0.11). Median ages at MACE procedure and follow-up were 7.0 and 8.2 years, respectively, and all used the MACE ≥3x/week. They were less likely to be ambulators (54.8 vs 71.9%, P = 0.03). In patients with a MACE, 64 (55.7%) had total fecal continence, compared with 29 (50.9%) without a MACE (P = 0.62). In the MACE group, ambulators were more likely to be continent compared with non-ambulatory patients (65.1 vs 44.2%, P = 0.04) (Table). Although not statistically significant, a similar difference was observed in the non-MACE group (56.1 vs 37.5%, P = 0.25). In the MACE group, continent and incontinent patients, regardless of ambulatory status, had similar rates of MACE use, additive use and time for MACE completion (P ≥ 0.43). MACE ambulators were more likely to be continent than MACE non-ambulators on multivariate analysis (OR 3.26, P = 0.01). DISCUSSION: This study reported higher than typical FI rates since: (1) it used a stringent definition of total fecal continence; (2) patients without FI were perhaps less likely to participate; and (3) it relied on patient-reported rather than clinician-reported outcomes. This cross-sectional study should not be interpreted as "MACE procedure is ineffective;" this would require a longitudinal study. The present findings may not apply to young children or those with significant developmental delay (patients excluded from the study). CONCLUSIONS: Ambulatory patients with SB are 50% more likely to have total fecal continence on long-term follow-up, particularly after a MACE procedure. Ambulatory status is a significant confounder of FI and should be considered in future analyses.

Long-term follow-up of composite bladder augmentation incorporating stomach in a multi-institutional cohort of patients with cloacal exstrophy.

INTRODUCTION: Composite bladder augmentation, incorporating gastric and bowel segments, has the theoretical advantage of metabolic neutrality while potentially avoiding the morbidities of gastrocystoplasty, such as hematuria-dysuria syndrome. The most common indication for this operation is a paucity of bowel, such as in cloacal exstrophy. Despite several early descriptive studies of this technique, there are no reports, to date, of long-term follow-up in this population. OBJECTIVE: To describe the outcomes of composite bladder augmentation utilizing stomach in a cohort of cloacal exstrophy patients. MATERIALS AND METHODS: A retrospective review of cloacal exstrophy patients who underwent composite bladder augmentation from 1984 to 2006 at two institutions was performed. The incidence of mortality and morbidities related to augmentation was evaluated. RESULTS: Eleven patients with cloacal exstrophy underwent composite bladder augmentation. Median age at initial augmentation was 6.4 years (interquartile range (IQR) 4.4-9.1). Median follow-up was 13.2 years (IQR 11.2-24.6). The Summary table describes the types of composite bladder augmentations. Of the three patients with pre-operative metabolic acidosis, two improved with composite bladder augmentation and one developed metabolic alkalosis. Three developed hematuria-dysuria syndrome: one improved with staged ileocystoplasty, and two had persistent symptoms successfully treated with H2 receptor blockers. Two of 11 developed symptomatic bladder stones. There were no reported bladder perforations, bladder malignancies, conversions to incontinent urinary diversions, or deaths. CONCLUSION: With long-term follow-up, very few patients developed metabolic acidosis/alkalosis after composite bladder augmentation. The composite bladder augmentation will continue to be used in patients with cloacal exstrophy, in order to minimize the impact on the pre-existing short gut in these patients.

Long-term outcomes of the Kropp and Salle urethral lengthening bladder neck reconstruction procedures.

INTRODUCTION: The Kropp and Salle procedures have shown good short-term outcomes for managing neuropathic urinary incontinence. However, few studies have assessed their long-term results. OBJECTIVE: This study aimed to evaluate the long-term outcomes of Kropp and Salle procedures, including: dryness, secondary interventions for incontinence or complications, upper urinary tract changes, and use of urethral catheterizations. STUDY DESIGN: Consecutive patients undergoing Kropp and Salle procedures at the present institution (1983-2012) were retrospectively reviewed. Patients with <1-year follow-up or prior bladder neck (BN) continence procedures were excluded. Data were collected on postoperative dryness per urethra at 4-hourly and 3-hourly intervals, secondary interventions, lab tests, and imaging. Non-parametric tests were used for statistical analysis. RESULTS: Thirty-eight patients had Kropp (K: 30 boys) and 12 had Salle procedures (S: 8 boys). Patients underwent surgery at similar median ages (K: 7.4 vs S: 8.7 years old, P = 0.51) and had similar median follow-up (6.9 vs 10.3 years, P = 0.10). Most patients had myelomeningocele, a prior/concomitant bladder augmentation (K: 73.7%, S: 58.3%) and catheterizable channel (K: 81.6%, S: 50.0%). Differences in all outcomes between Kropp and Salle procedures were statistically non-significant. The majority of patients did not have additional BN procedures for dryness (K: 84.2%, S: 66.7%). Of this group, K: 81.3% and S: 75.0% were dry for ≥4 h, K: 93.8% and S: 87.5% were dry for ≥3 h between catheterizations (Table). Of the minority of patients who underwent additional BN procedures for dryness (K: 15.8%, S: 33.3%), most achieved dryness for ≥4 h (K: 66.7%, S: 100%) and ≥3 h (100% for both). Among patients without an initial catheterizable channel, 57.1% had one subsequently created after a Kropp procedure, and 33.3% after a Salle. Among patients without bladder augmentation, approximately half underwent delayed augmentation (K: 50.0%, S: 40.0%). Ultimately, most patients required a secondary intervention under anesthesia for incontinence or complications (K: 79.0%, S: 66.7%). Few patients developed worsening hydronephrosis, vesicoureteral reflux or renal function (K: 2.6%, S: 0.0%). At the end of follow-up, few patients catheterized per urethra (K: 10.5%, S: 33.3%). DISCUSSION: This was a retrospective study without urodynamic data. Originating from a tertiary center, the results may not apply to other clinical settings. CONCLUSIONS: At the present institution the Kropp and Salle procedures attained similar dryness in 75-81% at 4-hourly intervals and 88-94% at 3-hourly intervals without additional BN procedures. Few patients required subsequent BN procedures to achieve dryness. However, the overall need for secondary procedures during long-term follow-up was high for both procedures.

Is renal scintigraphy necessary after heminephrectomy in children?

INTRODUCTION: Heminephrectomy remains an excellent option for a poorly functioning moiety in a duplicated collecting system. A primary concern during heminephrectomy is the potential for a significant functional loss in the remaining ipsilateral moiety. As the gold standard for the assessment of differential renal function, renal scintigraphy is often used in the postoperative evaluation of children undergoing heminephrectomy. However, this imaging modality is costly, invasive, and associated with exposure to radiation. Doppler renal ultrasound (RUS) avoids these concerns and is able to evaluate for structural and functional abnormalities. OBJECTIVE: The present study sought to compare Doppler RUS to renal scintigraphy in determining the viability of the remaining ipsilateral moiety in children who underwent heminephrectomy for a poorly functioning moiety in a duplicated collecting system. MATERIALS AND METHODS: The institutional database of children who underwent open heminephrectomy for a poorly functioning moiety in a duplicated collecting system between 2006 and 2013 was reviewed. Only children who underwent both a postoperative Doppler RUS and renal scan were included. A blinded pediatric radiologist independently reviewed all Doppler RUS. Vascular flow on Doppler RUS was correlated with the preservation of renal function in the remaining ipsilateral moiety on renal scintigraphy. RESULTS: A total of 29 children were identified for inclusion. Demographic and operative data are provided in Table. The average pre-operative and postoperative differential renal function in the ipsilateral kidney was 41.6% and 38% on renal scintigraphy, respectively, for an average decrease of 3.6% (-18% to +12%). Doppler RUS demonstrated the presence of vascular flow to the remaining ipsilateral moieties of all children after heminephrectomy. Renal scintigraphy confirmed the viability of these moieties in all children. DISCUSSION: The first study comparing Doppler RUS to renal scintigraphy was performed to determine the viability of the remaining ipsilateral moiety after heminephrectomy. While no cases of complete functional loss were observed, an average decrease of 3.6% in the ipsilateral renal function favorably compared with other series of children undergoing open heminephrectomy. The limitations of the study included its retrospective design at a single institution. The interpretation of Doppler RUS by an individual pediatric radiologist may also have lead to interobserver variability and impacted the reproducibility of the study, while the absence of any cases of complete functional loss may have impacted its generalizability. CONCLUSIONS: Doppler RUS is an accurate imaging modality for determining the viability of the remaining ipsilateral moiety after heminephrectomy and may obviate the need for renal scintigraphy.

A comparison of the Monti and spiral Monti procedures: A long-term analysis.

INTRODUCTION/BACKGROUND: The Monti ileovesicostomy provides an excellent substitution for an appendicovesicostomy when the appendix is unavailable or suitable for use. The spiral Monti is a useful modification to the traditional Monti as it allows creation of a longer channel when needed. In 2007, the short-term outcomes were reported; they compared traditional and spiral Monti in 188 patients with an average follow-up of 43 months. In the present population, a total of 25 subfasical revisions were performed in 21 patients: nine (8.3%) subfascial revisions in the traditional Monti (TM) patients and 12 (15.2%) subfascial revisions in the spiral Monti (SM) patients. The study found an increased risk of subfascial revisions of either TM or SM when the stoma was located at the umbilicus versus right lower quadrant (16.8% vs 6.3%, P < 0.05). On subgroup analysis, this increased subfascial revision rate appeared to be driven by SM channels to the umbilicus rather than other stomal locations, but this trend was not statistically significant. OBJECTIVE: It was hypothesized that with longer follow-up, the spiral Monti would require more subfascial revisions due to progressive lengthening of the channel. STUDY DESIGN: A retrospective chart review was performed for all patients undergoing a traditional Monti (TM) or spiral Monti (SM) procedure at the present institution (1997-2013). Patient demographics, bowel segment used, stomal location, channel or stomal revisions, number of anesthetic endoscopic procedures performed, and indications for revision were reviewed. Kaplan-Meier analysis and Cox proportional hazards modeling was used for analysis. RESULTS: Of the 296 patients identified, 146 had Monti procedures and 150 had spiral Monti procedures (median follow-up 7.7 years). Median age at surgery was 10.6 years. Myelomeningocele was the most common underlying cause of neuropathic bladder, totaling 169 (57.1%) patients. Stomas were located at the umbilicus (106, 35.8%), right lower quadrant (183, 61.8%) and left lower quadrant (seven, 2.4%). Median follow-up for the entire cohort was 7.7 years (range: 1 month-15.7 years). Stomal stenosis rate was 7.4%, and 96.6% of the channels were continent. A total of 87 revisions were performed in 74 patients (25.0%). Of these, 55 were subfascial revisions in 49 patients (16.6%). The umbilical spiral Monti on univariate and multivariate analysis was found to be over twice as likely to undergo subfascial revision. DISCUSSION: The majority of patients with a Monti channel had durable results and did not require further channel surgery with long-term follow-up. Spiral Monti channels to the umbilicus were more than twice as likely to undergo subfascial revision compared to all other Monti channels. Overall, one in three umbilical SM channels required a subfascial revision at 10 years after the initial surgery, compared to one in six of all other Monti channels. The study was limited by being a retrospective, single-center series; however, it does represent the largest series of pure SM and TM patients. It focused only on surgical interventions, thus was likely to underestimate the overall risk of complications, as some complications were managed conservatively. As in all studies, some patients were lost to follow-up and inevitably some of these may have had complications. Correction for this was attempted through survival analysis. CONCLUSION: The present study reported durable and reliable long-term results with Monti and spiral Monti procedures based on a large patient cohort. Spiral Monti to the umbilicus was more than twice as likely to require a subfascial revision.

Ultrasound classification of solitary renal cysts in children.

INTRODUCTION: Solitary renal cysts are typically incidentally found in children who have undergone renal ultrasound (US). The main concern is a cystic tumor. There is no US-based grading system for children to guide management. OBJECTIVE: To evaluate a US-based, modified Bosniak grading system in order to differentiate between simple (grade I or II) and complex (grade II or IV) renal cysts and guide management in children. STUDY DESIGN: This was a retrospective (2003-2011) study of 212 children (114 females), age range one day to 17 years (mean 8.4 years), with solitary renal cysts diagnosed by US. Two radiologists, who were independent and blinded to clinical information, graded the cysts using the modified Bosniak classification system. In children with more than one year of follow-up US, the change (>10%) in cyst diameter was evaluated. Inter-observer variability (Kappa) was calculated. RESULTS: Radiologists one and two saw simple renal cysts in 96.2-96.6% (204-205/212) of the children. Ten children had complex renal cysts, as rated by either of the radiologists. There was good inter-observer agreement (kappa = 0.65) for simple versus complex cysts. In 20.2% (18/89) of the children, the cysts increased in size. A definitive diagnosis was obtained in 8.5% (18/212) of the children. A cystic tumor (multilocular cystic nephroma) was found in one child (Figure) with a complex cyst (graded III by both radiologists). DISCUSSION: The use of a modified Bosniak classification system to grade renal cysts was found to have good inter-observer variability (kappa = 0.65) in differentiating between simple and complex renal cysts. Using this classification, few (<4%) renal cysts were classified as complex. Cystic tumors are rare and the only cystic tumor (multilocular cystic nephroma) was classified as complex renal cysts by the two radiologists. Growth of simple, solitary renal cyst is common (20.2%) and, therefore, if not associated with other imaging findings, is not an indication for a cystic tumor. There were limitations inherent in the retrospective nature of the study and because only one child had a cystic tumor. CONCLUSION: The modified Bosniak classification system demonstrated good inter-observer agreement, and identified the single tumor as a complex cyst. The vast majority of solitary renal cysts in children are simple and if asymptomatic, they require no other imaging evaluation. Complex renal cysts are uncommon and should be evaluated with a pre-intravenous and postintravenous contrast CT scan to exclude a tumor.

Assessment of uric acid and lipid peroxidation in serum and urine after hypoxia-ischemia neonatal in rats.

The aim of this study was to evaluate urinary uric acid (UA) and lipid peroxidation levels, plasma myeloperoxidase (MPO) and adenosine deaminase (ADA) activities, and serum UA in neonatal rats subjected to hypoxia-ischemia neonatal HI model. The relevance of the findings is the fact that urinary lipid peroxidation and UA levels were significantly higher in 8 days in HI group when compared with the control, returning to baseline levels 60 days after HI. Hence, being an indication of purinic degradation during these first days post-HI. Furthermore, the higher levels of malondialdehyde (MDA) in urine in this period may be related to inadequate scavenging abilities of the immature nervous system and being noninvasive it may suggest the use of urinary MDA measurement as a marker for lipid peroxidation after HI insult. In application terms, these findings can help develop therapeutic interventions as soon as 8 days after HI.