Human umbilical cord allograft associated with higher pediatric urethrocutaneous fistula repair success rates.

BACKGROUND: Urethrocutaneous fistula (UCF) formation is a known complication following hypospadias repair, affecting between 5 and 70% of cases. Moreover, approximately 30% of patients experience refistulization after UCF repair. The use of extracellular matrices, such as AmnioCord, a dehydrated human umbilical cord allograft manufactured by MiMedx®, may mitigate high rates of refistulization. OBJECTIVE: To determine whether the use of AmnioCord during UCF repair is associated with reduced incidence of subsequent UCFs among pediatric patients. DESIGN, SETTING, AND PARTICIPANTS: Electronic medical records were retrospectively reviewed among 60 patients who underwent at least one UCF repair at a pediatric hospital in a large urban setting in the U.S. between January 2012-June 2018. Patients were followed through January 2024. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adjusted generalized estimating equation regression models were used to assess the association between AmnioCord use and rates of refistulization, while controlling for confounding variables. RESULTS: The number of fistula presentations per patient ranged from one to four; 53.3% had one fistula, 30.0% had two, and 16.6% had three or more. Overall fistula repair success rate was 56.8% but significantly differed by AmnioCord use in adjusted modelling; 69.4% of cases that received AmnioCord were successfully repaired, compared to 47.2% of cases that did not receive AmnioCord. In adjusted models, patients who received AmnioCord had 2.66 times greater odds of surgical success than patients who did not receive AmnioCord (95% CI:1.13-6.24; p = 0.02). CONCLUSIONS: This study demonstrates a positive association between AmnioCord use and successful UCF closure among pediatric patients.

[Temporal analysis of the prevalence of congenital hypospadias in the municipality of Gela]. / Analisi temporale della prevalenza di ipospadia congenita nel comune di Gela.

OBJECTIVES: to evaluate the risk profile of hypospadias in Gela, an Italian National Priority Contaminated Site (NPCS) located in Sicily Region (Southern Italy), characterized by a significant excess of hypospadias in newborn residents compared to data from reference on regional, national, and international basis and, until 2014, by the presence of a petrochemical plant. DESIGN: geographical analyses were conducted by comparing the prevalence of the Gela municipality to prevalence found in Sicily, in a territorial area bordering Gela (ALG), and in the NPCSs of Milazzo and Priolo. The geographical comparisons were conducted for the period 2010-2020, the trend within the Gela NPCS was evaluated by comparing two subperiods (2010-2014 and 2015-2020). SETTING AND PARTICIPANTS: children up to 1 year of age with hypospadias resident in the municipality of Gela in the period 2010-2020. MAIN OUTCOMES MEASURES: crude odds ratios (OR) and respective 95% confidence intervals (95%CI) were used to compare the prevalence observed in Gela and that detected in the comparison areas. RESULTS: excess risk for hypospadias was highlighted in 2010-2020 in Gela vs Sicily (OR 4.45; 95%CI 3.45-5.75), vs ALG (OR 4.29; 95%CI 3.02-6.10), and vs the NPCSs of Milazzo (OR 2.32; 95%CI 1.32-4.07) and Priolo (OR 2.37; 95%CI 1.55-3.62). The between-period comparisons in Gela did not show an important difference between 2010-2014 and 2015-2020 (OR 1.37; 95%CI 0.83-2.24), with a prevalence of 98.9 and 72.4 per 10,000, respectively. CONCLUSIONS: the prevalence of hypospadias in 2015-2020 remains very high, although decreasing when compared to 2010-2014 period. The Gela data, despite the refinery being closed after 2014, suggest a complex situation in which multiple risk factors may play a role.

The effect of preoperative hormonal stimulation on the urethral plate; A histologic and histochemical study.

AIM OF THE WORK: Preoperative hormone stimulation (PHS) is used to increase the glans size and may improve the cosmetic appearance after hypospadias surgery. The exact effect of PHS on different penile tissues remains unclear and controversial. Previous studies showed that PHS increased vessel density in the foreskin. However, the effect of PHS on the urethral has never been studied before. In this study we examine the PHS effects on the urethral plate. MATERIALS AND METHODS: Specimens of the urethral plate and the underlying tissue were excised to correct severe chordee in 16 children with proximal and perineal hypospadias with severe chordee in 2 groups. Group A consisted of 8 children received PHS prior to surgery. Group B included 8 children with proximal and perineal hypospadias with severe chordee who did not receive PHS and served as a control group. Specimens were examined blindly using hematoxylin-eosin and elastic van-Gieson stain as well as factor 8 and SMA antibodies. RESULTS: The median age of Group A was 13 (range 10-20) months. The median age of Group B (without prior PHS) was 17 (range 14-29) months (p = 0,03). The median vessel-density in group A (82 vessels per mm2) was significantly higher than in Group B (65 per mm2), (p < 0.05). The median vessel diameter was also significantly higher in Group A (13 µm) than in Group B (11 µm), (p < 0.05). The median epithelial layer thickness in Group A was 110 µm and in Group B 98 µm, but showed no statistical significance (p = 0,16). There was no significant change in dartos fascia layer thickness or androgen receptor expression. There was no visual change in the organization of elastic fibers. CONCLUSION: This study is the first study to document the effect of PHS on the urethral plate in hypospadias with severe chordee. PHS significantly increased the median vessel-density as well as median vessel diameter as compared to a matching control group. The findings of the study may justify PHS administration before the first operation to improve the vascularity and may reduce the severity of chordee.

PTPN11 and FLNA variants in a boy with ambiguous genitalia, short stature, and non-specific dysmorphic features.

Noonan syndrome is a congenital disorder characterized by distinctive facial appearance, congenital heart defects, short stature, and skeletal dysplasia. Although boys with Noonan syndrome frequently exhibit cryptorchidism, a mild form of 46,XY disorders of sex development (DSD), they barely manifest more severe genital abnormalities. Here, we report a boy with ambiguous genitalia, short stature, and non-specific dysmorphic features. He had no cardiac abnormalities or skeletal dysplasia. His score in the Noonan syndrome diagnostic criteria (36 of 157 points, 23%) was lower than the cutoff for diagnosis (50%). Whole-exome sequencing identified a de novo heterozygous variant (c.922A>G: p.Asn308Asp) in PTPN11 and a maternally inherited hemizygous variant (c.1439C>T: p.Pro480Leu) in FLNA. The PTPN11 variant was a known causative mutation for Noonan syndrome. FLNA is a causative gene for neurodevelopmental and skeletal abnormalities and has also been implicated in 46,XY DSD. The p.Pro480Leu variant of FLNA was assessed as deleterious by in silico analyses. These results provide evidence that whole-exome sequencing is a powerful tool for diagnosing patients with atypical disease manifestations. Furthermore, our data suggest a possible role of digenic mutations as phenotypic modifiers of Noonan syndrome.

Case Report: Urethral Diverticulum after Tubularised Incised Plate Repair of Distal Hypospadias: An Uncommon Complication.

Introduction: A urethral diverticulum can be defined as a pocket that forms from the lining of the urethra and protrudes into the surrounding tissue, a condition which causes voiding dysfunction and may result as a rare complication of hypospadias repair surgery. Case report: We report the case of a 2-year-old child who presented to us in 2019 complaining of a thin forceful stream, ballooning of the ventral aspect of the penis while voiding, and post-void dribbling. He has a history of undergoing a tubularised incised plate urethroplasty for distal penile hypospadias at 18-months-old. Ultrasound showed increased post-void residual volume and cystourethroscopy confirmed a urethral diverticulum extending from the subcorona to the base of the penis. The patient underwent partial excision of diverticulum, urethroplasty, and meatoplasty. He was followed-up 3 months later with complete resolution of his symptoms and a normal urinary stream with no urethral ballooning or dribbling. Conclusion: Urethral diverticulum may present as a complication post hypospadias repair. Although it is rare, we believe that it is important for the patient's parents to understand the possibility and know of the signs and symptoms in addition to attending regular outpatient clinic appointments in order to facilitate early management if needed. Furthermore, it is highly important for physicians to assess newborns for hypospadias before carrying out circumcision as it is a contraindication for the procedure.

The possible role of epigenetics in the etiology of hypospadias.

INTRODUCTION: Hypospadias is a common malformation of the genitourinary system and is thought with a complex interplay between genetics and environmental factors likely contributing to its pathogenesis. This study aimed to investigate the receptor gene expressions of sex hormones, FGFR2, FGF8 and BMP7 and DNA methylations in these genes as an epigenetic mark, which may play a role in the etiology of hypospadias. MATERIAL AND METHODS: The samples from the foreskin of 20 patients with hypospadias and 20 healthy children who underwent circumcision operations were collected. AR, ESR1, FGF8, FGFR2 and BMP7 gene expressions and DNA methylation rates of these genes were investigated in tissues. RESULTS: While ESR1, FGFR2 and BMP7 gene expressions were found to be significantly higher in the hypospadias group, AR gene expression was found to be lower. In the hypospadias group, DNA methylation rates were found to be significantly higher in the ESR1, FGF8 and FGFR2 genes, but lower in the AR gene (Table). DISCUSSION: Recent clinical studies suggest that epigenetic modifications may play a significant role in genital development, potentially contributing to the etiology of hypospadias. Our recent study demonstrated significant differences in foreskin AR, ESR1, and FGFR2 gene expression between patients with hypospadias and controls. To address this, the present study investigated DNA methylation levels of these same genes in hypospadias patients, hypothesizing that epigenetic modifications might be responsible for the observed gene expression changes. We again observed abnormalities in AR, ESR1, and FGFR2 gene expression in hypospadias patients. Furthermore, we found that DNA methylation patterns associated with these genes differed significantly between hypospadias and control groups. CONCLUSIONS: Our study demonstrates significant alterations in DNA methylation of sex hormone receptor genes (ESR1 and AR), FGFR2, and FGF8, which correlate with abnormal expression of these genes in hypospadias cases. These findings suggest a potential role for epigenetic modifications in hypospadias etiology.

Optimal timing for plastic surgical procedures for common congenital anomalies: A review.

Apart from listening to the cry of a healthy newborn, it is the declaration by the attending paediatrician in the labour room that the child is normal which brings utmost joy to parents. The global incidence of children born with congenital anomalies has been reported to be 3%-6% with more than 90% of these occurring in low- and middle-income group countries. The exact percentages/total numbers of children requiring surgical treatment cannot be estimated for several reasons. These children are operated under several surgical disciplines, viz, paediatric-, plastic reconstructive, neuro-, cardiothoracic-, orthopaedic surgery etc. These conditions may be life-threatening, e.g., trachea-oesophageal fistula, critical pulmonary stenosis, etc. and require immediate surgical intervention. Some, e.g., hydrocephalus, may need intervention as soon as the patient is fit for surgery. Some, e.g., patent ductus arteriosus need 'wait and watch' policy up to a certain age in the hope of spontaneous recovery. Another extremely important category is that of patients where the operative intervention is done based on their age. Almost all the congenital anomalies coming under care of a plastic surgeon are operated as elective surgery (many as multiple stages of correction) at appropriate ages. There are advantages and disadvantages of intervention at different ages. In this article, we present a review of optimal timings, along with reasoning, for surgery of many of the common congenital anomalies which are treated by plastic surgeons. Obstetricians, paediatricians and general practitioners/family physicians, who most often are the first ones to come across such children, must know to guide the parents appropriately and convincingly impress upon the them as to why their child should not be operated immediately and also the consequences of too soon or too late.

Transitional Urology in Korea: Initial Insights Through a Cross-Sectional Study.

PURPOSE: In Korea, the field of transitional urology (TU) is in its nascent stages, with its introduction only beginning. This study aims to evaluate the existing state of TU prior to implementing a transition protocol, and to identify key areas of focus for the development of an effective transition protocol. METHODS: From June 1, 2021 to May 31, 2023, clinical data were retrospectively collected for patients who visited the adult urology or pediatric urology outpatient departments of this hospital and were aged 10 or older, with medical conditions falling under the category of TU. We analyzed the patient distribution across different disease groups. The transitional stages were categorized from T1, indicating initial care by pediatric urologists, to T4, denoting complete transition to adult care. 'T4x' was used for patients with unknown medical histories, and 'T4only' for those who had never been under pediatric urology care. RESULTS: During a 2-year period, a total of 1,484 patients received outpatient care for diseases in TU field. The most prevalent diseases were hypospadias (40.4%), spinal bifida (37.3%), and congenital ureteral anomalies (17.7%), with other conditions accounting for 4.6%. Among 553 spinal bifida patients, only 5.3% completed transitional care (T4), while 80.1% were in the initial phase (T1). For patients introduced to adult urology (T2-T4), 37.7% reached T4, highlighting a marked increase in transition completion within this subset (P<0.001). CONCLUSION: TU in Korea is in its nascent stage, with a significant gap in the initiation and completion of transitional care for patients with congenital urologic conditions. Early initiation and active engagement in transitional care are crucial for successful transition. This study highlights the need for structured transition protocols to address the complex needs of this patient population.

Long-term Effects of Pre-operative Testosterone and Dihydrotestosterone on Glans Width in Boys With Hypospadias.

BACKGROUND: Small glans width is a risk factor for urethroplasty complications. This study aimed to assess and compare short- and long-term effects of two pre-operative topical androgen treatment protocols on maximum glans width. Furthermore, to evaluate post-operative complications when surgery was delayed >3 months following hormonal treatment completion. METHODS: Topical 2.5% dihydrotestosterone (February 2016-July 2018) and 5% testosterone (August 2018-December 2022) treatment protocols, completed >3 months before surgery, were offered to all children with proximal hypospadias and small glans width requiring urethroplasty. Serial glans width measurements were collected prospectively pre- and post-androgen treatment. Demographic data and complications were collected retrospectively. RESULTS: A significant increase in mean glans width was observed following both dihydrotestosterone (6.1 mm [95% CI 4.3-7.9 mm] pre-dihydrotestosterone to 14.9 mm [13.2-16.6 mm, p < 0.0001] post-dihydrotestosterone in 11 children) and testosterone (10.5 mm [9.9-11.1 mm] pre-testosterone to 14.6 mm [13.7-15.5 mm, p < 0.0001] post-testosterone in 32 children). Serial post-treatment measurements showed no loss of gained width >1 year after treatment completion. Mean increase in glans width from pre-treatment measurement at 0-3 months, 4-12 months and >12 months following treatment was 7 mm (95% CI 3.8-10.2), 9 mm (7.2-10.8) and 10 mm (7.3-12.7) post-dihydrotestosterone and 4.4 mm (95% CI 3.4-5.4 mm), 4.3 mm (3.5-5.2) and 5.1 mm (4-6.2) post-testosterone respectively. Complications were noted in 4/22 patients who received topical androgen prior to initial hypospadias surgery and had completed all surgical stages. CONCLUSIONS: Both treatment protocols produced a significant, sustained increase in glans width. Delaying hypospadias surgery for >3 months following androgen application may circumvent androgen induced vascularity and poor wound healing. LEVEL OF EVIDENCE: Level IV. TYPE OF STUDY: Treatment study.

Teaching hypospadias repair by utilising a novel 3D-printed silicon model: An initial assessment using structured trainee and trainer feedback.

INTRODUCTION: Simulated paediatric surgical training is inherently advantageous and flourishing. Moreover, several working conditions resulted in reduced training hours, index and subspecialty cases encountered, and the COVID-19 pandemic affected elective surgery backlogs, hence training opportunities. Hypospadias repair is technically-demanding and requires a spectrum of dissective and reconstructive skills. We therefore aimed to test a 3D-printed silicon model for hypospadias repair, in the context of hands-on surgical training. MATERIAL AND METHODS: Twenty-Seven trainees, under the supervision of 15 instructors, completed the activity. They were given a seminar to show the relevant anatomy, and 8 key steps of the exercise: (1)-degloving; (2)-urethral plate marking; (3)-incision; (4)-tubularisation; (5)-glansplasty/glanuloplasty; (6)-dartos layer preparation; (7)-preputioplasty and (8)-skin closure. Each trainee completed a structured feedback assessment. An on-site trainer supervised and evaluated each exercise. Trainees and trainers rated the model through the above steps from unsatisfactory-(1/5) to excellent-(5/5), presented herein via cross-sectional analysis. RESULTS: Eleven-(40.7 %) trainees were in years:1-3 of specialist training, 10-(37 %) were in years:4-6, and 6-(22.2 %) were beyond year-6. Two-(7.4 %) trainees had nil-hypospadias experience, 16-(59.2 %) previously assisted in procedures or performed steps, 5-(18.5 %) performed whole procedures supervised and 4-(14.8 %) independently. Twenty-(74 %) trainees and 15-(100 %) instructors judged the model to resemble the anomaly. Seventeen-(63 %) trainees and 13-(86.6 %) instructors rated the material needle-penetrability ≥3/5, compared to human tissue. Sixteen-(59 %) trainees and 13-(86.6 %) instructors rated the material suture holding ≥3/5. Eleven-(73.3 %) trainees and 13-(86.6 %) instructors rated sutures' evenness and edge coaptability ≥3/5. DISCUSSION: Hypospadias is an index operation, which requires precision skills. Simulated training in Paediatric Surgery and Urology is gaining importance. 3D-printed models are gaining a key role in simulated training. The study presents a novel 3D-printed high-fidelity silicon-based hypospadias model designed for hands-on training. A structured pathway to divide a standard hypospadias repair into key steps is displayed to ensure skill acquisition and stabilisation. CONCLUSION: This 3D-printed silicon-based hypospadias model is proven useful for hands-on training. The fidelity can still improve, especially regarding suture holding of the material. LEVEL OF EVIDENCE: LEVEL III.

Evaluation of postoperative complications of hypospadias using high-frequency ultrasound imaging.

PURPOSE: Various complications following hypospadias surgery present distinct manifestations when examined with ultrasound. Utilizing high-frequency ultrasound, clinicians can promptly identify these complications and initiate appropriate treatment. The aim of this study is to catalogue the ultrasonographic presentations of various postoperative complications following hypospadias surgery, thereby providing a reference for ultrasonographic diagnosis. METHODS: Ultrasonic images of post-hypospadias surgery from October 1, 2015, to June 30, 2023, recorded at the Plastic Surgery Hospital of the Chinese Academy of Medical Sciences, serve as the basis for this investigation. Drawing on patient clinical diagnoses, this study compiles and selects representative ultrasound images of diverse complications. RESULTS: The study encompassed a total of 121 subjects; 26 demonstrated urethral stricture on ultrasonic images, two presented local urethral dilation, six showed intraurethral hair-like structures, 17 revealed intraurethral septum, two exhibited intraurethral fold, one had urethral calculus, one displayed urethral calcification, 12 indicated intraurethral urine accumulation, and two showed urethral diverticulum. CONCLUSION: Ultrasound examination is helpful for postoperative diagnosis following hypospadias, detecting complications such as urethral stricture, urethral hair growth, and urethral diverticulum, which can help doctors choose appropriate clinical treatment strategies.

Application of intraoperative structured light scanning to enable post-operative evaluation of digital and 3D-printed penile models.

BACKGROUND: Penile phenotype in hypospadias is currently assessed visually or manually (e.g., ruler, goniometer) for clinical, education, and research applications. However, these methods lack precision and accuracy across raters and cannot be reevaluated retrospectively following a surgical repair. The project aim was to evaluate the precision and reliability of penile dimensions obtained from digital and three dimensional (3D) printed models created from intraoperative (OR) structured light scans (SLS) during primary pediatric penile procedures. METHODS: Boys ages 1 month to 6 years underwent first- or single-stage penile surgery at a single institution were enrolled in this prospective study (IRB #20-000143). For each patient, immediately following placement of a stay suture under consistent manual tension, intra-operative dimension measurements with a ruler were obtained. A digital 3D model was created prior to penile repositioning using an Artec Space Spider scanner and Artec Studio 13 software. Following the case, two different raters completed 10 digital measurements of each generated model in Autodesk Fusion 360. These digital models were subsequently 3D printed and two different raters completed 10 manual dimension measurements of each 3D printed model using a ruler. A one-way random effects intraclass correlation coefficient (ICC) evaluated measures of agreement between and within raters, respectively. Analyses were conducted in R version 4.2. RESULTS: Six scans were obtained (hypospadias: 4, circumcision: 2). Intra-rater assessments showed excellent precision across repeated digital measurements; manual measurements of 3D printed models had excellent reliability for glans width and penile length but poor to good reliability for glans height. Inter-rater reliability was good to excellent for glans width (0.77-0.95) and good for penile length (0.71-0.88). However, there was poor inter-rater reliability for glans height (0-0.14). Following training regarding glans height location, there was an improvement in precision and repeatability of manual and digital measurements. CONCLUSION: Digital measurement of OR-derived 3D models resulted in excellent repeatability for each rater and improved between-rater reliability over manual measurement of 3D printed models alone, ensuring that images can be compared by various surgeons both now and in the future. SLS is promising as a novel modality to digitally generate 3D models, thereby informing phenotypic analysis for research and education. Further development of digital measurement methods to ensure consistency between raters for quantitative assessment of additional parameters and assessment of the technology within the pre-operative environment for surgical planning is planned.

The impact of audiovisual information on parental anxiety levels prior to hypospadias surgery: A prospective single center cohort study.

BACKGROUND: Most parents have anxiety before a pediatric surgical procedure. Parental anxiety may impair the parents' ability to cope with new or stressful situations while their children are undergoing surgery. By effectively improving the education of parents regarding the diagnosis, treatment, and potential complications of hypospadias and surgical repair, it might be feasible to reduce their anxiety during this process. OBJECTIVE: To determine whether structured audiovisual information would reduce parents' anxiety levels compared to classic verbal information. MATERIAL AND METHODS: The diagnosis was made and, treatment options were explained, and State-Trait Anxiety Inventory Form - State Anxiety (STAI-I) forms were filled out by parents at the first consultation. In the second consultation, parents were divided into structured audio-visual-information (Group-1) and classic verbal information (Group-2) groups. Following these consultations, all parents in both groups filled out STAI-I again. Parents filled out the forms for the last time on the postoperative-14th-day and the results were compared. RESULTS: A total of 124 (51.2%) parents were informed with structured-audiovisual-informational material and 118 parents (48.8%) were informed with classic verbal information. First STAI-I scores were 57.65 ± 5.17 and 56.91 ± 5.28 for Group-1 and Group-2, respectively, and there was no difference between the groups (p = 0.709). The STAI-I scores after the second consultation were 44.82 ± 5.65 and 49.42 ± 2.81 for Group-1 and Group-2, respectively. Parental anxiety decreased in both groups following the second consultation. Notably, a statistically significant superiority was found between the groups in favor of Group-1 (p = 0.001). DISCUSSION: Parents whose children will undergo hypospadias surgery experience significant anxiety. We observed that informing patients adequately and in appropriate language using a suitable method was associated with less anxiety. Preoperative parental anxiety is influenced by several variables, including parent age, parent gender, child age, lack of knowledge, and concerns over complications or pain. Although we are unable to alter the factors of child age and parent gender, we can impact parents' concerns regarding postoperative pain and anesthesia by enhancing their comprehension of the procedure via providing them of sufficient and accurate information. CONCLUSION: Providing parents with structured audio-visual information about the preoperative and postoperative period before hypospadias surgery is associated with lower parental anxiety levels. Supplying structured audiovisual information regarding the preoperative and postoperative periods can help parents have an improved comprehension of the procedure and minimize their anxiety.

Epigenetic insights to pediatric uropathology: Celebrating the fundamental biology vision of Tony Khoury.

INTRODUCTION: Many pediatric urology conditions affect putatively normal tissues or appear too commonly to be based solely on specific DNA mutations. Understanding epigenetic mechanisms in pediatric urology, therefore, has many implications that can impact cell and tissue responses to settings, such as environmental and hormonal influences on urethral development, uropathogenic infections, obstructive stimuli, all of which originate externally or extracellularly. Indeed, the cell's response to external stimuli is often mediated epigenetically. In this commentary, we highlight work on the critical role that epigenetic machinery, such as DNA methyltransferases (DNMTs), Enhancer of Zeste Polycomb Repressive Complex 2 Subunit (EZH2), and others play in regulating gene expression and cellular functions in three urological contexts. DESIGN: Animal and cellular constructs were used to model clinical pediatric uropathology. The hypertrophy, trabeculation, and fibrosis of the chronically obstructed bladder was explored using smooth muscle cell models employing disorganised vs. normal extracellular matrix (ECM), as well as a new animal model of chronic obstructive bladder disease (COBD) which retains its pathologic features even after bladder de-obstruction. Cell models from human and murine hypospadias or genital tubercles (GT) were used to illustrate developmental responses and epigenetic dependency of key developmental genes. Finally, using bladder urothelial and organoid culture systems, we examined activity of epigenetic machinery in response to non uropathogenic vs. uropathogenic E.coli (UPEC). DNMT and EZH2 expression and function were interrogated in these model systems. RESULTS: Disordered ECM exerted a principal mitogenic and epigenetic role for on bladder smooth muscle both in vitro and in CODB in vivo. Key genes, e.g., BDNF and KCNB2 were under epigenetic regulation in actively evolving obstruction and COBD, though each condition showed distinct epigenetic responses. In models of hypospadias, estrogen strongly dysregulated WNT and Hox expression, which was normalized by epigenetic inhibition. Finally, DNA methylation machinery in the urothelium showed specific activation when challenged by uropathogenic E.coli. Similarly, UPEC induces hypermethylation and downregulation of the growth suppressor p16INK4A. Moreover, host cells exposed to UPEC produced secreted factors inducing epigenetic responses transmissible from one affected cell to another without ongoing bacterial presence. DISCUSSION: Microenvironmental influences altered epigenetic activity in the three described urologic contexts. Considering that many obstructed bladders continue to display abnormal architecture and dysfunction despite relief of obstruction similar to after resection of posterior valves or BPH, the epigenetic mechanisms described highlight novel approaches for understanding the underlying smooth muscle myopathy of this crucial clinical problem. Similarly, there is evidence for an epigenetic basis of xenoestrogen on development of hypospadias, and UTI-induced pan-urothelial alteration of epigenetic marks and propensity for subsequent (recurrent) UTI. The impact of mechanical, hormonal, infectious triggers on genitourinary epigenetic machinery activity invite novel avenues for targeting epigenetic modifications associated with these non-cancer diseases in urology. This includes the use of deactivated CRISPR-based technologies for precise epigenome targeting and editing. Overall, we underscore the importance of understanding epigenetic regulation in pediatric urology for the development of innovative therapeutic and management strategies.

Evaluation of USG-guided novel sacral erector spinae block for postoperative analgesia in pediatric patients undergoing hypospadias repair: A randomized controlled trial.

Background and Aims: Erector spinae plane block (ESPB) has been found to be simple, safe, and effective at thoracic and lumbar levels. There is no randomized controlled trial evaluating its effectiveness at sacral level. The present study was conducted to evaluate its effectiveness at sacral level for postoperative analgesia in pediatric patients undergoing hypospadias repair. Material and Methods: Forty children of 2-7 years with ASA grade I or II were included. They were randomly allocated to one of the two groups of 20 patients each. After induction of general anesthesia, patients of group I were given ultrasound-guided sacral ESPB with 1 ml/kg of 0.25% bupivacaine, and patients of group II were not given block. Postoperatively, pain was assessed using face, legs, activity, cry, consolability (FLACC) scale at 0 hour, every 15 min up to 1 hour, every half an hour up to 2 hours, 2 hourly up to 12 hours, and at 18th hour and 24th hour postoperatively. At FLACC score ≥4, rescue analgesia was given using 15 mg/kg paracetamol infusion. Primary objective was to compare postoperative analgesic (paracetamol) consumption, and secondary objective was time to first rescue analgesia. Results: Mean postoperative paracetamol consumption was 360 ± 156.60 mg in group I and 997.50 ± 310.87 mg in group II (P = 0.001). Time to first rescue analgesia was 906 ± 224.51 min in group I and 205.00 ± 254.92 min in group II (P = 0.001). Conclusion: Sacral ESPB has been found to be effective in reducing postoperative analgesic consumption in pediatric patients undergoing hypospadias repair.

Comparison of hypospadias phenotype pixel segmentation to GMS score.

BACKGROUND: Hypospadias phenotype assessment determines if the anatomy is favorable for reconstruction. Glans-Urethral Meatus-Shaft (GMS) has been adopted in an effort to standardize hypospadias classification. While extremely subjective, GMS has been widely used to classify the severity of the phenotype to predict surgical outcomes. The use of digital image analysis has proven to be feasible and prior efforts by our team have demonstrated that machine learning algorithms can emulate an expert's assessment of the phenotype. Nonetheless, the creation of these image recognition algorithms is highly subjective. In order to reduce a subjective input in the evaluation of the phenotype, we propose a novel approach to analyze the anatomy using digital image pixel analysis and to compare the results using the GMS score. Our hypothesis is that pixel cluster segmentation can discriminate between favorable and unfavorable anatomy. OBJECTIVE: To evaluate whether image segmentation and digital pixel analysis are able to analyze favorable vs unfavorable hypospadias anatomy in a less subjective manner than GMS score. METHODS: A total of 148 patients with different types of hypospadias were classified by 1 of 5 independent experts following the GMS score into "favorable" (GG), "moderately favorable" (GM) and "unfavorable" (GP) glans. From there, 592 images were generated using digital image segmentation. 584 were included for final analysis due to certain images being excluded for poor image quality or inadequate capture of target anatomy. For each image, the region of interest was segmented separately by two evaluators into "glans," "urethral plate," "foreskin" and "periurethral plate". The values obtained for each segmented region using machine-learning statistical pixel k-means cluster analysis were analyzed and compared to the GMS score given to that image using an ANOVA analysis. RESULTS: Analysis of image segmentation demonstrated that k-means pixel cluster analysis discriminated "favorable" vs "unfavorable" urethral plates. There was a significant difference between scores when comparing the GG and GM groups (p = 0.03) and GG and GP groups (p = 0.05). Pixel cluster analysis could not discriminate between "moderately favorable" and "unfavorable" urethral plates. CONCLUSIONS: Through our analysis, we found significant pairwise difference for different tissue qualities. Digital image segmentation and statistical k-means cluster analysis can discriminate anatomical features in a similar way to the GMS score. Future research can target discerning between different tissue qualities in an effort to predict surgical outcomes for hypospadias repair.

Development and verification of machine learning model based on anogenital distance, penoscrotal distance, and 2D:4D finger ratio before puberty to predict hypospadias classification.

Objectives: To describe the anatomical abnormalities of hypospadias before puberty using current commonly used anthropometric index data and predict postoperative diagnostic classification. Methods: Children with hypospadias before puberty who were initially treated at Sichuan Provincial People's Hospital from April 2021 to September 2022 were selected. We recorded their preoperative penoscrotal distance, anogenital distance, 2D:4D finger ratio, and postoperative hypospadias classification. The receiver operating character curve was used for univariate analysis of the diagnostic predictive value of each index for hypospadias classification in the training set. Binary logistic regression, random forest, and support vector machine models were constructed. In addition, we also prospectively collected data from October 2022 to September 2023 as a test set to verify the constructed machine learning models. Results: This study included 389 cases, with 50 distal, 167 midshaft, and 172 proximal cases. In the validation set, the sensitivity of the binary LR, RF, and SVM was 17%, 17% and 0% for identifying the distal type, 61%, 55% and 64% for identifying the midshaft type, and 56%, 60% and 48% for identifying the proximal type, respectively. The sensitivity of the three-classification RF and SVM models was 17% and 17% for distal type, 64% and 73% for midshaft type, 60% and 60% for proximal type, respectively. In the Testing set, the sensitivity of the binary LR, RF and SVM was 6%, 0% and 0% for identifying the distal type, 64%, 55% and 66% for identifying the midshaft type, and 48%, 62% and 39% for identifying the proximal type, respectively. The sensitivity of the three-classification RF and SVM models was 12% and 0% for distal type, 57% and 77% for midshaft type, and 65% and 53% for proximal type, respectively. Compared with binary classification models, the sensitivity of the three-classification models for distal type was not improved. Conclusion: Anogenital distance and penoscrotal distance have a favorable predictive value for midshaft and proximal hypospadias, among which AGD2, with higher test efficiency and stability, is recommended as the preferred anogenital distance indicator. The 2D:4D finger ratio (RadioL, RadioR) has little predictive value for hypospadias classification.

Maternal PM2.5 exposure and hypospadias risk in Chinese offspring: Insights from a nationwide surveillance-based study.

Research on the association between maternal PM2.5 exposure and hypospadias risk in male offspring, particularly in highly polluted areas, has been limited and inconsistent. This study leveraged data from China's National Population-based Birth Defects Surveillance System spanning the years 2013 to 2019, and employed sophisticated machine learning models to estimate daily PM2.5 levels and other pollutants for mothers at a 1-km resolution and a 6-km buffer surrounding maternal residences. Multivariate logistic regression analyses were performed to evaluate the relationship between PM2.5 exposure and hypospadias risk. For sensitivity analyses, stratification analysis was conducted, and models for one-pollutant and two-pollutants, as well as distributed lag nonlinear models, were constructed. Of the 1194,431 boys studied, 1153 cases of hypospadias were identified. A 10 µg/m3 increase in maternal PM2.5 exposure during preconception and the first trimester was associated with an elevated risk of isolated hypospadias, with Odds Ratios (ORs) of 1.102 (95% CI: 1.023-1.188) and 1.089 (95% CI: 1.007-1.177) at the 1-km grid, and 1.122 (95% CI: 1.034-1.218) and 1.143 (95% CI: 1.048-1.246) within the 6-km buffer. Higher quartiles of PM2.5 exposure were associated with increased odds ratios compared to the lowest quartile. These findings highlight a significant association between PM2.5 exposure during the critical conception period and an elevated risk of isolated hypospadias in children, emphasizing the need for targeted interventions to reduce PM2.5 exposure among expectant mothers.