Management of 220 adolescents and adults with complications of hypospadias repair during childhood

Objective:The goal of hypospadias repair is to achieve normal voiding and good penile cosmesis with minimal complications.Some urethroplasties deteriorate from childhood to adolescence and late stage failures have been reported.We report our experience with adult patients who have had a previous repair during childhood and present with a late complication.Methods:We reviewed the records of 220 patients aged 15e39 years old with a history of hypospadias repair who presented to our clinic.Forty-five patients with chordee,39 with urethral strictures,11 urethral fistulae,five with hairy urethras,three with urethral diverticula,and 117 patients with an abnormal glans or subterminal meatus were repaired.Results:Median follow-up was 14 months.Two patients had persistent chordee.Island skin flap urethroplasty afforded one patient with a urethral fistula and another with a recurrent urethral stricture,while the buccal mucosa group had one fistula which healed spontaneously and two recurrent strictures.For the patients undergoing glanular repairs,seven had dehiscence or breakdown of the repair.All other operations were successful.Conclusion:Complications of childhood hypospadias repair may present later in life as some urethroplasties deteriorate with time.We now recommend to parents of children with repaired proximal hypospadias to come for follow-up as their child transitions to adolescence.

A pilot study of the association between genetic polymorphisms involved in estrogen signaling and infant male genital phenotypes

Single nucleotide polymorphisms （SNPs） in genes that influence development of the male reproductive tract have been associated with male genitourinary abnormalities. However, no studies have tested the relationship between SNPs and intermediate phenotypes such as anogenital distance （AGD）, anoscrotal distance （ASD） and penile width （PW）. We tested whether 24 common SNPs in eight genes that influence male genital development were associated with intermediate phenotypes in 106 healthy male infants from the Study for Future Families. We used DNA from buccal smears and linear regression models to assess the relationship between anogenital measurements and SNP genotypes with adjustment for covariates. We found that the rs2077647 G allele, located in the coding region of estrogen receptor alpha （ESR1）, was associated with a shorter AGD （P=0.02; -7.3 mm, 95% confidence interval （CI）： -11.6 to -3.1）, and the rs10475 T allele, located in the 3＇ untranslated region of activating transcription factor 3 （ATF3）, was associated with a shorter ASD （-4.3 mm, 95% Ch -7.2 to -1.4）, although this result was not significant （P=0.07） after controlling for multiple comparisons. We observed no association between PW and the SNPs tested. Minor alleles for two SNPs in genes that regulate estrogen signaling during male genital development were associated with AGD and ASD, although the significance of the association was marginal. Our findings suggest that AGD and ASD are influenced by heritable factors in genes known to be associated with frank male genital abnormalities such as hvpospadias and crvotorchidism.

Interventional Radiology Procedures after Pediatric Pyeloplasty and Ureteral Reimplantation in Patients with Postoperative Obstruction

Introduction: Obstructive complication after pyeloplasty or ureteral reimplant surgery is a rare though worrisome problem in pediatric urology. These are often complex patients with complicated post-operative courses that at times require interventional radiology procedures. The current literature is lacking in guiding principles to manage these complications. In this study we have reviewed these difficult to manage patients at our children’s hospital over the past 15 years. Methods: A list of patients who underwent interventional radiology procedures to place nephrostomy tubes or internal double-J ureteral stents was compared a list of patients undergoing pyeloplasty or reimplant procedures. These lists were cross-referenced to a list of patients undergoing cystoscopic removal of double-J stents. This small patient group does not represent all complications but those with radiology intervention. Results: At our institution, during the years 1998-2011 we performed 458 pyeloplasties and 3003 open ureteral reimplant procedures. 14 (0.4%) met all of the inclusion criteria. The long term outcome of these problems showed 11 of these patients went on to stability or improvement with either percutaneous drainage or JJ stent placement alone, and three of the reimplant patients ultimately required redo surgery. Of our pyeloplasty patients only three required percutaneous nephrostomy tube, and one went on to JJ stent placement (0.66% of pyeloplasties). No patients in the pyeloplasty group needed surgical revision. Of patients how had undergone ureteral reimplantation, with or without tapering, seven of them underwent interventional radiology procedures (0.23% of reimplant patients). Conclusion: Pediatric urology patients with persistent obstruction after pyeloplasties and ureteral reimplantation surgery with or without tapering who needed interventional radiology rescue procedure resolved or stabilized in 11 of 14 patients. Surgical revision was performed in only 3 of our 14 patients after months of conservative trial after interventional radiologic procedures.

Multiplex gene editing reduces oxalate production in primary hyperoxaluria type 1

Targeting key enzymes that generate oxalate precursors or substrates is an alternative strategy to eliminate primary hyperoxaluria type I(PH1),the most common and lifethreatening type of primary hyperoxaluria.The compact Clustered Regularly Interspaced Short Palindromic Repeats(CRISPR)from the Prevotella and Francisella 1(Cpf1)protein simplifies multiplex gene editing and allows for all-in-one adeno-associated virus(AAV)delivery.We hypothesized that the multiplex capabilities of the Cpf1system could help minimize oxalate formation in PH1 by simultaneously targeting the hepatic hydroxyacid oxidase 1(Hao1)and lactate dehydrogenase A(Ldha)genes.Study cohorts included treated PH1 rats(Agxt Q84X rats injected with AAV-AsCpf1 at 7 days of age),phosphate-buffered saline(PBS)-injected PH1 rats,untreated PH1 rats,and age-matched wild-type(WT)rats.The most efficient and specific CRISPR RNA(crRNA)pairs targeting the rat Hao1and Ldha genes were initially screened ex vivo.In vivo experiments demonstrated efficient genome editing of the Hao1 and Ldha genes,primarily resulting in small deletions.This resulted in decreased transcription and translational expression of Hao1 and Ldha.Treatment significantly reduced urine oxalate levels,reduced kidney damage,and alleviated nephrocalcinosis in rats with PH1.No liver toxicity,ex-liver genome editing,or obvious offtarget effects were detected.We demonstrated the AAVAsCpf1 system can target multiple genes and rescue the pathogenic phenotype in PH1,serving as a proof-ofconcept for the development of multiplex genome editingbased gene therapy.

Robot-assisted extravesical ureteral reimplantation with ureteral tailoring and dismembering for complex obstructed megaureter

Dear Editor,The advantages of robotic technology including improved dexterity and visualization are particularly evident in challenging reconstructive procedures of the lower urinary tract[1,2].A recent literature review confirmed the feasibility and efficacy of robot-assisted ureteral reimplantation in case of complex anatomy or prior surgery[3].Intra-corporeal ureteral tapering and dismembering are also feasible options using robot-assisted surgery[4].

Regenerative medicine based applications to combat stress urinary incontinence

Stress urinary incontinence(SUI), as an isolated symptom, is not a life threatening condition. However, the fear of unexpected urine leakage contributes to a significant decline in quality of life parameters for afflicted patients. Compared to other forms of incontinence, SUI cannot be easily treated with pharmacotherapy since it is inherently an anatomic problem. Treatment options include the use of bio-injectable materials to enhance closing pressures, and the placement of slings to bolster fascial support to the urethra. However, histologic findings of degeneration in the incontinent urethral sphincter invite the use of tissues engineering strategies to regenerate structures that aid in promoting continence. In this review, we will assess the role of stem cells in restoring multiple anatomic and physiological aspects of the sphincter. In particular, mesenchymal stem cells and CD34+cells have shown great promise to differentiate into muscular and vascular components,respectively. Evidence supporting the use of cytokines and growth factors such as hypoxia-inducible factor1-alpha, vascular endothelial growth factor, basic fi-broblast growth factor, hepatocyte growth factor and insulin-like growth factor further enhance the viability and direction of differentiation. Bridging the benefits of stem cells and growth factors involves the use of synthetic scaffolds like poly(1,8-octanediol-co-citrate)(POC) thin films. POC scaffolds are synthetic, elastomeric polymers that serve as substrates for cell growth,and upon degradation, release growth factors to the microenvironment in a controlled, predictable fashion.The combination of cellular, cytokine and scaffold elements aims to address the pathologic deficits to urinary incontinence, with a goal to improve patient symptoms and overall quality of life.

LL-37 induced cystitis and the receptor for advanced glycation end-products (RAGE) pathway

To elucidate pathways in bladder inflammation, we employed our physiologically relevant LL-37 induced cystitis model. Based on inflammatory studies involving other organ systems implicating the receptor for advanced glycation end-products (RAGE), we first hypothesized that RAGE is critically involved in LL-37 induced cystitis. We further hypothesized that?a common RAGE ligand high mobility group box 1 (HMGB1) is up-regulated in bladders challenged with LL-37. Finally, we hypothesized that NF-κB dependent inflammatory genes are activated in LL-37 induced cystitis. Testing our first hypothesis, C57Bl/6 mice were challenged with either saline (control) or 320 μM of LL-37 intravesically for 1 hr. After 12 or 24 hours, tissues were examined with immunohistochemistry (IHC) for RAGE, and both mRNA and protein isolation for respective qRT-PCR and Western Blot analysis. Our second hypothesis was tested by employing HMGB1 IHC. Testing our final hypothesis, qRT-PCR was performed investigating five genes: TNFα, IL-6, IL-1β, GM-CSF, COX-2. In control and LL-37 challenged tissues, IHC for RAGE revealed similar qualitative expression. Evaluation with qRT-PCR and Western Blot for RAGE revealed diminished expression at the mRNA and protein level within LL-37 challenged bladders. IHC for HMGB1 revealed a moderate qualitative increase within LL-37 challenged tissues. Finally, with the exception of TNFα, all NF-κB dependent inflammatory genes yielded substantial up-regulation. We have employed our LL-37 induced cystitis model to gain insight to wards a possible mechanistic pathway involved in bladder inflammation. This work provides data for future studies involving the inflammatory ligand HMGB1, RAGE, and receptor pathways that activate NF-κB.

Kidney Stones in Transfusion-Dependent Thalassemia: Prevalence and Risk Factors

Purpose: As patients with transfusion-dependent thalassemia (TDT) are living longer, novel morbidities are being recognized. The purpose of this review is to summarize the current knowledge regarding the prevalence and risk factors of nephrolithiasis in patients with TDT. Methods: A non-systematic, narrative review of the current literature published up to August 2021 was conducted. Results: Nephrolithiasis has been reported in 18% - 59% of patients with TDT, which is at least twice the prevalence in the general US population. The risk factors for nephrolithiasis can be classified into behavioral (dietary and lifestyle), environmental, metabolic, disease-specific, and genetic factors. While clarifying the true prevalence of nephrolithiasis in different age groups and diagnostic categories of TDT requires further research, prevention, and management of nephrolithiasis is a growing clinical concern. Physicians should be aware of the potential increased risk of stone disease in splenectomized and diabetic patients as well as those treated with certain chelation regimens. Conclusions: The etiology of nephrolithiasis and potential TDT-specific risk factors that may put patients at greater risk are highlighted. There is insufficient evidence at this time to recommend universal screening for nephrolithiasis using ultrasound. Evidence-based recommendations on monitoring, prevention, and management of nephrolithiasis in TDT are provided.

Benign penile skin anomalies in children:a primer for pediatricians

Background:Abnormalities involving the skin coverage of the penis are diffi cult to defi ne,but they can significantly alter penile appearance,and be a cause of parental concern.Data sources:The present review was based on a non-systematic search of the English language medical literature using a combination of key words including"penile skin anomalies"and the specific names of the different conditions.Results:Conditions were addressed in the following order,those mainly affecting the prepuce(phimosis,balanitis xerotica obliterans,balanitis,paraphimosis),those which alter penile configuration(inconspicuous penis and penile torsion),and lastly focal lesions(cysts,nevi and vascular lesions).Most of these anomalies are congenital,have no or minimal influence on urinary function,and can be detected on clinical examination.Spontaneous improvement is possible.In the majority of cases undergoing surgery,the potential psychological implications of genital malformation on patient development are the main reason for treatment,and the age generally recommended for surgery is after 12 months of age.Conclusion:This review provides the pediatrician with a handy tool to identify the most common penile skin anomalies,counsel parents adequately,make sensible and evidence based choices for management,and recognize complications or untoward outcomes in patients undergoing surgery.

Commentary on"Spongiosum-combined glanuloplasty reduces glans complications after proximal hypospadias repair"

Dear Editor,We read the recent article by Lyu et al.^(1)with great interest and appreciate their efforts in describing a new technique for glansplasty in children with proximal hypospadias.In this article,the images that locate the diverted corpus spongiosum are almost the same as those described using the glanular-frenular collar(GFC)technique.^(2)We would therefore like to thank the authors for adopting the GFC technique as a model for their reconstructive technique.

A stepwise treatment approach to neonatal genital prolapse

INTRODUCTION Neonatal genital prolapse (NGP) is a rare phenomenon that is typically associated with spinal cord malformations. Several treatment methods have been described, on a case report basis, ranging from digital reduction, the intravaginal self-retaining device for pelvic support, to more invasive partial labial fusion. In this report, we describe a case of severe congenital neonatal genital prolapse and the management approach pursued.