Posterior Tibial Nerve Stimulation in Children with Lower Urinary Tract Dysfunction: A Mixed-Methods Analysis of Experiences, Quality of Life and Treatment Effect.

BACKGROUND: Posterior tibial nerve stimulation (PTNS) is one of the treatment modalities for children with therapy-refractory lower urinary tract dysfunction (LUTD). This study used a mixed-methods analysis to gain insight into the experiences of children treated with PTNS and their parents, the effect of treatment on quality of life (QOL) and the effect of PTNS on urinary symptoms. METHODS: Quantitative outcomes were assessed through a single-centre retrospective chart analysis of all children treated with PTNS in a group setting between 2016-2021. Voiding parameters and QOL scores before and after treatment were compared. Qualitative outcomes were assessed by an explorative study involving semi-structured interviews transcribed verbatim and inductively analysed using the constant-comparative method. RESULTS: The data of 101 children treated with PTNS were analysed. Overall improvement of LUTD was seen in 42% and complete resolution in 10%. Average and maximum voided volumes significantly increased. QOL improved in both parents and children independent of the actual effect on urinary symptoms. Interviews revealed PTNS to be well-tolerated. Facilitating PTNS in a group setting led to feelings of recognition in both children and parents. CONCLUSIONS: PTNS is a good treatment in children with therapy-refractory LUTD and provides valuable opportunities for peer support if given in a group setting.

Congenital Adrenal Hyperplasia-Current Insights in Pathophysiology, Diagnostics, and Management.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21-hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000, there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in CAH with special attention to these new developments.

Sex Assignment and Diagnostics in Infants with Ambiguous Genitalia - A Single-Center Retrospective Study.

Ambiguous genitalia affect 1 in 5,000 live births. Diagnostic procedures can be time-consuming, and often the etiology cannot be established in this group of individuals with differences/disorders of sex development (DSD). We aimed to evaluate the clinical presentation, sex assignment, and diagnostic workup in these patients. In this retrospective observational study, we included infants who presented with ambiguous genitalia from 2006 to 2016 at the Radboudumc (Radboud University Medical Center) DSD expert center. Relevant data were collected from patient records. Sixty-two 46,XY and fourteen 46,XX individuals were included. Sex was assigned in the first days of life and based on the combination of presence or absence of a uterus on ultrasound, AMH level, palpable gonads, and the karyotype (corresponded in 96% of the patients). In 86% of the 46,XX DSD subjects, a diagnosis was made, whereas in only 15/62 (24%) of the 46,XY DSD individuals, etiology was determined. In 52 individuals, genetic testing was performed resulting in a diagnosis in 24 patients (46%). AMH, hCG-stimulated testosterone, and dihydrotestosterone levels contributed to determining etiology, whilst basal testosterone and basal dihydrotestosterone did not. Establishing a diagnosis in infants with ambiguous genitalia is complex and challenging; this study aids to enhance this process and improve current practice.

Preoperative Illnesses in Children Do Not Increase the Risk of Complications After Hypospadias Repair.

BACKGROUND: Preoperative illnesses might induce immunosuppression and subsequently increase morbidity after surgery. Several studies have tried to identify risk factors for complications after hypospadias correction, but effects of illnesses in the weeks just before surgery are unknown. We aimed to determine the associations between preoperative illnesses not severe enough to postpone surgery and short-term complications after hypospadias repair in children. METHODS: In this retrospective cohort study, data were collected from 681 children with anterior or middle type hypospadias that had initial 1-stage repair in the period 1983-2012 in the Radboudumc, The Netherlands. The associations between common illnesses, such as common cold, fever and ear infection, within 2 weeks before repair, and postoperative complications, such as urethrocutaneous fistula, wound dehiscence and stenosis, within 2 months and 1 year after surgery, were analyzed using multivariable logistic regression analyses. RESULTS: Of the 681 boys, 22% had preoperative illnesses, most often common cold, and 14% had postoperative complications. Children with preoperative illnesses had fewer postoperative complications within 2 months (n = 13, 9%) than children without preoperative illnesses (n = 79, 16%), resulting in a 50% risk reduction (odds ratio: 0.49; 95% confidence interval: 0.26-0.93). Preoperative infections (common cold, fever and ear infection), in particular, reduced the risk of postoperative infections (wound and urinary tract infections; odds ratio: 0.37; 95% confidence interval: 0.14-0.98). Results were similar for complications within 1 year. CONCLUSIONS: Common preoperative illnesses not severe enough to postpone surgery did not increase the postoperative complication risk and even seemed to have a protective effect, especially for postoperative infections. Consequently, there is no reason to alter preoperative screening.

The Impact of γ-Irradiation and EtO Degassing on Tissue Remodeling of Collagen-based Hybrid Tubular Templates.

Clinical implementation of novel products for tissue engineering and regenerative medicine requires a validated sterilization method. In this study, we investigated the effect of γ-irradiation and EtO degassing on material characteristics in vitro and the effect on template remodeling of hybrid tubular constructs in a large animal model. Hybrid tubular templates were prepared from type I collagen and Vicryl polymers and sterilized by 25 kGray of γ-irradiation or EtO degassing. The in vitro characteristics were extensively studied, including tensile strength analysis and degradation studies. For in vivo evaluation, constructs were subcutaneously implanted in goats for 1 month to form vascularized neo-tissue. Macroscopic and microscopic appearances of the γ- and EtO-sterilized constructs slightly differed due to additional processing required for the COL-Vicryl-EtO constructs. Regardless of the sterilization method, incubation in urine resulted in fast degradation of the Vicryl polymer and decreased strength (<7 days). Incubation in SBF was less invasive, and strength was maintained for at least 14 days. The difference between the two sterilization methods was otherwise limited. In contrast, subcutaneous implantation showed that the effect of sterilization was considerable. A well-vascularized tube was formed in both cases, but the γ-irradiated construct showed an organized architecture of vasculature and was mechanically more comparable to the native ureter. Moreover, the γ-irradiated construct showed advanced tissue remodeling as shown by enhanced ECM production. This study shows that the effect of sterilization on tissue remodeling cannot be predicted by in vitro analyses alone. Thus, validated sterilization methods should be incorporated early in the development of tissue engineered products, and this requires both in vitro and in vivo analyses.

Ureteral Reconstruction in Goats Using Tissue-Engineered Templates and Subcutaneous Preimplantation.

Repair of long ureteral defects often requires long graft tissues and extensive surgery. This is associated with complications, including a lack of suitable tissue and graft site morbidity. Tissue engineering may provide an attractive alternative to the autologous graft tissues. In this study, ureteral repair using (preimplanted) tubular collagen-Vicryl templates was evaluated in a new goat model. Tubular templates were prepared from tubularized Vicryl meshes and 0.7% type-I collagen (length = 6 cm, inner diameter = 6 mm, wall thickness = 3 mm). In total, twelve goats were used and evaluated after 3 months. Eight goats were implanted with the collagen-Vicryl templates and in four goats the templates were first preimplanted in the subcutis and subsequently used as ureteral graft. Template implantation was successful in 92% of the goats(11/12). During follow-up, 82% of the animals (9/11) survived without signs of discomfort. Two animals were sacrificed prematurely due to kidney perforation by the stent and urine leakage. Two other animals presented with stenosis of the neoureter due to stent migration. After preimplantation, the templates were remodeled mostly to autologous tissue with similar mechanical characteristics as the native ureter. Goats grafted with preimplanted templates presented with predominantly healthy kidneys, whereas the goats grafted with the collagen-Vicryl templates presented with fibrotic and inflamed regions in the kidneys. The use of preimplanted tissue templates showed favorable results compared with direct functional implantation of the templates. Partial remodeling toward autologous tissue and similar mechanical characteristics likely improved the integration in the ureteral tissue. Preimplantation of tissue-engineered templates should therefore be considered when two-stage procedures using a nephrostomy catheter are indicated or when planning allows for additional time to treatment.

Bladder Regeneration Using Multiple Acellular Scaffolds with Growth Factors in a Bladder.

INTRODUCTION: Tissue engineering may become an alternative to current bladder augmentation techniques. Large scaffolds are needed for clinically significant augmentation, but can result in fibrosis and graft shrinkage. The purpose of this study was to investigate the use of multiple scaffolds instead of one large scaffold, to enhance bladder tissue regeneration and bladder capacity. Second, acellular collagen, collagen-heparin, and collagen-heparin scaffolds with growth factors (GFs) were used and the biological activity of the different scaffolds was compared in a large animal model. MATERIALS AND METHODS: Scaffolds were made of bovine type I collagen with or without heparin (Ø = 3.2 cm). Collagen-heparin scaffolds were loaded with GFs, vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), and heparin-binding epidermal growth factor (HB-EGF). Three identical scaffolds prepared from collagen (COL-group), collagen with heparin (COLHEP-group), or collagen-heparin with growth factors (COLHEPGF-group) were implanted in one porcine bladder. The outcome was compared with sham-operated animals (Sham-group), in which no scaffold was used. Urodynamic evaluation was performed before surgery and 3 months after bladder reconstruction, together with histological evaluation. RESULTS: Survival rate was 92%, 12 animals completed the study, 3 of every group, 1 animal developed peritonitis due to urine leakage and was sacrificed. The regenerated area was largest in the COLHEP-group, and least in the COL-group (p = 0.002). Histological evaluation revealed a normal urothelial layer and good angiogenesis in all groups, and comparable ingrowth of smooth muscle cells. Urodynamics showed no statistically significant differences in bladder capacity and compliance between groups. Bladder capacity and compliance was very high in this animal model, which made it impossible to study the increase due to augmentation. CONCLUSIONS: Implantation of multiple collagen-heparin scaffolds in one bladder is feasible in a porcine model, resulting in tissue almost indistinguishable from native tissue involving all cell layers of the bladder. Collagen scaffolds with heparin incorporated resulted in a larger area of regenerated tissue. To reach clinically significant augmentation, multiple larger collagen-heparin scaffolds, with or without GFs, need to be tested to study the largest possible diameter of scaffold and number of used scaffolds still resulting in well-vascularized tissue.

Clinical protocol levels are required in laboratory animal surgery when using medical devices: experiences with ureteral replacement surgery in goats.

It is common to test medical devices in large animal studies that are or could also be used in humans. In this short report we describe the use of a ureteral J-stent for the evaluation of biodegradable tubular constructs for tissue reconstruction, and the regeneration of ureters in Saanen goats. Similarly to a previous study in pigs, the ureteral J-stent was blindly inserted until some resistance was met. During evaluation of the goats after three months, perforation of the renal cortex by the stent was observed in four out of seven animals. These results indicated that blind stent placement was not possible in goats. In four new goats, clinical protocols were followed using X-ray and iodinated contrast fluids to visualize the kidney and stent during stent placement. With this adaptation the stents were successfully placed in the kidneys of these four new goats with minimal additional effort. It is likely that other groups in other fields ran into similar problems that could have been avoided by following clinical protocols. Therefore, we would like to stress the importance of following clinical protocols when using medical devices in animals to prevent unnecessary suffering and to reduce the number of animals needed.

Tubular Constructs as Artificial Urinary Conduits.

PURPOSE: A readily available artificial urinary conduit might be substituted for autologous bowel in standard urinary diversions and minimize bowel associated complications. However, the use of large constructs remains challenging as host cellular ingrowth and/or vascularization is limited. We investigated large, reinforced, collagen based tubular constructs in a urinary diversion porcine model and compared subcutaneously pre-implanted constructs to cell seeded and basic constructs. MATERIALS AND METHODS: Reinforced tubular constructs were prepared from type I collagen and biodegradable Vicryl® meshes through standard freezing, lyophilization and cross-linking techniques. Artificial urinary conduits were created in 17 female Landrace pigs, including 7 with a basic untreated construct, 5 with a construct seeded with autologous urothelial and smooth muscle cells, and 5 with a free graft formed by subcutaneous pre-implantation of a basic construct. All pigs were evaluated after 1 month. RESULTS: The survival rate was 94%. At evaluation 1 basic and 1 cell seeded conduit were occluded. Urinary flow was maintained in all conduits created with pre-implanted constructs. Pre-implantation of the basic construct resulted in a vascularized tissue tube, which could be used as a free graft to create an artificial conduit. The outcome was favorable compared to that of the other conduits. Urinary drainage was better, hydroureteronephrosis was limited and tissue regeneration was improved. CONCLUSIONS: Subcutaneous pre-implantation of a basic reinforced tubular construct resulted in a vascularized autologous tube, which may potentially replace bowel in standard urinary diversions. To our knowledge we introduce a straightforward 2-step procedure to create artificial urinary conduits in a large animal model.

Bladder Regeneration Using a Smart Acellular Collagen Scaffold with Growth Factors VEGF, FGF2 and HB-EGF.

Tissue engineering may become an alternative to current bladder augmentation techniques. Large scaffolds are needed for clinically significant augmentation, but can result in fibrosis and graft shrinkage. The purpose of this study was to investigate whether smart acellular collagen-heparin scaffolds with growth factors (GFs) VEGF, FGF2, and HB-EGF enhance bladder tissue regeneration and bladder capacity in a large animal model of diseased bladder. Scaffolds of bovine type I collagen with heparin and VEGF, FGF2, and HB-EGF measuring 3.2 cm in diameter were prepared. In 23 fetal sheep, a bladder exstrophy was surgically created at 79 days of gestation. One week after birth (at full term), the bladder was reconstructed by primary closure (PC group) or using a collagen-heparin scaffold with GFs (COLGF group) and compared to a historical group reconstructed with a collagen scaffold without GFs (COL group). Functional (video urodynamics) and histological evaluation was performed 1 and 6 months after bladder repair. The overall survival rate was 57%. Cystograms were normal in all animals, except for low-grade reflux in all groups. Urodynamics showed no statistically significant differences in bladder capacity and compliance between groups. Histological evaluation at 1 month revealed increased urothelium formation, improved angiogenesis, and enhanced ingrowth of smooth muscle cells (SMCs) in the COLGF group compared to the COL group. At 6 months, improved SMC ingrowth was found in the COLGF group compared to the COL group; both scaffold groups showed normal urothelial lining and standard extracellular matrix development. Bladder regeneration using a collagen-heparin scaffold with VEGF, FGF2, and HB-EGF improved bladder tissue regeneration in a large animal model of diseased bladder. Larger GF-loaded constructs need to be tested to reach clinically significant augmentation.

Tissue engineering of diseased bladder using a collagen scaffold in a bladder exstrophy model.

OBJECTIVE: To compare the regenerative capacity of diseased bladder in a large animal model of bladder exstrophy with regeneration in healthy bladder using a highly porous collagen scaffold. MATERIALS AND METHODS: Highly porous bovine type I collagen scaffolds with a diameter of 32 mm were prepared. In 12 fetal sheep a bladder exstrophy was surgically created at 79 days' gestation. Lambs were born at full term (140 days' gestation). After 1 week the bladder lesion was reconstructed and augmented with a collagen scaffold (group 1). In nine normal newborn lambs the bladder was augmented with a collagen scaffold 1 week after birth (group 2). Functional (video-urodynamics) and histological evaluation was performed at 1 and 6 months after surgery. RESULTS: The survival rate was 58% in group 1 and 100% in group 2. Cystograms were normal in all lambs, besides low-grade reflux in both groups. Urodynamics showed comparable capacity between both groups and a trend to lower compliance in group 1. Histological evaluation at 1 month revealed a non-confluent urothelial layer, an immature submucosa, and initial ingrowth of smooth muscle cells. At 6 months both groups showed normal urothelial lining, standard extracellular matrix development, and smooth muscle cell ingrowth. CONCLUSIONS: Bladder tissue regeneration with a collagen scaffold in a diseased bladder model and in healthy bladder resulted in comparable functional and histological outcome, with a good quality of regenerated tissue involving all tissue layers. Improvements may still be needed for larger augmentations or more severely diseased bladders.

Treatment response of an outpatient training for children with enuresis in a tertiary health care setting.

PURPOSE: To evaluate treatment effectiveness for children with enuresis, according to the definitions of the International Children's Continence Society (ICCS, 2006). MATERIAL AND METHODS: Children ≥6 years of age followed a 4-month outpatient treatment consisted of a visit during which history regarding enuresis was taken, causes were explained and therapeutic tips & tricks were discussed. All children received a booklet about enuresis and were trained with an alarm and/or pharmacological therapy. At baseline, 4, 10 and 16 months, the number of wet nights during the previous 28 days and the use of medication were assessed. Success of treatment was determined using ICCS definitions of treatment outcome. RESULTS: 66 children with enuresis were included (48 boys/18 girls) in this retrospective study. Mean age: 11(± 2.6) years. 91%(n = 60) of the children had non-monosymptomatic enuresis. Results at 4 months: 46% full, 15% good, 21% partial response (n = 66). At 10 months: 55% full, 4% good, 29% partial response (n = 49). At 16 months: 53% full, 6% good, 25% partial response (n = 34). Overall, use of pharmacological therapy showed a decline in time. CONCLUSION: According to the ICCS definitions, outpatient treatment for enuresis shows a good overall treatment response, and these results can be used to compare with other studies in the future.

Routine bladder biopsies in men with bladder outlet obstruction?

OBJECTIVES: To establish whether routine evaluation of light microscopic changes in bladder biopsies in men with graded bladder outlet obstruction correlates with urodynamic parameters and to evaluate the performance of two pathologists in bladder biopsy interpretation. METHODS: In 63 consecutive patients presenting with lower urinary tract symptoms suggestive of bladder outlet obstruction, the workup included bladder biopsies, which were semiquantitatively and independently evaluated by two pathologists for fibrosis, elastosis, muscle cell degeneration, inflammation, and additional remarkable findings. Furthermore, as determined by their general impression, the pathologists gave a diagnosis of normal or graded abnormality. The pathologists' performance was compared and the clinical and urodynamic data were correlated to the consensus histologic diagnoses. RESULTS: Fifty-four of 63 cases could be evaluated. The intraobserver and interobserver reproducibility were reasonable, with a kappa of 0.35 and 0.50, respectively. The consensus diagnosis of abnormal bladder biopsy correlated with impaired bladder compliance and capacity. However, no correlation was found between the presence and severity of histologic abnormalities and Schäfer class, urethral resistance factor, instability, postvoid residual urine volume, symptom score, and prostate volume. CONCLUSIONS: Although abnormal bladder biopsies correlated significantly with impaired bladder capacity and compliance, routine evaluation of bladder biopsies is not indicated in the evaluation of bladder outlet obstruction.

Long-term risk of re-treatment of patients using alpha-blockers for lower urinary tract symptoms.

PURPOSE: The efficacy of alpha-adrenoceptor blockers for the treatment of lower urinary tract symptoms has been proven in numerous studies. However, little is known about the efficacy of the longer term. We investigated the long-term risk of re-treatment in patients using alpha-adrenoceptor blockers for lower urinary tract symptoms and the parameters that influence this risk. MATERIALS AND METHODS: We reviewed the files of 316 patients with lower urinary tract symptoms treated at our department with the alpha-blockers terazosin, alfuzosin or tamsulosin. Using followup data up to 3 years, we calculated re-treatment percentages in each treatment group. Using extended followup of 5 years, we calculated the predictive value of various baseline characteristics for re-treatment. RESULTS: The re-treatment rates were 27% for tamsulosin, 37% for alfuzosin and 49% for terazosin. The re-treatment rates of patients with mild, moderate and severe lower urinary tract symptoms were 27%, 33% and 70%, respectively. Patients with a maximum urine flow of less or more than 10 ml. per second had a re-treatment rate of 58% and 47%, respectively. Patients with a prostate volume of less or more than 40 ml. had a re-treatment rate of 48% and 72%, respectively. Patients who were urodynamically unobstructed versus obstructed patients had a re-treatment rate of 44% and 59%, respectively. CONCLUSIONS: Patients given alpha-blockers for lower urinary tract symptoms have a high risk of re-treatment. Tamsulosin has a markedly lower re-treatment percentage than alfuzosin and terazosin. Severe symptoms, poor urine flow, an enlarged prostate and urodynamically proven bladder outlet obstruction increase the risk of treatment failure. Preselection of the most suitable candidates for alpha-blockade may reduce this risk.