Development of a Novel Prediction Tool for Response to First-Line Treatments of Monosymptomatic Nocturnal Enuresis: A Randomized, Controlled, International, Multicenter Study (DRYCHILD).

PURPOSE: Nocturnal urine volume and bladder reservoir function are key pathogenic factors behind monosymptomatic nocturnal enuresis (MNE). We investigated the predictive value of these together with other demographic and clinical variables for response to first-line treatments in children with MNE. MATERIALS AND METHODS: A randomized, controlled, international, multicenter study was conducted in 324 treatment-naïve children (6-14 years old) with primary MNE. The children were randomized to treatment with or without prior consideration of voiding diaries. In the group where treatment choice was based on voiding diaries, children with nocturnal polyuria and normal maximum voided volume (MVV) received desmopressin (dDAVP) treatment, and children with reduced MVV and no nocturnal polyuria received an enuresis alarm. In the other group, treatment with dDAVP or alarm was randomly allocated. RESULTS: A total of 281 children (72% males) were qualified for statistical analysis. The change of responding to treatment was 21% higher in children where treatment was individualized compared to children where treatment was randomly selected (risk ratio = 1.21 [1.02-1.45], P = .032). In children with reduced MVV and no nocturnal polyuria (35% of all children), individualized treatment was associated with a 46% improvement in response compared to random treatment selection (risk ratio = 1.46 [1.14-1.87], P = .003). Furthermore, we developed a clinically relevant prediction model for response to dDAVP treatment (receiver operating characteristic curve 0.85). CONCLUSIONS: The present study demonstrates that treatment selection based on voiding diaries improves response to first-line treatment, particularly in specific subtypes. Information from voiding diaries together with clinical and demographic information provides the basis for predicting response. CLINICAL TRIAL REGISTRATION NO.: NCT03389412.

Discontinuing absorbent pants in children with bedwetting: a randomized controlled trial.

The objective of this study is to examine the effect of discontinuing wearing protective garments (absorbent pyjama pants - APP) in children with severe childhood nocturnal enuresis (NE). The study employs a multicenter, parallel, randomized controlled trial. Following a 4-week run-in period, participants were randomly allocated in a 2:1 group allocation to discontinue or continue using APP. The research was conducted across seven European pediatric incontinence centers. The study included treatment-naïve children aged 4-8 years with severe (7/7 wet nights per week) mono-symptomatic NE, who had used nighttime protection for at least 6 months prior to the study. The study consisted of a 4-week run-in period (± 7 days), where all children slept wearing APP (DryNites®). At week 4 (± 7 days), if meeting randomization criteria (7/7 wet nights during the last week of run-in), participants were randomized to continue to sleep in APP or to discontinue their use for a further 4 weeks, with the option of another 4 weeks in the extension period. The primary outcome was the difference between groups of wet nights during the last week of intervention. Quality of life (QoL) and sleep were secondary endpoints. In total, 105 children (43 girls and 62 boys, mean age 5.6 years [SD 1.13]) were randomized (no-pants group n = 70, pants group n = 35). Fifteen children (21%) in the no-pants group discontinued early due to stress related to the intervention. Children in the no-pants group experienced fewer wet nights compared to the pants group during the last week (difference 2.3 nights, 95% CI 1.54-3.08; p < 0.0001). In the no-pants group, 20% responded to the intervention, of whom 13% had a full response. Clinical improvement was detected within 2 weeks. Sleep and QoL were reported as negatively affected by APP discontinuation in the extension period but not in the core period.    Conclusion: A ~ 10% complete resolution rate was associated with discontinuing APP. While statistically significant, the clinical relevance is debatable, and the intervention should be tried only if the family is motivated. Response was detectable within 2 weeks. Discontinuing APP for 4-8 weeks was reported to negatively affect QoL and sleep quality. No severe side effects were seen.Trial registration: Clinicaltrials.gov Identifier: NCT04620356; date registered: September 23, 2020. Registered under the name: "Effect of Use of DryNites Absorbent Pyjama Pants on the Rate of Spontaneous Resolution of Paediatric Nocturnal Enuresis (NE)."

The genetics of incontinence: A scoping review.

The genetic causes underlying incontinence in both children and adults have begun to be unravelled during the last decades. The aim of this scoping review is to synthesize current knowledge on the genetics of childhood and adult urinary and faecal incontinence, identify similarities between different incontinence subgroups, and identify knowledge gaps to aid future research. PRISMA-ScR was used, and 76 studies were included. Early epidemiological family and twin studies suggest high heritability of incontinence. Linkage studies provide evidence for the existence of rare genetic variants; however, these variants have not been identified. Later candidate gene association studies and recent genome-wide association studies provide the first preliminary evidence that common risk variants also play a role. The genetics of incontinence in children and adults has predominantly been studied separately, but this review identifies for the first time the endothelin system as a potential common pathophysiological pathway. Overall, these findings strengthen the hypothesis that genetic variants play a prominent role in the pathogenesis of incontinence. Future research should include hypothesis-free studies of rare and common variants in large well-characterized cohorts with incontinence. Studies should include different age groups and ethnicities and both sexes to fully reveal the genetics of incontinence.

Transcutaneous electrical nerve stimulation as add-on therapy in children receiving anticholinergics and/or mirabegron for refractory daytime urinary incontinence: A retrospective cohort study.

AIMS: To investigate if children with daytime urinary incontinence (DUI) and overactive bladder (OAB) refractory to standard urotherapy and medicinal treatment, would experience improvement in symptoms after add-on treatment with transcutaneous electrical nerve stimulation (TENS). METHODS: Children were retrospectively enrolled from tertiary referral centers at Aarhus and Aalborg University Hospitals. All data were retrieved from the patients' journals. All children were prescribed TENS as an add-on treatment to the highest-tolerable dose of medicinal treatment in a standardized regime of 2 h a day for around 3 months. Primary endpoints were the number of wet days per week (WDPW) and incontinence episodes per day. Effect of treatment was defined as greater or equal to 50% reduction in the frequency of DUI episodes. Secondary endpoints were to establish predictive factors for the effect of treatment using logistic regression. RESULTS: Seventy-six children diagnosed with DUI and OAB refractory to treatment with standard urotherapy and pharmacological treatment, at the age of 5-16 years were included from February 2017 to February 2020. A reduction in WDPW (from 6.31 [5.86-6.61] to 4.27 [3.45-4.90], p < 0.05) and incontinence episodes per day (from 2.45 [1.98-2.91] to 1.43 [1.07-1.80], p < 0.05) was observed. Twelve patients became completely dry. At 6 months follow-up, seven of the 12 complete responders had relapsed while five remained dry. A history of constipation before TENS was a predictor of poor treatment response (p = 0.016). CONCLUSIONS: TENS as add-on to anticholinergic treatment seems effective in a number of children with treatment-refractory DUI.

Pitfalls in Diagnosing Urinary Tract Infection in Children below the Age of 2: Suprapubic Aspiration vs Clean-Catch Urine Sampling.

PURPOSE: Reliable urine samples are of eminent importance when diagnosing urinary tract infections (UTIs) in children. Noninvasive procedures are convenient but likely to be contaminated. This study aimed to compare the diagnostic accuracy of urine samples obtained by the midstream clean-catch method (CCU) to urine obtained by suprapubic aspiration (SPA) and to evaluate the ability of urinary dipstick to predict true infection. MATERIALS AND METHODS: Retrospectively, data on children <2 years of age seen at our center for suspicion of UTI who had a CCU and a SPA performed the same day were included. Any growth in SPA was considered significant, whereas for CCU we tested 2 cutoff values of 104 and 105 CFU/ml, along with urinary dipstick results. RESULTS: A total of 223 children were included. Using a cutoff of ≥104 CFU/ml, 16.6% of the cohort (37 cases) would be misdiagnosed if relying only on CCU. Using ≥105 CFU/ml, the rate was 24.6% (55 cases). Evaluating leukocyte esterase on urinary dipstick, a large difference between using CCU (sensitivity 94.7%, specificity 14.4%) and SPA (sensitivity 78.9%, specificity 82.2%) became obvious. CONCLUSIONS: A large number of children will be misdiagnosed if relying on CCU specimens compared to SPA. Relying on a negative leukocyte esterase dipstick test to rule out a UTI is not sufficient in a child with high suspicion of such an infection. SPA is a safe procedure, and we thus recommend its use to avoid delay of treatment and unnecessary invasive followup investigations.

Risk factors for kidney scarring and vesicoureteral reflux in 421 children after their first acute pyelonephritis, and appraisal of international guidelines.

BACKGROUND: Acute pyelonephritis (AP) is a common bacterial infection in childhood. Follow-up guidelines on these children are controversial. This study aimed to identify risk factors for kidney scarring and vesicoureteral reflux (VUR). Furthermore, international follow-up guidelines were used for simulation to evaluate sensitivity and specificity. METHODS: Urinary culture-confirmed first-time AP patients (aged 0-14 years) were enrolled (n = 421) from review of patient charts. All underwent kidney ultrasound (US) and a technetium-99m-dimercaptosuccinic acid (DMSA) scan or technetium-99m-mercaptoacetyltriglycine scinti-renography (MAG3) at 4-6 months of follow-up. The international guidelines used for simulation were from the National Institute of Health UK (NICE), the American Association of Paediatrics (AAP) and the Swedish Paediatric Society (SPS). RESULTS: 17.8% presented with an abnormal DMSA/MAG3 at follow-up, 7.1% were diagnosed with VUR grades III-V and 4.7% were admitted for surgery. Non-Escherichia coli infections, abnormal kidney US, elevated creatinine and delayed response to treatment (>48 h) were risk factors for abnormal DMSA findings and VUR grades III-V. NICE and SPS guidelines showed best sensitivity in diagnosing VUR grades III-V (75%) compared with AAP (56%). CONCLUSIONS: Risk factors are helpful in identifying the children in need of further investigations and minimizing invasive work-up for the rest. International guidelines on follow-up detect a varying number of children with kidney damage and/or significant VUR. Future work must focus on identifying more specific risk factors, better imaging, or specific biomarkers, to enhance sensitivity and specificity in detecting the children at high risk for developing recurrent infections and/or nephropathy.

Dissatisfaction with school toilets is associated with bladder and bowel dysfunction.

Poor quality of school toilets is reportedly an issue in many countries and has been correlated with toilet refusal in children. The aim of this study was to evaluate the association between perceived school toilet quality, behaviour regarding toilet visits, and symptoms of bladder and bowel dysfunction (BBD). Pupils in Danish schools were invited to complete online questionnaires regarding toilet behaviour, perception of school toilet standards/quality, and symptoms of BBD. Teachers at the same schools were asked about the quality of the toilets. We recruited 19,577 children from 252 different schools. More than half of the children (50% boys and 60% girls) were dissatisfied with the toilet facilities. One-fourth of the children (28% of girls, 23% of boys) reported avoiding the use of school toilets. We found a strong correlation between being dissatisfied with school toilets, toilet avoidance, and symptoms of BBD.Conclusion: The majority of Danish children are unhappy with their school toilet facilities. Symptoms of BBD are associated with subjective toilet dissatisfaction and toilet visit postponement. Because children spend a significant part of their day at school, access to satisfactory toilet facilities is of utmost importance for their well-being. What is Known • Bladder and bowel dysfunction is common in childhood with urinary incontinence, constipation, and faecal incontinence being cardinal symptoms. • Behaviour regarding toilet visits contributes to the aetiology, and we know that toilet avoidance can lead to abnormal bladder and bowel function. What is New • Most children are not satisfied with their school toilets, and many avoid toilet visits. • Dissatisfaction with the school toilets is related to toilet avoidance and bladder and bowel dysfunction in school children regardless of age and gender.

A novel variant in the SLC12A1 gene in two families with antenatal Bartter syndrome.

AIM: Bartter syndrome is an autosomal-recessive inherited disease in which patients present with hypokalaemia and metabolic alkalosis. We present two apparently nonrelated cases with antenatal Bartter syndrome type I, due to a novel variant in the SLC12A1 gene encoding the bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2 in the thick ascending limb of the loop of Henle. METHODS: Blood samples were received from the two cases and 19 of their relatives, and deoxyribonucleic acid was extracted. The coding regions of the SLC12A1 gene were amplified using polymerase chain reaction, followed by bidirectional direct deoxyribonucleic acid sequencing. RESULTS: Each affected child in the two families was homozygous for a novel inherited variant in the SLC12A1gene, c.1614T>A. The variant predicts a change from a tyrosine codon to a stop codon (p.Tyr538Ter). The two cases presented antenatally and at six months of age, respectively. CONCLUSION: The two cases were homozygous for the same variant in the SLC12A1 gene, but presented clinically at different ages. This could eventually be explained by the presence of other gene variants or environmental factors modifying the phenotypes. The phenotypes of the patients were similar to other patients with antenatal Bartter syndrome.

Inappropriate arginine vasopressin levels and hyponatremia associated with cyclic vomiting syndrome.

We herein describe two children who presented with attacks of severe cyclic vomiting. The primary case was a 2.5-year-old girl with a history of several admissions with vomiting and altered mental status. She was diagnosed with cyclic vomiting syndrome (CVS). During her attacks she developed significant hyponatremia on several occasions, which prompted us to measure plasma arginine vasopressin (AVP) levels during attacks. We found inappropriately high AVP levels with concomitant hyponatremia. We also measured plasma AVP and plasma sodium in another child with CVS who did not develop manifest hyponatremia but showed inappropriately elevated plasma AVP levels. Since the standard treatment of CVS consists of fluids, high plasma AVP levels may lead to dilutional hyponatremia. We would therefore like to emphasize the importance of close assessment of electrolyte levels in patients with CVS to avoid water intoxication.

Persistent neurogenic bladder dysfunction due to infantile botulism.

We present a child, 5 months of age, diagnosed with infantile botulism, showing the signs of neurogenic bladder dysfunction. The patient presented with progressive muscle weakness, hypotonia, suckling and swallowing problems and absent peripheral reflexes at clinical examination. Botulinum neurotoxin type A was detected in her serum, confirming the diagnosis. Starting at day 6, the girl presented with a urinary retention initially necessitating free bladder drainage and subsequently intermittent catheterisation. After 6 weeks in intensive care, the patient recovered but the bladder underactivity persisted. Four months following recovery, a urodynamic evaluation was performed, showing a near normal detrusor activity and normal bladder emptying, and the catheterisation was ceased. At 6 months, the girl was diagnosed with a urinary tract infection and bladder emptying problems, which persisted, and clean intermittent catheterisation was started. The final urodynamic evaluation, a year and a half after her initial presentation, revealed a normal detrusor activity and an adequate bladder emptying.