Causes of death among people with myelomeningocele: A multi-institutional 47-year retrospective study.

PURPOSE: This study aimed to analyze organ system-based causes and non-organ system-based mechanisms of death (COD, MOD) in people with myelomeningocele (MMC), comparing urological to other COD. METHODS: A retrospective review was performed of 16 institutions in Canada/United States of non-random convenience sample of people with MMC (born > = 1972) using non-parametric statistics. RESULTS: Of 293 deaths (89% shunted hydrocephalus), 12% occurred in infancy, 35% in childhood, and 53% in adulthood (documented COD: 74%). For 261 shunted individuals, leading COD were neurological (21%) and pulmonary (17%), and leading MOD were infections (34%, including shunt infections: 4%) and non-infectious shunt malfunctions (14%). For 32 unshunted individuals, leading COD were pulmonary (34%) and cardiovascular (13%), and leading MOD were infections (38%) and non-infectious pulmonary (16%). COD and MOD varied by shunt status and age (p < = 0.04), not ambulation or birthyear (p > = 0.16). Urology-related deaths (urosepsis, renal failure, hematuria, bladder perforation/cancer: 10%) were more likely in females (p = 0.01), independent of age, shunt, or ambulatory status (p > = 0.40). COD/MOD were independent of bladder augmentation (p = >0.11). Unexplained deaths while asleep (4%) were independent of age, shunt status, and epilepsy (p >= 0.47). CONCLUSION: COD varied by shunt status. Leading MOD were infectious. Urology-related deaths (10%) were independent of shunt status; 26% of COD were unknown. Life-long multidisciplinary care and accurate mortality documentation are needed.

Retrograde incision from orifice (RIO) technique for endoscopic incision of ureterocele: 15 years of outcomes.

INTRODUCTION: Management of obstructing ureterocele often includes endoscopic transurethral incision (TUI) that can be challenging secondary to uncertainty in anatomic landmarks with risk of serious complications. To this end, we innovated a technique using predictable landmarks that begins endoscopic incision at the ureterocele orifice and extends retrograde proximal to the bladder neck (Figure). OBJECTIVE: With over 15 years of experience in performing this retrograde incision from orifice (RIO) technique, we aimed to examine post-operative outcomes and risk of surgical failure after RIO compared to traditional TUI techniques for ureteroceles. We hypothesized that clinical outcomes after RIO would be superior to traditional endoscopic approaches to decompression of obstructing ureterocele in infants. STUDY DESIGN: A retrospective study of patients ≤12 months old who underwent TUI ureterocele at our institution between 2007 and -2021 was conducted. Pre-, intra- and post-operative characteristics were compared between patients who underwent RIO vs non-RIO TUI. Primary outcome was post-incision febrile urinary tract infection (fUTI). Secondary outcome was a composite failure measure of fUTI, secondary surgery, de novo bladder outlet obstruction, or vesicoureteral reflux. Multivariable Cox proportional hazard models were fitted to compare the time-to-event risk of primary and secondary outcomes between groups. RESULTS: Ninety patients with 92 ureteroceles were included (49 RIO, 43 non-RIO). Median follow-up from TUI was 33 months. RIO had a shorter median operative duration (27 vs 35 min, p = 0.021). Primary and secondary outcomes were similar between groups (fUTI: 29% RIO vs 19% non-RIO, p = 0.27; composite failure 54% RIO vs 69% non-RIO, p = 0.15). In multivariable Cox proportional hazard models, there was no significant difference in risk of fUTI (RIO aHR 0.98, 95% CI 0.38-2.54, p = 0.97) or composite failure (RIO aHR 0.80, 95% CI 0.45-1.44, p = 0.46) between TUI techniques. DISCUSSION: RIO technique for TUI ureterocele is attractive in that it uses predictable anatomic landmarks making it simple to perform. In analyzing this 15-year institutional experience of TUI ureterocele, RIO showed similar success to non-RIO endoscopic incisions. This study is a retrospective, non-randomized, single-institutional study over 15 years and is therefore subject to change in surgeon practice over time and variable practices between providers. CONCLUSIONS: Given comparable success and durability over time to other TUI ureterocele techniques, and with the advantage of operator ease using consistent anatomic landmarks, RIO is a worthy option for endoscopic ureterocele decompression.

Targeted siRNA nanocarrier: a platform technology for cancer treatment.

The small arginine-rich protein protamine condenses complete genomic DNA into the sperm head. Here, we applied its high RNA binding capacity for spontaneous electrostatic assembly of therapeutic nanoparticles decorated with tumour-cell-specific antibodies for efficiently targeting siRNA. Fluorescence microscopy and DLS measurements of these nanocarriers revealed the formation of a vesicular architecture that requires presence of antibody-protamine, defined excess of free SMCC-protamine, and anionic siRNA to form. Only these complex nanoparticles were efficient in the treatment of non-small-cell lung cancer (NSCLC) xenograft models, when the oncogene KRAS was targeted via EGFR-mediated delivery. To show general applicability, we used the modular platform for IGF1R-positive Ewing sarcomas. Anti-IGR1R-antibodies were integrated into an antibody-protamine nanoparticle with an siRNA specifically against the oncogenic translocation product EWS/FLI1. Using these nanoparticles, EWS/FLI1 knockdown blocked in vitro and in vivo growth of Ewing sarcoma cells. We conclude that these antibody-protamine-siRNA nanocarriers provide a novel platform technology to specifically target different cell types and yet undruggable targets in cancer therapy by RNAi.

Surgical management of myelocystocele: a single-center experience with long-term functional outcomes.

OBJECTIVE: Myelocystocele (MCC) is an uncommon form of skin-covered spinal dysraphism. The authors aimed to present long-term functional outcomes of patients treated for MCC with and without associated abnormalities of cloacal development (ACD). METHODS: All patients with MCC and at least one tethered cord release (TCR) treated at a single institution between 1982 and 2019 were retrospectively reviewed. Demographic, operative, and functional outcome data were analyzed. RESULTS: Of 51 children with MCC, 30 (58.8%) had MCC only and 21 (41.2%) had associated ACD (MCC/ACD). Thirty-two patients (62.7%) had undergone one TCR, while 19 patients (37.3%) had multiple TCRs. Urinary continence assessment was possible in 41 patients (80.4%), and bowel continence assessment was possible in 43 patients (84.3%) who were either older than 6 years or toilet trained. Although patients with MCC only were more likely to void volitionally (p = 0.0001), there was no difference in overall bladder continence based on the presence of ACD (p = 0.15) or the need for additional untethering procedures (p = 0.15). Those with MCC only were more likely to have overall bowel continence (p = 0.0001) and not require any management (p = 0.002), while those with MCC/ACD were more likely to have an ileostomy (p = 0.01). Of the 30 patients with MCC only, 29 (96.7%) were able to ambulate in the community. Of 21 patients with MCC/ACD, 14 (66.7%) were able to ambulate in the community, 5 (23.8%) were not ambulating, and 2 (9.5%) were therapeutic ambulators. A greater proportion of children in the MCC cohort were ambulating in the community (p = 0.01). There was no difference in community ambulation based on the number of TCRs (p > 0.99), but those with multiple TCRs were more likely to use braces (p = 0.01) and require lower-extremity orthopedic surgery (p = 0.01). CONCLUSIONS: Patients born with an MCC, with or without an associated ACD, attained long-term favorable outcomes in bladder and bowel continence and ambulation.

Post-operative complications following masculinizing genitoplasty in moderate to severe genital atypia: results from a multicenter, observational prospective cohort study.

INTRODUCTION: Differences of sex development (DSD) are congenital conditions in which there is atypical chromosomal, gonadal and/or phenotypic sex. A phenotype of severe genital atypia in patients raised as male is a relatively rare occurrence and standards for management are lacking. Decision making for early surgical planning in these rare cases includes, but is not limited to, degree of atypia, location of testes, and presence of Mϋllerian remnants. In this study we describe surgical approaches and short-term outcomes for masculinizing genitoplasty in moderate to severe genital atypia in young patients raised male, for whom parents opted for early surgery. METHODS: This NIH-sponsored study is an ongoing, observational, multicenter investigation assessing medical, surgical and psychological outcomes in children and their parents affected by atypical genitalia due to DSD. Participants were prospectively enrolled from 12 children's hospitals across the United States that specialize in DSD care. Criteria for child enrollment were a Quigley score of 3-6 in those with a 46, XY or 45,X/46, XY chromosome complement, age <3 years with no previous genitoplasty; patients were included independent of whether genitoplasty was performed. Cosmesis was graded according to a 4-point Likert scale and complications per the Clavian-Dindo classification. RESULTS: Of the 31 participants, 30 underwent hypospadias repair and 1 patient did not undergo a genitoplasty procedure. The majority of participants (22) received a staged hypospadias repair. Seventeen complications were identified in 12 of the 31 children (41%) at 12 months of follow up. Glans dehiscence and urethrocutaneous fistula were the most common complications. Orchiopexy was performed in 14 (44%) and streak gonads were removed in 4 (13%) participants. Both parents and surgeons reported improved cosmesis after surgery when compared to baseline. CONCLUSION: Genitoplasty was chosen by parents for the majority of children eligible for study. No single surgical approach for masculinizing moderate to severe genital ambiguity in young patients with 46, XY or 45,X/46, XY DSD was adopted by all surgeons. Complications occurred in 41% of those who underwent genitoplasty for severe hypospadias. Overall, appearance of the genitals, as determined by parents and surgeons, improved following genitoplasty. Outcomes of early genitoplasty are needed to guide families when making decisions about such procedures for their young children.

Distress Trajectories for Parents of Children With DSD: A Growth Mixture Model.

OBJECTIVE: This study identifies trajectories of parent depressive symptoms after having a child born with genital atypia due to a disorder/difference of sex development (DSD) or congenital adrenal hyperplasia (CAH) and across the first year postgenitoplasty (for parents who opted for surgery) or postbaseline (for parents who elected against surgery for their child). Hypotheses for four trajectory classes were guided by parent distress patterns previously identified among other medical conditions. METHODS: Participants included 70 mothers and 50 fathers of 71 children diagnosed with a DSD or CAH with reported moderate to high genital atypia. Parents were recruited from 11 US DSD specialty clinics within 2 years of the child's birth and prior to genitoplasty. A growth mixture model (GMM) was conducted to identify classes of parent depressive symptoms over time. RESULTS: The best fitting model was a five-class linear GMM with freely estimated intercept variance. The classes identified were termed "Resilient," "Recovery," "Chronic," "Escalating," and "Elevated Partial Recovery." Four classes have previously been identified for other pediatric illnesses; however, a fifth class was also identified. The majority of parents were classified in the "Resilient" class (67.6%). CONCLUSIONS: This study provides new knowledge about the trajectories of depressive symptoms for parents of children with DSD. Future studies are needed to identify developmental, medical, or familial predictors of these trajectories.

Association between intra-operative meatal mismatch and urethrocutaneous fistula development in hypospadias repair.

INTRODUCTION: The Glans-Meatus-Shaft (GMS) Score is a pre-operative phenotypic scoring system used to assess hypospadias severity and risk for post-operative complications. The 'M' component is based on pre-operative meatal location, but meatal location sometimes changes after penile degloving, resulting in 'meatal mismatch.' OBJECTIVE: To identify: 1) the incidence and clinical predictors of meatal mismatch, and 2) the association of meatal mismatch with post-operative urethrocutaneous fistula development. STUDY DESIGN: We performed a retrospective cohort study on patients who underwent primary hypospadias repair at a single center from 2011 to 2018. Meatal mismatch was defined as: upstaging (meatus moving more proximally after degloving), downstaging (moving more distally after degloving), or none. Covariates included: pre-degloving meatal location, chordee severity, penoscrotal anatomy, pre-operative testosterone, and number of stages for repair. To test the association between meatal mismatch and fistula development, we constructed two, nested, multivariable Cox proportional hazards regression models with and without meatal mismatch and compared them with the likelihood ratio test. A sensitivity analysis excluded patients with <6 months of follow-up. RESULTS: Of 485 patients, 99 (20%) exhibited meatal mismatch, including 75 (15%) with upstaging and 24 (5%) patients with downstaging (Figure). Meatal mismatch was significantly associated with penoscrotal webbing, number of stages for repair, and pre-degloving meatal location, with downstaging being associated with more proximal meatal location. Over a median follow-up of 7.3 months (interquartile range 2.0-20.9), fistulae developed in 56 (12%) patients. On multivariable analysis, meatal upstaging was associated with a 3-fold increased risk of fistula development (Hazards Ratio [HR]: 3.04, 95% Confidence Interval [CI]: 1.44-6.45) compared to no mismatch. Meatal downstaging had similar risk of fistula development compared to no mismatch (HR: 0.99, 95% CI: 0.29-3.35). Multi-stage compared to single-stage repair was associated with reduced risk of fistula development (HR: 0.24, 95% CI: 0.09-0.66). The likelihood ratio test favored the model that included meatal mismatch. The sensitivity analysis showed similar findings. DISCUSSION: Our short-term results suggest that meatal mismatch may be an important additional consideration to the GMS score as a tool to assess hypospadias severity, counsel families, and predict outcomes. Longer-term studies are needed to enhance the precision of risk stratification in hypospadias. CONCLUSIONS: Meatal mismatch occurred in 20% of patients undergoing hypospadias repair. Among this cohort, meatal upstaging was associated with a 3-fold increased risk of post-operative urethrocutaneous fistula development.

Variability in Kidney Function Estimates in Emerging Adults With Spina Bifida: Implications for Transitioning From Pediatric to Adult Care.

OBJECTIVE: To examine the variability of estimated glomerular filtration rate (eGFR) in emerging adults with spina bifida (SB) by comparing multiple equations across the transitional age period, hypothesizing that creatinine (Cr)-based equations show greater variability than cystatin-C (CysC)- or combination-based equations. METHODS: A retrospective cohort study was performed from 2012 to 2017 at a multidisciplinary SB clinic. Emerging adults were defined as patients ages 18-28 years old. Four pediatric, 3 adult, and 3 averaged eGFR equations were considered. Cross-sectional variability in eGFR data was assessed using coefficients of variation, chronic kidney disease (CKD) stage classification, and pairwise percent relative difference in eGFR between analogous pediatric and adult equations based on included lab values. Longitudinal changes in eGFR over time were compared across equations using a covariance pattern model accounting for repeated measures. RESULTS: Seventy-five emerging adults with SB (median age 21.8 years; 55% female; 83% with myelomeningocele) were included in cross-sectional analyses. Adult equations gave higher median eGFRs by 22%-27% and generally milder CKD stage classification than analogous pediatric equations. In longitudinal analyses (median follow-up of 22 months), all equations conferred negative eGFR changes over time (range -1.9 to -4.3 mL/min/1.73m2 per year) that were not significantly different. CONCLUSION: In emerging adults with SB, adult equations demonstrated higher median eGFRs by 22%-27% compared to analogous pediatric equations, even with Cystatin-C, and generally downstaged CKD stage classification. The same eGFR equation should be used for serial kidney function monitoring in emerging adults with SB who transition care from pediatric to adult services.

Diagnostic Test Characteristics of Ultrasound Based Hydronephrosis in Identifying Low Kidney Function in Young Patients with Spina Bifida: A Retrospective Cohort Study.

PURPOSE: Kidney dysfunction in spina bifida is usually detected by low estimated glomerular filtration rate or ultrasound based hydronephrosis. We assessed the diagnostic test characteristics of hydronephrosis for detecting low estimated glomerular filtration rate, hypothesizing that hydronephrosis has low sensitivity compared to cystatin C based estimated glomerular filtration rate. MATERIALS AND METHODS: We conducted a single center, retrospective cohort study, including patients with spina bifida from 2012-2017 with 2 kidneys and complete data needed to calculate estimated glomerular filtration rate via multiple pediatric (age 1-17.9 years) or adult (age ≥18 years) estimating equations. We evaluated the association of hydronephrosis status (high grade, low grade or none) with estimated glomerular filtration rate, adjusting for small kidney size and scarring, and calculated diagnostic test characteristics of hydronephrosis for low estimated glomerular filtration rate. RESULTS: We analyzed 247 patients (176 children and 71 adults). Mean±SD age was 13.7±6.6 years, and 81% of patients had myelomeningocele. Hydronephrosis (77% low grade) was found in 35/176 children and 18/71 adults. Hydronephrosis was associated with low estimated glomerular filtration rate in stepwise fashion, independent of kidney size and scarring. However, across cystatin C based pediatric equations, any hydronephrosis (compared to none) had 23%-48% sensitivity, and high grade hydronephrosis (compared to none or low grade) had 4%-15% sensitivity for estimated glomerular filtration rate <90 ml/min/1.73 m2, which remained unchanged after excluding small kidneys and scarring. Across cystatin C based adult equations, any and high grade hydronephrosis had 55%-75% and 40%-100% sensitivity, respectively, for estimated glomerular filtration rate <90 ml/min/1.73 m2, although with wide confidence intervals. Specificity was higher with high grade vs any hydronephrosis. Sensitivities were higher for estimated glomerular filtration rate <60 ml/min/1.73 m2. CONCLUSIONS: Hydronephrosis was associated with low estimated glomerular filtration rate but had poor sensitivity for cystatin C based estimated glomerular filtration rate <90 ml/min/1.73 m2, especially among children with spina bifida.

Prooxidative chain transfer activity by thiol groups in biological systems.

Cysteine is arguably the best-studied biological amino acid, whose thiol group frequently participates in catalysis or ligand binding by proteins. Still, cysteine's unusual biological distribution has remained mysterious, being strikingly underrepresented in transmembrane domains and on accessible protein surfaces, particularly in aerobic life forms ("cysteine anomaly"). Noting that lipophilic thiols have been used for decades as radical chain transfer agents in polymer chemistry, we speculated that the rapid formation of thiyl radicals in hydrophobic phases might provide a rationale for the cysteine anomaly. Hence, we have investigated the effects of dodecylthiol and related compounds in isolated biomembranes, cultivated human cells and whole animals (C. elegans). We have found that lipophilic thiols at micromolar concentrations were efficient accelerators, but not inducers of lipid peroxidation, catalyzed fatty acid isomerization to trans-fatty acids, and evoked a massive cellular stress response related to protein and DNA damage. These effects were specific for lipophilic thiols and were absent with thioethers, alcohols or hydrophilic compounds. Catalytic chain transfer activity by thiyl radicals appears to have deeply influenced the structural biology of life as reflected in the cysteine anomaly. Chain transfer agents represent a novel class of biological cytotoxins that selectively accelerate oxidative damage in vivo.

Illness Uncertainty Longitudinally Predicts Distress Among Caregivers of Children Born With DSD.

OBJECTIVE: A subset of parents of children with disorders/differences of sex development (DSD) including ambiguous genitalia experience clinically elevated levels of anxious and depressive symptoms. Research indicates that uncertainty about their child's DSD is associated with parent psychosocial distress; however, previous studies have been cross-sectional or correlational in nature. The current study is the first to examine the longitudinal trajectory of the relationship between caregiver-perceived uncertainty about their child's DSD and caregiver anxious and depressive symptoms across the first 12 months following genital surgery in young children, or if surgery was not performed, the first 12 months following study entry. METHODS: One hundred and thirteen caregivers (Mage = 32.12; 57.5% mothers; 72.6% Caucasian) of children (N = 70; Mage = 9.81 months; 65.7% female) with DSD were recruited from 12 DSD specialty clinics in the United States. Caregivers completed psychosocial measures at baseline, 6 and 12 months following genitoplasty, or study entry if parents elected not to have surgery for their child. RESULTS: Caregiver illness uncertainty and both anxious and depressive symptoms were highest at baseline and decreased over time (ps < .05). Caregiver illness uncertainty predicted symptoms of anxious and depressive symptoms across all time points (ps < .05). CONCLUSIONS: Caregivers' perceptions of uncertainty about their child's DSD are highest soon after diagnosis, and uncertainty continues to predict both anxious and depressive symptoms across time. Thus, the initial diagnostic period is a critical time for psychological assessment and intervention, with parent illness uncertainty being an important clinical target.

Are pressure pop-offs beneficial to the bladder in boys with posterior urethral valves?

BACKGROUND: Pressure pop-offs, such as high-grade vesicoureteral reflux with renal dysplasia, have historically been considered beneficial for renal and bladder outcomes in boys with posterior urethral valves (PUV). Recent longer-term studies have called into question the beneficial effects of pop-offs on renal function. OBJECTIVE: To evaluate how pop-offs affect bladder outcomes in boys with PUV. STUDY DESIGN: At a single-center, the electronic medical records of boys with PUV who underwent valve ablation from 2000 to 2014 were retrospectively reviewed for bladder and continence outcomes. Patients were excluded due to presentation after one year of age, age at last follow-up <1 year, lack of urodynamic study (UDS), lack of voiding cystourethrogram, or concomitant prune belly syndrome. Between patients with and without pop-offs, the following outcomes were compared: prevalence of significant hydronephrosis (Society for Fetal Urology grade 3 or 4) prior to valve ablation and at last follow-up, nadir creatinine level, classification of initial UDS, type of medical and/or surgical interventions, dryness during the day and toilet-training status at last follow-up (among patients ≥4 years), and age at toilet-training. For patients with multiple UDS, initial and latest UDS were compared. RESULTS: 48 patients met inclusion criteria, of whom 31 (65%) had pop-offs and 17 (35%) did not. Median age at last follow-up was 5.9 years (range: 1.0-12.2 years). Patients with pop-offs were more likely to have unsafe initial UDS (26% vs. 12%, p = 0.15) but less likely to have high voiding pressures at their latest UDS (15% vs. 50%, p = 0.03). Patients with pop-offs were more likely to have used clean intermittent catheterization (26% vs. 0%, p = 0.04) and were less likely to be toilet-trained by age 4 (76% vs. 100%, p = 0.15) or dry during the day at last follow-up (56% vs. 92%, p = 0.06). Toilet-trained patients with pop-offs were toilet-trained by an earlier age than patients without pop-offs (3 vs 4 years, p = 0.04). DISCUSSION: The results of the present retrospective study show that patients with pop-offs required more extensive interventions to achieve continence, and achieved continence and toilet-training less frequently than patients without pop-offs. Additionally, our results demonstrated that patients with pop-offs had worse bladder dynamics initially, which may suggest that pop-offs are a manifestation of more excessive pressure build-up prior to valve ablation. CONCLUSIONS: Among boys with posterior urethral valves who present in the first year of life, pop-offs do not appear to impart significant benefit to bladder outcomes and may indicate more severe bladder dysfunction.

Post-operative complications following feminizing genitoplasty in moderate to severe genital atypia: Results from a multicenter, observational prospective cohort study.

Disorders/differences of sex development (DSD) are congenital conditions in which there is atypical chromosomal, gonadal and/or phenotypic sex. While there remains controversy around the traditionally binary concept of sex, most patients with DSD are reared either male or female depending on their genetic sex, gonadal sex, genital phenotype and status of their internal genital tract. This study uses prospective data from 12 institutions across the United States that specialize in DSD care. We focused on patients raised female. Eligible patients had moderate to severe genital atypia (defined as Prader score >2), were ≤2 years of age at entry, and had no prior genitoplasty. The aim of this study is to describe early post operative complications for young patients undergoing modern approaches to feminizing genitoplasty. Of the 91 participants in the cohort, 57 (62%) were reared female. The majority had congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (n = 52), 1 had ovo-testicular syndrome, 2 had mixed gonadal dysgenesis and 2 had partial androgen insensitivity syndrome (PAIS). Of the 50 participants who received early genitoplasty, 43 (86%) had follow-up at 6-12 months post-surgery. Thirty-two participants (64%) received a clitoroplasty, 31 (62%) partial urogenital mobilization and 4 (8%) total urogenital sinus mobilization. Eighteen percent (9/50) experienced post-surgical complications with 7 (14%) being rated as Clavien-Dindo grade III. Both parents and surgeons reported improved satisfaction with genital appearance of participants following surgery compared to baseline. This information on post-operative complications associated with contemporary approaches to feminizing genitoplasty performed in young children will help guide families when making decisions about whether or not to proceed with surgery for female patients with moderate to severe genital atypia.

Estimated kidney function in children and young adults with spina bifida: A retrospective cohort study.

AIMS: Current estimated glomerular filtration rate (eGFR) equations may be inaccurate in patients with spina bifida (SB) because of reduced muscle mass and stature. Cross-sectional and longitudinal variability of eGFR were analyzed in these patients across multiple equations, hypothesizing greater variability in creatinine-based than cystatin-C (Cys-C)-based equations. METHODS: This retrospective cohort study included children (age, 1-17.9 years) and adults (≥18 years) with SB from 2002-2017 at a large SB clinic. Those without all data needed to calculate eGFR were excluded. Four pediatric and three adult eGFR equations were compared for cross-sectional outcomes of eGFR and elevated office blood pressures using chronic kidney disease (CKD) stage classification, and for longitudinal outcome of eGFR slope over time using covariance pattern models accounting for repeated measures. RESULTS: One hundred and eighty two children and 75 adults had greater than or equal to 1 set of data measurements; 118 and 52, respectively, had greater than or equal to 2 sets. The pediatric bedside Schwartz equation had the highest median eGFR and coefficient of variation. CKD stage classification by eGFR showed large differences across equations in children, with rates of eGFR < 60 and <90 ml/min/1.73 m2 ranging from 2%-9% and 5%-69%, respectively. Only one equation showed a significant inverse association between eGFR and blood pressure. Longitudinally, eGFR slopes over time were different across pediatric equations (P < .001) but not adult equations. The bedside Schwartz equation had a positive eGFR slope; the other Cys-C-containing equations had negative slopes. CONCLUSIONS: Creatinine-based equations in children with SB vary considerably from cystatin-C-containing equations in calculating both single point-in-time eGFR values and eGFR trends over time.

Predictors of Psychosocial Distress in Parents of Young Children with Disorders of Sex Development.

PURPOSE: We evaluated demographic, financial and support predictors of distress for parents of young children with disorders of sex development including atypical genital development, and characterized early parental experiences. This work extends our previous findings to identify those parents at risk for distress. MATERIALS AND METHODS: Participants included mothers (76) and fathers (63) of a child (78) diagnosed with disorders of sex development characterized by moderate to severe genital atypia. Parents completed a demographic questionnaire, measures of anxious and depressive symptoms, quality of life, illness uncertainty and posttraumatic stress symptoms, and rated their satisfaction with the appearance of their child's genitalia. RESULTS: Depressive and posttraumatic stress symptoms of caregivers were comparable to standardized norms while levels of anxious symptoms were below norms. A subset of parents reported clinically elevated symptoms. Overall 26% of parents reported anxious symptoms, 24% reported depressive symptoms and 17% reported posttraumatic stress symptoms. Levels of illness uncertainty were lower than those of parents of children with other chronic illnesses. Differences by parent sex emerged, with mothers reporting greater distress. Lower income, increased medical care and travel expenses, and having no other children were related to increased psychosocial distress. CONCLUSIONS: Early psychosocial screening is recommended for parents of children with disorders of sex development. Clinicians should be aware that financial burden and lack of previous parenting experience are risk factors for distress.

Baseline Characteristics of Infants With Atypical Genital Development: Phenotypes, Diagnoses, and Sex of Rearing.

PURPOSE: Little is known about the phenotypes, diagnoses, and sex of rearing of infants with atypical genital development in the United States. As part of a multicenter study of these infants, we have provided a baseline report from US difference/disorder of sex development clinics describing the diagnoses, anatomic features, and sex of rearing. We also determined whether consensus guidelines are followed for sex designation in the United States. METHODS: Eligible participants had moderate-to-severe genital atypia, were aged <3 years, and had not undergone previous genitoplasty. Karyotype, genetic diagnosis, difference/disorder of sex development etiology, family history, and sex of rearing were collected. Standardized examinations were performed. RESULTS: Of 92 subjects, the karyotypes were 46,XX for 57%, 46,XY for 34%, and sex chromosome abnormality for 9%. The median age at the baseline evaluation was 8.8 months. Most 46,XX subjects (91%) had congenital adrenal hyperplasia (CAH) and most 46,XY subjects (65%) did not have a known diagnosis. Two individuals with CAH underwent a change in sex of rearing from male to female within 2 weeks of birth. The presence of a uterus and shorter phallic length were associated with female sex of rearing. The most common karyotype and diagnosis was 46,XX with CAH, followed by 46,XY with an unknown diagnosis. Phenotypically, atypical genitalia have been most commonly characterized by abnormal labioscrotal tissue, phallic length, and urethral meatus location. CONCLUSIONS: An increased phallic length was positively associated with rearing male. Among the US centers studied, sex designation followed the Consensus Statement recommendations. Further study is needed to determine whether this results in patient satisfaction.

Robot-Assisted Laparoscopic Reoperative Repair for Failed Pyeloplasty in Children: An Updated Series.

PURPOSE: Reoperative pyeloplasty is commonly used in children with recurrent obstruction after pyeloplasty. We previously reported on reoperative robot-assisted laparoscopic repair for failed pyeloplasty in 16 children and concluded that short-term and intermediate outcomes were comparable to open reoperative repair. In this updated series we describe longer term outcomes from an extended study. MATERIALS AND METHODS: We retrospectively reviewed outcomes of consecutive children with prior failed primary pyeloplasty who underwent robot-assisted laparoscopic reoperative repair at a single institution from January 2008 to June 2018. RESULTS: Overall, 36 children 0.6 to 15.2 years old (median 3.7) underwent robot-assisted laparoscopic reoperative repair (pyeloplasty in 31, ureterocalicostomy in 5) at a median of 24.3 months (range 3.9 to 136.7) after primary repair. Median reoperative time was 285.0 minutes (range 207 to 556) and median length of stay was 1 day (1 to 8). Crossing vessels were present in 8 of 30 children (26.7%) with prior open repair and in 0 of 6 with prior minimally invasive repair. Clavien-Dindo grade 1 to 2 perioperative complications occurred in 4 children (11.1%) and grade 3 to 5 complications in 2 (5.6%). Median followup was 35.3 months (range 1.4 to 108.3), with 18 children (50.0%) being followed for more than 3 years. Postoperative ultrasound in 34 children revealed improvement in 31 (91.2%), stability in 2 (5.9%) and worsening hydronephrosis in 1 (2.9%). All 11 children undergoing preoperative and postoperative diuretic renography demonstrated stable or improved differential renal function. All children were symptom-free at last followup. CONCLUSIONS: To our knowledge, this is the largest series of robot-assisted laparoscopic reoperative repair for failed pyeloplasty in children. Our results indicate the feasibility, efficacy, safety and durability of this procedure.

Psychological Adjustment of Parents of Children Born with Atypical Genitalia 1 Year after Genitoplasty.

PURPOSE: We examined the psychological adjustment of parents of children born with moderate to severe genital atypia 12 months after their child underwent genitoplasty. MATERIALS AND METHODS: Parents were recruited longitudinally from a multicenter collaboration of 10 pediatric hospitals with specialty care for children with disorders/differences of sex development and/or congenital adrenal hyperplasia. Parents completed measures of depressive and anxious symptoms, illness uncertainty, quality of life, posttraumatic stress and decisional regret. RESULTS: Compared to levels of distress at baseline (before genitoplasty) and 6 months after genitoplasty, data from 25 mothers and 20 fathers indicated significant improvements in all psychological distress variables. However, a subset of parents continued endorsing clinically relevant distress. Some level of decisional regret was endorsed by 28% of parents, although the specific decision that caused regret was not specified. CONCLUSIONS: Overall the majority of parents were coping well 1 year after their child underwent genitoplasty. Level of decisional regret was related to having a bachelor's level of education, increased levels of illness uncertainty preoperatively and persistent illness uncertainty at 12 months after genitoplasty but was unrelated to postoperative complications.

Effect of melanoma cells on proliferation and migration of activated hepatic stellate cells in vitro.

Melanoma is a highly aggressive tumor of the skin. The clinical outcome is determined by the presence or absence of metastases, and the liver is a common site of distant metastases. Hepatic metastasis is causing activation of hepatic stellate cells (HSC), which form the stroma of hepatic metastases and are increasingly recognized as a crucial component of the pro- metastatic liver microenvironment. Most studies have focused on the effects of HSC on (metastasizing) tumor cells. Here, we aimed to analyze functional in vitro effects of conditioned medium (CM) of twelve different human melanoma cell lines on LX2 cells and HSChtert cells, two well established human activated HSC cell lines. CM from melanoma cells significantly induced HSC proliferation and acted as chemoattractant for HSC in Boyden chamber assays. The CM effects significantly varied between different HSC as well as melanoma cells. Interestingly, CM from melanoma cell lines derived from melanoma metastases (WM239A, WM9, WM1158, WM1232, 451Lu and 1205Lu) had a stronger effect on proliferation of HSChtert cells than CM derived from primary melanoma tumors (SbCl2, WM3211, WM35, WM278, WM1366 and WM793). Moreover, we observed a significant correlation between the chemoattractive effects of CM from the different melanoma cells on HSChtert and LX2 cells. In contrast, the melanoma CM effects on the proliferation of the two HSC lines did not show a significant correlation. In summary, our data indicate that melanoma cells metastasizing to the liver have the potential to attract HSC and to induce HSC proliferation, respectively. Still, it appears that melanoma effects on HSC migration and proliferation are mediated via different soluble factors indicating the complexity of melanoma-HSC interaction. Furthermore, the intensity of at least some functional effects varies between different human tumor cells and HSC which may point to mechanisms explaining diverse hepatic metastasis in melanoma patients.