Treatment Strategies and Outcome of the Exstrophy–Epispadias Complex in Germany: Data From the German CURE-Net

Introduction: To evaluate the impact of reconstructive strategies and post-operative management on short- and long-term surgical outcome and complications of classical bladder exstrophy (CBE) patients' comprehensive data of the multicenter German-wide Network for Congenital Uro-Rectal malformations (CURE-Net) were analyzed. Methods: Descriptive analyses were performed between 34 prospectively collected CBE patients born since 2009, median 3 months old [interquartile range (IQR), 2–4 months], and 113 cross-sectional patients, median 12 years old (IQR, 6–21 years). Results: The majority of included individuals were males (67%). Sixty-eight percent of the prospectively observed and 53% of the cross-sectional patients were reconstructed using a staged approach (p = 0.17). Although prospectively observed patients were operated on at a younger age, the post-operative management did not significantly change in the years before and after 2009. Solely, in prospectively observed patients, peridural catheters were used significantly more often (p = 0.017). Blood transfusions were significantly more frequent in males (p = 0.002). Only half of all CBE individuals underwent inguinal hernia repair. Cross-sectional patients after single-stage reconstructions showed more direct post-operative complications such as upper urinary tract dilatations (p = 0.0021) or urinary tract infections (p = 0.023), but not more frequent renal function impairment compared to patients after the staged approach (p = 0.42). Continence outcomes were not significantly different between the concepts (p = 0.51). Self-reported continence data showed that the majority of the included CBE patients was intermittent or continuous incontinent. Furthermore, subsequent consecutive augmentations and catheterizable stomata did not significantly differ between the two operative approaches. Urinary diversions were only reported after the staged concept. Conclusions: In this German multicenter study, a trend toward the staged concept was observed. While single-stage approaches tended to have initially more complications such as renal dilatation or urinary tract infections, additional surgery such as augmentations and stomata appeared to be similar after staged and single-stage reconstructions in the long term

Copy number variations in 375 patients with oesophageal atresia and/or tracheoesophageal fistula

Oesophageal atresia (OA) with or without tracheoesophageal fistula (TOF) are rare anatomical congenital malformations whose cause is unknown in over 90% of patients. A genetic background is suggested, and among the reported genetic defects are copy number variations (CNVs). We hypothesized that CNVs contribute to OA/TOF development. Quantifying their prevalence could aid in genetic diagnosis and clinical care strategies. Therefore, we profiled 375 patients in a combined Dutch, American and German cohort via genomic microarray and compared the CNV profiles with their unaffected parents and published control cohorts. We identified 167 rare CNVs containing genes (frequency<0.0005 in our in-house cohort). Eight rare CNVs - in six patients - were de novo, including one CNV previously associated with oesophageal disease. (hg19 chr7:g.(143820444-143839360)-(159119486-159138663)del) 1.55% of isolated OA/TOF patients and 1.62% of patients with additional congenital anomalies had de novo CNVs. Furthermore, three (15q13.3, 16p13.3 and 22q11.2) susceptibility loci were identified based on their overlap with known OA/TOF-associated CNV syndromes and overlap with loci in published CNV association case-control studies in developmental delay. Our study suggests that CNVs contribute to OA/TOF development. In addition to the identified likely deleterious de novo CNVs, we detected 167 rare CNVs. Although not directly disease-causing, these CNVs might be of interest, as they can act as a modifier in a multiple hit model, or as the second hit in a recessive condition

Double-blinded, placebo-controlled, randomized und multicenter study for the effect and safety of an injection of Botulinum toxin A for the treatment of chronic plantar fasciitis

Die Applikation von 200 Einheiten Botulinumtoxin A (Dysport ®) nach einem standardisiertem Injektionsschema zeigte bei 20 behandelten Probanden keinen signifikanten Vorteil zur Schmerzreduktion im Vergleich zur mit Placebo behandelten Kontrollgruppe mit 20 Probanden. Jedoch war in der BoNT-A Gruppe eine 25%ige Responderrate gegenüber 5% in der Placebogruppe festzustellen, wenngleich das Signifikanzniveau nicht erreicht wurde (p = 0.18). Zusammenfassend betrachtet hat sich der Schmerzintensitätsscore bei Bewegung (Maximalschmerz) und in Ruhe (Minimalschmerz) der letzten 48 Stunden in beiden Behandlungsgruppen verbessert. In Woche 18 ist eine durchschnittliche Reduzierung des Schmerzintensitätsscore im Vergleich zu den Ausgangswerten häufiger in der Dysport® Gruppe als in der Placebogruppe zu verzeichnen, wenn auch nicht signifikant (in Ruhe war der Unterschied zwischen den beiden kleinsten Quadratisches Mittel der beiden Gruppen -8.84 cm *Tag, 13.3, p = 0.423; in Bewegung: - 4.2 cm *Tag; 16.3; p = 0.682). Der Gerbershagen Score zur Erfassung der Schmerzchronizität, erhoben bei der Erstuntersuchung in Woche 1 und bei der Abschlussuntersuchung in Woche 18, blieb für die Mehrheit der Probanden in beiden Gruppen gleich (BoNT-A: 53.3%, Placebo: 80%). Wenn der Score jedoch abnahm, dann mit einem höheren Anteil in der Verum-Gruppe (n=6; 40%) als bei den mit Placebo behandelten Probanden (n=3; 20%). Es gab keine signifikanten Unterschiede zwischen den Gruppen hinsichtlich der Veränderung des kleinsten Quadratischen Mittels zu den Ausgangswerten in den Parametern Schmerzschwelle (Differenz war -8.1 kg/cm²*Tag, p = 0.438) und Druckschwelle (0.59 kg/cm²*Tag, p = 0.937) oder Dorsalextension und Plantarflexion des betroffenen Fußes (Differenz -0.8; 5.3; p = 0.800) in Woche 18. Nach 6 Wochen des Follow-Up schätzten 52.7% der BoNT-A Gruppe ihren Zustand leicht bzw. viel besser ein, verglichen dazu waren es nur 40% in der Placebogruppe. In Woche 18 gaben 63.1% der Patienten in der Verumgruppe an, dass eine leichte bzw. große Verbesserung stattgefunden hat, in der Placebogruppe waren es 55%. Seit der Einführung des therapeutischen Wirkstoffs BoNT-A hat dieser einen hohen Stellenwert in der Behandlung von muskuloskelettalen Krankheitsbildern eingenommen. Unsere Studie konnte zeigen, dass die gefächerte Injektion von 200 Einheiten Dysport® an den knöchernen Ansatz der Plantarfaszie den refraktären Schmerz der Plantarfasziitis mildern kann. Es traten bei den Studienteilnehmern keine relevanten Nebenwirkungen auf. Jedoch bedarf es noch weiteren größer angelegten, prospektiven, placebokontrollierten Langzeitstudien, um die positiven Effekte von BoNT-A bei der chronischen Plantarfasziitis sicher bestätigen zu können.Objectives: Botulinum toxin A (BoNT-A) is used as an alternative treatment for chronic orthopedic conditions. This study was conducted to investigate the efficacy and safety of BoNT-A on pain and functional outcome in patients with chronic plantar fasciitis. Methods: In this short-term, randomized, multicenter, doubleblind, placebo-controlled study, patients (N=40) were randomized to receive 200 units of BoNT-A (Dysport) or saline placebo. The injection was administered in a fan-shaped manner directly at the calcaneal origin of the plantar fascia. The primary outcome measure was the proportion of responders at week 6 [Z50% decrease from baseline in pain score (visual analog scale) while moving during the previous 48 h). Global assessments were performed by the patient and physician at each visit up to week 18. Results: More patients in the BoNT-A group achieved a response at week 6 (25% vs. 5% for placebo; P=0.18). Differences between treatments were in favor of BoNT-A on secondary measures of pain, but did not reach statistical significance. In the BoNT-A group, 52.7% (vs. 40% for placebo) assessed their condition as slightly/significantly improved at week 6. At study endpoint (week 18), 63.1% of the BoNT-A group perceived an improvement versus 55% of the placebo group. There was no difference in global assessment between physician and patient. No adverse events related to treatment were noted. Discussion: There is a need for larger, prospective, long-term, placebo-controlled studies to fully establish the role of BoNT-A for the treatment of plantar fasciitis

Urological Outcome after Fetal Spina Bifida Repair: Data from the Zurich Cohort

INTRODUCTION Neurogenic lower urinary tract dysfunction (NLUTD) represents a severe burden for patients with open spina bifida (OSB). The effect of fetal OSB repair on the urological outcome remains unclear, as controversial data exist. The aim of this study was to further increment existing outcome data and to demonstrate that our earlier published positive preliminary results are not erratic. METHODS Data from standardized urological follow-up appointments of patients with fetal OSB repair operated at our center were analyzed. Data were obtained from urodynamic studies (UDSs) and radiologic exams performed in the newborn (gestational age 37-39 weeks), at ages of 6, 12, 18, and 24 months, and then at yearly intervals. RESULTS Of 82 patients (mean age 2.6 years, range 6 months to 7 years), 26 (32%) had a normal bladder function as demonstrated by UDSs. Of the 56 (68%) patients with NLUTD, 29 (51%) patients showed initially a normal UDS, but developed NLUTD in the follow-up, 19 (66%) of them spontaneously and another 10 (34%) in association with growth and development, or surgery of inclusion cysts. Radiologic abnormalities (upper tract dilatation and vesico-uretero-renal reflux) were seen in 15%, mainly patients with NLUTD. CONCLUSION Our results add an important set of information to the existing body of evidence. The data reconfirm our earlier published favorable preliminary results and support other studies that show a possible benefit of prenatal OSB repair on the urological outcome, but they also demonstrate that the positive effect remains limited

An integrated process for planning, delivery, and stewardship of urban nature-based solutions: The Connecting Nature Framework

Mainstreaming nature-based solutions in cities has grown in scale and magnitude in recent times but is still considered to be the main challenge for transitioning our cities and their communities to be more climate resilient and liveable: environmentally, economically, and socially. Furthermore, taking nature-based solutions to the next level, and scaling them out to all urban contexts to achieve a greater impact, is proving to be slow and often conflicts with other transitioning initiatives such as energy generation, mobility and transport initiatives, and infilling to combat sprawl. So, the task is neither easy nor straightforward; there are many barriers to this novel transition, especially when it comes to collaborative approaches to implementing nature-based solutions with diverse urban communities and within city authorities themselves. This paper reports on a new process that is systematically co-produced and captured as a framework for planning nature-based solutions that emerged during the Connecting Nature project. The Connecting Nature Framework is a three-stage, iterative process that involves seven key activity areas for mainstreaming nature-based solutions: technical solutions, governance, financing and business models, nature-based enterprises, co-production, reflexive monitoring, and impact assessment. The tested and applied framework is designed to address and overcome barriers to the implementation of nature-based solutions in cities via a co-created, iterative, and reflective approach. The planning process guided by the proposed framework has already yielded promising results with some of the cities of the project, though further usage and its adoption by other cities is needed to explore its potential in different contexts especially in the Global South. The paper concludes with suggestions on how this may be realised

Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia

Introduction: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development. Methods: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal. Results: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants. Conclusion: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF