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Contains fulltext : 305111.pdf (Publisher’s version ) (Open Access)

BACKGROUND: Registries are important in rare disease research. The Anorectal Malformation Network (ARM-Net) registry is a well-established European patient registry collecting demographic, clinical, and functional outcome data. We assessed the quality of this registry through review of the structure, data elements, collected data, and user experience. MATERIAL AND METHODS: Design and data elements were assessed for completeness, consistency, usefulness, accuracy, validity, and comparability. An intra- and inter-user variability study was conducted through monitoring and re-registration of patients. User experience was assessed via a questionnaire on registration, design of registry, and satisfaction. RESULTS: We evaluated 119 data elements, of which 107 were utilized and comprised 42 string and 65 numeric elements. A minority (37.0%) of the 2278 included records had complete data, though this improved to 83.5% when follow-up elements were excluded. Intra-observer variability demonstrated 11.7% incongruence, while inter-observer variability was 14.7%. Users were predominantly pediatric surgeons and typically registered patients within 11-30 min. Users did not experience any significant difficulties with data entry and were generally satisfied with the registry, but preferred more longitudinal data and patient-reported outcomes. CONCLUSIONS: The ARM-Net registry presents one of the largest ARM cohorts. Although its collected data are valuable, they are susceptible to error and user variability. Continuous evaluations are required to maintain relevant and high-quality data and to achieve long-term sustainability. With the recommendations resulting from this study, we call for rare disease patient registries to take example and aim to continuously improve their data quality to enhance the small, but impactful, field of rare disease research. LEVEL OF EVIDENCE: V.

Contains fulltext : 296544.pdf (Publisher’s version ) (Open Access), BACKGROUND: Registries are important in rare disease research. The Anorectal Malformation Network (ARM-Net) registry is a well-established European patient registry collecting demographic, clinical, and functional outcome data. We assessed the quality of this registry through review of the structure, data elements, collected data, and user experience. MATERIAL AND METHODS: Design and data elements were assessed for completeness, consistency, usefulness, accuracy, validity, and comparability. An intra- and inter-user variability study was conducted through monitoring and re-registration of patients. User experience was assessed via a questionnaire on registration, design of registry, and satisfaction. RESULTS: We evaluated 119 data elements, of which 107 were utilized and comprised 42 string and 65 numeric elements. A minority (37.0%) of the 2278 included records had complete data, though this improved to 83.5% when follow-up elements were excluded. Intra-observer variability demonstrated 11.7% incongruence, while inter-observer variability was 14.7%. Users were predominantly pediatric surgeons and typically registered patients within 11-30 min. Users did not experience any significant difficulties with data entry and were generally satisfied with the registry, but preferred more longitudinal data and patient-reported outcomes. CONCLUSIONS: The ARM-Net registry presents one of the largest ARM cohorts. Although its collected data are valuable, they are susceptible to error and user variability. Continuous evaluations are required to maintain relevant and high-quality data and to achieve long-term sustainability. With the recommendations resulting from this study, we call for rare disease patient registries to take example and aim to continuously improve their data quality to enhance the small, but impactful, field of rare disease research. LEVEL OF EVIDENCE: V.

Item does not contain fulltext, Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 × 10(-8); odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10-5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 × 10(-10); OR = 1.47; 95% CI, 1.38-1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 × 10(-16); OR = 1.75; 95% CI, 1.64-1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% ± 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes.

Background: Although infantile fever is harmless in most cases, many parents feel insecure when having to deal with it because important information is often missing. For educational purposes, an information video on fever in children was developed, which is also intended to serve as an onboarding element of a health app. The aim of the present work was to record the attitude of parents and adults on the topic of fever before and after the presentation of the information video, as well as its evaluation.Methods: Between May and November 2020, a total of 123 adults from three groups with different backgrounds (students, parents and educators) were interviewed using a questionnaire that was completed before and after the one-time presentation of an educational information video clip.Results: Several significant outcomes were recorded in attitude change toward managing fever, with no significant difference between groups. After viewing the informational video clip, 74% of participants would take body temperature rectally more often. In the after-questionnaire, 83% of participants agreed that they would now be more cautious about using fever-reducing medications. Before the video clip, 75% of the participants thought fever was "rather useful"; after, 93%. The level of temperature played a minor role as a reason for fever reduction. The information content and quality of the video were rated positively. Discussion: This study shows that a short information video is capable of bringing about a subjectively perceived intentional change in the attitude to dealing with fever, motivating a change in behavior, and reducing uncertainty in dealing with fever. Since the change in attitude was measured immediately after viewing the video clip, no statement can be made about the medium to long-term effect.Conclusion: The information video clip can be classified as a short-term fever education tool for which at least short-term effective is demonstrated. Long-term and possible syner, Hintergrund: Obwohl kindliches Fieber in den meisten Fällen harmlos ist, fühlen sich viele Eltern im Umgang damit unsicher, weil oft wichtige Informationen fehlen. Zu Aufklärungszwecken wurde ein Informationsvideo über Fieber bei Kindern entwickelt, das auch als Onboarding-Element einer Gesundheits-App dienen soll. Ziel der vorliegenden Arbeit war es, die Einstellung von Eltern und Erwachsenen zum Thema Fieber vor und nach der Präsentation des Informationsvideos sowie dessen Evaluation zu erfassen.Methoden: Zwischen Mai und November 2020 wurden insgesamt 123 Erwachsene in drei Gruppen mit unterschiedlichem Hintergrund (Studenten, Eltern und Pädagogen) mittels eines Fragebogens befragt, der vor und nach der einmaligen Präsentation eines Aufklärungsvideos ausgefüllt wurde.Ergebnisse: Es wurden mehrere signifikante Ergebnisse in Bezug auf die Veränderung der Einstellung zum Umgang mit Fieber festgestellt, wobei es keine signifikanten Unterschiede zwischen den Gruppen gab. Nach der Vorführung des Informationsvideoclips würden 74 % der Teilnehmer die Körpertemperatur häufiger rektal messen. In der Nachbefragung stimmten 83% der Teilnehmer zu, dass sie nun vorsichtiger mit fiebersenkenden Medikamenten umgehen würden. Vor dem Videoclip hielten 75% der Teilnehmer Fieber für "eher nützlich", danach waren es 93%. Die Höhe der Temperatur spielte als Grund für die Fiebersenkung eine untergeordnete Rolle. Der Informationsgehalt und die Qualität des Videos wurden positiv bewertet. Diskussion: Diese Studie zeigt, dass ein kurzes Informationsvideo in der Lage ist, eine subjektiv wahrgenommene intentionale Veränderung der Einstellung zum Umgang mit Fieber herbeizuführen, zu einer Verhaltensänderung zu motivieren und die Unsicherheit im Umgang mit Fieber zu verringern. Da die Einstellungsänderung unmittelbar nach dem Betrachten des Videoclips gemessen wurde, kann keine Aussage über die mittel- bis langfristige Wirkung getroffen werden.Schlussfolgerung: Der Informationsvideoclip kann

Aim: Male patients with anorectal malformations (ARM) are classified according to presence and level of the recto-urinary fistula. This is traditionally established by a preoperative high-pressure distal colostogram that may be variably interpreted by different surgeons. The aim of this study was to evaluate the inter- and intraobserver variation in the assessment by pediatric surgeons of preoperative colostograms with respect to the level of the recto-urinary fistula. Materials and Methods: Sixteen pediatric surgeons from 14 European centers belonging to the ARM-Net Consortium twice scored 130 images of distal colostograms taken in sagittal projection at a median age of 66 days of life (range: 4–1,106 days). Surgeons were asked to classify the fistula in bulbar, prostatic, bladder-neck, no fistula, and “unclear anatomy” example. Their assessments were compared with the intraoperative findings (kappa) for two scoring rounds with an interval of 6 months (intraobserver variation). Agreement among the surgeons' scores (interobserver variation) was also calculated using Krippendorff's alpha. A kappa over 0.75 is considered excellent, between 0.40 and 0.75 fair to good, and below 0.40 poor. Surgeons were asked to score the images in “poor” and “good” quality and to provide their years of experience in ARM treatment. Results: Agreement between the image-based rating of surgeons and the intraoperative findings ranges from 0.06 to 0.45 (mean 0.31). Interobserver variation is higher (Krippendorff's alpha between 0.40 and 0.45). Years of experience in ARM treatment does not seem to influence the scoring. The mean intraobserver variation between the two rounds is 0.64. Overall, the quality of the images is considered poor. Images categorized as having a good quality result in a statistically significant higher kappa (mean: 0.36 and 0.37 in the first and second round, respectively) than in the group of bad-quality images (mean: 0.25 and 0.23, respectively). Conclusions: There i

Contains fulltext : 205341.pdf (publisher's version ) (Open Access)

Introduction Anorectal malformations (ARM) are rare congenital malformations, resulting from disturbed hindgut development. A genetic etiology has been suggested, but evidence for the involvement of specific genes is scarce. We evaluated the contribution of rare and low-frequency coding variants in ARM etiology, as

Contains fulltext : 173200.pdf (publisher's version ) (Open Access), Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 x 10-08). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 x 10-19. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development.

Contains fulltext : 170996.pdf (publisher's version ) (Closed access), The purpose of our study was to investigate the importance of amniotic fluid (AF) for fetal growth during late gestation using esophageal atresia (EA) patients as a model. In this retrospective cohort study, we compared the z-scores adapted for birth weights (BW z-scores) for each of 517 European newborns with congenital pre-gastric intestinal atresia, i.e., EA, to a European reference population. To account for the influence of the intestinal atresia on fetal growth per se, we compared adapted birth weights for each of 504 European newborns with post colonic intestinal atresia (anorectal malformation (ARM) with atresia of the anus) to the same European reference population. Analysis of the complete cohort showed (i) a significantly higher rate of small for gestational age newborns among EA compared to ARM newborns (p < 0.001) and (ii) significantly lower BW z-scores among EA compared to ARM newborns (p < 0.001). BW z-scores of EA newborns were significantly lower in term compared to preterm newborns with an inverse correlation with gestational age (GA) (Spearman correlation coefficient, r = -0.185, p < 0.001). CONCLUSIONS: Enteral uptake of AF seems to play a pivotal role in fetal growth during late gestation. WHAT IS KNOWN: * Peak velocity of fetal weight gain occurs at 33 weeks of gestation and continues until birth. During this period, fetal growth is mainly characterized by cellular hypertrophy. * Amniotic fluid (AF) comprises large amounts of hormones and growth regulators. What is New: * A significantly higher rate of small for gestational age and lower birth weights and z-scores are observed among newborn infants with congenital pre-gastric intestinal atresia. * These findings suggest that enteral uptake of AF is a major predictor for fetal growth during late gestation.

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) and anorectal malformations (ARM) represent the severe ends of the fore- and hindgut malformation spectra. Previous research suggests that environmental factors are implicated in their etiology. These risk factors might indicate the influence of specific etiological mechanisms on distinct developmental processes (e.g. fore- vs. hindgut malformation). The present study compared environmental factors in patients with isolated EA/TEF, isolated ARM, and the combined phenotype during the periconceptional period and the first trimester of pregnancy in order to investigate the hypothesis that fore- and hindgut malformations involve differing environmental factors. Patients with isolated EA/TEF (n = 98), isolated ARM (n = 123), and the combined phenotype (n = 42) were included. Families were recruited within the context of two German multicenter studies of the genetic and environmental causes of EA/TEF (great consortium) and ARM (CURE-Net). Exposures of interest were ascertained using an epidemiological questionnaire. Chi-square, Fisher's exact, and Mann-Whitney U-tests were used to assess differences between the three phenotypes. Newborns with isolated EA/TEF and the combined phenotype had significantly lower birth weights than newborns with isolated ARM (P = 0.001 and P < 0.0001, respectively). Mothers of isolated EA/TEF consumed more alcohol periconceptional (80%) than mothers of isolated ARM or the combined phenotype (each 67%). Parental smoking (P = 0.003) and artificial reproductive techniques (P = 0.03) were associated with isolated ARM. Unexpectedly, maternal periconceptional multivitamin supplementation was most frequent among patients with the most severe form of disorder, i.e. the combined phenotype (19%). Significant differences in birth weight were apparent between the three phenotype groups. This might be attributable to the limited ability of EA/TEF fetuses to swallow amniotic fluid, thus d

Contains fulltext : 155206.pdf (Publisher’s version ) (Open Access), The ARM-Net (anorectal malformation network) consortium held a consensus meeting in which the classification of ARM and preoperative workup were evaluated with the aim of improving monitoring of treatment and outcome. The Krickenbeck classification of ARM and preoperative workup suggested by Levitt and Pena, used as a template, were discussed, and a collaborative consensus was achieved. The Krickenbeck classification is appropriate in describing ARM for clinical use. The preoperative workup was slightly modified. In males with a visible fistula, no cross-table lateral X-ray is needed and an anoplasty or (mini-) posterior sagittal anorectoplasty can directly be performed. In females with a small vestibular fistula (Hegar size <5 mm), a primary repair or colostomy is recommended; the repair may be delayed if the fistula admits a Hegar size >5 mm, and in the meantime, gentle painless dilatations can be performed. In both male and female perineal fistula and either a low birth weight (<2,000 g) or severe associated congenital anomalies, prolonged preoperative painless dilatations might be indicated to decrease perioperative morbidity caused by general anesthesia. The Krickenbeck classification is appropriate in describing ARM for clinical use. Some minor modifications to the preoperative workup by Levitt and Pena have been introduced in order to refine terminology and establish a comprehensive preoperative workup.

Item does not contain fulltext, Anorectal malformations (ARM) have a low prevalence, patients need specialized surgical care, and in many cases, patients born with ARM even need life-long aftercare. Due to its low prevalence most patients are still treated in low-volume pediatric surgical centers without any adequate monitoring of the outcome. Data on prevalence, comparison of different surgical techniques, and prospective outcome measurements are still scarce and difficult to interpret. In 2010, a consortium was founded (ARM-Net consortium) including several European pediatric surgical centers to collaborate more in research and share knowledge on ARM. One of the structures started by the consortium was an ARM-Net registry for the inclusion of all future patients treated in these centers. With this review, we report the structure of the ARM-Net registry, some of the results, and discuss the challenges we faced and still face after its introduction in 2010.

The ARM-Net (anorectal malformation network) consortium held a consensus meeting in which the classification of ARM and preoperative workup were evaluated with the aim of improving monitoring of treatment and outcome. The Krickenbeck classification of ARM and preoperative workup suggested by Levitt and Peña, used as a template, were discussed, and a collaborative consensus was achieved. The Krickenbeck classification is appropriate in describing ARM for clinical use. The preoperative workup was slightly modified. In males with a visible fistula, no cross-table lateral X-ray is needed and an anoplasty or (mini-) posterior sagittal anorectoplasty can directly be performed. In females with a small vestibular fistula (Hegar size <5 mm), a primary repair or colostomy is recommended; the repair may be delayed if the fistula admits a Hegar size >5 mm, and in the meantime, gentle painless dilatations can be performed. In both male and female perineal fistula and either a low birth weight (<2,000 g) or severe associated congenital anomalies, prolonged preoperative painless dilatations might be indicated to decrease perioperative morbidity caused by general anesthesia. The Krickenbeck classification is appropriate in describing ARM for clinical use. Some minor modifications to the preoperative workup by Levitt and Peña have been introduced in order to refine terminology and establish a comprehensive preoperative workup.