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Aim: To investigate liver biochemistry in infants screened for biliary atresia (BA) at the time of hepatobiliary scintigraphy (HS) and to evaluate the effect of change in threshold for HS., Methods: Infants born from 2010 to 2021, who underwent HS <6 months postpartum for BA, were included and data sourced from electronic medical records. The change in threshold in 2018 from ≥20 (and/or if conjugated bilirubin exceeds 20% of total bilirubin) to ≥17 μM (regardless of total bilirubin) was evaluated., Results: In the cohort of 635 infants, 48 had BA, 247 had AATD, and the remaining 343 were categorised as 'other'. After the threshold adjustment, HS timing was unaffected (p = 0.27), but the annual HS rate rose from 39 to 87, yet evaluations following the new guideline only accounted for 12%. All liver parameters were elevated in the BA group compared with the additional groups (p < 0.001). Amongst the 104 patients with non-excretory HS, gamma-glutamyl transferase (p < 0.001) and alanine aminotransferase (p = 0.002) remained elevated for BA. The lowest conjugated bilirubin measured in BA children was 36 μM., Conclusion: After threshold change, HS use increased without earlier BA diagnostics, but most were not due to the new guideline. Alanine aminotransferase and gamma-glutamyl transferase should be considered in BA diagnostics., (© 2024 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Gastroschisis prevalence has increased for decades with corresponding increases in the need for immediate and follow-up care. Such care can be complicated by presence of co-occurring malformations. This study explores prevalence of gastroschisis and co-occurring malformations among a 28-year cohort of Danish live-born infants., Methods: This retrospective cohort study used data from 1,695,992 infants born in Denmark during 1994-2021 and registered in the neonatal screening program. Infants were identified from the Danish Civil Registration System and Danish National Patient Register accessed through the Danish Biobank Register. Data on co-occurring malformations were ascertained to classify infants as syndromic or non-syndromic (either isolated or with co-occurring major malformations) and on selected infant and parental characteristics. Poisson regression models were used to estimate prevalence and corresponding 95% confidence intervals (CIs)., Results: Prevalence (per 10,000 live births) of gastroschisis was 1.64 (CI: 1.45-1.84). Temporal trend analyses showed a statistically significant annual increase of 2.8% (CI: 1.4-3.3). Infants with gastroschisis most often presented as isolated (77.7%; CI: 72.3-82.5), followed by those with co-occurring malformations (21.9%; CI: 17.2-27.3) or a diagnosed syndrome (0.4%, CI: <0.1-2.0). Among infants with co-occurring malformations, cardiovascular (10.9%; CI: 6.8; 12.2) and intestinal (9.0%; CI: 5.9-12.2) malformations were most frequently recorded. Prevalence was higher among infants classified as premature but not influenced by infant sex or parental nativity., Conclusion: Gastroschisis prevalence in Denmark increased during 1994-2021, similar to international reports, without increase in co-occurring malformations. Future work with this cohort will characterize healthcare received, comorbidities, and outcomes across the lifespan., Levels of Evidence: Level III (High-quality prospective cohort study)., Competing Interests: Conflicts of interest The authors declare that they have no known competing financial interests or personal relationships that may have influenced the work in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Omphalocele is a congenital abdominal wall defect associated with a high risk of morbidity and mortality, with co-occurring congenital malformations often being the most important prognostic factor. High rates of spontaneous and medical terminations have been reported among pregnancies with omphalocele and co-occurring malformations. Few studies have focused on co-occurring malformations, particularly non-gastrointestinal malformations among live births. This study examined birth prevalence of omphalocele and co-occurring major malformations among a 25-year Danish liveborn cohort., Methods: This nationwide retrospective prevalence study used data from the Danish National Patient Register and Danish Civil Registration System for infants who were delivered in Denmark during 1997-2021 and included in the Danish neonatal screening biobank. Diagnoses of omphalocele and co-occurring malformations were ascertained and prevalence estimated using Poisson regression., Results: Among 1,498,685 live births, 147 infants with omphalocele were identified, yielding a combined and stable prevalence (per 10,000 infants) of 0.98 (95% CI 0.83-1.15). Over one-half (53.7%) presented with one or more major malformations, and an additional 17.0% were diagnosed with a syndrome., Conclusions: Omphalocele birth prevalence in Denmark was stable over a recent 25-year period. The proportion of infants with co-occurring major malformations or diagnosed syndrome has important implications for long-term healthcare demands., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Previous communication: This is the first submission of the manuscript to the journal. This manuscript or parts of it is not being considered for publication by another journal, nor has it been published or posted elsewhere. Ethical considerations: All data were from publicly available sources; thus, approvals from neither scientific ethics committees nor data authorities were required as per Danish law and regulations. Declaration of generative AI in scientific writing: AI and/or AI-assisted technologies were not used in the writing of this manuscript., (© 2024. The Author(s).)

Aim: To determine if children with neonatal cholestatic liver disease had concurrent and later findings on brain imaging studies that could be attributed and the cholestasis to contribute to the understanding of the impaired neuropsychological development., Methods: Ovid MEDLINE and EMBASE were searched on July 21, 2022, and updated on March 26, 2023. Studies with children under 18 years of age with neonatal cholestasis and a brain scan at the time of diagnosis or later in life were included. Excluded studies were non-English, non-human, reviews or conference abstracts. Data were extracted on demographics, brain imaging findings, treatment and outcome. The results were summarised by disease categories. Risk of bias was assessed using JBI critical appraisal tools., Results: The search yielded 12 011 reports, of which 1261 underwent full text review and 89 were eligible for inclusion. Haemorrhage was the most common finding, especially in children with bile duct obstruction, including biliary atresia. Some findings were resolved after liver transplantation., Conclusion: Children with neonatal cholestasis had changes in brain imaging, which might play a role in impaired neuropsychological development, but longitudinal clinical research with structured assessment is needed to better qualify the aetiology of the impairment., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: Malignant liver tumours in children are rare and national outcomes for this tumour entity are rarely published. This study mapped paediatric liver tumours in Denmark over 35 years and reported on the incidence, outcomes and long-term adverse events., Methods: We identified all liver tumours from the Danish Childhood Cancer Registry and reviewed the case records for patient and tumour characteristics, treatment and clinical outcome., Results: We included 79 patients in the analyses. Overall crude incidence was ~2.29 per 1 million children (<15 yr) per year, with 61 hepatoblastomas (HB), 9 hepatocellular carcinomas and 9 other hepatic tumours. Overall 5-year survival was 84%, 78% and 44%, respectively. Nine patients had underlying liver disease or predisposition syndrome. Seventeen children underwent liver transplantation, with two late complications, biliary stenosis and liver fibrosis. For HB, age ≥ 8 years and diagnosis prior to 2000 were significant predictors of a poorer outcome. Adverse events included reduced renal function in 10%, reduced cardiac function in 6% and impaired hearing function in 60% (19% needed hearing aids). Behavioural conditions requiring additional support in school were registered in 10 children., Conclusions: In Denmark, incidences of malignant liver tumours during the last four decades have been increasing, as reported in the literature. HB survival has improved since the year 2000 and is comparable with international results. Reduced hearing is the major treatment-related side effect and affects approximately 60% of patients.

Background: Biliary atresia (BA) is a rare cholangiopathy where one of the proposed aetiological mechanisms is an infectious viral trigger. Coronavirus disease-19 (COVID) lockdown restrictions were implemented to reduce the transmission of infections. Strictness of lockdown varied across European countries. This study aimed to investigate if there was an association between strictness of lockdown and change in isolated BA (IBA) incidence in Europe., Methods: We approached European centres involved in the European Reference Network RARE-LIVER. We included IBA patients born between 2015 and June 2020. We calculated the number of IBA patients born per centre per month. The Stringency Index (SI) was used as lockdown strictness indicator. The association between percentage change of mean number of IBA patients born per month and the SI was assessed., Results: We included 412 IBA patients from thirteen different centres. The median number of patients per month did not change: 6 (1-15) pre-lockdown and 7 (6-9) during lockdown ( p = 0.34). There was an inverse association between SI and percentage change in IBA (B = -0.73, p = 0.03). Median age at Kasai portoenterostomy (days) did not differ between time periods (51 (9-179) vs. 53 (19-126), p = 0.73)., Conclusion: In this European study, a stricter COVID-lockdown was seemingly accompanied by a simultaneous larger decrease in the number of IBA patients born per month in the lockdown. Results should be interpreted with caution due to the assumptions and limitations of the analysis.

Infants with neonatal cholestasis are prone to neurodevelopmental deficits, however, the underlying pathogenesis is unclear. Lipid malabsorption and accumulation of potentially neurotoxic molecules in the blood such as bile acids are important yet relatively unexplored pathways. Here, we developed a translational piglet model to understand how the molecular bile acid and lipid composition of the brain is affected by this disease and relates to motor function. Piglets (8-days old) had bile duct ligation or sham surgery and were fed a formula diet for 3 weeks. Alongside sensory-motor deficits observed in bile duct-ligated animals, we found a shift toward a more hydrophilic and conjugated bile acid profile in the brain. Additionally, comprehensive lipidomics of the cerebellum revealed a decrease in total lipids including phosphatidylinositols and phosphatidylserines and increases in lysophospholipid species. This was paralleled by elevated cerebellar expression of genes related to inflammation and tissue damage albeit without significant impact on the brain transcriptome. This study offers new insights into the developing brain's molecular response to neonatal cholestasis indicating that bile acids and lipids may contribute in mediating motor deficits., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: Hirschsprung's disease (HSCR) is a serious congenital bowel disorder with a prevalence of 1/5000. Currently, there is a lack of systematically developed guidelines to assist clinical decision-making regarding diagnostics and management., Aims: This guideline aims to cover the diagnostics and management of rectosigmoid HSCR up to adulthood. It aims to describe the preferred approach of ERNICA, the European Reference Network for rare inherited and congenital digestive disorders., Methods: Recommendations within key topics covering the care pathway for rectosigmoid HSCR were developed by an international workgroup of experts from 8 European countries within ERNICA European Reference Network from the disciplines of surgery, medicine, histopathology, microbiology, genetics, and patient organization representatives. Recommendation statements were based on a comprehensive review of the available literature and expert consensus. AGREE II and GRADE approaches were used during development. Evidence levels and levels of agreement are noted., Results: Thirty-three statements within 9 key areas were generated. Most recommendations were based on expert opinion., Conclusion: In rare or low-prevalence diseases such as HSCR, there remains limited availability of high-quality clinical evidence. Consensus-based guidelines for care are presented.

Background: Incidence and long-term outcomes of choledochal malformations (CMs) in children remain unclear., Methods: Clinical characteristics, operative details, complications, and follow-up data were collected from eight pediatric surgical centers in Sweden, Norway, Denmark, and Finland, which also answered a questionnaire addressing management practices., Results: During 2000-2017, 126 pediatric CMs were diagnosed, corresponding an incidence of 1:37,400. Diagnostic, treatment, and follow-up practices varied markedly. Of patients with complete clinical data (n = 119), 85% and 11% had type I and IV CMs and were managed by open hepaticojejunostomy at median age of 2.5 (interquartile range 0.46-5.8) years. Associated malformations were more common in fusiform and type IV (23%) than cystic CMs (8%, p = 0.043). Pancreaticobiliary maljunction was more frequently confirmed in patients presenting with pancreatitis (26% vs. 7%, p = 0.005) and with fusiform CMs (56% vs. 25%, p = 0.001). Cholangitis/pancreatitis episodes, occurring in 12% during postoperative follow-up of 4.0 (2.0-7.9) years, associated with longer surveillance (OR 1.32, 95% CI 1.13-1.54, p < 0.001). However, only two thirds of centers continued follow-up until adulthood. No malignancies were reported., Conclusions: CM incidence was higher than traditionally reported among Western populations. Although open hepaticojejunostomy carries good short-term outcomes, long-term morbidity is noteworthy. Standardized evidence-based management strategies and long-term follow-up are encouraged., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background/purpose: Biliary atresia is the most common reason for newborn cholestasis and pediatric liver transplantation. Even after normalization of serum bilirubin after portoenterostomy, most patients require liver transplantation by adulthood due to expanding fibrosis. We addressed contemporary outcomes of biliary atresia in the Nordic countries., Methods: Data on center and patients characteristics, diagnostic practices, surgical treatment, adjuvant medical therapy after portoenterostomy, follow-up and outcomes were collected from all the Nordic centers involved with biliary atresia care during 2005-2016., Results: Of the 154 patients, 148 underwent portoenterostomy mostly by assigned surgical teams at median age of 64 (interquartile range 37-79) days, and 95 patients (64%) normalized their serum bilirubin concentration while living with native liver. Postoperative adjuvant medical therapy, including steroids, ursodeoxycholic acid and antibiotics was given to 137 (93%) patients. Clearance of jaundice associated with young age at surgery and favorable anatomic type of biliary atresia, whereas annual center caseload >3 patients and diagnostic protocol without routine liver biopsy predicted early performance of portoenterostomy. The cumulative 5-year native liver and overall survival estimate was 53% (95% CI 45-62) and 88% (95% CI 83-94), respectively. Portoenterostomy age <65days and annual center caseload >3 patients were predictive for long-term native liver survival, while normalization of serum bilirubin after portoenterostomy was the major predictor of both native liver and overall 5-year survival., Conclusions: The outcomes of biliary atresia in the Nordic countries compared well with previous European studies. Further improvement should be pursued by active measures to reduce patient age at portoenterostomy., Retrospective Prognosis Study: Level II., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: The aim of this study was to evaluate the validity of (99m)Technetium-trimethylbromo-iminodiacetic acid hepatobiliary scintigraphy (HS) for the diagnosis of biliary atresia (BA)., Methods: From January 2005 to December 2009, a total of 47 infants with conjugated hyperbilirubinaemia (> 20 micromol/l total bilirubin of which 20% is conjugated) underwent HS. BA was suspected if no tracer was visualised in the gut 24 hours post-injection. The results of the HSs were compared with the gold standard, laparotomy with antegrade cholangiography findings., Results: Considering the final diagnosis based on the gold standard, the sensitivity, specificity, positive predictive value and negative predictive value (NPV) of the HS in the diagnosis of BA was 100%, 63.6%, 53.8%, and 100%, respectively. The accuracy was 74.5%. BA patients with non-draining HS had significantly higher levels of gamma-glutamyl transpeptidase (GGTP) than non-BA patients with non-draining HS (p = 0.019) or draining HS (p = 0.0001)., Conclusions: HS plays an important role in the diagnostic strategy of infantile jaundice due to conjugated hyperbilirubinaemia. It is a non-invasive method that only seldomly calls for sedation. A high sensitivity and NPV prevent un-necessary surgery. Because of the low specificity of HS in diagnosing BA, it should be part of a multimodality imaging strategy when the result supports a clinical suspicion of BA. In cases with non-draining HS and normal GGTP blood levels, supplemental imaging modalities are especially needed., Funding: none., Trial Registration: not relevant.

A newborn female was hospitalized due to metabolic acidosis and conjugated hyperbilirubinaemia. Extrahepatic biliary atresia (EHBA) was suspected why a (99m)Tc-mebrofenin cholescintigraphy was performed. It showed poor hepatocyte tracer uptake and no drainage to the gut. The hepatocyte dysfunction was caused by an obstructing adrenal gland neuroblastoma later visualised by ultrasound and MRI. The cholescintigraphy is a non-invasive modality to exclude or confirm the suspicion of EHBA. Furthermore neonatal conjugated hyperbilirubinaemia demands the use of a multimodality imaging strategy for differential diagnosis to EHBA.

Introduction: The epidemiology of appendicitis seems to be changing; the proportion of complicated appendicitis cases is growing. The outcome of childhood appendectomy in Denmark has not previously been evaluated nationwide in Denmark., Material and Methods: Data on all Danish children treated for appendicitis were obtained from the National Patient Registry. Reoperation, readmittance or length of hospital stay (LOS) exceeding five days were considered nonsatisfactory outcomes., Results: A total of 2,617 children, 55% boys and 45% girls, were operated at 32 hospitals. Their mean age was 11.1 years. Mortality was 0%. A laparoscopic procedure was used in 34% of the cases. The medians of the postoperative LOS were one day for both the open and laparoscopic appendectomy groups, the corresponding means were 2.5 and 2.0 days (p<0.05). 4.5% had one or more reoperations. 18% had a LOS>5 days or readmittance. The typical reasons were wound infection, need for prolonged antibiotics treatment and simple, prolonged recovery., Conclusion: The Danish practice for appendicitis has acceptable rates of reoperation, medians and means of LOS, and a rate of readmission which is comparable to that reported in other studies. However, a nonsatisfactory outcome after appendectomy in about 20% calls for improvement and further studies., Funding: Not relevant., Trial Registration: Not relevant.

Introduction: The organization and results after cystectomy in Denmark are unknown., Materials and Methods: Based upon the Danish National Hospital Register and discharge notes, postoperative hospitalization, readmission within 30 days, re-operations and mortality after cystectomy in Denmark in the period January 1, 2000-December 31, 2005 were assessed., Results: There were 995 cystectomies with a median postoperative hospital stay of 18.9 days (including readmissions) and hospital mortality of 3.7%. The operations were performed in seven departments without difference in outcome between departments. Morbidity was observed in 58%, 16.8% of which were re-operated for wound or urinary diversion complications., Conclusion: It is concluded that cystectomy should be performed in only five departments in Denmark, and the results suggest that an intensified multicenter collaboration should be initiated to improve outcome.

Three experiments using the Reicher task show that performance on low-frequency words is disrupted if the incorrect alternative forms a higher frequency word. This neighborhood frequency effect occurs for both energy and pattern masks and for different sets of items. When the upcoming word is primed and its accessibility is enhanced, the neighborhood frequency effect is eliminated. Experiments 4a and 4b tested the neighborhood frequency effect using a same-different task and a signal-detection analysis. Neighborhood frequency affected the decision criterion but not the sensitivity of the perceptual system. Experiment 5 showed that many words with a frequency in the range from 1 to 5 per million are not recognized out of context. These results are consistent with the hypothesis that frequency effects in the Reicher task are caused by a bias in the decision system and can be simulated with the stochastic activation-verification model.

To evaluate the effect of photodynamic therapy on human parotid tumors we used tumor specimens obtained from parotid surgery on a consecutive group of patients. The tumors were transplanted into a subcutaneous pocket of nude mice. The original human tumors were pleomorphic adenoma (four), adenolymphoma (one), acinic cell carcinoma (one), sarcoma (one) and low-grade adenocarcinoma (one). The most aggressive growth was seen in the low-grade adenocarcinoma. We re-implanted this tumor on ten mice bilaterally, and treated the tumors with photodynamic therapy (PDT), resulting in a mean depth of tumor necrosis of 5.4 mm (1-10 mm). In three cases we found vital tumor cells in the periphery of the tumor after treatment, with several new blood vessels in the surrounding tissue, indicating a great potential for neo-angiogenesis in this tumor. In order to evaluate the possible nerve damage subsequent to the photodynamic therapy, the ischiadic nerve in 24 lower limbs of nude mice were investigated. In one case only the macroscopical and histological investigation revealed signs of nerve damage. The current study demonstrates that the nude mice implantation model is excellent to investigate growth in both malignant and benign parotid tumors, and to test new therapeutic modalities. Photodynamic therapy seems to have a possible role in the future management of the malignant lesions of the parotid gland, in cases where radical surgery for some reason is not achievable.

This therapy is best understood as light activated chemotherapy. The chemotherapeutic agents, so-called photosensitizers, are relatively harmless without light. The photosensitizer is given systemically and is concentrated or retained in malignant tissue, the activating light is applied locally. The therapy is approved in The United States of America, Canada, The Netherlands, France, Germany and Japan for treatment of certain malignancies. An approval is pending at The Danish National Board of Health. Photodynamic therapy is potentially curative for many superficial or luminal tumours, and can eradicate micrometastases in the tumour bed.