Necrotizing enterocolitis: a potential protective role for intestinal alkaline phosphatase as lipopolysaccharide detoxifying enzyme.

Introduction: Necrotizing enterocolitis (NEC) is a life-threatening inflammatory disease. Its onset might be triggered by Toll-Like Receptor 4 (TLR4) activation via bacterial lipopolysaccharide (LPS). We hypothesize that a deficiency of intestinal alkaline phosphatase (IAP), an enzyme secreted by enterocytes that dephosphorylates LPS, may contribute to NEC development. Methods: In this prospective pilot study, we analyzed intestinal resection specimens from surgical NEC patients, and from patients undergoing Roux-Y reconstruction for hepatobiliary disease as controls. We assessed IAP activity via enzymatic stainings and assays and explored IAP and TLR4 co-localization through immunofluorescence. Results: The study population consisted of five NEC patients (two Bell's stage IIb and three-stage IIIb, median (IQR) gestational age 25 (24-28) weeks, postmenstrual age at diagnosis 28 (26-31) weeks) and 11 controls (unknown age). There was significantly lower IAP staining in NEC resection specimens [49 (41-50) U/g of protein] compared to controls [115 (76-144), P = 0.03]. LPS-dephosphorylating activity was also lower in NEC patients [0.06 (0-0.1)] than in controls [0.3 (0.2-0.5), P = 0.003]. Furthermore, we observed colocalization of IAP and TLR4 in NEC resection specimens. Conclusion: This study suggests a significantly lower IAP level in resection specimens of NEC patients compared to controls. This lower IAP activity suggests a potential role of IAP as a protective agent in the gut, which needs further confirmation in larger cohorts.

Core Outcome Set for Necrotizing Enterocolitis Treatment Trials.

BACKGROUND AND OBJECTIVES: Variability in outcome reporting in necrotizing enterocolitis (NEC) treatment trials hinders conducting meta-analyses and implementing novel treatments. We aimed to develop a core outcome set (COS) for NEC treatment trials including outcome measures most relevant to patients and physicians, from NEC diagnosis to adulthood. METHODS: Clinicians and/or researchers from low-middle- and high-income countries were approached based on their scientific contributions to NEC literature, and patients and parents through local organizations. We presented participants with 45 outcomes used in NEC research, identified through a systematic review. To achieve consensus, outcomes were rated on a scale of 1 to 9 in 3 online Delphi rounds, and discussed at a final consensus meeting. RESULTS: Seventy-one participants from 25 countries completed all Delphi rounds, including 15 patients and family representatives. Thirteen outcomes reached consensus in one of the stakeholder groups and were included in the consensus meeting, 6 outcomes reached consensus in both groups. Twenty-seven participants from both high- and low-middle-income countries attended the online consensus meeting, including family representatives and NEC patients. After discussion and a final vote, 5 outcomes reached consensus to be included: mortality, NEC-related mortality, short bowel syndrome, quality of life, and neurodevelopmental impairment. CONCLUSIONS: This NEC COS includes 5 predominantly long-term outcomes agreed upon by clinicians, patients, and family representatives. Use of this international COS will help standardize outcome selection in clinical trials, ensure these are relevant to those most affected by NEC care, and, ultimately, improve the care of infants with NEC.

Ischemia modified albumin as a marker of hypoxia in preterm infants in the first week after birth.

BACKGROUND: Tissue hypoxia remains a leading cause of morbidity and mortality in preterm infants. Current biomarkers often detect irreversible hypoxic cellular injury (i.e. lactate) and are non-specific. A new biomarker is needed which detects tissue hypoxia before irreversible damage occurs. AIMS: To investigate the relation between serum ischemia modified albumin (IMA), a marker of hypoxia; and analytic variables, patient related variables and conditions associated with hypoxia, in preterm infants. STUDY DESIGN: Retrospective cohort study. SUBJECTS: Infants with a gestational age < 30 weeks and/or birth weight < 1000 g. OUTCOME MEASURES: We collected two remnant blood samples in the first week after birth and measured IMA. IMA/albumin ratio (IMAR) was used to adjust for albumin. We assessed correlations between IMA(R) and analytic variables (albumin, lipemia- and haemolysis index); mean-2 h SpO2; mean-2 h variability of regional splanchnic oxygen saturation (rsSO2), measured using near-infrared spectroscopy; and patent ductus arteriosus (PDA). RESULTS: Sixty-five infants were included. Albumin, the lipemia- and haemolysis index correlated negatively with IMA (r:-0.620, P<0.001; r:-0.458, P<0.001; and r:-0.337, P=0.002). IMAR correlated negatively with SpO2 (rho:-0.614, P<0.001). Lower rsSO2 variability correlated with higher IMAR values (rho:-0.785, n=14, P=0.001 and rho:-0.773, n=11, P=0.005). Infants with a hemodynamic significant PDA (hsPDA) had higher IMAR values than infants without PDA (0.13 [0.11-0.28], n=16 vs. 0.11 [0.08-0.20], n=29, P=0.005 and 0.11 [0.09-0.18], n=13 vs. 0.09 [0.06-0.17], n=37, P=0.026). CONCLUSIONS: When adjusted for albumin, the lipemia- and haemolysis index, IMAR has potential value as a marker for systemic hypoxia in preterm infants, considering the associations with SpO2, variability of rsSO2, and hsPDA.

Human precision-cut cystic duct and gallbladder slices: a novel method for studying cholangiopathies.

Background and aims: Precision-cut tissue slices (PCTS) are widely used as an ex vivo culture tissue culture technique to study pathogeneses of diseases and drug activities in organs in vitro. A novel application of the PCTS model may be in the field of translational research into cholangiopathies such as biliary atresia. Therefore, the aim of this study was to apply the precision-cut slice technique to human bile duct and gallbladder tissue. Methods: Cystic duct and gallbladder tissue derived from patients undergoing a cholecystectomy were collected, preserved and used for preparation of precision-cut cystic duct slices (PCCDS) and precision-cut gallbladder slices (PCGS). The PCCDS and PCGS were prepared using a mechanical tissue slicer and subsequently incubated for 24 and 48 h respectively in William's Medium E (WME) culture medium. Viability was assessed based on ATP/protein content and tissue morphology [hematoxylin and eosin (H&E) staining]. Results: It was shown that viability, assessed by the ATP/protein content and morphology, of the PCCDS (n = 8) and PCGS (n = 8) could be maintained over the 24 and 48 h incubation period respectively. ATP/protein content of the PCCDS increased significantly from 0.58 ± 0.13 pmol/µg at 0 h to 2.4 ± 0.29 pmol/µg after 24 h incubation (P = .0003). A similar significant increase from 0.94 ± 0.22 pmol/µg at 0 h to 3.7 ± 0.41 pmol/µg after 24 h (P = .0005) and 4.2 ± 0.47 pmol/µg after 48 h (P = .0002) was observed in the PCGS. Morphological assessment of the PCCDS and PCGS showed viable tissue at 0 h and after 24 and 48 h incubation respectively. Conclusion: This study is the first to report on the use of the PCTS model for human gallbladder and cystic duct tissue. PCCDS and PCGS remain viable for an incubation period of at least 24 h, which makes them suitable for research purposes in the field of cholangiopathies, including biliary atresia.

Outcome Reporting in Interventional Necrotizing Enterocolitis Studies: A Systematic Review.

BACKGROUND: Despite an increasing necrotizing enterocolitis (NEC) incidence, treatment strategies have failed to make major advancements towards improved NEC outcomes. Heterogeneity in outcome reporting and a lack of treatment efficacy studies potentially hamper these advancements. We aimed to analyze outcome reporting in recent interventional NEC studies. METHODS: We performed a systematic review identifying interventional studies on NEC between 1st of January 2016 and 1st of June 2023 in MEDLINE, Embase, CENTRAL and Cochrane reviews. Systematic reviews, clinical trials and change-in-practice cohort studies reporting any therapeutic intervention for NEC patients (Bell's stage ≥ IIa) were eligible. We excluded studies on NEC diagnostics or prevention and non-English publications. Outcomes were categorized into five core areas and presented descriptively. The review was registered with PROSPERO (CRD42022302712). RESULTS: Out of 1.642 screened records, 65 were eligible for full-text review and 15 were finally included for data extraction. Median number of reported outcomes per article was six (range 1-19). We identified 66 unique outcomes, which were mapped to 53 outcome terms. Thirty-four out of the 53 of the outcome terms (64%) were only reported in a single article. Mortality was the most reported outcome (11/15 articles, 73%). Core area 'Adverse outcomes' contained the most outcome terms (n = 19), whereas 'Life impact' contained the least outcome terms (n = 4) and was represented in 3 articles (20%). CONCLUSIONS: Considerable heterogeneity in outcome reporting and a paucity of outcomes concerning 'Life impact' exist in interventional NEC studies. Development of a NEC core outcome set may improve consistency and patient-relevance in outcome reporting. STUDY TYPE: Systematic Review and Meta-Analyses. LEVEL OF EVIDENCE: III.

The role of intestinal alkaline phosphatase in the development of necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a devastating neonatal disease that affects neonates worldwide and often leads to high morbidity and mortality rates. Despite extensive research, the cause of NEC remains unclear, and current treatment options are limited. An important novel finding is the potential role of intestinal Alkaline Phosphatase (IAP) in both pathogenesis and treatment of NEC. IAP can play a vital role in detoxifying liposaccharides (LPS), a key mediator of many pathological processes, thereby reducing the inflammatory response associated with NEC. Furthermore, IAP can help prevent dysbiosis, improve intestinal perfusion, and promote autophagy. In this comprehensive review, we present evidence of the possible connection between IAP and the LPS/Toll-like receptor 4 (TLR4) pathway, impaired gut immunity, and dysbiosis in the preterm gut. Based on these findings, the administration of exogenous IAP might provide promising preventive and therapeutic avenues for the management of NEC.

Gene expression in the intestine of newborn piglets after hypoxia-reoxygenation.

BACKGROUND: In preterm infants, intestinal hypoxia may partly contribute to the pathophysiology of necrotizing enterocolitis through changes in gene expression. Splanchnic hypoxia can be detected with monitoring of regional splanchnic oxygen saturation (rsSO2). Using a piglet model of asphyxia, we aimed to correlate changes in rsSO2 to gene expression. METHODS: Forty-two newborn piglets were randomized to control or intervention groups. Intervention groups were subjected to hypoxia until they were acidotic and hypotensive. Next, they were reoxygenated for 30 min according to randomization, i.e., 21% O2, 100% O2, or 100% O2 for 3 min followed by 21% O2, and observed for 9 h. We continuously measured rsSO2 and calculated mean rsSO2 and variability of rsSO2 (rsCoVar = SD/mean). Samples of terminal ileum were analyzed for mRNA expression of selected genes related to inflammation, erythropoiesis, fatty acid metabolism, and apoptosis. RESULTS: The expression of selected genes was not significantly different between control and intervention groups. No associations between mean rsSO2 and gene expression were observed. However, lower rsCoVar was associated with the upregulation of apoptotic genes and the downregulation of inflammatory genes (P < 0.05). CONCLUSION: Our study suggests that hypoxia and reoxygenation cause reduced vascular adaptability, which seems to be associated with the upregulation of apoptosis and downregulation of inflammation. IMPACT: Our results provide important insight into the (patho)physiological significance of changes in the variability of rsSO2. Our findings may advance future research and clinical practice regarding resuscitation strategies of preterm infants.

Development of an international core outcome set for treatment trials in necrotizing enterocolitis-a study protocol.

AIM: Necrotizing enterocolitis (NEC) is the most lethal disease of the gastrointestinal tract of preterm infants. New and existing management strategies need clinical evaluation. Large heterogeneity exists in the selection, measurement, and reporting of outcome measures in NEC intervention studies. This hampers meta-analyses and the development of evidence-based management guidelines. We aim to develop a Core Outcome Set (COS) for NEC that includes the most relevant outcomes for patients and physicians, from moment of diagnosis into adulthood. This COS is designed for use in NEC treatment trials, in infants with confirmed NEC. METHODS: This study is designed according to COS-STAD (Core Outcome Set-STAndards for Development) recommendations and the COMET (Core Outcome Measures in Effectiveness Trials) Initiative Handbook. We obtained a waiver from the Ethics Review Board and prospectively registered this study with COMET (Study 1920). We will approach 125 clinicians and/or researchers from low-middle and high-income countries based on their scientific output (using SCIVAL, a bibliometric tool). Patients and parents will be approached through local patient organisations. Participants will be separated into three panels, to assess differences in priorities between former patients and parents (1. lay panel), clinicians and researchers involved in the neonatal period (2. neonatal panel) and after the neonatal period (3. post-neonatal panel). They will be presented with outcomes currently used in NEC research, identified through a systematic review, in a Delphi process. Eligible outcome domains are also identified from the patients and parents' perspectives. Using a consensus process, including three online Delphi rounds and a final face-to-face consensus meeting, the COS will be finalised and include outcomes deemed essential to all stakeholders: health care professionals, parents and patients' representatives. The final COS will be reported in accordance with the COS-Standards for reporting (COS-STAR) statement. CONCLUSIONS: Development of an international COS will help to improve homogeneity of outcome measure reporting in NEC, will enable adequate and efficient comparison of treatment strategies, and will help the interpretation and implementation of clinical trial results. This will contribute to high-quality evidence regarding the best treatment strategy for NEC in preterm infants.

Neurodevelopment in patients with biliary atresia up to toddler age: Outcomes and predictability.

AIM: To assess neurodevelopment in young patients with biliary atresia (BA) and to determine the predictive value of General Movement Assessment (GMA) at infant age for neurodevelopmental impairments at toddler age. METHOD: Infants diagnosed with BA were prospectively included in a longitudinal study. Neurodevelopmental status was previously assessed before Kasai porto-enterostomy (KPE) and one month after KPE using Prechtl's GMA, including motor optimality scores. At 2-3 years, neurodevelopment was assessed using the Bayley Scales of Infant Development, and compared to the Dutch norm population. The predictive value of GMA at infant age for motor skills and cognition at toddler age was determined. RESULTS: Neurodevelopment was assessed in 41 BA patients. At toddler age (n = 38, age 29 ± 5 months, 70 % liver transplantation), 13 (39 %) patients scored below-average on motor skills, and 6 (17 %) patients on cognition. Abnormal GMA after KPE predicted both below-average motor skills and cognitive score at toddler age (sensitivity, 91 % and 80 %; specificity 83 % and 67 %; negative predictive value, 94 % and 94 %; and, positive predictive value, 77 % and 33 %, resp.). INTERPRETATION: One-third of toddlers with BA show impaired motor skills. GMA post-KPE has a high predictive value to identify infants with BA at risk of neurodevelopmental impairments.

Surgery or comfort care for neonates with surgical necrotizing enterocolitis: Lessons learned from behavioral artificial intelligence technology.

Background: Critical decision making in surgical necrotizing enterocolitis (NEC) is highly complex and hard to capture in decision rules due to case-specificity and high mortality risk. In this choice experiment, we aimed to identify the implicit weight of decision factors towards future decision support, and to assess potential differences between specialties or centers. Methods: Thirty-five hypothetical surgical NEC scenarios with different factor levels were evaluated by neonatal care experts of all Dutch neonatal care centers in an online environment, where a recommendation for surgery or comfort care was requested. We conducted choice analysis by constructing a binary logistic regression model according to behavioral artificial intelligence technology (BAIT). Results: Out of 109 invited neonatal care experts, 62 (57%) participated, including 45 neonatologists, 16 pediatric surgeons and one neonatology physician assistant. Cerebral ultrasound (Relative importance = 20%, OR = 4.06, 95% CI = 3.39-4.86) was the most important factor in the decision surgery versus comfort care in surgical NEC, nationwide and for all specialties and centers. Pediatric surgeons more often recommended surgery compared to neonatologists (62% vs. 57%, p = 0.03). For all centers, cerebral ultrasound, congenital comorbidity, hemodynamics and parental preferences were significant decision factors (p < 0.05). Sex (p = 0.14), growth since birth (p = 0.25), and estimated parental capacities (p = 0.06) had no significance in nationwide nor subgroup analyses. Conclusion: We demonstrated how BAIT can analyze the implicit weight of factors in the complex and critical decision for surgery or comfort care for (surgical) NEC. The findings reflect Dutch expertise, but the technique can be expanded internationally. After validation, our choice model/BAIT may function as decision aid.

Incidence of Isolated Biliary Atresia during the COVID Lockdown in Europe: Results from a Collaborative Project by RARE-Liver.

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.

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency.

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.

Safety and Feasibility of Indocyanine Green Fluorescence Angiography in Pediatric Gastrointestinal Surgery: A Systematic Review.

BACKGROUND: Although ICG-FA may be valuable in assessing anastomotic perfusion, reliable data on its use in pediatric gastrointestinal surgery is lacking. This systematic review analyzes whether ICG is useful for intestinal perfusion assessment in pediatric gastrointestinal surgery and safe to use in neonates. METHODS: Systematic searches of PubMed, EMBASE & MEDLINE and CENTRAL were performed (last conducted December 6, 2021). The main inclusion criteria were (1) use of ICG for intestinal perfusion assessment and (2) use of ICG in young infants. Exclusion criteria were lack of an English or Dutch full-text and MINORS quality score <60%. Data was presented in overview tables. The usefulness in pediatric gastrointestinal surgery was assessed by surgical outcome. Safety of ICG in neonates was assessed by complication or adverse event occurrence. RESULTS: Regarding intestinal perfusion assessment, four studies were included, reporting 45 patients (median age 1.5 years). ICG was considered useful for anastomotic blood flow evaluation and intraoperative determination of resection length. Regarding ICG safety in neonates, eight studies were included, reporting 46 infants (median age 24.9 days), of which 18 neonates. All but one studies reported the absence of complications or adverse events. Two studies reported subcutaneous dye retention, which fully disappeared within two weeks. CONCLUSION: Although the number of available studies is small, ICG might be useful for intraoperative intestinal perfusion assessment, perhaps even more than conventional clinical assessment. Furthermore, its safety profile looks promising in neonates. Larger prospective studies are necessary to confirm these assumptions and seem warranted given the safety profile. LEVELS OF EVIDENCE: Since this is a systematic review, a Level of Evidence for clinical studies cannot be determined for this manuscript.

The short-term effects of RBC transfusions on intestinal injury in preterm infants.

BACKGROUND: Anemic preterm infants may require red blood cell (RBC) transfusions to maintain sufficient oxygen supply to vital organs. Transfusion treatment, however, may have adverse intestinal effects. We aimed to investigate the short-term effects of RBC transfusions, hypothesizing to find signs of oxidative stress and intestinal injury, possibly related to levels of splanchnic (re-)oxygenation. METHODS: We prospectively included preterm infants (gestational age < 32 weeks). We measured urinary biomarkers for oxidative stress (8-isoprostane) and intestinal cell injury (intestinal fatty acid-binding protein, I-FABP) shortly before and after RBC transfusion. Splanchnic oxygen saturation (rsSO2) and rsSO2 variability were assessed simultaneously. RESULTS: Twenty-nine preterm infants received 58 RBC transfusions at various postnatal ages. Six of them developed necrotizing enterocolitis (NEC) after transfusion. Urinary 8-isoprostane and I-FABP increased following RBC transfusion (median 282-606 pg/ml and 4732-6968 pg/ml, p < 0.01), more pronounced in infants who developed NEC. Change in I-FABP correlated with change in 8-isoprostane (rho = 0.623, p < 0.01). Lower rsSO2 variability, but not higher mean rsSO2 was associated with higher 8-isoprostane and I-FABP levels after transfusion. CONCLUSIONS: Preterm RBC transfusions are associated with concomitant signs of oxidative stress and intestinal injury, parallel with lower variability in splanchnic oxygenation. This may represent the early pathogenetic process of transfusion-associated NEC. IMPACT: Red blood cell (RBC) transfusions in preterm infants are associated with a near 2-fold increase in urinary biomarkers for oxidative stress (8-isoprostane) and intestinal cell injury (intestinal fatty acid-binding protein, I-FABP). Magnitude of change in I-FABP strongly correlated with the magnitude of 8-isoprostane change, suggesting a role for oxidative stress in the pathogenesis of intestinal injury. Lower splanchnic oxygen saturation variability following RBC transfusion was associated with higher 8-isoprostane and I-FABP levels. Loss of splanchnic variability after RBC transfusion may result from increased oxidative stress and its concomitant intestinal injury, possibly representing the early pathogenetic process of transfusion-associated necrotizing enterocolitis.

The prevalence of non-accidental trauma among children with polytrauma: A nationwide level-I trauma centre study.

OBJECTIVE: We aimed to investigate the prevalence and characteristics of non-accidental trauma (NAT) in children with polytrauma treated at level-I trauma centres (TC). SUMMARY OF BACKGROUND: Data 6-10% Of children who present at the emergency department with injuries, sustain polytrauma. Polytrauma may result from either accidental (AT) or NAT, i.e. inflicted or neglect. The prevalence of NAT among children with polytrauma is currently unclear. METHODS: This is a retrospective study that included children (0-18 years) with an Injury Severity Score >15, who presented at one of the 11 Level-I trauma centers (TC) in the Netherlands between January 1, 2010 and January 1, 2016. Outcomes were classified based on the conclusions of the Child Abuse and Neglect-team. Cases in which conclusions were unavailable and there was no clear accidental cause of injuries were reviewed by an expert panel. RESULTS: The study included 1623 children, 1452 (89%) were classified as AT, 171 (11%) as NAT; 39 (2,4%) inflicted and 132 (8,1%) neglect. Of pre-school aged children (<5 years) 41% sustained NAT (OR26.73, 95%CI 17.70-40.35), 35/342 (10%) inflicted and 104/342 (31%) neglect. Admission due to 'cardiopulmonary arrest' was the result of inflicted trauma (30% vs 0%,p < 0.001). NAT had a higher mortality rate (16% vs 10%, p = 0.006). Indicators of NAT were: (near-)drowning (OR10.74, 95%CI 5.94-19.41), burn (OR8.62, 95%CI 4.08-18.19) and fall from height (OR2.18, 95%CI 1.56-3.02). CONCLUSIONS: NAT was the cause of polytrauma in 11% of children in our nationwide level-I TC study; 41% of these polytrauma were the result of NAT experienced by preschool-aged children. Our data show the importance of awareness for NAT.

Prevalence of inflicted and neglectful femur shaft fractures in young children in national level I trauma centers.

BACKGROUND: The prevalence of inflicted femur fractures in young children varies (1.5-35.2%), but these data are based on small retrospective studies with high heterogeneity. Age and mobility of the child seem to be indicators of inflicted trauma. OBJECTIVE: This study describes other factors associated with inflicted and neglectful trauma that can be used to distinguish inflicted and neglectful from accidental femur fractures. MATERIALS AND METHODS: This retrospective study included children (0-6 years) who presented with an isolated femur fracture at 1 of the 11 level I trauma centers in the Netherlands between January 2010 and January 2016. Outcomes were classified based on the conclusions of the Child Abuse and Neglect teams or the court. Cases in which conclusions were unavailable and there was no clear accidental cause were reviewed by an expert panel. RESULTS: The study included 328 children; 295 (89.9%) cases were classified as accidental trauma. Inflicted trauma was found in 14 (4.3%), while 19 (5.8%) were cases of neglect. Indicators of inflicted trauma were age 0-5 months (29%, positive likelihood ratio [LR +] 8.35), 6-12 months (18%, LR + 5.98) and 18-23 months (14%, LR + 3.74). Indicators of neglect were age 6-11 months (18%, LR + 4.41) and age 18-23 months (8%, LR + 1.65). There was no difference in fracture morphology among groups. CONCLUSION: It is unlikely that an isolated femur fracture in ambulatory children age > 24 months is caused by inflicted trauma/neglect. Caution is advised in children younger than 24 months because that age is the main factor associated with inflicted trauma/neglect and inflicted femur fractures.

Biliary Atresia in 2021: Epidemiology, Screening and Public Policy.

Biliary atresia (BA) is a rare newborn liver disease with significant morbidity and mortality, especially if not recognized and treated early in life. It is the most common cause of liver-related death in children and the leading indication for liver transplantation in the pediatric population. Timely intervention with a Kasai portoenterostomy (KPE) can significantly improve prognosis. Delayed disease recognition, late patient referral, and untimely surgery remains a worldwide problem. This article will focus on biliary atresia from a global public health perspective, including disease epidemiology, current national screening programs, and their impact on outcome, as well as new and novel BA screening initiatives. Policy challenges for the implementation of BA screening programs will also be discussed, highlighting examples from the North American, European, and Asian experience.