Publications by authors named "Simon Eaton"

261 Publications

Enhancing the utility of antroduodenal manometry in pediatric intestinal pseudo-obstruction.

Neurogastroenterol Motil 2021 Sep 16:e14259. Epub 2021 Sep 16.

Neurogastroenterology & Motility Unit, Gastroenterology Department, Great Ormond Street Hospital for Children, London, UK.

Background: Antroduodenal manometry (ADM) and histopathology are currently employed to aid the diagnosis of pediatric intestinal pseudo-obstruction (PIPO). Limited data are available on the reliability of ADM analysis and its correlation with histopathology. We aimed to develop a protocol for enhanced analysis of ADM contractile patterns, including a scoring system, and explore whether this provided better correlation with histopathology.

Methods: Children referred with suspected PIPO between April 2012-December 2019 who underwent both ADM and full-thickness biopsies were included. ADM tracings were analyzed using both standard (conventional ADM) and novel (enhanced ADM) motility parameters. A novel ADM score (GLASS score) was generated based on the enhanced ADM analysis. Conventional and enhanced ADM analyses were then correlated with histopathology.

Results: Forty patients were included. Using conventional clinical criteria, 29 of these were diagnosed with PIPO and the other 11 with non-PIPO diagnoses. Twenty-three of the PIPO patients had abnormal histopathology: 6 myopathy, 4 neuropathy, 3 neuro-myopathy, and 10 non-specific changes. No agreement in diagnosis was found between conventional ADM analysis and histopathology (ϰ = 0.068; p = 0.197), whereas the latter significantly correlated with enhanced ADM analysis (ϰ = 0.191; p = 0.003). The enhanced ADM score was significantly higher in PIPO versus non-PIPO (16.0 vs. 8.0; p < 0.001).

Conclusions: As opposed to conventional analysis protocols, the newly developed enhanced ADM analysis and associated score is not only able to discriminate between PIPO and non-PIPO patients, but also between distinct histopathological pathologies. Further studies are required to assess the utility of enhanced ADM analysis in larger populations.
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http://dx.doi.org/10.1111/nmo.14259DOI Listing
September 2021

Energy compensation and adiposity in humans.

Curr Biol 2021 Aug 26. Epub 2021 Aug 26.

Unité Mixte de Recherche en Nutrition et Alimentation, CNESTEN, Université Ibn Tofail URAC39, Regional Designated Center of Nutrition Associated with AFRA/IAEA, Kénitra, Morocco.

Understanding the impacts of activity on energy balance is crucial. Increasing levels of activity may bring diminishing returns in energy expenditure because of compensatory responses in non-activity energy expenditures. This suggestion has profound implications for both the evolution of metabolism and human health. It implies that a long-term increase in activity does not directly translate into an increase in total energy expenditure (TEE) because other components of TEE may decrease in response-energy compensation. We used the largest dataset compiled on adult TEE and basal energy expenditure (BEE) (n = 1,754) of people living normal lives to find that energy compensation by a typical human averages 28% due to reduced BEE; this suggests that only 72% of the extra calories we burn from additional activity translates into extra calories burned that day. Moreover, the degree of energy compensation varied considerably between people of different body compositions. This association between compensation and adiposity could be due to among-individual differences in compensation: people who compensate more may be more likely to accumulate body fat. Alternatively, the process might occur within individuals: as we get fatter, our body might compensate more strongly for the calories burned during activity, making losing fat progressively more difficult. Determining the causality of the relationship between energy compensation and adiposity will be key to improving public health strategies regarding obesity.
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http://dx.doi.org/10.1016/j.cub.2021.08.016DOI Listing
August 2021

Commentary on blood group AB is associated with poor outcomes in infants with Necrotizing enterocolitis.

Authors:
Simon Eaton

J Pediatr Surg 2021 Jul 18. Epub 2021 Jul 18.

UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom. Electronic address:

This is a commentary on the manuscript titled "Blood Group AB is Associated with Poor Outcomes in Infants with Necrotizing Enterocolitis" by Dos Santos Martins R, Kool E, Kalteren W, et al.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.07.009DOI Listing
July 2021

COVID-19 pandemic experiences of parents caring for children with oesophageal atresia/tracheo-oesophageal fistula.

BMJ Paediatr Open 2021 18;5(1):e001077. Epub 2021 May 18.

Centre for Outcomes and Experience Research in Children's Health, Illness and Disability (ORCHID), Great Ormond Street Hospital For Children NHS Trust, London, UK.

Purpose: The COVID-19 pandemic has resulted in a global health crisis of unparalleled magnitude. The direct risk to the health of children is low. However, disease-containment measures have society-wide impacts. This study explored the pandemic experiences of parents of children with oesophageal atresia/tracheo-oesophageal fistula (OA/TOF) in the UK.

Design: A phenomenological approach underpinned use of an asynchronous online forum method, in collaboration with a patient support group. Data were evaluated using thematic analysis.

Results: The online forum ran between 7 November and 18 December 2020 with 109 participants.Pandemic experiences were divided into themes relating to healthcare and disease containment. Participants described positive experiences with remote healthcare but identified limitations. Delays and cancellations led to escalation of care to an emergency level, slower developmental progress and feelings of being abandoned by services. Inpatient care was perceived as safe but caring alone was emotionally and practically challenging. Disease containment themes revealed anxiety regarding health risks, 'collateral' damage to well-being because of isolation, and an impact on finances and employment. Parents described a transition from worry about direct health risks to concern about the impact of isolation on socialisation and development. A process of risk-benefit analysis led some to transition to a more 'normal life', while others continued to isolate. Benefits to their child's health from isolation were reported.

Conclusions: Parents' experiences of caring for a child with OA/TOF during the pandemic were varied. Rapid adoption of telehealth has demonstrated the enormous potential of remote healthcare delivery but requires refinement to meet the needs of the individual. Future pandemic planning should aim to retain community healthcare services to avoid escalation of care to an emergency, manage chronic and developmental concerns, and support parental well-being. Accurate and consistent disease-specific information is highly valued by parents. Third sector organisations are ideally positioned to support this.
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http://dx.doi.org/10.1136/bmjpo-2021-001077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136802PMC
May 2021

Outcomes in Hirschsprung's disease with coexisting learning disability.

Eur J Pediatr 2021 Jun 11. Epub 2021 Jun 11.

Department of Specialist Neonatal and Paediatric Surgery, Great Ormond Street Hospital for Children, London, UK.

This study describes functional and health-related quality of life (HRQoL) outcomes in patients with Hirschsprung's disease (HSCR) with associated learning disability or neurodevelopmental delay (LD), completing a core outcome set for HSCR. This was a cross-sectional study from a tertiary pediatric surgery center. Patients treated between 1977 and 2013 were prospectively contacted to complete an outcomes survey. Children under 12 and older patients with LD were assisted to complete these by a proxy. Bowel and urologic function were assessed (Rintala's BFS and modified DanPSS) along with HRQoL (PedsQL/GIQLI/SF-36). Thirty-two patients with LD were compared to 186 patients with normal cognition. Patients with LD had 76% survival over the follow-up period, compared to 99% in the remainder of the cohort. Poor functional outcomes were common in the patients with LD, considerably higher than cognitively normal patients: with weekly issues withholding stool, soiling and fecal accidents in over half of patients surveyed (44-60%), and urinary incontinence in 46%. Use of permanent stoma was significantly higher (22% vs. 4%; p = 0.001). HRQoL was worse in domains of physical functioning in adults and children but not for social or emotional domains in adults. Subgroup analysis of patients with Down syndrome suggested similar functional results but better QoL. Multivariate analysis demonstrated a dramatically higher incidence of poor continence outcomes in patients with LD (adjusted OR 9.6 [4.0-23]).Conclusions: We provide LD-specific outcomes showing inferior function but similar HRQoL to other patients with HSCR, this is much needed in the counselling of families of these children. What is Known: • Hirschsprung's disease is commonly associated with syndromes or other anomalies with resultant cognitive impairments. • The outcomes for these patients specifically have been poorly described in the literature. What is New: • Objective functional and quality of life surveys demonstrate significant differences from patients without cognitive impairment. • Patients with learning disability Patients with associated LD were almost ten times more likely to have an associated poor functional outcome, with very little impact on proxy-reported quality of life.
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http://dx.doi.org/10.1007/s00431-021-04129-5DOI Listing
June 2021

Growth, body composition, and cardiovascular and nutritional risk of 5- to 10-y-old children consuming vegetarian, vegan, or omnivore diets.

Am J Clin Nutr 2021 06;113(6):1565-1577

Childhood Nutrition Research Centre, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.

Background: Plant-based diets (PBDs) are increasingly recommended for human and planetary health. However, comprehensive evidence on the health effects of PBDs in children remains incomplete, particularly in vegans.

Objectives: To quantify differences in body composition, cardiovascular risk, and micronutrient status of vegetarian and vegan children relative to omnivores and to estimate prevalence of abnormal micronutrient and cholesterol status in each group.

Methods: In a cross-sectional study, Polish children aged 5-10 y (63 vegetarian, 52 vegan, 72 matched omnivores) were assessed using anthropometry, deuterium dilution, DXA, and carotid ultrasound. Fasting blood samples, dietary intake, and accelerometry data were collected.

Results: All results are reported relative to omnivores. Vegetarians had lower gluteofemoral adiposity but similar total fat and lean mass. Vegans had lower fat indices in all regions but similar lean mass. Both groups had lower bone mineral content (BMC). The difference for vegetarians attenuated after accounting for body size but remained in vegans (total body minus the head: -3.7%; 95% CI: -7.0, -0.4; lumbar spine: -5.6%; 95% CI: -10.6, -0.5). Vegetarians had lower total cholesterol, HDL, and serum B-12 and 25-hydroxyvitamin D [25(OH)D] without supplementation but higher glucose, VLDL, and triglycerides. Vegans were shorter and had lower total LDL (-24 mg/dL; 95% CI: -35.2, -12.9) and HDL (-12.2 mg/dL; 95% CI: -17.3, -7.1), high-sensitivity C-reactive protein, iron status, and serum B-12 (-217.6 pmol/L; 95% CI: -305.7, -129.5) and 25(OH)D without supplementation but higher homocysteine and mean corpuscular volume. Vitamin B-12 deficiency, iron-deficiency anemia, low ferritin, and low HDL were more prevalent in vegans, who also had the lowest prevalence of high LDL. Supplementation resolved low B-12 and 25(OH)D concentrations.

Conclusions: Vegan diets were associated with a healthier cardiovascular risk profile but also with increased risk of nutritional deficiencies and lower BMC and height. Vegetarians showed less pronounced nutritional deficiencies but, unexpectedly, a less favorable cardiometabolic risk profile. Further research may help maximize the benefits of PBDs in children.
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http://dx.doi.org/10.1093/ajcn/nqaa445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176147PMC
June 2021

Long-term surgical and patient-reported outcomes of Hirschsprung Disease.

J Pediatr Surg 2021 Sep 13;56(9):1502-1511. Epub 2021 Feb 13.

Specialist Neonatal and Paediatric Surgery, Great Ormond Street Hospital for Children, London, UK. Electronic address:

Background: Information is needed regarding the complex relationships between long-term functional outcomes and health-related quality of life (HRQoL) in Hirschsprung's Disease (HSCR). We describe long-term outcomes across multiple domains, completing a core outcome set through to adulthood.

Methods: HSCR patients operated at a single center over a 35-year period (1978-2013) were studied. Patients completed detailed questionnaires on bowel and urologic function, and HRQOL. Patients with learning disability (LD) were excluded. Outcomes were compared to normative data. Data are reported as median [IQR] or mean (SD).

Results: 186 patients (median age 28 [18-32] years; 135 males) completed surveys. Bowel function was reduced (BFS 17 [14-19] vs. 19 [19-20], p < 0•0001;η = 0•22). Prevalence and severity of fecal soiling and fecal awareness improved with age (p < 0•05 for both). Urinary incontinence was more frequent than controls, most of all in 13-26y females (65% vs. 31%,p = 0•003). In adults, this correlated independently with constipation symptoms (OR 3.18 [1.4-7.5],p = 0.008). HRQoL outcomes strongly correlated with functional outcome: 42% of children demonstrated clinically significant reductions in overall PedsQL score, and poor bowel outcome was strongly associated with impaired QOL (B = 22•7 [12•7-32•7],p < 0•001). In adults, GIQLI scores were more often impacted in patients with extended segment disease. SF-36 scores were reduced relative to population level data in most domains, with large effect sizes noted for females in General Health (g = 1.19) and Social Wellbeing (g = 0.8).

Conclusion: Functional impairment is common after pull-through, but bowel function improves with age. Clustering of poor functional outcomes across multiple domains identifies a need for early recognition and long-term support for these patients.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.01.043DOI Listing
September 2021

Biochemical characterization of proliferative and differentiated SH-SY5Y cell line as a model for Parkinson's disease.

Neurochem Int 2021 05 5;145:105009. Epub 2021 Mar 5.

Genetics and Genomic Medicine, GOS Institute of Child Health, University College London, London, UK; Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK. Electronic address:

Parkinson's disease is a multifactorial neurodegenerative disease. The cellular pathology includes dopamine depletion, decrease in mitochondrial complex I enzyme activity, lysosomal glucocerebrosidase enzyme activity and glutathione levels. The SH-SY5Y human neuroblastoma cell line is one of the most widely used cell line models for Parkinson's disease. However, the consensus on its suitability as a model in its proliferative or differentiated state is lacking. In this study, we characterized and compared the biochemical processes most often studied in PD. This in proliferative and differentiated phenotypes of SH-SY5Y cells and several differences were found. Most notably, extracellular dopamine metabolism was significantly higher in differentiated SH-SY5Y. Furthermore, there was a greater variability in glutathione levels in proliferative phenotype (+/- 49%) compared to differentiated (+/- 16%). Finally, enzyme activity assay revealed significant increase in the lysosomal enzyme glucocerebrosidase activity in differentiated phenotype. In contrast, our study has found similarities between the two phenotypes in mitochondrial electron transport chain activity and tyrosine hydroxylase protein expression. The results of this study demonstrate that despite coming from the same cell line, these cells possess some key differences in their biochemistry. This highlights the importance of careful characterization of relevant disease pathways to assess the suitability of cell lines, such as SH-SY5Y cells, for modelling PD or other diseases, i.e. when using the same cell line but different differentiation states.
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http://dx.doi.org/10.1016/j.neuint.2021.105009DOI Listing
May 2021

Conservative treatment for uncomplicated appendicitis in children: the CONTRACT feasibility study, including feasibility RCT.

Health Technol Assess 2021 Feb;25(10):1-192

Department of Health Services Research, Institute of Population Health Sciences, University of Liverpool, Liverpool, UK.

Background: Although non-operative treatment is known to be effective for the treatment of uncomplicated acute appendicitis in children, randomised trial data comparing important outcomes of non-operative treatment with those of appendicectomy are lacking.

Objectives: The objectives were to ascertain the feasibility of conducting a multicentre randomised controlled trial comparing the clinical effectiveness and cost-effectiveness of a non-operative treatment pathway with appendicectomy for the treatment of uncomplicated acute appendicitis in children.

Design: This was a mixed-methods study, which included a feasibility randomised controlled trial, embedded and parallel qualitative and survey studies, a parallel health economic feasibility study and the development of a core outcome set.

Setting: This study was set in three specialist NHS paediatric surgical units in England.

Participants: Children (aged 4-15 years) clinically diagnosed with uncomplicated acute appendicitis participated in the feasibility randomised controlled trial. Children, their families, recruiting clinicians and other health-care professionals involved in caring for children with appendicitis took part in the qualitative study. UK specialist paediatric surgeons took part in the survey. Specialist paediatric surgeons, adult general surgeons who treat children, and children and young people who previously had appendicitis, along with their families, took part in the development of the core outcome set.

Interventions: Participants in the feasibility randomised controlled trial were randomised to a non-operative treatment pathway (broad-spectrum antibiotics and active observation) or appendicectomy.

Main Outcome Measures: The primary outcome measure was the proportion of eligible patients recruited to the feasibility trial.

Data Sources: Data were sourced from NHS case notes, questionnaire responses, transcribed audio-recordings of recruitment discussions and qualitative interviews.

Results: Overall, 50% (95% confidence interval 40% to 59%) of 115 eligible patients approached about the trial agreed to participate and were randomised. There was high acceptance of randomisation and good adherence to trial procedures and follow-up (follow-up rates of 89%, 85% and 85% at 6 weeks, 3 months and 6 months, respectively). More participants had perforated appendicitis than had been anticipated. Qualitative work enabled us to communicate about the trial effectively with patients and families, to design and deliver bespoke training to optimise recruitment and to understand how to optimise the design and delivery of a future trial. The health economic study indicated that the main cost drivers are the ward stay cost and the cost of the operation; it has also informed quality-of-life assessment methods for future work. A core outcome set for the treatment of uncomplicated acute appendicitis in children and young people was developed, containing 14 outcomes. There is adequate surgeon interest to justify proceeding to an effectiveness trial, with 51% of those surveyed expressing a willingness to recruit with an unchanged trial protocol.

Limitations: Because the feasibility randomised controlled trial was performed in only three centres, successful recruitment across a larger number of sites cannot be guaranteed. However, the qualitative work has informed a bespoke training package to facilitate this. Although survey results suggest adequate clinician interest to make a larger trial possible, actual participation may differ, and equipoise may have changed over time.

Conclusions: A future effectiveness trial is feasible, following limited additional preparation, to establish appropriate outcome measures and case identification. It is recommended to include a limited package of qualitative work to optimise recruitment, in particular at new centres.

Future Work: Prior to proceeding to an effectiveness trial, there is a need to develop a robust method for distinguishing children with uncomplicated acute appendicitis from those with more advanced appendicitis, and to reach agreement on a primary outcome measure and effect size that is acceptable to all stakeholder groups involved.

Trial Registration: Current Controlled Trials ISRCTN15830435.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 10. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958256PMC
February 2021

Surgical Management of Pediatric Inguinal Hernia: A Systematic Review and Guideline from the European Pediatric Surgeons' Association Evidence and Guideline Committee.

Eur J Pediatr Surg 2021 Feb 10. Epub 2021 Feb 10.

Division of General and Thoracic Surgery, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

Introduction:  Inguinal hernia repair represents the most common operation in childhood; however, consensus about the optimal management is lacking. Hence, recommendations for clinical practice are needed. This study assesses the available evidence and compiles recommendations on pediatric inguinal hernia.

Materials And Methods:  The European Pediatric Surgeons' Association Evidence and Guideline Committee addressed six questions on pediatric inguinal hernia repair with the following topics: (1) open versus laparoscopic repair, (2) extraperitoneal versus transperitoneal repair, (3) contralateral exploration, (4) surgical timing, (5) anesthesia technique in preterm infants, and (6) operation urgency in girls with irreducible ovarian hernia. Systematic literature searches were performed using PubMed, MEDLINE, Embase (Ovid), and The Cochrane Library. Reviews and meta-analyses were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement.

Results:  Seventy-two out of 5,173 articles were included, 27 in the meta-analyses. Laparoscopic repair shortens bilateral operation time compared with open repair. In preterm infants, hernia repair after neonatal intensive care unit (NICU)/hospital discharge is associated with less respiratory difficulties and recurrences, regional anesthesia is associated with a decrease of postoperative apnea and pain. The review regarding operation urgency for irreducible ovarian hernia gained insufficient evidence of low quality.

Conclusion:  Laparoscopic repair may be beneficial for children with bilateral hernia and preterm infants may benefit using regional anesthesia and postponing surgery. However, no definite superiority was found and available evidence was of moderate-to-low quality. Evidence for other topics was less conclusive. For the optimal management of inguinal hernia repair, a tailored approach is recommended taking into account the local facilities, resources, and expertise of the medical team involved.
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http://dx.doi.org/10.1055/s-0040-1721420DOI Listing
February 2021

CONservative TReatment of Appendicitis in Children: a randomised controlled feasibility Trial (CONTRACT).

Arch Dis Child 2021 Jan 13. Epub 2021 Jan 13.

Centre for Surgical Research and NIHR Bristol Biomedical Research Centre, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Objective: To establish the feasibility of a multicentre randomised controlled trial to assess the effectiveness and cost-effectiveness of a non-operative treatment pathway compared with appendicectomy in children with uncomplicated acute appendicitis.

Design: Feasibility randomised controlled trial with embedded qualitative study to inform recruiter training to optimise recruitment and the design of a future definitive trial.

Setting: Three specialist paediatric surgery centres in the UK.

Patients: Children (aged 4-15 years) with a clinical diagnosis of uncomplicated acute appendicitis.

Interventions: Appendicectomy or a non-operative treatment pathway (comprising broad-spectrum antibiotics and active observation).

Main Outcome Measures: Primary outcome measure was the proportion of eligible patients recruited. Secondary outcomes evaluated adherence to interventions, data collection during follow-up, safety of treatment pathways and clinical course.

Results: Fifty per cent of eligible participants (95% CI 40 to 59) approached about the trial agreed to participate and were randomised. Repeated bespoke recruiter training was associated with an increase in recruitment rate over the course of the trial from 38% to 72%. There was high acceptance of randomisation, good patient and surgeon adherence to trial procedures and satisfactory completion of follow-up. Although more participants had perforated appendicitis than had been anticipated, treatment pathways were found to be safe and adverse event profiles acceptable.

Conclusion: Recruitment to a randomised controlled trial examining the effectiveness and cost-effectiveness of a non-operative treatment pathway compared with appendicectomy for the treatment of uncomplicated acute appendicitis in children is feasible.

Trial Registration Number: ISRCTN15830435.
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http://dx.doi.org/10.1136/archdischild-2020-320746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311091PMC
January 2021

Beclin-1-mediated activation of autophagy improves proximal and distal urea cycle disorders.

EMBO Mol Med 2021 Feb 28;13(2):e13158. Epub 2020 Dec 28.

Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.

Urea cycle disorders (UCD) are inherited defects in clearance of waste nitrogen with high morbidity and mortality. Novel and more effective therapies for UCD are needed. Studies in mice with constitutive activation of autophagy unravelled Beclin-1 as druggable candidate for therapy of hyperammonemia. Next, we investigated efficacy of cell-penetrating autophagy-inducing Tat-Beclin-1 (TB-1) peptide for therapy of the two most common UCD, namely ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) deficiencies. TB-1 reduced urinary orotic acid and improved survival under protein-rich diet in spf-ash mice, a model of OTC deficiency (proximal UCD). In Asl mice, a model of ASL deficiency (distal UCD), TB-1 increased ureagenesis, reduced argininosuccinate, and improved survival. Moreover, it alleviated hepatocellular injury and decreased both cytoplasmic and nuclear glycogen accumulation in Asl mice. In conclusion, Beclin-1-dependent activation of autophagy improved biochemical and clinical phenotypes of proximal and distal defects of the urea cycle.
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http://dx.doi.org/10.15252/emmm.202013158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863400PMC
February 2021

Response to Comment on "Non-operative Treatment Versus Appendectomy for Acute Nonperforated Appendicitis in Children: Five-year follow up of a Randomized Controlled Pilot Trial".

Ann Surg 2020 Dec 2. Epub 2020 Dec 2.

Department of Women's and Children's Health, Karolinska Institutet Stockholm, Sweden Department of Women's and Children's Health, Karolinska Institutet Stockholm, Sweden Department of Pediatric Surgery, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden; Department of Women's and Children's Health Karolinska Institutet, Stockholm, Sweden Surgery Unit, UCL Institute of Child Health, London, United Kingdom; Department of Pediatric Surgery, Great Ormond Street Hospital, London, United Kingdom Department of Women's and Children's Health, Karolinska Institutet Stockholm, Sweden Department of Pediatric Surgery, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden; Department of Women's and Children's Health Karolinska Institutet, Stockholm, Sweden.

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http://dx.doi.org/10.1097/SLA.0000000000004399DOI Listing
December 2020

The Microfluidic Environment Reveals a Hidden Role of Self-Organizing Extracellular Matrix in Hepatic Commitment and Organoid Formation of hiPSCs.

Cell Rep 2020 12;33(9):108453

Great Ormond Street Institute of Child Health, University College London, WC1N1EH London, UK; Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, 201210 Shanghai, China; Department of Industrial Engineering, University of Padova, 35131 Padova, Italy; Venetian Institute of Molecular Medicine (VIMM), 35129 Padova, Italy. Electronic address:

The specification of the hepatic identity during human liver development is strictly controlled by extrinsic signals, yet it is still not clear how cells respond to these exogenous signals by activating secretory cascades, which are extremely relevant, especially in 3D self-organizing systems. Here, we investigate how the proteins secreted by human pluripotent stem cells (hPSCs) in response to developmental exogenous signals affect the progression from endoderm to the hepatic lineage, including their competence to generate nascent hepatic organoids. By using microfluidic confined environment and stable isotope labeling with amino acids in cell culture-coupled mass spectrometry (SILAC-MS) quantitative proteomic analysis, we find high abundancy of extracellular matrix (ECM)-associated proteins. Hepatic progenitor cells either derived in microfluidics or exposed to exogenous ECM stimuli show a significantly higher potential of forming hepatic organoids that can be rapidly expanded for several passages and further differentiated into functional hepatocytes. These results prove an additional control over the efficiency of hepatic organoid formation and differentiation for downstream applications.
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http://dx.doi.org/10.1016/j.celrep.2020.108453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237389PMC
December 2020

The liposomal delivery of hydrophobic oxidovanadium complexes imparts highly effective cytotoxicity and differentiating capacity in neuroblastoma tumour cells.

Sci Rep 2020 10 7;10(1):16660. Epub 2020 Oct 7.

Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK.

Oxidovanadium complexes with organic ligands are well known to have cytotoxic or differentiating capabilities against a range of cancer cell types. Their limited use in clinical testing though has resulted largely from uncertainties about the long-term toxicities of such complexes, due in part to the speciation to vanadate ions in the circulation. We hypothesised that more highly stable complexes, delivered using liposomes, may provide improved opportunities for oxidovanadium applications against cancer. In this study we sourced specifically hydrophobic forms of oxidovanadium complexes with the explicit aim of demonstrating liposomal encapsulation, bioavailability in cultured neuroblastoma cells, and effective cytotoxic or differentiating activity. Our data show that four ethanol-solubilised complexes with amine bisphenol, aminoalcohol bisphenol or salan ligands are equally or more effective than a previously used complex bis(maltolato)oxovanadium(V) in neuroblastoma cell lines. Moreover, we show that one of these complexes can be stably incorporated into cationic liposomes where it retains very good bioavailability, apparently low speciation and enhanced efficacy compared to ethanol delivery. This study provides the first proof-of-concept that stable, hydrophobic oxidovanadium complexes retain excellent cellular activity when delivered effectively to cancer cells with nanotechnology. This offers the improved prospect of applying oxidovanadium-based drugs in vivo with increased stability and reduced off-target toxicity.
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http://dx.doi.org/10.1038/s41598-020-73539-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542164PMC
October 2020

Remote ischemic conditioning counteracts the intestinal damage of necrotizing enterocolitis by improving intestinal microcirculation.

Nat Commun 2020 10 2;11(1):4950. Epub 2020 Oct 2.

Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.

Necrotizing enterocolitis (NEC) is a devastating disease of premature infants with high mortality rate, indicating the need for precision treatment. NEC is characterized by intestinal inflammation and ischemia, as well derangements in intestinal microcirculation. Remote ischemic conditioning (RIC) has emerged as a promising tool in protecting distant organs against ischemia-induced damage. However, the effectiveness of RIC against NEC is unknown. To address this gap, we aimed to determine the efficacy and mechanism of action of RIC in experimental NEC. NEC was induced in mouse pups between postnatal day (P) 5 and 9. RIC was applied through intermittent occlusion of hind limb blood flow. RIC, when administered in the early stages of disease progression, decreases intestinal injury and prolongs survival. The mechanism of action of RIC involves increasing intestinal perfusion through vasodilation mediated by nitric oxide and hydrogen sulfide. RIC is a viable and non-invasive treatment strategy for NEC.
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http://dx.doi.org/10.1038/s41467-020-18750-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532542PMC
October 2020

Bifidobacterium breve BBG-001 and intestinal barrier function in preterm babies: Exploratory Studies from the PiPS Trial.

Pediatr Res 2021 05 18;89(7):1818-1824. Epub 2020 Sep 18.

Homerton University Hospital, NHS Foundation Trust, London, UK.

Background: Uncertainty remains about the role of probiotics to prevent necrotising enterocolitis (NEC) some of which arises from the variety of probiotic interventions used in different trials, many with no prior evidence of potential efficacy. Mechanistic studies of intestinal barrier function embedded in a large probiotic trial could provide evidence about which properties of probiotics might be important for NEC prevention thus facilitating identification of strains with therapeutic potential.

Methods: Intestinal permeability, stool microbiota, SCFAs and mucosal inflammation were assessed from the second postnatal week in babies enrolled to a randomised controlled trial of B. breve BBG-001 (the PiPS trial). Results were compared by allocation and by stool colonisation with the probiotic.

Results: Ninety-four preterm babies were recruited across six nested studies. B. breve BBG-001 content was higher by allocation and colonisation; Enterobacteriaceae and acetic acid levels were higher by colonisation. No measure of intestinal barrier function showed differences. The PiPS trial found no evidence of efficacy to reduce NEC.

Conclusions: That the negative results of the PiPS trial were associated with failure of this probiotic to modify intestinal barrier function supports the possibility that the tests described here have the potential to identify strains to progress to large clinical trials.

Impact: Uncertainty about the therapeutic role of probiotics to prevent necrotising enterocolitis is in part due to the wide range of bacterial strains with no previous evidence of efficacy used in clinical trials. We hypothesised that mechanistic studies embedded in a probiotic trial would provide evidence about which properties of probiotics might be important for NEC prevention. The finding that the probiotic strain tested, Bifidobacterium breve BBG-001, showed neither effects on intestinal barrier function nor clinical efficacy supports the possibility that these tests have the potential to identify strains to progress to large clinical trials.
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http://dx.doi.org/10.1038/s41390-020-01135-5DOI Listing
May 2021

Activation of Wnt signaling by amniotic fluid stem cell-derived extracellular vesicles attenuates intestinal injury in experimental necrotizing enterocolitis.

Cell Death Dis 2020 09 14;11(9):750. Epub 2020 Sep 14.

Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.

Necrotizing enterocolitis (NEC) is a devastating intestinal disease primarily affecting preterm neonates and causing high morbidity, high mortality, and huge costs for the family and society. The treatment and the outcome of the disease have not changed in recent decades. Emerging evidence has shown that stimulating the Wnt/β-catenin pathway and enhancing intestinal regeneration are beneficial in experimental NEC, and that they could potentially be used as a novel treatment. Amniotic fluid stem cells (AFSC) and AFSC-derived extracellular vesicles (EV) can be used to improve intestinal injury in experimental NEC. However, the mechanisms by which they affect the Wnt/β-catenin pathway and intestinal regeneration are unknown. In our current study, we demonstrated that AFSC and EV attenuate NEC intestinal injury by activating the Wnt signaling pathway. AFSC and EV stimulate intestinal recovery from NEC by increasing cellular proliferation, reducing inflammation and ultimately regenerating a normal intestinal epithelium. EV administration has a rescuing effect on intestinal injury when given during NEC induction; however, it failed to prevent injury when given prior to NEC induction. AFSC-derived EV administration is thus a potential emergent novel treatment strategy for NEC.
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http://dx.doi.org/10.1038/s41419-020-02964-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490270PMC
September 2020

Engineering transplantable jejunal mucosal grafts using patient-derived organoids from children with intestinal failure.

Nat Med 2020 10 7;26(10):1593-1601. Epub 2020 Sep 7.

Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, London, UK.

Intestinal failure, following extensive anatomical or functional loss of small intestine, has debilitating long-term consequences for children. The priority of patient care is to increase the length of functional intestine, particularly the jejunum, to promote nutritional independence. Here we construct autologous jejunal mucosal grafts using biomaterials from pediatric patients and show that patient-derived organoids can be expanded efficiently in vitro. In parallel, we generate decellularized human intestinal matrix with intact nanotopography, which forms biological scaffolds. Proteomic and Raman spectroscopy analyses reveal highly analogous biochemical profiles of human small intestine and colon scaffolds, indicating that they can be used interchangeably as platforms for intestinal engineering. Indeed, seeding of jejunal organoids onto either type of scaffold reliably reconstructs grafts that exhibit several aspects of physiological jejunal function and that survive to form luminal structures after transplantation into the kidney capsule or subcutaneous pockets of mice for up to 2 weeks. Our findings provide proof-of-concept data for engineering patient-specific jejunal grafts for children with intestinal failure, ultimately aiding in the restoration of nutritional autonomy.
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http://dx.doi.org/10.1038/s41591-020-1024-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116539PMC
October 2020

Cerebral Oxygenation in Preterm Infants With Necrotizing Enterocolitis.

Pediatrics 2020 09;146(3)

Homerton University Hospital National Health Service Foundation Trust, London, United Kingdom;

Background And Objectives: Preterm infants with necrotizing enterocolitis (NEC) are known to have worse neurodevelopmental outcomes, but there is no substantial evidence to support an underlying pathophysiology. We aimed to examine whether cerebral oxygenation differs in those infants who develop NEC compared to cerebral oxygenation in those who do not.

Methods: We examined 48 infants <30 weeks' gestation admitted to a tertiary level NICU from October 2016 to May 2018. Infants with birth weight less than or equal to the second percentile, abnormal antenatal dopplers or twin-to-twin-transfusion-syndrome were excluded. Cerebral oximetry measurements were performed by using a near-infrared spectroscopy (NIRS) monitor weekly for 60 minutes, allowing measurement of cerebral tissue oxygenation index from the first week of life to 36 weeks postconceptional age. Weekly clinical status was also recorded. NEC was defined as greater than or equal to Bell stage 2.

Results: The median birth weight was 884 g (range of 460-1600 g), the median weeks' gestational age was 26 + 3/7 (23 + 0/7 to 29 + 6/7), and 52% were girls. In total, 276 NIRS measurements were completed, and 7 infants developed NEC. NIRS measurements from 1 infant with NEC and 4 infants without NEC who developed hemorrhagic parenchymal infarcts were excluded from analysis. Infants who developed NEC had significantly lower cerebral tissue oxygenation index than those who did not ( = .011), even when adjusted for confounders, including gestational age, birth weight, patent ductus arteriosus, enteral feeds, sex, ethnicity, and hemoglobin.

Conclusions: Infants with NEC have significantly lower cerebral tissue oxygenation throughout their neonatal intensive care stay in comparison with those who did not develop NEC. This is a novel finding and could explain their worse neurodevelopmental outcome.
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http://dx.doi.org/10.1542/peds.2020-0337DOI Listing
September 2020

ERNICA Consensus Conference on the Management of Patients with Long-Gap Esophageal Atresia: Perioperative, Surgical, and Long-Term Management.

Eur J Pediatr Surg 2021 Jun 15;31(3):214-225. Epub 2020 Jul 15.

Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.

Introduction:  Evidence supporting best practice for long-gap esophageal atresia is limited. The European Reference Network for Rare Inherited Congenital Anomalies (ERNICA) organized a consensus conference on the management of patients with long-gap esophageal atresia based on expert opinion referring to the latest literature aiming to provide clear and uniform statements in this respect.

Materials And Methods:  Twenty-four ERNICA representatives from nine European countries participated. The conference was prepared by item generation, item prioritization by online survey, formulation of a final list containing items on perioperative, surgical, and long-term management, and literature review. The 2-day conference was held in Berlin in November 2019. Anonymous voting was conducted via an internet-based system using a 1 to 9 scale. Consensus was defined as ≥75% of those voting scoring 6 to 9.

Results:  Ninety-seven items were generated. Complete consensus (100%) was achieved on 56 items (58%), e.g., avoidance of a cervical esophagostomy, promotion of sham feeding, details of delayed anastomosis, thoracoscopic pouch mobilization and placement of traction sutures as novel technique, replacement techniques, and follow-up. Consensus ≥75% was achieved on 90 items (93%), e.g., definition of long gap, routine pyloroplasty in gastric transposition, and avoidance of preoperative bougienage to enable delayed anastomosis. Nineteen items (20%), e.g., methods of gap measurement were discussed controversially (range 1-9).

Conclusion:  This is the first consensus conference on the perioperative, surgical, and long-term management of patients with long-gap esophageal atresia. Substantial statements regarding esophageal reconstruction or replacement and follow-up were formulated which may contribute to improve patient care.
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http://dx.doi.org/10.1055/s-0040-1713932DOI Listing
June 2021

Antenatal corticosteroids and outcomes in gastroschisis: A multicenter retrospective cohort study.

Prenat Diagn 2020 07 24;40(8):991-997. Epub 2020 May 24.

UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children, London, UK.

Objective: In gastroschisis, there is evidence to suggest that gut dysfunction develops secondary to bowel inflammation; we aimed to evaluate the effect of maternal antenatal corticosteroids administered for obstetric reasons on time to full enteral feeds in a multicenter cohort study of gastroschisis infants.

Methods: A three center, retrospective cohort study (1992-2013) with linked fetal/neonatal gastroschisis data was conducted. The primary outcome measure was time to full enteral feeds (a surrogate measure for bowel function) and secondary outcome measure was length of hospital stay. Analysis included Mann-Whitney and Cox regression.

Results: Of 500 patients included in the study, 69 (GA at birth 34 [25-38] weeks) received antenatal corticosteroids and 431 (GA at birth 37 [31-41] weeks) did not. Antenatal corticosteroids had no effect on the rate of reaching full feeds (Hazard ratio HR 1.0 [95% CI: 0.8-1.4]). However, complex gastroschisis (HR 0.3 [95% CI: 0.2-0.4]) was associated with an increased time to reach full feeds and later GA at birth (HR 1.1 per week increase in GA [95% CI: 1.1-1.2]) was associated with a decreased time to reach full feeds.

Conclusion: Maternal antenatal corticosteroids use, under current antenatal steroid protocols, in gastroschisis is not associated with an improvement in neonatal outcomes such as time to full enteral feeds or length of hospital stay.
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http://dx.doi.org/10.1002/pd.5727DOI Listing
July 2020

Laparoscopic Injection of Tissue Adhesives for Inguinal Hernia Repair in a Rabbit Model: Results of an Experimental Comparative Study with the Standard Laparoscopic Inguinal Hernia Repair.

J Laparoendosc Adv Surg Tech A 2020 Jul 8;30(7):847-853. Epub 2020 May 8.

Pediatric Surgery Unit, Great Ormond Street Hospital, London, United Kingdom.

The injection of tissue adhesives has been proposed as an alternative to standard laparoscopic inguinal hernia repair but no evidence is available in the pediatric population. This study aimed to evaluate safety, efficacy, and feasibility of injection of tissue adhesives for inguinal hernia repair in a rabbit model. Thirty-six New Zealand White male rabbits underwent laparoscopic inguinal hernia repair. In each animal, the hernia defect was repaired using glue on the right side and purse-string suture on the left side. The animals were divided in 3 groups, each 1 of 12 animals, according to the glue used: Glubran 2 (cyanoacrylate), Histoacryl (cyanoacrylate), and BioGlue (bovine serum albumin-based). For each group, 6 animals were sacrificed at 7 days postoperatively, and 6 animals at 90 days postoperatively. Histopathological exam of testis and spermatic bundle was performed. The hernia defect was successfully closed on both sides in all cases. The injection of glue was faster than suture repair ( = .001). Postoperative complications (epiploon-parietal adhesions, spermatic vessel ectasia, and hydrocele) rate was significantly higher on the right side compared to the left side at both short- and long-term follow-up ( = .001). Furthermore, a lower maturity of testicles treated by adhesive compared with suture was histologically demonstrated at both short- and long-term follow-up ( = .001). The present experimental study confirmed the feasibility and efficacy of inguinal hernia repair by injection of tissue adhesive. However, several critical issues emerged about the safety of this technique. The use of glue was associated with higher incidence of postoperative complications and significant decrease of testicular maturity compared with standard suture repair. Based upon these preliminary results, repair using suture remains the standard of care for inguinal hernia in children. Further experimental studies are needed to assess the safety of injection of tissue adhesives for pediatric inguinal hernia repair.
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http://dx.doi.org/10.1089/lap.2020.0015DOI Listing
July 2020

Microbiota-Derived Metabolites Suppress Arthritis by Amplifying Aryl-Hydrocarbon Receptor Activation in Regulatory B Cells.

Cell Metab 2020 04 25;31(4):837-851.e10. Epub 2020 Mar 25.

Centre for Rheumatology Research, Division of Medicine, UCL, London WC1E 6JF, UK. Electronic address:

The differentiation of IL-10-producing regulatory B cells (Bregs) in response to gut-microbiota-derived signals supports the maintenance of tolerance. However, whether microbiota-derived metabolites can modulate Breg suppressive function remains unknown. Here, we demonstrate that rheumatoid arthritis (RA) patients and arthritic mice have a reduction in microbial-derived short-chain fatty acids (SCFAs) compared to healthy controls and that in mice, supplementation with the SCFA butyrate reduces arthritis severity. Butyrate supplementation suppresses arthritis in a Breg-dependent manner by increasing the level of the serotonin-derived metabolite 5-Hydroxyindole-3-acetic acid (5-HIAA), which activates the aryl-hydrocarbon receptor (AhR), a newly discovered transcriptional marker for Breg function. Thus, butyrate supplementation via AhR activation controls a molecular program that supports Breg function while inhibiting germinal center (GC) B cell and plasmablast differentiation. Our study demonstrates that butyrate supplementation may serve as a viable therapy for the amelioration of systemic autoimmune disorders.
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http://dx.doi.org/10.1016/j.cmet.2020.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156916PMC
April 2020

Insufflation in minimally invasive surgery: Is there any advantage in staying low?

J Pediatr Surg 2020 Jul 26;55(7):1356-1362. Epub 2020 Jan 26.

Specialist Neonatal and Paediatric Surgery, Great Ormond Street Hospital, Paediatric Surgery, London, United Kingdom; Stem Cell and Regenerative Medicine Section, DBC, University College London, Great Ormond Institute of Child Health, London, United Kingdom. Electronic address:

Aim: Minimally invasive repair of esophageal atresia with tracheoesophageal fistula (EA/TEF) and congenital diaphragmatic hernia (CDH) is feasible and confers benefits compared to thoracotomy or laparotomy. However, carbon dioxide (CO) insufflation can lead to hypercapnia and acidosis. We sought to determine the effect of lower insufflation pressures on patients' surrogate markers for CO absorption - arterial partial pressure of CO (PaCO), end tidal CO (EtCO) and pH.

Methods: Single center retrospective review, including neonates without major cardiac anomaly. Selected patients formed 2 groups: Historical pressure (HP) group and low pressure (LP) group. We reported on the patients' preoperative characteristics that potentially confound the degree of CO absorption or elimination. Outcome measures were perioperative PaCO, EtCO, arterial pH and anesthetic time.

Results: 30 patients underwent minimally invasive surgery for CDH and 24 patients for EA/TEF with similar distribution within the HP and LP group. For CDH patients as well as for EA/TEF patients, there were no significant differences in their preoperative characteristics or surgery duration comparing HP and LP groups. With a decrease in insufflation pressure in CDH patients, there were a significant decrease (p = 0.002) in peak PaCO and an improvement in nadir pH (p = 0.01). For the EA/TEF patients, the decrease in insufflation pressure was associated with a significant decrease (p = 0.03) in peak EtCO. Considering all 54 patients, we found EtCO to be highly significantly inversely correlated with pH and positively correlated with intraoperative PaCO (p < 0.001). Baseline Hb was inversely correlated with mean EtCO (p < 0.001).

Conclusion: With lower insufflation pressures, CDH patients had significantly improved hypercapnia and acidosis, while EA/TEF patients had significantly reduced EtCO. EtCO was correlated with acidosis and hypercapnia.

Type Of Study: Retrospective case control study.

Level Of Evidence: Level III.
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http://dx.doi.org/10.1016/j.jpedsurg.2019.11.026DOI Listing
July 2020

Fundoplication to preserve allograft function after lung transplant: Systematic review and meta-analysis.

J Thorac Cardiovasc Surg 2020 Sep 24;160(3):858-866. Epub 2019 Nov 24.

Department of Oesophagogastric Surgery, Royal Surrey County Hospital, Guildford, United Kingdom.

Background: ARS has been adopted in select patients with lung transplant for the past 2 decades in many centers. Outcomes have been reported sporadically. No pooled analysis of retrospective series has been performed.

Objective: This review and pooled analysis sought to demonstrate objective evidence of improved graft function in lung transplant patients undergoing antireflux surgery (ARS).

Methods: In accordance with Meta-analyses of Observational Studies in Epidemiology guidelines, a search of PubMed Central, Medline, Google Scholar, and Cochrane Library databases was performed. Articles documenting spirometry data pre- and post-ARS were reviewed and a random-effects model meta-analysis was performed on forced expiratory volume in 1 second (FEV1) values and the rate of change of FEV1.

Results: Six articles were included in the meta-analysis. Regarding FEV1 before and after ARS, we observed a small increase in FEV1 values in studies reporting raw values (2.02 ± 0.89 L/1 sec vs 2.14 ± 0.77 L/1 sec; n = 154) and % of predicted (77.1% ± 22.1% vs 81.2% ± 26.95%; n = 45), with a small pooled Cohen d effect size of 0.159 (P = .114). When considering the rate of change of FEV1 we observed a significant difference in pre-ARS compared with post-ARS (-2.12 ± 2.76 mL/day vs +0.05 ± 1.19 mL/day; n = 103). There was a pooled effect size of 1.702 (P = .013), a large effect of ARS on the rate of change of FEV1 values.

Conclusions: This meta-analysis of retrospective observational studies demonstrates that ARS might benefit patients with declining FEV1, by examining the rate of change of FEV1 during the pre- and postoperative periods.
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http://dx.doi.org/10.1016/j.jtcvs.2019.10.185DOI Listing
September 2020

Liposomal delivery of hydrophobic RAMBAs provides good bioavailability and significant enhancement of retinoic acid signalling in neuroblastoma tumour cells.

J Drug Target 2020 07 14;28(6):643-654. Epub 2020 Jan 14.

Great Ormond Street Institute of Child Health, UCL, London, UK.

Retinoid treatment is employed during residual disease treatment in neuroblastoma, where the aim is to induce neural differentiation or death in tumour cells. However, although therapeutically effective, retinoids have only modest benefits and suffer from poor pharmacokinetic properties. , retinoids induce CYP26 enzyme production in the liver, enhancing their own rapid metabolic clearance, while retinoid resistance in tumour cells themselves is considered to be due in part to increased CYP26 production. Retinoic acid metabolism blocking agents (RAMBAs), which inhibit CYP26 enzymes, can improve retinoic acid (RA) pharmacokinetics in pre-clinical neuroblastoma models. Here, we demonstrate that in cultured neuroblastoma tumour cells, RAMBAs enhance RA action as seen by morphological differentiation, AKT signalling and suppression of MYCN protein. Although active as retinoid enhancers, these RAMBAs are highly hydrophobic and their effective delivery in humans will be very challenging. Here, we demonstrate that such RAMBAs can be loaded efficiently into cationic liposomal particles, where the RAMBAs achieve good bioavailability and activity in cultured tumour cells. This demonstrates the efficacy of RAMBAs in enhancing retinoid signalling in neuroblastoma cells and shows for the first time that liposomal delivery of hydrophobic RAMBAs is a viable approach, providing novel opportunities for their delivery and application in humans.
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http://dx.doi.org/10.1080/1061186X.2019.1710157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609071PMC
July 2020

Extracellular matrix hydrogel derived from decellularized tissues enables endodermal organoid culture.

Nat Commun 2019 12 11;10(1):5658. Epub 2019 Dec 11.

Stem Cell and Regenerative Medicine Section, University College London GOS Institute of Child Health, London, UK.

Organoids have extensive therapeutic potential and are increasingly opening up new avenues within regenerative medicine. However, their clinical application is greatly limited by the lack of effective GMP-compliant systems for organoid expansion in culture. Here, we envisage that the use of extracellular matrix (ECM) hydrogels derived from decellularized tissues (DT) can provide an environment capable of directing cell growth. These gels possess the biochemical signature of tissue-specific ECM and have the potential for clinical translation. Gels from decellularized porcine small intestine (SI) mucosa/submucosa enable formation and growth of endoderm-derived human organoids, such as gastric, hepatic, pancreatic, and SI. ECM gels can be used as a tool for direct human organoid derivation, for cell growth with a stable transcriptomic signature, and for in vivo organoid delivery. The development of these ECM-derived hydrogels opens up the potential for human organoids to be used clinically.
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http://dx.doi.org/10.1038/s41467-019-13605-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906306PMC
December 2019

Nonoperative Treatment Versus Appendectomy for Acute Nonperforated Appendicitis in Children: Five-year Follow Up of a Randomized Controlled Pilot Trial.

Ann Surg 2020 06;271(6):1030-1035

Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

Objective: The aim of this study was to evaluate the safety and feasibility of nonoperative treatment of acute nonperforated appendicitis in children during 5 years of follow-up.

Methods: A 4-year follow-up of a previous randomized controlled pilot trial, including 50 children with acute nonperforated appendicitis, was performed. The patients were initially randomized to nonoperative treatment with antibiotics or appendectomy with 1-year follow-up previously reported. Data were extracted from the computerized notes and telephone interviews.The primary outcome was treatment failure, defined as need for a secondary intervention under general anesthesia, related to the previous diagnosis of acute nonperforated appendicitis.

Results: The children were followed up for at least 5 years [median 5.3 (range 5.0-5.6)] after inclusion. There were no failures in the appendectomy group (0/26) and 11 failures in the nonoperative group (11/24). Nine failures had occurred during the first year after inclusion, 2 of whom had histologically confirmed appendicitis. There were 2 further patients with recurrent acute appendicitis 1 to 5 years after inclusion. Both these patients had uncomplicated laparoscopic appendectomies for histologically confirmed acute appendicitis. There were no losses to follow-up.

Conclusions: At 5 years of follow-up 46% of children treated with antibiotics for acute nonperforated appendicitis had undergone an appendectomy, although acute appendicitis was only histologically confirmed in 4/24 (17%). Treatment with antibiotics seems to be safe in the intermediate-term; none of the children previously treated nonoperatively re-presented with complicated appendicitis.
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http://dx.doi.org/10.1097/SLA.0000000000003646DOI Listing
June 2020
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