ORCID Profile
0000-0002-2637-8859
Current Organisations
Novo Nordisk
,
University College London
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Publisher: Cold Spring Harbor Laboratory
Date: 24-06-2020
DOI: 10.1101/2020.06.24.167049
Abstract: Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global public health emergency. COVID-19 typically manifests as a respiratory illness but an increasing number of clinical reports describe gastrointestinal (GI) symptoms. This is particularly true in children in whom GI symptoms are frequent and viral shedding outlasts viral clearance from the respiratory system. By contrast, fetuses seem to be rarely affected by COVID-19, although the virus has been detected in placentas of affected women. These observations raise the question of whether the virus can infect and replicate within the stomach once ingested. Moreover, it is not yet clear whether active replication of SARS-CoV-2 is possible in the stomach of children or in fetuses at different developmental stages. Here we show the novel derivation of fetal gastric organoids from 8-21 post-conception week (PCW) fetuses, and from pediatric biopsies, to be used as an in vitro model for SARS-CoV-2 gastric infection. Gastric organoids recapitulate human stomach with linear increase of gastric mucin 5AC along developmental stages, and expression of gastric markers pepsinogen, somatostatin, gastrin and chromogranin A. In order to investigate SARS-CoV-2 infection with minimal perturbation and under steady-state conditions, we induced a reversed polarity in the gastric organoids (RP-GOs) in suspension. In this condition of exposed apical polarity, the virus can easily access viral receptor angiotensin-converting enzyme 2 (ACE2). The pediatric RP-GOs are fully susceptible to infection with SARS-CoV-2, where viral nucleoprotein is expressed in cells undergoing programmed cell death, while the efficiency of infection is significantly lower in fetal organoids. The RP-GOs derived from pediatric patients show sustained robust viral replication of SARS-CoV-2, compared with organoids derived from fetal stomachs. Transcriptomic analysis shows a moderate innate antiviral response and the lack of differentially expressed genes belonging to the interferon family. Collectively, we established the first expandable human gastric organoid culture across fetal developmental stages, and we support the hypothesis that fetal tissue seems to be less susceptible to SARS-CoV-2 infection, especially in early stages of development. However, the virus can efficiently infect gastric epithelium in pediatric patients, suggesting that the stomach might have an active role in fecal-oral transmission of SARS-CoV-2.
Publisher: Authorea, Inc.
Date: 12-07-2021
DOI: 10.22541/AU.162605830.04721325/V1
Abstract: Background: While pregnant women have been identified as a potentially at-risk group concerning COVID-19 infection, little is known regarding the susceptibility of the fetus to infection. Co-expression of ACE2 and TMPRSS2 has been identified as a pre-requisite for infection, and expression across different tissues is known to vary between children and adults. However, the expression of these proteins in the fetus is unknown. Methods: We performed a retrospective analysis of single cell data repositories. This data was then validated at both gene and protein level by performing qRT-PCR and two-colour immunohistochemistry on a library of second-trimester human fetal tissues. Findings: TMPRSS2 is present at both gene and protein level in the predominantly epithelial fetal tissues analysed. ACE2 is present at significant levels, only in the fetal intestine and kidney and is not expressed in the fetal lung. The placenta is also negative for the two proteins both during development and at term. Interpretation: This dataset indicates that the lungs are unlikely to be a viable route of SARS-CoV2 fetal infection. The fetal kidney, despite presenting both the proteins required for the infection, is anatomically protected from the exposure to the virus. However, the GI tract is likely to be susceptible to infection due to its high co-expression of both proteins, as well as its exposure to potentially infected amniotic fluid. Funding: This work was made possible by an MRC / UKRI COVID-19 Rapid response initiative grant (MR/V028480/1).
Publisher: Wiley
Date: 18-02-2020
DOI: 10.1111/JPC.14810
Publisher: Wiley
Date: 13-01-2020
DOI: 10.1111/JPC.14774
Abstract: This paper describes the incidence and outcomes of childhood renal malignancies in Australia using national population-based data from the Australian Childhood Cancer Registry. De-identified data for children (0-14 years) diagnosed with renal malignancies from 1983 to 2015 inclusive were extracted. Cause-specific (CSS) and event-free survival up to 20 years from diagnosis were estimated using the cohort method. Adjusted excess mortality hazard ratios were calculated using a multivariable flexible parametric survival model. Details relating to second primary malignancies (SPMs) were also examined. There were 1046 children diagnosed with renal malignancies in Australia between 1983 and 2015 (91% nephroblastoma), generating an annual age-standardised incidence rate of 8 per million children, which remained constant over the study period. CSS was 89% (95% confidence interval = 87-91%) and 88% (86-90%) at 5 and 20 years, respectively, and 5-year event-free survival was 82% (80-84%). Five-year CSS did not change over the study period and was highest for nephroblastoma (91%). Of the 94% of patients achieving remission, 15% relapsed and subsequent 5-year CSS was 49% (40%-58%). Eleven children were diagnosed with SPM (standardised incidence ratio = 2.9, 95% confidence interval = 1.6-5.3, P < 0.001), and five of them (45%) died within 5 years of the second diagnosis. Children treated for renal malignancies in Australia have excellent long-term survival, which is unchanged since 1983. SPMs are uncommon following treatment for childhood renal cancer but carry a poor prognosis. Relapse carries a similarly poor prognosis to SPM but is more common. These data are comparable to registry outcomes in similarly developed nations.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2021
DOI: 10.1007/S00383-020-04821-X
Abstract: Knowledge of gastric epithelial homeostasis remains incomplete, lacking human-specific models for study. This study establishes a protocol for deriving gastric epithelial organoids from paediatric gastric biopsies, providing a platform for modelling disease and developing translational therapies. Full-thickness surgical s les and endoscopic mucosal biopsies were obtained from six patients. Gastric glands were isolated by a chemical chelation protocol and then plated in 3D culture in Matrigel ® droplets in chemically defined medium. After formation, organoids were passaged by single cell dissociation or manual disaggregation. Cell composition and epithelial polarity of organoids were assessed by bright field microscopy and immunofluorescence analysis, comparing them to native paediatric gastric tissue. Gastric glands were successfully isolated from all six patients who were aged 4 months to 16 years. Gastric glands from all patients sealed to form spherical gastric organoids. These organoids could be passaged by manual disaggregation or single cell dissociation, remaining proliferative up to 1 year in culture. Organoids retained normal epithelial cell polarity, with the apical surface orientated towards the central lumen. Organoids expressed markers of mature gastric epithelial cell types, except for parietal cells. Gastric organoids can be reliably generated from paediatric biopsies and are a representative in vitro model for studying gastric epithelium.
Publisher: Wiley
Date: 18-11-2021
Abstract: Pregnant women have been identified as a potentially at‐risk group concerning COVID‐19 infection, but little is known regarding the susceptibility of the fetus to infection. Co‐expression of ACE2 and TMPRSS2 has been identified as a prerequisite for infection, and expression across different tissues is known to vary between children and adults. However, the expression of these proteins in the fetus is unknown. We performed a retrospective analysis of a single cell data repository. The data were then validated at both gene and protein level by performing RT‐qPCR and two‐colour immunohistochemistry on a library of second‐trimester human fetal tissues. TMPRSS2 is present at both gene and protein level in the predominantly epithelial fetal tissues analysed. ACE2 is present at significant levels only in the fetal intestine and kidney, and is not expressed in the fetal lung. The placenta also does not co‐express the two proteins across the second trimester or at term. This dataset indicates that the lungs are unlikely to be a viable route of SARS‐CoV2 fetal infection. The fetal kidney, despite presenting both the proteins required for the infection, is anatomically protected from the exposure to the virus. However, the gastrointestinal tract is likely to be susceptible to infection due to its high co‐expression of both proteins, as well as its exposure to potentially infected amniotic fluid. This work provides detailed mechanistic insight into the relative protection & vulnerabilities of the fetus & placenta to SARS‐CoV‐2 infection by scRNAseq & protein expression analysis for ACE2 & TMPRSS2. The findings help to explain the low rate of vertical transmission.
Publisher: Informa UK Limited
Date: 08-2013
Publisher: Cold Spring Harbor Laboratory
Date: 06-2023
DOI: 10.1101/2023.05.31.539801
Abstract: Despite advances in prenatal diagnosis, it is still difficult to predict severity and outcomes of many congenital malformations. New patient-specific prenatal disease modelling may optimise personalised prediction. We and others have described the presence of mesenchymal stem cells in amniotic fluid (AFSC) that can generate induced pluripotent stem cells (iPSCs). The lengthy reprogramming processes, however, limits the ability to define in idual phenotypes or plan prenatal treatment. Therefore, it would be advantageous if fetal stem cells could be obtained during pregnancy and expanded without reprogramming. Using single cell analysis, we characterised the cellular identities in amniotic fluid (AF) and identified viable epithelial stem rogenitor cells of fetal intestinal, renal and pulmonary origin. With relevance for prenatal disease modelling, these cells could be cultured to form clonal epithelial organoids manifesting small intestine, kidney and lung identity. To confirm this, we derived lung organoids from AF and tracheal fluid (TF) cells of Congenital Diaphragmatic Hernia (CDH) fetuses and found that they show differences to non-CDH controls and can recapitulate some pathological features of the disease. Amniotic Fluid Organoids (AFO) allow investigation of fetal epithelial tissues at clinically relevant developmental stages and may enable the development of therapeutic tools tailored to the fetus, as well as to predicting the effects of such therapies.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.JPEDSURG.2014.10.059
Abstract: The purpose of this study is to present a summary of paediatric Spigelian hernia (SH) reported to date, and discuss possible aetiology of SH associated with ipsilateral ectopic testis (SH-ET). Search of PubMed, Medline, Embase, and CINAHL was performed using keywords "Spigelian hernia". The following were extracted from articles describing paediatric SH: demographics, site and contents of SH, comorbidities, proposed aetiology, presence of ipsilateral inguinal canal (IC) and gubernaculum (G). There were 78 patients with 88 hernias (69 male, 19 female), including 55 male (19 left, 22 right, 7 bilateral) and 16 female (5 left, 5 right, 3 bilateral) nontraumatic SHs. In nontraumatic male SH, 29 hernias contained testis (10 left, 11 right, 4 bilateral), 15 did not, 10 had no data. Of 29 SH-EH, 15 were lacking IC and G, 3 were missing IC (no G data) and 2 had absent G (no IC data). The combination of SH and cryptorchidism is increasingly recognised as a distinct syndrome. However, there is controversy as to the pathogenic mechanism of this association. We hypothesise SH-ET develops because the G, and therefore IC and line of descent, become cranially 'mislocated' along the mammary line, which overlies the Spigelian fascia. SH is rare in children. SH-ET may result by testicular descent to an ectopic site along the embryological mammary line.
Publisher: Springer Science and Business Media LLC
Date: 24-02-2022
DOI: 10.1007/S00383-022-05074-6
Abstract: To undertake a pilot study estimating patient-level costs of care for paediatric short bowel syndrome (SBS) from the healthcare provider perspective. A pilot group of patients with anatomical SBS was selected at a single specialist tertiary centre in the United Kingdom. The Patient Level Information and Costing System (PLICS) was used to extract costing data for all hospital-based activities related to SBS, from the implementation of PLICS in 2016 to April 2021. Patient-specific and pooled data were reported descriptively in per patient-year terms. Five patients had full PLICS data available for the 5-year study period and 2 patients had 4 years of data. The median cost for hospital care of SBS was £52,834 per patient-year (range £1804–£331,489). The key cost drivers were inpatient beds, pharmacy, and staffing costs, which made up 60% of annual costs. In the first 3 years following index admission ( n = 2), there was a steady decline in the annual cost of care to a level comparable with patients with established SBS. Patient-level cost of care analysis for SBS is feasible using PLICS. Hospital-related costs vary widely between and within in idual patients over time. Key drivers of cost are related to complications of SBS.
Publisher: Cold Spring Harbor Laboratory
Date: 15-03-2021
DOI: 10.1101/2021.03.09.21253012
Abstract: While a substantial proportion of adults infected with SARS-CoV-2 progress to develop severe disease, children rarely manifest respiratory complications. Therefore, understanding differences in the local and systemic response to SARS-CoV-2 infection between children and adults may provide important clues about the pathogenesis of SARS-CoV-2 infection. To address this, we first generated a healthy reference multi-omics single cell data set from children (n=30) in whom we have profiled triple matched s les: nasal and tracheal brushings and PBMCs, where we track the developmental changes for 42 airway and 31 blood cell populations from infancy, through childhood to adolescence. This has revealed the presence of naive B and T lymphocytes in neonates and infants with a unique gene expression signature bearing hallmarks of innate immunity. We then contrast the healthy reference with equivalent data from severe paediatric and adult COVID-19 patients (total n=27), from the same three types of s les: upper and lower airways and blood. We found striking differences: children with COVID-19 as opposed to adults had a higher proportion of innate lymphoid and non-clonally expanded naive T cells in peripheral blood, and a limited interferon-response signature. In the airway epithelium, we found the highest viral load in goblet and ciliated cells and describe a novel inflammatory epithelial cell population. These cells represent a transitional regenerative state between secretory and ciliated cells they were found in healthy children and were enriched in paediatric and adult COVID-19 patients. Epithelial cells display an antiviral and neutrophil-recruiting gene signature that is weaker in severe paediatric versus adult COVID-19. Our matched blood and airway s les allowed us to study the spatial dynamics of infection. Lastly, we provide a user-friendly interface for this data 1 as a highly granular reference for the study of immune responses in airways and blood in children.
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.BPG.2021.101769
Abstract: Several paediatric gastrointestinal diseases result in life-shortening organ failure. For many of these conditions, current therapeutic options are suboptimal and may not offer a cure. Regenerative medicine is an inter-disciplinary field involving biologists, engineers, and clinicians that aims to produce cell and tissue-based therapies to overcome organ failure. Exciting advances in stem cell biology, materials science, and bioengineering bring engineered gastrointestinal cell and tissue therapies to the verge of clinical trial. In this review, we summarise the requirements for bioengineered therapies, the possible sources of the various cellular and non-cellular components, and the progress towards clinical translation of oesophageal and intestinal tissue engineering to date.
Publisher: IGI Global
Date: 08-06-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2012
DOI: 10.1016/J.JURO.2012.04.105
Abstract: Long-term outcomes of hypospadias surgery, particularly urinary function, have not been examined thoroughly. Uroflowmetry can be used to evaluate long-term functional outcomes by assessing flow shape and the rate of micturition. We assessed urethral function using uroflowmetry in adolescents after undergoing hypospadias repair in infancy and compared this with age matched controls. After human research ethics committee approval (HREC 28111A), 17 boys 13 to 15 years old with no history of urological or neurological disorders underwent uroflowmetry (65 separate voids) to determine standard values for boys of this age. Then 60 boys age 13 to 15 years who had undergone treatment for hypospadias in early infancy were seen for long-term followup and underwent uroflow assessment. Standard urinary flow rates were established in the 13 to 15-year-old control group and represented on a nomogram. In the boys who underwent hypospadias surgery the urine flow rates were significantly lower compared to the control nomogram (p <0.0001), with half the patients having uroflow rates below 1 SD from the control mean but without symptoms. Boys with significant preoperative chordee were more likely to have poorer urinary flow (p <0.04). A poor urinary flow rate also was significantly associated with post-void residual bladder volume (p <0.03). There was no correlation with original meatal location, number of operations, presence of postoperative complications, current anatomy and lower urinary tract symptoms (eg post-void dribble, hesitancy, incontinence). At long-term followup after hypospadias surgery urinary flow rates were significantly lower compared to age matched controls but still fell within the normal range. In the hypospadias cohort there was no significant association with lower urinary tract symptoms and poor urinary flow. Detection of poor urinary flow may indicate incomplete bladder emptying. The presence of severe chordee preoperatively is a significant risk factor for poor urinary flow rates on long-term followup.
Publisher: ANU Press
Date: 25-07-2018
Publisher: Springer Science and Business Media LLC
Date: 03-03-2022
DOI: 10.1038/S41575-022-00586-X
Abstract: Short bowel syndrome (SBS), a condition defined by insufficient absorptive intestinal epithelium, is a rare disease, with an estimated prevalence up to 0.4 in 10,000 people. However, it has substantial morbidity and mortality for affected patients. The mainstay of treatment in SBS is supportive, in the form of intravenous parenteral nutrition, with the aim of achieving intestinal autonomy. The lack of a definitive curative therapy has led to attempts to harness innate developmental and regenerative mechanisms to engineer neo-intestine as an alternative approach to addressing this unmet clinical need. Exciting advances have been made in the field of intestinal tissue engineering (ITE) over the past decade, making a review in this field timely. In this Review, we discuss the latest advances in the components required to engineer intestinal grafts and summarize the progress of ITE. We also explore some key factors to consider and challenges to overcome when transitioning tissue-engineered intestine towards clinical translation, and provide the future outlook of ITE in therapeutic applications and beyond.
Publisher: Elsevier BV
Date: 07-2021
Publisher: Springer Science and Business Media LLC
Date: 22-12-2021
DOI: 10.1038/S41586-021-04345-X
Abstract: It is not fully understood why COVID-19 is typically milder in children 1–3 . Here, to examine the differences between children and adults in their response to SARS-CoV-2 infection, we analysed paediatric and adult patients with COVID-19 as well as healthy control in iduals (total n = 93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood s les. In the airways of healthy paediatric in iduals, we observed cells that were already in an interferon-activated state, which after SARS-CoV-2 infection was further induced especially in airway immune cells. We postulate that higher paediatric innate interferon responses restrict viral replication and disease progression. The systemic response in children was characterized by increases in naive lymphocytes and a depletion of natural killer cells, whereas, in adults, cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. We provide evidence that dendritic cells initiate interferon signalling in early infection, and identify epithelial cell states associated with COVID-19 and age. Our matching nasal and blood data show a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were substantially reduced in paediatric patients. Together, we provide several mechanisms that explain the milder clinical syndrome observed in children.
Publisher: Springer Science and Business Media LLC
Date: 16-11-2021
DOI: 10.1038/S41467-021-26762-2
Abstract: COVID-19 typically manifests as a respiratory illness, but several clinical reports have described gastrointestinal symptoms. This is particularly true in children in whom gastrointestinal symptoms are frequent and viral shedding outlasts viral clearance from the respiratory system. These observations raise the question of whether the virus can replicate within the stomach. Here we generate gastric organoids from fetal, pediatric, and adult biopsies as in vitro models of SARS-CoV-2 infection. To facilitate infection, we induce reverse polarity in the gastric organoids. We find that the pediatric and late fetal gastric organoids are susceptible to infection with SARS-CoV-2, while viral replication is significantly lower in undifferentiated organoids of early fetal and adult origin. We demonstrate that adult gastric organoids are more susceptible to infection following differentiation. We perform transcriptomic analysis to reveal a moderate innate antiviral response and a lack of differentially expressed genes belonging to the interferon family. Collectively, we show that the virus can efficiently infect the gastric epithelium, suggesting that the stomach might have an active role in fecal-oral SARS-CoV-2 transmission.
Publisher: BMJ
Date: 11-2019
Abstract: Presented here is the case of a 21-year-old man, with a family history of unilateral renal agenesis, who presented with obstruction of his solitary functioning right kidney. Initially thought to be secondary to an obturator fossa hernia on endoscopic and retrograde pyelography assessment, diagnosis of obstruction secondary to an aberrant middle rectal artery was determined at laparotomy and ision of this vessel relieved the patient’s obstruction without any short-term or long-term complications. To the best of the authors’ knowledge, this is the first reported case in the literature of hydroureteronephrosis secondary to an aberrant middle rectal artery.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2009
DOI: 10.1016/J.JURO.2009.02.089
Abstract: We evaluated long-term outcomes in boys treated for hypospadias at Royal Children's Hospital, Melbourne. Boys who underwent hypospadias surgery were reviewed at ages 13 to 15 years. Surgical results were evaluated using the Hypospadias Objective Scoring Evaluation. Lower urinary tract function was assessed using uroflowmetry and symptom questionnaire. Self-report surveys measured quality of life, patient satisfaction, memory of surgery, psychosexual outcomes and parent satisfaction with care. By Hypospadias Objective Scoring Evaluation score 80% of patients had an excellent surgical outcome. Two independent reviewers assessed lower urinary tract function as normal in 82% and 86% of cases, respectively. Quality of life scores were comparable to published values in normal children. Parents rated the institution highly. Overall 90% and 81% of boys were satisfied with the body and genital appearance, respectively. Those dissatisfied with genital appearance had poorer psychosexual outcomes than satisfied patients. When surgery was completed before age 5 years, boys had no perioperative memories. An association was found between no recollection of surgery and satisfaction with body appearance. Objective surgical and functional outcomes are excellent after early surgery. Post-repair quality of life is comparable to published data on normal children. Parents are pleased with care. Most boys are satisfied with the body and genital appearance. However, those dissatisfied with genital appearance must be identified in the interest of psychosexual development. The association between no recollection of treatment and satisfaction with body appearance suggests that surgery should be completed before age 5 years when possible to allow the development of good body image in adolescence.
Publisher: Elsevier BV
Date: 12-2019
Publisher: Wiley
Date: 16-04-2018
DOI: 10.1111/ANS.14532
Publisher: BMJ Publishing Group Ltd and British Thoracic Society
Date: 11-2021
Publisher: Wiley
Date: 13-05-2022
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2020
End Date: 2021
Funder: UK Research and Innovation
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