Anatomy and embryology of tracheo-esophageal fistula

Anomalies in tracheo-esophageal development result in a spectrum of congenital malformations ranging from, most commonly, esophageal atresia with or without trachea-esophageal fistula (EA+/-TEF) to esophageal web, duplication, stricture, tracheomalacia and tracheal agenesis. Despite the relative frequency of EA, however, the underlying etiology remains unknown and is likely due to a combination of genetic, epigenetic and environmental factors. In recent years, animal models have dramatically increased our understanding of the molecular and morphological processes involved in normal esophageal development during the key stages of anterior-posterior regionalization, dorsal-ventral patterning and morphogenic separation. Moreover, the use of animal models in conjunction with increasingly advanced techniques such as genomic sequencing, sophisticated live imaging studies and organoid models have more recently cast light on potential mechanisms involved in EA pathogenesis. This article aims to unravel some of the mysteries behind the anatomy and embryology of EA whilst providing insights into future directions for research

Post-natal erythromycin exposure and risk of infantile hypertrophic pyloric stenosis: a systematic review and meta-analysis

PURPOSE: Macrolide antibiotics, erythromycin, in particular, have been linked to the development of infantile hypertrophic pyloric stenosis (IHPS). Our aim was to conduct a systematic review of the evidence of whether post-natal erythromycin exposure is associated with subsequent development of IHPS. METHODS: A systematic review of postnatal erythromycin administration and IHPS was performed. Papers were included if data were available on development (yes/no) of IHPS in infants exposed/unexposed to erythromycin. Data were meta-analysed using Review Manager 5.3. A random effects model was decided on a priori due to heterogeneity of study design; data are odds ratio (OR) with 95 % CI. RESULTS: Nine papers reported data suitable for analysis; two randomised controlled trials and seven retrospective studies. Overall, erythromycin exposure was significantly associated with development of IHPS [OR 2.45 (1.12-5.35), p = 0.02]. However, significant heterogeneity existed between the studies (I (2) = 84 %, p < 0.0001). Data on erythromycin exposure in the first 14 days of life was extracted from 4/9 studies and identified a strong association between erythromycin exposure and subsequent development IHPS [OR 12.89 (7.67-2167), p < 0.00001]. CONCLUSION: This study demonstrates a significant association between post-natal erythromycin exposure and development of IHPS, which seems stronger when exposure occurs in the first 2 weeks of life

Leveraging mechanobiology and biophysical cues in lung organoids for studying lung development and disease

Lung organoids have emerged as powerful tools for studying lung distal diseases by recapitulating the cellular diversity and microenvironment of the lung tissue. This review article highlights the advancements in leveraging mechanobiology and biophysical cues in lung organoid engineering to improve their physiological relevance and disease modelling capabilities. We discuss the role of mechanobiology in lung development and homeostasis, as well as the integration of biophysical cues in the design and culture of lung organoids. Furthermore, we explore how these advancements have contributed to the understanding of lung distal diseases pathogenesis. We also discuss the challenges and future directions in harnessing mechanobiology and biophysical cues in lung organoid research. This review showcases the potential of lung organoids as a platform to investigate the underappreciated impacts of biophysical and biomechanical properties in enhancing lung organoids complexity and functionality, and ultimately provide new insight into embryonic lung development and pulmonary distal diseases pathogenesis

Have Cherenkov telescopes detected a new light boson?

Recent observations by H.E.S.S. and MAGIC strongly suggest that the Universe is more transparent to very-high-energy gamma rays than previously thought. We show that this fact can be reconciled with standard blazar emission models provided that photon oscillations into a very light Axion-Like Particle occur in extragalactic magnetic fields. A quantitative estimate of this effect indeed explains the observed data and in particular the spectrum of blazar 3C279.Comment: 3 pages, 1 figure, Proceeding of the "Eleventh International Workshop on Topics in Astroparticle and Underground Physics" (TAUP), Roma, Italy, 1 - 5 July 2009 (to be published in the Proceedings

The Host Immune Response to Tissue-Engineered Organs: Current Problems and Future Directions

As the global health burden of chronic disease increases, end-stage organ failure has become a costly and intractable problem. De novo organ creation is one of the long-term goals of the medical community. One of the promising avenues is that of tissue engineering: the use of biomaterials to create cells, structures, or even whole organs. Tissue engineering has emerged from its nascent stage, with several proof-of-principle trials performed across various tissue types. As tissue engineering moves from the realm of case trials to broader clinical study, three major questions have emerged: (1) Can the production of biological scaffolds be scaled up accordingly to meet current and future demands without generating an unfavorable immune response? (2) Are biological scaffolds plus or minus the inclusion of cells replaced by scar tissue or native functional tissue? (3) Can tissue-engineered organs be grown in children and adolescents given the different immune profiles of children? In this review, we highlight current research in the immunological response to tissue-engineered biomaterials, cells, and whole organs and address the answers to these questions

Regenerative medicine for childhood gastrointestinal diseases

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

Paediatric gastric organoids as a tool for disease modelling and clinical translation

Purpose: 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. Methods: Full-thickness surgical samples 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. Results: 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. Conclusion: Gastric organoids can be reliably generated from paediatric biopsies and are a representative in vitro model for studying gastric epithelium

In vitro models of fetal lung development to enhance research into congenital lung diseases

PURPOSE: This paper aims to build upon previous work to definitively establish in vitro models of murine pseudoglandular stage lung development. These can be easily translated to human fetal lung samples to allow the investigation of lung development in physiologic and pathologic conditions. METHODS: Lungs were harvested from mouse embryos at E12.5 and cultured in three different settings, i.e., whole lung culture, mesenchyme-free epithelium culture, and organoid culture. For the whole lung culture, extracted lungs were embedded in Matrigel and incubated on permeable filters. Separately, distal epithelial tips were isolated by firstly removing mesothelial and mesenchymal cells, and then severing the tips from the airway tubes. These were then cultured either in branch-promoting or self-renewing conditions. RESULTS: Cultured whole lungs underwent branching morphogenesis similarly to native lungs. Real-time qPCR analysis demonstrated expression of key genes essential for lung bud formation. The culture condition for epithelial tips was optimized by testing different concentrations of FGF10 and CHIR99021 and evaluating branching formation. The epithelial rudiments in self-renewing conditions formed spherical 3D structures with homogeneous Sox9 expression. CONCLUSION: We report efficient protocols for ex vivo culture systems of pseudoglandular stage mouse embryonic lungs. These models can be applied to human samples and could be useful to paediatric surgeons to investigate normal lung development, understand the pathogenesis of congenital lung diseases, and explore novel therapeutic strategies

Long-term feeding issue and its impact on the daily life of congenital diaphragmatic hernia survivors: results of the first patient-led survey

BACKGROUND: CDH UK is a registered charity governed by a volunteer committee and providing informal support to patients, families and healthcare workers affected directly or indirectly with congenital diaphragmatic hernia (CDH) internationally. This is the first patient-led survey undertaken by CDH UK aiming for highlighting the feeding problems and their impact on the daily life of CDH survivors. METHODS: Answers from CDH survivors were collected through an online questionnaire (SurveyMonkey®) undertaken by CDH UK. The questionnaire contained questions about their feeding problems and support they were receiving for it. MAIN RESULTS: Overall, 151 patients answered some parts of the survey and 102 patients completed the questionnaire. Overall, 116 (76.8%) responders reported suffering from any type of feeding issue. Gastric acid reflux (GER) and growth retardation were the commonest symptoms experienced by 97 (91.5%) and 72 (62.2%) responders, respectively. Only 18 (17.0%) responders have received any written information on feeding or details of patient/parent support. Eighty (75.5%) responders are satisfied with the level of support they are receiving, but 78 (76.4%) answered that the whole experience associated with the disease has been very or extremely stressful. CONCLUSIONS: CDH survivors frequently have various issues with feeding, which may not be adequately supported or discussed clinically. It is desirable to assist the patients to reliable resources of long-term support, including multidisciplinary team (MDT) approach

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

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. Data availability statement: No data are available. Although data have been anonymised, we have not made data available to protect the identity of those involved in the research, due to the detail provided by participants