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OBJECTIVES: the MOMS randomized trial has demonstrated that prenatal spina bifida aperta (SBA) repair via open approach is safe and effective for both mother and fetus, yet half of the infants have incomplete reversal of hindbrain herniation and no improvement in neuromotor function. One contributing factor may be the incompleteness of the neurosurgical repair causing persistent in utero leakage of cerebrospinal fluid (CSF) and exposure of the spinal cord to the amniotic fluid until birth. We aim to investigate the neurostructural and neurofunctional efficacy of the watertightness of prenatal SBA repair. METHODS: a superiority study was conducted in the validated SBA fetal lamb model and powered (n=7 per group). Outcomes of lambs undergoing watertight or non-watertight multilayer repairs through an open approach were compared to those in unrepaired SBA lambs at delivery (term=145 days). At ~75-day fetal lambs underwent standardized induction of lumbar SBA. At ~100 days, they were assigned to one of the three groups and subsequently to either watertight or non-watertight layered repair group based on an intraoperative watertightness test using subcutaneous fluoresceine injection. Finally, at 1-2 postnatal days, we assessed reversal of hindbrain herniation on Magnetic Resonance Imaging (MRI) as primary outcome. Secondary proxies of neuroprotection were CSF leakage at the repair site; hindlimb motor function based on joint movement score, locomotor grade and Motor Evoked Potentials (MEP); neuroprotection score encompassing live birth, hindbrain herniation reversal, absent CSF leakage and joint score =9/15; and brain and spinal cord histology and immunohistochemistry. As the watertightness test is not clinically usable, we developed a potential surrogate intraoperative quality score and assessed its relationship with improved outcomes. This four-point scoring system is based on visual assessment of the quality of the skin repair (suture inter-run distance =3mm, absence of tear and ischemia). RESULTS: Compared to unrepaired lambs, watertight repair was neuroprotective in 5/7 lambs (neuroprotection score of 4/4), as evidenced by a 100% reversal of hindbrain herniation on MRI; lower CSF leakage rate (14%); better hindlimb motor function evidenced by higher joint movement score, locomotor grade, and MEP area-under-the-curve and peak-to-peak amplitude; higher neuronal density in the hippocampus and corpus callosum; and higher reactive astrogliosis at the SBA lesion epicenter. Conversely, non-watertight SBA repair did not achieve the same level of neuroprotection (1/7) due to non-significant 86% hindbrain herniation reversal, no motor function improvement, high CSF leakage (43%), low brain neuron count in both regions and low spinal astroglial cell area at the epicenter. Like watertight layered repair, a high quality score (=2/3) was associated with improved outcomes yet watertightness test and quality score could not be used interchangeably due to results discrepancies. CONCLUSIONS: A watertight layered fetal SBA repair improves brain and spinal cord structure and function in the fetal lamb model. This translational research has important clinical implication and neurosurgical technique that achieves watertightness should be adopted in all fetal centers to improve neuroprotection. Future clinical studies could assess whether the high quality of the repair correlates with clinical outcomes for neuroprotection. This article is protected by copyright. All rights reserved.

Congenital diaphragmatic hernia can be diagnosed in the prenatal period and its severity can be measured by fetal imaging. There is now level I evidence that, in selected cases, Fetoscopic Endoluminal Tracheal Occlusion with a balloon increases survival to discharge from the neonatal unit as well as the risk for prematurity. Both effects are dependent on the time point of tracheal occlusion. Fetoscopic Endoluminal Tracheal Occlusion may also lead to iatrogenic death when the balloon cannot be timely retrieved. The implementation of the findings from our clinical studies, may also vary based on local conditions. These may be different in terms of available skill set, access to fetal therapy, as well as outcome based on local neonatal management. We encourage prior benchmarking of local outcomes with optimal postnatal management, based on large enough numbers and using identical criteria as in the recent trials. We propose to work further on prenatal prediction methods, and the improvement of fetal intervention. In this manuscript, we describe a research agenda from a fetal medicine perspective. This research should be in parallel with innovation in neonatal and pediatric (surgical) management of this condition.

Objective To assess the safety of Partial-Amniotic-Insufflation-of-heated-humidified-CO2 (hPACI) during fetoscopic spina bifida repair (fSB-repair). Method A simulated fSB-repair through an exteriorized uterus under hPACI was performed in 100-day fetal lambs (term = 145 days) under a laboratory anesthesia protocol (n = 5; group 1) which is known to induce maternal-fetal acidosis and hypercapnia. Since these may not occur clinically, we applied a clinical anesthesia protocol (n = 5; group 2), keeping maternal parameters within physiological conditions, that is, controlled maternal arterial carbon dioxide (CO2) pressure (pCO(2) = 30 mmHg), blood pressure (>= 67 mmHg), and temperature (37.1-39.8 degrees C). Our superiority study used fetal pH as the primary outcome. Results Compared to group 1, controlled anesthesia normalized fetal pH (7.23 +/- 0.02 vs. 7.36 +/- 0.02, p < 0.001), pCO(2) (70.0 +/- 9.1 vs. 43.0 +/- 1.0 mmHg, p = 0.011) and bicarbonate (27.8 +/- 1.1 vs. 24.0 +/- 0.9 mmol/L, p = 0.071) at baseline. It kept them within clinically acceptable limits (pH >= 7.23, pCO(2) = 120 min of hPACI as opposed to

PurposeThe 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 in the UK.DesignAn online forum was conducted using a private group on Facebook, in collaboration with a patient support group. Thematic analysis was used to identify key themes.ResultsThe online forum ran between 7th November-18th December 2020 with 109 participants. Themes related to healthcare and non-healthcare impacts. Parents experienced changes and limitations to healthcare access, 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, positive experiences with remote healthcare and a gradual easing of anxiety were also identified.Implications and relevanceThis study highlights the wide-ranging impact of the COVID-19 pandemic on children and their families. Although focussed on oesophageal atresia/tracheo-oesophageal fistula, the emerging themes will be relevant to many children with complex, chronic health conditions. There are implications for healthcare delivery, including telehealth, during and after the pandemic period. Accurate and consistent messaging is required. Third sector organisations are ideally positioned support this.

Open fetal surgery for spina bifida (SB) is safe and effective yet invasive. The growing interest in fetoscopic SB repair (fSB-repair) prompts the need for appropriate training. We aimed to develop and validate a high-fidelity training model for fSB-repair. fSB-repair was simulated in the abdominal cavity and on the stomach of adult rabbits. Laparoscopic fetal surgeons served either as novices (n = 2) or experts (n = 3) based on their experience. Technical performance was evaluated using competency Cumulative Sum (CUSUM) analysis and the group splitting method. Main outcome measure for CUSUM competency was a composite binary outcome for surgical success, i.e. watertight repair, operation time = 180 min and Objective-Structured-Assessment-of-Technical-Skills (OSATS) score = 18/25. Construct validity was first confirmed since competency levels of novices and experts during their six first cases using both methods were significantly different. Criterion validity was also established as 33 consecutive procedures were needed for novices to reach competency using learning curve CUSUM, which is a number comparable to that of clinical fSB-repair. Finally, we surveyed expert fetal surgeons worldwide to assess face and content validity. Respondents (26/49; 53%) confirmed it with = 71% of scores for overall realism = 4/7 and usefulness = 3/5. We propose to use our high-fidelity model to determine and shorten the learning curve of laparoscopic fetal surgeons and retain operative skills.

The development of human liver scaffolds retaining their 3-dimensional structure and extra-cellular matrix (ECM) composition is essential for the advancement of liver tissue engineering. We report the design and validation of a new methodology for the rapid and accurate production of human acellular liver tissue cubes (ALTCs) using normal liver tissue unsuitable for transplantation. The application of high shear stress is a key methodological determinant accelerating the process of tissue decellularization while maintaining ECM protein composition, 3D-architecture and physico-chemical properties of the native tissue. ALTCs were engineered with human parenchymal and non-parenchymal liver cell lines (HepG2 and LX2 cells, respectively), human umbilical vein endothelial cells (HUVEC), as well as primary human hepatocytes and hepatic stellate cells. Both parenchymal and non-parenchymal liver cells grown in ALTCs exhibited markedly different gene expression when compared to standard 2D cell cultures. Remarkably, HUVEC cells naturally migrated in the ECM scaffold and spontaneously repopulated the lining of decellularized vessels. The metabolic function and protein synthesis of engineered liver scaffolds with human primary hepatocytes reseeded under dynamic conditions were maintained. These results provide a solid basis for the establishment of effective protocols aimed at recreating human liver tissue in vitro.

Oesophageal tissue engineering is a therapeutic alternative when oesophageal replacement is required. Decellularised scaffolds are ideal as they are derived from tissue-specific extracellular matrix and are non-immunogenic. However, appropriate preservation may significantly affect scaffold behaviour. Here we aim to prove that an effective method for short- and long-term preservation can be applied to tissue engineered products allowing their translation to clinical application. Rabbit oesophagi were decellularised using the detergent-enzymatic treatment (DET), a combination of deionised water, sodium deoxycholate and DNase-I. Samples were stored in phosphate-buffered saline solution at 4°C (4°C) or slow cooled in medium with 10% Me2SO at -1°C/min followed by storage in liquid nitrogen (SCM). Structural and functional analyses were performed prior to and after 2 and 4 weeks and 3 and 6 months of storage under each condition. Efficient decellularisation was achieved after 2 cycles of DET as determined with histology and DNA quantification, with preservation of the ECM. Only the SCM method, commonly used for cell storage, maintained the architecture and biomechanical properties of the scaffold up to 6 months. On the contrary, 4°C method was effective for short-term storage but led to a progressive distortion and degradation of the tissue architecture at the following time points. Efficient storage allows a timely use of decellularised oesophagi, essential for clinical translation. Here we describe that slow cooling with cryoprotectant solution in liquid nitrogen vapour leads to reliable long-term storage of decellularised oesophageal scaffolds for tissue engineering purposes.

Contains fulltext : 168576.pdf (Publisher’s version ) (Open Access) In 2010, the congenital diaphragmatic hernia (CDH) EURO Consortium published a standardized neonatal treatment protocol. Five years later, the number of participating centers has been raised from 13 to 22. In this article the relevant literature is updated, and consensus has been reached between the members of the CDH EURO Consortium. Key updated recommendations are: (1) planned delivery after a gestational age of 39 weeks in a high-volume tertiary center; (2) neuromuscular blocking agents to be avoided during initial treatment in the delivery room; (3) adapt treatment to reach a preductal saturation of between 80 and 95% and postductal saturation >70%; (4) target PaCO2 to be between 50 and 70 mm Hg; (5) conventional mechanical ventilation to be the optimal initial ventilation strategy, and (6) intravenous sildenafil to be considered in CDH patients with severe pulmonary hypertension. This article represents the current opinion of all consortium members in Europe for the optimal neonatal treatment of CDH.