In Memoriam: Professor Marc R. de Leval (April 16, 1941-June 26, 2022) - a tribute.

This manuscript is a personal tribute to Professor Marc de Leval from two of his colleagues: Professor Martin J. Elliott and Professor John E. Deanfield. As stated by the authors: "Marc's career history is presented in the accompanying eulogy from the current Heart & Lung Team at Great Ormond Street Hospital (GOSH), allowing us to highlight Marc's personal qualities that made him such an inspirational colleague. … Marc was, as we have said, the cardiologist's surgeon. He was also the surgeon's cardiologist, bridging the two disciplines and fusing the team. He was delighted by the advent of interventional cardiology and did not see it as a threat or competition, but instead, as appropriate for the well-being of his patients. He recognised how traumatic surgery could be for patients and their families and sought to avoid it whenever possible by alternative treatments. Marc will be remembered with love and admiration by his many patients and their families, whose lives he changed. His technical skill, energy, devotion, humour, intellect and influence will be sorely missed. May he rest in peace."

Nomenclature for Pediatric and Congenital Cardiac Care: Unification of Clinical and Administrative Nomenclature - The 2021 International Paediatric and Congenital Cardiac Code (IPCCC) and the Eleventh Revision of the International Classification of Diseases (ICD-11).

Substantial progress has been made in the standardization of nomenclature for paediatric and congenital cardiac care. In 1936, Maude Abbott published her Atlas of Congenital Cardiac Disease, which was the first formal attempt to classify congenital heart disease. The International Paediatric and Congenital Cardiac Code (IPCCC) is now utilized worldwide and has most recently become the paediatric and congenital cardiac component of the Eleventh Revision of the International Classification of Diseases (ICD-11). The most recent publication of the IPCCC was in 2017. This manuscript provides an updated 2021 version of the IPCCC.The International Society for Nomenclature of Paediatric and Congenital Heart Disease (ISNPCHD), in collaboration with the World Health Organization (WHO), developed the paediatric and congenital cardiac nomenclature that is now within the eleventh version of the International Classification of Diseases (ICD-11). This unification of IPCCC and ICD-11 is the IPCCC ICD-11 Nomenclature and is the first time that the clinical nomenclature for paediatric and congenital cardiac care and the administrative nomenclature for paediatric and congenital cardiac care are harmonized. The resultant congenital cardiac component of ICD-11 was increased from 29 congenital cardiac codes in ICD-9 and 73 congenital cardiac codes in ICD-10 to 318 codes submitted by ISNPCHD through 2018 for incorporation into ICD-11. After these 318 terms were incorporated into ICD-11 in 2018, the WHO ICD-11 team added an additional 49 terms, some of which are acceptable legacy terms from ICD-10, while others provide greater granularity than the ISNPCHD thought was originally acceptable. Thus, the total number of paediatric and congenital cardiac terms in ICD-11 is 367. In this manuscript, we describe and review the terminology, hierarchy, and definitions of the IPCCC ICD-11 Nomenclature. This article, therefore, presents a global system of nomenclature for paediatric and congenital cardiac care that unifies clinical and administrative nomenclature.The members of ISNPCHD realize that the nomenclature published in this manuscript will continue to evolve. The version of the IPCCC that was published in 2017 has evolved and changed, and it is now replaced by this 2021 version. In the future, ISNPCHD will again publish updated versions of IPCCC, as IPCCC continues to evolve.

Site-Specific Protein Photochemical Covalent Attachment to Carbon Nanotube Side Walls and Its Electronic Impact on Single Molecule Function.

Functional integration of proteins with carbon-based nanomaterials such as nanotubes holds great promise in emerging electronic and optoelectronic applications. Control over protein attachment poses a major challenge for consistent and useful device fabrication, especially when utilizing single/few molecule properties. Here, we exploit genetically encoded phenyl azide photochemistry to define the direct covalent attachment of four different proteins, including the fluorescent protein GFP and a ß-lactamase binding protein (BBP), to carbon nanotube side walls. AFM showed that on attachment BBP could still recognize and bind additional protein components. Single molecule fluorescence revealed that on attachment to SWCNTs function was retained and there was feedback to GFP in terms of fluorescence intensity and improved resistance to photobleaching; GFP is fluorescent for much longer on attachment. The site of attachment proved important in terms of electronic impact on GFP function, with the attachment site furthest from the chromophore having the larger effect on fluorescence. Our approach provides a versatile and general method for generating intimate protein-CNT hybrid bioconjugates. It can be potentially applied to any protein of choice; the attachment position and thus interface characteristics with the CNT can easily be changed by simply placing the phenyl azide chemistry at different residues by gene mutagenesis. Thus, our approach will allow consistent construction and modulate functional coupling through changing the protein attachment position.

Outcome and prognostic features in paediatric pineoblastomas: analysis of cases from the Surveillance, Epidemiology, and End Results registry (1990-2007).

BACKGROUND: Paediatric pineoblastomas are rare central nervous system tumours. Patient and treatment factors associated with outcome are poorly defined and limited to small retrospective case series and single case reports. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) cancer registry, we investigated clinical and pathological factors associated with outcome in paediatric pineoblastomas. Paediatric patients (< 16 years old) with pineoblastomas diagnosed between 1990 and 2007 were identified from the SEER database. Kaplan-Meier survival analysis and Cox models were used to examine the effect of variables on overall survival. The variables analysed included patient's age at diagnosis, gender, race, tumour spread and size, surgical resection and the use of adjuvant radiotherapy. RESULTS: Seventy-eight patients were identified from the database. Twelve patients were excluded as 11 had no surgery and one patient was excluded as the surgical status was unknown. Analysis of the remaining 66 patients revealed a median age at diagnosis of 5.5 years. Three patients underwent biopsy. Seventeen patients underwent full and partial resection, respectively. A further 46 patients underwent surgery the nature of which was not recorded. Thirty-nine patients (59.1%) received adjuvant radiotherapy. Eight patients (12.1%) had both surgery (full or partial resection) and radiotherapy. The median overall survival was 40.5 months. Univariate analysis demonstrated that older age at diagnosis was the only positive predictor of overall survival. CONCLUSION: This study represents the largest analysis of paediatric pineoblastomas to date. The only clinically relevant prognostic factor was older age at diagnosis. The role of surgery and adjuvant radiotherapy on overall survival remains to be defined.

Approaches to single-molecule studies of metalloprotein electron transfer using scanning probe-based techniques.

The single-molecule properties of metalloproteins have provided an intensely active research area in recent years. This brief review covers some of the techniques used to prepare, measure and analyse the electron transfer properties of metalloproteins, concentrating on scanning tunnelling microscopy-based techniques and advances in attachment of proteins to electrodes.

Factors associated with recurrence and survival length following relapse in patients with neuroblastoma.

BACKGROUND: Despite therapeutic advances, survival following relapse for neuroblastoma patients remains poor. We investigated clinical and biological factors associated with length of progression-free and overall survival following relapse in UK neuroblastoma patients. METHODS: All cases of relapsed neuroblastoma, diagnosed during 1990-2010, were identified from four Paediatric Oncology principal treatment centres. Kaplan-Meier and Cox regression analyses were used to calculate post-relapse overall survival (PROS), post-relapse progression-free survival (PRPFS) between relapse and further progression, and to investigate influencing factors. RESULTS: One hundred eighty-nine cases were identified from case notes, 159 (84.0%) high risk and 17 (9.0%), unresectable, MYCN non-amplified (non-MNA) intermediate risk (IR). For high-risk patients diagnosed >2000, median PROS was 8.4 months (interquartile range (IQR)=3.0-17.4) and median PRPFS was 4.7 months (IQR=2.1-7.1). For IR, unresectable non-MNA patients, median PROS was 11.8 months (IQR 9.0-51.6) and 5-year PROS was 24% (95% CI 7-45%). MYCN amplified (MNA) disease and bone marrow metastases at diagnosis were independently associated with worse PROS for high-risk cases. Eighty percent of high-risk relapses occurred within 2 years of diagnosis compared with 50% of unresectable non-MNA IR disease. CONCLUSIONS: Patients with relapsed HR neuroblastomas should be treatment stratified according to MYCN status and PRPFS should be the primary endpoint in early phase clinical trials. The failure to salvage the majority of IR neuroblastoma is concerning, supporting investigation of intensification of upfront treatment regimens in this group to determine whether their use would diminish likelihood of relapse.

Training in paediatric cardiac surgery: the history and role of training in a different country and even overseas.

This paper presents a personal perspective on the value of training overseas in paediatric cardiac surgery. From personal experience and observation, I argue that travel does indeed broaden the mind and placing artificial constraints on movement of trainees is a negative move. We need to work with others, in other cultures to become rounded human beings. And to be an empathetic surgeon, you need to be a rounded human being.

Tracheal bioengineering: the next steps. Proceeds of an International Society of Cell Therapy Pulmonary Cellular Therapy Signature Series Workshop, Paris, France, April 22, 2014.

There has been significant and exciting recent progress in the development of bioengineering approaches for generating tracheal tissue that can be used for congenital and acquired tracheal diseases. This includes a growing clinical experience in both pediatric and adult patients with life-threatening tracheal diseases. However, not all of these attempts have been successful, and there is ongoing discussion and debate about the optimal approaches to be used. These include considerations of optimal materials, particularly use of synthetic versus biologic scaffolds, appropriate cellularization of the scaffolds, optimal surgical approaches and optimal measure of both clinical and biologic outcomes. To address these issues, the International Society of Cell Therapy convened a first-ever meeting of the leading clinicians and tracheal biologists, along with experts in regulatory and ethical affairs, to discuss and debate the issues. A series of recommendations are presented for how to best move the field ahead.

Right pulmonary artery sling in a single lung with bronchial isomerism.

Pulmonary artery slings are rare congenital anomalies seen only on the left side. The presence of right pulmonary artery (RPA) sling is extremely rare. We report a case of a RPA sling with a single lung associated with tracheal stenosis and its management.

PARC: a phase I/II study evaluating the safety and activity of pegylated recombinant human arginase BCT-100 in relapsed/refractory cancers of children and young adults.

Background: The survival for many children with relapsed/refractory cancers remains poor despite advances in therapies. Arginine metabolism plays a key role in the pathophysiology of a number of pediatric cancers. We report the first in child study of a recombinant human arginase, BCT-100, in children with relapsed/refractory hematological, solid or CNS cancers. Procedure: PARC was a single arm, Phase I/II, international, open label study. BCT-100 was given intravenously over one hour at weekly intervals. The Phase I section utilized a modified 3 + 3 design where escalation/de-escalation was based on both the safety profile and the complete depletion of arginine (defined as adequate arginine depletion; AAD <8µM arginine in the blood after 4 doses of BCT-100). The Phase II section was designed to further evaluate the clinical activity of BCT-100 at the pediatric RP2D determined in the Phase I section, by recruitment of patients with pediatric cancers into 4 individual groups. A primary evaluation of response was conducted at eight weeks with patients continuing to receive treatment until disease progression or unacceptable toxicity. Results: 49 children were recruited globally. The Phase I cohort of the trial established the Recommended Phase II Dose of 1600U/kg iv weekly in children, matching that of adults. BCT-100 was very well tolerated. No responses defined as a CR, CRi or PR were seen in any cohort within the defined 8 week primary evaluation period. However a number of these relapsed/refractory patients experienced prolonged radiological SD. Conclusion: Arginine depletion is a clinically safe and achievable strategy in children with cancer. The RP2D of BCT-100 in children with relapsed/refractory cancers is established at 1600U/kg intravenously weekly and can lead to sustained disease stability in this hard to treat population. Clinical trial registration: EudraCT, 2017-002762-44; ISRCTN, 21727048; and ClinicalTrials.gov, NCT03455140.

Stem-cell-based, tissue engineered tracheal replacement in a child: a 2-year follow-up study.

BACKGROUND: Stem-cell-based, tissue engineered transplants might offer new therapeutic options for patients, including children, with failing organs. The reported replacement of an adult airway using stem cells on a biological scaffold with good results at 6 months supports this view. We describe the case of a child who received a stem-cell-based tracheal replacement and report findings after 2 years of follow-up. METHODS: A 12-year-old boy was born with long-segment congenital tracheal stenosis and pulmonary sling. His airway had been maintained by metal stents, but, after failure, a cadaveric donor tracheal scaffold was decellularised. After a short course of granulocyte colony stimulating factor, bone marrow mesenchymal stem cells were retrieved preoperatively and seeded onto the scaffold, with patches of autologous epithelium. Topical human recombinant erythropoietin was applied to encourage angiogenesis, and transforming growth factor ß to support chondrogenesis. Intravenous human recombinant erythropoietin was continued postoperatively. Outcomes were survival, morbidity, endoscopic appearance, cytology and proteomics of brushings, and peripheral blood counts. FINDINGS: The graft revascularised within 1 week after surgery. A strong neutrophil response was noted locally for the first 8 weeks after surgery, which generated luminal DNA neutrophil extracellular traps. Cytological evidence of restoration of the epithelium was not evident until 1 year. The graft did not have biomechanical strength focally until 18 months, but the patient has not needed any medical intervention since then. 18 months after surgery, he had a normal chest CT scan and ventilation-perfusion scan and had grown 11 cm in height since the operation. At 2 years follow-up, he had a functional airway and had returned to school. INTERPRETATION: Follow-up of the first paediatric, stem-cell-based, tissue-engineered transplant shows potential for this technology but also highlights the need for further research. FUNDING: Great Ormond Street Hospital NHS Trust, The Royal Free Hampstead NHS Trust, University College Hospital NHS Foundation Trust, and Region of Tuscany.

A phase II single-arm study of irinotecan in combination with temozolomide (TEMIRI) in children with newly diagnosed high grade glioma: a joint ITCC and SIOPE-brain tumour study.

A multicenter, two stage phase II study, investigated irinotecan plus temozolomide in children with newly diagnosed high grade glioma. The primary endpoint was tumor response during a two-cycle treatment window, confirmed by external review committee. Patients received oral temozolomide 100 mg/(m(2) day) (days 1-5) and intravenous irinotecan 10 mg/(m(2) day) (days 1-5 and 8-12) for two 21-day cycles (three cycles for patients exhibiting objective tumor response). Standard treatment was then administered according to local investigator choice. In total 17 patients were enrolled and treated by local investigators. However, central pathology review found three patients did not have a diagnosis of high grade glioma and another four patients did not have evaluable disease according to independent central radiological review. The primary endpoint was based on the first ten evaluable patients as determined by the external review committee. Recruitment was stopped for futility after there were no complete or partial responses during the two-cycle treatment window in the first ten evaluable patients. Five patients had stable disease, and five progressed. Data for secondary endpoints including; time to tumor progression, time to treatment failure, and overall survival is reported. The safety profile of the treatment showed the combination was tolerable with two patients (11.8 %) having grade three nausea, and one (5.9 %) experiencing a grade four neutropenia, leading to permanent discontinuation from adjuvant treatment. Irinotecan plus temozolomide, although well tolerated did not improve outcome over historical controls in this setting.

Wavelet cross-correlation to investigate regional variations in cerebral oxygenation in infants supported on extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation can potentially affect cerebral blood flow dynamics and consequently influence cerebral autoregulation. We applied wavelet cross-correlation (WCC) between multichannel cerebral oxyhemoglobin concentration (HbO(2)) and mean arterial pressure (MAP), to assess regional variations in cerebral autoregulation. Six infants on veno-arterial (VA) ECMO were studied during sequential changes in the ECMO flows. WCC between MAP and HbO(2) for each flow period and each channel was calculated within three different frequency (wavelet scale) bands centered around 0.1, 0.16, and 0.3 Hz chosen to represent low frequency oscillations, ventilation, and respiration rates, respectively. The group data showed a relationship between maximum WCC and ECMO flow. During changes in ECMO flow, statistically significant differences in maximum WCC were found between right and left hemispheres. WCC between HbO(2) and MAP provides a useful method to investigate the dynamics of cerebral autoregulation during ECMO. Manipulations of ECMO flows are associated with regional changes in cerebral autoregulation which may potentially have an important bearing on clinical outcome.

Canonical correlation analysis in the study of cerebral and peripheral haemodynamics interrelations with systemic variables in neonates supported on ECMO.

Neonates supported on extracorporeal membrane oxygenation (ECMO) are at high risk of brain injury due to haemodynamic instability. In order to monitor cerebral and peripheral (muscle) haemodynamic and oxygenation changes in this population we used a dual-channel near-infrared spectroscopy (NIRS) system. In addition, to assess interrelations between NIRS and systemic variables, collected simultaneously, canonical correlation analysis (CCA) was employed. CCA can quantify the relationship between a set of variables and assess levels of dependency. In four out of five patients, systemic variables were found to be less inter-related with cerebral rather than peripheral NIRS measurements. Moreover, during ECMO flow manipulations, we found that the interrelation between the systemic and the NIRS cerebral/peripheral variables changed. The CCA method presented here can be used to assess differences between NIRS cerebral and NIRS peripheral responses due to systemic variations which may be indicative of physiological differences in the mechanisms that regulate oxygenation and/or haemodynamics of the brain and the muscle.

Successful surgical repair of complex Christmas-tree pattern tracheo-bronchial anatomy with stenosis.

Congenital anomalies of bronchial division are extremely rare. Presence of complete cartilaginous rings in bronchial tree with co-existent bronchial division anomalies make surgical correction more challenging, and needs a well-structured surgical pathway. We report a case of complex airway pattern similar to Christmas-tree appearance with associated stenosis due to complete rings, treated by modified sliding tracheoplasty with a successful outcome.

Living bioethics, theories and children's consent to heart surgery.

Background: This analysis is about practical living bioethics and how law, ethics and sociology understand and respect children's consent to, or refusal of, elective heart surgery. Analysis of underlying theories and influences will contrast legalistic bioethics with living bioethics. In-depth philosophical analysis compares social science traditions of positivism, interpretivism, critical theory and functionalism and applies them to bioethics and childhood, to examine how living bioethics may be encouraged or discouraged. Illustrative examples are drawn from research interviews and observations in two London paediatric cardiac units. This paper is one of a series on how the multidisciplinary cardiac team members all contribute to the complex mosaic of care when preparing and supporting families' informed consent to surgery. Results: The living bioethics of justice, care and respect for children and their consent depends on theories and practices, contexts and relationships. These can all be undermined by unseen influences: the history of adult-centric ethics; developmental psychology theories; legal and financial pressures that require consent to be defined as an adult contract; management systems and daily routines in healthcare that can intimidate families and staff; social inequalities. Mainstream theories in the clinical ethics literature markedly differ from the living bioethics in clinical practices. Conclusion: We aim to contribute to raising standards of respectful paediatric bioethics and to showing the relevance of virtue and feminist ethics, childhood studies and children's rights.

Crisis care for children and young people with mental health problems: national mapping, models of delivery, sustainability and experience (CAMH-Crisis2). A study protocol.

Background: One in six five 16-year-olds have a probable mental health difficulty. Of these, almost half of older teenagers and a quarter of 11-16-year-olds report having self-harmed or attempted suicide. Currently, there is little research into mental health crisis services for young people, with little understanding of what services exist, who uses them, or what works best. Question: 'How are mental health crisis responses for children and young people up to the age of 25 sustained, experienced and integrated within their local systems of services'? Objectives:     1.    To describe National Health Service (NHS), local authority, education and third sector approaches to the implementation and organisation of crisis care for children and young people across England and Wales.    2.   To identify eight contrasting case studies in which to evaluate how crisis services have developed and are currently organised, sustained, experienced and integrated within the context of their local systems of services.    3.   To compare and contrast these services in the context of the available international evidence, drawing out and disseminating clear implications for the design and delivery of future crisis responses for children and young people and their families. Methods: A sequential mixed methods approach, underpinned by normalisation process theory will be employed. A survey will create a detailed record of how crisis responses across England and Wales are organised, implemented and used. Subsequently, eight contrasting services in relation to geographic and socioeconomic setting, populations served, and service configuration will be identified as case studies. Interviews will be conducted with children, young people and parents/carers who have used the service, as well as commissioners, managers and practitioners. Operational policies and service usage data will also be examined. Analysis of how each service is provided, experienced, implemented and sustained will be conducted both inductively and deductively, reflecting normalisation process theory constructs.

BACKGROUND: There has been a sharp increase in children and young people experiencing extreme emotional distress and/or self-harm, which is also known as 'crisis'. Services for young people in crisis are a priority in the UK but little is currently known about what crisis services exist, who uses them, or what type of service works best. AIM AND OBJECTIVES: This project aims to explore the types of mental health crisis services currently available to children and young people up to the age of 25 in England and Wales, and to examine how they are organised, perceived and integrated within other local care systems. The objectives are to: 1. Find out what NHS, local authority, education and charity sector crisis services exist for children and young people across England and Wales, to describe the services and to create a database of them. 2. Identify eight contrasting services from the database and evaluate how these services are organised, perceived and integrated within local care systems. 3. Compare and contrast these services with the available international evidence, drawing out clear implications for the design and delivery of future crisis responses for children and young people and their families. METHODS: We will use a survey to create a database of crisis response services across England and Wales. From the database we will identify eight contrasting services and we will conduct interviews with children, young people and parents/carers who have used the service as well as managers and staff. We will look at how the services work and explore how they are used and by whom. We will compare and contrast each case study and consider findings of other research studies from around the world to draw clear, actionable, lessons for the future provision of high-quality crisis services for children and young people.

Identifying Optimal Acute Care Comparators to Inform the Evaluation of an Advanced Care at Home Pilot Program.

BACKGROUND: Hospital at Home (H@H) programs-which seek to deliver acute care within a patient's home-have become more prevalent over time. However, existing literature exhibits heterogeneity in program structure, evaluation design, and target population size, making it difficult to draw generalizable conclusions to inform future H@H program design. OBJECTIVE: The objective of this work was to develop a quality improvement evaluation strategy for a H@H program-the Kaiser Permanente Advanced Care at Home (KPACAH) program in Northern California-leveraging electronic health record data, chart review, and patient surveys to compare KPACAH patients with inpatients in traditional hospital settings. METHODS: The authors developed a 3-step recruitment workflow that used electronic health record filtering tools to generate a daily list of potential comparators, a manual chart review of potentially eligible comparator patients to assess individual clinical and social criteria, and a phone interview with patients to affirm eligibility and interest from potential comparator patients. RESULTS: This workflow successfully identified and enrolled a population of 446 comparator patients in a 5-month period who exhibited similar demographics, reasons for hospitalization, comorbidity burden, and utilization measures to patients enrolled in the KPACAH program. CONCLUSION: These initial findings provide promise for a workflow that can facilitate the identification of similar inpatients hospitalized at traditional brick and mortar facilities to enhance outcomes evaluations for the H@H programs, as well as to identify the potential volume of enrollees as the program expands.

Persistent disruption of ciliated epithelium following paediatric lung transplantation.

It is unclear whether ciliary function following lung transplantation is normal or not. Our aim was to study the ciliary function and ultrastructure of epithelium above and below the airway anastomosis and the peripheral airway of children following lung transplantation. We studied the ciliary beat frequency (CBF) and beat pattern, using high speed digital video imaging and ultrastructure by transmission electron microscopy, of bronchial epithelium from above and below the airway anastomosis and the peripheral airway of 10 cystic fibrosis (CF) and 10 non-suppurative lung disease (NSLD) paediatric lung transplant recipients. Compared to epithelium below the anastomosis, the epithelium above the anastomosis in the CF group showed reduced CBF (median (interquartile range): 10.5 (9.0-11.4) Hz versus 7.4 (6.4-9.2) Hz; p<0.01) and increased dyskinesia (median (IQR): 16.5 (12.9-28.2)% versus 42.2 (32.6-56.4)%; p<0.01). In both CF and NSLD groups, compared with epithelium above the anastomosis, the epithelium below the anastomosis showed marked ultrastructural abnormalities (median duration post-transplant 7-12 months). Ciliary dysfunction is a feature of native airway epithelium in paediatric CF lung transplant recipients. The epithelium below the airway anastomosis shows profound ultrastructural abnormalities in both CF and NSLD lung transplant recipients, many months after transplantation.

Direct binding of a redox protein for single-molecule electron transfer measurements.

An electron transfer protein is engineered with two thiol groups introduced at different positions in the molecular structure to allow robust binding to two gold electrodes. Atomic force microscopy and scanning tunneling microscopy single-molecule studies show that the engineered proteins: (1) bind to a gold electrode in defined orientation dictated by the thiol-pair utilised, and (2) have a higher conductance than the wild-type proteins indicating a more efficient electron transmission due to the strong gold-thiol contacts.