Testing the expensive-tissue hypothesis' prediction of inter-tissue competition using causal modelling with latent variables.

The expensive-tissue hypothesis (ETH) posited a brain-gut trade-off to explain how humans evolved large, costly brains. Versions of the ETH interrogating gut or other body tissues have been tested in non-human animals, but not humans. We collected brain and body composition data in 70 South Asian women and used structural equation modelling with instrumental variables, an approach that handles threats to causal inference including measurement error, unmeasured confounding and reverse causality. We tested a negative, causal effect of the latent construct 'nutritional investment in brain tissues' (MRI-derived brain volumes) on the construct 'nutritional investment in lean body tissues' (organ volume and skeletal muscle). We also predicted a negative causal effect of the brain latent on fat mass. We found negative causal estimates for both brain and lean tissue (-0.41, 95% CI, -1.13, 0.23) and brain and fat (-0.56, 95% CI, -2.46, 2.28). These results, although inconclusive, are consistent with theory and prior evidence of the brain trading off with lean and fat tissues, and they are an important step in assessing empirical evidence for the ETH in humans. Analyses using larger datasets, genetic data and causal modelling are required to build on these findings and expand the evidence base.

Tips for success, managing the paediatric patient in radiology.

Paediatric radiology is a fascinating and diverse field of medicine with many opportunities to gain expertise in a range of imaging modalities and body areas. Working with children makes imaging both rewarding and challenging, due to the wide range of patient ages encountered and the inherent variation in developmental needs. This requires a patient-focussed approach to manage their anxiety and ensure cooperation of the patient and their carers. Several approaches to dealing with children have been developed including recognising individual needs, empathising with the child and carers, and involving the use of play and a range of age-relevant preparation materials. All of these make the radiology imaging environment and encounter a more effective and collaborative process. The purpose of this manuscript is to present a practical guide to overcoming these challenges, by making the child the focus of their radiological examination.

"How I would like AI used for my imaging": children and young persons' perspectives.

OBJECTIVES: Artificial intelligence (AI) tools are becoming more available in modern healthcare, particularly in radiology, although less attention has been paid to applications for children and young people. In the development of these, it is critical their views are heard. MATERIALS AND METHODS: A national, online survey was publicised to UK schools, universities and charity partners encouraging any child or young adult to participate. The survey was "live" for one year (June 2022 to 2023). Questions about views of AI in general, and in specific circumstances (e.g. bone fractures) were asked. RESULTS: One hundred and seventy-one eligible responses were received, with a mean age of 19 years (6-23 years) with representation across all 4 UK nations. Most respondents agreed or strongly agreed they wanted to know the accuracy of an AI tool that was being used (122/171, 71.3%), that accuracy was more important than speed (113/171, 66.1%), and that AI should be used with human oversight (110/171, 64.3%). Many respondents (73/171, 42.7%) felt AI would be more accurate at finding problems on bone X-rays than humans, with almost all respondents who had sustained a missed fracture strongly agreeing with that sentiment (12/14, 85.7%). CONCLUSIONS: Children and young people in our survey had positive views regarding AI, and felt it should be integrated into modern healthcare, but expressed a preference for a "medical professional in the loop" and accuracy of findings over speed. Key themes regarding information on AI performance and governance were raised and should be considered prior to future AI implementation for paediatric healthcare. CLINICAL RELEVANCE STATEMENT: Artificial intelligence (AI) integration into clinical practice must consider all stakeholders, especially paediatric patients who have largely been ignored. Children and young people favour AI involvement with human oversight, seek assurances for safety, accuracy, and clear accountability in case of failures. KEY POINTS: Paediatric patient's needs and voices are often overlooked in AI tool design and deployment. Children and young people approved of AI, if paired with human oversight and reliability. Children and young people are stakeholders for developing and deploying AI tools in paediatrics.

How to report perinatal and paediatric postmortem CT.

Postmortem CT (PMCT) has become increasingly accepted alongside skeletal surveys as a critical part of investigation in childhood deaths, either as part of a suite of non-invasive investigations through parental choice, or comprehensive evaluation in a forensic setting. Whilst CT image acquisition and protocols have been published and are relatively standardised, CT imaging reporting remains highly variable, largely dependent upon reporter experience and expertise. The main "risk" in PMCT is the over-interpretation of normal physiological changes on imaging as pathological, potentially leading to misdiagnosis or overdiagnosis of the disease. In this article, we present a pragmatic standardised reporting framework, developed over a decade of PMCT reporting in children in our institution, with examples of positive and negative findings, so that it may aid in the interpretation of PMCT images with those less experienced in paediatric findings and postmortem imaging. CRITICAL RELEVANCE STATEMENT: Standardised reporting using a common framework with a sound understanding of normal postmortem changes that occur in children are crucial in avoiding common reporting errors at postmortem CT. KEY POINTS: Familiarity with postmortem imaging is required for useful image reporting, and reporting standards vary. Understanding normal postmortem change from significant abnormalities requires training and experience. Following a template may remind reporters what to include and help improve performance.

Post-mortem skeletal survey (PMSS) versus post-mortem computed tomography (PMCT) for the detection of corner metaphyseal lesions (CML) in children.

OBJECTIVES: Corner metaphyseal lesions (CMLs) are specific for child abuse but challenging to detect on radiographs. The accuracy of CT for CML detection is unknown. Our aim was to compare diagnostic accuracy for CML detection on post-mortem skeletal surveys (PMSS, plain radiography) versus post-mortem CT (PMCT). METHODS: A 10-year retrospective review was performed at a children's hospital for patients having PMSS, PMCT and histopathological correlation (reference standard) for suspected CMLs. Twenty-four radiologists independently reported the presence or absence of CMLs in all cases in a blinded randomised cross-over design across two rounds. Logistic regression models were used to compare accuracy between modalities. RESULTS: Twenty CMLs were reviewed for each of the 10 subjects (200 metaphyses in all). Among them, 20 CMLs were confirmed by bone histopathology. Sensitivity for these CMLs was significantly higher for PMSS (69.6%, 95% CI 61.7 to 76.7) than PMCT (60.5%, 95% CI 51.9 to 68.6). Using PMSS for detection of CMLs would yield one extra correct diagnosis for every 11.1 (95% CI 6.6 to 37.0) fractured bones. In contrast, specificity was higher on PMCT (92.7%, 95% CI 90.3 to 94.5) than PMSS (90.5%, 95% CI 87.6 to 92.8) with an absolute difference of 2.2% (95% CI 1.0 to 3.4, p < 0.001). More fractures were reported collectively by readers on PMSS (785) than on PMCT (640). CONCLUSION: PMSS remains preferable to PMCT for CML evaluation. Any investigation of suspected abuse or unexplained deaths should include radiographs of the limbs to exclude CMLs. CLINICAL RELEVANCE STATEMENT: In order to avoid missing evidence that could indicate child abuse as a contributory cause for death in children, radiographs of the limbs should be performed to exclude CMLs, even if a PMCT is being acquired. KEY POINTS: • Corner metaphyseal lesions (CMLs) are indicative for abuse, but challenging to detect. Skeletal surveys (i.e. radiographs) are standard practice; however, accuracy of CT is unknown. • Sensitivity for CML detection on radiographs is significantly higher than CT. • Investigation of unexplained paediatric deaths should include radiographs to exclude CMLs even if CT is also being performed.

Commercially available artificial intelligence tools for fracture detection: the evidence.

Missed fractures are a costly healthcare issue, not only negatively impacting patient lives, leading to potential long-term disability and time off work, but also responsible for high medicolegal disbursements that could otherwise be used to improve other healthcare services. When fractures are overlooked in children, they are particularly concerning as opportunities for safeguarding may be missed. Assistance from artificial intelligence (AI) in interpreting medical images may offer a possible solution for improving patient care, and several commercial AI tools are now available for radiology workflow implementation. However, information regarding their development, evidence for performance and validation as well as the intended target population is not always clear, but vital when evaluating a potential AI solution for implementation. In this article, we review the range of available products utilizing AI for fracture detection (in both adults and children) and summarize the evidence, or lack thereof, behind their performance. This will allow others to make better informed decisions when deciding which product to procure for their specific clinical requirements.

Body weight-based iodinated contrast immersion timing for human fetal postmortem microfocus computed tomography.

Objectives: The aim of this study was to evaluate the length of time required to achieve full iodination using potassium tri-iodide as a contrast agent, prior to human fetal postmortem microfocus computed tomography (micro-CT) imaging. Methods: Prospective assessment of optimal contrast iodination was conducted across 157 human fetuses (postmortem weight range 2-298 g; gestational age range 12-37 weeks), following micro-CT imaging. Simple linear regression was conducted to analyse which fetal demographic factors could produce the most accurate estimate for optimal iodination time. Results: Postmortem body weight (r2 = 0.6435) was better correlated with iodination time than gestational age (r2 = 0.1384), producing a line of best fit, y = [0.0304 × body weight (g)] - 2.2103. This can be simplified for clinical use whereby immersion time (days) = [0.03 × body weight (g)] - 2.2. Using this formula, for example, a 100-g fetus would take 5.2 days to reach optimal contrast enhancement. Conclusions: The simplified equation can now be used to provide estimation times for fetal contrast preparation time prior to micro-CT imaging and can be used to manage service throughput and parental expectation for return of their fetus. Advances in knowledge: A simple equation from empirical data can now be used to estimate preparation time for human fetal postmortem micro-CT imaging.

Postmortem imaging of fetuses at early gestations: A comparison of microfocus computed tomography with postmortem magnetic resonance at 9.4 T and postmortem ultrasound.

OBJECTIVE: To compare the diagnostic performance of postmortem ultrasound (PMUS), 9.4 T magnetic resonance imaging (MRI) and microfocus computed tomography (micro-CT) for the examination of early gestation fetuses. METHOD: Eight unselected fetuses (10-15 weeks gestational age) underwent at least 2 of the 3 listed imaging examinations. Six fetuses underwent 9.4 T MRI, four underwent micro-CT and six underwent PMUS. All operators were blinded to clinical history. All imaging was reported according to a prespecified template assessing 36 anatomical structures, later grouped into five regions: brain, thorax, heart, abdomen and genito-urinary. RESULTS: More anatomical structures were seen on 9.4 T MRI and micro-CT than with PMUS, with a combined frequency of identified structures of 91.9% and 69.7% versus 54.5% and 59.6 (p < 0.001; p < 0.05) respectively according to comparison groups. In comparison with 9.4 T MRI, more structures were seen on micro-CT (90.2% vs. 83.3%, p < 0.05). Anatomical structures were described as abnormal on PMUS in 2.7%, 9.4 T MRI in 6.1% and micro-CT 7.7% of all structures observed. However, the accuracy test could not be calculated because conventional autopsy was performed on 6 fetuses of that only one structure was abnormal. CONCLUSION: Micro-CT appears to offer the greatest potential as an imaging adjunct or non-invasive alternative for conventional autopsies in early gestation fetuses.

Neonatal Hip Loading in Developmental Dysplasia: Finite Element Simulation of Proximal Femur Growth and Treatment.

Background: Abnormal prenatal hip joint loading can lead to compromised hip joint function. Early intervention is crucial for favorable outcomes. Purpose: This study investigates the impact of treatment timing (initiation and duration) on cartilage growth and ossification in the proximal femur of infants with developmental dysplasia of the hip, a condition affecting newborns. Methods: We used a mechanobiological model to simulate proximal femur growth during treatment durations of 3 months, 6 months, and a late-start treatment. Results: The findings indicate that the timing of treatment initiation is crucial, while a longer treatment duration does not contribute to improved morphological development of the hip joint. Conclusions: Mechanobiological models of growth can be used to develop treatments and therapies that correct loading conditions. Growing bone is particularly sensitive to loading conditions, and altered loading during growth can affect bone shape and functionality.

Recommendations for neuroradiological examinations in children living with achondroplasia: a European Society of Pediatric Radiology and European Society of Neuroradiology opinion paper.

Children living with achondroplasia are at an increased risk of developing neurological complications, which may be associated with acute and life-altering events. To remediate this risk, the timely acquisition of effective neuroimaging that can help to guide clinical management is essential. We propose imaging protocols and follow-up strategies for evaluating the neuroanatomy of these children and to effectively identify potential neurological complications, including compression at the cervicomedullary junction secondary to foramen magnum stenosis, spinal deformity and spinal canal stenosis. When compiling these recommendations, emphasis has been placed on reducing scan times and avoiding unnecessary radiation exposure. Standardized imaging protocols are important to ensure that clinically useful neuroimaging is performed in children living with achondroplasia and to ensure reproducibility in future clinical trials. The members of the European Society of Pediatric Radiology (ESPR) Neuroradiology Taskforce and European Society of Neuroradiology pediatric subcommittee, together with clinicians and surgeons with specific expertise in achondroplasia, wrote this opinion paper. The research committee of the ESPR also endorsed the final draft. The rationale for these recommendations is based on currently available literature, supplemented by best practice opinion from radiologists and clinicians with subject-specific expertise.

An integrated single-cell analysis of human adrenal cortex development.

The adrenal glands synthesize and release essential steroid hormones such as cortisol and aldosterone, but many aspects of human adrenal gland development are not well understood. Here, we combined single-cell and bulk RNA sequencing, spatial transcriptomics, IHC, and micro-focus computed tomography to investigate key aspects of adrenal development in the first 20 weeks of gestation. We demonstrate rapid adrenal growth and vascularization, with more cell division in the outer definitive zone (DZ). Steroidogenic pathways favored androgen synthesis in the central fetal zone, but DZ capacity to synthesize cortisol and aldosterone developed with time. Core transcriptional regulators were identified, with localized expression of HOPX (also known as Hop homeobox/homeobox-only protein) in the DZ. Potential ligand-receptor interactions between mesenchyme and adrenal cortex were seen (e.g., RSPO3/LGR4). Growth-promoting imprinted genes were enriched in the developing cortex (e.g., IGF2, PEG3). These findings reveal aspects of human adrenal development and have clinical implications for understanding primary adrenal insufficiency and related postnatal adrenal disorders, such as adrenal tumor development, steroid disorders, and neonatal stress.

Lung viral infection modelling in a bioengineered whole-organ.

Lung infections are one of the leading causes of death worldwide, and this situation has been exacerbated by the emergence of COVID-19. Pre-clinical modelling of viral infections has relied on cell cultures that lack 3D structure and the context of lung extracellular matrices. Here, we propose a bioreactor-based, whole-organ lung model of viral infection. The bioreactor takes advantage of an automated system to achieve efficient decellularization of a whole rat lung, and recellularization of the scaffold using primary human bronchial cells. Automatization allowed for the dynamic culture of airway epithelial cells in a breathing-mimicking setup that led to an even distribution of lung epithelial cells throughout the distal regions. In the sealed bioreactor system, we demonstrate proof-of-concept for viral infection within the epithelialized lung by infecting primary human airway epithelial cells and subsequently injecting neutrophils. Moreover, to assess the possibility of drug screening in this model, we demonstrate the efficacy of the broad-spectrum antiviral remdesivir. This whole-organ scale lung infection model represents a step towards modelling viral infection of human cells in a 3D context, providing a powerful tool to investigate the mechanisms of the early stages of pathogenic infections and the development of effective treatment strategies for respiratory diseases.

Less-invasive autopsy for early pregnancy loss.

Autopsy investigations provide valuable information regarding fetal death that can assist in the parental bereavement process, and influence future pregnancies, but conventional autopsy is often declined by parents because of its invasive approach. This has led to the development of less-invasive autopsy investigations based on imaging technology to provide a more accessible and acceptable choice for parents when investigating their loss. Whilst the development and use of more conventional clinical imaging techniques (radiographs, CT, MRI, US) are well described in the literature for fetuses over 20 weeks of gestational age, these investigations have limited diagnostic accuracy in imaging smaller fetuses. Techniques such as ultra-high-field MRI (>3T) and micro-focus computed tomography have been shown to have higher diagnostic accuracy whilst still being acceptable to parents. By further developing and increasing the availability of these more innovative imaging techniques, parents will be provided with a greater choice of acceptable options to investigate their loss, which may in turn increase their uptake. We provide a narrative review focussing on the development of high-resolution, non-invasive imaging techniques to evaluate early gestational pregnancy loss.

Current utilization of pediatric postmortem imaging in North America: a questionnaire-based survey.

BACKGROUND: Postmortem imaging is used more widely as the number of conventional autopsies has decreased over the last several decades. It is widely accepted in Europe, Asia and Oceania, but there has been a delay in acceptance in North America. Education, scanning protocols, resourcing and clinical incentives are needed to support this emerging field. OBJECTIVE: To determine the use of postmortem imaging and define perceived barriers to its implementation with the goal of expanding postmortem imaging in the United States and Canada. MATERIALS AND METHODS: We sent an online survey to active members of the Society for Pediatric Radiology (SPR) addressing the use of postmortem imaging, indications, readers, practical aspects, anticipated barriers and potential solutions to more widespread use. RESULTS: More than 50% of the 50 institutions that returned surveys used postmortem computed tomography; 24% used postmortem magnetic resonance imaging. Most postmortem imaging cases were read by radiologists. Fewer than 50% had formal correlation with autopsy results or an established relationship with the local medical examiner. Seven institutions reported reimbursement for postmortem imaging. Major barriers to postmortem imaging included lack of funding and lack of interest among clinicians. Funding and education were seen as important issues requiring attention. CONCLUSION: While most responding institutions provide pediatric postmortem imaging, the modalities, protocols, reporting procedures and clinical correlation vary widely. A lack of funding and few opportunities for education are limiting factors. Attention to these issues along with active support from the SPR are seen as potential solutions to recognize the value and promote widespread acceptance of postmortem imaging.

Current and future funding streams for paediatric postmortem imaging: European Society of Paediatric Radiology survey results.

BACKGROUND: Perinatal and childhood postmortem imaging has been accepted as a noninvasive alternative or adjunct to autopsy. However, the variation in funding models from institution to institution is a major factor prohibiting uniform provision of this service. OBJECTIVE: To describe current funding models employed in European and non-European institutions offering paediatric postmortem imaging services and to discuss the perceived barriers to future postmortem imaging service provision. MATERIALS AND METHODS: A web-based 16-question survey was distributed to members of the European Society of Paediatric Radiology (ESPR) and ESPR postmortem imaging task force over a 6-month period (March-August 2021). Survey questions related to the radiologic and autopsy services being offered and how each was funded within the respondent's institute. RESULTS: Eighteen individual responses were received (13/18, 72.2% from Europe). Only one-third of the institutions (6/18, 33.3%) have fully funded postmortem imaging services, with the remainder receiving partial (6/18, 33.3%) or no funding (5/18, 27.8%). Funding (full or partial) was more commonly available for forensic work (13/18, 72%), particularly where this was nationally provided. Where funding was not provided, the imaging and reporting costs were absorbed by the institute. CONCLUSION: Increased access is required for the expansion of postmortem imaging into routine clinical use. This can only be achieved with formal funding on a national level, potentially through health care commissioning and acknowledgement by health care policy makers and pathology services of the value the service provides following the death of a fetus or child. Funding should include the costs involved in training, equipment, reporting and image acquisition.

Microfocus computed tomography for fetal postmortem imaging: an overview.

Over the last few years, fetal postmortem microfocus computed tomography (micro-CT) imaging has increased in popularity for both diagnostic and research purposes. Micro-CT imaging could be a substitute for autopsy, particularly in very early gestation fetuses for whom autopsy can be technically challenging and is often unaccepted by parents. This article provides an overview of the latest research in fetal postmortem micro-CT imaging with a focus on diagnostic accuracy, endovascular staining approaches, placental studies and the reversibility of staining. It also discusses new methods that could prove helpful for micro-CT of larger fetuses. While more research is needed, contrast-enhanced micro-CT has the potential to become a suitable alternative to fetal autopsy. Further research using this novel imaging tool could yield wider applications, such as its practise in imaging rare museum specimens.

Post-mortem perinatal imaging: what is the evidence?

Post-mortem imaging for the investigation of perinatal deaths is an acceptable tool amongst parents and religious groups, enabling a less invasive autopsy examination. Nevertheless, availability is scarce nationwide, and there is some debate amongst radiologists regarding the best practice and optimal protocols for performing such studies. Much of the published literature to date focusses on single centre experiences or interesting case reports. Diagnostic accuracy studies are available for a variety of individual imaging modalities (e.g. post-mortem CT, MRI, ultrasound and micro-CT), however, assimilating this information is important when attempting to start a local service.In this article, we present a comprehensive review summarising the latest research, recently published international guidelines, and describe which imaging modalities are best suited for specific indications. When the antenatal clinical findings are not supported by the post-mortem imaging, we also suggest how and when an invasive autopsy may be considered. In general, a collaborative working relationship within a multidisciplinary team (consisting of radiologists, radiographers, the local pathology department, mortuary staff, foetal medicine specialists, obstetricians and bereavement midwives) is vital for a successful service.

Lessons learned from pre-clinical testing of xenogeneic decellularized esophagi in a rabbit model.

Decellularization of esophagi from several species for tissue engineering is well described, but successful implantation in animal models of esophageal replacement has been challenging. The purpose of this study was to assess feasibility and applicability of esophageal replacement using decellularized porcine esophageal scaffolds in a new pre-clinical model. Following surgical replacement in rabbits with a vascularizing muscle flap, we observed successful anastomoses of decellularized scaffolds, cues of early neovascularization, and prevention of luminal collapse by the use of biodegradable stents. However, despite the success of the surgical procedure, the long-term survival was limited by the fragility of the animal model. Our results indicate that transplantation of a decellularized porcine scaffold is possible and vascular flaps may be useful to provide a vascular supply, but long-term outcomes require further pre-clinical testing in a different large animal model.