International Consensus Statement on the Radiological Screening of Contact Children in the Context of Suspected Child Physical Abuse.

Importance: Physical abuse is a common but preventable cause of long-term childhood morbidity and mortality. Despite the strong association between abuse in an index child and abuse in contact children, there is no guidance outlining how to screen the latter, significantly more vulnerable group, for abusive injuries. Consequently, the radiological assessment of contact children is often omitted, or variably performed, allowing occult injuries to go undetected and increasing the risk of further abuse. Objective: To report an evidence-based and consensus-derived set of best practices for the radiological screening of contact children in the context of suspected child physical abuse. Evidence Review: This consensus statement is supported by a systematic review of the literature and the clinical opinion of an internationally recognized group of 26 experts. The modified Delphi consensus process comprised 3 meetings of the International Consensus Group on Contact Screening in Suspected Child Physical Abuse held between February and June 2021. Findings: Contacts are defined as the asymptomatic siblings, cohabiting children, or children under the same care as an index child with suspected child physical abuse. All contact children should undergo a thorough physical examination and a history elicited prior to imaging. Contact children younger than 12 months should have neuroimaging, the preferred modality for which is magnetic resonance imaging, and skeletal survey. Contact children aged 12 to 24 months should undergo skeletal survey. No routine imaging is indicated in asymptomatic children older than 24 months. Follow-up skeletal survey with limited views should be performed if abnormal or equivocal at presentation. Contacts with positive findings should be investigated as an index child. Conclusions and Relevance: This Special Communication reports consensus recommendations for the radiological screening of contact children in the context of suspected child physical abuse, establishing a recognized baseline for the stringent evaluation of these at-risk children and providing clinicians with a more resilient platform from which to advocate for them.

Rate and severity of radiological features of physical abuse in children during the first UK-wide COVID-19 enforced national lockdown.

Rate and severity of radiological features of physical abuse in children during the first UK-wide COVID-19 enforced national lockdown. OBJECTIVE: To assess the number, type and outcome of radiological investigations for children presenting to hospital with suspected physical abuse (SPA; including abusive head trauma) during the first national COVID-19 enforced lockdown compared with the prelockdown period. DESIGN: Multicentre, retrospective, observational, interrupted time series analysis. SETTING: Eight secondary/tertiary paediatric centres between January 2018 and July 2020 inclusive. PARTICIPANTS: 1587 hospital assessed children undergoing radiographic skeletal surveys (SkS) and head CT imaging performed for SPA/child protection concerns. MAIN OUTCOME MEASURES: Incidence and severity of fractures identified on SkS; head injury (composed of incidence rates and ratios of skull fracture, intracranial haemorrhage (ICH) and hypoxic ischaemic injury (HII)) on head CT imaging; and ratio of antemortem and postmortem SkS. RESULTS: 1587 SkS were performed: 1282 (81%) antemortem, 762 (48%) male, and positive findings in 582 (37%). Median patient age was 6 months. There were 1.7 fractures/child prelockdown versus 1.1 fractures/child during lockdown. There was no difference between positive/negative SkS rates, the absolute ratio of antemortem/postmortem SkS or absolute numbers of head injury occurring between January 2018 and February 2020 and the lockdown period April-July 2020. Likewise, prelockdown incidence and rates of skull fracture 30/244 (12%), ICH 28/220 (13%) and HIE 10/205 (5%) were similar to lockdown, 142/1304 (11%), 171/1152 (15%) and 68/1089 (6%), respectively. CONCLUSION: The first UK COVID-19 lockdown did not lead to an increase in either the number of antemortem or postmortem radiological investigations performed for SPA, or the number or severity of fractures and intracranial injuries identified by these investigations.

Sibling screening in suspected abusive head trauma: a proposed guideline.

Abusive head trauma (AHT) is the leading cause of death from child abuse in children younger than 5 years. It is well documented that the infant contacts of children presenting with suspected AHT are at an increased risk of abuse when compared to the general infant population. Despite this association, a paucity of literature stratifies this risk and translates it to the clinic such that this high-risk group is stringently screened for abusive injuries. In this light, the authors propose a standardised screening method for all contact children of the index case and call for further consensus on the subject.

Abusive head trauma: neuroimaging mimics and diagnostic complexities.

Traumatic brain injury is responsible for approximately half of all childhood deaths from infancy to puberty, the majority of which are attributable to abusive head trauma (AHT). Due to the broad way patients present and the lack of a clear mechanism of injury in some cases, neuroimaging plays an integral role in the diagnostic pathway of these children. However, this nonspecific nature also presages the existence of numerous conditions that mimic both the clinical and neuroimaging findings seen in AHT. This propensity for misdiagnosis is compounded by the lack of pathognomonic patterns and clear diagnostic criteria. The repercussions of this are severe and have a profound stigmatic effect. The authors present an exhaustive review of the literature complemented by illustrative cases from their institutions with the aim of providing a framework with which to approach the neuroimaging and diagnosis of AHT.

Parenchymal brain injuries in abusive head trauma.

The consequences of abusive head trauma (AHT) can be devastating for both the individual child and for wider society. Death is undoubtedly a very real possibility, but even for those children who survive, there is often very significant morbidity with the potential for gross motor and cognitive impairment, behavioural problems, blindness and epilepsy, which can greatly affect their quality of life. Caring for such children places a vast financial and infrastructural burden on society that frequently extends well into adulthood. While few struggle to have any sympathy for the perpetrator, frequently the infant's father, it should be noted that a single solitary and momentary loss of complete control can have horrific and unforeseen consequences. A number of papers within this edition describe features of AHT and include descriptions of skull fractures and extra-axial haemorrhage, along with mimics of such phenomena. However, in this review we concentrate our attention on the myriad of parenchymal findings that can occur. Such parenchymal injuries include hypoxic-ischaemic damage, clefts, contusion and focal haemorrhage. We offer our perspectives on current thinking on these entities and put them in the context of the immensely important question - how do we recognise abusive head trauma?

A homozygous variant disrupting the PIGH start-codon is associated with developmental delay, epilepsy, and microcephaly.

Defective glycosylphosphatidylinositol (GPI)-anchor biogenesis can cause a spectrum of predominantly neurological problems. For eight genes critical to this biological process, disease associations are not yet reported. Scanning exomes from 7,833 parent-child trios and 1,792 singletons from the DDD study for biallelic variants in this gene-set uncovered a rare PIGH variant in a boy with epilepsy, microcephaly, and behavioral difficulties. Although only 2/2 reads harbored this c.1A > T transversion, the presence of ∼25 Mb autozygosity at this locus implied homozygosity, which was confirmed using Sanger sequencing. A similarly-affected sister was also homozygous. FACS analysis of PIGH-deficient CHO cells indicated that cDNAs with c.1A > T could not efficiently restore expression of GPI-APs. Truncation of PIGH protein was consistent with the utilization of an in-frame start-site at codon 63. In summary, we describe siblings harboring a homozygous c.1A > T variant resulting in defective GPI-anchor biogenesis and highlight the importance of exploring low-coverage variants within autozygous regions.

Delayed presentation of a caecal haematoma initially managed as appendicitis.

A 15-year-old boy with caecal haematoma required a right hemicolectomy due to development of small bowel obstruction and near caecal perforation having presented several days after an episode of minor trauma. The position of the caecum between intraperitoneal and extraperitoneal bowel requires special treatment considerations. This is a unique case in an adolescent because caecal haematoma usually presents acutely with abdominal pain.

Predicting benefit from anti-angiogenic agents in malignancy.

A high probability of benefit is desirable to justify the choice of anti-angiogenic therapy from an ever-expanding list of expensive new anticancer agents. However, biomarkers of response to cytotoxic agents are not optimal for predicting benefit from anti-angiogenic drugs. This discussion will focus on both preclinical and clinical research to identify biomarkers for anti-angiogenic therapies that can inform dosing, early clinical benefit, initial drug choice, emerging resistance and second-line treatments.

Segregation of partly melted molecules: isolation of CpG islands by polyacrylamide gel electrophoresis.

The technique of segregation of partly melted molecules (SPM) is a convenient and efficient method to isolate DNA fragments associated with CpG islands. The approach is conceptually simple and uses denaturant gradient gel electrophoresis to separate DNA molecules digested with restriction endonucleases. The SPM methodology has successfully been applied to the identification of genes from anonymous, unsequenced DNA fragments and CpG islands methylated in human cancer. In this article the theoretical background and practical application of the SPM method is reviewed.

DNA methylation, a biomarker for colorectal cancer: implications for screening and pathological utility.

Currently up to one-third of colorectal cancer patients present with locally advanced or metastatic disease that precludes a surgical cure. Performance limitations and low uptake of current screening tools have fueled research to develop minimally invasive approaches that can detect early-stage neoplasms. The observation that altered DNA can be amplified from the stool or circulation has stimulated research on its use as a biomarker of occult neoplasia. De novo methylation of CpG islands 5' to certain tumor suppressor genes has been associated with epigenetic silencing. At certain loci this phenomenon is specific for neoplastic populations, and it is frequently detected at early stages in colorectal tumorigenesis. Accordingly, hypermethylation events have been proposed by researchers as ideal targets for the basis of a screening panel to detect peripheral tumor DNA. This critique reviews research findings on the use of epigenetic biomarkers in screening for occult neoplasia. In addition, the authors consider the pathological utility of epigenetic testing in refining tumor staging and predicting disease recurrence.

An overview of the analysis of DNA methylation in mammalian genomes.

DNA methylation at position C5 of the pyrimidine ring of cytosine in mammalian genomes has received a great deal of research interest due to its importance in many biological phenomena. It is associated with events such as epigenetic gene silencing and the maintenance of genome integrity. Aberrant DNA methylation, particularly that of chromosomal regions called CpG islands, is an important step in carcinogenesis. In order to elucidate methylation profiling of complex genomes, various methods have been developed. Many of these methods are based on the differential reactivity of cytosine and 5-methylcytosine to various chemicals. The combined use of these chemical reactions and other preexisting methods has enabled the discrimination of cytosine and 5-methylcytosine in complex genomes. The use of proteins that preferentially bind to methylated DNA has also successfully been used to discriminate between methylated and unmethylated sites. The chemical and structural dissection of the in vivo processes of enzymatic methylation and the binding of methyl-CpG binding proteins provides evidence for the complex mechanisms that nature has acquired. In this review we summarize the methods available for the discrimination between cytosine and 5-methylcytosine in complex genomes.

A comprehensive catalog of CpG islands methylated in human lung adenocarcinomas for the identification of tumor suppressor genes.

CpG island methylation is an important mechanism in gene silencing and is a key epigenetic event in cancer development. As yet, the number and identities of the genes that are inactivated in cancer cells has not been determined. In order to address this issue, we have performed a comprehensive isolation of CpG islands that are methylated in human lung adenocarcinomas. We have isolated approximately 200 CpG islands that are methylated in tumor DNA including those of known tumor-associated genes such as the HOXA5 gene. As the library contains the CpG islands of a number of known tumor suppressor genes it is highly likely that additional, previously unidentified tumor suppressor genes, will be present. On average, 1-2% of CpG islands were methylated specifically in tumors although this figure differed greatly between patients. This study provides an important resource in the search for genes inactivated in tumors and for the investigation of epigenetic dysregulation of gene expression by CpG island methylation.

HOX gene clusters are hotspots of de novo methylation in CpG islands of human lung adenocarcinomas.

CpG island methylation results in the silencing of the associated gene and is an important step in tumorigenesis. Following a comprehensive isolation of CpG islands that were methylated in human lung adenocarcinoma, we found that in cancer cells de novo CpG island methylation generally occurred in a sporadic manner. However, some methylated CpG islands appeared to cluster in discrete chromosomal regions. In this study, we have investigated the methylation status of CpG islands located at such chromosomal loci. We have found that many CpG islands at the HOXA and HOXD loci were methylated in human lung adenocarcinoma. The de novo methylation of these CpG islands was also observed in patient's DNA from noncancerous portions of lung tissue. These results indicate the presence of specific chromosomal regions that are susceptible to de novo methylation.