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Infants are at greatest risk of severe and fatal physical abuse yet they sometimes present for medical care multiple times with abusive injuries prior to being diagnosed with abuse and having protective actions taken. Efforts to identify these infants in a timely manner are critical to prevent repeated, escalating abuse and subsequent harm. Increasing the identification and evaluation of sentinel injuries has been highlighted as a strategy for improving timely detection of abuse in infants. Sentinel injuries are visible, minor, poorly explained injuries in young infants that raise concern for abuse. These injuries include cutaneous injuries such as bruising, subconjunctival hemorrhages and intra-oral injuries. Sentinel injuries can signal concurrent clinically occult but more serious injuries or precede more significant trauma from abuse. As such, sentinel injuries offer an opportunity to intervene and protect infants from further harm. A thorough physical exam is critical for detecting sentinel injuries. Imaging with skeletal survey and, when appropriate, neuroimaging are key components of the medical evaluation of sentinel injuries in these high-risk infants.

Trauma is the leading cause of morbidity and mortality in children, and rapid identification of organ injury is essential for successful treatment. Contrast-enhanced ultrasound (CEUS) is an appealing alternative to contrast-enhanced CT in the evaluation of children with blunt abdominal trauma, mainly with respect to the potential reduction of population-level exposure to ionizing radiation. This is particularly important in children, who are more vulnerable to the hazards of ionizing radiation than adults. CEUS is useful in hemodynamically stable children with isolated blunt low- to moderate-energy abdominal trauma to rule out solid organ injuries. It can also be used to further evaluate uncertain contrast-enhanced CT findings, as well as in the follow-up of conservatively managed traumatic injuries. CEUS can be used to detect abnormalities that are not apparent by conventional US, including infarcts, pseudoaneurysms and active bleeding. In this article we present the current experience from the use of CEUS for the evaluation of pediatric blunt abdominal trauma, emphasizing the examination technique and interpretation of major abnormalities associated with injuries in the liver, spleen, kidneys, adrenal glands, pancreas and testes. We also discuss the limitations of the technique and offer a review of the major literature on this topic in children, including an extrapolation of experience from adults.

Neutrophils are rapidly recruited to inflammatory sites where their coordinated migration forms clusters, a process termed neutrophil swarming. The factors that modulate early stages of neutrophil swarming are not fully understood, requiring the development of new in vivo models. Using transgenic zebrafish larvae to study endogenous neutrophil migration in a tissue damage model, we demonstrate that neutrophil swarming is a conserved process in zebrafish immunity, sharing essential features with mammalian systems. We show that neutrophil swarms initially develop around an individual pioneer neutrophil. We observed the violent release of extracellular cytoplasmic and nuclear fragments by the pioneer and early swarming neutrophils. By combining in vitro and in vivo approaches to study essential components of neutrophil extracellular traps (NETs), we provide in-depth characterisation and high-resolution imaging of the composition and morphology of these release events. Using a photoconversion approach to track neutrophils within developing swarms, we identify that the fate of swarm-initiating pioneer neutrophils involves extracellular chromatin release and that the key NET components gasdermin, neutrophil elastase, and myeloperoxidase are required for the swarming process. Together our findings demonstrate that release of cellular components by pioneer neutrophils is an initial step in neutrophil swarming at sites of tissue injury.

Abusive intra-abdominal injuries are less common than other types of injuries, such as fractures and bruises, identified in victims of child physical abuse, but they can be deadly. No single abdominal injury is pathognomonic for abuse, but some types and constellations of intra-abdominal injuries are seen more frequently in abused children. Identification of intra-abdominal injuries can be important clinically or forensically. Injuries that do not significantly change clinical management can still elevate a clinician’s level of concern for abuse and thereby influence subsequent decisions affecting child protection efforts. Abusive intra-abdominal injuries can be clinically occult, necessitating screening laboratory evaluations to inform decisions regarding imaging. Once detected, consideration of developmental abilities of the child, type and constellation of injuries, and the forces involved in any provided mechanism of trauma are necessary to inform assessments of plausibility of injury mechanisms and level of concern for abuse. Here we describe the clinical, laboratory and imaging evaluation of the abdomen in the setting of suspected child abuse.

Mycobacterium tuberculosis (MTB) remains a major challenge to global health made worse by the spread of multidrug resistance. We therefore examined whether stimulating intracellular killing of mycobacteria through pharmacological enhancement of macroautophagy might provide a novel therapeutic strategy. Despite the resistance of MTB to killing by basal autophagy, cell‐based screening of FDA‐approved drugs revealed two anticonvulsants, carbamazepine and valproic acid, that were able to stimulate autophagic killing of intracellular M. tuberculosis within primary human macrophages at concentrations achievable in humans. Using a zebrafish model, we show that carbamazepine can stimulate autophagy in vivo and enhance clearance of M. marinum , while in mice infected with a highly virulent multidrug‐resistant MTB strain, carbamazepine treatment reduced bacterial burden, improved lung pathology and stimulated adaptive immunity. We show that carbamazepine induces antimicrobial autophagy through a novel, evolutionarily conserved, mTOR‐independent pathway controlled by cellular depletion of myo‐inositol. While strain‐specific differences in susceptibility to in vivo carbamazepine treatment may exist, autophagy enhancement by repurposed drugs provides an easily implementable potential therapy for the treatment of multidrug‐resistant mycobacterial infection. Synopsis Carbamazepine reveals a novel mechanism of mTOR‐independent control of autophagy that may be manipulated pharmacologically and provides proof of principle that therapeutic autophagy stimulation can be an effective strategy to treat multidrug‐resistant tuberculosis. Functional screening of FDA‐approved drugs identified two anticonvulsants, carbamazepine and valproic acid, capable of enhancing autophagic killing of mycobacteria from primary human monocyte derived and alveolar macrophages. In vivo , carbamazepine enhanced clearance of M. marinum from zebrafish and multidrug‐resistant M. tuberculosis from mice at drug concentrations achievable in man during therapeutic dosing. Carbamazepine stimulates autophagy by blocking myo‐inositol uptake in macrophages, leading to decreased phosphatidylinositol, inositol trisphosphate, and cellular ATP but activation of AMP kinase. Graphical Abstract Carbamazepine reveals a novel mechanism of mTOR‐independent control of autophagy that may be manipulated pharmacologically and provides proof of principle that therapeutic autophagy stimulation can be an effective strategy to treat multidrug‐resistant tuberculosis.

During inflammation, dysregulated neutrophil behaviour can play a major role in a range of chronic inflammatory diseases, for many of which current treatments are generally ineffective. Recently, specific naturally occurring tanshinones have shown promising anti-inflammatory effects by targeting neutrophils in vivo, yet such tanshinones, and moreover, their isomeric isotanshinone counterparts, are still a largely underexplored class of compounds, both in terms of synthesis and biological effects. To explore the anti-inflammatory effects of isotanshinones, and the tanshinones more generally, a series of substituted tanshinone and isotanshinone analogues was synthesised, alongside other structurally similar molecules. Evaluation of these using a transgenic zebrafish model of neutrophilic inflammation revealed differential anti-inflammatory profiles in vivo, with a number of compounds exhibiting promising effects. Several compounds reduce initial neutrophil recruitment and/or promote resolution of neutrophilic inflammation, of which two also result in increased apoptosis of human neutrophils. In particular, the methoxy-substituted tanshinone 39 specifically accelerates resolution of inflammation without affecting the recruitment of neutrophils to inflammatory sites, making this a particularly attractive candidate for potential pro-resolution therapeutics, as well as a possible lead for future development of functionalised tanshinones as molecular tools and/or chemical probes. The structurally related β-lapachones promote neutrophil recruitment but do not affect resolution. We also observed notable differences in toxicity profiles between compound classes. Overall, we provide new insights into the in vivo anti-inflammatory activities of several novel tanshinones, isotanshinones, and structurally related compounds.

Neutrophil migration in zebrafish larvae is increasingly used as a model to study the response of these leukocytes to different determinants of the cellular inflammatory response. However, it remains challenging to extract comprehensive information describing the behaviour of neutrophils from the multi-dimensional data sets acquired with widefield or confocal microscopes. Here, we describe PhagoSight, an open-source software package for the segmentation, tracking and visualisation of migrating phagocytes in three dimensions. The algorithms in PhagoSight extract a large number of measurements that summarise the behaviour of neutrophils, but that could potentially be applied to any moving fluorescent cells. To derive a useful panel of variables quantifying aspects of neutrophil migratory behaviour, and to demonstrate the utility of PhagoSight, we evaluated changes in the volume of migrating neutrophils. Cell volume increased as neutrophils migrated towards the wound region of injured zebrafish. PhagoSight is openly available as MATLAB® m-files under the GNU General Public License. Synthetic data sets and a comprehensive user manual are available from http://www.phagosight.org.

There remains a need to identify novel pro-resolution drugs for treatment of inflammatory disease. To date, there are no neutrophil-specific anti-inflammatory treatments in clinical use, perhaps due to our lack of understanding of how drugs access this complex cell type. Here we present the first comprehensive description and expression of both major classes of drug transporters, SLC and ABC, in resting human blood neutrophils. Moreover, we have studied the expression of these carriers in the tractable model system, the zebrafish ( Danio rerio ), additionally examining the evolutionary relationship between drug transporters in zebrafish and humans. We anticipate that this will be a valuable resource to the field of inflammation biology and will be an important asset in future anti-inflammatory drug design.

Neutrophils are essential for host defence and are recruited to sites of inflammation in response to tissue injury or infection. For inflammation to resolve, these cells must be cleared efficiently and in a controlled manner, either by apoptosis or reverse migration. If the inflammatory response is not well-regulated, persistent neutrophils can cause damage to host tissues and contribute to the pathogenesis of chronic inflammatory diseases, which respond poorly to current treatments. It is therefore important to develop drug discovery strategies that can identify new therapeutics specifically targeting neutrophils, either by promoting their clearance or by preventing their recruitment. Our recent in vivo chemical genetic screen for accelerators of inflammation resolution identified a subset of compounds sharing a common chemical signature, the bicyclic benzopyrone rings. Here, we further investigate the mechanisms of action of the most active of this chemical series, isopimpinellin, in our zebrafish model of neutrophilic inflammation. We found that this compound targets both the recruitment and resolution phases of the inflammatory response. Neutrophil migration towards a site of injury is reduced by isopimpinellin and this occurs as a result of PI3K inhibition. We also show that isopimpinellin induces neutrophil apoptosis to drive inflammation resolution in vivo using a new zebrafish reporter line detecting in vivo neutrophil caspase-3 activity and allowing quantification of flux through the apoptotic pathway in real time. Finally, our studies reveal that clinically available ‘cromones’ are structurally related to isopimpinellin and have previously undescribed pro-resolution activity in vivo. These findings could have implications for the therapeutic use of benzopyrones in inflammatory disease.

Chest radiography is the modality of choice for the identification of rib fractures in young children and there is value for the development of computer-aided rib fracture detection in this age group. However, the automated identification of rib fractures on chest radiographs can be challenging due to the need for high spatial resolution in deep learning frameworks. A patch-based deep learning algorithm was developed to automatically detect rib fractures on frontal chest radiographs in children under 2 years old. A total of 845 chest radiographs of children 0–2 years old (median: 4 months old) were manually segmented for rib fractures by radiologists and served as the ground-truth labels. Image analysis utilized a patch-based sliding-window technique, to meet the high-resolution requirements for fracture detection. Standard transfer learning techniques used ResNet-50 and ResNet-18 architectures. Area-under-curve for precision-recall (AUC-PR) and receiver-operating-characteristic (AUC-ROC), along with patch and whole-image classification metrics, were reported. On the test patches, the ResNet-50 model showed AUC-PR and AUC-ROC of 0.25 and 0.77, respectively, and the ResNet-18 showed an AUC-PR of 0.32 and AUC-ROC of 0.76. On the whole-radiograph level, the ResNet-50 had an AUC-ROC of 0.74 with 88% sensitivity and 43% specificity in identifying rib fractures, and the ResNet-18 had an AUC-ROC of 0.75 with 75% sensitivity and 60% specificity in identifying rib fractures. This work demonstrates the utility of patch-based analysis for detection of rib fractures in children under 2 years old. Future work with large cohorts of multi-institutional data will improve the generalizability of these findings to patients with suspicion of child abuse.