CNS Embryonal Tumor with PLAGL Amplification, a New Tumor Type in Children and Adolescents: Insights from a Comprehensive MRI Analysis.

BACKGROUND AND PURPOSE: CNS embryonal tumor with PLAGL1/PLAGL2 amplification (ET, PLAGL) is a newly identified, highly malignant pediatric tumor. Systematic MRI descriptions of ET, PLAGL are currently lacking. MATERIALS AND METHODS: MRI data from 19 treatment-naïve patients with confirmed ET, PLAGL were analyzed. Evaluation focused on anatomical involvement, tumor localization, MRI signal characteristics, DWI behavior, and the presence of necrosis and hemorrhage. Descriptive statistics (median, interquartile range, percentage) were assessed. RESULTS: Ten patients had PLAGL1 and nine PLAGL2 amplifications. The solid components of the tumors were often multinodular with heterogeneous enhancement (mild to intermediate in 47% and intermediate to strong in 47% of cases). Non-solid components included cysts in 47% and necrosis in 84% of the cases. The tumors showed heterogeneous T2WI hyper-and isointensity (74%), relatively little diffusion restriction (ADC values < contralateral normal-appearing WM in 36% of cases with available DWI), and tendencies towards hemorrhage/calcification (42%). No reliable distinction was found between PLAGL1-and PLAGL2-amplified tumors or compared to other embryonal CNS tumors. CONCLUSIONS: The study contributes to understanding the imaging characteristics of ET, PLAGL. It underscores the need for collaboration in studying rare pediatric tumors and advocates for the use of harmonized imaging protocols for better characterization. ABBREVIATIONS: ATRT= atypical teratoid/rhabdoid tumor; ETMR= embryonal tumor with multilayered rosettes; ET, PLAGL= CNS embryonal tumor with PLAGL amplification; EVD= external ventricular drain; IQR: interquartile range; PLAGL1= pleomorphic adenoma gene-like 1; PLAGL2= pleomorphic adenoma gene-like 2; WHO= World Health Organization.

Assessment of the current and emerging criteria for the histopathological classification of lung neuroendocrine tumours in the lungNENomics project.

BACKGROUND: Six thoracic pathologists reviewed 259 lung neuroendocrine tumours (LNETs) from the lungNENomics project, with 171 of them having associated survival data. This cohort presents a unique opportunity to assess the strengths and limitations of current World Health Organization (WHO) classification criteria and to evaluate the utility of emerging markers. PATIENTS AND METHODS: Patients were diagnosed based on the 2021 WHO criteria, with atypical carcinoids (ACs) defined by the presence of focal necrosis and/or 2-10 mitoses per 2 mm2. We investigated two markers of tumour proliferation: the Ki-67 index and phospho-histone H3 (PHH3) protein expression, quantified by pathologists and automatically via deep learning. Additionally, an unsupervised deep learning algorithm was trained to uncover previously unnoticed morphological features with diagnostic value. RESULTS: The accuracy in distinguishing typical from ACs is hampered by interobserver variability in mitotic counting and the limitations of morphological criteria in identifying aggressive cases. Our study reveals that different Ki-67 cut-offs can categorise LNETs similarly to current WHO criteria. Counting mitoses in PHH3+ areas does not improve diagnosis, while providing a similar prognostic value to the current criteria. With the advantage of being time efficient, automated assessment of these markers leads to similar conclusions. Lastly, state-of-the-art deep learning modelling does not uncover undisclosed morphological features with diagnostic value. CONCLUSIONS: This study suggests that the mitotic criteria can be complemented by manual or automated assessment of Ki-67 or PHH3 protein expression, but these markers do not significantly improve the prognostic value of the current classification, as the AC group remains highly unspecific for aggressive cases. Therefore, we may have exhausted the potential of morphological features in classifying and prognosticating LNETs. Our study suggests that it might be time to shift the research focus towards investigating molecular markers that could contribute to a more clinically relevant morpho-molecular classification.

Perspectives on the future of host-microbe biology from the Council on Microbial Sciences of the American Society for Microbiology.

Host-microbe biology (HMB) stands on the cusp of redefinition, challenging conventional paradigms to instead embrace a more holistic understanding of the microbial sciences. The American Society for Microbiology (ASM) Council on Microbial Sciences hosted a virtual retreat in 2023 to identify the future of the HMB field and innovations needed to advance the microbial sciences. The retreat presentations and discussions collectively emphasized the interconnectedness of microbes and their profound influence on humans, animals, and environmental health, as well as the need to broaden perspectives to fully embrace the complexity of these interactions. To advance HMB research, microbial scientists would benefit from enhancing interdisciplinary and transdisciplinary research to utilize expertise in diverse fields, integrate different disciplines, and promote equity and accessibility within HMB. Data integration will be pivotal in shaping the future of HMB research by bringing together varied scientific perspectives, new and innovative techniques, and 'omics approaches. ASM can empower under-resourced groups with the goal of ensuring that the benefits of cutting-edge research reach every corner of the scientific community. Thus, ASM will be poised to steer HMB toward a future that champions inclusivity, innovation, and accessible scientific progress.

Diagnosis of metaphyseal fractures in infants and young children with suspected inflicted injury: a systematic review of cross-sectional imaging techniques.

AIM: To compare the diagnostic accuracy, advantages, and disadvantages of different medical imaging techniques for detecting metaphyseal fractures (also known as classic metaphyseal lesions [CMLs]) in infants and young children with suspected inflicted trauma. MATERIALS AND METHODS: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist and Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool criteria. Predefined keywords were used to search online databases for English articles published between 1 January 1980 and 31 March 2023. RESULTS: The initial search revealed 83 studies, only five of which met the inclusion criteria. The sensitivity and specificity of positron-emission tomography (PET) were 67% and 99%, respectively. The sensitivity and specificity of ultrasound were 55-61% and 96-97%, respectively. The sensitivity of magnetic resonance imaging (MRI) whole-body screening was 31%. The sensitivity of bone scintigraphy was 17% in one and 35% in a second study. Computed tomography was not used to detect CMLs in any diagnostic accuracy study. CONCLUSION: This systematic review has identified only a small number of relevant studies. In addition to the skeletal survey, PET and ultrasound may be helpful for the diagnosis of CMLs in infants and young children with suspected abuse; however, ultrasound has greater potential than PET due to its higher specificity, lack of radiation exposure, low cost, and wider availability.

Review of standard paediatric neuroradiology MRI protocols from 12 UK tertiary paediatric hospitals: is there much variation between centres?

AIM: To investigate how magnetic resonance imaging (MRI) examinations are protocolled in tertiary paediatric neuroradiology centres around the UK for some of the more common presentations encountered in paediatric neuroradiology, and to identify any variations of note. MATERIALS AND METHODS: All 19 UK tertiary paediatric neuroradiology centres registered with the British Society of Neuroradiologists-Paediatric Group were contacted and asked if they could provide a copy of their standard MRI protocols. Twelve responded (63%) and 10 of the more common presentations were selected and the standard acquired sequences obtained at each participating centre were compared. Where available the collated protocols were also compared against current published guidance. RESULTS: The basic sequences carried out by centres around the UK are similar; however, there are lots of variations overall. The only standardised protocol currently being implemented nationally in paediatric imaging is that for brain tumours. Otherwise, chosen protocols are generally dependent on the preferences and technical capabilities of individual centres. Suggested published protocols also exist for non-accidental injury (NAI), multiple sclerosis, epilepsy, and head and neck imaging. CONCLUSIONS: The differences in MRI protocolling depend in part on technical capabilities and in part on the experience and preferences of the paediatric neuroradiologists at each centre. For most presentations, there is no consensus as to what constitutes the perfect protocol. The present results will be useful for specialist centres who may wish to review their current protocols, and for more generalist centres to use as a reference to guide their MRI protocolling.

Recipient Cell Factors Influence Interbacterial Competition Mediated by Two Distinct Burkholderia dolosa Contact-Dependent Growth Inhibition Systems.

Contact-dependent growth inhibition (CDI) systems mediate interbacterial antagonism between Gram-negative bacteria by delivering the toxic portion of a large surface protein (termed BcpA in Burkholderia species) to the cytoplasm of neighboring bacteria. Translocation of the antibacterial polypeptide into recipient cells requires specific recipient outer and inner membrane proteins, but the identity of these factors outside several model organisms is unknown. To identify genes involved in CDI susceptibility in the Burkholderia cepacia complex member Burkholderia dolosa, a transposon mutagenesis selection approach was used to enrich for mutants resistant to BcpA-1 or BcpA-2. Subsequent analysis showed that candidate regulatory genes contributed modestly to recipient cell susceptibility to B. dolosa CDI. However, most candidate deletion mutants did not show the same phenotypes as the corresponding transposon mutants. Whole-genome resequencing revealed that these transposon mutants also contained unique mutations within a three gene locus (wabO, BDAG_01006, and BDAG_01005) encoding predicted lipopolysaccharide (LPS) biosynthesis enzymes. B. dolosa wabO, BDAG_01006, or BDAG_01005 mutants were resistant to CDI and produced LPS with altered core oligosaccharide and O-antigen. Although BcpA-1 and BcpA-2 are dissimilar and expected to utilize different outer membrane receptors, intoxication by both proteins was similarly impacted by LPS changes. Together, these findings suggest that alterations in cellular regulation may indirectly impact the efficiency of CDI-mediated competition and demonstrate that LPS is required for intoxication by two distinct B. dolosa BcpA proteins. IMPORTANCEContact-dependent growth inhibition (CDI) system proteins, produced by many Gram-negative bacteria, are narrow spectrum antimicrobials that inhibit the growth of closely related neighboring bacteria. Here, we use the opportunistic pathogen Burkholderia dolosa to identify genes required for intoxication by two distinct CDI system proteins. Our findings suggest that B. dolosa recipient cells targeted by CDI systems are only intoxicated if they produce full-length lipopolysaccharide. Understanding the mechanisms underlying antagonistic interbacterial interactions may contribute to future therapeutic development.

Patterning and mechanics of somite boundaries in zebrafish embryos.

The body axis of vertebrates is subdivided into repetitive compartments called somites, which give rise primarily to the segmented architecture of the musculoskeletal system in the adult body. Somites form in a sequential and rhythmic manner in embryos and a physical boundary separates each somite from the rest of the unsegmented tissue and adjoining somites. Precise positioning of somite boundaries and determination of boundary cell fate in a select group of cells is thought to be driven by gene expression patterns and morphogen gradients. This pre-patterning step is followed by a mechanical process involving actomyosin activation in boundary cells and formation of an extracellular matrix that results in morphological boundary formation. While genes involved in somite boundary formation have been identified, there are many open questions about the underlying pre-patterning dynamics and mechanics and how these processes are coupled to generate a morphological boundary. Here, focusing on segmentation of zebrafish embryos as a model, we review pre-patterning processes critical for boundary formation and how cytoskeletal activity drives tissue separation. Our outlook is that this system holds exciting new avenues for unearthing general principles of boundary formation in developing embryos.

Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans.

Could nose-to-brain pathways mediate the effects of peptides such as oxytocin (OT) on brain physiology when delivered intranasally? We address this question by contrasting two methods of intranasal administration (a standard nasal spray, and a nebulizer expected to improve OT deposition in nasal areas putatively involved in direct nose-to-brain transport) to intravenous administration in terms of effects on regional cerebral blood flow during two hours post-dosing. We demonstrate that OT-induced decreases in amygdala perfusion, a key hub of the OT central circuitry, are explained entirely by OT increases in systemic circulation following both intranasal and intravenous OT administration. Yet we also provide robust evidence confirming the validity of the intranasal route to target specific brain regions. Our work has important translational implications and demonstrates the need to carefully consider the method of administration in our efforts to engage specific central oxytocinergic targets for the treatment of neuropsychiatric disorders.

Bioinformatic analysis suggests potential mechanisms underlying parasitoid venom evolution and function.

Hymenopteran parasitoid wasps are a diverse collection of species that infect arthropod hosts and use factors found in their venoms to manipulate host immune responses, physiology, and behaviour. Whole parasitoid venoms have been profiled using proteomic approaches, and here we present a bioinformatic characterization of the venom protein content from Ganaspis sp. 1, a parasitoid that infects flies of the genus Drosophila. We find evidence that diverse evolutionary processes including multifunctionalization, co-option, gene duplication, and horizontal gene transfer may be acting in concert to drive venom gene evolution in Ganaspis sp.1. One major role of parasitoid wasp venom is host immune evasion. We previously demonstrated that Ganaspis sp. 1 venom inhibits immune cell activation in infected Drosophila melanogaster hosts, and our current analysis has uncovered additional predicted virulence functions. Overall, this analysis represents an important step towards understanding the composition and activity of parasitoid wasp venoms.

Shortage of paediatric radiologists acting as an expert witness: position statement from the British Society of Paediatric Radiology (BSPR) National Working Group on Imaging in Suspected Physical Abuse (SPA).

One of the most challenging areas of radiological imaging in children is the diagnosis of physical abuse. There is a dearth of paediatric radiologists willing to act as expert witnesses, particularly in the family courts. There are a number of reasons why radiologists may not be interested or willing to put themselves forward to work as expert witnesses in this field. A group of imaging experts recently formed the "British Society of Paediatric Radiology (BSPR) Working Group on Imaging in Suspected Physical Abuse (SPA)". The group comprises radiologists and neuroradiologists with current or previous experience of providing expert witness reports to the court in cases of SPA. The group met in January 2019 to explore pragmatic solutions to the chronic inefficiencies in both medical and legal practices and the challenges that arise from working in a legal arena with different structures, goals, and assessment criteria. Key issues concerned organisational inefficiencies, variable support from National Health Service Trusts and the Royal College of Radiologists to conduct this work, and the risk/benefit of involvement. This work is important for the patient, parents, and society in general, and highly rewarding for clinical practitioners who are involved, but there are several issues with current practices that discourage active participation. With several members of the group either retired or close to retirement, the shortage of experts is becoming a pressing issue within the UK, which requires an engaged multidisciplinary group to come up with creative solutions. Here, the group provide a consensus opinion highlighting the current barriers and potential facilitators to increasing the number of radiologists willing to provide opinions to the court.

Burkholderia cepacia Complex Contact-Dependent Growth Inhibition Systems Mediate Interbacterial Competition.

Burkholderia species, including opportunistic pathogens in the Burkholderia cepacia complex (Bcc), have genes to produce contact-dependent growth inhibition (CDI) system proteins. CDI is a phenomenon in which Gram-negative bacteria use the toxic C terminus of a polymorphic surface-exposed exoprotein, BcpA, to inhibit the growth of susceptible bacteria upon direct cell-cell contact. Production of a small immunity protein, BcpI, prevents autoinhibition. Although CDI systems appear widespread in Gram-negative bacteria, their function has been primarily examined in several model species. Here we demonstrate that genes encoding predicted CDI systems in Bcc species exhibit considerable diversity. We also show that Burkholderia multivorans, which causes pulmonary infections in patients with cystic fibrosis, expresses genes that encode two CDI systems, both of which appear distinct from the typical Burkholderia-type CDI system. Each system can mediate intrastrain interbacterial competition and contributes to bacterial adherence. Surprisingly, the immunity-protein-encoding bcpI gene of CDI system 1 could be mutated without obvious deleterious effects. We also show that nonpathogenic Burkholderia thailandensis uses CDI to control B. multivorans growth during coculture, providing one of the first examples of interspecies CDI and suggesting that CDI systems could be manipulated to develop therapeutic strategies targeting Bcc pathogens.IMPORTANCE Competition among bacteria affects microbial colonization of environmental niches and host organisms, particularly during polymicrobial infections. The Bcc is a group of environmental bacteria that can cause life-threatening opportunistic infections in patients who have cystic fibrosis or are immunocompromised. Understanding the mechanisms used by these bacterial pathogens to compete with one another may lead to the development of more effective therapies. Findings presented here demonstrate that a Bcc species, Burkholderia multivorans, produces functional CDI system proteins and that growth of this pathogen can be controlled by CDI system proteins produced by neighboring Burkholderia cells.

Pseudodacryocystitis: paediatric case series of infected atypical ethmoid air cells masquerading as recurrent dacryocystitis.

PurposeTo highlight the clinical and surgical considerations in treating patients with apparent recurrent acute dacryocystitis with a patent lacrimal system.MethodsThree children referred to a tertiary unit as recurrent acute dacryocystitis were reviewed retrospectively. Imaging and subsequent surgical intervention revealed the underlying diagnosis.ResultsAll three cases presented with recurrent abscesses in the region of the lacrimal sac that failed to respond to incision and drainage. The lesions were lower and more lateral to the usual location of a sac abscess and closer to the inferior orbital rim. All three cases were found to have patent lacrimal systems on syringing, and all were found to have infected, low-lying, anteriorly placed aberrant ethmoid air cells on computed tomography and magnetic resonance imaging. These were confirmed on subsequent surgical exploration.ConclusionsInfected low-lying ethmoid air cells can mimic dacryocystitis with recurrent abcesses. In cases where a patent nasolacrimal system is demonstrated and a more inferolateral location of the swelling than would be expected in dacryocystitis is seen, imaging is warranted to ensure the appropriate intervention is undertaken. Anterior ethmoidectomy as opposed to dacryocystorhinostomy is the appropriate treatment in these cases.

The effect of light touch on balance control during overground walking in healthy young adults.

Balance control is essential for safe walking. Adding haptic input through light touch may improve walking balance; however, evidence is limited. This research investigated the effect of added haptic input through light touch in healthy young adults during challenging walking conditions. Sixteen individuals walked normally, in tandem, and on a compliant, low-lying balance beam with and without light touch on a railing. Three-dimensional kinematic data were captured to compute stride velocity (m/s), relative time spent in double support (%DS), a medial-lateral margin of stability (MOSML) and its variance (MOSMLCV), as well as a symmetry index (SI) for the MOSML. Muscle activity was evaluated by integrating electromyography signals for the soleus, tibialis anterior, and gluteus medius muscles bilaterally. Adding haptic input decreased stride velocity, increased the %DS, had no effect on the MOSML magnitude, decreased the MOSMLCV, had no effect on the SI, and increased activity of most muscles examined during normal walking. During tandem walking, stride velocity and the MOSMLCV decreased, while %DS, MOSML magnitude, SI, and muscle activity did not change with light touch. When walking on a low-lying, compliant balance beam, light touch had no effect on walking velocity, MOSML magnitude, or muscle activity; however, the %DS increased and the MOSMLCV and SI decreased when lightly touching a railing while walking on the balance beam. The decreases in the MOSMLCV with light touch across all walking conditions suggest that adding haptic input through light touch on a railing may improve balance control during walking through reduced variability.

The potential for epigenetic analysis of paediatric CNS tumours to improve diagnosis, treatment and prognosis.

Tumours of central nervous system (CNS) origin are the second most prevalent group of cancers in children, yet account for the majority of childhood cancer-related deaths. Such tumours show diverse location, cell type of origin, disease course and long-term outcome, both across and within tumour types, making treatment problematic and contributing to the relatively modest progress in reducing mortality over recent decades. As technological advances begin to reveal the genetic landscape of all cancers, it is becoming increasingly clear that genetic disruption represents only one 'layer' of molecular disruption associated with disease aetiology. Obtaining a full understanding of tumour behaviour requires an understanding of the cellular and molecular pathways disrupted during tumourigenesis, particularly in relation to gene expression. The utility of such an approach has allowed stratification of cancers such as medulloblastoma into subgroups based on molecular features, with potential to refine risk prediction. Given that epigenetic disruption is a universal feature of all human cancers, it is logical to speculate that interrogating epigenetic marks may help to further define the molecular profile, and therefore the clinical trajectory, of tumours. An integrated approach to build a molecular 'signature' of individual tumours that incorporates traditional morphological and demographic information, genetic and transcriptome analysis, in addition to epigenomics (DNA methylation and non-coding RNA analysis), offers tremendous promise to (i) inform treatment approach, (ii) facilitate accurate early identification (preferably at diagnosis) of variable risk groups (both good and poor prognosis groups), and (iii) track disease progression in childhood CNS tumours.

Adaptation of gait termination on a slippery surface in Parkinson's disease.

Parkinson's disease (PD) causes instability and difficulty adapting to changing environmental and task demands. We examined the effects of PD on the adaptation of gait termination (GT) on a slippery surface under unexpected and cued circumstances. An unexpected slip perturbation during GT was followed by a slip perturbation during GT under two conditions: planned over multiple steps and cued one step prior to GT. Feed forward and feedback-based responses to the perturbation were compared to determine (1) how PD affects the ability to integrate adaptive feed forward and feedback-based GT strategies on a slippery surface, (2) if adaptations can be implemented when GT is required within one step, and (3) if behaviour changes with repeated exposure. Similar to the control group (n=10), the PD group (n=8) adapted and integrated feed forward and feedback-based components of GT under both stop conditions. Feed forward adaptations included a shorter, wider step, and appropriate stability margin modifications. Feedback-based adaptations included a longer, wider subsequent step. When cued to stop quickly, both groups maintained most of these adaptations: foot angle at contact increased in the first cued stop but adapted with practice. The group with PD differed in their ability to adapt GT with slower, wider steps and less stability.