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Objectives: To assess the diagnostic accuracy of nerve thickening on MRI to predict early-stage postlaminar optic nerve invasion (PLONI) in retinoblastoma. Furthermore, this study aimed to incorporate measurements into a multiparametric model for radiological determination of PLONI., Methods: In this retrospective multicenter case-control study, high-spatial-resolution 3D T2-weighted MR images were used to measure the distal optic nerve. Histopathology was the reference standard for PLONI. Two neuroradiologists independently measured the optic nerve width, height, and surface at 0, 3, and 5 mm from the most distal part of the optic nerve. Subsequently, PLONI was scored on contrast-enhanced T1-weighted and 3D T2-weighted images, blinded for clinical data. Optic nerve measurements with the highest diagnostic accuracy for PLONI were incorporated into a prediction model for radiological determination of PLONI., Results: One hundred twenty-four retinoblastoma patients (median age, 22 months [range, 0-113], 58 female) were included, resulting in 25 retinoblastoma eyes with histopathologically proven PLONI and 206 without PLONI. ROC analysis of axial optic nerve width measured at 0 mm yielded the best area under the curve of 0.88 (95% confidence interval: 0.79, 0.96; p < 0.001). The optimal width cutoff was ≥ 2.215 mm, with a sensitivity of 84% (95% CI: 64, 95%) and specificity of 83% (95% CI: 75, 89%) for detecting PLONI. Combining width measurements with the suspicion of PLONI on MRI sequences resulted in a prediction model with an improved sensitivity and specificity of respectively up to 88% and 92%., Conclusion: Postlaminar optic nerve thickening can predict early-stage postlaminar optic nerve invasion in retinoblastoma., Clinical Relevance Statement: This study provides an additional tool for clinicians to help determine postlaminar optic nerve invasion, which is a risk factor for developing metastatic disease in retinoblastoma patients., Key Points: • The diagnostic accuracy of contrast-enhanced MRI for detecting postlaminar optic nerve invasion is limited in retinoblastoma patients. • Optic nerve thickening can predict postlaminar optic nerve invasion. • A prediction model combining MRI features has a high sensitivity and specificity for detecting postlaminar optic nerve invasion., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

With the aim of describing the activities of nurses in mobile home palliative care teams in the Brussels Region, the study Nursing practices in palliative care in Brussels outpatient mobile teams took the cultural intermediary model as its theoretical framework. This model is based on in-depth research into the history of the nursing discipline. This article provides an overview of this European conceptual model, its integration into a descriptive study, and highlights some of its contributions., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

This retrospective multicenter study examines therapy-induced orbital and ocular MRI findings in retinoblastoma patients following selective intra-arterial chemotherapy (SIAC) and quantifies the impact of SIAC on ocular and optic nerve growth. Patients were selected based on medical chart review, with inclusion criteria requiring the availability of posttreatment MR imaging encompassing T2-weighted and T1-weighted images (pre- and post-intravenous gadolinium administration). Qualitative features and quantitative measurements were independently scored by experienced radiologists, with deep learning segmentation aiding total eye volume assessment. Eyes were categorized into three groups: eyes receiving SIAC (Rb-SIAC), eyes treated with other eye-saving methods (Rb-control), and healthy eyes. The most prevalent adverse effects post-SIAC were inflammatory and vascular features, with therapy-induced contrast enhancement observed in the intraorbital optic nerve segment in 6% of patients. Quantitative analysis revealed significant growth arrest in Rb-SIAC eyes, particularly when treatment commenced ≤ 12 months of age. Optic nerve atrophy was a significant complication in Rb-SIAC eyes. In conclusion, this study highlights the vascular and inflammatory adverse effects observed post-SIAC in retinoblastoma patients and demonstrates a negative impact on eye and optic nerve growth, particularly in children treated ≤ 12 months of age, providing crucial insights for clinical management and future research.

Background MYCN -amplified RB1 wild-type ( MYCN A RB1 +/+ ) retinoblastoma is a rare but clinically important subtype of retinoblastoma due to its aggressive character and relative resistance to typical therapeutic approaches. Because biopsy is not indicated in retinoblastoma, specific MRI features might be valuable to identify children with this genetic subtype. Purpose To define the MRI phenotype of MYCN A RB1 +/+ retinoblastoma and evaluate the ability of qualitative MRI features to help identify this specific genetic subtype. Materials and Methods In this retrospective, multicenter, case-control study, MRI scans in children with MYCN A RB1 +/+ retinoblastoma and age-matched children with RB1 -/- subtype retinoblastoma were included (case-control ratio, 1:4; scans acquired from June 2001 to February 2021; scans collected from May 2018 to October 2021). Patients with histopathologically confirmed unilateral retinoblastoma, genetic testing ( RB1/MYCN status), and MRI scans were included. Associations between radiologist-scored imaging features and diagnosis were assessed with the Fisher exact test or Fisher-Freeman-Halton test, and Bonferroni-corrected P values were calculated. Results A total of 110 patients from 10 retinoblastoma referral centers were included: 22 children with MYCN A RB1 +/+ retinoblastoma and 88 control children with RB1 -/- retinoblastoma. Children in the MYCN A RB1 +/+ group had a median age of 7.0 months (IQR, 5.0-9.0 months) (13 boys), while children in the RB1 -/- group had a median age of 9.0 months (IQR, 4.6-13.4 months) (46 boys). MYCN A RB1 +/+ retinoblastomas were typically peripherally located (in 10 of 17 children; specificity, 97%; P < .001) and exhibited plaque or pleomorphic shape (in 20 of 22 children; specificity, 51%; P = .011) with irregular margins (in 16 of 22 children; specificity, 70%; P = .008) and extensive retina folding with vitreous enclosure (specificity, 94%; P < .001). MYCN A RB1 +/+ retinoblastomas showed peritumoral hemorrhage (in 17 of 21 children; specificity, 88%; P < .001), subretinal hemorrhage with a fluid-fluid level (in eight of 22 children; specificity, 95%; P = .005), and strong anterior chamber enhancement (in 13 of 21 children; specificity, 80%; P = .008). Conclusion MYCN A RB1 +/+ retinoblastomas show distinct MRI features that could enable early identification of these tumors. This may improve patient selection for tailored treatment in the future. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Rollins in this issue.

Purpose: Pathological conditions associated with the optic nerve (ON) can cause structural changes in the nerve. Quantifying these changes could provide further understanding of disease mechanisms. We aim to develop a framework that automatically segments the ON separately from its surrounding cerebrospinal fluid (CSF) on magnetic resonance imaging (MRI) and quantifies the diameter and cross-sectional area along the entire length of the nerve., Approach: Multicenter data were obtained from retinoblastoma referral centers, providing a heterogeneous dataset of 40 high-resolution 3D T2-weighted MRI scans with manual ground truth delineations of both ONs. A 3D U-Net was used for ON segmentation, and performance was assessed in a tenfold cross-validation ( n = 32 ) and on a separate test-set ( n = 8 ) by measuring spatial, volumetric, and distance agreement with manual ground truths. Segmentations were used to quantify diameter and cross-sectional area along the length of the ON, using centerline extraction of tubular 3D surface models. Absolute agreement between automated and manual measurements was assessed by the intraclass correlation coefficient (ICC)., Results: The segmentation network achieved high performance, with a mean Dice similarity coefficient score of 0.84, median Hausdorff distance of 0.64 mm, and ICC of 0.95 on the test-set. The quantification method obtained acceptable correspondence to manual reference measurements with mean ICC values of 0.76 for the diameter and 0.71 for the cross-sectional area. Compared with other methods, our method precisely identifies the ON from surrounding CSF and accurately estimates its diameter along the nerve's centerline., Conclusions: Our automated framework provides an objective method for ON assessment in vivo ., (© 2023 The Authors.)

In Belgium, continuous sedation in palliative care is considered a symptomatic treatment. There is no specific legislation to govern it. Its proper use is based on a set of recommendations that ensure both effective treatment and respect for the patient's preferences, within a rigorous ethical framework., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Developmental gene expression is often controlled by distal regulatory DNA elements called enhancers. Distant enhancer action is restricted to structural chromosomal domains that are flanked by CTCF-associated boundaries and formed through cohesin chromatin loop extrusion. To better understand how enhancers, genes and CTCF boundaries together form structural domains and control expression, we used a bottom-up approach, building series of active regulatory landscapes in inactive chromatin. We demonstrate here that gene transcription levels and activity over time reduce with increased enhancer distance. The enhancer recruits cohesin to stimulate domain formation and engage flanking CTCF sites in loop formation. It requires cohesin exclusively for the activation of distant genes, not of proximal genes, with nearby CTCF boundaries supporting efficient long-range enhancer action. Our work supports a dual activity model for enhancers: its classic role of stimulating transcription initiation and elongation from target gene promoters and a role of recruiting cohesin for the creation of chromosomal domains, the engagement of CTCF sites in chromatin looping and the activation of distal target genes., (© 2022. The Author(s).)

Background: This systematic review and meta-analysis sought to assess the extent to which pretreatment depression or depressive symptoms are related to prognosis in patients with head and neck cancer (HNC)., Methods: Medline, EMbase, Scopus, and The Cochrane Library databases were searched. A meta-analysis was done to generate a forest plot and pooled hazard ratio (HR) with 95% CI for overall survival (OS). RevMan 5.3 and Meta Essentials were used for statistical analysis., Results: Based on seven studies involving 1743 patients, the results showed that HNC patients with pretreatment depression or depressive symptoms had worse OS than patients without depression or depressive symptoms, with an HR of 1.33, 95% CI 1.16-1.52, p = <0.0001. There is heterogeneity in the pooled summary effect (I 2  = 80%, p < 0.0001)., Conclusions: Pretreatment depression or depressive symptoms may indicate worse OS in patients with HNC. The pooled analysis demonstrated a statistically significant effect. These results were limited by mild heterogeneity., (© 2021 Wiley Periodicals LLC.)

Colorectal cancer stem cells (CSCs) express Lgr5 and display extensive stem cell-like multipotency and self-renewal and are thought to seed metastatic disease. Here, we used a mouse model of colorectal cancer (CRC) and human tumor xenografts to investigate the cell of origin of metastases. We found that most disseminated CRC cells in circulation were Lgr5 - and formed distant metastases in which Lgr5 + CSCs appeared. This plasticity occurred independently of stemness-inducing microenvironmental factors and was indispensable for outgrowth, but not establishment, of metastases. Together, these findings show that most colorectal cancer metastases are seeded by Lgr5 - cells, which display intrinsic capacity to become CSCs in a niche-independent manner and can restore epithelial hierarchies in metastatic tumors., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Various species of the intestinal microbiota have been associated with the development of colorectal cancer 1,2 , but it has not been demonstrated that bacteria have a direct role in the occurrence of oncogenic mutations. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin 3 . This compound is believed to alkylate DNA on adenine residues 4,5 and induces double-strand breaks in cultured cells 3 . Here we expose human intestinal organoids to genotoxic pks + E. coli by repeated luminal injection over five months. Whole-genome sequencing of clonal organoids before and after this exposure revealed a distinct mutational signature that was absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature was detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in colorectal cancer. Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.

The significance of cardiac stem cell (CSC) populations for cardiac regeneration remains disputed. Here, we apply the most direct definition of stem cell function (the ability to replace lost tissue through cell division) to interrogate the existence of CSCs. By single-cell mRNA sequencing and genetic lineage tracing using two Ki67 knockin mouse models, we map all proliferating cells and their progeny in homoeostatic and regenerating murine hearts. Cycling cardiomyocytes were only robustly observed in the early postnatal growth phase, while cycling cells in homoeostatic and damaged adult myocardium represented various noncardiomyocyte cell types. Proliferative postdamage fibroblasts expressing follistatin-like protein 1 (FSTL1) closely resemble neonatal cardiac fibroblasts and form the fibrotic scar. Genetic deletion of Fstl1 in cardiac fibroblasts results in postdamage cardiac rupture. We find no evidence for the existence of a quiescent CSC population, for transdifferentiation of other cell types toward cardiomyocytes, or for proliferation of significant numbers of cardiomyocytes in response to cardiac injury., Competing Interests: Conflict of interest statement: H.C. is co-principal investigator (co-PI) on a Dutch grant on organs-on-a-chip with C.L.M. as co-PI, however, on an unrelated topic., (Copyright © 2018 the Author(s). Published by PNAS.)

Background: Genome-wide transcriptome analysis has greatly advanced our understanding of the regulatory networks underlying basic cardiac biology and mechanisms driving disease. However, so far, the resolution of studying gene expression patterns in the adult heart has been limited to the level of extracts from whole tissues. The use of tissue homogenates inherently causes the loss of any information on cellular origin or cell type-specific changes in gene expression. Recent developments in RNA amplification strategies provide a unique opportunity to use small amounts of input RNA for genome-wide sequencing of single cells., Methods: Here, we present a method to obtain high-quality RNA from digested cardiac tissue from adult mice for automated single-cell sequencing of both the healthy and diseased heart., Results: After optimization, we were able to perform single-cell sequencing on adult cardiac tissue under both homeostatic conditions and after ischemic injury. Clustering analysis based on differential gene expression unveiled known and novel markers of all main cardiac cell types. Based on differential gene expression, we could identify multiple subpopulations within a certain cell type. Furthermore, applying single-cell sequencing on both the healthy and injured heart indicated the presence of disease-specific cell subpopulations. As such, we identified cytoskeleton-associated protein 4 as a novel marker for activated fibroblasts that positively correlates with known myofibroblast markers in both mouse and human cardiac tissue. Cytoskeleton-associated protein 4 inhibition in activated fibroblasts treated with transforming growth factor β triggered a greater increase in the expression of genes related to activated fibroblasts compared with control, suggesting a role of cytoskeleton-associated protein 4 in modulating fibroblast activation in the injured heart., Conclusions: Single-cell sequencing on both the healthy and diseased adult heart allows us to study transcriptomic differences between cardiac cells, as well as cell type-specific changes in gene expression during cardiac disease. This new approach provides a wealth of novel insights into molecular changes that underlie the cellular processes relevant for cardiac biology and pathophysiology. Applying this technology could lead to the discovery of new therapeutic targets relevant for heart disease., (© 2018 American Heart Association, Inc.)

Nursing practice is founded on numerous theories. While life sciences use evidence to design the most effective practices from a biomedical point of view, human sciences sometimes struggle to corroborate the perception of patients as caregivers in their humanised practice. This article presents a perspective of care in a resolutely human dimension, where the main objective is to be of use to the person., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The regeneration-capable flatworm Macrostomum lignano is a powerful model organism to study the biology of stem cells in vivo. As a flatworm amenable to transgenesis, it complements the historically used planarian flatworm models, such as Schmidtea mediterranea . However, information on the transcriptome and markers of stem cells in M. lignano is limited. We generated a de novo transcriptome assembly and performed the first comprehensive characterization of gene expression in the proliferating cells of M. lignano , represented by somatic stem cells, called neoblasts, and germline cells. Knockdown of a selected set of neoblast genes, including Mlig-ddx39 , Mlig-rrm1 , Mlig-rpa3 , Mlig-cdk1 , and Mlig-h2a , confirmed their crucial role for the functionality of somatic neoblasts during homeostasis and regeneration. The generated M. lignano transcriptome assembly and gene expression signatures of somatic neoblasts and germline cells will be a valuable resource for future molecular studies in M. lignano ., Competing Interests: The authors declare that no competing interests exist.

Cycling Lgr5+ stem cells fuel the rapid turnover of the adult intestinal epithelium. The existence of quiescent Lgr5+ cells has been reported, while an alternative quiescent stem cell population is believed to reside at crypt position +4. Here, we generated a novel Ki67RFP knock-in allele that identifies dividing cells. Using Lgr5-GFP;Ki67RFP mice, we isolated crypt stem and progenitor cells with distinct Wnt signaling levels and cell cycle features and generated their molecular signature using microarrays. Stem cell potential of these populations was further characterized using the intestinal organoid culture. We found that Lgr5high stem cells are continuously in cell cycle, while a fraction of Lgr5low progenitors that reside predominantly at +4 position exit the cell cycle. Unlike fast dividing CBCs, Lgr5low Ki67- cells have lost their ability to initiate organoid cultures, are enriched in secretory differentiation factors, and resemble the Dll1 secretory precursors and the label-retaining cells of Winton and colleagues. Our findings support the cycling stem cell hypothesis and highlight the cell cycle heterogeneity of early progenitors during lineage commitment., (© 2014 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Objectives: With the aging of HIV populations, vascular contributions to neuropathogenesis are increasingly important. Indirect analyses of cerebral small vessel disease have been performed, but there have been no direct studies of human brain to elucidate risk factors for arteriolar sclerosis., Methods: Mean arteriolar wall thickness (sclerotic index, SI) was measured in the deep cerebral white matter of 126 brains (96 HIV+, 30 HIV-). Correlations with SI were performed for age, sex, race, hypertension, hyperlipidemia, diabetes, obesity, cirrhosis, hepatitis C virus (HCV) infection, herpes infection, HIV infection, HIV risk, cocaine use, CD4 count, plasma HIV load, and combination antiretroviral therapy (cART) at the time of death., Results: Age, hypertension, race, HCV, and cirrhosis were associated with SI; of the HIV variables, only cART at death was associated with SI. To address colinearity, partial correlations were run with HCV and cirrhosis, hypertension and race, and hypertension and age. With HCV controlled, cirrhosis lost significance; with hypertension controlled, age lost significance. For the entire sample, HCV, African American race, and hypertension accounted for 15% of SI variance in multivariate analysis. Each was independently associated with SI, and HCV had the largest effect. For the HIV sample, inclusion of cART in the model increased R (2) to 0.205, with only HCV, hypertension, and cART remaining significant or trend level., Conclusions: This tissue-based analysis of cerebral arteriolar disease demonstrates that HCV constitutes an independent risk, in addition to African American race, hypertension, and cART. Further study is needed to understand what aspects of HCV and cART contribute to cerebrovascular neuropathogenesis.

Objective: Loci on mouse chromosome 2 have previously been associated with ethanol consumption. Here, we used a limited access choice paradigm in which mice consume large quantities of ethanol (2-3 g/kg/2 h) with a high preference (>80%). In addition, mouse chromosome substitution strains were used to further evaluate the contribution of chromosome 2 to ethanol consumption., Methods and Results: First, we compared the two parental inbred mouse strains, C57BL/6J and A/J, in the limited access choice paradigm for ethanol intake and ethanol preference, as well as for ethanol metabolism and taste sensitivity. Then, the effect of chromosome 2 substitution on these measures was determined. Compared with C57BL/6J mice, A/J and C57BL/6J-Chr 2/NaJ (CSS-2) mice showed profoundly reduced ethanol intake and preference. The strains were not different with regard to ethanol metabolism or taste sensitivity. Limited access ethanol consumption in F2 progeny derived from reciprocal C57BL/6J xCSS-2 and CSS-2 xC57BL/6J intercrosses and subsequent quantitative trait loci mapping identified two loci: one locus on chromosome 2 for ethanol intake and a separate locus on distal chromosome 2 for ethanol preference. This latter locus was dependent on the grandparental origin., Conclusion: Using a limited access choice paradigm, we found that mouse chromosome 2 carries an allelic variant of a locus for ethanol intake and a distinct locus selective for ethanol preference. The heritability of alcoholism has been suggested to be parent-specific, perhaps resulting from genetic imprinting. Our findings suggest that grandparent-influenced vulnerability for ethanol consumption is conferred by genes on chromosome 2, providing important new leads to enhance our understanding of the heritability of alcoholism.