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A child’s ability to participate in active school travel (AST) is complicated by several factors. Of particular note are parental controls, which are informed by their perceptions of the local built and social environments, assessments of their child’s skills, and convenience preferences, among other considerations. However, there is currently a lack of AST-specific scales that include validated parental perception measures related to such notable barriers and enablers, or those that tend to frame their AST decision-making processes. Framed within the social-ecological model of health behaviour, the aims of the present paper were thus threefold, specifically to (1) outline and test the construct validity of measures delineating parental perceptions of barriers and enablers to AST, (2) evaluate the reliability and consistency of the developed measures, and (3) connect these measures to develop broader constructs for use in the Perceived Active School Travel Enablers and Barriers–Parent (PASTEB–P) questionnaire. To achieve these aims, a mixed-methods approach featuring cognitive interviews and surveys, along with qualitative (thematic analysis) and quantitative (Cohen’s Kappa, McDonald’s Omega, and confirmatory factor analysis) analyses, was applied across two studies. The validation processes of the two studies resulted in the development of fifteen items comprising seven distinct constructs (barriers: AST Skills, Convenience, Road Safety, Social Safety, and Equipment Storage; enablers: Supportive Environment and Safe Environment) related to parental perceptions of AST. The developed PASTEB–P questionnaire can be used to inform and evaluate AST intervention programming and can be applied for AST research purposes.

Tissue expression datasets

File contains Supplementary Methods

Supplementary Figure 3 Evaluation of DLL3 expression in tumor types other than SCLC.

Supplementary Figure 6 A, Expression of human CD25, CD69, PD-1, and 4-1BB on human CD4+ T cells isolated from mouse lungs harboring SHP-77 tumors 168 hours after treatment with AMG 757 or a control HLE BiTE® molecule. B, Expression of human CD25, CD69, PD-1, and 4-1BB on human CD8+ T cells isolated from mouse lungs harboring SHP-77 tumors 168 hours after treatment with either AMG 757 or a control HLE BiTE® molecule. *P < 0.05; **P < 0.01; *** P< 0.001

Purpose:Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a high relapse rate, limited therapeutic options, and poor prognosis. We investigated the antitumor activity of AMG 757, a half-life extended bispecific T-cell engager molecule targeting delta-like ligand 3 (DLL3)—a target that is selectively expressed in SCLC tumors, but with minimal normal tissue expression.Experimental Design:AMG 757 efficacy was evaluated in SCLC cell lines and in orthotopic and patient-derived xenograft (PDX) mouse SCLC models. Following AMG 757 administration, changes in tumor volume, pharmacodynamic changes in tumor-infiltrating T cells (TILs), and the spatial relationship between the appearance of TILs and tumor histology were examined. Tolerability was assessed in nonhuman primates (NHPs).Results:AMG 757 showed potent and specific killing of even those SCLC cell lines with very low DLL3 expression (Conclusions:AMG 757 has a compelling safety and efficacy profile in preclinical studies making it a viable option for targeting DLL3-expressing SCLC tumors in the clinical setting.

This file contains Supplementary Tables 1-5

Supplementary Figure 1 DLL3 is differentially expressed in SCLC tumors and cell lines compared with normal tissues.

Supplementary Figure 2 Representative photomicrographs of DLL3 immunostaining (brown color) in normal human tissues using immunohistochemistry.

Supplementary Figure 5 A, DLL3 RNA expression levels in a panel of SCLC patient-derived xenograft (PDX) models compared with positive (NCI-H82) and negative (NCI-H460) control SCLC cell lines. Data are reported as relative quantification normalized to NCI-H460 cell line expression. B, DLL3 protein expression levels in a panel of SCLC PDX models compared with positive (NCI-H82) and negative (NCI-H460) control SCLC cell lines. GAPDH, glyceraldehyde 3-phosphate dehydrogenase.

Supplementary FIgure 4 AMG 757 demonstrated antitumor activity in the WM266-4 melanoma xenograft model.

Background: Malaria impacts >24 million children globally, resulting in >300,000 child deaths annually in low- and middle-income countries (LMICs). Little is known about the association between malarial infection and its impact on cognition and behavior. Our objective was to determine the association between different types of malaria infection with cognitive and behavioral outcomes among children living in LMICs.Methods: We systematically searched and reviewed the literature using six online bibliographic databases on 2/10/2022. Studies included involved children

Gastric cancer; Metastasectomy; Oligometastasis Cáncer gástrico; Metastasectomía; Oligometástasis Càncer gàstric; Metastasectomia; Oligometàstasi Background Local treatment improves the outcomes for oligometastatic disease (OMD, i.e. an intermediate state between locoregional and widespread disseminated disease). However, consensus about the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer is lacking. The aim of this study was to develop a multidisciplinary European consensus statement on the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer. Methods In total, 65 specialists in the multidisciplinary treatment for oesophagogastric cancer from 49 expert centres across 16 European countries were requested to participate in this Delphi study. The consensus finding process consisted of a starting meeting, 2 online Delphi questionnaire rounds and an online consensus meeting. Input for Delphi questionnaires consisted of (1) a systematic review on definitions of oligometastatic oesophagogastric cancer and (2) a discussion of real-life clinical cases by multidisciplinary teams. Experts were asked to score each statement on a 5-point Likert scale. The agreement was scored to be either absent/poor (2 years, either upfront local treatment or systemic treatment followed by restaging was considered as treatment (fair agreement). Conclusion The OMEC project has resulted in a multidisciplinary European consensus statement for the definition, diagnosis and treatment of oligometastatic oesophagogastric adenocarcinoma and squamous cell cancer. This can be used to standardise inclusion criteria for future clinical trials.

Stress‐induced apoptosis is mediated primarily through the intrinsic pathway that involves caspase‐9. We previously reported that in caspase‐9‐deficient cells, a protein complex containing ATG5 and Fas‐associated death domain (FADD) facilitated caspase‐8 activation and cell death in response to endoplasmic reticulum (ER) stress. Here, we investigated whether this complex could be activated by other forms of cell stress. We show that diverse stress stimuli, including etoposide, brefeldin A and paclitaxel, as well as heat stress and gamma‐irradiation, caused formation of a complex containing ATG5‐ATG12, FADD and caspase‐8 leading to activation of downstream caspases in caspase‐9‐deficient cells. We termed this complex the ‘stressosome’. However, in these cells, only ER stress and heat shock led to stressosome‐dependent cell death. Using in silico molecular modelling, we propose the structure of the stressosome complex, with FADD acting as an adaptor protein, interacting with pro‐caspase‐8 through their respective death effector domains (DEDs) and interacting with ATG5‐ATG12 through its death domain (DD). This suggests that the complex could be regulated by cellular FADD‐like interleukin‐1β‐converting enzyme–inhibitory protein (cFLIPL), which was confirmed experimentally. This study provides strong evidence for an alternative mechanism of caspase‐8 activation involving the stressosome complex.

Before the arrival of white-nose syndrome in North America, the northern long-eared bat (Myotis septentrionalis) was a common cavity-roosting bat species in central Appalachian hardwood forests. Two successive prescribed burns on the Fernow Experimental Forest, West Virginia, in 2008 and 2009, were shown to positively affect maternity colony day-roost availability and condition in the near-term. However, whether immediate benefits were temporary and if burned forests actually experienced an accelerated loss of trees and snags possibly suitable for bats more than background loss in unburned forests became an important question following the species’ threatened designation. In 2016, we revisited 81 of 113 northern long-eared bat maternity colony day-roosts initially discovered in 2007–2009 with the objective of ascertaining if these trees and snags were still standing and thus potentially “available” for bat use. Initial tree or snag stage condition class and original year of discovery were contributory factors determining availability by 2016, whereas exposure to prescribed fire and tree/snag species decay resistance were not. Because forest managers may consider using habitat enhancement to improve northern long-eared bat survival, reproduction, and juvenile recruitment and must also protect documented day-roosts during forestry operations, we conclude that initial positive benefits from prescribed burning did not come at the expense of subsequent day-roost loss greater than background rates in these forests at least for the duration we examined.

This in-process project report describes a critical youth-led participatory heritage project that seeks to document, preserve, and make digitally accessible oral histories, archives, and artifacts of an urban, predominantly African American high school with a rich history and legacy. As a long-standing community institution, the narratives emerging from this high school are intricately connected with the larger story of the city of Philadelphia. This article uses an equity-based lens to demonstrate how youth-led participatory heritage can contribute to youth empowerment, critical consciousness development, and critical digital literacies. Implications for schools and communities experiencing gentrification, displacement, and community change are provided, including how participatory heritage with youth can utilize collaborative, asset-based efforts to foster change that allows youth and communities to have agency over their individual and collective stories, community history and legacy, and their futures.

PURPOSE: To define instructions for delineation of target volumes in the neoadjuvant setting in oesophageal cancer. MATERIALS AND METHODS: Radiation oncologists of five European centres participated in the following consensus process: [1] revision of published (MEDLINE) and national/institutional delineation guidelines; [2] first delineation round of five cases (patient 1-5) according to national/institutional guidelines; [3] consensus meeting to discuss the results of step 1 and 2, followed by a target volume delineation proposal; [4] circulation of proposed instructions for target volume delineation and atlas for feedback; [5] second delineation round of five new cases (patient 6-10) to peer review and validate (two additional centres) the agreed delineation guidelines and atlas; [6] final consensus on the delineation guidelines depicted in an atlas. Target volumes of the delineation rounds were compared between centres by Dice similarity coefficient (DSC) and maximum/mean undirected Hausdorff distances (Hmax/Hmean). RESULTS: In the first delineation round, the consistency between centres was moderate (CTVtotal: DSC = 0.59-0.88; Hmean = 0.2-0.4 cm). Delineations in the second round were much more consistent. Lowest variability was obtained between centres participating in the consensus meeting (CTVtotal: DSC: p

Purpose: Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a high relapse rate, limited therapeutic options, and poor prognosis. We investigated the antitumor activity of AMG 757, a half-life extended bispecific T-cell engager molecule targeting delta-like ligand 3 (DLL3)—a target that is selectively expressed in SCLC tumors, but with minimal normal tissue expression. Experimental Design: AMG 757 efficacy was evaluated in SCLC cell lines and in orthotopic and patient-derived xenograft (PDX) mouse SCLC models. Following AMG 757 administration, changes in tumor volume, pharmacodynamic changes in tumor-infiltrating T cells (TILs), and the spatial relationship between the appearance of TILs and tumor histology were examined. Tolerability was assessed in nonhuman primates (NHPs). Results: AMG 757 showed potent and specific killing of even those SCLC cell lines with very low DLL3 expression ( Conclusions: AMG 757 has a compelling safety and efficacy profile in preclinical studies making it a viable option for targeting DLL3-expressing SCLC tumors in the clinical setting.

Highlights • Implantation of solid gold markers safe. • Inter-fractional motion for markers in distal oesophagus largest cranio-caudally. • Reduced radiotherapy treatment margins with soft-tissue vs. bony-anatomy matching. • Impact of intra-fractional baseline shifts on margin calculation rather small., Purpose To prospectively evaluate the feasibility of solid gold marker placement in oesophageal cancer patients and to quantify inter-fractional and intra-fractional (baseline shift) marker motion during radiation treatment. Radiotherapy target margins and matching strategies were investigated. Materials/methods Thirty-four markers were implanted by echo-endoscopy in 10 patients. Patients received a planning 4D CT, daily pre-treatment cone-beam CT (CBCT) and a post-treatment CBCT for at least five fractions. For fractions with both pre- and post-treatment CBCT, marker displacement between planning CT and pre-treatment CBCT (inter-fractional) and between pre-treatment and post-treatment CBCT (intra-fractional; only for fractions without rotational treatment couch correction) were calculated in left–right (LR), cranio-caudal (CC) and anterior-posterior (AP) direction after bony-anatomy and soft-tissue matching. Systematic/random setup errors were estimated; treatment margins were calculated. Results No serious adverse events occurred. Twenty-three (67.6%) markers were visible during radiotherapy (n = 3 middle oesophagus, n = 16 distal oesophagus, n = 4 proximal stomach). Margins for inter-fractional displacement after bony-anatomy match depended on the localisation of the primary tumour and were 11.2 mm (LR), 16.4 mm (CC) and 8.2 mm (AP) for distal markers. Soft-tissue matching reduced the CC margin for these markers (16.4 mm to 10.5 mm). The mean intra-fractional shift of 12 distal markers was 0.4 mm (LR), 2.3 mm (CC) and 0.7 mm (AP). Inclusion of this shift resulted in treatment margins for distal markers of 12.8 mm (LR), 17.3 mm (CC) and 10.4 mm (AP) after bony-anatomy matching and 12.4 mm (LR), 11.4 mm (CC) and 9.7 mm (AP) after soft-tissue matching. Conclusion This study demonstrated that the implantation of gold markers was safe, albeit less stable compared to other marker types. Inter-fractional motion was largest cranio-caudally for markers in the distal oesophagus, which was reduced after soft-tissue compared to bony-anatomy matching. The impact of intra-fractional baseline shifts on margin calculation was rather small.

BACKGROUND Minocycline blocks microglial TNF signaling and downstream NF-κB activation, which reduces the mesenchymal phenotype in preclinical models of GBM. Primary analysis of the D-TERMINED trial identified a maximal tolerated dose (MTD) of oral minocycline at 150 mg BID in combination with temozolomide and radiation. In the overall population, the secondary objective of improved PFS was not met. Here, response is further stratified by biomarkers delineating mesenchymal subtype (OLIG2, CD44), microglial activation (IBA-1), and NF-κB signaling (P-p65). METHODS Patients with newly diagnosed high-grade glioma received continuous oral minocycline during concurrent chemoradiation and adjuvant temozolomide. Twenty patients were included in the MTD efficacy population. Within this cohort, immunohistochemistry for OLIG2, CD44, IBA-1, and P-p65 was performed on nineteen patient tumor samples. For each biomarker, the mean percent positivity or number/HPF was compared between patients who exceeded or did not exceed expected PFS. Spearman correlation coefficients were also generated for pairwise comparison of these biomarkers. RESULTS In patients with high PFS, 12.7% of tumor cells were positive for OLIG-2, 36.5% for CD44, and 23.9% for P-p65, with 41.7 cells/HPF positive for IBA-1. Comparatively, in patients with low PFS, 9.4% of tumor cells were positive for OLIG-2 (p = 0.59), 34.1% for CD44 (p = 0.77), and 22.3% for P-p65 (p = 0.85), with 31.1 cells/HPF positive for IBA-1 per HPF (p = 0.38). The only biomarkers demonstrating significant relationship were P-p65 and IBA-1, with a rank correlation of 0.637 (p = 0.007). CONCLUSIONS Exploratory analysis of D-TERMINED concludes that OLIG-2, CD44, IBA-1, and P-p65 are not predictive of improved PFS within high-grade glioma patients treated with SOC and minocycline. Concurrent use of minocycline with chemoradiation is therefore not indicated in these or unselected populations. Significant correlation is seen between IBA-1 and P-p65, biomarkers of microglial activation and NF-κB signaling. SPONSORSHIP: Funding provided by the Musella Foundation and NIH grant P30CA042014.

Background and purpose: This study aims to investigate how accurate our deep learning (DL) dose prediction models for intensity modulated radiotherapy (IMRT) and pencil beam scanning (PBS) treatments, when chained with normal tissue complication probability (NTCP) models, are at identifying esophageal cancer patients who are at high risk of toxicity and should be switched to proton therapy (PT). Materials and methods: Two U-Net were created, for photon (XT) and proton (PT) plans, respectively. To estimate the dose distribution for each patient, they were trained on a database of 40 uniformly planned patients using cross validation and a circulating test set. These models were combined with a NTCP model for postoperative pulmonary complications. The NTCP model used the mean lung dose, age, histology type, and body mass index as predicting variables. The treatment choice is then done by using a ΔNTCP threshold between XT and PT plans. Patients with ΔNTCP ≥ 10% were referred to PT. Results: Our DL models succeed in predicting dose distributions with a mean error on the mean dose to the lungs (MLD) of 1.14 ± 0.93% for XT and 0.66 ± 0.48% for PT. The complete automated workflow (DL chained with NTCP) achieved 100% accuracy in patient referral. The average residual (ΔNTCP ground truth - ΔNTCP predicted) is 1.43 ± 1.49%. Conclusion: This study evaluates our DL dose prediction models in a broader patient referral context and demonstrates their ability to support clinical decisions.

While proton therapy offers an excellent dose conformity and sparing of organs at risk, this can be compromised by uncertainties, e.g. organ motion. This study aimed to investigate the influence of cardiac motion on the contoured oesophagus using electrocardiogram-triggered imaging and to assess the impact of this motion on the robustness of proton therapy plans in oesophageal cancer patients. Limited cardiac-induced motion of the oesophagus was observed with a negligible impact on the robustness of proton therapy plans. Therefore, our data suggest that cardiac motion may be safely ignored in the robust optimisation strategy for proton planning in oesophageal cancer. ispartof: PHYSICS & IMAGING IN RADIATION ONCOLOGY vol:16 pages:50-53 ispartof: location:Netherlands status: published

Purpose: To compare dose distributions and robustness in treatment plans from eight European centres in preparation for the European randomized phase-III PROTECT-trial investigating the effect of proton therapy (PT) versus photon therapy (XT) for oesophageal cancer.Materials and methods: All centres optimized one PT and one XT nominal plan using delineated 4DCT scans for four patients receiving 50.4 Gy (RBE) in 28 fractions. Target volume receiving 95% of prescribed dose (V95%(iCTVtotal)) should be >99%. Robustness towards setup, range, and respiration was evaluated. The plans were recalculated on a surveillance 4DCT (sCT) acquired at fraction ten and robustness evaluation was performed to evaluate the effect of respiration and inter-fractional anatomical changes.Results: All PT and XT plans complied with V95% (iCTVtotal) >99% for the nominal plan and V95% (iCTVtotal) >97% for all respiratory and robustness scenarios. Lung and heart dose varied considerably between centres for both modalities. The difference in mean lung dose and mean heart dose between each pair of XT and PT plans was in median [range] 4.8 Gy [1.1;7.6] and 8.4 Gy [1.9;24.5], respectively. Patients B and C showed large inter-fractional anatomical changes on sCT. For patient B, the minimum V95% (iCTVtotal) in the worst-case robustness scenario was 45% and 94% for XT and PT, respectively. For patient C, the minimum V95% (iCTVtotal) was 57% and 72% for XT and PT, respectively. Patient A and D showed minor inter-fractional changes and the minimum V95%(iCTVtotal) was >85%.Conclusion: Large variability in dose to the lungs and heart was observed for both modalities. Inter-fractional anatomical changes led to larger target dose deterioration for XT than PT plans. (C) 2022 The Author(s). Published by Elsevier B.V.

PURPOSE/OBJECTIVES: To develop normal tissue complication probability (NTCP) models for postoperative pulmonary and cardiac complications and one-year mortality after preoperative chemoradiotherapy and surgery in oesophageal cancer patients. METHODS: 691 patients from two institutions (2002-2017) were included; 134 treated with protons. Multivariable logistic regression analyses on 601 patients studied the predictive value of clinical/treatment-related (gender, age, body mass index (BMI), smoking, cardiac comorbidity, chronic obstructive pulmonary disease, histology, cT/N) and dosimetric variables (absolute/relative lung/heart volumes receiving or spared from xGy, mean doses, planning target volume) for the presence of pulmonary complications, cardiac complications and one-year mortality. Model validation was performed using a nonrandom split-sample of 90 patients. Model performance was assessed by AUC and calibration plots. RESULTS: Respectively 144/601 (24.0%) and 165/601 (27.5%) patients developed a pulmonary or cardiac complication. For pulmonary complications, an NTCP model with optimism-corrected AUC of 0.75 (95%CI = 0.73-0.76) was obtained. The model contained mean lung dose (OR = 1.15, 95%CI = 1.09-1.22, p

Prurigo nodularis is a debilitating skin condition that is classified as rare by the Genetic and Rare Diseases Information Center (GARD) and the National Organization for Rare Diseases (NORD). There are currently no estimates of the prevalence of prurigo nodularis in England.We aimed to address this data gap by describing the epidemiology of prurigo nodularis in a representative dataset derived from the English National Health Service.The study utilized data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics inpatient data. Patients with a diagnosis of prurigo nodularis were selected by clinical code in the primary care or inpatient datasets. Case definition was based on a minimum of two distinct diagnoses to maximize specificity. Point prevalence was calculated for the midpoint of 2018 and incidence rates from 2008 to 2018 were presented. For those classified as incident cases, demographic and clinical characteristics were reported. In sensitivity analyses the case definition was modified to relax the multiple diagnosis criteria and to restrict cases to those diagnosed within a maximum of 4 or 10 years of the midpoint prevalence date.Overall, 11 656 patients within the dataset had at least one prurigo nodularis diagnosis. Following application of the relevant inclusion criteria, 2743 patients formed the point prevalent cohort; the estimated prevalence was 3·27 patients per 10 000 population [95% confidence interval (CI) 3·15-3·40]. In sensitivity analyses the estimated prevalence ranged from 2·24 (95% CI 2·14-2·34) to 6·98 (95% CI 6·80-7·16). Incidence over the study period was 2·88 per 100 000 patient-years. Comorbidity was relatively high in this population, notably for atopic dermatitis (52·2%), depression (41·1%) and anxiety (35·4%).This study supports the NORD/GARD classification of prurigo nodularis as a rare disease with a prevalence of 3·27 patients per 10 000 population, which equates to 18 471 patients living with the disease in England in 2018. The relatively high prevalence of comorbidity observed for these patients may increase the complexity of management.