Visualization, Adaptation, and Transformation of Procedural Grammars

Procedural shape grammars are powerful tools for the automatic generation of highly detailed 3D content from a set of descriptive rules. It is easy to encode variations in stochastic and parametric grammars, and an uncountable number of models can be generated quickly. While shape grammars offer these advantages over manual 3D modeling, they also suffer from certain drawbacks. We present three novel methods that address some of the limitations of shape grammars. First, it is often difficult to grasp the diversity of models defined by a given grammar. We propose a pipeline to automatically generate, cluster, and select a set of representative preview images for a grammar. The system is based on a new view attribute descriptor that measures how suitable an image is in representing a model and that enables the comparison of different models derived from the same grammar. Second, the default distribution of models in a stochastic grammar is often undesirable. We introduce a framework that allows users to design a new probability distribution for a grammar without editing the rules. Gaussian process regression interpolates user preferences from a set of scored models over an entire shape space. A symbol split operation enables the adaptation of the grammar to generate models according to the learned distribution. Third, it is hard to combine elements of two grammars to emerge new designs. We present design transformations and grammar co-derivation to create new designs from existing ones. Algorithms for fine-grained rule merging can generate a large space of design variations and can be used to create animated transformation sequences between different procedural designs. Our contributions to visualize, adapt, and transform grammars makes the procedural modeling methodology more accessible to non-programmers

PARTICIPATORY DEVELOPMENT OF THE HAMLET KIRCHBÜHL, SWITZERLAND

The traditional settlement structure of many Swiss regions was typically characterised by dispersed small settlements, providing an important basis for agriculture. As industrialisation and structural change have accelerated, these hamlets are increasingly losing their original purpose. However, many of them are of high value in terms of their building culture and heritage. Trying to preserve them adequately presents both architectural and socio-economic challenges. In order to address these difficulties, we developed a new strategy for the hamlet of Kirchbühl, in the town of Sempach. By bringing together experts’ viewpoints and the viewpoints of the key stakeholders in a participatory process, we aimed to identify potential conflicts between the different views and address them early on in the development of new guidelines. For each work-package, the goals were defined with the aim of formulating a set of principles and recommendations for planners, builders and the public authorities. The results of the participatory elements have shown that it was possible to integrate the local viewpoints continuously into the ongoing process and the guidelines. A clear line of conflict emerged between the practical vision of the owners and inhabitants and a more preservationist vision of some authorities. Thus, a more direct dialogue between the local stakeholders and the experts should be aimed for in future projects. The ex-post process reflection has also shown that the process needs to be tightened financially and temporally, to be able to carry it out in other municipalities

The Digital Bee Brain: Integrating and Managing Neurons in a Common 3D Reference System

The honeybee standard brain (HSB) serves as an interactive tool for relating morphologies of bee brain neurons and provides a reference system for functional and bibliographical properties (http://www.neurobiologie.fu-berlin.de/beebrain/). The ultimate goal is to document not only the morphological network properties of neurons collected from separate brains, but also to establish a graphical user interface for a neuron-related data base. Here, we review the current methods and protocols used to incorporate neuronal reconstructions into the HSB. Our registration protocol consists of two separate steps applied to imaging data from two-channel confocal microscopy scans: (1) The reconstruction of the neuron, facilitated by an automatic extraction of the neuron's skeleton based on threshold segmentation, and (2) the semi-automatic 3D segmentation of the neuropils and their registration with the HSB. The integration of neurons in the HSB is performed by applying the transformation computed in step (2) to the reconstructed neurons of step (1). The most critical issue of this protocol in terms of user interaction time – the segmentation process – is drastically improved by the use of a model-based segmentation process. Furthermore, the underlying statistical shape models (SSM) allow the visualization and analysis of characteristic variations in large sets of bee brain data. The anatomy of neural networks composed of multiple neurons that are registered into the HSB are visualized by depicting the 3D reconstructions together with semantic information with the objective to integrate data from multiple sources (electrophysiology, imaging, immunocytochemistry, molecular biology). Ultimately, this will allow the user to specify cell types and retrieve their morphologies along with physiological characterizations

Locally advanced adrenocortical carcinoma in children and adolescents — enigmatic and challenging cases

Background: Locally advanced tumors account for approximately 50% of children and adolescents with adrenocortical carcinoma (ACC), and of these, up to 50% relapse. We explored the five-item microscopic score and the pS-GRAS score for guiding management. Methods: Data from children and adolescents with COG stage II and III ACC registered in the MET studies were included. The five-item and pS-GRAS score were retrospectively calculated. Results: By December 2021, 55 patients with stage II and III (stage II n = 18, stage III n = 37) had been reported. Median age was 4.3 years [0.1–17.8], median duration of follow-up 6.0 years [0–16.7]. 3-year event-free survival (EFS) rate was 76.5% and 49.8% (p = 0.088), respectively. In stage II tumors, neither the five-item score (p = 0.872) nor pS-GRAS grouping (p = 0.218) had any effect as prognostic factors. In stage III patients, EFS was impaired in tumors with unfavorable histology according to the five-item score (100% vs. 30.8%, p = 0.018). No difference was observed for pS-GRAS groups (p = 0.798). Conclusions: In patients with COG stage III, but not stage II, the five-item score affected EFS. Further studies are needed to identify patients at risk in COG stage II

Outcome for pediatric adreno-cortical tumors is best predicted by the COG stage and five-item microscopic score — report from the German MET studies

Background: Adrenocortical tumors (ACTs) encompassing the adrenocortical adenoma (ACA), carcinoma (ACC), and tumors of undetermined malignant potential (ACx) are rare endocrine neoplasms with a poor prognosis. We report on pediatric ACT patients registered with the Malignant Endocrine Tumor studies and explore the EXPeRT recommendations for management. Patients: Data from the ACT patients (<18 years) were analyzed. For the risk prediction, the patients were retrospectively assigned to the COG stages and the five-item score. Results: By December 2021, 161 patients with ACT (ACA n = 51, ACx n = 19, and ACC n = 91) had been reported (the median age at the diagnosis was 4.3 years with a range of 0.1–17.8), with lymph node and distant metastases in 10.7% and 18.9% of the patients with ACC/ACx. The mean follow-up was 4.5 years (with a range of 0–16.7). The three-year overall (OS) and event-free survival (EFS) rates were 65.5% and 50.6%. In the univariate analyses, the OS was impaired for patients aged ≥ 4 years (p = 0.001) with the initial biopsy (p = 0.016), tumor spillage (p = 0.028), incomplete tumor resection (p < 0.001), unfavorable histology (p = 0.047), and COG stages III/IV (p = 0.002). Multivariate analysis revealed COG stages III/IV and an unfavorable five-item score as independent negative prognostic factors for the EFS and OS. Conclusions: Age defines the clinical presentation and prognosis in pediatric ACTs. The outcome is best predicted by the COG stage and five-item score

Refractory and relapsed paediatric ACC in the MET studies – a challenging situation necessitating novel diagnostic and therapeutic concepts

Background Paediatric adrenocortical carcinomas (ACC) are highly aggressive malignancies with a dismal prognosis in advanced and metastatic disease. Little is known about outcome of patients with refractory and relapsed (r/r) disease. Procedure National retrospective multicentre study including r/r ACC diagnosed in patients aged <18 years registered in the MET studies between January 1997 and December 2021 Results A total of 16 patients (5 male; median age 12.9 years) with refractory disease were included. Median time to progression was 0.6 years [0.0-1.3]. Site of progression was locoregional (n=1), distant (n=3), and combined (n=12). 3-year overall (OS) and progression-free (PFS) survival were both 0%. Thirty patients with relapse (11 male; median age 7.3 years) were identified. Median time to relapse was 0.7 years [0.1-3.2]. Site of relapse was locoregional (n=8), distant (n=15), and combined (n=7). At last follow-up, 20 patients had died of disease or complications or were alive with disease, 10 patients were in second complete remission (median follow-up: 6.8 years [0-10.5]). 3-year OS and PFS following relapse were 39.1% and 31.9%. Survival was superior in patients with distant relapse (59.6%) compared to locoregional (28.6%) and combined (14.3%) (p=0.028) and in patients with complete surgical resection of all sites of recurrence (70.0%) compared to incomplete (21.4%) and no surgery (0%) (p=0.003). Conclusions For patients nonresponsive to first-line therapy or who experience relapse, prognosis is dismal and options are scarce. Site of relapse and resectability define prognosis. Novel therapeutic concepts are needed to improve the outcome of paediatric patients with r/r ACC

Antimicrobial use in pediatric oncology and hematology in Germany and Austria, 2020/2021: a cross-sectional, multi-center point-prevalence study with a multi-step qualitative adjudication process

Background Due to the high risk of severe infection among pediatric hematology and oncology patients, antimicrobial use is particularly high. With our study, we quantitatively and qualitatively evaluated, based on institutional standards and national guidelines, antimicrobial usage by employing a point-prevalence survey with a multi-step, expert panel approach. We analyzed reasons for inappropriate antimicrobial usage. Methods This cross-sectional study was conducted at 30 pediatric hematology and oncology centers in 2020 and 2021. Centers affiliated to the German Society for Pediatric Oncology and Hematology were invited to join, and an existing institutional standard was a prerequisite to participate. We included hematologic/oncologic inpatients under 19 years old, who had a systemic antimicrobial treatment on the day of the point prevalence survey. In addition to a one-day, point-prevalence survey, external experts individually assessed the appropriateness of each therapy. This step was followed by an expert panel adjudication based upon the participating centers’ institutional standards, as well as upon national guidelines. We analyzed antimicrobial prevalence rate, along with the rate of appropriate, inappropriate, and indeterminate antimicrobial therapies with regard to institutional and national guidelines. We compared the results of academic and non-academic centers, and performed a multinomial logistic regression using center- and patient-related data to identify variables that predict inappropriate therapy. Findings At the time of the study, a total of 342 patients were hospitalized at 30 hospitals, of whom 320 were included for the calculation of the antimicrobial prevalence rate. The overall antimicrobial prevalence rate was 44.4% (142/320; range 11.1–78.6%) with a median antimicrobial prevalence rate per center of 44.5% (95% confidence interval [CI] 35.9–49.9). Antimicrobial prevalence rate was significantly higher (p < 0.001) at academic centers (median 50.0%; 95% CI 41.2–55.2) compared to non-academic centers (median 20.0%; 95% CI 11.0–32.4). After expert panel adjudication, 33.8% (48/142) of all therapies were labelled inappropriate based upon institutional standards, with a higher rate (47.9% [68/142]) when national guidelines were taken into consideration. The most frequent reasons for inappropriate therapy were incorrect dosage (26.2% [37/141]) and (de-)escalation/spectrum-related errors (20.6% [29/141]). Multinomial, logistic regression yielded the number of antimicrobial drugs (odds ratio, OR, 3.13, 95% CI 1.76–5.54, p < 0.001), the diagnosis febrile neutropenia (OR 0.18, 95% CI 0.06–0.51, p = 0.0015), and an existing pediatric antimicrobial stewardship program (OR 0.35, 95% CI 0.15–0.84, p = 0.019) as predictors of inappropriate therapy. Our analysis revealed no evidence of a difference between academic and non-academic centers regarding appropriate usage. Interpretation Our study revealed there to be high levels of antimicrobial usage at German and Austrian pediatric oncology and hematology centers with a significant higher number at academic centers. Incorrect dosing was shown to be the most frequent reason for inappropriate usage. Diagnosis of febrile neutropenia and antimicrobial stewardship programs were associated with a lower likelihood of inappropriate therapy. These findings suggest the importance of febrile neutropenia guidelines and guidelines compliance, as well as the need for regular antibiotic stewardship counselling at pediatric oncology and hematology centers. Funding European Society of Clinical Microbiology and Infectious Diseases, Deutsche Gesellschaft für Pädiatrische Infektiologie, Deutsche Gesellschaft für Krankenhaushygiene, Stiftung Kreissparkasse Saarbrücken

There is inadequate evidence to support the division of the genus Borrelia

There are surely scientific, genetic or ecological 60 arguments which show that differences exist between the relapsing fever (RF) spirochaetes and the Lyme borreliosis (LB) group of spirochaetes, both of which belong to the genus Borrelia. In a recent publication, Adeolu and Gupta (Adeolu & 63 Gupta, 2014) proposed dividing the genus Borrelia into two genera on the basis of genetic differences revealed by comparative genomics. The new genus name for the LB group of spirochaetes, Borreliella, has subsequently been entered in GenBank for some species of the group and in a validation list (List of new names and new combinations previously effectively, but not validly, published) (Oren & Garrity, 2015). However, rapidly expanding scientific knowledge and considerable conflicting evidence combined with the adverse consequences of splitting the genus Borrelia make such a drastic step somewhat premature. In our opinion, the basis of this division rests on preliminary evidence and should be rescinded

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy1,2,3. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations2. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes1,3. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1)1,3,4. Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.This work was supported by an Alex's Lemonade Stand Young Investigator Award (S.C.M.), The CIHR Banting Fellowship (S.C.M.), The Cancer Prevention Research Institute of Texas (S.C.M., RR170023), Sibylle Assmus Award for Neurooncology (K.W.P.), the DKFZ-MOST (Ministry of Science, Technology & Space, Israel) program in cancer research (H.W.), James S. McDonnell Foundation (J.N.R.) and NIH grants: CA154130 (J.N.R.), R01 CA169117 (J.N.R.), R01 CA171652 (J.N.R.), R01 NS087913 (J.N.R.) and R01 NS089272 (J.N.R.). R.C.G. is supported by NIH grants T32GM00725 and F30CA217065. M.D.T. is supported by The Garron Family Chair in Childhood Cancer Research, and grants from the Pediatric Brain Tumour Foundation, Grand Challenge Award from CureSearch for Children’s Cancer, the National Institutes of Health (R01CA148699, R01CA159859), The Terry Fox Research Institute and Brainchild. M.D.T. is also supported by a Stand Up To Cancer St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113)