Glioblastoma disrupts cortical network activity at multiple spatial and temporal scales.

The emergence of glioblastoma in cortical tissue initiates early and persistent neural hyperexcitability with signs ranging from mild cognitive impairment to convulsive seizures. The influence of peritumoral synaptic density, expansion dynamics, and spatial contours of excess glutamate upon higher order neuronal network modularity is unknown. We combined cellular and widefield imaging of calcium and glutamate fluorescent reporters in two glioblastoma mouse models with distinct synaptic microenvironments and infiltration profiles. Functional metrics of neural ensembles are dysregulated during tumor invasion depending on the stage of malignant progression and tumor cell proximity. Neural activity is differentially modulated during periods of accelerated and inhibited tumor expansion. Abnormal glutamate accumulation precedes and outpaces the spatial extent of baseline neuronal calcium signaling, indicating these processes are uncoupled in tumor cortex. Distinctive excitability homeostasis patterns and functional connectivity of local and remote neuronal populations support the promise of precision genetic diagnosis and management of this devastating brain disease.

Traumatic brain injury disrupts state-dependent functional cortical connectivity in a mouse model.

Traumatic brain injury (TBI) is the leading cause of death in young people and can cause cognitive and motor dysfunction and disruptions in functional connectivity between brain regions. In human TBI patients and rodent models of TBI, functional connectivity is decreased after injury. Recovery of connectivity after TBI is associated with improved cognition and memory, suggesting an important link between connectivity and functional outcome. We examined widespread alterations in functional connectivity following TBI using simultaneous widefield mesoscale GCaMP7c calcium imaging and electrocorticography (ECoG) in mice injured using the controlled cortical impact (CCI) model of TBI. Combining CCI with widefield cortical imaging provides us with unprecedented access to characterize network connectivity changes throughout the entire injured cortex over time. Our data demonstrate that CCI profoundly disrupts functional connectivity immediately after injury, followed by partial recovery over 3 weeks. Examining discrete periods of locomotion and stillness reveals that CCI alters functional connectivity and reduces theta power only during periods of behavioral stillness. Together, these findings demonstrate that TBI causes dynamic, behavioral state-dependent changes in functional connectivity and ECoG activity across the cortex.

Cerebrospinal fluid cfDNA sequencing for classification of central nervous system glioma.

PURPOSE: Primary central nervous system (CNS) gliomas can be classified by characteristic genetic alterations. In addition to solid tissue obtained via surgery or biopsy, cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) is an alternative source of material for genomic analyses. EXPERIMENTAL DESIGN: We performed targeted next-generation sequencing (NGS) of CSF cfDNA in a representative cohort of 85 patients presenting at two neurooncological centers with suspicion of primary or recurrent glioma. Copy-number variation (CNV) profiles, single nucleotide variants (SNVs), and small insertions/ deletions (indels) were combined into a molecular-guided tumor classification. Comparison with the solid tumor was performed for 38 cases with matching solid tissue available. RESULTS: Cases were stratified into four groups: glioblastoma (n = 32), other glioma (n = 19), non-malignant (n = 17) and non-diagnostic (n = 17). We introduced a molecular-guided tumor classification, which enabled identification of tumor entities and/ or cancer specific alterations in 75.0 % (n = 24) of glioblastoma and 52.6 % (n = 10) of other glioma cases. The overlap between CSF and matching solid tissue was highest for CNVs (26-48 %) and SNVs at pre-defined gene loci (44 %), followed by SNVs/ indels identified via uninformed variant calling (8-14 %). A molecular-guided tumor classification was possible for 23.5 % (n = 4) of non-diagnostic cases. CONCLUSIONS: We developed a targeted sequencing workflow for CSF cfDNA as well as a strategy for interpretation and reporting of sequencing results based on a molecular-guided tumor classification in glioma.

The IHI Rochester Report 2022 on Healthcare Informatics Research: Resuming After the CoViD-19.

In 2020, the CoViD-19 pandemic spread worldwide in an unexpected way and suddenly modified many life issues, including social habits, social relationships, teaching modalities, and more. Such changes were also observable in many different healthcare and medical contexts. Moreover, the CoViD-19 pandemic acted as a stress test for many research endeavors, and revealed some limitations, especially in contexts where research results had an immediate impact on the social and healthcare habits of millions of people. As a result, the research community is called to perform a deep analysis of the steps already taken, and to re-think steps for the near and far future to capitalize on the lessons learned due to the pandemic. In this direction, on June 09th-11th, 2022, a group of twelve healthcare informatics researchers met in Rochester, MN, USA. This meeting was initiated by the Institute for Healthcare Informatics-IHI, and hosted by the Mayo Clinic. The goal of the meeting was to discuss and propose a research agenda for biomedical and health informatics for the next decade, in light of the changes and the lessons learned from the CoViD-19 pandemic. This article reports the main topics discussed and the conclusions reached. The intended readers of this paper, besides the biomedical and health informatics research community, are all those stakeholders in academia, industry, and government, who could benefit from the new research findings in biomedical and health informatics research. Indeed, research directions and social and policy implications are the main focus of the research agenda we propose, according to three levels: the care of individuals, the healthcare system view, and the population view.

[Motivational Reasons and Perceptions about Future Participation of Older People in the Research and Development Process of Health Technologies: a Mixed Methods Study]. / Motivationsgründe und Vorstellungen über eine zukünftige Beteiligung älterer Menschen im Forschungs- und Entwicklungsprozess von Gesundheitstechnologien ­ eine Mixed Methods-Studie.

BACKGROUND: Although digital approaches for disease prevention in older people have a high potential and are being used more often, there are still inequalities in access and use. One reason could be that in technology development future users are insufficiently taken into consideration, or involved very late in the process using inappropriate methods. The aim of this work was to analyze the motivation of older people participating, and their perceptions of future participation in the research and development process of health technologies aimed at health care for older people. METHODOLOGY: Quantitative and qualitative data from one needs assessment and two evaluation studies were analyzed. The quantitative data were analyzed descriptively and the qualitative data were analyzed content-analytically with inductive-deductive category formation. RESULTS: The median age of the 103 participants (50 female) was 75 years (64-90), most of whom were interested in using technology and had prior experience of study participation. Nine categories for participation motivation were derived. A common motivation for participation was to promote and support their own health. Respondents were able to envision participation both at the beginning of the research process and at its end. In terms of technique development, different ideas were expressed, but there was a general interest in technological development. Methods that would enable exchange with others were favored most. CONCLUSIONS: Differences in motivation to participate and ideas about participation were identified. The results provide important information from the perspective of older people and complement the existing state of research.

Glioma epileptiform activity and progression are driven by IGSF3-mediated potassium dysregulation.

Seizures are a frequent pathophysiological feature of malignant glioma. Recent studies implicate peritumoral synaptic dysregulation as a driver of brain hyperactivity and tumor progression; however, the molecular mechanisms that govern these phenomena remain elusive. Using scRNA-seq and intraoperative patient ECoG recordings, we show that tumors from seizure patients are enriched for gene signatures regulating synapse formation. Employing a human-to-mouse in vivo functionalization pipeline to screen these genes, we identify IGSF3 as a mediator of glioma progression and dysregulated neural circuitry that manifests as spreading depolarization (SD). Mechanistically, we discover that IGSF3 interacts with Kir4.1 to suppress potassium buffering and found that seizure patients exhibit reduced expression of potassium handlers in proliferating tumor cells. In vivo imaging reveals that dysregulated synaptic activity emanates from the tumor-neuron interface, which we confirm in patients. Our studies reveal that tumor progression and seizures are enabled by ion dyshomeostasis and identify SD as a driver of disease.

Designing and applying technology for prevention-Lessons learned in AEQUIPA and its implications for future research and practice.

Almost all Western societies are facing the challenge that their population structure is changing very dynamically. Already in 2019, ten countries had a population share of at least 20 percent in the age group of 64 years and older. Today's society aims to improve population health and help older people live active and independent lives by developing, establishing, and promoting safe and effective interventions. Modern technological approaches offer tremendous opportunities but pose challenges when preventing functional decline. As part of the AEQUIPA Prevention Research Network, the use of technology to promote physical activity in older people over 65 years of age was investigated in different settings and from various interdisciplinary perspectives, including technology development and evaluation for older adults. We present our findings in three main areas: (a) design processes for developing technology interventions, (b) older adults as a user group, and (c) implications for the use of technology in interventions. We find that cross-cutting issues such as time and project management, supervision of participants, ethics, and interdisciplinary collaboration are of vital importance to the success of the work. The lessons learned are discussed based on the experiences gained in the overall AEQUIPA network while building, particularly on the experiences from the AEQUIPA sub-projects TECHNOLOGY and PROMOTE. Our experiences can help researchers of all disciplines, industries, and practices design, study and implement novel technology-based interventions for older adults to avoid pitfalls and create compelling and meaningful solutions.

Impact of Activity Tracker Usage in Combination with a Physical Activity Intervention on Physical and Cognitive Parameters in Healthy Adults Aged 60+: A Randomized Controlled Trial.

Regular physical activity (PA) is of central importance for healthy aging and has a well-known impact on helping older adults maintain their cognitive and physical health. Thus, we aimed to compare the effectiveness of two physical activity interventions primarily conducted at home (print-based or web-based vs. web-based plus the use of an activity tracker) on cognitive and physical health parameters in older adults. Data of participants (n = 551, 60-80 years) were analyzed after being randomly allocated to a waitlist control group (CG), a web-based or print-based intervention group (IG) or a web-based intervention group that also included the use of an activity tracker (AG). Measured parameters were grip strength, endurance (two-minute step test), gait speed (four-meter walk test), cognition (Simon task; balanced integration score (BIS), reaction time and accuracy) and physical self-concept (Physical Self-Description Questionnaire (PSDQ)). We found the highest effect sizes in all measured dimensions for AG (grip strength, endurance, gait speed, reaction time, physical self-concept), followed by IG (endurance, gait speed, reaction time, physical self-concept) and CG (endurance, gait speed, BIS). Findings suggest that a combined web-based and activity tracker intervention may improve physical functions, physical self-concept, and cognition in community-dwelling older adults.

Web-Based Versus Print-Based Physical Activity Intervention for Community-Dwelling Older Adults: Crossover Randomized Trial.

BACKGROUND: Fewer than half of older German adults engage in the recommended levels of endurance training. OBJECTIVE: The study aim is to compare the acceptance and effectiveness of two interventions for physical activity (PA) promotion among initially inactive community-dwelling older adults ≥60 years in a 9-month, crossover randomized trial. METHODS: Participants were recruited in person and randomized to one of the following interventions for self-monitoring PA: a print-based intervention (PRINT: 113/242, 46.7%) or a web-based intervention (WEB: 129/242, 53.3%). Furthermore, 29.5% (38/129) of those in the web-based intervention group received a PA tracker in addition to WEB (WEB+). After randomization, the participants and researchers were not blinded. The participants' baseline intervention preferences were retrospectively assessed. All the intervention groups were offered 10 weekly face-to-face group sessions. Afterward, participants could choose to stay in their group or cross over to one of the other groups, and group sessions were continued monthly for another 6 months. 3D accelerometers to assess PA and sedentary behavior (SB) at baseline (T0), 3-month follow-up (T1), and 9-month follow-up (T2) were used. Adherence to PA recommendations, attendance of group sessions, and intervention acceptance were assessed using self-administered paper-based questionnaires. Linear mixed models were used to calculate differences in moderate to vigorous PA (MVPA) and SB between time points and intervention groups. RESULTS: Of the 242 initially recruited participants, 91 (37.6%) were randomized to the WEB group; 38 (15.7%) to the WEB+ group; and 113 (46.7%) to the PRINT group. Overall, 80.6% (195/242) of the participants completed T1. Only 0.4% (1/242) of the participants changed from the WEB group to the PRINT group and 6.2% (15/242) moved from the PRINT group to the WEB group (WEB-WEB: 103/249, (41.4%); PRINT-PRINT: 76/249, 30.5%) when offered to cross over at T1. Furthermore, 66.1% (160/242) of participants completed T2. MVPA in minutes per day increased between baseline and T1, but these within-group changes disappeared after adjusting for covariates. MVPA decreased by 9 minutes per day between baseline and T2 (ßtime=-9.37, 95% CI -18.58 to -0.16), regardless of the intervention group (WEB vs PRINT: ßgroup*time=-3.76, 95% CI -13.33 to 5.82, WEB+ vs PRINT: ßgroup*time=1.40, 95% CI -11.04 to 13.83). Of the participants, 18.6% (38/204) met the PA recommendations at T0, 16.4% (26/159) at T1, and 20.3% (28/138) at T2. For SB, there were no significant group differences or group-by-time interactions at T1 or T2. Intervention acceptance was generally high. The use of intervention material was high to moderate at T1 and decreased by T2. CONCLUSIONS: There was little movement between intervention groups at T1 when given the choice, and participation was not associated with increases in PA or decreases in SB over time. TRIAL REGISTRATION: German Clinical Trials Register DRKS00016073; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00016073.

Comparative evaluation of T-cell receptors in experimental glioma-draining lymph nodes.

BACKGROUND: Glioblastomas, the most common primary malignant brain tumors, are considered immunologically cold malignancies due to growth in an immune sanctuary site. While peptide vaccines have shown to generate intra-tumoral antigen-specific T cells, the identification of these tumor-specific T cells is challenging and requires detailed analyses of tumor tissue. Several studies have shown that CNS antigens may be transported via lymphatic drainage to cervical lymph nodes, where antigen-specific T-cell responses can be generated. Therefore, we investigated whether glioma-draining lymph nodes (TDLN) may constitute a reservoir of tumor-reactive T cells. METHODS: We addressed our hypothesis by flow cytometric analyses of chicken ovalbumin (OVA)-specific CD8+ T cells as well as T-cell receptor beta (TCRß) next-generation-sequencing (TCRß-NGS) of T cells from tumor tissue, TDLN, spleen, and inguinal lymph nodes harvested from experimental mouse GL261 glioma models. RESULTS: Longitudinal dextramer-based assessment of specific CD8+ T cells from TDLN did not show tumor model antigen reactivity. Unbiased immunogenomic analysis revealed a low overlap of TCRß sequences from glioma-infiltrating CD8+ T cells between mice. Enrichment scores, calculated by the ratio of productive frequencies of the different TCRß-CDR3 amino-acid (aa) rearrangements of CD8+ T cells derived from tumor, TDLN, inguinal lymph nodes, and spleen demonstrated a higher proportion of tumor-associated TCR in the spleen compared to TDLN. CONCLUSIONS: In experimental glioblastoma, our data did not provide evidence that glioma-draining cervical lymph nodes are a robust reservoir for spontaneous glioma-specific T cells highlighting the requirement for detailed analyses of glioma-infiltrating T cells for the discovery of tumor-specific TCR.

Application of Activity Trackers among Nursing Home Residents-A Pilot and Feasibility Study on Physical Activity Behavior, Usage Behavior, Acceptance, Usability and Motivational Impact.

The aim of this study was to assess physical activity and sedentary behavior, as well as the usage behavior, usability, acceptance, and motivational impact of an applied activity tracker among nursing home residents. Physical activity and usage behavior were measured among 22 residents (68 to 102 years) by use of a commercial activity tracker worn during waking hours for 77 days on average. Usability, acceptance, and motivational impact of the tracker were examined using an adapted questionnaire. Participants walked, on average, 1007 ± 806 steps per day and spent, on average, more than 9 h (77.2% of their waking time) sedentary. The average steps/day increased significantly within the first five weeks of wearing the activity tracker. The acceptance rate was high (94.4%). The tracker was used for 65.4% of the individual study period, and usage behavior did not significantly change during the first five wearing weeks. Participants with a usage time of ≥50% walked significantly more steps per day than those with a lower usage. Overall, we were able to reveal that the residents were highly inactive and sedentary. The results support the feasibility of a long-term application of activity trackers to assess or even increase physical activity behavior.

Implementation and Effects of Information Technology-Based and Print-Based Interventions to Promote Physical Activity Among Community-Dwelling Older Adults: Protocol for a Randomized Crossover Trial.

BACKGROUND: Despite the known health benefits of physical activity (PA), less than half and less than one-third of older adults in Germany reach the PA recommendations for endurance training and strength training, respectively, of the World Health Organization. The aim of this study is to investigate the implementation and effectiveness over the course of 9 months of two interventions (information technology [IT]-based vs print-based) for PA promotion among initially inactive older adults in a randomized, crossover trial. This study is part of a large research consortium (2015-2021) investigating different aspects of PA promotion. The IT-based intervention was previously developed and refined, while the print-based intervention was newly developed during this funding phase. OBJECTIVE: We aim to compare the effectiveness and examine the preferences of study participants regarding both delivery modes. METHODS: Our target sample size was 390 initially inactive community-dwelling older adults aged ≥60 years at baseline (3-month follow-up [T1]: expected n=300; 9-month follow-up [T2]: expected n=240) who were randomized to one of two interventions for self-monitoring PA: IT-based (50%) or print-based (50%) intervention. In addition, 30% of the IT-based intervention group received a PA tracker. At T1, participants in both groups could choose whether they prefered to keep their assigned intervention or cross over to the other group for the following 6 months (T2). Participants' intervention preferences at baseline were collected retrospectively to run a post hoc matched-mismatched analysis. During the initial 3-month intervention period, both intervention groups were offered weekly group sessions that were continued monthly between T1 and T2. A self-administered questionnaire and 3D accelerometers were employed to assess changes in PA between baseline, T1, and T2. Adherence to PA recommendations, attendance at group sessions, and acceptance of the interventions were also tracked. RESULTS: The funding period started in February 2018 and ends in January 2021. We obtained institutional review board approval for the study from the Medical Association in Bremen on July 3, 2018. Data collection was completed on January 31, 2020, and data cleaning and analysis started in February 2020. We expect to publish the first results by the end of the funding period. CONCLUSIONS: Strategies to promote active aging are of particular relevance in Germany, as 29% of the population is projected to be ≥65 years old by 2030. Regular PA is a key contributor to healthy aging. This study will provide insights into the acceptance and effectiveness of IT-based vs print-based interventions to promote PA in initially inactive individuals aged ≥60 years. Results obtained in this study will improve the existing evidence base on the effectiveness of community-based PA interventions in Germany and will inform efforts to anchor evidence-based PA interventions in community structures and organizations via an allocation of permanent health insurance funds. TRIAL REGISTRATION: German Registry of Clinical Trials DRKS00016073; https://tinyurl.com/y983586m. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15168.

Pathogenesis of peritumoral hyperexcitability in an immunocompetent CRISPR-based glioblastoma model.

Seizures often herald the clinical appearance of gliomas or appear at later stages. Dissecting their precise evolution and cellular pathogenesis in brain malignancies could inform the development of staged therapies for these highly pharmaco-resistant epilepsies. Studies in immunodeficient xenograft models have identified local interneuron loss and excess glial glutamate release as chief contributors to network disinhibition, but how hyperexcitability in the peritumoral microenvironment evolves in an immunocompetent brain is unclear. We generated gliomas in WT mice via in utero deletion of key tumor suppressor genes and serially monitored cortical epileptogenesis during tumor infiltration with in vivo electrophysiology and GCAMP7 calcium imaging, revealing a reproducible progression from hyperexcitability to convulsive seizures. Long before seizures, coincident with loss of inhibitory cells and their protective scaffolding, gain of glial glutamate antiporter xCT expression, and reactive astrocytosis, we detected local Iba1+ microglial inflammation that intensified and later extended far beyond tumor boundaries. Hitherto unrecognized episodes of cortical spreading depolarization that arose frequently from the peritumoral region may provide a mechanism for transient neurological deficits. Early blockade of glial xCT activity inhibited later seizures, and genomic reduction of host brain excitability by deleting MapT suppressed molecular markers of epileptogenesis and seizures. Our studies confirmed xenograft tumor-driven pathobiology and revealed early and late components of tumor-related epileptogenesis in a genetically tractable, immunocompetent mouse model of glioma, allowing the complex dissection of tumor versus host pathogenic seizure mechanisms.

Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas.

Intrinsic malignant brain tumors, such as glioblastomas are frequently resistant to immune checkpoint blockade (ICB) with few hypermutated glioblastomas showing response. Modeling patient-individual resistance is challenging due to the lack of predictive biomarkers and limited accessibility of tissue for serial biopsies. Here, we investigate resistance mechanisms to anti-PD-1 and anti-CTLA-4 therapy in syngeneic hypermutated experimental gliomas and show a clear dichotomy and acquired immune heterogeneity in ICB-responder and non-responder tumors. We made use of this dichotomy to establish a radiomic signature predicting tumor regression after pseudoprogression induced by ICB therapy based on serial magnetic resonance imaging. We provide evidence that macrophage-driven ICB resistance is established by CD4 T cell suppression and Treg expansion in the tumor microenvironment via the PD-L1/PD-1/CD80 axis. These findings uncover an unexpected heterogeneity of response to ICB in strictly syngeneic tumors and provide a rationale for targeting PD-L1-expressing tumor-associated macrophages to overcome resistance to ICB.

Effects of Two Web-Based Interventions and Mediating Mechanisms on Stage of Change Regarding Physical Activity in Older Adults.

BACKGROUND: Web-based, theory-driven interventions effectively promote older adults' physical activity. Social-cognitive mechanisms of their effect on stage of change need to be further researched. METHODS: Older adults were randomly allocated to intervention group 1 (10-week online physical activity program), intervention group 2 (same program plus activity tracker), or delayed intervention control group; n = 351 were analyzed (59.6% of originally allocated individuals). Stages of change for recommended endurance and strength training and social-cognitive predictors of physical activity were assessed using questionnaires at baseline and follow-up. Intervention effects and mediation were investigated using mixed-effects ANOVA and ordinal least squares regression. RESULTS: Direct effects on stage of change were found for intervention group 1 regarding endurance training (bintervention group 1  = 0.44, 95% confidence interval [0.15, 0.73]), and both groups regarding strength training (bintervention group 1  = 1.02, [0.71, 1.33], bintervention group 2  = 1.24, [0.92, 1.56]). Social-cognitive predictor changes in task self-efficacy, intention, and action planning explained intervention effect on stage of change, but not to the full extent. CONCLUSIONS: The results indicate significant web-based intervention effects on physical activity stage, partly mediated by changes in task self-efficacy, intention, and action planning.

Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course.

The "isomorphic subtype of diffuse astrocytoma" was identified histologically in 2004 as a supratentorial, highly differentiated glioma with low cellularity, low proliferation and focal diffuse brain infiltration. Patients typically had seizures since childhood and all were operated on as adults. To define the position of these lesions among brain tumours, we histologically, molecularly and clinically analysed 26 histologically prototypical isomorphic diffuse gliomas. Immunohistochemically, they were GFAP-positive, MAP2-, OLIG2- and CD34-negative, nuclear ATRX-expression was retained and proliferation was low. All 24 cases sequenced were IDH-wildtype. In cluster analyses of DNA methylation data, isomorphic diffuse gliomas formed a group clearly distinct from other glial/glio-neuronal brain tumours and normal hemispheric tissue, most closely related to paediatric MYB/MYBL1-altered diffuse astrocytomas and angiocentric gliomas. Half of the isomorphic diffuse gliomas had copy number alterations of MYBL1 or MYB (13/25, 52%). Gene fusions of MYBL1 or MYB with various gene partners were identified in 11/22 (50%) and were associated with an increased RNA-expression of the respective MYB-family gene. Integrating copy number alterations and available RNA sequencing data, 20/26 (77%) of isomorphic diffuse gliomas demonstrated MYBL1 (54%) or MYB (23%) alterations. Clinically, 89% of patients were seizure-free after surgery and all had a good outcome. In summary, we here define a distinct benign tumour class belonging to the family of MYB/MYBL1-altered gliomas. Isomorphic diffuse glioma occurs both in children and adults, has a concise morphology, frequent MYBL1 and MYB alterations and a specific DNA methylation profile. As an exclusively histological diagnosis may be very challenging and as paediatric MYB/MYBL1-altered diffuse astrocytomas may have the same gene fusions, we consider DNA methylation profiling very helpful for their identification.

Transcriptional profiling of medulloblastoma with extensive nodularity (MBEN) reveals two clinically relevant tumor subsets with VSNL1 as potent prognostic marker.

Medulloblastoma with extensive nodularity (MBEN) is one of the few central nervous system (CNS) tumor entities occurring in infants which is traditionally associated with good to excellent prognosis. Some MBEN, however, have been reported with an unfavorable clinical course. We performed an integrated DNA/RNA-based molecular analysis of a multi-institutional MBEN cohort (n = 41) to identify molecular events which might be responsible for variability in patients' clinical outcomes. RNA sequencing analysis of this MBEN cohort disclosed two clear transcriptome clusters (TCL) of these CNS tumors: "TCL1 MBEN" and "TCL2 MBEN" which were associated with various gene expression signatures, mutational landscapes and, importantly, prognosis. Thus, the clinically unfavorable "TCL1 MBEN" subset revealed transcriptome signatures composed of cancer-associated signaling pathways and disclosed a high frequency of clinically relevant germline PTCH1/SUFU alterations. In contrast, gene expression profiles of tumors from the clinically favorable "TCL2 MBEN" subgroup were associated with activation of various neurometabolic and neurotransmission signaling pathways, and germline SHH-pathway gene mutations were extremely rare in this transcriptome cluster. "TCL2 MBEN" also revealed strong and ubiquitous expression of VSNL1 (visinin-like protein 1) both at the mRNA and protein level, which was correlated with a favorable clinical course. Thus, combining mutational and epigenetic profiling with transcriptome analysis including VSNL1 immunohistochemistry, MBEN patients could be stratified into clinical risk groups of potential value for subsequent treatment planning.

Effects of two web-based interventions promoting physical activity among older adults compared to a delayed intervention control group in Northwestern Germany: Results of the PROMOTE community-based intervention trial.

Regular physical activity (PA) is of central importance for healthy ageing. However, in Germany, only 42% of older adults currently reach the PA recommendations of the World Health Organization. The aim of this study was to examine the effects of two web-based interventions on PA in adults aged 65-75 years living in Northwestern Germany compared to a delayed intervention control group (CG). 589 older adults were randomized to one of the three groups. Participants in intervention group 1 (IG1) received access to a web-based intervention for ten weeks assisting them in self-tracking PA behavior. Participants in IG2 received the intervention of IG1 and additionally an activity tracker to objectively track PA behavior. To analyze differences in objectively measured moderate-to-vigorous PA and sedentary time between baseline and follow-up (12 weeks after baseline), linear mixed models were used. The interaction effects revealed a decrease in minutes spent on moderate-to-vigorous PA in bouts of 10 min by 11 min per week in IG1 participants (ß = -11.08, 95% CI: (-35.03; 12.87)). In comparison, IG2 participants were 7 min more physically active at follow-up (ß = 7.48, 95% CI: (-17.64; 32.60)). Sedentary time in bouts of 30 min per week increased in IG1 participants (ß = 106.77, 95% CI: (-47.69; 261.23)) and decreased in IG2 participants at follow-up (ß = -16.45, 95% CI: (-178.83; 145.94)). Participation in the two web-based interventions did not lead to significant increases in moderate-to-vigorous PA or significant decreases in sedentary time compared to the CG. The study was registered at the German Clinical Trials Register (DRKS00010052, 07-11-2016).