Greifswald Medical School

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder and phobias) are highly prevalent, often onset early and cause substantial global disability. Although distinct in their clinical presentations, they probably represent differential expressions of a dysregulated threat-response system. Here, we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 out of the 58 associations replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism implicated in ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.

STUDY OBJECTIVES:Increasing evidence points towards sleep apnea as a modifiable risk factor for neurodegeneration. This study investigates the longitudinal effect of sleep apnea on brain structures in a general population. METHODS:Data from the Study of Health in Pomerania with baseline laboratory-based polysomnography and magnetic resonance imaging (MRI) (2008-2012) and 7-year follow-up MRI (2016-2019) were used. Sleep apnea was characterized by the apnea-hypopnea index, oxygen desaturation index, mean sleep oxygen saturation, and arousal index; self-reported sleep quality using the Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index. Total brain volume, regional and total gray matter thickness, white matter hyperintensity burden, and brain age were derived from 1.5 tesla T1 and fluid-attenuated inversion recovery sequences. Associations between sleep apnea and follow-up MRI measures were examined using linear regression adjusted for age, sex, intracranial volume, total sleep time, follow-up duration, and baseline MRI values. Restricted cubic splines were used in all continuous variables to model non-linear effects. RESULTS:387 participants were included (age 50.7 ± 12.4 years, 47.3 per cent female). Neither apnea-hypopnea index nor oxygen desaturation index showed significant longitudinal effects. Lower mean sleep oxygen saturation was associated with reduced total brain volume, while a higher arousal index was linked to increase brain age and decreased global and regional gray matter thickness. Self-reported sleep quality correlated with total brain volume changes. CONCLUSIONS:Unlike prior cross-sectional findings, traditional sleep apnea indices were not associated with structural brain changes over 7 years. Instead, sleep fragmentation emerged as a key factor in brain atrophy. Targeting sleep fragmentation may offer neuroprotective benefits.

The FAIR principles guide data stewardship towards maximizing the value of scientific data while offering a high level of flexibility to accommodate differences in standards and scientific practices. Research communities have developed and implemented domain-specific workflows to make their data FAIR. This work compares the implementation of two externally developed structured FAIRification workflows-a generic workflow and a domain-specific workflow- using the example of metadata captured in diabetes research in Germany and applying the FAIR data maturity model developed by the Research Data Alliance. Interestingly, the implementation of both workflows required similar resources and led us to achieve the same FAIRness rating. We therefore conclude that the adaptations made in the FAIRification workflow for health research data improve efficiency but do not necessarily lead to higher FAIRness scores when applied to core data sets. Based on the results of our workflow comparison, we identified a list of requirements that should be met for the FAIRification of a core data set regardless of the workflow employed. In the future, FAIR data strategies and infrastructure should be planned and implemented as early as possible in the FAIRification journey. It is anticipated that this comparative analysis will help establish standard operating procedures for the FAIRification of core data sets for health studies.

INTRODUCTION:Since 2015, the Federal Joint Committee (G-BA)'s Innovation Fund has been supporting projects in health services research and new health service models ("Neue Versorgungsformen", NVF). By the end of 2022, 211 projects in the NVF category had been funded. A key objective is the transfer of successful projects into standard care. This article analyzes previous projects regarding their incorporation into routine care based on transfer recommendations of the Innovation Fund Committee ("Innovationsausschuss" IA). METHOD:Descriptive analysis of all projects completed by August 1, 2023 with transfer recommendations in the "NVF" funding stream. Presentation by topic, project duration, time until IA transfer decision, categorization, and number of institutions and organizations (recipients) addressed per project, their feedback published on the G-BA website, response rates per recipient group, and a content classification and interpretation of exemplary feedback. Recommendations based on the results and their discussion in an expert workshop. RESULTS:Out of 57 NVF projects, 17 had a transfer recommendation. A total of 57 feedback responses were received from a total of 431 recipients addressed by the IA across these projects. Response rates varied significantly. One-third of inquiries to the G-BA and its member organizations received a response (31%), while only every fifth inquiry to federal states (18%) and professional societies (18%) got a response. Less than one in ten inquiries to the Federal Ministry of Health (8%), administrative bodies (6%), and the German Medical Association (0%) received a response. Project-specific feedback within a recipient group was often contradictory or limited to regional scope. DISCUSSION AND CONCLUSION:The transfer process reveals significant structural and procedural obstacles regarding the incorporation of projects evaluated as successful into routine health care. To ensure that funding from the innovation fund is most effectively used, there needs to be a realistic chance of successful transfer of positive project outcomes into routine care. The DNVF recommends stronger involvement of rule-competent institutions, mandatory publication of responses, structured moderation of the transfer process, expanding types of selective contracts, financing of implementation phases and of studies drawing on results across successful NVF projects.

The cellular composition that defines the tumor ecosystem plays a crucial role in determining the response of tumors to immune checkpoint inhibitors (ICi) and to pharmacological blockade of BRAF (BRAFi). However, the compositional changes that likely shape the ecosystems of primary melanomas for metastasis to the brain on the one hand and the progression of brain metastases on the other remain unclear. In this study, we resolved the spatial landscapes of progressive melanoma brain metastases (MBM) by profiling 13 regions from 8 distinct metastases, together with one matched primary tumor spanning various stages of tumor development and therapeutic intervention. Single cell resolved spatial transcriptomics-based profiling uncovered distinct and common patterns of MBM progression. Our approach revealed remarkable cellular and spatial heterogeneity and identified key tumor subsets of MET or NGFR expressing cell populations. Moreover, spatial profiling of tumors which have progressed under ICi or BRAFi identified BZW2+ tumor cells contributing to an immune-suppressive microenvironment, preventing immune cell infiltration and dispersion within the tumor. Elevated BZW2 expression was associated with resistance to ICi therapy and is inversely correlated with the antigen transporter TAP1. Spatially-aware automated profiling of immune cell-enriched areas revealed ″hot″ niches characterized by tumor cell expression of TAP1, PD-L2, HLA-DRA whereas ″cold″ niches featured high levels of particularly BZW2 and SOX4. The latter suppressor of translation and transcriptional regulator was co-localized with the clinically targetable MET receptor in a subset of tumor cells that exhibit immune evasion features. In summary, we provide for the first time, spatially resolved landscapes of MBM that reveal insights into the cellular heterogeneity of tumors and the mechanisms underlying immune escape. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the German Federal Ministry of Education and Research (BMBF): NATON, No. 01KX2121 to H.R. and Seed funding from University Medicine Greifswald to K.P. and by the European Regional Development Fund (EFRE) (Target-H; FV-2024-0022) to JR. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of Charite-Universitaetsmedizin Berlin and of Universitaetsmedizin Greifswald gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data generated in this study will be made publicly available by deposition in GEO (Gene Expression Omnibus) and Zenodo.