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Tau plays a key role in Alzheimer’s disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPTRx) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPTRx. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPTRx or placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPTRx pharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPTRx and 12 to placebo. Adverse events were reported in 94% of MAPTRx-treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPTRx-treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPTRx groups. Clinicaltrials.gov registration number: NCT03186989.

ImportanceDiagnostic incidence data for syndromes associated with frontotemporal lobar degeneration (FTLD) in multinational studies are urgent in light of upcoming therapeutic approaches.ObjectiveTo assess the incidence of FTLD across Europe.Design, Setting, and ParticipantsThe Frontotemporal Dementia Incidence European Research Study (FRONTIERS) was a retrospective cohort study conducted from June 1, 2018, to May 31, 2019, using a population-based registry from 13 tertiary FTLD research clinics from the UK, the Netherlands, Finland, Sweden, Spain, Bulgaria, Serbia, Germany, and Italy and including all new FTLD-associated cases during the study period, with a combined catchment population of 11 023 643 person-years. Included patients fulfilled criteria for the behavioral variant of frontotemporal dementia (BVFTD), the nonfluent variant or semantic variant of primary progressive aphasia (PPA), unspecified PPA, progressive supranuclear palsy, corticobasal syndrome, or frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS). Data were analyzed from July 19 to December 7, 2021.Main Outcomes and MeasuresRandom-intercept Poisson models were used to obtain estimates of the European FTLD incidence rate accounting for geographic heterogeneity.ResultsBased on 267 identified cases (mean [SD] patient age, 66.70 [9.02] years; 156 males [58.43%]), the estimated annual incidence rate for FTLD in Europe was 2.36 cases per 100 000 person-years (95% CI, 1.59-3.51 cases per 100 000 person-years). There was a progressive increase in FTLD incidence across age, reaching its peak at the age of 71 years, with 13.09 cases per 100 000 person-years (95% CI, 8.46-18.93 cases per 100 000 person-years) among men and 7.88 cases per 100 000 person-years (95% CI, 5.39-11.60 cases per 100 000 person-years) among women. Overall, the incidence was higher among men (2.84 cases per 100 000 person-years; 95% CI, 1.88-4.27 cases per 100 000 person-years) than among women (1.91 cases per 100 000 person-years; 95% CI, 1.26-2.91 cases per 100 000 person-years). BVFTD was the most common phenotype (107 cases [40.07%]), followed by PPA (76 [28.46%]) and extrapyramidal phenotypes (69 [25.84%]). FTD-ALS was the rarest phenotype (15 cases [5.62%]). A total of 95 patients with FTLD (35.58%) had a family history of dementia. The estimated number of new FTLD cases per year in Europe was 12 057.Conclusions and RelevanceThe findings suggest that FTLD-associated syndromes are more common than previously recognized, and diagnosis should be considered at any age. Improved knowledge of FTLD incidence may contribute to appropriate health and social care planning and in the design of future clinical trials.

Journal of nephrology JN (2022). doi:10.1007/s40620-022-01454-2, Published by Springer, Milano

Gastric cancer (2022). doi:10.1007/s10120-022-01347-0, Published by Springer, Tokyo

Autoimmune encephalitis (AE) can be classified into antibody-defined subtypes, which can manifest with immunotherapy-responsive movement disorders sometimes mimicking non-inflammatory etiologies. In the elderly, anti-leucin-rich-glioma-inactivated-1 (LGI1) and contactin-associated-protein-like-2 (CASPR2) antibody-associated diseases compose a relevant fraction of AE. Patients with LGI1 autoantibodies are known to present with limbic encephalitis and additionally faciobrachial dystonic seizures (FBDS) may occur. However, the clinical spectrum of CASPR2 autoantibody-associated disorders is more diverse including limbic encephalitis, Morvan`s syndrome, peripheral nerve hyperexcitability syndrome, ataxia, pain and sleep disorders. Reports on unusual, sometimes isolated and immunotherapy-responsive movement disorders in CASPR2-autoantibody associated syndromes have caused substantial concern regarding necessity of autoantibody-testing in patients with movement disorders. Therefore, we aimed to systematically assess their prevalence and manifestation in patients with CASPR2 autoimmunity. This international, retrospective cohort study included patients with CASPR2 autoimmunity from participating expert centers in Europe. Patients with ataxia and/or movement disorders were analyzed in detail using questionnaires and video recordings. We recruited a comparator group with anti-leucin-rich-glioma-inactivated-1 (LGI1) encephalitis from the GENERATE network. Characteristics were compared according to serostatus. We identified 164 patients with CASPR2 autoantibodies. Of these, 149 (90.8%) had only CASPR2- and 15 (9.1%) both CASPR2- and LGI1-autoantibodies. Compared to 105 patients with LGI1 encephalitis, patients with CASPR2 autoantibodies more often had movement disorders and/or ataxia (35.6% versus 3.8%; p

International audience; Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions. To address these issues, we assembled a group of multidisciplinary experts to discuss our current understanding of microglial states as a dynamic concept and the importance of addressing microglial function. Here, we provide a conceptual framework and recommendations on the use of microglial nomenclature for researchers, reviewers, and editors, which will serve as the foundations for a future white paper.

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume. This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Programme, Neurodegenerative Disease Research (JPND). Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Part of the work described in this study was carried out in the context of the Parelsnoer Institute (PSI). PSI was part of and funded by the Dutch Federation of University Medical Centers and has received initial funding from the Dutch Government (from 2007-2011). Since 2020, this work was carried out in the context of Parelsnoer clinical biobanks at Health-RI (https://www.health-ri.nl/initiatives/parelsnoer).Part of the genotyping included in this work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Alfredo Ramirez is also supported by the German Research Foundation (DFG) grants Nr: RA 1971/6-1, RA1971/7-1, and RA 1971/8-1. We would like to thank patients and controls who participated in this project. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Grifols SA, Fundacion bancaria 'La Caixa', Fundacio ACE, and CIBERNED. A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de hacer Europa'). The position held by I.dR. is funded by grant. FI20/00215. PFIS Contratos Predoctorales de Formacion en Investigacion en Salud. We would like to thank UCL Genomics, London, UK, for performing the genotyping analyses of the samples within the Gothenburg H70 Birth Cohort Studies and Clinical AD Sweden. The recruitment and clinical characterization of research participants at Washington University were supported by NIH P30AG066444, and P01AG003991. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenom ics.wustl.edu/)and the Departments of Neurology and Psychiatry at Washington University School of Medicine. Research at the Belgian EADB site is funded in part by the Alzheimer Research Foundation (SAO-FRA), The Research Foundation Flanders (FWO), and the University of Antwerp Research Fund. FK is supported by a BOF DOCPRO fellowship of the University of Antwerp Research Fund. The work of Valdecilla was supported by grants from the Instituto de Salud Carlos III (Fondo de Investigacion Sanitario, PI08/0139, PI12/02288, PI16/01652, and PI20/01011), the JPND (DEMTEST PI11/03028), the CIBERNED, and the Siemens Healthineers. We thank the Valdecilla Biobank (PT17/0015/0019), integrated into the Spanish Biobank Network, for their support and collaboration in sample collection and management. Our heartfelt thanks to the participants of the Valdecilla Cohort for their generosity. The work of ADGEN was supported by EU Joint Programme-Neurodegenerative Disease Research (301220) and the Academy of Finland (338182). The DELCODE study (Study-ID:BN012) was supported and conducted by the German Center for Neurodegenerative Diseases (DZNE). The data samples were provided by the DELCODE study group. Details and participating sites can be found at www.dzne.de/en/research/studies/clinical-studies/delco de. The German Dementia Competence Network (KND) is funded by the German Federal Ministry of Education and Research (BMBF) grants Number: 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434, 01GI0711. WF, SvdL, HHolstege, CT and PhS are recipients of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and HealthHolland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD (www.aboard-project.nl).ABOARD also receives funding from de Hersenstichting, Edwin Bouw Fonds and Gieskes-Strijbisfonds. IEJ was partially supported by NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). AZ was supported by the Swedish Alzheimer Foundation (AF-939988, AF-930582, AF-646061, AF-741361), and the Dementia Foundation (2020-04-13, 2021-0417). ISk was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALFagreement (ALF 716681), the Swedish Research Council (no 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2019-01096), Swedish Research Council for Health, Working Life and Welfare (no 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 20050762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 20132496), Swedish Brain Power, Hjarnfonden, Sweden (FO2016-0214, FO2018-0214, FO2019-0163), the Alzheimer's Association Zenith Award (ZEN-01-3151), the Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159), the Alzheimer's Association (IIRG-03-6168, IIRG-09-131338) and the Bank of Sweden Tercentenary Foundation. SK was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-81392, ALF GBG-771071), the Swedish Alzheimer Foundation (AF-842471, AF-737641, AF-939825), and the Swedish Research Council (2019-02075). MW was supported by the Swedish Research Council 2016-01590. DP was supported by BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018-02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (2018092016862), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB was supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjarnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG06839801), and the Alzheimer's Association 2021 Zenith Award (ZEN-21848495). CC receives support from the National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG064614), and the Chuck Zuckerberg Initiative (CZI).

IntroductionThe efficacy and effectiveness of digital interventions for depression are both well-established. However, precise effect size estimates for mediators transmitting the effects of digital interventions are not available; and integrative insights on the specific mechanisms of change in internet- and mobile-based interventions (IMIs)—as related to key features like delivery type, accompanying support and theoretical foundation—are largely pending.ObjectiveWe will conduct a systematic review and individual participant data meta-analysis (IPD-MA) evaluating the mediators associated with therapeutic change in various IMIs for depression in adults.MethodsWe will use three electronic databases (i.e., Embase, Medline/PubMed, PsycINFO) as well as an already established database of IPD to identify relevant published and unpublished studies. We will include (1) randomized controlled trials that examine (2) mediators of (3) guided and unguided (4) IMIs with (5) various theoretical orientations for (6) adults with (7) clinically relevant symptoms of depression (8) compared to an active or passive control condition (9) with depression symptom severity as primary outcome. Study selection, data extraction, as well as quality and risk of bias (RoB) assessment will be done independently by two reviewers. Corresponding authors of eligible primary studies will be invited to share their IPD for this meta-analytic study. In a 1-stage IPD-MA, mediation analyses (e.g., on potential mediators like self-efficacy, emotion regulation or problem solving) will be performed using a multilevel structural equation modeling approach within a random-effects framework. Indirect effects will be estimated, with multiple imputation for missing data; the overall model fit will be evaluated and statistical heterogeneity will be assessed. Furthermore, we will investigate if indirect effects are moderated by different variables on participant- (e.g., age, sex/gender, symptom severity), study- (e.g., quality, studies evaluating the temporal ordering of changes in mediators and outcomes), and intervention-level (e.g., theoretical foundation, delivery type, guidance).DiscussionThis systematic review and IPD-MA will generate comprehensive information on the differential strength of mediators and associated therapeutic processes in digital interventions for depression. The findings might contribute to the empirically-informed advancement of psychotherapeutic interventions, leading to more effective interventions and improved treatment outcomes in digital mental health. Besides, with our novel approach to mediation analyses with IPD-MA, we might also add to a methodological progression of evidence-synthesis in psychotherapy process research.Study registration with Open Science Framework (OSF)https://osf.io/md7pq/.

We conducted a multi-omics study of SARS-CoV-2 and SARS-CoV and profiled their interactomes as well as their influence on host transcriptome, proteome, ubiquitinome and phosphoproteome. We further discovered both direct acting and host-directed antivirals that concomitantly inhibit both viral and host methyltransferases, which we demonstrate is required to efficiently suppress SARS-CoV-2 replication. Wir führten eine Multi-omics-Studie von SARS-CoV-2 und SARS-CoV durch und erstellten Profile ihrer Interaktome sowie ihres Einflusses auf das Transkriptom, Proteom, Ubiquitinom und Phosphoproteom des Wirts. Darüber hinaus entdeckten wir sowohl direkt wirkende als auch auf wirtsgerichtete Virostatika, die gleichzeitig sowohl virale als auch Wirts-Methyltransferasen hemmen, was nachweislich erforderlich ist, um die Replikation von SARS-CoV-2 effizient zu unterdrücken.

The advancements made in drug-eluting stent technology has reformed the standards of treatment of coronary artery disease. However, despite these improvements, stent failure in form of stent thrombosis or in-stent restenosis persists. In this regard, longer-term clinical data along with insights from intravascular imaging modalities and pharmacotherapy may allow the identification of predisposing factors more clearly. Die Fortschritte in der Technologie der medikamentenfreisetzenden Stents haben die Grundsätze für die Behandlung der koronaren Herzkrankheit reformiert. Trotz dieser Verbesserungen kommt es jedoch immer wieder zum Stentversagen in Form von einer Stentthrombose oder In-Stent-Restenose. In diesem Zusammenhang könnten längerfristige klinische Daten zusammen mit den Erkenntnissen aus der intravaskulären Bildgebung und der Pharmakotherapie eine genauere Identifizierung der prädisponierenden Faktoren ermöglichen.

This study examined the effect of rare PDE5A variants on coronary artery disease risk from several genetic and pharmacological aspects. Our study provides evidence of a putative causal effect of PDE5A overexpression on coronary artery disease and myocardial infarction. Furthermore, these findings vigorously promote PDE5 inhibition as a promising strategy to encounter coronary artery disease. However, this remains to be studied. Im Rahmen dieser Studie wurde genetisch und pharmakologisch untersucht, wie sich das Tragen seltener PDE5A Varianten auf das Risiko für koronare Herzerkrankungen auswirkt. In diesem Zusammenhang konnten wir einen mutmaßlich kausalen Zusammenhang zwischen einer PDE5A Überexpression und einem erhöhtem Risiko für koronare Herzerkrankungen feststellen. Diese Erkenntnisse erwecken den Eindruck, dass die Anwendung eines PDE5-Hemmers bei koronaren Herzerkrankungen von großem Nutzen sein könnte, was jedoch weiterer Untersuchungen bedarf.

This thesis addresses the annotated data insufficiency in medical imaging from three perspectives. First, we augment the model with data generated via random linear interpolation at the input and hidden spaces. Second, using a dynamic learning policy, we seek other data resources using federated learning, peer learning, and knowledge sharing. Lastly, we extracted the knowledge from unlabeled data using self-supervised learning via virtual embeddings and self-consistency. In dieser Arbeit wird der Mangel an kommentierten Daten in der medizinischen Bildgebung aus drei Perspektiven betrachtet. Erstens erweitern wir das Modell mit Daten, die durch zufällige lineare Interpolation im Eingabe- und im verborgenen Raum erzeugt werden. Zweitens suchen wir mithilfe einer dynamischen Lernstrategie nach anderen Datenressourcen, indem wir föderiertes Lernen, Peer-Learning und Wissensaustausch einsetzen. Schließlich extrahieren wir das Wissen aus unbeschrifteten Daten durch selbstüberwachtes Lernen mittels virtueller Einbettungen und Selbstkonsistenz.

NTCP serves as species-specific key factor for HBV entry. Identification of suitable animal NTCP may allow discovering potential HBV animal models. In this study, we identified NTCP from rabbits, cats and horses as suitable to allow HBV binding and uptake. Of note, HBV infection was increased by expressing horse instead of human NTCP on HepG2 and AML12 cells. Thus, horse NTCP may allow to create new in vitro and in vivo models of HBV infection and help to clarify NTCPs mode of action during HBV entry. NTCP dient als spezies-spezifischer Schlüsselfaktor für die Bindung des HBV an Leberzellen. Die Identifikation geeigneter NTCP aus dem Tierreich sollte helfen, neue Infektionsmodelle zu generieren. In dieser Arbeit wurden Kaninchen-, Katzen- und Pferde-NTCP als Kandidaten für eine HBV-Infektion identifiziert. Nach Expression des NTCP vom Pferd in permissiven Zellen war eine HBV Infektion effizienter als mit dem humanen Analog, was es zu einem vielversprechenden Protein macht, um in vitro als auch in vivo Modelle zu schaffen.

Die Hypothese dieser Arbeit behauptet, dass der Xdh- und Blvrb-vermittelte ROS-Umgang potenziell einen Vorteil für die (Hirn-)Kolonisation darstellt. In dieser Arbeit wurde ein stabiler Knockout von Xdh in der hoch-kolonisierenden Kolonkarzinom Zelllinie CT26 mittels eines CRISPR/Cas9-vermittelten Ansatzes generiert. Zusätzlich wurden Xdh und Blvrb pharmakologisch inhibiert. Die Gen- bzw. Protein-Expression nach der Enzymmodulation wurde mittels qRT-PCR und Western Blot untersucht. Darüber hinaus wurde der Einfluss auf die ROS Produktion der Karzinomzellen analysiert. Interessanterweise rief die genetische Herunterregulation von Xdh große Effekte in der Kolonkarzinom Zelllinie CT26 hervor, während die pharmakologische Inhibition die Expression und/oder Aktivität von beiden Enzymen nicht beeinflussen konnte. Die Generierung des stabilen Xdh-defizienten Klons wird in der Zukunft ermöglichen, dessen Wirkung in einer immunkompetenten Umgebung zu untersuchen, und somit die Einsetzbarkeit als Therapieziel gegen Hirnmetastasen zu testen., The hypothesis of this work is that the Xdh- and Blvrb-mediated ROS coping serves as a potential advantage in (brain-)colonization. In this work, a stable knock-out of Xdh in the cell line CT26 has been generated via a CRISPR/Cas9-mediated approach. Additionally, Xdh and Blvrb have been inhibited pharmacologically. The gene and protein expression after enzymatic modulation were investigated via qRT-PCR and Western Blot. Furthermore, the influence on the ROS production of the tumor cells was analyzed. Interestingly, the genetic downregulation of Xdh in the colon cancer cell line CT26 showed great effects, while the pharmacologic inhibition did not influence expression and/or activity of both enzymes. The generation of the stable Xdh-deficient clone will enable to further investigate its effect in an immunocompetent environment in the future and therefore the potential as a therapeutic target against brain metastasis.

Chronic pulmonary infection is a hallmark of cystic fibrosis (CF) and requires continuous antibiotic treatment. In this context, Pseudomonas aeruginosa (Pa) is of special concern since colonizing strains frequently acquire multiple drug resistance (MDR). Bactericidal/permeability-increasing protein (BPI) is a neutrophil-derived, endogenous protein with high bactericidal potency against Gram-negative bacteria. However, a significant range of people with CF (PwCF) produce anti-neutrophil cytoplasmic antibodies against BPI (BPI-ANCA), thereby neutralizing its bactericidal function. In accordance with literature, we describe that 51.0% of a total of 39 PwCF expressed BPI-ANCA. Importantly, an orthologous protein to human BPI (huBPI) derived from the scorpionfish Sebastes schlegelii (scoBPI) completely escaped recognition by these autoantibodies. Moreover, scoBPI exhibited high anti-inflammatory potency towards Pa LPS and was bactericidal against MDR Pa derived from PwCF at nanomolar concentrations. In conclusion, our results highlight the potential of highly active orthologous proteins of huBPI in treatment of MDR Pa infections, especially in the presence of BPI-ANCA.

Background: Identifying novel biomarkers that are both specific and sensitive to periprosthetic joint infection (PJI) has the potential to improve diagnostic accuracy and ultimately enhance patient outcomes. Therefore, the aim of this systematic review is to identify and evaluate the effectiveness of novel biomarkers for the diagnosis of PJI. Methods: We searched the MEDLINE, EMBASE, PubMed, and Cochrane Library databases from January 1, 2018, to September 30, 2022, using the search terms “periprosthetic joint infection,” “prosthetic joint infection,” or “periprosthetic infection” as the diagnosis of interest and the target index, combined with the term “marker.” We excluded articles that mentioned established biomarkers such as CRP, ESR, Interleukin 6, Alpha defensin, PCT (procalcitonin), and LC (leucocyte cell count). We used the MSIS, ICM, or EBJS criteria for PJI as the reference standard during quality assessment. Results: We collected 19 studies that analyzed fourteen different novel biomarkers. Proteins were the most commonly analyzed biomarkers (nine studies), followed by molecules (three studies), exosomes (two studies), DNA (two studies), interleukins (one study), and lysosomes (one study). Calprotectin was a frequently analyzed and promising marker. In the scenario where the threshold was set at ≥50-mg/mL, the calprotectin point-of-care (POC) performance showed a high sensitivity of 98.1% and a specificity of 95.7%. Conclusion: None of the analyzed biomarkers demonstrated outstanding performance compared to the established parameters used for standardized treatment based on established PJI definitions. Further studies are needed to determine the benefit and usefulness of implementing new biomarkers in diagnostic PJI settings.

We examine the mortality effects of a 1947 school reform in Japan, which extended compulsory schooling from primary to secondary school by as much as 3 years. The abolition of secondary school fees also indicates that those affected by the reform likely came from disadvantaged families who could have benefited the most from schooling. Even in this relatively favorable setting, we fail to find that the reform improved later-life mortality up to the age of 87 years, although it significantly increased years of schooling. This finding suggests limited health returns to schooling at the lower level of educational attainment., CINCH working paper series, vol. 2023, no. 02

Pancreatic ductal adenocarcinoma or pancreatic cancer (PDAC) exhibits a strong propensity to neural invasion (NI), but the molecular mechanisms of NI are unclear. Recent studies showed that central nervous system tumors like gliomas can make glutamatergic synapses with neurons, which they exploit for their growth. Purpose: We explored whether a similar glutamatergic neuronal input over the glutamate-NMDAR signaling into the cancer cells fosters their growth and promotes NI. Method: Analysis of the glutamate receptor profile of human and murine PDAC cell lines. Cultured PDAC cell lines were treated with L-Glutamate or DRG (dorsal root ganglion) conditioned medium (CM) or cocultured with DRG, and the effects of GluN2D (encoded by GRIN2D) and the transduction molecules of Glutamate-GluN2D-NMDAR signaling were quantified in the neuroinvasive and non-neuroinvasive pancreatic cancer cells. Results: Here we first profiled the glutamate receptor profile of human and murine PDAC cell lines on the CCLE database and correlated this pattern to the neuro-invasiveness of our cell lines. We show that the glutamate receptor subtype GluN2D (encoded by GRIN2D) was specifically involved in cell migration and invasion of the neuroinvasive pancreatic cancer cells mediated by L-Glutamate or DRG (dorsal root ganglion) conditioned medium (CM). Importantly, these phenotypic features could be completely reversed after GluN2D antagonist and GRIN2D siRNA treatment, however, not in non-neuroinvasive pancreatic cancer cells. The transduction molecules of Glutamate-GluN2D-NMDAR signaling were be activated and up-regulated by co-culture with DRG or through DRG CM. In co-cultures of neurons and PDAC cancer cells, GRIN2D, GRIN1, and the NMDAR-interaction partners PSD95 were upregulated in neuro-invasive PDAC cells exposed to neurons whereas synaptobrevin-1 and vGlut-2 were notably on axons that extended from neurons and synapsed on PDAC cells. This finding was not observed in non-neuroinvasive PDAC cells. Mechanistically, glutamate or DRG CM treatment led to the enrichment of the transcription factor EZH2 on the Grin2d promotor through the EZH2-E2F1-Rb pathway. Conclusion: Neurons promote the migration of PDAC towards neurons in a glutamate-fueled manner via GluN2D mediated Glutamate-NMDAR signaling, which is regulated by the upstream EZH2-E2F1-RB pathway. This molecular machinery between synapse-triggered PDAC migration represents a novel targetable pathway. Das duktale Adenokarzinom der Bauchspeicheldrüse (PDAC) neigt stark zur neuronalen Invasion (NI), aber die molekularen Mechanismen der NI sind unklar. Aktuell Studien haben gezeigt, dass Tumore des zentralen Nervensystems wie Gliome glutamaterge Synapsen mit Neuronen bilden können, die mithilfe Nervenzelle für ihr Wachstum fördern. Zweck: Wir untersuchten ob ein ähnlicher glutamaterger neuronaler Input über den Glutamat-NMDAR-Signalweg in die Krebszellen deren Wachstum fördert und die NI begünstigt. Methode: Analyse des Glutamatrezeptorprofils von menschlichen und murinen PDAC-Zelllinien. Die kultivierten PDAC-Zelllinien wurden mit L-Glutamat oder DRG (dorsal root ganglion) konditioniertem Medium (CM) behandelt oder mit DRG kokultiviert, und die Auswirkungen von GluN2D (kodiert durch GRIN2D) und die Transduktionsmoleküle der Glutamat-GluN2D-NMDAR-Signalübertragung wurden in den neuroinvasiven und nicht-neuroinvasiven Pankreaskrebszellen quantifiziert. Ergebnisse: Hier haben wir zunächst das Glutamatrezeptorprofil menschlicher und muriner PDAC-Zelllinien in der CCLE-Datenbank profiliert und dieses Muster mit der Neuroinvasivität unserer Zelllinien korreliert. Wir konnten zeigen, dass der Glutamatrezeptor-Subtyp GluN2D (kodiert durch GRIN2D) spezifisch an der Zellmigration und Invasion der neuroinvasiven Pankreaskrebszellen beteiligt war, die durch L-Glutamat oder DRG (dorsal root ganglion) konditioniertes Medium (CM) vermittelt wird. Wichtig konnten diese phänotypischen Merkmale nach Behandlung mit einem GluN2D-Antagonisten und GRIN2D siRNA vollständig rückgängig gemacht werden, jedoch nicht in nicht-neuroinvasiven Pankreaskrebszellen. Die Transduktionsmoleküle der Glutamat-GluN2D-NMDAR-Signalübertragung wurden durch Ko-Kultur mit DRG oder durch DRG-CM aktiviert und hochreguliert. In Ko-Kulturen von Neuronen und PDAC-Krebszellen wurden GRIN2D, GRIN1 und die NMDAR-Interaktionspartner PSD95 in neuroinvasiven PDAC-Zellen, die Neuronen ausgesetzt waren, hochreguliert, wohingegen Synaptobrevin-1 und vGlut-2 sich insbesondere auf Axonen befanden, die von Neuronen ausgingen und auf PDAC-Zellen synapsierten. Dieser Befund wurde bei nicht-neuroinvasiven PDAC-Zellen nicht beobachtet. Mechanistisch gesehen führte die Behandlung mit Glutamat oder DRG-CM zur Anreicherung des Transkriptionsfaktors EZH2 am Grin2d-Promotor über den EZH2-E2F1-Rb-Weg. Schlussfolgerung: Neuronen fördern die Migration von PDAC in Richtung Neuronen auf eine Glutamat-getriebene Weise über GluN2D-vermittelte Glutamat-NMDAR-Signale, die durch den vorgeschalteten EZH2-E2F1-RB-Weg reguliert werden. Diese molekulare Maschinerie zwischen Synapsen-getriggerter PDAC-Migration stellt einen neuartigen, zielgerichteten Weg dar.

Integrating functional layers such as digital holographic microscopy analysis and unbiased drug screening into precision oncology allowed us to retrieve more detailed information about adaptive processes in tumor evolution and treatment-imposed pressure in pancreatic cancer than genomic and transcriptomic analysis alone. This information can be used in future to overcome chemoresistance, guide treatment decisions and longitudinally monitor treatment response. Die Integration funktioneller Schichten wie digital holographische Mikroskopie und automatisierte Wirkstoffscreenings in die Präzisionsonkologie erlaubte es, detailliertere Informationen über adaptive Prozesse in der Tumorevolution und den behandlungsbedingten Druck im Pankreaskarzinom zu erhalten als Genom- und Transkriptomanalysen allein. Diese Daten können genutzt werden, um Resistenzen zu überwinden, Behandlungsentscheidungen zu treffen und das Ansprechen auf die Behandlung zu überwachen.

Conventional 2D cultures are commonly used in cancer research though they come with limitations such as the lack of microenvironment or reduced cell heterogeneity. In this study, we investigated in what respect a scaffold-based (Matrigel™) 3D culture technique can ameliorate the limitations of 2D cultures. NGS-based bulk and single-cell sequencing of matched pairs of 2D and 3D models showed an altered transcription of key immune regulatory genes in around 36% of 3D models, indicating the reoccurrence of an immune suppressive phenotype. Changes included the presentation of different HLA surface molecules as well as cellular stressors. We also investigated the 3D tumor organoids in a co-culture setting with tumor-infiltrating lymphocytes (TILs). Of note, lymphocyte-mediated cell killing appeared less effective in clearing 3D models than their 2D counterparts. IFN-γ release, as well as live cell staining and proliferation analysis, pointed toward an elevated resistance of 3D models. In conclusion, we found that the scaffold-based (Matrigel™) 3D culture technique affects the transcriptional profile in a subset of GBM models. Thus, these models allow for depicting clinically relevant aspects of tumor-immune interaction, with the potential to explore immunotherapeutic approaches in an easily accessible in vitro system.

Aims Oesophageal fistula represents a rare but dreadful complication of atrial fibrillation catheter ablation. Data on its incidence, management, and outcome are sparse. Methods and results This international multicentre registry investigates the characteristics of oesophageal fistulae after treatment of atrial fibrillation by catheter ablation. A total of 553 729 catheter ablation procedures (radiofrequency: 62.9%, cryoballoon: 36.2%, other modalities: 0.9%) were performed, at 214 centres in 35 countries. In 78 centres 138 patients [0.025%, radiofrequency: 0.038%, cryoballoon: 0.0015% (P < 0.0001)] were diagnosed with an oesophageal fistula. Peri-procedural data were available for 118 patients (85.5%). Following catheter ablation, the median time to symptoms and the median time to diagnosis were 18 (7.75, 25; range: 0–60) days and 21 (15, 29.5; range: 2–63) days, respectively. The median time from symptom onset to oesophageal fistula diagnosis was 3 (1, 9; range: 0–42) days. The most common initial symptom was fever (59.3%). The diagnosis was established by chest computed tomography in 80.2% of patients. Oesophageal surgery was performed in 47.4% and direct endoscopic treatment in 19.8% and conservative treatment in 32.8% of patients. The overall mortality was 65.8%. Mortality following surgical (51.9%) or endoscopic treatment (56.5%) was significantly lower as compared to conservative management (89.5%) [odds ratio 7.463 (2.414, 23.072) P < 0.001]. Conclusion Oesophageal fistula after catheter ablation of atrial fibrillation is rare and occurs mostly with the use of radiofrequency energy rather than cryoenergy. Mortality without surgical or endoscopic intervention is exceedingly high.

Antibiotics represent an essential pillar in the treatment of respiratory infections (RI). Overuse of antibiotics in avoidable cases and inappropriate application in bacterial infections facilitate treatment resistance, threatening their effectiveness and causing a significant healthcare challenge. We therefore assessed the savings potential for antibiotics in ambulant care of selected RI (bronchitis and cough, pharyngitis, rhinosinusitis) in several European countries based on market research data for the year 2019. Number of antibiotic packages sold in pharmacies varied, with highest values in Serbia and France, and lowest in Sweden and Switzerland. Selected RI contributed nearly half of overall ambulant antibiotic prescriptions, with around one fifth given for bronchitis and cough; the vast majority was estimated to be of viral origin with potentially avoidable antibiotic use. Antibiotic consumption for selected RI in eight European countries (Austria, Belgium, the Czech Republic, France, Germany, Poland, Slovakia, and Switzerland) amounted to nearly 100 million, with an overall savings potential between 66.2 and 83.7 million packages. The highest estimated volume of avoidable antibiotics was in France (44.7 million, 0.80 per capita), and lowest in Switzerland (1.4 million, 0.18 per capita). Due to substantial savings potential, prudent use of antibiotics and adequate application of alternatives should be promoted in daily practice.

This paper investigates the potential of new technologies to reduce disparities in the provision of healthcare services. Differences in providers’ skills may cause variation in patient outcomes. The adoption of innovations, like robots, can attenuate this problem if technological gains are decreasing in users’ skills or may exacerbate existing variation in performance otherwise. I show that, in England, the diffusion of surgical robots coincided with an improvement in average surgical performance and a convergence in outcomes between high and lower-skilled surgeons for prostate cancer patients. I study whether this pattern can be attributed to the adoption of robots using the universe of inpatient admissions to the National Health Service (NHS). To identify the effects of robotic surgery on patient outcomes, I exploit quasi-random variation in the geographic allocation of robots, allowing for selection and heterogeneity in treatment effects. I find that robots shorten patients’ length of stay in hospital and decrease the incidence of adverse events from surgery, but their effects significantly depend on surgeons’ skills. The robot has little impact on the performance of highly skilled surgeons, while lower skilled surgeons gain the most from it. I also uncover a strong pattern of negative selection on both observable and unobservable characteristics. Although the attainable gains are higher for lower-skilled surgeons, they use the robot the least. My results suggest that the potential benefit of a new technology largely depends on how it combines with the skills of the individual users., CINCH working paper series, vol. 2023, no. 01

The Hitchiker’s Guide to Machine Learning for Biomedical Image Analysis is a dissertation for tackling biomedical image analysis problems with machine learning. It covers the whole iterative workflow from dataset curation, network training, evaluation, and interpretation of results to refining the model in three parts. Peer-reviewed academic contributions and an outlook complete the dissertation. The Hitchiker’s Guide to Machine Learning for Biomedical Image Analysis ist eine Dissertation zur Bearbeitung biomedizinischer Bildanalyseprobleme mittels maschinellem Lernen. In drei Teilen wird der gesamte iterative Arbeitsablauf vom Kuratieren von Datensätzen, Netzwerktraining, Evaluation und Interpretation von Ergebnissen, bis hin zum Verfeinern von Modellen behandelt. Akademische Veröffentlichen, sowie ein Ausblick komplettieren die Dissertation.

Purpose For patients with triple negative breast cancer (TNBC), the optimal time to initiate neoadjuvant chemotherapy (TTNC) is unknown. This study evaluates the association between TTNC and survival in patients with early TNBC. Methods A retrospective study using data from of a cohort of TNBC patients diagnosed between January 1, 2010 to December 31, 2018 registered in the Tumor Centre Regensburg was performed. Data included demographics, pathology, treatment, recurrence, and survival. Interval to treatment was defined as days from pathology diagnosis of TNBC to first dose of neoadjuvant chemotherapy (NACT). The Kaplan–Meier and Cox regression methods were used to evaluate the impact of TTNC on overall survival (OS) and 5 year OS. Results A total of 270 patients were included. Median follow up was 3.5 years. The 5-year OS estimates according to TTNC were 77.4%, 66.9%, 82.3%, 80.6%, 88.3%, 58.3%, 71.1% and 66.7% in patients who received NACT within 0–14, 15–21, 22–28, 29–35, 36–42, 43–49, 50–56 and > 56 days after diagnosis. Patients who received systemic therapy early had the highest estimated mean OS of 8.4 years, while patients who received systemic therapy after more than 56 days survived an estimated 3.3 years. Conclusion The optimal time interval between diagnosis and NACT remains to be determined. However, starting NACT more than 42 days after diagnosis of TNBC seems to reduce survival. Therefore, it is strongly recommended to carry out the treatment in a certified breast center with appropriate structures, in order to enable an adequate and timely care.

Graft-versus-host disease (GvHD), a significant threat after allogeneic hematopoietic stem cell transplantation (aHSCT), limits the success of cancer treatment. By adapting and establishing single-cell and spatial methods, we analyzed immune infiltration in gastrointestinal biopsies of GvHD patients. We could prove a link to the gut microbiome via regulatory T cells and show that GvHD is an antigen-specific disease driven by anatomically distributed CD8 T cell clonotypes. Our findings suggest new therapies, like microbiome interventions, to improve the efficiency of aHSCT. Die Graft-versus-Host-Reaktion (GvHR), eine schwere Komplikation nach allogener, hämatopoetischer Stammzelltransplantation (aHSZT), mindert den Erfolg von Tumor Behandlungen. Mithilfe von neu etablierten oder angepassten Methoden haben wir Immun-Zell Infiltrate in gastrointestinalen Biopsien von GvHR Patienten untersucht. Wir konnten eine Verbindung zum Mikrobiom über regulatorische T Zellen bestätigen und zeigen, dass GvHR eine Antigen-spezifische Krankheit ist, welche von anatomisch verteilten CD8 T Zellen angetrieben wird. Die Ergebnisse führen zu neuen Therapieansätzen, wie der Mikrobiom-Intervention, um die Effizienz aHSZT zu verbessern.

Aufmerksamkeit ist eine wichtige kognitive Operation, die mehrere Prozesse betrifft, zu welchen Konzentration, Orientierung, Filterung und Verarbeitung von Inputs, das Aufrechterhalten des Fokus und endogene Kontrolle gehören (Colombo, 2001; Hendry et al., 2019). Es wird angenommen, dass Aufmerksamkeit die Allokation von kognitiven Ressourcen, die Priorisierung und Aktualisierung eintreffender Informationen und die Regulierung von Verhalten in der frühkindlichen Entwicklung unterstützen kann (Colombo et al., 2011; Esterman & Rothlein, 2019). Die Fähigkeit zur Steuerung von Aufmerksamkeit in frühen Jahren wird häufig als entscheidend für die spätere Entwicklung von Selbstregulation angesehen (Posner et al., 2016; Rueda, Posner, et al., 2005), welche verbunden ist mit der akademischen Leistung und Lernleistung im späteren Leben (Best et al., 2011; Morgan et al., 2019). Beeinträchtigungen von Aufmerksamkeit und Selbstregulation sind oft mit neurologischen Entwicklungsstörungen verbunden, wie beispielsweise einer Aufmerksamkeitsdefizits- oder einer Hyperaktivitätsstörung (Barkley, 1997; Sjöwall et al., 2013; Sonuga-Barke et al., 2010) oder einer Autismus-Spektrum-Störung (Gilotty et al., 2002; Matson et al., 2013; Samson et al., 2014). Der Blick nach vorn – vom Säugling zum Kleinkind Die Entwicklungsliteratur verlässt sich zur Messung der Aufmerksamkeitssteuerung stark auf die Messung unterschiedlichen Blickverhaltens (Bornstein, 1985; Colombo et al., 1999; Gredebäck et al., 2009). Verschiedene Parameter des Blickverhaltens wurden verwendet, um unterschiedliche Aspekte der Aufmerksamkeitssteuerung zu erfassen, wie beispielsweise die Latenz der Ausrichtung zu Stimuli (Pyykkö et al., 2020), die Blickdauer auf Stimuli (Johansson et al., 2015) oder die Verarbeitungsgeschwindigkeit visueller Stimuli (Blankenship et al., 2019). Obwohl berichtet wurde, dass verschiedene Aspekte der Entwicklung der Aufmerksamkeitssteuerung über die ersten 2 Lebensjahre stabil sind (Brandes-Aitken et al., 2019; Colombo et al., 2004; Rose & Feldman, 1987; Rose et al., 2001), basieren die meisten Ergebnisse auf einem einzelnen und kurzen Beobachtungszeitraum (z. B. 5 Minuten). In dieser Arbeit wird eine datengetriebene Methodik eingesetzt, um einen longitudinalen Datensatz zu untersuchen, der Daten zum Blickverhalten im Alter von 6, 10 und 18 Monaten enthält. Auf diese Weise sind wir im Stande, Entwicklungsänderungen der Aufmerksamkeitssteuerung aus verschiedenen Perspektiven zu beobachten. Vor allem konnte auf diese Weise eine stabile und robuste Messgröße identifiziert und etabliert werden, die verwendet werden kann, um zu anderen Variablen in Bezug gesetzt zu werden, beispielsweise in der vorliegenden Arbeit zur Selbstregulation und zur mütterlichen psychischen Gesundheit. Aufmerksamkeit im Säuglingsalter wird oft als Frühindikator oder Prädiktor für Selbstregulationsfunktionen genutzt. Selbstregulationsfunktionen wiederum, häufig unter Betonung von Effortful Control und exekutiven Funktionen (Posner & Rothbart, 2000; Rothbart & Rueda, 2005; Rothbart, Sheese, et al., 2011), korreliert mit individuellen akademischen Leistungen, der Lebenszufriedenheit und dem Arbeitsmarkterfolg (Ahmed et al., 2019; Best et al., 2011; Brock et al., 2009; Morgan et al., 2019). Es wurde vorgeschlagen, dass Aufmerksamkeit grundlegend für die Entwicklung von Selbstregulationsfunktionen ist (Colombo & Cheatham, 2006; Posner & Rothbart, 2009; Rueda, Posner, et al., 2004). Auf dieser Basis haben mehrere jüngere Studien einen positiven Zusammenhang zwischen Aufmerksamkeit und Selbstregulation in den frühen Lebensjahren festgestellt (Blankenship et al., 2019; Cuevas & Bell, 2014; Geeraerts et al., 2019; Papageorgiou et al., 2014). In der vorliegenden Arbeit wurde die Literatur gesichtet, die diesen Zusammenhang aufstellt, und die Gesamtevidenz geprüft. Obwohl zwar empirische Hinweise darauf existieren, die diese Feststellung unterstützen, sind die Ergebnisse nicht konsistent. Des Weiteren werden basierend auf den gleichen Annahmen experimentelle Ergebnisse präsentiert, welche den Zusammenhang zwischen Messgrößen der Aufmerksamkeit im Säuglingsalter (auf Basis der datengetriebenen Methodik) und der Selbstregulationsfunktionen im Alter von 18 und 30 Monaten untersuchen. Die vorliegenden Resultate, ebenso wie der Literaturüberblick unterstützen die Behauptung eines Zusammenhangs zwischen Aufmerksamkeit und Selbstregulation nicht, zumindest nicht im Kleinkindalter. Der Blick zurück – vom Säugling zu Schwangerschaft und Kindheit der Mutter Vor dem Hintergrund der Wichtigkeit von Aufmerksamkeit im Säuglingsalter und der zuvor beschriebenen Rolle in der späteren Entwicklung haben Studien zu Säuglingsalter und Kindheit versucht, diejenigen Risikofaktoren zu identifizieren, welche die Aufmerksamkeitsentwicklung beeinträchtigen könnten. Dies legt den nachträglichen Fokus der Betrachtung auf die In-Utero-Periode und sogar Kindheitserfahrungen der Mutter. Es existieren substantielle Hinweise darauf, dass mütterliche Stressfaktoren kortikale und subkortikale Verknüpfungen von Säuglingen beeinflussen (Rifkin-Graboi et al., 2013; Scheinost et al., 2020) und negative Auswirkungen auf die kognitive Entwicklung von Kindern haben kann (Keim et al., 2011; Kingston et al., 2015; Laplante et al., 2004; Tarabulsy et al., 2014). Des Weiteren wurde in jüngeren Studien berichtet, dass negative mütterliche Kindheitserfahrungen einen kumulativen Effekt auf die mütterliche psychische Gesundheit haben kann (Sacchi et al., 2020; Weltz et al., 2016) und wiederum zu strukturellen Konsequenzen für die neuronale Entwicklung in-utero führen kann (Andescavage et al., 2017; Moog et al., 2018). Im Einklang mit diesen Ergebnissen haben mehrere umfangreiche Studien einen negativen Zusammenhang zwischen mütterlichem Stress und Kindheitstraumata, aufmerksamkeitsbezogenen Problemen (Ross et al., 2020; Wang & Dix, 2017), Aufmerksamkeitsdefizits-/Hyperaktivitätssymptomen (Moon et al., 2021; Mulraney et al., 2019; Vizzini et al., 2019) und einem erhöhten Autismusrisiko (Roberts et al., 2013) ihrer Kinder gezeigt. Obgleich eine umfangreiche Literatur zeigt, dass mütterlicher Stress die Aufmerksamkeit von Kindern beeinflusst, sind die zugrundeliegenden Mechanismen weiterhin unbekannt. In der vorliegenden Arbeit wurden die theoretischen Erklärungsansätze und die empirische Beweislage zum Zusammenhang von mütterlichen Stressfaktoren und Aufmerksamkeit des Nachwuchses untersucht. Im nächsten Schritt wurden, um ein besseres Verständnis für die zugrundeliegenden Mechanismen zu entwickeln, verschiedene Aspekte der mütterlichen psychischen Gesundheit (z. B. depressive Symptome, Symptome von Angstgefühlen und negative mütterliche Kindheitserfahrungen) und ihr Zusammenhang mit der Aufmerksamkeit von Säuglingen untersucht, basierend auf der gleichen Stichprobe anhand der Aufmerksamkeitsmessgrößen und unter Hinzufügen mütterlichen Daten von der Schwangerschaft bis 12 Monate nach der Geburt. Im Gesamten behandelt die vorliegende Arbeit drei Hauptthesen, welche in zwei verbundenen Veröffentlichungen untersucht werden. Erstens wurde die Entwicklung von Aufmerksamkeit im Alter von 6, 10 und 18 Monaten unter Verwendung von etwa 0,5 Millionen Fixierungen von Eye-Tracking-Messungen untersucht und mittels einer datengetriebenen Methode analysiert. Nach der Entwicklung von stabilen und robusten Aufmerksamkeitsmessgrößen, wurde das zweite Ziel umgesetzt, den Zusammenhang mit Selbstregulationsfunktionen zu untersuchen. Drittens wurde unter Verwendung der robusten Aufmerksamkeitsmessgrößen untersucht, ob rückblickend negative mütterliche Kindheitserfahrungen und mütterliche Stressfaktoren während der Schwangerschaft die Aufmerksamkeit von Säuglingen beeinflussen (Tu et al., 2021). Im Ergebnis zeigt sich (1) ein hoher Grad an Stabilität und interne Konsistenz zweier Aspekte der Aufmerksamkeitssteuerung von 6 bis 18 Monaten unter Verwendung einer datengetriebenen Methodik; (2) die Abwesenheit eines signifikanten Zusammenhangs zwischen Aufmerksamkeitssteuerung im Säuglingsalter und Selbstregulation im Kleinkindalter, welche eine weithin angenommene Verbindung zumindest im Kleinkindalter nicht bestätigt; und (3) einen signifikanten Einfluss von mütterlichen psychologischen Stressfaktoren, die in Verbindung zu negativen mütterlichen Kindheitserfahrungen stehen, auf die dauerhafte Aufmerksamkeit von Säuglingen. Zusammenfassend bietet die vorliegende Arbeit tiefere Einblicke in die Entwicklung von Aufmerksamkeit im Säuglingsalter und trägt zu einer wachsenden Literatur bei, die nahelegt, dass Prävention und Intervention sowohl für Mütter als auch für Säuglinge bereits vor der Schwangerschaft ansetzen sollten. Gleichzeitig zeigt die vorliegende Arbeit auf, dass das Forschungsfeld dringend weitere Untersuchungen zu den Entwicklungspfaden benötigen, die zu Selbstregulation führen. Dies unterstreicht die mehrstufige Natur von Entwicklungsprozessen. Zum jetzigen Zeitpunkt besteht nur wenig Evidenz, dass Aufmerksamkeit im frühen Säuglingsalter stark und auf besondere Weise mit Selbstregulation in der Kindheit in Zusammenhang stünde. Eine Theoriebasis und überprüfbare Modelle, die spezifisch für die Bewertung von früh entstehenden Grundlagen der Selbstregulation entwickelt werden, wären essenzielle Modelle, die der Komplexität der Aufgabe gerecht werden können.:1. Introduction p.7 1.1 Attentional Control in Infancy p.10 1.1.1 Development of Attentional Control in Infancy p.10 1.1.2 The Application of a Data-driven Method for Attention Measures Using Eye-tracking Data p.13 1.2 Attention and Self-regulatory Functions p.19 1.2.1 Distinct yet Approximate Aspects of Self-regulatory Functions in Early Years of Life p.19 1.2.2 The Relation between Attentional Control and Self-regulatory Functions p.20 1.3 Maternal Distress and Infants’ Attention p.26 1.3.1 Cross-generational Effects on Offspring’s Attention p.26 1.3.2 A Multi-dimensional Investigation of the Impact of Maternal Distress on Infants’ Attention p.27 2. Experimental Work p.33 2.1 Publication 1 – Experimental Work: Tu et al., (2022) p.35 2.2 Publication 2 – Experimental Work: Tu et al., (2021) p.51 3. General Discussion and Outlook p.67 3.1 Implications and Questions from the Experimental Work p.67 3.2 Optimizing the Design for Future Studies p.70 4. Summary p.73 3.1 English Summary p.73 3.2 Deutsche Zusammenfassung p.76 References p.80 Appendix p.96 A.1 Supplementary Information p.96 A.2 Author Contributions to the Publications p.97 A.3 Declaration of Authenticity p.99 A.4 Curriculum Vitae p.100 A.5 List of Publications p.102 A.6 Conference Contributions p.102 A.7 Acknowledgements p.103

Research focusing on the pathophysiology of neurodegenerative disorders has undergone a fundamental shift towards a network perspective in the last decades. Besides regional aggregation of misfolded proteins and changes in cellular metabolism, accompanying changes of synaptic activity evolve and evoke dysregulation within neural circuits including remote brain regions. Modern theories of neurodegeneration propose a stereotypic pattern of these cerebral pathologies, which partly are in vivo accessible by multimodal neuroimaging techniques. The most often used indirect measurement of functional network integrity is resting-state functional magnetic resonance imaging, which depends on a complex interplay of hemodynamics, blood volume, and blood flow. Less is known about a potential metabolic component underlying resting-state networks in healthy brains and changes thereof in neurodegeneration and the influence of different transmitter systems. The current work therefore sought to investigate the association between functional resting-state networks and metabolic network activity and focused on metabolic consequences of nigrostriatal and striatocortical dysfunction in Parkinson’s disease. In the current work, a multimodal data set of the TP10 KFO219 cohort was analyzed regarding 1) the impact of nigrostriatal dopamine depletion on resting-state networks and 2) the relation between changes in functional connectivity and metabolic network activity. The first study addressed the subset of the KFO219 TP10 cohort who completed the trimodal imaging protocol (42 patients vs. 14 controls). Dopamine deficiency in Parkinson’s patients was examined by voxel-wise comparison of 6-[18F]fluoro-L-Dopa positron emission tomography scans. Resulting clusters served as seeds for restingstate functional connectivity maps that were compared between both groups by voxelwise t-tests. Metabolic activity was extracted from 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography scans for respective cortical clusters with striatocortical dysconnectivity and the relation to functional connectivity values was analyzed. In a separate study, functional and metabolic resting-state networks were obtained by performing spatial independent component analyses in a subset of the same cohort who underwent 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography and functional magnetic resonance imaging (56 vs 16) and completed neuropsychological testing. Multimodally obtained regions of interest in the default mode network were defined and metabolic activity as well as metabolic connectivity compared to functional connectivity differences between patients without or with mild cognitive impairment and healthy controls. Moreover, a third study was initiated in the context of the present work with the aim of establishing a dynamic 2-[18F]fluoro-2-deoxy-D-glucose positronemission tomography acquisition with a constant infusion protocol for examining interregional metabolic connectivity on single subject level and enable comparable analysis of hemodynamic and metabolic fluctuations in Parkinson’s disease. In the first study, a significant association between striatocortical functional connectivity changes of the data-driven defined dopamine depleted posterior putamen and metabolic activity of the cortical target area in the inferior parietal cortex was found in Parkinson’s disease. Interestingly, striatocortical connectivity of the inferior parietal cortex was associated with motor and cognitive impairment. In a second study, the multivariate approach revealed a moderate spatial convergence for the posterior default mode network in functional and metabolic data. For all multimodally obtained default mode network regions, a significant trend towards an increment of metabolic deficits from healthy controls via unimpaired patients to patients with mild cognitive impairment was identified. In addition, posterior default mode network regions with the strongest metabolic deficits and gradual decline in comparison to controls, also showed the strongest increases in both metabolic and functional connectivity compared to controls. The verification of the applicability of a constant infusion dynamic 2-[18F]fluoro-2-deoxy- D-glucose positron emission tomography protocol in Parkinson’s disease patients was started in a self-initiated study, which finished the acquisition phase with 10 participants per group by the time the current work was submitted. Together the first two studies highlight the added value of multimodal imaging in investigating human brain function and the pathophysiology of neurodegenerative disorders, in particular their great potential for identifying links between individual pathologies. The second study partly continued, and answered questions raised in response to the first study, which hinted at an involvement of default mode network regions in cognitive symptoms of Parkinson’s disease and a relation between functional network degeneration and metabolic activity. The current work shows exemplary the complementarity of both measures of brain network activity and their individual significance for cognitive symptoms in Parkinson’s disease. The presented work highlights how multimodal resting-state studies can provide new insights into the (patho-)physiological network organization of brain activity by confirming insights obtained by one modality and deepen our understanding of disease processes. The selfinitiated study further laid the ground for multimodal characterization of metabolic and hemodynamic network changes on single-subject level and the evaluation of dynamic positron emission tomography-based connectivity as metabolic network marker for Parkinson’s disease.

Background: Entamoeba gingivalis (E. gingivalis) is an anaerobic protozoan that is strongly associated with inflamed periodontal pockets. It is able to invade the mucosal epithelium of the human host, where it can feed on epithelial cells and elicit a severe innate immune response. Unlike other Entamoeba species, it is considered that E. gingivalis cannot form cysts, because it is a non-infectious protozoan. The lack of encystation capability would make it susceptible to periodontal treatment. However, it is not clear how the human host becomes infected with E. gingivalis trophozoites. We investigated the ability of E. gingivalis to encapsulate in response to an unfavorable environment in vitro. Methods: Different strains of E. gingivalis, isolated from inflamed periodontal pocket samples, were cultured for 8 days in the presence or absence of the antimicrobials amoxycillin and metronidazole. To reveal cyst formation, we investigated the morphology and ultrastructure of the amoeba by light, fluorescence, transmission and scanning electron microscopy. We also used the fluorescent dye calcofluor white M2R to demonstrate chitin present in the cyst wall. Results: We observed exocysts and an intra-cystic space separating the encapsulated trophozoite from the environment. Remarkably, cysts showed a smooth surface, polygonal edges and smaller size compared to free-living trophozoites. In addition, encapsulated trophozoites that detached from the cyst wall had a dense cytoplasma without phagocytic vesicles. The cyst walls consisted of chitin as in other Entamoba species. The encapsulated trophozoids were mononuclear after antibioticinduced encapsulation. Discussion: We conclude that E. gingivalis cyst formation has significant implications for dissemination and infection and may explain why established treatment approaches often fail to halt periodontal tissue destruction during periodontitis and peri-implantitis.

Background This study evaluated if genetic variations in the WNT family members and RUNX2 are associated with craniofacial maturation, investigating dental and skeletal maturity in children and teenagers. Methods Radiographs from pre-orthodontic treatment of Brazilian patients (7 to 17 years-old) were used to assess dental (panoramic radiographs) and skeletal maturity (cephalometric radiographs). The chronological age (CA) was calculated based on the date of birth and the time the radiographs were performed. For the dental maturity analysis, the Demirjian (1973) method was used and a delta [dental age - chronological age (DA-CA)] was calculated. For the skeletal maturity analysis, the Baccetti et al. (2005) method was used and the patients were classified as “delayed skeletal maturation”, “advanced skeletal maturation” or “normal skeletal maturation”. DNA isolated from buccal cells was used for genotyping of two genetic variations in WNT family genes: rs708111 (G > A) in WNT3A and rs1533767 (G > A) in WNT11; and two genetic variations in RUNX2: rs1200425 (G > A) and rs59983488 (G > T). A statistical analysis was performed and values of p < 0.05 indicated a significant difference. Results There were no associations between dental maturity and genotypes (p > 0.05). In the skeletal maturity analysis, the allele A in the rs708111 (WNT3A) was statistically more frequent in patients with delayed skeletal maturation (Prevalence Ratio = 1.6; 95% Confidence Interval = 1.00 to 2.54; p-value = 0.042). Conclusions The rs708111 in the WNT3A gene impacts on skeletal maturation.

Purpose For resolving anterior dental crowding or spacing, it is of key interest in personalised orthodontic diagnostics and treatment planning to predict the extent of space gained or lost in the anterior dental arch by changing incisor inclination or position. To facilitate the determination of anterior arch length (AL) and to predict its alterations following tooth movements, a mathematical–geometrical model, based on a third-degree parabola, was established. The aim of this study was to validate this model and assess its diagnostic precision. Methods This retrospective diagnostic study evaluated 50 randomly chosen dental casts taken before (T0) and after (T1) orthodontic treatment with fixed appliances. Plaster models were digitally photographed, allowing two-dimensional digital measurements of arch width, depth and length. A computer programme based on the mathematical–geometrical model to be validated was created to calculate AL for any given arch width and depth. Mean differences and correlation coefficients as well as Bland–Altman plots were used to compare the measured and the calculated (predicted) AL, evaluating the precision of the model. Results Inter- and intrarater reliability tests showed reliable measurements of arch width, depth and length. Measured and calculated (predicted) AL revealed high concordance according to concordance correlation coefficient (CCC), intraclass correlation coefficient (ICC), and Bland–Altman analyses and negligible differences between the mean values. Conclusions The mathematical–geometrical model calculated anterior AL without significant difference to the measured AL, indicating its validity. The model can thus be used clinically for predicting alterations of AL following therapeutic changes of incisor inclination/position.

The German Centre for Cardiovascular Research (DZHK) is one of the German Centres for Health Research and aims to conduct early and guideline-relevant studies to develop new therapies and diagnostics that impact the lives of people with cardiovascular disease. Therefore, DZHK members designed a collaboratively organised and integrated research platform connecting all sites and partners. The overarching objectives of the research platform are the standardisation of prospective data and biological sample collections among all studies and the development of a sustainable centrally standardised storage in compliance with general legal regulations and the FAIR principles. The main elements of the DZHK infrastructure are web-based and central units for data management, LIMS, IDMS, and transfer office, embedded in a framework consisting of the DZHK Use and Access Policy, and the Ethics and Data Protection Concept. This framework is characterised by a modular design allowing a high standardisation across all studies. For studies that require even tighter criteria additional quality levels are defined. In addition, the Public Open Data strategy is an important focus of DZHK. The DZHK operates as one legal entity holding all rights of data and biological sample usage, according to the DZHK Use and Access Policy. All DZHK studies collect a basic set of data and biosamples, accompanied by specific clinical and imaging data and biobanking. The DZHK infrastructure was constructed by scientists with the focus on the needs of scientists conducting clinical studies. Through this, the DZHK enables the interdisciplinary and multiple use of data and biological samples by scientists inside and outside the DZHK. So far, 27 DZHK studies recruited well over 11,200 participants suffering from major cardiovascular disorders such as myocardial infarction or heart failure. Currently, data and samples of five DZHK studies of the DZHK Heart Bank can be applied for.

Motor skill learning relies on neural plasticity in the motor and limbic systems. However, the spatial and temporal characteristics of these changes—and their microstructural underpinnings—remain unclear. Eighteen healthy males received 1 hour of training in a computer-based motion game, 4 times a week, for 4 consecutive weeks, while 14 untrained participants underwent scanning only. Performance improvements were observed in all trained participants. Serial myelin- and iron-sensitive multiparametric mapping at 3T during this period of intensive motor skill acquisition revealed temporally and spatially distributed, performance-related microstructural changes in the grey and white matter across a corticospinal-cerebellar-hippocampal circuit. Analysis of the trajectory of these transient changes suggested time-shifted cascades of plasticity from the dominant sensorimotor system to the contralateral hippocampus. In the cranial corticospinal tracts, changes in myelin-sensitive metrics during training in the posterior limb of the internal capsule were of greater magnitude in those who trained their upper limbs vs. lower limb trainees. Motor skill learning is associated with waves of grey and white matter plasticity, across a broad sensorimotor network.

BACKGROUND AND PURPOSE: Target delineation in glioblastoma is still a matter of extensive research and debate. This guideline aims to update the existing joint European consensus on delineation of the clinical target volume (CTV) in adult glioblastoma patients.MATERIAL AND METHODS: The ESTRO Guidelines Committee identified 14 European experts in close interaction with the ESTRO clinical committee and EANO who discussed and analysed the body of evidence concerning contemporary glioblastoma target delineation, then took part in a two-step modified Delphi process to address open questions.RESULTS: Several key issues were identified and are discussed including i) pre-treatment steps and immobilisation, ii) target delineation and the use of standard and novel imaging techniques, and iii) technical aspects of treatment including planning techniques and fractionation. Based on the EORTC recommendation focusing on the resection cavity and residual enhancing regions on T1-sequences with the addition of a reduced 15 mm margin, special situations are presented with corresponding potential adaptations depending on the specific clinical situation.CONCLUSIONS: The EORTC consensus recommends a single clinical target volume definition based on postoperative contrast-enhanced T1 abnormalities, using isotropic margins without the need to cone down. A PTV margin based on the individual mask system and IGRT procedures available is advised; this should usually be no greater than 3 mm when using IGRT.

The global number of people with Alzheimer’s disease (AD) doubles every 5 years. It has been established that unless an effective treatment for AD is found, the incidence of AD will triple by 2060. However, pharmacological therapies for AD have failed to show effectiveness and safety. Therefore, the search for alternative methods for treating AD is an urgent problem in medicine. The lymphatic drainage and removal system of the brain (LDRSB) plays an important role in resistance to the progression of AD. The development of methods for augmentation of the LDRSB functions may contribute to progress in AD therapy. Photobiomodulation (PBM) is considered to be a non-pharmacological and safe approach for AD therapy. Here, we highlight the most recent and relevant studies of PBM for AD. We focus on emerging evidence that indicates the potential benefits of PBM during sleep for modulation of natural activation of the LDRSB at nighttime, providing effective removal of metabolites, including amyloid-β, from the brain, leading to reduced progression of AD. Our review creates a new niche in the therapy of brain diseases during sleep and sheds light on the development of smart sleep technologies for neurodegenerative diseases. RSF RF Governmental Academic leadership program Priority 2030 proposed by the First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University)

Introduction: Regular physical activity provides many health benefits to older adults. As a well-known form of physical activity, cycling can be an appropriate means for older people to meet WHO recommendations and to improve their health. In addition, cycling can help to protect the environment and reduce greenhouse gas emissions. The primary aim of this scoping review is to identify the currently available scientific evidence and gaps of research in this field. Methods: A systematic search in seven databases resulted in 7,192 studies. After the exclusion of duplicates, studies were screened by two independent reviewers in a two-stage process. Based on previously defined inclusion criteria, 123 studies were included. Data extraction was based on a descriptive analytical method, and seven categories for the main topics of studies were developed. Data were extracted by three reviewers to analyze different characteristics of included articles such as age range, study design, data type, gender, type of bicycle, and country of origin. Results: The included studies covered the following topics: (1) traffic safety, (2) cycling as physical activity or for transport, (3) health benefits, (4) environmental factors, (5) facilitators and barriers, (6) application of technology and (7) promotion of cycling. Results show that the majority of studies were performed in both younger (60–79 years) and older (80+ years) adults. Most studies had an observational study design, used conventional bicycles, and were based on quantitative methods. Researchers from the United States, Netherlands, and Japan published the highest number of studies related to cycling. Discussion: Traffic safety was the most prevalent focus of the included studies. Gaps were identified with regard to studies focusing on the promotion of cycling, application of technology, as well as facilitators and barriers of cycling. While research on traffic safety should continue to be a high priority for public health, potentially more research should focus on how to get older people to bicycle more. This is warranted by the proven individual and planetary health benefits of cycling and the urgency of combating climate change.

Cystic fibrosis (CF) is a monogenetic disease caused by an impairment of the cystic fibrosis transmembrane conductance regulator (CFTR). CF affects multiple organs and is associated with acute and chronic inflammation. In 2020, Elexacaftor–Tezacaftor–Ivacaftor (ETI) was approved to enhance and restore the remaining CFTR functionality. This study investigates cellular innate immunity, with a focus on neutrophil activation and phenotype, comparing healthy volunteers with patients with CF before (T1, n = 13) and after six months (T2, n = 11) of ETI treatment. ETI treatment reduced sweat chloride (T1: 95 mmol/l (83|108) vs. T2: 32 mmol/l (25|62), p < 0.01, median, first|third quartile) and significantly improved pulmonal function (FEV1 T1: 2.66 l (1.92|3.04) vs. T2: 3.69 l (3.00|4.03), p < 0.01). Moreover, there was a significant decrease in the biomarker human epididymis protein 4 (T1: 6.2 ng/ml (4.6|6.3) vs. T2: 3.0 ng/ml (2.2|3.7), p < 0.01) and a small but significant decrease in matrix metallopeptidase 9 (T1: 45.5 ng/ml (32.5|140.1) vs. T2: 28.2 ng/ml (18.2|33.6), p < 0.05). Neutrophil phenotype (CD10, CD11b, CD62L, and CD66b) and function (radical oxygen species generation, chemotactic and phagocytic activity) remained largely unaffected by ETI treatment. Likewise, monocyte phenotype and markers of platelet activation were similar at T1 and T2. In summary, the present study confirmed a positive impact on patients with CF after ETI treatment. However, neither beneficial nor harmful effects of ETI treatment on cellular innate immunity could be detected, possibly due to the study population consisting of patients with well-controlled CF.

Background Chronic kidney disease (CKD) causes congestive heart failure (CHF) with systolic dysfunction and left ventricular hypertrophy (LVH), which is a major contributor to increased mortality in CKD patients. It remains unclear whether cardiovascular changes that occur during the course of CKD can be reversed when renal function is restored by transplantation. Methods To investigate this, chronic kidney disease was established in F344 rats by subtotal nephrectomy (SNx) for 8 weeks, followed by transplantation of a functional kidney from an isogenic F344 donor. SNx rats without transplantation and sham-operated animals served as controls. Renal function was assessed before and throughout the experiment. In addition, cardiac ultrasound was performed at weeks 0, 8, 12 and 16. At the end of the experiment, intra-arterial blood pressure was measured and kidneys and hearts were histologically and molecularly examined. Results Eight weeks after SNx, rats developed marked renal dysfunction associated with significant glomerulosclerosis and tubulointerstitial fibrosis, but also an increase in left ventricular mass. After transplantation, renal function normalized but relative heart weight and ventricular mass as assessed by ultrasound scans showed no reduction compared with SNx controls. However, left ventricular wall thickness, fractional shortening and ejection fraction was normalized by renal transplantation. At 8 weeks after kidney transplantation, cardiac expression of BNP and FGF23 was also at levels comparable to healthy controls, whereas these factors were significantly increased in SNx rats. Cardiac fibrosis, as measured by fibronectin mRNA expression, was completely normalized, whereas cardiac fibronectin protein was still slightly but not significantly increased in transplanted animals compared to controls. In addition, the myofibroblast marker collagen 1, as assessed by immunohistochemistry, was significantly increased in SNx rats and also normalized by renal transplantation. Interestingly, CD68+ macrophages were significantly reduced in the hearts of SNx rats and in transplanted animals at slightly higher levels compared to controls. Conclusion Restoration of renal function by kidney transplantation normalized early cardiac changes at most functional and molecular levels, but did not completely reverse LVH. However, further studies are needed to determine whether restoration of renal function can also reverse LVH at a later time point.

This dissertation identified c-REL as a substrate of the ubiquitin proteasome system (UPS) in B-cell lymphomas. The deubiquitinase (DUB) OTUD4 was identified as c-REL interacting protein regulating its ubiquitination, stability, and nuclear accumulation in diffuse large B-cell lymphoma (DLBCL) and pancreatic ductal adenocarcinoma (PDAC) cell lines. Moreover, OTUD4 depletion impaired the expansion of DLBCL and PDAC cell lines, hence OTUD4 was presented as a possible new target in cancer therapy. Diese Dissertation identifizierte c-REL als Substrat des Ubiquitin-Proteasom-Systems (UPS) in B-Zell-Lymphomen. Die Deubiquitinase (DUB) OTUD4 wurde als c-REL-interagierendes Protein identifiziert, das seine Ubiquitination, Stabilität und Kernakkumulation in Zelllinien des diffusen großzelligen B-Zell-Lymphoms (DLBCL) und des duktalen Adenokarzinoms des Pankreas (PDAC) reguliert. Darüber hinaus beeinträchtigte die OTUD4-Depletion die Expansion von DLBCL- und PDAC-Zelllinien, weshalb OTUD4 als mögliches neues Ziel in der Krebstherapie präsentiert wurde.

Purpose Third molar agenesis (TMA) is the most common craniofacial anomaly and has been associated with craniofacial patterns in different populations. Therefore, the aim of this retrospective cross-sectional study was to assess a possible association between craniofacial patterns and TMA in German orthodontic patients. Methods Patients undergoing orthodontic treatment with dental records including anamnesis, pretreatment lateral cephalograms and orthopantomograms were evaluated. Cephalometric analyses were conducted digitally and lines, angles and proportions were measured to investigate craniofacial morphology. Skeletal classes were determined by the individualised Wits appraisal and ANB angle. The TMA was identified with the help of orthopantomograms. Patients showing agenesis of at least one third molar were included in the TMA group. Statistical analysis was performed to assess the association between TMA and craniofacial patterns (α of p ≤ 0.05). Results A total of 148 patients were included, 40 (27.0%) presented at least one missing tooth (TMA group) and 108 (73.0%) showed full dentition (control group). Skeletal class determined by the individualised Wits appraisal revealed statistical significance between the TMA and control groups (p = 0.022), in which TMA patients were 11 times more likely to present with an individualised skeletal class III (odds ratio 11.3, 95% confidence interval 1.7–139.5). Skeletal cephalometric analysis revealed no statistical differences between TMA and control groups for any further angular, linear and proportional parameters. Conclusion Third molar agenesis was associated with skeletal class III determined by the individualised Wits appraisal.

Introduction: Immune checkpoint inhibitors (ICI), e.g., targeting programmed cell death protein 1-ligand 1 (PD-L1) or its receptor PD-1, have markedly improved the therapy of many cancers but so far failed in pancreatic ductal adenocarcinoma (PDAC). Macrophages represent one of the most abundant immune cell populations within the tumor microenvironment (TME) of PDAC being able to either support or restrain tumor progression depending on their phenotype. To better understand treatment failure of PD-L1/PD-1 inhibitors in PDAC, this study examined PD-L1 expression in the context of a dynamic TME in PDAC with a particular focus on the impact of macrophages. Methods: Formalin-fixed and paraffin embedded tissue samples of primary PDAC tissues and corresponding liver metastases were used for immunohistochemical analyses. Serial sections were stained with antibodies detecting Pan-Cytokeratin, CD68, CD163, CD8, and PD-L1.To investigate whether the PD-1/PD-L1 axis and macrophages contribute to immune escape of PDAC cells, a stroma enriched 3D spheroid coculture model was established in vitro, using different PDAC cell lines and macrophages subtypes as well as CD8+ T cells. Functional and flow cytometry analyses were conducted to characterize cell populations. Results: Immunohistochemical analyses revealed that PD-L1 is mainly expressed by stroma cells, including macrophages and not PDAC cells in primary PDAC tissues and corresponding liver metastases. Notably, high local abundance of macrophages and strong PD-L1 staining were commonly found at invasion fronts of tumoral lesions between CD8+ T cells and tumor cells. In order to investigate whether PD-L1 expressing macrophages impact the response of PDAC cells to treatment with PD-L1/PD-1 inhibitors, we developed a spheroid model comprising two different PDAC cell lines and different ratios of in vitro differentiated primary M1- or M2-like polarized macrophages. In line with our in situ findings, high PD-L1 expression was observed in macrophages rather than PDAC cells, which was further increased by the presence of PDAC cells. The effector phenotype of co-cultured CD8+ T cells exemplified by expression of activation markers and release of effector molecules was rather enhanced by PDAC macrophage spheroids, particularly with M1-like macrophages compared to mono-culture spheroids. However, this was not associated with enhanced PDAC cell death. ICI treatment with either Durvalumab or Pembrolizumab alone or in combination with Gemcitabine hardly affected the effector phenotype of CD8+ T cells along with PDAC cell death. Thus, despite strong PD-L1 expression in macrophages, ICI treatment did not result in an enhanced activation and cytotoxic phenotype of CD8+ T cells. Conclusion: Overall, our study revealed novel insights into the interplay of PDAC cells and macrophages in the presence of ICI.

Colorectal cancer (CRC) is the third most common cancer worldwide. The main treatment options are laparoscopic (LS) and open surgery (OS), which might differ in their impact on the cellular immunity so indispensable for anti-infectious and antitumor defense. MEDLINE, Embase, Web of Science (SCI-EXPANDED), the Cochrane Library, Google Scholar, ClinicalTrials.gov, and ICTRP (WHO) were systematically searched for randomized controlled trials (RCTs) comparing cellular immunity in CRC patients of any stage between minimally invasive and open surgical resections. A random effects-weighted inverse variance meta-analysis was performed for cell counts of natural killer (NK) cells, white blood cells (WBCs), lymphocytes, CD4+ T cells, and the CD4+/CD8+ ratio. The RoB2 tool was used to assess the risk of bias. The meta-analysis was prospectively registered in PROSPERO (CRD42021264324). A total of 14 trials including 974 participants were assessed. The LS groups showed more favorable outcomes in eight trials, with lower inflammation and less immunosuppression as indicated by higher innate and adaptive cell counts, higher NK cell activity, and higher HLA-DR expression rates compared to OS, with only one study reporting lower WBCs after OS. The meta-analysis yielded significantly higher NK cell counts at postoperative day (POD)4 (weighted mean difference (WMD) 30.80 cells/µL [19.68; 41.92], p < 0.00001) and POD6–8 (WMD 45.08 cells/µL [35.95; 54.21], p < 0.00001). Although further research is required, LS is possibly associated with less suppression of cellular immunity and lower inflammation, indicating better preservation of cellular immunity.

Systemic inflammation is established as part of late-stage severe lung disease, but molecular, functional, and phenotypic changes in peripheral immune cells in early disease stages remain ill defined. Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small-airway inflammation, emphysema, and severe breathing difficulties. Using single-cell analyses we demonstrate that blood neutrophils are already increased in early-stage COPD, and changes in molecular and functional neutrophil states correlate with lung function decline. Assessing neutrophils and their bone marrow precursors in a murine cigarette smoke exposure model identified similar molecular changes in blood neutrophils and precursor populations that also occur in the blood and lung. Our study shows that systemic molecular alterations in neutrophils and their precursors are part of early-stage COPD, a finding to be further explored for potential therapeutic targets and biomarkers for early diagnosis and patient stratification.

Biologicals have dominated the therapeutic scenery in inflammatory bowel diseases (IBDs), namely ulcerative colitis (UC) and Crohn’s disease (CD), for the past 20 years. The development of tofacitinib was the starting point for an era of small molecules after the era of biologicals. These new agents may challenge the use of biological agents in the future. They share properties that appeal to both patients and physicians. Low production costs, a lack of immunogenicity, and ease of use are only some of their benefits. On the other hand, patients and their physicians must manage the potential side effects of small molecules such as JAK inhibitors or S1P1R modulators. Here, we present agents that have already entered the clinical routine and those that are still being investigated in clinical trials.

Ventilator-induced diaphragm dysfunction (VIDD) is a common sequela of intensive care unit (ICU) treatment requiring mechanical ventilation (MV) and neuromuscular blockade (NMBA). It is characterised by diaphragm weakness, prolonged respirator weaning and adverse outcomes. Dissociative glucocorticoids (e.g., vamorolone, VBP-15) and chaperone co-inducers (e.g., BGP-15) previously showed positive effects in an ICU-rat model. In limb muscle critical illness myopathy, preferential myosin loss prevails, while myofibrillar protein post-translational modifications are more dominant in VIDD. It is not known whether the marked decline in specific force (force normalised to cross-sectional area) is a pure consequence of altered contractility signaling or whether diaphragm weakness also has a structural correlate through sterical remodeling of myofibrillar cytoarchitecture, how quickly it develops, and to which extent VBP-15 or BGP-15 may specifically recover myofibrillar geometry. To address these questions, we performed label-free multiphoton Second Harmonic Generation (SHG) imaging followed by quantitative morphometry in single diaphragm muscle fibres from healthy rats subjected to five or 10 days of MV + NMBA to simulate ICU treatment without underlying confounding pathology (like sepsis). Rats received daily treatment of either Prednisolone, VBP-15, BGP-15 or none. Myosin-II SHG signal intensities, fibre diameters (FD) as well as the parameters of myofibrillar angular parallelism (cosine angle sum, CAS) and in-register of adjacent myofibrils (Vernier density, VD) were computed from SHG images. ICU treatment caused a decline in FD at day 10 as well as a significant decline in CAS and VD from day 5. Vamorolone effectively recovered FD at day 10, while BGP-15 was more effective at day 5. BGP-15 was more effective than VBP-15 in recovering CAS at day 10 although not to control levels. In-register VD levels were restored at day 10 by both compounds. Our study is the first to provide quantitative insights into VIDD-related myofibrillar remodeling unravelled by SHG imaging, suggesting that both VBP-15 and BGP-15 can effectively ameliorate the structure-related dysfunction in VIDD.

Background Myocarditis represents one of the most common causes of Sudden Cardiac Death in children. Myocardial involvement during a viral infection is believed to be higher as a consequence of intensive exertion. Recommendations for return to sports are based on cohort and case studies only. This study aims to investigate the relationship between physical activity and myocarditis in the young. Patient Every patient in the MYKKE registry fulfilling criteria for suspicion of myocarditis was sent a questionnaire regarding the physical activity before, during and after the onset of myocarditis. Method This study is a subproject within the MYKKE registry, a multicenter registry for children and adolescents with suspected myocarditis. The observation period for this analysis was 93 months (September 2013–June 2021). Anamnestic, cardiac magnetic resonance images, echocardiography, biopsy and laboratory records from every patient were retrieved from the MYKKE registry database. Results 58 patients (mean age 14.6 years) were enrolled from 10 centers. Most patients participated in curricular physical activity and 36% in competitive sports before the onset of myocarditis. There was no significant difference of heart function at admission between the physically active and inactive subjects (ejection fraction of 51.8 ± 8.6% for the active group vs. 54.4 ± 7.7% for the inactive group). The recommendations regarding the return to sports varied widely and followed current guidelines in 45%. Most patients did not receive an exercise test before returning to sports. Conclusion Sports before the onset of myocarditis was not associated with a more severe outcome. There is still a discrepancy between current literature and actual recommendations given by health care providers. The fact that most participants did not receive an exercise test before being cleared for sports represents a serious omission.

Introduction: We previously reported that malignant hypertension is associated with impaired capillary density of target organs. Here, we tested the hypothesis that stabilization of hypoxia-inducible factor (HIF) in a modified “preconditioning” approach prevents the development of malignant hypertension. To stabilize HIF, we employed pharmacological inhibition of HIF prolyl hydroxylases (PHD), that profoundly affect HIF metabolism. Methods: Two-kidney, one-clip renovascular hypertension (2K1C) was induced in rats; controls were sham operated. 2K1C rats received either intermittent injections of the PHD inhibitor ICA (2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate) or placebo. Thirty-five days after clipping, the frequency of malignant hypertension was assessed (based on weight loss and the occurrence of characteristic vascular lesions). In addition, kidney injury was compared between all ICA treated versus all placebo treated 2K1C, regardless of the occurrence of malignant hypertension. HIF stabilization was evaluated by immunohistochemistry, and HIF target gene expression by RT-PCR. Results: Blood pressure was elevated to the same degree in ICA- and placebo-treated 2K1C compared to control rats. ICA treatment did not affect the frequency of malignant hypertension or the extent of kidney tissue fibrosis, inflammation, or capillary density. There was a trend towards higher mortality and worse kidney function in ICA-treated 2K1C rats. ICA increased the number of HIF-1α-positive renal tubular cell nuclei and induced several HIF-1 target genes. In contrast, expression of HIF-2α protein as well as HIF-2 target genes were markedly enhanced by 2K1C hypertension, irrespective of ICA treatment. Discussion: We conclude that intermittent PHD inhibition did not ameliorate severe renovascular hypertension in rats. We speculate that the unexpected strong renal accumulation of HIF-2α in renovascular hypertension, which could not be further augmented by ICA, may contribute to the lack of a benefit from PHD inhibition.

Introduction: The ongoing COVID-19 pandemic is placing an extraordinary burden on our health care system with its limited resources. Accurate triage of patients is necessary to ensure medical care for those most severely affected. In this regard, biomarkers could contribute to risk evaluation. The aim of this prospective observational clinical study was to assess the relationship between urinary N-terminal pro-brain natriuretic peptide (NT-proBNP) and acute kidney injury (AKI) as well as severe disease in patients with COVID-19. Methods: 125 patients treated with an acute respiratory infection in the emergency department of the University Hospital Regensburg were analyzed. These patients were divided into a COVID-19 cohort (n = 91) and a cohort with infections not caused by severe acute respiratory syndrome-coronavirus-2 (n = 34). NT-proBNP was determined from serum and fresh urine samples collected in the emergency department. Clinical endpoints were the development of AKI and a composite one consisting of AKI, intensive care unit admission, and in-hospital death. Results: 11 (12.1%) COVID-19 patients developed AKI during hospitalization, whereas 15 (16.5%) reached the composite endpoint. Urinary NT-proBNP was significantly elevated in COVID-19 patients who suffered AKI or reached the composite endpoint (each p < 0.005). In a multivariate regression analysis adjusted for age, chronic kidney disease, chronic heart failure, and arterial hypertension, urinary NT-proBNP was identified as independent predictor of AKI (p = 0.017, OR = 3.91 [CI: 1.28–11.97] per standard deviation [SD]), as well as of the composite endpoint (p = 0.026, OR 2.66 [CI: 1.13–6.28] per SD). Conclusion: Urinary NT-proBNP might help identify patients at risk for AKI and severe disease progression in COVID-19.

Vertebral artery (VA) involvement in giant cell arteritis (GCA) has rarely been reported. We aimed to evaluate the prevalence, patients’ characteristics, and immunotherapies used in patients with GCA and VA involvement at diagnosis and 1 year follow-up, retrospectively including patients being diagnosed between January 2011 and March 2021 in our department. Clinical features, laboratory data, VA imaging, immunotherapy, and 1 year follow-up data were analyzed. Baseline characteristics were compared to GCA patients without VA involvement. Among all 77 cases with GCA, 29 patients (37.7%) had VA involvement, as diagnosed by imaging and/or clinical signs and symptoms. Gender distribution and erythrocyte sedimentation rate (ESR) were significantly different in the groups with and without VA involvement, with more women being affected (38/48 patients, 79.2%) and a significantly higher median ESR in patients without VA involvement (62 vs. 46 mm/h; p = 0.012). MRI and/or CT showed vertebrobasilar stroke at GCA diagnosis in 11 cases. 67/77 patients (87.0%) received high-dose intravenous glucocorticosteroids (GCs) at diagnosis, followed by oral tapering. Six patients were treated with methotrexate (MTX), one with rituximab, and five with tocilizumab (TCZ). 2/5 TCZ patients achieved clinical remission after 1 year, vertebrobasilar stroke within the first year occurred in 2/5 patients. Diagnosis of VA involvement might be underrecognized in GCA patients. VA imaging should be performed in elderly patients with vertebrobasilar stroke presenting with GCA symptoms, not to miss GCA as the etiology of stroke. Efficacy of immunotherapies in GCA with VA affection and long-term outcomes need to be investigated further.