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Marion Ortner,1 Christine Hauser,2 Christoph Schmaderer,2 Claudia Muggenthaler,1 Alexander Hapfelmeier,3 Christian Sorg,1,4 Janine Diehl-Schmid,1 Alexander Kurz,1 Hans Förstl,1 Benno Ikenberg,5 Konstantin Kotliar,6 Holger Poppert,5,7,* Timo Grimmer1,* 1Technical University of Munich, School of Medicine, Klinikum Rechts der Isar, Department of Psychiatry and Psychotherapy, Munich, Germany; 2Technical University of Munich, School of Medicine, Klinikum Rechts der Isar, Department of Nephrology, Munich, Germany; 3Technical University of Munich, School of Medicine, Klinikum Rechts der Isar, Institute for Medical Statistics and Epidemiology, Munich, Germany; 4Technical University of Munich, School of Medicine, Klinikum Rechts der Isar, Department of Diagnostic and Interventional Neuroradiology, Munich, Germany; 5Technical University of Munich, School of Medicine, Klinikum Rechts der Isar, Department of Neurology, Munich, Germany; 6Department of Medical Engineering and Technomathematics, FH Aachen, Jülich, Germany; 7Department of Neurology, Helios Dr. Horst Schmid Kliniken Wiesbaden, Wiesbaden, Germany*These authors contributed equally to this workCorrespondence: Marion OrtnerTechnical University of Munich, School of Medicine, Klinikum Rechts der Isar, Department of Psychiatry and Psychotherapy, Moehlstr. 26 81675, Muenchen, GermanyTel +49 89 4140 6463Fax +49 89 4140 4923Email marion.ortner@tum.dePurpose: Impaired paravascular drainage of β-Amyloid (Aβ) has been proposed as a contributing cause for sporadic Alzheimer’s disease (AD), as decreased cerebral blood vessel pulsatility and subsequently reduced propulsion in this pathway could lead to the accumulation and deposition of Aβ in the brain. Therefore, we hypothesized that there is an increased impairment in pulsatility across AD spectrum.Patients and Methods: Using transcranial color-coded duplex sonography (TCCS) the resistance and pulsatility index (RI; PI) of the middle cerebral artery (MCA) in healthy controls (HC, n=14) and patients with AD dementia (ADD, n=12) were measured. In a second step, we extended the sample by adding patients with mild cognitive impairment (MCI) stratified by the presence (MCI-AD, n=8) or absence of biomarkers (MCI-nonAD, n=8) indicative for underlying AD pathology, and compared RI and PI across the groups. To control for atherosclerosis as a confounder, we measured the arteriolar-venular-ratio of retinal vessels.Results: Left and right RI (p=0.020; p=0.027) and left PI (p=0.034) differed between HC and ADD controlled for atherosclerosis with AUCs of 0.776, 0.763, and 0.718, respectively. The RI and PI of MCI-AD tended towards ADD, of MCI-nonAD towards HC, respectively. RIs and PIs were associated with disease severity (p=0.010, p=0.023).Conclusion: Our results strengthen the hypothesis that impaired pulsatility could cause impaired amyloid clearance from the brain and thereby might contribute to the development of AD. However, further studies considering other factors possibly influencing amyloid clearance as well as larger sample sizes are needed.Keywords: pulsatility index, PI, resistance index, RI, biomarker, mild cognitive impairment, MCI, Alzheimer’s dementia

Abstract Background Long-lasting symptoms with a possible relation to psychosomatic comorbidity have been described following COVID-19. However, data is sparse in general practice. The trial’s objective was to investigate the time-dependent frequency of disease symptoms and relation to psychosomatic comorbidity and daily life impairment (DLI). Methods Comparative cohort study of patients reporting a previous SARS-CoV-2 infection and uninfected controls in general practice. Participants were recruited in 14 general practices in the greater Munich area. Data collection was questionnaire based with a 12 months follow-up. Descriptive statistics, multivariable regression and bivariate correlations were used for analysis. Results A total of n = 204 cases infected up to 42 months ago (n = 141 Omicron, n = 63 earlier variants), and n = 119 controls were included. Disease symptoms were substantially more prevalent in cases (55–79% vs. 43% within one year of infection). This difference also appeared in the multivariable analysis adjusting for socio-demographics and psychosomatic comorbidity with odds ratios (OR) of 4.15 (p

Background & Aims: Although chronic diarrhea and constipation are common, the treatment is symptomatic because their pathophysiology is poorly understood. Accumulating evidence suggests that the microbiota modulates gut function, but the underlying mechanisms are unknown. We therefore investigated the pathways by which microbiota modulates gastrointestinal motility in different sections of the alimentary tract. Methods: Gastric emptying, intestinal transit, muscle contractility, acetylcholine release, gene expression, and vasoactive intestinal polypeptide (VIP) immunoreactivity were assessed in wild-type and Myd88-/-Trif-/- mice in germ-free, gnotobiotic, and specific pathogen-free conditions. Effects of transient colonization and antimicrobials as well as immune cell blockade were investigated. VIP levels were assessed in human full-thickness biopsies by Western blot. Results: Germ-free mice had similar gastric emptying but slower intestinal transit compared with specific pathogen-free mice or mice monocolonized with Lactobacillus rhamnosus or Escherichia coli, the latter having stronger effects. Although muscle contractility was unaffected, its neural control was modulated by microbiota by up-regulating jejunal VIP, which co-localized with and controlled cholinergic nerve function. This process was responsive to changes in the microbial composition and load and mediated through toll-like receptor signaling, with enteric glia cells playing a key role. Jejunal VIP was lower in patients with chronic intestinal pseudo-obstruction compared with control subjects. Conclusions: Microbial control of gastrointestinal motility is both region- and bacteria-specific; it reacts to environmental changes and is mediated by innate immunity-neural system interactions. By regulating cholinergic nerves, small intestinal VIP plays a key role in this process, thus providing a new therapeutic target for patients with motility disorders.

Unaccompanied refugees are a high-risk group for trauma-induced psychiatric disorders. Besides traumatic experiences pre- and during migration, post-migration stressors such as insecure residency status affect refugees’ mental health and foster aggressive emotions. High levels of psychological distress and psychopathology distort time perspectives. Consequently, an insecure residency status linked to distress may influence a refugee’s time perspective. This study investigated psychological distress, PTSD symptoms, aggressive emotions, and time perspectives in 33 unaccompanied adolescent refugees with and without secure residency status in Germany. Refugees with precarious residency status showed higher levels of overall distress and aggression than individuals with secure residency status. Both groups revealed a distorted time perspective profile, but individuals with a residence permit showed a stronger orientation toward the present hedonistic perspective than those without a permit. Higher aggressive emotions were related to insecure status, higher levels of psychological distress, more pronounced PTSD symptoms, and lower orientation to future time perspective. Distorted time perspectives among refugees may be caused by traumatic experiences and having been uprooted, independently of their residency status in the host country. A higher future orientation may buffer the association between distorted time perspectives and aggressive emotions in the highly stressed group of unaccompanied adolescent refugees.

Abstract Background Clinical trials evaluating anti-CD20-mediated B-cell depletion in multiple sclerosis (MS) and neuromyelitis optica (NMO) generated encouraging results. Our recent studies in the MS model experimental autoimmune encephalomyelitis (EAE) attributed clinical benefit to extinction of activated B-cells, but cautioned that depletion of naïve B-cells may be undesirable. We elucidated the regulatory role of un-activated B-cells in EAE and investigated whether anti-CD20 may collaterally diminish regulatory B-cell properties in treatment of neuroimmunological disorders. Methods Myelin oligodendrocyte glycoprotein (MOG) peptide-immunized C57Bl/6 mice were depleted of B-cells. Functional consequences for regulatory T-cells (Treg) and cytokine production of CD11b+ antigen presenting cells (APC) were assessed. Peripheral blood mononuclear cells from 22 patients receiving anti-CD20 and 23 untreated neuroimmunological patients were evaluated for frequencies of B-cells, T-cells and monocytes; monocytic reactivity was determined by TNF-production and expression of signalling lymphocytic activation molecule (SLAM). Results We observed that EAE-exacerbation upon depletion of un-activated B-cells closely correlated with an enhanced production of pro-inflammatory TNF by CD11b+ APC. Paralleling this pre-clinical finding, anti-CD20 treatment of human neuroimmunological disorders increased the relative frequency of monocytes and accentuated pro-inflammatory monocyte function; when reactivated ex vivo, a higher frequency of monocytes from B-cell depleted patients produced TNF and expressed the activation marker SLAM. Conclusions These data suggest that in neuroimmunological disorders, pro-inflammatory APC activity is controlled by a subset of B-cells which is eliminated concomitantly upon anti-CD20 treatment. While this observation does not conflict with the general concept of B-cell depletion in human autoimmunity, it implies that its safety and effectiveness may further advance by selectively targeting pathogenic B-cell function.

Introduction Uncomplicated urinary tract infections (uUTIs) in women are common infections encountered in primary care. Evidence suggests that rapid point-of-care tests (POCTs) to detect bacteria and erythrocytes in urine at presentation may help primary care clinicians to identify women with uUTIs in whom antibiotics can be withheld without influencing clinical outcomes. This pilot study aims to provide preliminary evidence on whether a POCT informed management of uUTI in women can safely reduce antibiotic use.Methods and analysis This is an open-label two-arm parallel cluster-randomised controlled pilot trial. 20 general practices affiliated with the Bavarian Practice-Based Research Network (BayFoNet) in Germany were randomly assigned to deliver patient management based on POCTs or to provide usual care. POCTs consist of phase-contrast microscopy to detect bacteria and urinary dipsticks to detect erythrocytes in urine samples. In both arms, urine samples will be obtained at presentation for POCTs (intervention arm only) and microbiological analysis. Women will be followed-up for 28 days from enrolment using self-reported symptom diaries, telephone follow-up and a review of the electronic medical record. Primary outcomes are feasibility of patient enrolment and retention rates per site, which will be summarised by means and SDs, with corresponding confidence and prediction intervals. Secondary outcomes include antibiotic use for UTI at day 28, time to symptom resolution, symptom burden, number of recurrent and upper UTIs and re-consultations and diagnostic accuracy of POCTs versus urine culture as the reference standard. These outcomes will be explored at cluster-levels and individual-levels using descriptive statistics, two-sample hypothesis tests and mixed effects models or generalised estimation equations.Ethics and dissemination The University of Würzburg institutional review board approved MicUTI on 16 December 2022 (protocol n. 109/22-sc). Study findings will be disseminated through peer-reviewed publications, conferences, reports addressed to clinicians and the local citizen’s forums.Trial registration number ClinicalTrials.gov NCT05667207.

BackgroundThe Rho-kinase (ROCK) inhibitor Fasudil has shown symptomatic and disease-modifying effects in Parkinson’s disease (PD) models in vitro and in vivo. In Japan, Fasudil has been approved for the treatment of subarachnoid haemorrhage since 1995 and shows a favourable safety profile.Objectives/designTo investigate the safety, tolerability, and symptomatic efficacy of ROCK-inhibitor Fasudil in comparison to placebo in a randomized, national, multicenter, double-blind phase IIa study in patients with PD.Methods/analysisWe plan to include 75 patients with at least ‘probable’ PD (MDS criteria), Hoehn and Yahr stages 1–3, and age 30–80 years in 13 German study sites. Patients must be non-fluctuating and their response to PD medication must have been stable for 6 weeks. Patients will be randomly allocated to treatment with the oral investigational medicinal product (IMP) containing either Fasudil in two dosages, or placebo, for a total of 22 days. As primary analysis, non-inferiority of low/high dose of Fasudil on the combined endpoint consisting of occurrence of intolerance and/or treatment-related serious adverse events (SAEs) over 22 days will be assessed in a sequential order, starting with the lower dose. Secondary endpoints will include tolerability alone over 22 days and occurrence of treatment-related SAEs (SARs) over 22 and 50 days and will be compared on group level. Additional secondary endpoints include efficacy on motor and non-motor symptoms, measured on established scales, and will be assessed at several timepoints. Biomaterial will be collected to determine pharmacokinetics of Fasudil and its active metabolite, and to evaluate biomarkers of neurodegeneration.Ethics/registration/discussionAfter positive evaluation by the competent authority and the ethics committee, patient recruitment started in the 3rd quarter of 2023. ROCK-PD is registered with Eudra-CT (2021-003879-34) and clinicaltrials.gov (NCT05931575). Results of this trial can pave way for conducting extended-duration studies assessing both symptomatic efficacy and disease-modifying properties of Fasudil.

IntroductionBased on two diagnostic accuracy studies in high-prevalence settings, two distinctly different combinations of cut-off values have been recommended to identify persons at risk for somatic symptom disorder (SSD) with the combination of the Patient-Health Questionnaire-15 (PHQ-15) and the Somatic Symptom Disorder—B Criteria Scale (SSD-12). We investigated whether the reported sensitivity and specificity of both recommended cut-off combinations are transferable to primary care.MethodsIn a cross-sectional study, 420 unselected adult primary care patients completed PHQ-15 and SSD-12. Patients scoring ≥9 and ≥ 23 (recommended cut-off combination #1) or ≥ 8 and ≥ 13 (recommended cut-off combination #2) were considered test-positive for SSD, respectively. To assess the validity of the reported sensitivity and specificity in different low- to high-prevalence settings, we compared correspondingly expected proportions of test positives to the proportion observed in our sample.ResultsBased on combination #1, 38 participants (9%) were found to be test positive, far fewer than expected, based on the reported values for sensitivity and specificity (expected minimum frequency 30% with a true prevalence ≥1%). This can only be explained by a lower sensitivity and higher specificity in primary care. For combination #2, 98 participants (23%) were test positive, a finding consistent with a true prevalence of SSD of 15% or lower.DiscussionOur analyzes strongly suggest that the sensitivity and specificity estimates reported for combination #1 are not applicable to unselected primary care patients and that the cut-off for the SSD (≥23) is too strict. Cut-off combination #2 seems more applicable but still needs to be tested in studies that compare screening findings by questionnaires with validated diagnostic interviews as reference standards in primary care populations.

The aim of this study is to assess adolescent refugees' psychological distress and examine how reliably caseworkers can assess distress through a proxy-report instrument. The distress of 102 unaccompanied refugees between 16 and 21 years of age housed in youth welfare accommodations in Germany was assessed by self-report using the Brief Symptom Checklist and by proxy-report through the Child Behavior Checklist. Independent of residence status, the self and proxy ratings reveal that more than half of the refugees suffer from increased levels of psychological distress, particularly from anxiety and somatisation. There was a moderate positive correlation between the total scales of the two instruments. The high number of clinically meaningful distress poses a great challenge to caseworkers in facilities for unaccompanied refugees. The Child Behavior Checklist can be a suitable measure to detect clinically meaningful problems, but its validity seems to depend on a good relationship between caseworker and refugee.

ABSTRACT To assess the long-term survival of patients with enterococcal bloodstream infections (BSI), encompassing various species and resistance patterns compared to Escherichia coli (E. coli) BSI. Between 2010–2019, 3,290 enterococcal and 3,415 E. coli BSI were retrospectively screened in seven hospitals in Munich, Germany. All vancomycin-resistant (VRE), vancomycin/linezolid-resistant (LVRE), and linezolid-resistant (LRE) Enterococcus faecium (ECFM) BSI were included. Enterococcus faecalis (ECFA), vancomycin/linezolid-susceptible ECFM, and E. coli BSI were randomly assigned. Cox regression analysis was used to assess survival as the primary endpoint and was adjusted for limiting prognostic factors, which were measured for their importance using a random forest model (RFM). We analyzed 952 patients with 916 episodes of enterococcal BSI and 193 episodes of E. coli BSI. RFM identified multimorbidity and markers for disease severity as most indicative of low survival in enterococcal BSI. The 5-year survival was significantly lower for enterococcal BSI than for E. coli BSI (23.9% vs 42.3%; P < 0.001). This difference remained significant in the Cox regression analysis after adjusting for 17 prognostic factors and excluding patients with limited life expectancy (metastatic tumor disease, Charlson-Comorbidity-Index ≥5). Adjusted 5-year survival was similar for E. coli and ECFA but significantly different between ECFA and ECFM (29.2% vs 21.7%; P = 0.002). The analysis conducted on monomicrobial ECFM and VRE BSI indicated that their respective 5-year survival was similar (19.6% vs. 21.2%; P = 0.753). ECFM BSI seems to be an independent risk factor for poor long-term survival. However, additional vancomycin resistance does not appear to be a contributing factor. IMPORTANCE The present study provides a substantial contribution to literature, showing that patients with enterococcal bloodstream infections (BSI) have a lower survival rate than those with Escherichia coli (E. coli) bloodstream infections after adjusting for 17 limiting prognostic factors and excluding patients with a limited life expectancy [metastatic tumor disease, Charlson Comorbidity Index (CCI) (greater than or equal to) 5]. This difference in the 5-year long-term survival was mainly driven by Enterococcus faecium (ECFM) bloodstream infections, with vancomycin resistance not being a significant contributing factor. Our findings imply that E. faecium bloodstream infections seem to be an independent risk factor for poor long-term outcomes. As such, future research should confirm this relationship and prioritize investigating its causality through prospective studies.

ABSTRACTGlobally, enteropathogenic bacteria are a major cause of morbidity and mortality.1-3 Campylobacter, Salmonella, Shiga-toxin-producing Escherichia coli, and Listeria are among the top five most commonly reported zoonotic pathogens in the European Union.4 However, not all individuals naturally exposed to enteropathogens go on to develop disease. This protection is attributable to colonization resistance (CR) conferred by the gut microbiota, as well as an array of physical, chemical, and immunological barriers that limit infection. Despite their importance for human health, a detailed understanding of gastrointestinal barriers to infection is lacking, and further research is required to investigate the mechanisms that underpin inter-individual differences in resistance to gastrointestinal infection. Here, we discuss the current mouse models available to study infections by non-typhoidal Salmonella strains, Citrobacter rodentium (as a model for enteropathogenic and enterohemorrhagic E. coli), Listeria monocytogenes, and Campylobacter jejuni. Clostridioides difficile is included as another important cause of enteric disease in which resistance is dependent upon CR. We outline which parameters of human infection are recapitulated in these mouse models, including the impact of CR, disease pathology, disease progression, and mucosal immune response. This will showcase common virulence strategies, highlight mechanistic differences, and help researchers from microbiology, infectiology, microbiome research, and mucosal immunology to select the optimal mouse model.

Non-linear regression modeling is common in epidemiology for prediction purposes or estimating relationships between predictor and response variables. Restricted cubic spline (RCS) regression is one such method, for example, highly relevant to Cox proportional hazard regression model analysis. RCS regression uses third-order polynomials joined at knot points to model non-linear relationships. The standard approach is to place knots by a regular sequence of quantiles between the outer boundaries. A regression curve can easily be fitted to the sample using a relatively high number of knots. The problem is then overfitting, where a regression model has a good fit to the given sample but does not generalize well to other samples. A low knot count is thus preferred. However, the standard knot selection process can lead to underperformance in the sparser regions of the predictor variable, especially when using a low number of knots. It can also lead to overfitting in the denser regions. We present a simple greedy search algorithm using a backward method for knot selection that shows reduced prediction error and Bayesian information criterion scores compared to the standard knot selection process in simulation experiments. We have implemented the algorithm as part of an open-source R-package, knutar.

Background: Comorbidities in people with multiple sclerosis (PwMS) can affect disease course and quality of life. Objectives: To investigate comorbidities in the five years after diagnosis, timing of comorbidity occurrence, age and sex effects, and differences between multiple sclerosis (MS) and other chronic autoimmune diseases (AIDs). Methods: In this retrospective cohort study, we systematically assessed differences in diagnosis frequencies in newly diagnosed PwMS (n = 9,880) compared to matched controls (noAID, n = 29,640) and individuals with other AIDs (psoriasis, n = 29,640; Crohn's disease, n = 9,880). Results: Some comorbidities of PwMS are similarly frequent in other AIDs, while others, such as depression, are more prevalent in PwMS (odds ratio (OR) vs noAID = 2.03(1.94–2.13)). We found that personality disorders are more frequently recorded in PwMS before (OR = 1.34(1.21–1.49)) and after MS diagnosis (OR = 1.32(1.16–1.5)), especially in women (OR = 1.39(1.2–1.6)). PwMS are more frequently diagnosed with Lyme disease (OR = 1.98(1.69–2.33)), which was predominantly recorded by general practitioners after presentation with neurological symptoms. We observed lower acute tonsillitis frequencies in PwMS (OR = 0.8(0.75–0.85)). Conclusions: Our results suggest that PwMS might have a generally increased risk for specific personality disorders. More frequent Lyme disease recordings for PwMS suggest misdiagnoses of MS symptoms. Lower tonsillitis frequencies suggest a link between MS and protection from specific infections. [ABSTRACT FROM AUTHOR]