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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

Abstract Root exudates contain specialised metabolites that shape the plant’s root microbiome. How host-specific microbes cope with these bioactive compounds, and how this ability affects root microbiomes, remains largely unknown. We investigated how maize root bacteria metabolise benzoxazinoids, the main specialised metabolites of maize. Diverse and abundant bacteria metabolised the major compound in the maize rhizosphere MBOA (6-methoxybenzoxazolin-2(3H)-one) and formed AMPO (2-amino-7-methoxy-phenoxazin-3-one). AMPO forming bacteria were enriched in the rhizosphere of benzoxazinoid-producing maize and could use MBOA as carbon source. We identified a gene cluster associated with AMPO formation in microbacteria. The first gene in this cluster, bxdA encodes a lactonase that converts MBOA to AMPO in vitro. A deletion mutant of the homologous bxdA genes in the genus Sphingobium, did not form AMPO nor was it able to use MBOA as a carbon source. BxdA was identified in different genera of maize root bacteria. Here we show that plant-specialised metabolites select for metabolisation-competent root bacteria. BxdA represents a benzoxazinoid metabolisation gene whose carriers successfully colonize the maize rhizosphere and thereby shape the plant’s chemical environmental footprint.

Abstract Background Bile acids (BAs) are steroid-derived molecules with important roles in digestion, the maintenance of host metabolism, and immunomodulation. Primary BAs are synthesized by the host, while secondary BAs are produced by the gut microbiome through transformation of the former. The regulation of microbial production of secondary BAs is not well understood, particularly the production of 7-dehydroxylated BAs, which are the most potent agonists for host BA receptors. The 7-dehydroxylation of cholic acid (CA) is well established and is linked to the expression of a bile acid-inducible (bai) operon responsible for this process. However, little to no 7-dehydroxylation has been reported for other host-derived BAs (e.g., chenodeoxycholic acid, CDCA or ursodeoxycholic acid, UDCA). Results Here, we demonstrate that the 7-dehydroxylation of CDCA and UDCA by the human isolate Clostridium scindens is induced when CA is present, suggesting that CA-dependent transcriptional regulation is required for substantial 7-dehydroxylation of these primary BAs. This is supported by the finding that UDCA alone does not promote expression of bai genes. CDCA upregulates expression of the bai genes but the expression is greater when CA is present. In contrast, the murine isolate Extibacter muris exhibits a distinct response; CA did not induce significant 7-dehydroxylation of primary BAs, whereas BA 7-dehydroxylation was promoted upon addition of germ-free mouse cecal content in vitro. However, E. muris was found to 7-dehydroxylate in vivo. Conclusions The distinct expression responses amongst strains indicate that bai genes are regulated differently. CA promoted bai operon gene expression and the 7-dehydroxylating activity in C. scindens strains. Conversely, the in vitro activity of E. muris was promoted only after the addition of cecal content and the isolate did not alter bai gene expression in response to CA. The accessory gene baiJ was only upregulated in the C. scindens ATCC 35704 strain, implying mechanistic differences amongst isolates. Interestingly, the human-derived C. scindens strains were also capable of 7-dehydroxylating murine bile acids (muricholic acids) to a limited extent. This study shows novel 7-dehydroxylation activity in vitro resulting from the presence of CA and suggests distinct bai gene expression across bacterial species.

Abstract Background We define teacher wait time (TWT) as a pause between a teacher question and the following response given by a student. TWT is valuable because it gives students time to activate prior knowledge and reflect on possible answers to teacher questions. We seek to gain initial insights into the phenomenon of TWT in medical education and give commensurate recommendations to clinical teachers. Methods We observed n = 719 teacher questions followed by wait time. These were video-recorded in 29 case-based seminars in undergraduate medical education in the areas of surgery and internal medicine. The seminars were taught by 19 different clinical teachers. The videos were coded with satisfactory reliability. Time-to-event data analysis was used to explore TWT overall and independently of question types. Results In our sample of case-based seminars, about 10% of all teacher questions were followed by TWT. While the median duration of TWT was 4.41 s, we observed large variation between different teachers (median between 2.88 and 10.96 s). Based on our results, we recommend that clinical teachers wait for at least five, but not longer than 10–12 s after initial questions. For follow-up and reproduction questions, we recommend shorter wait times of 5–8 s. Conclusions The present study provides insights into the frequency and duration of TWT and its dependence on prior questions in case-based seminars. Our results provide clinical teachers with guidance on how to use TWT as an easily accessible tool that gives students time to reflect on and respond to teacher questions.

Objectives To develop a new questionnaire for the diagnostic assessment of depression adapted to the primary care setting by combining psychiatric criteria and heuristics of general practitioners (GPs). Psychometric evaluation of the new questionnaire and first validity evidence.Design The questionnaire was developed using cognitive interviews with think-aloud technique. Factorial validity was then examined in a cross-sectional study.Setting Primary care. Five general practices in Bavaria, Germany.Participants 15 GPs, 4 psychiatrists/psychotherapists and 13 patients participated in cognitive expert interviews. A primary care sample of N=277 consecutive patients participated in the cross-sectional study.Methods After consultation with experts and literature research, the questionnaire contained a self-rating part for patients and an external part for GPs. Items were then iteratively optimised using cognitive interviews. Factorial validity was examined. To estimate internal consistency, Cronbach’s α was calculated. Validity was assessed by correlating the new questionnaire and the Patient Health Questionnaire-9 (PHQ-9).Results The preliminary version of the two-part ‘Questionnaire for the assessment of DEpression SYmptoms in Primary Care’ (DESY-PC) comprised 52 items for patients (DESY-PAT-1: questions about patient’s environment; DESY-PAT-2: questions about depression-specific symptoms) and 21 items for GPs (DESY-GP). The analysis of the DESY-PAT-1 revealed a one-factor solution (‘environmental factors’) with Cronbach’s α of 0.55. The items of the DESY-PAT-2 were assigned to three factors, ‘depressive cognitions’, ‘suicidality’ and ‘symptoms of fatigue’, with Cronbach’s α of 0.86, 0.79 and 0.85, respectively. Factorial analysis revealed two factors for the DESY-GP: ‘depression symptoms’ and ‘medical history/external factors’. Cronbach’s α was 0.90 and 0.59, respectively. After factorial analysis, the DESY-PAT was reduced to 28 items, and the DESY-GP was reduced to 15 items. Correlations of the DESY-PC with the PHQ-9 were high and significant, indicating convergent validity.Conclusions The new questionnaire represents an innovative extension of depression questionnaires and could be particularly suitable for general practices.

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 This study aimed to examine the association of prior mental health diagnoses with the onset of Post-COVID-19 condition (PCC). We conducted a retrospective comparative cohort study and secondary analysis of routinely collected claims data from participants in statutory health insurance in Bavaria, Germany, from January 2015 to June 2022. Study participants were 619,560 patients with confirmed COVID-19, 42,969 with other respiratory tract infection (ORI), and 438,023 controls. Using diagnoses coded according to the German modification of the ICD-10, the associations between prior mental health diagnoses and a PCC diagnosis (primary outcome) or associated symptoms (secondary outcomes) were estimated using multiple Cox proportional hazards regression models. Mental disorders (hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.30–1.42), anxiety (HR 1.14, 95% CI 1.07–1.20), depression (HR 1.25, 95% CI 1.19–1.30) and somatoform disorders (HR 1.30, 95% CI 1.24–1.36) were associated with higher risks for PCC. Mental disorders were associated with the same or even greater risk for a diagnosis of malaise and fatigue in the control cohort (HR 1.71, 95% CI 1.52–1.93) and ORI cohort (HR 1.43, 95% CI 1.20–1.72), than in the COVID-19 cohort (HR 1.43, 95% CI 1.35–1.51). In summary, prior mental comorbidity was associated with an increased risk of PCC and its associated symptoms in all cohorts, not specifically in COVID-19 patients.

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.

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.

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.

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.

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.

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 Background Case-based group discussions (CBGD) are a specific, interaction-focused format dedicated to fostering medical students’ skills in applying basic biomedical knowledge to patient cases. Existing conceptions of CBGD suggest that a gradient towards increased opportunities for students to make elaborative verbal contributions is an important element of such seminars. To verify this assumption, we investigate empirically if clinical teachers progress from more basic, knowledge-oriented questions towards more advanced, elaboration-oriented questions in such seminars. Methods We videotaped 21 different clinical teachers and 398 medical students in 32 CBGD-seminars on surgery and internal medicine. We coded closed-reproductive and open-elaborative teacher questions as well as reproductive and elaborative student responses to these questions. Inter-rater reliability was satisfactory. To determine trends regarding the teacher questions / student responses, we compared eight time-segments of equal duration per seminar. Results Overall, clinical teachers asked more closed-reproductive than open-elaborative questions. Students gave more reproductive than elaborative responses. Regarding the frequencies of these forms of teacher questions / student responses, we found no significant differences over time. Conclusions Clinical teachers did not deliberately modify the types of questions over time to push students towards more elaborative responses. We conclude that the critical question to which degree promising teaching approaches are actually put into clinical teaching practice should be raised more purposefully in medical education research.

Abstract Background Asthma education programs (AEPs) have been shown to increase quality of life and reduce emergency treatments and hospital admissions. Despite the proven benefits, only a minority of asthma patients attend such programs. To increase the number of educated patients, an online education program (electronic AEP, eAEP) for asthma patients has been developed. The present study aims to investigate the effectiveness of the eAEP in terms of asthma knowledge, asthma control and emergency treatments in general practice settings. Methods This is a cluster randomized controlled trial including 100 patients with bronchial asthma from 20 general practices in Bavaria, Germany. General practices will be randomly assigned to either the intervention or control group. Patients in the intervention group will receive access to the eAEP and instructions to complete this program within two weeks. Patients in the control group will receive usual care including a referral to face-to-face AEP (fAEP) by a certified primary care physician or a pulmonologist according to guideline recommendations. Furthermore, patients of both the intervention and control groups will be invited to a follow-up consultation in their general practice after completion of the eAEP and fAEP (three weeks and twelve weeks after study inclusion, respectively) to discuss any open issues. Outcomes for both groups will be assessed at baseline (t0), after two weeks (t1), three months (t2) and six months (t3). The primary outcome is the comparison of asthma knowledge gain between intervention and control groups after completion of the eAEP (two weeks after study inclusion) and fAEP (twelve weeks after study inclusion), respectively. Secondary outcomes include asthma control, frequency of emergency treatments, patient autonomy as well as attitudes towards asthma medication. Discussion The results of the present trial will provide knowledge about the effectiveness of an online education program for asthma patients compared to usual care in primary care. Trial registration German Clinical Trials Register (DRKS), DRKS00028805 . Registered 22 April 2022.

Abstract Tumour budding (TB) has been associated with adverse clinicopathological factors and poor survival in a plethora of therapy‐naïve carcinoma entities including gastric adenocarcinoma (GC). As conventional histopathological grading is usually omitted in the post‐neoadjuvant setting of GC, our study aimed to investigate the prognostic impact of TB in GCs resected after neoadjuvant therapy. We evaluated TB according to the criteria from the International Tumour Budding Consensus Conference (ITBCC) in 167 post‐neoadjuvant resections of intestinal‐type GC and correlated the results with overall survival (OS) and clinicopathological parameters. GCs were categorised into Bd1 (0–4 buds, low TB), Bd2 (5–9 buds, intermediate TB), and Bd3 (≥10 buds, high TB). Carcinomas with intermediate and high TB were significantly enriched in higher ypTNM stages and strongly associated with reduced 5‐year OS in univariable analyses (p

Background: Multiple sclerosis (MS) is a chronic neuroinflammatory disease affecting about 2.8 million people worldwide. Disease course after the most common diagnoses of relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) is highly variable and cannot be reliably predicted. This impairs early personalized treatment decisions. Objectives: The main objective of this study was to algorithmically support clinical decision-making regarding the options of early platform medication or no immediate treatment of patients with early RRMS and CIS. Design: Retrospective monocentric cohort study within the Data Integration for Future Medicine (DIFUTURE) Consortium. Methods: Multiple data sources of routine clinical, imaging and laboratory data derived from a large and deeply characterized cohort of patients with MS were integrated to conduct a retrospective study to create and internally validate a treatment decision score [Multiple Sclerosis Treatment Decision Score (MS-TDS)] through model-based random forests (RFs). The MS-TDS predicts the probability of no new or enlarging lesions in cerebral magnetic resonance images (cMRIs) between 6 and 24 months after the first cMRI. Results: Data from 65 predictors collected for 475 patients between 2008 and 2017 were included. No medication and platform medication were administered to 277 (58.3%) and 198 (41.7%) patients. The MS-TDS predicted individual outcomes with a cross-validated area under the receiver operating characteristics curve (AUROC) of 0.624. The respective RF prediction model provides patient-specific MS-TDS and probabilities of treatment success. The latter may increase by 5–20% for half of the patients if the treatment considered superior by the MS-TDS is used. Conclusion: Routine clinical data from multiple sources can be successfully integrated to build prediction models to support treatment decision-making. In this study, the resulting MS-TDS estimates individualized treatment success probabilities that can identify patients who benefit from early platform medication. External validation of the MS-TDS is required, and a prospective study is currently being conducted. In addition, the clinical relevance of the MS-TDS needs to be established.

Background: In chronically ill patients, medication adherence during implementation can be crucial for treatment success and can decrease health costs. In some populations, regression models do not show this relationship. We aim to estimate subgroup-specific and personalized effects to identify target groups for interventions.Methods: We defined three cohorts of patients with type 1 diabetes (n = 12,713), type 2 diabetes (n = 85,162) and hyperlipidemia (n = 117,485) from German claims data between 2012 and 2015. We estimated the association of adherence during implementation in the first year (proportion of days covered) and mean total costs in the three following years, controlled for sex, age, Charlson’s Comorbidity Index, initial total costs, severity of the disease and surrogates for health behavior. We fitted three different types of models on training data: 1) linear regression models for the overall conditional associations between adherence and costs, 2) model-based trees to identify subgroups of patients with heterogeneous adherence effects, and 3) model-based random forests to estimate personalized adherence effects. To assess the performance of the latter, we conditionally re-estimated the personalized effects using test data, the fixed structure of the forests, and fixed effect estimates of the remaining covariates.Results: 1) our simple linear regression model estimated a positive adherence effect, that is an increase in total costs of 10.73 Euro per PDC-point and year for diabetes type 1, 3.92 Euro for diabetes type 2 and 1.92 Euro for hyperlipidemia (all p ≤ 0.001). 2) The model-based tree detected subgroups with negative estimated adherence effects for diabetes type 2 (-1.69 Euro, 24.4% of cohort) and hyperlipidemia (-0.11 Euro, 36.1% and -5.50 Euro, 5.3%). 3) Our model-based random forest estimated personalized adherence effects with a significant proportion (4.2%–24.1%) of negative effects (up to -8.31 Euro). The precision of these estimates was high for diabetes type 2 and hyperlipidemia patients.Discussion: Our approach shows that tree-based models can identify patients with different adherence effects and the precision of personalized effects is measurable. Identified patients can form target groups for adherence-promotion interventions. The method can also be applied to other outcomes such as hospitalization risk to maximize positive health effects of an intervention.