Search

Abstract In contemporary healthcare, effective risk stratification in the general population is vital amidst rising chronic disease rates and an ageing demographic. Deceleration Capacity of the heart rate (DC), derived from 24-hour Holter electrocardiograms, holds promise in risk stratification for cardiac patients. However, the potential of short-term electrocardiograms of five minutes duration for population screening has not been fully explored. Our study aims to investigate the utility of Deceleration Capacity derived from short-term electrocardiograms as a scalable, fully-automated screening tool for predicting long-term mortality risk in the general population. Within a cohort of a representative population-based survey in Germany (KORA-KMC-study), 823 participants with sinus rhythm aged 27 to 76 years at enrollment (females 47.4%) were followed for a median of 13.4 years (IQR 13.1–13.6). All-cause mortality was defined as the primary endpoint and observed in 159 participants. Deceleration Capacity was calculated from 5-minute 12-lead electrocardiograms by a fully automated approach. Participants were divided into three predefined risk categories: DCcategory0 – low-risk (> 4.5ms); DCcategory1 – intermediate-risk (2.5-4.5ms); and DCcategory2 – high-risk (≤ 2.5ms). More than two-thirds of the participants (n = 564, 68.5%) fell into DCcategory0, about one-fifth (n = 168, 20.4%) into DCcategory1, and about one-tenth (n = 91, 11.1%) into DCcategory2. Estimated 13-years mortality in the risk groups was 16.7%, 23.5%, and 49.1%, respectively (p

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 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.

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.

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.

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.

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 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

Abstract We investigated the clinical impact of elevated microsatellite instability at selected tetranucleotide (EMAST) repeats in the context of neoadjuvant chemotherapy (CTx) in gastric/gastro‐oesophageal adenocarcinomas. We analysed 583 resected tumours (272 without and 311 after CTx) and 142 tumour biopsies before CTx. If at least two or three of the five tetranucleotide repeat markers tested showed instability, the tumours were defined as EMAST (2+) or EMAST (3+), respectively. Expression of mismatch repair proteins including MSH3 was analysed using immunohistochemistry. Microsatellite instability (MSI) and Epstein–Barr virus (EBV) positivity were determined using standard assays. EMAST (2+) and (3+) were detected in 17.8 and 11.5% of the tumours, respectively. The frequency of EMAST (2+) or (3+) in MSI‐high (MSI‐H) tumours was 96.2 or 92.5%, respectively, demonstrating a high overlap with this molecular subtype, and the association of EMAST and MSI status was significant (each overall p

Abstract Survivors of an acute myocardial infarction with diabetes mellitus retain an increased mortality risk. Reliable assessment of individual risk is required for effective and cost-efficient medical care in these patients. The Polyscore is a previously established risk predictor consisting of seven autonomic tests derived from electrocardiogram, blood pressure, and respiration. The Polyscore allows classification of survivors of myocardial infarction in groups at low, intermediate and high mortality risk. The aim of this study was to investigate the prognostic value of the Polyscore in diabetic survivors of acute myocardial infarction, which may be impaired by the presence of diabetic autonomic neuropathy. Survivors of an acute myocardial infarction were included in a prospective cohort study during hospitalisation due to the index event at two university hospitals in Munich, Germany. The Polyscore was determined from simultaneous non-invasive 30-min recordings of electrocardiogram, continuous arterial blood pressure, and respiration which were performed in all participants. Patients were followed for 5 years. The primary and secondary outcomes were all-cause mortality and cardiac mortality. 184 of 941 enrolled patients (19.6%) suffered from diabetes mellitus. 5-year-mortality was higher in diabetic patients (15.2%) compared to non-diabetic patients (5.8%). A multivariable Cox regression model confirmed the Polyscore as a strong predictor of mortality in diabetic post-MI patients (intermediate risk: HR 6.56, 95% CI 1.61–26.78, p = 0.004, mortality 22.8%; high risk: HR 18.76, 95% CI 4.35–80.98, 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.

Different immunohistochemical programmed death-ligand 1 (PD-L1) assays and scorings have been reported to yield variable results in triple-negative breast cancer (TNBC). We compared the analytical concordance and reproducibility of four clinically relevant PD-L1 assays assessing immune cell (IC) score, tumor proportion score (TPS), and combined positive score (CPS) in TNBC. Primary TNBC resection specimens (n = 104) were stained for PD-L1 using VENTANA SP142, VENTANA SP263, DAKO 22C3, and DAKO 28–8. PD-L1 expression was scored according to guidelines on virtual whole slide images by four trained readers.The mean PD-L1 positivity at IC-score ≥1% and CPS ≥1 ranged between 53% and 75% with the highest positivity for SP263 and comparable levels for 22C3, 28–8, and SP142. Inter-assay agreement was good between 28–8 and 22C3 across all scores and cut-offs (kappa 0.68–0.74) and for both assays with SP142 at IC-score ≥1% and CPS ≥1 (kappa 0.61–0.67). The agreement between SP263 and all other assays was substantially lower for all scores. Inter-reader agreement for each assay was good to excellent for IC-score ≥1% (kappa 0.73–0.78) and CPS ≥1 (kappa 0.68–0.74), fair to good for CPS ≥10 (kappa 0.52–0.67) and TPS ≥1% (kappa 0.53–0.72). The percentage of overlapping cases in the positive/negative category was >90% between IC-score ≥1% and CPS ≥1 but below when comparing IC-score ≥1% with CPS ≥10. We demonstrate an overall good inter-reader agreement for all PD-L1 assays in TNBC along with assay specific differences in positivity and concordances, which may aid to select the right test strategy in routine diagnostics.

Abstract Background This study aimed to investigate the knowledge, attitudes, behaviors, and COVID-19 vaccine hesitancy of people with migratory backgrounds among Turkish- and German-speaking patients in Munich. Methods Primary outcomes were the intention to get vaccinated for COVID-19 and COVID-19 knowledge levels (25 true/false items). Other variables included demographics, attitudes to COVID-19 and vaccination (7 items), and behaviors regarding COVID-19 (7 items). The attitude and behavior questions had 5-point Likert scales. Of the 10 Turkish-speaking family physicians in Munich, six agreed to administer Turkish or German questionnaires to consecutive patients in February 2021. Furthermore, participants with either citizenship, country of origin, native language, or place of birth being non-German were categorized as “Having a migratory background.” Data from 420 respondents were analyzed. Results Women constituted 41.4% (n = 174), the mean age was 42.2 ± 15.5 years, 245 (58.3%) preferred the Turkish questionnaire, 348 (82.9%) had a migratory background, and 197 (47.9%) intended to be vaccinated. The mean knowledge, attitude, and behavioral scores were 21.5 ± 3.2 (max = 25), 3.7 ± 0.8 (max = 5), and 4.0 ± 0.5 (max = 5). While 42.3% (n = 145) of the participants with a migratory background considered getting vaccinated, this proportion was 76.5% (n = 52) for non-immigrant Germans (Chi-square = 26.818, p

Abstract The study aimed to evaluate the diagnostic accuracy of contact history and clinical symptoms and to develop decision rules for ruling-in and ruling-out SARS-CoV-2 infection in family practice. We performed a prospective diagnostic study. Consecutive inclusion of patients coming for COVID-PCR testing to 19 general practices. Contact history and self-reported symptoms served as index test. PCR testing of nasopharyngeal swabs served as reference standard. Complete data were available from 1141 patients, 605 (53.0%) female, average age 42.2 years, 182 (16.0%) COVID-PCR positive. Multivariable logistic regression showed highest odds ratios (ORs) for “contact with infected person” (OR 9.22, 95% CI 5.61–15.41), anosmia/ageusia (8.79, 4.89–15.95), fever (4.25, 2.56–7.09), and “sudden disease onset” (2.52, 1.55–4.14). Patients with “contact with infected person” or “anosmia/ageusia” with or without self-reported “fever” had a high probability of COVID infection up to 84.8%. Negative response to the four items “contact with infected person, anosmia/ageusia, fever, sudden disease onset” showed a negative predictive value (NPV) of 0.98 (95% CI 0.96–0.99). This was present in 446 (39.1%) patients. NPV of “completely asymptomatic,” “no contact,” “no risk area” was 1.0 (0.96–1.0). This was present in 84 (7.4%) patients. To conclude, the combination of four key items allowed exclusion of SARS-CoV-2 infection with high certainty. With the goal of 100% exclusion of SARS-CoV-2 infection to prevent the spread of SARS-CoV-2 to the population level, COVID-PCR testing could be saved only for patients with negative response in all items. The decision rule might also help for ruling-in SARS-CoV-2 infection in terms of rapid assessment of infection risk.

Background The efficacy and safety of ticagrelor versus prasugrel in patients with acute coronary syndrome and prior myocardial infarction (MI) remain unstudied. We aimed to assess the treatment effect of ticagrelor versus prasugrel according to prior MI status in patients with ACS. Methods and Results Patients with acute coronary syndrome planned for an invasive strategy and randomized to ticagrelor or prasugrel in the ISAR‐REACT (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment) 5 trial were included. The primary end point was the composite of 1‐year all‐cause death, MI, or stroke; the secondary safety end point was the composite of 1‐year Bleeding Academic Research Consortium type 3 to 5 bleeding. The study included 4015 patients (prior MI=631 patients; no prior MI=3384 patients). As compared with patients without prior MI, the primary end point occurred more frequently in patients with prior MI (12.6% versus 7.2%; hazard ratio [HR], 1.78 [95% CI, 1.38–2.29]); the secondary safety end point appears to differ little between patients with and without prior MI (5.8% versus 5.7%, respectively; HR, 1.02 [95% CI, 0.71–1.45]). With regard to the primary end point, ticagrelor versus prasugrel was associated with an HR of 1.62 (95% CI, 1.03–2.55) in patients with prior MI and an HR of 1.28 (95% CI, 0.99–1.65) in patients without prior MI (Pint=0.37). With regard to the secondary safety end point, ticagrelor versus prasugrel was associated with an HR of 1.28 (95% CI, 0.56–2.91) in patients with prior MI and an HR of 1.13 (95% CI, 0.82–1.55) in patients without prior MI (Pint=0.79). Conclusions Patients with acute coronary syndrome and prior MI are at higher risk for recurrent ischemic but not bleeding events. Prasugrel is superior to ticagrelor in reducing the risk of ischemic events without a tradeoff in bleeding regardless of prior MI status. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01944800.

Abstract Background Lung emphysema is an important phenotype of chronic obstructive pulmonary disease (COPD), and CT scanning is strongly recommended to establish the diagnosis. This study aimed to identify criteria by which physicians with limited technical resources can improve the diagnosis of emphysema. Methods We studied 436 COPD patients with prospective CT scans from the COSYCONET cohort. All items of the COPD Assessment Test (CAT) and the St George’s Respiratory Questionnaire (SGRQ), the modified Medical Research Council (mMRC) scale, as well as data from spirometry and CO diffusing capacity, were used to construct binary decision trees. The importance of parameters was checked by the Random Forest and AdaBoost machine learning algorithms. Results When relying on questionnaires only, items CAT 1 & 7 and SGRQ 8 & 12 sub-item 3 were most important for the emphysema- versus airway-dominated phenotype, and among the spirometric measures FEV1/FVC. The combination of CAT item 1 (≤ 2) with mMRC (> 1) and FEV1/FVC, could raise the odds for emphysema by factor 7.7. About 50% of patients showed combinations of values that did not markedly alter the likelihood for the phenotypes, and these could be easily identified in the trees. Inclusion of CO diffusing capacity revealed the transfer coefficient as dominant measure. The results of machine learning were consistent with those of the single trees. Conclusions Selected items (cough, sleep, breathlessness, chest condition, slow walking) from comprehensive COPD questionnaires in combination with FEV1/FVC could raise or lower the likelihood for lung emphysema in patients with COPD. The simple, parsimonious approach proposed by us might help if diagnostic resources regarding respiratory diseases are limited. Trial registration ClinicalTrials.gov, Identifier: NCT01245933, registered 18 November 2010, https://clinicaltrials.gov/ct2/show/record/NCT01245933 .

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.

Understanding immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial to contain the COVID-19 pandemic. Using a multiplex approach, serum IgG responses against the whole SARS-CoV-2 proteome and the nucleocapsid proteins of endemic human coronaviruses (HCoVs) were measured in SARS-CoV-2-infected donors and healthy controls. COVID-19 severity strongly correlated with IgG responses against the nucleocapsid (N) of SARS-CoV-2 and possibly with the number of viral antigens targeted. Furthermore, a strong correlation between COVID-19 severity and serum responses against N of endemic alpha- but not betacoronaviruses was detected. This correlation was neither caused by cross-reactivity of antibodies, nor by a general boosting effect of SARS-CoV-2 infection on pre-existing humoral immunity. These findings raise the prospect of a potential disease progression marker for COVID-19 severity that allows for early stratification of infected individuals.

Summary: Background: Fractional exhaled nitric oxide (FeNO) is promising for diagnosing asthma and could replace bronchial provocation (BP). To date, cut-off values have been derived by post hoc analysis only. The aim was to validate the diagnostic accuracy for predefined FeNO cut-off values and the predictive value for responsiveness to inhaled corticosteroids (ICS). Methods: We conducted a prospective, diagnostic, multicentre study with patients attending three private practices of pneumologists in Upper Bavaria, Germany, from July 3, 2020 to Jan 21, 2022. Index test was FENO measurement. Reference standard was Tiffeneau ratio (FEV1/VC) or airway resistance as assessed by whole body plethysmography, with additional BP or bronchodilation test. Follow-up was performed after 12 weeks. Analyses of Receiver Operating Characteristics curves were conducted to determine the diagnostic accuracy and predictive value of FeNO. Findings: 308 patients with complete follow-up were recruited, 186 (60·4%) were female, average age was 44·7 years, 161 (52·3%) had asthma. Regarding diagnostic accuracy, the area under the curve (AUC) was 0·718 (95% CI 0·661–0·775; p 50 ppb was 0·24 (95% CI 0·18–0·32), specificity 0·99 (0·95–1·0), positive predictive value (PPV) 0·95 (0·84–0·99), negative predictive value (NPV) 0·54 (0·48–0·60). In 66 patients with ´wheezing´ and ´allergic rhinitis´, the sensitivity at FeNO >33 ppb was 0·49 (0·34–0·64), specificity 0·88 (0·64–0·99), PPV 0·92 (0·75–0·99), NPV 0·38 (0·23–0·54). In 68 patients with ICS medication, responsiveness was predicted at the cut-off >43 ppb, with a sensitivity of 0·55 (95%CI 0·36–0·74), specificity 0·82 (0·66–0·92), PPV 0·70 (0·47–0·87), NPV 0·71 (0·56–0·84). Interpretation: FeNO measurement allows a valid ruling-in of an asthma diagnosis, whereas ruling-out of asthma is not possible. Enhanced probability of ICS responsiveness is also given with increased FeNO values. Funding: Circassia Germany gave 25% discount on the purchase of three NIOX VERO devices.

Abstract Background The influence of lifestyle factors on the quality of life, incidence and tumor recurrence has been evaluated in several studies and is gaining increasing importance in cancer research. However, the extent of the influence of such lifestyle factors on the quality of life of cancer patients remains largely unclear, as does the number of patients actually pursuing these lifestyle changes. The purpose of this study was to examine the prevalence and predictors of lifestyle changes in patients with gynecological cancer. Methods The survey consisted of a pseudonymous questionnaire that was conducted from January to May 2014 via a telephone interview with 141 patients with a gynaecological malignancy who had undergone surgery at our Department of Gynaecology and Obstetrics. Lifestyle factors (diet, physical activity, stress level, alcohol and nicotine consumption) prior to and after the diagnosis of cancer were evaluated. Results 89% (n = 125) of the patients reported lifestyle changes after being diagnosed with cancer. There was a significant association between the implementation of lifestyle changes and age as well as the use of complementary medicine. Nutrition: 66% of the patients (n = 93) consumed more fruit and vegetables and 65% ate less meat (n = 92). Physical activity: 37% (n = 52) reported no change in their exercise routine, 36% (n = 51) described a decrease, 27% (n = 38) an increase in their physical activity. Subjective feeling of stress: 77% of the patients (n = 108) described a reduction in their perceived level of stress. Nicotine consumption: 63% (n = 12) of the 19 patients who were smokers at the time of the diagnosis quit or reduced smoking thereafter. Alcohol consumption: 47% (n = 61/129) of the patients reduced their alcohol consumption. Conclusions Most of the patients from our study group implemented lifestyle changes after being diagnosed with cancer. Prospective randomized trials are needed in order to determine the benefit of lifestyle changes (physical activity, dietary habits and stress reduction) for cancer survivors. The potential impact of lifestyle on the quality of life and the trajectory of the disease should be discussed with all oncological patients.

Abstract Most research articles presenting new data analysis methods claim that “the new method performs better than existing methods,” but the veracity of such statements is questionable. Our manuscript discusses and illustrates consequences of the optimistic bias occurring during the evaluation of novel data analysis methods, that is, all biases resulting from, for example, selection of datasets or competing methods, better ability to fix bugs in a preferred method, and selective reporting of method variants. We quantitatively investigate this bias using an example from epigenetic analysis: normalization methods for data generated by the Illumina HumanMethylation450K BeadChip microarray.

Burns are leading causes of mortality and morbidity, including prolonged hospitalization, disfigurement, and disability. Erythropoietin (EPO) is a well-known hormone causing erythropoiesis. However, EPO may play a role in healing acute and chronic wounds due to its anti-inflammatory and pro-regenerative effects. Therefore, the large, prospective, placebo-controlled, randomized, double-blind, multi-center clinical trial “EPO in Burns” was initiated to investigate the effects of EPO versus placebo treatment in severely burned patients. The primary endpoint of “EPO in Burns” was defined as the time elapsed until complete re-epithelialization of a defined split skin graft donor site. Additional analyses of post hoc defined subgroups were performed in view of the primary endpoint. The verum (n 45) and control (n 39) groups were compared with regard to the time it took for study wounds (a predefined split skin graft donor site) to reach the three stages of wound healing (re-epithelialization levels). In addition, the effects of gender (females n 18) and concomitant medications insulin (n 36), non-steroidal anti-inflammatory drugs (NSAIDs) (n 41), and vasopressor agents (n 43) were tested. Life tables were used to compare study groups (EPO vs. placebo) within subgroups. The Cox regression model was applied to evaluate interactions between the study drug (EPO) and concomitant medications for each re-epithelialization level. Using our post hoc defined subgroups, we observed a lower chance of wound healing for women compared to men (in terms of hazard ratio: hr100%: 5.984 [95%-CI: (0.805–44.490), p = 0.080]) in our study population, regardless of the study medication. In addition, results indicated an earlier onset of re-epithelialization in the first days of EPO treatment (EPO: 10% vs. Placebo: 3%). Moreover, the interpretation of the hazard ratio suggested EPO might have a positive, synergistic effect on early stages of re-epithelialization when combined with insulin [hr50%: 1.307 (p = 0.568); hr75%: 1,199 (p = 0.715)], as well as a stabilizing effect on critically ill patients [reduced need for vasopressors in the EPO group (EPO: 44% vs. Placebo 59%)]. However, additional high-quality data from clinical trials designed to address these endpoints are required to gain further insight into these effects.

Background After the ‘first wave’ in spring 2020, opinions regarding the threat and measures against COVID-19 seemed to vary among German general practitioners (GPs). Objectives To systematically investigate opinions and to identify subgroups of GPs sharing similar views. Methods A questionnaire was sent to all 210 practices accredited for undergraduate teaching of family medicine at the Medical Faculty of the Technical University of Munich. Questions addressed personal opinions regarding risks, dilemmas, restrictions and their relaxation associated with COVID-19, and personal fears, symptoms of depression and anxiety. Patterns of strong opinions (‘archetypes’) were identified using archetypal analysis, a statistical method seeking extremal points in the multidimensional data. Results One hundred and sixty-one GPs sent back a questionnaire (response rate 77%); 143 (68%) with complete data for all 38 relevant variables could be included in the analysis. We identified four archetypes with subgroups of GPs tending in the direction of these archetypes: a small group of ‘Sceptics’ (n = 12/8%) considering threats of COVID-19 as overrated and measures taken as exaggerated; ‘Hardliners’ (n = 34/24%) considering threats high and supporting strong measures; ‘Balancers’ (n = 77/54%) who also rated the threats high but were more critical about potentially impairing the quality of life of elderly people and children; and ‘Anxious’ GPs (n = 20/14%) tending to report more fear, depressive and anxiety symptoms. Conclusion Among the participants in this survey, opinions regarding the threat and the measures taken against COVID-19 during the ‘first wave’ in Germany in spring 2020 varied greatly.

Abstract Background Safe diagnosis of periprosthetic joint infection (PJI) is of utmost importance for successful exchange arthroplasty. However, current diagnostic tools show insufficient accuracy in the clinically common and challenging chronic low-grade infections. To close this diagnostic gap, reliable (bio)markers display the most promising candidates. Antimicrobial peptides (AMPs) are part of the innate immune response towards microbial growth. Recently we could show significant intraarticular levels of human cathelicidin LL-37 and β-defensin-3 (HBD-3) with high diagnostic accuracy in PJI synovial fluid. Consequently, these promising biomarkers were evaluated in PJI synovial membrane and synoviocytes, which may significantly facilitate histological diagnosis of PJI to improve outcome of septic joint replacement. Methods In this prospective single-center controlled clinical study (diagnostic level II), consecutive patients with total hip (THR) and knee (TKR) replacements were included undergoing primary arthroplasty (n = 8), surgical revision due to aseptic loosening (n = 9) and septic arthroplasty with coagulase-negative staphylococci (n = 8) according to the criteria of the Musculoskeletal Infection Society (MSIS). Semiquantitative immunohistochemical (IHC) analysis of LL-37, HBD-3 and HBD-2 in synovial membrane and isolated synoviocytes based on Total Allred Score (TS) and Immunoreactive Remmele and Stegner score (IRS) was performed. For statistical analysis, SPSS 26.0/R3.6.3 (p 0.23) upon PJI with a lower diagnostic accuracy (AUC = 0.65) in analogy to our previous findings with synovial fluid. Conclusions Our results implicate AMPs as promising and specific biomarkers for the histological diagnosis of PJI.

Objectives: Adjuvant chemotherapy decision in patients with hormone receptor positive, HER2 negative breast cancer (BC) is challenging. Ki-67 is widely used for adjuvant therapy decision in BC. The multigene assay EndoPredict (EP) has shown to provide valid and additional information about the risk of recurrence compared to traditional pathological factors. In this study, we compared Ki-67 with EP assay generated risk groups. Methods: We analyzed the results from prospective EP testing (n = 373) and tumor proliferation assessed by Ki-67 staining in luminal breast cancer. We statistically investigated the association of both parameters and probed for equivalence in risk stratification. Results: Evaluation of Ki-67 was feasible in 307 (82%) BC specimens with known EP test results. The EPscore (now called 12-gene molecular score) delineated 140 low and 167 high scores. After combining the EPscore with pathological tumor stage and nodal status, we received 203 EPclin low-risk and 104 EPclin high-risk classifications. EPscore and EPclin were significantly associated with Ki-67 indices and tumor grade (p

Ascitic fluid infection is a serious complication of liver cirrhosis. The distinction between the more common spontaneous bacterial peritonitis (SBP) and the less common secondary peritonitis in patients with liver cirrhosis is crucial due to the varying treatment approaches. This retrospective multicentre study was conducted in three German hospitals and analysed 532 SBP episodes and 37 secondary peritonitis episodes. Overall, >30 clinical, microbiological, and laboratory parameters were evaluated to identify key differentiation criteria. Microbiological characteristics in ascites followed by severity of illness and clinicopathological parameters in ascites were the most important predictors identified by a random forest model to distinguish between SBP and secondary peritonitis. To establish a point-score model, a least absolute shrinkage and selection operator (LASSO) regression model selected the ten most promising discriminatory features. By aiming at a sensitivity of 95% either to rule out or rule in SBP episodes, two cut-off scores were defined, dividing patients with infected ascites into a low-risk (score ≥ 45) and high-risk group (score < 25) for secondary peritonitis. Overall, the discrimination of secondary peritonitis from SBP remains challenging. Our univariable analyses, random forest model, and LASSO point score may help clinicians with the crucial differentiation between SBP and secondary peritonitis.

BackgroundScreening questionnaires are not sufficient to improve diagnostic quality of depression in primary care. The additional consideration of the general practitioner's (GP's) assessment could improve the accuracy of depression diagnosis. The aim of this study was to examine whether the GP rating supports a reliable depression diagnosis indicated by the PHQ-9 over a period of three months.MethodsWe performed a secondary data analysis from a previous study. PHQ-9 scores of primary care patients were collected at the time of recruitment (t1) and during a follow-up 3 months later (t2). At t1 GPs independently made a subjective assessment whether they considered the patient depressive (yes/no). Two corresponding groups with concordant and discordant PHQ-9 and GP ratings at t1 were defined. Reliability of the PHQ-9 results at t1 and t2 was assessed within these groups and within the entire sample by Cohen's Kappa, Pearson's correlation coefficient and Bland-Altman plots.Results364 consecutive patients from 12 practices in the region of Upper Bavaria/Germany participated in this longitudinal study. 279 patients (76.6%) sent back the questionnaire at t2. Concordance of GP rating and PHQ-9 at t1 led to higher replicability of PHQ-9 results between t1 and t2. The reliability of PHQ-9 was higher in the concordant subgroup (κ = 0.507) compared to the discordant subgroup (κ = 0.211) (p = 0.064). The Bland-Altman Plot showed that the deviation of PHQ-9 scores at t1 and t2 decreased by about 15% in the concordant subgroup. Pearson's correlation coefficient between PHQ-9 scores at t1 and t2 increased significantly if the GP rating was concordant with the PHQ-9 at t1 (r = 0.671) compared to the discordant subgroup (r = 0.462) (p = 0.044).ConclusionsThe combination of PHQ-9 and GP rating might improve diagnostic decision making regarding depression in general practices. PHQ-9 positive results might be more reliable and accurate, when a concordant GP rating is considered.

This study is aimed at assessing the distinctive features of patients with infected ascites and liver cirrhosis and developing a scoring system to allow for the accurate identification of patients not requiring abdominocentesis to rule out infected ascites. A total of 700 episodes of patients with decompensated liver cirrhosis undergoing abdominocentesis between 2006 and 2020 were included. Overall, 34 clinical, drug, and laboratory features were evaluated using machine learning to identify key differentiation criteria and integrate them into a point-score model. In total, 11 discriminatory features were selected using a Lasso regression model to establish a point-score model. Considering pre-test probabilities for infected ascites of 10%, 15%, and 25%, the negative and positive predictive values of the point-score model for infected ascites were 98.1%, 97.0%, 94.6% and 14.9%, 21.8%, and 34.5%, respectively. Besides the main model, a simplified model was generated, containing only features that are fast to collect, which revealed similar predictive values. Our point-score model appears to be a promising non-invasive approach to rule out infected ascites in clinical routine with high negative predictive values in patients with hydropic decompensated liver cirrhosis, but further external validation in a prospective study is needed.

Abstract Background Case-based learning (CBL) is a highly interactive instructional format widely used in medical education. One goal of CBL is to integrate basic biomedical knowledge and its application to concrete patient cases and their clinical management. In this context, we focus the role of teacher questions as triggers for reproductive vs. elaborative student responses. Specifically, our research questions concern the kinds of questions posed by clinical teachers, the kinds of responses given by students, the prediction of student responses based upon teacher questions, and the differences between the two medical disciplines in focus of our study, internal medicine and surgery. Methods We analyse 19 videotaped seminars (nine internal medicine, ten surgery) taught by clinicians and attended by advanced medical students. Multiple raters performed a low-inference rating process using a theory-based categorical scheme with satisfactory interrater-reliability. Results We found that medical teachers mostly posed initial (instead of follow-up) questions and that their questions were more often closed (instead of open). Also, more reasoning (than reproductive) questions were posed. A high rate of student non-response was observed while elaborative and reproductive student responses had a similar prevalence. In the prediction context, follow-up reasoning questions were associated with low non-response and many elaborative answers. In contrast, the highest student non-response rate followed open reproduction questions and initial reasoning questions. Most reproductive statements by students were made following closed reproduction questions. Conclusions These results deepen our understanding of interactive, questions-driven medical teaching and provide an empirical basis for clinical teachers to use questions in didactically fruitful ways.

Abstract Epstein–Barr virus positivity (EBV(+)) and high‐microsatellite instability (MSI‐H) have been identified as molecular subgroups in gastric carcinoma. The aim of our study was to determine the prognostic and predictive relevance of these subgroups in the context of platinum/5‐fluorouracil (5‐FU) based preoperative chemotherapy (CTx). Additionally, we investigated the clinical relevance of the low‐MSI (MSI‐L) phenotype. We analysed 760 adenocarcinomas of the stomach or the gastro‐oesophageal junction encompassing 143 biopsies before CTx and 617 resected tumours (291 without and 326 after CTx). EBV was determined by PCR and in situ hybridisation for selected cases. MSI was analysed by PCR using five microsatellite markers and classified as MSI‐H and MSI‐L. Frequencies of EBV(+), MSI‐H and MSI‐L in the biopsies before CTx were 4.2, 10.5 and 4.9% respectively. EBV(+) or MSI‐H did not correlate with response, but MSI‐L was associated with better response (p = 0.011). In the resected tumours, frequencies of EBV(+), MSI‐H and MSI‐L were 3.9, 9.6 and 4.5% respectively. Overall survival (OS) was significantly different in the non‐CTx group (p = 0.014). Patients with EBV(+) tumours showed the best OS, followed by MSI‐H. MSI‐L was significantly associated with worse OS (hazard ratio [HR], 2.21; 95% confidence interval [CI], 1.21–4.04, p = 0.01). In the resected tumours after CTx, MSI‐H was also associated with increased OS (HR, 0.54; 95% CI, 0.26–1.09, p = 0.085). In multivariable analysis, molecular classification was an independent prognostic factor in the completely resected (R0) non‐CTx group (p = 0.035). In conclusion, MSI‐H and EBV(+) are not predictive of response to neoadjuvant platinum/5‐FU based CTx, but they are indicative of a good prognosis. In particular, MSI‐H indicates a favourable prognosis irrespective of treatment with CTx. MSI‐L predicts good response to CTx and its negative prognostic effect for patients treated with surgery alone suggests that MSI‐L might help to identify patients with potentially high‐benefit from preoperative CTx.

Abstract Background Neuroactive steroids seem to be implicated in a variety of neurophysiological and behavioral processes, such as sleep, learning, memory, stress, feeding and aging. Numerous studies have also addressed this implication in various cerebral disorders and diseases. Yet, the correlation and association between steroids in the periphery, e.g. blood, and the central compartments, e.g. cerebrospinal fluid (CSF), have not yet been comprehensively assessed. As the brain is not directly accessible, and the collection of human CSF usually requires invasive procedures, easier accessible compartments, such as blood, have always attracted attention. However, studies in humans are scarce. In the present study we determined estradiol, progesterone and testosterone levels in CSF and serum of 22 males without cerebral disorders or diseases. Results Samples were taken under conditions corresponding closest to basal conditions with patients expecting only spinal anesthesia and minor surgery. All samples per patient were collected concomitantly. Total estradiol, progesterone and testosterone concentrations were measured by electro-chemiluminescence immunoassay. The strength of correlation was assessed by Spearman’s rank correlation coefficient. Correlation analysis revealed merely weak to very weak correlations for estradiol, progesterone and testosterone respectively between the CSF and serum compartments. Conclusions Total steroid levels of estradiol, progesterone and testosterone in CSF and serum of males without neurological disorders were determined. Weak to very weak correlations between CSF and serum were found thus suggesting that concentrations in the periphery do not parallel concentrations in the central compartments. Further research is needed to clarify to what extent and under which conditions serum levels of estradiol, progesterone and testosterone may possibly serve as a biomarker reflecting the respective concentrations in the CSF or in the brain.

Abstract In computational biology and other sciences, researchers are frequently faced with a choice between several computational methods for performing data analyses. Benchmarking studies aim to rigorously compare the performance of different methods using well-characterized benchmark datasets, to determine the strengths of each method or to provide recommendations regarding suitable choices of methods for an analysis. However, benchmarking studies must be carefully designed and implemented to provide accurate, unbiased, and informative results. Here, we summarize key practical guidelines and recommendations for performing high-quality benchmarking analyses, based on our experiences in computational biology.

Introduction The measurement of fractional exhaled nitric oxide (FeNO) is promising for diagnosing asthma and might substitute for bronchial provocation (BP) tests. To evaluate the diagnostic accuracy of FeNO within a confirmatory study, the following hypotheses will be tested: (1) A FeNO cut-off >50 ppb (parts per billion) is suitable for diagnosing asthma (sensitivity 35%, specificity 95%); (2) If the clinical symptoms ‘allergic rhinitis’ and ‘wheezing’ are present, asthma can be diagnosed at FeNO >33 ppb with a positive predictive value (PPV) >70% and (3) A FeNO >33 ppb can predict responsiveness to inhaled corticosteroid (ICS) with a PPV >70%.Methods and analysis A prospective diagnostic study will be conducted in three practices of pneumologists in Germany. 300 patients suspected of suffering from asthma will be included. As an index test, patients perform FeNO measurement with the device NIOX VERO. As reference a test, patients are examined with whole bodyplethysmography and BP, if necessary. After 3 months, patients with an asthma diagnosis will be examined again to verify the diagnosis and evaluate ICS responsiveness. Patients who did not receive an asthma diagnosis at the initial examination will be phoned after 3 months and asked about persistent respiratory symptoms to exclude false negative findings. As a primary target, sensitivity and specificity of FeNO >50 ppb will be determined. As a secondary target the PPV for asthma at FeNO >33 ppb, when the symptoms ‘allergic rhinitis’ and ‘wheezing’ are present, will be calculated. Regarding ICS responsiveness, the PPV of FeNO >33 ppb will be determined.Ethics and dissemination The study was approved by the Ethical Committee of the Technical University of Munich (Reference number 122/20 S). The major results will be published in peer-reviewed academic journals and disseminated through conferences.Trial registration number DRKS00021125.

BackgroundRisk factors of severe COVID-19 have mainly been investigated in the hospital setting. We investigated pre-defined risk factors for testing positive for SARS-CoV-2 infection and cardiovascular or pulmonary complications in the outpatient setting.MethodsThe present cohort study makes use of ambulatory claims data of statutory health insurance physicians in Bavaria, Germany, with polymerase chain reaction (PCR) test confirmed or excluded SARS-CoV-2 infection in first three quarters of 2020. Statistical modelling and machine learning were used for effect estimation and for hypothesis testing of risk factors, and for prognostic modelling of cardiovascular or pulmonary complications.ResultsA cohort of 99 811 participants with PCR test was identified. In a fully adjusted multivariable regression model, dementia (odds ratio (OR) = 1.36), type 2 diabetes (OR = 1.14) and obesity (OR = 1.08) were identified as significantly associated with a positive PCR test result. Significant risk factors for cardiovascular or pulmonary complications were coronary heart disease (CHD) (OR = 2.58), hypertension (OR = 1.65), tobacco consumption (OR = 1.56), chronic obstructive pulmonary disease (COPD) (OR = 1.53), previous pneumonia (OR = 1.53), chronic kidney disease (CKD) (OR = 1.25) and type 2 diabetes (OR = 1.23). Three simple decision rules derived from prognostic modelling based on age, hypertension, CKD, COPD and CHD were able to identify high risk patients with a sensitivity of 74.8% and a specificity of 80.0%.ConclusionsThe decision rules achieved a high prognostic accuracy non-inferior to complex machine learning methods. They might help to identify patients at risk, who should receive special attention and intensified protection in ambulatory care.

The competence centre for Residency Training in Family Medicine Bavaria (CCRTB) was established to improve the quality of postgraduate medical education by offering training and mentoring programmes for residents, and by providing train-the-trainer and mentoring courses for supervisors. Beyond that, regional Residency Training Networks (RTN) on avoluntary basis were developed to facilitate structured and efficient clinical rotation programs. Primary aim was to investigate the burden of burnout and the development of professionalism among CCRTB-residencies within a cross-sectional study. Secondary aim was to evaluate differences between CCRTB-residents with and without participation in aregional RTN. Burnout was determined with the Maslach Burnout Inventory (MBI), comprising the scales emotional exhaustion, depersonalization, and personal accomplishment. Ambulatory professionalization was evaluated using the German Professional Scale (Pro-D), comprising the scales professionalism towards the patient, towards other professionals, towards society, and towards oneself. Statistical significance of group differences was calculated by nonparametric tests. Multivariable linear regression modelling was performed to estimate the independent impact of professionalization and RTN participation on burnout scores. 347 CRRTB residents in ambulatory postgraduate training were invited, 212 (61.1%) participated, and 197 (92.9%) were included in our analyses. Lower emotional exhaustion and depersonalization, and increased personal accomplishment was associated with increased professionalisation, which was significant for nearly all Pro-D scales (p ≤ 0.05). RTN residents showed higher professionalism towards the patient (p = 0.031), other professionals (p = 0.012), and towards the society (p = 0.007) than residents of unstructured programs, and higher levels of personal accomplishment (p < 0.05). Early and efficient professionalization might be akey to reduce burnout and to establish asatisfying career in family medicine. Train-the-trainer and mentoring concepts should be implemented regularly for the training of residents. Thus, increased engagement in medical didactics should be aprerequisite for accreditation as atraining practice for residents.

Background and Purpose: To identify factors associated with prior stroke at presentation in patients with cryptogenic stroke (CS) and patent foramen ovale (PFO).Methods: We studied cross-sectional data from the International PFO Consortium Study (NCT00859885). Patients with first-ever stroke and those with prior stroke at baseline were analyzed for an association with PFO-related (right-to-left shunt at rest, atrial septal aneurysm, deep venous thrombosis, pulmonary embolism, and Valsalva maneuver) and PFO-unrelated factors (age, gender, BMI, hypertension, diabetes mellitus, hypercholesterolemia, smoking, migraine, coronary artery disease, aortic plaque). A multivariable analysis was used to adjust effect estimation for confounding, e.g., owing to the age-dependent definition of study groups in this cross-sectional study design.Results: We identified 635 patients with first-ever and 53 patients with prior stroke. Age, BMI, hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, and right-to-left shunt (RLS) at rest were significantly associated with prior stroke. Using a pre-specified multivariable logistic regression model, age (Odds Ratio 1.06), BMI (OR 1.06), hypercholesterolemia (OR 1.90) and RLS at rest (OR 1.88) were strongly associated with prior stroke.Based on these factors, we developed a nomogram to illustrate the strength of the relation of individual factors to prior stroke.Conclusion: In patients with CS and PFO, the likelihood of prior stroke is associated with both, PFO-related and PFO-unrelated factors.

In this explorative mixed-method pilot study, we set out to have a closer look at the largely under-recognized and under-investigated symptom of thick mucus in patients with ALS and its impact on patients and relatives. Thick mucus is a highly distressing symptom for both patients and caregivers. It complicates the use of non-invasive ventilation and is therefore an important prognostic factor of survival. Methods: In our preliminary study, we used a cross-sectional design, including ten ALS patients with thick mucus who were matched to ten ALS patients without thick mucus. Lung function tests and laboratory and sputum analysis were performed and questionnaires administered in order to determine associated factors of thick mucus accumulation. In a qualitative study using semi-structured interviews, we analysed the impact of thick mucus on patients and caregivers. Results: Reduced respiratory parameters as well as a higher degree of bulbar impairment were associated with the presence of thick mucus. Quality of life of patients and caregivers was strongly impaired by thick mucus accumulation. Conclusions: Thick mucus in patients with ALS has a strong impact on quality of life. Reduced cough flow and severely impaired bulbar function appear to be indicative parameters. We suggest that healthcare providers actively explore the presence of thick mucus in their patients and that it becomes included in commonly used screening tools.

Introduction and aims. We aimed to explore the impact of infection diagnosed upon admission and of other clinical baseline parameters on mortality of cirrhotic patients with emergency admissions.Material and methods. We performed a prospective observational monocentric study in a tertiary care center. The association of clinical parameters and established scoring systems with short-term mortality up to 90 days was assessed by univariate and multivariable Cox regression analysis. Akaike’s Information Criterion (AIC) was used for automated variable selection. Statistical interaction effects with infection were also taken into account.Results. 218 patients were included. 71.2% were male, mean age was 61.1 ± 10.5 years. Mean MELD score was 16.2 ± 6.5, CLIF-consortium Acute on Chronic Liver Failure-score was 34 ± 11. At 28, 90 and 365 days, 9.6%, 26.0% and 40.6% of patients had died, respectively. In multivariable analysis, respiratory organ failure [Hazard Ratio (HR) = 0.15], albumin substitution (HR = 2.48), non-HCC-malignancy (HR = 4.93), CLIF-C-ACLF (HR = 1.10), HCC (HR = 3.70) and first episode of ascites (HR = 0.11) were significantly associated with 90-day mortality. Patients with infection had a significantly higher 90-day mortality (36.3 vs. 20.1%, p = 0.007). Cultures were positive in 32 patients with resistance to cephalosporins or quinolones in 10, to ampicillin/sulbactam in 14 and carbapenems in 6 patients.Conclusion. Infection is common in cirrhotic ED admissions and increases mortality. The proportion of resistant microorganisms is high. The predictive capacity of established scoring systems in this setting was low to moderate.

Abstract Background Although integrative medicine is gaining increasing attention and is claiming more and more its place in modern health care, it still plays a marginal role in conventional maternity care. The present study aims to examine the patterns of Complementary and Alternative Medicine (CAM) use and the demand for integrative therapies, including CAM, relaxation therapies, nutritional counseling, and psychological assistance, among women in pregnancy and childbed. Methods The survey was conducted from April 2017 to July 2017 by means of a pseudo-anonymous 38-item questionnaire at the Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich. Eligible participants were women hospitalized due to pregnancy related complications and women in childbed. Descriptive statistics were generated to determine patterns of CAM use and demand for integrative therapeutic approaches. Univariate analysis was used to detect associations between patients’ characteristics and their interest in the different integrative therapies. Furthermore, binary logistic regression was used to estimate the odds ratio of demand for CAM. Results A total of 394 out of 503 patients participated in the survey (78%). 60% declared using CAM in general, 45% specifically in relation to their pregnancy or childbed. Most commonly used modalities were vitamins (31% of all patients), yoga (24%), and herbal supplements (23%). Most popular sources of recommendation of CAM use were midwives and gynecologists. Integrative therapy options patients would have wanted alongside conventional maternity care were CAM (64%), relaxation therapies (44%), dietary counseling (28%), and psychological counseling (15%). Furthermore, associations between patients’ sociodemographic characteristics and their demand for integrative therapies were identified. Conclusions The results of this study demonstrate that there is a considerable demand for integrative medicine and widespread use of CAM among women during pregnancy and childbed in Germany. Maternity health care providers should be aware of these findings in order to be able to better address patients’ needs and wishes. Our study findings should be interpreted with regard to patients in an hospital setting.

Polarisation of metastasising cancer cells in circulation has not been investigated before. Here the authors identify single cell polarity as a distinct polarisation state of single cells in liquid phase, and show that perturbing single cell polarity affects attachment, adhesion, transmigration and metastasis in vitro and in vivo.

Abstract Background Little is known about ICU physicians’ self-confidence and knowledge related to palliative care. Our objective was to investigate self-confidence and knowledge of German ICU physicians related to palliative care, and to assess the impact of work experience, gender, specialty and additional certifications in pain or palliative medicine. Methods In a multicentre prospective observational study ICU physicians of ten hospitals were asked to rate their self-confidence and to complete a multiple choice questionnaire for the assessment of knowledge. Beyond descriptive statistics and non-parametric tests for group comparisons, linear regression analysis was used to assess the impact of independent variable on self-confidence and knowledge. Spearman‘s rank test was calculated. Results 55% of answers in the knowledge test were correct and more than half of the participants rated themselves as “rather confident” or “confident”. Linear regression analysis revealed that an additional certificate in either pain or palliative medicine significantly increased both knowledge and self-confidence, but only 15 out of 137 participants had at least one of those certificates. Relation between self-confidence and the results of the knowledge test was weak (r = 0.270 in female) and very weak (r = −0.007 in male). Conclusions Although the questionnaire needs improvement according to the item analysis, it appears that, with respect to palliative care, ICU Physicians’ self-confidence is not related to their knowledge. An additional certificate in either pain or palliative medicine was positively correlated to both self-confidence and knowledge. However, only a minority of the participants were qualified through such a certificate.

Abstract Neurovascular coupling can be directly assessed by retinal vessel response to flickering light using optical imaging methods. The response is altered in a number of ocular and cardiovascular diseases. Whether it is altered in Alzheimer’s disease (AD) is investigated. Retinal vessel reaction to monochromatic flicker stimulation was examined by Dynamic Vessel Analyzer independent of the commercial software in elderly subjects: 15 patients with mild-to-moderate dementia due to AD (ADD); 24 patients with mild cognitive impairment due to AD (MCI); 15 cognitively healthy controls (HC). Retinal vessels in ADD showed a more emphasized and delayed reactive dilation as compared to HC. In MCI, these aspects still differed from those seen in ADD. Maximal arterial reaction was increased and dilation was delayed in ADD as compared to HC (p = 0.004 and p

Abstract Background The goal of medical research is to develop interventions that are in some sense superior, with respect to patient outcome, to interventions currently in use. Similarly, the goal of research in methodological computational statistics is to develop data analysis tools that are themselves superior to the existing tools. The methodology of the evaluation of medical interventions continues to be discussed extensively in the literature and it is now well accepted that medicine should be at least partly “evidence-based”. Although we statisticians are convinced of the importance of unbiased, well-thought-out study designs and evidence-based approaches in the context of clinical research, we tend to ignore these principles when designing our own studies for evaluating statistical methods in the context of our methodological research. Main message In this paper, we draw an analogy between clinical trials and real-data-based benchmarking experiments in methodological statistical science, with datasets playing the role of patients and methods playing the role of medical interventions. Through this analogy, we suggest directions for improvement in the design and interpretation of studies which use real data to evaluate statistical methods, in particular with respect to dataset inclusion criteria and the reduction of various forms of bias. More generally, we discuss the concept of “evidence-based” statistical research, its limitations and its impact on the design and interpretation of real-data-based benchmark experiments. Conclusion We suggest that benchmark studies—a method of assessment of statistical methods using real-world datasets—might benefit from adopting (some) concepts from evidence-based medicine towards the goal of more evidence-based statistical research.