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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., Highlights • Different PD-L1 IHC assays and scorings may show variable results in TNBC. • Overall good assay concordance between SP142, 22C3, and 28–8 at IC-score 1%. • Overall good assay concordance between SP142, 22C3, and 28–8 at CPS 1. • SP142 is less optimal for CPS assessment at higher cut-offs. • SP263 assay is not interchangeable with the other three PD-L1 assays.

Objectives The aim of this study was to assess the safety and efficacy of ticagrelor versus prasugrel for patients with acute coronary syndrome (ACS) according to their estimated glomerular filtration rates (eGFRs). Background The outcomes of ticagrelor versus prasugrel in patients with ACS according to eGFR have not been defined. Methods Patients (n = 4,012) were categorized into 3 groups: low eGFR ( Results Patients with low eGFRs had a higher risk for the primary endpoint compared with patients with intermediate eGFRs (adjusted HR: 1.89; 95% CI: 1.46-2.46]) and those with high eGFRs (adjusted HR: 2.33; 95% CI: 1.57-3.46). A risk excess for low eGFR was also observed for bleeding (adjusted HR: 1.55 [95% CI: 1.12-2.13] vs intermediate eGFR; adjusted HR: 1.59 [95% CI: 1.01-2.50] vs high eGFR). However, eGFR did not affect the relative efficacy and safety of ticagrelor versus prasugrel. In patients with low eGFR, the primary endpoint occurred in 20.5% with ticagrelor and in 14.7% with prasugrel (HR: 1.47; 95% CI: 1.04-2.08; P = 0.029); there was no significant difference in bleeding. Conclusions These results show that among patients with ACS, reduction of eGFR is associated with increased risk for ischemic and bleeding events but has no significant impact on the relative efficacy and safety of ticagrelor versus prasugrel. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome [ISAR-REACT 5]; NCT01944800 )

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. Supplementary Information The online version contains supplementary material available at 10.1186/s12931-021-01837-2.

BACKGROUND: Drug-coated balloons (DCB) and drug-eluting stents (DES) represent the currently recommended treatments for in-stent restenosis (ISR). Optical coherence tomography (OCT) allows detailed neointimal characterisation which can guide treatment strategies. AIMS: The aims of this study were first, to assess the relation between neointimal pattern and clinical outcomes following in-stent restenosis (ISR) treatment, and second, to explore a potential interaction between neointimal pattern and treatment modality relative to clinical outcomes. METHODS: Patients undergoing OCT-guided treatment (DCB or DES) of ISR in three European centres were included. Based on the median of distribution of non-homogeneous neointima quadrants, patients were categorised into low and high inhomogeneity groups. RESULTS: A total of 197 patients (low inhomogeneity=100 and high inhomogeneity=97) were included. There were no significant differences in terms of major adverse cardiac events (MACE) (p=0.939) or target lesion revascularisation (TLR) (p=0.732) between the two groups. The exploratory analysis showed a significant interaction between neointimal pattern and treatment modality regarding MACE (pint=0.006) and TLR (pint=0.022). DES showed a significant advantage over DCB in the high (MACE: HR 0.26 [0.10-0.65], p=0.004; TLR: HR 0.28 [0.11-0.69], p=0.006), but not in the low inhomogeneity group (MACE: p=0.917; TLR: p=0.797). CONCLUSIONS: In patients with ISR treated with DCB or DES, there were no significant differences in terms of MACE or TLR between the low and high inhomogeneity groups. A significant interaction was observed between treatment modality and neointimal pattern with an advantage of DES over DCB in the high and no difference in the low inhomogeneity group. This warrants confirmation from prospective dedicated studies.

Aims Dynamic retinal vessel analysis (DVA) provides a noninvasive way to asses microvascular function in patients and potentially to improve predictions of individual cardiovascular (CV) risk. The aim of our study was to use untargeted machine learning on DVA in order to improve CV mortality prediction and to identify corresponding response alterations. Methods and results We adopted a workflow consisting of noise reduction and extraction of independent components within DVA signals. Predictor performance was assessed in survival random forest models. Applying our technique to the prediction of all-cause mortality in a cohort of 214 hemodialysis patients resulted in the selection of a component which was highly correlated to maximal venous dilation following flicker stimulation (vMax), a previously identified predictor, confirming the validity of our approach. When fitting for CV mortality as the outcome of interest, a combination of three components derived from the arterial signal resulted in a marked improvement in predictive performance. Clustering analysis suggested that these independent components identified groups of patients with substantially higher CV mortality. Conclusions Our results provide a machine learning workflow to improve the predictive performance of DVA and identify groups of hemodialysis patients at high risk of CV mortality. Our approach may also prove to be promising for DVA signal analysis in other CV disease states. Translational perspective DVA is a noninvasive technique which can help to assess microvascular dysfunction, one of the driving factors of CV disease. This study demonstrates a machine learning method which improves DVA interpretation for the estimation of CV risk in hemodialysis patients. Similar techniques can help doctors to identify high risk patients for timely therapeutic interventions and to monitor the effects of these interventions.

Background: Subgroup analyses are frequently used to assess heterogeneity of treatment effects in randomised clinical trials. Inconsistent, improper and incomplete implementation, reporting and interpretation have been identified as ongoing challenges. Further, subgroup analyses were frequently criticised because of unreliable or potentially misleading results. More recently, recommendations and guidelines have been provided to improve the reporting of data in this regard. Methods: This systematic review was based on a literature search within the digital archives of three selected medical journals, The New England Journal of Medicine, The Lancet and Circulation. We reviewed articles of randomised clinical trials in the domain of cardiovascular disease which were published in 2015 and 2016. We screened and evaluated the selected articles for the mode of implementation and reporting of subgroup analyses. Results: We were able to identify a total of 130 eligible publications of randomised clinical trials. In 89/130 (68%) articles, results of at least one subgroup analysis were presented. This was dependent on the considered journal (p Conclusion: Compared to previous reviews in this context, we observed improvements in the reporting of subgroup analyses of cardiovascular randomised clinical trials. Nonetheless, critical shortcomings, such as inconsistent reporting of the implementation and insufficient pre-specification, persist.

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.

Background: Data on the comparative efficacy and safety of ticagrelor versus prasugrel in patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention are limited. We assessed the efficacy and safety of ticagrelor versus prasugrel in a head-to-head comparison in patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention. Methods: In this prespecified subgroup analysis, we included 1653 patients with ST-segment–elevation myocardial infarction randomized to receive ticagrelor or prasugrel in the setting of the ISAR REACT-5 trial (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5). The primary end point was the incidence of death, myocardial infarction, or stroke at 1 year after randomization. The secondary end point was the incidence of bleeding defined as BARC (Bleeding Academic Research Consortium) type 3 to 5 bleeding at 1 year after randomization. Results: The primary end point occurred in 83 patients (10.1%) in the ticagrelor group and in 64 patients (7.9%) in the prasugrel group (hazard ratio, 1.31 [95% CI, 0.95–1.82]; P =0.10). One-year incidence of all-cause death (4.9% versus 4.7%; P =0.83), stroke (1.3% versus 1.0%; P =0.46), and definite stent thrombosis (1.8% versus 1.0%; P =0.15) did not differ significantly in patients assigned to ticagrelor or prasugrel. One-year incidence of myocardial infarction (5.3% versus 2.8%; hazard ratio, 1.95 [95% CI, 1.18–3.23]; P =0.010) was higher with ticagrelor than with prasugrel. BARC type 3 to 5 bleeding occurred in 46 patients (6.1%) in the ticagrelor group and in 39 patients (5.1%) in the prasugrel group (hazard ratio, 1.22 [95% CI, 0.80–1.87]; P =0.36). Conclusions: In patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention, there was no significant difference in the primary end point between prasugrel and ticagrelor. Ticagrelor was associated with a significant increase in the risk for recurrent myocardial infarction. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01944800.

Background Current guidelines recommend intensified platelet inhibition by prasugrel or ticagrelor in patients with unstable angina (UA) or non-ST-segment elevation (NSTE) myocardial infarction (MI). Objectives This study sought to investigate the benefits and risks of ticagrelor as compared with prasugrel in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and planned invasive management. Methods This post hoc analysis combines the pre-specified subgroups of UA and NSTEMI of the randomized ISAR-REACT 5 trial. It included 1,179 patients assigned to ticagrelor and 1,186 assigned to prasugrel. Ticagrelor was started immediately after randomization and prasugrel after coronary angiography. The primary endpoint was a composite of death, MI, or stroke during 1-year follow-up, and the safety endpoint was Bleeding Academic Research Consortium class 3–5. Results The primary endpoint was reached in 101 (8.7%) patients in the ticagrelor and in 73 (6.3%) patients in the prasugrel group (hazard ratio [HR]: 1.41; 95% confidence interval [CI]: 1.04 to 1.90). The HR for all-cause death was 1.43 (95% CI: 0.93 to 2.21) and that for MI 1.43 (95% CI: 0.94 to 2.19). The safety endpoint occurred in 49 (5.2%) patients in the ticagrelor and in 41 (4.7%) patients in the prasugrel group (HR: 1.09; 95% CI: 0.72 to 1.65). Landmark analysis revealed persistence of the efficacy advantage with prasugrel after the first month. Conclusions In patients with NSTE-ACS, we found that prasugrel was superior to ticagrelor in reducing the combined 1-year risk of death, MI, and stroke without increasing the risk of bleeding. Due to the post hoc nature of the analysis, these findings need confirmation by further studies. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome; NCT01944800 )

Objectives The aim of this study was to assess the efficacy and safety of ticagrelor versus prasugrel in patients with diabetes mellitus (DM) presenting with acute coronary syndromes (ACS)...

Zusammenfassung. Fragestellung: Unbegleitete minderjährige Flüchtlinge (UMF) sind eine besonders vulnerable Gruppe bezüglich psychischer Erkrankungen. Sie stellen daher nicht nur für die kinder- und jugendpsychiatrische und psychotherapeutische Versorgung, sondern auch für Einrichtungen der Jugendhilfe eine große Herausforderung dar. Die Studie untersucht die Wirksamkeit des Stabilisierungstrainings für jugendliche Flüchtlinge mit Traumafolgestörungen in stationären Jugendhilfeeinrichtungen. Methodik: Die randomisierte Kontrollgruppenstudie mit Prä-Post-Design wurde im naturalistischen Setting durchgeführt. Neun Wohngruppen für UMF wurden zufällig der Interventions- oder Wartekontrollbedingung zugewiesen. Die psychische Belastung von 46 UMF wurde sowohl durch Selbst- als auch durch Fremdurteil erfasst. Als Intervention wurde das Stabilisierungstraining für jugendliche Flüchtlinge mit Traumafolgestörungen von jeweils zwei pädagogischen MitarbeiterInnen in den Wohngruppen durchgeführt. Ergebnisse: Die Trainingsteilnahme führte zu einer Reduzierung der subjektiv erlebten allgemeinen psychischen Belastung. Die psychische Belastung im Selbsturteil war in der Interventionsgruppe nach Trainingsende signifikant niedriger als in der Wartekontrollgruppe. Die Wirksamkeit des Trainings wird durch das verwendete Fremdbeurteilungsmaß offenbar nicht abgebildet. Schlussfolgerungen: Das Stabilisierungstraining kann ein geeignetes Instrument zur präklinischen Versorgung junger Geflüchteter und damit eine wichtige Grundlage für eine weiterführende Psychotherapie sein. Für die Bewertung des Trainingseffekts erscheint das Selbsturteil der Betroffenen bedeutsamer als Fremdbeurteilungen.

Background & Aims Paneth cells (PCs) synthesize and secrete antimicrobial peptides that are key mediators of host-microbe interactions, establishing a balance between intestinal microflora and enteric pathogens. We observed that their number increases in experimental portal hypertension and aimed to investigate the mechanisms by which these cells can contribute to the regulation of portal pressure. Methods We first treated Math1Lox/LoxVilcreERT2 mice with tamoxifen to induce the complete depletion of intestinal PCs. Subsequently, we performed partial portal vein or bile duct ligation. We then studied the effects of these interventions on hemodynamic parameters, proliferation of blood vessels and the expression of genes regulating angiogenesis. Intestinal organoids were cultured and exposed to different microbial products to study the composition of their secreted products (by proteomics) and their effects on the proliferation and tube formation of endothelial cells (ECs). In vivo confocal laser endomicroscopy was used to confirm the findings on blood vessel proliferation. Results Portal hypertension was significantly attenuated in PC-depleted mice compared to control mice and was associated with a decrease in portosystemic shunts. Depletion of PCs also resulted in a significantly decreased density of blood vessels in the intestinal wall and mesentery. Furthermore, we observed reduced expression of intestinal genes regulating angiogenesis in Paneth cell depleted mice using arrays and next generation sequencing. Tube formation and wound healing responses were significantly decreased in ECs treated with conditioned media from PC-depleted intestinal organoids exposed to intestinal microbiota-derived products. Proteomic analysis of conditioned media in the presence of PCs revealed an increase in factors regulating angiogenesis and additional metabolic processes. In vivo endomicroscopy showed decreased vascular proliferation in the absence of PCs. Conclusions These results suggest that in response to intestinal flora and microbiota-derived factors, PCs secrete not only antimicrobial peptides, but also pro-angiogenic signaling molecules, thereby promoting intestinal and mesenteric angiogenesis and regulating portal hypertension. Lay summary Paneth cells are present in the lining of the small intestine. They prevent the passage of bacteria from the intestine into the blood circulation by secreting substances to fight bacteria. In this paper, we discovered that these substances not only act against bacteria, but also increase the quantity of blood vessels in the intestine and blood pressure in the portal vein. This is important, because high blood pressure in the portal vein may result in several complications which could be targeted with novel approaches.

Bone volume changes following vascularized bone flaps and possible confounding factors over time are described in the literature with some controversy. The purpose of this study was to evaluate the bone volume behavior of two frequently used free flaps.Computed tomography (CT) scans were examined with regard to bone volume using the software program ITK-SNAP for all patients who required mandibular reconstruction with a free fibula flap (FFF, conventionally vs assisted by computer-aided design/computer-aided manufacturing (CAD/CAM)) or iliac crest flap (DCIA) following mandibular resection because of benign or malign processes, between August 2010 and August 2015. Clinical data, complication rates, and CT scans were analyzed retrospectively. Additionally, complication rates (microvascular revision, flap loss, postoperative fistula or dehiscence, and postoperative bone exposure) were compared within early (≤30 days), late (31st-100th day), and overall (≤100th day) postoperative time intervals.113 cases, comprizing 89 FFF and 24 DCIA cases, were included. FFF showed superior bone volume behavior over the DCIA flap. Multivariable regression models assessed the relationships between the following and bone volume behavior: interval between operation and CT scan (p 0.683), age (p = 0.004), gender (p = 0.006), BMI (p = 0.400), adjuvant radiation therapy (p = 0.334), reconstruction with DCIA flap (p 0.0001), number of segments (p = 0.02), and incidence of dental implant insertion (p = 0.45).The bone volume of FFFs remains stable. DCIA flaps show a higher bone volume reduction, but the postoperative course might be associated with fewer complications. Time interval between operation and CT scan, age, gender, reconstruction with DCIA flap, and number of fibula segments contributed significantly to bone volume behavior.

The authors discuss minimally invasive and noninvasive cardiac output monitoring technologies available in the clinical practice and how to evaluate these systems objectively.

Young refugees are a high-risk group for mental disorders, particularly for posttraumatic stress disorder (PTSD). Individuals with PTSD suffer from an altered time perspective with a focus on negative experiences in the past and a disregard for positive life events and the future. This study investigates time perspectives and psychological distress in 30 adolescent refugees from Syria and Afghanistan in Germany. Time perspective was assessed using the Zimbardo Time Perspective Inventory. The refugees exhibited a distorted time perspective that is common for individuals with PTSD: a high orientation toward the negative past and a low orientation toward the positive past and future. A high orientation toward the negative past was associated with high levels of general psychological distress, PTSD symptoms, and depression. A low orientation toward the future was related to high levels of anxiety. Taking time perspective and corresponding beliefs into consideration may be advantageous when treating refugees with trauma-related disorders.

BACKGROUND Invasive coronary angiography (ICA) still causes a significant amount of radiation exposure for patients and operators. In February 2017, the Azurion system was introduced, a new-generation fluoroscopy image acquisition and processing system. Radiation exposure in patients undergoing ICA was assessed comparing the novel Azurion 7 F12 angiography system to its predecessor Allura Xper in a randomized manner. METHODS Radiation exposure was prospectively analyzed in 238 patients undergoing diagnostic ICA. Patients were randomly assigned to the novel Azurion system (119 patients) or its predecessor Allura Xper system (119 patients). In each patient, 8 predefined standard projections (5 left coronary artery, 3 right coronary artery) were performed. Image quality was quantified by grading of the images on the basis of a 5-point grading system. RESULTS Radiation dose area product was significantly lower in the Azurion group 109 (interquartile range [IQR 75-176] cGy cm) compared with the Allura Xper group 208 [IQR 134-301] cGy cm (P

Background: Complementary and alternative medicine (CAM) use is common among cancer patients. Data indicated that CAM use correlates with younger age, higher education levels, higher income, and less physician consultations. However, non-CAM use and predictors for non-CAM use are less clear among breast and gynecological cancer patients. Objectives: The purpose of this study was to determine the prevalence of non-CAM use and to investigate factors that might influence non-CAM use. Methods: The survey was conducted in breast cancer patients from January to May 2013 and in gynecological cancer patients from January to May 2014 with 2 pseudoanonymous questionnaires: one for CAM users (109 questions) and one for non-CAM users (85 questions). The survey was conducted via a telephone interview with 333 patients. Eligible participants were women with breast cancer (n = 285) and gynecological cancer (n = 291) who had undergone surgery at the Department of Gynecology and Obstetrics at the Technical University Munich, Germany, in the years 2012 (breast cancer) and 2011–2013 (gynecological cancer). Descriptive statistics were generated to determine patterns of non-CAM use. Univariable analysis was used to detect patient characteristics associated with noninterest in the different CAM therapies. Results: A total of 333 of 576 patients participated in the survey (58%). Fifty-eight percent (n = 192/333) were diagnosed with breast cancer and 42% (n = 141/333) with gynecological cancer. The overall prevalence of non-CAM use was 42% (n = 139/333). Eighty-one percent (n = 112/139) of the non-CAM users stated to have received no recommendation for CAM use, although 53% (n = 73/139) would have liked to receive information from their physician. As reasons for the nonuse of CAM therapies, 76% (n = 106/139) nonusers declared that they did not believe CAM use was necessary since the conventional therapy was considered sufficient, 44% (n = 61/139) reported a lack of information, 31% (n = 43/139) a fear of fraud, and 22% (n = 31/139) a fear of interactions and side effects of CAM. Sixty-eight percent (n = 95/139) of the patients stated that they would resort to CAM if the disease progressed while only 27% (n = 37/139) would still not use any CAM with progression of disease. Five percent (7/139) did not give any information regarding possible future CAM use with disease progression. Seventy-three percent (n = 102/139) would both welcome more physicians with qualifications in complementary medicine and supported an integration of CAM into our health care system. Furthermore, statistically significant correlations between patients’ sociodemographic characteristics and their nonuse of complementary therapies were identified. Conclusions: Our data demonstrate a high overall interest in CAM even in non-CAM users. Health care professionals should be aware of this in order to be able to better address patients’ needs. It is necessary to explore the use of CAM with cancer patients, educate them about potentially beneficial therapies even in the light of the limited available evidence, and work towards an integrated model of health care. Therefore, we implemented a counseling service as an outpatient program (ZIGG) for integrative medicine concepts and evidence-based complementary treatments to discuss integrative health approaches proactively with cancer patients in our cancer center in 2013.

Background The relative merits of ticagrelor as compared with prasugrel in patients with acute coronary syndromes for whom invasive evaluation is planned are uncertain. Methods In this mul...

Background: Institutional programs such as antibiotic stewardship (ABS) programs offer possibilities to monitor and modify antibiotic usage with the aim of reducing antibiotic resistance. In orthop...

Objectives The aim of this study was to assess the safety and efficacy of ticagrelor versus prasugrel for patients with acute coronary syndrome (ACS) according to their glomerular filtration rate (GFR). Background The outcomes of ticagrelor versus prasugrel in patients with ACS according to GFR have not been defined. Methods Patients (n=3985) with GFR available were categorized in three groups according to the tertiles of GFR. The primary endpoint was a composite of all-cause death, myocardial infarction and stroke at 1 year. Results The primary endpoint occurred significantly more often in patients with low GFR compared to high GFR as well as in patients with low GFR compared to intermediate GFR (picture 1). Patients in the lowest GFR group had significantly higher ischemic and bleeding risks than patients in the intermediate (hazard ratio [HR] 1.93 and 1.68) or high GFR groups (HR 3.52 and 2.96). In the group with low GFR, the primary endpoint occurred in 103 of 677 ticagrelor patients (15.4%) and in 72 of 652 prasugrel patients (11.2%; (HR=1.45, [1.07–1.96], p=.016, picture 2). In addition, each single component of the primary endpoint and stent thrombosis were numerically lower with prasugrel compared with ticagrelor. Occurrence of myocardial infarction was 3.7% with prasugrel compared to 6.6% with ticagrelor (p=0.019). BARC 3–5 bleeding events were similar with ticagrelor and prasugrel (8.8% versus 7.1%, p=0.278). In the intermediate and high GFR group the primary endpoint and bleeding events were similar between prasugrel and ticagrelor. Conclusions The incidence of a composite endpoint (all-cause death, myocardial infarction or stroke) occurred less frequently in patients who received prasugrel compared to patients who received ticagrelor in the low GFR population, whereas rate of bleeding events was similar. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Supported by a grant (FKZ 81X1600501) from the German Center for Cardiovascular Research and the Deutsches Herzzentrum München, Germany. Primary endpoint according to GFRLow GFR: Prasugrel versus Ticagrelor

The mammalian mucosal immune system acts as a multitasking mediator between bodily function and a vast diversity of microbial colonists. Depending on host–microbial interaction type, mucosal immune responses have distinct functions. Immunity to pathogen infection functions to limit tissue damage, clear or contain primary infection, and prevent or lower the severity of a secondary infection by conferring specific long-term adaptive immunity. Responses to nonpathogenic commensal or mutualistic microbes instead function to tolerate continuous colonization. Mucosal innate immune and epithelial cells employ a limited repertoire of innate receptors to program the adaptive immune response accordingly. Pathogen versus nonpathogen immune discrimination appears to be very robust, as most individuals successfully maintain life-long mutualism with their nonpathogenic microbiota, while mounting immune defense to pathogenic microbe infection specifically. However, the process is imperfect, which can have immunopathological consequences, but may also be exploited medically. Normally innocuous intestinal commensals in some individuals may drive serious inflammatory autoimmunity, whereas harmless vaccines can be used to fool the immune system into mounting a protective anti-pathogen immune response. In this article, we review the current knowledge on mucosal intestinal bacterial immune recognition focusing on TH17 responses and identify commonalities between intestinal pathobiont and vaccine-induced TH17 responses.

Background The Cancer Genome Atlas (TCGA) consortium described EBV positivity(+), high microsatellite instability (MSI-H), genomic stability (GS) and chromosomal instability (CIN) as molecular subtypes in gastric carcinomas (GC). We investigated the predictive and prognostic value of these subtypes with emphasis on CIN in the context of neoadjuvant chemotherapy (CTx) in GC. Methods TCGA subgroups were determined for 612 resected adenocarcinomas of the stomach and gastro-oesophageal junction (291 without, 321 with CTx) and 143 biopsies before CTx. EBV and MSI-H were analysed by standard assays. CIN was detected by multiplex PCRs analysing 22 microsatellite markers. Besides the TCGA classification, CIN was divided into four CIN-subgroups: low, moderate, substantial, high. Mutation profiling was performed for 52 tumours by next-generation sequencing. Results EBV(+) (HR, 0.48; 95% CI, 0.23–1.02), MSI-H (HR, 0.56; 95% CI, 0.35–0.89) and GS (HR, 0.72; 95% CI, 0.45–1.13) were associated with increased survival compared to CIN in the resected tumours. Considering the extended CIN-classification, CIN-substantial was a negative prognostic factor in uni- and multivariable analysis in resected tumours with CTx (each p p = 0.026), but was not prognostically relevant. Conclusion A refined CIN classification reveals tumours with different biological characteristics and potential clinical implications.

Importance It is unclear whether ticagrelor or prasugrel hydrochloride is superior for patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI). Objective To assess the safety and efficacy of ticagrelor vs prasugrel for patients with ACS treated with PCI. Design, Setting, and Participants A prespecified analysis was performed of a postrandomization subgroup of 3377 patients who presented with ACS and were treated with PCI in the investigator-initiated, multicenter, phase 4, open-label Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5 randomized clinical trial, conducted from September 1, 2013, to February 28, 2018. Statistical analysis was performed from September 1, 2020, to January 30, 2021. Analysis was performed according to the intention-to-treat principle. Interventions Patients were randomly assigned to a ticagrelor-based or prasugrel-based strategy. This analysis focuses on the subgroup of patients who underwent PCI that was formed after randomization. Main Outcomes and Measures The primary end point was a composite consisting of all-cause death, myocardial infarction, or stroke at 12 months. The safety end point was Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding. Results The ticagrelor group comprised 1676 patients (1323 men [78.9%]; mean [SD] age, 64.4 [12.0] years), and the prasugrel group comprised 1701 patients (1341 men [78.8%]; mean [SD] age, 64.7 [12.0] years). The primary end point occurred for 162 patients (9.8%) in the ticagrelor group and 120 patients (7.1%) in the prasugrel group (hazard ratio [HR], 1.41; 95% CI, 1.11-1.78;P = .005). Myocardial infarction occurred in 88 patients (5.3%) in the ticagrelor group compared with 55 patients (3.8%) in the prasugrel group (HR, 1.67; 95% CI, 1.19-2.34;P = .003). The safety end point, BARC type 3 to 5 bleeding, occurred in 84 of 1672 patients (5.3%) in the ticagrelor group and 78 of 1680 patients (4.9%) in the prasugrel group (HR; 1.10; 95% CI, 0.81-1.50;P = .54). Conclusions and Relevance Among patients presenting with ACS who were treated with PCI, the incidence of the primary composite end point occurred less frequently for patients who received prasugrel compared with those who received ticagrelor. The incidence of bleeding events was comparable between the 2 groups. These results suggest that, for patients presenting with ACS who undergo PCI, a prasugrel-based strategy is superior to a ticagrelor-based strategy. However, because these observations are based on a postrandomization subgroup, these findings should be regarded as hypothesis generating and dedicated randomized clinical trials may be warranted to confirm these findings. Trial Registration ClinicalTrials.gov Identifier:NCT01944800

Importance The assessment of new antithrombotic agents with a favorable safety profile is clinically relevant. Objective To test the efficacy and safety of revacept, a novel, lesion-directed antithrombotic drug, acting as a competitive antagonist to platelet glycoprotein VI. Design, Setting, and Participants A phase 2 randomized clinical trial; patients were enrolled from 9 centers in Germany from November 20, 2017, to February 27, 2020; follow-up ended on March 27, 2020. The study included patients with stable ischemic heart disease (SIHD) undergoing elective percutaneous coronary intervention (PCI). Interventions Single intravenous infusion of revacept, 160 mg, revacept, 80 mg, or placebo prior to the start of PCI on top of standard antithrombotic therapy. Main Outcomes and Measures The primary end point was the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin to at least 5 times the upper limit of normal within 48 hours from randomization. The safety end point was bleeding type 2 to 5 according to the Bleeding Academic Research Consortium criteria at 30 days. Results Of 334 participants (median age, 67.4 years; interquartile range, 60-75.1 years; 253 men [75.7%]; and 330 White participants [98.8%]), 120 were allocated to receive the 160-mg dose of revacept, 121 were allocated to receive the 80-mg dose, and 93 received placebo. The primary end point showed no significant differences between the revacept and placebo groups: 24.4%, 25.0%, and 23.3% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .98). The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, with a median 26.5 AU × min (interquartile range, 0.5-62.2 AU × min) in the revacept, 160 mg, group; 43.5 AU × min (interquartile range, 22.8-99.5 AU × min) in the revacept, 80 mg, group; and 41.0 AU × min (interquartile range, 31.2-101.0 AU × min) in the placebo group (P = .02), while adenosine 5′-diphosphate–induced aggregation was not affected. Revacept did not increase Bleeding Academic Research Consortium type 2 or higher bleeding at 30 days compared with placebo: 5.0%, 5.9%, and 8.6% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .36). Conclusions and Relevance Revacept did not reduce myocardial injury in patients with stable ischemic heart disease undergoing percutaneous coronary intervention. There were few bleeding events and no significant differences between treatment arms. Trial Registration ClinicalTrials.gov Identifier:NCT03312855

Cardiac output (CO) is a key hemodynamic variable that can be minimally invasively estimated by pulse wave analysis. Multi-beat analysis is a novel pulse wave analysis method. In this prospective observational clinical method comparison study, we compared CO estimations by multi-beat analysis with CO measured by intermittent pulmonary artery thermodilution (PATD) in adult patients treated in the intensive care unit (ICU) after off-pump coronary artery bypass surgery (OPCAB). We included patients after planned admission to the ICU after elective OPCAB who were monitored with a radial arterial catheter and a pulmonary artery catheter. At seven time points, we determined CO using intermittent PATD (PATD-CO; reference method) and simultaneously recorded the radial arterial blood pressure waveform that we later used to estimate CO using multi-beat analysis (MBA-CO; test method) with the Argos monitor (Retia Medical; Valhalla, NY, USA). Blood pressure waveforms impaired by inappropriate damping properties or artifacts were excluded. We compared PATD-CO and MBA-CO using Bland–Altman analysis accounting for repeated measurements, the percentage error, and the concordance rate derived from four-quadrant plot analysis (15% exclusion zone). We analyzed 167 CO values of 31 patients. Mean PATD-CO was 5.30 ± 1.22 L/min and mean MBA-CO was 5.55 ± 1.82 L/min. The mean of the differences between PATD-CO and MBA-CO was 0.08 ± 1.10 L/min (95% limits of agreement: − 2.13 L/min to + 2.29 L/min). The percentage error was 40.7%. The four-quadrant plot-derived concordance rate was 88%. CO estimation by multi-beat analysis of the radial arterial blood pressure waveform (Argos monitor) shows reasonable agreement compared with CO measured by intermittent PATD in adult patients treated in the ICU after OPCAB.

Pulse wave analysis enables stroke volume to be estimated from an arterial blood pressure waveform. Multi-beat analysis is a novel pulse wave analysis method. We aimed to investigate cardiac output (CO) estimations using multi-beat analysis of the radial arterial blood pressure waveform in patients undergoing off-pump coronary artery bypass surgery (OPCAB) using intermittent pulmonary artery thermodilution (PATD) as the reference method. This was a prospective clinical method comparison study. In 58 patients, we measured CO using PATD (PATD-CO; reference method) and simultaneously recorded the radial arterial blood pressure waveform that we used for off-line estimation of CO based on multi-beat analysis (MBA-CO; test method) using the Argos CO monitor (Retia Medical; Valhalla, NY, USA). The final analysis was performed using 572 paired CO measurements. We performed Bland–Altman analysis accounting for multiple observations per patient. To describe the ability of the test method to track changes in CO over time we computed four-quadrant plots using a central exclusion zone of 15% and calculated the concordance rate. Mean PATD-CO was 4.13 ± 1.26 L/min and mean MBA-CO was 4.31 ± 1.25 L/min. The mean of the differences between PATD-CO and MBA-CO was − 0.20 L/min with a standard deviation of ± 1.14 L/min and 95% limits of agreement of − 2.48 to + 2.08 L/min. The concordance rate for CO changes between PATD-CO and MBA-CO was 89%. CO estimations using multi-beat analysis (Argos monitor) show reasonable agreement and trending ability compared with PATD-CO as the reference method in adult patients during OPCAB.

Objectives The purpose of the study was to investigate the impact of oral anticoagulation (OAC) type on clinical outcomes 1 year after transcatheter aortic valve replacement (TAVR). Background Non–vitamin K oral anticoagulants (NOACs) are superior to vitamin K antagonists (VKAs) in nonvalvular atrial fibrillation (AF), while their comparative performance among patients in need of OAC undergoing TAVR is underinvestigated. Methods The study enrolled 962 consecutive patients who underwent TAVR in 4 tertiary European centers and were discharged on either NOACs (n = 326) or VKAs (n = 636). By using propensity scores for inverse probability of treatment weighting (IPTW), the comparison of treatment groups was adjusted to correct for potential confounding. Results Mean age and Society of Thoracic Surgeons score of the population were 81.3 ± 6.3 years and 4.5% (interquartile range: 3.0% to 7.3%); 52.5% were women and a balloon-expandable valve was used in 62.7% of cases. The primary outcome of interest, combined incidence of all-cause mortality, myocardial infarction, and any cerebrovascular event at 1-year after TAVR, was 21.2% with NOACs versus 15.0% with VKAs (hazard ratio [HR]: 1.44; 95% confidence interval [CI]: 1.00 to 2.07; p = 0.050, IPTW-adjusted). The 1-year incidence of any Bleeding Academic Research Consortium bleeds and all-cause mortality were comparable between the NOAC and VKA groups, 33.9% versus 34.1% (HR: 0.97; 95% CI: 0.74 to 1.26; p = 0.838, IPTW-adjusted) and 16.5% versus 12.2% (HR: 1.36; 95% CI: 0.90 to 2.06; p = 0.136, IPTW-adjusted), respectively. Conclusions Chronic use of both NOACs and VKAs among patients in need of OAC after TAVR are comparable regarding 1-year bleeding risk. The higher ischemic event rate observed with NOACs needs to be evaluated in large randomized trials.

BACKGROUND AND AIM In contrast to the first peak of multi-organ failure in acute pancreatitis, the second peak is mostly triggered by septic complications. Our aim was to analyze the spectrum of pathogens and antimicrobial resistance development in relation to the time-course of the disease and its clinical outcome. METHODS One hundred twenty-two patients with acute necrotizing pancreatitis undergoing pancreas puncture at two tertiary academic medical centers in Germany were retrospectively analyzed. RESULTS At species level, there was a change in spectrum from Enterococcus faecalis (∆d150 - d1 = 14.6% - 16.7% = -2.1%) to Enterococcus faecium (∆d150 - d1 = 93.1% - 16.3% = 76.8%) (P

Background and study aims Acute pancreatitis (AP) is one of the most common gastrointestinal disorders leading to hospitalization and the most frequent complication of endoscopic retrograde cholangiopancreatography (ERCP). Besides pharmaco-prophylaxis, pancreatic stenting has been demonstrated to protect from post-ERCP pancreatitis (PEP). However, it remains unclear which patients benefit from pancreatic stenting. We therefore hypothesized that in an unselected population, inadvertent cannulation of the pancreatic duct during first-time ERCP increases risk of PEP and that this risk can be significantly reduced by pancreatic stenting. Patients and methods This study was a multicenter, prospective, randomized controlled trial conducted at four European centers. A total of 167 patients undergoing first-time ERCP were enrolled in this trial. In the case of inadvertent cannulation of the pancreatic duct, patients were randomly assigned to receive either a 5 French plastic pancreatic stent of various length or no routine prophylactic intervention for PEP. Results A total of 167 patients were included in the final analysis. Prophylactic stent insertion significantly reduced the rate of PEP during first-time ERCP (odds ratio 0.43; 95% confidence interval 0.19 – 0.98; P = 0.04). The number needed to treat to prevent one case of PEP by prophylactic stent insertion after inadvertent cannulation of the pancreatic duct was 8.1 for the intention-to-treat population. Conclusion In an unselected patient population, inadvertent cannulation of the pancreatic duct during first-time ERCP is associated with a high risk for PEP. This risk can be significantly reduced by prophylactic pancreatic stenting, which is a safe and feasible procedure.

Background: The EndoPredict test is a clinico-molecular test that has been validated to predict the likelihood of distant metastases and late relapse inpatients (pts) with hormone receptor positive (HR+), HER2-negative (HER2-) early breast cancer and up to three positive lymph nodes. However, so far prospective outcome results of pts in whom decision on use of adjuvant chemotherapy (CTX) was based on Endopredict has not been available. Here we present three year outcome data of pts, whose adjuvant systemic therapy recommendation was based on EndoPredict test result. Methods: Pts with HR+, HER2- early breast cancer with 0-3 positive lymph nodes were enrolled at a single institution (Interdisciplinary Breast Center of Klinikum rechts der Isar, Munich, Germany). The Endopredict test was carried out on all tumor samples. Demographic, clinical and pathological data as well as EPclin risk class were assessed for each patient at baseline. Therapy recommendations were given during an interdisciplinary tumor board. Pts were evaluated for treatment compliance, local recurrence, distant metastases and survival (cut-off date of last follow up: July 31st 2017). Censored time-to-event outcomes were analysed by cox proportional hazards models. Additional estimates of the event-free-survival were given by the Kaplan-Meier method. Hypothesis testing was conducted on two-sided exploratory 5% significance levels. Results: A total of 373 consecutive pts were enrolled between March 2012 and March 2015. Median age was 59.9 (range: 29.1-88.9) years. In 39% of pts tumorsize was >2cm, 24% of pts were node positive, 16% had G3 tumors, in 21% of pts ki67 was ≥25% and in 13% progesterone receptor was Conclusion: These first prospective outcome results show, that EPclin in clinical routine is a valid clinico-molecular marker to predict DFS and guide decision of adjuvant CTX use in HR+, HER2- early breast cancer pts with 0-3 positive lymph nodes. Citation Format: Ettl J, Anders S, Hapfelmeier A, Noske A, Paepke S, Weichert W, Klein E, Kiechle M. First prospective outcome data for the clinico-molecular test Endopredict® in hormone receptor positive, HER2-negative early breast cancer in clinical routine [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-11.

Objectives To assess the ability of multislice detector computed tomography (MDCT) to differentiate old versus acute/subacute vertebral fractures (VF) and to identify characteristic MDCT imaging signs. Methods 74 consecutive patients demonstrated 192 VF that were classified as either acute/subacute or old based on magnetic resonance imaging, MDCT, and clinical information as reference standard. Classification as acute/subacute versus old fractures based on MDCT alone was evaluated on a Likert scale by 2 independent radiologists. Morphologic MDCT features of fractures, such as trabecular compaction or fracture line, were recorded. Receiver operating characteristic analyses and Cohen's κ were used to assess the discriminatory power of the MDCT and interrater agreement, respectively. Results Out of all 192 VF, 148 fractures were acute/subacute and 44 were old according to the reference standard. Receiver operating characteristic analyses of sole MDCT assessment showed very good identification of acute/subacute VF, with areas under the curve of 0.854 and 0.861 for readers 1 and 2, respectively. When indeterminate findings were treated as acute/subacute fractures, sensitivity and specificity were 97.2% and 58.1% for reader 1 and 94.5% and 65.1% for reader 2. Interrater agreement regarding fracture age was good (weighted Cohen's κ = 0.607). Trabecular compression/callus distinct from the cortex (double compaction sign) was present in approximately half of acute/subacute VF and highly specific for acute/subacute VF (specificity = 93.2% and 88.6% for readers 1 and 2, respectively). Conclusion The acuity of VF can be assessed by MDCT alone with high sensitivity and in case of a double compaction sign with high specificity.

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.

Magnetic resonance imaging (MRI), including diffusion-weighted imaging (DWI), is an excellent tool for diagnosing intracranial infection, with limitations in previous neurosurgical intervention. This study aimed to evaluate the accuracy of DWI in the diagnosis of postoperative intracranial infection.We retrospectively evaluated all consecutive patients with intracranial infection undergoing a neurosurgical intervention who had preoperative MRI, including DWI. Patients were divided into 2 groups: spontaneous intracranial infection (SI) and postoperative intracranial infection (PI). A control group (CG) of patients who had undergone brain surgery without any signs of subsequent infection was also included. Qualitatively, MRI data were evaluated for the presence of intracranial infection. Sensitivity, specificity, and positive and negative predictive values for PI as opposed to no infection were determined. Quantitatively, areas with diffusion restriction within the surgery/abscess cavity were identified for the 3 groups using semiautomated segmentation. Group differences regarding apparent diffusion coefficient (ADC) ratios were evaluated. Receiver operating characteristic curve analysis was used to identify a point in time beyond which ADC ratios might show reasonable discriminatory power between the PI and CG groups.A total of 78 patients were included (38 in the SI group, 20 in the PI group, 20 in the CG group). Sensitivity, specificity, and positive and negative predictive values in the diagnosis of PI were 80%, 95%, 4%, and 100%, respectively. Median ADC was significantly higher in the PI group compared with the SI group (0.98 vs. 0.69; P0.001) but lower compared with the CG group (1.24; P = 0.16). The analysis suggested a possible differentiation of PI and CG after a time interval of approximately 100 days/3 months.DWI is of limited value in evaluating postoperative brain infection. Our data show a trend toward DWI regaining its validity at approximately 3 months after surgery.

Objective Dealing with uncertainty is a core competence for physicians. To evaluate the impact of an educational intervention on family medicine residents’ (FMRs’) intention to request diagnostic tests and their attitudes toward uncertainty. Methods Nonrandomized controlled trial. Intervention group (IG) FMRs participated in interactive “dealing with uncertainty” seminars comprising statistical lessons and diagnostic reasoning. Control group (CG) FMRs participated in seminars without in-depth diagnostic lessons. FMRs completed the Dealing with Uncertainty Questionnaire (DUQ), comprising the Diagnostic Action and Diagnostic Reasoning scales. The Physicians’ Reaction to Uncertainty (PRU) questionnaire, comprising 4 scales (Anxiety Due to Uncertainty, Concern about Bad Outcomes, Reluctance to Disclose Uncertainty to Patients, and Reluctance to Disclose Mistakes to Physicians) was also completed. Follow-up was performed 3 months later. Differences were calculated with repeated-measures analysis of variance. Results In total, 107 FMRs of the IG and 102 FMRs of the CG participated at baseline and follow-up. The mean (SD) Diagnostic Action scale score decreased from 24.0 (4.8) to 22.9 (5.1) in the IG and increased in the CG from 23.7 (5.4) to 24.1 (5.4), showing significant group difference ( P = 0.006). The Diagnostic Reasoning scale increased significantly ( P = 0.025) without a significant group difference ( P = 0.616), from 19.2 (2.6) to 19.7 (2.4) in the IG and from 18.1 (3.3) to 18.8 (3.2) in the CG. The PRU scale Anxiety Due to Uncertainty decreased significantly ( P = 0.029) without a significant group difference ( P = 0.116), from 20.5 (4.8) to 18.5 (5.5) in the IG and from 19.9 (5.5) to 19.0 (6.0) in the CG. Conclusion The structured seminar reduced self-rated diagnostic test requisition. The change in Anxiety Due to Uncertainty and Diagnostic Reasoning might be due to an unspecific accompanying effect of the extra-occupational seminars for residents.

Background Risk 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. Methods The 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. Results A 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%. Conclusions The 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.

A crucial mode of action of trastuzumab is the labeling of HER2-positive (HER2+) tumor cells for the eradication by natural killer (NK) cells, a process called antibody-dependent cellular cytotoxicity (ADCC). However, despite widespread HER2 expression among cancer entities, only a fraction, with robust HER2 overexpression, benefits from trastuzumab therapy. ADCC requires both sufficient lymphocytic infiltration and close binding of the immune cells to the antibody-tagged tumor cells. We hypothesized that the chemokine CX3CL1 could improve both processes, as it is synthesized as a membrane-bound, adhesive form that is eventually cleaved into a soluble, chemotactic protein. Here, we show that CX3CL1 overexpression is a positive prognostic marker in breast cancer. CX3CL1 overexpression attracted tumor-suppressive lymphocytes, including NK cells, and inhibited tumor growth and lung metastasis in the syngeneic 4T1 breast cancer mouse model. In HER2+ SKBR3, MDA-MB-453, and HT-29 tumor cells, CX3CL1 overexpression increased NK cell–mediated cytotoxicity in vitro and acted synergistically with trastuzumab. Even though CX3CL1 did not further improve trastuzumab efficacy in vivo in the trastuzumab-sensitive MDA-MB-453 model, it compensated for NK-cell depletion and prolonged survival. In the HER2 low–expressing HT-29 model, however, CX3CL1 overexpression not only prolonged survival time but also overcame trastuzumab resistance in a partly NK cell–dependent manner. Taken together, these findings identify CX3CL1 as a feasible pharmacologic target to enable trastuzumab therapy in HER2 low–expressing cancers and render it a potential predictive biomarker to determine therapy responders.

IntroductionThe 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 analysisA 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 disseminationThe 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 numberDRKS00021125.

OBJECTIVES: The objective of the study is to determine the impact of changing reference standards (RS), namely spirometry vs. whole-body plethysmography (WBP), on estimation of the diagnostic accuracy of fractional exhaled nitric oxide (FeNO) and clinical signs and symptoms (CSS) as index tests regarding asthma diagnosis. STUDY DESIGN AND SETTING: This was a diagnostic study conducted in 393 patients attending a private practice of pneumologists with complaints suspicious of asthma. First, the index tests were compared with the diagnostic results of spirometry in terms of forced expiratory volume in the first second (FEV1) responsiveness. Second, the index tests were compared with the results of WBP in terms of specific airway resistance and FEV1 responsiveness. Areas under the curve (AUC) were compared with a generalized estimating equation approach based on binary logistic regression. RESULTS: FeNO values and CSS 'wheezing' and 'allergic rhinitis' showed higher specificities (P

Aims Present society is constantly ageing and elderly frequently suffer from conditions that are difficult and/or costly to treat if detected late. Effective screening of the elderly is therefore needed so that those requiring detailed clinical work-up are identified early. We present a prospective validation of a screening strategy based on a Polyscore of seven predominantly autonomic, non-invasive risk markers. Methods and results Within a population-based survey in Germany (INVADE study), participants aged ≥60 years were enrolled between August 2013 and February 2015. Seven prospectively defined Polyscore components were obtained during 30-min continuous recordings of electrocardiogram, blood pressure, and respiration. Out of 1956 subjects, 168 were excluded due to atrial fibrillation, implanted pacemaker, or unsuitable recordings. All-cause mortality over a median 4-year follow-up was prospectively defined as the primary endpoint. The Polyscore divided the investigated population (n = 1788, median age: 72 years, females: 58%) into three predefined groups with low (n = 1405, 78.6%), intermediate (n = 326, 18.2%), and high risk (n = 57, 3.2%). During the follow-up, 82 (4.6%) participants died. Mortality in the Polyscore-defined risk groups was 3.4%, 7.4%, and 17.5%, respectively (P Conclusion The Polyscore-based mortality risk assessment from short-term non-invasive recordings is effective in the elderly general population, especially those aged 60–74 years. Implementation of a comprehensive Polyscore screening of this age group is proposed to advance preventive medical care.

Background The efficacy and safety of a reduced dose of prasugrel versus a standard dose of ticagrelor in elderly patients or those with a low body weight presenting with an acute coronary syndrome (ACS) are unknown. Objective To investigate the effect of an age- and weight-adapted dose of prasugrel versus a standard dose of ticagrelor in patients with ACS. (ClinicalTrials.gov: NCT01944800). Design Prespecified analysis of the multicenter, randomized ISAR-REACT 5 trial. Setting 23 centers in Germany and Italy. Patients 3997 patients with ACS planned for invasive management. Intervention Participants were randomly assigned to receive a standard dose of ticagrelor or prasugrel (reduced dose in the elderly or low-weight group and standard dose in the neither elderly nor low-weight group). Measurements The efficacy end point was a composite of death, myocardial infarction, or stroke, and the safety end point was bleeding, both at 12 months. Results In the elderly or low-weight group, the efficacy end point occurred in 12.7% of patients assigned to receive prasugrel and 14.6% of those assigned to receive ticagrelor (hazard ratio [HR], 0.82 [95% CI, 0.60 to 1.14]); in the neither elderly nor low-weight group, the efficacy end point occurred in 4.8% of patients assigned to receive prasugrel and 7.3% of those assigned to receive ticagrelor (HR, 0.65 [CI, 0.48 to 0.88]; P for interaction > 0.2). In the elderly or low-weight group, Bleeding Academic Research Consortium type 3 to 5 bleeding occurred in 8.1% of patients assigned to receive prasugrel and 10.6% of those assigned to receive ticagrelor (HR, 0.72 [0.46 to 1.12]), and in 3.7% and 3.8%, respectively, of patients in the neither elderly nor low-weight group (HR, 0.98 [CI, 0.65 to 1.47]; P for interaction > 0.2). Limitation The study is a subgroup analysis. Conclusion In elderly or low-weight patients with ACS, a reduced dose of prasugrel compared with the standard dose of ticagrelor is associated with maintained anti-ischemic efficacy while protecting these patients against the excess risk for bleeding. Primary funding source German Center for Cardiovascular Research and Deutsches Herzzentrum Munchen.