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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.

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: 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)...

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

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...

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: 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.

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

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.

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.

Background Invasive pulse wave analysis is used in peri-operative settings to estimate cardiac output (CO). The 'pressure recording analytical method' (PRAM) implemented in the MostCareUp CO monitor is an invasive pulse wave analysis method using high-frequency sampling and analysis of the pulse wave to directly estimate the arterial impedance as a key variable of the proprietary CO estimation algorithm. Objective To compare CO estimated by PRAM (PRAM-CO; test method) with CO measured by pulmonary artery thermodilution (PATD-CO; reference method). Design Prospective observational method comparison study. PRAM-CO and PATD-CO were assessed simultaneously at five time points with at least 20 min between measurements. Arterial pressure waveforms were carefully checked for damping artefacts and a proprietary electronic filter of the MostCareUp CO monitor was used to optimise waveform quality. Setting ICU of a German university hospital from August 2018 until April 2019. Patients We included adult patients admitted to the ICU after elective off-pump coronary artery bypass surgery who were monitored with a radial arterial catheter and a pulmonary artery catheter. Patients with severe heart valve insufficiency or persistent arrhythmia were excluded. Main outcome measures and analysis PATD-CO and PRAM-CO were compared using Bland-Altman analysis accounting for repeated measurements, the percentage error and trending analysis (four-quadrant plot, concordance rate). Results We analysed 195 paired CO values of 41 patients. Mean PATD-CO and PRAM-CO were 4.99 ± 1.02 and 4.92 ± 1.05 l min, respectively. PATD-CO and PRAM-CO ranged from 3.04 to 8.74 and 2.79 to 8.01 l min, respectively. The mean of the differences between PATD-CO and PRAM-CO was -0.08 ± 0.74 l min with 95% limits of agreement of -1.55 to +1.40 l min. The percentage error was 29.8%. The concordance rate in four-quadrant plot analysis was 92%. Conclusion Using the system's electronic waveform filter PRAM-CO shows good agreement and trending ability compared with PATD-CO in adults after off-pump coronary artery bypass surgery.

Introduction In mice there might be an association between sleep deprivation and amyloid β plasma levels. Hence, we examined whether amyloid plasma levels are associated with sleep duration or fragmentation in 17 psychiatrists on-call. Methods Amyloid β (Aβ)42, Aβ40, and soluble amyloid precursor protein β (sAPP-β) plasma concentrations were measured at the beginning and end of 90 on-call nights, and analyzed using generalized linear models. Results In on-call nights, a 10.7% reduction of Aβ42 was revealed overnight. Every single short sleep interruption diminished this reduction by 5.4%, as well as every pg/mL of sAPP-β by 1.2%, each copy of APOE e4 by 10.6%, and each year of professional experience by 3.0%. Discussion The extent of sleep fragmentation diminishes the physiological overnight reduction of Aβ42 but not Aβ40 plasma levels in the same direction as the enzyme for Aβ42 production, the genetic risk factor for Alzheimer's disease (AD), and on-call experience. Might on-call duty and sleep fragmentation in general alter the risk for AD?

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.

BACKGROUND AND AIM Mortality of cirrhotic patients after emergency care admission is high, and prognostic factors can help in prioritizing patients. The aim of our study was to assess the association between levels of cardiac troponin T (cTnT) and 1-year mortality in patients with liver cirrhosis without known cardiac disease, who were admitted to the emergency department (ED). METHODS All patients with cirrhosis presented to the ED from October 2009 until August 2015 who had an initial cTnT value measured with the first lab panel were retrospectively analyzed with a follow-up of 365 days. RESULTS Of a total of 237 cirrhotic ED patients, cTnT measurements were available for 87 (63% men, mean age 58.9 ± 11.0 years, and median Model for End-stage Liver Disease score was 15 [25th-75th percentile: 10-19]). Chronic Liver Failure Consortium acute-on-chronic liver failure (CLIF-C-ACLF) score was 33. Forty-three patients (49%) had cTnT values above the normal range (14 ng/L), of which 19 (22%) had values over 30 ng/L. Two patients were lost to follow-up. In multivariable analysis, both CLIF-C-ACLF (hazard ratio 1.072 per point increase; 95% confidence interval 1.029-1.117; P

The aim of this investigation was to identify patient's characteristics and periprocedural variables related to periprocedural transfusion in transfemoral Transcatheter Aortic Valve Implantation (tf-TAVI).Transfusion of allogenic red-blood cells (RBC) in tf-TAVI and the number of transfused units has been linked to an increased 30-day mortality. In line with the trend of minimization and cost-effectiveness, transfusion should be avoided, wherever possible.Between 2007 and 2015, 1,734 procedures were analyzed from our prospective registry for RBC-transfusion. Multiple logistic regression analysis was used to identify the dependent variables.Transfusion was considered necessary in 14% (n = 243) of the patients. Female gender (OR [95% CI]) (1.680 [1.014-2.783]) and preprocedural moderate (7.594 [4.404-13.095]) and severe anemia (8.202 [0.900-74.752]) according to WHO were the most important preprocedural variables. Periprocedural, pericardial effusion (12.109 [3.753-39.063]), emergency extracorporeal circulation (54.5288 [6.178-481.259]) and major vascular injury (2.647 [1.412-4.962]) were related to transfusion. The same applies to moderate (4.255 [1.859-9.740]) and severe anemia (31.567 [8.560-116.416]) as well as periprocedural experience (0.072 [0.035-0.149] - 0.141[0.079-0.251], P 0.001) CONCLUSION: Procedural experience, serious adverse events, low pre- and periprocedural Hb levels and female gender were the main variables relating to transfusion. Even in experienced high-volume centers, transfusion is still necessary in a considerable number of patients.

ObjectiveCancer cachexia is a paraneoplastic syndrome comprising involuntary weight loss and muscle depletion (sarcopenia). Although weight loss has been associated with poor clinical outcome, there is only limited information on the prevalence and prognostic impact of sarcopenia in ovarian cancer so far.MethodsTotal skeletal muscle mass was determined by computed tomography image analysis of the third lumbar skeletal muscle cross-sectional area in 128 patients with advanced serous ovarian cancer. Longitudinal change of muscle mass was studied in 209 consecutive computed tomography scans from 43 patients. Association with survival was determined using Cox proportional hazards model.ResultsThe prevalence of sarcopenia at first diagnosis was 11% (12/105; 95% confidence interval [CI], 6%–20%). Sarcopenic patients had a significantly reduced progression-free (hazard ratio, 2.64; 95% CI, 1.24–5.64;P= 0.012) and overall survival (hazard ratio, 3.17; 95% CI, 1.29–7.80;P= 0.012). On multivariable analysis, these prognostic effects remained significant after adjustment for age, International Federation of Gynecology and Obstetrics stage, and postsurgical residual disease. Longitudinal analyses identified both patients with loss and gain of muscle mass. However, change in muscle mass over time was not associated with survival.ConclusionsBaseline sarcopenia is a prognostic factor in advanced serous ovarian cancer. Identification of sarcopenic patients and early enrollment in physical or nutritional education programs might thus be a feasible way to improve outcome and should be further evaluated in prospective clinical trials.

BACKGROUND: Asthma education (AE) is associated with reduced hospitalization and disability. We compared the effectiveness of an electronic AE program (eAEP) with a conventional face-to-face AE program (presence-based AEP; pAEP) for asthma knowledge (AK) with regard to self-management. METHODS: A randomized controlled pilot study was conducted in a pulmonary reha- bilitation clinic. AK was determined by means of the Asthma Knowledge Test (AKT). The change in AKT score within each group was calculated with a paired t-test. Group differences were estimated with adjusted linear regression models. RESULTS: In the intervention group (n = 41), the AKT score increased from 41.57 (standard deviation 5.63) at baseline to 45.82 (3.84) after completion of the eAEP (p < 0.001), and again to 47.20 (3.78) after completion of the pAEP (p = 0.046). In the control group (n = 41), the score increased from 41.73 (4.74) at baseline to 45.72 (3.65) after completion of the pAEP (p < 0.001). There was no relevant differ- ence in knowledge gain between the eAEP and the pAEP group after completion of the corresponding educational sessions (p = 0.881). The AKT score was higher in the eAEP group after obligatory participation in pAEP than in the group that only completed the pAEP (p = 0.020). CONCLUSION: An internet-based AEP could help to reduce the knowledge deficits of a large proportion of patients with asthma.

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. CA extern

Purpose Prospectively collected outcome data of patients (pts) whose adjuvant systemic therapy recommendation was based on the clinico-molecular test EndoPredict® (EP) are presented. Methods Pts with ER-positive, HER2-negative early breast cancer with 0–3 positive lymph nodes were enrolled. The EP was carried out on all tumor samples. Pts were evaluated for treatment compliance, local recurrence, distant metastases and overall survival. Censored time-to-event outcomes were analysed by Cox proportional hazards models. Additional estimates of the event-free-survival were calculated by the Kaplan–Meier method. Hypothesis testing was conducted on two-sided exploratory 5% significance levels. Results 373 consecutive pts were enrolled. EP classified 238 pts (63.8%) as low risk and 135 pts (36.2%) as high risk. Median follow-up was 41.6 months. Risk for disease recurrence or death in EPclin high-risk patients was twofold higher in comparison with EPclin low-risk patients (hazard ratio (HR) 2.05 (95% CI 0.85–4.96; p = 0.110). Patients with EPclin high risk were at significant higher risk of distant metastases than patients with EPclin low risk (HR 5.18; 95% CI 1.04–25.74; p = 0.0443). EPclin high-risk patients who actually underwent adjuvant CTX had a 3-year-DFS of 96.3% (95% CI 92.2–100) in contrast to EPclin high-risk patients without CTX (3-year-DFS: 91.5% (95% CI 82.7–100%); HR 0.32; 95% CI 0.10–1.05; p = 0.061). Conclusion These first prospective outcome results show that EP, in clinical routine, is a valid clinico-molecular test, to predict DFS and to guide decision of adjuvant CTX use in ER-positive, HER2-negative early breast cancer pts with 0–3 positive lymph nodes. Adjuvant CTX seems to be beneficial for EPclin high-risk patients.

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, Highlights • Comparison of prospective EndoPredict tests with Ki-67 in a large breast cancer cohort. • EPscore and EPclin were significantly associated with Ki-67 indices. • Ki-67 values above 25% partly overlap with high-risk EP test results. • Ki-67 less than 25% was not reliable in predicting a low-risk EP profile. • EP testing is useful, particularly in breast cancer with low and intermediate Ki-67 levels.

ObjectiveTo investigate whether immune cell composition and content of neutrophil extracellular traps (NETs) in relation to clinical outcome are different between acute ischemic stroke (AIS) and acute myocardial infarction (AMI), we performed histologic analysis and correlated results with clinical and procedural parameters.MethodsWe retrieved thrombi from patients with AIS (n = 71) and AMI (n = 72) during endovascular arterial recanalization and analyzed their immune cell composition and NET content by immunohistology. We then associated thrombus composition with procedural parameters and outcome in AIS and with cardiac function in patients with AMI. Furthermore, we compared AIS thrombi with AMI thrombi and differentiated Trial of Org 10172 in Acute Stroke Treatment classifications to address potential differences in thrombus pathogenesis.ResultsAmounts of leukocytes (p = 0.133) and neutrophils (p = 0.56) were similar between AIS and AMI thrombi. Monocytes (p = 0.0052), eosinophils (p < 0.0001), B cells (p < 0.0001), and T cells (p < 0.0001) were more abundant in stroke compared with AMI thrombi. NETs were present in 100% of patients with AIS and 20.8% of patients with AMI. Their abundance in thrombi was associated with poor outcome scores in patients with AIS and with reduced ejection fraction in patients with AMI.ConclusionIn our detailed histologic analysis of arterial thrombi, thrombus composition and especially abundance of leukocyte subsets differed between patients with AIS and AMI. The presence and amount of NETs were associated with patients' outcome after AIS and AMI, supporting a critical impact of NETs on thrombus stability in both conditions.

Background and aims We aimed at studying the association of three major human monocyte subsets after percutaneous transluminal angioplasty (PTA) in patients with femoropopliteal disease. Methods We prospectively studied 67 sequential patients (40 male, 27 female; mean age 71 ± 11 years) treated with femoropopliteal angioplasty. Multi-color flow cytometry characterized monocyte subsets from venous blood for expression of CD14 and CD16 and intracellular myeloperoxidase (MPO) prior to, and 3, 6 and 12 months post PTA. Analyses tested associations between monocyte subsets and risk for restenosis. Results 16/67 patients (24%) developed restenosis within 12 months after PTA. Patients with hyperlipidemia had increased risk for restenosis (HR = 1.7, 95% CI 0.7–2.9, p = 0.001). Increased baseline monocytes associated with an increased risk of late restenosis (HR = 4.9, 95% CI: 1.3–18.6, p = 0.047). CD14 ++ CD16 ++ ‘intermediate' monocytes assessed at baseline, and after 3, 6, and 12 months significantly associated with the risk for subsequent restenosis: HR = 3.9 (95% CI: 2.4–6.5, p = 0.029), HR = 5.7 (95% CI = 0.7–44.7, p = 0.013), HR = 6.5 (95% CI: 2.5–16.9, p = 0.001) and HR = 1.5 (95% CI = 1.4–15.5 p = 0.001), respectively. Moreover, the probability for freedom of restenosis decreased with increased levels of intermediate subsets at 12 months after PTA. Additionally, intracellular MPO expression in CD14 ++ CD16 ++ measured at 3, 6 and 12 months associated with an increased restenosis risk (HR = 1.5, 95% CI: 0.8–2.1, p = 0.214, HR = 1.9, 95% CI: 1.0–2.3 p = 0.051 and HR = 1.4, 95% CI: 1.0–1.8, p = 0.052). Conclusions Our results imply altered innate immunity after angioplasty. Elevated CD14 ++ CD16 ++ intermediate monocyte frequencies and increased MPO expression may identify individuals at heightened risk for restenosis.

The life expectancy of HIV-infected patients has recently been increasing. Although the mortality and morbidity associated with AIDS is decreasing, those associated with cardiovascular diseases and percutaneous coronary intervention (PCI) are receiving greater attention. Only limited data regarding coronary restenosis are available in these patients.In this prospective, systematic angiographic follow-up study, we enrolled HIV patients who underwent PCI for de-novo lesions and subsequent routine angiographic follow-up for 6-8 months. Angiographic restenosis was defined as stenosis of at least 50% of the in-segment area.Univariate and multivariate analyses were performed to evaluate restenosis and its predictors.Between May 2002 and March 2014, 47 patients with HIV underwent PCI in two high-volume centers in Munich, Germany. Of these patients, 41 with 131 de-novo lesions underwent invasive surveillance. One-quarter of the lesions treated subsequently presented with restenosis. Univariate analysis indicated that CD8 T-cell levels (P = 0.006), serum cholesterol (P = 0.042) and low-density lipoprotein-cholesterol (P = 0.042) levels at baseline, total number of stents (P = 0.047), and C-reactive protein level (P = 0.001) at follow-up were associated with restenosis. Multivariate analysis indicated that CD8 T-cell levels (P = 0.006) and persistent C-reactive protein elevation at 6-month follow-up (P = 0.00013) were independent predictors of restenosis.Inflammation, represented by CD8 T-cell levels, and persistent C-reactive protein elevation are independent predictors of angiographic restenosis and should therefore be closely monitored in HIV patients undergoing PCI.

In the converging fields of neuroendocrinology and behavioural neuroscience, the interaction between peripheral secretion and central release of oxytocin in humans has not yet been comprehensively assessed. As the human brain is not directly accessible and as the collection of human cerebrospinal fluid (CSF) usually requires invasive procedures, easier accessible compartments such as blood or saliva attract increasing attention. In this study, we prospectively determined oxytocin concentrations in the three compartments plasma, CSF and saliva of fifty critically ill patients with neurological and neurosurgical diseases. All samples per patient were collected concomitantly. Oxytocin was measured by a highly sensitive and specific radioimmunoassay. Strength of correlation was assessed by the Spearman rank correlation coefficient. Correlation analyses revealed modest to strong correlations for oxytocin between the saliva and CSF compartments while predominantly weak correlations were found between the CSF and plasma as well as between the plasma and saliva compartments. In conclusion, we demonstrated modest to strong correlations between the saliva and CSF compartment suggesting that saliva oxytocin may help to assess CSF oxytocin levels. In contrast, plasma oxytocin failed to correspond well with CSF oxytocin levels as predominantly weak correlations were found between the CSF and plasma as well as between the plasma and saliva compartments which are unlikely to have a biological relevance. Further research is needed to clarify to what extent saliva oxytocin may serve as a biomarker reflecting brain oxytocin activity. This article is protected by copyright. All rights reserved.

Transcatheter aortic valve implantation (TAVI) is a treatment strategy for patients with severe aortic stenosis. Although general anaesthesia (TAVI-GA) and sedation (TAVI-S) have previously been described for TAVI, the difference in safety and efficacy of both methods has not been studied in a randomized trial.The INSERT trial was a single centre, controlled parallel-group trial with balanced randomization. Sixty-six patients (68-94 yr) with acquired aortic stenosis undergoing transfemoral CoreValve™ were assigned to TAVI-GA or TAVI-S. Comparable operative risk was determined from risk-scores (EUROscore, STS-Score). Monitoring and anaesthetic drugs were standardized. Near-Infrared-Spectroscopy was used to monitor cerebral-oxymetry blinded. Primary outcome was the perioperative cumulative cerebral desaturation. As secondary outcomes, changes in neurocognitive function and respiratory and haemodynamic adverse events were evaluated.Of 66 included patients, 62 (TAVI-GA: n=31, TAVI-S: n=31) were finally analysed. Baseline characteristics were comparable. In 24 patients (39%) cerebral desaturation was observed. Cumulative cerebral desaturation was comparable (TAVI-GA:(median [IQR]) (0[0/1308] s%) vs. TAVI-S:(0[0/276] s%); P=0.505) between the groups. Neurocognitive function did not change within and between groups. Adverse events were more frequently observed in TAVI-S patients (P0.001). Bradypnoea (n=16, 52%) and the need for airway manoeuvres (n=11, 36%) or bag-mask-ventilation (n=6, 19%) were the most common respiratory adverse events.Cerebral desaturation occurred in both patient groups, but there was no significant difference between the two groups. Based on primary outcome, both methods were shown to be comparable. Neurocognitive outcome was similar. The higher incidence of adverse events in the sedation group suggests a potential advantage of general anaesthesia.NCT 01251328.

The CNAP system allows continuous noninvasive arterial pressure measurement based on the volume clamp method using a finger cuff. We aimed to evaluate the agreement between arterial pressure measurements noninvasively obtained using the CNAP device and arterial catheter-derived arterial pressure measurements in intensive care unit patients. In 55 intensive care unit patients, we simultaneously recorded arterial pressure values obtained by an arterial catheter placed in the abdominal aorta through the femoral artery (criterion standard) and arterial pressure values determined noninvasively using CNAP. We performed Bland–Altman analysis and calculated the percentage error. The mean difference (±standard deviation, 95 % limits of agreement, percentage error) between noninvasive (CNAP) and invasively assessed arterial pressure was for mean arterial pressure +1 mmHg (±9 mmHg, −16 to +19 mmHg, 22 %), for systolic arterial pressure −10 mmHg (±16 mmHg, −42 to +21 mmHg, 27 %), and for diastolic arterial pressure +7 mmHg (±9 mmHg, −10 to +24 mmHg, 28 %). Our results indicate a reasonable accuracy and precision for the determination of mean and diastolic arterial pressure by noninvasive continuous arterial pressure measurements using the volume clamp method compared with the criterion standard (invasive arterial catheter). Systolic arterial pressure is determined less accurately and precisely.

Perioperative chemotherapy is an established treatment of advanced gastric cancer patients. Treatment selection is based on clinical staging (cT). We aimed to establish and validate a prognostic score including clinical and molecular factors, to optimize treatment decisions for these patients.We analyzed 626 carcinomas of the stomach and of the gastro-esophageal junction from two academic centers including primarily resected and pre-/perioperatively treated patients. Patients were divided into a training (N = 269) and validation (N = 357) set. Expression of 11 target genes was measured by quantitative PCR in resected tumors. A risk score to predict overall survival (OS) was generated and validated. Intra-tumoral heterogeneity was assessed by analyzing 50 tumor areas from 10 patients.A risk score including the expression of CCL5, CTNNB1, EXOSC3 and LZTR1 and the clinical parameters cT, tumor localization and histopathologic type suggested two groups with a significant difference in OS [hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.17-0.52]. The risk score was successfully validated in an independent cohort (HR 0.32; 95% CI 0.21-0.51; P 0.001) as well as in subgroups of primarily resected (HR 0.30; 95% CI 0.17-0.54; P 0.001) and pre-/perioperatively treated patients (HR 0.37; 95% CI 0.17-0.81; P = 0.009). A significant difference in OS of high- and low-risk patients was also found in primarily resected patients with intestinal (HR 0.45; 95% CI 0.23-0.90; P = 0.020) and nonintestinal-type carcinomas (HR 0.1; 95% CI 0.02-0.42; P 0.001). Intra-tumor heterogeneity analysis indicated a classification reliability of 95% for a supposed analysis of three biopsies.The identified risk score could substantially contribute to an improved management of gastric cancer patients in the context of perioperative chemotherapy.

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

Insulin resistance is the underlying mechanism for the metabolic syndrome and associated dyslipidaemia that theoretically implies a practical tool for identifying individuals at risk for cardiovascular disease and type-2-diabetes. Another screening tool is the hypertriglyceremic-waist phenotype (HTW). There is important impact of the ethnic background but a lack of studied European populations for the association of the triglyceride/high-density lipoprotein cholesterol (HDL-C) ratio and insulin resistance. This observational, retrospective study evaluated lipid ratios and the HTW for predicting the metabolic syndrome/insulin resistance in 1932 non-diabetic individuals from Germany in the fasting state and during a glucose tolerance test. The relations of triglyceride/HDL-C, total-cholesterol/HDL-C, and low-density lipoprotein cholesterol/HDL-C with 5 surrogate estimates of insulin resistance/sensitivity and metabolic syndrome were analysed by linear regression analysis and receiver operating characteristics (ROC) in participants with normal (n=1 333) or impaired fasting glucose (n=599), also for the impact of gender. Within the lipid ratios, triglyceride/HDL-C had the strongest associations with insulin resistance/sensitivity markers. In the prediction of metabolic syndrome, diagnostic accuracy was good for triglyceride/HDL-C (area under the ROC curve 0.817) with optimal cut-off points (in mg/dl units) of 2.8 for men (80% sensitivity, 71% specificity) and 1.9 for women (80% sensitivity, 75% specificity) and fair for HTW and HOMA-IR (area under the curve 0.773 and 0.761). These data suggest the triglyceride/HDL-C ratio as a physiologically relevant and practical index for predicting the concomitant presence of metabolic syndrome, insulin resistance and dyslipidaemia for therapeutic and preventive care in apparently healthy European populations.

The sickest-first principle in donor-liver allocation can be implemented by allocating organs to patients with cirrhosis with the highest Model for End-Stage Liver Disease (MELD) scores. For patients with other risk factors, standard exceptions (SEs) and nonstandard exceptions (NSEs) have been developed. We investigated whether this system of matched MELD scores achieves similar outcomes on the liver transplant waiting list for various diagnostic groups in Eurotransplant (ET) countries with MELD-based individual allocation (Belgium, the Netherlands, and Germany). A retrospective analysis of the ET wait-list outflow from December 2006 until December 2015 was conducted to investigate the relation of the unified MELD-based allocation to the risk of a negative wait-list outcome (death on the waiting list or delisting as too sick) as opposed to a positive wait-list outcome (transplantation or delisting as recovered). A total of 16,926 patients left the waiting list with a positive (11,580) or negative (5346) outcome; 3548 patients had a SE, and 330 had a NSE. A negative outcome was more common among patients without a SE or NSE (34.3%) than among patients with a SE (22.6%) or NSE (18.6%; P < 0.001). Analysis by model-based recursive partitioning detected 5 risk groups with different relations of matched MELD to a negative outcome. In Germany, we found the following: (1) no SE or NSE, SE for biliary sepsis (BS); (2) SE for hepatocellular carcinoma (HCC), hepatopulmonary syndrome (HPS), or portopulmonary hypertension (PPH); and (3) SE for primary sclerosing cholangitis (PSC) or polycystic liver disease (PcLD). In Belgium and the Netherlands, we found the following: (4) SE or NSE, or SE for HPS or PPH; and (5) SE for BS, HCC, PcLD, or PSC. In conclusion, SEs and NSEs do not even out risks across different diagnostic groups. Patients with SEs or NSEs appear advantaged toward patients with cirrhosis without SEs or NSEs. Liver Transplantation 23 1256-1265 2017 AASLD.

Background We recently reported that nocturnal respiratory rate (NRR) predicts non-sudden cardiac death in survivors of myocardial infarction (MI). Here, we present the details of the technique deriving NRR from ECG recordings. Methods Continuous ECG and respiratory chest excursions were simultaneously recorded in 941 MI survivors who were followed-up for 5-years. Mean respiratory rate was derived from the ECG based on RR intervals, QRS amplitudes, and QRS vectors and compared to chest belt measurements. NRR was calculated from Holter-ECGs accordingly using the same ECG processing. Results Directly-measured and ECG-derived respiratory rates were in good agreement. Areas under the ROC curve for 10-min-ECG- and Holter-derived respiratory rate were well in the confidence intervals of that of the chest belt measurement. The optimum dichotomy of NRR for the prediction of mortality was ≥ 18.6 breaths per minute. Conclusions The mean respiratory rate can be precisely derived from continuous ECGs.

Liver cirrhosis, myeloproliferative disorders (MPDs) and prothrombotic mutations are aetiologic factors for portal vein thrombosis (PVT). The role and frequency of thrombophilic genetic risk factors in cirrhotic patients is not well established. In this case–control study, we investigated the frequency of Janus kinase 2 (JAK2) (JAK2 V617F), Factor V Leiden (FVL G1691A), and Prothrombin (G20210A) mutations in cirrhotic patients with PVT (LCi+/PVT+ group, n = 21) in comparison with two control collectives (cirrhotic patients without PVT, LCi+/PVT− group, n = 43; PVT patients without liver cirrhosis, LCi−/PVT+ group, n = 29). In the LCi+/PVT+ group, JAK2 V617F was present in 2/21 patients (10 %; p = 0.104 compared to LCi+/PVT−; p = 0.092 compared to LCi−/PVT+), whereas 0/43 LCi+/PVT− patients (0 %; p

Summary Background Knowledge of the bacterial spectrum for acute cholangitis is essential for adequate empiric antibiotic treatment. Aim To analyse the relation of proton pump inhibitors (PPI) with biliary pathogens in patients with acute cholangitis. Methods This retrospective study identified 278 patients with 318 acute cholangitis episodes using an endoscopic database. The relationship between PPI and microbiological outcomes was assessed by logistic and poisson regression analysis for binary and count data. Results In total, 882 pathogens were isolated, of which, 120 cholangitis episodes occurred with PPI; 198 cholangitis episodes without PPI. Multivariate poisson regression analysis showed that PPI use resulted in a 23% increase in the number of biliary pathogens [3.14 vs. 2.55 (Δ = 0.59), P

Background Radial artery applanation tonometry technology can be used for continuous non-invasive measurement of arterial pressure (AP). The purpose of this study was to evaluate this AP monitoring technology in intensive care unit (ICU) patients in comparison with invasive AP monitoring using a radial arterial catheter. Methods In 24 ICU patients (German university hospital), AP values were simultaneously recorded on a beat-to-beat basis using radial artery applanation tonometry (T-Line system; Tensys Medical, San Diego, CA, USA) and a radial arterial catheter (contralateral arm). The primary endpoint of the study was to investigate the accuracy and precision of the non-invasively assessed AP measurements with the Bland–Altman method based on averaged 10 beat AP epochs (n=2993 10 beat epochs). Results For mean AP (MAP), systolic AP (SAP), and diastolic AP (DAP), we observed a bias (±standard deviation of the bias; 95% limits of agreement; percentage error) of +2 mm Hg (±6; −11 to +15 mm Hg; 15%), −3 mm Hg (±15; −33 to +27 mm Hg; 23%), and +5 mm Hg (±7; −9 to +19 mm Hg; 22%), respectively. Conclusions In ICU patients, MAP and DAP measurements obtained using radial artery applanation tonometry show clinically acceptable agreement with invasive AP determination with a radial arterial catheter. While the radial artery applanation tonometry technology also allows SAP measurements with high accuracy, its precision for SAP measurements needs to be further improved.

Purpose The aims of our study were to determine first circadian influences on central concentrations of the neuropeptides oxytocin and arginine-vasopressin and second to investigate if these central concentrations are associated with those in the peripheral compartments blood and saliva in neurocritical care patients. We therefore included patients with external ventricular drain who attended a neurosurgical intensive care unit and were not exposed to painful or stressful stimuli during the sampling period. For this purpose, blood, cerebrospinal fluid and saliva were collected in a 24-hour-interval at the timepoints 06:00, 12:00, 18:00 and 24:00. Results In none of the three body fluids examined, significant time-dependent fluctuations of oxytocin and arginine-vasopressin concentrations could be detected during the 24-hour sampling period. The only exception was the subgroup of postmenopausal women whose oxytocin concentrations in cerebrospinal fluid at 12:00 were significantly higher than at 18:00. Correlations of blood and cerebrospinal fluid and blood and saliva neuropeptide levels were very weak to weak at each timepoint. Cerebrospinal fluid and saliva oxytocin levels showed a moderate correlation at 06:00 but did correlate very weak at the other timepoints. Conclusions Central as well as peripheral oxytocin and arginine-vasopressin concentrations in neurocritical care patients did not show significant diurnal fluctuations. No strong correlations between central and peripheral neuropeptide concentrations could be detected under basal conditions. If investigators even though decide to use saliva concentrations as surrogate parameter for central neuropeptide activity, they have to consider that correlations of cerebrospinal fluid and saliva oxytocin seem to be highest in the early morning.