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A high body mass index (BMI) is often associated with metabolic syndrome, which is accompanied by systemic low-grade chronic inflammation. Here, we analyzed whether BMI, other components of metabolic syndrome, and/or inflammatory markers correlate with left ventricular geometry, function, and infarct size as assessed by serial cardiac magnetic resonance imaging (MRI) after a first (clinically evident) ST-elevation MI (STEMI).Within the Etiology, Titre-Course, and effect on Survival (ETiCS) study, cardiac MRI conducted 7-9 days and 12 months after MI enabled longitudinal characterization of patients with a first STEMI along with serial routine blood counts and multiplex cytokine measurements.Of 91 locally included STEMI patients, 47% were overweight (25 kg/mBoth BMI and HbA1c correlated negatively with LVEF only early, but not late after STEMI. Peak CRP evolved as strongest predictor of cardiac function at all time points independent of the metabolic syndrome.

Cellular communication network factor 1 (CCN1) is an independent predictor of MACE after ACS and elevated levels correlated with infarct size after STEMI. We compared the prognostic accuracy of baseline levels of CCN1, NT-proBNP, hsTnT, and ST2 and changes in levels over time to predict the development of structural and functional alterations typical of LV remodelling.Serial 3-T cMRI scans were performed to determine LVEF, LVEDV, LVESV, infarct size, and relative infarct size, which were correlated with serial measurements of the four biomarkers. The prognostic significance of these biomarkers was assessed by multiple logistic regression analysis by examining their performance in predicting dichotomized cardiac MRI values 12 months after STEMI based on their median. For each biomarker three models were created using baseline (BL), the Δ value (BL to 6 months), and the two values together as predictors. All models were adjusted for age and renal function. Receiver operator curves were plotted with area under the curve (AUC) to discriminate the prognostic accuracy of individual biomarkers for MRI-based structural or functional changes.A total of 44 predominantly male patients (88.6%) from the ETiCS (Etiology, Titre-Course, and Survival) study were identified at a mean age of 55.5 ± 11.5 (SD) years treated by successful percutaneous coronary intervention (97.7%) at a rate of 95.5% stent implantation within a median pain-to-balloon time of 260 min (IQR 124-591). Biomarkers hsTnT and ST2 were identified as strong predictors (AUC 0.7) of LVEDV and LVEF. BL measurement to predict LVEF [hsTnT: AUC 0.870 (95% CI: 0.756-0.983), ST2: AUC 0.763 (95% CI: 0.615-0.911)] and the Δ value BL-6M [hsTnT: AUC 0.870 (95% CI: 0.756-0.983), ST2: AUC 0.809 (95% CI: 0.679-0.939)] showed a high prognostic value without a significant difference for the comparison of the BL model vs. the Δ-value model (BL-6M) for hsTnT (P = 1) and ST2 (P = 0.304). The combined model that included baseline and Δ value as predictors was not able to improve the ability to predict LVEF [hsTnT: AUC 0.891 (0.791-0.992), P = 0.444; ST2: AUC 0.778 (0.638-0.918), P = 0.799]. Baseline levels of CCN1 were closely associated with LVEDV at 12 months [AUC 0.708 (95% CI: 0.551-0.865)] and infarct size [AUC 0.703 (95% CI: 0.534-0.872)].Baseline biomarker levels of hsTnT and ST2 were the strongest predictors of LVEF and LVEDV at 12 months after STEMI. The association of CCN1 with LVEDV and infarct size warrants further study into the underlying pathophysiology of this novel biomarker.

BACKGROUND There are more than 350,000 digital health interventions (DHIs) in the app stores. To ensure that they are effective and safe to use, they should be assessed for compliance with best practice standards. OBJECTIVE The objective of this paper was to examine the compliance of DHIs with best practice standards and to compute statistical benchmarks for assessing user experience (UX), professional/clinical assurance (PCA) and data privacy (DP). We also compared the quality of DHIs across different healthcare domains. METHODS Assessment data were collected from 2040 DHIs using the Organisation for the Review of Care and Health Applications – ORCHA Baseline Review (OBR) assessment tool. As part of the assessment, each DHI received a score out of 100 for each of the abovementioned domains (UX, PCA, DP). The domain scores were combined to make up the overall ORCHA quality score. Inferential statistics, probability distributions, Kruskal-Wallis and Dunn tests were used to conduct the data analysis. RESULTS 53.7% of the DHIs demonstrated satisfactory or high quality with scores of 65 or higher. The overall median OBR quality score (ORCHA score) for all DHIs was 63±22 (median ± interquartile range) out of 100. For the three assessment domains, DHI’s scored the highest for the UX assessment (75.21±8.40), followed by DP (65.73±17.54) and PCA (52.60±44.18) assessments. DHIs related to urology (n=20, 74.50±10.50) typically scored highest, followed by DHIs related to respiratory conditions (n=110, 74.00±12.00). DHIs within areas such as women’s health (n=89, 58.00±18.00), ophthalmology (n=69, 49.00±14.00), sexual health (n=69, 57.00±20.00), dental care (n=35, 59.00±21.50) and allergy management (n=17, 54.00±14.00) typically scored the lowest. CONCLUSIONS There is a high level of variability in the quality of DHIs across different healthcare domains, with an urgent need to improve compliance with best practices in some areas. Possible explanations for the observed differences might include varied market maturity and commercial interests within the different healthcare domains. More investment to support the development of higher quality DHIs in areas such as women’s health, ophthalmology, dental care and allergy management is needed.

Tissue-intrinsic error-correction mechanisms allow epithelial cells to detect aberrant neighboring cells and cause their removal from the tissue. The molecular mechanisms which grant cells the ability to compare their internal states is unknown. Here we demonstrate that comparison of cell identity, created by cell-fate-specifying transcription factors and patterning pathways, is conveyed through a specific set of cell surface molecules. We demonstrate that Drosophila imaginal discs express a range of cell surface molecules previously implicated in neuronal axon guidance processes, such as members of the Robo, Teneurin, Ephrin, Toll-like or atypical Cadherin families. Expression of these molecules is regulated by intrinsic fate-patterning pathways of the disc but also by aberrant expression of oncogenic RasV12. Importantly, mosaic clones deregulating individual cell surface molecules are sufficient to induce all hallmarks of ’interface surveillance’, a tissue-intrinsic error-correction mechanism previously shown to be induced by cells with aberrant activation of fate-patterning pathways. Specifically, cells with deregulated expression of Robo2 and Robo3 induce actomyosin enrichment, bilateral JNK signaling and apoptosis at mosaic clone interfaces in imaginal discs. Moreover, deregulation of Robo2 levels, which is normally expressed in a complex endogenous pattern, induces these interface surveillance hallmarks in a Robo2-pattern-specific manner. Taken together, our work indicates that these cell surface molecules mediate cell fate recognition in epithelial tissues and thereby contribute to the maintenance of epithelial health by initiating detection and removal of aberrant cells during development and adult tissue homeostasis.

BackgroundCOVID-19 vaccination is a key prevention strategy to reduce the spread and severity of SARS-CoV-2 infections, especially among highly exposed healthcare workers (HCWs). However, vaccine-related inability to work among HCWs could overstrain healthcare systems.MethodsThis study examined sick leave and intake of pro re nata (PRN) medication after the first, second and third COVID-19 vaccination in HCWs. Subgroup analyses were performed for different vaccines, gender, healthcare professions, and for HCWs aged at least 30 years. Data was collected by using an electronic questionnaire.FindingsAmong 1,704 HCWs enrolled, in total 595 (34·9%) HCWs were on sick leave following at least one COVID-19 vaccination, leading to a total number of 1,550 sick days. Both the absolute sick days and the rate of HCWs on sick leave significantly increased with each subsequent vaccination. Comparing BNT162b2mRNA and mRNA-1273 the difference in sick leave was not significant after the second dose, but mRNA-1273 induced a significantly longer and more frequent sick leave after the third.InterpretationA considerable number of HCWs have been on sick leave after COVID-19 vaccination, staff absences increase with each additional dose, depend on the vaccine, and vary between HCWs’ gender, and profession. In the light of further COVID-19 infection waves and booster vaccinations, there is a risk of additional staff shortages due to post-vaccination inability to work, which could acutely overload healthcare systems and jeopardise patient care. These findings will aid further vaccination campaigns to minimise the impact of staff absences on the healthcare system.FundingThis study was funded by the Federal Ministry for Education and Science (BMBF) via a grant provided to the University Hospital of Wuerzburg by the Network University Medicine on COVID-19 (B-FAST, grant-No 01KX2021) as well as by the Free State of Bavaria with COVID-research funds provided to the University of Wuerzburg, Germany. Nils Petri is supported by the German Research Foundation (DFG) funded scholarship UNION CVD.

Against the background of the current COVID-19 infection dynamics with its rapid spread of SARS-CoV-2 variants of concern (VOC), the immunity and the vaccine prevention of healthcare workers (HCWs) against SARS-CoV-2 continues to be of high importance. This observational cross-section study assesses factors influencing the level of anti-SARS-CoV-2-spike IgG after SARS-CoV-2 infection or vaccination. One thousand seven hundred and fifty HCWs were recruited meeting the following inclusion criteria: age ≥18 years, PCR-confirmed SARS-CoV-2 infection convalescence and/or at least one dose of COVID-19 vaccination. anti-SARS-CoV-2-spike IgG titers were determined by SERION ELISA agile SARS-CoV-2 IgG. Mean anti-SARS-CoV-2-spike IgG levels increased significantly by number of COVID-19 vaccinations (92.2 BAU/ml for single, 140.9 BAU/ml for twice and 1144.3 BAU/ml for threefold vaccination). Hybrid COVID-19 immunized respondents (after infection and vaccination) had significantly higher antibody titers compared with convalescent only HCWs. Anti-SARS-CoV-2-spike IgG titers declined significantly with time after the second vaccination. Smoking and high age were associated with lower titers. Both recovered and vaccinated HCWs presented a predominantly good humoral immune response. Smoking and higher age limited the humoral SARS-CoV-2 immunity, adding to the risk of severe infections within this already health impaired collective.

BackgroundA third dose of COVID-19 vaccination (‘COVID booster vaccination’) has become established as an important measure to strengthen the immune response against SARS-CoV-2. In contrast, seasonal influenza vaccination has been an important infection prevention measure for years, especially among highly exposed healthcare workers (HCWs). Coadministration of vaccines against COVID-19 and seasonal influenza could be an efficient strategy to protect HCWs from two major viral respiratory infections. Yet, the immunogenicity and safety of coadministration remains to be evaluated.MethodsThis study examines the differences in Anti-SARS-CoV-2-Spike IgG antibody formation as well as side effects based on a digital questionnaire after a third COVID-19 vaccination with or without coadministration of a seasonal quadrivalent influenza vaccine (Influvac Tetra vaccine 2021/2022). 1,231 HCWs were recruited who received a mRNA-based booster COVID-19 vaccination (mRNA-1273 or BNT162b2mRNA) after basic immunisation with BNT162b2mRNA twice. Anti-SARS-CoV-2-Spike IgG levels were determined at least 14 days after vaccination by SERION ELISA agile SARS-CoV-2 IgG.FindingsAnti-SARS-CoV-2-Spike IgG concentrations were by 25·4% lower in individuals with coadministration of the seasonal quadrivalent influenza vaccination than without (pInterpretationCoadministration of the seasonal quadrivalent influenza vaccine significantly limits the levels in Anti-SARS-CoV-2-Spike IgG levels, with a more restricted elevation in case of a BNT162b2mRNA booster vaccination compared with mRNA-1273 vaccine. The reduced humoral immune response in case of coadministration needs to be considered in seasonal vaccination recommendations, although the consequences of lower Anti-SARS-CoV-2-Spike IgG levels for the protection against SARS-CoV-2 infection and severe COVID-19 disease course are currently unknown. An augmented mRNA-based COVID-19 vaccine dosage may compensate for the restricted immunogenicity in case of coadministration.FundingThis study was funded by the Federal Ministry for Education and Science (BMBF) through a grant provided to the University Hospital of Wuerzburg by the Network University Medicine on COVID-19 (B-FAST, grant-No 01KX2021) as well as by the Free State of Bavaria with COVID-research funds provided to the University of Wuerzburg, Germany. Nils Petri is supported by the German Research Foundation (DFG) funded scholarship UNION CVD.Research in contextEvidence before this studyFor evaluation of the previously published evidence, PubMed and medRxiv were searched for the terms “influenza vaccination”, “influenza vaccine”, “influenza”, “flu”, “seasonality”, combined with “coadministration”, “concomitant”, “COVID-19 vaccination”, “COVID-19 vaccine”, “SARS-CoV-2”, in title or abstract, published between 1st of January 2020 and 18th of May 2022.To date, it is unclear if coadministration of COVID-19 and influenza vaccine is effective and safe, particularly in the cohort of healthcare workers (HCWs) as key public health stakeholders. For the subunit COVID-19 vaccine NVX-CoV2373, an impairment of Anti-SARS-CoV-2-Spike IgG levels has been shown in individuals coadministered with a seasonal influenza vaccine. The two previously published studies on coadministration of a mRNA-based COVID-19 and a seasonal quadrivalent influenza vaccine have reported a restriction of humoral Anti-SARS-CoV-2-Spike immune response in the coadministration group. These examinations were conducted with limited correspondence to real-life conditions and in smaller cohorts. Additionally, these former studies do not consider the important aspect of side effects as a possible direct effect of the prevention measure on the availability of public health care in combination with Anti-SARS-CoV-2-Spike IgG levels. In summary, the humoral immunogenicity and side effects of a coadministered third COVID-19 and a seasonal influenza vaccine are still unclear and the limited available data is not transferable to the general public.Added value of this studyWe performed the first large-scale real-life evaluation of humoral immunogenicity and side effects of COVID-19 and influenza vaccine coadministration in HCWs. Anti-SARS-CoV-2-Spike IgG levels were significantly lower in the coadministered cohort compared to the not coadministered control group, stratified by third COVID-19 vaccine (BNT162b2mRNA or mRNA-1273). Anti-SARS-CoV-2-Spike IgG post-vaccine elevation was lower among BNT162b2mRNA vaccinated HCWs than in those vaccinated with mRNA-1273 as a third COVID-19 vaccination. The influence of the seasonal quadrivalent influenza vaccine is evaluated in a cohort including 1,231 HCWs in total, covering a broad age range. Coadministration did not lead to an increase in side effects, which is a central requirement for considering the option of coadministration, given the role of HCWs as key personnel in maintaining health care capacities.Implications of all the available evidenceOur data suggest, that coadministration of third mRNA-based COVID-19 and quadrivalent seasonal influenza vaccine is safe and immunogenic, although it leads to a slightly reduced Anti-SARS-CoV-2-Spike antibody formation. While the clinical impact of the observed reduction in humoral Anti-SARS-CoV-2-Spike immune response for protection against SARS-CoV-2 infection and severe COVID-19 disease is still unclear, influenza vaccination remains an important infection prevention measure, especially among highly exposed HCWs. The coadministration does not increase side effects but may improve vaccination rate. A higher-dosed mRNA-based COVID-19 vaccine may compensate for the restricted immunogenicity in case of seasonal influenza vaccine coadministration. Our results will support the development of public health recommendations for coadministration of COVID-19 and influence vaccines in anticipation of the imminent infection waves in the coming winter season.

BackgroundThe COVID-19 pandemic has spurred large-scale, inter-institutional research efforts. To enable these efforts, researchers must agree on dataset definitions that not only cover all elements relevant to the respective medical specialty but that are also syntactically and semantically interoperable. Following such an effort, the German Corona Consensus (GECCO) dataset has been developed previously as a harmonized, interoperable collection of the most relevant data elements for COVID-19-related patient research. As GECCO has been developed as a compact core dataset across all medical fields, the focused research within particular medical domains demands the definition of extension modules that include those data elements that are most relevant to the research performed in these individual medical specialties.ObjectiveTo (i) specify a workflow for the development of interoperable dataset definitions that involves a close collaboration between medical experts and information scientists and to (ii) apply the workflow to develop dataset definitions that include data elements most relevant to COVID-19-related patient research inimmunization, pediatrics, andcardiology.MethodsWe developed a workflow to create dataset definitions that are (i) content-wise as relevant as possible to a specific field of study and (ii) universally usable across computer systems, institutions, and countries, i.e., interoperable. We then gathered medical experts from three specialties (immunization, pediatrics, andcardiology) to the select data elements most relevant to COVID-19-related patient research in the respective specialty. We mapped the data elements to international standardized vocabularies and created data exchange specifications using HL7 FHIR. All steps were performed in close interdisciplinary collaboration between medical domain experts and medical information scientists. The profiles and vocabulary mappings were syntactically and semantically validated in a two-stage process.ResultsWe created GECCO extension modules for theimmunization, pediatrics, andcardiologydomains with respect to the pandemic requests. The data elements included in each of these modules were selected according to the here developed consensus-based workflow by medical experts from the respective specialty to ensure that the contents are aligned with the respective research needs. We defined dataset specifications for a total number of 48 (immunization), 150 (pediatrics), and 52 (cardiology) data elements that complement the GECCO core dataset. We created and published implementation guides and example implementations as well as dataset annotations for each extension module.ConclusionsThese here presented GECCO extension modules, which contain data elements most relevant to COVID-19-related patient research inimmunization, pediatricsandcardiology, were defined in an interdisciplinary, iterative, consensus-based workflow that may serve as a blueprint for the development of further dataset definitions. The GECCO extension modules provide a standardized and harmonized definition of specialty-related datasets that can help to enable inter-institutional and cross-country COVID-19 research in these specialties.

A series of hydroxy-functionalized phosphonium salts were studied as bifunctional catalysts for the conversion of CO2 with epoxides under mild and solvent-free conditions. The reaction in the presence of a phenol-based phosphonium iodide proceeded via a first order rection kinetic with respect to the substrate. Notably, in contrast to the aliphatic analogue, the phenol-based catalyst showed no product inhibition. The temperature dependence of the reaction rate was investigated, and the activation energy for the model reaction was determined from an Arrhenius-plot (Ea =39.6 kJ mol-1 ). The substrate scope was also evaluated. Under the optimized reaction conditions, 20 terminal epoxides were converted at room temperature to the corresponding cyclic carbonates, which were isolated in yields up to 99 %. The reaction is easily scalable and was performed on a scale up to 50 g substrate. Moreover, this method was applied in the synthesis of the antitussive agent dropropizine starting from epichlorohydrin and phenylpiperazine. Furthermore, DFT calculations were performed to rationalize the mechanism and the high efficiency of the phenol-based phosphonium iodide catalyst. The calculation confirmed the activation of the epoxide via hydrogen bonding for the iodide salt, which facilitates the ring-opening step. Notably, the effective Gibbs energy barrier regarding this step is 97 kJ mol-1 for the bromide and 72 kJ mol-1 for the iodide salt, which explains the difference in activity.

Acute ischemic cardiac injury predisposes one to cognitive impairment, dementia, and depression. Pathophysiologically, recent positron emission tomography data suggest astroglial activation after experimental myocardial infarction (MI). We analyzed peripheral surrogate markers of glial (and neuronal) damage serially within 12 months after the first ST-elevation MI (STEMI). Serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were quantified using ultra-sensitive molecular immunoassays. Sufficient biomaterial was available from 45 STEMI patients (aged 28 to 78 years, median 56 years, 11% female). The median (quartiles) of GFAP was 63.8 (47.0, 89.9) pg/mL and of NfL 10.6 (7.2, 14.8) pg/mL at study entry 0–4 days after STEMI. GFAP after STEMI increased in the first 3 months, with a median change of +7.8 (0.4, 19.4) pg/mL (p = 0.007). It remained elevated without further relevant increases after 6 months (+11.7 (0.6, 23.5) pg/mL; p = 0.015), and 12 months (+10.3 (1.5, 22.7) pg/mL; p = 0.010) compared to the baseline. Larger relative infarction size was associated with a higher increase in GFAP (ρ = 0.41; p = 0.009). In contrast, NfL remained unaltered in the course of one year. Our findings support the idea of central nervous system involvement after MI, with GFAP as a potential peripheral biomarker of chronic glial damage as one pathophysiologic pathway.

Dibenzocycloheptanones (dibenzotropones) were prepared by Bronsted acid mediated intramolecular alkyne-carbonyl metathesis (ACM) reactions. The cyclization precursors are readily available by Sonogashira reaction of 2-bromobenzoyl chloride with terminal alkynes, followed by Suzuki reactions with benzaldehydes. The ACM reactions are highly modular and atom economic and allow for the construction of two regioisomeric series of dibenzotropones.

Abstract. Introduction: Researchers have repeatedly discovered an association between depression and autonomic cardiac dysregulation in adults. However, corresponding data concerning minors are still rare. Method: For this exploratory, cross-sectional study, we included N = 43 minors (age range 9–17 years). The subjects were depressive subjects with or without antidepressant medication (N = 23) or healthy control children (HC) (N = 20). We assessed several indices of cardiac functioning using long-term electrocardiogram data (mean heart rate, HR, and several parameters of heart rate variability, HRV). We hypothesized that increased HR and reduced HRV are associated with depressive disorders. Furthermore, we assessed the impact of age, sex, and antidepressant medication on HR and HRV. Results: When sex and age were controlled for, HR was significantly increased in depressive minors compared to HC. However, our preliminary data suggest that this might not be the case in medicated patients, and there were no differences between groups regarding HRV parameters. There was no significant correlation in the whole sample between severity of depression and both HR and HRV. In the subsample of patients with depression, antidepressant medication was associated with lower HR and higher indices of HRV. Conclusion: The data indicate an association between depression and altered autonomic cardiac regulation, which can already manifests in minors.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Following the publication of the above article, the Editor was notified that an error occurred in which all images were published with incorrect versions. The Editor has taken the decision that the manuscript is no longer acceptable in its current form, nor with a corrigendum, as the extensive changes to the figures and publication would lead to ambiguity for our readers. We have therefore made the decision to retract this manuscript from Cancer Letters with the possibility of resubmission and republication of the manuscript in its corrected form after peer review.

Metastatic small cell lung cancer (SCLC) is not curable. While SCLC is initially sensitive to chemotherapy, remissions are short-lived. The relapse is induced by chemotherapy-selected tumor stem cells, which express the AC133 epitope of the CD133 stem cell marker. We studied the effectiveness of AC133-specific CAR T cells post-chemotherapy using human primary SCLC and an orthotopic xenograft mouse model. AC133-specific CAR T cells migrated to SCLC tumor lesions, reduced the tumor burden, and prolonged survival in a humanized orthotopic SCLC model, but were not able to entirely eliminate tumors. We identified CD73 and PD-L1 as immune-escape mechanisms and combined PD-1-inhibition and CD73-inhibition with CAR T cell treatment. This triple-immunotherapy induced cures in 25% of the mice, without signs of graft-versus-host disease or bone marrow failure. AC133

Because of its size, anatomical similarities, and now also accessibility to genetic manipulations, pigs are used as animal models for human diseases and immune system development. However, expression and function of CD28, the most important costimulatory receptor expressed by T cells, so far is poorly understood in this species. Using a newly generated mAb (mAb 3D11) with specificity for pig CD28, we detected CD28 on CD8+ and CD4+ αβ T cells. Among γδ T cells, CD28 expression was restricted to a small CD2+ subpopulation of phenotypically naive cells. Functionally, CD28 ligation with mAb 3D11-costimulated porcine T cells, enhanced proliferation and cytokine secretion in vitro. We used a second, likewise newly generated but superagonistic, anti-CD28 mAb (CD28-SA; mAb 4D12) to test the function of CD28 on porcine T cells in a pilot study in vivo. Injection of the CD28-SA into pigs in vivo showed a very similar dose-response relationship as in humans (i.e., 100 µg/kg body weight [BW]) of CD28-SA induced a cytokine release syndrome that was avoided at a dose of 10 µg/kg BW and below. The data further suggest that low-dose (10 µg/kg BW) CD28-SA infusion was sufficient to increase the proportion of Foxp3+ regulatory T cells among CD4+ T cells in vivo. The pig is thus a suitable animal model for testing novel immunotherapeutics. Moreover, data from our pilot study in pigs further suggest that low-dose CD28-SA infusion might allow for selective expansion of CD4+ regulatory T cells in humans.

Die zwei Theorieblocke zu den Fallstudien im Teil „Offentliche Politik und Evaluation“ befassen sich mit den Dimensionen von Politik und dem Politikkonzept. Der nachfolgende Theorieblock befasst sich mit den Dimensionen von Politik.

Die zwei Theorieblocke zu den Fallstudien im Teil VII „Offentliche Politik und Evaluation“ beschaftigen sich mit den Dimensionen von Politik und dem Politikkonzept.

Die Fallstudien zum Themenbereich Offentliche Politik und Evaluation widmen sich der Erstellung von Politikkonzepten, deren Umsetzung, den erzielten Wirkungen in der Gesellschaft sowie der Evaluation von offentlichen Politiken. In dieser ersten Fallstudie geht es um die Erstellung eines Politikkonzepts fur die Integrationspolitik eines Kantons.

A series of hydroxy‐functionalized phosphonium salts were studied as bifunctional catalysts for the conversion of CO2 with epoxides under mild and solvent‐free conditions. The reaction in the presence of a phenol‐based phosphonium iodide proceeded via a first order rection kinetic with respect to the substrate. Notably, in contrast to the aliphatic analogue, the phenol‐based catalyst showed no product inhibition. The temperature dependence of the reaction rate was investigated, and the activation energy for the model reaction was determined from an Arrhenius‐plot (E a=39.6 kJ mol−1). The substrate scope was also evaluated. Under the optimized reaction conditions, 20 terminal epoxides were converted at room temperature to the corresponding cyclic carbonates, which were isolated in yields up to 99 %. The reaction is easily scalable and was performed on a scale up to 50 g substrate. Moreover, this method was applied in the synthesis of the antitussive agent dropropizine starting from epichlorohydrin and phenylpiperazine. Furthermore, DFT calculations were performed to rationalize the mechanism and the high efficiency of the phenol‐based phosphonium iodide catalyst. The calculation confirmed the activation of the epoxide via hydrogen bonding for the iodide salt, which facilitates the ring‐opening step. Notably, the effective Gibbs energy barrier regarding this step is 97 kJ mol−1 for the bromide and 72 kJ mol−1 for the iodide salt, which explains the difference in activity., CO2 fixation: Phenol‐functionalized phosphonium salts are efficient catalysts for the synthesis of cyclic carbonates under mild and solvent‐free conditions. Their superior activity is elucidated by kinetic investigations and DFT calculations.

Aims We quantified the concurring dynamics affecting total and hippocampal brain volume and cognitive function in patients with chronic heart failure (HF) over a period of three years. Methods and results A total of 148 patients with mild stable HF entered this monocentric prospective cohort study: mean age 64.5 (10.8) years; 16.2% female; 77% in New York Heart Association functional classes I–II; 128 and 105 patients attended follow-up visits after 1 and 3 years, respectively. The assessment included cardiological, neurological, psychological work-up, and brain magnetic resonance imaging. Total and regional brain volumes were quantified using an operator-independent fully automated approach and reported normalized to the mean estimated intracranial volume. At baseline, the mean hippocampal volume was ∼13% lower than expected. However, the 3-year progressive hippocampal volume loss was small: −62 mm3 [95% confidence interval (CI) −81 to −42, P Conclusion In patients with predominantly mild HF, the markedly reduced hippocampal volume observed at baseline was associated with impaired cognitive function, but no accelerated deterioration in cognition and brain atrophy became evident over a mid-term period of three years.

Background Vaccination (vac) strategies to maintain remissions in AML have been pursued for decades. The usage of recombinant proteins instead of peptides allows a potential immune response to multiple epitopes, hence could be offered to all patients (pts) independent of HLA expression. Wilms' tumor 1 (WT1) protein is highly immunogenic and frequently overexpressed in AML, thus ranked as a very promising target for novel immunotherapies. Here we report a single-center experience of a phase I/II clinical trial (NCT01051063) of a first-in-human vac strategy based on WT1 recombinant protein (WT1-A10) together with vaccine adjuvant AS01 B in 5 elderly AML pts. Patients and Methods Key eligibility criteria: overexpression of WT1 transcripts in AML blasts at diagnosis (qRT-PCR); 1 or 2 induction chemotherapies, with partial remission (PR) or morphologic complete remission with incomplete blood count recovery (CRi). The vaccine consisted of WT1-A10, a truncated WT-1 protein retaining the N-terminus (amino acids 2-281) of full length WT1 protein (429 aa) linked to the first 11 amino acids of trimethylamine N-oxide reductase signal peptide via one histidine residue combined with the liquid AS01 B adjuvant. AS01 B is an Adjuvant System containing MPL (3-O-desacyl-4´-monophosphoryl lipid A), QS-21 (Quillaja saponaria Molina, fraction 21) and liposome (50µg MPL and 50µg QS-21). One human dose of WT1-A10 + AS01 B contained 200 μg of WT1-A10 antigen. Pts received the vaccine by i.m. injection. To assess cellular response, antigen-specific stimulation of cultured PBMCs was performed with a pool of 123 15mer peptides covering the entire WT1 (1μg/ml/peptide), together with irrelevant re-stimulation plus negative control peptide. CD4 + and CD8 + T cells were serially assessed by intracellular flow cytometry for their ability to produce both IFN-γ and TNF upon antigen stimulation. Results A total of 5 pts (median age 69, range 63-75) were enrolled on the WT1 protein-based vac study at our institution (Table 1), receiving a total of 62 vac after a median of 3 courses (1-5) of standard chemotherapy. The repeated vac had an acceptable safety profile and were thus well tolerated. 2/5 pts experienced therapy-related toxicity, injection site pain (CTCAE v.3, grade 2) and injection site inflammation (CTCAE v.3, grade 1). Symptoms were of mild / moderate severity and resolved completely. No hematologic toxicity was noted. With a median progression-free survival of 28.8 mths (range 1-59) and median overall survival (OS) of 35.4 mths (range 3-75) from the 1st vac, this older patient cohort showed above-average clinical outcome (Table 1), pointing to a potential clinical efficacy of WT1-based vac therapy. All vaccinated pts showed highly elevated WT1 ratios before WT1-based vac therapy and normal levels after vac (Fig. 1A). Two pts demonstrated early relapse after 3 WT1 protein-based vac, and clinical benefit was observed in 3 pts: one achieved complete and sustained measurable residual disease clearance (NPM1 ratios) during WT1 vac, resulting in molecular CR at the 18th vac. The pt died from unrelated reasons 5.5 years after initial diagnosis of AML, 3.5 years after the last WT1 vac, with continued molecular CR. One pt maintained long-term hematological and molecular remission over 59 mths, until molecular relapse occurred 11 mths after the final, 21 st vac. Interestingly, in one case, a complete clonal switch occurred at hematologic relapse following 18 vac, with loss of WT1 overexpression: while the clone at initial diagnosis harbored FLT3, NPM1 and SRSF2 mutations, BRAF, KRAS and STAG2 mutations were detected at relapse (Fig. 1B), pointing to an ongoing suppression of the WT1 expressing AML clone. Flow cytometry studies were conducted in one pt to elucidate specific cellular immune responses. We noted CD4 + T cell immune responses by strong IFN-γ and TNF expression (Fig. 1C), suggestive of efficient immune stimulation post-vac, while CD8 + T cells failed to upregulate these key cytokines. Conclusions This vac strategy showed good feasibility, with a very acceptable safety profile, and appeared to extend remissions beyond the expected duration, together with MRD clearance. Thus, our data provide evidence of potential clinical efficacy of WT1 protein-based vac therapy in AML pts, making this maintenance approach an attractive alternative to more complex strategies, particularly in elderly pts with comorbidities. Figure 1 Figure 1. Disclosures Döhner: Abbvie: Consultancy, Honoraria; Jazz Roche: Consultancy, Honoraria; Daiichi Sankyo: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Celgene/BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Agios and Astex: Research Funding. Schmitt: MSD: Membership on an entity's Board of Directors or advisory committees; TolerogenixX: Current holder of individual stocks in a privately-held company; Bluebird Bio: Other: Travel grants; Hexal: Other: Travel grants, Research Funding; Novartis: Other: Travel grants, Research Funding; Kite Gilead: Other: Travel grants; Apogenix: Research Funding. Lübbert: Teva: Research Funding; Janssen: Research Funding; Cheplapharm: Research Funding; Aristopharm: Research Funding; Syros: Honoraria; Pfizer: Honoraria; Janssen: Honoraria, Research Funding; Imago BioSciences: Honoraria; Hexal: Honoraria; Astex: Honoraria; Abbvie: Honoraria.

A novel rhenium complex bearing a non-innocent PNP pincer ligand was prepared. This novel catalyst is active in hydrogen autotransfer reactions to form new C-C and C-N bonds. More specifically, valuable alkylations of ketones and sulfonamides with primary alcohols are herein presented. In addition, the first examples of rhenium-catalysed synthesis of pyrroles are described by dehydrogenative coupling of diols, amines and ketones.

Climate services are becoming the backbone to translate climate knowledge, data & information into climate-informed decision-making at all levels, from public administrations to business operators. It is essential to assess the technical and scientific quality of the provided climate data and information products, including their value to users, to establish the relation of trust between providers of climate data and information and various downstream users. The climate data and information products (i.e., from satellite, in-situ and reanalysis) shall be fully traceable, adequately documented and uncertainty quantified and can provide sufficient guidance for users to address their specific needs and feedbacks. This paper discusses details on how to apply the quality assurance framework to deliver timely assessments of the quality and usability of Essential Climate Variable (ECV) products. It identifies an overarching structure for the quality assessment of single product ECVs (i.e., consists of only one single variable), multi-product ECVs (i.e., more than one single parameter), thematic products (i.e., water, energy and carbon cycles), as well as the usability assessment. To support a traceable climate service, other than rigorously evaluating the technical and scientific quality of ECV products, which represent the upstream of climate services, how the uncertainty propagates into the resulting benefit (utility) for the users of the climate service needs to be detailed.

Aims Both anxiety and depression are common and independent outcome predictors in patients after myocardial infarction (MI). However, it is unclear whether and how anti-depressants influence remodeling after MI. Thus, we studied cardiac remodeling in mice after experimental MI under treatment with citalopram, a selective serotonin reuptake inhibitor widely used as antidepressant. Methods and results Treatment with citalopram versus saline was applied via osmotic pump after coronary artery ligation. Two different groups were studied: early treatment during the healing phase (starting immediately after surgery), or late treatment in the remodeling phase (starting 7 days after surgery). Late treatment did not change mortality or left ventricular remodeling after MI over the period of 6 weeks. However, in the early treatment group mortality was increased in citalopram-treated mice predominantly due to left ventricle rupture without differences in infarct size. Remodeling 4 weeks after MI was not altered by the treatment. Neither infiltration of inflammatory cells, as determined by FACS analysis of myocardial tissue, nor mRNA-expression of inflammatory cytokines changed 3 days after MI in the early treatment group. However, extracellular matrix functioning was altered: There was a significant increase of MMP13 in citalopram treated animals after MI. Pretreatment with the MMP inhibitor PD 166793 prevented left ventricular ruptures and demonstrated a tendency to improved survival after citalopram treatment. Conclusions Treatment with antidepressant citalopram in the acute but not in the late phase after MI significantly increased mortality in mice by disturbing early healing. Pharmacological MMP inhibition partially reversed the deleterious effects of citalopram.

Graphical abstract, In experimental animal research body temperature (BT) is measured for the objective determination of an animals’ physiological condition. Invasive, probe-based measurements are stressful and can influence experimental outcome. Alternatively BT can be determined touch-free from the emitted heat of the organism at a single spot using infrared thermometers [1]. To get visual confirmation and find more appropriate surfaces for measurement a hand-held thermal imager was equipped with a self-made, cheap, 3D-printable close-up lens system that reproducibly creates eight-time magnified thermal images and improves sensitivity. This setup was used to establish ocular surface temperature (OST), representing the temperature of the brain-heart axis, as a touch-free alternative for measurement of BT in mice, rats, rabbits and humans.OST measurement after isoflurane exposure and myocardial infarction (MI) experiments in mice revealed high physiological relevance and sensitivity, the possibility to discriminate between MI and sham operations in one hour and even long-term outcome-predictive capabilities of OST after MI. Summarized here we present: • Self-made close-up lens for thermal imaging cameras for eight-time magnification • Establishment of OST for touch-free determination of BT in rodents and humans • Short- and long-term predictive capabilities of OST in experimental MI in mice.