The "TIDE"-Algorithm for the Weaning of Patients With Cardiogenic Shock and Temporarily Mechanical Left Ventricular Support With Impella Devices. A Cardiovascular Physiology-Based Approach.

Objectives: Mechanical circulatory support (MCS) is often required to stabilize therapy-refractory cardiogenic shock patients. Left ventricular (LV) unloading by mechanical ventricular support (MVS) via percutaneous devices, such as with Impella® axial pumps, alone or in combination with extracorporeal life support (ECLS, ECMELLA approach), has emerged as a potential clinical breakthrough in the field. While the weaning from MCS is essentially based on the evaluation of circulatory stability of patients, weaning from MVS holds a higher complexity, being dependent on bi-ventricular function and its adaption to load. As a result of this, weaning from MVS is mostly performed in the absence of established algorithms. MVS via Impella is applied in several cardiogenic shock etiologies, such as acute myocardial infarction (support over days) or acute fulminant myocarditis (prolonged support over weeks, PROPELLA). The time point of weaning from Impella in these cohorts of patients remains unclear. We here propose a novel cardiovascular physiology-based weaning algorithm for MVS. Methods: The proposed algorithm is based on the experience gathered at our center undergoing an Impella weaning between 2017 and 2020. Before undertaking a weaning process, patients must had been ECMO-free, afebrile, and euvolemic, with hemodynamic stability guaranteed in the absence of any inotropic support. The algorithm consists of 4 steps according to the acronym TIDE: (i) Transthoracic echocardiography under full Impella-unloading; (ii) Impella rate reduction in single 8-24 h-steps according to patients hemodynamics (blood pressure, heart rate, and ScVO2), including a daily echocardiographic assessment at minimal flow (P2); (iii) Dobutamine stress-echocardiography; (iv) Right heart catheterization at rest and during Exercise-testing via handgrip. We here present clinical and hemodynamic data (including LV conductance data) from paradigmatic weaning protocols of awake patients admitted to our intensive care unit with cardiogenic shock. We discuss the clinical consequences of the TIDE algorithm, leading to either a bridge-to-recovery, or to a bridge-to-permanent LV assist device (LVAD) and/or transplantation. With this protocol we were able to wean 74.2% of the investigated patients successfully. 25.8% showed a permanent weaning failure and became LVAD candidates. Conclusions: The proposed novel cardiovascular physiology-based weaning algorithm is based on the characterization of the extent and sustainment of LV unloading reached during hospitalization in patients with cardiogenic shock undergoing MVS with Impella in our center. Prospective studies are needed to validate the algorithm.

Case Report First-in-Man Method Description: Left Ventricular Unloading With iVAC2L During Veno-Arterial Extracorporeal Membrane Oxygenation: From Veno-Arterial Extracorporeal Membrane Oxygenation to ECMELLA to EC-iVAC®.

Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is increasingly used in bi-ventricular failure with cardiogenic shock to maintain systemic perfusion. Nonetheless, it tends to increase left ventricular (LV) afterload and myocardial oxygen demand. In order to mitigate these negative effects on the myocardium, an Impella CP® (3.5 L/min Cardiac Output) can be used in conjunction with V-A ECMO (ECMELLA approach). We implemented this strategy in a patient with severe acute myocarditis complicated by cardiogenic shock. Due to a hemolysis crisis, Impella CP® had to be substituted with PulseCath iVAC2L®, which applies pulsatile flow to unload the LV. A subsequent improvement in LV systolic function was noted, with increased LV ejection fraction (LVEF), LV end-diastolic diameter (LVEDD) reduction, and a reduction in plasma free hemoglobin. This case documents the efficacy of iVAC2L in replacing Impella CP as a LV vent during V-A ECMO, with less hemolysis.

The Quest for the Best Dual Orexin Receptor Antagonist (Daridorexant) for the Treatment of Insomnia Disorders.

Since its discovery in 1998, the orexin system has been of interest to the research community as a potential therapeutic target for the treatment of sleep/wake disorders, stress and anxiety disorders, addiction or eating disorders. It consists of two G protein-coupled receptors, the orexin 1 and orexin 2 receptors, and two neuropeptides with agonistic effects, the orexin A and orexin B peptides. Herein we describe our efforts leading to the identification of a promising set of dual orexin receptor antagonists (DORAs) which subsequently went through physiology-based pharmacokinetic and pharmacodynamic modelling>[1] and finally led to the selection of daridorexant, currently in phase 3 clinical trials for the treatment of insomnia disorders.

Mode-of-action of the PROPELLA concept in fulminant myocarditis.

AIMS: Haemodynamic load induces cardiac remodelling via mechano-transduction pathways, which can further trigger inflammatory responses. We hypothesized that particularly in an inflammatory disorder such as myocarditis, a therapeutic strategy is required which, in addition to providing adequate circulatory support, unloads the left ventricle, decreases cardiac wall stress, and mitigates inflammatory responses. METHODS AND RESULTS: Axial flow pumps such as the Impella systems comply with these requirements. Here, we report a potential mode-of-action of prolonged Impella support (PROPELLA concept) in fulminant myocarditis, including a decrease in cardiac immune cell presence, and integrin α1, α5, α6, α10 and ß6 expression during unloading. CONCLUSION: PROPELLA may provide benefits beyond its primary function of mechanical circulatory support in the form of additional disease-altering effects, which may contribute to enhanced myocardial recovery/remission in patients with chronic fulminant myocarditis.

Mechanical Unloading by Fulminant Myocarditis: LV-IMPELLA, ECMELLA, BI-PELLA, and PROPELLA Concepts.

Mechanical circulatory support (MCS) is often required to stabilize patients with acute fulminant myocarditis with cardiogenic shock. This review gives an overview of the successful use of left-sided Impella in the setting of fulminant myocarditis and cardiogenic shock as the sole means of MCS as well as in combination with right ventricular (RV) support devices including extracorporeal life support (ECLS) (ECMELLA) or an Impella RP (BI-PELLA). It further provides evidence from endomyocardial biopsies that in addition to giving adequate support, LV unloading by Impella exhibits disease-modifying effects important for myocardial recovery (i.e., bridge-to-recovery) achieved by this newly termed "prolonged Impella" (PROPELLA) concept in which LV-IMPELLA 5.0, implanted via an axillary approach, provides support in awake, mobilized patients for several weeks. Finally, this review addresses the question of how to define the appropriate time point for weaning strategies and for changing or discontinuing unloading in fulminant myocarditis.

The CardioMEMS system in the clinical management of end-stage heart failure patients: three case reports.

BACKGROUND: Recent clinical trials have shown that pulmonary artery pressure-guided therapy via the CardioMEMS™ system reduces the risk of recurrent hospitalizations in chronic heart failure (HF) patients. The CardioMEMS™ pressure sensor is percutaneously implanted in a branch of the pulmonary artery and allows telemetric pressure monitoring via a receiver. According to the most recent ESC guidelines, this technology has currently a class IIb indication in patients with class III New York Heart Association symptoms and a previous hospitalization for congestive heart failure within the last year, regardless of ejection fraction. Aim of this guided-therapy is multifold, including an early prediction of upcoming decompensation, optimization of patients' therapy and thereby avoidance of hospital admissions. In addition, it can be used during acute decompensation events as a novel tool to direct intra-hospital therapeutic interventions such as inotropes infusion or left ventricular (LV) assist device monitoring, with the aim of achieving an optimal volume status. CASE PRESENTATION: We present a case series of three end-stage HF patients with reduced ejection fraction (HFrEF) who received a CardioMEMS™ device as an aid in their clinical management. The CardioMEMS™ system enabled a closer non-invasive hemodynamic monitoring of these patients and guided the extent of therapeutic interventions. Patients were free from device- or system-related complications. In addition, no pressure-sensor failure was observed. Two patients received a 24-h infusion of the calcium sensitizer levosimendan. One patient showed a refractory acute decompensation and underwent LV assist device (LVAD) implantation as a bridge to cardiac transplantation. Switching a patient with recurrent hospitalizations to the Angiotensin Receptor Neprilysin Inhibitor (ARNI, Sacubitril-Valsartan) on top of the optimal heart failure-therapy improved its subjective condition and hemodynamics, avoiding further hospitalization. CONCLUSIONS: Our case series underlines the potential impact of CardioMEMS™ derived data in the daily clinical management of end-stage HF patients. The new concept to combine CardioMEMS™ in the setting of an outpatient levosimendan program as well as a bridge to LVAD-implantation/heart transplantation looks promising but needs further investigations.

Pollen-mediated gene flow and seed exchange in small-scale Zambian maize farming, implications for biosafety assessment.

Gene flow in agricultural crops is important for risk assessment of genetically modified (GM) crops, particularly in countries with a large informal agricultural sector of subsistence cultivation. We present a pollen flow model for maize (Zea mays), a major staple crop in Africa. We use spatial properties of fields (size, position) in three small-scale maize farming communities in Zambia and estimate rates of cross-fertilisation between fields sown with different maize varieties (e.g. conventional and transgene). As an additional factor contributing to gene flow, we present data on seed saving and sharing among farmers that live in the same communities. Our results show that: i) maize fields were small and located in immediate vicinity of neighboring fields; ii) a majority of farmers saved and shared seed; iii) modeled rates of pollen-mediated gene flow showed extensive mixing of germplasm between fields and farms and iv) as a result, segregation of GM and non-GM varieties is not likely to be an option in these systems. We conclude that the overall genetic composition of maize, in this and similar agricultural contexts, will be strongly influenced both by self-organised ecological factors (pollen flow), and by socially mediated intervention (seed recycling and sharing).

Daring the Challenge and Thinking Big: The Value of Early Process R&D.

The production of the L/T channel blocker ACT-280778 required the enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one (1) as key building block. As the published routes towards 1 are very low yielding (<0.5% yield) and comprise many steps that are not acceptable for scale-up, a series of processes to 1 was developed to match the increasing requirements from first kg-batches to clinical supplies. The three routes are characterized by an individual asset. (1) The first route contains a scale-up of a Diels-Alder reaction with highly reactive reagents and afforded 90 kg enantiomerically pure 1. To mitigate safety risks, a flow reactor was developed for the high-temperature Diels-Alder reaction. This route relied on an efficient enantiomer separation on a »-ton scale by HPLC. (2) A Crystallization Induced Diastereomer Transformation (CIDT) during an intramolecular aldol reaction was the pivotal step of a first enantioselective route that starts with the Shibasaki reaction. (3) The 2(nd) enantioselective route represents a rare example of organocatalysis on scale and allowed to skip six out of nine steps with a significant impact on the cost of goods. This simple way to 1 opened up a short synthesis of Hayashi's chiral diene ligands (bod*) that were so far lacking an affordable access. Some of these novel C1-symmetrical dienes have shown very high enantioselectivities in Rh-catalyzed additions of arylboronates.

A promoter polymorphism -945C>G in the connective tissue growth factor in heart failure patients with mechanical circulatory support: a new marker for bridge to recovery?

OBJECTIVES: Mechanical circulatory support (MCS) creates improvement of cardiac function in a small portion of patients with idiopathic dilated cardiomyopathy (iDCM). Among other factors, cardiomyocyte hypertrophy seems to represent an important prerequisite for MCS-related cardiac recovery. We have previously shown that connective tissue growth factor (CTGF) leads to adaptive cardiomyocyte hypertrophy associated with a protective cardiac function in transgenic mice. To test whether a functional genetic variant in the CTGF promoter impacts MCS-related cardiac recovery, three groups of iDCM patients with and without cardiac recovery on MCS were genotyped. METHODS: The CTGF promoter variant (c.-945C>G) was analysed in 314 patients with iDCM receiving medical treatment only (Group I). Forty-nine iDCM patients who were either weaned from MCS for more than 6 months (Group II; n=20) or bridged to cardiac transplantation (Group III: n=29) were also genotyped. Patients on MCS were followed up for at least 12 months. Clinical characteristics and outcome on MCS were correlated with the respective genotypes. RESULTS: The c.-945C>G allele frequencies in 314 iDCM patients (Group I) were similar to controls deposited in the HapMap database or those published in a recent study. There were no differences in allele prevalence between patients with mild to moderate iDCM (Group I) compared with patients with severe iDCM requiring MCS (Groups II and III). Intriguingly, 50% of patients who were weaned from MCS (Group II) were homozygous for the G allele compared with only 17.2% of patients included in Group III, which is a significant difference (P=0.03). CONCLUSIONS: Homozygosity of the promoter-activating G allele in the CTGF_c.-945C>G variant is overrepresented in patients with cardiac recovery on MCS when compared with iDCM patients without cardiac recovery. Further studies are needed to evaluate c.-945C>G as a genetic predictor for clinical outcome on MCS.

Novel S1P(1) receptor agonists--part 3: from thiophenes to pyridines.

In preceding communications we summarized our medicinal chemistry efforts leading to the identification of potent, selective, and orally active S1P1 agonists such as the thiophene derivative 1. As a continuation of these efforts, we replaced the thiophene in 1 by a 2-, 3-, or 4-pyridine and obtained less lipophilic, potent, and selective S1P1 agonists (e.g., 2) efficiently reducing blood lymphocyte count in the rat. Structural features influencing the compounds' receptor affinity profile and pharmacokinetics are discussed. In addition, the ability to penetrate brain tissue has been studied for several compounds. As a typical example for these pyridine based S1P1 agonists, compound 53 showed EC50 values of 0.6 and 352 nM for the S1P1 and S1P3 receptor, respectively, displayed favorable PK properties, and penetrated well into brain tissue. In the rat, compound 53 maximally reduced the blood lymphocyte count for at least 24 h after oral dosing of 3 mg/kg.

Novel S1P1 receptor agonists--part 1: From pyrazoles to thiophenes.

From a high-throughput screening campaign aiming at the identification of novel S1P1 receptor agonists, the pyrazole derivative 2 emerged as a hit structure. Medicinal chemistry efforts focused not only on improving the potency of the compound but in particular also on resolving its inherent instability issue. This led to the discovery of novel bicyclo[3.1.0]hexane fused thiophene derivatives. Compounds with high affinity and selectivity for S1P1 efficiently reducing the blood lymphocyte count in the rat were identified. For instance, compound 85 showed EC50 values of 7 and 2880 nM on S1P1 and S1P3, respectively, had favorable pharmacokinetic properties in rat and dog, distributed well into brain tissue, and efficiently and dose dependently reduced the blood lymphocyte count in the rat. After oral administration to spontaneously hypertensive rats, the S1P1 selective compound 85 showed no effect on mean arterial blood pressure and affected the heart rate during the wake phase of the animals only.

Analysis of two-dimensional photonic band gaps of any rod shape and conductivity using a conical-integral-equation method.

The conical-boundary-integral-equation method has been proposed for calculation of the sensitive optical response of two-dimensional photonic band gaps (PBGs), including dielectric, absorbing, and high-conductive rods of various shapes working in any wavelength range. It is possible to determine the diffracted field by computing the scattering matrices separately for any grating boundary profile. The computation of the matrices is based on the solution of a 2×2 system of singular integral equations at each interface between two different materials. The advantage of our integral formulation is that the discretization of the integral equation system and the factorization of the discrete matrices, which takes the majority of the computing time, are carried out only once for a boundary. It turns out that a small number of collocation points per boundary combined with a high convergence rate can provide an adequate description of the dependence on diffracted energy of very different PBGs illuminated at arbitrary incident and polarization angles. The numerical results presented describe the significant impact of rod shape on diffraction in PBGs supporting polariton-plasmon excitation, particularly in the vicinity of resonances and at high filling ratios. The diffracted energy response calculated vs the array cell geometry parameters was found to vary from a few up to a few hundred percent. The influence of other types of anomalies (i.e., waveguide anomalies, cavity modes, Fabry-Perot and Bragg resonances, Rayleigh orders, etc.), conductivity, and polarization states on the optical response is demonstrated.

Regulation of 7B2 mRNA translation: dissecting the role of its 5'-untranslated region.

7B2 is a chaperone for the prohormone/proneuropeptide convertase PC2. Its mRNA is readily detectable in most neuronal and endocrine cells; the protein, in contrast, is often found at relatively low levels, suggesting that translation of the corresponding mRNA may be repressed. Because the 5' untranslated region (5'-UTR) of this mRNA is relatively long and burdened with multiple AUGs, it has been speculated that it contributes to this repression. In this report, the influence of this region was assessed using in vitro and ex vivo approaches. The results showed that, in a cell-free system, full-length 7B2 mRNA was a poor template for translation. Its translatability dramatically improved when its 5'-UTR was truncated or when it was replaced with the 5'-UTR of carboxypeptidase E mRNA. These observations were confirmed in transfected mouse insulinoma MIN6 cells and human embryonic kidney HEK293 cells. Acute exposure of MIN6 cells to high glucose increased endogenous 7B2 biosynthesis without affecting the levels of its mRNA, suggesting that translation repression of this mRNA can be relieved by physiological stimuli.

The potential of spatial information in human biomonitoring by example of two German environmental epidemiology studies.

This study aimed at statistically investigating the association between the internal exposure of children and young adults to uranium (U) and epidemiologically relevant external determinants of exposure. The investigation was performed with data from two studies within the framework of the German health-related environmental monitoring program: The German Environmental Survey for Children (GerES IV) conducted by the Federal Environment Agency (Umweltbundesamt) with data on 1,780 children 3-14 years of age and their home environment and the German Environmental Specimen Bank (ESB, section: human specimens) with data on 2,253 students 20-29 years of age. Both studies provided data on the U levels in human urine for all probands. GerES IV furthermore provided an extensive environmental and demographic database on, e.g., U levels in drinking water. The data from GerES IV and ESB were linked by GIS to spatially relevant exposure information, including background values of U in stream sediments and in upper and lower soils, U levels in mosses and particulate matter in the lower atmosphere, precipitation and elevation as well as forest density. Bivariate correlation analysis and two decision tree models showed moderate but significant associations between U in human urine and U levels in drinking water, stream sediments and upper and lower soils. Future investigations considering additional epidemiologically relevant data sets may differentiate the results. Furthermore, the sample design of future environmental epidemiology studies should take the spatial evaluation of the data into greater account.

Potential malaria outbreak in Germany due to climate warming: risk modelling based on temperature measurements and regional climate models.

PURPOSE: Climate warming can change the geographic distribution and intensity of the transmission of vector-borne diseases such as malaria. The transmitted parasites usually benefit from increased temperatures as both their reproduction and development are accelerated. Lower Saxony (northwestern Germany) has been a malaria region until the 1950s, and the vector species are still present throughout Germany. This gave reason to investigate whether a new autochthonous transmission could take place if the malaria pathogen was introduced again in Germany. MATERIALS AND METHODS: The spatial distribution of potential temperature-driven malaria transmissions was investigated using the basic reproduction rate (R (0)) to model and geostatistically map areas at risk of an outbreak of tertian malaria based on measured (1961-1990, 1991-2007) and predicted (1991-2020, 2021-2050, 2051-2080) monthly mean air temperature data. RESULTS: From the computations, maps were derived showing that during the period 1961-1990, the seasonal transmission gate ranges from 0 to 4 months and then expands up to 5 months in the period 1991-2007. For the projection of future trends, the regional climate models REMO and WettReg were used each with two different scenarios (A1B and B1). Both modelling approaches resulted in prolonged seasonal transmission gates in the future, enabling malaria transmissions up to 6 months in the climate reference period 2051-2080 (REMO, scenario A1B). DISCUSSION: The presented risk prognosis is based on the R (0) formula for the estimation of the reproduction of the malaria pathogen Plasmodium vivax. The presented model focuses on mean air temperatures; thus, other driving factors like the distribution of water bodies (breeding habitats) or population density are not integrated. Nevertheless, the modelling presented in this study can help identify areas at risk and initiate prevention. The described findings may also help in the investigation and assessment of related diseases caused by temperature-dependent vectors and pathogens, including those being dangerous for livestock as well, e.g. insect-borne bluetongue disease transmitted by culicoids.

2-imino-thiazolidin-4-one derivatives as potent, orally active S1P1 receptor agonists.

Sphingosine-1-phosphate (S1P) is a widespread lysophospholipid which displays a wealth of biological effects. Extracellular S1P conveys its activity through five specific G-protein coupled receptors numbered S1P(1) through S1P(5). Agonists of the S1P(1) receptor block the egress of T-lymphocytes from thymus and lymphoid organs and hold promise for the oral treatment of autoimmune disorders. Here, we report on the discovery and detailed structure-activity relationships of a novel class of S1P(1) receptor agonists based on the 2-imino-thiazolidin-4-one scaffold. Compound 8bo (ACT-128800) emerged from this series and is a potent, selective, and orally active S1P(1) receptor agonist selected for clinical development. In the rat, maximal reduction of circulating lymphocytes was reached at a dose of 3 mg/kg. The duration of lymphocyte sequestration was dose dependent. At a dose of 100 mg/kg, the effect on lymphocyte counts was fully reversible within less than 36 h. Pharmacokinetic investigation of 8bo in beagle dogs suggests that the compound is suitable for once daily dosing in humans.

Information system for monitoring environmental impacts of genetically modified organisms.

BACKGROUND, AIM AND SCOPE: European legislation stipulates that genetically modified organisms (GMO) have to be monitored to identify potential adverse environmental effects. A wealth of different types of monitoring data from various sources including existing environmental monitoring programmes is expected to accumulate. This requires an information system to efficiently structure, process and evaluate the monitoring data. METHODS: A structure for an Information System for Monitoring GMO (ISMO) was developed by a multidisciplinary research team. It is based on the requirement to organise all relevant information in a logical, readily accessible and functional manner. RESULTS: For the ISMO, we present a combination of three interrelated components: Firstly, an ISMO should comprise a knowledge database structured according to information related to the different scale levels of biological organisation relevant to GMO monitoring and scientific hypotheses on cause-effects which should be validated by monitoring data. Secondly, a monitoring database should be part of an ISMO containing GMO-specific monitoring data and meta-data. This monitoring database should be linked with monitoring data from other monitoring programmes which are relevant for GMO-related questions. Thirdly, an ISMO should encompass a database covering administrative and procedural data. Neither national nor international approaches to an ISMO exist yet. CONCLUSIONS: An ISMO as designed in this paper could support competent authorities in both the GMO notification process and in post-market monitoring. This includes evaluating the environmental risks of experimentally releasing GMO and placing them on the market, assessing monitoring plans and evaluating monitoring results. The ISMO should be implemented on both the national and international level, preferably combining different administrative scales. Harmonisation approaches towards GMO monitoring data are at an initial stage, but they are a precondition to coordinated GMO monitoring and to successfully implementing an ISMO. It is recommended to set up a legal basis and to agree on common strategies for the data coordination and harmonisation.

Solving conical diffraction grating problems with integral equations.

Off-plane scattering of time-harmonic plane waves by a plane diffraction grating with arbitrary conductivity and general surface profile is considered in a rigorous electromagnetic formulation. Integral equations for conical diffraction are obtained involving, besides the boundary integrals of the single and double layer potentials, singular integrals, the tangential derivative of single-layer potentials. We derive an explicit formula for the calculation of the absorption in conical diffraction. Some rules that are expedient for the numerical implementation of the theory are presented. The efficiencies and polarization angles compared with those obtained by Lifeng Li for transmission and reflection gratings are in a good agreement. The code developed and tested is found to be accurate and efficient for solving off-plane diffraction problems including high-conductive gratings, surfaces with edges, real profiles, and gratings working at short wavelengths.