Publications by authors named "Tobias Graf"

56 Publications

A Comprehensive Assessment of All-Oleate Polysorbate 80: Free Fatty Acid Particle Formation, Interfacial Protection and Oxidative Degradation.

Pharm Res 2021 Mar 12;38(3):531-548. Epub 2021 Mar 12.

Pharmaceutical Development, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA.

Purpose: Enzymatic polysorbate (PS) degradation and resulting free fatty acid (FFA) particles are detrimental to biopharmaceutical drug product (DP) stability. Different types and grades of polysorbate have varying propensity to form FFA particles. This work evaluates the homogenous all-oleate (AO) PS80 alongside heterogeneous PS20 and PS80 grades in terms its propensity to form FFA particles and other important attributes like interfacial protection and oxidation susceptibility.

Methods: FFA particle formation rates were compared by degrading PS using non-immobilized hydrolases and fast degrading DP formulations. Interfacial protection of monoclonal antibodies (mAbs) was assessed by agitation studies in saline using non-degraded and degraded PS. Several antioxidants were assessed for their ability to mitigate AO PS80 oxidation and subsequent mAb oxidation by a 40°C placebo stability study and a 2, 2'-Azobis (2-amidinopropane) dihydrochloride stress model, respectively.

Results: Visible and subvisible particles were significantly delayed in AO PS80 formulations compared with heterogeneous PS20 and PS80 formulations. Non-degraded AO PS80 was less protective of mAbs against the air-water interface compared with heterogeneous PS20. Interfacial protection by AO PS80 improved upon degradation owing to high surface activity of FFAs. Diethylenetriaminepentaacetic acid (DTPA) completely mitigated AO PS80 oxidation unlike L-methionine and N-Acetyl-DL-Tryptophan. However, DTPA did not mitigate radical mediated mAb oxidation.

Conclusion: AO PS80 is a promising alternative to reduce FFA particle formation compared with other PS types and grades. However, limitations observed here---such as lower protection against interfacial stresses and higher propensity for oxidation---need to be considered in assessing the risk/benefit ratio in using AO PS80.
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http://dx.doi.org/10.1007/s11095-021-03021-zDOI Listing
March 2021

Short communication: In vitro pilot study: Are monolithic 3Y-TZP zirconia crowns too strong for titanium Implants?

Int J Prosthodont 2021 Mar 3. Epub 2021 Mar 3.

Purpose: To report on pilot tests for a planned study on single implant-supported crowns made from different restorative materials using finite element analysis (FEA) and in vitro load-to-failure testing.

Materials And Methods: Within this pilot study, FEA was conducted using Ansys 2019 R2 to simulate stress and deformation for implant-supported crowns made of lithium disilicate ceramic (LiS2) and zirconia (3Y-TZP). Additionally, an in vitro load to failure test was conducted using two specimens per group to evaluate the failure mode and to confirm the findings from the FEA.

Results/conclusion: FEA revealed stress areas at the palatal cervical areas of the crowns. In the load to failure test, both hybrid abutment crowns made of LiS2 fractured (410 N and 510 N) before plastic deformation of the metal implant components occurred. The monolithic hybrid abutment crowns made of 3Y-TZP did not fracture until tests were interrupted at 646-N and 690-N occlusal force, when plastic deformation of the metal implant components was visually observed.
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http://dx.doi.org/10.11607/ijp.7322DOI Listing
March 2021

Extracorporeal life support in patients with acute myocardial infarction complicated by cardiogenic shock - Design and rationale of the ECLS-SHOCK trial.

Am Heart J 2021 04 8;234:1-11. Epub 2021 Jan 8.

Institut für Herzinfarktforschung, Ludwigshafen, Germany.

Background: In acute myocardial infarction complicated by cardiogenic shock the use of mechanical circulatory support devices remains controversial and data from randomized clinical trials are very limited. Extracorporeal life support (ECLS) - venoarterial extracorporeal membrane oxygenation - provides the strongest hemodynamic support in addition to oxygenation. However, despite increasing use it has not yet been properly investigated in randomized trials. Therefore, a prospective randomized adequately powered clinical trial is warranted.

Study Design: The ECLS-SHOCK trial is a 420-patient controlled, international, multicenter, randomized, open-label trial. It is designed to compare whether treatment with ECLS in addition to early revascularization with percutaneous coronary intervention or alternatively coronary artery bypass grafting and optimal medical treatment is beneficial in comparison to no-ECLS in patients with severe infarct-related cardiogenic shock. Patients will be randomized in a 1:1 fashion to one of the two treatment arms. The primary efficacy endpoint of ECLS-SHOCK is 30-day mortality. Secondary outcome measures such as hemodynamic, laboratory, and clinical parameters will serve as surrogate endpoints for prognosis. Furthermore, a longer follow-up at 6 and 12 months will be performed including quality of life assessment. Safety endpoints include peripheral ischemic vascular complications, bleeding and stroke.

Conclusions: The ECLS-SHOCK trial will address essential questions of efficacy and safety of ECLS in addition to early revascularization in acute myocardial infarction complicated by cardiogenic shock.
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http://dx.doi.org/10.1016/j.ahj.2021.01.002DOI Listing
April 2021

SARS-CoV-2 Infection in Asymptomatic Patients Hospitalized for Cardiac Emergencies: Implications for Patient Management.

Front Cardiovasc Med 2020 18;7:599299. Epub 2020 Dec 18.

Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) e.V., Partner Site Munich Heart Alliance, Munich, Germany.

The coronavirus disease (COVID-19) pandemic imposed diverse challenges on the health care system. Morbidity and mortality of non-COVID-19 emergencies might also have changed because hospitals may not be able to provide optimal care due to restructured resources and uncertainties how to deal with potentially infected patients. It has been recommended to stratify treatment of cardiovascular emergencies according to cardiovascular risk. However, data on the prevalence of asymptomatic SARS-CoV-2 infection in patients presenting with cardiac emergencies remain scarce. We retrospectively analyzed patients' data from a tertiary cardiology department between April 15 and May 31, 2020. All patients were screened on admission for COVID-19 symptoms using a questionnaire and body temperature measurements. All hospitalized patients were routinely screened using nasopharyngeal swab testing. In total, we counted 710 urgent and emergency admissions. Nasopharyngeal swab tests were available in 689 (97%) patients, 409 and 280 of which presented as urgent and emergency admissions, respectively. Among 280 emergency admissions, none tested positive for SARS-CoV-2. In cardiac emergency patients which were screened negative for COVID-19 symptoms, the prevalence of SARS-CoV-2 infection in regions with a modest overall prevalence is low. This finding might be helpful to better determine timing of emergency procedures and reasonable usage of protective equipment during the COVID-19 crisis and the future.
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http://dx.doi.org/10.3389/fcvm.2020.599299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793638PMC
December 2020

Cardiovascular outcome in patients with adrenal insufficiency-a therapeutic dilemma.

Endocrine 2021 Jan 5. Epub 2021 Jan 5.

University of Luebeck, Luebeck, Germany.

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http://dx.doi.org/10.1007/s12020-020-02571-3DOI Listing
January 2021

Hemocompatibility of new magnetically-levitated centrifugal pump technology compared to the CentriMag adult pump.

Sci Rep 2020 12 16;10(1):22055. Epub 2020 Dec 16.

Department of Thoracic and Cardiovascular Surgery, University Medical Center Tuebingen, Hoppe-Seyler Str. 3, 72076, Tübingen, Germany.

The specific hemocompatibility properties of mechanical-circulatory-support (MCS)-pump technologies have not previously been described in a comparable manner. We thus investigated the hemocompatibility-indicating marker of a new magnetically-levitated (MagLev) centrifugal pump (MT-Mag) in a human, whole-blood mock-loop for 360 min using the MCS devices as a driving component. We compared those results with the CentriMag adult (C-Mag) device under the same conditions according to ISO10993-4. Blood samples were analyzed via enzyme-linked-immunosorbent-assay (ELISA) for markers of coagulation, complement system, and the inflammatory response. The time-dependent activation of the coagulation system was measured by detecting thrombin-anti-thrombin complexes (TAT). The activation of the complement system was determined by increased SC5b-9 levels in both groups. A significant activation of neutrophils (PMN-elastase) was detected within the C-Mag group, but not in the MT-Mag group. However, the amount of PMN-elastase at 360 min did not differ significantly between groups. The activation of the complement and coagulation system was found to be significantly time-dependent in both devices. However, coagulation activation as determined by the TAT level was lower in the MT-Mag group than in the C-Mag group. This slight disparity could have been achieved by the optimized secondary flow paths and surface coating, which reduces the interaction of the surface with blood.
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http://dx.doi.org/10.1038/s41598-020-78709-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744571PMC
December 2020

Questioning coverage values determined by 2D western blots: A critical study on the characterization of anti-HCP ELISA reagents.

Biotechnol Bioeng 2021 Mar 4;118(3):1116-1126. Epub 2020 Dec 4.

Roche Diagnostics GmbH, Penzberg, Germany.

Host cell proteins (HCPs) constitute a major class of process-related impurities, whose substantial clearance must be demonstrated by suitable analytical methods to warrant product quality and reduce potential safety risks for patients. In this regard, enzyme linked immunosorbent assays (ELISAs), which primarily rely on the quality of the HCP reference standard (immunogen) and HCP-specific polyclonal antibodies, are considered the gold standard for HCP monitoring. For the qualification of the employed antibodies, two-dimensional (2D) western blots (2D-WBs) are the preferred technique to determine the coverage, though a number of practical constraints are well recognized. By using several orthogonal approaches, such as affinity-based mass spectrometry and indirect ELISA, the present study revealed potential detection gaps (i.e., noncovered HCPs) of conventional 2D-WBs, which can be primarily attributed to two different root causes: (i) low amounts of proteins or antibodies being unable to overcome the detection limit and (ii) western blot artifacts due to the loss of conformational epitopes through protein denaturation hindering HCP-antibody recognition. In contrast, the lack of specific antibodies against certain (particularly, low molecular weight) HCPs, as proposed in previous studies, seems to play only a minor role. Together, these findings imply that CHO-HCP ELISA antibodies are better than qualification studies by 2D-WBs indicate.
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http://dx.doi.org/10.1002/bit.27635DOI Listing
March 2021

Left Ventricular Unloading Is Associated With Lower Mortality in Patients With Cardiogenic Shock Treated With Venoarterial Extracorporeal Membrane Oxygenation: Results From an International, Multicenter Cohort Study.

Circulation 2020 Dec 9;142(22):2095-2106. Epub 2020 Oct 9.

German Center for Cardiovascular Research (DZHK), partner site Hamburg/Lübeck/Kiel, Germany (B.S., P.M.B., A.B., S. Blankenberg, S.D., M.E., I.E., D.F., N.F., T.G., P.K., C.N., D.W.).

Background: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used to treat cardiogenic shock. However, VA-ECMO might hamper myocardial recovery. The Impella unloads the left ventricle. This study aimed to evaluate whether left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO was associated with lower mortality.

Methods: Data from 686 consecutive patients with cardiogenic shock treated with VA-ECMO with or without left ventricular unloading using an Impella at 16 tertiary care centers in 4 countries were collected. The association between left ventricular unloading and 30-day mortality was assessed by Cox regression models in a 1:1 propensity score-matched cohort.

Results: Left ventricular unloading was used in 337 of the 686 patients (49%). After matching, 255 patients with left ventricular unloading were compared with 255 patients without left ventricular unloading. In the matched cohort, left ventricular unloading was associated with lower 30-day mortality (hazard ratio, 0.79 [95% CI, 0.63-0.98]; =0.03) without differences in various subgroups. Complications occurred more frequently in patients with left ventricular unloading: severe bleeding in 98 (38.4%) versus 45 (17.9%), access site-related ischemia in 55 (21.6%) versus 31 (12.3%), abdominal compartment in 23 (9.4%) versus 9 (3.7%), and renal replacement therapy in 148 (58.5%) versus 99 (39.1%).

Conclusions: In this international, multicenter cohort study, left ventricular unloading was associated with lower mortality in patients with cardiogenic shock treated with VA-ECMO, despite higher complication rates. These findings support use of left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO and call for further validation, ideally in a randomized, controlled trial.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688081PMC
December 2020

Simultaneous quantification of polysorbate 20 and poloxamer 188 in biopharmaceutical formulations using evaporative light scattering detection.

J Pharm Biomed Anal 2021 Jan 16;192:113640. Epub 2020 Sep 16.

F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070, Basel, Switzerland. Electronic address:

Polysorbates and Poloxamer 188 constitute the most common surfactants used in biopharmaceutical formulations owing to their excellent protein-stabilizing properties and good safety profiles. In recent years, however, a vast number of reports concerning potential risk factors closely related with their applications, such as the accumulation of degradation products, their inherent heterogeneity and adsorption effects of proteins at silicon/oil interfaces have drawn the focus to potential alternatives. Apart from tedious efforts to evaluate new excipient candidates, the use of mixed formulations leveraging combinations of well-established surfactants appears to be a promising approach to eliminate or, at least, minimize and postpone adverse effects associated with the single compounds. Due to the similar molecular properties of non-ionic surfactants, however, baseline separation of these mixtures, which is mandatory for their reliable quantification, poses a great challenge to analytical scientists. For this purpose, the present work describes the development of a robust mixed-mode liquid chromatography method coupled to evaporative light scattering detection (mixed-mode LC-ELSD) for simultaneous determination of the (intact) Polysorbate 20 and Poloxamer 188 content in biopharmaceutical formulations containing monoclonal antibodies. Extensive qualification and validation studies, comprising the evaluation of method specificity, robustness, linearity, accuracy and precision according to ICH guidelines, demonstrated its suitability for quality control studies. A case study on the storage stability of a formulated antibody was conducted to underline the method's practical utility. Finally, the versatility of the developed approach was successfully tested by quantifying Polysorbate 20-related surfactants, such as Polysorbate 80 and super-refined Polysorbate.
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http://dx.doi.org/10.1016/j.jpba.2020.113640DOI Listing
January 2021

Infection.

N Engl J Med 2020 09;383(12):1167

University Heart Center Lübeck, Lübeck, Germany.

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http://dx.doi.org/10.1056/NEJMicm1916407DOI Listing
September 2020

Therapy limitation in octogenarians in German intensive care units is associated with a longer length of stay and increased 30 days mortality: A prospective multicenter study.

J Crit Care 2020 12 1;60:58-63. Epub 2020 Aug 1.

Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Hospital Düsseldorf, Germany. Electronic address:

Purpose: The approach to limit therapy in very old intensive care unit patients (VIPs) significantly differs between regions. The focus of this multicenter analysis is to illuminate, whether the Clinical Frailty Scale (CFS) is a suitable tool for risk stratification in VIPs admitted to intensive care units (ICUs) in Germany. Furthermore, this investigation elucidates the impact of therapeutic limitation on the length of stay and mortality in this setting.

Methods: German cohorts' data from two multinational studies (VIP-1, VIP-2) were combined. Univariate and multivariate logistic regression were used to evaluate associations with mortality.

Results: 415 acute VIPs were included. Frail VIPs (CFS > 4) were older (85 [IQR 82-88] vs. 83 [IQR 81-86] years p < .001) and suffered from an increased 30-day-mortality (43.4% versus 23.9%, p < .0001). CFS was an independent predictor of 30-day-mortality in a multivariate logistic regression model (aOR 1.23 95%CI 1.04-1.46 p = .02). Patients with any limitation of life-sustaining therapy had a significantly increased 30-day mortality (86% versus 16%, p < .001) and length of stay (144 [IQR 72-293] versus 96 [IQR 47.25-231.5] hours, p = .026).

Conclusion: In German ICUs, any limitation of life-sustaining therapy in VIPs is associated with a significantly increased ICU length of stay and mortality. CFS reliably predicts the outcome.
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http://dx.doi.org/10.1016/j.jcrc.2020.07.024DOI Listing
December 2020

Extracorporeal life support system during cardiovascular procedures: Insights from the German Lifebridge registry.

Artif Organs 2020 Dec 25;44(12):1259-1266. Epub 2020 Jul 25.

Department of Medicine, Division of Cardiology, Pulmonary Diseases and Vascular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.

The frequency of mechanical circulatory support (MCS) device application has increased in recent years. Besides implantation in the emergency setting, such as circulatory arrest, MCS is also increasingly used electively to ensure hemodynamic stability in high-risk patients, for example, during percutaneous coronary interventions (PCI), valve interventions or off-pump coronary bypass surgery. Lifebridge (Zoll Medical GmbH, Germany) is a compact percutaneous MCS device widely used in daily clinical routine. The present study aimed to investigate the indications, feasibility, and outcomes after use of Lifebridge in cardiac interventions, evaluating a large-scale multicenter database. A total of 60 tertiary cardiovascular centers were questioned regarding application and short-term outcomes after the use of the Lifebridge system (n = 160 patients). Out of these 60 centers, eight consented to participate in the study (n = 39 patients), where detailed data were collected using standardized questionnaires. Demographic and clinical characteristics of the patient population, procedural as well as follow-up data were recorded and analyzed. In 60 interrogated centers, Lifebridge was used in 74% of emergency cases and 26% in the setting of planned interventions. The subcohort interrogated in detail displayed the same distribution of application scenarios, while the main cardiovascular procedure was high-risk PCI (82%). All patients were successfully weaned from the device and 92% (n = 36) of the patients studied in detail survived after 30 days. As assessed 30 days after insertion of the device, bleeding requiring red blood cell (RBC) transfusion constituted the main complication, occurring in 49% of cases. In our analysis of clinical data, the use of Lifebridge in cardiac intervention was shown to be feasible. Further prospective studies are warranted to identify patients who benefit from hemodynamic MCS support despite the increased rate of RBC transfusion due to challenges in access sites during cardiovascular procedures.
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http://dx.doi.org/10.1111/aor.13760DOI Listing
December 2020

Controlled polysorbate 20 hydrolysis - A new approach to assess the impact of polysorbate 20 degradation on biopharmaceutical product quality in shortened time.

Eur J Pharm Biopharm 2020 Jul 20;152:318-326. Epub 2020 May 20.

Pharma Technical Development Analytics, Roche Diagnostics GmbH, Nonnenwald 2, Penzberg 82377, Germany. Electronic address:

Hydrolysis of polysorbate in biopharmaceutical liquid formulations upon long-term storage represents a risk factor, since reduction of the intact surfactant concentration may compromise protein stability. Moreover, accumulation of polysorbate degradation products is associated with the formation of particulates potentially affecting drug product stability and quality. These effects are conventionally assessed by real-time end-of-shelf life studies constituting an integral yet lengthy process of formulation development. To accelerate this procedure, we describe here a powerful tool to conduct shake stress studies based on the controlled hydrolysis of polysorbate 20 by beads-immobilized lipases. For this purpose, the production of stable, partially degraded material characterized by a representative presence of non-emulsifying degradants such as ethoxylated sorbitan and free fatty acids was monitored by state-of-the-art chromatographic methods ensuring realistic pharmaceutical conditions. Freeze-thaw, shaking and shipping stress studies of a mAb formulation did not only demonstrate that this approach is useful to determine the critical degradation level impairing drug product quality, but furthermore revealed significant differences in protective effects depending on the hydrolysis pattern. As these results emphasize, the outlined strategy may support formulation scientists to unveil the interrelationship between polysorbate hydrolysis products and stabilization of the active pharmaceutical ingredient in a holistic and time-saving manner.
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http://dx.doi.org/10.1016/j.ejpb.2020.05.017DOI Listing
July 2020

The Use of Extracorporeal Life Support in a Patient Suffering from Venlafaxine Intoxication. A Case Report.

J Crit Care Med (Targu Mures) 2020 Apr 6;6(2):120-123. Epub 2020 May 6.

Department of Cardiology, Angiology and Intensive Care, Medicine Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany.

Very few reports exist on serious cardiac complications associated with intake of serotonin-noradrenaline reuptake inhibitors. This paper describes and discusses the case of a patient who ingested a dose of 17.5 g venlafaxine. She developed a full serotonergic syndrome leading to multi-organ failure, including refractory cardiovascular shock, which was managed by early implantation of an extracorporeal life support (ECLS) system as a bridging strategy. This intervention was successful and resulted in full recovery of the patient.
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http://dx.doi.org/10.2478/jccm-2020-0014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216027PMC
April 2020

Monitoring modifications in biopharmaceuticals: Toolbox for a generic and robust high-throughput quantification method.

J Chromatogr B Analyt Technol Biomed Life Sci 2020 May 11;1148:122134. Epub 2020 May 11.

F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland. Electronic address:

Monoclonal antibodies (mAbs) constitute one of the most important and fastest growing sector within the pharmaceutical industry. The variety of different formats and the large molecule sizes of the mAbs result in an inherent complexity. In addition, the posttranslational modifications (PTMs) that can occur during production, formulation and storage pose a major analytical challenge for their characterization. These PTMs may affect the safety, efficacy and/or pharmacokinetic profile of the medicinal product. Therefore, strict quality and stability monitoring, in particular of (potentially) critical quality attributes (CQAs), is mandatory. Focusing on these needs, a toolbox for different approaches of peptide mapping in the routine quality control (QC) environment was developed. This toolbox includes an automated sample preparation with an optimized buffer system in combination with a Single Quad LC-MS system, which provides the flexibility to handle a high-throughput workflow. Our results demonstrate that a Single Quad LC-MS system is suitable for a routine work environment to monitor modifications by using a user-friendly system.
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http://dx.doi.org/10.1016/j.jchromb.2020.122134DOI Listing
May 2020

Recent advances in LC-MS based characterization of protein-based bio-therapeutics - mastering analytical challenges posed by the increasing format complexity.

J Pharm Biomed Anal 2020 Jul 10;186:113251. Epub 2020 Mar 10.

Roche Diagnostics GmbH, Nonnenwald 2, 82377 Penzberg, Germany. Electronic address:

Alongside the success of protein-based bio-therapeutics over the last decades and facilitated by advances both in protein engineering and manufacturing, new product formats progressively enter into the biopharmaceutical industry's pipelines with major implications on the analytical methods used for their characterization. While conventional approaches have proved sufficient for standard (IgG-like) molecules, the increased complexity of novel formats requires proper adjustments of the employed methodologies, in particular with regard to separation-based techniques coupled to UV/FLD detection. After introducing the status quo for the characterization of biopharmaceuticals in quality control settings, this review provides a comprehensive portrayal of emerging LC-MS based technologies, which have already demonstrated their potential to complement the existing analytical toolbox. In this context, the benefits of native LC-MS and two-/multidimensional LC-MS applications to assess product attributes while preserving the higher-order structure are discussed based on challenges arising from the analysis of complex product formats.
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http://dx.doi.org/10.1016/j.jpba.2020.113251DOI Listing
July 2020

Clinical Nutrition in Critical Care Medicine - Guideline of the German Society for Nutritional Medicine (DGEM).

Clin Nutr ESPEN 2019 10 9;33:220-275. Epub 2019 Jul 9.

Department for Nutritional Medicine, University of Hohenheim, Fruwirthstr. 12, 70599, Stuttgart, Germany. Electronic address:

Purpose: Enteral and parenteral nutrition of adult critically ill patients varies in terms of the route of nutrient delivery, the amount and composition of macro- and micronutrients, and the choice of specific, immune-modulating substrates. Variations of clinical nutrition may affect clinical outcomes. The present guideline provides clinicians with updated consensus-based recommendations for clinical nutrition in adult critically ill patients who suffer from at least one acute organ dysfunction requiring specific drug therapy and/or a mechanical support device (e.g., mechanical ventilation) to maintain organ function.

Methods: The former guidelines of the German Society for Nutritional Medicine (DGEM) were updated according to the current instructions of the Association of the Scientific Medical Societies in Germany (AWMF) valid for a S2k-guideline. According to the S2k-guideline classification, no systematic review of the available evidence was required to make recommendations, which, therefore, do not state evidence- or recommendation grades. Nevertheless, we considered and commented the evidence from randomized-controlled trials, meta-analyses and observational studies with adequate sample size and high methodological quality (until May 2018) as well as from currently valid guidelines of other societies. The liability of each recommendation was described linguistically. Each recommendation was finally validated and consented through a Delphi process.

Results: In the introduction the guideline describes a) the pathophysiological consequences of critical illness possibly affecting metabolism and nutrition of critically ill patients, b) potential definitions for different disease phases during the course of illness, and c) methodological shortcomings of clinical trials on nutrition. Then, we make 69 consented recommendations for essential, practice-relevant elements of clinical nutrition in critically ill patients. Among others, recommendations include the assessment of nutrition status, the indication for clinical nutrition, the timing and route of nutrient delivery, and the amount and composition of substrates (macro- and micronutrients); furthermore, we discuss distinctive aspects of nutrition therapy in obese critically ill patients and those treated with extracorporeal support devices.

Conclusion: The current guideline provides clinicians with up-to-date recommendations for enteral and parenteral nutrition of adult critically ill patients who suffer from at least one acute organ dysfunction requiring specific drug therapy and/or a mechanical support device (e.g., mechanical ventilation) to maintain organ function. The period of validity of the guideline is approximately fixed at five years (2018-2023).
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http://dx.doi.org/10.1016/j.clnesp.2019.05.002DOI Listing
October 2019

Platelets and Immune Responses During Thromboinflammation.

Front Immunol 2019 26;10:1731. Epub 2019 Jul 26.

University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany.

Besides mediating hemostatic functions, platelets are increasingly recognized as important players of inflammation. Data from experiments in mice and men revealed various intersection points between thrombosis, hemostasis, and inflammation, which are addressed and discussed in this review in detail. One such example is the intrinsic coagulation cascade that is initiated after platelet activation thereby further propagating and re-enforcing wound healing or thrombus formation but also contributing to the pathophysiology of severe diseases. FXII of the intrinsic pathway connects platelet activation with the coagulation cascade during immune reactions. It can activate the contact system thereby either creating an inflammatory state or accelerating inflammation. Recent insights into platelet biology could show that platelets are equipped with complement receptors. Platelets are important for tissue remodeling after injury has been inflicted to the endothelial barrier and to the subendothelial tissue. Thus, platelets are increasingly recognized as more than just cells relevant for bleeding arrest. Future insights into platelet biology are to be expected. This research will potentially offer novel opportunities for therapeutic intervention in diseases featuring platelet abundance.
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http://dx.doi.org/10.3389/fimmu.2019.01731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676797PMC
October 2020

Efficacy and Safety of Cryoballoon Ablation in Patients With Heart Failure and Reduced Left Ventricular Ejection Fraction - A Multicenter Study.

Circ J 2019 07 28;83(8):1653-1659. Epub 2019 Jun 28.

University Heart Center Luebeck, Medical Clinic II (Department of Cardiology, Angiology and Intensive Care Medicine), Sektion Elektropjysiologie, University Hospital Schleswig-Holstein.

Background: Second-generation cryoballoon (CB2)-based pulmonary vein isolation (PVI) has demonstrated encouraging results in the treatment of atrial fibrillation (AF). This study sought to assess data on the safety, efficacy and clinical success of CB2-based PVI in patients with heart failure (HF) and reduced ejection fraction (HFrEF).Methods and Results:CB2-based PVI was performed in 551 consecutive patients in 3 highly experienced EP centers. Patients with HF and LVEF ≤40% were included (HFrEF group, n=50/551, 9.1%). Data were compared with propensity score-matched patients without HF and preserved left ventricular EF (LVEF) (n=50, control group). The median LVEF was HFrEF: 37% (35, 40) and control: 55% (55, 55), P<0.0001. Major periprocedural complications were registered in 4/50 (8%, HFrEF group) and 3/50 (6%, control group), P=0.695. The 12-month freedom from AF recurrence was 73.1% (95% confidence interval (CI): 61-88, HFrEF group) and 72.6% (95% CI: 61-87, control group), P=0.25. NYHA class decreased from 2.4±0.8 (baseline) to 1.7±0.8 at 12-month follow-up (P<0.0001). LVEF improved from a median of 37% (35, 40) prior to ablation to a median of 55% (40, 55), P<0.0001.

Conclusions: CB2-based PVI in patients with HFrEF appeared to be safe, was associated with comparable periprocedural complications and showed promising clinical success rates equal to those for patients with preserved LVEF. NYHA class and LVEF significantly improved at 12-month follow-up.
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http://dx.doi.org/10.1253/circj.CJ-19-0151DOI Listing
July 2019

Inflammatory and Molecular Pathways in Heart Failure-Ischemia, HFpEF and Transthyretin Cardiac Amyloidosis.

Int J Mol Sci 2019 May 10;20(9). Epub 2019 May 10.

Department of Cardiology, Angiology and Intensive Care, Medicine Medical Clinic II, University Heart Center Lübeck, 23562 Lübeck, Germany.

Elevated pro-inflammatory biomarkers and cytokines are associated with morbidity and mortality in heart failure (HF). Preclinical and clinical studies have shown multiple inflammatory mechanisms causing cardiac remodeling, dysfunction and chronic failure. Therapeutics in trials targeting the immune response in heart failure and its effects did not result in evident benefits regarding clinical endpoints and mortality. This review elaborates pathways of immune cytokines in pathogenesis and worsening of heart failure in clinical and cellular settings. Besides the well-known mechanisms of immune activation and inflammation in atherosclerosis causing ischemic cardiomyopathy or myocarditis, attention is focused on other mechanisms leading to heart failure such as transthyretin (TTR) amyloidosis or heart failure with preserved ejection fraction. The knowledge of the pathogenesis in heart failure and amyloidosis on a molecular and cellular level might help to highlight new disease defining biomarkers and to lead the way to new therapeutic targets.
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http://dx.doi.org/10.3390/ijms20092322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540104PMC
May 2019

Safety and efficacy of endovascular ultrasound renal denervation in resistant hypertension: 12-month results from the ACHIEVE study.

J Hypertens 2019 09;37(9):1906-1912

Cardiology and Angiology II, University Heart Center Freiburg-Bad Krozingen, Bad Krozingen, Germany.

Objectives: First-generation radiofrequency renal denervation devices may have had limited efficacy due to incomplete circumferential ablation and dependence on individual operator technique. This study evaluated a next-generation catheter-based technology using ultrasound designed to maximize nerve coverage using circumferential ultrasound energy.

Methods: This was a prospective, multicenter, nonrandomized, postmarket study evaluating the safety and efficacy of an endovascular ultrasound renal denervation system (Paradise) in patients who met the European Society of Hypertension/European Society of Cardiology definition of resistant hypertension. Major exclusion criteria included renal artery stenosis and renal insufficiency. Patients were followed for 12 months. Safety and efficacy endpoints included procedural safety and renal artery patency, as well as changes in systolic office and 24-h ambulatory bllod pressure (BP) measurement.

Results: A total of 96 patients from eight European sites were included. Mean age was 63.9 years and 41% of patients were female. At baseline, mean 24-h ambulatory BP was 156.2/88.4 ± 15.4/12.7 mmHg, and mean office BP was 176.2/95.0 ± 20.6/16.0 mmHg. Patients were on average on 5.1 ± 2.5 antihypertensive agents. At 12 months, the average 24-h ambulatory BP change was -7.5/-3.8 ± 18.3/10.6 mmHg (P = 0.0007; P = 0.0024) with an average office BP change of -15.0/-7.0 ± 27.0/12.3 mmHg (P < 0.0001 for both). At 12 months, there was a single patient death unrelated to the device or procedure.

Conclusion: This single-arm study represents the largest cohort of patients treated with endovascular ultrasound renal denervation to date. Within this trial, the therapy appeared safe and resulted in sustained reductions in both office BP and 24-h ambulatory BP through 12 months.
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http://dx.doi.org/10.1097/HJH.0000000000002120DOI Listing
September 2019

Real-world clinical experience with the percutaneous extracorporeal life support system: Results from the German Lifebridge Registry.

Clin Res Cardiol 2020 Jan 26;109(1):46-53. Epub 2019 Apr 26.

Division of Cardiology, Pulmonary Diseases and Vascular Medicine, Department of Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.

Background: The concept of percutaneous extracorporeal life support (ECLS) is based on immediate cardiovascular stabilization allowing for sufficient end-organ perfusion, thus improving the outcome in patients with circulatory arrest. Lifebridge (Zoll Medical GmbH, Germany) is a portable ECLS device designed for rapid application due to its automated set-up.

Methods: A total of 60 tertiary cardiovascular centers were interrogated with regard to application and short-term results after use of Lifebridge ECLS system. Detailed data were collected by standardized case report forms in all centers consented to participate in the study. Demographic and clinical baseline characteristics of the patient population, procedural and follow-up data were recorded and analyzed.

Results: In total, 444 patients were analyzed regarding mortality. The detailed study cohort consisted of 112 patients. A total of 80% of the study subjects represented patients post cardiopulmonary resuscitation, 43% were in cardiogenic shock and 50% suffered from acute myocardial infarction. The survival rates were 36% immediately after device implementation and 16% after 30 days. Multivariable analysis revealed that only serum lactate concentration at admission could be proven as independent predictor of patients' outcome. Patients with lactate concentrations above 10 mmol/L exhibited > 95% mortality (p < 0.05 versus below 10 mmol/L).

Conclusion: The present study provides real-world clinical data of patients treated with a transportable automated ECLS system. In conclusion, Lifebridge is a safely applicable cardiorespiratory stabilization tool associated with acceptable complication rates. Nevertheless, mortality rates were high in these critically ill patients, especially in those showing high lactate concentrations at admission.
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http://dx.doi.org/10.1007/s00392-019-01482-2DOI Listing
January 2020

Monitoring polysorbate hydrolysis in biopharmaceuticals using a QC-ready free fatty acid quantification method.

J Chromatogr B Analyt Technol Biomed Life Sci 2019 May 26;1116:1-8. Epub 2019 Mar 26.

F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland. Electronic address:

Hydrolysis of the non-ionic surfactant polysorbate upon long-term storage poses significant challenges to development of biopharmaceutical liquid formulations. Low concentrations of intact surfactant may compromise its protective properties and thus affect protein stability. In addition, accumulation of polysorbate hydrolysis products is increasingly put into context with the formation of visible and subvisible particulates based on the low solubility of the main degradation products. Despite of this potential negative impact on product quality, quantification of the released free fatty acids is performed commonly in an indirect and consequently insensitive manner by determining the remaining PS content or by cumbersome methods, which are unsuitable for routine testing in quality control laboratories. For this purpose, this study describes the development and qualification of a label-free, reliable liquid-chromatography single quad mass detector (LC-QDa)-based method capable of resolving slight changes in the free fatty acid profile which can be readily integrated into quality control facilities. The practical utility of the herein described method is outlined by a case study on the real-time storage stability of a formulated monoclonal antibody.
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http://dx.doi.org/10.1016/j.jchromb.2019.03.030DOI Listing
May 2019

[ECG signs of acute coronary syndrome].

Herzschrittmacherther Elektrophysiol 2019 Mar 1;30(1):89-101. Epub 2019 Mar 1.

Medizinische Klinik II/Kardiologie, Angiologie und Intensivmedizin, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Deutschland.

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http://dx.doi.org/10.1007/s00399-019-0613-3DOI Listing
March 2019

Immediate unselected coronary angiography versus delayed triage in survivors of out-of-hospital cardiac arrest without ST-segment elevation: Design and rationale of the TOMAHAWK trial.

Am Heart J 2019 03 11;209:20-28. Epub 2018 Dec 11.

Herzzentrum Leipzig-Universitätsklinik für Kardiologie, Leipzig, Germany.

Patients experiencing out-of-hospital cardiac arrest (OHCA) without ST-segment elevation are a heterogenic group with a variety of underlying causes. Up to one-third of patients display a significant coronary lesion compatible with myocardial infarction as OHCA trigger. There are no randomized data on patient selection and timing of invasive coronary angiography after admission. METHODS AND RESULTS: The TOMAHAWK trial randomly assigns 558 patients with return of spontaneous circulation after OHCA with no obvious extracardiac origin of cardiac arrest and no ST-segment elevation/left bundle-branch block on postresuscitation electrocardiogram to either immediate coronary angiography or initial intensive care assessment with delayed/selective angiography in a 1:1 ratio. The primary end point is 30-day all-cause mortality. Secondary analyses will be performed with respect to initial rhythm, electrocardiographic patterns, myocardial infarction as underlying cause, neurological outcome, as well as clinical and laboratory markers. Clinical follow-up will be performed at 6 and 12 months. Safety end points include bleeding and stroke. CONCLUSION: The TOMAHAWK trial will address the unresolved issue of timing and general indication of angiography after OHCA without ST-segment elevation.
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http://dx.doi.org/10.1016/j.ahj.2018.12.005DOI Listing
March 2019

[DGEM Guideline "Clinical Nutrition in Critical Care Medicine" - short version].

Anasthesiol Intensivmed Notfallmed Schmerzther 2019 Jan 8;54(1):63-73. Epub 2019 Jan 8.

Purpose: Variations of clinical nutrition may affect outcome of critically ill patients. Here we present the short version of the updated consenus-based guideline (S2k classification) "Clinical nutrition in critical care medicine" of the German Society for Nutritional Medicine (DGEM) in cooperation with 7 other national societies. The target population of the guideline was defined as critically ill adult patients who suffer from at least one acute organ dysfunction requiring specific drug therapy and/or a mechanical support device (e.g. mechanical ventilation) to maintain organ function.

Methods: The former guidelines of the German Society for Nutritional Medicine (DGEM) were updated according to the current instructions of the Association of the Scientific Medical Societies in Germany (AWMF) valid for a S2k-guideline. We considered and commented the evidence from randomized-controlled trials, meta-analyses and observational studies with adequate sample size and high methodological quality (until May 2018) as well as from currently valid guidelines of international societies. The liability of each recommendation was indicated using linguistic terms. Each recommendation was finally validated and consented by a Delphi process.

Results: The short version presents a summary of all 69 consented recommendations for essential, practice-relevant elements of clinical nutrition in the target population. A specific focus is the adjustment of nutrition according to the phases of critical illness, and to the individual tolerance to exogenous substrates. Among others, recommendations include the assessment of nutritional status, the indication for clinical nutrition, the timing, route, magnitude and composition of nutrition (macro- and micronutrients) as well as distinctive aspects of nutrition therapy in obese critically ill patients and those with extracorporeal support devices.

Conclusion: The current short version of the guideline provides a concise summary of the updated recommendations for enteral and parenteral nutrition of adult critically ill patients who suffer from at least one acute organ dysfunction requiring pharmacological and/or mechanical support. The validity of the guideline is approximately fixed at five years (2018 - 2023).
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http://dx.doi.org/10.1055/a-0805-4118DOI Listing
January 2019

After standard dosage of piperacillin plasma concentrations of drug are subtherapeutic in burn patients.

Naunyn Schmiedebergs Arch Pharmacol 2019 02 27;392(2):229-241. Epub 2018 Oct 27.

Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.

Infections are a major problem in patients with burn diseases. Mortality is high despite antibiotic therapy as studies are controversial concerning drug underdosing. The aims of this prospective, observational study were to monitor plasma concentrations of piperacillin during standard piperacillin/tazobactam treatment in 20 burn patients and 16 controls from the intensive care unit (ICU) and to optimize doses by in silico analyses. Piperacillin/tazobactam (4/0.5 g, tid) was administered over 0.5 h. Blood samples were taken at 1, 4, and 7.5 h after the end of the infusion. Free piperacillin plasma concentrations were determined. Pharmacokinetic parameters and in silico analysis results were calculated using the freeware TDMx. The primary target was defined as percentage of the day (fT; fT) when piperacillin concentrations exceeded 1xMIC/4xMIC (minimum inhibitory concentration), considering a MIC breakpoint of 16 mg/L for Pseudomonas aeruginosa. In an off-label approach, two burn patients were treated with 8/1 g piperacillin/tazobactam, 3 h qid. fT (55 ± 22% vs. 77 ± 24%) and fT (17 ± 11% vs. 30 ± 11%) were lower in burn than in ICU patients after 4/0.5 g, 0.5 h, tid. In silico analyses indicated that fT (93 ± 12% burn, 97 ± 4% ICU) and fT (62 ± 23% burn, 84 ± 19% ICU) values increase by raising the piperacillin dosage to 8/1 g qid and prolonging the infusion time to 3 h. Off-label treatment results were similar to in silico data for burn patients (84%fT and 47%fT). Standard dosage regimens for piperacillin/tazobactam resulted in subtherapeutic piperacillin concentrations in burn and ICU patients. Dose adjustments via in silico analyses can help to optimize antibiotic therapy and to predict respective concentrations in vivo. Trial registration: NCT03335137, registered 07.11.2017, retrospectively.
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http://dx.doi.org/10.1007/s00210-018-1573-6DOI Listing
February 2019