Publications by authors named "Martin Schulz"

170 Publications

Utilization of drugs with reports on potential efficacy or harm on COVID-19 before, during, and after the first pandemic wave.

Pharmacoepidemiol Drug Saf 2021 Jul 9. Epub 2021 Jul 9.

German Institute for Drug Use Evaluation (DAPI), Berlin, Germany.

Purpose: Conflicting information on potential benefits of drugs as well as reports on hypothetical harm of commonly used drugs in COVID-19 treatment have challenged clinicians and healthcare systems. We analyzed the change in ambulatory drug utilization before, during, and after the first wave of the pandemic in 2020.

Methods: We explored dispensing data of nearly 19 000 pharmacies at the expense of the statutory health insurance funds covering 88% of Germany's population. We analyzed utilization of publicly discussed drugs with conflicting information. Drug utilization as number of packages dispensed per week from January to June 2020, reflecting 314 million claims, was compared with 2019.

Results: Utilization of hydroxychloroquine increased +110% during March 2020 and then slightly decreased until week April 13-19. Renin-angiotensin-aldosterone system inhibitors and simvastatin/atorvastatin increased, +78% and +74%, respectively, and subsequently decreased below 2019 levels. Utilization of azithromycin and all systemic antibiotics decreased continuously from March 2-8 until June to levels considerably lower compared to 2019 (June 22-28: azithromycin: -55%, all systemic antibiotics: -27%). Pneumococcal vaccines utilization initially increased +373%, followed by supply shortages. Paracetamol utilization showed an initial increase of +111%, mainly caused by an increase of over-the-counter dispensings.

Conclusions: Apart from the pandemic itself, the data suggest that dissemination of misinformation and unsound speculations as well as supply shortages influenced drug prescribing, utilization, and purchasing behavior. The findings can inform post-pandemic policy to prevent unfounded over- and underprescribing and off-label use as well as drug shortages during a public health crisis.
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http://dx.doi.org/10.1002/pds.5324DOI Listing
July 2021

The evidence for pharmacist care in outpatients with heart failure: a systematic review and meta-analysis.

ESC Heart Fail 2021 Jul 8. Epub 2021 Jul 8.

Department of Medicine, ABDA - Federal Union of German Associations of Pharmacists, Berlin, Germany.

Aims: Patients with heart failure (HF) have poor outcomes, including poor quality of life, and high morbidity and mortality. In addition, they have a high medication burden due to the multiple drug therapies now recommended by guidelines. Previous reviews, including studies in hospital settings, provided evidence that pharmacist care improves outcomes in patients with HF. Because most HF is managed outside of hospitals, we aimed to synthesize the evidence for pharmacist care in outpatients with HF.

Methods And Results: We conducted a systematic literature search in PubMed of randomized controlled trials (RCTs) and integrated the evidence on patient outcomes in a meta-analysis. We found 24 RCTs performed in 10 countries, including 8029 patients. The data revealed consistent improvements in medication adherence (independent of the measuring instrument) and knowledge, physical function, and disease and medication management. Sixteen RCTs were included in meta-analyses. Differences in all-cause mortality (odds ratio (OR) = 0.97 [95% CI, 0.84-1.12], Q-statistic, P = 0.49, I  = 0%), all-cause hospitalizations (OR = 0.86 [0.73-1.03], Q-statistic, P = 0.01, I  = 45.5%), and HF hospitalizations (OR = 0.89 [0.77-1.02], Q-statistic, P = 0.11, I  = 0%) were not statistically significant. We also observed an improvement in the standardized mean difference for generic quality of life of 0.75 ([0.49-1.01], P < 0.01), with no indication of heterogeneity (Q-statistic, P = 0.64; I  = 0%).

Conclusions: Results indicate that pharmacist care improves medication adherence and knowledge, symptom control, and some measures of quality of life in outpatients with HF. Given the increasing complexity of guideline-directed medical therapy, pharmacists' unique focus on medication management, titration, adherence, and patient teaching should be considered part of the management strategy for these vulnerable patients.
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http://dx.doi.org/10.1002/ehf2.13508DOI Listing
July 2021

Reply to: Gene therapy to cure haemophilia: Is robust scientific inquiry the missing factor?

Haemophilia 2021 Jun 22. Epub 2021 Jun 22.

Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, South Yorkshire, UK.

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http://dx.doi.org/10.1111/hae.14367DOI Listing
June 2021

Biglycan: A regulator of hepatorenal inflammation and autophagy.

Matrix Biol 2021 Jun 10. Epub 2021 Jun 10.

Institute of Pharmacology and Toxicology, Goethe University, Frankfurt, Germany. Electronic address:

Soluble biglycan, a small leucine-rich proteoglycan, plays a significant role in several pathologies as it has emerged as an extracellular matrix-derived danger-associated molecular pattern. Biglycan is released from the extracellular matrix in response to tissue injury and, as a canonical danger signal, interacts with innate immune receptors, Toll-like receptors 2 and 4, thereby triggering a sustained inflammatory response. Recent evidence indicates that biglycan acts as a molecular switch between inflammation and autophagy by a specific interaction with the Toll-like co-receptor CD14 and CD44, respectively. Biglycan-evoked autophagy further contributes to the anti-inflammatory M2 macrophage polarization, inflammation resolution and tissue repair. These multivalent roles of soluble biglycan have been well characterized in inflammatory kidney diseases. In chronic liver diseases, increased levels of soluble biglycan have been described for years, leading to utilization of biglycan serum levels as a non-invasive biomarker for fibrosis. Hepatorenal dysfunction represents a classic example of inter-organ crosstalk, in which functional and molecular alterations of the cirrhotic liver can promote the development of renal failure. In patients with liver cirrhosis, development of hepatorenal syndrome is associated with high mortality. In this review, we will discuss the crucial role of soluble biglycan in inflammation and autophagy and its possible implications for hepatorenal dysfunction. We propose a novel concept of hepatorenal crosstalk, that is, biglycan produced by the cirrhotic liver could constitute a circulating "messenger" for the kidneys triggering inflammation and/or autophagy ultimately affecting disease outcome.
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http://dx.doi.org/10.1016/j.matbio.2021.06.001DOI Listing
June 2021

Site-specific resolution of enthesitis in patients with axial spondyloarthritis treated with tumor necrosis factor inhibitors.

Arthritis Res Ther 2021 06 9;23(1):165. Epub 2021 Jun 9.

Department of Rheumatology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.

Background: Enthesitis is a hallmark of spondyloarthritis (SpA) with a substantial impact on quality of life. Reports of treatment effectiveness across individual enthesitis sites in real-world patients with axial SpA (axSpA) are limited. We investigated the evolution of enthesitis following tumor necrosis factor inhibitor (TNFi) initiation in axSpA patients, both cumulatively and at specific axial and peripheral sites.

Methods: AxSpA patients in the Swiss Clinical Quality Management Registry were included if they initiated a TNFi, had an available Maastricht Ankylosing Spondylitis Enthesitis Score, modified to include the plantar fascia (mMASES, 0-15), at start of treatment and after 6 and/or 12 months and ≥12 months follow-up. Logistic regression models were utilized to analyze explanatory variables for enthesitis resolution.

Results: Overall, 1668 TNFi treatment courses (TCs) were included, of which 1117 (67%) had active enthesitis at baseline. Reduction in mMASES at the 6- and 12-month timepoints was experienced in 72% and 70% of TCs, respectively. Enthesitis resolution at 6/12 months occurred in 37.9%/43.0% of all TNFi TCs and 40.7%/50.9% of first TNFi TCs. At 6 months, a significant reduction in the frequency of enthesitis was observed at all sites, except for the Achilles tendon and plantar fascia among first TNFi TCs, while at 12 months, reduction was significant at all sites in both TC groups. Enthesitis resolved in 60.3-77% across anatomical sites, while new incident enthesitis occurred in 4.0-13.5% of all TNFi TCs at 12 months. Both baseline and new-incident enthesitis occurred most frequently at the posterior superior iliac spine and the fifth lumbar spinous process. Younger age and lower mMASES at baseline were predictors of complete enthesitis resolution, while female sex and second- or later-line TNFi treatment were associated with persistence of enthesitis at 12 months.

Conclusion: In real-world axSpA patients treated with a TNFi, enthesitis improved in the majority of patients across all anatomical sites. Significant improvement at the Achilles and plantar fascia entheses was observed only at 12 months. Complete and site-specific enthesitis resolution occurred in ≥40% and ≥60% of TCs evaluated at 12 months, with a low incidence of new site-specific enthesitis.

Trial Registration: Not applicable.
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http://dx.doi.org/10.1186/s13075-021-02534-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188725PMC
June 2021

[How do generic quotas work? An analysis using HIV infection as an example].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2021 May 14;64(5):625-634. Epub 2021 Apr 14.

Abteilung für Infektionsepidemiologie, Robert Koch-Institut, Seestraße 10, 13353, Berlin, Deutschland.

Background: Instruments controlling statutory healthcare medical supply have long been a topic of debate in health policy reform discussions. Over the years, a variety of tools have been developed, most of which are aimed at controlling drug expenditure. The instruments controlling regional prescriptions primarily focus on controlling behavioural patterns of the prescribing physicians. Important to note is the increased use of indication-directed quotas, primarily of drug leads and/or generics/biosimilars. These are now also available in the area of the human immunodeficiency virus (HIV), such as the generic quotas for HIV medications introduced in Bavaria and Berlin in 2020.

Objective: The aim of this article is to analyse the benefits and limitations of generic quota solutions in HIV care using statutory health insurance drug prescription data and to outline recommendations for action.

Results: It was observed that the quota potential for generics in the area of patent-free drugs in HIV care has already been largely exhausted. This can be explained by HIV prescribers supporting product exchange on the prescription.

Discussion: The best-case scenario in terms of regulation has almost been reached. This is due to a suitable set of instruments, including the framework agreement for medical supply as well as prescribing according to guidelines - in conjunction with the Pharmaceuticals Market Reorganisation Act (AMNOG) and reference prices for drugs. Conforming with guidelines and (existing) single-tablet regimens play an integral role in maintaining good quality of care.
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http://dx.doi.org/10.1007/s00103-021-03312-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087608PMC
May 2021

Pharmacists' perception of educational material to improve patient safety: A cross-sectional study on practices and awareness in Germany.

Medicine (Baltimore) 2021 Mar;100(11):e25144

Drug Commission of German Pharmacists (AMK), Heidestraße 7.

Abstract: Educational material (EM) addresses particular safety information of medicinal products to healthcare professionals and patients. Since 2016, German national competent authorities label approved EM with a Blue Hand symbol. However, data is scarce regarding its usability as a safety communication tool in pharmacies to improve patient safety. The purpose of this study is to investigate for the first time pharmacists' awareness and perception of EM in the setting of community and hospital pharmacies in Germany.The Drug Commission of German Pharmacists surveyed its nationwide network of 677 community and 51 hospital reference pharmacies, to investigate their awareness and perception of EM. The survey was conducted between January 16 and February 10, 2020 using SurveyMonkey. Data were analyzed using Microsoft Excel.A total of 373 community and 32 hospital pharmacists participated; response rates were 55.1% and 62.8%, respectively. Overall, 320 (85.8%) community and all hospital pharmacists confirmed awareness of EM. Community and hospital pharmacists fully (n = 172, 46.9% and n = 9, 28.1%) or rather (n = 109, 29.7% and n = 10, 31.3%) agreed that EM for healthcare professionals is suitable to reduce risks of medicinal products. Moreover, 237 (64.7%) community and 17 (53.1%) hospital pharmacists confirmed to inform patients or care facilities about EM. Asking pharmacists on their personal perception of EM, the refinement of readability and accessibility was indicated.Pharmacists confirm awareness of EM and its suitability as a safety communication tool. However, from a pharmacists' perspective, the applicability and readability of EM still needs further adjustment to improve patient safety.
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http://dx.doi.org/10.1097/MD.0000000000025144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982216PMC
March 2021

Adherence to, and patient convenience of, prolonged-release tacrolimus in stable kidney and liver transplant recipients after conversion from immediate-release tacrolimus in routine clinical practice in Switzerland.

Swiss Med Wkly 2021 Feb 18;151:w20453. Epub 2021 Feb 18.

Division of Nephrology, University Hospital Zurich, Switzerland.

Aims Of The Study: Non-adherence to immunosuppressive therapy in patients following solid organ transplantation is associated with an increased risk of transplant rejection and graft loss. A high pill burden can adversely affect patients’ implementation of their treatment regimens and may lead to omitting doses of medication. The aim of this study was to investigate medication implementation adherence in liver and kidney transplant recipients converted from twice-daily, immediate-release tacrolimus to once-daily, prolonged-release tacrolimus.

Methods: This multicentre, non-interventional, observational, 12-month study evaluated implementation adherence in routine practice at five hospitals in Switzerland. Patients attended four clinical visits: at baseline (pre-conversion), and then at week 2, month 6 and month 12 post-conversion. Implementation was defined as consistently taking medication at the correct time and at the correct dose in order to achieve target tacrolimus trough levels. Implementation adherence was evaluated in three ways: using the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) interview questionnaire (at baseline and month 12), investigator-rated patient adherence (recorded at all visits), and tacrolimus trough levels (assessed throughout the study; sub-therapeutic levels were predefined by the investigator on an individual patient basis, over-therapeutic levels were defined as tacrolimus trough levels >15 ng/ml). The primary composite endpoint was non-adherence according to the BAASIS at month 12, any post-conversion investigator adherence rating of “poor”, or sub-therapeutic or over-therapeutic tacrolimus trough levels at month 6 or 12. Secondary endpoints included: individual components of the composite non-adherence primary endpoint, tacrolimus pill burden, patient satisfaction, and adverse drug reactions.

Results: Seventy-five patients received prolonged-release tacrolimus; 68 patients (46 kidney and 22 liver transplant recipients) completed the study. Of these 68 patients, 24 had missing data for at least one component of the primary endpoint; therefore, data for the primary composite endpoint were evaluable for 44 patients. Most (81.8%; 36/44) patients were non-adherent for the composite endpoint. Sub-therapeutic tacrolimus trough levels outside of the predefined therapeutic range were the largest contributor to the composite endpoint, and were detected in 62.0% (31/50) of patients. Overall non-adherence according to the BAASIS was similar pre-conversion (30.7%) and at 12 months post-conversion (28.3%). Investigators rated adherence as “poor” for two patients. Prolonged-release tacrolimus decreased tacrolimus pill burden in 66.7% of patients. All patients were very satisfied / satisfied with prolonged-release tacrolimus; 75.0% found it easier to remember to take prolonged-release versus immediate-release tacrolimus. Twenty percent of patients reported adverse drug reactions, with infections being the most frequently reported (9.3%).

Conclusion: Overall, 1-year non-adherence rates were similar following conversion from immediate-release to prolonged-release tacrolimus; however, prolonged-release tacrolimus intake was more convenient. No new safety signals were detected.
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http://dx.doi.org/10.4414/smw.2021.20453DOI Listing
February 2021

Acute-on-chronic liver failure: a global disease.

Gut 2021 Feb 25. Epub 2021 Feb 25.

Translational Hepatology, Department of Internal Medicine I, Goethe University Frankfurt, Frankfurt am Main, Germany

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http://dx.doi.org/10.1136/gutjnl-2020-323973DOI Listing
February 2021

Silicon Suboxides as Driving Force for Efficient Light-Enhanced Hydrogen Generation on Silicon Nanowires.

Small 2021 Feb 1;17(8):e2007650. Epub 2021 Feb 1.

Leibniz Institute of Photonic Technology, Albert Einstein Str. 9, Jena, 07745, Germany.

Efficient light-stimulated hydrogen generation from top-down produced highly doped n-type silicon nanowires (SiNWs) with silver nanoparticles (AgNPs) in water-containing medium under white light irradiation is reported. It is observed that SiNWs with AgNPs generate at least 2.5 times more hydrogen than SiNWs without AgNPs. The authors' results, based on vibrational, UV-vis, and X-ray spectroscopy studies, strongly suggest that the sidewalls of the SiNWs are covered by silicon suboxides, by up to a thickness of 120 nm, with wide bandgap semiconductor properties that are similar to those of titanium dioxide and remain stable during hydrogen evolution in a water-containing medium for at least 3 h of irradiation. Based on synchrotron studies, it is found that the increase in the silicon bandgap is related to the energetically beneficial position of the valence band in nanostructured silicon, which renders these promising structures for efficient hydrogen generation.
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http://dx.doi.org/10.1002/smll.202007650DOI Listing
February 2021

Primary healthcare policy and vision for community pharmacy and pharmacists in Germany.

Pharm Pract (Granada) 2021 Jan-Mar;19(1):2248. Epub 2021 Jan 20.

RPh, PhD, FFIP, FESCP. Adjunct Professor. Director, Department of Medicine, Federal Union of German Associations of Pharmacists (ABDA). Berlin (Germany).

Germany is the highest populated country in Europe with a population of 82.3 million in 2019. As in many other developed countries, it has an aging population. Approximately 10% of the gross domestic product is spent on healthcare. The healthcare system is characterized by its accessibility. Patients are generally free to choose their primary care physicians, both family doctors and specialists, pharmacy, dentist, or emergency service. Up to a certain income, health insurance is mandatory with the statutory health insurance (SHI) system, covering 88% of the population. Major challenges are the lack of cooperation and integration between the different sectors and healthcare providers. This is expected to change with the introduction of a telematic infrastructure that is currently being implemented. It will not only connect all providers in primary and secondary care in a secure network but will also enable access to patients' electronic record/medical data and at the same time switch from paper to electronic prescriptions. Approximately 52,000 of the 67,000 pharmacists are working in approximately 19,000 community pharmacies. These pharmacies are owner-operated by a pharmacist. Pharmacists may own up to three subsidiaries nearby to their main pharmacy. Community pharmacy practice mainly consists of dispensing drugs, counselling patients on drug therapy and safety, and giving advice on lifestyle and healthy living. Many cognitive pharmaceutical services have been developed and evaluated in the past 20 years. Discussions within the profession and with stakeholders on the national level on the roles and responsibilities of pharmacists have resulted in nationally agreed guidelines, curricula, and services. However, cognitive services remunerated by the SHI funds on the national level remain to be negotiated and sustainably implemented. A law passed in November 2020 by parliament will regulate the remuneration of pharmaceutical services by the SHI funds with an annual budget of EUR 150 million. The type of services and their remuneration remain to be negotiated in 2021. The profession has to continue on all levels to advocate for a change in pharmacy practice by introducing pharmacy services into routine care.
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http://dx.doi.org/10.18549/PharmPract.2021.1.2248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844970PMC
January 2021

High Dynamic Range Digital Assay Enabled by Dual-Volume Centrifugal Step Emulsification.

Anal Chem 2021 02 22;93(5):2854-2860. Epub 2021 Jan 22.

Hahn-Schickard, Georges-Koehler-Allee 103, 79110 Freiburg, Germany.

We implement dual-volume centrifugal step emulsification on a single chip to extend the dynamic range of digital assays. Compared to published single-volume approaches, the range between the lower detection limit (LDL) and the upper limit of quantification (ULQ) increases by two orders of magnitude. In comparison to existing multivolume approaches, the dual-volume centrifugal step emulsification requires neither complex manufacturing nor specialized equipment. Sample metering into two subvolumes, droplet generation, and alignment of the droplets in two separate monolayers are performed automatically by microfluidic design. Digital quantification is demonstrated by exemplary droplet digital loop-mediated isothermal amplification (ddLAMP). Within 5 min, the reaction mix is split into subvolumes of 10.5 and 2.5 μL, and 2,5k and 176k droplets are generated with diameters of 31.6 ± 1.4 and 213.9 ± 7.5 μm, respectively. After 30 min of incubation, quantification over 5 log steps is demonstrated with a linearity of ≥ 0.992.
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http://dx.doi.org/10.1021/acs.analchem.0c04182DOI Listing
February 2021

Two-dimensional shear wave elastography predicts survival in advanced chronic liver disease.

Gut 2021 Jan 21. Epub 2021 Jan 21.

Department of Radiology, Beaujon University Hospital, Clichy, France.

Objective: Liver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients.

Design: This international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation.

Results: After screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM.

Conclusion: The M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals.
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http://dx.doi.org/10.1136/gutjnl-2020-323419DOI Listing
January 2021

"Dear Doctor" Warning Letter (Rote-Hand-Brief) on Hydrochlorothiazide and Its Impact on Antihypertensive Prescription.

Dtsch Arztebl Int 2020 Oct;117(41):687-688

Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Universität des Saarlandes, Homburg/Saar, Deutsches Arzneiprüfungsinstitut e. V. (DAPI), Berlin; Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig; Institut für Pharmakologie, Center for Cardiovascular Research, Charité - Universitätsmedizin Berlin; Arzneimittelkommission der Deutschen Apotheker (AMK), Berlin; Institut für Pharmazie, Freie Universität Berlin.

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http://dx.doi.org/10.3238/arztebl.2020.0687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851968PMC
October 2020

Safety and efficacy of nonacog alfa for the treatment of haemophilia B in children younger than 6 years of age in a routine clinical care setting: the EUREKIX registry study.

Haemophilia 2021 Jan 5;27(1):e60-e68. Epub 2020 Dec 5.

Regional Reference Center for Inherited Bleeding Disorders, University Hospital of Parma, Parma, Italy.

Introduction: European regulatory authorities request postmarketing safety and efficacy data for factor IX (FIX) products.

Aim: Collect additional clinical data from routine nonacog alfa use in children aged <6 years with haemophilia B.

Methods: The EUREKIX registry included retrospective and prospective data collection phases. Safety was assessed via adverse drug reactions (ADRs)/adverse events (AEs) and events of special interest (ESIs) as the primary objective; efficacy was evaluated via annualised bleeding rates (ABRs).

Results: The retrospective phase comprised 37 subjects. Of these, 25 had severe haemophilia B. One subject experienced 2 ADRs; another experienced 4 ESIs of hypersensitivity. Median ABR in subjects receiving a predominantly on-demand regimen (prophylaxis <50% of time; n = 11) was 2.0; median ABR was 3.8 in those receiving predominantly prophylactic treatment (prophylaxis ≥50% of time; n = 24). Joint bleeding was infrequent (median ABR, 0.4; n = 35). The prospective phase included 26 subjects, with 17 continuing from the retrospective phase. A total of 20 subjects had severe haemophilia B. Three subjects experienced 7 treatment-related AEs; 3 experienced 4 ESIs. Median ABR was 4.5 and 1.1 in subjects who received predominantly on-demand (n = 5) or prophylactic treatment (n = 19), respectively; the overall median ABR for joint bleeding events was 0.0.

Conclusions: Overall, nonacog alfa treatment effectively controlled bleeding events, with no new safety signals identified. These data support the safety and efficacy of nonacog alfa in routine clinical settings in children aged <6 years.
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http://dx.doi.org/10.1111/hae.14215DOI Listing
January 2021

Learnings from Regional Market Dynamics of Originator and Biosimilar Infliximab and Etanercept in Germany.

Pharmaceuticals (Basel) 2020 Oct 21;13(10). Epub 2020 Oct 21.

Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium.

Drug budget and prescription control measures are implemented regionally in Germany, meaning that the uptake of pharmaceuticals, including biosimilars, can vary by region. We examine regional market dynamics of tumor necrosis factor alpha (TNFα) inhibitor originators and biosimilars in Germany and studied the influence of biosimilar policies on these dynamics. This study is based on: (1) a literature review in which German biosimilar policies are identified, (2) the analysis of dispensing data (2010-2018) for the class of TNFα inhibitors, and (3) ten semi-structured interviews investigating prescribers' and insurers' views on factors potentially influencing biosimilar uptake. The analysis of biosimilar market shares of infliximab and etanercept revealed wide variations across the 17 German Regional Associations of Statutory Health Insurance Accredited Physicians (PA regions). Quantitative analyses indicated that biosimilar market shares for infliximab and etanercept were significantly lower in former East Germany when compared to former West Germany regions. Through qualitative interview analyses, this study showed that the use of infliximab and etanercept biosimilars across Germany is primarily influenced by (1) the regional-level implementation of biosimilar quotas and the presence of monitoring/sanctioning mechanisms to ensure adherence to these quotas, (2) the different insurer-manufacturer discount contracts, and (3) gainsharing arrangements established at the insurer-prescriber level.
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http://dx.doi.org/10.3390/ph13100324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590006PMC
October 2020

Impact of angiotensin receptor blocker product recalls on antihypertensive prescribing in Germany.

J Hum Hypertens 2020 Oct 14. Epub 2020 Oct 14.

German Institute for Drug Use Evaluation, Berlin, Germany.

In Germany, ~8 million patients take angiotensin receptor blockers (ARBs) and 2.25 million of them valsartan. In 2018, contamination of generic ARBs with probable carcinogenic nitrosamines resulted in more than 30 recalls. The impact of such a huge recall has never been explored in Europe. We analyzed the utilization of valsartan, all ARBs, and other alternative antihypertensive drugs in Germany. We used our database of anonymized dispensing data from >80% of community pharmacies at the expense of the statutory health insurance (SHI) funds from January 2017 to December 2019. We analyzed 290.8 million prescriptions, including all oral mono- and fixed-dose combinations of ARBs and plausible alternatives, i.e. ACE inhibitors (ACEi), beta-blockers (BB), and calcium channel blockers (CCB). Utilization was calculated by defined daily doses per 1000 SHI-insured persons per day (DID). Valsartan use decreased substantially after the recalls in July 2018 from 39.0 to 14.2 DID (-64%) in the second quarter of 2019 and to 16.9 DID (-57%) in the fourth quarter of 2019. Simultaneously, the use of alternative ARBs increased from 77.7 DID in the second quarter of 2018 to 121.9 DID (+57%) in the fourth quarter of 2019, mainly due to an increase of candesartan dispensing to 99.8 DID (+73%). There were no changes in the utilization of ACEi, BB, or CCB. The majority of recalled generic valsartan products were replaced by other ARBs, predominantly candesartan, despite documented drug shortages. In contrast to previous safety warnings/recalls, our data do not suggest an under-prescription of antihypertensives during this period.
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http://dx.doi.org/10.1038/s41371-020-00425-zDOI Listing
October 2020

Pharmacy practice research - A call to action.

Res Social Adm Pharm 2020 Nov 4;16(11):1602-1608. Epub 2020 Aug 4.

Pharmaceutical Care Research Group, Faculty of Pharmacy, University of Granada, Spain.

Pharmacists have a societal duty of care. How to best provide that type of care requires scientific study. Pharmacy practice is a scientific discipline that studies the different aspects of the practice of pharmacy, and its impact on health care systems, medicine use, and patient care. Its scope has expanded globally to encompass clinical, behavioural, economic, and humanistic implications of the practice of pharmacy, as well as practice change and implementation in routine practice of innovations such as health interventions and patient-care services. The development, impact evaluation, implementation, and sustainability of health interventions and patient-care services represents a key research area for pharmacy practice. An approach for conducting these is provided. There is evidence that collaborative national and international research in this area is growing, showing an increased contribution to global health research. The role of universities and pharmacy professional associations in supporting the advancement of pharmacy through pharmacy practice research is also discussed. Finally, a call to action for pharmacy practice research, education, and practice is made.
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http://dx.doi.org/10.1016/j.sapharm.2020.07.031DOI Listing
November 2020

Development and implementation of blood pressure screening and referral guidelines for German community pharmacists.

J Clin Hypertens (Greenwich) 2020 10 30;22(10):1807-1816. Epub 2020 Aug 30.

Internal Medicine III - Cardiology, Angiology and Intensive Care Medicine, University Hospital of Saarland, Saarland University, Homburg/Saar, Germany.

Involvement of community pharmacists in the detection and control of hypertension improves patient care. However, current European or North-American guidelines do not provide specific guidance how to implement collaboration between pharmacists and physicians, especially when and how to refer patients with undetected or uncontrolled hypertension to a physician. The German Society of Cardiology and the ABDA - Federal Union of German Associations of Pharmacists developed and tested referral recommendations for community pharmacists, embedded in two guideline worksheets. The project included a guideline-directed blood pressure (BP) measurement and recommendations when patients should be referred to their physician. A "red flag" referral within 4 weeks was recommended when SBP was >140 mm Hg or DBP >90 mm Hg (for subjects <80 years), and >160 mm Hg or >90 mm Hg (≥80 years) in undetected individuals, or >130 mm Hg or >80 mm Hg (<65 years) and >140 mm Hg or >80 mm Hg (≥65 years) in treated patients. BP was measured in 187 individuals (86 with known hypertension, mean [±SD] age 62 ± 15 years, 64% female, and 101 without known hypertension, 47 ± 16 years, 75% female) from 17 community pharmacies. In patients with hypertension, poorly controlled BP was detected in 55% (n = 47) and were referred. A total of 16/101 subjects without a history of hypertension were referred to their physician because of uncontrolled BP. Structured BP testing in pharmacies identified a significant number of subjects with undetected/undiagnosed hypertension and patients with poorly controlled BP. Community pharmacists could play a significant role in collaboration with physicians to improve the management of hypertension.
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http://dx.doi.org/10.1111/jch.14020DOI Listing
October 2020

Photoinduced Charge Accumulation and Prolonged Multielectron Storage for the Separation of Light and Dark Reaction.

J Am Chem Soc 2020 Sep 3;142(37):15722-15728. Epub 2020 Sep 3.

Institute of Physical Chemistry, Friedrich Schiller University Jena, Helmholtzweg 4, 07743 Jena, Germany.

The utilization of solar energy is restricted by the intermittent nature of solar influx. We present novel noble-metal free complexes that can be photochemically charged in the presence of sacrificial electron donors and remain stable in its charged form for over 14 h. This allows the doubly reduced Cu(I) 4-imidazolate complex to be stored after photochemical charging and used as a reagent in dark reactions, such as the reduction of methyl viologen or oxygen. Combined UV-vis/EPR spectroelectrochemistry indicates that a two-electron reduction is induced by introducing sacrificial electron donors that facilitate proton-coupled electron transfer. Repeated photochemical reduction and chemical oxidation reveals that the complex retained a charging capacity of 72% after four cycles. We demonstrate a chemical system that can decouple photochemical processes from the day-night cycle, which has been a barrier to realizing utilization of solar energy in photochemical processes on a global scale.
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http://dx.doi.org/10.1021/jacs.0c03779DOI Listing
September 2020

Role of MLCT States in the Franck-Condon Region of Neutral, Heteroleptic Cu(I)-4-imidazolate Complexes: A Spectroscopic and Theoretical Study.

J Phys Chem A 2020 Aug 11;124(33):6607-6616. Epub 2020 Aug 11.

Institute of Physical Chemistry, Friedrich Schiller University Jena, Helmholtzweg 4, 07743 Jena, Germany.

The impact of the electronic structure of a series of 4-imidazolate ligands in neutral, heteroleptic Cu(I) complexes is investigated. Remarkable broad and strong ligand-dependent absorption in the visible range of the electromagnetic spectrum renders the studied complexes promising photosensitizers for photocatalytic applications. The electronic structure of the Cu(I) complexes and the localization of photoexcited states in the Franck-Condon region are unraveled by means of UV-vis absorption and resonance Raman (rR) spectroscopy supported by time-dependent density functional theory (TD-DFT) calculations. The visible absorption bands stem from a superposition of bright metal-to-ligand charge-transfer (MLCT) and π-π* as well as weakly absorbing MLCT states. Additionally, the analysis of involved molecular orbitals and rR spectra upon excitation of MLCT and π-π* states highlights the impact of the electronic structure of the 4-imidazolate ligands on the properties of the corresponding Cu(I) complexes to avail a toolbox for predictive studies and efficient complex design.
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http://dx.doi.org/10.1021/acs.jpca.0c04351DOI Listing
August 2020

The impact of pharmacist/physician care on quality of life in elderly heart failure patients: results of the PHARM-CHF randomized controlled trial.

ESC Heart Fail 2020 Jul 23. Epub 2020 Jul 23.

Department of Cardiology, University Hospital, Leipzig University, Leipzig, Germany.

Aims: Patients with heart failure (HF) have impaired quality of life (QoL). The randomized controlled trial PHARM-CHF investigated whether an interdisciplinary intervention consisting of regular contacts with the community pharmacy and weekly dosing aids improves medication adherence in patients with HF. It is unknown how an intervention involving frequent structured pharmacy visits affects QoL. Our aim was to explore adherence to the intervention and effects on QoL.

Methods And Results: Among 237 patients, n = 110 were randomized to pharmacy care and n = 127 to usual care. The pharmacy care group received a medication review followed by (bi-)weekly dose dispensing and counselling. The median follow-up was 2.0 years [inter-quartile range (IQR) 1.2-2.7]. Median interval between pharmacy visits was 8.4 days (IQR 8.0-10.3) and the visits lasted in median 14 min (IQR 10-15). Median adherence to the intervention was 96% (IQR 84-100). QoL at 365 days was predefined as a main secondary and at 730 days as another secondary endpoint in PHARM-CHF. QoL was measured by the Minnesota Living with Heart Failure Questionnaire; and for 111 patients (n = 47 in the pharmacy care group and n = 64 in the usual care group), data were available at baseline, and after 365 and 730 days (mean age 74 years; 41% female). Improvement in QoL was numerically higher in the pharmacy care group after 365 days and was significantly better after 730 days (difference in total scores -7.7 points [-14.5 to -1.0]; P = 0.026) compared to the usual care group. In all subgroups examined, this treatment effect was preserved. Improvements in the physical and emotional dimensions were numerically higher in the pharmacy care group after 365 days and were significantly better after 730 days: -4.0 points [-6.9 to -1.2]; P = 0.006, and -1.9 points [-3.7 to -0.1]; P = 0.039, respectively.

Conclusions: A pharmacy-based interdisciplinary intervention was well received by the patients and suggests clinically important improvements in QoL.
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http://dx.doi.org/10.1002/ehf2.12904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754956PMC
July 2020

Point-of-care testing system for digital single cell detection of MRSA directly from nasal swabs.

Lab Chip 2020 07;20(14):2549-2561

Hahn-Schickard, Georges-Koehler-Allee 103, 79110 Freiburg, Germany.

We present an automated point-of-care testing (POCT) system for rapid detection of species- and resistance markers in methicillin-resistant Staphylococcus aureus (MRSA) at the level of single cells, directly from nasal swab samples. Our novel system allows clear differentiation between MRSA, methicillin-sensitive S. aureus (MSSA) and methicillin-resistant coagulase-negative staphylococci (MR-CoNS), which is not the case for currently used real-time quantitative PCR based systems. On top, the novel approach outcompetes the culture-based methods in terms of its short time-to-result (1 h vs. up to 60 h) and reduces manual labor. The walk-away test is fully automated on the centrifugal microfluidic LabDisk platform. The LabDisk cartridge comprises the unit operations swab-uptake, reagent pre-storage, distribution of the sample into 20 000 droplets, specific enzymatic lysis of Staphylococcus spp. and recombinase polymerase amplification (RPA) of species (vicK) - and resistance (mecA) -markers. LabDisk actuation, incubation and multi-channel fluorescence detection is demonstrated with a clinical isolate and spiked nasal swab samples down to a limit of detection (LOD) of 3 ± 0.3 CFU μl-1 for MRSA. The novel approach of the digital single cell detection is suggested to improve hospital admission screening, timely decision making, and goal-oriented antibiotic therapy. The implementation of a higher degree of multiplexing is required to translate the results into clinical practice.
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http://dx.doi.org/10.1039/d0lc00294aDOI Listing
July 2020

Short-Term Western Diet Aggravates Non-Alcoholic Fatty Liver Disease (NAFLD) With Portal Hypertension in TGR(mREN2)27 Rats.

Int J Mol Sci 2020 May 7;21(9). Epub 2020 May 7.

Department of Internal Medicine I, Goethe University Frankfurt, 60323 Frankfurt, Germany.

Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity. Especially, the development of fibrosis and portal hypertension in NAFLD patients requires treatment. Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with portal hypertension but without obesity. This study investigated the additional role of obesity in this model on the development of portal hypertension and fibrosis. Obesity was induced in twelve-week old TGR(mREN2)27 rats after receiving Western diet (WD) for two or four weeks. Liver fibrosis was assessed using standard techniques. Hepatic expression of transforming growth factor-β1 (TGF-β1), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, as well as the chemoattractant Ccl2, interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) were analyzed. Assessment of portal and systemic hemodynamics was performed using the colored microsphere technique. As expected, WD induced obesity and liver fibrosis as confirmed by Sirius Red and Oil Red O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were increased during feeding of WD, indicating infiltration of macrophages into the liver, even though this increase was statistically not significant for the EGF module-containing mucin-like receptor (Emr1) mRNA expression levels. Of note, portal pressure increased with the duration of WD compared to animals that received a normal chow. Besides obesity, WD feeding increased systemic vascular resistance reflecting systemic endothelial and splanchnic vascular dysfunction. We conclude that transgenic TGR(mREN2)27 rats are a suitable model to investigate NAFLD development with liver fibrosis and portal hypertension. Tendency towards elevated expression of Emr1 is associated with macrophage activity point to a significant role of macrophages in NAFLD pathogenesis, probably due to a shift of the renin-angiotensin system towards a higher activation of the classical pathway. The hepatic injury induced by WD in TGR(mREN2)27 rats is suitable to evaluate different stages of fibrosis and portal hypertension in NAFLD with obesity.
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http://dx.doi.org/10.3390/ijms21093308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246932PMC
May 2020

Revisited: Therapeutic and toxic blood concentrations of more than 1100 drugs and other xenobiotics.

Crit Care 2020 05 6;24(1):195. Epub 2020 May 6.

Institute of Legal Medicine, University Medical Centre Hamburg-Eppendorf, Butenfeld 34, 22529, Hamburg, Germany.

In order to assess the significance of drug/substance levels measured in intensive care medicine and clinical and forensic toxicology as well as for therapeutic drug monitoring, it is essential that a comprehensive collection of data is readily available. We revisited and expanded our 2012 compilation of therapeutic and toxic plasma concentration ranges as well as half-lives of now more than 1100 drugs and other xenobiotics.Data have been abstracted from original papers, text books, and previous compilations and have been completed with data collected in our own forensic and clinical toxicology laboratories. We compiled the data presented in the table and the corresponding annotations over the past 30+ years. A previous compilation was completely double-checked, revised, and updated, if necessary. In addition, more than 200 substances, especially drugs who have been introduced since 2012 to the market as well as illegal drugs and other xenobiotics which became known to cause intoxications were added. We carefully referenced all data. Moreover, the annotations providing details were updated and revised, when necessary.For more than 1100 drugs and other xenobiotics, therapeutic ("normal") and, if data was available, toxic, and comatose-fatal plasma/blood concentrations as well as elimination half-lives were compiled in a table.In case of intoxications, the blood concentration of the substance and/or metabolite better predicts the clinical severity of the case when compared to the assumed amount and time of ingestion. Comparing and contrasting the clinical case against the data provided, including the half-life, may support the decision for or against further intensive care. In addition, the data provided are useful for the therapeutic monitoring of pharmacotherapies, to facilitate the diagnostic assessment and monitoring of acute and chronic intoxications as well as to support forensic and clinical expert opinions.
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http://dx.doi.org/10.1186/s13054-020-02915-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201985PMC
May 2020

Rebleeding and mortality risk are increased by ACLF but reduced by pre-emptive TIPS.

J Hepatol 2020 11 24;73(5):1082-1091. Epub 2020 Apr 24.

Unit of Gastroenterology and Digestive Endoscopy, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.

Background & Aims: The relationship between acute-on-chronic liver failure (ACLF) and acute variceal bleeding (AVB) is poorly understood. Specifically, the prevalence and prognosis of ACLF in the context of AVB is unclear, while the role of transjugular intrahepatic portosystemic shunt (TIPS) in the management in patients with ACLF has not been described to date.

Methods: A multicenter, international, observational study was conducted in 2,138 patients from 34 centers between 2011 and 2015. ACLF was defined and graded according to the EASL-CLIF consortium definition. Placement of pre-emptive TIPS (pTIPS) was based on individual center policy. Patients were followed-up for 1 year, until death or liver transplantation. Cox regression and competing risk models (Gray's test) were used to identify independent predictors of rebleeding or mortality.

Results: At admission, 380/2,138 (17.8%) patients had ACLF according to EASL-CLIF criteria (grade 1: 38.7%; grade 2: 39.2%; grade 3: 22.1%). The 42-day rebleeding (19% vs. 10%; p <0.001) and mortality (47% vs. 10%; p <0.001) rates were higher in patients with ACLF and increased with ACLF grades. Of note, the presence of ACLF was independently associated with rebleeding and mortality. pTIPS placement improved survival in patients with ACLF at 42 days and 1 year. This effect was also observed in propensity score matching analysis of 66 patients with ACLF, of whom 44 received pTIPs and 22 did not.

Conclusions: This large multicenter international real-life study identified ACLF at admission as an independent predictor of rebleeding and mortality in patients with AVB. Moreover, pTIPS was associated with improved survival in patients with ACLF and AVB.

Lay Summary: Acute variceal bleeding is a deadly complication of liver cirrhosis that results from severe portal hypertension. This study demonstrates that the presence of acute-on-chronic liver failure (ACLF) is the strongest predictor of mortality in patients with acute variceal bleeding. Importantly, patients with ACLF and acute variceal (re)bleeding benefit from pre-emptive (early) placement of a transjugular intrahepatic portosystemic shunt.
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http://dx.doi.org/10.1016/j.jhep.2020.04.024DOI Listing
November 2020

Versatile Tool for Droplet Generation in Standard Reaction Tubes by Centrifugal Step Emulsification.

Molecules 2020 Apr 21;25(8). Epub 2020 Apr 21.

Hahn-Schickard, Georges-Koehler-Allee 103, 79110 Freiburg, Germany.

We present a versatile tool for the generation of monodisperse water-in-fluorinated-oil droplets in standard reaction tubes by centrifugal step emulsification. The microfluidic cartridge is designed as an insert into a standard 2 mL reaction tube and can be processed in standard laboratory centrifuges. It allows for droplet generation and subsequent transfer for any downstream analysis or further use, does not need any specialized device, and manufacturing is simple because it consists of two parts only: A structured substrate and a sealing foil. The design of the structured substrate is compatible to injection molding to allow manufacturing at large scale. Droplets are generated in fluorinated oil and collected in the reaction tube for subsequent analysis. For sample sizes up to 100 µL with a viscosity range of 1 mPa·s-4 mPa·s, we demonstrate stable droplet generation and transfer of more than 6 × 10 monodisperse droplets (droplet diameter 66 µm ± 3 µm, CV ≤ 4%) in less than 10 min. With two application examples, a digital droplet polymerase chain reaction (ddPCR) and digital droplet loop mediated isothermal amplification (ddLAMP), we demonstrate the compatibility of the droplet production for two main amplification techniques. Both applications show a high degree of linearity (ddPCR: R ≥ 0.994; ddLAMP: R ≥ 0.998), which demonstrates that the cartridge and the droplet generation method do not compromise assay performance.
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http://dx.doi.org/10.3390/molecules25081914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221521PMC
April 2020

Systemic MCP-1 Levels Derive Mainly From Injured Liver and Are Associated With Complications in Cirrhosis.

Front Immunol 2020 11;11:354. Epub 2020 Mar 11.

Department of Internal Medicine 1, University Hospital, University Bonn, Bonn, Germany.

Monocyte chemotactic protein-1 (MCP-1) is a potent chemoattractant for monocytes. It is involved in pathogenesis of several inflammatory diseases. Hepatic MCP-1 is a readout of macrophage activation. While inflammation is a major driver of liver disease progression, the origin and role of circulating MCP-1 as a biomarker remains unclear. Hepatic CC-chemokine ligand 2 () expression and F4/80 staining for Kupffer cells were measured and correlated in a mouse model of chronic liver disease (inhalative CCl for 7 weeks). Next, hepatic RNA levels of were measured in explanted livers of 39 patients after transplantation and correlated with severity of disease. Changes in MCP-1 were further evaluated in a rat model of experimental cirrhosis and acute-on-chronic liver failure (ACLF). Finally, we analyzed portal and hepatic vein levels of MCP-1 in patients receiving transjugular intrahepatic portosystemic shunt insertion for complications of portal hypertension. In this mouse model of fibrotic hepatitis, hepatic expression of ( = 0.009) and the amount of F4/80 positive cells in the liver ( < 0.001) significantly increased after induction of hepatitis by CCl compared to control animals. Moreover, strong correlation of hepatic expression and F4/80 positive cells were seen ( = 0.023). Furthermore, in human liver explants, hepatic transcription levels of correlated with the MELD score of the patients, and thus disease severity ( = 0.007). The experimental model of ACLF in rats revealed significantly higher levels of MCP-1 plasma ( = 0.028) and correlation of hepatic expression ( = 0.69, = 0.003). Particularly, plasma MCP-1 levels did not correlate with peripheral blood monocyte expression. Finally, higher levels of MCP-1 were observed in the hepatic compared to the portal vein ( = 0.01) in patients receiving TIPS. Similarly, a positive correlation of MCP-1 with Child-Pugh score was observed ( = 0.018). Further, in the presence of ACLF, portal and hepatic vein levels of MCP-1 were significantly higher compared to patients without ACLF (both = 0.039). Circulating levels of MCP-1 mainly derive from the injured liver and are associated with severity of liver disease. Therefore, liver macrophages contribute significantly to disease progression. Circulating MCP-1 may reflect the extent of hepatic macrophage activation.
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http://dx.doi.org/10.3389/fimmu.2020.00354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078155PMC
March 2021

The Development and Outcome of Acute-on-Chronic Liver Failure After Surgical Interventions.

Liver Transpl 2020 02 24;26(2):227-237. Epub 2019 Dec 24.

Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, Frankfurt, Germany.

Acute-on-chronic liver failure (ACLF) is a syndrome with high short-term mortality. Precipitating events, including hemorrhage and infections, contribute to ACLF development, but the role of surgery remains unknown. We investigated the development of ACLF in patients with cirrhosis undergoing surgery. In total, 369 patients with cirrhosis were included in the study. The clinical and laboratory data were collected prior to and on days 1-2, 3-8, and 9-28, and at 3 and 12 months after surgery. Surgery type was classified as limited or extensive, as well as liver and nonliver surgery. A total of 39 patients had baseline ACLF. Surgery was performed during acute decompensation in 35% of the rest of the 330 patients, and 81 (24.5%) developed ACLF within 28 days after surgery. Surrogate markers of systemic inflammation were similar in patients who developed ACLF or not. Age, sex, serum sodium, baseline bacterial infection, and abdominal nonliver surgery were independent predictors for the development of ACLF after surgery. Patients who developed ACLF within 28 days after surgery had a higher mortality at 3, 6, and 12 months. Survival did not differ between patients with ACLF at surgery and those developing ACLF after surgery. Development of ACLF within 28 days after surgery and elevated alkaline phosphatase and international normalized ratio were independent predictors of 90-day mortality. Independent predictors of 1-year all-cause mortality were alkaline phosphatase, Model for End-Stage Liver Disease score, and preoperative hepatic encephalopathy, whereas nonliver surgery was associated with improved survival. ACLF frequently develops in patients with cirrhosis undergoing surgery, especially in those with active bacterial infection, lower serum sodium, and kidney or coagulation dysfunction. Prognoses of ACLF both at and after surgery are similarly poor. Patients with cirrhosis should be carefully managed perioperatively.
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http://dx.doi.org/10.1002/lt.25675DOI Listing
February 2020

Trends in dispensing oral emergency contraceptives and safety issues: a survey of German community pharmacists.

Int J Clin Pharm 2019 Dec 28;41(6):1499-1506. Epub 2019 Sep 28.

Drug Commission of German Pharmacists (AMK), Heidestraße 7, 10557, Berlin, Germany.

Background Oral emergency contraceptives containing levonorgestrel or ulipristal acetate are available without prescription and only in pharmacies in Germany since March 2015. Due to this change community pharmacists are responsible for evaluating whether the product is appropriate and to educate women on proper use. Objective To measure the utilization of emergency contraceptives without a prescription and describe potential concerns and safety issues identified by community pharmacists in Germany. Setting The Drug Commission of German Pharmacists' nationwide network of reference pharmacies which includes 860 community pharmacies. Methods Reference community pharmacies were asked to participate in the eleven-questions online survey. Respondents were asked to recall their experiences with oral emergency contraceptives in the past 3 months. Data were collected between January 8 and February 19, 2018. Main outcome measure The survey focused on the utilization of emergency contraceptives without a prescription in Germany, and on the pharmacists' experiences with (potential) problems and concerns regarding safe use. Results In total, 555 community pharmacies (64.5%) participated. Overall 38.2% of community pharmacists stated they dispensed six to ten courses of emergency contraceptives within the past 3 months. In addition, 54.3% of the pharmacists estimated they dispensed emergency contraceptives exclusively without prescription and 35.9% dispensed more than 30% of emergency contraceptives during night-time and emergency services. Moreover, 82.8% of pharmacists stated that emergency contraceptives were requested not by the women concerned but a third person and 44.3% identified uncertainties in woman's self-diagnosis. Three out of four pharmacists had concerns about the effective and safe use of emergency contraceptives. In situations suggesting sexually transmitted diseases, or suspicion for use of force, 59.5% and 55.8% of the pharmacists, respectively, dispensed emergency contraceptives. In cases of acute health impairment or chronic disease, or (potentially) relevant drug/drug interaction, the vast majority (91.0% and 90.5%) did not. Here, most pharmacists referred to gynecologists. Conclusion Pharmacists had safety concerns when dispensing emergency contraceptives. Professional expertise in evaluating the need for oral emergency contraceptives and the proper use is needed.
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http://dx.doi.org/10.1007/s11096-019-00911-6DOI Listing
December 2019
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