From evidence to care delivery: Opportunities and risks in health and science policy. A position paper of the Association of the Scientific Medical Societies in Germany (AWMF).

Objective: After over 25 years of developing clinical practice guidelines, the Association of the Scientific Medical Societies in Germany (AWMF) held a symposium to discuss the following topics in order to improve the way evidence is implemented in the delivery of care: expansion of the data pool for guideline development, the regulatory policy framework for this expansion, the transfer of clinical practice guideline statements to medical practice, the associated opportunities and risks resulting from the European legislation.

Methods: The AWMF held its Berlin Forum on 27 April 2022 where experts from scientific medical societies and national institutions in the healthcare sector reported their experiences and perceptions on the topics mentioned. Three writing groups compiled the key statements from these contributions to and discussions made at the Berlin Forum into a position paper.

Pathology in the legal framework of European and German medical device law: Operation, use and in-house manufacture of in vitro diagnostic medical devices.

Institutes for pathology act as operators, users and in-house manufacturers of in vitro diagnostic medical devices and are subject to national and European regulations depending on their function. The entry into force of the EU regulation on medical devices (Regulation (EU) 2017/745, MDR) and the EU regulation on in vitro diagnostic medical devices (Regulation (EU) 2017/746, IVDR) resulted in a need for regulatory adjustments to German medical device law. This has created a new legal framework in which institutes for pathology operate, depending on their function as users, operators or in-house manufacturers of in vitro diagnostic medical devices.

Therapeutic Drug Monitoring of Elexacaftor, Tezacaftor, and Ivacaftor in Adult People with Cystic Fibrosis.

Background/objectives: Elexacaftor, tezacaftor, and ivacaftor (ETI) have significantly improved lung function in people with cystic fibrosis (pwCF). Despite exceptional improvements in most cases, treatment-related inter-subject variability and drug-drug interactions that complicate modulator therapy have been reported.

Methods: This retrospective analysis presents data on the serum concentration of ETI in our pwCF with full or reduced dosage from August 2021 to December 2023 via routine therapeutic drug monitoring (TDM).

Understanding isotopes, isomers, and isobars in mass spectrometry.

Mass spectrometry (MS) is a versatile analytical tool used in various fields such as biochemistry, pharmacology, omics, and clinical analysis for determining and quantifying compounds based on their molecular mass and structure through the mass-to-charge ratio. While MS offers high specificity and selectivity, it encounters challenges including matrix effects, in-source fragmentation, and other interferences caused by natural isotopic abundance, as well as isomeric and isobaric compounds. These challenges can impede accurate qualitative and quantitative analysis.

Isotope-dilution-LC-MS/MS candidate reference measurement procedure for cefepime in human serum.

Background: Reference measurement procedures are an essential element in the standardization and comparability of analytical measurement results in laboratory medicine. No LC-MS/MS-based reference measurement procedure for cefepime in serum has been published previously.

Materials And Methods: An isotope-dilution based two-dimensional LC-MS/MS reference measurement procedure for cefepime concentrations in human serum was developed and tested.

Standardization via Post Column Infusion-A Novel and Convenient Quantification Approach for LC-MS/MS.

Mass spectrometry (MS) is a widely used analytical technique including medical diagnostics, forensic toxicology, food and water analysis. The gold standard for quantifying compounds involves using stable isotope-labeled internal standards (SIL-IS). However, when these standards are not commercially available, are prohibitively expensive, or are extremely difficult to synthesize, alternative external quantification techniques are employed.

Spuriously low immunosuppressant results due to incomplete hemolysis - A pitfall in transplant patient therapeutic drug monitoring.

Objective: Therapeutic drug monitoring (TDM) plays a crucial role in transplantation medicine when it comes to immunosuppressants like Tacrolimus, Cyclosporine A, Sirolimus, and Everolimus. The analysis involves using immunometric or mass spectrometric methods on whole blood samples. Hemolysis of the samples is necessary for the assessment.

Can linezolid be validly measured in endotracheal aspiration in critically ill patients? A proof-of-concept trial.

Background: Therapeutic drug monitoring (TDM) of anti-infectives such as linezolid is routinely performed in blood of intensive care unit (ICU) patients to optimize target attainment. However, the concentration at the site of infection is considered more important for a successful therapy. Until now, bronchoalveolar lavage (BAL) is the gold standard to measure intrapulmonary concentrations of anti-infective agents.

Die EU-Verordnung für In-vitro-Diagnostika (IVDR) in der Praxis: Umsetzung und Anwendung - Ergebnisse einer öffentlichen Veranstaltung der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) im März 2023.

In order to discuss first experiences with the implementation of the EU Regulation on In Vitro Diagnostic Medical Devices (IVDR) about one year after its entry into force, the German Association of the Scientific Medical Societies (AWMF e.V.) organized a full-day public webinar.

Report from the HarmoSter study: different LC-MS/MS androstenedione, DHEAS and testosterone methods compare well; however, unifying calibration is a double-edged sword.

Objectives: Current liquid chromatography-tandem mass spectrometry (LC-MS/MS) applications for circulating androgen measurements are technically diverse. Previously, variable results have been reported for testosterone. Data are scarce for androstenedione and absent for dehydroepiandrosterone sulfate (DHEAS).

Extracorporeal adsorption of protective and toxic bile acids and bilirubin in patients with cholestatic liver dysfunction: a prospective study.

Background: The release of toxic bile acids (BAs) in the blood of critically ill patients with cholestatic liver dysfunction might lead to the damage of various organs. Their extracorporeal elimination using the cytokine adsorber Cytosorb (CS) (adsorption of especially hydrophobic molecules < 60 kDa) might be promising, but data proving a potential adsorption are missing so far.

Methods: The prospective Cyto-SOVLE study (NCT04913298) included 20 intensive care patients with cholestatic liver dysfunction, continuous kidney replacement therapy, total bilirubin concentration > 10 mg/dl and the application of CS into the dialysis circuit.

[Regulation (EU) 2017/746 (IVDR): practical implementation of annex I in pathology].

Background: Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) imposes several conditions on pathology institutes that develop and use in-house in vitro diagnostic medical devices (IH-IVDs). However, not all of these conditions need to be implemented immediately after the IVDR entered into force on 26 May 2022. Based on an amending regulation of the European Parliament and the Council of the European Union, the requirements for IH-IVDs will be phased in.

Non-Invasive Zinc Protoporphyrin Screening Offers Opportunities for Secondary Prevention of Iron Deficiency in Blood Donors.

Background: Frequent blood donors are at high risk of developing iron deficiency. Currently, there is no potent screening during blood donation to detect iron deficient erythropoiesis (IDE) before anemia develops and deferral from donation is inevitable.

Study Design And Methods: In addition to capillary and venous hemoglobin, the iron status of 99 frequent blood donors was assessed by various venous blood parameters and zinc protoporphyrin IX (ZnPP).

A suggested protocol for value assignment using isotope-dilution-LC-MS/MS in reference measurement procedures - Exemplary application for ciprofloxacin in serum.

Background: Reference measurement procedures for assigning values to calibration materials play a crucial role in the concept of metrological traceability in laboratory medicine. ISO standard 15,193 specifies the requirements for such measurement procedures, albeit in a very general terms.

Materials And Methods: A standard structure of analysis series for value assignment by LC-MS/MS was developed and tested,this structure was complemented by a spreadsheet file for result calculation, metadata evaluation, and finally validation and confirmation of individual analysis runs and individual results, and measurement uncertainty evaluation.

Competence-based catalog of learning objectives for the subject area of quality management in medical studies - position paper of the working group Quality Management in Education, Training and Continuing Education of the Society for Quality Management in Health Care (GQMG).

Background: Traditionally, direct medical competences are taught in medical studies, whereas leadership and quality management competences are hardly taught, although graduates are already confronted with management tasks at the beginning of their clinical work. With the upcoming amendment of the Medical Licensing Regulations, this topic area will probably be addressed and must be adequately taught by the faculties. The learning objectives in the area of quality management listed in the current working version of the German National Catalogue of Learning Objectives in Medicine (NKLM) 2.

Rules for mass spectrometry applications in the clinical laboratory.

MS-based analytical methods now play an important role in medical laboratory analysis. Predominantly triple-stage mass spectrometry is used for the quantification of small molecule biomarkers and xenobiotics in blood and urine. The spectrum of applications ranges from completely in-house developed analytical methods, to industrially manufactured kit solutions used on generic equipment, to the first closed MS-based analysis systems.

Structure and content of the EU-IVDR : Current status and implications for pathology.

Background: Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) was passed by the European Parliament and the Council of the European Union on 5 April 2017 and came into force on 26 May 2017. A new amending regulation, which introduces a phased implementation of the IVDR with new transitional provisions for certain in vitro diagnostic medical devices (IVDs) and a later date of application of some requirements for in-house devices for healthcare facilities, was adopted on 15 December 2021. The combined use of CE-certified IVDs (CE-IVDs), in-house IVDs (IH-IVDs), and research use only (RUO) devices are a cornerstone of diagnostics in pathology departments and crucial for optimal patient care.

Semi-automated serum steroid profiling with tandem mass spectrometry.

Objectives: Highly selective and sensitive multi-analyte methods for the analysis of steroids are attractive for the diagnosis of endocrine diseases. Commercially available kits are increasingly used for this purpose. These methods involve laborious solid phase extraction, and the respective panels of target analytes are incomplete.

Therapeutic drug monitoring in breast cancer therapy - LC-MS/MS method for quantification of the CDK4/6 inhibitors abemaciclib, palbociclib, ribociclib, and major metabolites abemaciclib M20 and M2 in human serum.

The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib were approved by the U.S. Food and Drug Administration (FDA) and European Medicine Agency for the treatment of breast cancer between 2015 and 2018.