Recommendations for blood sampling in emergency departments from the European Society for Emergency Medicine (EUSEM), European Society for Emergency Nursing (EuSEN), and European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group for the Preanalytical Phase. Executive summary.

AIM: Blood Sampling Guidelines have been developed to target European emergency medicine-related professionals involved in the blood sampling process (e.g. physicians, nurses, phlebotomists working in the ED), as well as laboratory physicians and other related professionals. The guidelines population focus on adult patients. The development of these blood sampling guidelines for the ED setting is based on the collaboration of three European scientific societies that have a role to play in the preanalytical phase process: EuSEN, EFLM, and EUSEM. The elaboration of the questions was done using the PICO procedure, literature search and appraisal was based on the GRADE methodology. The final recommendations were reviewed by an international multidisciplinary external review group. RESULTS: The document includes the elaborated recommendations for the selected sixteen questions. Three in pre-sampling, eight regarding sampling, three post-sampling, and two focus on quality assurance. In general, the quality of the evidence is very low, and the strength of the recommendation in all the questions has been rated as weak. The working group in four questions elaborate the recommendations, based mainly on group experience, rating as good practice. CONCLUSIONS: The multidisciplinary working group was considered one of the major contributors to this guideline. The lack of quality information highlights the need for research in this area of the patient care process. The peculiarities of the emergency medical areas need specific considerations to minimise the possibility of errors in the preanalytical phase.

Nephrolithiasis Associated with Nephrocalcinosis Is Primarily Composed of Carbonate Apatite.

INTRODUCTION: This study was designed to determine the mineral composition of calculi in nephrocalcinosis with nephrolithiasis, diagnose the underlying disease, and monitor the course of renal function in patients with nephrocalcinosis-nephrolithiasis. METHODS: Renal calculi extruded in a series of 8 patients with nephrocalcinosis were analysed using Fourier transmission infrared spectrometry. In 4 patients, next-generation sequencing using a nephrocalcinosis-nephrolithiasis panel was performed to determine the nature of the underlying disease. In addition, longitudinal analysis of renal function was performed in all patients. RESULTS: Seven patients revealed carbonate apatite as the sole constituent of renal calculi. One patient showed a mixed composition of dicalcium phosphate dihydrate/carbonate apatite at first analysis yet in subsequent episodes also had calculi composed of pure carbonate apatite. Further molecular analysis displayed distal renal tubular acidosis in 2 of 4 patients who consented to sequencing. No known genetic defect could be found in the other two cases. In line with prior reports, decline of renal function was dependent on underlying disease. Distal renal tubular acidosis revealed a progressive course of renal failure, whereas other causes showed stable renal function in long term analysis. CONCLUSION: Nephrocalcinosis with nephrolithiasis is a rare condition with heterogeneous aetiology. Yet mineral composition of renal calculi predominantly consisted of pure carbonate apatite. This uniform finding is similar to subcutaneous calcifications of various origins and might propose a general principle of tissue calcification. Progressive decline of renal function was found in distal renal tubular acidosis, whereas other conditions remained stable over time.

Analytical interference of intravascular contrast agents with clinical laboratory tests: a joint guideline by the ESUR Contrast Media Safety Committee and the Preanalytical Phase Working Group of the EFLM Science Committee.

The Contrast Media Safety Committee of the European Society of Urogenital Radiology has, together with the Preanalytical Phase Working Group of the EFLM Science Committee, reviewed the literature and updated its recommendations to increase awareness and provide insight into these interferences.

Analytical interference of intravascular contrast agents with clinical laboratory tests: a joint guideline by the ESUR Contrast Media Safety Committee and the Preanalytical Phase Working Group of the EFLM Science Committee.

The Contrast Media Safety Committee of the European Society of Urogenital Radiology has, together with the Preanalytical Phase Working Group of the EFLM Science Committee, reviewed the literature and updated its recommendations to increase awareness and provide insight into these interferences. CLINICAL RELEVANCE STATEMENT: Contrast Media may interfere with clinical laboratory tests. Awareness of potential interference may prevent unwanted misdiagnosis. KEY POINTS: • Contrast Media may interfere with clinical laboratory tests; therefore awareness of potential interference may prevent unwanted misdiagnosis. • Clinical Laboratory tests should be performed prior to radiological imaging with contrast media or alternatively, blood or urine collection should be delayed, depending on kidney function.

Disruption of laboratory activities during the COVID-19 pandemic: results of an EFLM Task Force Preparation of Labs for Emergencies (TF-PLE) survey.

Background: The EFLM Task Force Preparation of Labs for Emergencies (TF-PLE) created a survey that has been distributed to its members for gathering information on the key hazards experienced by European medical laboratories during the COVID-19 pandemic. Methods: The survey was distributed to over 12,000 potential contacts (laboratory workers) via an EFLM newsletter, with responses collected between May 8 and June 8, 2023. Results: Two hundred replies were collected and examined from European laboratories. 69.7% and 78.1% of all responders said they were short on non-COVID and COVID reagents, respectively. Exactly half of respondents (50.0%) said that they could not complete all laboratory tests required for a specific period, but this figure climbed to 61.2% for COVID tests. Finally, 72.3% of respondents expressed exhaustion during the pandemic, and 61.2% reported increasing patient hostility. Conclusions: The COVID-19 pandemic had a significant impact on laboratory medicine in Europe. Cultural change, proactive planning, and even re-engineering in some parts of the laboratory industry may thus be necessary to prepare for future challenges.

Factors Affecting SARS-CoV-2 IgG Production after Vaccination and/or Disease: A Large-Scale Seroprevalence Study.

This study aimed at identifying factors influencing SARS-CoV-2-specific IgG antibody levels after vaccination and/or infection. Between January 2022 and March 2023, 2000 adults (≥18 years, Salzburg, Austria) participated in this population-based seroprevalence study by providing 3 mL of blood to detect SARS-CoV-2-specific IgG antibodies using an anti-SARS-CoV-2 IgG quantitative assay and by completing a self-designed questionnaire including anthropometric factors, vaccination information, and medical history. For 77 of the participants, a time-course study up to 24 weeks post vaccination or quarantine end was performed. Convalescent-only subjects had the lowest median antibody titer (65.6 BAU/mL) compared to vaccinated and hybrid immunized subjects (p-value < 0.0001) The type of vaccine as well as vaccine combinations significantly influenced the levels of SARS-CoV-2 spike-protein-specific IgG, ranging from a median antibody level of 770.5 BAU/mL in subjects who were vaccinated only to 3020.0 BAU/mL in hybrid immunized subjects (p-value < 0.0001). Over time, a significant decline in the levels of neutralizing antibodies was found. Depending on the subpopulation analyzed, further significant influencing factors included sex assigned at birth, disease severity, chronic diseases, and medication. A hybrid immunization resulted in more robust immune responses. Nevertheless, there were multiple other factors impacting these responses. This knowledge should be included in future vaccination strategies and serve as a guide in the development of personalized medicine.

The platelet transcriptome and proteome in Alzheimer's disease and aging: an exploratory cross-sectional study.

Introduction: Alzheimer's disease (AD) and aging are associated with platelet hyperactivity. However, the mechanisms underlying abnormal platelet function in AD and aging are yet poorly understood. Methods: To explore the molecular profile of AD and aged platelets, we investigated platelet activation (i.e., CD62P expression), proteome and transcriptome in AD patients, non-demented elderly, and young individuals as controls. Results: AD, aged and young individuals showed similar levels of platelet activation based on CD62P expression. However, AD and aged individuals had a proteomic signature suggestive of increased platelet activation compared with young controls. Transcriptomic profiling suggested the dysregulation of proteolytic machinery involved in regulating platelet function, particularly the ubiquitin-proteasome system in AD and autophagy in aging. The functional implication of these transcriptomic alterations remains unclear and requires further investigation. Discussion: Our data strengthen the evidence of enhanced platelet activation in aging and provide a first glimpse of the platelet transcriptomic changes occurring in AD.

Potentials and pitfalls of ChatGPT and natural-language artificial intelligence models for the understanding of laboratory medicine test results. An assessment by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group on Artificial Intelligence (WG-AI).

OBJECTIVES: ChatGPT, a tool based on natural language processing (NLP), is on everyone's mind, and several potential applications in healthcare have been already proposed. However, since the ability of this tool to interpret laboratory test results has not yet been tested, the EFLM Working group on Artificial Intelligence (WG-AI) has set itself the task of closing this gap with a systematic approach. METHODS: WG-AI members generated 10 simulated laboratory reports of common parameters, which were then passed to ChatGPT for interpretation, according to reference intervals (RI) and units, using an optimized prompt. The results were subsequently evaluated independently by all WG-AI members with respect to relevance, correctness, helpfulness and safety. RESULTS: ChatGPT recognized all laboratory tests, it could detect if they deviated from the RI and gave a test-by-test as well as an overall interpretation. The interpretations were rather superficial, not always correct, and, only in some cases, judged coherently. The magnitude of the deviation from the RI seldom plays a role in the interpretation of laboratory tests, and artificial intelligence (AI) did not make any meaningful suggestion regarding follow-up diagnostics or further procedures in general. CONCLUSIONS: ChatGPT in its current form, being not specifically trained on medical data or laboratory data in particular, may only be considered a tool capable of interpreting a laboratory report on a test-by-test basis at best, but not on the interpretation of an overall diagnostic picture. Future generations of similar AIs with medical ground truth training data might surely revolutionize current processes in healthcare, despite this implementation is not ready yet.

Erroneous potassium results: preanalytical causes, detection, and corrective actions.

Potassium is one of the most requested laboratory tests. Its level is carefully monitored and maintained in a narrow physiological range. Even slightly altered potassium values may severely impact the patient's health, which is why an accurate and reliable result is of such importance. Even if high-quality analytics are available, there are still numerous ways in which potassium measurements may be biased, all of which occur in the preanalytical phase of the total laboratory testing process. As these results do not reflect the patient's in-vivo status, such results are referred to as pseudo-hyper/hypokalemia or indeed pseudo-normokalemia, depending on the true potassium result. Our goal in this review is to present an in-depth analysis of preanalytical errors that may result in inaccurate potassium results. After reviewing existing evidence on this topic, we classified preanalytical errors impacting potassium results into 4 categories: 1) patient factors like high platelet, leukocytes, or erythrocyte counts; 2) the sample type 3) the blood collection procedure, including inappropriate equipment, patient preparation, sample contamination and others and 4) the tube processing. The latter two include sample transport and storage conditions of whole blood, plasma, or serum as well as sample separation and subsequent preanalytical processes. In particular, we discuss the contribution of hemolysis, as one of the most frequent preanalytical errors, to pseudo-hyperkalemia. We provide a practical flow chart and a tabular overview of all the discussed preanalytical errors including possible underlying mechanisms, indicators for detection, suggestions for corrective actions, and references to the according evidence. We thereby hope that this manuscript will serve as a resource in the prevention and investigation of potentially biased potassium results.

Recommendation for the design of stability studies on clinical specimens.

OBJECTIVES: Knowledge of the stability of analytes in clinical specimens is a prerequisite for proper transport and preservation of samples to avoid laboratory errors. The new version of ISO 15189:2022 and the European directive 2017/746 increase the requirements on this topic for manufacturers and laboratories. Within the project to generate a stability database of European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group Preanalytical Phase (WG-PRE), the need to standardise and improve the quality of published stability studies has been detected, being a manifest deficit the absence of international guidelines for the performance of stability studies on clinical specimens. METHODS: These recommendations have been developed and summarised by consensus of the WG-PRE and are intended primarily to improve the quality of sample stability claims included in information for users provided by assay supplier companies, according to the requirements of the new European regulations and standards for accreditation. RESULTS: This document provides general recommendations for the performance of stability studies, oriented to the estimation of instability equations in the usual working conditions, allowing flexible adaptation of the maximum permissible error specifications to obtain stability limits adapted to the intended use. CONCLUSIONS: We present this recommendation based on the opinions of the EFLM WG-PRE group for the standardisation and improvement of stability studies, with the intention to improve the quality of the studies and the transferability of their results to laboratories.

Where is laboratory medicine headed in the next decade? Partnership model for efficient integration and adoption of artificial intelligence into medical laboratories.

OBJECTIVES: The field of artificial intelligence (AI) has grown in the past 10 years. Despite the crucial role of laboratory diagnostics in clinical decision-making, we found that the majority of AI studies focus on surgery, radiology, and oncology, and there is little attention given to AI integration into laboratory medicine. METHODS: We dedicated a session at the 3rd annual European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) strategic conference in 2022 to the topic of AI in the laboratory of the future. The speakers collaborated on generating a concise summary of the content that is presented in this paper. RESULTS: The five key messages are (1) Laboratory specialists and technicians will continue to improve the analytical portfolio, diagnostic quality and laboratory turnaround times; (2) The modularized nature of laboratory processes is amenable to AI solutions; (3) Laboratory sub-specialization continues and from test selection to interpretation, tasks increase in complexity; (4) Expertise in AI implementation and partnerships with industry will emerge as a professional competency and require novel educational strategies for broad implementation; and (5) regulatory frameworks and guidances have to be adopted to new computational paradigms. CONCLUSIONS: In summary, the speakers opine that the ability to convert the value-proposition of AI in the laboratory will rely heavily on hands-on expertise and well designed quality improvement initiative from within laboratory for improved patient care.

The preanalytical phase - from an instrument-centred to a patient-centred laboratory medicine.

In order to guarantee patient safety, medical laboratories around the world strive to provide highest quality in the shortest amount of time. A major leap in quality improvement was achieved by aiming to avoid preanalytical errors within the total testing process. Although these errors were first described in the 1970s, it took additional years/decades for large-scale efforts, aiming to improve preanalytical quality by standardisation and/or harmonisation. Initially these initiatives were mostly on the local or national level. Aiming to fill this void, in 2011 the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) working group "Preanalytical Phase" (WG-PRE) was founded. In the 11 years of its existence this group was able to provide several recommendations on various preanalytical topics. One major achievement of the WG-PRE was the development of an European consensus guideline on venous blood collection. In recent years the definition of the preanalytical phase has been extended, including laboratory test selection, thereby opening a huge field for improvement, by implementing strategies to overcome misuse of laboratory testing, ideally with the support of artificial intelligence models. In this narrative review, we discuss important aspects and milestones in the endeavour of preanalytical process improvement, which would not have been possible without the support of the Clinical Chemistry and Laboratory Medicine (CCLM) journal, which was one of the first scientific journals recognising the importance of the preanalytical phase and its impact on laboratory testing quality and ultimately patient safety.

The preanalytical process in the emergency department, a European survey.

OBJECTIVES: Clinical decision-making in emergency medicine is under constant pressure from demand and performance requirements, with blood tests being a fundamental part of this. However, the preanalytical process has received little attention. Therefore, this study aimed to investigate the quality of preanalytical phase processes in European emergency departments (EDs) from the perspectives of the three main providers: clinicians, nurses, and laboratory specialists. METHODS: This online survey, distributed among European EDs and laboratories, was supported by the European Society for Emergency Nursing (EUSEN), European Society for Emergency Medicine (EuSEM), and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM). The size of the centres, the European region, the responder's profession and the country's economic condition were used as co-variables. RESULTS: We included 376 responses from all ED-related professions from 306 European centres. In 66.9% of all ED visits, at least one blood test was performed. Tests were requested mostly by nurses (44.6%) using electronic Order/Entry systems (65.4%). Only a minority (19%) reported not using laboratory quality indicators (QIs). Most responders defined the TAT starting point "when the laboratory receives the sample" (66.1%), defining the goal to be "less than 60 min" (69.9%), but only 42.4% of the centres estimated achieving this goal. CONCLUSIONS: Our survey illustrates the current situation on preanalytical blood sample processing in European EDs from the clinical and laboratory perspectives. The results emphasise the importance of the IT infrastructure and QI usage in this process and highlight some differences between European regions.

Disruption vs. evolution in laboratory medicine. Current challenges and possible strategies, making laboratories and the laboratory specialist profession fit for the future.

Since beginning of medical diagnostics, laboratory specialists have done an amazing job, continuously improving quality, spectrum and speed of laboratory tests, currently contributing to the majority of medical decision making. These improvements are mostly of an incremental evolutionary fashion, meaning improvements of current processes. Sometimes these evolutionary innovations are of a radical fashion, such as the invention of automated analyzers replacing manual testing or the implementation of mass spectrometry, leading to one big performance leap instead of several small ones. In few cases innovations may be of disruptive nature. In laboratory medicine this would be applicable to digitalization of medicine or the decoding of the human genetic material. Currently, laboratory medicine is again facing disruptive innovations or technologies, which need to be adapted to as soon as possible. One of the major disruptive technologies is the increasing availability and medical use of artificial intelligence. It is necessary to rethink the position of the laboratory specialist within healthcare settings and the added value he or she can provide to patient care. The future of the laboratory specialist profession is bright, as it the only medical profession comprising such vast experience in patient diagnostics. However, laboratory specialists need to develop strategies to provide this expertise, by adopting to the quickly evolving technologies and demands. This opinion paper summarizes some of the disruptive technologies as well as strategies to secure and/or improve the quality of diagnostic patient care and the laboratory specialist profession.

Diagnostic Workup of Microcytic Anemia: An Evaluation of Underuse or Misuse of Laboratory Testing in a Hospital Setting Using the AlinIQ System.

CONTEXT.­: Underuse of laboratory testing has been previously investigated in preselected populations, such as documented malpractice claims. However, these numbers might not reflect real-life situations. OBJECTIVE.­: To evaluate the underuse and misuse of laboratory follow-up testing in a real-life hospital patient population with microcytic anemia, using laboratory results ordered during routine patient care. DESIGN.­: From all patients in whom a microcytic anemia was detected during routine diagnostics in 2018, all available laboratory data were collected and screened for appropriateness of diagnostic workup of iron deficiency and thalassemia. Subgroup analysis was performed for patient groups with mean corpuscular volume values 75 to 79 µm3 (group 1), 65 to 74 µm3 (group 2), and <65 µm3 (group 3). RESULTS.­: A total of 2244 patients with microcytic anemia were identified. Follow-up testing for iron deficiency was not performed in 761 cases (34%). For inconclusive ferritin levels due to elevated C-reactive protein results (n = 336), reticulocyte hemoglobin content or soluble transferrin receptor levels were missing in 86 cases (26%). In patients with suspected thalassemia (n = 127), follow-up testing for hemoglobin variants was not performed in 70 cases (55%). Subgroup analysis showed that the frequency of underuse of iron status as well as thalassemia/hemoglobinopathy testing decreased from group 1 to group 3. When considering relevant preexisting anemia diagnoses, laboratory tests were underused in 904 cases (40.3%). CONCLUSIONS.­: Because 40% (n = 904) of the patients with microcytic anemia were potentially not followed up correctly, laboratory specialists are advised to act by implementing demand management strategies in collaboration with clinicians to overcome underuse of laboratory tests and to improve patient safety.

Conventional and Pro-Inflammatory Pathways of Fibrinolytic Activation in Non-Traumatic Hyperfibrinolysis.

Hyperfibrinolysis (HF) frequently occurs after severe systemic hypoperfusion during major trauma and out-of-hospital cardiac arrest (OHCA). In trauma-induced HF, hypoperfusion, the activation of protein C (APC), and the release of tissue plasminogen activator (t-PA) have been identified as the driving elements of premature clot breakdown. The APC pathway also plays a role in inflammatory responses such as neutrophil extracellular trap formation (NETosis), which might contribute to lysis through cleavage of fibrin by neutrophil elastases. We investigated whether the APC and the plasminogen pathway were general drivers of HF, even in the absence of a traumatic incident. Additionally, we were interested in inflammatory activation such as the presence of NETs as potential contributing factors to HF. A total of 41 patients with OHCA were assigned to a HF and a non-HF group based on maximum lysis (ML) in thromboelastometry. Thrombin-antithrombin (TAT)-complex, soluble thrombomodulin (sTM), APC-PC inhibitor complex, t-PA, PAI-1, t-PA-PAI-1 complex, plasmin-antiplasmin (PAP), d-dimers, neutrophil elastase, histonylated DNA (hDNA) fragments, and interleukin-6 were assessed via immunoassays in the HF group vs. non-HF. APC-PC inhibitor complex is significantly higher in HF patients. Antigen levels of t-PA and PAI-1 do not differ between groups. However, t-PA activity is significantly higher and t-PA-PAI-1 complex significantly lower in the HF group. Consistent with these results, PAP and d-dimers are significantly elevated in HF. HDNA fragments and neutrophil elastase are not elevated in HF patients, but show a high level of correlation, suggesting NETosis occurs in OHCA as part of inflammatory activation and cellular decay. Just as in trauma, hypoperfusion, the activation of protein C, and the initiation of the plasminogen pathway of fibrinolysis manifest themselves in the HF of cardiac arrest. Despite features of NETosis being detectable in OHCA patients, early pro-inflammatory responses do not appear be associated with HF in cardiac arrest.

An international study on activated partial thromboplastin time prolongation. Part 2: Interpretative commenting.

BACKGROUND: Providing evidence-based interpretative comments (IC) is an integral task of clinical laboratory professionals. It may be of special relevance for coagulation testing, where pathological first-line tests could trigger more specialized tests. Our aim was to evaluate the quality of ICs provided to the physician in two samples with activated partial thromboplastin time (APTT) prolongation. MATERIAL AND METHODS: Two lyophilized plasma samples and their respective fictional clinical cases (case 1: heparin contamination and case 2: factor VIII deficiency) were sent to European laboratories for APTT and APTT mixing test measurement, and elaboration of ICs based on their results. The quality of ICs was evaluated in terms of analytical classification, laboratory interpretation, advice to physician, clarity, length and whether the clinical question was answered. RESULTS: A total of 214 laboratories were included. Classification of the analytical result was stated in 57 % of comments. Laboratory interpretation was found in 91 % of comments for case 1 and 83.3 % for case 2, among which 9.3 % and 6.5 % were considered wrong, respectively. Advice for the requesting physician was provided in 65.8 % of comments for case 1 and 61.2 % for case 2, among which 36 % and 4.7 % were considered wrong, respectively. More than 70 % of comments for both cases were evaluated as clear and of an adequate length. CONCLUSION: A significant number of laboratories provide clear interpretations and helpful advice for the management of altered coagulation results. Nevertheless, the finding of several confusing and misleading comments highlights the need for recommendations on elaboration of interpretative comments.