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The SARS-CoV-2 infection is characterized by both systemic and organ hyper-thromboinflammation, with a clinical course ranging from mild up-to critical systemic dysfunction and death. In patients with coronavirus disease 2019 (COVID-19) the monocyte/macrophage population is deeply involved as both trigger and target, assuming the value of useful diagnostic/prognostic marker of innate cellular immunity. Several studies correlated morphological and immunophenotypic alterations of circulating monocytes with clinical outcomes in COVID-19 patients, concluding that monocyte distribution width (MDW) may retain clinical value in stratifying the risk of disease worsening. Through an electronic search in Medline and Scopus we performed an updated literature review and meta-analysis aimed to explore the association between increased MDW levels and illness severity in COVID-19 patients, deciphering role(s) and function(s) of monocytes in the harmful network underlining SARS-CoV-2 infection. We found that significantly elevated MDW values were frequently present in COVID-19 patients who developed unfavorable clinical outcomes, compounded by a significant association between monocyte anisocytosis and SARS-CoV-2 outcomes. These findings suggest that blood MDW index and its scatter plot could represent useful routine laboratory tools for early identification of patients at higher risk of unfavorable COVID-19 and for monitoring the progression of viral infection, clinical outcomes, and therapeutic efficacy throughout hospitalization. According to this evidence, therapeutic decisions in patients with SARS-CoV-2 infection could benefit from monitoring MDW value, with administration of drugs limiting thrombo-inflammation due to monocyte hyper-activation in patients with severe/critical COVID-19 disease., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

This study is aimed at developing a simple epidemiologic model that could help predict the impaired neutralization of new SARS-CoV-2 variants. We explored the potential association between neutralization of recent and more prevalent SARS-CoV-2 sublineages belonging to the Omicron family (i.e., BA.4/5, BA.4.6, BA.2.75.2, BQ.1.1 and XBB.1) expressed as FFRNT50 (>50% suppression of fluorescent foci fluorescent focus reduction neutralization test) in recipients of four doses of monovalent mRNA-based coronavirus disease 2019 (COVID-19) vaccines, with epidemiologic variables like emergence date and number of spike protein mutations of these sublineages, cumulative worldwide COVID-19 cases and cumulative number of COVID-19 vaccine doses administered worldwide at the time of SARS-CoV-2 Omicron sublineage emergence. In the univariate analysis, the FFRNT50 value for the different SARS-CoV-2 Omicron sublineages was significantly associated with all such variables except with the number of spike protein mutations. Such associations were confirmed in the multivariate analysis, which enabled the construction of the equation: “−0.3917 × [Emergence (date)] + 1.403 × [COVID-19 cases (million)] − 121.8 × [COVID-19 Vaccine doses (billion)] + 18,250”, predicting the FFRNT50 value of the five SARS-CoV-2 Omicron sublineages with 0.996 accuracy (p = 0.013). We have shown in this work that a simple mathematical approach, encompassing a limited number of widely available epidemiologic variables, such as emergence date of new variants and number of COVID-19 cases and vaccinations, could help identifying the emergence and surge of future lineages with major propensity to impair humoral immunity.

Background and Aim: SARS-CoV-2 infection spawns from an asymptomatic condition to a fatal disease. Age, comorbidities, and several blood biomarkers are associated with infection outcome. We searched for biomarkers by untargeted and targeted proteomic analysis of saliva, a source of viral particles and host proteins., Methods: Saliva samples from 19 asymptomatic and 16 symptomatic SARS-CoV-2 infected subjects, and 20 controls were analyzed by LC-MS/MS for untargeted peptidomic (flow through of 10 kDa filter) and proteomic (trypsin digestion of filter retained proteins) profiling., Results: Peptides from 53 salivary proteins were identified. ADF was detected only in controls, while IL1RA only in infected subjects. PRPs, DSC2, FABP5, his-1, IL1RA, PRH1, STATH, SMR3B, ANXA1, MUC7, ACTN4, IGKV1-33 and TGM3 were significantly different between asymptomatic and symptomatic subjects. Retained proteins were 117, being 11 highly different between asymptomatic and symptomatic (fold change ≥2 or ≤-2). After validation by LC-MS/MS-SRM (selected reaction monitoring analysis), the most significant discriminant proteins at PCA were IL1RA, CYSTB, S100A8, S100A9, CA6, and FABP5., Conclusions: The differentially abundant proteins involved in innate immunity (S100 proteins), taste (CA6 and cystatins), and viral binding to the host (FABP5), appear to be of interest for use as potential biomarkers and drugs targets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aims: The role of inflammation markers in myocarditis is unclear. We assessed the diagnostic and prognostic correlates of C-reactive protein (CRP) at diagnosis in patients with myocarditis. Methods and results: We retrospectively enrolled patients with clinically suspected (CS) or biopsy-proven (BP) myocarditis, with available CRP at diagnosis. Clinical, laboratory and imaging data were collected at diagnosis and at follow-up visits. To evaluate predictors of death/heart transplant (Htx), a machine-learning approach based on random forest for survival data was employed. We included 409 patients (74% males, aged 37 ± 15, median follow-up 2.9 years). Abnormal CRP was reported in 288 patients, mainly with CS myocarditis (p < 0.001), recent viral infection, shorter symptoms duration (p = 0.001), chest pain (p < 0.001), better functional class at diagnosis (p = 0.018) and higher troponin I values (p < 0.001). Death/Htx was reported in 13 patients, of whom 10 had BP myocarditis (overall 10-year survival 94%). Survival rates did not differ according to CRP levels (p = 0.23). The strongest survival predictor was LVEF, followed by anti-nuclear auto-antibodies (ANA) and BP status. Conclusions: Raised CRP at diagnosis identifies patients with CS myocarditis and less severe clinical features, but does not contribute to predicting survival. Main death/Htx predictors are reduced LVEF, BP diagnosis and positive ANA.

This review is an integral part of the special issue for the 60 years of the journal Clinical Chemistry and Laboratory Medicine ( CCLM ). The aim of the review is to highlight the role of the clinical laboratory since the emergence of the "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), which causes Coronavirus disease 2019 (COVID-19), with special focus on the contribution of the journal in generating knowledge in SARS-CoV-2 diagnosis. As of October 30, 2022, a total of 186 CCLM publications were dedicated to COVID-19. Of importance, major International Federation of Clinical Chemistry (IFCC) guidelines related to the diagnosis of COVID-19 were published in CCLM . Between early-2020 and late October 2022, COVID-19 publications represented around 27% of all articles in CCLM , highlighting the willingness of the editorial board to help the field in order to better describe and diagnose this new emerging disease. First launched in 1963 under the name "Zeitschrift für Klinische Chemie", the Journal was entirely devoted to clinical chemistry in the strict sense. The various topics published in relation to COVID-19 including its diagnosis, its impact on biochemical or hematological measures, as well as biosafety measures, is the perfect example that shows that the journal has greatly diversified over time., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

The background to this debate is now well-known: an EU policy decision to tighten controls on the devices and diagnostics sector led to the adoption of a regulation in 2017 with a schedule for implementation over coming years - a timetable extended still further by last-minute legislation in early 2022, to provide the sector and regulators with more time to adapt to the changes. Discussions among experts organised in April by the European Alliance for Personalized Medicine (EAPM) exposed continuing challenges that cannot be fully resolved by the recent deferral of implementation deadlines. One salient problem is that there is little awareness of the In Vitro Diagnostic Regulation (IVDR) across Europe, and only limited awareness of the different structures of national systems involved in implementing IVDR, with consequent risks for patient and consumer access to in vitro diagnostics (IVDs). The tentative conclusion from these consultations is that despite a will across the sector to seek workable solutions, the obstacles remain formidable, and the potential solutions so far proposed remain more a matter of aspirations than of clear pathways., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

The analytical quality of the clinical laboratory results has shown a significant improvement over the past decades, thanks to the joint efforts of different stakeholders, while the comparability among the results produced by different laboratories and methods still presents some critical issues. During these years, Clinical Chemistry and Laboratory Medicine ( CCLM ) published several papers on the harmonization issue over all steps in the Total Testing Process, training an important number of laboratory professionals in evaluating and monitoring all the criticisms inherent to the pre-analytical, as well as analytical and post analytical phases: from the consensus statement on the most informative testing in emergency setting, to the prevention and detection of hemolysis or to patients identification and tube labeling procedures, as far as to different approaches to harmonize hormones measurements or to describe new reference methods or to harmonize the laboratory report. During these years the commitment of the journal, devoted to the harmonization processes has allowed to improve the awareness on the topic and to provide specific instruments to monitor the rate of errors and to improve patients safety., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

As testing for infectious diseases moves from manual, biological testing such as complement fixation to high throughput automated autoanalyzer, the methods for controlling these assays have also changed to reflect those used in clinical chemistry. However, there are many differences between infectious disease serology and clinical chemistry testing, and these differences have not been considered when applying traditional quality control methods to serology. Infectious disease serology, which is highly regulated, detects antibodies of varying classes and to multiple and different antigens that change according to the organisms' genotype/serotype and stage of disease. Although the tests report a numerical value (usually signal to cut-off), they are not measuring an amount of antibodies, but the intensity of binding within the test system. All serology assays experience lot-to-lot variation, making the use of quality control methods used in clinical chemistry inappropriate. In many jurisdictions, the use of the manufacturer-provided kit controls is mandatory to validate the test run. Use of third-party controls, which are highly recommended by ISO 15189 and the World Health Organization, must be manufactured in a manner whereby they have minimal lot-to-lot variation and at a level where they detect exceptional variation. This paper outlines the differences between clinical chemistry and infectious disease serology and offers a range of recommendations when addressing the quality control of infectious disease serology., (© 2022 Wayne J. Dimech et al., published by De Gruyter, Berlin/Boston.)

Due to the many technical limitations of molecular biology, the possibility to sustain enormous volumes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostic testing relies strongly on the use of antigen rapid diagnostic tests (Ag-RDTs). Besides a limited analytical sensitivity, the manually intensive test procedures needed for performing these tests, very often performed by unskilled personnel or by the patients themselves, may contribute to considerably impair their diagnostic accuracy. We provide here an updated overview on the leading preanalytical drawbacks that may impair SARS-CoV-2 Ag-RDT accuracy, and which encompass lower diagnostic sensitivity in certain age groups, in asymptomatic subjects and those with a longer time from symptoms onset, in vaccine recipients, in individuals not appropriately trained to their usage, in those recently using oral or nasal virucidal agents, in oropharyngeal swabs and saliva, as well as in circumstances when instructions provided by the manufacturers are unclear, incomplete or scarcely readable and intelligible. Acknowledging these important preanalytical limitations will lead the way to a better, more clinically efficient and even safer use of this important technology, which represents an extremely valuable resource for management of the ongoing pandemic., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Genetic counselors are healthcare professionals who are trained in both medical genetics and counseling to help guide individuals through what is known about genetic predispositions toward a variety of diseases, how they are inherited, and what impact this information can have on them and their partners and families. The range and scope of practice of GC has greatly expanded beyond where it started and now, it is employed in a variety of clinical and research settings. The traditional approach to GC involves meeting with a counselor in person. However, with the increasing availability of online resources, more people are seeking information about genetic disorders online. This shift has led to the development of online GC services. Indeed, genetic counselors are no strangers to improvements in terms of adopting digital solutions in their clinical routine, however, there are few studies assessing genetic counselors' attitudes regarding existing digital tools. Genome Access ® is a digital platform that improves patient knowledge in the field of genetic diseases and supports specialists throughout different stages of counseling. This study aims to present Genome Access and discuss the importance of adopting digital technologies designed specifically for GC and what tools these solutions should include., Competing Interests: Authors AC, MP, and MC were employed by Kaleidos SCS onlus., (Copyright © 2022 Cazzaniga, Plebani and Crimi.)

Objective: To identify the potential prognostic value of lymphocyte subsets in COVID-19 patients, where lymphopenia is a common finding., Methods: In 353 COVID-19 inpatients and 40 controls T cell subsets with markers of senescence and exhaustion were studied by flow cytometry., Results: In severe illness, total lymphocytes B, NK, and all T subsets were dampened. Senescent CD4+, but mainly CD8+ T cells, increased in patients with respect to controls. The most significant index predicting fatal outcome was neutrophils/CD3+ T ratio., Conclusion: In conclusion, an altered T cell pattern underlies COVID-19 severity and is involved in predicting the outcome., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: We assessed the inter-method bias of total (tPSA) and free (fPSA) prostate-specific antigen (PSA) immunoassays to establish if tPSA-based risk thresholds for advanced prostate cancer (PCa), obtained from one method (Roche) can be converted into the corresponding concentrations assayed by other methods. Then we evaluated the impact of the bias of tPSA and fPSA on the estimation of the %f/tPSA ratio and performed a re-calibration of the proposed thresholds for the %f/tPSA ratio according to the assay used., Methods: tPSA and fPSA were measured in 135 and 137 serum samples, respectively by Abbott Alinity i, Beckman Access Dxl, Roche Cobas e801, and Siemens Atellica IM analytical platforms. Scatterplots, Bland-Altman diagrams, Passing-Bablok (PB) were used to inspect and estimate the systematic and proportional bias between the methods. The linear equations with confidence intervals of the parameter estimates were used to transform the tPSA risk thresholds for advanced PCa into the corresponding concentrations measurable by the other analytical methods. To construct a correction coefficient for converting the %f/tPSA ratio from one method to the other, PB and non-parametric boostrapping were used., Results: The inter-method bias is not constant but strictly linear allowing the conversion of PSA results obtained from Roche into the other assays, which underestimate tPSA vs. Roche. Siemens and Abbott vs. Roche and Beckman assays, being characterized by a positive and a negative proportional bias for tPSA and fPSA measurements, tend to overestimate the %f/tPSA ratio., Conclusions: There is a consistent risk to miss advanced PCa, if appropriate conversion factors are not applied., (© 2022 the author(s), published by De Gruyter, Berlin/Boston.)

Objectives: The rapid, accurate and safe detection of SARS-CoV-2 is the key to improving surveillance and infection containment. The aim of the present study was to ascertain whether, after heat/chemical inactivation, SARS-CoV-2 N antigen chemiluminescence (CLEIA) assay in saliva remains a valid alternative to molecular testing., Methods: In 2022, 139 COVID-19 inpatients and 467 healthcare workers were enrolled. In 606 self-collected saliva samples (Salivette), SARS-CoV-2 was detected by molecular (TaqPath rRT-PCR) and chemiluminescent Ag assays (Lumipulse G). The effect of sample pre-treatment (extraction solution-ES or heating) on antigen recovery was verified., Results: Salivary SARS-CoV-2 antigen assay was highly accurate (AUC=0.959, 95% CI: 0.943-0.974), with 90% sensitivity and 92% specificity. Of the 254 antigen positive samples, 29 were false positives. We demonstrated that heterophilic antibodies could be a cause of false positive results. A significant antigen concentration decrease was observed after ES treatment (p=0.0026), with misclassification of 43 samples. Heat had a minimal impact, after treatment the correct classification of cases was maintained., Conclusions: CLEIA SARS-CoV-2 salivary antigen provides accurate, timely and high-throughput results that remain accurate also after heat inactivation, thus ensuring a safer work environment. This supports the use of salivary antigen detection by CLEIA in surveillance programs., (© 2022 the author(s), published by De Gruyter, Berlin/Boston.)

Obejctives: Serosurveys can be used to monitor COVID-19 seroprevalence and conduct surveillance. Dried blood spot (DBS), used increasingly as a valuable sample to assay severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies (Ab), has several advantages, particularly in infants, due to the limited amount of blood required and its utility in testing a large number of samples in a limited time-frame. We evaluated SARS-CoV-2 IgG Ab prevalence in newborn DBS in the Trentino region of Italy, during the time period January 2020 - December 2021., Methods: Anti-SARS-CoV-2 IgG levels were determined in DBS by means of Anti-SARS-CoV-2 QuantiVac IgG ELISA assay (Euroimmun, Lubeck, Germany)., Results: Analyses included 2,400 DBS from newborns (54% M, 46% F), samples being collected 2-3 days after birth. The first DBS that tested positive for anti-SARS-CoV-2 IgG antibodies was found in March 2020 and, up to May 2020, only 4 positive results were detected overall. Starting from June 2020, the positivity thresholds increased according to the epidemiological waves of the COVID-19 pandemic in Italy, with a robust increment in the winters of 2020 and 2021. The percentage of positive DBS rose from 0 to 6% to 10-47%, in 2020 and 2021, respectively., Conclusions: This study demonstrates DBS is a suitable tool for both epidemiological purposes and surveillance in the SARS-CoV-2 pandemic, particularly in newborns and pregnant women, saving blood waste and sparing patients any discomfort., (© 2022 the author(s), published by De Gruyter, Berlin/Boston.)

The EFLM recommends not to implement the race-free Chronic Kidney Disease Epidemiology Consortium (CKD-EPI) equation in European laboratories and to keep the 2009 version of the CKD-EPI equation, without applying a race correction factor. This recommendation is completely in line with a recent Editorial published by the European Renal Association who has also proposed to change to a novel equation only when it has considerably better performance, trying to reach global consensus before implementing such a new glomerular filtration rate (GFR) estimation equation. In Europe, this equation could be for instance the new European Kidney Function Consortium (EKFC) equation, which is population-specific, developed from European cohorts and accurate from infants to the older old. Beyond serum creatinine, the estimating equations based on cystatin C will probably gain in popularity, especially because cystatin C seems independent of race. Finally, we must keep in mind that all GFR equations remain an estimation of GFR, especially rough at the individual level. Measuring GFR with a reference method, such as iohexol clearance, remains indicated in specific patients and/or specific situations, and here also, the role of the clinical laboratories is central and should still evolve positively in the future., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Purpose: Vitamin K deficiency and hence a high level of plasma dephosphorylated undercarboxylated matrix Gla protein (dp-ucMGP) is frequent in patients on hemodialysis. This group is recommended to restrict their potassium intake which often leads to restriction of vitamin K rich foods. A menaquinone-7 (MK-7) supplement has been shown to decrease dp-ucMGP, but it has yet to be examined if a vitamin K rich diet could be equally effective., Patients and Methods: A prospective randomized crossover intervention trial with two arms; 6 weeks of 360 μg MK-7 tablet/day and 6 weeks of a vitamin K rich diet with a 3-week washout period in between. Participants were 10 patients in hemodialysis and the primary outcome measures were changes in dp-ucMGP, total MGP (tMGP), and undercarboxylated osteocalcin (ucOC). Furthermore, the level of potassium and phylloquinone in broccoli was determined after different durations of boiling., Results: During the MK-7 intervention the dp-ucMGP and ucOC decreased significantly compared to baseline (-0.42 [-0.93; -0.22] nmol/L ( p =<0.01) and -1.85 [-2.91; -1.30] nmol/L ( p <0.01)), while these were unchanged during the dietary intervention (0.03 [-0.64; 0.37] nmol/L ( p =1.00) and 0.30 [-1.71; 1.41] nmol/L ( p =0.77)). Between the two interventions there was a greater decrease in ucOC ( p =0.02) during the MK-7 compared to the dietary period. No significant changes in the total MGP levels were found in any of the periods. The retention of potassium following boiling for 2 minutes and 8 minutes was 76% and 49%, respectively, while for phylloquinone the retention was 92%, and independent of duration of boiling., Conclusion: A daily MK-7 supplement for 6 weeks lowered dp-ucMGP and ucOC significantly, while a vitamin K rich diet was not able to induce any significant effect. Boiled broccoli maintains a reasonable content of phylloquinone while potassium is extracted and is a reasonable source of phylloquinone for patients on hemodialysis., Competing Interests: The authors declare no conflict of interest., (© 2022 Lentz et al.)

The ability of the current grading systems to predict optimal outcomes in stroke patients with favourable collaterals remains unexplored. We evaluated differences in the performance of grading systems between Careggi Collateral Score and ASITN/SIR collateral score to predict clinical and radiological outcomes in stroke patients with favourable collaterals who underwent thrombectomy. We included stroke patients receiving thrombectomy within 360 min after symptom onset with MCA occlusion and favourable collaterals (i.e., without poor collaterals) defined by ASITN/SIR collateral score between 2 and 4. Using ordinal regression, we estimated the association of each CCS and ASITN/SIR grade with mRS shift (0-6) at 3 months, NIHSS score (0-42) and ASPECT score (10-0) at baseline, TICI score (3-0), infarct growth, cerebral bleeding, and cerebral edema grading at 24 h by calculating the odds ratios (ORs) with two-sided 95% confidence intervals after adjustment for predefined variables. Using the best collateral grade (CCS = 4) as reference, ORs of the CCS grades were associated in the direction of unfavourable outcome on 3-month mRS shift (2.325 for CCS = 3; 5.092 for CCS = 2), in the direction of more severe baseline NIHSS score (5.434 for CCS = 3; 16.041 for CCS = 2), 24-h infarct growth (2.659 for CCS = 3; 8.288 for CCS = 4) and 24-h cerebral edema (1.057 for CCS = 3; 5.374 for CCS = 2) shift. ORs of the ASITN/SIR grades were associated in the direction of more severe baseline NIHSS score (4.332 for ASITN/SIR = 3; 16.960 for ASITN/SIR = 2) and 24-h infarct growth (2.138 for ASITN/SIR = 3; 7.490 for ASITN/SIR = 2) shift. The AUC ROC of CCS and ASITN/SIR for predicting 3-month mRS score 0-1 were 0.681 (95% CI: 0.562-0.799; p = 0.009) and 0.599 (95% CI: 0.466-0.73; p = 0.156), respectively. CCS = 4 and ASITN/SIR ≥ 3 were the optimal cut-offs to predict 3-month mRS score 0-1, respectively. CCS grading system performed better than the ASITN/SIR collateral score predicting 3-month mRS score and 24-h CED grading in stroke patients with favourable collaterals who received thrombectomy for MCA occlusion., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Alemtuzumab-induced autoimmune thyroid events (AIATEs) are the most common adverse effects observed in relapsing-remitting multiple sclerosis (RRMS) patients. This study aims to explore the clinical and biochemical characteristics of such AIATEs, and to examine the risk factors for their occurrence, particularly for the worst clinical phenotype of fluctuating Graves' disease (GD)., Design, Patients, Measurements: We retrospectively analysed a real-life single-centre consecutive series of 57 RRMS patients treated with alemtuzumab whose clinical and biochemical parameters were collected before starting the treatment and then monthly during their follow-up., Results: AIATEs developed in 39% of patients a mean 17 months ± 11 after the first cycle of alemtuzumab. The most common AIATEs were GD (64%), followed by Hashimoto's thyroiditis with hypothyroidism (23%), TSH-receptor-antibody (TRAb)-positive hypothyroidism (9%), and silent thyroiditis (4%). GD showed a fluctuating course in 57% of cases. Baseline positivity for anti-thyroperoxidase antibodies, and higher absolute titers of anti-thyroglobulin and anti-thyroperoxidase antibodies correlated significantly with the risk of developing AIATEs, but TRAb positivity did not. Higher TRAb titers at the time of GD being diagnosed correlated strongly with a greater risk of the fluctuating GD phenotype. On ROC curve analysis, we found that a cut-off of 7.3 IU/L could be used to predict the risk of developing a fluctuating GD, with a positive predictive value of 100%., Conclusions: TRAb levels measured with commercial automatic methods at the time of a patient being diagnosed with alemtuzumab-induced GD emerged as a novel biomarker for predicting a fluctuating disease phenotype, with an influence on subsequent therapeutic decisions and patients' follow-up., (© 2021 John Wiley & Sons Ltd.)

Background: Patient-based real-time quality control (PBRTQC), a complement to traditional QC, may eliminate matrix effect from QC materials, realize real-time monitoring as well as cut costs. However, the accuracy of PBRTQC has not been satisfactory as physicians expect till now. Our aim is to set up a artificial intelligence-based QC for small error detection in real laboratory settings. Taking tPSA as our unique research subject, data extraction, data stimulation, data partition, model construction and evaluation were designed., Methods: 84241 deidentified results for tPSA were extracted from Laboratory Information System of Aviation General Hospital. The data set was accumulated by way of data simulation. Independent training and test datasets were separated. After three classification models (RF, SVM and DNN) in ML constructed and weighted by information entropy, a multi-model fusion algorithm was generated. Performance of the fusion model was evaluated by comparing with optimal PBRTQC., Results: For 4 PBRTQC methods, MovSO showed overall better performance for 0.2 μg/L bias and optimal MNPed was equal to 200. For the fusion model, MNPeds were less than 12 for all biases, and ACC surpassed MovSO nearly 100 times. Except for 0.01 μg/L bias, ACC was more than 0.9 for the rest of biases. FPR was apparently lower than MovSO, only 0.2% and 0.1%., Conclusion: The fusion model shows outstanding performance and reduces incorrect and omitting error detection, adaptable for the real settings., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Fibroblast growth factor 23 (FGF23) plays a key role in the pathophysiology of chronic kidney disease (CKD) and of the associated cardiovascular diseases, ranking on the crossroads of several evolving areas with a relevant impact on the health-care system (ageing, treatment of CKD and prevention from cardiovascular and renal events). In this review, we will critically appraise the overall issues concerning the clinical usefulness of FGF23 determination in CKD, focusing on the analytical performances of the methods, aiming to assess whether and how the clinical introduction of FGF23 may promote cost-effective health care policies in these patients., Content: Our comprehensive critical appraisal of the literature revealed that we are currently unable to establish the clinical usefulness of FGF23 measured by ELISA in CKD, as stability issues and suboptimal analytical performances are the major responsible for the release of misleading results. The meta-analytical approach has failed to report unambiguous evidence in face of the wide heterogeneity of the results from single studies., Summary and Outlook: Our review has largely demonstrated that the clinical usefulness depends on a thorough analytical validation of the assay. The recent introduction of chemiluminescent intact-FGF23 (iFGF23) assays licensed for clinical use, after passing a robust analytical validation, has allowed the actual assessment of preliminary risk thresholds for cardiovascular and renal events and is promising to capture the iFGF23 clinically relevant changes as a result of a therapeutic modulation. In this perspective, the analytical optimization of FGF23 determination may allow a marriage between physiology and epidemiology and a merging towards clinical outcomes., (© 2022 the author(s), published by De Gruyter, Berlin/Boston.)

Quality in laboratory medicine is defined as "an unfinished journey", as the more essential the laboratory information provided, the more assured its quality should be. In the past decades, the Journal Clinical Chemistry and Laboratory Medicine has provided a valuable forum for garnering new insights into the analytical and extra-analytical phases of the testing cycle, and for debating crucial aspects of quality in clinical laboratories. The impressive number of papers published in the Journal is testimony to the efforts made by laboratory professionals, national and international scientific societies and federations in the quest to continuously improve upon the pre-, intra- and post-analytical steps of the testing cycle, thus enhancing the quality of laboratory information. The paper appearing in this special issue summarizes the most important and interesting contributions published in the Journal , thus updating our knowledge on quality in laboratory medicine and offering further stimuli to identify the most valuable measures of quality in clinical laboratories., (© 2022 the author(s), published by De Gruyter, Berlin/Boston.)

Artificial intelligence plays an important role in contemporary medicine. In this short note, we emphasize that philosophy played a role in the development of artificial intelligence. We argue that research in computability theory, the theoretical foundation of modern computer science, was motivated by a philosophical question: can we characterize precisely the class of problems that can be solved by algorithms? We suggest that reflecting on the connection between philosophy and artificial intelligence helps realize that philosophical and scientific progress are connected., (© 2022 the author(s), published by De Gruyter, Berlin/Boston.)

Background: Quantification of SARS-CoV-2 antigens by means of rapid, high-throughput and fully-automated techniques has been proposed as a feasible alternative to overcome the current shortage of resources for routine molecular diagnostics. To this end, we provide here a systematic review of diagnostic accuracy of DiaSorin Liaison SARS-CoV-2 antigen immunoassay., Methods: An electronic search was conduced in Medline and Scopus, with no language or date restrictions (up to January 20, 2022), for identifying all published studies articles in which the diagnostic performance of the DiaSorin Liaison SARS-CoV-2 antigen immunoassay was compared with molecular diagnostic techniques., Results: The electronic search identified a final number of 11 studies, totalling 4449 oro- and naso-pharyngeal specimens. The pooled diagnostic sensitivity, specificity and area under the curve (AUC) of the Liaison SARS-CoV-2 antigen immunoassay in all samples were 0.51 (95%CI, 0.49-0.54), 1.00 (95%CI, 1.00-1.00) and 0.994 (95%CI, 0.990-0.998), respectively, whilst the overall concordance with molecular diagnostics was 82.1%. The pooled diagnostic sensitivity, specificity and AUC of the Liaison SARS-CoV-2 antigen immunoassay in specimens with high viral load (i.e., cycle threshold values <25-30) were 0.79 (95%CI, 0.75-0.82), 1.00 (95%CI, 0.99-1.00) and 0.911 (95%CI, 0.879-0.943), respectively, whilst the overall concordance with molecular diagnostics in such samples increased to 94.2%., Conclusion: The results of this systematic literature review suggest that there is sufficient accuracy of the DiaSorin Liaison SARS-CoV-2 antigen immunoassay in samples with high viral loads that would enable its reliable usage for identifying superspreaders, who are responsible for the vast majority of transmission events., Competing Interests: None, (Copyright © 2022 International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). All rights reserved.)

Aims: Compared with adult patients, clinical manifestations of children's coronavirus disease-2019 (COVID-19) are generally perceived as less severe. The objective of this study was to evaluate cardiac involvement in previously healthy children with asymptomatic or mildly symptomatic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection., Methods and Results: We analysed a cohort of 53 paediatric patients (29 males, 55%), mean age 7.5 ± 4.7 years, who had a confirmed diagnosis of SARS-CoV-2 infection and were asymptomatic or only mildly symptomatic for COVID-19. Patients underwent standard transthoracic echocardiogram and speckle tracking echocardiographic study at least 3 months after diagnosis. Thirty-two age, sex, and body surface area comparable healthy subjects were used as control group. Left ventricular ejection fraction was within normal limits but significantly lower in the cases group compared to controls (62.4 ± 4.1% vs. 65.2 ± 5.5%; P = 0.012). Tricuspid annular plane systolic excursion (20.1 ± 3 mm vs. 19.8 ± 3.4 mm; P = 0.822) and left ventricular (LV) global longitudinal strain (-21.9 ± 2.4% vs. -22.6 ± 2.5%; P = 0.208) were comparable between the two groups. Regional LV strain analysis showed a significant reduction of the LV mid-wall segments strain among cases compared to controls. Furthermore, in the cases group, there were 14 subjects (26%) with a regional peak systolic strain below -16% (-2.5 Z score in our healthy cohort) in at least two segments. These subjects did not show any difference regarding symptoms or serological findings., Conclusion: SARS-CoV-2 infection may affect left ventricular deformation in 26% of children despite an asymptomatic or only mildly symptomatic acute illness. A follow-up is needed to verify the reversibility of these alterations and their impact on long-term outcomes., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Major adverse cardiovascular events are frequently observed in patients undergoing major non-cardiac surgery during the peri-operative period. At this time, the possibility to predict cardiovascular events remains limited, despite the introduction of several algorithms to calculate the risk of adverse events, mainly death and major adverse cardiovascular events (MACE) based on the clinical history, risk factors (sex, age, lipid profile, serum creatinine) and non-invasive cardiac exams (electrocardiogram, echocardiogram, stress tests). The cardiac-specific biomarkers natriuretic peptides (NPs) and cardiac troponins (cTn) have been proposed as additional tools for risk prediction in the peri-operative period, particularly for the identification of myocardial injury in patients undergoing major non-cardiac surgery. The prognostic information from the measurement of BNP/NT-proBNP and hs-cTn is independent and complementary to other important indicators of risk, also including ECG and imaging techniques. Elevated levels of cardiac-specific biomarkers before surgery are associated with a markedly higher risk of MACE during the peri-operative period. BNP/NT-proBNP and hs-cTn should be measured in all patients during the clinical evaluation before surgery, particularly during intermediate- or high-risk surgery, in patients aged >65 years and/or with comorbidities. Several questions remain to be assessed in dedicated clinical studies, such as how to optimize the management of patients with raised cardiac specific biomarkers before surgery, and whether a strategy based on biomarker measurement improves patient outcomes and is cost-effective., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: Patient-based real-time quality control (PBRTQC) has gained attention as an alternative/integrative tool for internal quality control (iQC). However, it is still doubted for its performance and its application in real clinical settings. We aim to generate a newly and easy-to-access patient-based real-time QC by machine learning (ML) traceable to standard reference data with assigned values by National Institute of Metrology of China (NIM), and to compare it with PBRTQC for clinical validity evaluation., Methods: For five representative biochemistry analytes, 1,195 000 patient testing results each were collected. After data processing, independent training and test sets were divided. Machine learning internal quality control (MLiQC) was set up by Random Forest in ML and was validated by way of both metrology algorithm traceability and 4 PBRTQC methods recommended by IFCC analytical working group., Results: MLiQC were established. As an example of albumin (ALB) at the critical bias, the uncertainty of MLiQC was 0.14%, which was evaluated by standard reference data produced by NIM. Compared with four optimal PBRTQC methods at critical bias, the average of the number of patient samples from a bias introduced until detected (ANPed) of MLiQC averagely decreased from 600 to 20. The median and 95 quantiles of NPeds (MNPed and 95NPed) of MLiQC were superior to all optimal PBRTQCs above 90% for all test items., Conclusions: MLiQC is highly superior to PBRTQC and well-suited in real settings. The validation of the model from two aspects of algorithm traceability and clinical effectiveness confirms its satisfactory performance., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

The infectious respiratory condition COVID-19 manifests a clinical course ranging from mild/moderate up-to critical systemic dysfunction and death linked to thromboinflammation. During COVID-19 infection, neutrophil extracellular traps participating in cytokine storm and coagulation dysfunction have emerged as diagnostic/prognostic markers. The characterization of NET identified that mainly histones, have the potential to initiate and propagate inflammatory storm and thrombosis, leading to increased disease severity and decreased patient survival. Baseline assessment and serial monitoring of blood histone concentration may be conceivably useful in COVID-19. We performed a literature review to explore the association among increased circulating levels of histones, disease severity/mortality in COVID-19 patients, and comparison of histone values between COVID-19 and non-COVID-19 patients. We carried out an electronic search in Medline and Scopus, using the keywords "COVID-19" OR "SARS-CoV-2" AND "histone" OR "citrullinated histones" OR "hyperhistonemia", between 2019 and present time (i.e., June 07th, 2022), which allowed to select 17 studies, totaling 1,846 subjects. We found that substantially elevated histone values were consistently present in all COVID-19 patients who developed unfavorable clinical outcomes. These findings suggest that blood histone monitoring upon admission and throughout hospitalization may be useful for early identification of higher risk of unfavorable COVID-19 progression. Therapeutic decisions in patients with SARS-CoV-2 based on the use of histone cut-off values may be driven by drugs engaging histones, finally leading to the limitation of cytotoxic, inflammatory, and thrombotic effects of circulating histones in viral sepsis., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

During the last few years, clinical laboratories have faced a sea change, from facilities producing a high volume of low-cost test results, toward a more integrated and patient-centered service. Parallel to this paradigm change, the digitalization of healthcare data has made an enormous quantity of patients' data easily accessible, thus opening new scenarios for the utilization of artificial intelligence (AI) tools. Every day, clinical laboratories produce a huge amount of information, of which patients' results are only a part. The laboratory information system (LIS) may include other "relevant" compounding data, such as internal quality control or external quality assessment (EQA) results, as well as, for example, timing of test requests and of blood collection and exams transmission, these data having peculiar characteristics typical of big data, as volume, velocity, variety, and veracity, potentially being used to generate value in patients' care. Despite the increasing interest expressed in AI and big data in laboratory medicine, these topics are approaching the discipline slowly for several reasons, attributable to lack of knowledge and skills but also to poor or absent standardization, harmonization and problematic regulatory and ethical issues. Finally, it is important to bear in mind that the mathematical postulation of algorithms is not sufficient for obtaining useful clinical tools, especially when biological parameters are not evaluated in the appropriate context. It is therefore necessary to enhance cooperation between laboratory and AI experts, and to coordinate and govern processes, thus favoring the development of valuable clinical tools., (© 2022 the author(s), published by De Gruyter, Berlin/Boston.)

Importance: Understanding the long-term immune response against SARS-CoV-2 infection in children is crucial to optimize vaccination strategies. Although it is known that SARS-CoV-2 antibodies may persist in adults 12 months after infection, data are limited in the pediatric population., Objective: To examine long-term anti-SARS-CoV-2 spike receptor-binding domain (S-RBD) IgG kinetics in children after SARS-CoV-2 infection., Design, Setting, and Participants: In this single-center, prospective cohort study, patients were enrolled consecutively from April 1, 2020, to August 31, 2021, at the COVID-19 Family Cluster Follow-up Clinic, Department of Women's and Children's Health, University Hospital of Padua. A cohort of 252 COVID-19 family clusters underwent serologic follow-up at 1 to 4, 5 to 10, and more than 10 months after infection with quantification of anti-S-RBD IgG by chemiluminescent immunoassay., Exposures: SARS-CoV-2 infection., Results: Among 902 study participants, 697 had confirmed SARS-CoV-2 infection, including 351 children or older siblings (mean [SD] age, 8.6 [5.1] years) and 346 parents (mean [SD] age, 42.5 [7.1] years). Among 697 cases, 674 (96.7%) were asymptomatic or mild. Children had significantly higher S-RBD IgG titers than older patients across all follow-up time points, with an overall median S-RBD IgG titer in patients younger than 3 years 5-fold higher than adults (304.8 [IQR, 139.0-516.6] kBAU/L vs 55.6 [24.2-136.0] kBAU/L, P < .001). Longitudinal analysis of 56 study participants sampled at least twice during follow-up demonstrated the persistence of antibodies up to 10 months from infection in all age classes, despite a progressive decline over time., Conclusions and Relevance: In this cohort study of Italian children and adults following SARS-CoV-2 infection different kinetics of SARS-CoV-2 antibodies were found across several age classes of individuals with asymptomatic or mild COVID-19, which could help in optimizing COVID-19 vaccination strategies and prevention policies. This work provides further evidence of sustained immune response in children up to 1 year after primary SARS-CoV-2 infection.

Background: The continuous emergence of SARS-CoV-2 variants of concern (VOC) with immune escape properties, such as Delta (B.1.617.2) and Omicron (B.1.1.529), questions the extent of the antibody-mediated protection against the virus. Here we investigated the long-term antibody persistence in previously infected subjects and the extent of the antibody-mediated protection against B.1, B.1.617.2 and BA.1 variants in unvaccinated subjects previously infected, vaccinated naïve and vaccinated previously infected subjects., Methods: Blood samples collected 15 months post-infection from unvaccinated (n=35) and vaccinated (n=41) previously infected subjects (Vo' cohort) were tested for the presence of antibodies against the SARS-CoV-2 spike (S) and nucleocapsid (N) antigens using the Abbott, DiaSorin, and Roche immunoassays. The serum neutralising reactivity was assessed against B.1, B.1.617.2 (Delta), and BA.1 (Omicron) SARS-CoV-2 strains through micro-neutralisation. The antibody titres were compared to those from previous timepoints, performed at 2- and 9-months post-infection on the same individuals. Two groups of naïve subjects were used as controls, one from the same cohort (unvaccinated n=29 and vaccinated n=20) and a group of vaccinated naïve healthcare workers (n=61)., Results: We report on the results of the third serosurvey run in the Vo' cohort. With respect to the 9-month time point, antibodies against the S antigen significantly decreased (P=0.0063) among unvaccinated subjects and increased (P<0.0001) in vaccinated individuals, whereas those against the N antigen decreased in the whole cohort. When compared with control groups (naïve Vo' inhabitants and naïve healthcare workers), vaccinated subjects that were previously infected had higher antibody levels (P<0.0001) than vaccinated naïve subjects. Two doses of vaccine elicited stronger anti-S antibody response than natural infection (P<0.0001). Finally, the neutralising reactivity of sera against B.1.617.2 and BA.1 was 4-fold and 16-fold lower than the reactivity observed against the original B.1 strain., Conclusions: These results confirm that vaccination induces strong antibody response in most individuals, and even stronger in previously infected subjects. Neutralising reactivity elicited by natural infection followed by vaccination is increasingly weakened by the recent emergence of VOCs. While immunity is not completely compromised, a change in vaccine development may be required going forward, to generate cross-protective pan-coronavirus immunity in the global population., (© 2022. The Author(s).)

Aims: Outcome predictors in myocarditis are not well defined; we aimed at identifying predictors of death, heart transplantation (HTx) and relapse before the introduction of immunosuppression., Methods and Results: From 1992 to 2012, 466 consecutive patients (68% male, mean age 37 ± 17 years, single centre recruitment, median follow-up 50 months) were included, of whom 216 had clinically suspected and 250 biopsy-proven myocarditis. Serum anti-heart (AHA) and anti-intercalated disk (AIDA) autoantibodies were measured by indirect immunofluorescence. Univariable and multivariable analyses of clinical and diagnostic features at diagnosis were performed. Survival free from death or HTx at 10 years was 83% in the whole study population and was lower in biopsy-proven versus clinically suspected myocarditis (76% vs. 94%, p < 0.001). Female gender (hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.1-6.5), fulminant presentation (HR 13.77, 95% CI 9.7-261.73), high-titre organ-specific AHA (HR 4.2, 95% CI 1.2-14.7) and anti-nuclear antibodies (ANA) (HR 5.2, 95% CI 2.1-12.8) were independent predictors of death or HTx; higher echocardiographic left ventricular ejection fraction (LVEF) at diagnosis was protective, with a 0.93-fold risk reduction for each 1% LVEF increase (95% CI 0.89-0.96). History of myocarditis at diagnosis (HR 8.5, 95% CI 3.5-20.7) was an independent predictor of myocarditis relapse at follow-up; older age was protective (HR 0.95, 95% CI 0.91-0.99). Predictors of death, HTx and relapse did not differ in biopsy-proven versus clinically suspected myocarditis., Conclusions: Young age and a previous myocarditis were independent relapse predictors; female gender, fulminant onset, lower LVEF at presentation and high-titre organ-specific AHA and ANA were independent predictors of death and HTx, suggesting that autoimmune features predict worse prognosis., (© 2022 European Society of Cardiology.)

Background: Coronavirus disease 2019 (COVID-19) can be more severe in infants than in older children. To date, only a few case series have reported data on neonates with COVID-19, including mostly asymptomatic neonates who were tested because of exposure to maternal SARS-CoV-2 infection. This study summarises nationwide epidemiological data, clinical characteristics, treatment and outcomes of neonates presenting with symptomatic SARS-CoV-2 infection., Methods: Data were prospectively collected through the Swiss Paediatric Surveillance Unit from hospitalised neonates with laboratory-confirmed SARS-CoV-2 infection (positive polymerase chain reaction on a respiratory sample) from 1 March 2020 to 31 September 2021. All 29 paediatric hospitals in Switzerland reported cases., Results: In total, 73 neonates were included; 7 (10%) were preterm. The median age at presentation was 17 days (interquartile range [IQR] 11-23); 40 (55%) were female. The majority of neonates (64, 88%) were admitted from home. Nine (12%) had a pre-existing medical condition. Overall, the most common symptom recorded was fever in 52 (71%), followed by rhinorrhoea or nasal congestion in 32 (44%) and respiratory distress in 19 (26%). Twenty (27%) neonates presented with fever without a source. Seven (10%) neonates were admitted to an intensive care unit (5 for respiratory failure and 2 for monitoring). One (1%) neonate required inotropic support. The median length of hospital stay in term neonates was 4 days (IQR 3-5). Two (3%) were treated with corticosteroids and 1 (1%) with remdesivir. In total, 60 (82%) neonates had contact with a known or suspected SARS-CoV-2 index case. All of the 71 neonates for whom data were available were discharged to their homes without symptoms., Conclusion: In neonates, COVID-19 mainly presents with fever, and symptoms of upper and lower respiratory tract infection. The clinical course is mostly mild, requiring a short period of hospitalisation. COVID-19 needs to be added as a differential diagnosis in neonates who present with fever without a source. However, the presence of SARS-CoV-2 should not deter from the search for a serious bacterial infection. Further data from surveillance studies are needed to better understand COVID-19 in neonates, guide therapy and to evaluate whether the clinical spectrum is changing with new SARS-CoV-2 variants.

T cells play a prominent role in orchestrating the immune response to viral diseases, but their role in the clinical presentation and subsequent immunity to SARS-CoV-2 infection remains poorly understood. As part of a population-based survey of the municipality of Vo', Italy, conducted after the initial SARS-CoV-2 outbreak, we sampled the T cell receptor (TCR) repertoires of the population 2 months after the initial PCR survey and followed up positive cases 9 and 15 months later. At 2 months, we found that 97.0% (98 of 101) of cases had elevated levels of TCRs associated with SARS-CoV-2. T cell frequency (depth) was increased in individuals with more severe disease. Both depth and diversity (breadth) of the TCR repertoire were positively associated with neutralizing antibody titers, driven mostly by CD4+ T cells directed against spike protein. At the later time points, detection of these TCRs remained high, with 90.7% (78 of 96) and 86.2% (25 of 29) of individuals having detectable signal at 9 and 15 months, respectively. Forty-three individuals were vaccinated by month 15 and showed a significant increase in TCRs directed against spike protein. Taken together, these results demonstrate the central role of T cells in mounting an immune defense against SARS-CoV-2 that persists out to 15 months.

Alkaline phosphatase (ALP) is an evolutionary conserved enzyme and widely used biomarker in clinical practice. Tissue-nonspecific alkaline phosphatase (TNALP) is one of four human isozymes that are expressed as distinct TNALP isoforms after posttranslational modifications, mainly in bone, liver, and kidney tissues. Beyond the well-known effects on bone mineralization, the bone ALP (BALP) isoforms (B/I, B1, B1x, and B2) are also involved in the pathogenesis of ectopic calcification. This narrative review summarizes the recent clinical investigations and mechanisms that link ALP and BALP to inflammation, metabolic syndrome, vascular calcification, endothelial dysfunction, fibrosis, cardiovascular disease, and mortality. The association between ALP, vitamin K, bone metabolism, and fracture risk in patients with chronic kidney disease (CKD) is also discussed. Recent advances in different pharmacological strategies are highlighted, with the potential to modulate the expression of ALP directly and indirectly in CKD-mineral and bone disorder (CKD-MBD), e.g., epigenetic modulation, phosphate binders, calcimimetics, vitamin D, and other anti-fracture treatments. We conclude that the significant evidence for ALP as a pathogenic factor and risk marker in CKD-MBD supports the inclusion of concrete treatment targets for ALP in clinical guidelines. While a target value below 120 U/L is associated with improved survival, further experimental and clinical research should explore interventional strategies with optimal risk-benefit profiles. The future holds great promise for novel drug therapies modulating ALP.

Perinatal sepsis constitutes a medical emergency and is still one of the major causes of mortality and morbidity. The possibility of an early diagnosis of sepsis is still debated and controversial. In particular, clinical symptoms can be hidden by the association of sepsis with other perinatal diseases and/or by therapeutic strategies performed. In this context, there is evidence that the accuracy of standard of care diagnostic parameters (i.e. blood culture, C-reactive protein, procalcitonin) can be biased by additional confounding factors (gestational age, birth-weight, acute-chronic hypoxia). Therefore, the inclusion in clinical daily practice of new biomarkers of sepsis is of utmost importance. Of a panel of biomarkers, Presepsin (P-SEP) plays an important role in the development and response of the immune system and as an early marker of sepsis both in adult and pediatric patients. Therefore, in the present review we aim to offer an overview of the role of P-SEP in the early detection of perinatal sepsis as a trustworthy marker according to actual statements of official international institutions. Future perspectives regard the possibility of a longitudinal non-invasive biological fluids P-SEP assessment thus limiting the sample stress in high risk newborns., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: The VES-Matic 5 is an automated analyzer that assesses erythrocyte sedimentation rate based on a modified Westergren sedimentation technique. Instrument performance was established by addressing the recommendations of the International Council for Standardization in Haematology., Methods: Comparison against the reference Westergren method was performed for all samples, and further for the low, middle, and upper third of the analytical range. Intra-run precision, inter-run precision, and interference studies were further assessed. This study included the evaluation of reference ranges., Results: The comparison of methods by Passing-Bablok analysis has shown a good agreement without systematic or proportional differences. The regression equation was y =-0.646 + 0.979x. The mean bias of -0.542 was obtained by Bland-Altman analysis and the upper limit of 8.03 with the lower limit of -9.11 can be considered clinically acceptable. Intra-run and inter-run precision were good for each parameter and interference studies did not show any significant bias with exception of anemia samples, which showed a proportional difference when comparing high erythrocyte sedimentation rate values. Using the local adult reference population, we verified the reference ranges in comparison to those available in the literature, and according to the Clinical Laboratory Standards Institute (CLSI) EP28-A3C document. We determined the upper limit partitioned by gender and the following age groups: from 18 to 50, from 50 to 70, and over 70., Conclusions: The VES-Matic 5 analyzer presented good comparability with the reference method. As there are commercial quality control and suitable external quality assessment (EQA) material and programs, the VES-Matic 5 can be employed appropriately for routine purposes., (© 2022 Elisa Piva et al., published by De Gruyter, Berlin/Boston.)

Objectives: The reported prevalence of TSH-receptor (TSHR) autoantibodies (TRAb) in patients with chronic thyroiditis (CT) range from 0 to 48%. The objective was to study the prevalence of TRAb in patients with CT and hypothyroidism and to correlate it with gender, age, thyroid dimensions, TSH levels, and autoimmune diseases., Methods: The study comprised 245 patients with CT and hypothyroidism (median age 42 years, 193 females, 52 males) and 123 Italian healthy subjects matched for sex and age as controls. TRAb were tested with ELISA using a >2.5 IU/L cut off for positivity. TSHR blocking (TBAb) and TSHR stimulating autoantibodies (TSAb) were measured in 12 TRAb-positive patients using bioassays with Chinese hamster ovary (CHO) cells expressing wild-type or R255D-mutated TSHR., Results: TRAb positivity was found in 32/245 (13.1%) patients and significantly correlated (p<0.05) with TSH levels. TRAb positivity was significantly higher in males vs. females (p=0.034), in females 16-45 years of age vs. >45 years of age (p<0.05) and in patients with reduced vs. normal/increased thyroid dimensions (p<0.05). Linear regression analysis showed a correlation between TRAb concentrations with age (p<0.05) and TRAb concentrations with TSH (p<0.01). In bioassay with TSHR-R255D all 12 patients tested were TBAb-positive while 33% were also TSAb-positive suggesting the presence of a mixture of TRAbs with different biological activities in some patients., Conclusions: TRAb have been found in patients with CT and hypothyroidism. A mixture of TBAb and TSAb was found in some patients and this may contribute to the pathogenesis of thyroid dysfunction during the course of the disease., (© 2022 Mariella Giannone et al., published by De Gruyter, Berlin/Boston.)

Objectives: The waning of humoral immunity after COVID-19 vaccine booster (third dose) has not yet been fully evaluated. This study updates data on anti-SARS-CoV-2 spike protein receptor binding domain (S-RBD) binding antibodies (bAb) and neutralizing antibodies (NAb) levels in individuals with homologous vaccination 3-4 months after receiving the booster dose., Methods: Fifty-five healthcare workers (HCW) from Padova University-Hospital were asked to collect serum samples for determining antibodies (Ab) at 12 (t 12 ) and 28 (t 28 ) days, at 6 months (t 6m ) after their first Comirnaty/BNT162b2 inoculation, and 3-4 months after receiving the 3rd homologous booster dose. HCW were monitored weekly for SARS-CoV-2 infection. Ab titers were measured by two chemiluminescent immunoassays, one targeting the S-RBD immunoglobulin G (IgG), and one surrogate viral neutralization test (sVNT), measuring NAb., Results: Twenty of the HCW had natural COVID-19 infection (COVID+) at different times, before either the first or the second vaccination. Median S-RBD IgG and NAb levels and their interquartile ranges 3-4 months after the 3rd dose were 1,076 (529-3,409) kBAU/L and 15.8 (11.3-38.3) mg/L, respectively, for COVID-, and 1,373 (700-1,373) kBAU/L and 21 (12.8-53.9) mg/L, respectively, for COVID+. At multivariate regression analyses, with age and gender included as covariates, S-RBD IgG bAb and sVNT NAb levels were closely associated with the time interval between serological determination and the 3rd vaccine dose (log 10 β coeff =-0.013, p=0.012 and log 10 β coeff =-0.010, p=0.025) for COVID+, whereas no such association was found in COVID- individuals., Conclusions: The third booster dose increases anti-SARS-CoV-2 Ab levels, elevated levels persisting for up to 3-4 months. Waning of Ab levels appears to be less pronounced for COVID+ individuals., (© 2022 Andrea Padoan et al., published by De Gruyter, Berlin/Boston.)

This document, endorsed by the IFCC Working Group on SARS-CoV-2 Variants, aims to update previous indications for diagnosing acute SARS-CoV-2 infection, taking into consideration the evidence that has emerged after the origin and spread of new lineages and sub-lineages of the virus characterized by mutated genetics and altered biochemical, biological and clinical characteristics. These indications encompass the use of different diagnostic strategies in specific clinical settings, such as high risk of SARS-CoV-2 infection (symptomatic patients), low risk of SARS-CoV-2 infection (asymptomatic subjects) at hospital admission/contact tracing, testing in asymptomatic subjects, in epidemiologic surveys and/or population screening, along with tentative indications for identification of new lineages and/or sub-lineages of SARS-CoV-2., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)