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Sepsis remains a significant global health challenge due to its high mortality and morbidity, compounded by the difficulty of early detection given its variable clinical manifestations. The integration of machine learning (ML) into laboratory medicine for timely sepsis identification and outcome forecasting is an emerging field of interest. This comprehensive review assesses the current body of research on ML applications for sepsis within the realm of laboratory diagnostics, detailing both their strengths and shortcomings. An extensive literature search was performed by two independent investigators across PubMed and Scopus databases, employing the keywords "Sepsis," "Machine Learning," and "Laboratory" without publication date limitations, culminating in January 2023. Each selected study was meticulously evaluated for various aspects, including its design, intent (diagnostic or prognostic), clinical environment, demographics, sepsis criteria, data gathering period, and the scope and nature of features, in addition to the ML methodologies and their validation procedures. Out of 135 articles reviewed, 39 fulfilled the criteria for inclusion. Among these, the majority (30 studies) were focused on devising ML algorithms for diagnosis, fewer (8 studies) on prognosis, and one study addressed both aspects. The dissemination of these studies across an array of journals reflects the interdisciplinary engagement in the development of ML algorithms for sepsis. This analysis highlights the promising role of ML in the early diagnosis of sepsis while drawing attention to the need for uniformity in validating models and defining features, crucial steps for ensuring the reliability and practicality of ML in clinical setting., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Aims: The monitoring of yearly distributions of HbA 2 measured has been indicated as a reliable indicator of worldwide standardization., Materials and Methods: Measurements/year of HbA 2 have been collected over three consecutive years in 15 Italian laboratories each using the same analytical method over three years period. HbA 2 distributions, cleaned of replicated measurements, were compared by the overlapping area of the raw probability density functions expressed by coefficient eta (η), and by comparing the reference intervals for the central part of each distribution estimated by the indirect method refineR using the R package "refineR"., Results: According to the overlapping areas analysis the distributions/year of the data provided by 4 centers able to perform at least 1000 measurements/year were similar in 2 consecutive years. Moreover, the reference intervals provided by 2 centers using the same analytical methods in two separate locations over the three consecutive years, were very similar. The highest overlap (99.7 %) was observed in one center over two consecutive years. The overlapping areas were very high (93.6-95.7%) in 8 out of 9 inter-comparisons., Conclusion: Despite the limitations of this study the yearly distribution of the HbA 2 measured in various centers appears a reliable tool to test HbA 2 standardization over different centers using different analytical methods., 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 © 2023 Elsevier B.V. All rights reserved.)

Sepsis is a life-threatening syndrome due to a dysregulated host response to infection, which can be caused by bacterial, viral, or fungal infection. Thus, it is crucial to know how the different microorganisms influence the levels of a biomarker. In the last decade, monocyte distribution width (MDW) has emerged as a promising sepsis biomarker, especially in acute settings, such as the Emergency Department and Intensive Care Unit. In this article, we explore the relationship between MDW and the different pathogens causing infection. Noteworthy, MDW is not a biological molecule, but it is calculated by a mathematical formula based on monocyte characteristics. Monocytes represent the first line defence against microorganisms and undergo activation upon infection, independently from the invading pathogen. According to the knowledge on the biomarker biology and the few literatures evidence, MDW may be considered a biomarker of sepsis, independent of the causative pathogen. However, further investigations are warranted before drawing definite conclusion., 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 © 2023. Published by Elsevier B.V.)

Background and Aims: Glycated albumin (GA) may assess glycometabolic control over a short period of time respect to HbA 1c , and its use to screen for gestational diabetes in pregnancy has been suggested. To this regard few data on reference intervals (RI) for GA on Europid women have been collected, only from cross-sectional investigations. Aim of this work has been to collect trimester-specific RI for GA in physiological pregnancies, following a longitudinal prospective study., Methods: Forty-five healthy pregnant Europid women have been enrolled for whom a GDM screening test was scheduled at 24-28 weeks, in 5 different Italian centers. Only those negative to the OGTT were included. The women had 4 successive visits at 6-10 weeks of gestation, at 16-18 weeks, at 24-28 weeks and at the end of pregnancy. ALT, AST, total bilirubin, C-reactive protein, cholinesterase, creatinine, GGT, glycated albumin, iron, total serum proteins, transferrin were measured in duplicate on aliquots of serum samples by a central laboratory., Results: The RI (2.5-97.5 percentiles) for GA were 11.1-14.8 % (I visit), 10.9-15.6 % (II visit), 10.6-14.1 % (III visit) and 10.7-14.3 % (IV visit). The RI of other biomarkers confirmed previously published data. The RI for serum cholinesterase we present are novel, and were 5049-9906 U/L (Iv), 4212-8965 U/L (IIv), 3518-8470 U/L (IIIv) and 3945-8727 U/L (IVv)., Conclusions: Trimester-specific RI are important for using GA and serum cholinesterase in pregnancy. However, considering the high inter-individual variability of both markers, the use of longitudinal interpretations of the individual variations of both proteins during pregnancy should be preferred., 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 © 2023 Elsevier B.V. All rights reserved.)

Background and Aim: Myasthenia gravis (MG) is a B lymphocyte-mediated disease affecting neuromuscular transmission. The clinical course of MG is unpredictable due to the fluctuating nature and heterogeneity of the disease. Increased levels of free light chains (FLC), which reflect B cell activation, have been detected in different autoimmune disorders. In this study, we evaluated the potential role of FLC as diagnostic and prognostic biomarkers of MG., Materials and Methods: 74 MG patients and 52 healthy individuals were included in the study. Serum FLC levels were measured by turbidimetric assay (Freelite, The Binding Site Group Ltd) on the Optilite Analyser System in both groups. In MG patients, anti-AChR and anti-MuSK autoantibodies were detected by enzyme-linked immunosorbent assay., Results: MG patients displayed significantly higher serum κ and total FLC levels than controls, respectively for κFLC 16.0 vs 13.8 mg/L and for total FLC 29.8 vs 25.9 mg/L. Moreover, increased κFLC levels were observed in seropositive MG patients. No association was observed between serum FLC levels and clinical manifestations of disease as well as with severity, age at MG onset, thymoma and treatment., Conclusion: Increased levels of κFLC and total FLC could serve as biomarkers to support the diagnosis of MG., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Aims: Glycated albumin (GA) could represent a useful biomarker in pregnant women for diagnosing and monitoring gestational diabetes mellitus (GDM). The establishment of reference intervals (RI) is mandatory before assessing its clinical usefulness. The RIs of GA in healthy pregnant women are not well defined. The aim of the current study was to establish the RI in a cohort consisting of Caucasian pregnant women without overt diabetes mellitus or gestational diabetes mellitus., Methods: The study included 183 healthy pregnant women. GA was measured on plasma by an enzymatic method (quantILab Glycated Albumin, IL Werfen, Germany). The RI was calculated by the non-parametric and robust methods., Results: The RI of GA in the whole population was 10.16% (90%CI 9.60-10.70) and 15.44% (90%CI 14.90-16.90). GA levels decreased during pregnancy, with lower levels in the third trimester: 10.11 (90%CI 9.48-10.79) and 15.72 (90%CI 15.15-16.27) in the first trimester, 10.49 (90%CI 10.05-10.96) and 15.49 (90%CI 15.05-15.92) in the second trimester, 9.84 (90%CI 9.50-10.22) and 14.57 (90%CI 14.11-15.01) in the third trimester. Finally, a weak negative correlation was found between GA levels and body mass index., Conclusion: This is the first study establishing the RIs of GA in Caucasian healthy pregnant women., (Copyright © 2021. Published by Elsevier B.V.)

Background: The aim of the study was to accurately establish the reference interval (RI) of monocyte distribution width (MDW) in healthy blood donors by the direct method using different statistical approaches., Methods: MDW was measured in 486 subjects. RI of MDW was calculated by the non-parametric method, the robust method and, the Harrell-Davis bootstrap method and using different tests to identify potential outliers (Dixon-Reed and Tukey)., Results: Lower and upper reference limits of the RI calculated by the non-parametric method were, 16.22 (90%CI 15.78-16.47) - 23.15 (90%CI 22.80-24.10) (without outlier removal), and 16.44 (90%CI 16.21-16.67) - 22.99 (90%CI 22.33-23.22) (after outlier removal). The RIs based on the robust method were, respectively, 16.29-22.98 (without) and 16.50-22.67 (with outlier removal). Finally, the RIs calculated by the Harrell-Davis bootstrap method, without or after outlier removal, were 16.19-23.24 and 16.43-22.93. Thus, the RIs obtained by the three calculation methods were very similar. Additionally, no RI partition was done since no significant gender or age association was found., Conclusions: Our results support the use of a unique RI of MDW, independently of sex and age., 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 © 2020 Elsevier B.V. All rights reserved.)

Background & Aims: Circulating auto-antibodies targeting conformational antigens on cytochrome P4502E1 (CYP2E1) are detectable in patients with chronic hepatitis C (CHC) and are associated with more severe necro-inflammation. This study investigated the antigen specificity and the possible origin of these auto-antibodies., Methods: CYP2E1 site-directed mutagenesis and molecular simulation were used to characterize the epitope specificity of CHC-associated anti-CYP2E1 auto-antibodies., Results: Immunoprecipitation experiments using differently mutated human CYP2E1s revealed that conformational anti-CYP2E1 antibodies targeted two epitopes located on the molecule surface in an area between Lys(324)-Glu(346) at J-K'' helices overlapping. Such epitopes were not recognized by the sera targeting linear CYP2E1 antigens. The CYP2E1(324-346) peptide showed good homology with two sequences (NS5b(438-449) and NS5b(456-465)) within the NS5b protein of hepatitis C virus (HCV). Consistently, conformational anti-CYP2E1 IgG bind to GST-conjugated NS5b(438-449) and NS5b(456-465) more efficiently than those recognizing CYP2E1 linear antigens. Competition experiments confirmed the cross-reactivity of conformational anti-CYP2E1 IgG with both NS5b(438-449) and NS5b(456-465). Moreover, mice immunized with GST-conjugated NS5b(438-449) or NS5b(456-465) peptides developed antibodies recognizing human CYP2E1., Conclusions: In CHC patients cross-reactivity between CYP2E1 and specific sequences in HCV-NS5b protein can promote the development of auto-antibodies targeting conformational epitopes on the CYP2E1 surface that might contribute to hepatic injury., (Copyright 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

We previously reported that autoantibodies against cytochrome P4502E1 (CYP2E1) are frequent in patients with chronic hepatitis C. As autoimmune reactions are increasingly detected after orthotopic liver transplantation (OLT), this study investigates prevalence and significance of anti-CYP2E1 autoantibodies in 46 patients with post-OLT recurrent hepatitis C. IgG against recombinant human CYP2E1 above the control threshold was detected in 19 out 46 (41%) sera collected immediately before OLT and in 15 out 46 (33%) sera collected at the time of the 12 months follow-up liver biopsy. Although anti-CYP2E1 reactivity was not modified by OLT, the patients with persistently elevated anti-CYP2E1 IgG (n = 12; 26%) showed significantly higher prevalence of recurrent hepatitis with severe necroinflammation and fibrosis than those persistently negative or positive only either before or after OLT. Moreover, the probability of developing severe necroinflammation was significantly higher in persistently anti-CYP2E1-positive subjects. Multivariate regression and Cox analysis confirmed that the persistence of anti-CYP2E1 IgG, together with a history of acute cellular rejection and donor age >50 years, was an independent risk factor for developing recurrent hepatitis C with severe necroinflammation. We propose that autoimmune reactions involving CYP2E1 might contribute to hepatic damage in a subgroup of transplanted patients with recurrent hepatitis C.

Background/aims: The contribution of oxidative stress to the pathogenesis of chronic hepatitis C (CHC) is still poorly elucidated. This study investigated the relationship between oxidative stress, insulin resistance, steatosis and fibrosis in CHC., Methods: IgG against malondialdehyde-albumin adducts and HOMA-IR were measured as markers of oxidative stress and insulin resistance, respectively, in 107 consecutive CHC patients., Results: Oxidative stress was present in 61% of the patients, irrespective of age, gender, viral load, BMI, aminotransferase level, histology activity index (HAI) and HCV genotype. Insulin resistance and steatosis were evident in 80% and 70% of the patients, respectively. In the patients infected by HCV genotype non-3, but not in those with genotype 3 infection HOMA-IR (p<0.03), steatosis (p=0.02) and fibrosis (p<0.05) were higher in the subjects with oxidative stress than in those without. Multiple regression analysis revealed that, HOMA-IR (p<0.01), fibrosis (p<0.01) and oxidative stress (p<0.05) were independently associated with steatosis, whereas steatosis was independently associated with oxidative stress (p<0.03) and HOMA-IR (p<0.02). Steatosis (p<0.02) and HAI (p=0.007) were also independent predictors of fibrosis., Conclusions: In patients infected by HCV genotype non-3, oxidative stress and insulin resistance contribute to steatosis, which in turn exacerbates both insulin resistance and oxidative stress and accelerates the progression of fibrosis.

The aim of the study was to determine if occupational exposure to hydrofluorocarbons (HFC) and hydrochlorofluorocarbons (HCFC) generates autoimmune responses against CYP2E1. HFCs and HCFCs have replaced the chlorofluorocarbons (CFC) in e.g. refrigeration installations and air-conditioning systems. During the substitution period, refrigeration mechanics reported symptoms like asthma, influenza-like reactions, and joint troubles. These symptoms resemble those of chronic inflammatory diseases with an autoimmune component. Since exposure to structurally similar chemicals, e.g. halothane, has previously been associated with autoimmune responses and diseases, autoimmunity among the refrigeration mechanics might hypothetically explain the reported inflammatory symptoms. Serum from 44 Swedish men, occupationally exposed to halogenated hydrocarbons, was screened for antibodies against CYP2E1 with enzyme-linked immunosorbent assay. Thirty of the workers had asthma, joint problems or influenza-like symptoms whereas 14 of them had no such symptoms. They were all selected from a cohort of 280 refrigeration mechanics. Unexposed, healthy, Swedish men (n=35) constituted control group. The study was approved by the Ethics Committee at Karolinska Institutet. No increase in autoantibodies against CYP2E1 was detected among the occupationally exposed workers as compared to the unexposed controls. Further, there was no difference in antibody titer between the exposed workers with symptoms and the exposed, asymtomatic workers or the unexposed controls. The present study does not completely exclude a connection between exposure and effect but makes the relation less likely at these exposure levels.

Background/aims: Chronic hepatitis C (CHC) is often associated with auto-immune reactions. In the light of the role of alcohol in promoting CHC progression, we have investigated the possible presence of auto-reactivity against the ethanol-inducible cytochrome P4502E1 (CYP2E1) in CHC patients with and without alcohol consumption., Methods: The IgG reactivity against recombinant human CYP2E1 was evaluated by solid-phase immunoassays in 102 CHC patients with different alcohol consumption and 59 HCV-free controls., Results: Auto-antibodies against CYP2E1 were significantly (p<0.0001) increased in CHC patients as compared to controls. Anti-CYP2E1 IgG above the 97th percentile in the controls were evident in 41 (40%) CHC patients. Competition experiments revealed that CYP2E1 recognition was not due to the cross-reactivity with CYP2D6. The detection of anti-CYP2E1 IgG was unrelated to alcohol consumption and no difference in gender, age, aminotransferase levels and virus genotype was evident among the patients with or without anti-CYP2E1 auto-antibodies. However, anti-CYP2E1 auto-reactivity was significantly (p=0.025) associated with the severity of periportal/periseptal interface hepatitis. Moreover, confocal microscopy demonstrated that anti-CYP2E1 IgG associated with CHC recognized CYP2E1 exposed on the outer side of hepatocyte plasma membranes., Conclusions: HCV infection favours the breaking of self-tolerance against CYP2E1 that might contribute to hepatocyte injury.

Background/aims: Circulating anti-phospholipid antibodies (aPL) are often present in patients with alcoholic liver disease (ALD). The observations that defects in the disposal of apoptotic corpses leads to the development of aPL prompted us to investigate whether ALD-associated aPL might recognize antigens in apoptotic cells., Methods: Apoptosis was induced in HuT-78 human T-lymphoma and HepG2 hepatoma cells by, respectively, FAS ligation with CH11 monoclonal antibodies or the incubation with ethanol (400 mmol/L)., Results: Flow cytometry revealed that IgG from ALD patients with high aPL titers selectively bind to the surface of apoptotic, but not to viable cells. No binding was instead evident using either control or aPL-negative ALD sera. ELISA assays using different oxidized phospholipids as antigens showed that anti-phospholipid reactivity of ALD sera was mainly directed towards oxidized cardiolipin and phosphatidylserine. The pre-adsorption of aPL-positive sera with oxidized phosphatidylserine, but not with oxidized cardiolipin, lowered aPL binding to apoptotic HuT-78 cells by about 50%. No effect was instead observed by pre-adsorption with oxidation-protected phospholipids or with human serum albumin adducted with different lipid peroxidation products., Conclusions: aPL associated with ALD target apoptotic cells by specifically recognizing oxidized phosphatidylserine, suggesting a possible link between hepatocyte apoptosis and anti-phospholipid auto-reactivity in ALD.

This report presents a comparison of the effects of cis- and trans-diamminedichloroplatinum complexes on in vitro platelet functions. Pretreatment of platelets with cis-platinum (cisplatin) induced a slow, dose-dependent (0.1-0.45 mM), increase in the cytosolic Ca2+ concentration, pleckstrin (47 kDa) phosphorylation and serotonin secretion, as well as a slight shape modification with emission of a few pseudopodia. All these effects were remarkably increased in platelets exposed to trans-platinum (transplatin). The rise in cytosolic Ca2+ concentration and serotonin secretion evoked by stimulation of platelets with thrombin were not significantly influenced by cellular exposure to cis-platinum, whereas they were enhanced and inhibited, respectively, by exposure to trans-platinum. Trans-platinum also inhibited thrombin-promoted platelet aggregation to a greater extent than the cis-isomer. While the viscosity of platelet rich-plasma tended to decrease in the presence of cis-platinum, it tended to increase in the presence of trans-platinum. Taken together, these results indicate that the effects on platelet functions of the efficacious antitumor complex cis-platinum is rather different from that of the inactive complex trans-platinum. Therefore, the in vitro tests of platelet functions employed in this study might provide an index of antitumor drug toxicity and serve as a preliminary indicator of therapeutic efficacy.