Monocyte distribution width (MDW) kinetic for monitoring sepsis in intensive care unit.

OBJECTIVES: Monocyte distribution width (MDW) is a measure of monocyte anisocytosis. In this study, we assessed the role of MDW, in comparison to C-reactive protein (CRP), procalcitonin (PCT), and lactate, as a screening and prognostic biomarker of sepsis in intensive care unit (ICU) by longitudinally measuring it in the first 5 days of hospital stay. METHODS: We considered all consecutive patients admitted to the ICU. At admission, patients were classified as septic or not according to Sepsis-3 criteria. MDW, CRP, PCT, and lactate were measured daily in the first 5 days of hospitalization. ICU mortality was also recorded. RESULTS: We included 193 patients, 62 with sepsis and 131 without sepsis (controls). 58% and 26 % of the patients, with and without sepsis respectively, died during ICU stay. MDW showed the highest accuracy for sepsis detection, superior to CRP, PCT, and lactate (AUC of 0.840, 0.755, 0.708, 0.622, respectively). At admission, no biomarker predicts ICU mortality in patients with sepsis. The kinetic of all biomarkers during the first 5 days of hospitalization was associated with ICU mortality. Noteworthy, above all, the kinetic of MDW showed the best accuracy. Specifically, an increase or decrease in MDW from day 1-4 and 5 was significantly associated with mortality or survival, respectively. CONCLUSIONS: MDW is a reliable diagnostic and prognostic sepsis biomarker, better than traditional biomarkers.

Molecular Biomarkers of Neurodegenerative Disorders: A Practical Guide to Their Appropriate Use and Interpretation in Clinical Practice.

Neurodegenerative disorders (NDs) represent a group of different diseases characterized by the progressive degeneration and death of the nervous system's cells. The diagnosis is challenging, especially in the early stages, due to no specific clinical signs and symptoms. In this context, laboratory medicine could support clinicians in detecting and differentiating NDs. Indeed, biomarkers could indicate the pathological mechanisms underpinning NDs. The ideal biofluid for detecting the biomarkers of NDs is cerebrospinal fluid (CSF), which has limitations, hampering its widespread use in clinical practice. However, intensive efforts are underway to introduce high-sensitivity analytical methods to detect ND biomarkers in alternative nonivasive biofluid, such as blood or saliva. This study presents an overview of the ND molecular biomarkers currently used in clinical practice. For some diseases, such as Alzheimer's disease or multiple sclerosis, biomarkers are well established and recommended by guidelines. However, for most NDs, intensive research is ongoing to identify reliable and specific biomarkers, and no consensus has yet been achieved.

The role of Killer immunoglobulin-like receptors (KIRs) in the genetic susceptibility to non-celiac wheat sensitivity (NCWS).

OBJECTIVES: Non-celiac wheat sensitivity (NCWS) is an emerging clinical condition characterized by gastrointestinal and extraintestinal symptoms following the ingestion of gluten-containing foods in patients without celiac disease (CD) or wheat allergy. Despite the great interest for NCWS, the genetic risk factors still need to be fully clarified. In this study, we first assessed the possible contribution of KIR genes and KIR haplotypes on the genetic predisposition to NCWS. METHODS: Fifty patients with NCWS, 50 patients with CD, and 50 healthy controls (HC) were included in this study. KIR genes and KIR genotyping were investigated in all subjects by polymerase chain reaction with the sequence oligonucleotide probe (PCR-SSOP) method using Luminex technology. RESULTS: We found a statistically different distribution of some KIR genes among NCWS, CD, and HC. Specifically, NCWS showed a decreased frequency of KIR2DL1, -2DL3, -2DL5, -2DS2, -2DS3, -2DS4, -2DS5, and -3DS1 genes, and an increased frequency of -3DL1 gene respect to both CD and HC. No difference was detected in the KIR haplotype expression. At the multivariate analysis, KIR2DL5, -2DS4, and -2DS5 were independent predictors of NCWS. CONCLUSIONS: Our findings suggest a role of KIR genes in NCWS susceptibility, with KIR2DL5, -2DS4, and -2DS5 having a protective effect. Further large-scale multicentric studies are required to validate these preliminary findings.

A machine learning strategy to mitigate the inappropriateness of procalcitonin request in clinical practice.

Aim: The aim of this study was to develop machine learning (ML) models to mitigate the inappropriate request of Procalcitonin (PCT) in clinical wards. Material and methods: We built six different ML models based on both demographical data, i.e., sex and age, and laboratory parameters, i.e., cell blood count (CBC) parameters, inclusive of monocyte distribution width (MDW), and C-reactive protein (CRP). The dataset included 1667 PCT measurements of different patients. Based on a PCT cut-off of 0.50 ng/mL, we found 1090 negative (65.4%) and 577 positive (34.6%) results. We performed a 70:15:15 train:validation:test splitting based on the outcome. Results: Random Forest, Support Vector Machine and eXtreme Gradient Boosting showed optimal performances for predicting PCT positivity, with an area under the curve ranging from 0.88 to 0.89. Conclusions: The ML models developed could represent a useful tool to predict PCT positivity, avoiding unusefulness PCT requests. ML models are based on laboratory tests commonly ordered together with PCT but have the great advantage to be easy to measure and low-cost.

Exosomal miRNAs as Biomarkers of Ischemic Stroke.

Exosomes are small lipid bilayer membrane particles released from all living cells into the extracellular environment. They carry several molecules and have a critical role in cell-cell communication under physiological and pathological conditions. In recent decades, exosomes, and especially their cargo, have emerged as a promising tool for several clinical conditions. However, the literature has become increasingly unambiguous in defining the role of exosomes in chronic cerebrovascular diseases. Because they can pass through the blood-brain barrier, they have great potential to reflect intracerebral changes. They can, thus, provide valuable insight into the mechanisms of central nervous system diseases. The purpose of this review is to describe the literature on the role of exosomal miRNA, which represents the most widely investigated exosomal biomarker, in strokes. First, we provide an overview of exosomes, from biology to isolation and characterization. Then, we describe the relationship between exosomes and stroke pathogenesis. Finally, we summarize the human studies evaluating exosomal miRNA biomarkers of stroke. Although the collective literature supports the potential use of exosomal miRNA as biomarkers of ischemic stroke, there are still several limitations hampering their introduction into clinical practice.

Monocyte distribution width (MDW) in sepsis.

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.

Detection of Antibodies against the Acetylcholine Receptor in Patients with Myasthenia Gravis: A Comparison of Two Enzyme Immunoassays and a Fixed Cell-Based Assay.

The detection of serum anti-acetylcholine receptor (AChR) antibodies is currently an important tool for diagnosing myasthenia gravis (MG) since they are present in about 85% of MG patients. Many serological tests are now available. Nevertheless, results from these tests can be different in some patients. The aim of this study is to compare the sensitivity of a commercially available fixed cell-based assay (F-CBA) to that of enzyme-linked immunosorbent assay (ELISA) kits for anti-AChR detection in patients with a diagnosis of MG. Overall, 143 patients with a confirmed MG diagnosis were included in the study. The detection and measurement of serum anti-AChR antibodies were performed by three analytical methods, namely, a competitive ELISA (cELISA), an indirect ELISA (iELISA), and an F-CBA, according to the manufacturers' instructions. Anti-AChR antibody titers were positive in 94/143 (66%) using the cELISA, in 75/143 (52%) using the iELISA and in 61/143 (43%) using the F-CBA (adult and/or fetal). Method agreement, evaluated by concordant pairs and Cohen's kappa, was as follows: cELISA-iELISA: 110/143 (77%), k = 0.53 (95%CI 0.40-0.66); cELISA-F-CBA: 108/143 (76%), k = 0.53 (95%CI 0.41-0.66); iELISA-F-CBA: 121/143 (85%), k = 0.70 (95%CI 0.57-0.80). Our findings show that the cELISA has better analytical performance than the iELISA and F-CBA. However, the iELISA and F-CBA show the highest concordance.

The Role of TAR DNA Binding Protein 43 (TDP-43) as a CandiDate Biomarker of Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.

BACKGROUND: TAR DNA-binding protein 43 (TDP-43) aggregation in neuronal cells is recognized as a hallmark of amyotrophic lateral sclerosis (ALS). Although the literature strongly supports the pathogenetic role of TDP-43 in ALS pathogenesis, the role of TDP-43 as a biomarker of ALS is controversial. We performed a systematic review and meta-analysis to assess the diagnostic performance of TDP-43 for ALS. METHODS: Relevant publications were identified by a systematic literature search on PubMed and Web of Science from their inception to 8 April 2022. RESULTS: Seven studies, including 472 individuals, of whom 254 had ALS according to the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, met the inclusion criteria for our meta-analysis. According to the random-effects model, CSF TDP-43 levels are higher in ALS patients compared with control groups. CONCLUSIONS: CSF TDP-43 could represent a biomarker of ALS, but further studies are mandatory before drawing conclusions.

Monocyte Distribution Width (MDW) as a biomarker of sepsis: An evidenced-based laboratory medicine approach.

Monocyte Distribution Width (MDW) is a new generation cell blood count parameter providing a measure of monocyte anisocytosis. In the last decades, it has emerged as a reliable biomarker of sepsis in the acute setting, especially emergency department, and intensive care unit. MDW has several advantages over commonly used sepsis biomarkers, including low-cost, ease and speed of measurement. The clinical usefulness of MDW has been established in several studies and some clinical laboratory medicines have already implemented it in their routine. In this article, we describe the analytical and clinical features of MDW to guide its appropriate use in clinical practice by integrating the research evidence with real-world laboratory experience. The proper use of a biomarker is critical for improving patients' care and outcome as well as ensuring healthcare quality.

Evaluation of the analytical performance of three chemiluminescence serological assays for detecting anti-SARS-CoV-2 antibodies.

The serology surveillance of SARS-CoV-2 antibodies represents a useful tool for monitoring protective immunity in the population. We compared the performance of three SARS-CoV-2 antibody serological immunoassays in 600 vaccinated subjects after the BNT162b2 mRNA COVID-19 vaccine. All serum samples were evaluated by three different immunoassays for detecting anti-SARS-COV-2 antibodies. All SARS-CoV-2 antibody serological immunoassays could detect, when present, a post-vaccine humoral immune response. Median (interquartile range, IQR) anti-S-RBD IgG, Access SARS-CoV-2 IgG (1st IS) and Access SARS-CoV-2 IgG II levels of the subjects investigated were, respectively, 687 BAU/mL (131-2325), 419 IU/mL (58-1091) and 104 AU/mL (14-274). By studying a cohort of unvaccinated subjects, without previous COVID-19 infection, we found a high specificity for all methods. A high correlation was found between IgG titres. Considering the kinetics of subjects with multiple doses, we observed that percentage decreasing gradients were comparable across methods. Our results suggest that all the SARS-CoV-2 antibody serological immunoassays evaluated in this study are suitable for monitoring IgG titers over time. This study contributes to a better understanding of antibody response in vaccinated subjects using some currently available assays.

Endothelial Dysfunction and Chronic Inflammation: The Cornerstones of Vascular Alterations in Age-Related Diseases.

Vascular diseases of the elderly are a topic of enormous interest in clinical practice, as they have great epidemiological significance and lead to ever-increasing healthcare expenditures. The mechanisms underlying these pathologies have been increasingly characterized over the years. It has emerged that endothelial dysfunction and chronic inflammation play a diriment role among the most relevant pathophysiological mechanisms. As one can easily imagine, various processes occur during aging, and several pathways undergo irreversible alterations that can promote the decline and aberrations that trigger the diseases above. Endothelial dysfunction and aging of circulating and resident cells are the main characteristics of the aged organism; they represent the framework within which an enormous array of molecular abnormalities occur and contribute to accelerating and perpetuating the decline of organs and tissues. Recognizing and detailing each of these dysfunctional pathways is helpful for therapeutic purposes, as it allows one to hypothesize the possibility of tailoring interventions to the damaged mechanism and hypothetically limiting the cascade of events that drive the onset of these diseases. With this paper, we have reviewed the scientific literature, analysing the pathophysiological basis of the vascular diseases of the elderly and pausing to reflect on attempts to interrupt the vicious cycle that connotes the diseases of aging, laying the groundwork for therapeutic reasoning and expanding the field of scientific research by moving from a solid foundation.

Role of Multiple Vitamin D-Related Polymorphisms in Multiple Sclerosis Severity: Preliminary Findings.

BACKGROUND: Multiple Sclerosis (MS) is a multifactorial disease whose pathogenesis is the result of interaction among genetic, epigenetic, and environmental factors. Among these, a role for vitamin D hypovitaminosis has emerged in recent decades. Vitamin D levels are influenced by both environmental and genetic factors. Single nucleotide polymorphisms (SNPs) in genes codifying for molecules involved in vitamin D metabolism have been associated with an increased risk of developing MS. However, few studies assessed the association of such SNPs with the severity of the disease. The aim of this observational study was to evaluate the potential association among vitamin D status, MS severity, and vitamin D-related SNPs, alone or in combination. METHODS: In a cohort of 100 MS patients, we genotyped 18 SNPs in the following genes: NAD synthetase 1, CYP2R1, vitamin D binding protein, vitamin D receptor, Retinoid X Receptor-α, KLOTHO, CYP24A1, and CYP27A1. Serum 25(OH)D3 levels were measured by high-performance liquid chromatography. Genotyping was performed by real-time polymerase chain reaction or PCR-RFLP. RESULTS: We did not find any association between SNPs, alone or in combination, and MS severity. CONCLUSION: In this study, we make an initial evaluation of the possible influence of several SNPs in vitamin D-related genes on MS severity.

Evaluation of Alpha-Synuclein Cerebrospinal Fluid Levels in Several Neurological Disorders.

(1) Background: Alpha-synuclein (α-syn) is a presynaptic neuronal protein that regulates several neuronal functions. In recent decades, the role of α-syn as a biomarker of neurodegenerative diseases has been explored, especially in synucleinopathies. However, only a few studies have assessed its role as biomarker in other neurological disorders. The aim of the study was to evaluate cerebrospinal fluid (CSF) α-syn levels in several neurological disorders; (2) Methods: We measured CSF α-syn levels by a commercial ELISA kit in 158 patients classified in the following group: controls, Alzheimer's Disease (AD), cerebrovascular diseases, inflammatory central nervous system diseases, other neurological diseases, Parkinson's Disease (PD), and peripheral neuropathy; (3) Results: Patients with PD showed the lowest and patients with AD the highest levels of CSF α-syn (1372 vs. 2912 pg/mL, respectively, p < 0.001). In AD patients, α-syn levels were significantly associated with tau proteins; (4) Conclusions: α-syn could represent a biomarker of neurodegenerative diseases.

Prostate health index (PHI) as a reliable biomarker for prostate cancer: a systematic review and meta-analysis.

OBJECTIVES: Prostate cancer (PCa) represents the second most common solid cancer in men worldwide. In the last decades, the prostate health index (PHI) emerged as a reliable biomarker for detecting PCa and differentiating between non-aggressive and aggressive forms. However, before introducing it in clinical practice, more evidence is required. Thus, we performed a systematic review and meta-analysis for assessing the diagnostic performance of PHI for PCa and for detecting clinically significant PCa (csPCa). METHODS: Relevant publications were identified by a systematic literature search on PubMed and Web of Science from inception to January 11, 2022. RESULTS: Sixty studies, including 14,255 individuals, met the inclusion criteria for our meta-analysis. The pooled sensitivity and specificity of PHI for PCa detection was 0.791 (95%CI 0.739-0.834) and 0.625 (95%CI 0.560-0.686), respectively. The pooled sensitivity and specificity of PHI for csPCa detection was 0.874 (95%CI 0.803-0.923) and 0.569 (95%CI 0.458-0.674), respectively. Additionally, the diagnostic odds ratio was 6.302 and 9.206, respectively, for PCa and csPCa detection, suggesting moderate to good effectiveness of PHI as a diagnostic test. CONCLUSIONS: PHI has a high accuracy for detecting PCa and discriminating between aggressive and non-aggressive PCa. Thus, it could be useful as a biomarker in predicting patients harbouring more aggressive cancer and guiding biopsy decisions.

Longitudinal analysis of anti-SARS-CoV-2 S-RBD IgG antibodies before and after the third dose of the BNT162b2 vaccine.

Immunosurveillance by evaluating anti-spike protein receptor-binding domain (S-RBD) antibodies represents a useful tool to estimate the long immunity against Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection. The aim of this study was to evaluate the kinetics of antibody response in vaccine recipients. We measured anti-S-RBD IgG levels by indirect chemiluminescence immunoassay on Maglumi 800 (SNIBE, California) in 1013 healthy individuals naïve to SARS-CoV2 infection after two and three COVID-19 vaccine doses. We found that anti-S-RBD IgG levels are higher in females than males. Antibody levels gradually decrease to a steady state after four months since the peak, and the decay is independent of age, sex, vaccine doses, and baseline antibodies titer. The third dose induces a high anti-S-RBD IgG reactivity in individuals with previous high responses and triggers a moderate-high anti-S-RBD IgG reactivity. The assessment of anti-S-RBD IgG levels is essential for monitoring long-term antibody response. A third SARS-CoV-2 vaccine dose is associated with a significant immunological response. Thus, our results support the efficacy of the vaccine programs and the usefulness of the third dose.

Monocyte distribution width (MDW) as a screening tool for early detecting sepsis: a systematic review and meta-analysis.

OBJECTIVES: Monocyte distribution has recently emerged as a promising biomarker of sepsis, especially in acute setting, such as Emergency Department and Intensive Care Unit. This study aimed to evaluate the accuracy of monocyte distribution width (MDW) for early detecting patients with sepsis by performing a systemic review and meta-analysis of published studies. METHODS: Relevant publications were identified by a systematic literature search on PubMed and Google Scholar from inception to September 07, 2021. Studies were divided into two groups based on the sepsis criteria applied, namely sepsis-2 or sepsis-3. RESULTS: Ten studies including 9,475 individuals, of whom 1,370 with sepsis (742 according Sepsis-2 and 628 according to Sepsis-3), met the inclusion criteria for our meta-analysis. The pooled sensitivity and specificity were 0.789 and 0.777 for Sepsis-2 criteria, 0.838 and 0.704 for Sepsis-3 criteria. CONCLUSIONS: MDW represents a reliable biomarker for sepsis screening.

The role of serum free light chain as biomarker of Myasthenia Gravis.

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.

Neurogranin as a Reliable Biomarker for Synaptic Dysfunction in Alzheimer's Disease.

(1) Background: Neurogranin is a post-synaptic protein expressed in the neurons of the hippocampus and cerebral cortex. It has been recently proposed as a promising biomarker of synaptic dysfunction, especially in Alzheimer's disease (AD). However, more efforts are needed before introducing it in clinical practice, including the definition of its reference interval (RI). The aim of the study was to establish the RI of cerebrospinal fluid (CSF) neurogranin levels in controls and individuals with non-neurodegenerative neurological diseases; (2) We included a total of 136 individuals that were sub-grouped as follows: AD patients (n = 33), patients with non-neurodegenerative neurological diseases (n = 70) and controls (33). We measured CSF neurogranin levels by a commercial ELISA kit. CSF RI of neurogranin was calculated by a robust method; (3) Results: AD patients showed increased levels of neurogranin. We also found that neurogranin was significantly correlated with T-tau, P-tau and mini mental state examination in AD patients. The lower and upper reference limits of the RI were 2.9 (90%CI 0.1-10.8) and 679 (90%CI 595-779), respectively; (4) Conclusion: This is the first study establishing the RI of CSF neurogranin.