Publications by authors named "Tommaso Trenti"

125 Publications

Accuracy of the serological detection of IgG and IgM to SARS-Cov-2: a prospective, cross-sectional study.

Eur J Clin Microbiol Infect Dis 2021 Apr 10. Epub 2021 Apr 10.

Clinical Microbiology Unit, University Hospital Polyclinic, Modena, Italy.

In response to the rapidly evolving of SARS-CoV-2 infection, numerous serological tests have been developed but their sensitivity and specificity are unclear. We collected serum samples of patients and health-care professionals to assess the accuracy of chemiluminescent (CLIA) and two lateral flow immunochromatographic assays (LFIA) to determine IgG and IgM antibodies to SARS-CoV-2 virus. We calculated the φ correlation for qualitative results and test accuracy, adopting the following case definition: either real-time-PCR positivity or serological positivity with at least two different tests. We analyzed 259 samples, obtaining strong correlation between CLIA and both LFIA for IgG (φ=0.9), and moderate correlation for IgM (φ=0.6). For patients, the sensitivity was suboptimal for all methods (CLIA 81%, LFIA A 85%, LFIA B 78%), while it was poor in asymptomatic health-care workers (CLIA 50%, LFIA A 50%, LFIA B 33%). Overall, CLIA is more sensitive and specific for the determination of both IgG and IgM, whilst both LFIA methods reported good sensitivity and specificity for IgG, but scarce sensitivity for the IgM determination. The determination of SARS-CoV-2-specific IgG is useful to detect infection 6 days from symptom onset.
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http://dx.doi.org/10.1007/s10096-021-04224-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036011PMC
April 2021

iVar, an Interpretation-Oriented Tool to Manage the Update and Revision of Variant Annotation and Classification.

Genes (Basel) 2021 Mar 8;12(3). Epub 2021 Mar 8.

Center for Genome Research, University of Modena and Reggio Emilia, 41125 Modena, Italy.

The rapid evolution of Next Generation Sequencing in clinical settings, and the resulting challenge of variant reinterpretation given the constantly updated information, require robust data management systems and organized approaches. In this paper, we present iVar: a freely available and highly customizable tool with a user-friendly web interface. It represents a platform for the unified management of variants identified by different sequencing technologies. iVar accepts variant call format (VCF) files and text annotation files and elaborates them, optimizing data organization and avoiding redundancies. Updated annotations can be periodically re-uploaded and associated with variants as historically tracked attributes, i.e., modifications can be recorded whenever an updated value is imported, thus keeping track of all changes. Data can be visualized through variant-centered and sample-centered interfaces. A customizable search function can be exploited to periodically check if pathogenicity-related data of a variant has changed over time. Patient recontacting ensuing from variant reinterpretation is made easier by iVar through the effective identification of all patients present in the database carrying a specific variant. We tested iVar by uploading 4171 VCF files and 1463 annotation files, obtaining a database of 4166 samples and 22,569 unique variants. iVar has proven to be a useful tool with good performance in terms of collecting and managing data from a medium-throughput laboratory.
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http://dx.doi.org/10.3390/genes12030384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001268PMC
March 2021

Homocysteine (Hcy) assessment to predict outcomes of hospitalized Covid-19 patients: a multicenter study on 313 Covid-19 patients.

Clin Chem Lab Med 2021 Mar 25. Epub 2021 Mar 25.

Division of Clinical Pathology, Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.

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http://dx.doi.org/10.1515/cclm-2021-0168DOI Listing
March 2021

Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies.

Int J Mol Sci 2021 Feb 14;22(4). Epub 2021 Feb 14.

Department of Laboratory Medicine and Pathology, Diagnostic Hematology and Clinical Genomics, AUSL/AOU Policlinico, 41124 Modena, Italy.

The Philadelphia-negative myeloproliferative neoplasms (MPNs) are malignancies of the hematopoietic stem cell (HSC) arising as a consequence of clonal proliferation driven by somatically acquired driver mutations in discrete genes (JAK2, CALR, MPL). In recent years, along with the advances in molecular characterization, the role of immune dysregulation has been achieving increasing relevance in the pathogenesis and evolution of MPNs. In particular, a growing number of studies have shown that MPNs are often associated with detrimental cytokine milieu, expansion of the monocyte/macrophage compartment and myeloid-derived suppressor cells, as well as altered functions of T cells, dendritic cells and NK cells. Moreover, akin to solid tumors and other hematological malignancies, MPNs are able to evade T cell immune surveillance by engaging the PD-1/PD-L1 axis, whose pharmacological blockade with checkpoint inhibitors can successfully restore effective antitumor responses. A further interesting cue is provided by the recent discovery of the high immunogenic potential of JAK2V617F and CALR exon 9 mutations, that could be harnessed as intriguing targets for innovative adoptive immunotherapies. This review focuses on the recent insights in the immunological dysfunctions contributing to the pathogenesis of MPNs and outlines the potential impact of related immunotherapeutic approaches.
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http://dx.doi.org/10.3390/ijms22041906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918142PMC
February 2021

Cytomegalovirus reactivation after hematopoietic stem cell transplant with CMV-IG prophylaxis: A monocentric retrospective analysis.

J Med Virol 2021 Feb 12. Epub 2021 Feb 12.

Section of Hematology, Department of Medical and Surgical Sciences, Azienda Ospedaliero-Universitaria di Modena, University of Modena and Reggio Emilia, Modena, Italy.

Human cytomegalovirus (CMV) represents the most common viral infection after hematopoietic stem cell transplant (HSCT), mainly occurring as reactivation from latency in seropositive patients, with a different prevalence based on the extent and timing of seroconversion in a specific population. Here, we retrospectively analyzed a cohort of patients who underwent HSCT at our Institution between 2013 and 2018, all of whom were prophylactically treated with CMV-IG (Megalotect Biotest®), to define the incidence and clinical outcomes of CMV reactivation and clinically significant infection. CMV infection occurred in 69% of our patient series, mainly resulting from reactivation, and CMV clinically significant infection (CS-CMVi) occurred in 48% of prophylactically treated patients. CMV infection and CS-CMVi impacted neither on relapse incidence nor on overall survival nor on relapse-free survival. Moreover, a very low incidence of CMV end-organ disease was documented. CMV-IG used alone as prophylactic therapy after HSCT does not effectively prevent CMV reactivation.
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http://dx.doi.org/10.1002/jmv.26861DOI Listing
February 2021

Kinetics and biological characteristics of humoral response developing after SARS-CoV-2 infection: implications for vaccination.

Clin Chem Lab Med 2021 Jan 21. Epub 2021 Jan 21.

Department of Laboratory Medicine, University Hospital of Padova, Padova, Italy.

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http://dx.doi.org/10.1515/cclm-2021-0038DOI Listing
January 2021

Dynamic angiopoietin-2 assessment predicts survival and chronic course in hospitalized patients with COVID-19.

Blood Adv 2021 02;5(3):662-673

Internal and Emergency Medicine, Ospedale Civile Baggiovara-Azienda Ospedaliero-Universitaria Modena, Modena, Italy.

This study examined the association between dynamic angiopoietin-2 assessment and COVID-19 short- and long-term clinical course. We included consecutive hospitalized patients from 1 February to 31 May 2020 with laboratory-confirmed COVID-19 from 2 Italian tertiary referral centers (derivation cohort, n = 187 patients; validation cohort, n = 62 patients). Serum biomarker levels were measured by sandwich enzyme-linked immunosorbent assay. Lung tissue from 9 patients was stained for angiopoietin-2, Tie2, CD68, and CD34. Cox model was used to identify risk factors for mortality and nonresolving pulmonary condition. Area under the receiver operating characteristic curve (AUROC) was used to assess the accuracy of 3- and 10-day angiopoietin-2 for in-hospital mortality and nonresolving pulmonary condition, respectively. Three-day angiopoietin-2 increase of at least twofold from baseline was significantly associated with in-hospital mortality by multivariate analysis (hazard ratio [HR], 6.69; 95% confidence interval [CI], 1.85-24.19; P = .004) with AUROC = 0.845 (95% CI, 0.725-0.940). Ten-day angiopoietin-2 of at least twofold from baseline was instead significantly associated with nonresolving pulmonary condition by multivariate analysis (HR, 5.33; 95% CI, 1.34-11.77; P ≤ .0001) with AUROC = 0.969 (95% CI, 0.919-1.000). Patients with persistent elevation of 10-day angiopoietin-2 levels showed severe reticular interstitial thickening and fibrous changes on follow-up computed tomography scans. Angiopoietin-2 and Tie2 were diffusely colocalized in small-vessel endothelia and alveolar new vessels and macrophages. Angiopoietin-2 course is strongly associated with COVID-19 in-hospital mortality and nonresolving pulmonary condition. Angiopoietin-2 may be an early and useful predictor of COVID-19 clinical course, and it could be a relevant part of disease pathogenesis. Angiopoietin-2 blockade may be a COVID-19 treatment option.
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http://dx.doi.org/10.1182/bloodadvances.2020003736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876870PMC
February 2021

Characterization of New Deletion Associated with Hereditary Breast Cancer.

Genes (Basel) 2021 Jan 21;12(2). Epub 2021 Jan 21.

Centre for Regenerative Medicine, University of Modena and Reggio Emilia, 41125 Modena, Italy.

Next-generation sequencing (NGS)-based cancer risk screening with multigene panels has become the most successful method for programming cancer prevention strategies. germ-line heterozygosity has been described to increase tumor susceptibility. In particular, families carrying heterozygous germ-line variants of gene have a 5- to 9-fold risk of developing breast cancer. Recent studies identified as the second most mutated gene after in BRCA-negative patients. Nowadays, more than 170 missense variants and several truncating mutations have been identified in gene. Here, we present the molecular characterization of a new deletion, identified thanks to the CNV algorithm implemented in the NGS analysis pipeline. An automated workflow implementing the SOPHiA Genetics' Hereditary Cancer Solution (HCS) protocol was used to generate NGS libraries that were sequenced on Illumina MiSeq Platform. NGS data analysis allowed us to identify a new inactivating deletion of exons 19-27 of gene. The deletion was characterized both at the DNA and RNA level.
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http://dx.doi.org/10.3390/genes12020136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911716PMC
January 2021

-Mutated Myeloid Neoplasms with <20% Blasts: A Really Distinct Clinico-Pathologic Entity?

Int J Mol Sci 2020 Nov 26;21(23). Epub 2020 Nov 26.

Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria di Modena, Policlinico, 41124 Modena, Italy.

Nucleophosmin () gene mutations rarely occur in non-acute myeloid neoplasms (MNs) with <20% blasts. Among nearly 10,000 patients investigated so far, molecular analyses documented mutations in around 2% of myelodysplastic syndrome (MDS) cases, mainly belonging to MDS with excess of blasts, and 3% of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) cases, prevalently classified as chronic myelomonocytic leukemia. These uncommon malignancies are associated with an aggressive clinical course, relatively rapid progression to overt acute myeloid leukemia (AML) and poor survival outcomes, raising controversies on their classification as distinct clinico-pathologic entities. Furthermore, fit patients with -mutated MNs with <20% blasts could benefit most from upfront intensive chemotherapy for AML rather than from moderate intensity MDS-directed therapies, although no firm conclusion can currently be drawn on best therapeutic approaches, due to the limited available data, obtained from small and mainly retrospective series. Caution is also suggested in definitely diagnosing -mutated MNs with blast count <20%, since -mutated AML cases frequently present dysplastic features and multilineage bone marrow cells showing abnormal cytoplasmic NPM1 protein delocalization by immunohistochemical staining, therefore belonging to -mutated clone regardless of blast morphology. Further prospective studies are warranted to definitely assess whether mutations may become sufficient to diagnose AML, irrespective of blast percentage.
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http://dx.doi.org/10.3390/ijms21238975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730332PMC
November 2020

Sphingosine-1 phosphate induces cAMP/PKA-independent phosphorylation of the cAMP response element-binding protein (CREB) in granulosa cells.

Mol Cell Endocrinol 2021 01 12;520:111082. Epub 2020 Nov 12.

Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Background And Aims: Sphingosine-1 phosphate (S1P) is a lysosphingolipid present in the ovarian follicular fluid. The role of the lysosphingolipid in gonads of the female is widely unclear. At nanomolar concentrations, S1P binds and activates five specific G protein-coupled receptors (GPCRs), known as S1P, modulating different signaling pathways. S1P and S1P are highly expressed in human primary granulosa lutein cells (hGLC), as well as in the immortalized human primary granulosa cell line hGL5. In this study, we evaluated the signaling cascade activated by S1P and its synthetic analogues in hGLC and hGL5 cells, exploring the biological relevance of S1PR-stimulation in this context.

Methods And Results: hGLC and hGL5 cells were treated with a fixed dose (0.1 μM) of S1P, or by S1P- and S1P-specific agonists SEW2871 and CYM5541. In granulosa cells, S1P and, at a lesser extent, SEW2871 and CYM5541, potently induced CREB phosphorylation. No cAMP production was detected and pCREB activation occurred even in the presence of the PKA inhibitor H-89. Moreover, S1P-dependent CREB phosphorylation was dampened by the mitogen-activate protein kinase (MEK) inhibitor U0126 and by the L-type Ca channel blocker verapamil. The complete inhibition of CREB phosphorylation occurred by blocking either S1P or S1P with the specific receptor antagonists JTE-013 and TY52156, or under PLC/PI3K depletion. S1P-dependent CREB phosphorylation induced FOXO1 and the EGF-like epiregulin-encoding gene (EREG), confirming the exclusive role of gonadotropins and interleukins in this process, but did not affect steroidogenesis. However, S1P or agonists did not modulate granulosa cell viability and proliferation in our conditions.

Conclusions: This study demonstrates for the first time that S1P may induce a cAMP-independent activation of pCREB in granulosa cells, although this is not sufficient to induce intracellular steroidogenic signals and progesterone synthesis. S1P-induced FOXO1 and EREG gene expression suggests that the activation of S1P-S1PR axis may cooperate with gonadotropins in modulating follicle development.
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http://dx.doi.org/10.1016/j.mce.2020.111082DOI Listing
January 2021

Effects of whole-body cryotherapy on the innate and adaptive immune response in cyclists and runners.

Immunol Res 2020 12 7;68(6):422-435. Epub 2020 Nov 7.

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.

The study aimed to identify the effects of whole-body cryotherapy (WBC) on immunological, hormonal, and metabolic responses of non-professional male athletes. Ten cyclists and ten middle-distance runners received 3 once-a-day sessions of WBC. Before initiating and after the final WBC session, a full set of hematologic parameters, serum chemistry profile, hormones, circulating mitochondrial (mt) DNA levels, cytokines, and chemokines concentration were evaluated. The phenotype of monocyte, T cells, and B cells was analyzed. mRNA expression of 6 genes involved in inflammasome activation (NAIP, AIM2, NLRP3, PYCARD, IL-1β, and IL-18) was quantified. WBC reduced glucose and C and S protein and increased HDL, urea, insulin-like growth factor (IGF)-1, follicle-stimulating hormone, IL-18, IL-1RA, CCL2, and CXCL8. Intermediate and non-classical monocyte percentages decreased, and the CD14, CCR5, CCR2, and CXCR4 expressions changed in different subsets. Only IL-1β mRNA increased in monocytes. Finally, a redistribution of B and T cell subsets was observed, suggesting the migration of mature cells to tissue. WBC seems to induce changes in both innate and adaptive branches of the immune system, hormones, and metabolic status in non-professional male athletes, suggesting a beneficial involvement of WBC in tissue repair.
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http://dx.doi.org/10.1007/s12026-020-09165-1DOI Listing
December 2020

Health status is related to testosterone, estrone and body fat: moving to functional hypogonadism in adult men with HIV.

Eur J Endocrinol 2021 Jan;184(1):107-122

Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Objective: Hypogonadism is common in HIV-infected men. The relationship between health status, sex steroids and body composition is poorly known in HIV. The aim was to investigate the association between health status (comorbidities/frailty), body composition, and gonadal function in young-to-middle-aged HIV-infected men.

Design: Prospective, cross-sectional, observational study.

Methods: HIV-infected men aged <50 years and ongoing Highly Active Antiretroviral Therapy were enrolled. Serum total testosterone (TT), estradiol (E2), estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, LH and FSH by immunoassay. Free testosterone (cFT) was calculated by Vermeulen equation. Body composition was assessed by dual-energy X-ray absorptiometry and abdominal CT scan. Multimorbidity (MM) and frailty were defined as ≥3 comorbidities and by a 37-item index, respectively.

Results: A total of 316 HIV-infected men aged 45.3 ± 5.3 years were enrolled. Body fat parameters were inversely related to cFT and TT, and directly related to E1 and E2/testosterone (TS) ratio. Patients with MM had lower cFT (P < 0.0001) and TT (P = 0.036), and higher E1 (P < 0.0001) and E2/TS ratio (P = 0.002). Frailty was inversely related to cFT (R2 = 0.057, P < 0.0001) and TT (R2 = 0.013, P = 0.043), and directly related to E1 (R2 = 0.171, P < 0.0001), E2 (R2 = 0.041, P = 0.004) and E2/TS ratio (R2 = 0.104, P < 0.0001).

Conclusions: Lower TT and cFT, higher E1, E2/TS ratio and visceral fat were independently associated to poor health status and frailty, being possible hallmarks of unhealthy conditions in adult HIV-infected men. Overall, MM, frailty and body fat mass are strictly associated to each other and to sex steroids, concurring together to functional male hypogonadism in HIV.
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http://dx.doi.org/10.1530/EJE-20-0855DOI Listing
January 2021

Kappa Index Versus CSF Oligoclonal Bands in Predicting Multiple Sclerosis and Infectious/Inflammatory CNS Disorders.

Diagnostics (Basel) 2020 Oct 21;10(10). Epub 2020 Oct 21.

Neurology Unit, Azienda Ospedaliero-Universitaria of Modena, 41126 Modena, Italy.

Background: Cerebrospinal fluid (CSF) kappa free light chains (KFLC) are gaining increasing interest as markers of intrathecal immunoglobulin synthesis. The main aim of this study was to assess the diagnostic accuracy (AUC) of the kappa index (CSF/serum KFLC divided by the CSF/serum albumin ratio) compared to CSF oligoclonal IgG bands (OCB) in predicting Multiple Sclerosis (MS) or a central nervous system infectious/inflammatory disorder (CNSID).

Methods: We enrolled patients who underwent a diagnostic spinal tap throughout two years. KFLC levels were determined using a Freelite assay (Binding Site) and the turbidimetric Optilite analyzer.

Results: Of 540 included patients, 223 had a CNSID, and 84 had MS. The kappa index was more sensitive (0.89 versus 0.85) and less specific (0.84 versus 0.89), with the same AUC (0.87) as OCB for MS diagnosis (optimal cut-off: 6.2). Adding patients with a single CSF IgG band to the OCB-positive group slightly increased the AUC (0.88). Likewise, the kappa index (cut-off: 3.9) was more sensitive (0.67 versus 0.50) and less specific (0.81 versus 0.97), with the same AUC (0.74) as OCB, for a CNSID diagnosis.

Conclusion: The kappa index and CSF OCB have comparable diagnostic accuracies for a MS or CNSID diagnosis and supply the clinician with useful, complementary information.
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http://dx.doi.org/10.3390/diagnostics10100856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589948PMC
October 2020

Two human menopausal gonadotrophin (hMG) preparations display different early signaling in vitro.

Mol Hum Reprod 2020 12;26(12):894-905

Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

Commercial hMG drugs are marketed for the treatment of infertility and consist of highly purified hormones acting on receptors expressed in target gonadal cells. Menopur® and Meriofert® are combined preparation of FSH and hCG and are compared in vitro herein. To this purpose, the molecular composition of the two drugs was analyzed by immunoassay. The formation of FSH receptor and LH/hCG receptor (FSHR; LHCGR) heteromer, intracellular Ca2+ and cAMP activation, β-arrestin 2 recruitment and the synthesis of progesterone and estradiol were evaluated in transfected HEK293 and human primary granulosa lutein cells treated by drugs administered within the pg-mg/ml concentration range. Molecular characterization revealed that Meriofert® has a higher FSH:hCG ratio than Menopur® which, in turn, displays the presence of LH molecules. While both drugs induced similar FSHR-LHCGR heteromeric formations and intracellular Ca2+ increase, Meriofert® had a higher potency than Menopur® in inducing a cAMP increase. Moreover, Meriofert® revealed a higher potency than Menopur® in recruiting β-arrestin 2, likely due to different FSH content modulating the tridimensional structure of FSHR-LHCGR-β-arrestin 2 complexes, as evidenced by a decrease in bioluminescence resonance energy transfer signal. This drug-specific activation of intracellular signaling pathways is consistent with the molecular composition of these preparations and impacts downstream progesterone and estradiol production, with Menopur® more potent than Meriofert® in inducing the synthesis of both the steroids. These findings are suggestive of distinct in-vivo activities of these preparations, but require cautious interpretation and further validation from clinical studies.
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http://dx.doi.org/10.1093/molehr/gaaa070DOI Listing
December 2020

Hemoadsorption cartridge and coronavirus disease 2019 infections: A case report and brief literature review.

Artif Organs 2021 May 29;45(5):E130-E135. Epub 2020 Nov 29.

School of Anaesthesia and Intensive Care, University of Modena and Reggio Emilia, Modena, Italy.

The cytokine storm has been frequently reported to occur in patients with severe coronavirus disease 2019 (COVID-19). Data from the literature suggest that elevated levels of inflammatory mediators, such as interleukin (IL)-6, IL-8, and tumor necrosis factor, indicate a severe course or the fatality of the disease. Several therapeutic options have been employed to treat critically ill patients, including hemoadsorption of inflammatory mediators. We here present a case of severe acute respiratory syndrome caused by COVID-19 and acute renal failure. The patient was admitted to our intensive care unit and treated with mechanical ventilation, renal replacement therapy, and hemoadsorption to reduce the cytokine release syndrome, which plays a fundamental role in the clinical presentation of COVID-19 patients. We also discuss the potential advantages of reducing cytokine plasma levels using a hemoadsorption cartridge.
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http://dx.doi.org/10.1111/aor.13846DOI Listing
May 2021

Elevated levels of nitrous dioxide are associated with lower AMH levels: a real-world analysis.

Hum Reprod 2020 11;35(11):2589-2597

Department of Medical Specialties, Azienda Ospedaliero-Universitaria of Modena, Ospedale Civile of Baggiovara, Modena, Italy.

Study Question: Are there any associations between environmental pollutants and ovarian reserve, expressed by anti-Mullerian hormone (AMH) serum levels?

Summary Answer: In this first real-world approach to demonstrate the relationship between air pollutants and serum AMH levels, adverse associations were observed for nitrogen dioxide (NO2) but not with particulate matter.

What Is Known Already: In recent years, air pollution has emerged as a potential disrupter to the homeostasis of physiological hormones, possibly affecting human reproduction. Although the influence of age and smoking on AMH levels is largely accepted, the relationship between AMH and the environment has not currently been established.

Study Design, Size, Duration: A longitudinal, observational, retrospective, real-world study was carried out, including all AMH measurements performed in a single laboratory from January 2007 to October 2017.

Participants/materials, Setting, Methods: Serum AMH data were connected to patients' age and residential address, to include air pollution data after geo-localisation. The air pollution considered daily particulate matter (PM) and NO2 values.

Main Results And The Role Of Chance: A total of 1463 AMH measurements were collected (mean 1.94 ng/ml, median 0.90 ng/ml). AMH was inversely related to patients' age in women older than 25 years (adjusted R-squared 0.120, P < 0.001), but not in those younger than 25 years (adjusted R-squared 0.068, P = 0.055). AMH levels were inversely related to environmental pollutants, such as PM10 (Rho = -0.088, P = 0.001), PM2.5 (Rho = -0.062, P = 0.021) and NO2 (Rho = -0.111, P < 0.001). After subdividing the dataset into quartiles for PM10 and PM2.5, the influence of age on AMH serum levels was found to be a stronger influence than that exerted by PM (P = 0.833 and P = 0.370, respectively). On the contrary, considering NO2 quartiles, higher AMH levels were observed in third quartile compared to fourth quartile, even after adjustment for age (P = 0.028), indicating a stronger influence of NO2 exposure on AMH serum levels. Considering an AMH cut-off of 0.3 ng/ml, a significant higher frequency of women with severe ovarian reserve reduction in the fourth quartile was shown only for NO2 (P = 0.010).

Limitations, Reasons For Caution: Several limitations should be underlined, such as the lack of information about work and life habits of each patient and the retrospective nature of the analysis performed on real-world data.

Wider Implications Of The Findings: Although the genetic component is highly predictive for defining the ovarian reserve at birth, potentially modifiable environmental factors could influence the rate of decline in AMH and ovarian reserve during adulthood.

Study Fundingcompeting Interest(s): Authors have neither funding nor competing interests to declare.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deaa214DOI Listing
November 2020

COVID-19: more than a cytokine storm.

Crit Care 2020 09 4;24(1):549. Epub 2020 Sep 4.

Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia; Hematology Unit, AOU Policlinico, Via Del Pozzo 71, 41124, Modena, Italy.

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http://dx.doi.org/10.1186/s13054-020-03267-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472946PMC
September 2020

A proof of evidence supporting abnormal immunothrombosis in severe COVID-19: naked megakaryocyte nuclei increase in the bone marrow and lungs of critically ill patients.

Platelets 2020 Nov 28;31(8):1085-1089. Epub 2020 Aug 28.

Institute of Pathology, University of Modena and Reggio Emilia , Modena, Italy.

Coronavirus disease 2019 (COVID-19) is a global public health emergency with many clinical facets, and new knowledge about its pathogenetic mechanisms is deemed necessary; among these, there are certainly coagulation disorders. In the history of medicine, autopsies and tissue sampling have played a fundamental role in order to understand the pathogenesis of emerging diseases, including infectious ones; compared to the past, histopathology can be now expanded by innovative techniques and modern technologies. For the first time in worldwide literature, we provide a detailed postmortem and biopsy report on the marked increase, up to 1 order of magnitude, of naked megakaryocyte nuclei in the bone marrow and lungs from serious COVID-19 patients. Most likely related to high interleukin-6 serum levels stimulating megakaryocytopoiesis, this phenomenon concurs to explain well the pulmonary abnormal immunothrombosis in these critically ill patients, all without molecular or electron microscopy signs of megakaryocyte infection.
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http://dx.doi.org/10.1080/09537104.2020.1810224DOI Listing
November 2020

Predictive value of serum uric acid levels for adverse maternal and perinatal outcomes in pregnant women with high blood pressure. A systematic review and meta-analysis.

Eur J Obstet Gynecol Reprod Biol 2020 Sep 22;252:447-454. Epub 2020 Jul 22.

Department of Laboratory Medicine, OCSAE, Azienda USL of Modena, Via Pietro Giardini 1355, 41126, Modena, Italy. Electronic address:

Objective: High serum uric acid seems to be associated with pre-eclampsia. The expected utility of uric acid is related to the probability of occurrence of maternal and neonatal complications. We evaluated the accuracy of uric acid in predicting adverse maternal and perinatal outcomes in pregnant women with high blood pressure.

Methods: We performed an electronic search for studies evaluating the accuracy of high serum uric acid levels in pregnant women with high blood pressure. The assessment of risk of bias was performed using the QUIPS tool. For each included study, we collected data about study characteristics and diagnostic test accuracy to construct 2 × 2 tables. Pooled sensitivity (Se), specificity (Sp) and diagnostic odds ratio (DOR) were estimated using a bivariate model. Grading the quality of the evidence was assessed using the GRADE approach.

Results: Twenty-one studies, testing more than 6,000 women, met the inclusion criteria. The majority of studies were at low risk of bias. Ten studies evaluated the role of serum uric acid to predict pre-eclampsia, the pooled Se was 0.74 (95%CI 0.71-0.77), Sp was 0.66 (95%CI 0.63-0.68), and DOR was 9.67 (95%CI 4.57-20.47). The overall quality of evidence was evaluated as low. The GRADE rating was downgraduate for risk of bias and inconsistency.

Conclusions: No robust evidence currently exists to suggest that uric acid measurement is useful in predicting maternal and perinatal adverse outcomes.
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http://dx.doi.org/10.1016/j.ejogrb.2020.07.042DOI Listing
September 2020

The Combined Use of Tocilizumab and Hemoadsorption in a Patient with SARS-COV-2-19-Associated Pneumonia: A Case Report.

Nephron 2020 21;144(9):459-462. Epub 2020 Jul 21.

Department of Laboratory Medicine and Pathological Anatomy, Azienda Ospedaliera Universitaria e Azienda USL di Modena, Modena, Italy.

The SARS-COV-2-19-associated respiratory involvement is caused by the massive release of inflammatory cytokines ultimately leading to interstitial pneumonia and acute respiratory distress syndrome (ARDS). In the absence of an effective antiviral treatment, a reasonable causal approach could be constituted by the neutralization of these substances. The authors describe the clinical course of a patient with SARS-COV-2-19 interstitial pneumonia treated with the combination of an anti-interleukin 6 (IL-6) agent (tocilizumab) and hemoadsorption (HA). This combination was used to abate the surge of inflammatory mediators leading to the lung damage. Blood levels of IL-6 and C-reactive protein (CRP) were measured before the initiation of the treatment and in the following 3 days. At the end of the treatment, the values of IL-6 and CRP decreased from 1,040 to 415 pg/mL and from 229 to 59 mg/L, respectively. The gas exchanges and the chest imaging rapidly improved, and the patient was extubated 10 days later. The combination of tocilizumab and HA could be valuable in the treatment of SARS-COV-2-19-associated pneumonia and ARDS that are caused by the release of inflammatory mediators.
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http://dx.doi.org/10.1159/000509738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445375PMC
September 2020

Evidence on clinical relevance of cardiovascular risk evaluation in the general population using cardio-specific biomarkers.

Clin Chem Lab Med 2020 Jul 21;59(1):79-90. Epub 2020 Jul 21.

Dipartimento di Medicina di Laboratorio, Azienda Ospedaliera Universitaria di Padova, Padova, Italy.

In recent years, the formulation of some immunoassays with high-sensitivity analytical performance allowed the accurate measurement of cardiac troponin I (cTnI) and T (cTnT) levels in reference subjects. Several studies have demonstrated the association between the risk of major cardiovascular events and cardiac troponin concentrations even for biomarker values within the reference intervals. High-sensitivity cTnI and cTnT methods (hs-cTn) enable to monitor myocardial renewal and remodelling, and to promptly identify patients at highest risk ofheart failure. An early and effective treatment of individuals at higher cardiovascular risk may revert the initial myocardial remodelling and slow down heart failure progression. Specific clinical trials should be carried out to demonstrate the efficacy and efficiency of the general population screening by means of cost-benefit analysis, in order to better identify individuals at higher risk for heart failure (HF) progression with hs-cTn methods.
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http://dx.doi.org/10.1515/cclm-2020-0310DOI Listing
July 2020

Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19.

Seizure 2020 10 15;81:18-20. Epub 2020 Jul 15.

Neurology Unit, OCB Hospital, Azienda Ospedaliera Universitaria di Modena, Italy; Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia, Modena Italy. Electronic address:

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http://dx.doi.org/10.1016/j.seizure.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362825PMC
October 2020

Testing for SARS-CoV-2 (COVID-19): a systematic review and clinical guide to molecular and serological in-vitro diagnostic assays.

Reprod Biomed Online 2020 09 14;41(3):483-499. Epub 2020 Jun 14.

School of Medicine, University of Glasgow, Glasgow, UK; NIHR Bristol Biomedical Research Centre Bristol, UK; The Fertility Partnership, Oxford, UK.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated coronavirus disease 2019 (COVID-19) pandemic has demanded rapid upscaling of in-vitro diagnostic assays to enable mass screening and testing of high-risk groups, and simultaneous ascertainment of robust data on past SARS-CoV-2 exposure at an individual and a population level. To meet the exponential demand in testing, there has been an accelerated development of both molecular and serological assays across a plethora of platforms. The present review discusses the current literature on these modalities, including nucleic acid amplification tests, direct viral antigen tests and the rapidly expanding laboratory-based and point of care serological tests. This suite of complementary tests will inform crucial decisions by healthcare providers and policy makers, and understanding their strengths and limitations will be critical to their judicious application for the development of algorithmic approaches to treatment and public health strategies.
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http://dx.doi.org/10.1016/j.rbmo.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293848PMC
September 2020

Frequency and Results of Cryoglobulin Retesting in 4,963 Patients: Comment on the Article by Kolopp-Sarda et al.

Arthritis Rheumatol 2020 11 8;72(11):1955-1956. Epub 2020 Oct 8.

University of Modena and Reggio Emilia Modena, Italy, on behalf of the Italian Group for the Study of Cryoglobulinemia (GISC) of Modena, Italy.

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http://dx.doi.org/10.1002/art.41434DOI Listing
November 2020

Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with COVID-19 pneumonia.

Nat Commun 2020 07 6;11(1):3434. Epub 2020 Jul 6.

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia School of Medicine, Via Campi 287, 41125, Modena, Italy.

The immune system of patients infected by SARS-CoV-2 is severely impaired. Detailed investigation of T cells and cytokine production in patients affected by COVID-19 pneumonia are urgently required. Here we show that, compared with healthy controls, COVID-19 patients' T cell compartment displays several alterations involving naïve, central memory, effector memory and terminally differentiated cells, as well as regulatory T cells and PD1CD57 exhausted T cells. Significant alterations exist also in several lineage-specifying transcription factors and chemokine receptors. Terminally differentiated T cells from patients proliferate less than those from healthy controls, whereas their mitochondria functionality is similar in CD4 T cells from both groups. Patients display significant increases of proinflammatory or anti-inflammatory cytokines, including T helper type-1 and type-2 cytokines, chemokines and galectins; their lymphocytes produce more tumor necrosis factor (TNF), interferon-γ, interleukin (IL)-2 and IL-17, with the last observation implying that blocking IL-17 could provide a novel therapeutic strategy for COVID-19.
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http://dx.doi.org/10.1038/s41467-020-17292-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338513PMC
July 2020

Effects of acute hCG stimulation on serum INSL3 and 25-OH vitamin D in Klinefelter syndrome.

Andrology 2020 11 12;8(6):1720-1727. Epub 2020 Jul 12.

Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria of Modena, Modena, Italy.

Background: It has recently been suggested that the hypergonadotropic hypogonadism characterizing Klinefelter syndrome (KS) might not be due to a steroidogenic dysfunction per se, but mainly to an altered testosterone (T) secretion into the bloodstream. However, the Leydig cell functionality remains incompletely studied in KS, and new markers should be considered. Previous data indicated that chronic hCG stimulation influences the production of both insulin-like peptide 3 (INSL3) and 25-hydroxy-vitamin D (25-VD) in eugonadal men.

Aim Of The Study: To evaluate INSL3 and 25-VD serum levels, as markers of Leydig cell functionality, in association with sex steroids, after an acute hCG test in a group of KS patients and healthy volunteers.

Methods: A retrospective analysis of a prospective case-control clinical trial was carried out. KS patients (n = 11) and age-matched healthy controls (n = 11) provided a basal blood sample (V0) immediately followed by a single intramuscular injection of hCG 5000 IU. Blood samples were taken in the following five days (V1-V5).

Results: At baseline, INSL3 was lower in KS patients compared with controls (P = .007). When adjusted for INSL3 levels, the production of steroids was similar between KS patients and controls. 25-VD was in the insufficient range both in KS patients and in controls and was not different (P = .064). Acute hCG stimulation increased neither INSL3 nor 25-VD in both KS patients and controls. In controls, an inverse correlation was detected between INSL3 levels and body mass index (P = .020) and waist circumference (P = .020).

Conclusions: INSL3 secretion is independent from steroidogenesis, and its production is mostly not influenced by acute hCG stimulation both in KS men and in controls. INSL3 serum levels should be considered as a marker of Leydig cell differentiation and numbers rather than steroidogenesis. 25-VD serum levels are also not increased by a single acute hCG administration, which was not able to restore the normal concentrations of 25-VD.
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http://dx.doi.org/10.1111/andr.12851DOI Listing
November 2020

Multilevel approach to male fertility by machine learning highlights a hidden link between haematological and spermatogenetic cells.

Andrology 2020 09 21;8(5):1021-1029. Epub 2020 Jun 21.

Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Background: Male infertility represents a complex clinical condition requiring an accurate multilevel assessment, in which machine learning technology, combining large data series in non-linear and highly interactive ways, could be innovatively applied.

Methods: A longitudinal, observational, retrospective, big data study was carried out, applying for the first time the ML in the context of male infertility. A large database including all semen samples collected between 2010 and 2016 was generated, together with blood biochemical examinations, environmental temperature and air pollutants exposure. First, the database was analysed with principal component analysis and multivariable linear regression analyses. Second, classification analyses were performed, in which patients were a priori classified according to semen parameters. Third, machine learning algorithms were applied in a training phase (80% of the entire database) and in a tuning phase (20% of the data set). Finally, conventional statistical analyses were applied considering semen parameters and those other variables extracted during machine learning.

Results: The final database included 4239 patients, aggregating semen analyses, blood and environmental parameters. Classification analyses were able to recognize oligozoospermic, teratozoospermic, asthenozoospermic and patients with altered semen parameters (0.58 accuracy, 0.58 sensitivity and 0.57 specificity). Machine learning algorithms detected three haematological variables, that is lymphocytes number, erythrocyte distribution and mean globular volume, significantly related to semen parameters (0.69 accuracy, 0.78 sensitivity and 0.41 specificity).

Conclusion: This is the first machine learning application to male fertility, detecting potential mathematical algorithms able to describe patients' semen characteristics changes. In this setting, a possible hidden link between testicular and haematopoietic tissues was suggested, according to their similar proliferative properties.
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http://dx.doi.org/10.1111/andr.12826DOI Listing
September 2020