Maurizio Simmaco

Scopus Publications

Preclinical and clinical study on type 3 metabotropic glutamate receptors in Parkinson’s disease
Luisa Di Menna, Marika Alborghetti, Maria Ilenia De Bartolo, Marina Borro, Giovanna Gentile, Manuela Zinni, Matteo Bologna, Carolina Cutrona, Giovanna D’Errico, Tiziana Imbriglio,et al.
Springer Science and Business Media LLC

Assessment of plasma resolvin levels in women with breast cancer and their associations with disease presentation and immunohistochemical characteristics
Alessio Molfino, Giovanni Imbimbo, Gerardo Salerno, Luana Lionetto, Alessandro De Luca, Maria Ludovica Costanzo, Maurizio Simmaco, Maurizio Muscaritoli, and Maria Ida Amabile
Springer Science and Business Media LLC

Recognizing and preventing unacknowledged prescribing errors associated with polypharmacy
Giovanna Gentile, Antonio Del Casale, Ottavia De Luca, Gerardo Salerno, Sara Spirito, Martina Regiani, Matteo Regiani, Saskia Preissner, Monica Rocco, Robert Preissner,et al.
Springer Science and Business Media LLC

Correction to: Clinical impact of drug-drug interactions on abemaciclib in the real-world experience of AB-ITALY study (npj Breast Cancer, (2024), 10, 1, (58), 10.1038/s41523-024-00657-z)
Simone Scagnoli, Simona Pisegna, Angela Toss, Roberta Caputo, Michelino De Laurentiis, Michela Palleschi, Ugo de Giorgi, Enrico Cortesi, Agnese Fabbri, Alessandra Fabi,et al.
Springer Science and Business Media LLC

Clinical impact of drug-drug interactions on abemaciclib in the real-world experience of AB-ITALY study
Simone Scagnoli, Simona Pisegna, Angela Toss, Roberta Caputo, Michelino De Laurentiis, Michela Palleschi, Ugo de Giorgi, Enrico Cortesi, Agnese Fabbri, Alessandra Fabi,et al.
Springer Science and Business Media LLC
AbstractAbemaciclib demonstrated clinical benefit in women affected by HR+/HER2− advanced breast cancer (aBC). Drug-drug interactions (DDIs) can lead to reduced treatment efficacy or increased toxicity. This retro-prospective study aimed to evaluate outcomes, DDIs’ impact, and toxicities of abemaciclib combined with endocrine therapy in a real-world setting. Patients from 12 referral Italian hospitals with HR+/HER2− aBC who received abemaciclib were included. Clinical data about comorbidities, concurrent medications, outcomes, and adverse events (AE) were collected. Drug-PIN® (Personalized Interactions Network) is a tool recognizing the role of multiple interactions between active and/or pro-drug forms combined with biochemical and demographic patient data. The software was used to define the Drug-PIN score and Drug-PIN tier (green, yellow, dark yellow, and red) for each patient. Univariate and multivariate analyses were performed to identify predictors of patients’ PFS or toxicity. One hundred seventy-three patients were included. 13% of patients had >75years. The overall response rate (ORR) was 63%. The general population’s median PFS (mPFS) was 22 months (mo), while mOS were not reached. Patients treated with abemaciclib in combination with AI and fulvestrant had a mPFS of 36 and 19 mo, respectively. The most common toxicities were diarrhea, asthenia, and neutropenia detected in 63%,49%, and 49% of patients. The number of concomitant medications and comorbidities were not associated with survival outcomes (22 vs 17 mo, p = 0.068, p = 0.99). Drug-PIN tier from dark yellow to red and Drug-PIN score >12 were associated with shorter PFS compared to no/low-risk DDIs and score <12 (15 vs 23, p = 0.005, p = 0.0017). Drug interaction was confirmed as an independent biomarker in a multivariate model (p = 0.02). No difference in any grade AE, severe toxicities, and diarrhea were detected among different age subgroups. No association was found between Drug-PIN score or Drug-PIN tier and overall toxicity (p = 0.44), severe AEs (p = 0.11), or drug reduction (p = 0.27). The efficacy and safety of abemaciclib plus ET were confirmed in a real-world setting, even in the elderly population and patients with comorbidities. Evaluation of DDIs with Drug-PIN appears to be an independent predictor of PFS.

Opioid Use and Gut Dysbiosis in Cancer Pain Patients
Flaminia Coluzzi, Maria Sole Scerpa, Chiara Loffredo, Marina Borro, Joseph V. Pergolizzi, Jo Ann LeQuang, Elisa Alessandri, Maurizio Simmaco, and Monica Rocco
MDPI AG
Opioids are commonly used for the management of severe chronic cancer pain. Their well-known pharmacological effects on the gastrointestinal system, particularly opioid-induced constipation (OIC), are the most common limiting factors in the optimization of analgesia, and have led to the wide use of laxatives and/or peripherally acting mu-opioid receptor antagonists (PAMORAs). A growing interest has been recently recorded in the possible effects of opioid treatment on the gut microbiota. Preclinical and clinical data, as presented in this review, showed that alterations of the gut microbiota play a role in modulating opioid-mediated analgesia and tolerability, including constipation. Moreover, due to the bidirectional crosstalk between gut bacteria and the central nervous system, gut dysbiosis may be crucial in modulating opioid reward and addictive behavior. The microbiota may also modulate pain regulation and tolerance, by activating microglial cells and inducing the release of inflammatory cytokines and chemokines, which sustain neuroinflammation. In the subset of cancer patients, the clinical meaning of opioid-induced gut dysbiosis, particularly its possible interference with the efficacy of chemotherapy and immunotherapy, is still unclear. Gut dysbiosis could be a new target for treatment in cancer patients. Restoring the physiological amount of specific gut bacteria may represent a promising therapeutic option for managing gastrointestinal symptoms and optimizing analgesia for cancer patients using opioids.

Is the Hedgehog Pathway Involved in the Pathophysiology of Schizophrenia? A Systematic Review of Current Evidence of Neural Molecular Correlates and Perspectives on Drug Development
Antonio Del Casale, Martina Nicole Modesti, Giovanna Gentile, Cecilia Guariglia, Stefano Ferracuti, Maurizio Simmaco, and Marina Borro
MDPI AG
Among the pathophysiological correlates of schizophrenia, recent research suggests a potential role for the Hedgehog (Hh) signalling pathway, which has been traditionally studied in embryonic development and oncology. Its dysregulation may impact brain homeostasis, neuroplasticity, and potential involvement in neural processes. This systematic review provides an overview of the involvement of Hh signalling in the pathophysiology of schizophrenia and antipsychotic responses. We searched the PubMed and Scopus databases to identify peer-reviewed scientific studies focusing on Hh and schizophrenia, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, finally including eight studies, including three articles focused on patients with schizophrenia, two animal models of schizophrenia, two animal embryo studies, and one cellular differentiation study. The Hh pathway is crucial in the development of midbrain dopaminergic neurons, neuroplasticity mechanisms, regulating astrocyte phenotype and function, brain-derived neurotrophic factor expression, brain glutamatergic neural transmission, and responses to antipsychotics. Overall, results indicate an involvement of Hh in the pathophysiology of schizophrenia and antipsychotic responses, although an exiguity of studies characterises the literature. The heterogeneity between animal and human studies is another main limitation. Further research can lead to better comprehension and the development of novel personalised drug treatments and therapeutic interventions.

Oxidative stress and optical coherence tomography angiography evaluation of choriocapillaris and retinal vessel density in children with obstructive sleep apnea
Solmaz Abdolrahimzadeh, Melania Evangelisti, Irene Gattazzo, Marta Arpinelli, Giovanni Di Nardo, Di Staso Federico, Maurizio Simmaco, Gerardo Salerno, Pasquale Parisi, Gianluca Scuderi,et al.
Springer Science and Business Media LLC

The Drug-PIN® support in elderly diabetics with high polypathology scores by the MCPS: A preliminary approach to reduce the risk of polypharmacy

Hard-to-heal peripheral wounds infected with Corynebacterium striatum: a prospective study
Edoardo Virgilio, Mariacarmela Solmone, Alessandro Scardigno, Piera Fradiani, Diego Ceci, Antonella Teggi, Gino Enea Di Domenico, Ilaria Cavallo, Fabrizio Ensoli, Marina Borro,et al.
Mark Allen Group
Objective: To investigate Corynebacterium striatum as a nosocomial pathogen infecting hard-to-heal peripheral wounds, such as skin wounds, soft tissue abscesses and osteomyelitis. As of 2023, the medical community were alerted against the risk of emerging systemic and central infections; on the other hand literature on peripheral cutaneous regions is still scarce. Method: In this study, two groups of patients with similar lesions which were infected were compared: one group with the presence of the coryneform rod, the other without. Results: In total, Corynebacterium striatum was cultured from 62 patients and 131 samples. Corynebacterium striatum infection correlated well with the presence of: foot ulcer; venous leg ulcer; altered ambulation and/or altered foot loading; peripheral vascular and arterial disease; hospitalisation; malignancy; spinal cord injury; and recent administration of antibiotics (p<0.05 for all associations). Patients with Corynebacterium striatum had a lower overall survival rate compared to patients in the non-Corynebacterium striatum group (28.6 versus 31.6 months, respectively; p=0.0285). Multivariate analysis revealed that Corynebacterium striatum infection was an independent factor for poor prognosis (p<0.0001). Conclusion: In view of the findings of our study, Corynebacterium striatum appears to be an important opportunistic pathogen infecting peripheral tissues and complicating wound healing. Given its numerous and worrying virulence factors (such as multidrug resistance and biofilm production), particular attention should be given to this pathogen by professional wound care providers in nosocomial and outpatient environments.

The Impact of Drug–Drug Interactions on the Toxicity Profile of Combined Treatment with BRAF and MEK Inhibitors in Patients with BRAF-Mutated Metastatic Melanoma
Silvia Mezi, Andrea Botticelli, Simone Scagnoli, Giulia Pomati, Giulia Fiscon, Federica De Galitiis, Francesca Romana Di Pietro, Sofia Verkhovskaia, Sasan Amirhassankhani, Simona Pisegna,et al.
MDPI AG
Background: BRAF and MEK inhibition is a successful strategy in managing BRAF-mutant melanoma, even if the treatment-related toxicity is substantial. We analyzed the role of drug–drug interactions (DDI) on the toxicity profile of anti-BRAF/anti-MEK therapy. Methods: In this multicenter, observational, and retrospective study, DDIs were assessed using Drug-PIN software (V 2/23). The association between the Drug-PIN continuous score or the Drug-PIN traffic light and the occurrence of treatment-related toxicities and oncological outcomes was evaluated. Results: In total, 177 patients with advanced BRAF-mutated melanoma undergoing BRAF/MEK targeted therapy were included. All grade toxicity was registered in 79% of patients. Cardiovascular toxicities occurred in 31 patients (17.5%). Further, 94 (55.9%) patients had comorbidities requiring specific pharmacological treatments. The median Drug-PIN score significantly increased when the target combination was added to the patient’s home therapy (p-value < 0.0001). Cardiovascular toxicity was significantly associated with the Drug-PIN score (p-value = 0.048). The Drug-PIN traffic light (p = 0.00821) and the Drug-PIN score (p = 0.0291) were seen to be significant predictors of cardiotoxicity. Patients with low-grade vs. high-grade interactions showed a better prognosis regarding overall survival (OS) (p = 0.0045) and progression-free survival (PFS) (p = 0.012). The survival analysis of the subgroup of patients with cardiological toxicity demonstrated that patients with low-grade vs. high-grade DDIs had better outcomes in terms of OS (p = 0.0012) and a trend toward significance in PFS (p = 0.068). Conclusions: DDIs emerged as a critical issue for the risk of treatment-related cardiovascular toxicity. Our findings support the utility of DDI assessment in melanoma patients treated with BRAF/MEK inhibitors.

Frequencies of Combined Dysfunction of Cytochromes P450 2C9, 2C19, and 2D6 in an Italian Cohort: Suggestions for a More Appropriate Medication Prescribing Process
Giovanna Gentile, Ottavia De Luca, Antonio Del Casale, Gerardo Salerno, Maurizio Simmaco, and Marina Borro
MDPI AG
Improper drug prescription is a main cause of both drug-related harms (inefficacy and toxicity) and ineffective spending and waste of the healthcare system’s resources. Nowadays, strategies to support an improved, informed prescription process may benefit from the adequate use of pharmacogenomic testing. Using next-generation sequencing, we analyzed the genomic profile for three major cytochromes P450 (CYP2C9, CYP2C19, CYP2D6) and studied the frequencies of dysfunctional isozymes (e.g., poor, intermediate, or rapid/ultra-rapid metabolizers) in a cohort of 298 Italian subjects. We found just 14.8% of subjects with a fully normal set of cytochromes, whereas 26.5% of subjects had combined cytochrome dysfunction (more than one isozyme involved). As improper drug prescription is more frequent, and more burdening, in polytreated patients, since drug–drug interactions also cause patient harm, we discuss the potential benefits of a more comprehensive PGX testing approach to support informed drug selection in such patients.

Integrative metabolomics science in Alzheimer's disease: Relevance and future perspectives
Simone Lista, Raúl González-Domínguez, Susana López-Ortiz, Álvaro González-Domínguez, Héctor Menéndez, Juan Martín-Hernández, Alejandro Lucia, Enzo Emanuele, Diego Centonze, Bruno P. Imbimbo,et al.
Elsevier BV

DRD2, DRD3, and HTR2A Single-Nucleotide Polymorphisms Involvement in High Treatment Resistance to Atypical Antipsychotic Drugs
Antonio Del Casale, Maurizio Simmaco, Martina Nicole Modesti, Clarissa Zocchi, Jan Francesco Arena, Irene Bilotta, Alessandro Alcibiade, Giuseppe Sarli, Lorenzo Cutillo, Giulia Antonelli,et al.
MDPI AG
Background: The objective of this study was to investigate the DRD2 rs1800497, rs1799732, rs1801028, DRD3 rs6280, and HTR2A rs6314, rs7997012, and rs6311 single-nucleotide polymorphism (SNP) correlations with resistance to second-generation antipsychotics (SGAs) in a real-world sample of patients with treatment-resistant mental disorders. Methods: We divided 129 participants into a high treatment resistance (HTR) group (current treatment with two SGAs, or clozapine, or classic neuroleptics for a failure of previous SGAs trials) and a low treatment resistance (LTR) group (current treatment with one atypical antipsychotic). We used Next-Generation Sequencing on DNA isolated from peripheral blood samples to analyze the polymorphisms. We performed logistic regression to search for predictors of HTR membership. Results: A diagnosis of schizophrenia significantly predicted the HTR membership compared to other diagnoses. Other predictors were the DRD3 rs6280 C|T (OR = 22.195) and T|T (OR = 18.47) vs. C|C, HTR2A rs7997012 A|G vs. A|A (OR = 6.859) and vs. G|G (OR = 2.879), and DRD2 rs1799732 I|I vs. D|I (OR = 12.079) genotypes. Conclusions: A diagnosis of schizophrenia and the DRD2 rs1799732, DRD3 rs6280, and HTR2A rs7997012 genotypes can predict high treatment resistance to SGAs.

The Impact of Non-Andrological Medications on Semen Characteristics, Oxidative Stress and Inflammatory Parameters
Gerardo Salerno, Marina Borro, Vincenzo Visco, Soraya Olana, Francesca Gargano, Salvatore Raffa, Virginia Zamponi, Camilla Mancini, Antongiulio Faggiano, Maurizio Simmaco,et al.
MDPI AG
Background and Objectives: The aim of this study was to evaluate the impact of medications on oxidative stress, inflammatory biomarkers and semen characteristics in males with idiopathic infertility. Materials and Methods: In this observational case-control clinical study, 50 men with idiopathic infertility were enrolled, of whom 38 (the study group) were on pharmacological treatment and 12 made up the control group. The study group was clustered according to the medications (Group A: anti-hypertensive, n = 10; Group B: thyroxine, n = 6; Group C: non-steroidal anti-inflammatory drugs, n = 13; Group D: miscellaneous, n = 6; Group E: lipid-lowering drugs, n = 4). Semen analyses were performed according to WHO 2010 guidelines. Interleukins (IL)-10, IL-1 beta, IL-4, IL-6, Tumor Necrosis Factor- alpha (TNF-alpha) and IL-1 alpha were determined using a solid-phase sandwich immunoassay. The diacron reactive oxygen metabolites, d-ROMs test, was performed by means of a colorimetric determination of reactive oxygen metabolites and measured with a spectrophotometer. Beta-2-microglobulin and cystatin-C were measured with an immunoturbidimetric analyzer. Results: No differences between the study and control groups for age and macroscopic and microscopic semen characteristics were found, nor were any differences found after clustering according to the drug categories. IL-1 alpha and IL-10 were significantly lower in the study group compared with the control group; IL-10 was significantly lower in groups A, B, C and D compared with the control group. Furthermore, a direct correlation between IL-1 alpha, IL-10 and TNF-alpha and leukocytes was found. Conclusions: Despite the sample size limitations, the data suggest a correlation between drug use and activation of the inflammatory response. This could clarify the pathogenic mechanism of action for several pharmacological classes on male infertility.

The Third Dose of BNT162b2 COVID-19 Vaccine Does Not “Boost” Disease Flares and Adverse Events in Patients with Rheumatoid Arthritis
Andrea Picchianti Diamanti, Assunta Navarra, Gilda Cuzzi, Alessandra Aiello, Simonetta Salemi, Roberta Di Rosa, Chiara De Lorenzo, Daniele Vio, Giandomenico Sebastiani, Mario Ferraioli,et al.
MDPI AG
Data on the risk of adverse events (AEs) and disease flares in autoimmune rheumatic diseases (ARDs) after the third dose of COVID-19 vaccine are scarce. The aim of this multicenter, prospective study is to analyze the clinical and immunological safety of BNT162b2 vaccine in a cohort of rheumatoid arthritis (RA) patients followed-up from the first vaccine cycle to the third dose. The vaccine showed an overall good safety profile with no patient reporting serious AEs, and a low percentage of total AEs at both doses (40/78 (51.3%) and 13/47 (27.7%) patients after the second and third dose, respectively (p < 0.002). Flares were observed in 10.3% of patients after the end of the vaccination cycle and 12.8% after the third dose. Being vaccinated for influenza was inversely associated with the onset of AEs after the second dose, at both univariable (p = 0.013) and multivariable analysis (p = 0.027). This result could allow identification of a predictive factor of vaccine tolerance, if confirmed in larger patient populations. A higher disease activity at baseline was not associated with a higher incidence of AEs or disease flares. Effectiveness was excellent after the second dose, with only 1/78 (1.3%) mild breakthrough infection (BI) and worsened after the third dose, with 9/47 (19.2%) BI (p < 0.002), as a probable expression of the higher capacity of the Omicron variants to escape vaccine recognition.

Opinion paper on the systematic application of integrated bioinformatic tools to actuate routine precision medicine in poly-treated patients
Marina Borro, Gerardo Salerno, Giovanna Gentile, and Maurizio Simmaco
Walter de Gruyter GmbH
Abstract Precision Medicine is a reality in selected medical areas, as oncology, or in excellent healthcare structures, but it is still far to reach million patients who could benefit from this medical concept. Here, we sought to highlight how the time is ripe to achieve horizontal delivery to a significant larger audience of patients, represented by the poly-treated patients. Combination therapies are frequent (especially in the elderly, to treat comorbidities) and are related to decreased drug safety and efficacy, disease’s exacerbation, additional treatments, hospitalization. But the recent development and validation of bioinformatic tools, aimed to automatic evaluation and optimization of poly-therapies, according to the unique individual characteristics (including genotype), is ready to change the daily approach to pharmacological prescription.

Fatigue in Patients on Chronic Hemodialysis: The Role of Indoleamine 2,3-Dioxygenase (IDO) Activity, Interleukin-6, and Muscularity
Alessio Molfino, Giovanni Imbimbo, Maria Ida Amabile, Thomas Ammann, Luana Lionetto, Gerardo Salerno, Maurizio Simmaco, Maria Grazia Chiappini, and Maurizio Muscaritoli
MDPI AG
Fatigue is a frequent symptom in hemodialysis (HD), and the indolamine-2,3-dioxygenase (IDO) metabolic trap has been hypothesized in the pathogenesis of fatigue. The association between IDO activity according to fatigue and its relationship with muscle mass and function in HD patients was verified. Chronic HD patients were considered, and fatigue was assessed. The plasma kynurenines and tryptophan ratio (Kyn/Trp), as surrogate of IDO activity, and interleukin (IL)-6 were measured. Muscularity was assessed by BIA and muscle strength by hand-grip dynamometer. 50 HD patients were enrolled, and fatigue was present in 24% of the cohort. Patients with fatigue showed higher Kyn/Trp (p = 0.005), were older (p = 0.007), and IL-6 levels resulted higher than in non-fatigue patients (p < 0.001). HD patients with fatigue showed lower intracellular water (surrogate of muscle mass) (p < 0.001), as well as lower hand grip strength (p = 0.02). The Kyn/Trp ratio positively correlated with IL-6 and ECW/ICW (p = 0.004 and p = 0.014). By logistic regression analysis, higher ICW/h2 was associated with lower odds of fatigue (OR, 0.10; 95% CI, 0.01 to 0.73). In conclusion, our cohort fatigue was associated with a higher Kyn/Trp ratio, indicating a modulation of IDO activity. The Kyn/Trp ratio correlated with IL-6, suggesting a potential role of IDO and inflammation in inducing fatigue and changes in muscularity.

Machine Learning and Pharmacogenomics at the Time of Precision Psychiatry
Antonio Del Casale, Giuseppe Sarli, Paride Bargagna, Lorenzo Polidori, Alessandro Alcibiade, Teodolinda Zoppi, Marina Borro, Giovanna Gentile, Clarissa Zocchi, Stefano Ferracuti,et al.
Bentham Science Publishers Ltd.
Abstract: Traditional medicine and biomedical sciences are reaching a turning point because of the constantly growing impact and volume of Big Data. Machine Learning (ML) techniques and related algorithms play a central role as diagnostic, prognostic, and decision-making tools in this field. Another promising area becoming part of everyday clinical practice is personalized therapy and pharmacogenomics. Applying ML to pharmacogenomics opens new frontiers to tailored therapeutical strategies to help clinicians choose drugs with the best response and fewer side effects, operating with genetic information and combining it with the clinical profile. This systematic review aims to draw up the state-of-the-art ML applied to pharmacogenomics in psychiatry. Our research yielded fourteen papers; most were published in the last three years. The sample comprises 9,180 patients diagnosed with mood disorders, psychoses, or autism spectrum disorders. Prediction of drug response and prediction of side effects are the most frequently considered domains with the supervised ML technique, which first requires training and then testing. The random forest is the most used algorithm; it comprises several decision trees, reduces the training set's overfitting, and makes precise predictions. ML proved effective and reliable, especially when genetic and biodemographic information were integrated into the algorithm. Even though ML and pharmacogenomics are not part of everyday clinical practice yet, they will gain a unique role in the next future in improving personalized treatments in psychiatry.

Predicting Dihydropyrimidine Dehydrogenase Deficiency and Related 5-Fluorouracil Toxicity: Opportunities and Challenges of DPYD Exon Sequencing and the Role of Phenotyping Assays
Ottavia De Luca, Gerardo Salerno, Donatella De Bernardini, Maria Simona Torre, Maurizio Simmaco, Luana Lionetto, Giovanna Gentile, and Marina Borro
MDPI AG
Deficiency of dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is associated with severe toxicity induced by the anti-cancer drug 5-Fluorouracil (5-FU). DPYD genotyping of four recommended polymorphisms is widely used to predict toxicity, yet their prediction power is limited. Increasing availability of next generation sequencing (NGS) will allow us to screen rare variants, predicting a larger fraction of DPD deficiencies. Genotype–phenotype correlations were investigated by performing DPYD exon sequencing in 94 patients assessed for DPD deficiency by the 5-FU degradation rate (5-FUDR) assay. Association of common variants with 5-FUDR was analyzed with the SNPStats software. Functional interpretation of rare variants was performed by in-silico analysis (using the HSF system and PredictSNP) and literature review. A total of 23 rare variants and 8 common variants were detected. Among common variants, a significant association was found between homozygosity for the rs72728438 (c.1974+75A>G) and decreased 5-FUDR. Haplotype analysis did not detect significant associations with 5-FUDR. Overall, in our sample cohort, NGS exon sequencing allowed us to explain 42.5% of the total DPD deficiencies. NGS sharply improves prediction of DPD deficiencies, yet a broader collection of genotype–phenotype association data is needed to enable the clinical use of sequencing data.

Opposite Effect of Thyroid Hormones on Oxidative Stress and on Mitochondrial Respiration in COVID-19 Patients
Claudia De Vitis, Carlo Capalbo, Alessandra Torsello, Christian Napoli, Valentina Salvati, Chiara Loffredo, Giovanni Blandino, Giulia Piaggio, Francesca Romana Auciello, Flaminia Pelliccia,et al.
MDPI AG
Background: Thyroid hormones (TH)s are master regulators of mitochondrial activity and biogenesis. Nonthyroidal illness syndrome (NTIS) is generally considered an adaptative response to reduced energy that is secondary to critical illness, including COVID-19. COVID-19 has been associated with profound changes in the cell energy metabolism, especially in the cells of the immune system, with a central role played by the mitochondria, considered the power units of every cell. Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects and alters mitochondrial functions, both to influence its intracellular survival and to evade host immunity. Aim of the study: This study was undertaken to analyze the oxidative balance and mitochondrial respiration in COVID-19 patients with and without NTIS to elucidate the role that thyroid hormones (TH)s play in this context. Methods: In our cohort of 54 COVID-19 patients, admitted to our University Hospital during the COVID-19 pandemic, we evaluated the generation of reactive oxygen species (ROS) by measuring the serum levels of derivatives of reactive oxygen metabolites (dROMs), and we analyzed the antioxidant capacity by measuring the serum biological antioxidant potential (BAP). We then analyzed the mitochondrial respiration in peripheral blood mononuclear cells (PBMC)s of 28 of our COVID-19 patients, using the seahorse instrument (Agilent). Results were correlated with the serum levels of THs and, in particular, of FT3. In addition, the role of T3 on bioelectrical impedance analysis (BIA) and mitochondrial respiration parameters was directly evaluated in two COVID-19 patients with NTIS, in which treatment with synthetic liothyronine (LT3) was given both in vivo and in vitro. Results: In our COVID-19 patients with NTIS, the dROMs values were significantly lower and the BAP values were significantly higher. Consequently, the oxidative stress index (OSi), measured as BAP/dROMs ratio was reduced compared to that observed in COVID-19 patients without NTIS, indicating a protective role exerted by NTIS on oxidative stress. In our COVID-19 patients, the mitochondrial respiration, measured in PBMCs, was reduced compared to healthy controls. Those with NTIS showed a reduced maximal respiratory capacity and a reduced proton leak, compared to those with normal FT3 serum values. Such lowered mitochondrial respiratory capacity makes the cells more vulnerable to bioenergetic exhaustion. In a pilot study involving two COVID-19 patients with NTIS, we could reinforce our previous observation regarding the role of T3 in the maintenance of adequate peripheral hydroelectrolytic balance. In addition, in these two patients, we demonstrated that by treating their PBMCs with LT3, both in vitro and in vivo, all mitochondrial respiration parameters significantly increased. Conclusions: Our results regarding the reduction in the serum levels of the reactive oxygen species (ROS) of COVID-19 patients with NTIS support the hypothesis that NTIS could represent an adaptative response to severe COVID-19. However, beside this beneficial effect, we demonstrate that, in the presence of an acute reduction of FT3 serum levels, the mitochondrial respiration is greatly impaired, with a consequent establishment of a hypoenergetic state of the immune cells that may hamper their capacity to react to massive viral infection.

4BNT162b2 mRNA COVID-19 vaccine and semen: What do we know?
Soraya Olana, Rossella Mazzilli, Gerardo Salerno, Virginia Zamponi, Maria Grazia Tarsitano, Maurizio Simmaco, Donatella Paoli, and Antongiulio Faggiano
Wiley
BACKGROUND The effects of mRNA Covid-19 -vaccine on sperm parameters is not known. The aim of this study was to evaluate the effect of BNT162b2 mRNA Covid-19 vaccine on human semen, comparing sperm parameters before and after vaccine inoculation. MATERIALS AND METHODS In this single centre prospective study, voluntary subjects undergone mRNA vaccine from February to July 2021 were enrolled. Study population included male subjects, aged between 18 and 45 years, who completed the BNT162b2 mRNA Covid-19 vaccine cycle. All subjects were evaluated before the first dose of vaccine (T0) and after three months (T1) with semen analysis and further analysis on seminal plasma, including colorimetric determination of reactive oxygen metabolites (d-ROM test), electrolytes, and interleukin 6 (IL-6) assessment by ELISA technology. RESULTS The experimental sample included 47 subjects (age: 29.3±6.0 years, range 24-32; BMI: 23.15±2.5 Kg/m2 , range 19.2-28.0). All the subjects reported no systemic side effects. No significant differences were observed in all sperm parameters in T0 compared to T1. A sub-analysis was performed in oligoazoospermic and asthenozoospermic subjects, confirming the same results. Electrolytes analysis also showed no significant differences before and after vaccine inoculation. Finally, no significant differences were observed in T0 compared to T1 for d-ROM test and IL-6. DISCUSSION AND CONCLUSION In this study, no significative differences in sperm parameters before and after vaccine inoculations were found. Furthermore, oxidative stress analysis, activity of cell membrane and as a marker of inflammation IL-6, were not affected by the mRNA Covid-19 vaccine. These results suggest that this vaccine is safe on male semen quality. This article is protected by copyright. All rights reserved.

Age-Related Dynamics of Serum Anti-Spike IgG Ab after the Third Dose of BNT162b2 Vaccine in a Naive Health Care Workers Population
Gerardo Salerno, Giovanna Gentile, Ottavia De Luca, Giuseppe Costanzi, Gloria Cirelli, Barbara Di Simone Di Giuseppe, Laura Marcellini, Paolo Anibaldi, Adriano Marcolongo, Maurizio Simmaco,et al.
Mary Ann Liebert Inc
The kinetics of postvaccination serum anti-Spike IgG concentration were determined in 1,541 health care workers (Sant'Andrea Hospital of Rome, Italy) with no prior infection by SARS-COV-2. Anti-Spike IgG were measured at 3, 12, and 24 weeks after the completion of the primary vaccine cycle (two doses of the BNT162b2 vaccine by Biontech/Pfizer) and 3 weeks apart a third BNT162b2 dose. Stratification of the study population by age (decades from 21-30 to 61-70) highlighted that 24 weeks after cycle completion all age groups had an order of magnitude reduction in serum IgG titers. Considering older adults (age 61-70), they had significantly lower serum IgG titers at each time point compared with younger people, except after the booster dose, which induced similar and elevated IgG titers despite the age.

SARS-CoV-2 Transmission Control Measures in the Emergency Department: The Role of Rapid Antigenic Testing in Asymptomatic Subjects
Marina Borro, Gerardo Salerno, Andrea Montori, Andrea Petrucca, Paolo Anibaldi, Adriano Marcolongo, Rita Bonfini, Maurizio Simmaco, and Iolanda Santino
MDPI AG
Limiting transmission of SARS-CoV-2 from asymptomatic people assumes the paramount importance of keeping fragile subjects protected. We evaluated the utility of rapid SARS-CoV-2 antigen testing in asymptomatic subjects attending emergency departments in non-COVID-19 areas, using a single nasopharyngeal swab specimen collected in universal transport medium to perform both rapid antigen testing and rRT-PCR (used as reference standard) in a cohort of 899 patients. In the overall sample, the rapid antigen test had 43.9% sensitivity, 100% specificity, 100% positive predictive value, 93.6% negative predictive value. Considering subjects with rRT-PCR cycle threshold ≤30, the test had 80.4% sensitivity, 100% specificity, 100% positive predictive value, 98.8% negative predictive value. Considering subjects with rRT-PCR cycle threshold ≤25, the test had 94.7% sensitivity, 100% specificity, 100% positive predictive value and 99.7% negative predictive value. Despite low sensitivity, routine application of rapid antigen testing in the emergency department can lead to isolation in less than 30 min of about a half of asymptomatic COVID-19 subjects assigned to non-COVID-19 areas by clinical triage. The rapid test correctly identified 94.7% of asymptomatic patients with cycle threshold ≤ 25 that are supposed to be more infective; thus, it could be a useful measure to contain viral transmission in non-COVID-19 areas.

Dopamine DRD2 and DRD3 Polymorphisms Involvement in Nicotine Dependence in Patients with Treatment-Resistant Mental Disorders
Antonio del Casale, Marco Paolini, Giovanna Gentile, Marina Borro, Clarissa Zocchi, Federica Fiaschè, Alessio Padovano, Teodolinda Zoppi, Martina Nicole Modesti, Ottavia De Luca,et al.
MDPI AG
Patients affected by mental disorders smoke more than the general population. The reasons behind this habit are genetic, environmental, etc. This study aims to investigate the correlations between some polymorphisms and the smoking habits and nicotine dependence in patients with psychiatric disorders. We recruited 88 patients with treatment-resistant mental disorders, including 35 with major depressive disorder, 43 with bipolar spectrum disorder, and 10 with schizophrenia spectrum disorder. We carried out a clinical and psychometric assessment on current smoking habits, years of smoking, number of daily cigarettes, and level of nicotine addiction. The patients performed a peripheral blood sample for DNA analyses of different polymorphisms. We searched for correlations between the measures of nicotine addiction and analysed genotypes. The expression of the T allele of the DRD2 rs1800497 and DRD3 rs6280 polymorphisms significantly correlated with a lower level of nicotine dependence and lower use of cigarettes. We did not find significant correlations between nicotine dependence and OPRM1 rs1799971, COMT rs4680 and rs4633 polymorphisms, CYP2A6 rs1801272 and rs28399433, or 5-HTTLPR genotype. Concluding, DRD2 rs1800497 and DRD3 rs6280 polymorphisms are involved in nicotine dependence and cigarette smoking habits in patients with treatment-resistant mental disorders

Maurizio Simmaco

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