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Maria Stella Graziani

Deputy Director
Martina Zaninotto

Associate Editors
Ferruccio Ceriotti
Davide Giavarina
Bruna Lo Sasso
Giampaolo Merlini
Martina Montagnana
Andrea Mosca
Paola Pezzati
Rossella Tomaiuolo
Matteo Vidali

EIC Assistant
Francesco Busardò

International Advisory Board Khosrow Adeli Canada
Sergio Bernardini Italy
Marcello Ciaccio Italy
Eleftherios Diamandis Canada
Philippe Gillery France
Kjell Grankvist Sweden
Hans Jacobs The Netherlands
Eric Kilpatrick UK
Magdalena Krintus Poland
Giuseppe Lippi Italy
Mario Plebani Italy
Sverre Sandberg Norway
Ana-Maria Simundic Croatia
Tommaso Trenti Italy
Cas Weykamp The Netherlands
Maria Willrich USA
Paul Yip Canada

Biomedia srl
Via L. Temolo 4, 20126 Milano

Responsible Editor
Giuseppe Agosta

Editorial Secretary
Chiara Riva
Biomedia srl
Via L. Temolo 4, 20126 Milano
Tel. 0245498282


ISSN print: 0393 – 0564
ISSN digital: 0392- 7091

Biochimica Clinica: VOL.46 N.4

Scarica intero fascicolo
Sostanze psicoattive legali, illegali, classiche e di nuova sintesi: le sfide della medicina di laboratorio
Biochimica Clinica 2022; 46(4) 273-275
DOI: 10.19186/BC_2022.073
Pubblicato online il: 28.11.2022
Editoriale - Editorial
Disruptive innovations in laboratory medicine: saliva as a disruptive specimen
M. Plebani  | 
Biochimica Clinica 2022; 46(4) 276-278
DOI: DOI: 10.19186/BC_2022.070
Pubblicato online il: 28.11.2022
Editoriale - Editorial
Vaccini bivalenti contro COVID-19
G. Lippi  |  C. Mattiuzzi  | 
Biochimica Clinica 2022; 46(4) 279-82
DOI: 10.19186/BC_2022.076
Pubblicato online il: 28.11.2022
Editoriale - Editorial
New psychoactive substances: a descriptive review
New psychoactive substances: a descriptive review

New psychoactive substances (NPS) are psychotropic drugs, that are used as alternatives to the classical scheduled drugs of abuse and are not under control of the United Nations’ 1961 Narcotic Drugs/1971 Psychotropic Substances conventions. NPS is a umbrella generic term including new synthetic and natural drugs such as synthetic cannabinoids, synthetic opioids, hallucinogens, synthetic cathinones and other stimulants. Many NPS were originally developed as therapeutic drug candidates and/or as pharmacological tools to investigate endogenous systems, although none of them were clinically tested. Due to the absence of experimental and clinical data of on NPS, pharmacological and toxicological data are rarely available. Therefore, NPS use may induce unknown and unexpected effects, including acute and chronic toxic effects, as reported in numerous cases of intoxication and deaths in Europe and worldwide. The rapid emergence of a large number of NPS on the global drug market poses a significant risk to public health and a challenge to drug policy. The present manuscript provides an updated review of the large number of new/novel/emerging psychoactive substances and their associated psychopathological consequences.

Biochimica Clinica 2022; 46(4) 283-291
DOI: 10.19186/BC_2022.061
Pubblicato online il: 12.10.2022
Rassegne - Reviews
Saliva: challenges, possibilities, and limits of the diagnostic use Part 1 - Anatomical and basic pathophysiological aspects
Saliva: challenges, possibilities, and limits of the diagnostic use Part 1 - Anatomical and basic pathophysiological aspects

This review presents a detailed description of the saliva physiology (sources, composition, regulation of secretion) illustrating the complexity of this body fluid and its relationship with the pathophysiology of many organs. The knowledge of these aspects are of paramount importance to deeply understand main sources of variability, in keeping under control the pre-analytical phase and also to try to explain some contradictory results found in literature. Saliva is a biofluid with very interesting advantages: it is easy to self-collect, transport, and store. It is expected that saliva will have a key future role in the diagnosis of many diseases (metabolic disorders, cancer, oral and dental diseases, etc.) and useful for point-of-care testing. Part I of this review is a basic introduction to the saliva biological complexity; part II will follow, dealing with issues related to the pre-analytical and analytical phase.

TAG: saliva   salivary glands   saliva composition   saliva secretion  
Biochimica Clinica 2022; 46(4) 292-300
DOI: 10.19186/BC_2022.068
Pubblicato online il: 27.10.2022
Rassegne - Reviews
Test di generazione della trombina nella coagulopatia da COVID-19
Thrombin generation test in COVID-19 related coagulopathy

Introduction: critically ill COVID-19 patients are known to have a coagulopathy characterized by increased levels of  D-dimer (DD) associated to a thrombotic risk and a significant increase in mortality. However, it is not known whether the associated COVID-19 coagulopathy is due to a prothrombotic state or is caused by endothelial dysfunction and inflammation. Aim of our study, was to better characterize the hypercoagulability  state of COVID-19 patients using Thrombin Generation analyser (ST Genesia®, Diagnostica Stago, Asnières, France).
Methods: a total of 46 non-critically ill hospitalized COVID-19 patients were compared to 19 critically ill COVID-19 patients utilizing calibrated automated thrombography and other biochemical, hematological and coagulation parameters.
Results: critically ill patients had a significant increase in C reactive protein (CRP), interleukin-6 (IL-6), prothrombin time (PT), DD and a significant decrease in lymphocytes count. No significant differences in Thrombin Generation Test (TGT) parameters were  observed between  the two groups of patients with the only exception of the “Lag Time” parameter.
Discussion: the obtained results confirmed increased levels of DD and PT in critically ill COVID-19 patients. Of note, disease severity did not cause an increase in Thrombin Generation when compared to non-critically COVID-19 patients. The significantly prolonged Lag Time in critically ill COVID-19 patients without decreased endogenous thrombin potential suggests an hypocoagulability state in these patients. The relevance of this finding is uncertain and may appear counterintuitive since these patients are expected to have a hypercoagulability status, and requires further research.

TAG: Test di generazione della trombina   COVID-19   coagulopatia  
Biochimica Clinica 2022; 46(4) 301-309
DOI: 10.19186/BC_2022.044
Pubblicato online il: 07.07.2022
Contributi Scientifici - Scientific Papers
Valutazione di un metodo POCT ad elevata sensibilità per la troponina cardiaca: confronto con una strumentazione automatizzata di laboratorio
Evaluation of a high-sensitivity cardiac troponin point-of-care assay: a comparison with a laboratory platform
R. Aloe  |  P. Avanzini  |  R. Musa  |  P. Cerati  |  M. Di pietro  | 

Introduction: until recently, high-sensitivity in cTn testing has been adequately performed exclusively by laboratory platforms, whereas point-of-care systems lack the required analytical performance. The Quidel TriageTrue High Sensitivity Troponin I Test (TriageTrue) is a novel point-of-care test that meets the IFCC definition of a high-sensitivity troponin assay. The aim of this study is to evaluate the performance of the TriageTrue assay versus the Beckman Coulter Access hsTnI assay, performed in a central laboratory analyzer.

Methods: the TriageTrue assay was carried out on Quidel Triage MeterPro; the Access Troponin I-hs assay was carried out on Beckman Coulter UniCel DxI 800. The two assays have been compared by a linearity study and by evaluating the agreement through a Passing-Bablok regression analysis and a Bland-Altman plot. In addition, the analytical performance of TriageTrue itself has been checked by performing an intra-assay precision study for two levels of troponin, including values at the 99th percentile.

Results: in comparing TriageTrue versus the Beckman Coulter Access hsTnI, a satisfactory linearity for the tested range (3.13-800 ng/L) has been observed; the precision study results demonstrate that the TriageTrue CV was less than 10% for all the three concentrations tested (21.5, 124.3 and 550 ng/L respectively).

Conclusions: the definition of a high linearity can be derived from the elevated Spearman’s correlation coefficient of 1.000 (p <0.001) which indicates that the values obtained by TriageTrue and by Beckman Coulter hsTnI are highly monotonically related, and thus have a high level of comparability.

TAG: troponina-hs   point-of-care   infarto miocardico acuto  
Biochimica Clinica 2022; 46(4) 309-316
DOI: 10.19186/BC_2022.049
Pubblicato online il: 03.08.2022
Contributi Scientifici - Scientific Papers
Sviluppo e validazione di un nuovo metodo in UHPLC-MS/MS per la determinazione di cannabidiolo e di tetraidrocannabinolo e relativi metaboliti in matrice pilifera. Applicazione su pazienti trattati con cannabis medica
A new UHPLC-MS/MS method to assess cannabidiol and Δ9-tetrahydrocannabinol and respective metabolites in hair. Application to patients treated with medical cannabis.

Introduction: several countries have recently approved the use of cannabis flowering tops with standardized amount of Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD) for the treatment of different diseases. Therapeutic monitoring of medical cannabis products administered to patients for the established pathologies is rarely carried out. 
Methods: the aim of this study is to develope, and fully validate an ultra-high-performance liquid chromatography-tandem mass spectrometry method to quantify Δ9-THC, CBD, and metabolites, i.e., 11-nor-9-carboxy-THC (THC-COOH), 11-hydroxy-THC (11-OH-THC) cannabidiol-7-oic acid (7-COOH-CBD), 7-hydroxycannabidiol (7-OH-CBD), 6-α-hydroxycannabidiol (6-α-OH-CBD) and 6-β-hydroxycannabidiol (6-β-OH-CBD) in hair samples of patients treated with medical cannabis. 
Results: the validation results indicate that the method is accurate (average inter/intra-day CV, <10%), precise (inter/ intra-day imprecision, <10%), and fast (10 minutes run time). Average hair concentrations in four patients treated with different formulations of medical cannabis were 2.75 ng/mg Δ9-THC, 2.87 ng/mg 11-OH-THC, and 0.32 ng/mg THC-COOH (n = 3); 1.65 ng/mg CBD, 2.73 ng/mg 7-OH-CBD, 1.29 ng/mg 7-COOH-CBD, 0.35 ng/mg 6-α-OH-CBD, and 0.03 ng/mg 6-β-OH-CBD. 
Discussion: the proposed method proved to be suitable for a fast and sensitive determination of all target compounds allowing high throughput testing in individuals monitored for medical cannabis treatments.


TAG: UHPLC-MS/MS   cannabis medica   matrice pilifera  
Biochimica Clinica 2022; 46(4) 317
DOI: 10.19186/BC_2022.065
Pubblicato online il: 05.10.2022
Contributi Scientifici - Scientific Paper
Sviluppo e validazione di un metodo analitico per la misurazione in neonati dell'ormone della crescita in campioni eluiti da carte filtro
Development and validation of a method for the measurement of growth hormone in newborns on dried blood spots.

Introduction: severe deficiency of Growth Hormone (GHD) of the newborn is a rare but potentially life-threatening disease. GH can be measured during the first week of life when levels are physiologically higher. Aim of the study was to validate a method to measure GH in newborns from dried blood spots (DBS) for reference interval estimation. Methods: whole EDTA-blood and serum were  collected from patients attending the Endocrinology Unit. 50 µL of EDTA-blood was spotted onto Guthrie cards (LTA Srl) which were air dried at room temperature (RT) for 4 hours and processed or stored at -20°C up to 8 months. Three disks (5.5 mm) were punched out into a 2 mL polypropylene tube and 250 µL of PBS1x were added. Samples were incubated at RT for 16 hours and then centrifuged at 12 500 rpm for 1 min. GH in supernatants or undiluted sera was determined by Immulite 2000 (Siemens Healthineers) and a calibration curve was built. Results: linearity was verified (R2 >0.99) up to 50 µg/L. At 1 µg/L, considered the Limit of Quantification (LOQ), CV% resulted to be 11%. Repeatability at 8 concentrations (from 1.5 to 50 µg/L) ranged from 2.4% to 11.1%. At 7 µg/L, the cut-off previously reported by literature for GHD, CV% was 3.7%. Within-laboratory imprecision, evaluated in a period of 8 months at two different concentrations (3.4 µg/L and 10.1 µg/L) was 13% and 5.9%, respectively. Conclusions. The new method displayed good analytical performances, suggesting it can be used to measure GH in newborns using DBS for reference interval estimation.

TAG: ormone della crescita   neonati   dried blood spot  
Biochimica Clinica 2022; 46(4) 325
DOI: 10.19186/BC_2022.063
Pubblicato online il: 12.10.2022
Contributi Scientifici - Scientific Papers
Strategie di sequenziamento: l’esempio del tumore testicolare in un trio familiare
Genome sequencing strategies: the example of testicular cancer in a familial trio
M. Nunziato  | 

Testicular cancer is the most common malignancy in men under the age of 50. In 1972 for the first time, the carcinoma in situ was mentioned and in particular the tumor of mixed germ cells in situ; this type of tumor, in fact, originates in the testicles but can also be found in other parts of the body. The diagnosis of these tumors involves the use of instrumental tests, usually carried out together with some laboratory tests including the determination of tumor markers; these, when increased, can be of help in indicating the presence of the disease. In recent years, there has been a sharp increase in the number of testicular cancer cases diagnosed especially in young males all over the world. Although the understanding of the molecular causes underlying this neoplasm is very limited, Next Generation Sequencing (NGS) strategies can help to shed light on complex and multifactorial pathologies such as in the case of testicular cancer. In addition, a new nucleic acid sequencing strategy is gaining ground: the third generation Oxford Nanopore Technology (ONT), which, allows to obtain a “picture” of the DNA in each individual as complete as possible, by providing very long genome sequences. The aim of this paper is to illustrate how the use of combined nucleic acid sequencing strategies has allowed to analyze the presence of mutations in a family trio where the boy (proband) was affected by testicular neoplasia. The combined sequencing of the genome and the methyloma can be of help in understanding the possible causative or predisposing mutations.

TAG: tumore testicolare   sequenziamento di II generazione   sequenziamento di III generazione  
Biochimica Clinica 2022; 46(4) 331
DOI: 10.19186/BC_2022.051
Pubblicato online il: 03.08.2022
Opinioni - Opinions
Dalla sepsi al COVID-19: il ruolo emergente di MDW
From sepsis to COVID-19: the emerging role of Monocyte Distribution Width (MDW).
G. Riva  |  V. Nasillo  |  M. Luppi  |  E. Tagliafico  |  T. Trenti  | 

Immune activation of the monocyte-macrophage population plays a pivotal role in the systemic hyper-inflammatory response, typically observed during severe dysimmune diseases, such as sepsis and COVID-19. In this commentary, we have reviewed the literature data on the novel cytometric marker of monocyte activation, known as MDW (Monocyte Volume Distribution Width), a monocyte dimensional parameter obtainable by blood count examination, which has recently been approved for clinical use as “Early Sepsis Indicator” (ESId), in patients accessing the Emergency Department. In particular, in this Opinion paper, we highlight the main clinical applications and relevant perspectives of this new test: from its use for (early) diagnosis of sepsis, in different hospital settings, to its emerging prognostic role in patients with COVID-19, as a biomarker of disease severity. In view of the reported evidence, we discuss the clinico-pathological notion that, basically, severe COVID-19 can be considered a new form of viral sepsis. Further clinical studies are needed to better understand the pre-analytical and analytical variables of this parameter, correlate MDW dynamics with those of other humoral and cytometric markers, and validate the new diagnostic and prognostic applications of MDW on large multicenter case series.

TAG: monociti   COVID-19   sepsi  
Biochimica Clinica 2022; 46(4) 336
DOI: 10.19186/BC_2022.060
Pubblicato online il: 16.09.2022
Opinioni - Opinions
La sfida del riconoscimento del professionista in Medicina di Laboratorio in Europa: gli strumenti a disposizione per aumentarne la visibilità e la qualità
The challenge of recognising Laboratory Medicine professionals in Europe: available tools to increase their expertise and visibility
P. Zaupa  |  J. Turkman  |  M. Zaninotto  |  D. Basso  | 


 Laboratory Medicine is essential in all steps of patient care and to maintain and improve its value, promoting its recognition and visibility is vital, but such endeavor is hampered by a lack of harmonization across the European Union (EU). Specialists have different names, pre-graduate education, legal status and specialist training. Thanks to the European Directive 2013/55/EU, automatic recognition of a profession is possible if one third of EU nations agree on the adoption of a “Common Training Framework’’ (CTF), which defines the common set of knowledge, skills and competences needed to pursue a profession. The EFLM Syllabus was used as a base upon which to build the CTF regarding specialist training, along with EFLM’s Equivalence of Standards (EoS) for pre- and post-specialty requirements. Professionals who trained following the Syllabus and meet EFLM’s EoS can be added to the EFLM’s European Register of Specialists in Laboratory Medicine. Standardization of specialist training is required to improve the quality of our profession and will allow specialists to work in different countries more easily. This is further facilitated by the EFLMLabX platform. The adoption of the CTF, the continuous harmonization process, the EFLM’s Register and its available tools to improve specialists’ skills and competences will increase the visibility of our profession, facilitating its recognition process by the European Parliament. This undertaking is not only needed for the recognition of our profession, but to also improve its quality across all European countries, which will positively reflect on patient care.

TAG: Common Training Framework   EFLM syllabus   formazione specialistica  
Biochimica Clinica 2022; 46(4) 342
DOI: 10.19186/BC_2022.058
Pubblicato online il: 05.09.2022
Documenti - Documents
Indicazioni per l’armonizzazione degli intervalli terapeutici dei farmaci antibatterici
Indications for the harmonization of the therapeutic intervals of antibacterial drugs.

In the last years infections due to multi-drug resistant Gram-positive and Gram-negative bacteria have increased. The accurate measurement of plasma concentrations of antibacterial drugs is crucial to identify antimicrobial therapies based on pharmacokinetics/pharmacodynamics (PK/PD) strategies. The aim of this paper is to provide an overview of the currently available information on PK/PD, minimal inhibitory concentration (MIC) and their relationships, for optimal antibacterial treatment in daily practice. Relevant papers reporting PK/PD data on different antibiotics, administered intravenously for the treatment of infections due to bacteria with reduced sensitivity or overt resistance to antibiotics, have been retrieved from the PubMed database. The classes of drugs considered were: beta-lactams, aminoglycosides, glycopeptides, lipopeptides, fluoroquinolones, tetracyclines, polymyxins and oxazolidinones. A short summary was prepared for each class of drugs and for specific drugs as well, including data on the mechanism of action, spectrum of activity and resistance, PK/PD index and target values related to MIC. 

TAG: TDM   antimicrobial drugs   therapeutic intervals  
Biochimica Clinica 2022; 46(4) 347
DOI: 10.19186/BC_2022.059
Pubblicato online il: 02.09.2022
Documenti - Documents
Risultati preliminari per la definizione dell’intervallo di riferimento per l’indoxyl solfato (indicano) nelle urine: precisazione
Biochimica Clinica 2022; 46(4) 354
DOI: 10.19186/BC_2022.064
Pubblicato online il: 28.09.2022
Lettere all'Editore - Letters to the Editors
Efficacia delle Linee Guida per la coagulazione: traguardo consolidato o punto di partenza?
Biochimica Clinica 2022; 46(4) 355
DOI: 10.19186/BC_2022.066
Pubblicato online il: 27.10.2022
Lettere all'Editore - Letters to the Editors
Efficacia delle Linee Guida per la coagulazione: traguardo consolidato o punto di partenza? La posizione del Gruppo di Studio SIBioC Emostasi e Trombosi
Biochimica Clinica 2022; 46(4) 357
DOI: 10.19186/BC_2022.067
Pubblicato online il: 27.10.2022
Lettere all'Editore - Letters to the Editors
In ricordo di Dante Valente
Biochimica Clinica 2022; 46(4) 358
Notizie SIBioC - SIBioC News
Alte concentrazioni di IL-6 nel liquido di dialisi peritoneale in un paziente affetto da peritonite
High levels of IL-6 on peritoneal dialysate in a patient with peritonitis.
G. Canu  |  G. Alfano  |  S. Tagliavini  |  T. Trenti  |  M. Varani  | 

Icodextrin has been associated with sterile peritonitis in patients on peritoneal dialysis. This peritonitis causes a cloudy effluent and mild abdominal discomfort, both resolved after the discontinuation of icodextrin. We report here a case of icodextrin-associated peritonitis coupled with high level of interleukin-6 (IL-6) on peritoneal dialysate. After the rechallenge with icodextrin, the Interleukin -6 (IL-6) increase was 9.8 fold higher, while the increase of the leucocyte count was only 4.3 fold higher compared to baseline. The icodextrin discontinuation induced a decrease of IL-6 and leucocyte count to baseline values while the peritoneal dialysate became clear. In conclusion, IL-6 could be considered a sensitive biomarker for the diagnosis of icodextrin-associated peritonitis.

TAG: peritonite   interleuchina-6   dialisi peritoneale  
Biochimica Clinica 2022; 46(4) e22
DOI: 10.19186/BC_2022.034
Pubblicato online il: 20.05.22
Casi Clinici - Case Report
Importanti informazioni dall’esame dello striscio periferico
Important information from the peripheral smear examination

Rarely, platelets can interact with other blood elements, forming platelet aggregates. This paper presents an isolated case of platelet satellitism around neutrophils, lymphocytes and monocytes with platelet phagocytosis by both neutrophils and monocytes. The subject was an 89-year-old woman with breast cancer on anti-estrogenic hormone cancer therapy. Whole blood sample collected in a tube with K2EDTA anticoagulant was analysed within 4 hours, using Sysmex XN-9000 analyzer. The complete blood count presented the following results: white blood cell 4.0x109/L, red blood cell 3.58x1012/L, haemoglobin 116 g/L, haematocrit 34.9%, mean corpuscular volume 97.5 fL, mean corpuscular haemoglobin 32.5 pg, mean corpuscular haemoglobin concentration 332 g/L, red blood cell distribution width 14.6% and platelet 136x109/L. The present case report describes the platelet satellitism around neutrophils, lymphocytes and monocytes and the interesting, and very rare phenomenon of platelet phagocytosis by not only neutrophils but also by monocytes.

TAG: satellitismo piastrinico   fagocitosi piastrinica   pseudotrombocitopenia isolata  
Biochimica Clinica 2022; 46(4) e25
DOI: 10.19186/BC_2022.035
Pubblicato online il: 26.05.22
Casi Clinici - Case Report
Falsely elevated Digoxin levels detected in patient on concomitant use of Enzalutamide

Enzalutamide may cause falsely elevated Digoxin levels using chemiluminescent microparticle immunoassay analytical method.
This report describes the case of an 81 year old man treated with Enzalutamide since 2019 and Digoxin for the last 15 days before emergency ward admission with falsely elevated Digoxin levels.
The study reveals an analytical interference with the chemiluminescent immunoassay utilized concerning falsely elevated Digoxin levels with concomitant use of Enzalutamide.
In agreement with similar reports in the literature, patients on Enzalutamide, should have the Digoxin levels measured with alternative methods.

TAG: Digoxin   Enzalutamide   analytical interference  
Biochimica Clinica 2022; 46(4) e28
DOI: 10.19186/BC_2022.043
Pubblicato online il: 28.06.2022
Caso Clinico - Case Report
Approccio combinato tra il monitoraggio terapeutico del farmaco (TDM) e farmacogenetica per l’applicazione della medicina personalizzata nella pratica clinica
Combined approach of TDM and pharmacogenetics for application of personalized medicine in the clinical practice


 Therapeutic Drug Monitoring (TDM) can be defined as the assessing of the adequacy of the drug plasma concentrations to a target concentration or to a concentration window at a specific time in a dosing interval. Following appropriate clinical interpretation and according to the drug pharmacokinetic/pharmacodynamic (PK/PD) properties, this evaluation can guide dosing optimization. However, finding the optimal dosing in order to guarantee a therapeutic exposure remains complicated. Sources of PK variability, including age, genetic heritage, and disease conditions, influence the chances of achieving adequate therapeutic outcomes. Another important aspect related to drug efficacy and safety is the Pharmacogenetics (PGx). Genetic variants or single nucleotide polymorphisms (SNPs) in genes encoding for metabolizing enzymes and membrane carriers, may affect drug response and/or toxicity. A combination of TDM and PGx could represent a personalized approach in clinical practice especially for off-label drugs used in polytherapy and characterized by a narrow therapeutic index. TDM combined to PGx represents an useful tool that could help clinicians in tailoring pharmacological therapies. We present here three case reports related to pediatric patients who have shown adverse drug reactions in response to therapies with phenytoin (PHT), voriconazole (VO) and isoniazid (INH).

TAG: medicina personalizzata   farmacogenetica   TDM  
Biochimica Clinica 2022; 46(4) e31
DOI: 10.19186/BC_2022.045
Pubblicato online il: 06.07.2022
Casi Clinici - Case Report