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Pierachille Santus,1 Fabiano Di Marco,2 Fulvio Braido,3 Marco Contoli,4 Angelo Guido Corsico,5 Claudio Micheletto,6 Girolamo Pelaia,7 Dejan Radovanovic,1 Paola Rogliani,8 Laura Saderi,9 Nicola Scichilone,10 Silvia Tanzi,11 Manlio Vella,11 Silvia Boarino,11 Giovanni Sotgiu,9 Paolo Solidoro12 1Department of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di Milano, Division of Respiratory Diseases, Ospedale L. Sacco, ASST Fatebenefratelli-Sacco, Milano, Italy; 2Department of Health Sciences, Università degli Studi di Milano Pneumology, ASST Papa Giovanni XXIII, Bergamo, Italy; 3Department of Internal Medicine (DiMI), Respiratory Unit for Continuity of Care, IRCCS Ospedale Policlinico San Martino, University of Genova, Genova, Italy; 4Department of Translational Medicine, Respiratory Section, University of Ferrara, Ferrara, Italy; 5Department of Medical Sciences and Infective Diseases, Unit of Respiratory Diseases, IRCCS Policlinico San Matteo Foundation and University of Pavia Medical School, Pavia, Italy; 6Cardio-Thoracic Department, Respiratory Unit, University Integrated Hospital, Verona, Italy; 7Dipartimento di Scienze della Salute, Università Magna Graecia, Catanzaro, Italy; 8Department of Experimental Medicine, Unit of Respiratory Medicine, University of Rome ”Tor Vergata”, Division of Respiratory Medicine, University Hospital ”Tor Vergata”, Rome, Italy; 9Department of Medicine, Surgery and Pharmacy, University of Sassari, Sassari, Italy; 10Biomedical Department of Internal and Specialist Medicine, University of Palermo, Palermo, Italy; 11AstraZeneca Italia, Milan, Italy; 12Department of Medical Sciences, University of Turin, S.C. Pneumologia, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Torino, ItalyCorrespondence: Pierachille Santus, Università degli Studi di Milano, Via G.B. Grassi 74, Milano, 20157, Italy, Tel +39 0239042801, Fax +39 0239042473, Email pierachille.santus@unimi.itObjective: To describe the burden of moderate to severe exacerbations and all-cause mortality; the secondary objectives were to analyze treatment patterns and changes over follow-up.Design: Observational, multicenter, retrospective, cohort study with a three year follow-up period.Setting: Ten Italian academic secondary- and tertiary-care centers.Participants: Patients with a confirmed diagnosis of COPD referring to the outpatient clinics of the participating centers were retrospectively recruited.Primary and Secondary Outcome Measures: Annualized frequency of moderate and severe exacerbations stratified by exacerbation history prior to study enrollment. Patients were classified according to airflow obstruction, GOLD risk categories, and divided in 4 groups: A = no exacerbations; B = 1 moderate exacerbation; C = 1 severe exacerbation; D = ≥ 2 moderate and/or severe exacerbations. Overall all-cause mortality stratified by age, COPD category, and COPD therapy. A logistic regression model assessed the association of clinical characteristics with mortality.Results: 1111 patients were included (73% males), of which 41.5% had a history of exacerbations. As expected, the proportion of patients experiencing ≥ 1 exacerbation during follow-up increased according to pre-defined study risk categories (B: 79%, C: 84%, D: 97.4%). Overall, by the end of follow-up, 45.5% of patients without a history of exacerbation experienced an exacerbation (31% of which severe), and 13% died. Deceased patients were significantly older, more obstructed and hyperinflated, and more frequently active smokers compared with survivors. Severe exacerbations were more frequent in patients that died (23.5%, vs 10.2%; p-value: 0.002). Chronic heart failure and ischemic heart disease were the only comorbidities associated with a higher odds ratio (OR) for death (OR: 2.2, p-value: 0.001; and OR: 1.9, p-value: 0.007). Treatment patterns were similar in patients that died and survivors.Conclusion: Patients with a low exacerbation risk are exposed to a significant future risk of moderate/severe exacerbations. Real life data confirm the strong association between mortality and cardiovascular comorbidities in COPD.Keywords: pulmonary disease chronic obstructive, heart failure, ischaemic heart disease, respiratory medicine, public health

Daniele Roberto Giacobbe,1,2 Eugenio Ciacco,3 Corrado Girmenia,4 Federico Pea,5,6 Gian Maria Rossolini,7,8 Giovanni Sotgiu,9 Carlo Tascini,10 Mario Tumbarello,11,12 Pierluigi Viale,5,6 Matteo Bassetti1,2 On behalf of the ISGRI-SITA (Italian Study Group on Resistant Infections of the Italian Society of Anti-infective Therapy)1Clinica Malattie Infettive, Ospedale Policlinico San Martino – IRCCS, Genoa, Italy; 2Department of Health Sciences, University of Genoa, Genoa, Italy; 3Pharmacy Unit, S. Salvatore Hospital, ASL1 Abruzzo, L’Aquila, Italy; 4Hematology, Dipartimento Medicina Traslazionale e di Precisione, AOU Policlinico Umberto I, Sapienza University of Rome, Rome, Italy; 5Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy; 6University Hospital IRCCS Policlinico Sant’Orsola Bologna, Bologna, Italy; 7Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; 8Clinical Microbiology and Virology Unit, Florence Careggi University Hospital, Florence, Italy; 9Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy; 10SOC Malattie Infettive, Azienda Sanitaria Integrata, University of Udine, Udine, Italy; 11Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; 12Dipartimento di Sicurezza e Bioetica, Università Cattolica del Sacro Cuore, Rome, ItalyCorrespondence: Daniele Roberto GiacobbeClinica Malattie Infettive, Ospedale Policlinico San Martino – IRCCS, L.go R. Benzi 10, Genoa 16132, ItalyTel +390105554658Email daniele.roberto.giacobbe@gmail.comAbstract: Infections due to multidrug-resistant Gram-negative bacteria (MDR-GNB), especially when carbapenem resistant, have been very difficult to manage in the last fifteen years, owing to the paucity of dependable therapeutic options. Cefiderocol is a siderophore cephalosporin recently approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) that may have the potential to fill some of the remaining gaps in the treatment of MDR-GNB infections. Among others, cefiderocol demonstrated in vitro activity against carbapenem-resistant Acinetobacter baumannii and metallo-β-lactamases producers. Clinical data from both registrative studies and post-marketing experiences are essential to confirm whether these promises from in vitro studies could readily translate into clinical practice, as well as to delineate the precise place in therapy for cefiderocol for the treatment of MDR-GNB in the near future. Because of its unique potential, it is essential to provide both randomized controlled trials (RCT) and real-life data to improve the ability of clinicians to exploit its benefit in both empirical and targeted treatment of MDR-GNB infections. In this narrative review, we discuss the emerging data from pivotal RCT and initial real-life experiences on the use of cefiderocol for the treatment of MDR-GNB infections.Keywords: cefiderocol, siderophore, Pseudomonas, Acinetobacter, Enterobacterales, antimicrobial resistance

Niccolò Riccardi,1,2,* Simone Villa,1,3,* Riccardo Alagna,1,4 Andrea Giacomelli,1,5 Laura Saderi,1,6 Daniela Maria Cirillo,1,4 Giorgio Besozzi,1 Giovanni Sotgiu,1,6 Luigi Codecasa1,7 1StopTB Italia Onlus, Milan 20159, Italy; 2Department of Infectious - Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Verona 37024, Italy; 3Centre for Multidisciplinary Research in Health Science, University of Milan, Milan 20122, Italy; 4IRCCS San Raffaele Scientific Institute, Milan 20132, Italy; 5III Infectious Diseases Unit, ASST Fatebenefratelli Sacco, Milan 20157, Italy; 6Clinical Epidemiology and Medical Statistics Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari 07100, Italy; 7Regional TB Reference Centre, Istituto Villa Marelli, Niguarda Hospital, Milan 20159, Italy*These authors contributed equally to this workCorrespondence: Niccolò RiccardiDepartment of Infectious - Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Via Don A. Sempreboni N.5, 37024, Negrar di Valpolicella, Verona, ItalyTel +39 045 601 6420Email niccolo.riccardi@yahoo.itAbstract: The emerge of drug-resistant tuberculosis (TB) strain in recent decades is hampering the efforts of the international community to eliminate the disease worldwide. The World Health Organization (WHO) has drafted many strategies to achieve this ambitious goal. In the very beginning, the aim was to standardize inadequate regimens used in many countries and, thereafter, evolved to tackle the social determinants which hinder TB elimination. However, following the path of narrowing the clinical vision to deal with TB, there is an increased need to personalize the treatment considering both patients and pathogen unique characteristics. In our narrative review, we report the advantages and the backwards in developing a method to implement the concept of precision medicine to the treatment of TB. In this dissertation, we highlight the importance to address different aspects of the diseases encompassing the host and pathogen features, as well as the needs to further implement an adequate follow-up based on the available resources. Nevertheless, many things may hamper the vision of precision medicine in TB, such as the complexity and the costs to develop novel compounds and the costs related to global-scale implementation of patient-centered follow-up. To achieve the ambitious goal of TB elimination, a radical change in TB treatment is needed in order to give a more comprehensive approach based both on patients’ peculiarities and driven by drug susceptibility tests and whole-genome sequencing.Keywords: tuberculosis, drug-resistance, treatment, tailored, StopTB

Giustino Varrassi,1 Franco De Conno,2 Luciano Orsi,3 Filomena Puntillo,4 Giovanni Sotgiu,5 John Zeppetella,6 Furio Zucco7 1Paolo Procacci Foundation, Rome, Italy; 2Palliative Care, Pain Therapy and Rehabilitation Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; 3SC Cure Palliative ASST Carlo Poma, Mantova, Italy; 4Anesthesia and Intensive Care Unit, Department of Emergency and Organ Transplants, University Hospital of Bari, Bari, Italy; 5Clinical Epidemiology and Medical Statistics Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy; 6St Claire’s Hospice, Hastingwood, UK; 7Azienda Ospedaliera Salvini, Garbagnate Milanese, ItalyCorrespondence: Giustino VarrassiPaolo Procacci Foundation, Via Tacito 7, Rome 00193, ItalyEmail giuvarr@gmail.comBackground: In patients with cancer, the prevalence of pain is high, and pain management is often challenging despite the wide availability of drugs and guidelines.Methods: This Delphi survey was organized within the Rational Use of Analgesics (RUA) Group projects to reach a consensus among Italian palliative care specialists on pain assessment and management. Items were identified from recent publications on cancer pain and guidelines.Results: This survey included input from 190 palliative care specialists representing all Italian territory. A consensus was reached on 17 statements. Items concerning pain assessment achieved over 70% agreement amongst the participants. Items on principles of pain management and management according to type of pain, including breakthrough cancer-related pain and neuropathic pain also achieved high levels of agreement.Conclusion: Results from the RUA project showed that Italian palliative care specialists had a particular interest in items related to pain challenges, in addition to the evaluation and control of pain associated with cancer. However, some discrepancies between current guidelines and clinical practice were observed.Keywords: cancer, pain, breakthrough cancer pain, neuropathic pain, Delphi survey

Federica Foglietta,1 Giulio C Spagnoli,2,3 Manuele Giuseppe Muraro,2 Marco Ballestri,4 Andrea Guerrini,4 Claudia Ferroni,4 Annalisa Aluigi,4 Giovanna Sotgiu,4 Greta Varchi4 1Department of Drug Science & Technology, University of Torino, Torino, Italy; 2Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland; 3Institute of Translational Pharmacology, CNR, Rome, Italy; 4Institute for Organic Synthesis & Photoreactivity, National Research Council, Bologna, Italy Purpose: Taxanes are highly effective cytotoxic drugs for progressing breast cancer treatment. However, their poor solubility and high toxicity urge the development of innovative formulations of potential clinical relevance. Materials and methods: By using a simple and straightforward aggregation method, we have generated paclitaxel (PTX) loaded in keratin nanoparticles (KER-NPs-PTX). Their activities were tested against human breast cancer MCF-7 and MDA MB 231 cell lines in conventional two-dimensional (2D) cultures and in a dynamic three-dimensional (3D) model with perfused bioreactor (p3D). Moreover, KER-NPs-PTX activity was compared to free PTX and to PTX loaded in albumin nanoparticles (HSA-NPs-PTX). Cell viability, induction of apoptosis, and gene expression analysis were used as readouts. Results: In 2D cultures, KER-NPs-PTX was able to inhibit tumor cell viability and to induce apoptosis similarly to PTX and HSA-NPs-PTX. In the p3D model, a lower sensitivity of tumor cells to treatments was observed. Importantly, only KER-NPs-PTX was able to induce a statistically significant increase in apoptotic cell percentages following 24 h treatment for MCF-7 (16.7±4.0 early and 11.3±4.9 late apoptotic cells) and 48 h treatment for MDA MB 231 (21.3±11.2 early and 10.5±1.8 late apoptotic cells) cells. These effects were supported, at least for MCF-7 cells, by significant increases in the expression of proapoptotic BAX gene (5.8±0.5) 24 h after treatment and of cleaved caspase 3 (CC3) protein. Conclusion: KER-NPs-PTX, generated by a simple procedure, is characterized by high water solubility and enhanced PTX-loading ability, as compared to HSA-NPs-PTX. Most importantly, it appears to be able to exert effective anticancer activities on breast cancer cells cultured in 2D or in p3D models. Keywords: keratin, nanoparticles, paclitaxel, breast cancer, perfused three-dimensional models

Roberto Canaparo,1,* Greta Varchi,2,* Marco Ballestri,2 Federica Foglietta,1 Giovanna Sotgiu,2 Andrea Guerrini,2 Andrea Francovich,3 Pierluigi Civera,3 Roberto Frairia,4 Loredana Serpe1 1Department of Drug Science and Technology, University of Torino, Torino, Italy; 2Institute of the Organic Synthesis and Photoreactivity, National Research Council, Bologna, Italy; 3Departments of Electronics, Politecnico of Torino, Torino, Italy; 4Department of Medical Science, University of Torino, Torino, Italy *These authors contributed equally to this work Purpose: Sonodynamic therapy is a developing noninvasive modality for cancer treatment, based on the selective activation of a sonosensitizer agent by acoustic cavitation. The activated sonosensitizer agent might generate reactive oxygen species leading to cancer cell death. We investigated the potential poly-methyl methacrylate core-shell nanoparticles (NPs) loaded with meso-tetrakis (4-sulfonatophenyl) porphyrin (TPPS) have to function as an innovative sonosensitizing system, ie, TPPS-NPs. Methods: Shockwaves (SWs) generated by a piezoelectric device were used to induce acoustic cavitation. The cytotoxic effect of the sonodynamic treatment with TPPS-NPs and SWs was investigated on the human neuroblastoma cell line, SH-SY5Y. Cells were exposed for 12 hours to TPPS-NPs (100 µg/mL) and then to SWs (0.43 mJ/mm2 for 500 impulses, 4 impulses/second). Treatment with SWs, TPPS and NPs alone or in combination was carried out as control. Results: There was a statistically significant decrease in SH-SY5Y cell proliferation after the sonodynamic treatment with TPPS-NPs and SWs. Indeed, there was a significant increase in necrotic (16.91% ± 3.89%) and apoptotic (27.45% ± 3.03%) cells at 48 hours. Moreover, a 15-fold increase in reactive oxygen species production for cells exposed to TPPS-NPs and SWs was observed at 1 hour compared with untreated cells. A statistically significant enhanced mRNA (messenger ribonucleic acid) expression of NRF2 (P

Giovanni Sotgiu1, Paolo Nieddu2, Laura Mameli2, Enrico Sorrentino2, Pietro Pirina3, Alberto Porcu4, Stefano Madeddu1, Manuela Idini1, Maddalena Di Martino1, Giuseppe Delitala2, Ida Mura1, Maria Pina Dore21Epidemiology and Medical Statistics Unit, Department of Biomedical Sciences, 2Clinica Medica, 3Pneumologia, 4Chirurgia dell’Obesità, University of Sassari, Sassari, ItalyBackground: The relationship between patient and physician is a complex interaction that includes multiple factors. The objective of this study was to explore Italian patients’ preferences regarding physician appearance.Methods: A questionnaire was developed to survey patients in different medical and surgical settings; each subject was asked to choose one picture of either a male or female physician from a selection of different attires (professional, casual, surgical scrubs, trendy, and careless). Patients were also surveyed about issues such as the presence of a name tag, hair length, trousers on women, amount of makeup, presence of tattoos, and body piercing. Statistical analysis was performed using a Chi-square test.Results: A total of 765 questionnaires (534 completed from patients waiting for an internal medicine visit and 231 for other subspecialties) were completed. The majority (45%) of patients preferred the gastroenterologist to wear a surgical scrub with a white coat. For the other specialists, patients accepted either scrubs or formal dress under a white coat (P ≤ 0.05), with a name tag. Trendy attire was preferred by nine patients (1.1%). The entire sample judged it inappropriate for clinicians to have long hair, visible tattoos, body piercing, and, for women, to wear trousers and use excessive makeup.Conclusion: This is the first study conducted in Italy regarding physician attire. As in other Western countries, Italian patients favor physicians in professional attire with a white coat. Wearing professional dress is part of “etiquette based medicine” and may favorably influence clinician–patient relationships and patient compliance.Keywords: physician attire, appearance, etiquette medicine

BACKGROUND: Increasing evidence suggests that post-TB lung disease (PTLD) causes significant morbidity and mortality. The aim of these clinical standards is to provide guidance on the assessment and management of PTLD and the implementation of pulmonary rehabilitation (PR).METHODS: A panel of global experts in the field of TB care and PR was identified; 62 participated in a Delphi process. A 5-point Likert scale was used to score the initial ideas for standards and after several rounds of revision the document was approved (with 100% agreement).RESULTS: Five clinical standards were defined: Standard 1, to assess patients at the end of TB treatment for PTLD (with adaptation for children and specific settings/situations); Standard 2, to identify patients with PTLD for PR; Standard 3, tailoring the PR programme to patient needs and the local setting; Standard 4, to evaluate the effectiveness of PR; and Standard 5, to conduct education and counselling. Standard 6 addresses public health aspects of PTLD and outcomes due to PR.CONCLUSION: This is the first consensus-based set of Clinical Standards for PTLD. Our aim is to improve patient care and quality of life by guiding clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage PTLD.

OBJECTIVE: Laparoscopic cholecystectomy (LC) is the gold standard for most benign gallbladder diseases. Early discharge (<24 hours) has the same outcomes as longer (>24 hours) hospital stay. Nevertheless, the rate of delayed discharge >24 hours range from 4.6% to 37%. The primary endpoint of this Italian nationwide study is to analyze the prevalence of patients undergoing elective LC who experienced a delayed discharge >24 hours and identify potential limiting factors of early discharge. Results from these analyses will be used to select patients who can be safely discharged on the same day after surgery. Secondary endpoints will be to evaluate the patient's quality of life (QoL), assess the direct health costs associated with late discharge, and quantify the patient's involvement in the treatment process. PATIENTS AND METHODS: This prospective, observational study was conducted following a resident-led model and the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. All patients were treated according to the local hospital protocol and received routine care as standard therapy. RESULTS: We expected to obtain the enrollment of at least 500 patients based on an assumed difference in discharge delay between the reference and the recruitable population of 6% and the identification of factors related to discharge failure within 24 h. Early discharge after LC leads to advantages both in terms of clinical outcomes and quality of life of the patient, and it is highly effective in terms of health costs and shortening the waiting list. However, clinical reality differs from the results of randomized studies by a complex series of non-objectionable real-world data influencing treatment plans. Therefore, we expected to identify independent predictors and factors of failure of early discharge. CONCLUSIONS: Clinical reality often differs from randomized trial results. In Italy, the vast majority of delayed discharges after LC may not be related to surgery and can be prevented both with logistical reorganization and with a readjustment of the trust reimbursement policies. [ABSTRACT FROM AUTHOR]