Comparison of “IN-REC-SUR-E” and LISA in preterm neonates with respiratory distress syndrome: a randomized controlled trial (IN- REC-LISA trial)

Comparison of “IN-REC-SUR-E” and LISA in preterm neonates with respiratory distress syndrome: a randomized controlled trial (IN- REC-LISA trial) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparison of “IN-REC-SUR-E” and LISA in preterm neonates with respiratory distress syndrome: a randomized controlled trial (IN- REC-LISA trial) Giovanni Vento, Angela Paladini, Claudia Aurilia, Senem Alkan Ozdemir, and 250 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3994255/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background : Surfactant is a well-established therapy for preterm neonates affected by respiratory distress syndrome (RDS). Goals of different methods of surfactant administration are to reduce duration of mechanical ventilation and the severity of bronchopulmonary dysplasia (BPD), however the optimal administration method remains unknown. This study compares the effectiveness of the INtubate-RECruit-SURfactant-Extubate (IN-REC-SUR-E) technique with the less invasive surfactant administration (LISA) technique, in increasing BPD-free survival of preterm infants. This is an international unblinded multicenter randomized controlled study in which preterm infants will be randomized into two groups to receive IN-REC-SUR-E or LISA surfactant administration. Methods : In this study 382 infants born at 24 +0 -27 +6 weeks’ gestation, not intubated in the delivery room and failing nasal continuous positive airway pressure (nCPAP) or nasal intermittent positive pressure ventilation (NIPPV) during the first 24 h of life, will be randomized 1:1 to receive IN-REC-SUR-E or LISA surfactant administration. The primary outcome is a composite outcome of death or BPD at 36 weeks’ postmenstrual age. Secondary outcomes are: BPD at 36 weeks’ postmenstrual age; death; pulse oximetry/fraction of inspired oxygen; severe intraventricular haemorrhage; pneumothorax; duration of respiratory support and oxygen therapy; pulmonary hemorrhage; patent ductus arteriosus undergoing treatment; percentage of infants receiving more doses of surfactant; periventricular leukomalacia, severe retinopathy of prematurity, necrotizing enterocolitis, sepsis; total in-hospital stay; systemic postnatal steroids; neurodevelopmental outcomes and respiratory function testing at 24 months of age. Randomization will be centrally provided using both stratification and permuted blocks with random block sizes and block order. Stratification factors will include centre and gestational age (24 +0 to 25 +6 weeks or 26 +0 to 27 +6 weeks). Analyses will be conducted in both intention-to-treat and per-protocol populations, utilizing a log-binomial regression model that corrects for stratification factors to estimate the adjusted relative risk (RR). Discussion : This trial is designed to provide robust data on the best method of surfactant administration in spontaneously breathing preterm infants born at 24 +0 -27 +6 weeks' gestation affected by RDS and failing nCPAP or NIPPV during the first 24 hours of life, comparing IN-REC-SUR-E to LISA technique, in increasing BPD-free survival at 36 weeks' postmenstrual age of life. Trial registration : ClinicalTrials.gov identifier NCT05711966 Preterm infants Lung recruitment HFOV INRECSURE LISA Surfactant Figures Figure 1 Administrative information Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/). Title {1} Comparison of “IN-REC-SUR-E” and LISA in preterm neonates with respiratory distress syndrome: a randomized controlled trial (IN- REC-LISA trial) Trial registration {2a and 2b}. ClinicalTrials.gov Identifier: NCT05711966. Status: recruiting. First Posted: 3/02/2023; Last Update Posted: 17/02/2023. Protocol version {3} Version 3, 25 October 2022 Funding {4} The study has received economic contributions by way of partial coverage of the expenses relating to its implementation. Author details {5a} Giovanni Vento 1 , Angela Paladini 1 , C. Aurilia 1 , S. Alkan Ozdemir 2 , V.P. Carnielli 3 , F. Cools 4 , S. Costa 1 , F. Cota 1 , C. Dani 5 , P.G. Davis 6 , S. Fattore 1 , C. Fè 1 , N. Finer 7 , F.P. Fusco 1 , C. Gizzi 8 , E. Herting 9 , M. Jian 10 , A. Lio 1 , G. Lista 11 , F. Mosca 12 , S. Nobile 1 , A. Perri 1 , S. Picone 13 , J.J. Pillow 14 , G. Polglase 15 , T. Pasciuto 16 , R. Pastorino 17 , M.Tana 1 , D. Tingay 20 , C. Tirone 1 , A.H. van Kaam 21 , M.L. Ventura 19 , A. Aceti 22 , M. Agosti 23 , G. Alighieri 24 , G. Ancora 25 , V. Angileri 26 , G. Ausanio 27 , S. Aversa 28 , E. Balestri 29 , E. Baraldi 30 , M.C. Barbini 23 , C. Barone 31 , R. Beghini 91 , C. Bellan 32 , A. Berardi 33 , I. Bernardo 27 , P. Betta 35 , M. Binotti 61 , B. Bizzarri 8 , G. Borgarello 36 , S. Borgione 34 , A. Borrelli 27 , R. Bottino 33 , G. Bracaglia 38 , I. Bresesti 23 , I. Burattini 3 , C. Cacace 39 , F. Calzolari 40 , M.F. Campagnoli 41 , L. Capasso 42 , M. Capozza 43 , M.G. Capretti 22 , J. Caravetta 13 , C. Carbonara 41 , V. Cardilli 44 , M. Carta 45 , F. Castoldi 11 , A. Castronovo 8 , E. Cavalleri 28 , F. Cavigioli 11 , S. Cecchi 46 , V. Chierici 23 , C. Cimino 47 , F. Cocca 48 , C. Cocca 48 , P. Cogo 49 , M. Coma 12 , V. Comito 50 , V. Condò 12 , C. Consigli 51 , R. Conti 65 , M. Corradi 40 , G. Corsello 45 , L.T. Corvaglia 22 , A. Costa 52 , A. Coscia 34 , F. Cresi 34 , F. Crispino 27 , P. D’Amico 54 , L. De Cosmo 55 , C. De Maio 36 , G. Del Campo 54 , S. Di Credico 89 , S. Di Fabio 56 , P. Di Nicola 41 , A. Di Paolo 57 , S. Di Valerio 89 , A. Distilo 84 , V. Duca 26 , A. Falcone 50 , R. Falsaperla 47 , V.A. Fasolato 58 , V. Fatuzzo 76 , F. Favini 59 , M.P. Ferrarello 52 , S. Ferrari 59 , F. Fiori Nastro 86 , C.A. Forcellini 91 , A. Fracchiolla 60 , A. Gabriele 72 , F. Galdo 69 , F. Gallini 77 , A. Gangemi 65 , G. Gargano 29 , D. Gazzolo 62 , M.P.Gentile 63 , S.Ghirardello 64 , F. Giardina 65 , L. Giordano 66 , E. Gitto 67 , M. Giuffrè 45 , T. Gokmen Yildirim 2 , L. Grappone 48 , F. Grasso 42 , I. Greco 68 , A. Grison 70 , R. Guglielmino 71 , I. Guidotti 33 , I. Guzzo 72 , N. La Forgia 43 , S. La Placa 52 , G. La Torre 74 , P. Lago 75 , L. Lanciotti 3 , A. Lavizzari 12 , F. Leo 29 , V. Leonardi 5 , D. Lestingi 24 , J. Li 10 , P. Liberatore 60 , D. Lodin 76 , R. Lubrano 90 , M. Lucente 84 , S. Luciani 77 , D. Luvarà 90 , G. Maffei 60 , A. Maggio 64 , L. Maggio 78 , K. Maiolo 71 , L. Malaigia 79 , G. Mangili 59 , A. Manna 31 , E.Maranella 56 , A. Marciano 44 , P.Marcozzi 78 , M. Marletta 35 , L. Marseglia 67 , D. Martinelli 74 , S. Martinelli 73 ,S. Massari 80 , L. Massenzi 81 , F. Matina 65 , L. Mattia 35 , G. Mescoli 18 , I.V.Migliore 82 , D.Minghetti 83 , I. Mondello 50 , S. Montano 5 , G. Morandi 58 , N. Mores 92 , S. Morreale 82 , I. Morselli 76 , M. Motta 18 , M. Napolitano 31 , D. Nardo 30 , A. Nicolardi 88 , S. Nider 69 , G. Nigro 84 , M. Nuccio 88 , L. Orfeo 77 , C. Ottaviano 78 , P. Paganin 18 , S. Palamides 57 , S. Palatta 57 , P. Paolillo 13 , M.G. Pappalardo 54 , E. Pasta 85 , L. Patti 64 , G. Paviotti 49 , R. Perniola 37 , G. Perotti 64 , S. Perrone 40 , F. Petrillo 53 , M.S. Piazza 82 , A. Piccirillo 66 , M. Pierro 79 , E. Piga 44 , G. A. Pingitore 84 , S. Pisu 16 , C. Pittini 49 , F. Pontiggia 32 , G. Pontrelli 90 , A. Primavera 62 , A. Proto 73 , L. Quartulli 24 , F. Raimondi 42 , L. Ramenghi 83 , M. Rapsomaniki 72 , A. Ricotti 87 , C. Rigotti 19 , M. Rinaldi 60 , F.M. Risso 28 , E. Roma 66 , E. Romanini 40 , V. Romano 77 , E. Rosati 37 , V. Rosella 86 , I. Rulli 67 , V. Salvo 80 , C. Sanfilippo 68 , A. Sannia 36 , A. Saporito 35 , A. Sauna 80 , E. Scapillati 51 , F. Schettini 55 , A. Scorrano 88 , S. Semeria Mantelli 85 , V. Sepporta 26 , P. Sindico 58 , A. Solinas 63 , E. Sorrentino 51 , E. Spaggiari 33 , A. Staffler 81 , M. Stella 79 , D. Termini 86 , G. Terrin 44 , A. Testa 90 , G. Tina 71 , M. Tirantello 76 , B. Tomasini 46 , F. Tormena 75 , L. Travan 69 , D. Trevisanuto 30 , V. Tulino 39 , L. Valenzano 53 , S. Vedovato 70 , S. Vendramin 75 , P.E. Villani 85 , S. Viola 61 , V. Viola 50 , G. Vitaliti 68 , M. Vitaliti 68 , P. Wanker 81 , Y. Yang 10 , S. Zanetta 61 , E. Zannin 19 Dipartimento Universitario Scienze della Vita e Sanità Pubblica, UOC di Neonatologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Università Cattolica del Sacro Cuore, Rome, Italy. email: [email protected] ; [email protected] ; claudia.aurilia@ policlinicogemelli.it; simonetta.costa@ policlinicogemelli.it; francesco.cota@ policlinicogemelli.it; [email protected] ; francescapaola.fusco@ policlinicogemelli.it; [email protected] ; [email protected] ; [email protected] ; [email protected] ; [email protected] ; claudia.fe@ policlinicogemelli.it; Health Science University Dr. Behcet Uz Children’s Hospital, Izmir, Turkey. [email protected] ; [email protected] Azienda Ospedaliero Universitaria Ospedali Riuniti, Ancona, Italy. [email protected] ; [email protected] ; [email protected] Department of Neonatology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101 - 1090 Brussel, Belgium. [email protected] Department of Mother and Child Health, Division of Neonatology and Neonatal Intensive Care Unit, Careggi University Hospital Florence, Italy. [email protected] ; [email protected] ; [email protected] Neonatal Services, Royal Women's Hospital, Melbourne, Australia. [email protected] School of Medicine, University of California, San Diego, San Diego, CA, USA (NNF); and Sharp Mary Birch Hospital for Women and Newborns, San Diego, CA 92123, USA (NNF, AK). [email protected] Unità operativa complessa di neonatologia e TIN Ospedale Sant’Eugenio, ASL ROMA 2, Rome, Italy. [email protected] ; [email protected] ; [email protected] Klinik für Kinder- und Jugendmedizin UNIVERSITÄTSKLINIKUM Schleswig-Holstein Campus Lübeck Ratzeburger Allee 160 │Haus A │23538 Lübeck, Germany. [email protected] Shengjing Hospital of China Medical University, Shenyang, China. [email protected] ; [email protected] Neonatologia e Terapia Intensiva Neonatale (TIN) Ospedale dei Bambini "V.Buzzi" ASST-FBF-Sacco Via Castelvetro, 32 20154 Milan, Italy. [email protected] ; [email protected] ; [email protected] Department of Clinical Sciences and Community Health, University of Milan. Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico. Via Della Commenda 12 – 20122 Milan, Italy. [email protected] ; [email protected] ; [email protected] ; [email protected] Policlinico Casilino, Rome, Italy. [email protected] ; [email protected] ; [email protected] Centre for Child Health Research and School of Human Sciences, The University of Western Australia, Perth, WA, Australia. [email protected] The Ritchie Centre Hudson Institute of Medical Research and Department of Obstetrics and Gynaecology, Monash University, Clayton, 3168 Victoria, Australia. [email protected] Research Core Facility Data Collection G-STeP, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy. [email protected] ; [email protected] Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168 Rome, Italy. - [email protected] Department of Woman and Child Health and Public Health – Public Health Area, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy. Ospedale Maggiore, Bologna, Italy. [email protected] ; [email protected] ; [email protected] Fondazione IRCCS San Gerardo dei Tintori Monza, Italy. [email protected] ; [email protected] ; [email protected] Neonatal Research, Murdoch Children’s Research Institute, Melbourne, Australia. [email protected] Department of Neonatology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. [email protected] Policlinico S. Orsola-Malpighi, Università di Bologna, Bologna, Italy. [email protected] ; [email protected] ; [email protected] Università degli Studi dell’Insubria, Varese, Italy. [email protected] ; [email protected] ; [email protected] ; [email protected] P.P. “A. Perrino” Brindisi-ASL BR, Italy. [email protected] ; [email protected] ; [email protected] Ospedale Infermi, Rimini, Italy. [email protected] Presidio Ospedaliero Ingrassia ASP Palermo, Italy. [email protected] ; [email protected] ; [email protected] Azienda Ospedaliera S.Anna-S.Sebastiano Caserta, Italy. [email protected] ; [email protected] ; [email protected] ; [email protected] Azienda Ospedaliera “Spedali Civili”, Brescia, Italy. [email protected] ; [email protected] ; [email protected] Arcispedale Santa Maria Nuova Reggio Emilia, Italy. [email protected] ; [email protected] ; [email protected] University of Padua, Padua, Italy. [email protected] ; [email protected] ; [email protected] Ospedale Evangelico Betania-Naples, Italy. [email protected] ; [email protected] ; [email protected] Azienda Ospedaliera Bolognini, Seriate (BG), Italy. [email protected] ; [email protected] AOU Policlinico Modena, Italy. [email protected] ; [email protected] ; [email protected] ; [email protected] Neonatologia Universitaria, Ospedale S.Anna – Città della Salute e della Scienza di Torino, Italy. [email protected] ; [email protected] ; [email protected] AOU Policlinico Vittorio Emanuele-Gaspare Rodolico Catania, Italy. [email protected] ; [email protected] ; [email protected] ; [email protected] Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy. [email protected] ; [email protected] ; [email protected] Azienda Ospedaliera Vito Fazzi, Lecce, Italy. [email protected] ; [email protected] Bel Colle Hospital, Viterbo, Italy. [email protected] Barone Romeo Hospital Patti (ME), Italy. [email protected] ; [email protected] Azienda OU Parma, Italy. [email protected] . [email protected] ; [email protected] ; [email protected] Ospedale PO S. Anna, AOU Città della Salute e della Scienza, Torino, Italy. [email protected] ; [email protected] ; [email protected] Federico II University, Naples, Italy. [email protected] ; [email protected] ; [email protected] Policlinico di Bari, Italy. [email protected] ; [email protected] Policlinico Umberto I, Rome, Italy. [email protected] ; [email protected] ; [email protected] ; [email protected] Università degli Studi, Palermo, Italy. [email protected] ; [email protected] ; [email protected] Azienda Ospedaliera Universitaria Senese, Siena, Italy. [email protected] ; [email protected] Azienda OU Policlinico “Rodolico-San Marco”, Catania. [email protected] ; [email protected] Ospedale San Pio, Benevento, Italy. [email protected] ; [email protected] ; [email protected] Azienda sanitaria universitaria Friuli Centrale, Udine, Italy. [email protected] ; [email protected] ; [email protected] AO Bianchi-Melacrino-Morelli Reggio Calabria, Italy. [email protected] ; [email protected] ; [email protected] ; [email protected] S.Pietro Fatebenefratelli, Rome, Italy. [email protected] ; [email protected] ; [email protected] Presidio Ospedaliero S. Antonio Abate – Azienda Sanitaria Provinciale, Trapani, Italy. [email protected] ; [email protected] ; [email protected] Di Venere Hospital Bari, Italy. [email protected] ; [email protected] . Azienda Ospedaliera per l’emergenza Cannizzaro, Catania, Italy; [email protected] ; [email protected] ; [email protected] U.O.C T.I.N. e Neonatologia, P.O.C Taranto "Santissima Annunziata, Italy; [email protected] ; [email protected] San Salvatore Hospital L’Aquila, Italy. [email protected] ; [email protected] Azienda Ospedaliera San Giovanni Addolorata, Rome, Italy. [email protected] ; [email protected] ; [email protected] Azienda Ospedaliera Carlo Poma Mantova, Italy. [email protected] ; [email protected] ; [email protected] ASST Papa Giovanni XXIII, Bergamo, Italy. [email protected] ; [email protected] ; [email protected] Azienda Ospedaliera-Universitaria Ospedali Riuniti Foggia, Italy. [email protected] ; [email protected] ; [email protected] ; [email protected] Maggiore Hospital Novara, Italy. [email protected] ; [email protected] ; [email protected] Ospedale “Ss Annunziata”, Chieti - Università degli Studi G. D’Annunzio Chieti-Pescara, Italy. [email protected] ; [email protected] Azienza Ospedaliera Universitaria di Ferrara, Italy. [email protected] ; [email protected] Università di Pavia, Italy. [email protected] ; [email protected] ; [email protected] ; [email protected] Ospedale Vincenzo Cervello, Palermo. [email protected] ; [email protected] ; [email protected] ; [email protected] Pineta Grande Castelvolturno (CE), Italy. [email protected] ; [email protected] ; [email protected] Università degli Studi, Messina, Italy. [email protected] ; [email protected] ; [email protected] ARNAS Civico Hospital Palermo, Italy. [email protected] ; [email protected] ; [email protected] ; [email protected] IRCCS materno-infantile Burlo Garofolo, Trieste, Italy. [email protected] ; [email protected] ; [email protected] San Bortolo Hospital Vicenza, Italy. [email protected] ; [email protected] ARNAS Garibaldi, Catania, Italy. [email protected] . [email protected] ; [email protected] Azienda Ospedaliera di Catanzaro “Pugliese Ciaccio”, Catanzaro, Italy. [email protected] ; [email protected] ; [email protected] Niguarda Hospital Milan. [email protected] ; alice.proto @ospedaleniguarda.it Ospedale Generale Regionale “F. Miulli” - Acquaviva delle Fonti – Brindisi, Italy. [email protected] ; [email protected] AO Cà Foncello Treviso, Italy. [email protected] ; [email protected] ; [email protected] Azienda Sanitaria Provinciale di Siracusa, PO Umberto 1°, Siracusa, Italy. [email protected] ; [email protected] ; [email protected] ; [email protected] Ospedale Fatebenefratelli Isola Tiberina Gemelli Isola, Rome, Italy. [email protected] ; [email protected] ; [email protected] ; [email protected] Azienda Ospedaliera San Camillo Forlanini, Rome, Italy. [email protected] ; [email protected] ; [email protected] Ospedale M. Bufalini, Cesena, Italy. [email protected] ; [email protected] ; [email protected] Ospedale “Giovanni Paolo II”, Ragusa, Italy. [email protected] ; [email protected] ; [email protected] Central Teaching Hospital of Bolzano/Bozen, Italy. [email protected] ; [email protected] ; [email protected] Azienda Sanitaria Provinciale, Enna, Italy. [email protected] ; [email protected] ; [email protected] Istituto Giannina Gaslini, Genova, Italy. [email protected] ; [email protected] Azienda Ospedaliera Cosenza, Italy. [email protected] ; [email protected] ; [email protected] ; [email protected] Fondazione Poliambulanza Brescia, Italy. [email protected] ; [email protected] ; [email protected] Ospedale Buccheri-La Ferla, Palermo, Italy. [email protected] ; [email protected] ; [email protected] SS Antonio e Biagio e Cesare Arrigo Hospital Alessandria, Italy. [email protected] Panico Hospital Tricase (LE), Italy. [email protected] ; [email protected] ; [email protected] S. Spirito Hospital Pescara, Italy. [email protected] ; [email protected] S. Maria Goretti Hospital Latina, Italy. [email protected] ; [email protected] ; [email protected] ; [email protected] Azienda Ospedaliera Universitaria Integrata di Verona, Italy. [email protected] ; [email protected] Dipartimento di Bioetica e Sicurezza, UOS di Farmacovigilanza, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore, Rome, Italy [email protected] Name and contact information for the trial sponsor {5b} The trial doesn’t have a sponsor. The promoter is: Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome Italy. Role of sponsor {5c} The trial doesn’t have a sponsor. There are no obligations towards the promoter other than reporting about the study and study results. Introduction Background and rationale {6a} Respiratory distress syndrome (RDS) represents the main cause of respiratory insufficiency in preterm infants and is one of the major causes of perinatal morbidity and mortality. Surfactant is a well-established therapy in neonatology. However, the optimal surfactant administration method remains unresolved, especially with the recent clinical focus on avoiding mechanical ventilation in preterm infants born before 28 weeks’ gestational age (i.e. extremely preterm infants). Duration of mechanical ventilation is a key determinant of the severity of bronchopulmonary dysplasia (BPD) ( 1 ). Although attractive and beneficial in clinical practice, the INtubate, SURfactant, Extubate (IN-SUR-E) method cannot be universally applied to all preterm neonates due to non-homogeneous surfactant distribution and lung derecruitment during intubation, resulting in failure of IN-SUR-E in the event of severe RDS. IN-SUR-E also has a failure rate in preterm infants ranging from 19–69% ( 2 , 3 ). Risk factors for failure of IN-SUR-E are low birth weight, low gestational age, the severity of initial respiratory disease, and a low haemoglobin concentration prior to surfactant administration ( 2 , 4 , 5 ). A recent randomized clinical trial showed that the application of a recruitment manoeuvre just before surfactant administration, followed by rapid extubation (INtubate-RECruit-SURfactant-Extubate [IN-REC-SUR-E]), decreased the need for mechanical ventilation during the first 72 h of life compared with IN-SUR-E technique in extremely preterm neonates, without increasing the risk of adverse neonatal outcomes ( 6 ). Recently, a less invasive surfactant administration (LISA) method was developed with surfactant introduced into the trachea of infants breathing spontaneously using a small catheter instead of an endotracheal tube ( 7 ). The popularity of LISA technique has increased because it potentially combines the benefits of early surfactant treatment with continuous positive airways pressure (CPAP) and consequent avoidance of mechanical ventilation. The last network meta-analyses on the comparative efficacy of methods for surfactant administration found that among preterm infants, LISA technique was associated with lower likelihood of mortality, need for mechanical ventilation and BPD compared with IN-SUR-E, but these findings did not include comparison to IN-REC-SUR-E method ( 8 ). More importantly, data for neonates < 28 weeks’ gestation are not as robust as for the higher gestational age groups due to a smaller number of neonates ( 9 ). Therefore, the safety and efficacy of LISA in this population remain to be confirmed, also considering that extreme prematurity is an independent risk factor for LISA failure ( 10 ). The same Authors of meta-analysis agree that data for neonates < 28 weeks are not as robust as for higher gestation age group and that lung recruitment before surfactant administration (IN-REC-SUR-E) represents a promising novel alternative; hence, future randomized evidence directly comparing it to LISA is warranted to draw conclusions concerning the optimal method of surfactant treatment, especially among extremely low gestational age newborns ( 11 ). We therefore designed this study to compare the IN-REC-SUR-E technique with LISA, as recently suggested ( 11 , 12 ), for evaluating the comparative effectiveness of these techniques in increasing the survival without BPD of extremely preterm infants. Objectives {7} The primary hypothesis of this study is that IN-REC-SUR-E via a high frequency oscillatory ventilation recruitment maneuver increases survival without BPD at 36 weeks’ postmenstrual age in spontaneously breathing infants born at 24 + 0 -27 + 6 weeks’ gestation and failing nasal CPAP or nasal intermittent positive pressure ventilation (NIPPV) during the first 24 hours of life compared to LISA treatment. To confirm this hypothesis, we planned an international multicenter randomized controlled study in which preterm infants will be randomized into two groups: one will receive surfactant with IN-REC-SUR-E modality and the other one will receive surfactant with LISA treatment. The study flow chart is detailed in Fig. 1. Trial design {8} The study is an unblinded multicenter randomized trial of IN-REC-SUR-E vs. LISA technique in infants born at 24 + 0 -27 + 6 weeks’ gestation. The methods of this study are reported according to SPIRIT 2013 Explanation and Elaboration: Guidance for protocols of clinical trials ( 13 ). Methods: Participants, interventions and outcomes Study setting {9} The following centers are involved in the recruitment for the trial: Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome Italy; S.Pietro Fatebenefratelli, Rome; Fatebenefratelli-Isola Tiberina, Rome; Policlinico Umberto I, Rome; Bel Colle Hospital Viterbo; Fondazione Poliambulanza Brescia; Fondazione MBBM - Ospedale San Gerardo Monza; Niguarda Hospital Milan; Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University Milan; Azienda Ospedaliera Carlo Poma Mantova; SS Antonio e Biagio e Cesare Arrigo Hospital Alessandria; Maggiore Hospital Novara; Azienda Ospedaliera-Universitaria Ospedali Riuniti Foggia; Azienda Ospedaliera Vito Fazzi Lecce; Careggi University Florence; Pineta Grande Castelvolturno; Azienda Ospedaliera S.Anna-S.Sebastiano Caserta; Maggiore Hospital Bologna; AOU Ferrara; AO Cosenza; Di Venere Hospital Bari; Panico Hospital Tricase; Central Teaching Hospital of Bolzano/Bozen; Arcispedale Santa Maria Nuova Reggio Emilia; Barone Romeo Hospital Patti; AOU Policlinico Vittorio Emanuele-Gaspare Rodolico Catania; Università degli Studi di Messina; ARNAS Civico Hospital Palermo; ARNAS Garibaldi, Catania; San Bortolo Hospital Vicenza; AOU Policlinico Modena; San Salvatore Hospital L’Aquila; AO Bianchi-Melacrino-Morelli Reggio Calabria; AO Cà Foncello Treviso; Ospedale PO S. Anna; AOU Città della Salute e della Scienza, Torino; Università di Pavia; Neonatologia Universitaria, Ospedale S.Anna – Città della Salute e della Scienza di Torino; Policlinico Casilino, Rome; Ospedale Evangelico Betania – Napoli; Federico II University, Napoli; University of Padua, Padua; Ospedale San Pio, Benevento; "V.Buzzi" Children's Hospital, ASST-FBF-Sacco, Milan; Ospedale “Ss Annunziata”, Chieti - Università degli Studi G. D’Annunzio Chieti-Pescara; Azienda Ospedaliera Bolognini, Seriate (BG); ASST Papa Giovanni XXIII, Bergamo; ASST Sette Laghi, Varese, Università degli Studi dell’Insubria; Azienda OU Policlinico “Rodolico-San Marco”, Catania; Policlinico S. Orsola-Malpighi, Università di Bologna, Bologna; Azienda Ospedaliera Universitaria Senese, Siena; Azienda Ospedaliera “Spedali Civili”, Brescia; Azienda Ospedaliera San Giovanni Addolorata, Roma; Azienda Ospedaliera S. Croce e Carle, Cuneo; Azienda Ospedaliera San Camillo Forlanini, Roma; IRCCS materno-infantile Burlo Garofolo, Trieste; Istituto Giannina Gaslini, Genova; Azienda sanitaria universitaria Friuli Centrale, Udine; Università degli Studi, Palermo; Ospedale “Sant’Eugenio”- ASL Roma 2, Roma; Ospedale Infermi, Rimini; Azienda Ospedaliero Universitaria Ospedali Riuniti, Ancona; Ospedale M. Bufalini, Cesena; Ospedale “Giovanni Paolo II”, Ragusa; Ospedale Buccheri-La Ferla, Palermo; Azienda Ospedaliera di Catanzaro “Pugliese Ciaccio”, Catanzaro; Azienda Sanitaria Provinciale di Siracusa, PO Umberto 1°, Siracusa; Presidio Ospedaliero Ingrassia ASP Palermo; Presidio Ospedaliero S. Antonio Abate – Azienda Sanitaria Provinciale, Trapani; Azienda Sanitaria Provinciale, Enna; Ospedale Vincenzo Cervello, Palermo; Azienda Ospedaliera per l’emergenza Cannizzaro, Catania; U.O.C T.I.N. e Neonatologia, P.O.C Taranto "Santissima Annunziata"; Azienda Ospedaliera Universitaria Parma; P.P. “A. Perrino” Brindisi – ASL BR; Università AOUC Policlinico Bari; Ospedale Generale Regionale “F. Miulli” - Acquaviva delle Fonti – BR; Dr. Behcet Uz Children’s Hospital, Izmir, Turkey; The Royal Children’s Hospital, Melbourne, Australia; Shengjing Hospital of China Medical University, Shenyang,China, S. Maria Goretti Hospital Latina, S. Spirito Hospital Pescara, Azienda Ospedaliera Universitaria Integrata di Verona. Eligibility criteria {10} Inclusion criteria Infants satisfying the following inclusion criteria will be eligible to participate: Born at 24 + 0 -27 + 6 in a tertiary neonatal intensive care unit participating in the trial (and) Breathing independently and sufficiently with only nasal CPAP or NIPPV for respiratory support (and) Written parental consent has been obtained (and) Failing nasal CPAP or NIPPV during the first 24 hours of life Exclusion criteria Severe birth asphyxia or a 5-minute Apgar score less than 3 Prior endotracheal intubation for resuscitation or insufficient respiratory drive Prolonged (> 21 days) premature rupture of membranes Presence of major congenital abnormalities with possible effects on cardiorespiratory function Hydrops fetalis Inherited disorders of metabolism Who will take informed consent? {26a} The fully trained specific researchers who are on-site will obtain informed prospective consent from participants. Written and oral information will, whenever possible, be offered to parents prior to birth if the mother is at risk for preterm delivery and the infant is likely to be eligible. Informed written consent will be signed from both the parents and sufficient time will be provided for consent. If parents do not speak the local language, consent will only be obtained if an independent interpreter is available. The informed consent will be obtained by the principal investigator of each participating center and their collaborators in charge. A senior investigator will be always available to discuss concerns raised by parents or clinicians during the course of the trial. Additional consent provisions for collection and use of participant data and biological specimens {26b} No additional consents are required. This trial does not involve collecting biological specimens for storage. Interventions Explanation for the choice of comparators {6b} Infants will be allocated to one of the two treatment groups (1:1) according to a restricted randomization procedure ( 14 ). A study investigator (TP) will generate the allocation sequences using both stratification and permuted blocks with random block sizes and block order. The assignment to intervention will be unmasked to all trial participants: parents, research staff, and medical team will be only aware of study group assignment after randomization procedures. Intervention description {11a} Management in the Delivery Room Neonates will be stabilized after birth with positive pressure using a neonatal mask and a T-piece system (for example Neopuff Infant Resuscitator ®, Fisher and Paykel, Auckland, New Zealand). All neonates will be started on nasal CPAP of at least 6 cm H 2 O via mask or nasal prongs ( 15 ). Newborns who do not breathe or who are persistently bradycardic (heart rate less than 100/min) within the first 60 seconds after birth will receive positive-pressure ventilation at a rate of 40 to 60 inhalations/min ( 15 ) with initial FiO 2 of 0.30. Infants that will be transitioned successfully to spontaneous breathing will be transferred to the neonatal intensive care unit on nasal CPAP (6–7 cm H 2 O) or NIPPV (PEEP 6–7 cm H 2 O, PIP 12–15 cm H 2 O, respiratory rate 30–40 breaths/minute). The decision to intubate and start invasive mechanical ventilation in the delivery room will be in accordance with the American Heart Association Guidelines ( 16 ). Method and timing of umbilical cord clamping will be as per standard practice at each site. CPAP or NIPPV Failure Criteria Nasal CPAP or NIPPV will be administered in the neonatal intensive care unit via nasal prongs or nasal mask using the standard method of each participating centre, with a pressure of 7–8 cm H 2 O or with a setting of peak inspiratory pressure of 12–15 cmH 2 O, positive end-expiratory pressure of 7–8 cmH 2 O and rate of 30–40 breaths/min, respectively. Infants will receive surfactant with IN-REC-SUR-E or LISA if they need a FiO 2 of 0.30 or greater to maintain a SpO 2 between 90–94% for at least 30 min, regardless of the non-invasive respiratory support used (CPAP or NIPPV). Infants will also be given surfactant if their clinical status deteriorates rapidly or if they will develop respiratory acidosis defined as a pCO 2 more than 65 mmHg (8.5 kPa) and a pH less than 7.20, or with lung ultrasound scoring > 8. A loading dose of intravenous caffeine citrate (20 mg/kg) will be given in the delivery room or immediately after admission to the neonatal intensive care unit (within 2 hours of life) and always prior to surfactant administration, followed by a morning intravenous/oral dose of 5–10 mg/kg/day as required. Premedications All neonates of both groups will receive pre-procedural medications, according to local protocols. Suggested schemes are: -Intravenous atropine (10 µg/kg) in one minute followed by intravenous fentanyl: 0.5 µg/kg by pump infusion in no less than 5 minutes (possibly repeatable dose if satisfactory analgosedation is not obtained) or -Intravenous atropine (10 µg/kg) in one minute followed by intravenous ketamine: 0.5 mg/kg in no less than one minute (possibly repeatable dose if satisfactory analgosedation is not obtained). Method of premedication will be documented in each participating centre. IN-REC-SUR-E group Infants randomly assigned to the IN-REC-SUR-E group will receive pre-intubation medications and will start after intubation on high-frequency oscillatory ventilation (HFOV) using the following ventilator settings: mean airway pressure 8 cmH 2 O; frequency 15 Hz; volume guarantee 1.5–1.7 mL/kg ( 17 ). The inspiratory to expiratory ratio will be 1:1. Infants will undergo an oxygenation guided lung recruitment procedure using stepwise increments then decrements in mean airway pressure to recruit and stabilise collapsed alveoli using the de Jaegere method ( 18 ). In particular, optimal recruitment is defined as adequate oxygenation using a FiO 2 of 0.25 or less. Starting at 8 cmH 2 O, the mean airway pressure will be increased stepwise (2 cmH 2 O every 2–3 minutes) as long as SpO 2 improves. The FiO 2 will be reduced stepwise, keeping SpO 2 within the target range (90–94%). The recruitment procedure will be stopped if oxygenation no longer improves or if the FiO 2 is equal to or less than 0.25. The corresponding mean airway pressure will be called the opening pressure. Next, the mean airway pressure will be reduced stepwise (1–2 cmH 2 O every 2–3 minutes) until the SpO 2 deteriorates (of at least 2–3 percentage points). The corresponding mean airway pressure will be called the closing pressure. After a second recruitment manoeuvre at the opening pressure for 2 minutes, the optimal mean airway pressure will be set 2 cmH 2 O above the closing pressure for at least 3 minutes Immediately after the recruitment procedure, infants in the IN-REC-SUR-E group will receive 200 mg/kg of poractant alfa (Chiesi Farmaceutici S.p.A., Parma, Italy) via a closed administration system in one or two aliquots, while continuing high-frequency oscillatory ventilation. Infants with sufficient respiratory drive will be extubated within 30 minutes after surfactant administration irrespective of the FiO 2 and will recommence on nasal CPAP (7–9 cm H 2 O) ( 19 ) or NIPPV. LISA Group By contrast, infants allocated to the LISA group will receive 200 mg/kg of poractant alfa (Chiesi Farmaceutici S.p.A., Parma, Italy) according to the following protocol: during nasal CPAP with a pressure of 7–8 cm H 2 O, surfactant will be administered over 0.5-3 min using the SurfCath™ tracheal instillation catheter (VYGON S.A. – Ecouen, France), or a 4–6 F end-hole catheter, according to local protocols. After pre-procedural medications, the catheters will be positioned during laryngoscopy with or without Magill forceps. The catheter will be connected to a syringe pre-filled with the surfactant, and the surfactant is instilled slowly. The infant’s mouth will be closed. In cases of apnoea or bradycardia, positive pressure ventilation will be performed until recovery by nasal prongs or mask or by endotracheal tube if necessary. After surfactant administration, CPAP (7–9 cm H 2 O) ( 19 ) or NIPPV will be provided unless failure criteria are met (see below). Transcutaneous PaCO 2 will be recorded during surfactant administration in both the procedures (IN-REC-SUR-E and LISA), if available. Changes in respiratory support settings is permitted to maintain transcutaneous CO 2 values in each sites accepted range. In both groups, maintaining a FiO 2 < 0.30 to obtain SpO 2 values in the desired range (90–94%) will drive weaning of the level of CPAP or in the rate of NIPPV in the following days. In the babies managed with CPAP, the decision as to whether to begin bilevel positive airway pressure or NIPPV to prevent the need for re-intubation in infants of both groups will be up to the neonatologist on duty and will be considered in the final analysis. Infants in both groups who meet the CPAP/NIPPV failure criteria again during the following 24 h will receive a second dose of surfactant (100 mg/kg of poractant alfa) according to the randomized group (IN-REC-SUR-E or LISA). The indications for invasive mechanical ventilation via endotracheal tube after IN-REC-SUR-E or LISA will be: - Poor oxygenation with FiO 2 of greater than 0.40 to maintain a SpO 2 between 90–94% despite CPAP (7–9 cm H 2 O) or NIPPV (with peak inspiratory pressure of 15–20 cmH 2 O, positive end-expiratory pressure of 6–8 cmH 2 O and rate of 40–60 breaths/min) - Respiratory acidosis (either capillary pCO 2 or PaCO 2 > 65 mm Hg [8.5 kPa] and pH < 7.20) - Apnoea (more than four episodes of apnoea per hour or more than two episodes of apnoea per hour requiring ventilation with bag and mask), despite optimal nasal CPAP, nasal intermittent positive pressure ventilation, or bilevel positive airway pressure. Criteria for discontinuing or modifying allocated interventions {11b} On the consent form, participants are informed that they can withdraw from the study at anytime without losing any rights to treatment, either current or future. Clinical data will be destroyed only if the right to be forgotten will be requested according to GDPR [ref: https://gdpr-info.eu/art-17-gdpr/ ]. In this case the record ID and the allocation arm will be traced and the reason for withdrawal will be recorded in the eCRF. The trial may be stopped if: during the trial or after interim analysis unwanted effects have occurred; new information becomes available and the experimentation is no longer in the best interests of this population; the agreed rules for participation in the trial are not followed; the trial is interrupted by the component authorities or by the promoter. Strategies to improve adherence to interventions {11c} Given the nature of the intervention only after adherence to the protocol by the participating centres, no specific strategy is envisaged to improve intervention adherence. Relevant concomitant care permitted or prohibited during the trial {11d} For ethical reasons, all types of care as usual are permitted during the trial. Provisions for post-trial care {30} There will not be a specific post-trial care. No harm of participation in the trial is expected. All preterm infants enrolled in trial, after discharge, will start a “preterm - follow up program” as a normal clinical practice for all preterm discharged from hospitals participating to the study. Infants enrolled in trials will be tested for neurodevelopmental outcomes and respiratory function at 24 months, last of the secondary outcomes (see section below). Outcomes {12} Primary outcome measure A composite outcome of death or bronchopulmonary dysplasia (BPD) at 36 weeks’ postmenstrual age ( 20 ) is the primary outcome because BPD represents the most severe respiratory morbidity of preterm infants and death is a competing risk. The diagnosis of BPD will be ascertained by a standardized test ( 21 ). Infants remaining on mechanical ventilation or CPAP at 36 weeks postmenstrual age, or those with a supplemental oxygen concentration ≥ 0.30 to obtain SpO 2 between 90–94% will receive a BPD diagnosis without additional testing. Infants with a supplemental oxygen concentration < 0.30 to obtain SpO 2 between 90–94% or those receiving high-flow nasal cannula therapy will undergo a timed stepwise reduction to room air without any flow. Those in whom the reduction will not be tolerated will receive a BPD diagnosis. Secondary outcome measures BPD at 36 weeks’ s postmenstrual age Grade of BPD at 36 weeks’ s postmenstrual age Death at 36 weeks’ s postmenstrual age or before discharge SpO 2 /FiO 2 at 3 days, 7 days, and thereafter every 7 days until 36 weeks postmenstrual age ( 22 ) Severe intraventricular hemorrhage (IVH) (grade 3 or 4 based on the Papile criteria) ( 23 ) Occurrence of air leaks including pneumothorax or pulmonary interstitial emphysema before discharge Need and duration of invasive respiratory support Duration of non-invasive respiratory support Duration of oxygen therapy Pulmonary hemorrhage PDAhs (Patent ductus arteriosus; haemodynamically significant), i.e. requiring pharmacological treatment with ibuprofen/indomethacin/acetaminophen). Percentage of infants receiving two or more doses of surfactant Incidence of PVL (periventricular leukomalacia) ( 24 ) Incidence of ROP (retinopathy of prematurity) grade 3 or above ( 25 ) Incidence of NEC (necrotizing enterocolitis) grade 2 or above ( 26 ) Incidence of sepsis defined as a positive blood culture or suggestive clinical and laboratory findings leading to treatment with antibiotics for at least 7 days despite absence of a positive blood culture Total in-hospital stay Use of systemic postnatal steroids Neurodevelopmental outcomes via Bayley scales of infant development-III and respiratory function testing at 24 months of age Other collected data The following data will be recorded for each infant: gestational age (GA), birth weight (BW), BW z score, sex, Apgar score at 5 minutes, antenatal steroid treatment (complete course), preterm PROM > 18 hours, diagnosis of clinical chorioamnionitis (defined as maternal fever, uterine tenderness, abdominal pain, foul smelling vaginal discharge, maternal and fetal tachycardia, elevated white blood cell count), maternal hypertension disorders, type of delivery. Participant timeline {13} All participants will complete the same outcome assessments as presented in Fig. 1 and Table 1. Sample size {14} We hypothesized that employing the IN-REC-SUR-E technique for surfactant administration in extremely preterm infants could lead to an increased survival rate without BPD at 36 weeks of postmenstrual age compared to the LISA approach, raising it from 65–80%. Our estimation of a 15% difference is grounded in data from the German Neonatal Network (GNN) regarding the LISA approach, findings from the recently published OPTIMIST trial ( 27 ), and updated information on the IN-REC-SUR-E technique from select Italian Centers, which continued its use post the conclusion of the INRECSURE study. To achieve 90% statistical power at a 0.05 significance level, we determined that 181 newborns must be enrolled in each group. Factoring in a 5% risk of including patients who do not meet the inclusion criteria after randomization, a total of 382 patients will be randomly assigned. Twins will be randomized separately. Recruitment {15} The obstetricians are aware of the study protocol and will inform the neonatologists of any case of high-risk preterm birth. Written and oral information will, whenever possible, be offered to parents prior to birth if the mother is at risk for preterm delivery and the infant is likely to be eligible. In the few cases of spontaneous preterm labor and consequent vaginal delivery, the informed consent will be obtained soon after the birth. A monthly accrual report about the study will be sent to participating centers. Assignment of interventions: allocation Sequence generation {16a} Infants will be allocated to one of the two treatment groups (1:1) according to a restricted randomization procedure ( 14 ). A biostatistician (TP) will generate the allocation sequences using both stratification and permuted blocks with random block sizes and block order. Stratification factors will include center and gestational age (24 + 0 to 25 + 6 weeks or 26 + 0 to 27 + 6 weeks). Concealment mechanism {16b} The table of allocation will not be disclosed to ensure concealment and the randomization will be provided through Research Electronic Data Capture (REDCap) web application ( https://redcap-irccs.policlinicogemelli.it/ ). The assignment to intervention will be unmasked to all trial participants: parents, research staff, and medical team will be only aware of study group assignment after randomization procedures. Implementation {16c} Enrolment and assigning participants to interventions will be performed as previously described. Assignment of interventions: Blinding Who will be blinded {17a} Except the biostatistician involved in the analysis, the assignment to intervention will be unmasked to all trial participants: parents, local site research staff, and medical team will be only aware of study group assignment after randomization procedures. Procedure for unblinding if needed {17b} Refer to above {17a}. Data collection and management Plans for assessment and collection of outcomes {18a} Local principal investigators are required to participate in preparatory meetings in which details of study protocol, data collection, IN-REC-SUR-E and LISA procedures will be accurately discussed. All centers will receive detailed written instruction on web-based data recording, and, to resolve any difficulties, it will be possible to contact the Research core facility Data Collection (Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore). Moreover, it will be ascertained that IN-REC-SUR-E and LISA procedures are followed similarly in all participating centers. Plans to promote participant retention and complete follow-up {18b} Each participating Investigator will be responsible for ensuring data quality. Each reported information will be systematically checked for consistency, completeness, data processing and monitoring. All study data will be: 1) screened for out-of-range data, with cross-checks for conflicting data within and between data collection forms by a data manager; 2) referred back to relevant centre for clarification in the event of missing items or uncertainty. The data manager will keep a record of all discrepancies and resolutions. The Chief Investigator and trial statistician will review the results generated for logic and for patterns or problems. Outlier data will be investigated. A monthly accrual report about the study will be sent to participating centers. Data management {19} A customized eCRF (eletronic Case Report Form) will be created for the study. Data processing will take place in compliance with current Italian and European legislation regarding General Data Protection Regulation. Data sharing with non-European Union centers will be performed according to Standard Contract Clauses. Each participating center will be identified by a 3 digit code and, within each center, patients will be identified with a progressive number. Pseudo-anonymized study data will be collected and managed using REDCap electronic data capture tools hosted at Fondazione Policlinico Universitario A. Gemelli, IRCCS ( https://redcap-irccs.policlinicogemelli.it/ ). REDCap is a secure, web-based application designed to support data capture for research studies, providing 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for importing data from external sources ( 28 , 29 ). To prevent possible data entry mistakes and to improve data quality, the eCRF will be implemented by design according to validation, branching and skipping logic quality criteria. Confidentiality {27} Only people officially registered as study investigators or data managers will receive a user login to access the REDCap web platform and enter/manage data. All collected data will be obtained from the clinical records. Each participating center must maintain appropriate medical and research records for this trial and regulatory/institutional requirement for the protection of confidentiality of study subjects. The Principal Investigator is responsible for assuring that the data collected are complete, accurate, and recorded in a timely manner. Clinical information will be collected at the following times: At trial entry: Information on eligibility; background information and randomization. Following randomization: all data above listed in “Primary outcome measure”, “secondary outcome measure”, and “Other collected data” sections. Further information will be collected on expected serious adverse events. Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} This trial does not involve collecting biological specimens for storage. Statistical methods Statistical methods for primary and secondary outcomes {20a} Analyses will adhere to both the intention-to-treat and per-protocol principles, following the recommendations outlined in the CONSORT guidelines, with the primary outcome evaluated in the intention-to-treat population ( 30 ). The intention-to-treat group will encompass all participants assigned to the study intervention, while the per-protocol population will comprise individuals who receive and complete the study intervention, meeting all study criteria. For the primary outcome, a log-binomial regression model will be employed, adjusting for the stratification factors of gestational age and study center to estimate the adjusted relative risk (RR). Additionally, we will calculate the absolute risk reduction and the number-needed-to-treat. Statistical analyses will be conducted using Stata software, version 16 Interim analyses {21b} An interim analysis for safety to evaluate the prespecified stopping rules will be done at 30% and 60% of recruitment by an independent statistician, masked to the treatment allocation. The prespecified clinical and safety stopping rules will be: in-hospital mortality rate more than 40%, a rate of severe intraventricular haemorrhage more than 30%, and a pneumothorax rate more than 10%, considering overall occurrences. The data and safety monitoring board will have unmasked access to all data and will discuss the interim analysis results with the steering committee in a joint meeting. The steering committee will then determine the trial's continuation and report to the central ethics committee. Methods for additional analyses (e.g. subgroup analyses) {20b} Subgroup analyses will be conducted to explore specific factors such as gestational age influencing the outcomes, providing a more nuanced understanding of the intervention's effects within distinct subpopulations. Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} Refer to above {20a}. Plans to give access to the full protocol, participant level-data and statistical code {31c} The datasets analysed during this trial are available from the corresponding author on reasonable request. Duration of study In this study, 382 infants will be recruited. The trial will terminate when the last recruited infant discharged from the hospital will be evaluated for neurodevelopmental outcome and respiratory function at 24 months of follow-up. The planned duration to randomization is 3 years. Oversight and monitoring Composition of the coordinating centre and trial steering committee {5d} A joint Trial Steering Committee (TSC) and Data and Safety Monitoring Board (DSMB) will provide supervision for the trial, providing advice to the Chief and Co-investigators on all aspects of the trial conduct and affording protection for patients by ensuring the trial is conducted according to Guidelines for Good Clinical Practice in Clinical Trials. Chief investigator and advisory board will chair the TSC. A trial manager, a statistician and other investigators will form the DSMB. The trial manager and other investigators will check randomly the accuracy and consistency of the data entered from the participating centres. The data will be reported to the PI and advisory board as “group A” and “group B”. An independent statistician, blinded for the treatment allocation, will perform the interim analysis. The statistician will report to the DSMB. The DSMB will have unblinded access to all data and will discuss the results of the interim analysis with the Steering Committee in a joint meeting. The Steering Committee will decide on the continuation of the trial and will report to the central Ethics Committee. Composition of the data monitoring committee, its role and reporting structure {21a} Refer to above {5d} Adverse event reporting and harms {22} Adverse events, device deficiency and incidents, as identified by the following definitions, will be recorded and reported to Manufacturer and the National Competent Authority as per applicable law, (For EU Centers Regulation 2017/745 and Centers in Italy Circular of the Ministry of Health Application of the EU Regulation 2017/745 of the European Parliament and of the Council, of 5 April 2017, in the field of clinical investigations relating to medical devices). Site investigators will report any adverse event to the Coordinating Center. In case of a serious event involving a medical device, serious incident, a report (For Centers located in Italy from Dispovigilance - https://www.salute.gov.it/DispoVigilancePortaleRapportoOperatoreWeb/ ) will be issued and sent to the Competent Authority, the Manufacturer and the Coordinating Center, as per national applicable law. Device deficiency will be reported by the investigators to the Coordinating Center and to the Manufacturer, as per applicable law. Adverse event means any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, including an abnormal laboratory finding, in subjects, users or other persons, in the context of a clinical investigation, whether or not related to the investigational device. Serious adverse event means any adverse event that led to any of the following: (a) death, (b) serious deterioration in the health of the subject, that resulted in any of the following: (i) life-threatening illness or injury, (ii) permanent impairment of a body structure or a body function, (iii) hospitalisation or prolongation of patient hospitalisation, (iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function, (v) chronic disease. Incident means any malfunction or deterioration in the characteristics or performance of a device made available on the market, including use-error due to ergonomic features, as well as any inadequacy in the information supplied by the manufacturer and any undesirable side-effect; ‘serious incident’ means any incident that directly or indirectly led, might have led or might lead to any of the following: (a) the death of a patient, user or other person, (b) the temporary or permanent serious deterioration of a patient's, user's or other person's state of health, (c) a serious public health threat; Device deficiency means any inadequacy in the identity, quality, durability, reliability, safety or performance of an investigational device, including malfunction, use errors or inadequacy in information supplied by the manufacturer. Safety end-point measures will include incidence, severity, and causality of reported serious adverse effects (SAE), namely changes in occurrence of the expected common complications of prematurity and clinical laboratory test assessments, and the development of unexpected SAEs in this high-risk population. All SAEs will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. All SAEs and serious incidence (SI) will be followed until satisfactory resolution or until the investigator responsible for the care of the participant deems the event to be chronic or the patient to be stable. Particular attention will be paid to the SAEs (in-hospital mortality, serious intraventricular hemorrhage and pneumothorax) considered stopping rules. They have to be inserted by local investigators in the eCRF and reported to the PI and advisory board as soon as possible, no later than 24 hours after their occurrence. Frequency and plans for auditing trial conduct {23} A monthly accrual report about the study will be sent to participating centers. Whenever a SAE/SI will be registered in REDcap’s eCRF a progressive ID will be attributed and a report will be sent to the local principal investigator in order to verify the appropriateness of the data and to facilitate the notification to the Chief investigators according to a standardized template. More in depth, all expected and unexpected SAEs/SIs, whether or not they are attributable to the study intervention, will be reviewed by the local principal investigators to determine if there is reasonable suspected causal relationship to the intervention. Revised data will be reported to Chief Investigators ( [email protected] ) who will report to Ethics Committee and inform all investigators to guaranty the safety of participants. The DSMB will be responsible to monitor adverse events. Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} Important protocol modifications will be reported to and need to be approved by all the medical-ethical committee. When modifications are approved, these will also be reported to the participants, and be added to the Trials paper and the study registration on ClinicalTri- als.gov. Dissemination plans {31a} The outcomes of this study about the effectiveness of the intervention will be reported in article(s) in international peer-reviewed journals. Both positive and negative outcomes will be reported. The outcomes will also be reported in professional magazines in the field and in magazines for parents. The results will be presented in participating care organizations and at scientific conferences. All presentations and publications are expected to protect the integrity of the major objectives of the study; data that break the blind will not be presented prior to the release of mainline results. Recommendations as to the timing of presentation of such endpoint data and the meetings at which they might be presented will be given by the Steering Committee. Substantive contributions to the design, conduct, interpretation, and reporting of the clinical trial will be recognized through the granting of authorship on the final trial report. Individuals who fulfill authorship criteria will have final authority over the manuscript content. Discussion The primary hypothesis of this trial is that surfactant administration by IN-REC-SUR-E, via a high frequency oscillatory ventilation recruitment maneuver, increases survival without BPD at 36 weeks of postmenstrual age in spontaneously breathing infants born at 24 + 0 -27 + 6 weeks' gestation affected by RDS, compared to LISA. Although surfactant replacement therapy is an established treatment in infants with RDS, identifying the safest and most effective way to administer surfactant is critically important but not well defined, especially in extremely preterm infants. It is plausible to expect that the therapeutic benefits of exogenous surfactant therapy will be maximized by quickly and uniformly aerating the lung beforehand. The IN-SUR-E method cannot be universally applied to all preterm neonates; risk factors for failure of IN-SUR-E are low birth weight, low gestational age, the severity of initial respiratory disease, and a low haemoglobin concentration prior to surfactant administration ( 2 , 4 , 5 ). New promising evidence from the randomized clinical trial INRECSURE showed that the application of a recruitment manoeuvre just before surfactant administration, followed by rapid extubation, decreased the need for mechanical ventilation during the first 72 h of life compared with IN-SUR-E technique in extremely preterm neonates, without increasing the risk of adverse neonatal outcomes ( 6 ). The recent LISA technique introduces surfactant into the trachea of spontaneously breathing infants via a small catheter instead of an endotracheal tube ( 7 ). LISA is now widespread and combines the benefits of early surfactant treatment with CPAP and consequent avoidance of mechanical ventilation. The last network meta-analyses on the comparative efficacy of methods for surfactant administration found that among preterm infants, LISA technique was associated with lower likelihood of mortality, need for mechanical ventilation and BPD compared with IN-SUR-E, but these findings did not include comparison to IN-REC-SUR-E method ( 8 ). More importantly, data for neonates < 28 weeks’ gestation are not as robust as for the higher gestation age groups due to a smaller number of neonates ( 9 ). For these reasons, the safety and efficacy of LISA in infants < 28 weeks remain to be confirmed and lung recruitment before surfactant administration (IN-REC-SUR-E) represents a promising new alternative. We therefore designed this study to compare the IN-REC-SUR-E technique with LISA, for evaluating the comparative effectiveness of these techniques in increasing the survival without BPD of extremely preterm infants. Trial status This is protocol version 3, 25 Oct 2022. Recruitment started on 9 January 2023. The trial is currently recruiting study subjects. The estimated study completion date is 15 April 2026. Abbreviations BPD bronchopulmonary dysplasia BW birth weight CTCAE Common Terminology Criteria for Adverse Events CPAP continuous positive airway pressure DSMB Data and Safety Monitoring Board eCRF eletronic Case Report Form FiO 2 fraction of inspired oxygen GA gestational age GNN German Neonatal Network HFOV high-frequency oscillatory ventilation IN-REC-SUR-E INtubate-RECruit-SURfactant-Extubate IN-SUR-E Intubate-Surfactant-Extubate IVH intraventricular hemorrhage LISA less invasive surfactant administration nCPAP nasal continuous positive airway pressure NEC necrotizing enterocolitis NICU neonatal intensive care unit NIPPV nasal intermittent positive pressure ventilation PDA patent ductus arteriosus PDAhs haemodynamically significant patent ductus arteriosus PROM premature rupture of membranes PVL periventricular leukomalacia RedCap Research Electronic Data Capture RDS respiratory distress syndrome ROP retinopathy of prematurity RR relative risk SpO2 pulse oximetry SAE serious adverse event SI serious incidence TSC Trial Steering Committee. Declarations Acknowledgements The authors want to thank all the parents of participants and the departments staff for cooperating and supporting the study. Authors’ contributions {31b} "GV is the Chief Investigator; he conceived the study, led the proposal and protocol development. Members of advisory board GV, AP, CA, SAO, VPC, FC, SC, FC, CD, PGD, NF, SF, FPF, CG, EH, MJ, AL, GL, FM, SN, AP, SP, JJP, GP, MT, DT, CT, AHVK and MLV contributed to study design and to development of the proposal. TP, RP and SP contributed to the methodology and statistical analysis of the study. All authors read and approved the final manuscript." Funding {4} The study has received economic contributions by way of partial coverage of the expenses relating to its implementation. The contributions have been appropriately declared to the competent Ethics Committee, in accordance with current legislation. Availability of data and materials {29} The datasets generated and/or analysed during the study are available from the corresponding author on reasonable request. Ethics approval and consent to participate {24} The research protocol has been approved by the Medical Ethics Committee of Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome Italy (NCT05711966 -last release 16 Feb 2023). The ethical bodies of the participating centers approved the study. Informed written consent will be signed from both parents and sufficient time will be provided for consent. If parents do not speak the local language, consent will only be obtained if an adult and independent interpreter is available. The parents will be informed that the study does not entail a blood sample or other more invasive interventions than maneuvers performed regularly in the neonatal intensive care unit (NICU). The informed consent will be obtained by the principal investigator of each participating center and his collaborators in charge. Consent for publication {32} No personal data is used in this protocol. Competing interests {28} The authors declare that they have no competing interests. References Svedenkrans J, Stoecklin B, Jones JG, Doherty DA, Pillow JJ. Physiology and Predictors of Impaired Gas Exchange in Infants with Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2019;200:471–80. Brix N, Sellmer A, Jensen MS, Pedersen LV, Henriksen TB. Predictors for an unsuccessful Intubation-SURfactant-Extubation procedure: a cohort study. BMC Pediatr. 2014;14:155–62. Lakkundi A, Wright I, de Waal K. Transitional hemodynamics in preterm infants with a respiratory management strategy directed at avoidance of mechanical ventilation. Early Hum Dev. 2014;90:409–12. Dani C, Corsini I, Bertini G, Fontanelli G, Pratesi S, Rubaltelli F. The INSURE method in preterm infants of less than 30 weeks’ gestation. J Matern Fetal Neonatal Med. 2010;23:1024–29. Cherif A, Hachani C, Khrouf N. Risk factors of the failure of surfactant treatment by transient intubation during nasal continuous positive airway pressure in preterm infants. Am J Perinatol. 2008;25:647–52. Vento G, Ventura ML, Pastorino R, van Kaam AH, Carnielli V, Cools F et al. Lung recruitment before surfactant administration in extremely preterm neonates with respiratory distress syndrome (IN-REC-SUR-E): a randomised, unblinded, controlled trial. Lancet Respir Med 2020 Jul 17:S2213- 2600(20)30179-X . doi: 10.1016/S2213-2600(20)30179-X. Kribs A. Minimally invasive surfactant therapy and noninvasive respiratory support. Clin Perinatol. 2016;43:755–71. Bellos I, Fitrou G, Panza R, et al. Comparative efficacy of methods for surfactant administration: a network meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2021;106:F474–88. Nobile S, Bottoni A, Giordano L, Paladini A, Vento G. Critical appraisal of the evidence underpinning the efficacy of less invasive surfactant administration. Arch Dis Child Fetal Neonatal Ed. 2021 Oct 16. Van Der Janssen LC, van Kaam AH, et al. Minimally invasive surfactant therapy failure: risk factors and outcome. Arch Dis Child Fetal Neonatal Ed. 2019;104:F636–42. Bellos I. Pandita A SurE for surfactant: response to letter. Arch Dis Child Fetal Neonatal Ed. 2021 Nov 29. Finer NN, Katheria A. Recruitment: the best way to IN-SUR-E surfactant delivery? Lancet Respir Med. 2020 Jul 17:S2213-2600(20)30242-3 10.1016/S2213-2600(20)30242-3 . Chan A, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, Dickersin K, Hróbjartsson A, Schulz KF, Parulekar WR, Krleza-Jeric K. A.Laupacis, D. Moher. Broglio K. Randomization in Clinical Trials: Permuted Blocks and Stratification. JAMA. 2018;319(21):2223–4. Sweet DG, Carnielli V, Greisen G, et al. European Consensus Guidelines on the management of Respiratory Distress Syndrome – 2022 Update. Neonatology. 2023;120(1):3–23. Aziz K, Lee HC, Escobedo MB, et al. Part 5: Neonatal Resuscitation 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Pediatrics. 2020. 10.1542/peds.2020-038505E . Tana M, Paladini A, Tirone C, Aurilia C, Lio, et al. Effects of High-Frequency Oscillatory Ventilation with volume guarantee during surfactant treatment in extremely low gestational age newborns with respiratory distress syndrome: an observational study. Front Pediatr. 2022;9:804807. De Jaegere A, van Veenendaal MB, Michiels A, van Kaam AH. Lung recruitment using oxygenation during open lung high-frequency ventilation in preterm infants. Am J Respir Crit Care Med. 2006;174:639–45. Buzzella B, Claure N, D'Ugard C, Bancalari E. A randomized controlled trial of two nasal continuous positive airway pressure levels after extubation in preterm infants. J Pediatr. 2014;164(1):46–51. Jobe A, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163(7):1723–9. Walsh MC, Szefler S, Davis J, Et. al. Summary proceedings from the Bronchopulmonary Dysplasia Group. Pediatrics 2006;117(3.pt 2):552–556. Nobile S, Marchionni P, Gidiucci C, Correani A, Palazzi ML, Spagnoli C, et al. Oxygen saturation/FIO2 ratio at 36 weeks’ PMA in 1005 preterm infants: Effect of gestational age and early respiratory disease patterns. Pediatr Pulmonol. 2019;54(5):637–43. Papile LS, Burstein J, Burstein R, Keffler H. Incidence and evolution of the sub-ependymal intraventricular hemorrhage ; a study of infants weighing less than 1500 grams. J Pediatr. 1978;92:529–34. De Vries LS, Eken P, Dubowitz LM. The spectrum of leukomalacia using cranial ultrasounds. Beha Brain Res. 1992;49:1–6. International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005;123:991–9. Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, Brotherton T. Neonatal necrotizing enterocolitis: Therapeutic decisions based upon clinical staging. Ann Surg. 1978;187:1–12. Dargaville PA, Kamlin COF, Orsini F, Wang X, De Paoli AG, et al. Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial. JAMA. 2021;326(24):2478–87. 10.1001/jama.2021.21892 . Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap) – A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inf. 2009;42(2):377–81. Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O’Neal L, McLeod L, Delacqua G, Delacqua F, Kirby J, Duda SN. REDCap Consortium, The REDCap consortium: Building an international community of software partners. J Biomed Inf. 2019 May;9. 10.1016/j.jbi.2019.103208] . Ranganathan P, Pramesh CS, Aggarwal R. Common pitfalls in statistical analysis: Intention-to-treat versus per-protocol analysis. Perspect Clin Res. 2016;7:144–46. Tables Table 1. Overview of enrolment, interventions and assessments. Tab. 1. -t 1 : befor or after birth ; 0: at the time of allocation ; t 1 : first surfactant administration within 2 hours of life ; t 2 *: possible second dose of surfactant during the following 24 h after the firs dose; t 3 : at discharge or death ; t 4 : follow up at 24 months of age. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Minor revision 15 May, 2024 Reviewers agreed at journal 19 Apr, 2024 Reviewers invited by journal 18 Apr, 2024 Editor assigned by journal 17 Apr, 2024 First submitted to journal 29 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3994255","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":292681557,"identity":"78b3544d-c5a7-415c-a673-ef5df418a0c8","order_by":0,"name":"Giovanni Vento","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Giovanni","middleName":"","lastName":"Vento","suffix":""},{"id":292681558,"identity":"23eb75c3-2085-4bd1-97d8-4ed34517f567","order_by":1,"name":"Angela Paladini","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-6344-5769","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":true,"prefix":"","firstName":"Angela","middleName":"","lastName":"Paladini","suffix":""},{"id":292681559,"identity":"03452780-88aa-4058-b5d6-0e1ee89e3d3e","order_by":2,"name":"Claudia Aurilia","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Claudia","middleName":"","lastName":"Aurilia","suffix":""},{"id":292681560,"identity":"94d0d4f5-59dc-40db-8d1f-89392992e41e","order_by":3,"name":"Senem Alkan Ozdemir","email":"","orcid":"","institution":"Health science university dr. Behcet Uz children's Hospital, Izmir","correspondingAuthor":false,"prefix":"","firstName":"Senem","middleName":"Alkan","lastName":"Ozdemir","suffix":""},{"id":292681561,"identity":"f4ab5461-0193-402f-91f2-6fa0a435f359","order_by":4,"name":"Virgilio Paolo Carnielli","email":"","orcid":"","institution":"AOU Ospedali Riuniti di Ancona: Azienda Ospedaliero Universitaria delle Marche","correspondingAuthor":false,"prefix":"","firstName":"Virgilio","middleName":"Paolo","lastName":"Carnielli","suffix":""},{"id":292681562,"identity":"b16beeb6-36da-495c-a7e5-d638cdaeb3a7","order_by":5,"name":"Filip Cools","email":"","orcid":"","institution":"UZ Brussel: Universitair Ziekenhuis Brussel","correspondingAuthor":false,"prefix":"","firstName":"Filip","middleName":"","lastName":"Cools","suffix":""},{"id":292681563,"identity":"5db1b4f1-867a-4ec9-b98a-b68eaed467e8","order_by":6,"name":"Simonetta Costa","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Simonetta","middleName":"","lastName":"Costa","suffix":""},{"id":292681564,"identity":"3431b94b-eca4-4127-8157-c22bdd96643e","order_by":7,"name":"Francesco Cota","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Cota","suffix":""},{"id":292681565,"identity":"e763e066-20e5-4062-bb42-0a4b63649835","order_by":8,"name":"Carlo Dani","email":"","orcid":"","institution":"University Hospital Careggi Department of Neonatology and Neonatal Intensive Care: Azienda Ospedaliera Universitaria Careggi Dipartimento di Neonatologia e Terapia Intensiva Neonatale","correspondingAuthor":false,"prefix":"","firstName":"Carlo","middleName":"","lastName":"Dani","suffix":""},{"id":292681566,"identity":"76fff79c-7210-4738-ada5-65816507cdb4","order_by":9,"name":"Peter G. Davis","email":"","orcid":"","institution":"Neonatal Service, The Royal Women's Hospital, Melbourne","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"G.","lastName":"Davis","suffix":""},{"id":292681567,"identity":"5fb75d7d-0b98-464d-b470-da364f938a22","order_by":10,"name":"Simona Fattore","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Simona","middleName":"","lastName":"Fattore","suffix":""},{"id":292681568,"identity":"af719dd2-760b-4d08-9772-4b4b2ff87fa8","order_by":11,"name":"Claudia Fè","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Claudia","middleName":"","lastName":"Fè","suffix":""},{"id":292681569,"identity":"0a2d9c93-d6ee-44cd-9710-9b1f486fb594","order_by":12,"name":"Neil Finer","email":"","orcid":"","institution":"Sharp Mary Birch Hospital for Women and Newborns","correspondingAuthor":false,"prefix":"","firstName":"Neil","middleName":"","lastName":"Finer","suffix":""},{"id":292681570,"identity":"e62585c0-0f48-4828-82c7-ad5dbeef5e4e","order_by":13,"name":"Francesca Paola Fusco","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"Paola","lastName":"Fusco","suffix":""},{"id":292681571,"identity":"25ccfc55-c4ca-43eb-a048-e67ee9903f82","order_by":14,"name":"Camilla Gizzi","email":"","orcid":"","institution":"UOC Neonatologia e TIN Ospedale Sant'Eugenio, Roma","correspondingAuthor":false,"prefix":"","firstName":"Camilla","middleName":"","lastName":"Gizzi","suffix":""},{"id":292681572,"identity":"e5c9c3e2-209e-4dd1-80c1-2d49ebef7339","order_by":15,"name":"Egbert Herting","email":"","orcid":"","institution":"Klinik fur Kinder- und Jugendmedizin II","correspondingAuthor":false,"prefix":"","firstName":"Egbert","middleName":"","lastName":"Herting","suffix":""},{"id":292681573,"identity":"bf7a0daa-bdac-47b5-9bae-25bc2e715ba7","order_by":16,"name":"Mao Jian","email":"","orcid":"","institution":"Shengjing Hospital of China Medical University","correspondingAuthor":false,"prefix":"","firstName":"Mao","middleName":"","lastName":"Jian","suffix":""},{"id":292681574,"identity":"6eaf3159-693e-482e-9aa6-9f7eba3329ec","order_by":17,"name":"Alessandra Lio","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Alessandra","middleName":"","lastName":"Lio","suffix":""},{"id":292681575,"identity":"3faf0c83-add8-4aa0-b04b-66175094dffd","order_by":18,"name":"Gianluca Lista","email":"","orcid":"","institution":"Vittore Buzzi Children's Hospital: Ospedale dei Bambini Vittore Buzzi","correspondingAuthor":false,"prefix":"","firstName":"Gianluca","middleName":"","lastName":"Lista","suffix":""},{"id":292681576,"identity":"86a46c2c-6b4a-465d-a97a-ab26752710e7","order_by":19,"name":"Fabio Mosca","email":"","orcid":"","institution":"La Fondazione IRCCS Ca' Granda Ospedale Maggiore di Milano Policlinico: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico","correspondingAuthor":false,"prefix":"","firstName":"Fabio","middleName":"","lastName":"Mosca","suffix":""},{"id":292681577,"identity":"72becc06-7183-4584-9801-b5a512ebb9be","order_by":20,"name":"Stefano Nobile","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Stefano","middleName":"","lastName":"Nobile","suffix":""},{"id":292681578,"identity":"afeac9bc-78c0-4896-89ab-ca1b5d6b5e2d","order_by":21,"name":"Alessandro Perri","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Alessandro","middleName":"","lastName":"Perri","suffix":""},{"id":292681579,"identity":"4b1b7e8e-c7b2-44c3-a3da-496c76c858ba","order_by":22,"name":"Simona Picone","email":"","orcid":"","institution":"Casilino General Hospital: Policlinico Casilino","correspondingAuthor":false,"prefix":"","firstName":"Simona","middleName":"","lastName":"Picone","suffix":""},{"id":292681580,"identity":"27d754c0-ae0b-44be-af87-1038c87aed3f","order_by":23,"name":"Jane Pillow","email":"","orcid":"","institution":"The University of Western Australia Medical School","correspondingAuthor":false,"prefix":"","firstName":"Jane","middleName":"","lastName":"Pillow","suffix":""},{"id":292681581,"identity":"82001991-370b-49e5-a396-3361cd126aea","order_by":24,"name":"Graeme Polglase","email":"","orcid":"","institution":"Hudson Institute of Medical Research","correspondingAuthor":false,"prefix":"","firstName":"Graeme","middleName":"","lastName":"Polglase","suffix":""},{"id":292681582,"identity":"9bf24c86-c218-45c9-bae9-79c1dfcdb13a","order_by":25,"name":"Tina Pasciutto","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Tina","middleName":"","lastName":"Pasciutto","suffix":""},{"id":292681583,"identity":"a3b24534-3c64-4df1-a783-33f09c5c762b","order_by":26,"name":"Roberta Pastorino","email":"","orcid":"","institution":"Università Cattolica del Sacro Cuore: Universita Cattolica del Sacro Cuore","correspondingAuthor":false,"prefix":"","firstName":"Roberta","middleName":"","lastName":"Pastorino","suffix":""},{"id":292681584,"identity":"04466ad0-4cef-476f-849b-81cd716190cf","order_by":27,"name":"Milena Tana","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Milena","middleName":"","lastName":"Tana","suffix":""},{"id":292681585,"identity":"1e84a9a3-ced8-41b4-b691-a61e4a230fab","order_by":28,"name":"David Tingay","email":"","orcid":"","institution":"Murdoch Children's Research Institute","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Tingay","suffix":""},{"id":292681586,"identity":"b48c1242-7c1d-4036-9e68-0dc108eb3624","order_by":29,"name":"Chiara Tirone","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Chiara","middleName":"","lastName":"Tirone","suffix":""},{"id":292681587,"identity":"33d561ed-5c8f-4e2e-abef-352adbadac77","order_by":30,"name":"Anton vankaam","email":"","orcid":"","institution":"Emma Childrens' Hospital UMC: Emma Kinderziekenhuis Amsterdam UMC","correspondingAuthor":false,"prefix":"","firstName":"Anton","middleName":"","lastName":"vankaam","suffix":""},{"id":292681588,"identity":"8dc9e443-1fa3-4afd-b4ca-c58d22d27fce","order_by":31,"name":"Maria Luisa Ventura","email":"","orcid":"","institution":"San Gerardo Hospital: Fondazione IRCCS San Gerardo dei Tintori","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Luisa","lastName":"Ventura","suffix":""},{"id":292681589,"identity":"cab27020-2095-4000-ba5a-20d51d711ae2","order_by":32,"name":"Arianna Aceti","email":"","orcid":"","institution":"University Hospital of Bologna Sant'Orsola-Malpighi Polyclinic: IRCCS Azienda Ospedaliero-Universitaria di Bologna Policlinico di Sant'Orsola","correspondingAuthor":false,"prefix":"","firstName":"Arianna","middleName":"","lastName":"Aceti","suffix":""},{"id":292681590,"identity":"1684e9e4-1c29-4c5d-aba7-375d750e0cec","order_by":33,"name":"Massimo Agosti","email":"","orcid":"","institution":"University of Insubria: Universita degli Studi dell'Insubria","correspondingAuthor":false,"prefix":"","firstName":"Massimo","middleName":"","lastName":"Agosti","suffix":""},{"id":292681591,"identity":"45636f85-122d-4d49-894a-67e9aec2ac1a","order_by":34,"name":"Gianni Alighieri","email":"","orcid":"","institution":"Antonio Perrino Hospital: Ospedale Antonio Perrino","correspondingAuthor":false,"prefix":"","firstName":"Gianni","middleName":"","lastName":"Alighieri","suffix":""},{"id":292681592,"identity":"faca03a2-3c6c-4f65-b056-99c4d4738921","order_by":35,"name":"Gina Ancora","email":"","orcid":"","institution":"Degli Infermi Hospital: Ospedale degli Infermi di Rimini","correspondingAuthor":false,"prefix":"","firstName":"Gina","middleName":"","lastName":"Ancora","suffix":""},{"id":292681593,"identity":"442f575f-5514-4871-bca6-1240057cb4c1","order_by":36,"name":"Vita Angileri","email":"","orcid":"","institution":"Presidio Ospedaliero Ingrassia ASP Palermo","correspondingAuthor":false,"prefix":"","firstName":"Vita","middleName":"","lastName":"Angileri","suffix":""},{"id":292681594,"identity":"19077c99-7cc8-4ece-b173-cd9d7d361fa4","order_by":37,"name":"Gaetano Ausanio","email":"","orcid":"","institution":"Azienda ospedaliera S.Anna-S.Sebastiano, Caserta","correspondingAuthor":false,"prefix":"","firstName":"Gaetano","middleName":"","lastName":"Ausanio","suffix":""},{"id":292681595,"identity":"e73e4c66-5b6a-4f97-8e11-5174928a5163","order_by":38,"name":"Salvatore Aversa","email":"","orcid":"","institution":"Azienda Ospedaliera Spedali Civili di Brescia: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia","correspondingAuthor":false,"prefix":"","firstName":"Salvatore","middleName":"","lastName":"Aversa","suffix":""},{"id":292681596,"identity":"e38be887-9d02-4129-9474-fe2084fd6e22","order_by":39,"name":"Eleonora Balestri","email":"","orcid":"","institution":"Arcispedale S Maria Nuova: Arcispedale Santa Maria Nuova di Reggio Emilia","correspondingAuthor":false,"prefix":"","firstName":"Eleonora","middleName":"","lastName":"Balestri","suffix":""},{"id":292681597,"identity":"45f9b3ec-56ec-42de-af6d-7b31c2fb67c3","order_by":40,"name":"Eugenio Baraldi","email":"","orcid":"","institution":"Padua University Hospital: Azienda Ospedale Universita Padova","correspondingAuthor":false,"prefix":"","firstName":"Eugenio","middleName":"","lastName":"Baraldi","suffix":""},{"id":292681598,"identity":"88230777-9d5e-4a24-ac8c-adeb9e7d3c0c","order_by":41,"name":"Maria Cristina Barbini","email":"","orcid":"","institution":"University of Insubria: Universita degli Studi dell'Insubria","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Cristina","lastName":"Barbini","suffix":""},{"id":292681599,"identity":"24070213-a23c-472f-8c68-072ccfa86ec0","order_by":42,"name":"Ciro Barone","email":"","orcid":"","institution":"Ospedale Evangelico Villa Betania: Fondazione Evangelica Betania","correspondingAuthor":false,"prefix":"","firstName":"Ciro","middleName":"","lastName":"Barone","suffix":""},{"id":292681600,"identity":"b602670d-f517-4952-a97a-b4d9478490fc","order_by":43,"name":"Renzo Beghini","email":"","orcid":"","institution":"Azienda Ospedaliera Universitaria Integrata Verona","correspondingAuthor":false,"prefix":"","firstName":"Renzo","middleName":"","lastName":"Beghini","suffix":""},{"id":292681601,"identity":"9751ad4d-2460-46e2-b1bb-dd040c0fd501","order_by":44,"name":"Cristina Bellan","email":"","orcid":"","institution":"Azienda Ospedaliera Bolognini Seriate: Ospedale Bolognini di Seriate","correspondingAuthor":false,"prefix":"","firstName":"Cristina","middleName":"","lastName":"Bellan","suffix":""},{"id":292681602,"identity":"0ef18648-5ca2-4442-8d55-6f40e6d34736","order_by":45,"name":"Alberto Berardi","email":"","orcid":"","institution":"Policlinic of Modena: Policlinico di Modena","correspondingAuthor":false,"prefix":"","firstName":"Alberto","middleName":"","lastName":"Berardi","suffix":""},{"id":292681603,"identity":"d4f712de-80c2-454f-89ab-12cf5aa5fd6b","order_by":46,"name":"Italo Bernardo","email":"","orcid":"","institution":"Azienda Ospedaliera S.Anna-S.Sebastiano. Caserta","correspondingAuthor":false,"prefix":"","firstName":"Italo","middleName":"","lastName":"Bernardo","suffix":""},{"id":292681604,"identity":"c781f63c-c7d0-46bf-b139-195d010d0841","order_by":47,"name":"Pasqua Betta","email":"","orcid":"","institution":"University Hospital Vittorio Emanuele Catania Polyclinic: Azienda Ospedaliero Universitaria Policlinico G Rodolico San Marco","correspondingAuthor":false,"prefix":"","firstName":"Pasqua","middleName":"","lastName":"Betta","suffix":""},{"id":292681605,"identity":"f9f3cbe3-19f1-4424-aacf-5d161a3c6ee0","order_by":48,"name":"Marco Binotti","email":"","orcid":"","institution":"Novara Hospital: Azienda Ospedaliero Universitaria Maggiore della Carita","correspondingAuthor":false,"prefix":"","firstName":"Marco","middleName":"","lastName":"Binotti","suffix":""},{"id":292681606,"identity":"14ffae83-6a2c-453e-a8f3-afc0b10eced0","order_by":49,"name":"Bianca Bizzarri","email":"","orcid":"","institution":"UOC Neonatologia Ospedale Sant'Eugenio, ASL Roma 2","correspondingAuthor":false,"prefix":"","firstName":"Bianca","middleName":"","lastName":"Bizzarri","suffix":""},{"id":292681607,"identity":"a299eb6b-c349-47db-8acf-7a5a99a8110f","order_by":50,"name":"Gabriella Borgarello","email":"","orcid":"","institution":"Azienda Ospedaliera S Croce e Carle Cuneo","correspondingAuthor":false,"prefix":"","firstName":"Gabriella","middleName":"","lastName":"Borgarello","suffix":""},{"id":292681608,"identity":"35842feb-e665-4d68-8c5c-c14217037c48","order_by":51,"name":"Silvia Borgione","email":"","orcid":"","institution":"Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino: Azienda Ospedaliero Universitaria Citta della Salute e della Scienza di Torino","correspondingAuthor":false,"prefix":"","firstName":"Silvia","middleName":"","lastName":"Borgione","suffix":""},{"id":292681609,"identity":"9521d469-9253-4b60-a42f-2379438c6d80","order_by":52,"name":"Angela Borrelli","email":"","orcid":"","institution":"Azienda Ospedaliera sant'Anna-San Sebastiano. Caserta","correspondingAuthor":false,"prefix":"","firstName":"Angela","middleName":"","lastName":"Borrelli","suffix":""},{"id":292681610,"identity":"cacc4979-c4c4-4156-bf9f-0ea0d6b706c3","order_by":53,"name":"Roberto Bottino","email":"","orcid":"","institution":"Policlinic of Modena: Policlinico di Modena","correspondingAuthor":false,"prefix":"","firstName":"Roberto","middleName":"","lastName":"Bottino","suffix":""},{"id":292681611,"identity":"78b6203c-01f4-444c-bd93-a81b3071e3e6","order_by":54,"name":"Giorgio Bracaglia","email":"","orcid":"","institution":"Belcolle Hospital, Viterbo","correspondingAuthor":false,"prefix":"","firstName":"Giorgio","middleName":"","lastName":"Bracaglia","suffix":""},{"id":292681612,"identity":"fb4ba6c4-f313-47e8-8e5b-2e57ba31158f","order_by":55,"name":"Ilia Bresesti","email":"","orcid":"","institution":"University of Insubria: Universita degli Studi dell'Insubria","correspondingAuthor":false,"prefix":"","firstName":"Ilia","middleName":"","lastName":"Bresesti","suffix":""},{"id":292681613,"identity":"b32fd493-4644-4df1-9275-06fca8852f4b","order_by":56,"name":"Ilaria Burattini","email":"","orcid":"","institution":"AOU Ospedali Riuniti di Ancona: Azienda Ospedaliero Universitaria delle Marche","correspondingAuthor":false,"prefix":"","firstName":"Ilaria","middleName":"","lastName":"Burattini","suffix":""},{"id":292681614,"identity":"96d02446-86e5-4fff-bcab-1d8399e91db7","order_by":57,"name":"Caterina Cacace","email":"","orcid":"","institution":"Barone Romeo Hospital Patti","correspondingAuthor":false,"prefix":"","firstName":"Caterina","middleName":"","lastName":"Cacace","suffix":""},{"id":292681615,"identity":"a37debb9-aee6-4573-9ba9-8dbdd2026301","order_by":58,"name":"Francesca Calzolari","email":"","orcid":"","institution":"University Hospital of Parma: Azienda Ospedaliero-Universitaria di Parma","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"","lastName":"Calzolari","suffix":""},{"id":292681616,"identity":"b8325d73-c2ee-4602-9314-a2be9895e61e","order_by":59,"name":"Maria Francesca Campagnoli","email":"","orcid":"","institution":"Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino: Azienda Ospedaliero Universitaria Citta della Salute e della Scienza di Torino","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Francesca","lastName":"Campagnoli","suffix":""},{"id":292681617,"identity":"79018971-5ce3-427c-b1c9-0f7f8531cd70","order_by":60,"name":"Letizia Capasso","email":"","orcid":"","institution":"University of Naples Federico II: Universita degli Studi di Napoli Federico II","correspondingAuthor":false,"prefix":"","firstName":"Letizia","middleName":"","lastName":"Capasso","suffix":""},{"id":292681618,"identity":"d9f245ce-5849-47ba-ae9e-f62255160c3d","order_by":61,"name":"Manuela Capozza","email":"","orcid":"","institution":"Policlinico di Bari Ospedale Giovanni XXIII: Azienda Ospedale Policlinico","correspondingAuthor":false,"prefix":"","firstName":"Manuela","middleName":"","lastName":"Capozza","suffix":""},{"id":292681619,"identity":"fa267840-d6e6-47e1-b566-ad0bbb7cb616","order_by":62,"name":"Mariagrazia Capretti","email":"","orcid":"","institution":"University of Bologna Hospital of Bologna Sant'Orsola-Malpighi Polyclinic: IRCCS Azienda Ospedaliero-Universitaria di Bologna Policlinico di Sant'Orsola","correspondingAuthor":false,"prefix":"","firstName":"Mariagrazia","middleName":"","lastName":"Capretti","suffix":""},{"id":292681620,"identity":"66a2e567-f14f-4bd1-aaeb-c33b2d736221","order_by":63,"name":"Jacopo Caravetta","email":"","orcid":"","institution":"Casilino General Hospital: Policlinico Casilino","correspondingAuthor":false,"prefix":"","firstName":"Jacopo","middleName":"","lastName":"Caravetta","suffix":""},{"id":292681621,"identity":"117f47df-211c-4102-aba0-32bbef998fff","order_by":64,"name":"Caterina Carbonara","email":"","orcid":"","institution":"Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino: Azienda Ospedaliero Universitaria Citta della Salute e della Scienza di Torino","correspondingAuthor":false,"prefix":"","firstName":"Caterina","middleName":"","lastName":"Carbonara","suffix":""},{"id":292681622,"identity":"f11dbaca-6111-4d40-8bfe-5db7e6425696","order_by":65,"name":"Viviana Cardilli","email":"","orcid":"","institution":"Umberto I Policlinico di Roma","correspondingAuthor":false,"prefix":"","firstName":"Viviana","middleName":"","lastName":"Cardilli","suffix":""},{"id":292681623,"identity":"1bbcc1cf-17b9-498a-b588-3a5ec575c700","order_by":66,"name":"Maurizio Carta","email":"","orcid":"","institution":"University of Palermo: Universita degli Studi di Palermo","correspondingAuthor":false,"prefix":"","firstName":"Maurizio","middleName":"","lastName":"Carta","suffix":""},{"id":292681624,"identity":"46f47c04-d155-495f-bd5a-fdbfa88adbaa","order_by":67,"name":"Francesca Castoldi","email":"","orcid":"","institution":"Vittore Buzzi Children's Hospital: Ospedale dei Bambini Vittore Buzzi","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"","lastName":"Castoldi","suffix":""},{"id":292681625,"identity":"9bd2a55c-5923-41ff-ac99-a592ef25476f","order_by":68,"name":"Antonella Castronovo","email":"","orcid":"","institution":"OUC e TIN Ospedale Sant'Eugenio, ASL Roma 2","correspondingAuthor":false,"prefix":"","firstName":"Antonella","middleName":"","lastName":"Castronovo","suffix":""},{"id":292681626,"identity":"8ab925d1-ef34-4856-88e0-fff8f3b4401a","order_by":69,"name":"Elisa Cavalleri","email":"","orcid":"","institution":"Azienda Ospedaliera Spedali Civili di Brescia: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia","correspondingAuthor":false,"prefix":"","firstName":"Elisa","middleName":"","lastName":"Cavalleri","suffix":""},{"id":292681627,"identity":"b47f6192-6ec4-492c-9411-5666b7dddddb","order_by":70,"name":"Francesco Cavigioli","email":"","orcid":"","institution":"Vittore Buzzi Children's Hospital: Ospedale dei Bambini Vittore Buzzi","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Cavigioli","suffix":""},{"id":292681628,"identity":"abe2b94f-d6a6-4514-a0c0-a1488823f903","order_by":71,"name":"Sara Cecchi","email":"","orcid":"","institution":"AOU Senese: Azienda Ospedaliera Universitaria Senese","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Cecchi","suffix":""},{"id":292681629,"identity":"140d3fbb-febe-4cf1-8cd4-6126e3751bb9","order_by":72,"name":"Valentina Chierici","email":"","orcid":"","institution":"University of Insubria: Universita degli Studi dell'Insubria","correspondingAuthor":false,"prefix":"","firstName":"Valentina","middleName":"","lastName":"Chierici","suffix":""},{"id":292681630,"identity":"066988a1-d29c-4f36-a431-83a5c5b8b375","order_by":73,"name":"Carla Cimino","email":"","orcid":"","institution":"University Hospital Gaspare Rodolico San Marco: Azienda Ospedaliero Universitaria Policlinico G Rodolico San Marco","correspondingAuthor":false,"prefix":"","firstName":"Carla","middleName":"","lastName":"Cimino","suffix":""},{"id":292681631,"identity":"1ab272a5-aea7-40bb-84d6-f66acbfc57d6","order_by":74,"name":"Francesco Cocca","email":"","orcid":"","institution":"San Pio Hospital of Benevento: Azienda Ospedaliera San Pio - Benevento","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Cocca","suffix":""},{"id":292681632,"identity":"59f841ea-d601-4d01-a91d-a33e3693c678","order_by":75,"name":"Carmen Cocca","email":"","orcid":"","institution":"San Pio Hospital of Benevento: Azienda Ospedaliera San Pio - Benevento","correspondingAuthor":false,"prefix":"","firstName":"Carmen","middleName":"","lastName":"Cocca","suffix":""},{"id":292681633,"identity":"41da5ea9-d7ee-4902-bc36-cd13a167da4f","order_by":76,"name":"Paola Cogo","email":"","orcid":"","institution":"University of Udine: Universita degli Studi di Udine","correspondingAuthor":false,"prefix":"","firstName":"Paola","middleName":"","lastName":"Cogo","suffix":""},{"id":292681634,"identity":"d08ec61c-d3b7-409e-860f-09c1ed53cd23","order_by":77,"name":"Martina Coma","email":"","orcid":"","institution":"Ospedale Maggiore di Milano Policlinico: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico","correspondingAuthor":false,"prefix":"","firstName":"Martina","middleName":"","lastName":"Coma","suffix":""},{"id":292681635,"identity":"703d148e-d3c6-457d-a031-8254124714d5","order_by":78,"name":"Valentina Comito","email":"","orcid":"","institution":"Bianchi-Melacrino-Morelli Hospital: Azienda Ospedaliera Bianchi-Melacrino-Morelli","correspondingAuthor":false,"prefix":"","firstName":"Valentina","middleName":"","lastName":"Comito","suffix":""},{"id":292681636,"identity":"7f9da297-b18f-404a-aa6b-9c3493bfaaaa","order_by":79,"name":"Valentin Condò","email":"","orcid":"","institution":"Ospedale Maggiore di Milano Policlinico: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico","correspondingAuthor":false,"prefix":"","firstName":"Valentin","middleName":"","lastName":"Condò","suffix":""},{"id":292681637,"identity":"984c1ccf-1523-4499-962e-382c461f5b2c","order_by":80,"name":"Chiara Consiglia","email":"","orcid":"","institution":"San Pietro Hospital: Ospedale San Pietro","correspondingAuthor":false,"prefix":"","firstName":"Chiara","middleName":"","lastName":"Consiglia","suffix":""},{"id":292681638,"identity":"93398acf-e7f4-4312-9ee6-1aa0199fff2e","order_by":81,"name":"Rossella Conti","email":"","orcid":"","institution":"Ospedale Cervello: Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello","correspondingAuthor":false,"prefix":"","firstName":"Rossella","middleName":"","lastName":"Conti","suffix":""},{"id":292681639,"identity":"72e3e50f-925a-441d-b245-c6e2fb61d913","order_by":82,"name":"Mara Corradi","email":"","orcid":"","institution":"University of Parma: Universita degli Studi di Parma","correspondingAuthor":false,"prefix":"","firstName":"Mara","middleName":"","lastName":"Corradi","suffix":""},{"id":292681640,"identity":"e2738460-4e13-43a3-b6a7-1f68a86b6e46","order_by":83,"name":"Giovanni Corsello","email":"","orcid":"","institution":"University of Palermo: Universidad de Palermo","correspondingAuthor":false,"prefix":"","firstName":"Giovanni","middleName":"","lastName":"Corsello","suffix":""},{"id":292681641,"identity":"016a09b8-7b43-465d-930c-b57a4d9d8269","order_by":84,"name":"Luigi T. Corvaglia","email":"","orcid":"","institution":"University of Bologna Hospital of Bologna Sant'Orsola-Malpighi Polyclinic: IRCCS Azienda Ospedaliero-Universitaria di Bologna Policlinico di Sant'Orsola","correspondingAuthor":false,"prefix":"","firstName":"Luigi","middleName":"T.","lastName":"Corvaglia","suffix":""},{"id":292681642,"identity":"083ea11b-9ab1-4723-80bc-ad22cc4e9b4c","order_by":85,"name":"Antonino Costa","email":"","orcid":"","institution":"ASP Trapani: Azienda Sanitaria Provinciale di Trapani","correspondingAuthor":false,"prefix":"","firstName":"Antonino","middleName":"","lastName":"Costa","suffix":""},{"id":292681643,"identity":"d41b1f0e-c1fc-4a79-a9ca-b55bcb9942ad","order_by":86,"name":"Alessandra Coscia","email":"","orcid":"","institution":"Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino: Azienda Ospedaliero Universitaria Citta della Salute e della Scienza di Torino","correspondingAuthor":false,"prefix":"","firstName":"Alessandra","middleName":"","lastName":"Coscia","suffix":""},{"id":292681644,"identity":"2aad8417-fda2-42a5-b3fa-687c735ccf48","order_by":87,"name":"Francesco Cresi","email":"","orcid":"","institution":"Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino: Azienda Ospedaliero Universitaria Citta della Salute e della Scienza di Torino","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Cresi","suffix":""},{"id":292681645,"identity":"09e4cd38-8ece-4378-8160-a2f27ad22234","order_by":88,"name":"Francesco Crespino","email":"","orcid":"","institution":"Azienda Ospedaliera sant'Anna-San Sebastiano, Caserta","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Crespino","suffix":""},{"id":292681646,"identity":"b53e5f68-778a-4bc5-ad70-b12eb420ffcc","order_by":89,"name":"Pietro D'Amico","email":"","orcid":"","institution":"Cannizzaro Hospital: Azienda Ospedaliera Cannizzaro","correspondingAuthor":false,"prefix":"","firstName":"Pietro","middleName":"","lastName":"D'Amico","suffix":""},{"id":292681647,"identity":"8e74cd50-a3ee-4ca6-a6a0-fbbc141717bd","order_by":90,"name":"Lucrezia De Cosmo","email":"","orcid":"","institution":"Ospedale SS Annunziata: Ospedale Santissima Annunziata","correspondingAuthor":false,"prefix":"","firstName":"Lucrezia","middleName":"","lastName":"De Cosmo","suffix":""},{"id":292681648,"identity":"eb33a2ca-d700-434f-882e-9206635ba878","order_by":91,"name":"Cinzia De Maio","email":"","orcid":"","institution":"Azienda Ospedaliera S. Croce e Carle Cuneo: Azienda Ospedaliera S Croce e Carle Cuneo","correspondingAuthor":false,"prefix":"","firstName":"Cinzia","middleName":"","lastName":"De Maio","suffix":""},{"id":292681649,"identity":"cb2978c5-83c7-4de9-9cdf-90a720535c0e","order_by":92,"name":"Giuliana Del Campo","email":"","orcid":"","institution":"Cannizzaro Hospital: Azienda Ospedaliera Cannizzaro","correspondingAuthor":false,"prefix":"","firstName":"Giuliana","middleName":"Del","lastName":"Campo","suffix":""},{"id":292681650,"identity":"5240ae1f-c6e5-4431-9137-9b66cf134fcc","order_by":93,"name":"Simona Di Credico","email":"","orcid":"","institution":"Pescara Hospital: Presidio Ospedaliero di Pescara","correspondingAuthor":false,"prefix":"","firstName":"Simona","middleName":"Di","lastName":"Credico","suffix":""},{"id":292681651,"identity":"34e31361-b4c8-4e22-9a8b-d4c850e3da26","order_by":94,"name":"Sandra Di Fabio","email":"","orcid":"","institution":"University of Aquila: Universita degli Studi dell'Aquila","correspondingAuthor":false,"prefix":"","firstName":"Sandra","middleName":"Di","lastName":"Fabio","suffix":""},{"id":292681652,"identity":"4e98cbc0-af60-463f-8fb4-fa2b8b6c8423","order_by":95,"name":"Paola Di Nicola","email":"","orcid":"","institution":"Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino: Azienda Ospedaliero Universitaria Citta della Salute e della Scienza di Torino","correspondingAuthor":false,"prefix":"","firstName":"Paola","middleName":"Di","lastName":"Nicola","suffix":""},{"id":292681653,"identity":"93866f11-ec6a-4bc2-8753-13d64bb9a182","order_by":96,"name":"Ambriogio Di Paolo","email":"","orcid":"","institution":"Hospital San Giovanni-Addolorata: Azienda ospedaliera San Giovanni-Addolorata","correspondingAuthor":false,"prefix":"","firstName":"Ambriogio","middleName":"Di","lastName":"Paolo","suffix":""},{"id":292681654,"identity":"5687de7c-6633-4e4c-8882-a87372bb9d28","order_by":97,"name":"Antonietta Distilo","email":"","orcid":"","institution":"Cosenza Hospital Districts: Azienda Ospedaliera di Cosenza","correspondingAuthor":false,"prefix":"","firstName":"Antonietta","middleName":"","lastName":"Distilo","suffix":""},{"id":292681655,"identity":"e32532a2-e314-4ed1-b31a-0923dbddbc60","order_by":98,"name":"Susanna Di Valerio","email":"","orcid":"","institution":"Pescara Hospital: Presidio Ospedaliero di Pescara","correspondingAuthor":false,"prefix":"","firstName":"Susanna","middleName":"Di","lastName":"Valerio","suffix":""},{"id":292681656,"identity":"23af5b22-da9e-4e3f-afc1-1ac7ad9ba7cb","order_by":99,"name":"Vincenzo Duca","email":"","orcid":"","institution":"University of Palermo: Universidad de Palermo","correspondingAuthor":false,"prefix":"","firstName":"Vincenzo","middleName":"","lastName":"Duca","suffix":""},{"id":292681657,"identity":"6db67b1b-b84f-4940-a567-e481687ef33c","order_by":100,"name":"Alessandra Falcone","email":"","orcid":"","institution":"Bianchi-Melacrino-Morelli Hospital: Azienda Ospedaliera Bianchi-Melacrino-Morelli","correspondingAuthor":false,"prefix":"","firstName":"Alessandra","middleName":"","lastName":"Falcone","suffix":""},{"id":292681658,"identity":"695497cc-c349-41e9-9055-a3047cecbcd8","order_by":101,"name":"Raffaele Falsaperla","email":"","orcid":"","institution":"University Hospital Gaspare Rodolico San Marco: Azienda Ospedaliero Universitaria Policlinico G Rodolico San Marco","correspondingAuthor":false,"prefix":"","firstName":"Raffaele","middleName":"","lastName":"Falsaperla","suffix":""},{"id":292681659,"identity":"2c39b31c-0554-43eb-8d7d-1c28dfa6e38b","order_by":102,"name":"Valeria Fasolato","email":"","orcid":"","institution":"Carlo Poma Hospital: Azienda Socio Sanitaria Territoriale di Mantova","correspondingAuthor":false,"prefix":"","firstName":"Valeria","middleName":"","lastName":"Fasolato","suffix":""},{"id":292681660,"identity":"4f4d64a2-2520-4c9b-b68c-dc2bc93f98eb","order_by":103,"name":"Valentina Fatuzzo","email":"","orcid":"","institution":"Umberto I di Siracusa Hospital: Ospedale Umberto I di Siracusa","correspondingAuthor":false,"prefix":"","firstName":"Valentina","middleName":"","lastName":"Fatuzzo","suffix":""},{"id":292681661,"identity":"d0ae6edd-a406-432e-8b3e-4f3bb5e36fec","order_by":104,"name":"Francesca Favini","email":"","orcid":"","institution":"Azienda Ospedaliera Ospedali Riuniti di Bergamo: Aziende Socio Sanitarie Territoriale Papa Giovanni XXIII","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"","lastName":"Favini","suffix":""},{"id":292681662,"identity":"e4962f09-36f1-469f-8f25-fb34c41bccfd","order_by":105,"name":"Maria Pia Ferrarello","email":"","orcid":"","institution":"Presidio Ospedaliero sant'Antonio Abate, Trapani","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Pia","lastName":"Ferrarello","suffix":""},{"id":292681663,"identity":"55846f08-3b5d-4688-a391-f84177a92577","order_by":106,"name":"Stefania Ferrari","email":"","orcid":"","institution":"Azienda Ospedaliera Ospedali Riuniti di Bergamo: Aziende Socio Sanitarie Territoriale Papa Giovanni XXIII","correspondingAuthor":false,"prefix":"","firstName":"Stefania","middleName":"","lastName":"Ferrari","suffix":""},{"id":292681664,"identity":"ef6be055-32fb-4b55-b058-b702cf2df74a","order_by":107,"name":"Francesca Fiori Nastro","email":"","orcid":"","institution":"Buccheri La Ferla Fatebenefratelli Hospital: Ospedale Buccheri La Ferla Fatebenefratelli","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"Fiori","lastName":"Nastro","suffix":""},{"id":292681665,"identity":"1646c0e3-5a3f-408d-8643-f49b13ec14c2","order_by":108,"name":"Carlo Alberto Forcellini","email":"","orcid":"","institution":"Azienda Ospedaliera Universitaria Integrata Verona","correspondingAuthor":false,"prefix":"","firstName":"Carlo","middleName":"Alberto","lastName":"Forcellini","suffix":""},{"id":292681666,"identity":"bbbcfd4f-aff1-4178-93ba-58d88ddc36a1","order_by":109,"name":"Annalisa Frachiolla","email":"","orcid":"","institution":"Ospedali Riuniti di Foggia: Azienda Ospedaliera Universitaria Foggia","correspondingAuthor":false,"prefix":"","firstName":"Annalisa","middleName":"","lastName":"Frachiolla","suffix":""},{"id":292681667,"identity":"40c1f6d1-020b-451d-8840-6714fb4c40b6","order_by":110,"name":"Angela Gabriele","email":"","orcid":"","institution":"Azienda Ospedaliera di Catanzaro Pugliese Ciaccio: Azienda Ospedaliera di Catanzaro Pugliese-Ciaccio","correspondingAuthor":false,"prefix":"","firstName":"Angela","middleName":"","lastName":"Gabriele","suffix":""},{"id":292681668,"identity":"2928d44e-bd2c-4ebc-807b-eca20fba21a2","order_by":111,"name":"Francesca Galdo","email":"","orcid":"","institution":"Burlo Garofalo Pediatric Institute: IRCCS materno infantile Burlo Garofolo","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"","lastName":"Galdo","suffix":""},{"id":292681669,"identity":"ebb4877c-bcb8-4942-9d4e-b2d98fd58fa5","order_by":112,"name":"Francesca Gallini","email":"","orcid":"","institution":"Ospedale Fatebenefratelli Isola Tiberina - Gemelli Isola","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"","lastName":"Gallini","suffix":""},{"id":292681670,"identity":"1e5aed08-d996-4068-8b94-6a4138812a01","order_by":113,"name":"Antonella Gangemi","email":"","orcid":"","institution":"Azienda ospedaliera Ospedali Riuniti Villa Sofia-Cervello: Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello","correspondingAuthor":false,"prefix":"","firstName":"Antonella","middleName":"","lastName":"Gangemi","suffix":""},{"id":292681671,"identity":"aee747d3-89c3-4e79-919c-735cffa9c8df","order_by":114,"name":"Giancarlo Gargano","email":"","orcid":"","institution":"Arcispedale Santa Maria Nuova di Reggio Emilia","correspondingAuthor":false,"prefix":"","firstName":"Giancarlo","middleName":"","lastName":"Gargano","suffix":""},{"id":292681672,"identity":"0ec96a5d-47de-40c6-b668-aabab32de46e","order_by":115,"name":"Diego Gazzolo","email":"","orcid":"","institution":"Università degli Studi Gabriele d'Annunzio Chieti e Pescara: Universita degli Studi Gabriele d'Annunzio Chieti Pescara","correspondingAuthor":false,"prefix":"","firstName":"Diego","middleName":"","lastName":"Gazzolo","suffix":""},{"id":292681673,"identity":"684db661-14fa-401d-8bc6-9f94da01a043","order_by":116,"name":"Maria Paola Gentile","email":"","orcid":"","institution":"University of Ferrara: Universita degli Studi di Ferrara","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Paola","lastName":"Gentile","suffix":""},{"id":292681674,"identity":"e8c9962a-607c-43f8-a404-a9a24f409fb0","order_by":117,"name":"Stefano Ghirardello","email":"","orcid":"","institution":"University of Pavia: Universita degli Studi di Pavia","correspondingAuthor":false,"prefix":"","firstName":"Stefano","middleName":"","lastName":"Ghirardello","suffix":""},{"id":292681675,"identity":"c7170373-818b-4974-8173-d0200e07dcbe","order_by":118,"name":"Fabio Giardina","email":"","orcid":"","institution":"Ospedale Cervello: Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello","correspondingAuthor":false,"prefix":"","firstName":"Fabio","middleName":"","lastName":"Giardina","suffix":""},{"id":292681676,"identity":"c84e3ebf-0290-4462-8f34-800c2ba6761c","order_by":119,"name":"Lucio Giordano","email":"","orcid":"","institution":"Pineta Grande Castelvolturno","correspondingAuthor":false,"prefix":"","firstName":"Lucio","middleName":"","lastName":"Giordano","suffix":""},{"id":292681677,"identity":"8f09c2b9-ca07-4275-b813-5dc6cc15b95f","order_by":120,"name":"Mario Giuffrè","email":"","orcid":"","institution":"University of Palermo: Universita degli Studi di Palermo","correspondingAuthor":false,"prefix":"","firstName":"Mario","middleName":"","lastName":"Giuffrè","suffix":""},{"id":292681678,"identity":"7d5ffba7-e07a-4e41-a97d-eaff32bbd575","order_by":121,"name":"Tuling Gokmen Yildirim","email":"","orcid":"","institution":"Health Science University Dr. Behcet UZ children's Hospital, Izmir","correspondingAuthor":false,"prefix":"","firstName":"Tuling","middleName":"Gokmen","lastName":"Yildirim","suffix":""},{"id":292681679,"identity":"8fae1494-1806-4b8e-b7f9-2480cf65e775","order_by":122,"name":"Lidia Grappone","email":"","orcid":"","institution":"San Pio Hospital of Benevento: Azienda Ospedaliera San Pio - Benevento","correspondingAuthor":false,"prefix":"","firstName":"Lidia","middleName":"","lastName":"Grappone","suffix":""},{"id":292681680,"identity":"72d3ac16-7001-49e9-856f-7f9d340b3c50","order_by":123,"name":"Fiorentino Grasso","email":"","orcid":"","institution":"University of Naples Federico II: Universita degli Studi di Napoli Federico II","correspondingAuthor":false,"prefix":"","firstName":"Fiorentino","middleName":"","lastName":"Grasso","suffix":""},{"id":292681681,"identity":"20045cf9-931a-4ef3-a6c9-93aeba71c491","order_by":124,"name":"Irene Greco","email":"","orcid":"","institution":"Palermo Hospital: Ospedale Civico Palermo","correspondingAuthor":false,"prefix":"","firstName":"Irene","middleName":"","lastName":"Greco","suffix":""},{"id":292681682,"identity":"52d0d43f-7e49-4e24-9001-70a0b61fdfc3","order_by":125,"name":"Alessandra Grison","email":"","orcid":"","institution":"San Bortolo Hospital: Ospedale San Bortolo di Vicenza","correspondingAuthor":false,"prefix":"","firstName":"Alessandra","middleName":"","lastName":"Grison","suffix":""},{"id":292681683,"identity":"93e60b0c-417d-4c81-b494-cd40b19c8421","order_by":126,"name":"Rosanna Guglielmino","email":"","orcid":"","institution":"Azienda Ospedaliera ARNAS Garibaldi: Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione Garibaldi","correspondingAuthor":false,"prefix":"","firstName":"Rosanna","middleName":"","lastName":"Guglielmino","suffix":""},{"id":292681684,"identity":"6dae9ac3-aacf-4ebe-952f-38977b21f9f7","order_by":127,"name":"Isotta Guidotti","email":"","orcid":"","institution":"Policlinic of Modena: Policlinico di Modena","correspondingAuthor":false,"prefix":"","firstName":"Isotta","middleName":"","lastName":"Guidotti","suffix":""},{"id":292681685,"identity":"bd19bbda-0a4d-4bf3-a2ca-ae70bdef8c59","order_by":128,"name":"Immacolata Guzzo","email":"","orcid":"","institution":"Azienda Ospedaliera Pugliese Ciaccio: Azienda Ospedaliera di Catanzaro Pugliese-Ciaccio","correspondingAuthor":false,"prefix":"","firstName":"Immacolata","middleName":"","lastName":"Guzzo","suffix":""},{"id":292681686,"identity":"7a8b4d05-a6fd-4cd6-b958-f3b718a91c4e","order_by":129,"name":"Nicola La Forgia","email":"","orcid":"","institution":"University Hospital Polyclinic of Bari: Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari","correspondingAuthor":false,"prefix":"","firstName":"Nicola","middleName":"La","lastName":"Forgia","suffix":""},{"id":292681687,"identity":"862d5a3d-09f0-47dc-98be-6d4f6a92449b","order_by":130,"name":"Simona La Placa","email":"","orcid":"","institution":"Ospedale S Antonio Abate, Trapani","correspondingAuthor":false,"prefix":"","firstName":"Simona","middleName":"La","lastName":"Placa","suffix":""},{"id":292681688,"identity":"11fc2e60-bbed-490c-872d-c13159d5cef5","order_by":131,"name":"Giuseppe La Torre","email":"","orcid":"","institution":"Ospedale Generale Regionale F Miulli: Ente Ecclesiastico Ospedale Generale Regionale Francesco Miulli","correspondingAuthor":false,"prefix":"","firstName":"Giuseppe","middleName":"La","lastName":"Torre","suffix":""},{"id":292681689,"identity":"8d6b7f96-97ae-4acb-9800-dfb6b0c57f3d","order_by":132,"name":"Paola Lago","email":"","orcid":"","institution":"AO Cà Foncello Treviso","correspondingAuthor":false,"prefix":"","firstName":"Paola","middleName":"","lastName":"Lago","suffix":""},{"id":292681690,"identity":"3e9f92ae-3713-41fd-a382-64d9ffc274ec","order_by":133,"name":"Lucia Lanciotti","email":"","orcid":"","institution":"AOU Ospedali Riuniti di Ancona: Azienda Ospedaliero Universitaria delle Marche","correspondingAuthor":false,"prefix":"","firstName":"Lucia","middleName":"","lastName":"Lanciotti","suffix":""},{"id":292681691,"identity":"d9e32054-c30c-4839-823f-62dee1887889","order_by":134,"name":"Anna Lavizzari","email":"","orcid":"","institution":"Ospedale Maggiore di Milano Policlinico: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Lavizzari","suffix":""},{"id":292681692,"identity":"a7587658-1b43-4bff-8a71-08346003e0f8","order_by":135,"name":"Francesco Leo","email":"","orcid":"","institution":"Arcispedale S Maria Nuova: Arcispedale Santa Maria Nuova di Reggio Emilia","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Leo","suffix":""},{"id":292681693,"identity":"65a530ad-4526-411f-969f-6a889cda58fe","order_by":136,"name":"Valentina Leonardi","email":"","orcid":"","institution":"University Hospital Careggi: Azienda Ospedaliero Universitaria Careggi","correspondingAuthor":false,"prefix":"","firstName":"Valentina","middleName":"","lastName":"Leonardi","suffix":""},{"id":292681694,"identity":"74e8cb23-4806-4a49-a5c7-dac51d07b75b","order_by":137,"name":"Juan Li","email":"","orcid":"","institution":"Shengjing Hospital of China Medical University","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Li","suffix":""},{"id":292681695,"identity":"ddd025be-08cd-4008-9514-8d52e74e35c6","order_by":138,"name":"Pio Liberatore","email":"","orcid":"","institution":"Ospedali Riuniti di Foggia: Azienda Ospedaliera Universitaria Foggia","correspondingAuthor":false,"prefix":"","firstName":"Pio","middleName":"","lastName":"Liberatore","suffix":""},{"id":292681696,"identity":"951d6255-9659-4c4b-a120-c24d9bfbe936","order_by":139,"name":"Danila Lodin","email":"","orcid":"","institution":"Umberto I di Siracusa Hospital: Ospedale Umberto I di Siracusa","correspondingAuthor":false,"prefix":"","firstName":"Danila","middleName":"","lastName":"Lodin","suffix":""},{"id":292681697,"identity":"7b8e2925-3ddb-4dd2-a62a-b94d87641cdf","order_by":140,"name":"Riccardo Lubrano","email":"","orcid":"","institution":"Azienda Unità Sanitaria Locale Latina: Azienda Sanitaria Locale Latina","correspondingAuthor":false,"prefix":"","firstName":"Riccardo","middleName":"","lastName":"Lubrano","suffix":""},{"id":292681698,"identity":"d33c86f6-9d55-4881-9f18-0273c1efaa39","order_by":141,"name":"Mariella Lucente","email":"","orcid":"","institution":"ASP Cosenza: Azienda Sanitaria Provinciale di Cosenza","correspondingAuthor":false,"prefix":"","firstName":"Mariella","middleName":"","lastName":"Lucente","suffix":""},{"id":292681699,"identity":"afdcdc91-047d-4fc7-bd1c-1d856e20b3d6","order_by":142,"name":"Stefano Luciani","email":"","orcid":"","institution":"Ospedale Fatebenefratelli Isola Tiberina - Gemelli Isola","correspondingAuthor":false,"prefix":"","firstName":"Stefano","middleName":"","lastName":"Luciani","suffix":""},{"id":292681700,"identity":"5bdb27d2-3948-46c7-bcbd-da5c329ab2a9","order_by":143,"name":"Dimenica Luvarà","email":"","orcid":"","institution":"Azienda Unità Sanitaria Locale Latina: Azienda Sanitaria Locale Latina","correspondingAuthor":false,"prefix":"","firstName":"Dimenica","middleName":"","lastName":"Luvarà","suffix":""},{"id":292681701,"identity":"0276feb8-5293-49bb-aa2a-b6bbd54dfc9f","order_by":144,"name":"Gianfranco Maffei","email":"","orcid":"","institution":"Ospedali Riuniti di Foggia: Azienda Ospedaliera Universitaria Foggia","correspondingAuthor":false,"prefix":"","firstName":"Gianfranco","middleName":"","lastName":"Maffei","suffix":""},{"id":292681702,"identity":"afc1a3d5-9638-4351-b97f-ca2fdbccbc3c","order_by":145,"name":"Alessandra Maggio","email":"","orcid":"","institution":"Policlinico San Matteo Pavia Fondazione IRCCS: Fondazione IRCCS Policlinico San Matteo","correspondingAuthor":false,"prefix":"","firstName":"Alessandra","middleName":"","lastName":"Maggio","suffix":""},{"id":292681703,"identity":"bc998d83-273a-41f3-b73a-90eaa06e5f8f","order_by":146,"name":"Luca Maggio","email":"","orcid":"","institution":"San Camillo Forlanini Hospital: Azienda Ospedaliera San Camillo Forlanini","correspondingAuthor":false,"prefix":"","firstName":"Luca","middleName":"","lastName":"Maggio","suffix":""},{"id":292681704,"identity":"aa99aff0-4730-4ccf-bea5-eb486dd44a6a","order_by":147,"name":"Kim Maiolo","email":"","orcid":"","institution":"Azienda Ospedaliera Garibaldi: Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione Garibaldi","correspondingAuthor":false,"prefix":"","firstName":"Kim","middleName":"","lastName":"Maiolo","suffix":""},{"id":292681705,"identity":"299ce5fe-7a38-45ee-ad92-f085a326f063","order_by":148,"name":"Laura Malaigia","email":"","orcid":"","institution":"Maurizio Bufalini Hospital: Ospedale M Bufalini di Cesena","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Malaigia","suffix":""},{"id":292681706,"identity":"1e597e7a-4d10-4189-a3cb-4592de105c7c","order_by":149,"name":"Giovanna Mangili","email":"","orcid":"","institution":"Azienda Ospedaliera Ospedali Riuniti di Bergamo: Aziende Socio Sanitarie Territoriale Papa Giovanni XXIII","correspondingAuthor":false,"prefix":"","firstName":"Giovanna","middleName":"","lastName":"Mangili","suffix":""},{"id":292681707,"identity":"cfc71860-b19b-41dc-b089-14f70fdbd4cf","order_by":150,"name":"Angelo Manna","email":"","orcid":"","institution":"Ospedale Evangelico Villa Betania: Fondazione Evangelica Betania","correspondingAuthor":false,"prefix":"","firstName":"Angelo","middleName":"","lastName":"Manna","suffix":""},{"id":292681708,"identity":"1ee985d5-57b7-4e4e-bde3-cd0fb445ff64","order_by":151,"name":"Eugenia Maranella","email":"","orcid":"","institution":"San Salvatore Hospital, L'Aquila","correspondingAuthor":false,"prefix":"","firstName":"Eugenia","middleName":"","lastName":"Maranella","suffix":""},{"id":292681709,"identity":"6a89c48f-5e1f-4ec5-8ed1-604df3a3d9e8","order_by":152,"name":"Alessandra Marciano","email":"","orcid":"","institution":"Umberto I Polyclinic of Rome: Umberto I Policlinico di Roma","correspondingAuthor":false,"prefix":"","firstName":"Alessandra","middleName":"","lastName":"Marciano","suffix":""},{"id":292681710,"identity":"0a8881bd-237a-4a35-b142-12aa5ea76758","order_by":153,"name":"Paola Marcozzi","email":"","orcid":"","institution":"San Camillo Forlanini Hospital: Azienda Ospedaliera San Camillo Forlanini","correspondingAuthor":false,"prefix":"","firstName":"Paola","middleName":"","lastName":"Marcozzi","suffix":""},{"id":292681711,"identity":"f23eeb81-6014-4a35-b17e-5e9452860c0c","order_by":154,"name":"Marisa Marletta","email":"","orcid":"","institution":"University Hospital Gaspare Rodolico San Marco: Azienda Ospedaliero Universitaria Policlinico G Rodolico San Marco","correspondingAuthor":false,"prefix":"","firstName":"Marisa","middleName":"","lastName":"Marletta","suffix":""},{"id":292681712,"identity":"adab93d2-7be6-4342-9f48-5bbea96d61f1","order_by":155,"name":"Lucia Marseglia","email":"","orcid":"","institution":"University of Messina: Universita degli Studi di Messina","correspondingAuthor":false,"prefix":"","firstName":"Lucia","middleName":"","lastName":"Marseglia","suffix":""},{"id":292681713,"identity":"407ca2d0-d0b2-4fbd-a846-f5b76b7751b5","order_by":156,"name":"Domenico Martinelli","email":"","orcid":"","institution":"Ospedale Generale Regionale F Miulli: Ente Ecclesiastico Ospedale Generale Regionale Francesco Miulli","correspondingAuthor":false,"prefix":"","firstName":"Domenico","middleName":"","lastName":"Martinelli","suffix":""},{"id":292681714,"identity":"4a9cc3dc-4a8b-48ed-bb2d-307ba3c420e0","order_by":157,"name":"Simona Massari","email":"","orcid":"","institution":"Azienda Sanitaria Provinciale di Ragusa","correspondingAuthor":false,"prefix":"","firstName":"Simona","middleName":"","lastName":"Massari","suffix":""},{"id":292681715,"identity":"24a56652-a52f-4f26-b842-38c5c1f1d3df","order_by":158,"name":"Luca Massenzi","email":"","orcid":"","institution":"Bolzano Hospital: Ospedale di Bolzano","correspondingAuthor":false,"prefix":"","firstName":"Luca","middleName":"","lastName":"Massenzi","suffix":""},{"id":292681716,"identity":"f66f5266-f8a2-4859-8eb8-a54e0f5d9f90","order_by":159,"name":"Federico Matina","email":"","orcid":"","institution":"Palermo Hospital: Ospedale Civico Palermo","correspondingAuthor":false,"prefix":"","firstName":"Federico","middleName":"","lastName":"Matina","suffix":""},{"id":292681717,"identity":"951545d5-a6b2-43d9-a5a6-2fb8b0d6015e","order_by":160,"name":"Loretta Mattia","email":"","orcid":"","institution":"University Hospital Gaspare Rodolico San Marco: Azienda Ospedaliero Universitaria Policlinico G Rodolico San Marco","correspondingAuthor":false,"prefix":"","firstName":"Loretta","middleName":"","lastName":"Mattia","suffix":""},{"id":292681718,"identity":"dc411535-1d5f-4e9c-9b73-90d0bb1e2b86","order_by":161,"name":"Giovanna Mescoli","email":"","orcid":"","institution":"University of Bologna: Universita di Bologna","correspondingAuthor":false,"prefix":"","firstName":"Giovanna","middleName":"","lastName":"Mescoli","suffix":""},{"id":292681719,"identity":"643f63f5-8d17-4202-b6e6-a3627c57832d","order_by":162,"name":"Ignazia Valentina Migliore","email":"","orcid":"","institution":"Azienda Sanitaria Provinciale di Enna","correspondingAuthor":false,"prefix":"","firstName":"Ignazia","middleName":"Valentina","lastName":"Migliore","suffix":""},{"id":292681720,"identity":"292c2aa5-9064-4418-86a9-911c6d8f248f","order_by":163,"name":"Diego Minghetti","email":"","orcid":"","institution":"Ospedale Pediatrico Gaslini: Istituto Giannina Gaslini","correspondingAuthor":false,"prefix":"","firstName":"Diego","middleName":"","lastName":"Minghetti","suffix":""},{"id":292681721,"identity":"ec56f5c8-5c79-435f-9325-07a0d296b10b","order_by":164,"name":"Isabella Mondello","email":"","orcid":"","institution":"Bianchi-Melacrino-Morelli Hospital: Azienda Ospedaliera Bianchi-Melacrino-Morelli","correspondingAuthor":false,"prefix":"","firstName":"Isabella","middleName":"","lastName":"Mondello","suffix":""},{"id":292681723,"identity":"bc7c5840-7b56-46b3-a354-666a0b4fbd04","order_by":165,"name":"Simona Montano","email":"","orcid":"","institution":"Azienda Ospedaliera Careggi: Azienda Ospedaliero Universitaria Careggi","correspondingAuthor":false,"prefix":"","firstName":"Simona","middleName":"","lastName":"Montano","suffix":""},{"id":292681725,"identity":"76e69c9b-9163-4372-9e0d-9629ea3b6493","order_by":166,"name":"Grazia Morandi","email":"","orcid":"","institution":"ASST Mantova: Azienda Socio Sanitaria Territoriale di Mantova","correspondingAuthor":false,"prefix":"","firstName":"Grazia","middleName":"","lastName":"Morandi","suffix":""},{"id":292681727,"identity":"7bf9e7ee-bdc3-4096-88c7-62c52e032133","order_by":167,"name":"Nadia Mores","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Nadia","middleName":"","lastName":"Mores","suffix":""},{"id":292681728,"identity":"9b6e125f-7727-4a58-9333-6fe3336f4170","order_by":168,"name":"Sabrina Morreale","email":"","orcid":"","institution":"ASP Enna: Azienda Sanitaria Provinciale di Enna","correspondingAuthor":false,"prefix":"","firstName":"Sabrina","middleName":"","lastName":"Morreale","suffix":""},{"id":292681729,"identity":"2074efe8-b9ab-4208-ab9e-2b2ccce8f2b9","order_by":169,"name":"Ezio Morselli","email":"","orcid":"","institution":"Ospedale Umberto I di Siracusa","correspondingAuthor":false,"prefix":"","firstName":"Ezio","middleName":"","lastName":"Morselli","suffix":""},{"id":292681730,"identity":"5a90ba21-99e0-40f4-a4dc-acecedc18f37","order_by":170,"name":"Mario Motta","email":"","orcid":"","institution":"Ospedale Maggiore Bologna","correspondingAuthor":false,"prefix":"","firstName":"Mario","middleName":"","lastName":"Motta","suffix":""},{"id":292681731,"identity":"f851b736-d2a6-4113-b529-7cd7c13ee04b","order_by":171,"name":"Marcello Napolitano","email":"","orcid":"","institution":"Villa Betania Evangelical Hospital: Fondazione Evangelica Betania","correspondingAuthor":false,"prefix":"","firstName":"Marcello","middleName":"","lastName":"Napolitano","suffix":""},{"id":292681732,"identity":"d1eae314-7b0f-4b9a-9d5d-326402652d31","order_by":172,"name":"Daniel Nardo","email":"","orcid":"","institution":"University of Padova: Universita degli Studi di Padova","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Nardo","suffix":""},{"id":292681733,"identity":"d13f7852-24bd-4297-82ec-b0996c76cb97","order_by":173,"name":"Aessandra Nicolardi","email":"","orcid":"","institution":"Panico Hospital, Tricase","correspondingAuthor":false,"prefix":"","firstName":"Aessandra","middleName":"","lastName":"Nicolardi","suffix":""},{"id":292681734,"identity":"59c7dead-02f2-4ad1-b05c-572b761f7822","order_by":174,"name":"Silvia Nider","email":"","orcid":"","institution":"Burlo Garofalo Pediatric Institute: IRCCS materno infantile Burlo Garofolo","correspondingAuthor":false,"prefix":"","firstName":"Silvia","middleName":"","lastName":"Nider","suffix":""},{"id":292681735,"identity":"a478c604-aec4-4058-80c3-631a4093c028","order_by":175,"name":"Gabriella Nigro","email":"","orcid":"","institution":"ASP Cosenza: Azienda Sanitaria Provinciale di Cosenza","correspondingAuthor":false,"prefix":"","firstName":"Gabriella","middleName":"","lastName":"Nigro","suffix":""},{"id":292681736,"identity":"778d280d-37d2-4a8a-bbc8-bb8e703f8e1b","order_by":176,"name":"Melissa Nuccio","email":"","orcid":"","institution":"Panico Hospital, Tricase","correspondingAuthor":false,"prefix":"","firstName":"Melissa","middleName":"","lastName":"Nuccio","suffix":""},{"id":292681737,"identity":"5f1f220c-7835-479e-9018-979329b05e0e","order_by":177,"name":"Luigi Orfeo","email":"","orcid":"","institution":"Ospedale Fatebenefratelli Isola Tiberina - Gemelli Isola","correspondingAuthor":false,"prefix":"","firstName":"Luigi","middleName":"","lastName":"Orfeo","suffix":""},{"id":292681738,"identity":"a9755816-ae79-4ec9-962e-9b46e7bb6757","order_by":178,"name":"Carla Ottaviano","email":"","orcid":"","institution":"San Camillo Forlanini Hospital: Azienda Ospedaliera San Camillo Forlanini","correspondingAuthor":false,"prefix":"","firstName":"Carla","middleName":"","lastName":"Ottaviano","suffix":""},{"id":292681739,"identity":"41475cfd-09dd-4f92-8232-cb9ffbb95786","order_by":179,"name":"Paola Paganin","email":"","orcid":"","institution":"Ospedale Maggiore, Bologna","correspondingAuthor":false,"prefix":"","firstName":"Paola","middleName":"","lastName":"Paganin","suffix":""},{"id":292681740,"identity":"7c400ba9-d739-4ed6-a9cd-c5b25d34ddae","order_by":180,"name":"Sabrina Palamides","email":"","orcid":"","institution":"San Giovanni-Addolorata Hospital: Azienda ospedaliera San Giovanni-Addolorata","correspondingAuthor":false,"prefix":"","firstName":"Sabrina","middleName":"","lastName":"Palamides","suffix":""},{"id":292681741,"identity":"d7140454-be1b-46ef-aec8-deeff26119e5","order_by":181,"name":"Sara Palatta","email":"","orcid":"","institution":"San Giovanni-Addolorata Hospital: Azienda ospedaliera San Giovanni-Addolorata","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Palatta","suffix":""},{"id":292681742,"identity":"91c842d4-f1e9-4b87-845c-aae14d3d4b91","order_by":182,"name":"Piermichele Paolillo","email":"","orcid":"","institution":"Casilino General Hospital: Policlinico Casilino","correspondingAuthor":false,"prefix":"","firstName":"Piermichele","middleName":"","lastName":"Paolillo","suffix":""},{"id":292681743,"identity":"f0eeec35-ca8e-4846-bc04-6884a197221f","order_by":183,"name":"Maria Grazia Pappalardo","email":"","orcid":"","institution":"Azienda Ospedaliera Cannizzaro","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Grazia","lastName":"Pappalardo","suffix":""},{"id":292681744,"identity":"002b34d0-3042-40ee-b478-e1e1c79e5879","order_by":184,"name":"Elisa Pasta","email":"","orcid":"","institution":"Poliambulanza Foundation Hospitals: Fondazione Poliambulanza Istituto Ospedaliero","correspondingAuthor":false,"prefix":"","firstName":"Elisa","middleName":"","lastName":"Pasta","suffix":""},{"id":292681745,"identity":"4e870d0c-e1b8-426c-96d5-ddfb527e0c58","order_by":185,"name":"Letizia Patti","email":"","orcid":"","institution":"Policlinico San Matteo Pavia Fondazione IRCCS: Fondazione IRCCS Policlinico San Matteo","correspondingAuthor":false,"prefix":"","firstName":"Letizia","middleName":"","lastName":"Patti","suffix":""},{"id":292681746,"identity":"a8743cb8-5076-4a64-97f0-d562b52ec801","order_by":186,"name":"Giulia Paviotti","email":"","orcid":"","institution":"Azienda sanitaria universitaria Friuli Centrale","correspondingAuthor":false,"prefix":"","firstName":"Giulia","middleName":"","lastName":"Paviotti","suffix":""},{"id":292681747,"identity":"fc6ed504-858a-4a7b-b16f-cd2d78def164","order_by":187,"name":"Roberto Perniola","email":"","orcid":"","institution":"Azienda Sanitaria Locale Lecce: ASL Lecce","correspondingAuthor":false,"prefix":"","firstName":"Roberto","middleName":"","lastName":"Perniola","suffix":""},{"id":292681748,"identity":"2bf419a3-afca-4188-9689-73c0be2aad4d","order_by":188,"name":"Gianfranco Perotti","email":"","orcid":"","institution":"Policlinico San Matteo Pavia Fondazione IRCCS: Fondazione IRCCS Policlinico San Matteo","correspondingAuthor":false,"prefix":"","firstName":"Gianfranco","middleName":"","lastName":"Perotti","suffix":""},{"id":292681749,"identity":"722d5279-25d4-469f-b677-5342562d97ef","order_by":189,"name":"Serafina Perrone","email":"","orcid":"","institution":"University of Parma: Universita degli Studi di Parma","correspondingAuthor":false,"prefix":"","firstName":"Serafina","middleName":"","lastName":"Perrone","suffix":""},{"id":292681750,"identity":"f76bb447-68a8-4bbe-a072-314c65eb8c8d","order_by":190,"name":"Flavia Petrillo","email":"","orcid":"","institution":"Ospedale Di Venere, Bari","correspondingAuthor":false,"prefix":"","firstName":"Flavia","middleName":"","lastName":"Petrillo","suffix":""},{"id":292681751,"identity":"97809c1c-123a-46fb-92da-f6c6cc1ef283","order_by":191,"name":"Maria Santa Piazza","email":"","orcid":"","institution":"Azienda Sanitaria Provinciale di Enna","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Santa","lastName":"Piazza","suffix":""},{"id":292681752,"identity":"56bb3297-35ea-457b-9813-cf87156e19f4","order_by":192,"name":"Alessandro Piccirillo","email":"","orcid":"","institution":"Ospedale Pineta Grande, Castelvolturno","correspondingAuthor":false,"prefix":"","firstName":"Alessandro","middleName":"","lastName":"Piccirillo","suffix":""},{"id":292681753,"identity":"0eb56305-2a56-4be7-a8c9-0c7f89f63bb6","order_by":193,"name":"Maria Pierro","email":"","orcid":"","institution":"Maurizio Bufalini Hospital: Ospedale M Bufalini di Cesena","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Pierro","suffix":""},{"id":292681754,"identity":"37e107d7-d942-4f33-809e-4acbbdc86617","order_by":194,"name":"Enrico Piga","email":"","orcid":"","institution":"Umberto I Polyclinic of Rome: Umberto I Policlinico di Roma","correspondingAuthor":false,"prefix":"","firstName":"Enrico","middleName":"","lastName":"Piga","suffix":""},{"id":292681755,"identity":"bb8ebc98-8656-4ad8-932a-3bc5a0c0d113","order_by":195,"name":"Giulia Anna Pingitore","email":"","orcid":"","institution":"ASP Cosenza: Azienda Sanitaria Provinciale di Cosenza","correspondingAuthor":false,"prefix":"","firstName":"Giulia","middleName":"Anna","lastName":"Pingitore","suffix":""},{"id":292681756,"identity":"b8ca32b5-2221-4501-a25d-fc6e4aa439db","order_by":196,"name":"Simona Pisu","email":"","orcid":"","institution":"Fondazione Policlinico Universitario Agostino Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Simona","middleName":"","lastName":"Pisu","suffix":""},{"id":292681757,"identity":"795e5ff8-eb7d-47e7-bca3-dcaf9e2e3690","order_by":197,"name":"Carla Pittini","email":"","orcid":"","institution":"University Hospital of Central Friuli: Azienda sanitaria universitaria Friuli Centrale","correspondingAuthor":false,"prefix":"","firstName":"Carla","middleName":"","lastName":"Pittini","suffix":""},{"id":292681758,"identity":"0734a93a-30d8-42fc-badb-cf21582ed667","order_by":198,"name":"Federica Pontiggia","email":"","orcid":"","institution":"A.O. Bolognini di Seriate Bergamo: Ospedale Bolognini di Seriate","correspondingAuthor":false,"prefix":"","firstName":"Federica","middleName":"","lastName":"Pontiggia","suffix":""},{"id":292681759,"identity":"f994bb72-7565-4bc3-8b9c-89ba66d1288f","order_by":199,"name":"Giovanna Pontrelli","email":"","orcid":"","institution":"Santa Maria Goretti, Latina","correspondingAuthor":false,"prefix":"","firstName":"Giovanna","middleName":"","lastName":"Pontrelli","suffix":""},{"id":292681760,"identity":"4a20c6a1-8bf7-47c8-85a0-0c5ad05a87ff","order_by":200,"name":"Adele Primavera","email":"","orcid":"","institution":"Ospedale SS Annunziata: Ospedale Santissima Annunziata","correspondingAuthor":false,"prefix":"","firstName":"Adele","middleName":"","lastName":"Primavera","suffix":""},{"id":292681761,"identity":"080a8164-877a-4450-887e-f4e6b695c68b","order_by":201,"name":"Alice Proto","email":"","orcid":"","institution":"Niguarda Ca Granda Hospital: Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda","correspondingAuthor":false,"prefix":"","firstName":"Alice","middleName":"","lastName":"Proto","suffix":""},{"id":292681762,"identity":"19104970-5179-4dda-bbaa-fa3be9d9767b","order_by":202,"name":"Lorenzo Quartulli","email":"","orcid":"","institution":"Di Summa - Perrino Brindisi Hospital: Ospedale Antonio Perrino","correspondingAuthor":false,"prefix":"","firstName":"Lorenzo","middleName":"","lastName":"Quartulli","suffix":""},{"id":292681763,"identity":"10d44156-e939-47a0-a946-150711edb8f8","order_by":203,"name":"Francesco Raimondi","email":"","orcid":"","institution":"Università degli Studi di Napoli Federico II: Universita degli Studi di Napoli Federico II","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Raimondi","suffix":""},{"id":292681764,"identity":"8637480f-00db-4a73-9948-b2793e3a6947","order_by":204,"name":"Luca Ramenghi","email":"","orcid":"","institution":"Ospedale Pediatrico Gaslini: Istituto Giannina Gaslini","correspondingAuthor":false,"prefix":"","firstName":"Luca","middleName":"","lastName":"Ramenghi","suffix":""},{"id":292681765,"identity":"15c1544a-91cd-4594-99c8-670ec383fc7e","order_by":205,"name":"Maria Rapsomaniki","email":"","orcid":"","institution":"Azienda Ospedaliera di Catanzaro Pugliese Ciaccio: Azienda Ospedaliera di Catanzaro Pugliese-Ciaccio","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Rapsomaniki","suffix":""},{"id":292681766,"identity":"960a29eb-5acf-42c2-8122-839bb434d9b8","order_by":206,"name":"Alberto Ricotti","email":"","orcid":"","institution":"Azienda Ospedaliera Nazionale Santi Antonio e Biagio e Cesare Arrigo Alessandria","correspondingAuthor":false,"prefix":"","firstName":"Alberto","middleName":"","lastName":"Ricotti","suffix":""},{"id":292681767,"identity":"b8ba7b65-311b-4142-b6ce-9688b0e5cc14","order_by":207,"name":"Camilla Rigotti","email":"","orcid":"","institution":"IRCCS San Gerardo dei Tintori Foundation Hospital: Fondazione IRCCS San Gerardo dei Tintori","correspondingAuthor":false,"prefix":"","firstName":"Camilla","middleName":"","lastName":"Rigotti","suffix":""},{"id":292681768,"identity":"73cc607c-739c-401b-92e7-a99b4d3b3bc3","order_by":208,"name":"Matteo Rinaldi","email":"","orcid":"","institution":"Foggia University Hospital: Azienda Ospedaliera Universitaria Foggia","correspondingAuthor":false,"prefix":"","firstName":"Matteo","middleName":"","lastName":"Rinaldi","suffix":""},{"id":292681769,"identity":"784dc955-19b7-4a02-8032-3cc038d880bb","order_by":209,"name":"Francesco Risso","email":"","orcid":"","institution":"ASST Spedali Civili di Brescia: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Risso","suffix":""},{"id":292681770,"identity":"d286b44b-dd31-4d31-9a8c-5f26d3f72bc5","order_by":210,"name":"Enza Roma","email":"","orcid":"","institution":"Ospedale Pineta Grande, Castelvolturno","correspondingAuthor":false,"prefix":"","firstName":"Enza","middleName":"","lastName":"Roma","suffix":""},{"id":292681771,"identity":"182a9aec-b300-4084-aef2-ce585c5758d0","order_by":211,"name":"Enzo Romanini","email":"","orcid":"","institution":"University of Parma: Universita degli Studi di Parma","correspondingAuthor":false,"prefix":"","firstName":"Enzo","middleName":"","lastName":"Romanini","suffix":""},{"id":292681772,"identity":"2d57845b-f2d3-4faa-8bd7-f0bd73f8e77e","order_by":212,"name":"Valerio Romano","email":"","orcid":"","institution":"Ospedale Fatebenefratelli Isola Tiberina - Gemelli Isola","correspondingAuthor":false,"prefix":"","firstName":"Valerio","middleName":"","lastName":"Romano","suffix":""},{"id":292681773,"identity":"e0516e24-1d2c-4781-812f-6e739a041807","order_by":213,"name":"Enrico Rosati","email":"","orcid":"","institution":"Azienda Sanitaria Locale Lecce: ASL Lecce","correspondingAuthor":false,"prefix":"","firstName":"Enrico","middleName":"","lastName":"Rosati","suffix":""},{"id":292681774,"identity":"c4712549-07ae-487d-ba0e-6b14d0589501","order_by":214,"name":"Vincenzo Rosella","email":"","orcid":"","institution":"Ospedale Buccheri La Ferla Fatebenefratelli","correspondingAuthor":false,"prefix":"","firstName":"Vincenzo","middleName":"","lastName":"Rosella","suffix":""},{"id":292681776,"identity":"89a889f7-091b-439e-abae-abebc39d75b9","order_by":215,"name":"Imma Rulli","email":"","orcid":"","institution":"University of Messina: Universita degli Studi di Messina","correspondingAuthor":false,"prefix":"","firstName":"Imma","middleName":"","lastName":"Rulli","suffix":""},{"id":292681777,"identity":"687656f8-18c5-4942-8493-8da515a16fc5","order_by":216,"name":"Vincenzo Salvo","email":"","orcid":"","institution":"ASP Ragusa: Azienda Sanitaria Provinciale di Ragusa","correspondingAuthor":false,"prefix":"","firstName":"Vincenzo","middleName":"","lastName":"Salvo","suffix":""},{"id":292681778,"identity":"e1c45ca6-b1fd-4bd1-a90f-95769e71bfd9","order_by":217,"name":"Cinzia Sanfilippo","email":"","orcid":"","institution":"Palermo Public Hospital: Ospedale Civico Palermo","correspondingAuthor":false,"prefix":"","firstName":"Cinzia","middleName":"","lastName":"Sanfilippo","suffix":""},{"id":292681779,"identity":"c350a206-8542-43ac-8c7f-d44c561adb97","order_by":218,"name":"Andrea Sannia","email":"","orcid":"","institution":"Azienda Ospedaliera S. Croce e Carle Cuneo: Azienda Ospedaliera S Croce e Carle Cuneo","correspondingAuthor":false,"prefix":"","firstName":"Andrea","middleName":"","lastName":"Sannia","suffix":""},{"id":292681782,"identity":"122ff258-f0e5-4b34-8889-a8a41f7e1777","order_by":219,"name":"Alessandro Saporito","email":"","orcid":"","institution":"University Hospital Vittorio Emanuele Catania Polyclinic: Azienda Ospedaliero Universitaria Policlinico G Rodolico San Marco","correspondingAuthor":false,"prefix":"","firstName":"Alessandro","middleName":"","lastName":"Saporito","suffix":""},{"id":292681784,"identity":"de522f05-bc14-4034-8d1a-925af73b55bf","order_by":220,"name":"Alessandra Sauna","email":"","orcid":"","institution":"Ospedale \"Giovanni Paolo II\", Ragusa","correspondingAuthor":false,"prefix":"","firstName":"Alessandra","middleName":"","lastName":"Sauna","suffix":""},{"id":292681786,"identity":"e088c081-aa8e-44b6-a5e6-59415ade53de","order_by":221,"name":"Eleonora Scapillati","email":"","orcid":"","institution":"San Pietro Hospital: Ospedale San Pietro","correspondingAuthor":false,"prefix":"","firstName":"Eleonora","middleName":"","lastName":"Scapillati","suffix":""},{"id":292681788,"identity":"2b14c312-cb28-4b12-b96d-d8106acb235f","order_by":222,"name":"Federico Schettini","email":"","orcid":"","institution":"Azienda Sanitaria Locale Taranto","correspondingAuthor":false,"prefix":"","firstName":"Federico","middleName":"","lastName":"Schettini","suffix":""},{"id":292681789,"identity":"0306b2a9-f445-4e22-869c-d72052ca1588","order_by":223,"name":"Antonio Scorrano","email":"","orcid":"","institution":"Panico Hospital, Tricase","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"","lastName":"Scorrano","suffix":""},{"id":292681791,"identity":"985eb21e-b87a-45b7-867f-ed60dbb84b90","order_by":224,"name":"Simona Semeria Mantelli","email":"","orcid":"","institution":"Poliambulanza Foundation Hospitals: Fondazione Poliambulanza Istituto Ospedaliero","correspondingAuthor":false,"prefix":"","firstName":"Simona","middleName":"Semeria","lastName":"Mantelli","suffix":""},{"id":292681793,"identity":"249a4adb-5907-4235-8636-20ee31d3c9bd","order_by":225,"name":"Vittoria Sepporta","email":"","orcid":"","institution":"Presidio ospedaliero Ingrassia, Palermo","correspondingAuthor":false,"prefix":"","firstName":"Vittoria","middleName":"","lastName":"Sepporta","suffix":""},{"id":292681796,"identity":"47ed3d57-2415-4abb-ad8f-2687a3b271f9","order_by":226,"name":"Paola Sindico","email":"","orcid":"","institution":"ASST Mantova: Azienda Socio Sanitaria Territoriale di Mantova","correspondingAuthor":false,"prefix":"","firstName":"Paola","middleName":"","lastName":"Sindico","suffix":""},{"id":292681798,"identity":"6d112f73-ac08-4f8a-adde-1e77dca0f390","order_by":227,"name":"Agostina Solinas","email":"","orcid":"","institution":"University of Ferrara: Universita degli Studi di Ferrara","correspondingAuthor":false,"prefix":"","firstName":"Agostina","middleName":"","lastName":"Solinas","suffix":""},{"id":292681800,"identity":"e4a8e767-adab-49e7-93b4-6bed2f9c7458","order_by":228,"name":"Elena Sorrentino","email":"","orcid":"","institution":"San Pietro Hospital: Ospedale San Pietro","correspondingAuthor":false,"prefix":"","firstName":"Elena","middleName":"","lastName":"Sorrentino","suffix":""},{"id":292681802,"identity":"7cb21dd5-66d7-4315-84df-387a02c87d41","order_by":229,"name":"Eugenio Spaggiari","email":"","orcid":"","institution":"Policlinic of Modena: Policlinico di Modena","correspondingAuthor":false,"prefix":"","firstName":"Eugenio","middleName":"","lastName":"Spaggiari","suffix":""},{"id":292681803,"identity":"dea8d6a8-97d6-4696-bc43-00d927910e31","order_by":230,"name":"Alex Staffler","email":"","orcid":"","institution":"Bolzano Hospital: Ospedale di Bolzano","correspondingAuthor":false,"prefix":"","firstName":"Alex","middleName":"","lastName":"Staffler","suffix":""},{"id":292681805,"identity":"330ee50a-49ec-4946-b3ac-04a0a01c3362","order_by":231,"name":"Marcello Stella","email":"","orcid":"","institution":"Ospedale Maurizio Bufalini: Ospedale M Bufalini di Cesena","correspondingAuthor":false,"prefix":"","firstName":"Marcello","middleName":"","lastName":"Stella","suffix":""},{"id":292681806,"identity":"765387ef-e6b9-4c34-b6c1-d59b4fd525e2","order_by":232,"name":"Donatella Termini","email":"","orcid":"","institution":"Buccheri La Ferla Fatebenefratelli Hospital: Ospedale Buccheri La Ferla Fatebenefratelli","correspondingAuthor":false,"prefix":"","firstName":"Donatella","middleName":"","lastName":"Termini","suffix":""},{"id":292681807,"identity":"c720d53a-ca3c-4c02-90ce-fdb850f4923e","order_by":233,"name":"Gianluca Terrin","email":"","orcid":"","institution":"Umberto I Polyclinic of Rome: Umberto I Policlinico di Roma","correspondingAuthor":false,"prefix":"","firstName":"Gianluca","middleName":"","lastName":"Terrin","suffix":""},{"id":292681808,"identity":"c1f9422e-0924-401a-b888-41af752c68f8","order_by":234,"name":"Alessia Testi","email":"","orcid":"","institution":"Ospedale Santa Maria Goretti, Latina","correspondingAuthor":false,"prefix":"","firstName":"Alessia","middleName":"","lastName":"Testi","suffix":""},{"id":292681809,"identity":"a56a67ae-ca43-4ea0-81c2-b2d647ef9ed7","order_by":235,"name":"Gabriella Tina","email":"","orcid":"","institution":"Azienda Ospedaliera ARNAS Garibaldi: Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione Garibaldi","correspondingAuthor":false,"prefix":"","firstName":"Gabriella","middleName":"","lastName":"Tina","suffix":""},{"id":292681810,"identity":"0f736d6f-7c26-49c5-8d2a-5ca581ccced4","order_by":236,"name":"Massimo Tirantello","email":"","orcid":"","institution":"Umberto I di Siracusa Hospital: Ospedale Umberto I di Siracusa","correspondingAuthor":false,"prefix":"","firstName":"Massimo","middleName":"","lastName":"Tirantello","suffix":""},{"id":292681811,"identity":"e6bf66ca-6c90-497e-b726-d2afabe20a95","order_by":237,"name":"Barbara Tomassini","email":"","orcid":"","institution":"AOU Senese: Azienda Ospedaliera Universitaria Senese","correspondingAuthor":false,"prefix":"","firstName":"Barbara","middleName":"","lastName":"Tomassini","suffix":""},{"id":292681812,"identity":"b2534f0f-e460-49b3-8b80-b938510604da","order_by":238,"name":"Francesca Tormena","email":"","orcid":"","institution":"AO Cà Foncello, Treviso","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"","lastName":"Tormena","suffix":""},{"id":292681813,"identity":"a1b5eaaf-ea4d-4b0f-ab8a-22bc1d80e9cf","order_by":239,"name":"Laura Travan","email":"","orcid":"","institution":"Burlo Garofalo Pediatric Institute: IRCCS materno infantile Burlo Garofolo","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Travan","suffix":""},{"id":292681814,"identity":"9e82dcba-0631-4c80-b371-2bf28e7193ca","order_by":240,"name":"Daniele Trevisanuto","email":"","orcid":"","institution":"University of Padova: Universita degli Studi di Padova","correspondingAuthor":false,"prefix":"","firstName":"Daniele","middleName":"","lastName":"Trevisanuto","suffix":""},{"id":292681815,"identity":"0348ab99-df6d-4b77-8eba-bc23792bee5e","order_by":241,"name":"Viviana Tulino","email":"","orcid":"","institution":"Barone Romeo hospital Patti","correspondingAuthor":false,"prefix":"","firstName":"Viviana","middleName":"","lastName":"Tulino","suffix":""},{"id":292681816,"identity":"f295457e-9f7f-41c8-8327-82edd6305029","order_by":242,"name":"Luigia Valenzano","email":"","orcid":"","institution":"Di Venere Hospital, Bari","correspondingAuthor":false,"prefix":"","firstName":"Luigia","middleName":"","lastName":"Valenzano","suffix":""},{"id":292681817,"identity":"edd77874-bf2f-4dc1-8e03-90436e2ce033","order_by":243,"name":"Stefania Vedovato","email":"","orcid":"","institution":"San Bortolo Hospital of Vicenza: Ospedale San Bortolo di Vicenza","correspondingAuthor":false,"prefix":"","firstName":"Stefania","middleName":"","lastName":"Vedovato","suffix":""},{"id":292681818,"identity":"f0acf123-9bf0-4a0d-acac-06df17785c59","order_by":244,"name":"Silvia Vendramin","email":"","orcid":"","institution":"AO Cà Foncello, Treviso","correspondingAuthor":false,"prefix":"","firstName":"Silvia","middleName":"","lastName":"Vendramin","suffix":""},{"id":292681819,"identity":"a5298da8-c920-47e3-ac14-3fc9cc053b05","order_by":245,"name":"Paolo Villani","email":"","orcid":"","institution":"Poliambulanza Foundation Hospitals: Fondazione Poliambulanza Istituto Ospedaliero","correspondingAuthor":false,"prefix":"","firstName":"Paolo","middleName":"","lastName":"Villani","suffix":""},{"id":292681820,"identity":"9c84e736-cf68-4a50-b785-cd1a7f8c6a55","order_by":246,"name":"Serena Viola","email":"","orcid":"","institution":"Novara Hospital: Azienda Ospedaliero Universitaria Maggiore della Carita","correspondingAuthor":false,"prefix":"","firstName":"Serena","middleName":"","lastName":"Viola","suffix":""},{"id":292681821,"identity":"c62ff3bc-8370-42c8-a22c-c24cd12f3cf5","order_by":247,"name":"Valeria Viola","email":"","orcid":"","institution":"Bianchi-Melacrino-Morelli Hospital: Azienda Ospedaliera Bianchi-Melacrino-Morelli","correspondingAuthor":false,"prefix":"","firstName":"Valeria","middleName":"","lastName":"Viola","suffix":""},{"id":292681822,"identity":"cfab7c6a-294b-4023-8160-e7288761bff2","order_by":248,"name":"Giuliana Vitaliti","email":"","orcid":"","institution":"Palermo Public Hospital: Ospedale Civico Palermo","correspondingAuthor":false,"prefix":"","firstName":"Giuliana","middleName":"","lastName":"Vitaliti","suffix":""},{"id":292681823,"identity":"2e60f2ca-49b8-4d86-b570-24fdd6e84900","order_by":249,"name":"Marcello Vitaliti","email":"","orcid":"","institution":"Palermo Public Hospital: Ospedale Civico Palermo","correspondingAuthor":false,"prefix":"","firstName":"Marcello","middleName":"","lastName":"Vitaliti","suffix":""},{"id":292681824,"identity":"69470105-8860-4c40-bb29-2640ee28e89e","order_by":250,"name":"Petra Wanker","email":"","orcid":"","institution":"Bolzano Hospital: Ospedale di Bolzano","correspondingAuthor":false,"prefix":"","firstName":"Petra","middleName":"","lastName":"Wanker","suffix":""},{"id":292681825,"identity":"532f5987-d7c9-44ca-b1cd-8fd55c8fc243","order_by":251,"name":"Yuchen Yang","email":"","orcid":"","institution":"Shengjing Hospital of China Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuchen","middleName":"","lastName":"Yang","suffix":""},{"id":292681826,"identity":"7a6d2ed9-922f-4abc-8ea4-0c269e0ab555","order_by":252,"name":"Sara Zanetta","email":"","orcid":"","institution":"Novara Hospital: Azienda Ospedaliero Universitaria Maggiore della Carita","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Zanetta","suffix":""},{"id":292681827,"identity":"f2efe2db-7b0c-466b-b39b-2469a3cf613d","order_by":253,"name":"Emanuela Zannin","email":"","orcid":"","institution":"Fondazione IRCCS San Gerardo dei Tintori","correspondingAuthor":false,"prefix":"","firstName":"Emanuela","middleName":"","lastName":"Zannin","suffix":""}],"badges":[],"createdAt":"2024-02-27 15:25:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3994255/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3994255/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55257911,"identity":"19e78e34-0c65-4db8-aba5-16a78b087ab2","added_by":"auto","created_at":"2024-04-24 20:55:50","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":372679,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow chart\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3994255/v1/8591f05cf911baa63854750d.jpeg"},{"id":55258178,"identity":"5c9a241b-1840-4dd5-8a80-bc3301c35996","added_by":"auto","created_at":"2024-04-24 21:03:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1918450,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3994255/v1/1c128d76-5f73-44de-aee0-05e46c9b1a5b.pdf"}],"financialInterests":"","formattedTitle":"Comparison of “IN-REC-SUR-E” and LISA in preterm neonates with respiratory distress syndrome: a randomized controlled trial (IN- REC-LISA trial)","fulltext":[{"header":"Administrative information","content":" \u003cp\u003eNote: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).\u003c/p\u003e\n\u003ctable\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eTitle\u0026nbsp;{1}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eComparison of \u0026ldquo;IN-REC-SUR-E\u0026rdquo; and LISA in preterm neonates with respiratory distress syndrome: a randomized controlled trial (IN- REC-LISA trial)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eTrial registration {2a and 2b}.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eClinicalTrials.gov Identifier: NCT05711966. Status: recruiting. First Posted: 3/02/2023; Last Update Posted: 17/02/2023.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eProtocol version {3}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eVersion 3, 25 October 2022\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eFunding {4}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eThe study has received economic contributions by way of partial coverage of the expenses relating to its implementation.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eAuthor details {5a}\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eGiovanni Vento\u003csup\u003e1\u003c/sup\u003e, Angela Paladini\u003csup\u003e1\u003c/sup\u003e, C. Aurilia\u003csup\u003e1\u003c/sup\u003e, S. Alkan Ozdemir\u003csup\u003e2\u003c/sup\u003e, V.P. Carnielli\u003csup\u003e3\u003c/sup\u003e, F. Cools\u003csup\u003e4\u003c/sup\u003e, S. Costa\u003csup\u003e1\u003c/sup\u003e, F. Cota\u003csup\u003e1\u003c/sup\u003e, C. Dani\u003csup\u003e5\u003c/sup\u003e, P.G. Davis\u003csup\u003e6\u003c/sup\u003e, S. Fattore\u003csup\u003e1\u003c/sup\u003e, C. F\u0026egrave;\u003csup\u003e1\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eN. Finer\u003csup\u003e7\u003c/sup\u003e, F.P. Fusco\u003csup\u003e1\u003c/sup\u003e, C. Gizzi\u003csup\u003e8\u003c/sup\u003e, E. Herting\u003csup\u003e9\u003c/sup\u003e, M. Jian\u003csup\u003e10\u003c/sup\u003e, A. Lio\u003csup\u003e1\u003c/sup\u003e, G. Lista\u003csup\u003e11\u003c/sup\u003e, F. Mosca\u003csup\u003e12\u003c/sup\u003e, S. Nobile\u003csup\u003e1\u003c/sup\u003e, A. Perri\u003csup\u003e1\u003c/sup\u003e, S. Picone\u003csup\u003e13\u003c/sup\u003e, J.J. Pillow\u003csup\u003e14\u003c/sup\u003e, G. Polglase\u003csup\u003e15\u003c/sup\u003e, T. Pasciuto\u003csup\u003e16\u003c/sup\u003e, R. Pastorino\u003csup\u003e17\u003c/sup\u003e, M.Tana\u003csup\u003e1\u003c/sup\u003e, D. Tingay\u003csup\u003e20\u003c/sup\u003e, C. Tirone\u003csup\u003e1\u003c/sup\u003e, A.H. van Kaam\u003csup\u003e21\u003c/sup\u003e, M.L. Ventura\u003csup\u003e19\u003c/sup\u003e, A. Aceti\u003csup\u003e22\u003c/sup\u003e, M. Agosti\u003csup\u003e23\u003c/sup\u003e, G. Alighieri\u003csup\u003e24\u003c/sup\u003e, G. Ancora\u003csup\u003e25\u003c/sup\u003e, V. Angileri\u003csup\u003e26\u003c/sup\u003e, G. Ausanio\u003csup\u003e27\u003c/sup\u003e, S. Aversa\u003csup\u003e28\u003c/sup\u003e, E. Balestri\u003csup\u003e29\u003c/sup\u003e, E. Baraldi\u003csup\u003e30\u003c/sup\u003e, M.C. Barbini\u003csup\u003e23\u003c/sup\u003e, C. Barone\u003csup\u003e31\u003c/sup\u003e, \u0026nbsp;R. Beghini\u003csup\u003e91\u003c/sup\u003e, C. Bellan\u003csup\u003e32\u003c/sup\u003e, A. Berardi\u003csup\u003e33\u003c/sup\u003e, I. Bernardo\u003csup\u003e27\u003c/sup\u003e, P. Betta\u003csup\u003e35\u003c/sup\u003e, M. Binotti\u003csup\u003e61\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eB. Bizzarri\u003csup\u003e8\u003c/sup\u003e, G. Borgarello\u003csup\u003e36\u003c/sup\u003e, S. Borgione\u003csup\u003e34\u003c/sup\u003e, A. Borrelli\u003csup\u003e27\u003c/sup\u003e, R. Bottino\u003csup\u003e33\u003c/sup\u003e, G. Bracaglia\u003csup\u003e38\u003c/sup\u003e, I. Bresesti\u003csup\u003e23\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eI. Burattini\u003csup\u003e3\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eC. Cacace\u003csup\u003e39\u003c/sup\u003e, F. Calzolari\u003csup\u003e40\u003c/sup\u003e, M.F. Campagnoli\u003csup\u003e41\u003c/sup\u003e, L. Capasso\u003csup\u003e42\u003c/sup\u003e, M. Capozza\u003csup\u003e43\u003c/sup\u003e, M.G. Capretti\u003csup\u003e22\u003c/sup\u003e, J. Caravetta\u003csup\u003e13\u003c/sup\u003e, C. Carbonara\u003csup\u003e41\u003c/sup\u003e, V. Cardilli\u003csup\u003e44\u003c/sup\u003e, M. Carta\u003csup\u003e45\u003c/sup\u003e, F. Castoldi\u003csup\u003e11\u003c/sup\u003e, A. Castronovo\u003csup\u003e8\u003c/sup\u003e, E. Cavalleri\u003csup\u003e28\u003c/sup\u003e, F. Cavigioli\u003csup\u003e11\u003c/sup\u003e, S. Cecchi\u003csup\u003e46\u003c/sup\u003e, V. Chierici\u003csup\u003e23\u003c/sup\u003e, C. Cimino\u003csup\u003e47\u003c/sup\u003e, F. Cocca\u003csup\u003e48\u003c/sup\u003e, C. Cocca\u003csup\u003e48\u003c/sup\u003e, P. Cogo\u003csup\u003e49\u003c/sup\u003e, M. Coma\u003csup\u003e12\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eV. Comito\u003csup\u003e50\u003c/sup\u003e, V. Cond\u0026ograve;\u003csup\u003e12\u003c/sup\u003e, C. Consigli\u003csup\u003e51\u003c/sup\u003e, R. Conti\u003csup\u003e65\u003c/sup\u003e, M. Corradi\u003csup\u003e40\u003c/sup\u003e, G. Corsello\u003csup\u003e45\u003c/sup\u003e, L.T. Corvaglia\u003csup\u003e22\u003c/sup\u003e, A. Costa\u003csup\u003e52\u003c/sup\u003e, A. Coscia\u003csup\u003e34\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eF. Cresi\u003csup\u003e34\u003c/sup\u003e, F. Crispino\u003csup\u003e27\u003c/sup\u003e, P. D\u0026rsquo;Amico\u003csup\u003e54\u003c/sup\u003e, L. De Cosmo\u003csup\u003e55\u003c/sup\u003e, C. De Maio\u003csup\u003e36\u003c/sup\u003e, G. Del Campo\u003csup\u003e54\u003c/sup\u003e, S. Di Credico\u003csup\u003e89\u003c/sup\u003e, S. Di Fabio\u003csup\u003e56\u003c/sup\u003e, P. Di Nicola\u003csup\u003e41\u003c/sup\u003e, A. Di Paolo\u003csup\u003e57\u003c/sup\u003e, S. Di Valerio\u003csup\u003e89\u003c/sup\u003e, A. Distilo\u003csup\u003e84\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eV. Duca\u003csup\u003e26\u003c/sup\u003e, A. Falcone\u003csup\u003e50\u003c/sup\u003e, R. Falsaperla\u003csup\u003e47\u003c/sup\u003e, V.A. Fasolato\u003csup\u003e58\u003c/sup\u003e, V. Fatuzzo\u003csup\u003e76\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eF. Favini\u003csup\u003e59\u003c/sup\u003e, M.P. Ferrarello\u003csup\u003e52\u003c/sup\u003e, S. Ferrari\u003csup\u003e59\u003c/sup\u003e, F. Fiori Nastro\u003csup\u003e86\u003c/sup\u003e, C.A. Forcellini\u003csup\u003e91\u003c/sup\u003e, A. Fracchiolla\u003csup\u003e60\u003c/sup\u003e, A. Gabriele\u003csup\u003e72\u003c/sup\u003e, F.\u003cins cite=\"mailto:Giovanni%20Vento\" datetime=\"2024-02-10T11:24\"\u003e\u0026nbsp;\u003c/ins\u003eGaldo\u003csup\u003e69\u003c/sup\u003e, F. Gallini\u003csup\u003e77\u003c/sup\u003e, A. Gangemi\u003csup\u003e65\u003c/sup\u003e, G. Gargano\u003csup\u003e29\u003c/sup\u003e, D. Gazzolo\u003csup\u003e62\u003c/sup\u003e, M.P.Gentile\u003csup\u003e63\u003c/sup\u003e, S.Ghirardello\u003csup\u003e64\u003c/sup\u003e, F. Giardina\u003csup\u003e65\u003c/sup\u003e, L. Giordano\u003csup\u003e66\u003c/sup\u003e, E. Gitto\u003csup\u003e67\u003c/sup\u003e, M. Giuffr\u0026egrave;\u003csup\u003e45\u003c/sup\u003e, T. Gokmen Yildirim\u003csup\u003e2\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eL. Grappone\u003csup\u003e48\u003c/sup\u003e, F. Grasso\u003csup\u003e42\u003c/sup\u003e, I. Greco\u003csup\u003e68\u003c/sup\u003e, A. Grison\u003csup\u003e70\u003c/sup\u003e, R. Guglielmino\u003csup\u003e71\u003c/sup\u003e, I. Guidotti\u003csup\u003e33\u003c/sup\u003e, I. Guzzo\u003csup\u003e72\u003c/sup\u003e, N. La Forgia\u003csup\u003e43\u003c/sup\u003e, S. La Placa\u003csup\u003e52\u003c/sup\u003e, G. La Torre\u003csup\u003e74\u003c/sup\u003e, P. Lago\u003csup\u003e75\u003c/sup\u003e, L. Lanciotti\u003csup\u003e3\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eA. Lavizzari\u003csup\u003e12\u003c/sup\u003e, F. Leo\u003csup\u003e29\u003c/sup\u003e, V. Leonardi\u003csup\u003e5\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eD. Lestingi\u003csup\u003e24\u003c/sup\u003e, J. Li\u003csup\u003e10\u003c/sup\u003e, P. Liberatore\u003csup\u003e60\u003c/sup\u003e, D. Lodin\u003csup\u003e76\u003c/sup\u003e, R. Lubrano\u003csup\u003e90\u003c/sup\u003e, M. Lucente\u003csup\u003e84\u003c/sup\u003e, S. Luciani\u003csup\u003e77\u003c/sup\u003e, D. Luvar\u0026agrave;\u003csup\u003e90\u003c/sup\u003e, G. Maffei\u003csup\u003e60\u003c/sup\u003e, A. Maggio\u003csup\u003e64\u003c/sup\u003e, L. Maggio\u003csup\u003e78\u003c/sup\u003e, K. Maiolo\u003csup\u003e71\u003c/sup\u003e, L. Malaigia\u003csup\u003e79\u003c/sup\u003e, G. Mangili\u003csup\u003e59\u003c/sup\u003e, A. Manna\u003csup\u003e31\u003c/sup\u003e, E.Maranella\u003csup\u003e56\u003c/sup\u003e, A. Marciano\u003csup\u003e44\u003c/sup\u003e, P.Marcozzi\u003csup\u003e78\u003c/sup\u003e, M. Marletta\u003csup\u003e35\u003c/sup\u003e, L. Marseglia\u003csup\u003e67\u003c/sup\u003e, D. Martinelli\u003csup\u003e74\u003c/sup\u003e, S. Martinelli\u003csup\u003e73\u003c/sup\u003e,S. Massari\u003csup\u003e80\u003c/sup\u003e, L. Massenzi\u003csup\u003e81\u003c/sup\u003e, F. Matina\u003csup\u003e65\u003c/sup\u003e, L. Mattia\u003csup\u003e35\u003c/sup\u003e, G. Mescoli\u003csup\u003e18\u003c/sup\u003e, I.V.Migliore\u003csup\u003e82\u003c/sup\u003e, D.Minghetti\u003csup\u003e83\u003c/sup\u003e, I. Mondello\u003csup\u003e50\u003c/sup\u003e, S. Montano\u003csup\u003e5\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eG. Morandi\u003csup\u003e58\u003c/sup\u003e, N. Mores\u003csup\u003e92\u003c/sup\u003e, S. Morreale\u003csup\u003e82\u003c/sup\u003e, I. Morselli\u003csup\u003e76\u003c/sup\u003e, M. Motta\u003csup\u003e18\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eM. Napolitano\u003csup\u003e31\u003c/sup\u003e, D. Nardo\u003csup\u003e30\u003c/sup\u003e, A. Nicolardi\u003csup\u003e88\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eS. Nider\u003csup\u003e69\u003c/sup\u003e, G. Nigro\u003csup\u003e84\u003c/sup\u003e, M. Nuccio\u003csup\u003e88\u003c/sup\u003e, L. Orfeo\u003csup\u003e77\u003c/sup\u003e, C. Ottaviano\u003csup\u003e78\u003c/sup\u003e, P. Paganin\u003csup\u003e18\u003c/sup\u003e, S. Palamides\u003csup\u003e57\u003c/sup\u003e, S. Palatta\u003csup\u003e57\u003c/sup\u003e, P. Paolillo\u003csup\u003e13\u003c/sup\u003e, M.G. Pappalardo\u003csup\u003e54\u003c/sup\u003e, E. Pasta\u003csup\u003e85\u003c/sup\u003e, L. Patti\u003csup\u003e64\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eG. Paviotti\u003csup\u003e49\u003c/sup\u003e, R. Perniola\u003csup\u003e37\u003c/sup\u003e, G. Perotti\u003csup\u003e64\u003c/sup\u003e, S. Perrone\u003csup\u003e40\u003c/sup\u003e, F. Petrillo\u003csup\u003e53\u003c/sup\u003e, M.S. Piazza\u003csup\u003e82\u003c/sup\u003e, A. Piccirillo\u003csup\u003e66\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eM. Pierro\u003csup\u003e79\u003c/sup\u003e, E. Piga\u003csup\u003e44\u003c/sup\u003e, G. A. Pingitore\u003csup\u003e84\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eS. Pisu\u003csup\u003e16\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eC. Pittini\u003csup\u003e49\u003c/sup\u003e, F. Pontiggia\u003csup\u003e32\u003c/sup\u003e, G. Pontrelli\u003csup\u003e90\u003c/sup\u003e, A. Primavera\u003csup\u003e62\u003c/sup\u003e, A. Proto\u003csup\u003e73\u003c/sup\u003e, L. Quartulli\u003csup\u003e24\u003c/sup\u003e, F. Raimondi\u003csup\u003e42\u003c/sup\u003e, L. Ramenghi\u003csup\u003e83\u003c/sup\u003e, M. Rapsomaniki\u003csup\u003e72\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eA. Ricotti\u003csup\u003e87\u003c/sup\u003e, C. Rigotti\u003csup\u003e19\u003c/sup\u003e, M. Rinaldi\u003csup\u003e60\u003c/sup\u003e, F.M. Risso\u003csup\u003e28\u003c/sup\u003e, E. Roma\u003csup\u003e66\u003c/sup\u003e, E. Romanini\u003csup\u003e40\u003c/sup\u003e, V. Romano\u003csup\u003e77\u003c/sup\u003e, E. Rosati\u003csup\u003e37\u003c/sup\u003e, V. Rosella\u003csup\u003e86\u003c/sup\u003e, I. Rulli\u003csup\u003e67\u003c/sup\u003e, V. Salvo\u003csup\u003e80\u003c/sup\u003e, C. Sanfilippo\u003csup\u003e68\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eA. Sannia\u003csup\u003e36\u003c/sup\u003e, A. Saporito\u003csup\u003e35\u003c/sup\u003e, A. Sauna\u003csup\u003e80\u003c/sup\u003e, E. Scapillati\u003csup\u003e51\u003c/sup\u003e, F. Schettini\u003csup\u003e55\u003c/sup\u003e, A. Scorrano\u003csup\u003e88\u003c/sup\u003e, S. Semeria Mantelli\u003csup\u003e85\u003c/sup\u003e, V. Sepporta\u003csup\u003e26\u003c/sup\u003e, P. Sindico\u003csup\u003e58\u003c/sup\u003e, A. Solinas\u003csup\u003e63\u003c/sup\u003e, E. Sorrentino\u003csup\u003e51\u003c/sup\u003e, E. Spaggiari\u003csup\u003e33\u003c/sup\u003e, A. Staffler\u003csup\u003e81\u003c/sup\u003e, M. Stella\u003csup\u003e79\u003c/sup\u003e, D. Termini\u003csup\u003e86\u003c/sup\u003e, G. Terrin\u003csup\u003e44\u003c/sup\u003e, A. Testa\u003csup\u003e90\u003c/sup\u003e, G. Tina\u003csup\u003e71\u003c/sup\u003e, M. Tirantello\u003csup\u003e76\u003c/sup\u003e, B. Tomasini\u003csup\u003e46\u003c/sup\u003e, F. Tormena\u003csup\u003e75\u003c/sup\u003e, L. Travan\u003csup\u003e69\u003c/sup\u003e, D. Trevisanuto\u003csup\u003e30\u003c/sup\u003e, V. Tulino\u003csup\u003e39\u003c/sup\u003e, L. Valenzano\u003csup\u003e53\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eS. Vedovato\u003csup\u003e70\u003c/sup\u003e, S. Vendramin\u003csup\u003e75\u003c/sup\u003e, P.E. Villani\u003csup\u003e85\u003c/sup\u003e, S. Viola\u003csup\u003e61\u003c/sup\u003e, V. Viola\u003csup\u003e50\u003c/sup\u003e, G. Vitaliti\u003csup\u003e68\u003c/sup\u003e, M. Vitaliti\u003csup\u003e68\u003c/sup\u003e, P. Wanker\u003csup\u003e81\u003c/sup\u003e, Y. Yang\u003csup\u003e10\u003c/sup\u003e, S. Zanetta\u003csup\u003e61\u003c/sup\u003e, E. Zannin\u003csup\u003e19\u003c/sup\u003e\u003c/p\u003e\n \u003col\u003e\n \u003cli\u003eDipartimento Universitario Scienze della Vita e Sanit\u0026agrave; Pubblica, UOC di Neonatologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Universit\u0026agrave; Cattolica del Sacro Cuore, Rome, Italy. email: [email protected]; [email protected]; claudia.aurilia@ policlinicogemelli.it; simonetta.costa@ policlinicogemelli.it; francesco.cota@ policlinicogemelli.it; [email protected]; francescapaola.fusco@ policlinicogemelli.it; [email protected]; [email protected]; [email protected]; [email protected]; [email protected]; claudia.fe@ policlinicogemelli.it;\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eHealth Science University Dr. Behcet Uz Children\u0026rsquo;s Hospital, Izmir, Turkey. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda Ospedaliero Universitaria Ospedali Riuniti, Ancona, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eDepartment of Neonatology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101 - 1090 Brussel, Belgium. [email protected]\u003c/li\u003e\n \u003cli\u003eDepartment of Mother and Child Health, Division of Neonatology and Neonatal Intensive Care Unit, Careggi University Hospital Florence, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eNeonatal Services, Royal Women\u0026apos;s Hospital, Melbourne, Australia. [email protected]\u003c/li\u003e\n \u003cli\u003eSchool of Medicine, University of California, San Diego, San Diego, CA, USA (NNF); and Sharp Mary Birch Hospital for Women and Newborns, San Diego, CA 92123, USA (NNF, AK). [email protected]\u003c/li\u003e\n \u003cli\u003eUnit\u0026agrave; operativa complessa di neonatologia e TIN Ospedale Sant\u0026rsquo;Eugenio, ASL ROMA 2, Rome, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eKlinik f\u0026uuml;r Kinder- und Jugendmedizin UNIVERSIT\u0026Auml;TSKLINIKUM Schleswig-Holstein Campus L\u0026uuml;beck Ratzeburger Allee 160 │Haus A │23538 L\u0026uuml;beck, Germany. [email protected] \u0026nbsp;\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eShengjing Hospital of China Medical University, Shenyang, China. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eNeonatologia e Terapia Intensiva Neonatale (TIN) Ospedale dei Bambini \u0026quot;V.Buzzi\u0026quot; ASST-FBF-Sacco Via Castelvetro, 32 20154 Milan, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eDepartment of Clinical Sciences and Community Health, University of Milan. Fondazione IRCCS C\u0026agrave; Granda Ospedale Maggiore Policlinico. Via Della Commenda 12 \u0026ndash; 20122 Milan, Italy. [email protected]; [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003ePoliclinico Casilino, Rome, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eCentre for Child Health Research and School of Human Sciences, The University of Western Australia, Perth, WA, Australia. [email protected] \u0026nbsp; \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe Ritchie Centre Hudson Institute of Medical Research and Department of Obstetrics and Gynaecology, Monash University, Clayton, 3168 Victoria, Australia. [email protected] \u0026nbsp; \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eResearch Core Facility Data Collection G-STeP, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eSection of Hygiene, University Department of Life Sciences and Public Health, Universit\u0026agrave;\u003c/li\u003e\n \u003c/ol\u003e\n \u003cp\u003eCattolica del Sacro Cuore, 00168 Rome, Italy. - [email protected]\u003c/p\u003e\n \u003cp\u003eDepartment of Woman and Child Health and Public Health \u0026ndash; Public Health Area, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.\u0026nbsp;\u003c/p\u003e\n \u003col start=\"18\"\u003e\n \u003cli\u003eOspedale Maggiore, Bologna, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eFondazione IRCCS San Gerardo dei Tintori Monza, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eNeonatal Research, Murdoch Children\u0026rsquo;s Research Institute, Melbourne, Australia. [email protected]\u003c/li\u003e\n \u003cli\u003eDepartment of Neonatology, Emma Children\u0026apos;s Hospital, Amsterdam UMC, University of Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. [email protected]\u003c/li\u003e\n \u003cli\u003ePoliclinico S. Orsola-Malpighi, Universit\u0026agrave; di Bologna, Bologna, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eUniversit\u0026agrave; degli Studi dell\u0026rsquo;Insubria, Varese, Italy. [email protected]; [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eP.P. \u0026ldquo;A. Perrino\u0026rdquo; Brindisi-ASL BR, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eOspedale Infermi, Rimini, Italy. [email protected]\u003c/li\u003e\n \u003cli\u003ePresidio Ospedaliero Ingrassia ASP Palermo, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda Ospedaliera S.Anna-S.Sebastiano Caserta, Italy. [email protected]; [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda Ospedaliera \u0026ldquo;Spedali Civili\u0026rdquo;, Brescia, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eArcispedale Santa Maria Nuova Reggio Emilia, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eUniversity of Padua, Padua, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eOspedale Evangelico Betania-Naples, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda Ospedaliera Bolognini, Seriate (BG), Italy. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAOU Policlinico Modena, Italy. [email protected]; [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eNeonatologia Universitaria, Ospedale S.Anna \u0026ndash; Citt\u0026agrave; della Salute e della Scienza di Torino, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAOU Policlinico Vittorio Emanuele-Gaspare Rodolico Catania, Italy. [email protected]; [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda Ospedaliera S. Croce e Carle, Cuneo, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda Ospedaliera Vito Fazzi, Lecce, Italy. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eBel Colle Hospital, Viterbo, Italy. [email protected]\u003c/li\u003e\n \u003cli\u003eBarone Romeo Hospital Patti (ME), Italy. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda OU Parma, Italy. [email protected]. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eOspedale PO S. Anna, AOU Citt\u0026agrave; della Salute e della Scienza, Torino, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eFederico II University, Naples, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003ePoliclinico di Bari, Italy. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003ePoliclinico Umberto I, Rome, Italy. [email protected]; [email protected]; [email protected]; [email protected]\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eUniversit\u0026agrave; degli Studi, Palermo, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda Ospedaliera Universitaria Senese, Siena, Italy. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda OU Policlinico \u0026ldquo;Rodolico-San Marco\u0026rdquo;, Catania. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eOspedale San Pio, Benevento, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda sanitaria universitaria Friuli Centrale, Udine, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAO Bianchi-Melacrino-Morelli Reggio Calabria, Italy. [email protected]; [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eS.Pietro Fatebenefratelli, Rome, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003ePresidio Ospedaliero S. Antonio Abate \u0026ndash; Azienda Sanitaria Provinciale, Trapani, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eDi Venere Hospital Bari, Italy. [email protected]; [email protected].\u003c/li\u003e\n \u003cli\u003eAzienda Ospedaliera per l\u0026rsquo;emergenza Cannizzaro, Catania, Italy; [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eU.O.C T.I.N. e Neonatologia, P.O.C Taranto \u0026quot;Santissima Annunziata, Italy; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eSan Salvatore Hospital L\u0026rsquo;Aquila, Italy. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda Ospedaliera San Giovanni Addolorata, Rome, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda Ospedaliera Carlo Poma Mantova, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eASST Papa Giovanni XXIII, Bergamo, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda Ospedaliera-Universitaria Ospedali Riuniti Foggia, Italy. [email protected]; [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eMaggiore Hospital Novara, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eOspedale \u0026ldquo;Ss Annunziata\u0026rdquo;, Chieti - Universit\u0026agrave; degli Studi G. D\u0026rsquo;Annunzio Chieti-Pescara, Italy. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienza Ospedaliera Universitaria di Ferrara, Italy. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eUniversit\u0026agrave; di Pavia, Italy. [email protected]; [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eOspedale Vincenzo Cervello, Palermo. [email protected]; [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003ePineta Grande Castelvolturno (CE), Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eUniversit\u0026agrave; degli Studi, Messina, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eARNAS Civico Hospital Palermo, Italy. [email protected]; [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eIRCCS materno-infantile Burlo Garofolo, Trieste, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eSan Bortolo Hospital Vicenza, Italy. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eARNAS Garibaldi, Catania, Italy. [email protected]. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda Ospedaliera di Catanzaro \u0026ldquo;Pugliese Ciaccio\u0026rdquo;, Catanzaro, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eNiguarda Hospital Milan. [email protected]; alice.proto @ospedaleniguarda.it\u003c/li\u003e\n \u003cli\u003eOspedale Generale Regionale \u0026ldquo;F. Miulli\u0026rdquo; - Acquaviva delle Fonti \u0026ndash; Brindisi, Italy. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAO C\u0026agrave; Foncello Treviso, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda Sanitaria Provinciale di Siracusa, PO Umberto 1\u0026deg;, Siracusa, Italy. [email protected]; [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eOspedale \u0026nbsp;Fatebenefratelli Isola Tiberina Gemelli Isola, Rome, Italy. [email protected]; [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda Ospedaliera San Camillo Forlanini, Rome, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eOspedale M. Bufalini, Cesena, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eOspedale \u0026ldquo;Giovanni Paolo II\u0026rdquo;, Ragusa, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eCentral Teaching Hospital of Bolzano/Bozen, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda Sanitaria Provinciale, Enna, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eIstituto Giannina Gaslini, Genova, Italy. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda Ospedaliera Cosenza, Italy. [email protected]; [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eFondazione Poliambulanza Brescia, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eOspedale Buccheri-La Ferla, Palermo, Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eSS Antonio e Biagio e Cesare Arrigo Hospital Alessandria, Italy. [email protected]\u003c/li\u003e\n \u003cli\u003ePanico Hospital Tricase (LE), Italy. [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eS. Spirito Hospital Pescara, Italy. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eS. Maria Goretti Hospital Latina, Italy. [email protected]; [email protected]; [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eAzienda Ospedaliera Universitaria Integrata di Verona, Italy. [email protected]; [email protected]\u003c/li\u003e\n \u003cli\u003eDipartimento di Bioetica e Sicurezza, UOS di Farmacovigilanza, Fondazione Policlinico Universitario A. Gemelli IRCCS - Universit\u0026agrave; Cattolica del Sacro Cuore, Rome, Italy [email protected]\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eName and contact information for the trial sponsor {5b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eThe trial doesn\u0026rsquo;t have a sponsor.\u0026nbsp;The promoter is:\u003c/p\u003e\n \u003cp\u003eFondazione Policlinico Universitario A. Gemelli IRCCS, Universit\u0026agrave; Cattolica del Sacro Cuore, 00168 Rome Italy.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.11580594679186%\" valign=\"top\"\u003e\n \u003cp\u003eRole of sponsor {5c}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.88419405320813%\" valign=\"top\"\u003e\n \u003cp\u003eThe trial doesn\u0026rsquo;t have a sponsor. There are no obligations towards the promoter other than reporting about the study and study results.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Introduction","content":"\n\u003ch3\u003eBackground and rationale {6a}\u003c/h3\u003e\n\u003cp\u003eRespiratory distress syndrome (RDS) represents the main cause of respiratory insufficiency in preterm infants and is one of the major causes of perinatal morbidity and mortality. Surfactant is a well-established therapy in neonatology. However, the optimal surfactant administration method remains unresolved, especially with the recent clinical focus on avoiding mechanical ventilation in preterm infants born before 28 weeks\u0026rsquo; gestational age (i.e. extremely preterm infants). Duration of mechanical ventilation is a key determinant of the severity of bronchopulmonary dysplasia (BPD) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Although attractive and beneficial in clinical practice, the INtubate, SURfactant, Extubate (IN-SUR-E) method cannot be universally applied to all preterm neonates due to non-homogeneous surfactant distribution and lung derecruitment during intubation, resulting in failure of IN-SUR-E in the event of severe RDS. IN-SUR-E also has a failure rate in preterm infants ranging from 19\u0026ndash;69% (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Risk factors for failure of IN-SUR-E are low birth weight, low gestational age, the severity of initial respiratory disease, and a low haemoglobin concentration prior to surfactant administration (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). A recent randomized clinical trial showed that the application of a recruitment manoeuvre just before surfactant administration, followed by rapid extubation (INtubate-RECruit-SURfactant-Extubate [IN-REC-SUR-E]), decreased the need for mechanical ventilation during the first 72 h of life compared with IN-SUR-E technique in extremely preterm neonates, without increasing the risk of adverse neonatal outcomes (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Recently, a less invasive surfactant administration (LISA) method was developed with surfactant introduced into the trachea of infants breathing spontaneously using a small catheter instead of an endotracheal tube (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). The popularity of LISA technique has increased because it potentially combines the benefits of early surfactant treatment with continuous positive airways pressure (CPAP) and consequent avoidance of mechanical ventilation. The last network meta-analyses on the comparative efficacy of methods for surfactant administration found that among preterm infants, LISA technique was associated with lower likelihood of mortality, need for mechanical ventilation and BPD compared with IN-SUR-E, but these findings did not include comparison to IN-REC-SUR-E method (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). More importantly, data for neonates\u0026thinsp;\u0026lt;\u0026thinsp;28 weeks\u0026rsquo; gestation are not as robust as for the higher gestational age groups due to a smaller number of neonates (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Therefore, the safety and efficacy of LISA in this population remain to be confirmed, also considering that extreme prematurity is an independent risk factor for LISA failure (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The same Authors of meta-analysis agree that data for neonates\u0026thinsp;\u0026lt;\u0026thinsp;28 weeks are not as robust as for higher gestation age group and that lung recruitment before surfactant administration (IN-REC-SUR-E) represents a promising novel alternative; hence, future randomized evidence directly comparing it to LISA is warranted to draw conclusions concerning the optimal method of surfactant treatment, especially among extremely low gestational age newborns (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). We therefore designed this study to compare the IN-REC-SUR-E technique with LISA, as recently suggested (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), for evaluating the comparative effectiveness of these techniques in increasing the survival without BPD of extremely preterm infants.\u003c/p\u003e\n\u003ch3\u003eObjectives {7}\u003c/h3\u003e\n\u003cp\u003eThe primary hypothesis of this study is that IN-REC-SUR-E via a high frequency oscillatory ventilation recruitment maneuver increases survival without BPD at 36 weeks\u0026rsquo; postmenstrual age in spontaneously breathing infants born at 24\u003csup\u003e+\u0026thinsp;0\u003c/sup\u003e-27\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e weeks\u0026rsquo; gestation and failing nasal CPAP or nasal intermittent positive pressure ventilation (NIPPV) during the first 24 hours of life compared to LISA treatment.\u003c/p\u003e \u003cp\u003eTo confirm this hypothesis, we planned an international multicenter randomized controlled study in which preterm infants will be randomized into two groups: one will receive surfactant with IN-REC-SUR-E modality and the other one will receive surfactant with LISA treatment.\u003c/p\u003e \u003cp\u003eThe study flow chart is detailed in Fig.\u0026nbsp;1.\u003c/p\u003e\n\u003ch3\u003eTrial design {8}\u003c/h3\u003e\n\u003cp\u003eThe study is an unblinded multicenter randomized trial of IN-REC-SUR-E vs. LISA technique in infants born at 24\u003csup\u003e+\u0026thinsp;0\u003c/sup\u003e-27\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e weeks\u0026rsquo; gestation.\u003c/p\u003e \u003cp\u003eThe methods of this study are reported according to SPIRIT 2013 Explanation and Elaboration: Guidance for protocols of clinical trials (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e"},{"header":"Methods: Participants, interventions and outcomes","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy setting {9}\u003c/h2\u003e \u003cp\u003e The following centers are involved in the recruitment for the trial: Fondazione Policlinico Universitario A. Gemelli IRCCS, Universit\u0026agrave; Cattolica del Sacro Cuore, Rome Italy; S.Pietro Fatebenefratelli, Rome; Fatebenefratelli-Isola Tiberina, Rome; Policlinico Umberto I, Rome; Bel Colle Hospital Viterbo; Fondazione Poliambulanza Brescia; Fondazione MBBM - Ospedale San Gerardo Monza; Niguarda Hospital Milan; Fondazione IRCCS C\u0026agrave; Granda Ospedale Maggiore Policlinico, University Milan; Azienda Ospedaliera Carlo Poma Mantova; SS Antonio e Biagio e Cesare Arrigo Hospital Alessandria; Maggiore Hospital Novara; Azienda Ospedaliera-Universitaria Ospedali Riuniti Foggia; Azienda Ospedaliera Vito Fazzi Lecce; Careggi University Florence; Pineta Grande Castelvolturno; Azienda Ospedaliera S.Anna-S.Sebastiano Caserta; Maggiore Hospital Bologna; AOU Ferrara; AO Cosenza; Di Venere Hospital Bari; Panico Hospital Tricase; Central Teaching Hospital of Bolzano/Bozen; Arcispedale Santa Maria Nuova Reggio Emilia; Barone Romeo Hospital Patti; AOU Policlinico Vittorio Emanuele-Gaspare Rodolico Catania; Universit\u0026agrave; degli Studi di Messina; ARNAS Civico Hospital Palermo; ARNAS Garibaldi, Catania; San Bortolo Hospital Vicenza; AOU Policlinico Modena; San Salvatore Hospital L\u0026rsquo;Aquila; AO Bianchi-Melacrino-Morelli Reggio Calabria; AO C\u0026agrave; Foncello Treviso; Ospedale PO S. Anna; AOU Citt\u0026agrave; della Salute e della Scienza, Torino; Universit\u0026agrave; di Pavia; Neonatologia Universitaria, Ospedale S.Anna \u0026ndash; Citt\u0026agrave; della Salute e della Scienza di Torino; Policlinico Casilino, Rome; Ospedale Evangelico Betania \u0026ndash; Napoli; Federico II University, Napoli; University of Padua, Padua; Ospedale San Pio, Benevento; \"V.Buzzi\" Children's Hospital, ASST-FBF-Sacco, Milan; Ospedale \u0026ldquo;Ss Annunziata\u0026rdquo;, Chieti - Universit\u0026agrave; degli Studi G. D\u0026rsquo;Annunzio Chieti-Pescara; Azienda Ospedaliera Bolognini, Seriate (BG); ASST Papa Giovanni XXIII, Bergamo; ASST Sette Laghi, Varese, Universit\u0026agrave; degli Studi dell\u0026rsquo;Insubria; Azienda OU Policlinico \u0026ldquo;Rodolico-San Marco\u0026rdquo;, Catania; Policlinico S. Orsola-Malpighi, Universit\u0026agrave; di Bologna, Bologna; Azienda Ospedaliera Universitaria Senese, Siena; Azienda Ospedaliera \u0026ldquo;Spedali Civili\u0026rdquo;, Brescia; Azienda Ospedaliera San Giovanni Addolorata, Roma; Azienda Ospedaliera S. Croce e Carle, Cuneo; Azienda Ospedaliera San Camillo Forlanini, Roma; IRCCS materno-infantile Burlo Garofolo, Trieste; Istituto Giannina Gaslini, Genova; Azienda sanitaria universitaria Friuli Centrale, Udine; Universit\u0026agrave; degli Studi, Palermo; Ospedale \u0026ldquo;Sant\u0026rsquo;Eugenio\u0026rdquo;- ASL Roma 2, Roma; Ospedale Infermi, Rimini; Azienda Ospedaliero Universitaria Ospedali Riuniti, Ancona; Ospedale M. Bufalini, Cesena; Ospedale \u0026ldquo;Giovanni Paolo II\u0026rdquo;, Ragusa; Ospedale Buccheri-La Ferla, Palermo; Azienda Ospedaliera di Catanzaro \u0026ldquo;Pugliese Ciaccio\u0026rdquo;, Catanzaro; Azienda Sanitaria Provinciale di Siracusa, PO Umberto 1\u0026deg;, Siracusa; Presidio Ospedaliero Ingrassia ASP Palermo; Presidio Ospedaliero S. Antonio Abate \u0026ndash; Azienda Sanitaria Provinciale, Trapani; Azienda Sanitaria Provinciale, Enna; Ospedale Vincenzo Cervello, Palermo; Azienda Ospedaliera per l\u0026rsquo;emergenza Cannizzaro, Catania; U.O.C T.I.N. e Neonatologia, P.O.C Taranto \"Santissima Annunziata\"; Azienda Ospedaliera Universitaria Parma; P.P. \u0026ldquo;A. Perrino\u0026rdquo; Brindisi \u0026ndash; ASL BR; Universit\u0026agrave; AOUC Policlinico Bari; Ospedale Generale Regionale \u0026ldquo;F. Miulli\u0026rdquo; - Acquaviva delle Fonti \u0026ndash; BR; Dr. Behcet Uz Children\u0026rsquo;s Hospital, Izmir, Turkey; The Royal Children\u0026rsquo;s Hospital, Melbourne, Australia; Shengjing Hospital of China Medical University, Shenyang,China, S. Maria Goretti Hospital Latina, S. Spirito Hospital Pescara, Azienda Ospedaliera Universitaria Integrata di Verona.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eEligibility criteria {10}\u003c/h2\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003eInclusion criteria\u003c/h2\u003e \u003cp\u003eInfants satisfying the following inclusion criteria will be eligible to participate:\u003c/p\u003e \u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eBorn at 24\u003csup\u003e+\u0026thinsp;0\u003c/sup\u003e-27\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e in a tertiary neonatal intensive care unit participating in the trial (and)\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eBreathing independently and sufficiently with only nasal CPAP or NIPPV for respiratory support (and)\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e Written parental consent has been obtained (and)\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eFailing nasal CPAP or NIPPV during the first 24 hours of life\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eExclusion criteria\u003c/h2\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSevere birth asphyxia or a 5-minute Apgar score less than 3\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePrior endotracheal intubation for resuscitation or insufficient respiratory drive\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eProlonged (\u0026gt;\u0026thinsp;21 days) premature rupture of membranes\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePresence of major congenital abnormalities with possible effects on cardiorespiratory function\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHydrops fetalis\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eInherited disorders of metabolism\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eWho will take informed consent? {26a}\u003c/h2\u003e \u003cp\u003e The fully trained specific researchers who are on-site will obtain informed prospective consent from participants. Written and oral information will, whenever possible, be offered to parents prior to birth if the mother is at risk for preterm delivery and the infant is likely to be eligible. Informed written consent will be signed from both the parents and sufficient time will be provided for consent. If parents do not speak the local language, consent will only be obtained if an independent interpreter is available. The informed consent will be obtained by the principal investigator of each participating center and their collaborators in charge. A senior investigator will be always available to discuss concerns raised by parents or clinicians during the course of the trial.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/h2\u003e \u003cp\u003eNo additional consents are required. This trial does not involve collecting biological specimens for storage.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eInterventions\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003eExplanation for the choice of comparators {6b}\u003c/h2\u003e \u003cp\u003eInfants will be allocated to one of the two treatment groups (1:1) according to a restricted randomization procedure (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). A study investigator (TP) will generate the allocation sequences using both stratification and permuted blocks with random block sizes and block order. The assignment to intervention will be unmasked to all trial participants: parents, research staff, and medical team will be only aware of study group assignment after randomization procedures.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eIntervention description {11a}\u003c/h2\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003eManagement in the Delivery Room\u003c/h2\u003e \u003cp\u003eNeonates will be stabilized after birth with positive pressure using a neonatal mask and a T-piece system (for example Neopuff Infant Resuscitator \u0026reg;, Fisher and Paykel, Auckland, New Zealand). All neonates will be started on nasal CPAP of at least 6 cm H\u003csub\u003e2\u003c/sub\u003eO via mask or nasal prongs (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Newborns who do not breathe or who are persistently bradycardic (heart rate less than 100/min) within the first 60 seconds after birth will receive positive-pressure ventilation at a rate of 40 to 60 inhalations/min (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) with initial FiO\u003csub\u003e2\u003c/sub\u003e of 0.30. Infants that will be transitioned successfully to spontaneous breathing will be transferred to the neonatal intensive care unit on nasal CPAP (6\u0026ndash;7 cm H\u003csub\u003e2\u003c/sub\u003eO) or NIPPV (PEEP 6\u0026ndash;7 cm H\u003csub\u003e2\u003c/sub\u003eO, PIP 12\u0026ndash;15 cm H\u003csub\u003e2\u003c/sub\u003eO, respiratory rate 30\u0026ndash;40 breaths/minute). The decision to intubate and start invasive mechanical ventilation in the delivery room will be in accordance with the American Heart Association Guidelines (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMethod and timing of umbilical cord clamping will be as per standard practice at each site.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eCPAP or NIPPV Failure Criteria\u003c/h2\u003e \u003cp\u003eNasal CPAP or NIPPV will be administered in the neonatal intensive care unit via nasal prongs or nasal mask using the standard method of each participating centre, with a pressure of 7\u0026ndash;8 cm H\u003csub\u003e2\u003c/sub\u003eO or with a setting of peak inspiratory pressure of 12\u0026ndash;15 cmH\u003csub\u003e2\u003c/sub\u003eO, positive end-expiratory pressure of 7\u0026ndash;8 cmH\u003csub\u003e2\u003c/sub\u003eO and rate of 30\u0026ndash;40 breaths/min, respectively. Infants will receive surfactant with IN-REC-SUR-E or LISA if they need a FiO\u003csub\u003e2\u003c/sub\u003e of 0.30 or greater to maintain a SpO\u003csub\u003e2\u003c/sub\u003e between 90\u0026ndash;94% for at least 30 min, regardless of the non-invasive respiratory support used (CPAP or NIPPV). Infants will also be given surfactant if their clinical status deteriorates rapidly or if they will develop respiratory acidosis defined as a pCO\u003csub\u003e2\u003c/sub\u003e more than 65 mmHg (8.5 kPa) and a pH less than 7.20, or with lung ultrasound scoring\u0026thinsp;\u0026gt;\u0026thinsp;8.\u003c/p\u003e \u003cp\u003eA loading dose of intravenous caffeine citrate (20 mg/kg) will be given in the delivery room or immediately after admission to the neonatal intensive care unit (within 2 hours of life) and always prior to surfactant administration, followed by a morning intravenous/oral dose of 5\u0026ndash;10 mg/kg/day as required.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003ePremedications\u003c/h2\u003e \u003cp\u003eAll neonates of both groups will receive pre-procedural medications, according to local protocols. Suggested schemes are:\u003c/p\u003e \u003cp\u003e-Intravenous atropine (10 \u0026micro;g/kg) in one minute followed by intravenous fentanyl: 0.5 \u0026micro;g/kg by pump infusion in no less than 5 minutes (possibly repeatable dose if satisfactory analgosedation is not obtained)\u003c/p\u003e \u003cp\u003eor\u003c/p\u003e \u003cp\u003e-Intravenous atropine (10 \u0026micro;g/kg) in one minute followed by intravenous ketamine: 0.5 mg/kg in no less than one minute (possibly repeatable dose if satisfactory analgosedation is not obtained).\u003c/p\u003e \u003cp\u003eMethod of premedication will be documented in each participating centre.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eIN-REC-SUR-E group\u003c/h2\u003e \u003cp\u003eInfants randomly assigned to the IN-REC-SUR-E group will receive pre-intubation medications and will start after intubation on high-frequency oscillatory ventilation (HFOV) using the following ventilator settings: mean airway pressure 8 cmH\u003csub\u003e2\u003c/sub\u003eO; frequency 15 Hz; volume guarantee 1.5\u0026ndash;1.7 mL/kg (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). The inspiratory to expiratory ratio will be 1:1. Infants will undergo an oxygenation guided lung recruitment procedure using stepwise increments then decrements in mean airway pressure to recruit and stabilise collapsed alveoli using the de Jaegere method (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). In particular, optimal recruitment is defined as adequate oxygenation using a FiO\u003csub\u003e2\u003c/sub\u003e of 0.25 or less. Starting at 8 cmH\u003csub\u003e2\u003c/sub\u003eO, the mean airway pressure will be increased stepwise (2 cmH\u003csub\u003e2\u003c/sub\u003eO every 2\u0026ndash;3 minutes) as long as SpO\u003csub\u003e2\u003c/sub\u003e improves. The FiO\u003csub\u003e2\u003c/sub\u003e will be reduced stepwise, keeping SpO\u003csub\u003e2\u003c/sub\u003e within the target range (90\u0026ndash;94%). The recruitment procedure will be stopped if oxygenation no longer improves or if the FiO\u003csub\u003e2\u003c/sub\u003e is equal to or less than 0.25. The corresponding mean airway pressure will be called the opening pressure. Next, the mean airway pressure will be reduced stepwise (1\u0026ndash;2 cmH\u003csub\u003e2\u003c/sub\u003eO every 2\u0026ndash;3 minutes) until the SpO\u003csub\u003e2\u003c/sub\u003e deteriorates (of at least 2\u0026ndash;3 percentage points). The corresponding mean airway pressure will be called the closing pressure. After a second recruitment manoeuvre at the opening pressure for 2 minutes, the optimal mean airway pressure will be set 2 cmH\u003csub\u003e2\u003c/sub\u003eO above the closing pressure for at least 3 minutes Immediately after the recruitment procedure, infants in the IN-REC-SUR-E group will receive 200 mg/kg of poractant alfa (Chiesi Farmaceutici S.p.A., Parma, Italy) via a closed administration system in one or two aliquots, while continuing high-frequency oscillatory ventilation. Infants with sufficient respiratory drive will be extubated within 30 minutes after surfactant administration irrespective of the FiO\u003csub\u003e2\u003c/sub\u003e and will recommence on nasal CPAP (7\u0026ndash;9 cm H\u003csub\u003e2\u003c/sub\u003eO) (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) or NIPPV.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eLISA Group\u003c/h2\u003e \u003cp\u003eBy contrast, infants allocated to the LISA group will receive 200 mg/kg of poractant alfa (Chiesi Farmaceutici S.p.A., Parma, Italy) according to the following protocol: during nasal CPAP with a pressure of 7\u0026ndash;8 cm H\u003csub\u003e2\u003c/sub\u003eO, surfactant will be administered over 0.5-3 min using the SurfCath\u0026trade; tracheal instillation catheter (VYGON S.A. \u0026ndash; Ecouen, France), or a 4\u0026ndash;6 F end-hole catheter, according to local protocols. After pre-procedural medications, the catheters will be positioned during laryngoscopy with or without Magill forceps. The catheter will be connected to a syringe pre-filled with the surfactant, and the surfactant is instilled slowly. The infant\u0026rsquo;s mouth will be closed. In cases of apnoea or bradycardia, positive pressure ventilation will be performed until recovery by nasal prongs or mask or by endotracheal tube if necessary. After surfactant administration, CPAP (7\u0026ndash;9 cm H\u003csub\u003e2\u003c/sub\u003eO) (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) or NIPPV will be provided unless failure criteria are met (see below).\u003c/p\u003e \u003cp\u003eTranscutaneous PaCO\u003csub\u003e2\u003c/sub\u003e will be recorded during surfactant administration in both the procedures (IN-REC-SUR-E and LISA), if available. Changes in respiratory support settings is permitted to maintain transcutaneous CO\u003csub\u003e2\u003c/sub\u003e values in each sites accepted range.\u003c/p\u003e \u003cp\u003eIn both groups, maintaining a FiO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.30 to obtain SpO\u003csub\u003e2\u003c/sub\u003e values in the desired range (90\u0026ndash;94%) will drive weaning of the level of CPAP or in the rate of NIPPV in the following days. In the babies managed with CPAP, the decision as to whether to begin bilevel positive airway pressure or NIPPV to prevent the need for re-intubation in infants of both groups will be up to the neonatologist on duty and will be considered in the final analysis.\u003c/p\u003e \u003cp\u003eInfants in both groups who meet the CPAP/NIPPV failure criteria again during the following 24 h will receive a second dose of surfactant (100 mg/kg of poractant alfa) according to the randomized group (IN-REC-SUR-E or LISA).\u003c/p\u003e \u003cp\u003eThe indications for invasive mechanical ventilation via endotracheal tube after IN-REC-SUR-E or LISA will be:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e- Poor oxygenation with FiO\u003csub\u003e2\u003c/sub\u003e of greater than 0.40 to maintain a SpO\u003csub\u003e2\u003c/sub\u003e between 90\u0026ndash;94% despite CPAP (7\u0026ndash;9 cm H\u003csub\u003e2\u003c/sub\u003eO) or NIPPV (with peak inspiratory pressure of 15\u0026ndash;20 cmH\u003csub\u003e2\u003c/sub\u003eO, positive end-expiratory pressure of 6\u0026ndash;8 cmH\u003csub\u003e2\u003c/sub\u003eO and rate of 40\u0026ndash;60 breaths/min)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e- Respiratory acidosis (either capillary pCO\u003csub\u003e2\u003c/sub\u003e or PaCO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;65 mm Hg [8.5 kPa] and pH\u0026thinsp;\u0026lt;\u0026thinsp;7.20)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e- Apnoea (more than four episodes of apnoea per hour or more than two episodes of apnoea per hour requiring ventilation with bag and mask), despite optimal nasal CPAP, nasal intermittent positive pressure ventilation, or bilevel positive airway pressure.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/h2\u003e \u003cp\u003e On the consent form, participants are informed that they can withdraw from the study at anytime without losing any rights to treatment, either current or future. Clinical data will be destroyed only if the right to be forgotten will be requested according to GDPR [ref: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gdpr-info.eu/art-17-gdpr/\u003c/span\u003e\u003cspan address=\"https://gdpr-info.eu/art-17-gdpr/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e]. In this case the record ID and the allocation arm will be traced and the reason for withdrawal will be recorded in the eCRF. The trial may be stopped if: during the trial or after interim analysis unwanted effects have occurred; new information becomes available and the experimentation is no longer in the best interests of this population; the agreed rules for participation in the trial are not followed; the trial is interrupted by the component authorities or by the promoter.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eStrategies to improve adherence to interventions {11c}\u003c/h2\u003e \u003cp\u003eGiven the nature of the intervention only after adherence to the protocol by the participating centres, no specific strategy is envisaged to improve intervention adherence.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/h2\u003e \u003cp\u003eFor ethical reasons, all types of care as usual are permitted during the trial.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eProvisions for post-trial care {30}\u003c/h2\u003e \u003cp\u003eThere will not be a specific post-trial care. No harm of participation in the trial is expected. All preterm infants enrolled in trial, after discharge, will start a \u0026ldquo;preterm - follow up program\u0026rdquo; as a normal clinical practice for all preterm discharged from hospitals participating to the study. Infants enrolled in trials will be tested for neurodevelopmental outcomes and respiratory function at 24 months, last of the secondary outcomes (see section below).\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eOutcomes {12}\u003c/h2\u003e \u003cdiv id=\"Sec24\" class=\"Section4\"\u003e \u003ch2\u003ePrimary outcome measure\u003c/h2\u003e \u003cp\u003eA composite outcome of death or bronchopulmonary dysplasia (BPD) at 36 weeks\u0026rsquo; postmenstrual age (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) is the primary outcome because BPD represents the most severe respiratory morbidity of preterm infants and death is a competing risk. The diagnosis of BPD will be ascertained by a standardized test (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Infants remaining on mechanical ventilation or CPAP at 36 weeks postmenstrual age, or those with a supplemental oxygen concentration\u0026thinsp;\u0026ge;\u0026thinsp;0.30 to obtain SpO\u003csub\u003e2\u003c/sub\u003e between 90\u0026ndash;94% will receive a BPD diagnosis without additional testing. Infants with a supplemental oxygen concentration\u0026thinsp;\u0026lt;\u0026thinsp;0.30 to obtain SpO\u003csub\u003e2\u003c/sub\u003e between 90\u0026ndash;94% or those receiving high-flow nasal cannula therapy will undergo a timed stepwise reduction to room air without any flow. Those in whom the reduction will not be tolerated will receive a BPD diagnosis.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eSecondary outcome measures\u003c/h2\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eBPD at 36 weeks\u0026rsquo; s postmenstrual age\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eGrade of BPD at 36 weeks\u0026rsquo; s postmenstrual age\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eDeath at 36 weeks\u0026rsquo; s postmenstrual age or before discharge\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSpO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e at 3 days, 7 days, and thereafter every 7 days until 36 weeks postmenstrual age (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSevere intraventricular hemorrhage (IVH) (grade 3 or 4 based on the Papile criteria) (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eOccurrence of air leaks including pneumothorax or pulmonary interstitial emphysema before discharge\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eNeed and duration of invasive respiratory support\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eDuration of non-invasive respiratory support\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eDuration of oxygen therapy\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePulmonary hemorrhage\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePDAhs (Patent ductus arteriosus; haemodynamically significant), i.e. requiring pharmacological treatment with ibuprofen/indomethacin/acetaminophen).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePercentage of infants receiving two or more doses of surfactant\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eIncidence of PVL (periventricular leukomalacia) (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e)\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eIncidence of ROP (retinopathy of prematurity) grade 3 or above (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eIncidence of NEC (necrotizing enterocolitis) grade 2 or above (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eIncidence of sepsis defined as a positive blood culture or suggestive clinical and laboratory findings leading to treatment with antibiotics for at least 7 days despite absence of a positive blood culture\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTotal in-hospital stay\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eUse of systemic postnatal steroids\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eNeurodevelopmental outcomes via Bayley scales of infant development-III and respiratory function testing at 24 months of age\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003eOther collected data\u003c/h2\u003e \u003cp\u003eThe following data will be recorded for each infant: gestational age (GA), birth weight (BW), BW z score, sex, Apgar score at 5 minutes, antenatal steroid treatment (complete course), preterm PROM\u0026thinsp;\u0026gt;\u0026thinsp;18 hours, diagnosis of clinical chorioamnionitis (defined as maternal fever, uterine tenderness, abdominal pain, foul smelling vaginal discharge, maternal and fetal tachycardia, elevated white blood cell count), maternal hypertension disorders, type of delivery.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e \u003ch2\u003eParticipant timeline {13}\u003c/h2\u003e \u003cp\u003eAll participants will complete the same outcome assessments as presented in Fig.\u0026nbsp;1 and Table\u0026nbsp;1.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec28\" class=\"Section2\"\u003e \u003ch2\u003eSample size {14}\u003c/h2\u003e \u003cp\u003eWe hypothesized that employing the IN-REC-SUR-E technique for surfactant administration in extremely preterm infants could lead to an increased survival rate without BPD at 36 weeks of postmenstrual age compared to the LISA approach, raising it from 65\u0026ndash;80%. Our estimation of a 15% difference is grounded in data from the German Neonatal Network (GNN) regarding the LISA approach, findings from the recently published OPTIMIST trial (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), and updated information on the IN-REC-SUR-E technique from select Italian Centers, which continued its use post the conclusion of the INRECSURE study. To achieve 90% statistical power at a 0.05 significance level, we determined that 181 newborns must be enrolled in each group. Factoring in a 5% risk of including patients who do not meet the inclusion criteria after randomization, a total of 382 patients will be randomly assigned. Twins will be randomized separately.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec29\" class=\"Section2\"\u003e \u003ch2\u003eRecruitment {15}\u003c/h2\u003e \u003cp\u003eThe obstetricians are aware of the study protocol and will inform the neonatologists of any case of high-risk preterm birth. Written and oral information will, whenever possible, be offered to parents prior to birth if the mother is at risk for preterm delivery and the infant is likely to be eligible. In the few cases of spontaneous preterm labor and consequent vaginal delivery, the informed consent will be obtained soon after the birth.\u003c/p\u003e \u003cp\u003eA monthly accrual report about the study will be sent to participating centers.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAssignment of interventions: allocation\u003c/h3\u003e\n\u003cdiv id=\"Sec31\" class=\"Section2\"\u003e \u003ch2\u003eSequence generation {16a}\u003c/h2\u003e \u003cp\u003eInfants will be allocated to one of the two treatment groups (1:1) according to a restricted randomization procedure (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). A biostatistician (TP) will generate the allocation sequences using both stratification and permuted blocks with random block sizes and block order. Stratification factors will include center and gestational age (24\u003csup\u003e+\u0026thinsp;0\u003c/sup\u003e to 25\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e weeks or 26\u003csup\u003e+\u0026thinsp;0\u003c/sup\u003e to 27\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e weeks).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec32\" class=\"Section2\"\u003e \u003ch2\u003eConcealment mechanism {16b}\u003c/h2\u003e \u003cp\u003eThe table of allocation will not be disclosed to ensure concealment and the randomization will be provided through Research Electronic Data Capture (REDCap) web application (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://redcap-irccs.policlinicogemelli.it/\u003c/span\u003e\u003cspan address=\"https://redcap-irccs.policlinicogemelli.it/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The assignment to intervention will be unmasked to all trial participants: parents, research staff, and medical team will be only aware of study group assignment after randomization procedures.\u003c/p\u003e \u003cdiv id=\"Sec33\" class=\"Section3\"\u003e \u003ch2\u003eImplementation {16c}\u003c/h2\u003e \u003cp\u003eEnrolment and assigning participants to interventions will be performed as previously described.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec34\" class=\"Section3\"\u003e \u003ch2\u003eAssignment of interventions: Blinding\u003c/h2\u003e \u003cdiv id=\"Sec35\" class=\"Section4\"\u003e \u003ch2\u003eWho will be blinded {17a}\u003c/h2\u003e \u003cp\u003eExcept the biostatistician involved in the analysis, the assignment to intervention will be unmasked to all trial participants: parents, local site research staff, and medical team will be only aware of study group assignment after randomization procedures.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eProcedure for unblinding if needed {17b}\u003c/h3\u003e\n\u003cp\u003eRefer to above \u003cb\u003e{17a}.\u003c/b\u003e\u003c/p\u003e \u003cdiv id=\"Sec37\" class=\"Section2\"\u003e \u003ch2\u003eData collection and management\u003c/h2\u003e \u003cdiv id=\"Sec38\" class=\"Section3\"\u003e \u003ch2\u003ePlans for assessment and collection of outcomes {18a}\u003c/h2\u003e \u003cp\u003eLocal principal investigators are required to participate in preparatory meetings in which details of study protocol, data collection, IN-REC-SUR-E and LISA procedures will be accurately discussed. All centers will receive detailed written instruction on web-based data recording, and, to resolve any difficulties, it will be possible to contact the Research core facility Data Collection (Fondazione Policlinico Universitario A. Gemelli IRCCS, Universit\u0026agrave; Cattolica del Sacro Cuore). Moreover, it will be ascertained that IN-REC-SUR-E and LISA procedures are followed similarly in all participating centers.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec39\" class=\"Section2\"\u003e \u003ch2\u003ePlans to promote participant retention and complete follow-up {18b}\u003c/h2\u003e \u003cp\u003eEach participating Investigator will be responsible for ensuring data quality. Each reported information will be systematically checked for consistency, completeness, data processing and monitoring. All study data will be: 1) screened for out-of-range data, with cross-checks for conflicting data within and between data collection forms by a data manager; 2) referred back to relevant centre for clarification in the event of missing items or uncertainty.\u003c/p\u003e \u003cp\u003eThe data manager will keep a record of all discrepancies and resolutions. The Chief Investigator and trial statistician will review the results generated for logic and for patterns or problems. Outlier data will be investigated.\u003c/p\u003e \u003cp\u003eA monthly accrual report about the study will be sent to participating centers.\u003c/p\u003e \u003cdiv id=\"Sec40\" class=\"Section3\"\u003e \u003ch2\u003eData management {19}\u003c/h2\u003e \u003cp\u003eA customized eCRF (eletronic Case Report Form) will be created for the study. Data processing will take place in compliance with current Italian and European legislation regarding General Data Protection Regulation. Data sharing with non-European Union centers will be performed according to Standard Contract Clauses. Each participating center will be identified by a 3 digit code and, within each center, patients will be identified with a progressive number. Pseudo-anonymized study data will be collected and managed using REDCap electronic data capture tools hosted at Fondazione Policlinico Universitario A. Gemelli, IRCCS (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://redcap-irccs.policlinicogemelli.it/\u003c/span\u003e\u003cspan address=\"https://redcap-irccs.policlinicogemelli.it/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). REDCap is a secure, web-based application designed to support data capture for research studies, providing 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for importing data from external sources (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). To prevent possible data entry mistakes and to improve data quality, the eCRF will be implemented by design according to validation, branching and skipping logic quality criteria.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eConfidentiality {27}\u003c/h3\u003e\n\u003cp\u003eOnly people officially registered as study investigators or data managers will receive a user login to access the REDCap web platform and enter/manage data. All collected data will be obtained from the clinical records. Each participating center must maintain appropriate medical and research records for this trial and regulatory/institutional requirement for the protection of confidentiality of study subjects. The Principal Investigator is responsible for assuring that the data collected are complete, accurate, and recorded in a timely manner. Clinical information will be collected at the following times:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAt trial entry: Information on eligibility; background information and randomization.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eFollowing randomization: all data above listed in \u0026ldquo;Primary outcome measure\u0026rdquo;, \u0026ldquo;secondary outcome measure\u0026rdquo;, and \u0026ldquo;Other collected data\u0026rdquo; sections.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eFurther information will be collected on expected serious adverse events.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThis trial does not involve collecting biological specimens for storage.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStatistical methods\u003c/b\u003e \u003c/p\u003e\n\u003ch3\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/h3\u003e\n\u003cp\u003eAnalyses will adhere to both the intention-to-treat and per-protocol principles, following the recommendations outlined in the CONSORT guidelines, with the primary outcome evaluated in the intention-to-treat population (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). The intention-to-treat group will encompass all participants assigned to the study intervention, while the per-protocol population will comprise individuals who receive and complete the study intervention, meeting all study criteria.\u003c/p\u003e \u003cp\u003eFor the primary outcome, a log-binomial regression model will be employed, adjusting for the stratification factors of gestational age and study center to estimate the adjusted relative risk (RR). Additionally, we will calculate the absolute risk reduction and the number-needed-to-treat. Statistical analyses will be conducted using Stata software, version 16\u003c/p\u003e\n\u003ch3\u003eInterim analyses {21b}\u003c/h3\u003e\n\u003cp\u003eAn interim analysis for safety to evaluate the prespecified stopping rules will be done at 30% and 60% of recruitment by an independent statistician, masked to the treatment allocation. The prespecified clinical and safety stopping rules will be: in-hospital mortality rate more than 40%, a rate of severe intraventricular haemorrhage more than 30%, and a pneumothorax rate more than 10%, considering overall occurrences. The data and safety monitoring board will have unmasked access to all data and will discuss the interim analysis results with the steering committee in a joint meeting. The steering committee will then determine the trial's continuation and report to the central ethics committee.\u003c/p\u003e\n\u003ch3\u003eMethods for additional analyses (e.g. subgroup analyses) {20b}\u003c/h3\u003e\n\u003cp\u003eSubgroup analyses will be conducted to explore specific factors such as gestational age influencing the outcomes, providing a more nuanced understanding of the intervention's effects within distinct subpopulations.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}\u003c/b\u003e \u003c/p\u003e \u003cp\u003eRefer to above \u003cb\u003e{20a}.\u003c/b\u003e\u003c/p\u003e\n\u003ch3\u003ePlans to give access to the full protocol, participant level-data and statistical code {31c}\u003c/h3\u003e\n\u003cp\u003eThe datasets analysed during this trial are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003ch3\u003eDuration of study\u003c/h3\u003e\n\u003cp\u003eIn this study, 382 infants will be recruited. The trial will terminate when the last recruited infant discharged from the hospital will be evaluated for neurodevelopmental outcome and respiratory function at 24 months of follow-up. The planned duration to randomization is 3 years.\u003c/p\u003e \u003cp\u003e \u003cb\u003eOversight and monitoring\u003c/b\u003e \u003c/p\u003e\n\u003ch3\u003eComposition of the coordinating centre and trial steering committee {5d}\u003c/h3\u003e\n\u003cp\u003e A joint Trial Steering Committee (TSC) and Data and Safety Monitoring Board (DSMB) will provide supervision for the trial, providing advice to the Chief and Co-investigators on all aspects of the trial conduct and affording protection for patients by ensuring the trial is conducted according to Guidelines for Good Clinical Practice in Clinical Trials. Chief investigator and advisory board will chair the TSC. A trial manager, a statistician and other investigators will form the DSMB. The trial manager and other investigators will check randomly the accuracy and consistency of the data entered from the participating centres. The data will be reported to the PI and advisory board as \u0026ldquo;group A\u0026rdquo; and \u0026ldquo;group B\u0026rdquo;. An independent statistician, blinded for the treatment allocation, will perform the interim analysis. The statistician will report to the DSMB. The DSMB will have unblinded access to all data and will discuss the results of the interim analysis with the Steering Committee in a joint meeting. The Steering Committee will decide on the continuation of the trial and will report to the central Ethics Committee.\u003c/p\u003e\n\u003ch3\u003eComposition of the data monitoring committee, its role and reporting structure {21a}\u003c/h3\u003e\n\u003cp\u003e \u003cem\u003eRefer to above {5d}\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eAdverse event reporting and harms {22}\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAdverse events, device deficiency and incidents, as identified by the following definitions, will be recorded and reported to Manufacturer and the National Competent Authority as per applicable law, (For EU Centers Regulation 2017/745 and Centers in Italy Circular of the Ministry of Health Application of the EU Regulation 2017/745 of the European Parliament and of the Council, of 5 April 2017, in the field of clinical investigations relating to medical devices).\u003c/p\u003e \u003cp\u003eSite investigators will report any adverse event to the Coordinating Center. In case of a serious event involving a medical device, serious incident, a report (For Centers located in Italy from Dispovigilance - \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.salute.gov.it/DispoVigilancePortaleRapportoOperatoreWeb/\u003c/span\u003e\u003cspan address=\"https://www.salute.gov.it/DispoVigilancePortaleRapportoOperatoreWeb/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) will be issued and sent to the Competent Authority, the Manufacturer and the Coordinating Center, as per national applicable law.\u003c/p\u003e \u003cp\u003eDevice deficiency will be reported by the investigators to the Coordinating Center and to the Manufacturer, as per applicable law.\u003c/p\u003e \u003cp\u003eAdverse event means any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, including an abnormal laboratory finding, in subjects, users or other persons, in the context of a clinical investigation, whether or not related to the investigational device.\u003c/p\u003e \u003cp\u003eSerious adverse event means any adverse event that led to any of the following: (a) death, (b) serious deterioration in the health of the subject, that resulted in any of the following: (i) life-threatening illness or injury, (ii) permanent impairment of a body structure or a body function, (iii) hospitalisation or prolongation of patient hospitalisation, (iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function, (v) chronic disease.\u003c/p\u003e \u003cp\u003eIncident means any malfunction or deterioration in the characteristics or performance of a device made available on the market, including use-error due to ergonomic features, as well as any inadequacy in the information supplied by the manufacturer and any undesirable side-effect; \u0026lsquo;serious incident\u0026rsquo; means any incident that directly or indirectly led, might have led or might lead to any of the following: (a) the death of a patient, user or other person, (b) the temporary or permanent serious deterioration of a patient's, user's or other person's state of health, (c) a serious public health threat;\u003c/p\u003e \u003cp\u003eDevice deficiency means any inadequacy in the identity, quality, durability, reliability, safety or performance of an investigational device, including malfunction, use errors or inadequacy in information supplied by the manufacturer.\u003c/p\u003e \u003cp\u003eSafety end-point measures will include incidence, severity, and causality of reported serious adverse effects (SAE), namely changes in occurrence of the expected common complications of prematurity and clinical laboratory test assessments, and the development of unexpected SAEs in this high-risk population. All SAEs will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. All SAEs and serious incidence (SI) will be followed until satisfactory resolution or until the investigator responsible for the care of the participant deems the event to be chronic or the patient to be stable. Particular attention will be paid to the SAEs (in-hospital mortality, serious intraventricular hemorrhage and pneumothorax) considered stopping rules. They have to be inserted by local investigators in the eCRF and reported to the PI and advisory board as soon as possible, no later than 24 hours after their occurrence.\u003c/p\u003e\n\u003ch3\u003eFrequency and plans for auditing trial conduct {23}\u003c/h3\u003e\n\u003cp\u003eA monthly accrual report about the study will be sent to participating centers.\u003c/p\u003e \u003cp\u003eWhenever a SAE/SI will be registered in REDcap\u0026rsquo;s eCRF a progressive ID will be attributed and a report will be sent to the local principal investigator in order to verify the appropriateness of the data and to facilitate the notification to the Chief investigators according to a standardized template. More in depth, all expected and unexpected SAEs/SIs, whether or not they are attributable to the study intervention, will be reviewed by the local principal investigators to determine if there is reasonable suspected causal relationship to the intervention. Revised data will be reported to Chief Investigators ([email protected]) who will report to Ethics Committee and inform all investigators to guaranty the safety of participants. The DSMB will be responsible to monitor adverse events.\u003c/p\u003e\n\u003ch3\u003ePlans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}\u003c/h3\u003e\n\u003cp\u003eImportant protocol modifications will be reported to and need to be approved by all the medical-ethical committee. When modifications are approved, these will also be reported to the participants, and be added to the Trials paper and the study registration on ClinicalTri- als.gov.\u003c/p\u003e \u003cp\u003e \u003cb\u003eDissemination plans {31a}\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe outcomes of this study about the effectiveness of the intervention will be reported in article(s) in international peer-reviewed journals. Both positive and negative outcomes will be reported. The outcomes will also be reported in professional magazines in the field and in magazines for parents. The results will be presented in participating care organizations and at scientific conferences. All presentations and publications are expected to protect the integrity of the major objectives of the study; data that break the blind will not be presented prior to the release of mainline results.\u003c/p\u003e \u003cp\u003eRecommendations as to the timing of presentation of such endpoint data and the meetings at which they might be presented will be given by the Steering Committee. Substantive contributions to the design, conduct, interpretation, and reporting of the clinical trial will be recognized through the granting of authorship on the final trial report. Individuals who fulfill authorship criteria will have final authority over the manuscript content.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe primary hypothesis of this trial is that surfactant administration by IN-REC-SUR-E, via a high frequency oscillatory ventilation recruitment maneuver, increases survival without BPD at 36 weeks of postmenstrual age in spontaneously breathing infants born at 24\u003csup\u003e+\u0026thinsp;0\u003c/sup\u003e-27\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e weeks' gestation affected by RDS, compared to LISA.\u003c/p\u003e \u003cp\u003eAlthough surfactant replacement therapy is an established treatment in infants with RDS, identifying the safest and most effective way to administer surfactant is critically important but not well defined, especially in extremely preterm infants. It is plausible to expect that the therapeutic benefits of exogenous surfactant therapy will be maximized by quickly and uniformly aerating the lung beforehand. The IN-SUR-E method cannot be universally applied to all preterm neonates; risk factors for failure of IN-SUR-E are low birth weight, low gestational age, the severity of initial respiratory disease, and a low haemoglobin concentration prior to surfactant administration (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). New promising evidence from the randomized clinical trial INRECSURE showed that the application of a recruitment manoeuvre just before surfactant administration, followed by rapid extubation, decreased the need for mechanical ventilation during the first 72 h of life compared with IN-SUR-E technique in extremely preterm neonates, without increasing the risk of adverse neonatal outcomes (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The recent LISA technique introduces surfactant into the trachea of spontaneously breathing infants via a small catheter instead of an endotracheal tube (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). LISA is now widespread and combines the benefits of early surfactant treatment with CPAP and consequent avoidance of mechanical ventilation. The last network meta-analyses on the comparative efficacy of methods for surfactant administration found that among preterm infants, LISA technique was associated with lower likelihood of mortality, need for mechanical ventilation and BPD compared with IN-SUR-E, but these findings did not include comparison to IN-REC-SUR-E method (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). More importantly, data for neonates\u0026thinsp;\u0026lt;\u0026thinsp;28 weeks\u0026rsquo; gestation are not as robust as for the higher gestation age groups due to a smaller number of neonates (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). For these reasons, the safety and efficacy of LISA in infants\u0026thinsp;\u0026lt;\u0026thinsp;28 weeks remain to be confirmed and lung recruitment before surfactant administration (IN-REC-SUR-E) represents a promising new alternative. We therefore designed this study to compare the IN-REC-SUR-E technique with LISA, for evaluating the comparative effectiveness of these techniques in increasing the survival without BPD of extremely preterm infants.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTrial status\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThis is protocol version 3, 25 Oct 2022. Recruitment started on 9 January 2023.\u003c/p\u003e \u003cp\u003eThe trial is currently recruiting study subjects. The estimated study completion date is 15 April 2026.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBPD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebronchopulmonary dysplasia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBW\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebirth weight\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCTCAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCommon Terminology Criteria for Adverse Events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCPAP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econtinuous positive airway pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDSMB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eData and Safety Monitoring Board\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eeCRF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eeletronic Case Report Form\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFiO\u003csub\u003e2\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efraction of inspired oxygen\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egestational age\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGNN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGerman Neonatal Network\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHFOV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehigh-frequency oscillatory ventilation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIN-REC-SUR-E\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eINtubate-RECruit-SURfactant-Extubate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIN-SUR-E\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntubate-Surfactant-Extubate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIVH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eintraventricular hemorrhage\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLISA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eless invasive surfactant administration\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003enCPAP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enasal continuous positive airway pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNEC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enecrotizing enterocolitis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNICU\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eneonatal intensive care unit\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNIPPV nasal intermittent positive pressure ventilation\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePDA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epatent ductus arteriosus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePDAhs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehaemodynamically significant patent ductus arteriosus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePROM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epremature rupture of membranes\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePVL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eperiventricular leukomalacia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRedCap\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eResearch Electronic Data Capture\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRDS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erespiratory distress syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eROP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eretinopathy of prematurity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erelative risk\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSpO2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epulse oximetry\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eserious adverse event\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eserious incidence\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTSC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTrial Steering Committee.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors want to thank all the parents of participants and the departments staff for cooperating and supporting the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions {31b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026quot;GV is the Chief Investigator; he conceived the study, led the proposal and protocol development. Members of advisory board GV, AP, CA, SAO, VPC, FC, SC, FC, CD, PGD, NF, SF, FPF, CG, EH, MJ, AL, GL, FM, SN, AP, SP, JJP, GP, MT, DT, CT, AHVK and MLV contributed to study design and to development of the proposal. TP, RP and SP contributed to the methodology and statistical analysis of the study. All authors read and approved the final manuscript.\u0026quot;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding {4}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study has received economic contributions by way of partial coverage of the expenses relating to its implementation. The contributions have been appropriately declared to the competent Ethics Committee, in accordance with current legislation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials {29}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate {24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe research protocol has been approved by the Medical Ethics Committee of Fondazione Policlinico Universitario A. Gemelli IRCCS, Universit\u0026agrave; Cattolica del Sacro Cuore, Rome Italy (NCT05711966 -last release 16 Feb 2023).\u0026nbsp;The ethical bodies of the participating centers approved the study.\u003c/p\u003e\n\u003cp\u003eInformed written consent will be signed from both parents and sufficient time will be provided for consent. If parents do not speak the local language, consent will only be obtained if an adult and independent interpreter is available. The parents will be informed that the study does not entail a blood sample or other more invasive interventions than maneuvers performed regularly in the neonatal intensive care unit (NICU). The informed consent will be obtained by the principal investigator of each participating center and his collaborators in charge.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication {32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo personal data is used in this protocol.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests {28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSvedenkrans J, Stoecklin B, Jones JG, Doherty DA, Pillow JJ. Physiology and Predictors of Impaired Gas Exchange in Infants with Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2019;200:471\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrix N, Sellmer A, Jensen MS, Pedersen LV, Henriksen TB. Predictors for an unsuccessful Intubation-SURfactant-Extubation procedure: a cohort study. BMC Pediatr. 2014;14:155\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLakkundi A, Wright I, de Waal K. Transitional hemodynamics in preterm infants with a respiratory management strategy directed at avoidance of mechanical ventilation. Early Hum Dev. 2014;90:409\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDani C, Corsini I, Bertini G, Fontanelli G, Pratesi S, Rubaltelli F. The INSURE method in preterm infants of less than 30 weeks\u0026rsquo; gestation. J Matern Fetal Neonatal Med. 2010;23:1024\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCherif A, Hachani C, Khrouf N. Risk factors of the failure of surfactant treatment by transient intubation during nasal continuous positive airway pressure in preterm infants. Am J Perinatol. 2008;25:647\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVento G, Ventura ML, Pastorino R, van Kaam AH, Carnielli V, Cools F et al. Lung recruitment before surfactant administration in extremely preterm neonates with respiratory distress syndrome (IN-REC-SUR-E): a randomised, unblinded, controlled trial. Lancet Respir Med 2020 Jul 17:S2213-\u003cdiv class=\"ExternalRefDOI\"\u003e2600(20)30179-X\u003c/div\u003e. doi: 10.1016/S2213-2600(20)30179-X.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKribs A. Minimally invasive surfactant therapy and noninvasive respiratory support. Clin Perinatol. 2016;43:755\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBellos I, Fitrou G, Panza R, et al. Comparative efficacy of methods for surfactant administration: a network meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2021;106:F474\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNobile S, Bottoni A, Giordano L, Paladini A, Vento G. Critical appraisal of the evidence underpinning the efficacy of less invasive surfactant administration. Arch Dis Child Fetal Neonatal Ed. 2021 Oct 16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVan Der Janssen LC, van Kaam AH, et al. Minimally invasive surfactant therapy failure: risk factors and outcome. Arch Dis Child Fetal Neonatal Ed. 2019;104:F636\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBellos I. Pandita A SurE for surfactant: response to letter. Arch Dis Child Fetal Neonatal Ed. 2021 Nov 29.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFiner NN, Katheria A. Recruitment: the best way to IN-SUR-E surfactant delivery? Lancet Respir Med. 2020 Jul 17:S2213-2600(20)30242-3 \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S2213-2600(20)30242-3\u003c/span\u003e\u003cspan address=\"10.1016/S2213-2600(20)30242-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChan A, Tetzlaff JM, G\u0026oslash;tzsche PC, Altman DG, Mann H, Berlin JA, Dickersin K, Hr\u0026oacute;bjartsson A, Schulz KF, Parulekar WR, Krleza-Jeric K. A.Laupacis, D. Moher.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBroglio K. Randomization in Clinical Trials: Permuted Blocks and Stratification. JAMA. 2018;319(21):2223\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSweet DG, Carnielli V, Greisen G, et al. European Consensus Guidelines on the management of Respiratory Distress Syndrome \u0026ndash; 2022 Update. Neonatology. 2023;120(1):3\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAziz K, Lee HC, Escobedo MB, et al. Part 5: Neonatal Resuscitation 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Pediatrics. 2020. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1542/peds.2020-038505E\u003c/span\u003e\u003cspan address=\"10.1542/peds.2020-038505E\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTana M, Paladini A, Tirone C, Aurilia C, Lio, et al. Effects of High-Frequency Oscillatory Ventilation with volume guarantee during surfactant treatment in extremely low gestational age newborns with respiratory distress syndrome: an observational study. Front Pediatr. 2022;9:804807.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe Jaegere A, van Veenendaal MB, Michiels A, van Kaam AH. Lung recruitment using oxygenation during open lung high-frequency ventilation in preterm infants. Am J Respir Crit Care Med. 2006;174:639\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBuzzella B, Claure N, D'Ugard C, Bancalari E. A randomized controlled trial of two nasal continuous positive airway pressure levels after extubation in preterm infants. J Pediatr. 2014;164(1):46\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJobe A, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163(7):1723\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalsh MC, Szefler S, Davis J, Et. al. Summary proceedings from the Bronchopulmonary Dysplasia Group. Pediatrics 2006;117(3.pt 2):552\u0026ndash;556.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNobile S, Marchionni P, Gidiucci C, Correani A, Palazzi ML, Spagnoli C, et al. Oxygen saturation/FIO2 ratio at 36 weeks\u0026rsquo; PMA in 1005 preterm infants: Effect of gestational age and early respiratory disease patterns. Pediatr Pulmonol. 2019;54(5):637\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePapile LS, Burstein J, Burstein R, Keffler H. Incidence and evolution of the sub-ependymal intraventricular hemorrhage ; a study of infants weighing less than 1500 grams. J Pediatr. 1978;92:529\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe Vries LS, Eken P, Dubowitz LM. The spectrum of leukomalacia using cranial ultrasounds. Beha Brain Res. 1992;49:1\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInternational Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005;123:991\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, Brotherton T. Neonatal necrotizing enterocolitis: Therapeutic decisions based upon clinical staging. Ann Surg. 1978;187:1\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDargaville PA, Kamlin COF, Orsini F, Wang X, De Paoli AG, et al. Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial. JAMA. 2021;326(24):2478\u0026ndash;87. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jama.2021.21892\u003c/span\u003e\u003cspan address=\"10.1001/jama.2021.21892\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap) \u0026ndash; A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inf. 2009;42(2):377\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O\u0026rsquo;Neal L, McLeod L, Delacqua G, Delacqua F, Kirby J, Duda SN. REDCap Consortium, The REDCap consortium: Building an international community of software partners. J Biomed Inf. 2019 May;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jbi.2019.103208]\u003c/span\u003e\u003cspan address=\"10.1016/j.jbi.2019.103208]\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRanganathan P, Pramesh CS, Aggarwal R. Common pitfalls in statistical analysis: Intention-to-treat versus per-protocol analysis. Perspect Clin Res. 2016;7:144\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. \u0026nbsp;Overview of enrolment, interventions and assessments.\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAlMAAAIGCAYAAABwAgqsAAAgAElEQVR4AeydQY4cO5Bk+ygNCJhzzE7HmLXQV5gLaNmrWcwBtO0jNKBFn0LbuYYGVv2f6EVZZCWLmRnMpAWQPxhO0ul8dDKssvSlf/n9z/V//+//pZh7CIRACIRACIRACITAlQT+hXYRU5DIPQRCIARCIARCIASuJ/AvElF8ru+WliEQAiEQAiEQAiEQAiLw55spPfyP//E/8gmD5EByIDmQHEgOJAeSAxdyoJeQf4mpvkGe9yPwL//yLi32A5AZh0AIhEAIhMABAX3x1F/v3pquQd8hz69PIGLq9dc4MwyBEAiBEPgcAaeVIqY+x/Kle0VMvfTyZnIhEAIhEAITBCKmJuDt1DViaqfVzlxDIARCIARGCERMjdDauG3E1MaLn6mHQAiEQAhcJBAxdRFPKiEQMQWJ3F+RwJcvX34rx/n8+vXrtz48u/vPnz9/f/v27a2Nylz0+/r165vp+/fv1s+PHz/e6mmvMeqFXbH1l/q6mBQPl6uXDX/E3rcjbvmhjZtf7cdc1Ie4a73K1S8x5h4Cr0IgYupVVvLO89BhmCsEXpEAgoG5KdcRHNgQLxJG9aKvExuIB8RUFRy9jWf541J/xVL7UefiwYfuutw86K+7i13zUD/i6NtQz9zkh1jog5iqbZytxpJyCDw7gYipZ1/BB8WvAzZXCLwiAQmnXjz180QwIFSo78WG7L1wQOT0oqgfV8/aZ+rvRAtj6u7i6cf9jJiS79qvnx8x1lhUZo6Ku4+DtrUNttxD4FUIREy9ykreeR4RU3cGHPenEUAg6H50OfGitr3YkK0XE4iIXkz1fRlDdr6Vki930Va+ufpxqyiiTb3341NX+9U2+JetvxB/iod29ZsptaeN69/7y3MIPBuBiKlnW7GT4o2YOgl8hr07AYSJclyfKlAYnDZ9XRUbtO3FhPrIr3zUC7tEBhciSu0viQ4XD/4Yh/n0d+bgYu/91jaIIfoTs+7MWe0p92IK+6V5VZ8ph8AzEYiYeqbVOjFWHci5QuBVCSAUEB79t1S9yIBDFRvYEA2IiV7k0A57FVP0/Wi/EQ/xcq9CR7Z+HoytO7HTl3v1QRvFCKNajz/iVnvKzN+1wZZ7CLwKgYipV1nJO89DB22uEHh1Aggc5XsVOYiXXkhUsQGbXkzgUz7q5fqqXmNfEkFqcxRP9f+Rn358te/nXdswL9n6qwot2vViijauf+8vzyHwbAQipp5txU6KV4dsrhDYgQDi5xox5doiJhANtOnFlMSGE00fiSCtwT3EFGJH42sOuqqY0rPidWdBbcf8ezFFzJXr2yD5Twi8AIGIqRdYxEdMwR2gjxg3Y4TAPQm4F79EQJ/vCAEJo3q5/ognRAPPVUzhr9rwq7GdyKJed/r38dQ2H/mpAoh+2BBCPDMXBBf1NRa11eWYyK54ar+3xvlPCLwIgYipF1nIe0+jf7nce7z4D4FHEUAgKMf5SBDU65J4QTzQV/cqkhBTtb5vU8dS3a3EVD8mz4q5F0rEQBvN4aM2tS39HQ+1i5CCUO6vSCBi6hVX9Q5z0mGYKwRCIARCIARC4G8CEVN/M4nFEIiYMlBiCoEQCIEQCIHfv39HTCUNriIQMXUVpjQKgRAIgRDYkEDE1IaL/pkpR0x9hlr6hEAIhEAI7EAgYmqHVb7BHCOmbgAxLkIgBEIgBF6SQMTUSy7r7ScVMXV7pvEYAiEQAiHwGgSuElNqlM/eDCSmkgN750DWP+ufHEgOJAeOc6CXhe/+H3iByxUC+WZqPgeyl8JwnkA8hMDtCeR8n2fqzveIqXmuL+chm21+Sd1mm/e6l4cw3Gu9M9vHEMj5Ps/ZnU0RU/NcX85DNtv8krrNNu91Lw9huNd6Z7aPIZDzfZ6zO5sipua5vpyHbLb5JXWbbd7rXh7CcK/1zmwfQyDn+zxndzZFTM1zfTkP2WzzS+o227zXvTyE4V7rndk+hkDO93nO7myKmJrn+nIestnml9Rttnmve3kIw73WO7N9DIGc7/Oc3dkUMTXP9eU8XLvZ+Ffm1b7//Pz58y5cvnz58jbWXZzf0KnbbB+5//r169vcdO+vOu8fP368tfv+/Xvf7K7PNYa7DvSP888wfERcjxgD1v2++vXr1yOGPxxD+1oxae/rImcfGVcfw2GwqbAEtH6fufqcrOeUziL51dm0w+XOpndUXYMdwGSO7wlcu9kQU/cSTu+j+u8nNrSru6dNh8SIeBndS3oZiTuf/uVU5/1IMaVxuWoM2O55H2V4z1ge7duxJjduEYv27mf2bS9kHiWm6v7rY7gFj518XHu+VybqU88CzitszyqmFPdnBKA7myKmasak/Ebg2s22i5j6jHhxm+1SenEYwbQXbvXl+pl4Lo19VNcfoEft7mUfZXivOM7wW9eb8cmNz4ggfOg+46cXMo8QU4/K98rolcvXnu8wIF/6H/Co153z6zPCpPp5ZHkmZnc2RUw9cvWeZKxrNxub7OhwrwcvL4fqm2TmQJY/XdjVVp/qHz9qx/jc1Va+6jM+1Z5DuffLT1nqSyxqIztzoI/Gv+Zym+1Svzov5lHb13rmIU5cNW71rxfzYw6VSc8an4xHH3HAhu+eDX1VzxpU/3VcfFy6jzK85OvZ6nrWih+m7IdL/Ps65Yeuuh5a26M1YSzWn5ckfulH3vGivZRrbnzmojrmzJhH+6+PQX37eIlHdfIn37VNHVdtdrrEY+QSO30uXeQVeaK2dT37/uQNa13XA1/U1bV0MRyN0+cJuamxOUMZg/3h/DubO5veUXUNnKPYXpvAtZutHk4kpe5sHJKZZxKYg5hNw7Oo4pPNRRs2KRuntlUbXWxQ/FVfxEJb6rTB2GTMm7ZsMOKm79tgH/xnZC8xPnEzD9m56rz7eGqd2tf+vW/mprlQhm1lIj91LfVcx+ljwBdzwBfMiEntrr1GGF7r81naVdbEXNfjI/7qr4+uvi1rc7QWtKeetZOvfp2pU571deSe2uhSLmgO+CUOtaP81vCf3KMf8ZBL/Tg1BvXHF+NoTH00DjHBhvF2uovFyKX2rMVRP9ZWa6VLfSpjlRmX9aTtpTrW9mjcS+P0ecLaM5c+5qMxnN2dTe+ougbOUWyvTYCk/2iW/aHVtz9KZvXT5ZJZY5Ps+Ku2uvH68ftn/CsO6rShdBGb2vSbTPV1TDa/2l57jewl4uRwcePVedf6Og9iqzZ8y3Z04U9z1oe2KmtcrhqDO+SqDd74uiYOxuE+wpA+r3KHNWvCnflV1s5Ge937q1+bvp5n1gxf2ifklnzoIg7V4Zc9pvpq05xqPjFOveNPY9KW/FQ8umoM7F3iUX1vq75Uf00cbwO96H9cTlyaqtprXS5d5IrWivXSnavaaCu/rCntWH+eaz9s3F1dtdU8UR/ygrkQh/qMXu5serfTXIPRQdL++Qlcu9k4KHlh9jMfTeY+2fGneDhYdSe+fvz+uW4W6tS3ftTGjVvHZIP2G5/43H1kL9U5yZeLp7ap8dQycVTuzNutEe2OeFYG8l1jqGXG5SBU/P24dS1o/9F9hOFHvp6t3vGtc3D1lT95UXOdHOjXpvpVmb4aQ1f1S87IR19X271VFjFFP3xSz52Y8Ftzj3jYf/hS21rGV79/qi+1cezou8NdPEYu8TpaN/zU/V3L1PdryBqQn8odXeQQdu7q318fjdPnRp8Xrn8/xtGzO5veUXUNjpzF/roErt1sHIBKWnd9Jpk1NhsLn9XGJlRdP37/XDcLddpQ/dVvMtVrTA4Q5iF/117X7iXG1njuQ7x13vVgcrFVW2XQx94z4Vn9dWlMGPCsGHVx6L09/POfaut9XYqj+qjlaxnWPq9Sruvt5lRZU+9sqsPOWrIWrDP1WluVee79KhfJLa1v9a061pycVX21XZoTYzOmnomXMdl/PMu3xlJb4lH/3lZ9qf5SHIz/ynfxGLnqGh71I6d0NnE+VQHkbPLFWiomtelzr46HD7XV59///d/f7kfj4JvcIC80hi781f51vEtldza9o+oaXHKYutckcO1mY5Mpad31UTLXDUj/3idtGKMehH3b/pm+2ix9LLVtv8kUixgcHebEeul+7V6qMVZ/2HXXVefNIeDq1LYeSP3cKgcYcJhwSFXWMPgoBvwSE77xxXwY621SH/znWoYfuHnK6rrebgJ9DlT+/Zqrv9aWlwhrwdr0/skf1eNL/VVmHK2vLtq6OvrSlnHJgZoj5J58MjdyjzHJLZ7xW2NQf/xqfF3yjS89f8T2rdML/0c8Ri/1IX/Ul7WFa7+2jjltWR+toy766pm1Z637te3jvjQOMRI34/DMWORj7/vSszub3lF1DS45TN1rErh2s7Ep1L7/KHH7Q+8ouftkJunxyaYT7XoQMj71/TN+8M/mwS/2Pi6NozZs/jputV1a/Wv3EvNRDPWCHRufdmrDPDQ/Lg4d5oZdd+ZHHT5Vh013+OEXfqpTPDUG9SVGfNBPdfhibfAFc7X56LqW4Ud+nrG+Z+3mcIl/v+ZaI65ap3Xqr1pf80Jrx5j0I+/UR5frW/2TB+QM+UBOYyd/8AsP3fsY5J/29Kef6mRTPy588bzbXTw+c8ENxvUcYV1ZT/mv7St/1fXrVc8OfDEOZ8hRzNeOg98aN2NU29E41e7OpndUXYPqIOU9CHx2s+1B57pZZi9dx+lSqzC8RCd1IfA5AjnfP8et9nJnU8RUJZTyG4FstvlEcJtt3uteHsJwr/XObB9DIOf7PGd3NkVMzXN9OQ/ZbPNL6jbbvNe9PIThXuud2T6GQM73ec7ubIqYmuf6ch6y2eaX1G22ea97eQjDvdY7s30MgZzv85zd2RQxNc/15Txks80vqdts81738hCGe613ZvsYAjnf5zm7syliap7ry3nIZptfUrfZ5r3u5SEM91rvzPYxBHK+z3N2Z1PE1DzXl/OQzTa/pG6zzXvdy0MY7rXeme1jCOR8n+fszqa/xJQa5bM3A2225MDeOZD1z/onB14zB3K+32Zde0n2l5j6f//v//3OZ28G2mzJgbkc0IsoDMPwVjmQfLqcS+FzmU/Nw5zv17Oq3GpZ+dZfEVMRj3+99LPZbrPZ6uZLeZxpXpCNWVg0Fm4vhc9lPpVZzvfrWVVutRwxFeH0l3CqCUI5m+02mw2euX+OZ16QjVtYNBZuP4XPZT6VWc7361lVbrUcMRUxFTH1oBzI4X6bA6seYDuXk0+X8yl8LvOpeydi6npWlVstR0w96EVaoT9jOZvtNpvtGdd+pZjzgmx5GBaNhcvR8LnMpzLL+X49q8qtliOmIqbyzdSDciCH+20OrHqA7VxOPl3Op/C5zKfunYip61lVbrW8tZj6P//n//xWEh19BEp1//qv//omOP7X//pff9qqLyD/4z/+44/9f/7P//lmV59Lfo/G1hj41b36xp9stKGefsT4v//3//7T5r/+67/eYlFstMdXf1dbfNe72tXnlMc338qHe82Dml+rrfPKDB/N6llYKLeOzpV7MnsWPvdkcK3vnO/j53nPVvnWX1v+33yIkP5FoiRzYgrxIqASLryMejHVA+cZMVVFD36w0caNRRvEEW2YRz3Aqphi/Bp3FYa1vpafYbNpHnCosa9SXvVwV36Tt+TPKsz6OFZgKF5niIOVWChPPjo3dEbpI146p8ixfh73el4hV+rczmBQx79UXvV8vybPLs3rkXURU//8ioeXyDViSodDTT4dEnrWhwOjb9MvKkIJUaT6XvTIn/z0fYlV7S+JKbVzfvGnsTXGR4ei2qsd/Va8j8zlrPhXO9zFgZwjD8mna3LiDI5nMzzakzux4Lz7SFCSW2Kmz0ftb83w7Fyp83Hnfa0/u7zi+X5tnp3NjvEjpj4hphAzCC8lIgt/KzHFS42XHAumOxtTd9ohnIiNA0z1HGrEhq8RAbLiZmMesK9zpm6l+0qHO1xqLslGPrm8o8+Z97MYwoUc6/fSGUzOYMH8uV+at5jxQ6Xa6/lS+1vXncHHzaE/k7XnXLszbVqfM8fvxya/uPf1Kz4r3/orv+YrfyBZi8m3Q2wKXkB64XDIIkw4ZOshQkLojuipPkgMfKiOet2p517HpIxfYsSX4nl1MaX5wRtGK95XOdwrmz7P+nyqbVcon8VQOQYr7a0dWYjB0VmyAo8+hrNypY9DzPiBT+W+foVnvZtWiEMxPFuewU351l8RUx+IKb1w9PLWBkG08BLqxRSg+zsHcxVaKnNQU69735ex1JZyL6ZkZwPji9jwR+xuDNpwX2WzcZjDTbFjq/PDRvwr3Fc53CsLcoMc6POptl2hfCZDflARI1go52CH7VH3M1iQL5xT7DPtx7M4HPE+g89RLOLDD+Vqw9nMuX3U71H2Vc535tvnGXbu4rYKO2JSvvVXxNQVYoqDFVHFocIL/aNvSj5KFl5qHFosmO701Z12JBZxyU5MCA9iw9cziinmzpw0RxjAinnVw4s5n3lf6XCHAzx1l61nSbtV7mcy5AUoFnVvidkZfM5gwd5izmIim/KnP1/OYFLHPINPHZ8yucIZLVY6m7DT7sz7amKqz7PKpj+zat2ZZeVbf0VMXSGmWFAloRaejcGBMiumlBTy7QQBh7rG5OXHRq1iSj54li9iI+FIWM0F29F9tc1W43TzEJd+vrXPGeVVDvc6d/JHDGUnr6/JiernUeUzGbr9yEvxUfOv45zBop49NRbZyaFqP7N8Bh83X/ZU5cO+49x2/R5pW+18P8ozMeFdJoaPZPTRWMq3/oqYukJMIZ60sFpUnnmB30JMsQnrhkM4sDH7TYl4qommGEnAmhD4uubFqf6170plt/E0p8pthXhXOdx7FspV8pb86dus8nwWw36fwePMfXEGC823/wFPudPb4HPm/Qw+br7sqXomq53O31XOqDPz2DFzeaZ2yjWd7co3vXNd37Nsyrf+ipi6QkxpwbSgJOGRmFJ9/9GmQighio4SAL/VR92U/SHvNi6iiRcmY2F/djHFPMSIucimD3Nd4b7K4e5YHOWXa3um7UyGMEI4aG9SPoPJGSx0hsBB89d5cyaDS9zP4OPi4awXt3/7t3974we7iCn/l2X2eSauvOvIv9XyTvnWX1uKKbcJYmuJrgR+Jh46pBBWq8S9yuG+Co/PxLESQx3u/Q8on5nTZ/uczaJ/uen5s3O5R7+z+RzNqf7wd9Tm0fZnOt/P3ndHa6N866+IqfLN1BG43ezPtNlWXZtVD/dVebm4wrD9gBMWjUVy5TILx6facr7P8RPLiKkIp6t+msxmu81mqwdYyuNMIyAas7BoLNxeCp/LfCqznO/Xs6rcajliKmIqYupBOZDD/TYHVj3Adi4nny7nU/hc5lP3TsTU9awqt1qOmHrQi7RCf8ZyNtttNtszrv1KMecF2fIwLBoLl6Phc5lPZZbz/XpWlVstXyWm1CifMEgOJAeSA8mB5EByIDngc+DDP4DeN8hzCIRACIRACIRACITAfxOQwOyvv/5vvqhQr0LDJVySA8mB5EByIDmQHFAO9NdfYqpvkOf9COh36rlCIARCIARCIAT+JhAx9TeTWAyBiCkDJaYQCIEQCIEQ+P37ur9nKqRCIGIqORACIRACIRACnkC+mfJcYu0IREx1QPIYAiEQAiEQAv8QiJhKKlxFIGLqKkxpFAIhEAIhsCGBiKkNF/0zU46Y+gy19AmBEAiBENiBQMTUDqt8gzlGTN0AYlyEQAiEQAi8JIGIqZdc1ttPKmLq9kzjMQRCIARC4DUIREy9xjrefRYRU3dHnAFCIARCIASelEDE1JMu3KPDjph6NPGMFwIhEAIh8CwEIqaeZaVOjjNi6uQFyPAhEAIhEALLEoiYWnZp1gosYmqt9Ug0IRACIRAC6xCImFpnLZaOJGJq6eVJcCEQAiEQAicSiJg6Ef4zDR0x9UyrlVhDIARCIAQeSSBi6pG0n3isiKknXryEHgIhEAIhcFcCEVN3xfs6zj8SU6p3ny9fvrxB+Pbt21v99+/f/0D59evXm+3r169vNtVd8vGn4+/fv/FHe8ahDb5+/PiB6d2dfrrXq/pV358/f9qY1E9tdSl+Pdex6Kc2stfx+nIdP+UQCIEQCIHnIxAx9XxrdkrEEgCXLtX3gqa2ryJFIkrXkZiqoqRvo36IFwkWLo2tGPA9IqacH/mqYgrhxHj1TjyVURVTtS0c6pi1PuUQCIEQCIHnIxAx9XxrdkrEVSi4AFR/rZhCmPRC6UgAIZQ0Lt/yqG1/KYb+W64qzGp74tW9j0c2fT4jpogrYqrSTjkEQiAEXptAxNRrr+/NZidxcelS/bViSm0lNj4jpvhmh2+gakx8QyTbkTCjPfGqD3Ej1PDzGTElv4ptVEwxppsXMeceAiEQAiGwJoGIqTXXZbmoJBIuXap3H76pQQQhciQerhFTvShBdLhYGEN+Geejb6Zopz70x1bFlJubYtNFTPSTnz5u4mUM+mLHR8QURHIPgRAIgechEDH1PGt1aqTXiCm+4XGBVhGBcKjfBKkPYqQXLurLRV+e650xRsQUokexKH75J44qpmoMdUyViUnjyofiZ259P2LsxVTvM88hEAIhEALPQyBi6nnW6tRIbymmJDqqYJIY0VVFjJ6rMGHyiBH3DQ6ixvmiP3eNj/ijrLtEUI0DsdWLIvzozriKifbMr+9H/BFTlWDKIRACIfDcBCKmnnv9Hha9xMGlC0Fy1KYXETyr35GYqqIL8cE3PhI89aLtka/aVuUaL2JINvmZEVPyXf1FTPXk8xwCIRACr0cgYur11vQuM5LQuHRVceLaIZ4QRWqjPvpcEkAIG75FUj/ESvXFt1gSQ7roJ/HlrhovbRmDZ/XVGGrbi6Lqk3gYG2Hn+jkO8tX7qP5TDoEQCIEQWJtAxNTa67NMdBIGly7VH30kLpyIQLRcElMaE6Gk9lz0ZUyE0FE97XTXpTt9esGE7yqman/K9HdCiPn2Igx7FYKKx/lgLrmHQAiEQAisTSBiau31WSY6RMgyASWQEAiBEAiBEFiEQMTUIguxehgRU6uvUOILgRAIgRA4i0DE1Fnkn2zciKknW7CEGwIhEAIh8DACEVMPQ/3cA0VMPff6JfoQCIEQCIH7EYiYuh/bl/IcMfVSy5nJhEAIhEAI3JBAxNQNYb6yq4ipV17dzC0EQiAEQmCGQMTUDL2N+kZMbbTYmWoIhEAIhMAQgYipIVz7No6Y2nftM/MQCIEQCIHLBCKmLvNJ7T8EIqaSCiEQAiEQAiHgCURMeS6xdgQipjogeQyBEAiBEAiBfwhETCUVriIQMXUVpjQKgRAIgRDYkEDE1IaL/pkpR0x9hlr6hEAIhEAI7EAgYmqHVb7BHCWmlCz5hEFyIDmQHEgOJAf+zoH+Vfsv1SBguUIg30zN50D2UhjOE2gekk+NhSuFj6PibTnfPZcRq8u3iKkRgpu0zWabX2i32ea97uUhDNt6h0Vj4Urh46h4W853z2XE6vItYmqE4CZts9nmF9pttnmve3kIw7beYdFYuFL4OCrelvPdcxmxunyLmBohuEnbbLb5hXabbd7rXh7CsK13WDQWrhQ+joq35Xz3XEasLt8ipkYIbtI2m21+od1mm/e6l4cwbOsdFo2FK4WPo+JtOd89lxGry7eIqRGCm7TNZptfaLfZ5r3u5SEM23qHRWPhSuHjqHhbznfPZcTq8i1iaoTgJm2z2eYX2m22ea97eQjDtt5h0Vi4Uvg4Kt6W891zGbG6fIuYGiG4SdtstvmFdptt3uteHsKwrXdYNBauFD6OirflfPdcRqwu3yKmRghu0jabbX6h3Wab97qXhzBs6x0WjYUrhY+j4m053z2XEavLt4ipEYKbtM1mm19ot9nmve7lIQzbeodFY+FK4eOoeFvOd89lxOryLWJqhOAmbbPZ5hfabbZ5r3t5CMO23mHRWLhS+Dgq3pbz3XMZsbp8i5gaIbhJ22y2+YV2m23e614ewrCtd1g0Fq4UPo6Kt+V891xGrC7fHiqmfv78+VsL6T7fvn17m8vXr1/f6n/9+vWb9tR9NFn5/fLly1uz79+/v/n58eOH7aZ2JJXaqKw+umoMtvOLG+GyyjRZK+VEf1HX289+dpvt7JiebfwwbCsWFo2FK4WPo+Jtq53vPsq1rS7fThFTl8RRFTKriCnFcSnmtZd9PLoVN5tEkz71QjBX2yplt9lWie1Z4gjDtlJh0Vi4Uvg4Kt624vnuI13X6vJtaTE1g5IX7dE3U9V3/81UrRsVdLXvs5ZX3GysA98e8qz7ipfbbCvGuXJMYdhWJywaC1cKH0fF21Y8332k61pdvi0tpnhh1m+FlAh8ZFeZF6rKfHuBmKKN6vStF1f99VAvpvh27D//8z//jMWY/TckfV/8c6cfd+y6EyN1zAM7cTB/Ylb7Ohf5oq3qYFDHwKfrW2NSWW1WvJgDeaHnVS+32VaNddW4wrCtTFg0Fq4UPo6Kt616vvto17S6fHv31nQNbjkVXoJazP6DkEAUuD8zVesUFz7oq2eEBC9eRAeipxcm8kMdL+c6DjHTD7+MiVhzf56n1qle8RHPJT/UMaZiJCaV8UV9HQcu/Th9W8356FKcq14IStZ51TjvvZdWnfct4wrDRjMsGgtXCh9HxdtWPt99xOtZXb69e2u6BrecRi9MnG9EQy+mEBCIBPVFRCBsnJiqoqHW81KWnxExxRwQXvJZY6pzYi5qQ4zUa/wjQYCYInbmjiCSD3yr3McAF/XrfTFXfBNPvcvfqhfzgf+qcd57L60671vGFYaNZlg0Fq4UPo6Kt618vvuI17O6fHv31nQNbjkNhEgVBb1/RMKRmKp9EQ0IFSUJAoWXLnUapwoYlUkqBAYv6KMYiBU/zId+1HNHBGkcPrStsdKeO7EjeJwf/KkP5f5+SUwRB2PWu/yseMGbtatru1q8995Lq833HvGEYaMaFo2FK4WPo+Jtq57vPto1rS7f3r01XYYz13UAACAASURBVINbToWXYRVEvf8jIYOgUD3XNWIKQaI+SiK9iHXxQlb5kphi3BozYqfG+ub0wn/ooxjks47fd6MtsbsYah/5rFxqXe+rn2ttS3nVzVbnqfmylsS90v3ee2mlud4rljBsZMOisXCl8HFUvG3V891Hu6bV5dvTiCkhreIFgaHE4BsKlXnBIiIQGb2IqGKmr3PjVDFVx2Y8t+R1jBq/ysSHYKrCsK+rfTU24zO32ldtHQfG6eeq9v214mZjjsQKg7ou1K1wd5tthbieKYYwbKsVFo2FK4WPo+JtK57vPtJ1rS7fThFTWsz+gyipQsZ9k1X78YLVi1WX6vCDIKGN6hAfaluFTi8wagxqy7N8cGHTOJcuxiFuhJ/6ECN1CB7sPOO/+mKe1BEPvrD3vvq50q7e6zyr/awyMVd2ioW59faz4qzjus1W61P+mEAYNkZh0Vi4Uvg4Kt622vnuo1zb6vKtqYPfv3+7BitPCaGEmHpkrIiXM8a+9zxX2mwIKQknd7EOqwmqZ9tLju3ZtjBsKxAWjYUrhY+j4m0rne8+wvWtLt+eSkzxzQwvTj3339A8Yhn4FdMZYz9iftls85TdZpv3upeHMGzrHRaNhSuFj6PibTnfPZcRq8u3pxJTI5NN288TyGb7PDt6us1GXe7XEQjDxiksGgtXCh9HxdtyvnsuI1aXbxFTIwQ3aZvNNr/QbrPNe93LQxi29Q6LxsKVwsdR8bac757LiNXlW8TUCMFN2mazzS+022zzXvfyEIZtvcOisXCl8HFUvC3nu+cyYnX5FjE1QnCTttls8wvtNtu81708hGFb77BoLFwpfBwVb8v57rmMWF2+RUyNENykbTbb/EK7zTbvdS8PYdjWOywaC1cKH0fF23K+ey4jVpdvEVMjBDdpm802v9Bus8173ctDGLb1DovGwpXCx1HxtpzvnsuI1eVbxNQIwU3aZrPNL7TbbPNe9/IQhm29w6KxcKXwcVS8Lee75zJidfkWMTVCcJO22WzzC+0227zXvTyEYVvvsGgsXCl8HBVvy/nuuYxYXb5FTI0Q3KRtNtv8QrvNNu91Lw9h2NY7LBoLVwofR8Xbcr57LiNWl28RUyMEN2mbzTa/0G6zzXvdy0MYtvUOi8bClcLHUfG2nO+ey4jV5VvE1AjBTdpqsylZ8gmD5EByIDnwWjmQ8/0269nLgYipnkief+cnl/kk0Aso1xyBMGz8wqKxcKXwcVS8Lee75zJidfkWMTVCcJO22WzzC+0227zXvTyEYVvvsGgsXCl8HBVvy/nuuYxYXb5FTI0Q3KRtNtv8QrvNNu91Lw9h2NY7LBoLVwofR8Xbcr57LiNWl28RUyMEN2mbzTa/0G6zzXvdy0MYtvUOi8bClcLHUfG2nO+ey4jV5VvE1AjBTdpms80vtNts81738hCGbb3DorFwpfBxVLwt57vnMmJ1+RYxNUJwk7bZbPML7TbbvNe9PIRhW++waCxcKXwcFW/L+e65jFhdvkVMjRDcpG022/xCu80273UvD2HY1jssGgtXCh9HxdtyvnsuI1aXbxFTIwQ3aZvNNr/QbrPNe93LQxi29Q6LxsKVwsdR8bac757LiNXlW8TUCMFN2mazzS+022zzXvfyEIZtvcOisXCl8HFUvC3nu+cyYnX5FjE1QnCTttls8wvtNtu81708hGFb77BoLFwpfBwVb8v57rmMWF2+RUyNENykbTbb/EK7zTbvdS8PYdjWOywaC1cKH0fF23K+ey4jVpdvEVMjBDdpm802v9Bus8173ctDGLb1DovGwpXCx1HxtpzvnsuI1eXb3cSUFuzLly9Xx6e26rPaQv/48eMtpu/fv189l2dvuNoakBu/fv36Cy11f1WcbHCb7eSQnm74MGxLFhaNhSuFj6Pibaud7z7Kta0u35YQUwgW3Ve7iO2VxNRHInfFzaaY+7i1JivGqhx2m2213F49njBsKxQWjYUrhY+j4m2rnpk+2jWtLt+WEFO8FCOm7p842ki9KOlHXXGz/fz58903hDzrvuLlNtuKca4cUxi21QmLxsKVwsdR8bYVz3cf6bpWl28PEVO8+L59+/b2ItdisqAIKWxqo4s+2Os3Q2oj+9evX/+8YPUskYBNz3yrhI/64q3tenFR64ivjl+X+FKc+rUUY+vO3NS/+qWNxuXq/dY6taFP75fY8a96Ytc8a7/Kg3HxXZ9XKTMn2DCvVeKrcbjNVutT/phAGDZGYdFYuFL4OCrepndArjkCLt/eUXUNPjukFgyRwsuPZ0QO4oKXJN9MUc/Lkv60R0xRrxgRCRIwVcQgGGo89OfP4KgOsUIdsVRx0rMgLuIgbt2pI2ZiYhzmTH0/rlj1vBin1jEOdcRL/Gqr+dW54refD89qv+rFfD6aw9nx33IvnT2Xs8YPw0Y+LBoLVwofR8XbVj7ffcTrWV2+vXtrugafnYYWjBceL3yEA8KCZ4QFAgBBUMeuNoSH/HLV8WTrnxUL8agOUaO2+FNcaqN6LgQSYgV736/aj+rqOP2cGQcGioFP9Q3LGk+dG5wQT3VM+ZFPOFS/tVznX+0rlOFW579CXH0Mt9xLve9dnsOwrXRYNBauFD6OiretfL77iNezunxrquHGf2i2vrQRAHqx60JMIWh4QSIkekGjPlUkIBBGxRRJpLv7IKaq2EDkuJd3jalfbldX4+7n3I/Dc41T84VltatMzP24dUzFWNv2MfOsNitezJ38qOu/Wrxus60W4+rxhGFbobBoLFwpfBwVb1v1fPfRrml1+fburekafHYq9aXNS/BaMYUgqGNXWy8Q1K6O5555AVMnf+6q7VSPqHFiysWBT+r4hkj2avtITOFHd+au2GDp4qltGZcxER7yoc+la9XNprhYN90/mselOd677pZ76d6xruo/DNvKhEVj4Urh46h426rnu492TavLtyXFVC9gegHRCwThHhFTff/atxc5CBknXohL/nTVuPs6vo2jbT9O7UtbhAPz41kigg3Rj0O8ryamWLM30OXbTXhiX+XuNtsqsT1LHGHYViosGgtXCh9Hxdt4d/jaWK8h4PJtSTGlySAStPD6VDHDi1VtuNSmflPRP1cBoj6IDvzjp69jrDp+bdvHWV/uiCLGqHWXxJT8933lo1741B2RpXrmdSSmGFf9Kr/ed30+u4zQ7ONlLr397Hg1vttsK8T1TDGEYVutsGgsXCl8HBVv698lvlWslwi4fHv3hnYNLjlM3WsSWGmzIaSOxCzicTVBlb00vzfCsDEMi8bClcLHUfG2lc53H+H6VpdvEVPrr9vDI8xmm0fuNtu81708hGFb77BoLFwpfBwVb8v57rmMWF2+RUyNENykbTbb/EK7zTbvdS8PYdjWOywaC1cKH0fF23K+ey4jVpdvEVMjBDdpm802v9Bus8173ctDGLb1DovGwpXCx1HxtpzvnsuI1eVbxNQIwU3aZrPNL7TbbPNe9/IQhm29w6KxcKXwcVS8Lee75zJidfkWMTVCcJO22WzzC+0227zXvTyEYVvvsGgsXCl8HBVvy/nuuYxYXb5FTI0Q3KRtNtv8QrvNNu91Lw9h2NY7LBoLVwofR8Xbcr57LiNWl28RUyMEN2mbzTa/0G6zzXvdy0MYtvUOi8bClcLHUfG2nO+ey4jV5VvE1AjBTdpms80vtNts81738hCGbb3DorFwpfBxVLwt57vnMmJ1+RYxNUJwk7bZbPML7TbbvNe9PIRhW++waCxcKXwcFW/L+e65jFhdvkVMjRDcpG022/xCu80273UvD2HY1jssGgtXCh9HxdtyvnsuI1aXbxFTIwQ3aZvNNr/QbrPNe93LQxi29Q6LxsKVwsdR8bac757LiNXlW8TUCMFN2mqzKVnyCYPkQHIgOfBaOZDz/Tbr2cuBiKmeSJ5/5yeX+STQCyjXHIEwbPzCorFwpfBxVLwt57vnMmJ1+RYxNUJwk7bZbPML7TbbvNe9PIRhW++waCxcKXwcFW/L+e65jFhdvkVMjRDcpG022/xCu80273UvD2HY1jssGgtXCh9HxdtyvnsuI1aXbxFTIwQ3aZvNNr/QbrPNe93LQxi29Q6LxsKVwsdR8bac757LiNXlW8TUCMFN2mazzS+022zzXvfyEIZtvcOisXCl8HFUvC3nu+cyYnX5FjE1QnCTttls8wvtNtu81708hGFb77BoLFwpfBwVb8v57rmMWF2+RUyNENykbTbb/EK7zTbvdS8PYdjWOywaC1cKH0fF23K+ey4jVpdvEVMjBDdpm802v9Bus8173ctDGLb1DovGwpXCx1HxtpzvnsuI1eVbxNQIwU3aZrPNL7TbbPNe9/IQhm29w6KxcKXwcVS8Lee75zJidfkWMTVCcJO22WzzC+0227zXvTyEYVvvsGgsXCl8HBVvy/nuuYxYXb5FTI0Q3KRtNtv8QrvNNu91Lw9h2NY7LBoLVwofR8Xbcr57LiNWl28RUyMEN2mbzTa/0G6zzXvdy0MYtvUOi8bClcLHUfG2nO+ey4jV5VvElCH47du3t3+f7suXL3/Vfv369a3u169fv3/+/PlWVvtHXjWGe4ybzTZP1W22ea+f96Bc1roqb/uLut5+9vNqDM/kERaX6YfPZT61Nud7pfG5ssu3iCnDUsnGR4KpXlXIPFJMVWFXY6ix3aqczTZP0m22ea9zHpRDNY/k7fv372+5Puf5Pr1XZHifmX7sNSwuMwqfy3xqbc73SuNzZZdvEVMdyx8/fvz5tklJ13/rVIXMo8SU4uhfgl3YN33MZpvH6TbbvNc5D+SrBJQunnVf8VqR4VmcwuIy+fC5zKfW5nyvND5XdvkWMdWxrGLJ/SRf63kZVcHFrwiVsPr0v1bBrrt8cSHiqMenYsCmu8asMai/xqht6Ks6vnngrnZ1XMavd7XJNUfAbbY5j7fpTR6Quwir23i/rZdVGd52ltd5C4vLnMLnMp9am/O90vhc2eXbu7ema/C5oZ63VxUbCKP6k3sVMryQEC+1TgT6/tU3AkhtKPNiqy88+VG/+s1UHaePAV8IJnwRIzFJvB1d2WxHZK63r7yXEOg1p66f2eNarszwcRT+e6SwuEw8fC7zqbU53yuNz5VdvkVMFZZ8O4So6YWKmh4JGUQMokVtqw3fl0QM4ynZ9aGtyvXFV2NAHGksrmpDTOHrmjiy2SD5+bvbbJ/3dtue5AR5flvvt/O2MsPbzfI6T2FxmVP4XOZTa3O+VxqfK7t8i5gqLKtIwXxJyCB+JF5qmb6IKfnlBYaooY3utNNYKvdtL8XgYkZMKabeF2Lq0os0m62uzufKbrN9ztNte5GnfDul51WvVRmewSssLlMPn8t8am3O90rjc2WXbxFThaWS7OjDS6eKF15MEi8IIpW5qu2SiEHwMAbPCC+9+G79zVTEFKt0n7vbbPcZacyr8ls5rEv3mldjnu7felWG95/53yOExd9MqiV8Ko3L5Yipy3yuqXX5FjH1D7kjsYMdkXQkpuSm1umZb4gkqnQpiXl5IbTUB/GEwFEbtb1GTFVBpzHwS7z4xhfzYay3wLr/ZLN1QD7x6DbbJ9zctAv5iNM+V7Cvcl+R4VlswuIy+fC5zKfW5nyvND5XdvkWMfUPS4QQ3w6BmBcOIoh2svdCRn14YSlh9VG7emHXHZ+qR0DJjo9eEKlOY9YY1JcY8U0/1UVMVfqPK7vN9rjR/x4JEd3nN/nR2//28HjLagwfT6CNGBaNhSuFj6PibXpP5Joj4PLtHVXXYG7I9H5GAtls86u20l5CSB19G4k4X01QrcRwPiPmPITFZX7hc5lPrc35Xml8ruzyLWLqcyxfulc22/zyus0273UvD2HY1jssGgtXCh9HxdtyvnsuI1aXbxFTIwQ3aZvNNr/QbrPNe93LQxi29Q6LxsKVwsdR8bac757LiNXlW8TUCMFN2mazzS+022zzXvfyEIZtvcOisXCl8HFUvC3nu+cyYnX5FjE1QnCTttls8wvtNtu81708hGFb77BoLFwpfBwVb8v57rmMWF2+RUyNENykbTbb/EK7zTbvdS8PYdjWOywaC1cKH0fF23K+ey4jVpdvEVMjBDdpm802v9Bus8173ctDGLb1DovGwpXCx1HxtpzvnsuI1eVbxNQIwU3aZrPNL7TbbPNe9/IQhm29w6KxcKXwcVS8Lee75zJidfkWMTVCcJO22WzzC+0227zXvTyEYVvvsGgsXCl8HBVvy/nuuYxYXb5FTI0Q3KRtNtv8QrvNNu91Lw9h2NY7LBoLVwofR8Xbcr57LiNWl28RUyMEN2mbzTa/0G6zzXvdy0MYtvUOi8bClcLHUfG2nO+ey4jV5VvE1AjBTdpms80vtNts81738hCGbb3DorFwpfBxVLwt57vnMmJ1+faXmFKjfMIgOZAcSA4kB5IDyYHkgM+BXnz9Jab6Bnnej0B+ctlvzTPjEAiBEAiB6whIYPZXxFRPJM+/I6aSBCEQAiEQAiHgCURMeS6xdgQipjogeQyBEAiBEAiBfwhETCUVriIQMXUVpjQKgRAIgRDYkEDE1IaL/pkpR0x9hlr6hEAIhEAI7EAgYmqHVb7BHCOmbgAxLkIgBEIgBF6SQMTUSy7r7ScVMXV7pvEYAiEQAiHwGgQipl5jHe8+i4ipuyPOACEQAiEQAk9KIGLqSRfu0WFHTD2aeMYLgRAIgRB4FgIRU8+yUifHGTF18gJk+BAIgRAIgWUJREwtuzRrBRYxtdZ6JJoQCIEQCIF1CERMrbMWS0cSMbX08iS4EAiBEAiBEwlETJ0I/5mGjph6ptVKrCEQAiEQAo8kEDH1SNpPPNYlMfXr16+3f7vv69evbzP8/v372/O3b9/ezVg+vnz58pv2enafnz9//lZfVyeb6vU5qpd/XdS/C+L37z++f/z48adM23qv4yjuemmuaquxVFf71bJYwEPjcTkGtV7t8MN8ZHO+alv6ME7uIRACIRAC9ycQMXV/xi8xgl7SRxfCoBdT6iNBwqXnXpRIQMgukVAvxFTtX+sRU71gQ9ioLT56kUIbxU2bj8bpY6xiirh6Dth7AUTs8FI7ONT5aEx9arvel/qqHq5HMRBL7iEQAiEQArcnEDF1e6Yv6VEv9aOrf4Hzwu+FgJ556eMLEXErMVXFEb6rQOljre2Jqd4RPoq9MpgRU4i5Oo7KcEPYMabu2GhTBaLqq+Dq/eY5BEIgBELgvgQipu7L92W8VyHRT6oXKLzwEQO8+PX8SDGlOPsxiU13XaNiCmH2WTEFK/xUlgg3YoNfnQPxw5Q5qo0TVPh049WxUw6BEAiBEPg8gYipz7Pbqqde1kcXAoGXOS987gioKgrwxbdHCAjsiBz1qR98HYmEfgxED9/s8KyYdY2MwzdK6tv7ka+eA3OBg+ZK3P18a3+ED3MhRvWvvnr/cKpCi/HwSZ/cQyAEQiAEbkcgYup2LF/ak17UR1cvIuoLvwoBxEH185GYQgTVPiojEhAQ3BFbtCcWxEsfA/F9NI7aEavKjxRT8NXcmE8VTJorscFB8eUKgRAIgRB4DIGIqcdwfvpR9JI+unjZ8wLvX/i84HshI3+IAMQOY4yIHPWhve71qrG5seh3jZiSX0QUc5J/rjoWNt0rD9r0caodAhEWlRc+GLcXU4zHfNSuxkZ97iEQAiEQArcnEDF1e6Yv6VEv56MLgXAkpqoQ6L85cgJH4yAKrhU56sOv4RAjxIsdIVR9jo6D4EHUVMHSc2B85o8AIh7qufexaIzKizF1xxd96x0/NbZan3IIhEAIhMBtCURM3Zbny3rTC/zo6kVELx7UDwFRxYHstxRTVehUIUE8vTjR+AiPKrDqPPGpdlz0kb86Ts+B9oyPAMIn4lPt4FDH6eOljey9r9pPjOHMWLWeuHIPgRAIgRC4DYGIqdtwfHkveoEfXb2I6MWD+iEEeMnjC7v61KsKFo1dP2p7JBLoV4UKbeWjFxW0r/4pH43DfNXuM2KKeTIOdwRSre956Vnta1sY4kd3Lubez5v63EMgBEIgBOYJREzNM9zCQ31BbzHhTDIEQiAEQiAEriQQMXUlqN2bRUztngGZfwiEQAiEwBGBiKkjMrG/IxAx9Q5HHkIgBEIgBELgD4GIqT8oUrhEIGLqEp3UhUAIhEAI7EwgYmrn1R+Ye8TUAKw0DYEQCIEQ2IpAxNRWy/35yUZMfZ5deoZACIRACLw2gYip117fm80uYupmKOMoBEIgBELgxQhETL3Ygt5rOhFT9yIbvyEQAiEQAs9OIGLq2VfwQfFHTD0IdIYJgRAIgRB4OgIRU0+3ZOcEHDF1DveMGgIhEAIhsD6BiKn112iJCCOmlliGBBECIRACIbAggYipBRdlxZAiplZclcQUAiEQAiGwAoGIqRVW4QlikJhSsuQTBsmB5EByIDmQHPg7B/pXefsn53//fnt59g3yvB+BfDM1v+Y6fHLNEQjDxi8sGgtXCh9HxdtyvnsuI1aXbxFTIwQ3aZvNNr/QbrPNe93LQxi29Q6LxsKVwsdR8bac757LiNXlW8TUCMFN2mazzS+022zzXvfyEIZtvcOisXCl8HFUvC3nu+cyYnX5FjE1QnCTttls8wvtNtu81708hGFb77BoLFwpfBwVb8v57rmMWF2+RUyNENykbTbb/EK7zTbvdS8PYdjWOywaC1cKH0fF23K+ey4jVpdvEVMjBDdpm802v9Bus8173ctDGLb1DovGwpXCx1HxtpzvnsuI1eVbxNQIwU3aZrPNL7TbbPNe9/IQhm29w6KxcKXwcVS8Lee75zJidfkWMTVCcJO22WzzC+0227zXvTyEYVvvsGgsXCl8HBVvy/nuuYxYXb5FTI0Q3KRtNtv8QrvNNu91Lw9h2NY7LBoLVwofR8Xbcr57LiNWl28RUyMEN2mbzTa/0G6zzXvdy0MYtvUOi8bClcLHUfG2nO+ey4jV5VvE1AjBTdpms80vtNts81738hCGbb3DorFwpfBxVLwt57vnMmJ1+RYxNUJwk7bZbPML7TbbvNe9PIRhW++waCxcKXwcFW/L+e65jFhdvk2JqZ8/f/7Wwnz79u0tDt31/OPHjz9x9W2+f//+1kbt6ufLly9/+qh/ratl9edy7X79+kX1b5VrX5Vd/2pTZ+ah2Im/96NnxnLj0P7r169/4nmWgmLPNUfAbbY5j/v1PoshZxT7G/JHdurveT+LBXPiTOSZ+5Gd+kfdz+bDPPUec2f+kZ1+j7yveL4rJuVSfx3Z+3aPfnb59u6t6RpcCpLDBTGihNHkazIheBBYqlObelAhWIDJBpX96MJPbcP4+NY4xCY/xEssR+NUP30f4pFvtdPFHOtYtHvGu+aWa47A6F6aG+01e5/JUGcD+1t0+YGJs+XRxM9kwVx15taznXOb+jPvK/Bh/u69U7nR7qz7iuc7+4t3s9hoD+qz4uXy7d1b0zW4NJFejGiR+HDo9G0QKtUvIEk43eUHH7WtykcCp7a7RuAcjaOxOUj7+BmjzuOaeOj3DHfNP9ccgdG9NDfaa/Y+m6H2AT8gab9TPoP22Sw0Z85pXnjiQ/kMJnXMFfgQD+8e8UJwHr3L6PPI+6rnO+9RsYDhI7mMjOXy7d1b0zW4NACCoiYNAoVNxrP8sBllqxcJhwrVYiNmajvKjMuzu7MYl3y5uj7Go7FqX+Z47YZhDHwQq+7UiQVCTnbaqI8+9WCnTndd+IAz8XFXf9o6dqrPNUdgdC/Njfaavc9myL7SPmQvnUX6bBbMmxce5xP2s++r8IGD8kUfvT8unbW0f+R95fNdvHjv1d86PZLPNWO5fHv31nQNLjnWomjyujh4dJeNw0dl2vSiCd+qly/VIwT03H8EmXr846O/0676qH2or7Y6D8SK+hM/Y7DYtCH+Opbrp/6Mi0+4qb3mDyN86s4Bxng8s0mJR77dHPAl37p4fnsw/1EsueYIjO6ludFes/cKDHU+aD+wt84ivQIL5v7R+UG7R95X4qN5c87375dHMjkaa+Xznfef3mkrXy7f3r01XYOjCTFpkqW+0HnZ0wYw2LWY/YdxEBcIB+zce5/Yj+79OMRyNA4xqp6xeh96Vp2u0U2Df/rLB/5Vpl4HFpfq6zNjMpf+cMOHxqAt6ySfda0Yo941Xq45AiN7aW6k1+29AkP2pvbUmdcKLDR/zhNx4Ye5M7kw9ip8iIf3iziJ2UrXyuc7766VY9Raunx799Z0DY6SgGThkOEnOLVHhGCjDS9xhATgqFdfbEcbFd8IiaP4ersWRx9EydE4xKwN0M+RsaswwXZtPPiv8dW4qIcRh1f1X22Ua0z40BjEVxmzDurrrtUT2cW8mm1kL60W+yrxnM1Q+0R7iXPgaL88gtfZLJijeIgL5yf2s++r8IGDzlDljXjps9K16vnOu0zvLL2n6ztvJX6KxeXbp8UUL2REjxaoJg3flsiOMMBWwfQ2+VCfSwdXP1b1d6lc+xE/sdFPbRSTLtemt3GowAE/R3fmRz1iR351aWzG1zMJRr1sjKk7B73KXHUOtS31/RjYuat/rjkCbrPNedyv95kM2VecQ9q39Xx79GqcyYK5cpbwrHOknkvYz7ivwId511zh/L72/YCPe95XPd9rPvFe7N/P9+Qy4tvl27u3pmtwNACiQMlCwtSNxcbTwnEg1Zc8fmmnuy4B/WixNY7a1ATFpjsHIT7ll8WhD21qzPhgAesciRc/HKx9H9od3fv2zFexwhHf+KANz5Uj/JgXMTMvnuVDF/OubPDL/SP+tMv9mMDIXjr2snfNmQz784W9yT579MqcyUJzZf6cjbJxFlbbo7kw3tl8iIPzlWfdOaOr7czyiue7GPGOgo3eYb2NurPvLt8+Laa0ICwKCVRf0Gw+YLDxeMlXGPiiD8/9vW5aREltU32SwLW+9ldb4q5tFAOX7MSPTXcEivypvvav5cqj9q9tqi8YuX61T42pZwYXoCQh1wAAIABJREFUDn211Ydx5Mf57+OrzymPE3CbbdzL3j3OYqg9ov3SX5wp/TnSt7vH81ksNBfOGHd2c97Uc/Me8//I55l8iI33CWcvdt05h6vtrLLye6Xr0r462otnx+/y7R1V1+DsoF99fETOPebJIeheDJfGW22zXYp11brspfmVCcPGMCwaC1cKH0fF23K+ey4jVpdvEVMjBCfb8pML3wx9VuxcG8alb7ou+chmu0Tnujq32a7rmVYQCENI+D/w2mpTSq5cnwM5369nddTS5VvE1BGtje3ZbPOL7zbbvNe9PIRhW++waCxcKXwcFW/L+e65jFhdvkVMjRDcpG022/xCu80273UvD2HY1jssGgtXCh9HxdtyvnsuI1aXbxFTIwQ3aZvNNr/QbrPNe93LQxi29Q6LxsKVwsdR8bac757LiNXlW8TUCMFN2mazzS+022zzXvfyEIZtvcOisXCl8HFUvC3nu+cyYnX5FjE1QnCTttls8wvtNtu81708hGFb77BoLFwpfBwVb8v57rmMWF2+RUyNENykbTbb/EK7zTbvdS8PYdjWOywaC1cKH0fF23K+ey4jVpdvEVMjBDdpm802v9Bus8173ctDGLb1DovGwpXCx1HxtpzvnsuI1eVbxNQIwU3aZrPNL7TbbPNe9/IQhm29w6KxcKXwcVS8Lee75zJidfkWMTVCcJO22WzzC+0227zXvTyEYVvvsGgsXCl8HBVvy/nuuYxYXb5FTI0Q3KRtNtv8QrvNNu91Lw9h2NY7LBoLVwofR8Xbcr57LiNWl28RUyMEN2mrzaZkyScMkgPJgeTAa+VAzvfbrGcvByKmeiJ5/p2fXOaTQC+gXHMEwrDxC4vGwpXCx1HxtpzvnsuI1eVbxNQIwU3aZrPNL7TbbPNe9/IQhm29w6KxcKXwcVS8Lee75zJidfkWMTVCcJO22WzzC+0227zXvTyEYVvvsGgsXCl8HBVvy/nuuYxYXb5FTI0Q3KRtNtv8QrvNNu91Lw9h2NY7LBoLVwofR8Xbcr57LiNWl28RUyMEN2mbzTa/0G6zzXvdy0MYtvUOi8bClcLHUfG2nO+ey4jV5VvE1AjBTdpms80vtNts81738hCGbb3DorFwpfBxVLwt57vnMmJ1+RYxNUJwk7bZbPML7TbbvNe9PIRhW++waCxcKXwcFW/L+e65jFhdvkVMjRDcpG022/xCu80273UvD2HY1jssGgtXCh9HxdtyvnsuI1aXbxFTIwQ3aZvNNr/QbrPNe93LQxi29Q6LxsKVwsdR8bac757LiNXlW8TUCMFN2mazzS+022zzXvfyEIZtvcOisXCl8HFUvC3nu+cyYnX5FjE1QnCTttls8wvtNtu81708hGFb77BoLFwpfBwVb8v57rmMWF2+RUyNENykbTbb/EK7zTbvdS8PYdjWOywaC1cKH0fF23K+ey4jVpdvW4qp79+/v/37cz9+/LD8vnz58u7fp6O9kpDPr1+//upb27n6vzosashmm18Yt9nmve7l4QyGOhOU/9++ffsLNnXa54++zmDBHJn3akyIT/cz+RDH169f33Ln58+fmP7cqVvhvbDi+X60547sf8CeVHD5tqWYupTYSnYtoASVLg6Sugl6scV6qh8ft6Fot/pdc8g1R8BttjmP+/U+iyF7Xvd6aV+cIaQUw1ksmP+KTIhtBT7EwruFZ91hV98htf7R5RXPd967dc9JvDsB/2hebjy3H9+9NV0D5+jZbUdiSPOSCFKysYhsjo82At9K0b4mxbPxWnGzPRvDXfbSPdflTIbsY+anZ33Ous5kwZxXY0Jcuq/AR3EgCnh/8LzS+2DV8513qDgiQOsar1R2+badmCK5jw5GFpSfQDlAlIDY3KKqXiINMXapLTHQh8TRnTpUudrIThs961P9U6e7LnwwR+bAHZ9uHrKpPtccAbfZ5jzu1/tshtoH2jPaa2fvibNZkH0rMSEm3Vfho1jqeax3AsKqxntm+excvjR3eCnGlX+74/Lt3VvTNbg08WesQ+wcJbjsdSE5SGXjg2hh/rSRHSFz5J96JY0uNh5jEp/qZdMd/7rr4pk4iFm+q0/a44vk5PmtsfmPxs01R2CHvTRH6OPeZzOse5O99nHU92lxNgtmtRITYtJ9FT7EVH9wxbbKfeXznfff0ftzFYYu3969NV2DVYK/VRy9EOn9IjQQJqqvB4gSUR+Eier1rH5cKtdn7Lozft+fBKe+9u/9I8hIOLWlfz8GbbW5uXrxhZ179YUt9zECO+ylMSLjrVdgqL2wwn5YgQUruAoT4tF9JT6Kh3cGZ3SN9ezyCvl8xID338oxKnaXb9uJKYREFTN1YbWIVcjUOjaI2mjRdbH4quPipxKe693V1TGpJz7EUN2U1Ua5iiV8aFz5qfHKBgP1dZfa55oj4DbbnMf9ep/NUPuIH1Tq/jpjJc5mwZxXYkJMuq/CR7FwJpM79d1QYz6rvOr5Dje9s8SuvvPOYnU0rsu3d29N1+DI2bPaSXAXP8Lj0sGJoGKDKDGPPk6syHdNZsYkcRSfPlwkGPWyI+B0Jx7EnerlHx+1LT77MbBzr/Fhy32MwA57aYzIeOszGbJvtD/Zo+z58ZnM9ziTBdGvxoS4dF+BD/HU85UfXKlb4b7q+S5uvOfYc7qveLl8205MVaHRL1IvTBA+VRTVzcHh0h+y2F0i0J86JZBiUh+EUy/maEO8dQ6MRQzETFLyLB+6+jnis95X3Ww1xtXLbrOtHvNq8Z3FkH2ovcXFvq1nAXWPuJ/FgrmtyITYdD+bD7FwHtc80Xnan+m0P+O+4vkubryjYKI919uoO/vu8m0rMYXaVTL1Hy0cBybCRAuGkKE9i8vhwnNdXARL9VPr8aU7YkexEV89xOlX+9QxiYP6fg5qqw/jqJ3zzzi6q02uOQJus8153K/3WQzZLz1x7YuzXopnsYDBikyITfez+SgGzu/+3P/ofVDn8Yjyauc7AlT8+uvMPdfHUp9dvr17a7oG1UHKtyeAyLm95/a7+9EXwGqb7R5s7u0ze2me8BkMJRqO8p+X5eh+midxrlhYlUnlekau1PHJDf0w667+h1zX5lG2o/x+1PivMI7Lt4ipB64sP6HwzRDfKt3rcGaDM961U81mu5bUcTu32Y5bp8YRCMNGJSwaC1cKH0fF23K+ey4jVpdvEVMjBDdpm802v9Bus8173ctDGLb1DovGwpXCx1HxtpzvnsuI1eVbxNQIwU3aZrPNL7TbbPNe9/IQhm29w6KxcKXwcVS8Lee75zJidfkWMTVCcJO22WzzC+0227zXvTyEYVvvsGgsXCl8HBVvy/nuuYxYXb5FTI0Q3KRtNtv8QrvNNu91Lw9h2NY7LBoLVwofR8Xbcr57LiNWl28RUyMEN2mbzTa/0G6zzXvdy0MYtvUOi8bClcLHUfG2nO+ey4jV5VvE1AjBTdpms80vtNts81738hCGbb3DorFwpfBxVLwt57vnMmJ1+RYxNUJwk7bZbPML7TbbvNe9PIRhW++waCxcKXwcFW/L+e65jFhdvkVMjRDcpG022/xCu80273UvD2HY1jssGgtXCh9HxdtyvnsuI1aXbxFTIwQ3aZvNNr/QbrPNe93LQxi29Q6LxsKVwsdR8bac757LiNXlW8TUCMFN2mazzS+022zzXvfyEIZtvcOisXCl8HFUvC3nu+cyYnX59peYUqN8wiA5kBxIDiQHkgPJgeSAz4FefP0lpvoGed6PQH5y2W/NM+MQCIEQCIHrCEhg9lfEVE8kz78jppIEIRACIRACIeAJREx5LrF2BCKmOiB5DIEQCIEQCIF/CERMJRWuIhAxdRWmNAqBEAiBENiQQMTUhov+mSlHTH2GWvqEQAiEQAjsQCBiaodVvsEcI6ZuADEuQiAEQiAEXpJAxNRLLuvtJxUxdXum8RgCIRACIfAaBCKmXmMd7z6LiKm7I84AIRACIRACT0ogYupJF+7RYUdMPZp4xguBEAiBEHgWAhFTz7JSJ8cZMXXyAmT4EAiBEAiBZQlETC27NGsFFjG11nokmhAIgRAIgXUIREytsxZLRxIxtfTyJLgQCIEQCIETCURMnQj/mYaOmHqm1UqsIRACIRACjyQQMfVI2k881rVi6uvXr2//jp/uR5d81U/f7tu3b+/qf/z48adJ7VfLX758+dNGBeKgzc+fP9/V65k63Wu81V471bgUU++j9lPbGkedA/3URvbary/X8S/V1XYph0AIhEAIPJZAxNRjeT/taHqRf3T9+vXrnTDQc39JtCB8aF+FDOIC8YMowpfioH/vm+fv37+/xUEfte/j1zOChzHVT5fq+BCH7PhRnfpUUcTY/Z341YfrqB9irY5Jn4+40S73EAiBEAiBxxOImHo886ccsYqBowkgYhAFiJPaXn6qeKp1KtMXIdTXq/9HYgoB0/flGTHj4lMbxtAdwYXwk02fz4gpxmN8fBMXc3diSmNe4oaP3EMgBEIgBB5PIGLq8cyfckS9zD+6+OZG7Y5e/rIf1akfgkJtnKCS/VoxpbbuQsyoHoFT2zFG/TaIb68Qap8RU/KrOTH+qJhSfyeojvzVOaUcAiEQAiFwPwIRU/dj+1Ke9SK/dPHNDQIB0dELIokX+eIjUVIv/FDfiwfs/b2KIsQFbYipjkN8tKlxyibBRqyqQ+Rhq2IKH/WuGHQxDv3kh/j6uBiDvjVe+jNG5Xbkr/ZPOQRCIARC4H4EIqbux/alPOslfuniZc9LXnf1kb2/qEMY9IJJ7anjjtjR80ffTKl/L8rUr78QL4xBrIyBSFG8GlNx1nlS34uiOg5iSvHIh3wz/74f8TgxJZ/0I17HrY6dcgiEQAiEwGMIREw9hvPTj6IX+KULoUAbxMylFz7iQb4RS/TXHbGi+l7o1HaXylWAqOwuYtddl8bry7Kp/4yYqvORv1ExRewfcaNd7iEQAiEQAo8hEDH1GM5PP4pe/kcXwklt3McJJXwhDI7aIEA+K6Y0DoLqSEypjcRTL6Bk55slzUsxzoip3t9nxZT8fMRNbXKFQAiEQAg8hkDE1GM4P/0ol8RUFRh1otgRQgijKiKqiFFfPdex8KG+ulSH6Klj1XLfphce+ERcIQaJq/anLWPyrL5uPjUOlRFjiEXG0hiMRx/iZK7Y3TiVm6unb+4hEAIhEAL3JxAxdX/GLzGCXv5HFwIIwUA7XvL1V318SyR/fGjPHTt3RI/qsbk741fBQrteoCBcqK8xyoZ4Yg4IHyem8FHv9O/FlObA2Phk3tj7WFV/iVsfI/5yD4EQCIEQeAyBiKnHcH76USQUcoVACIRACIRACPxNIGLqbyaxGAIRUwZKTCEQAiEQAiHw+/fviKmkwVUEIqauwpRGIRACIRACGxKImNpw0T8z5Yipz1BLnxAIgRAIgR0IREztsMo3mGPE1A0gxkUIhEAIhMBLEoiYesllvf2kIqZuzzQeQyAEQiAEXoNAxNRrrOPdZxExdXfEGSAEQiAEQuBJCURMPenCPTrsiKlHE894IRACIRACz0IgYupZVurkOCOmTl6ADB8CIRACIbAsgYipZZdmrcAiptZaj0QTAiEQAiGwDoGIqXXWYulIIqaWXp4EFwIhEAIhcCKBiKkT4T/T0BFTz7RaiTUEQiAEQuCRBCKmHkn7iceSmFKy5BMGyYHkQHIgOZAc+DsH+lf8u3/RVsByhUC+mZrPgeylMJwn0DwknxoLVwofR8Xbcr57LiNWl28RUyMEN2mbzTa/0G6zzXvdy0MYtvUOi8bClcLHUfG2nO+ey4jV5VvE1AjBTdpms80vtNts81738hCGbb3DorFwpfBxVLwt57vnMmJ1+RYxNUJwk7bZbPML7TbbvNe9PIRhW++waCxcKXwcFW/L+e65jFhdvkVMjRDcpG022/xCu80273UvD2HY1jssGgtXCh9HxdtyvnsuI1aXbxFTIwQ3aZvNNr/QbrPNe93LQxi29Q6LxsKVwsdR8bac757LiNXlW8TUCMFN2mazzS+022zzXvfyEIZtvcOisXCl8HFUvC3nu+cyYnX5FjE1QnCTttls8wvtNtu81708hGFb77BoLFwpfBwVb8v57rmMWF2+RUyNENykbTbb/EK7zTbvdS8PYdjWOywaC1cKH0fF23K+ey4jVpdvEVMjBDdpm802v9Bus8173ctDGLb1DovGwpXCx1HxtpzvnsuI1eVbxNQIwU3aZrPNL7TbbPNe9/IQhm29w6KxcKXwcVS8Lee75zJidfkWMTVCcJO22WzzC+0227zXvTyEYVvvsGgsXCl8HBVvy/nuuYxYXb5FTI0Q3KRtNtv8QrvNNu91Lw9h2NY7LBoLVwofR8Xbcr57LiNWl29PIaa0+F++fLlqrr9+/fqt9nyu6vSgRt+/f3+L68ePHw8a8XPDZLN9jlvt5TZbrU/5YwJh2BiFRWPhSuHjqHhbznfPZcTq8m15MfXz5883AfL169er5vrt27e39hJVK1wSUProWi22Iz7ZbEdkrre7zXZ977QUgTBseRAWjYUrhY+j4m053z2XEavLt+XFlL7F0eIjSD6asL7BWiVZEE8ShM90rcLvmZj1sbrN1rfJ82UCYdj4hEVj4Urh46h4W853z2XE6vJteTGFIOFXY0oEfUvFr8z0rLr+13uyy9bb6zdcCDXdEWH4pU5+VNc/A572aqcPog9/2Imjjt/31Rhcaqe+fDOnslgcXXBivCrgRn3JR645Am6zzXncr3cYtjUPi8bClcLHUfG2nO+ey4jV5du7t6ZrMDLAPdoiBHphhGhRYki4qB7BQx1CBAHDM6IEMYPwkR0bCYdIwQfP8tWP52KVb1392PhBQPGsdrqIiXGr77cG5T/U0ZdnMRn1pfbMvQyR4iCBFffS4BRObx6GbQnCorFwpfBxVLwt57vnMmJ1+ba8mNLCs/i9eNHkVYdgQQgdiQq1V1vaIzokZLiwIUQuPdOGvggi2XvxROy6q15xyzcX7TUHV9/H0ferc/horCNf+IQ3z2ffEZY9b8VF3dkx9uO7zda3yfNlAmHY+IRFY+FK4eOoeNtq57uPcm2ry7elxVQvKhAriCUECEKCel66VTixNNWmpOoTS89qw9U/1/5qgw/u9K2CRu2ITTETt4QTV7XRt9b3cdCPtrpzVRvla3zRX2OtdvXcFZ/mtGKsis1tttWYrh5PGLYVCovGwpXCx1HxtlXPTB/tmlaXb+/emq7BmVNBCCCW+EaFmHiZIiT0wq2J0r+AESzyg1DDt3z2tqPn2h/x1Let4km+a+zEUQUO7TUX5qV2umhfY32r+P37z68aYVDHUr8RX/isDLGdfYcBzHjWfcVrtb20IqOPYgrDRigsGgtXCh9HxdtWPN99pOtaXb4tLaYQAggFJQHiRZgRILxQVS/RwtXXI2gkfORT7Xk5q09vu/TMy5z+xMpzL+z62OszQozYa5wuLuane9+XuBBeI77wq9hWvGDMHGG9Yqxus60Y58oxhWFbnbBoLFwpfBwVb1v1fPfRrml1+fburekanDkVhIBenogGRILiqoKFF2ytVxt8KIH0kR9d9cX8ZjC2vk3/XH0TCy94hJzGRJTV2JgPcckXl3zpw4UvzdFdzB1fdZxRX/IvP6tecK58Vox1tb20IqOPYgrDRigsGgtXCh9HxdtWPt99xOtZXb69e2u6ButNIxHdm8DKmw1Bi2i9N4vP+s9e+iy51i8Mw6IRuFxKrlzmU2tXPt9rnCuXXb5FTK28YifFtupm4xs4vp06+qbuJGzvhnWb7V2DPHxIIAwborBoLFwpfBwVb1v1fPfRrml1+RYxteZanRrVqptNcfHrUN1X/lWf22ynLuoTDh6GbdHCorFwpfBxVLxt1fPdR7um1eVbxNSaa3VqVCtuNv7cGGD4M2f1z4dRt8LdbbYV4nqmGMKwrVZYNBauFD6OireteL77SNe1unyLmFp3vU6LbLXNxh/g73+tx5+f6u2ngSsDu81WqlO8gkAYNkhh0Vi4Uvg4Kt622vnuo1zb6vLtVDHFn325JTa+seDXQbf0/QhffAPD/3V4rzEvjbPSZkNIHf2Bc62z4l1NULnNdq+1fFW/YdhWNiwaC1cKH0fF21Y6332E61tdvp0qprSotxY9eqnK79HLd/VluofAdHO+NE42myM2ZnObbcxDWodhy4GwaCxcKXwcFW/L+e65jFhdvp0mphA9t/4zL/zqR99oPON1D4HpOFwaJ5vNERuzuc025iGtw7DlQFg0Fq4UPo6Kt+V891xGrC7fThNT/PpGC8un/5YKO/c6WX5NRR2/FsOuZwSb2vBNFb8Wko16xtW3NfoQG0KPMXRXfb1ko7/s+Nf4CDvGOeqPf2In1jqOynybRHvmfOtx5D/XHAG32eY87tc7DNuah0Vj4Urh46h4W853z2XE6vLt3VvTNRgZYKQtwgHBwjPfKCEc5BMxQtsqWFSv5EDk0I8+NXHopzr6qR6/+NFdH3zgW+JFdsQT9VX84EP+mZNsuhA9bo74Vlvq3zr98x9iVzvaEsctx9FwxFvHT3mMwCP30lhkz9M6DNtahUVj4Urh46h4W853z2XE6vLtNDFVxYEm0QsTCQYuxINEA+0QQLThrkSpH+zVBzZEiMQLftWXsalXHRdx67kXR/0YCDv61vYaU2NV4YRvxqef7r1NfRFTtxxHY8l3rjkCbrPNedyvdxi2NQ+LxsKVwsdR8bac757LiNXl27u3pmswMsBIWy0o3/ioH2KGb3kQHmrHR8IDexUhjIsP2uuOEHLipYol/DK+fCJu8N/bqEfo1DEQVgie2ld1jE1f1feiqI6L7zo3xXrrcTSmxsg1R+CRe2ku0nV7h2Fbm7BoLFwpfBwVb8v57rmMWF2+vXtrugYjA1zbFgFQxRRiRuIHoYFg4ln9art+PASHBAxjqK8u6vApWxUvdQz8IpZ4xidxKykpqw0+NAeEXRVntT1t5VMXvqv4YlzmjC+ebz0O42WzQeLz90ftpc9HuH7PMGxrFBaNhSuFj6PibTnfPZcRq8u3U8QUwkaLipioQqMXMaojAeiLsKCt7AgUiQxdEjqIHcSN2uhCkFCvO2O8NShtEGDVfy9+iAsf+Kdv35565oFv4iMG3amDFbHqGT+3GIcxmQPPuY8TcJtt3MvePcKwrX9YNBauFD6OirflfPdcRqwu304RU1UAaGH1QdRoQgifWlcTgP7UI54QVkBBhFDPs/rRFvGCjb7cax+1wZfq8UFfzUE2XfRDACG2EE9qgyhSfz6Iojcn//wHIUYb+sl+y3EYU+PkmiPgNtucx/16h2Fb87BoLFwpfBwVb8v57rmMWF2+vXtrugYjAzxTW8SNEy/PNI97xJrNNk91p700T8t7CMPGJSwaC1cKH0fF23K+ey4jVpdv24gpJVD99otvlfjmaATkq7fNZptfYbfZ5r3u5SEM23qHRWPhSuHjqHhbznfPZcTq8m0bMTUCave22WzzGeA227zXvTyEYVvvsGgsXCl8HBVvy/nuuYxYXb5FTI0Q3KRtNtv8QrvNNu91Lw9h2NY7LBoLVwofR8Xbcr57LiNWl28RU4Vg/4e5S9VUkT8wf8s/n3UPn0wymw0Sn7+7zfZ5b3v2DMO27mHRWLhS+Dgq3pbz3XMZsbp8i5gqBPm/5IrpJsVbiTT5QZDdyqebYDabozJmc5ttzENah2HLgbBoLFwpfBwVb8v57rmMWF2+RUwVgkoy/mqDYl6i+Mg/MJ/NNr/kbrPNe93LQxi29Q6LxsKVwsdR8bac757LiNXl29OIqfpXGfANkv5PPMpKEH34v/P4NVj9O6vq/80ncPTRnW96+Hug5KfWV5GFT7Wt42OnH4ujZ/pTV+/9t03UYeeZO7HjU8/ETxv392HV+NT+6JKPXHME3Gab87hf7zBsax4WjYUrhY+j4m053z2XEavLt3dvTddgZIB7tkUcIV4kBuq3NYgfBEYVF4qL/ggU/KiOvkoy1SM68MUzAkRtEC3qi2/EGs/VF31hhA/XR22IT/6J7ygeOCCgeFa/6ov+fT0xcdfclAv5hEFyIDmQHHitHMj5fpv15H3J/WnEFAKgihLEwp/JlG+AECPUVYGDkNGdC//yWcvUyx/CB6GGeLn07MZCHCmpmQN3xiMGPeNDc6jPsvdCr69nLPnjwnc/JvWKK9ccAb2Acs0RCMPGLywaC1cKH0fF23K+ey4jVpdv796arsHIAPdsqwTokwCRQZ3uEhwfCQjETxUTVXxV4cScqq22VX3/jFhRHWMhvGp7xc9FzHUuCCCEID6qTxhUX9VGGSGm8TSGYj66VJ9rjsDKe2luZo/rHYaNdVg0Fq4UPo6Kt+V891xGrC7f3r01XYORAe7VFqEhEcGFwEAk8CzBwbc11KlPFRCIEcQU/hEvVTipL/6oly/K+O6fESuy1+Rl7DqX3j/PxI8P4uVZYyOWqpiiXn4qlzqXOr7s9arxVnvK1xNYdS9dP4PzW4ZhW4OwaCxcKXwcFW/L+e65jFhdvj2FmEIwIC40aUQJAoNvh/SMgEBg9GKJevzhC4HBs8SILsSJ/CB0aPvRsxIXYcU8eGbxsBMv4/NcfahPfe7n1sdTY1dfxmLuxFDv2WyVxufKbrN9ztO+vcKwrX1YNBauFD6OirflfPdcRqwu355CTCF+EDeaNCJCiYG40F12xIjKupyAQHzRX3fEi/ogQqjvfdEW3+6ZGBFebkxXRzt81lh6saRYsRErPlUnX/pwwaaypI67/OSaI+A225zH/XqHYVvzsGgsXCl8HBVvy/nuuYxYXb69e2u6BiMDpO1rEMhmm1/H7KUwnCfQPCSfGgtXCh9HxdtyvnsuI1aXbxFTIwQ3aZvNNr/QbrPNe93LQxi29Q6LxsKVwsdR8bac757LiNXlW8TUCMFN2mazzS+022zzXvfyEIZtvcOisXCl8HFUvC3nu+cx2b3gAAAa5UlEQVQyYnX5FjE1QnCTttls8wvtNtu81708hGFb77BoLFwpfBwVb8v57rmMWF2+RUyNENykbTbb/EK7zTbvdS8PYdjWOywaC1cKH0fF23K+ey4jVpdvEVMjBDdpm802v9Bus8173ctDGLb1DovGwpXCx1HxtpzvnsuI1eVbxNQIwU3aZrPNL7TbbPNe9/IQhm29w6KxcKXwcVS8Lee75zJidfkWMTVCcJO22WzzC+0227zXvTyEYVvvsGgsXCl8HBVvy/nuuYxYXb5FTI0Q3KRtNtv8QrvNNu91Lw9h2NY7LBoLV1qBD3+5svsLkanjL392c3iULef7PGmXbxFT81xfzkM22/ySus0273UvD2HY1jssGgtXWoUPoqnGyL+SsYKQUlw53+vqfK7s8i1i6nMsX7pXNtv88rrNNu91Lw9h2NY7LBoLV1qFT/9PiPHMPw3mYn+0Lef7PHGXbxFT81xfzkM22/ySus0273UvD2HY1jssGgtXWokP30Tprn8Xtf5bqS72R9tyvs8Td/kWMTXP9eU8ZLPNL6nbbPNe9/IQhm29w6KxcKXV+PDrvhXP0hVjcmu6ss3lW8TUyit2UmzZbPPg3Wab97qXhzBs6x0WjYUrrcaHb6dW+1ZK7HK+uwwas7l8i5gaY7hF62y2+WV2m23e614ewrCtd1g0Fq60Eh/+nJR+xaezdKU/LyV2Od9dBo3ZXL5FTI0x3KJ1Ntv8MrvNNu91Lw9h2NY7LBoLV1qJj0SUPrr0zdRq5+lq8bj1XN3m8i1iavVVOyG+bLZ56G6zzXvdy0MYtvUOi8bClVbh8/379zfxVP8aBJ2n+jNUq1w53+dXwuVbxNQ815fzkM02v6Rus8173ctDGLb1DovGwpVW4KO/rFNnZ/9rPf78VG9383iELef7PGWXbxFT81xfzkM22/ySus0273UvD2HY1jssGgtXOpsPQuroD5zz674VBFXOd5dBYzaXbw8TUySTFrJ+LiUXX5leajOGIK2vIZDNdg2ly23cZrvcI7U9gTBsRMKisXCl8HFUvC3nu+cyYnX59jAxxf/ZUAPm7+Kov1+u9Qiwo/ra9pnKmtfKAjGbbT6b3Gab97qXhzBs6x0WjYUrhY+j4m053z2XEavLt4eJKS0g/4cDQSOW3D8MSZtXu38kIFeYbzbb/Cq4zTbvdS8PYdjWOywaC1cKH0fF23K+ey4jVpdvDxFTR79PrsKC/51U39hosRFa/F8Q2LkjzvpngNBf7fRRO138HSCq79vQlza9+KOeb9nwjV135oGNMWBAH925qo35qo44qK91+NOvQms82OnDGL0dHtTXe42t2lO+noDbbNf3TksRCMOWB2HRWLhS+Dgq3pbz3XMZsbp8a2/0Ox5eCB69+LmwSWzo0gJXUdDX8+enSARECgKDZ4kG2iIY8KtxEBXYdKcvv07kWW37S+MTQ41bZcSP+nMxjuqoJ+b+mTkrfuKkLc/4pq1ikR/mrPF08ax2tJVNl3zS783Q/afOr6vK45UE3Ga7smua/UMgDFsqhEVj4Urh46h4W853z2XE6vLtIWIKcaJFrB+EAUJBdRIGuhAAuuvqBcClZ3y8dSx99YzIQHRUm+IgFkQMPmo7YpKNuWlMYka0qF5zwldfT1+N2V/9/FSvmIm773vpWX0UBxcM3LhqU9vSJ/cxAm6zjXlI6zBsORAWjYUrhY+j4m053z2XEavLt/aGveM3U04Y1MB5uVcR0osDJQBCQn375yo0JGxUXz8IGmKpQgKRo7urJ1ZiqmKt2ijjW3fFwLyYJ/W9yGEc3et8sFdb37d/Zh7qWznUMnHgn7va5Joj4DbbnMf9eodhW/OwaCxcKXwcFW/L+e65jFhdvr17a7oGIwMctdXi6WV/dCFCqkipYgBxpHa6jp7VBwGjsi6eETRVkLw1KP4Yk77Uc3dxIk7Uphc0iCeJNF34Z54uFsbq65gHsWlcyurjnuXD1THG0V2+cs0RuNdemovquXqHYVuvsGgsXCl8HBVvy/nuuYxYXb69e2u6BiMDuLYIn/ri79v1IkT1WnDEAN8cIYguPVOHgEEA6flSLBqPz9E3Nvgmjl4s1ZgRP7Ihnmq95ljFFbGpjS7iJpbaFt+Iy4+ea1/Gge3bYN1/iKEz53GAwD320sDwL9E0DNsyhkVj4Urh46h4W853z2XE6vLt7mKqFyAuYC1uFVu88BELiBaExUfPiDP5paw4EB2IoRoL7WoctZ4yY8u3PvLLhQBiXPmqogVRo3oEFuPSB1+61/a1D0wZ+6Pn3tdHc9RYueYIuM0253G/3mHY1jwsGgtXCh9HxdtyvnsuI1aXb+/emq7ByADP3BZRg2B75rnMxp7NNksw/1v/PMEwrAx3Ppsrh6Ny+ByR+due8/1vJqMWl28RU+X/HPzoG5tR4M/aPpttfuXcZpv3upeHMGzrHRaNhSuFj6PibTnfPZcRq8u3iKkRgpu0zWabX2i32ea97uUhDNt6h0Vj4Urh46h4W853z2XE6vItYmqE4CZttdmULPmEQXIgOZAceK0cyPl+m/Xs5UDEVE8kz29/sD4Y5gjoBZRrjkAYNn5h0Vi4Uvg4Kt6Wb6Y8lxGry7eIqRGCm7TNZptfaLfZ5r3u5SEM23qHRWPhSuHjqHhbznfPZcTq8i1iaoTgJm2z2eYX2m22ea97eQjDtt5h0Vi4Uvg4Kt6W891zGbG6fIuYGiG4SdtstvmFdptt3uteHsKwrXdYNBauFD6OirflfPdcRqwu3yKmRghu0jabbX6h3Wab97qXhzBs6x0WjYUrhY+j4m053z2XEavLt4ipEYKbtM1mm19ot9nmve7lIQzbeodFY+FK4eOoeFvOd89lxOryLWJqhOAmbbPZ5hfabbZ5r3t5CMO23mHRWLhS+Dgq3pbz3XMZsbp8i5j6/fvPv9mnJOPDv3s3Avjebfm3//h3/e41XjbbPFm32ea97uUhDNt6h0Vj4Urh46h4W853z2XE6vJtezHFP6pcxROiZbV/p49/P3Bk0T/TNpvtM9Te93Gb7X2LPH1EIAwbobBoLFwpfBwVb8v57rmMWF2+bS+mvn///vZtVBVTI1Af2Vab4BH/fmA22/yqus0273UvD2HY1jssGgtXCh9HxdtyvnsuI1aXbxFT/4ipS0JFQkv1fOo3Vipj113ijKuv0zdeXIi42kbfPNWr+uXbMvz3MVXf6ifRxRj4qb8exFbHo6y6XHME3Gab87hf7zBsax4WjYUrhY+j4m053z2XEavLt3dvTddgZIBnbFvFDAKjChMECd9c1V+1IWgQOAge+aQOXzz3bUnsS+Pwq0i1lR9ixncdl7bEqT74Vj9dPMuXu4jJ1cV2HYEd99J1ZK5vFYaNVVg0Fq4UPo6Kt+V891xGrC7fthdTAogAUZLxQfTouX5jhHBRHwSLWwRXJ1/8mq6vrwIH4VXFjvqpv8bVp170rSJObbmqP+Za50Q77rUvttzHCLjNNuYhrc9gyF7hB5W6CtRxNtS6e5fPYMGcmPdqTIhP9zP5EAdnND+0Yteduv7srm0eVV7tfOdd6NhQ9yg2147j8q29cRdJyGsnc492CA0lm5K/PstWP//5n//59qx27sJHrcOG39q3brYq2OjfJxXPNSa1pa8OQC6+ydJLwNXTjrt85poj4DbbnMf9ep/FEPFQ95Doa1+cIaQ09lksyLoVmRDbCnyIhXOcZ91h58RCbfeo8ornu95n+tSLLwmqbZWy24/v3pquwSrBPyoOhI5ERy3341+qU1slbBVLbCj5reIGv2pPMiF42HyMhT+1rRuijuU2c42njsPY/b367uvyfB2B7KXrOF1qdSbDfh/pmf13KeZ71Z3JgjmtxoS4dF+Bj+LgrNYZXp97Yf5WedJ/Vjzf+3ciz7qveLl821pMoXxroiN6WES+AdKCssAcqlWY0I86Dh4EUfXTj8sGpC/1uutCXOlOWzYr4/JcY6pJyPiqr/OtbSivuNmI7VnubrM9S+yrxHk2Q+0D7Un245lczmbB3FdiQky6r8JHsXAm665zl7O5xntmedXznX3Ge5b335msjsZ2+ba1mBIoJbqSq34QQICsQqRuDIQNfWud+tZ+NYEZk3HYfDV5+r7qjwiiv2y0k414+jgUC+JO7T+6aqwftU29J+A2m28Z6xGBsxmyL+veO4r13vazWTC/lZgQk+6r8CEmztsVz9IVY4Ib77Nr3lP0OePu8m17MXXGQpwxJpsbQXYphpU326W4V6pzm22l+J4hlhUYai+ssB9WYEHOrMKEeHRfiY/iQXS6H2xr3GeUV8jno3nz7VT9YuGo7Zl2l28RU2euyIPG5mvTa9X+ypvtQcimh3GbbdrpZg7OZqgfQPhJWeUzr7NZMPeVmBCT7qvwUSz8hoDcueYH2DqXe5dXPd/re0ox6nnVy+VbxNSqq3WjuPhGSsnJrxU/cr3qZvso7pXq3WZbKb5niOVMhvyErAOdQ/7Ml+KZLMiV1ZgQl+4r8CEeiSh+cOWPZFC3wn3V811x8UMLon0FXi4Gl28RU47U5rZVN9szLYvbbM8U/wqxnsWQbxbqrxp4KV77A8mt+Z3FgnmsyITYdD+bD7EgOGueVJFAuzPvK57v7C+4kG8r/ppUMbp8i5hi9XL/Q2DFzfYnuCcpuM32JKEvE+ZZDPWtAj8hVxhnvhTPYsH8V2RCbLqfzUcxHH2DyZ+fOvObzcpqtfMdPv2v9RCmvb3O5ayyy7eIqbNWY+FxV9tsC6M6DM1ttsPGqbAEzmAo0XCU/7wsndCyE7ih8QwWhL8qE+LT/Uw+Gp/cOPomhW9eVhBUR/ldeT6qjJCq3wLXsbXXFO9qgsrlW8RUXbkblrV5Vtg4n5nSSpvtM/Gv0MdtthXieqYYwrCtVlg0Fq4UPo6Kt+V891xGrC7fIqZGCF7ZFjVdf29+ZdclmmWzzS+D22zzXvfyEIZtvcOisXCl8HFUvC3nu+cyYnX5FjF1QJCvtpV4ffKpTh8uvsLlq1760I8/TIe9fhXc19VfIfAVKHf117j9M3H049dvxojRxUB/7sTNc+7jBNxmG/eyd48wbOsfFo2FK4WPo+JtOd89lxGry7eIKUMQwUGVnhFPiJ8qiFSnNqqjHlGEwKE9f6hOQoe6j9qS/Agi2vMsPwgsfvesNsTEmGqni35VbDFX3Rmv2lIeI+A225iHtA7DlgNh0Vi4Uvg4Kt6W891zGbG6fIuY6ggiPKrQQHxIKPWiRd2VnAicvr6Kmm6oP//Ei/xySZgh3Pq+l54RdPhhHhJQlK/dRNe2Y6zc/ybgNtvfrWK5RCAMG52waCxcKXwcFW/L+e65jFhdvkVMdQSrcKKq2ijzLY/uSk4JFl0IF+pVhzjCH/cqnJyt79s/1/6qcx/iQGzRpopFxuauNrnmCLjNNudxv95h2NY8LBoLVwofR8Xbcr57LiNWl2/v3pquwcgAr9AWsVS/LUKAaH6IEuaKeEKc9N8eqa9s7qpiSPUIM7Xn14WKR9fRM74vjVPH5pszjX10ZbMdkbnenr10PaujlmHYyIRFY+FK4eOoeFvOd89lxOryLWKqI4jY6L9pQiwpEREiiB/ZEF+1Xq6r+KI9/RFufHtUhVgfx0fPtS/CS+MwBvFThwjrpv/2mM3mqIzZ3GYb85DWYdhyICwaC1cKH0fF23K+ey4jVpdvEVOGIN82Ken0QYioKeJEdokViRLEkeoRNaqvAgtfvYip7WsfYkBoffTcj13HqTFrjFpnpv82Z2eP7XoCbrNd3zstRSAMWx6ERWPhSuHjqHib3gG55gi4fHtH1TWYGzK9n5FANtv8qmUvheE8geYh+dRYuFL4OCrelvPdcxmxunyLmBohuEnbbLb5hXabbd7rXh7CsK13WDQWrhQ+joq35Xz3XEasLt8ipkYIbtJWm03Jkk8YJAeSA8mB18qBnO+3Wc9eDkRM9UTynD8zdYMc0Aso1xyBMGz8wqKxcKXwcVS8Ld9MeS4jVpdvEVMjBDdpm802v9Bus8173ctDGLb1DovGwpXCx1HxtpzvnsuI1eVbxNQIwU3aZrPNL7TbbPNe9/IQhm29w6KxcKXwcVS8Lee75zJidfkWMTVCcJO22WzzC+0227zXvTyEYVvvsGgsXCl8HBVvy/nuuYxYXb5FTI0Q3KRtNtv8QrvNNu91Lw9h2NY7LBoLVwofR8Xbcr57LiNWl28RUyMEN2mbzTa/0G6zzXvdy0MYtvUOi8bClcLHUfG2nO+ey4jV5VvE1AjBTdpms80vtNts81738hCGbb3DorFwpfBxVLwt57vnMmJ1+ba0mOr/GRQ9X7r4J1fqP/9yqf2j6piH/mmYa/5tvEfERUz8kzd1zGy2SuNzZbfZPudp315h2NY+LBoLVwofR8Xbcr57LiNWl2/LiikteF10/pHg/t+VkyhAPF0SCCOgbt2Wf39PfpmHhN/spXlrzp+59O8JVr7Vx5G9tkn5MgG32S73SG1PIAwbkbBoLFwpfBwVb8v57rmMWF2+LSmmEB/9tyaIJf7x377dJYEwAurWbZW8/GPIt/r2bNaPYuqFKfPOZoPE5+9us33e2549w7Cte1g0Fq4UPo6Kt+V891xGrC7flhNT/BrMfeOib2KUCNxV5iMQKksgILpoC6S+H6KsfluEQKOOvroj1uQXcUR9rVM9Vz8fYkMoUq8++vTfWGHXHfFDjNQRa42BtsRBW92JoR+rtqWc++cIuM32OU/79grDtvZh0Vi4Uvg4Kt6md0CuOQIu395RdQ3mhhzvfekbF8TQv//7v//1Z48QREoUtdOlMqKn94vwUDv8YuuFSO+LsRB8GqcmaB0X3wgXxpDP3g8iR3ZEFrFUP6qrfvr4alvV1bb4VYxq5646F1cf28cEVthLH0e5doswbOsTFo2FK4WPo+JtOd89lxGry7flxFQVFP3kal0vGPpn9a2ippZVhy+JC8oIl37cXojVeleHP/mmXgJJl+JgHN31rHa6mIPu+KDfW4N//oMgwg9jqJ8u6uWj+sRHPy527opppQsxCKcaG3XVtkLZbbYV4nqmGMKwrVZYNBauFD6Oiretdr77KNe2unx799Z0DR49pUsior44ERCIjb6f7Eoa2REXeu4/qsOve1lr/pfEB+PWvtVW+9aY5Jdx+5gkgKhz/PEjBroYr/cjO3U1vku+5U9+VrsUsz71IgeqbZXyCntpFRafjSMMG7mwaCxcKXwcFW9b8Xz3ka5rdfn27q3pGjx6Ou6bFMWAHQFRRYrqeSZeXrTqJyGhBJKwcJfq1P/o6n3Xdk6syB8JW0UAc9BdV62rPj+qq3NTWxcD/vo6WFyaL7HjY4V7LyB51n3Fa4W9tCKXkZjCsNEKi8bClcLHUfG2Fc93H+m6Vpdvy4kp4ZPI0ILzbQovzioAVF+/qeifERG8bPEp/9UfZbU/unpfGov4EEiIvCp0euHS++mf8as4EHDygR/V93V67mOgr+ZGPMTHmLofXYxzVH+WnbmwZszprHgujes226X2qfubQBg2JmHRWLhS+Dgq3rbq+e6jXdPq8m1JMSV8iB8EBt/mgBbBoHperlUg0J/2vU/aIkR6/7WfynW8Phl5yfexEhcvfXxU34gb9a3isI+31tXxiJt5EANCtPdDPf1qLJTVZtWLda08VozVbbYV41w5pjBsqxMWjYUrhY+j4m0rn+8+4vWsLt/evTVdg/WmkYjuTWDlzYaQRKDem8Vn/WcvfZZc6xeGYdEIXC4lVy7zqbUrn+81zpXLLt8iplZesZNiW3Wz8U0f307pedXLbbZVY101rjBsKxMWjYUrhY+j4m2rnu8+2jWtLt8iptZcq1OjWnWzKS79qlSX7iv/qs9ttlMX9QkHD8O2aGHRWLhS+Dgq3rbq+e6jXdPq8i1ias21OjWqFTcbf7YMMPyhfP7sG/ZV7m6zrRLbs8QRhm2lwqKxcKXwcVS8bcXz3Ue6rtXlW8TUuut1WmSrbTb+cH3/az3+/FRvPw1cGdhttlKd4hUEwrBBCovGwpXCx1HxttXOdx/l2laXbxFTa6/ZX9HpV1v3/vXWSpsNIXX0B875PyRXE1Rus/21mDFcJBCGDU9YNBauFD6OiretdL77CNe3unyLmFp/3f5EyK+2+HNDfyoOCvoV2KW/AuGg25+/cPSoPvaPCbjN9nGvtKgEwrDRCIvGwpXCx1Hxtogpz2XE6vItYmqE4Mlt9e2LNsLRtzQ1PL6xqX/fVK2/VM5mu0Tnujq32a7rmVYQCENI/P4dFo2FK4WPo+JtOd89lxGry7eIqRGCD26LeFLy68MfwuZXWjxTz7dQPHNX2Pz5ImyXBJna5Joj4DbbnMf9eodhW/OwaCxcKXwcFW/L+e65jFhdvr17a7oGIwOk7e0I9L/S488OaSOoDnGEgOLvXlLdUV8E1EffWmWzza9j9lIY/v/2zSjHQRgGosfh0ty1q/kYOURDWzdbpF1eJIRjTNi+2OkoZdcJ1AjkU7FIFnwSlexjfc9cOt6Ub4ipDsELY73rJGHkpiLwy+ejX9ctkGRbeFk8zbFpbD9DZ4ptpPGZnYrts5HuexcMa+5hUSySBZ9EJftY3zOXjjflG2KqQ/DC2Pm/9ubdJvdVGD78Yrp3rfxzoP5sx/hsUZY+kmJoawRSsa2NeL+7YVhzDotikSz4JCrZx/qeuXS8Kd8O35opoPMAYn+PwCymxt0mv0tl8eS+d6K8SyXBZdFl8eS+dqfOGsV2RuZ9P7X0PquzSBgWGVgUi2TBJ1HJPtb3zKXjTfmGmOoQvDDWgsi7SxJDKgKJKgsrndX8s537irN4moWWd60svNJHotgSlZ4vFVtvBKJhWDkAi2KRLPgkKtnH+p65dLwp3xBTHYIXxnoHSYk/HvKrWVzpmm2LKQsxXVP82HcsYuq7k5mK7btP/H+jw7DmFBbFIlnwSVSyT98LtDUCKd8OVFPA2iO5+y8SoNjWZ41aguE6gRqBfCoWyYJPopJ9rO+ZS8eb8g0x1SF4k1iKbX2iU7Gtj3qvEWBY8w2LYpEs+CQq2cf6nrl0vCnfDmJq27YHBwzIAXKAHCAHyAFygBw4z4FZfB3E1HyRPgQgAAEIQAACEIDAkcC+74/xQEwd+dCDAAQgAAEIQAACTwlISI0NMTXSwIYABCAAAQhAAAIvCCCmXgDiMgQgAAEIQAACEHhGYBZTP27BVvS4G6RxAAAAAElFTkSuQmCC\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTab. 1.\u003c/strong\u003e \u003cstrong\u003e-t\u003csub\u003e1\u003c/sub\u003e:\u0026nbsp;\u003c/strong\u003ebefor or after birth\u003cstrong\u003e; 0:\u0026nbsp;\u003c/strong\u003eat the time of allocation\u003cstrong\u003e; t\u003csub\u003e1\u003c/sub\u003e:\u0026nbsp;\u003c/strong\u003efirst surfactant administration within 2 hours of life\u003cstrong\u003e; t\u003csub\u003e2\u003c/sub\u003e*:\u0026nbsp;\u003c/strong\u003epossible second dose of surfactant during the following 24 h after the firs dose;\u003cstrong\u003e\u0026nbsp;t\u003csub\u003e3\u003c/sub\u003e:\u0026nbsp;\u003c/strong\u003eat discharge or death\u003cstrong\u003e; t\u003csub\u003e\u0026nbsp;4\u003c/sub\u003e:\u0026nbsp;\u003c/strong\u003efollow up at 24 months of age.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Preterm infants, Lung recruitment, HFOV, INRECSURE, LISA, Surfactant","lastPublishedDoi":"10.21203/rs.3.rs-3994255/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3994255/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eSurfactant is a well-established therapy for preterm neonates affected by respiratory distress syndrome (RDS). Goals of different methods of surfactant administration are to reduce duration of mechanical ventilation and the severity of bronchopulmonary dysplasia (BPD), however the optimal administration method remains unknown. This study compares the effectiveness of the INtubate-RECruit-SURfactant-Extubate (IN-REC-SUR-E) technique with the less invasive surfactant administration (LISA) technique, in increasing BPD-free survival of preterm infants. This is an international unblinded multicenter randomized controlled study in which preterm infants will be randomized into two groups to receive IN-REC-SUR-E or LISA surfactant administration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e:\u003cbr\u003e\nIn this study 382 infants born at 24\u003csup\u003e+0\u003c/sup\u003e-27\u003csup\u003e+6\u003c/sup\u003e weeks’ gestation, not intubated in the delivery room and failing nasal continuous positive airway pressure (nCPAP) or nasal intermittent positive pressure ventilation (NIPPV) during the first 24 h of life, will be randomized 1:1 to receive IN-REC-SUR-E or LISA surfactant administration. The primary outcome is a composite outcome of death or BPD at 36 weeks’ postmenstrual age. Secondary outcomes are: BPD at 36 weeks’ postmenstrual age; death; pulse oximetry/fraction of inspired oxygen; severe intraventricular haemorrhage; pneumothorax; duration of respiratory support and oxygen therapy; pulmonary hemorrhage; patent ductus arteriosus undergoing treatment; percentage of infants receiving more doses of surfactant; periventricular leukomalacia, severe retinopathy of prematurity, necrotizing enterocolitis, sepsis; total in-hospital stay; systemic postnatal steroids; neurodevelopmental outcomes and respiratory function testing at 24 months of age. Randomization will be centrally provided using both stratification and permuted blocks with random block sizes and block order. Stratification factors will include centre and gestational age (24\u003csup\u003e+0\u003c/sup\u003e to 25\u003csup\u003e+6\u003c/sup\u003e weeks or 26\u003csup\u003e+0\u003c/sup\u003e to 27\u003csup\u003e+6\u003c/sup\u003e weeks).\u003c/p\u003e\n\u003cp\u003eAnalyses will be conducted in both intention-to-treat and per-protocol populations, utilizing a log-binomial regression model that corrects for stratification factors to estimate the adjusted relative risk (RR).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eThis trial is designed to provide robust data on the best method of surfactant administration in spontaneously breathing preterm infants born at 24\u003csup\u003e+0\u003c/sup\u003e-27\u003csup\u003e+6\u003c/sup\u003e weeks' gestation affected by RDS and failing nCPAP or NIPPV during the first 24 hours of life, comparing IN-REC-SUR-E to LISA technique, in increasing BPD-free survival at 36 weeks' postmenstrual age of life.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e:\u0026nbsp; ClinicalTrials.gov identifier NCT05711966\u003c/p\u003e","manuscriptTitle":"Comparison of “IN-REC-SUR-E” and LISA in preterm neonates with respiratory distress syndrome: a randomized controlled trial (IN- REC-LISA trial)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-24 20:55:45","doi":"10.21203/rs.3.rs-3994255/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2024-05-15T16:58:49+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-04-19T14:08:50+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-18T08:35:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-17T09:59:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2024-03-01T04:50:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e4e70111-e901-4a8f-bb9a-c8ecc9bf71f1","owner":[],"postedDate":"April 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-06-10T11:59:52+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-24 20:55:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3994255","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3994255","identity":"rs-3994255","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}