PIANO NAZIONALE DI RIPRESA E RESILIENZA (PNRR) MISSIONE 6 - COMPONENTE 2

INVESTIMENTO 2.1 VALORIZZAZIONE E POTENZIAMENTO DELLA RICERCA BIOMEDICA DEL SSN

Convenzione attuativa tra la Direzione generale della ricerca ed innovazione in sanità del Ministero della salute, il Soggetto attuatore/beneficiario Fondazione Istituto Neurologico Xxxxx Xxxxx e il Principal Investigator della ricerca XXXX XXXXXXX, per la regolamentazione dello svolgimento del progetto Malattie Rare (MR) con codice progetto PNRR-MR1-2022-12376618, dal titolo RAre, but not aLone: a large Italian network to empower the impervious diaGNostic pathway of rare cerEbrovascular Diseases (ALIGNED);

Premesso che

VISTA la legge 7 agosto 1990, n. 241 “Nuove norme in materia di procedimento amministrativo e di diritto di accesso ai documenti amministrativi” e s.m.i.;

VISTA la legge 14 gennaio 1994 n. 20 “Disposizioni in materia di giurisdizione e controllo della Corte dei Conti” e s.m.i.;

VISTO l’articolo 12 bis, comma 3, del decreto legislativo 30 dicembre 1992, n. 502/1992 e s.m.i.; VISTO il decreto del Presidente del Consiglio dei Ministri 11 febbraio 2014, n. 59, recante il regolamento di organizzazione del Ministero della salute e, in particolare, gli articoli 1, comma 7, e 12, comma 2; VISTO il decreto del Presidente della Repubblica 28 marzo 2013, n. 44, recante il regolamento di riordino degli organi collegiali e degli altri organismi operanti presso il Ministero della salute e, in particolare gli artt. 3 e 4 che prevedono la composizione del Comitato tecnico sanitario;

VISTO il decreto del Ministro della salute 8 agosto 2013, registrato dall’Ufficio centrale di bilancio presso il Ministero della salute in data 13 agosto 2013, visto n. 934 e, in particolare, l’articolo 1, che dispone la ripartizione dei componenti tra le sezioni del Comitato tecnico sanitario;

VISTO il decreto del Ministro della salute 15 dicembre 2021, registrato dall’Ufficio centrale del bilancio presso il Ministero della salute in data 7 gennaio 2022, visto n. 33, recante la ricostituzione del Comitato tecnico sanitario, avente una durata di tre anni dalla data di insediamento;

VISTO il Regolamento (UE) 2021/241 del Parlamento europeo e del Consiglio del 12 febbraio 2021 che istituisce il dispositivo per la ripresa e la resilienza dell’Unione Europea;

VISTO il Piano Nazionale di Ripresa e Resilienza (PNRR) valutato positivamente con Decisione del Consiglio ECOFIN del 13 luglio 2021, notificata all’Italia dal Segretariato generale del Consiglio con nota LT161/21, del 14 luglio 2021, ed in particolare la Missione 6, Componente 2, Investimento 2.1 “Valorizzazione e potenziamento della ricerca biomedica del SSN”, che consiste nel “rafforzare il sistema della ricerca biomedica tramite due linee di intervento: a) il finanziamento di progetti Proof of Concept (PoC), sostenendo lo sviluppo di tecnologie con un basso grado di maturità tecnologica e promuovendo il trasferimento di tecnologie verso l'industria; b) il finanziamento di programmi o progetti di ricerca nel campo delle malattie rare e dei tumori rari e di altre malattie altamente invalidanti”;

VISTO il Regolamento (UE) 2018/1046 del 18 luglio 2018, che stabilisce le regole finanziarie applicabili al bilancio generale dell’Unione, che modifica i Regolamenti (UE) n. 1296/2013, n. 1301/2013, n. 1303/2013, n. 1304/2013, n. 1309/2013, n. 1316/2013, n. 223/2014, n. 283/2014 e la decisione n.

541/2014/UE e abroga il regolamento (UE, Euratom) n. 966/2012;

VISTO il decreto legge del 31 maggio 2021, n. 77, convertito con modificazioni dalla legge 29 luglio 2021, n. 108 «Governance del Piano nazionale di ripresa e resilienza e prime misure di rafforzamento delle strutture amministrative e di accelerazione e snellimento delle procedure»;

VISTO il decreto del Presidente del Consiglio dei ministri 9 luglio 2021 recante l’individuazione delle amministrazioni centrali titolari di interventi previsti nel PNRR, ai sensi dell’articolo 8, comma 1, del

citato decreto legge 31 maggio 2021, n. 77, convertito, con modificazioni, dalla legge 29 luglio 2021, n. 108;

VISTO il decreto del Ministro dell’economia e delle finanze del 6 agosto 2021 relativo all’assegnazione delle risorse in favore di ciascuna Amministrazione titolare degli interventi PNRR e corrispondenti milestone e target;

VISTO il decreto del Ministro della salute, di concerto con il Ministro dell’economia e delle finanze 15 settembre 2021, di istituzione dell’Unità di Missione del Ministero della salute titolare di interventi PNRR, ai sensi dell’articolo 8 del citato decreto legge n. 77 del 2021;

VISTO l’atto di indirizzo del Ministro del 12 ottobre 2021 con il quale sono stati individuati i relativi Soggetti Attuatori nell’ambito degli interventi e sub-interventi di investimento del piano Nazionale di ripresa e resilienza (PNRR) a titolarità del Ministero della salute;

VISTO il decreto legge 6 novembre 2021, n. 152 “Disposizioni urgenti per l'attuazione del Piano nazionale di ripresa e resilienza (PNRR) e per la prevenzione delle infiltrazioni mafiose”;

VISTA la legge 16 gennaio 2003, n. 3 “Disposizioni ordinamentali in materia di pubblica amministrazione” e, in particolare, l’articolo 11, comma 2-bis, ai sensi del quale “Gli atti amministrativi anche di natura regolamentare adottati dalle Amministrazioni di cui all’articolo 1, comma 2, del decreto legislativo 30 marzo 2001, n. 165, che dispongono il finanziamento pubblico o autorizzano l’esecuzione di progetti di investimento pubblico, sono nulli in assenza dei corrispondenti codici di cui al comma 1 che costituiscono elemento essenziale dell'atto stesso”;

VISTA la delibera del CIPE n. 63 del 26 novembre 2020 che introduce la normativa attuativa della riforma del CUP;

VISTO l’articolo 1, comma 1042, della legge 30 dicembre 2020, n. 178 ai sensi del quale con uno o più decreti del Ministro dell’economia e delle finanze sono stabilite le procedure amministrativo-contabili per la gestione delle risorse di cui ai commi da 1037 a 1050, nonché le modalità di rendicontazione della gestione del Fondo di cui al comma 1037;

VISTO l’articolo 1, comma 1043, secondo periodo, della legge 30 dicembre 2020, n. 178, ai sensi del quale al fine di supportare le attività di gestione, di monitoraggio, di rendicontazione e di controllo delle componenti del Next Generation EU, il Ministero dell'economia e delle finanze - Dipartimento della Ragioneria generale dello Stato sviluppa e rende disponibile un apposito sistema informatico;

VISTO l’articolo 17 del Regolamento (UE) 2020/852 che definisce gli obiettivi ambientali, tra cui il principio di non arrecare un danno significativo (DNSH, “Do no significant harm”), e la Comunicazione della Commissione UE 2021/C 58/01“Orientamenti tecnici sull’applicazione del principio «non arrecare un danno significativo» a norma del regolamento sul dispositivo per la ripresa e la resilienza”;

VISTI i principi trasversali previsti dal PNRR, quali, tra l’altro, il principio del contributo all’obiettivo climatico e digitale (c.d. tagging), il principio di parità di genere e l’obbligo di protezione e valorizzazione dei giovani;

VISTI gli obblighi di assicurare il conseguimento di target e milestone e degli obiettivi finanziari stabiliti nel PNRR;

VISTO il Regolamento delegato (UE) 2021/2106 della Commissione del 28 settembre 2021 che integra il regolamento (UE) 2021/241 del Parlamento europeo e del Consiglio, che istituisce il dispositivo per la ripresa e la resilienza, stabilendo gli indicatori comuni e gli elementi dettagliati del quadro di valutazione della ripresa e della resilienza, che prevede, in particolare, che “affinché il quadro di valutazione, compresi gli indicatori comuni, sia aggiornato in modo coerente e uniforme due volte l’anno, tutti gli Stati membri riferiscono alla Commissione due volte l’anno nell’ambito del semestre europeo sui progressi compiuti nella realizzazione dei piani per la ripresa e la resilienza, comprese le modalità operative, e sugli indicatori comuni.”

VISTE le “Linee Guida per lo svolgimento delle attività connesse al monitoraggio del PNRR”, predisposte dal Servizio Centrale per il PNRR, presso il Ministero dell’economia e delle finanze (MEF) - Dipartimento Ragioneria generale dello Stato (RGS), che descriveono le funzionalità del sistema informativo “ReGiS” sviluppato dal Ministero dell’economia e delle finanze – Dipartimento della Ragioneria Generale dello Stato in attuazione dell’articolo 1, comma 1043, della legge 30 dicembre 2020, n. 178;

VISTO il documento “Sistema di Gestione e Controllo (Xx.Xx.Xx.) PNRR - Ministero della salute”, adottato con Decreto del 29 luglio 2022;

VISTE le “Linee Guida per lo svolgimento delle attività di controllo e rendicontazione delle Misure PNRR di competenza delle Amministrazioni centrali e dei Soggetti attuatori”, predisposte dal Servizio Centrale per il PNRR, presso il Ministero dell’economia e delle finanze (MEF) - Dipartimento Ragioneria generale dello Stato (RGS), che contengono indicazioni procedurali per un corretto espletamento delle attività di controllo e rendicontazione delle spese e di Milestone & Target e di ogni altro adempimento previsto dalla normativa comunitaria e nazionale applicabile al PNRR, a norma dell’art. 8, punto 3, del decreto legge 77 del 31 maggio 2021, come modificato dalla legge di conversione 29 luglio 2021, n. 108;

VISTO il decreto del Presidente del Consiglio dei Ministri 15 settembre 2021 “Modalità, regole e strumenti per il conferimento dei dati”;

VISTA la Circolare MEF-RGS del 14 ottobre 2021, n. 21 “Piano Nazionale di Ripresa e Resilienza (PNRR) - Trasmissione delle Istruzioni Tecniche per la selezione dei progetti PNRR”;

VISTO il Decreto interministeriale del 7 dicembre 2021 per l’adozione delle linee guida volte a favorire la pari opportunità di genere e generazionali, nonché l'inclusione lavorativa delle persone con disabilità nei contratti pubblici finanziati con le risorse del PNRR e del PNC;

VISTA la Circolare MEF-RGS del 30 dicembre 2021, n. 32, recante “Guida operativa per il rispetto del principio di non arrecare danno significativo all’ambiente”;

VISTA la Circolare MEF-RGS del 31 dicembre 2021, n. 33 “Piano Nazionale di Ripresa e Resilienza (PNRR) – Nota di chiarimento sulla Circolare del 14 ottobre 2021, n. 21 - Trasmissione delle Istruzioni Tecniche per la selezione dei progetti PNRR – Addizionalità, finanziamento complementare e obbligo di assenza del c.d. doppio finanziamento”

VISTA la Circolare MEF-RGS del 21 giugno 2022, n. 27 “Monitoraggio delle misure PNRR”;

VISTA la Circolare MEF-RGS dell’11 agosto 2022, n. 30 sulle procedure di controllo e rendicontazione delle misure PNRR;

VISTA la Comunicazione della Commissione 2014/C 198/01 “Disciplina degli aiuti di Stato a favore di ricerca, sviluppo e innovazione” e s.m.i.;

VISTO il Regolamento (UE) n. 651/2014 della Commissione, del 17 giugno 2014, che dichiara alcune categorie di aiuti compatibili con il mercato interno in applicazione degli articoli 107 e 108 del trattato; VISTA la comunicazione della Commissione 2016/C 262/01 sulla nozione di aiuto di Stato di cui all'articolo 107, paragrafo 1, del trattato sul funzionamento dell'Unione europea;

VISTA la Comunicazione della Commissione del 19 marzo 2020, C(2020) 1863 “Quadro temporaneo per le misure di aiuto di Stato a sostegno dell'economia nell'attuale emergenza della COVID-19”, da ultimo rettificata attraverso la comunicazione del 18 novembre 2021, C(2021) 8442 “Sesta modifica del quadro temporaneo per le misure di aiuto di Stato a sostegno dell'economia nell'attuale emergenza della COVID- 19 e modifica dell'allegato della comunicazione della Commissione agli Stati membri sull'applicazione degli articoli 107 e 108 del trattato sul funzionamento dell'Unione europea all'assicurazione del credito all'esportazione a breve termine”;

VISTO il decreto del Ministro della salute 1° aprile 2022 che nella relativa tabella ha previsto ai punti

2.1.1 - proof of concept, 2.1.2 – tumori e malattie rare e 2.1.3 – malattie altamente invalidanti, la ripartizione degli interventi di investimento della Missione 6, Componente 2, Investimento 2.1 - del Piano Nazionale di Ripresa e Resilienza relativo all'innovazione, alla ricerca e alla digitalizzazione del Servizio sanitario nazionale e al potenziamento del sistema della ricerca biomedica;

VISTO il I° avviso pubblico per la presentazione e selezione di progetti di ricerca da finanziare nell’ambito del PNRR, pubblicato sul sito web del Ministero della salute il 20 aprile 2022 e sulla gazzetta ufficiale della Repubblica italiana, sulle seguenti tematiche: Proof of concept (PoC), Malattie Rare (MR) con esclusione dei tumori rari, Malattie Croniche non Trasmissibili (MCnT) ad alto impatto sui sistemi sanitari e socio-assistenziali (Fattori di rischio e prevenzione; Eziopatogenesi e meccanismi di malattia); VISTO il decreto direttoriale n. 27 del 2 novembre 2022, registrato con Visto n. 1054 dall’Ufficio centrale di bilancio in data 18 novembre 2022, con il quale è stata approvata la graduatoria dei progetti di ricerca PNRR- Missione 6 - Componente 2 - Investimento 2.1, afferenti alle tematiche progettuali Proof of Concept, Malattie rare, Malattie croniche non trasmissibili, ad alto impatto sui sistemi sanitari e socio- assistenziali (tematiche: Fattori di rischio e prevenzione; Eziopatogenesi e meccanismi di malattia), con il quale si è proceduto ad individuare il Soggetto attuatore/beneficiario e il Principal Investigator; VISTO l’art. 7 del decreto ministeriale 8 aprile 2015, recante il riordino degli uffici di livello dirigenziale non generale del Ministero della salute, ove vengono individuati gli uffici in cui si articola la Direzione

generale della ricerca e dell’innovazione in sanità, indicando le specifiche competenze assegnate agli uffici 3 e 4 della stessa;

VISTO il decreto direttoriale del 1° marzo 2022, registrato dall’Ufficio Centrale di Bilancio in data 4 marzo 2022, al n. 247, con il quale il Xxxx. Xxxxxxx Xxxxxxxxx è stato autorizzato, tra l’altro, all’esercizio del potere di spesa e l’ordine di servizio con il quale è stato delegato alla sottoscrizione delle convenzioni per i progetti risultati vincitori nel bando PNRR;

VISTO il messaggio trasmesso da questa amministrazione per il tramite della piattaforma WorkFlow della ricerca in data 13 dicembre 2022 con il quale è stato comunicato che la valutazione della proposta progettuale ha avuto esito positivo e che, pertanto, la stessa è stata ammessa a finanziamento;

tanto premesso si stipula e si conviene quanto segue tra

il Ministero della Salute (di seguito “Ministero”), in qualità di Amministrazione titolare, rappresentato dal xxxx. Xxxxxxx Xxxxxxxxx/ – Direttore dell’Ufficio 3 della Direzione generale della ricerca e dell’innovazione in sanità (di seguito “DGRIC”)

Il Soggetto attuatore/beneficiario del progetto, rappresentato dal Xxxx. Xxxxxxxx Xxxxxx Xxxxxx in qualità di legale rappresentante del Fondazione Istituto Neurologico Xxxxx Xxxxx, codice fiscale 01668320151 (di seguito “Soggetto attuatore-beneficiario”)

il Dr XXXX XXXXXXX (codice fiscale XXXXXX00X00X000X) in qualità di PRINCIPAL INVESTIGATOR del progetto con codice PNRR-MR1-2022-12376618 dal titolo RAre, but not aLone: a large Italian network to empower the impervious diaGNostic pathway of rare cerEbrovascular Diseases (ALIGNED)

di seguito congiuntamente definite le “Parti”

Art. 1 Premesse

1. Le premesse sono parte integrante e sostanziale della presente Convenzione.

2. Fa altresì parte integrante e sostanziale della presente Convenzione, quale oggetto della stessa, il progetto di ricerca, i cui contenuti sono definiti ed eventualmente aggiornati nel tempo, mediante condivisione delle parti, senza necessità di espressa nuova sottoscrizione della presente Convenzione.

Art. 2 Soggetto attuatore/beneficiario e Principal Investigator

Il Soggetto attuatore-beneficiario e il Principal Investigator sono i responsabili dell’attuazione del progetto in questione e della regolarità delle relative spese ai sensi del bando e della normativa vigente.

1. È individuato quale Xxxxxxxx attuatore/beneficiario Fondazione Istituto Neurologico Xxxxx Xxxxx

codice fiscale 01668320151

2. È individuato quale Principal investigator (di seguito anche “PI”) il xxxx. XXXX XXXXXXX, codice fiscale XXXXXX00X00X000X

Art. 3 Oggetto

1. La presente Convenzione disciplina i rapporti tra le Parti per la realizzazione del progetto codice

PNRR-MR1-2022-12376618 dal titolo RAre, but not aLone: a large Italian network to empower

the impervious diaGNostic pathway of rare cerEbrovascular Diseases (ALIGNED), nell’ambito della realizzazione degli obiettivi previsti dal PNRR, Missione 6 – Componente 2 – Investimento 2.1.

2. La presente Convenzione definisce, tra l’altro, gli obblighi delle Parti, le procedure di rendicontazione e quelle di pagamento.

3. Il soggetto attuatore-beneficiario e il Principal Investigator svolgono il progetto di ricerca secondo quanto riportato nel progetto presentato parte integrante della presente convenzione, e approvato dal Ministero e in ottemperanza a quanto previsto dall’Avviso pubblico.

Art. 4 Termini di attuazione del progetto, durata e importo della Convenzione

1. La presente convenzione ha la durata di 24 mesi prorogabile eventualmente di ulteriori 6 mesi come previsto dal successivo articolo 11.

2. L’attività di ricerca, da svolgersi nell’arco temporale della vigenza della convenzione, deve avere inizio improrogabilmente entro e non oltre il 20 maggio 2023, comunicando la data effettiva di avvio con nota sottoscritta digitalmente dal proprio rappresentante legale e dal Principal investigator della ricerca che deve essere trasmessa almeno 30 giorni prima dell’inizio effettivo, correlata di documentazione di cui al successivo comma 4.

3. Il Soggetto beneficiario entro e non oltre 15 giorni dall’invio della presente convenzione da parte del Ministero per la sottoscrizione provvede alla restituzione della convenzione firmata dal legale rappresentate e controfirmata dal Principal Investigator, tramite il sistema di monitoraggio del WFR, accompagnata dalla comunicazione del codice CUP MASTER del progetto e dei codici fiscali delle singole Unità operative. Le parti riconoscono che il bando di cui alle premesse prevede la decadenza dal finanziamento in caso di inadempienza della presente disposizione.

4. Il Soggetto beneficiario, entro e non oltre30 giorni precedenti la scadenza del termine di cui al comma 2 del presente articolo, pena la decadenza dal finanziamento, è tenuto a trasmettere - con nota sottoscritta digitalmente in maniera congiunta dal proprio rappresentante legale e dal Principal Investigator della ricerca - la seguente documentazione, soggetta a verifica da parte del Ministero al fine di autorizzare l’avvio del progetto:

a) la dichiarazione da parte del legale rappresentante e del Principal Investigator con cui si dichiari che il progetto in questione o parti significative di esso non siano oggetto di altri finanziamenti pubblici a favore dell’Ente attuatore-beneficiario o del Principal Investigator e che, in ogni caso, sarà posta in essere ogni iniziativa volta ad evitare il doppio finanziamento;

b) la dichiarazione da parte del legale rappresentante e del ricercatore responsabile di ciascuna unità operativa partecipante con cui si dichiari che per la propria attività attinente al progetto in questione o per parti significative di esso non siano oggetto di altri finanziamenti pubblici a favore dell’Unità operativa medesima o dei ricercatori di tali unità operative elencati nella proposta progettuale e che, in ogni caso, sarà posta in essere ogni iniziativa volta ad evitare il doppio finanziamento;

c) la dichiarazione da parte degli Enti che svolgono funzioni di unità operativa e dei relativi responsabili di accettazione dei termini della presente convenzione;

d) la dichiarazione con la quale il Soggetto beneficiario attesta che il Principal Investigator svolgerà la propria attività di ricerca, per l’intero periodo relativo all’attuazione del progetto, esclusivamente presso la propria sede o presso la struttura del S.S.N. afferente al medesimo, controfirmata dall’interessato;

e) il parere positivo del Comitato etico competente e/o l’autorizzazione di cui all’articolo 31 del decreto legislativo n. 26 del 4 marzo 2014 riguardante la sperimentazione animale, ove previsti;

f) la comunicazione del codice CUP delle singole Unità operative e per ognuna di esse anche il codice fiscale dei soggetti designati a operare sul sistema ReGiS attraverso specifico format excel che verrà condiviso da parte della Direzione genale della ricerca e dell’innovazione in sanità che dovrà essere restituito firmato digitalmente;

g) la traduzione in lingua italiana della proposta progettuale senza apportare alcuna modifica alla versione in inglese allegata alla presente convenzione.

5. Per la realizzazione delle attività, l’importo ammesso a finanziamento è pari a 1.000.000,00€ (Euro un milione/00) a valere sulle risorse assegnate per le tematiche progettuali, stanziate in base alla tabella allegata al decreto ministeriale 1° aprile 2022 ai punti 2.1.1 – 2.1.2 e 2.1.3, concernente la ripartizione degli interventi di investimento della Missione 6, Componente 2, Investimento 2.1 del Piano Nazionale di Ripresa e Resilienza relativo all'innovazione, alla ricerca e alla digitalizzazione del Servizio sanitario nazionale e al potenziamento del sistema della ricerca biomedica.

6. La presentazione della richiesta di pagamento della rata intermedia delle spese al Ministero, secondo le modalità previste dall’art. 13, paragrafo 13.1 del bando, dovrà essere effettuata, previo caricamento della documentazione a supporto nel sistema ReGiS, entro 10 giorni dall’invio della comunicazione da parte del Ministero dell’approvazione della relazione scientifica intermedia.

7. La presentazione della richiesta di pagamento finale delle spese al Ministero dovrà essere effettuata successivamente all’invio entro 30 giorni dalla data di conclusione del progetto eventualmente prorogata secondo i termini della presente convenzione della relazione scientifica finale e della relativa rendicontazione economica complessiva del progetto e avverrà solo dopo l’invio della comunicazione da parte del Ministero dell’approvazione della relazione scientifica finale.

8. Il mancato adempimento di quanto previsto dai commi 2 e 3 del presente articolo equivale alla rinuncia a realizzare il progetto e comporta la decadenza dal contributo previsto e la decadenza dal finanziamento.

Art. 5 Obblighi del Soggetto attuatore-beneficiario e del Principal Investigator

1. Con la sottoscrizione della presente Convenzione, il Soggetto attuatore-beneficiario e il Principal Investigator, per quanto di competenza, si obbligano a:

1) assicurare il rispetto di tutte le disposizioni previste dalla normativa comunitaria e nazionale, con particolare riferimento a quanto previsto dal Reg. (UE) 2021/241 e dal D. L. n. 77 del 31/05/2021, convertito con modificazioni dalla L. 29 luglio 2021, n. 108;

2) garantire il rispetto di eventuali previsioni normative, orientamenti o istruzioni tecniche emanate dal Ministero della salute, dal Ministero dell’economia e delle finanze, dalla Commissione Europea ovvero da altri soggetti coinvolti nell’attuazione verifica e controllo delle azioni relative al PNRR, anche successivamente alla sottoscrizione della presente Convenzione;

3) assicurare l’adozione di misure adeguate volte a rispettare il principio di sana gestione finanziaria secondo quanto disciplinato nel Regolamento finanziario (UE, Euratom) 2018/1046 e nell’art. 22 del Regolamento (UE) 2021/241, in particolare in materia di prevenzione e contrasto dei conflitti di interessi, delle frodi, della corruzione, del doppio finanziamento e di recupero e restituzione dei fondi che sono stati indebitamente assegnati;

4) rispettare, a pena di sospensione o revoca del finanziamento in caso di accertata violazione, il principio di “non arrecare danno significativo” (DSNH) agli obiettivi ambientali a norma dell’articolo 17 del Regolamento (UE) 2020/852, i principi trasversali previsti dal PNRR quali, tra l’altro, il principio del contributo all’obiettivo climatico e digitale (c.d. tagging), la parità di genere, producendo dati relativi ai destinatari effettivi dei progetti anche disaggregati per genere (in relazione agli articoli 2, 3, paragrafo 3, del TUE, 8, 10, 19 e 157 del TFUE, e 21 e 23 della Carta dei diritti fondamentali dell’Unione europea), l’obbligo di protezione e valorizzazione dei giovani ed eventuali ulteriori requisiti e condizionalità specifiche dell’investimento oggetto della presente Convenzione;

5) adottare proprie procedure interne, assicurando la conformità ai regolamenti comunitari e a quanto indicato dal Ministero nella descrizione delle funzioni e delle procedure in essere dal Ministero;

6) dare piena attuazione al progetto così come illustrato nel Programma di ricerca, ammesso a finanziamento dal Ministero, garantendo l’avvio tempestivo delle attività progettuali per non incorrere in ritardi attuativi e concludere il progetto nella forma, nei modi e nei tempi previsti, nel rispetto della tempistica prevista dal relativo cronoprogramma di attuazione e di sottoporre al Ministero le eventuali modifiche al progetto;

7) assicurare il rispetto della normativa vigente sugli aiuti di Stato;

8) assicurare il rispetto dei criteri di ammissibilità delle spese e delle quote percentuali previste dall’Avviso per le varie voci di costo, che saranno calcolate, a consuntivo, sulle spese rendicontate, al netto di eventuali economie riscontrate sul finanziamento assegnato e sulle sole spese eleggibili, dopo verifica da parte del Ministero;

9) garantire, nel caso in cui si faccia ricorso alle procedure di appalto, il rispetto di quanto previsto dal decreto legislativo n. 50/2016 e s.m.i.; rispettare, in caso di ricorso diretto ad esperti esterni all’Amministrazione, la conformità alla pertinente disciplina comunitaria e nazionale, nonché alle eventuali specifiche circolari/disciplinari che potranno essere adottati dal Ministero;

10) individuare eventuali fattori che possano determinare ritardi che incidano in maniera considerevole sulla tempistica attuativa e di spesa definita nel cronoprogramma, relazionando il Ministero sugli stessi;

11) mitigare e gestire i rischi connessi al progetto nonché porre in essere azioni mirate connesse all’andamento gestionale ed alle caratteristiche tecniche;

12) effettuare i controlli ordinari di gestione e di regolarità amministrativo-contabile previsti dalla normativa vigente, e le verifiche sul conflitto di interessi, sul doppio finanziamento e quelle previste dalla normativa antiriciclaggio (“titolare effettivo”);

13) utilizzare il sistema informatico “ReGiS, finalizzato a raccogliere, registrare e archiviare in formato elettronico i dati per ciascuna operazione necessari per la sorveglianza, la valutazione, la gestione finanziaria, la verifica e l’audit, secondo quanto previsto dall’art. 22.2 lettera d) del Regolamento (UE) 2021/241 e tenendo conto delle indicazioni che verranno fornite dagli organi competenti per il tramite del Ministero;

14) caricare sul portale Workflow della Ricerca e nel sistema “ReGiS” la documentazione tecnico scientifica sullo stato di avanzamento del progetto atta a comprovare il corretto svolgimento dello stesso;

15) caricare sul sistema informativo “ReGiS” la documentazione atta a comprovare il corretto svolgimento dei controlli ordinari previsti dalla normativa vigente in merito alle procedure di gara espletate per l’aggiudicazione degli eventuali appalti o subcontratti e eventuali altra documentazione richiesta dalle Amministrazioni centrali deputate alla gestione complessiva del PNRR;

16) garantire la correttezza, l’affidabilità e la congruenza con il tracciato informativo previsto per l’alimentazione del sistema informativo “ReGiS” dei dati di monitoraggio riferiti al CUP Master e ai CUP delle singole Unità operative sull’avanzamento finanziario, fisico e procedurale, e di quelli che comprovano il conseguimento degli obiettivi dell’intervento quantificati in base agli stessi indicatori adottati per le milestones e i target della misura e assicurarne l’inserimento con cadenza almeno bimestrale delle spese (nel termine massimo di 10 giorni successivi all’ultimo giorno del bimestre) nel portale Workflow della Ricerca e sul sistema informativo “ReGiS”, unitamente alla documentazione probatoria pertinente, salvo diversa comunicazione;

17) rispettare l’obbligo di indicazione del CUP su tutti gli atti amministrativo/contabili relativi al progetto e sui documenti collegati alle relative procedure di acquisto e fatturazione;

18) fornire tutte le informazioni richieste relativamente alle procedure e alle verifiche in relazione alle spese rendicontate conformemente alle procedure e agli strumenti adottati dal Ministero;

19) garantire la conservazione della documentazione progettuale in fascicoli cartacei e/o informatici per assicurare la completa tracciabilità delle operazioni - nel rispetto di quanto previsto all’art. 9, punto 4, del D.L. n. 77 del 31 maggio 2021, convertito con modificazioni dalla L. n. 108/2021 - che, nelle diverse fasi di controllo e verifica previste dal sistema di gestione e controllo del PNRR, dovranno essere messi prontamente a disposizione su richiesta dell’Amministrazione centrale titolare di intervento PNRR, del Servizio centrale per il PNRR del MEF, dell’Unità di Audit, della Commissione europea, dell’OLAF, della Corte dei Conti europea (ECA), della Procura europea (EPPO) e delle competenti Autorità giudiziarie nazionali, autorizzando la Commissione, l'OLAF, la Corte dei conti e l'EPPO a esercitare i diritti di cui all'articolo 129, paragrafo 1, del regolamento finanziario (UE; EURATOM) 1046/2018;

20) facilitare le verifiche dell’Ufficio competente per i controlli del Ministero, dell’Unità di Audit, della Commissione europea e di altri organismi autorizzati, che verranno eventualmente effettuate anche attraverso controlli in loco;

21) assicurare che le spese del Progetto di ricerca non siano oggetto, anche parzialmente, di altri finanziamenti, contributi o agevolazioni a valere su fondi pubblici nazionali e/o comunitari (divieto del doppio finanziamento);

22) garantire la disponibilità dei documenti giustificativi relativi alle spese sostenute e ai target realizzati così come previsto ai sensi dell’articolo 9 punto 4 del decreto legge n. 77 del 31/05/2021, convertito in legge 29 luglio 2021, n. 108;

23) predisporre i pagamenti secondo le procedure stabilite dal Ministero, nel rispetto del piano finanziario e cronogramma di spesa approvato, inserendo, allo scadere dei 12 e 24 mesi (prorogabili eventualmente di 6 mesi) nel portale Workflow della Ricerca e sul sistema informativo “ReGiS” i relativi documenti riferiti alle procedure e i giustificativi di spesa e pagamento necessari ai controlli ordinari di legalità e ai controlli amministrativo-contabili previsti dalla legislazione nazionale applicabile, nel rispetto di quanto previsto dall’articolo 22 del Reg. (UE) n. 2021/241 e dell’art. 9 del decreto legge n. 77 del 31/05/2021, convertito in legge 29 luglio 2021, n. 108 la documentazione;

24) assicurare che tutte le spese rendicontate siano state effettuate entro il periodo di svolgimento del progetto e che gli eventuali pagamenti per fatture emesse nel periodo di svolgimento del progetto siano completate entro i 30 giorni successivi alla scadenza progettuale e in tempo utile per il caricamento sul sistema di rendicontazione ReGiS;

25) inoltrare, allo scadere dei 12 e 24 mesi (prorogabili eventualmente di 6 mesi),le richieste di pagamento al Ministero tramite il portale Workflow della Ricerca e/o il sistema informativo “ReGiS” con allegata la rendicontazione dettagliata delle spese effettivamente sostenute e del contributo al perseguimento delle milestones e dei target associati alla misura PNRR di riferimento, unitamente ai documenti giustificativi appropriati secondo le tempistiche e le modalità riportate nei dispositivi attuativi;

26) garantire l’utilizzo di un conto corrente dedicato necessario per l’erogazione dei pagamenti e l’adozione di una contabilità separata o di un’apposita codificazione contabile e informatizzata per tutte le transazioni relative al progetto al fine di assicurare la tracciabilità dell’utilizzo delle risorse del PNRR;

27) assicurare, direttamente o attraverso le Istituzioni da esso dipendenti in cui saranno svolte le attività di ricerca, l’anticipazione delle somme necessarie allo svolgimento della ricerca;

28) partecipare, ove richiesto, alle riunioni convocate dal Ministero.

29) garantire, anche attraverso la trasmissione di relazioni periodiche sullo stato di avanzamento del progetto, che il Ministero riceva tutte le informazioni necessarie, relative alle linee di attività per l’elaborazione delle relazioni annuali di cui all’articolo 31 del Regolamento (UE) n. 2021/241, nonché qualsiasi altra informazione eventualmente richiesta;

30) conseguire il raggiungimento degli obiettivi dell’intervento, quantificati secondo gli stessi indicatori adottati per le milestones e i target della misura PNRR di riferimento, e fornire, su richiesta dal Ministero, le informazioni necessarie per la predisposizione delle dichiarazioni sul conseguimento di target e milestones e delle relazioni e documenti sull’attuazione dei progetti;

31) garantire il rispetto degli obblighi in materia di comunicazione e informazione previsti dall’art. 34 del Regolamento (UE) 2021/241 indicando nella documentazione progettuale che il progetto è finanziato nell’ambito del PNRR, con esplicito riferimento al finanziamento da parte dell’Unione europea e all’iniziativa Next Generation EU (ad es. utilizzando la frase “finanziato dall’Unione europea – Next Generation EU – PNRR M6C2 - Investimento 2.1 Valorizzazione e potenziamento della ricerca biomedica del SSN”), riportando nella documentazione progettuale il logo dell’Unione europea e fornire un’adeguata diffusione e promozione del progetto, anche online, sia web sia social, in linea con quanto previsto dalla Strategia di Comunicazione del PNRR;

32) fornire i documenti e le informazioni necessarie secondo le tempistiche previste e le scadenze stabilite dai Regolamenti comunitari e dal Ministero e per tutta la durata del progetto;

33) garantire una tempestiva diretta informazione agli organi preposti, tenendo informato il Ministero sull’avvio e l’andamento di eventuali procedimenti di carattere giudiziario, civile, penale o amministrativo che dovessero interessare le operazioni oggetto del progetto, comunicare le irregolarità, le frodi, i casi di corruzione e di conflitti di interessi, nonché i casi di doppio finanziamento, riscontrati a seguito delle verifiche di competenza e adottare le misure necessarie,

nel rispetto delle procedure adottate dallo stesso Ministero in linea con quanto indicato dall’art. 22 del Regolamento (UE) 2021/2041;

34) garantire che il Ministero riceva attraverso il sistema “ReGiS” tutte le informazioni necessarie per l’aggiornamento dell’indicatore comune n. 8 “Ricercatori che lavorano in centri di ricerca beneficiari di un sostegno”, riconducibile alla misura oggetto del presente avviso, tenuto conto che, ai sensi dell’art. 3, comma 3, del Regolamento delegato (UE) 2021/2106 della Commissione del 28 settembre 2021 che integra il regolamento (UE) 2021/241 del Parlamento europeo e del Consiglio, che istituisce il dispositivo per la ripresa e la resilienza “la comunicazione di informazioni per l’aggiornamento degli indicatori comuni ha luogo ogni anno entro il 28 febbraio e il 31 agosto. Il periodo di riferimento copre l’intero periodo di attuazione del piano, dal 1° febbraio 2020 in poi, se del caso, fino alle rispettive date limiti del 31 dicembre e del 30 giugno di ogni anno.”

Art. 6 Procedura di monitoraggio e rendicontazione della spesa e dei target

1. Il Ministero con la presente convenzione rappresenta alla controparte che il monitoraggio tecnico- scientifico sarà svolto dalla Direzione della Ricerca ed Innovazione in Sanità, mentre i controlli rispetto alla rendicontazione delle spese saranno svolte dall’Unità di missione per l'attuazione degli interventi del PNRR presso il Ministero della salute.

2. Il Soggetto attuatore-beneficiario, secondo le indicazioni fornite dal Ministero, deve registrare su base almeno bimestrale, entro 10 giorni successivi all’ultimo giorno del periodo considerato, i dati sull’avanzamento finanziario, fisico e procedurale del progetto nel sistema informatico “ReGiS” e implementare tale sistema con la documentazione specifica relativa a ciascuna procedura di affidamento e a ciascun atto giustificativo di spesa e di pagamento, al fine di consentire l’espletamento dei controlli amministrativo-contabili a norma dell’art. 22 del Reg. (UE) 2021/241 da parte dall’Unità di missione per l'attuazione degli interventi del PNRR presso il Ministero della salute.

3. Il Soggetto attuatore-beneficiario, allo scadere dei 12 e 24 mesi (prorogabili eventualmente di 6 mesi) deve trasmettere i dati sull’avanzamento tecnico-scientifico del progetto tramite il portale Workflow della Ricerca e il sistema “ReGiS” corredata di documentazione specifica relativa a ciascuna procedura di affidamento e a ciascun atto giustificativo di spesa e di pagamento, al fine di consentire l’espletamento dei controlli amministrativo-contabili e delle verifiche sullo stato di avanzamento del progetto.

4. Il Soggetto attuatore-beneficiario, pertanto, dovrà inoltrare allo scadere dei 12 e 24 mesi (prorogabili eventualmente di 6 mesi) tramite il portale Workflow della Ricerca e il sistema informatico “ReGiS”, la richiesta rendicontazione delle spese volte a supportare le richieste di pagamento che dovranno essere formalmente trasmesse all’Unità di Missione del Ministero comprensiva dell’elenco di tutte le spese effettivamente sostenute nel periodo di riferimento, gli avanzamenti relativi agli indicatori di intervento/progetto con specifico riferimento alle milestones e ai target del PNRR. Tale richiesta dovrà essere corredata dalla documentazione specificatamente indicata nelle procedure in essere del Ministero.

5. Le spese incluse nelle richieste di pagamento del Soggetto attuatore/beneficiario, se afferenti ad operazioni estratte a campione, sono sottoposte, per il tramite del Sistema Informatico “ReGiS”, alle verifiche, se del caso anche in loco da parte delle strutture deputate al controllo del Ministero.

6. Nello specifico, l’Unità di missione per l'attuazione degli interventi del PNRR del Ministero della Salute e eventuali altre amministrazioni coinvolte a diversi livelli di controllo eseguono le verifiche sulle procedure, sulle spese e sui target in conformità con quanto stabilito dall’art. 22 del Regolamento (UE) 2021/241 al fine di garantire la tutela degli interessi finanziari dell'Unione, la prevenzione, individuazione e rettifica di frodi, di casi di corruzione e di conflitti di interessi, nonché il recupero di somme erroneamente versate o utilizzate in modo non corretto.

7. La Direzione generale della Ricerca ed innovazione in sanità del Ministero della Salute svolge nel merito le funzioni di verifica tecnico-scientifica sullo stato di avanzamento del progetto in questione in coerenza con lo stato di rendicontazione delle spese.

Art. 7 Valutazione intermedia

1. Allo scadere dei 12 mesi dall’inizio dell’attività della ricerca e comunque non oltre trenta (30) giorni da tale termine, il Soggetto attuatore-beneficiario trasmette al Ministero tramite il portale Workflow della ricerca la relazione intermedia sullo stato d’attuazione scientifica della ricerca - sottoscritta digitalmente dal legale rappresentante del Soggetto attuatore/beneficiario e dal Principal Investigator

- contenente la descrizione delle attività progettuali svolte complessivamente e dalle singole unità operative, da cui risulti lo stato avanzamento lavori (SAL) e il regolare svolgimento della ricerca, secondo quanto riportato nel progetto approvato. Tale relazione deve contenere una sintesi, a cura del Principal Investigator, che illustri, nella globalità, lo stato di avanzamento dei lavori, inclusa la descrizione delle attività realizzate da eventuali Enti co-finanziatori e l’apporto fornito da eventuali xxxxxxxxxxxxx.Xx relazione intermedia, previa verifica tecnico-scientifica da parte della Direzione della Ricerca ed innovazione in sanità, sarà caricata dal Soggetto attuatore/beneficiario e dal Principal Investigator all’interno del sistema informativo “ReGiS”.

2. Il Ministero ha facoltà, previa comunicazione preventiva al Soggetto attuatore/beneficiario, di attivare le procedure per la sospensione del finanziamento e il recupero delle somme erogate, comprensive degli eventuali interessi legali maturati, qualora il Soggetto attuatore/beneficiario non adempia a quanto previsto entro i termini di cui al comma 1 del presente articolo.

3. La Direzione generale della Ricerca ed innovazione in sanità del Ministero della Salute, previa comunicazione preventiva al Soggetto attuatore/beneficiario, ha facoltà di comunicare all’Unità di missione per l'attuazione degli interventi del PNRR del medesimo Ministero, che sussistono le condizioni per non erogare le successive quote a rimborso, subordinandole all’ esito positivo del giudizio in ordine alla relazione finale, qualora la relazione intermedia, all’esito dell’istruttoria, non sia considerata idonea a dimostrare che siano stati pienamente raggiunti gli obiettivi medio termine o emerga che essa sia stata condotta non in piena conformità con quanto previsto nel progetto approvato. In tal caso il Ministero potrà procedere con il rimborso a saldo. Xxxxxxx non vengano rispettati i termini di cui alla presente convenzione, che non consentano la tempestiva erogazione dei fondi, il Soggetto attuatore/beneficiario esonera il Ministero da qualsiasi responsabilità per eventuali ritardi nell’erogazione delle somme spettanti.

4. Il Ministero, previa comunicazione preventiva al Soggetto attuatore/beneficiario, può sottoporre al Comitato tecnico sanitario sez. c), un dossier, qualora la relazione intermedia, all’esito della istruttoria ministeriale, non consenta di esprimere un compiuto motivato parere. La decisione del suddetto Comitato è vincolante per il Soggetto beneficiario ai fini del prosieguo della convenzione.

Art. 8 Valutazione finale

1. Fatta salva l’eventuale concessione di proroga della durata delle attività progettuali, al termine di ventiquattro mesi - e comunque non oltre trenta (30) giorni dopo la data fissata per il termine della ricerca – ai fini dell’erogazione del saldo, il Soggetto attuatore-beneficiario, con nota firmata digitalmente dal rappresentante legale, trasmette contestualmente al Ministero la seguente documentazione, redatta dal Principal Investigator e recante la firma digitale dello stesso:

- la relazione finale della ricerca, contenente quanto posto in essere anche da eventuali Enti cofinanziatori, che documenti, per ciascuna unità operativa, la coerenza delle attività svolte con il progetto approvato e gli obiettivi raggiunti;

- copia dei lavori pubblicati su riviste impattate a seguito dello svolgimento della ricerca;

- la rendicontazione delle spese sostenute con i fondi ministeriali;

- indicazioni del repository pubblico dove sono resi disponibili i dati grezzi progettuali e quelli utilizzati per le pubblicazioni scientifiche correlate.

- il rispetto dei costi sostenuti rispetto ai vincoli del bando in materia di gender e spese effettuate da parte di istituzioni nell’aree del meridione

2. La rendicontazione economica dovrà essere corredata da una relazione di certificazione e di apposita check list di verifica dei requisiti minimi del bando, rilasciata da un Revisore esterno indipendente, iscritto all’Ordine dei Dottori Commercialisti ed Esperti Contabili e al Registro dei Revisori Legali, in possesso dei requisiti richiesti dalla Direttiva 2014/56/UE del Parlamento europeo e del Consiglio, del 16 aprile 2014 , che modifica la direttiva 2006/43/CE relativa alle revisioni legali dei conti annuali

e dei conti consolidati, e dalla relativa legislazione nazionale di attuazione, che certifichi la regolarità amministrativo-contabile delle spese sostenute per la realizzazione del progetto, la loro conformità alla normativa di riferimento vigente, il rispetto delle condizionalità e di tutti i requisiti previsti dall’Avviso e dalla presente Convenzione il rispetto delle normative nazionali ed europee in materia e la congruenza con le attività svolte ed i risultati raggiunti.

3. Tutta la sopra richiamata documentazione deve essere redatta e trasmessa tramite il portale Workflow della ricerca e il sistema informatico “ReGiS” e secondo le indicazioni previste dal sistema informatico di monitoraggio economico e utilizzando congiuntamente il sistema di comunicazione del Workflow della ricerca, a disposizione dei destinatari istituzionali che può essere integrato con comunicazioni tramite posta elettronica certificata (PEC) da parte del Soggetto attuatore/beneficiario.

4. La documentazione di supporto deve essere a disposizione del Ministero e degli Organi di controllo e verifica del PNRR, presso il Soggetto attuatore/beneficiario, che deve provvedere alla relativa custodia.

5. La Direzione generale della Ricerca ed innovazione in sanità del Ministero della salute provvede ad applicare una decurtazione pari al 10% della rata del saldo, qualora la documentazione di cui al comma 1 del presente articolo sia trasmessa al Ministero in un periodo compreso tra il trentunesimo e il quarantesimo giorno dalla data di conclusione del progetto.

6. Il Ministero provvede ad applicare una decurtazione pari al 20% della rata del saldo, qualora la documentazione di cui al comma 1 del presente articolo sia trasmessa al Ministero in un periodo compreso tra il quarantunesimo e il cinquantesimo giorno dalla data di conclusione del progetto.

7. Il Ministero, previa comunicazione preventiva al Soggetto attuatore/beneficiario, attiva le procedure per la sospensione del finanziamento e la conseguente economia della rata finale, nonché per il recupero di tutte delle somme già erogate, anche quelle già utilizzate per il personale facente parte del gruppo della ricerca, comprensive degli interessi legali maturati, qualora la documentazione di cui al comma 1 del presente articolo non sia trasmessa al Ministero entro il cinquantesimo giorno dalla data di conclusione del progetto.

8. Il Ministero si riserva la facoltà di chiedere informazioni ed eventuale documentazione integrativa al Soggetto attuatore/beneficiario, che deve fornire riscontro entro e non oltre i successivi 15 giorni, qualora:

- la relazione finale non sia considerata idonea a dimostrare il regolare svolgimento della ricerca, in conformità a quanto previsto nel progetto e nel piano finanziario approvati;

- la rendicontazione risulti incompleta o incongruente sia sui dati contabili sia sulle descrizioni.

9. Il Ministero provvederà ad emettere la valutazione finale sulla base di quanto acquisito agli atti. In caso di mancato o esaustivo riscontro da parte del Soggetto attuatore/beneficiario delle richieste di cui al precedente comma, il Ministero comunica al Soggetto attuatore/beneficiario il parere negativo in ordine alla relazione finale e conseguentemente in ordine all’erogazione del saldo ed ha facoltà di chiedere la restituzione delle somme già erogate, comprensive degli interessi legali maturati, in caso di mancato riscontro oppure laddove dall’istruttoria della documentazione integrativa emerga che sono stati disattesi gli obiettivi di cui al progetto

10. Il Ministero, previa comunicazione preventiva al Soggetto attuatore/beneficiario, può sottoporre al Comitato tecnico sanitario sez. c) un dossier, qualora la relazione finale, all’esito della istruttoria ministeriale, non consenta di esprimere un compiuto motivato parere. La decisione del suddetto Comitato è vincolante per il Soggetto beneficiario ai fini del prosieguo della convenzione.

Art. 9 Verifica finanziaria preventiva

Il Soggetto attuatore-beneficiario, al fine dell’erogazione del finanziamento, deve trasmettere al Ministero della salute – Unità di missione per l’attuazione degli investimenti del PNRR, tramite il sistema “ReGiS” la rendicontazione economica corredata da certificato di verifica finanziaria, di cui al comma 2 dell’articolo 8 della presente convenzione, redatto in lingua inglese ed in italiano da parte di soggetti qualificati all’Audit a livello europea, che certifichi la correttezza della procedura di spese, la completezza della documentazione in base alle disposizioni del bando e alle norme nazionale e a quelle europee

Art. 10 Procedura di pagamento al Soggetto beneficiario

1. Le procedure di erogazione dei fondi su richiesta del Soggetto attuatore/beneficiario a titolo di anticipazione e a titolo di rimborso all’Unità di missione del Ministero della salute seguono le specifiche modalità in conformità con quanto indicato nell’Avviso e di seguito riportate:

- massimo 40% al momento della comunicazione, da parte del Soggetto beneficiario, dell’inizio dell’attività di ricerca, a titolo di anticipazione.

- quota a rimborso per un ulteriore per massimo un complessivo pari all’80% dopo l’invio, al 12° mese dall’inizio delle attività progettuali, da parte del Soggetto attuatore/beneficiario della relazione scientifica intermedia e dopo la sua approvazione, sulla base della presentazione delle richieste di pagamento a titolo di rimborso per le spese effettivamente sostenute dal Soggetto beneficiario, come risultanti dal sistema informatico di cui all’articolo 1, comma 1043, della legge 30 dicembre 2020, n, 178.

- quota a rimborso residuale a saldo, a conclusione della ricerca, dopo l’invio da parte del Soggetto attuatore/beneficiario della relazione scientifica finale e della rendicontazione economica, sulla base della presentazione della richiesta di pagamento finale attestante la conclusione del progetto, in coerenza con le risultanze del sistema di monitoraggio di cui all’articolo 1, comma 1043, della legge 30 dicembre 2020, n. 178.

2. A garanzia della coerenza con l’inizio dell’attività dichiarata, il Soggetto attuatore/beneficiario si impegna ad anticipare le risorse economiche necessarie, nell’eventualità in cui le somme da corrispondersi da parte del Ministero siano in regime di perenzione.

3. Xxxxxxx non vengano rispettati i termini di cui alla presente convenzione, che non consentano la tempestiva erogazione dei fondi, il Soggetto attuatore/beneficiario esonera il Ministero da qualsiasi responsabilità per eventuali ritardi nell’erogazione delle somme spettanti.

4. Al termine delle verifiche la Direzione generale della ricerca ed innovazione in sanità del Ministero della Salute comunicherà dall’Unità di missione per l'attuazione degli interventi del PNRR del Ministero Salute le risultanze delle verifiche per consentire l’effettuazione degli eventuali successivi pagamenti.

Art. 11 Variazioni del progetto e del piano dei costi

1. A partire dal 3° mese successivo all’avvio del progetto e fino a 3 mesi prima della scadenza del progetto, il Soggetto attuatore-beneficiario, con nota firmata dal proprio rappresentate legale e dal Principal Investigator, trasmessa tramite il portale Workflow della ricerca e il sistema informatico “ReGiS”, può proporre variazioni al progetto, coerenti con gli obiettivi progettuali, o alla distribuzione di fondi tra le unità operative, purché non comportino un aumento del finanziamento complessivo a carico del Ministero, che dovranno essere accolte con autorizzazione scritta del Ministero. La richiesta di modifica deve dimostrare le necessità scientifiche alla base della richiesta e l’equivalenza della modifica proposta rispetto al raggiungimento degli obiettivi progettuali previsti, modifica che avrà efficacia solo dopo l’approvazione da parte del Ministero con successivo necessario adeguamento del piano dei costi per il CUP Master e per i CUP delle singole Unità operative da parte del Soggetto attuatore-beneficiario.

2. Non è consentito al di fuori del periodo di cui al comma 1 avanzare richieste di modifica. In caso di eventuale necessità di un’ulteriore modifica progettuale è possibile presentare tale richiesta di modifica solo dopo 3 mesi dall’approvazione da parte del Ministero dell’ultima modifica progettuale della stessa tipologia ovverosia scientifica o economica.

3. Il piano dei costi, riportato nella proposta progettuale, è da ritenersi vincolante relativamente al solo totale del finanziamento assegnato e al riparto iniziale tra unità operative, mentre ha valore meramente indicativo per quanto riguarda la ripartizione tra voci di costo e le motivazioni fornite a giustificazione di tali costi.

4. La distribuzione delle somme tra le diverse voci di costo, nell’ambito di ogni singola unità operativa, è consentita sotto la responsabilità del Soggetto attuatore-beneficiario che ha presentato il progetto e che dovrà verificare il rispetto delle percentuali ed i vincoli previste dal bando.

5. Qualsiasi proposta emendativa deve essere adeguatamente motivata dal Principal Investigator per documentare che quanto richiesto risulti indispensabile per assicurare il raggiungimento degli obiettivi a suo tempo prefissati.

6. Solo dopo l’approvazione del Ministero, il soggetto attuatore/beneficiario potrà procedere all’applicazione delle modifiche di cui al comma 1 del presente articolo. In caso di eventuali inadempimenti al presente articolo il Ministero ha facoltà di procedere sia alla risoluzione della convenzione, dandone comunicazione al Soggetto attuatore/beneficiario, sia alla sospensione del finanziamento, nonché al recupero di tutto l’importo erogato.

Art. 12 Proroga

1. Il termine della ricerca può essere prorogato dal Ministero per un periodo massimo di 6 mesi dalla data di scadenza originale, solo a seguito di formale, motivata e documentata istanza firmata digitalmente dal legale rappresentante del Soggetto attuatore-beneficiario e dal Principal Investigator, trasmessa tramite il portale Workflow della ricerca.

2. La richiesta di cui al comma 1 può essere avanzata solo dopo la presentazione della relazione di medio termine ovverosia dopo 12 mesi dall’avvio progetto e fino a 3 mesi precedenti il termine del progetto, con formale e motivata istanza da parte del Soggetto attuatore-beneficiario e del Principal Investigator, che dimostri le necessità scientifiche alla base della richiesta rispetto alle necessità per il raggiungimento degli obiettivi progettuali previsti e avrà efficacia solo dopo l’approvazione da parte del Ministero.

Art. 13 Proprietà e diffusione dei risultati

1. La proprietà degli studi, dei prodotti e delle metodologie sviluppati nell’ambito del progetto è regolamentata dalla normativa vigente in materia, salvo particolari accordi stipulati tra le parti firmatarie del presente atto, ferma restando la possibilità dei soggetti istituzionali del Servizio Sanitario Nazionale di fruirne, previa richiesta alle parti firmatarie.

2. Nel caso in cui il Soggetto attuatore/beneficiario intenda trasferire ad altri soggetti qualsiasi diritto, anche parziale, relativo alla ricerca in questione, ai risultati della stessa o ad eventuali brevetti derivati deve darne preventiva comunicazione al Ministero.

3. Il Soggetto attuatore/beneficiario si impegna a garantire un’adeguata diffusione e promozione del progetto, anche online, sia sul web che sui social media.

4. Qualsiasi documento prodotto, ivi comprese le pubblicazioni scientifiche inerenti al progetto di ricerca oggetto della presente convenzione – per i quali deve essere assicurato l’accesso non oneroso al Ministero - deve contenere l’indicazione che il progetto è finanziato nell’ambito del PNRR, con un’esplicita dichiarazione che reciti "finanziato dall’Unione europea – Next Generation EU – PNRR M6C2 - Investimento 2.1 Valorizzazione e potenziamento della ricerca biomedica del SSN", l’emblema dell’Unione Europea ed il codice del progetto.

5. I prodotti di cui al precedente comma 4 devono essere resi pubblici attraverso sistemi che consentano l’immediata fruizione da parte del pubblico (ad esempio open-access) e non potranno essere oggetto di pubblicazione scientifica per la quale sia necessario il pagamento di una sottoscrizione ovvero il pagamento per la consultazione relativa L’eventuale violazione del presente comma, anche per una sola pubblicazione, sarà oggetto di una penale pari al 25% del finanziamento complessivo

6. Il Ministero non riconosce l’eleggibilità dei costi delle pubblicazioni sui propri fondi qualora in dette pubblicazioni non si faccia espressa menzione del finanziamento ottenuto nell’ambito del PNRR e del codice progetto.

7. Le parti convengono che il Ministero possa dare direttamente diffusione, anche attraverso il proprio sito web, dell’estratto della proposta progettuale e dei risultati della ricerca sia in forma completa che sintetica e delle pubblicazioni scientifiche da essa derivate.

Art. 14 Casi di riduzione, sospensione o revoca del contributo

1. Il Ministero procede a dichiarare la sospensione o revoca totale o parziale del finanziamento concesso, con conseguente eventuale restituzione delle somme già erogate, comprensive degli interessi legali maturati, nei seguenti casi:

a. modifiche ingiustificate alla composizione del gruppo di ricerca;

b. mancato rispetto dei vincoli previsti dall’Avviso;

c. mancato rispetto degli obblighi di cui all’art. 5 della presente Convenzione;

d. mancato raggiungimento, nei tempi assegnati, delle milestones e dei target previsti per lo svolgimento del progetto;

e. mancata o ritardata presentazione della relazione intermedia sullo stato d’attuazione della ricerca;

f. mancata o ritardata presentazione - oltre il cinquantesimo giorno dalla data di conclusione del progetto - della relazione finale della ricerca e della rendicontazione delle spese sostenute con i fondi ministeriali;

g. modifiche del progetto o variazioni nella distribuzione dei fondi tra le unità operative non autorizzate;

2. Il Ministero applica riduzioni finanziarie in misura variabile e/o consistenti nel mancato riconoscimento delle spese nei seguenti casi:

a. mancato rispetto dei criteri di ammissibilità di cui all’art. 10 dell’Avviso; spese eccedenti i massimali previsti per alcune categorie di spese dall’art. 10 dell’Avviso; costi delle pubblicazioni in cui non si faccia espressa menzione del finanziamento ottenuto nell’ambito del PNRR e del codice progetto;

b. riduzione finanziaria nella misura del 5% della rata del saldo nel caso in cui il Soggetto attuatore/beneficiario al termine delle attività progettuali inoltri copia dei lavori pubblicati su riviste impattate a seguito dello svolgimento della ricerca dalla quale risulti che solo alcune pubblicazioni prodotte recano la menzione del finanziamento ottenuto nell’ambito del PNRR e del codice progetto;

c. riduzione finanziaria nella misura del 10% della rata del saldo qualora la relazione finale della ricerca e la rendicontazione delle spese sostenute siano trasmesse al Ministero in un periodo compreso tra il trentunesimo e il quarantesimo giorno dalla data di conclusione del progetto;

d. riduzione finanziaria nella misura del 20% della rata del saldo qualora la relazione finale della ricerca e la rendicontazione delle spese sostenute siano trasmesse al Ministero in un periodo compreso tra il quarantunesimo e il cinquantesimo giorno dalla data di conclusione del progetto;

e. riduzione finanziaria nella misura del 5% dell’intero finanziamento nel caso in cui il Soggetto attuatore/beneficiario al termine delle attività progettuali inoltri copia dei lavori pubblicati su riviste impattate a seguito dello svolgimento della ricerca privi della menzione del finanziamento ottenuto nell’ambito del PNRR e del codice progetto;

f. riduzione finanziaria nella misura del 10% dell’intero finanziamento nel caso in cui il Soggetto attuatore/beneficiario al termine delle attività progettuali non inoltri la copia dei lavori pubblicati su riviste impattate a seguito dello svolgimento della ricerca e/o le indicazioni del repository pubblico dove sono resi disponibili i dati grezzi progettuali e quelli utilizzati per le pubblicazioni scientifiche correlate.

Art. 15 Risoluzione di controversie

1. Per qualsiasi controversia, il Soggetto attuatore-beneficiario può rivolgersi agli Uffici della Direzione generale della ricerca e dell’innovazione in sanità del Ministero della salute, che sottoporranno le eventuali problematiche al parere di competenza del Comitato tecnico sanitario (CTS) operante presso il Ministero. Le parti, con la sottoscrizione della presente convenzione, accettano fin d’ora il parere che sarà espresso dal Comitato tecnico sanitario (CTS) in caso di controversie sulla conduzione scientifica del progetto e le eventuali ricadute economiche.

2. Con la firma della presente convenzione il Principal Investigator accetta quanto previsto dal precedente comma 1.

3. Qualora a seguito della valutazione del CTS, di cui al comma 1 sussistano ulteriori eventuali controversie, diverse da quelle del comma 1, che dovessero sorgere in ordine al presente avviso il Foro competente è il Foro di Roma.

Art. 16 Risoluzione per inadempimento

1. Il Ministero potrà avvalersi della facoltà di risolvere la presente Convenzione qualora il Soggetto attuatore/beneficiario non rispetti gli obblighi imposti a suo carico e, comunque, pregiudichi l’assolvimento da parte dello stesso Ministero degli obblighi imposti dalla normativa comunitaria.

Art. 17 Diritto di recesso

1. Il Ministero potrà recedere in qualunque momento dagli impegni assunti con la presente Convenzione nei confronti del Xxxxxxxx attuatore/beneficiario qualora, a proprio giudizio, nel corso di svolgimento delle attività, intervengano fatti o provvedimenti che modifichino la situazione esistente all’atto della stipula della presente Convenzione o ne rendano impossibile o inopportuna la conduzione a termine.

Art. 18 Comunicazioni e scambio di informazioni

1. Ai fini della digitalizzazione dell’intero ciclo di vita del progetto, tutte le comunicazioni con il Ministero della salute devono avvenire attraverso il sistema di monitoraggio delle ricerche denominato Workflow della ricerca, a disposizione del Soggetto attuatore-beneficiario e laddove necessario attraverso il sistema messo a disposizione dal Ministero dell’Economie e Finanze denominato “ReGiS”.

2. Il Soggetto attuatore/beneficiario attraverso il proprio rappresentate legale, nonché il Principal Investigator devono firmare digitalmente tutti gli atti inerenti alla ricerca.

Art. 19 Tracciabilità dei flussi finanziari

1. Le parti si impegnano all’osservanza, per quanto di rispettiva competenza, delle disposizioni inerenti alla tracciabilità dei flussi finanziari di cui all’art. 3 della Legge 13 agosto 2010, n. 136 e s.m.i..

Art. 20 Protezione dei dati personali

1. Nel corso dell’esecuzione delle attività oggetto della presente Convenzione, ciascuna delle Parti potrà trovarsi nella condizione di dover trattare dati personali riferibili a dipendenti e/o collaboratori dell’altra Parte, motivo per cui le stesse si impegnano sin d’ora a procedere al trattamento di tali dati personali in conformità alle disposizioni di cui al Regolamento (UE) 2016/679 del Parlamento europeo e del Consiglio, del 27 aprile 2016, relativo alla protezione delle persone fisiche con riguardo al trattamento dei dati personali, nonché alla libera circolazione di tali dati e che abroga la direttiva 95/46/CE (Regolamento generale sulla protezione dei dati - GDPR) e successive norme nazionali di adeguamento.

2. Le Parti si impegnano a condurre le suddette attività di trattamento sulla base dei principi di correttezza, liceità, trasparenza e tutela della riservatezza dei soggetti interessati e per il solo ed esclusivo fine di perseguire le finalità di cui alla presente Convenzione, nonché degli eventuali obblighi di legge allo stesso connessi. Tali dati saranno trattati dalle Parti con sistemi cartacei e/o automatizzati

- ad opera di propri dipendenti e/o collaboratori che, in ragione della propria funzione e/o attività, hanno la necessità di trattarli, per le sole finalità suindicate e limitatamente al periodo di tempo necessario al loro conseguimento.

Art. 21 Efficacia

1. La presente convenzione, vincolante all'atto della sottoscrizione per il Soggetto attuatore-beneficiario e il Principal Investigator, diventerà efficace per il Ministero a seguito della registrazione da parte degli organi di controllo.

Art. 22 Disposizioni Finali

1. Per quanto non previsto dalla presente Convenzione si rinvia alle norme comunitarie e nazionali di riferimento.

Letto, confermato e sottoscritto con firma digitale, ai sensi del decreto legislativo 7 marzo 2005, n. 82 e s.m.i..

Roma, (data della sottoscrizione come quella dell’ultima firma digitale apposta) per il Ministero della salute

Xxxx. Xxxxxxx Xxxxxxxxx Direttore dell’Ufficio 3

Direzione generale della ricerca e dell’innovazione in sanità

per il Soggetto attuatore/beneficiario Xxxxxxxx Xxxxxx Xxxxxx, codice fiscale XXXXXX00X00X000X

(Legale rappresentante)

Per presa visione ed accettazione:

Il Principal Investigator - XXXX XXXXXXX, codice fiscale XXXXXX00X00X000X

1 - General information

Project code: PNRR-MR1-2022-12376618

PI / Coordinator: xxxxxxx Xxxx

Project topic: B2) Malattie rare: sviluppo di soluzioni trasversali che possano avere impatto su molteplici patologie in termini di ricerca e assistenza

Applicant Institution: Fondazione Istituto Neurologico Xxxxx

Xxxxx

Call section: Proposal title:

Malattie Rare

RAre, but not aLone: a large Italian network to empower the impervious diaGNostic pathway of rare cerEbrovascular Diseases (ALIGNED)

Duration in months: 24

MDC primary: Neurologia MDC secondary: Neurologia Project Classification IRG:

Brain Disorders and Clinical Neuroscience

Project Classification SS:

Brain Injury and Neurovascular Pathologies - BINP

Project Keyword 1:

Studies aimed at elucidating a role for age, gender, genetics, and environment in response to and recovery from acute brain injury.

Project Request: Animals:

Project total financing request to the MOH: € 1.000.000

Humans:

Clinical trial:

Free keywords: CADASIL, COL4A1, Fabry disease, Xxxxxxx and Xxxxx syndromes, Moyamoya arteriopathy, database, biobanks, omics, biomarkers, virtual hospital

Declarations

In case of a Synergy grant application 'Principal Investigator'(PI) means 'corresponding Principal Investigator on behalf of all Principal Investigators', and 'Host Institution' means 'corresponding Host Institution'.

1) The Principal Investigator declares to have the written consent of all participants on their participation and on the content of this proposal, as well as of any researcher mentioned in the proposal as participating in the project (either as other PI, team member or collaborator).	X
2) The Principal Investigator declares that the information contained in this proposal is correct and complete.	X
3) The Principal Investigator declares that all parts of this proposal comply with ethical principles (including the highest standards of research integrity — as set out, for instance, in the European Code of Conduct for Research Integrity — and including, in particular, avoiding fabrication, falsification, plagiarism or other research misconduct).	X
4) The Principal Investigator is only responsible for the correctness of the information relating to his/her own organisation. Each applicant remains responsible for the correctness of the information related to him and declared above.	X

Personal data protection

The assessment of your grant application will involve the collection and processing of personal data (such as your name, address and CV), which will be performed pursuant to Regulation (EC) No 45/2001 on the protection of individuals with regard to the processing of personal data by the Community institutions and bodies and on the free movement of such data. Unless indicated otherwise, your replies to the questions in this form and any personal data requested are required to assess your grant application in accordance with the specifications of the call for proposals and will be processed solely for that purpose. Details concerning the purposes and means of the processing of your personal data as well as information on how to exercise your rights are available in the privacy statement. Applicants may lodge a complaint about the processing of their personal data with the European Data Protection Supervisor at any time.

Abstract

Rare cerebrovascular diseases (rCVDs) include a large group of disorders, which may be possible causes of ischemic stroke at a young age. They are either genetically determined (i.e CADASIL, Fabry disease, COL4A1 syndrome) or acquired (i.e Xxxxxxx syndrome, Moyamoya arteriopathy) entities. The relatively low prevalence of these diseases only partially mitigates their economic and social burden and often confines them to an "orphan" status of care. With the present project, we intend to create a national and multidisciplinary network for the management of rCVD, with the main objective of integrating different centers located throughout the Italian territory, in order to fill the geographical gap that has always affected treatment and research facilities in Southern Italy. The research will move along two operational lines: clinical-organizational (conducted by U1 FINCB in Milano, U3 ASL2 Regione Abruzzo, and U4 Università dell'Aquila), aimed at producing a clinical network, technology transfer and knowlegde and punctual phenotyping of each rCVD, and neurobiological (conducted by U1 FINCB in Milano and U2 Proteomic and Metabolomic Unit of CCM in Milano), searching for drivers and risk markers of rCVD. The interaction between centers with different vocations (both preclinical research laboratories and hospital diagnosis and treatment centers) will be favored by the use of data sharing platforms and virtual meetings (i.e., Virtual Hospital model).The knowledge and expertise of each center will be made available to others, resulting in an enrichment of the entire staff involved in the network. A common and unique database, with stringent and aligned patient inclusion criteria, will be produced for each rCVD. This will enable the enhancement of Italian publications on rCVD, as well as possible participation in national and international clinical trials in the future. In addition, the project aims at harmonizing the use of diagnostic criteria and standardizing the executive protocols of instrumental examinations (radiological and laboratory ones). This will help avoiding the costly migration of patients from distant parts of Italy to seek "second opinions" or repeat the same diagnostic test. With this integrated and widespread network, the rCVD patients will be early identified and better followed up, preventing patients from feeling "left alone" with their rare disease.

Yes

In order to best review your application, do you agree that the above non-confidential proposal title and abstract can be used, without disclosing your identity, when contacting potential reviewers?

2 - Participants & contacts

Operative Units
Institution that perform as UO	CF Institution	Department / Division / Laboratory	Role in the project	Southern Italy	SSN
1 - Fondazione Istituto Neurologico Xxxxx Xxxxx	01668320151	Clinical Neuroscience and Neurosurgery Dept./Neurology IX/Neurobiology Lab	Patient and sample collection; clinical data- base; molecular/statistical analyses; project coordination and dissemination; virtual hospital		X
2 - Centro Cardiologico Monzino IRCCS	13055640158	Functional proteomics, metabolomics Unit	Proteomics/Metabolomics biological samples assays		X
3 - Azienda Sanitaria Locale ASL2 Abruzzo, Lanciano-Vasto-Chieti	02307130696	Radiology Unit	Patient enrollment; clinical data-base; sample collection; virtual hospital	X	X
4 - University of L'Aquila	01021630668	Biotechnological and Applied Clinical Sciences Dept	Patient enrollment; clinical and neuroradiological data- base; sample collection; virtual hospital	X

Principal Research Collaborators
Key Personnel Name	Operative Unit	Role in the project
1 - Xxxxx Xxxxx	Xxxxxxxxxx Istituto Neurologico Xxxxx Xxxxx	Co-PI e ulteriore collaboratore UO1
2 - XXXXX XXXXXXX	Azienda Sanitaria Locale ASL2 Abruzzo, Lanciano- Vasto-Chieti	Responsabile UO3
3 - Xxxxx Xxxxxx	University of L'Aquila	Responsabile UO4
4 - XXXXXXX XXXXXX	Xxxxxxxxxx Istituto Neurologico Xxxxx Xxxxx	Ulteriore collaboratore UO1
5 - Xxxxxxxxxxx Xxxxxxx Xxxxxxxx	Fondazione Istituto Neurologico Xxxxx Xxxxx	Ulteriore collaboratore UO1
6 Under 40 - Xxxxxxxx Xxxxx	Centro Cardiologico Monzino IRCCS	Responsabile UO2
7 Under 00 - XXXXXXX XXXXXXX XXXXXXX	Fondazione Istituto Neurologico Xxxxx Xxxxx	Ulteriore collaboratore UO1

Key Personnel Name	Co-PI	Resp. CE	Resp. Animal	Birth Date	Gender
1 - Xxxxx Xxxxx	X			17/02/1970	F
2 - XXXXX XXXXXXX				05/04/1972	M
3 - Xxxxx Xxxxxx				04/07/1974	F
4 - XXXXXXX XXXXXX				29/03/1962	M
5 - Xxxxxxxxxxx Xxxxxxx Xxxxxxxx				02/06/1975	M
6 Under 40 - Xxxxxxxx Xxxxx				16/08/1983	F
7 Under 00 - XXXXXXX XXXXXXX XXXXXXX				12/06/1985	M

Additional research collaborators under 40 to hire
Key Personnel Name	Operative Unit	Birth Date	Gender	Role in the project	Degree	Actual Pos. and Inst.
0 - XXXXXXXXXX XXXXXXXX	Xxxxxxx Sanitaria Locale ASL2 Abruzzo, Lanciano- Vasto-Chieti	23/07/1992	F	Additional Research Collaborators Under 40 To HIRE	Master's Degree in Medicine and Surgery	Università degli Studi "G. x'Xxxxxxxx" Chieti ¿ Pescara
1 - Xxxxxx Xxxxxx	University of L'Aquila	29/09/1989	M	Additional Research Collaborators Under 40 To HIRE	Master's Degree in Medicine and Surgery	AUSL Romagna, S. Xxxxx delle Croci Hospital of Ravenna

2.1 Administrative data of participating

Operative Unit Number 1:

Address: Fondazione IRCCS Xxxxxxxx Xxxxxxxxxxx Xxxxx Xxxxx, Xxxxx, 00000, Xxxxx

PEC: xxxx.xxxxxxx.xxx0@XXX.XX.xxxxx.xx

Operative Unit Number 2:

Address: Centro Cardiologico Monzino, Xxx Xxxxx Xxxxx, 0, 00000 Xxxxx, Xxxxx

PEC: xxxxxxxxx.xxxxxxxxxxxxxx@xxxxxxxxx.xx

Operative Unit Number 3:

Address: ASL2 Regione Abruzzo, Lanciano-Vasto-Chieti, Xxx Xxxxxxx Xxxxxxxxxx 00/00, 00000, Xxxxxx, Xxxxx

PEC: xxxxxxxxx.xxxxxxxx@xxx.xxx0xxxxxxx.xx

Operative Unit Number 4:

Address: Università degli Studi dell'Aquila, Palazzo Camponeschi, Xxxxxx Xxxxx Xxxxxxxxxx 0, 00000, X'Xxxxxx, Xxxxx

PEC: xxxxxx.xxxxx.xxx@xx.xxxxx.xx

Operative Unit Number 5 (self financing):

Address: NA

PEC: NA

2.2 Principal Investigator (PI) Profile

Last Name: xxxxxxx

First Name: Xxxx

Last name at birth:

Gender: F

Title: Principal investigator

Nationality: Italiana

Date of birth: 14/05/1972

Official H index (Scopus or Web of Science): 29.0

Country of residence: ITALY Country of Birth: ITALY Place of Birth: GENOVA

Scopus Author Id:6506729476 ORCID ID:0000-0002-2493-628X RESEARCH ID:AAK-2888-2021

Contact address

Current organisation name: Fondazione Istituto Neurologico Xxxxx Xxxxx

Current Department / Faculty / Institute / Laboratory name: Clinical Neuroscience and Neurosurgery

Dept./Neurology IX/Neurobiology Lab

Street: xxx xxxxxxx 00

Postcode / Cedex: 20133 Town: MILANO

Phone:x000000000000 Phone 2: x000000000000

Education / training
Educational institution and location	Degree	Field of study	From year	To year
Ministero dell'Istruzione, dell'Università e della Ricerca	Specialization / Specializzazione	National Scientific Qualification as Full Professor (ASN), Settore Concorsuale 06/D6 ¿ Neurologia (Ministero dell¿Istruzione, dell¿Università e della Ricerca; Bando D.D 2175), 6/11/2020- 6/11/2029 (Validity)	2020	2029
Ministero dell'Istruzione, dell'Università e della Ricerca	Specialization / Specializzazione	National Scientific Qualification as Associated Professor (ASN), Settore Concorsuale 06/D6 ¿ Neurologia (Ministero dell¿Istruzione, dell¿Università e della Ricerca; Bando D.D 1532/2016 ), 28/03/2017- 28/03/2023 (Validity) with extension (art. 16, comma1, L. 240/10)	2017	2023
Swiss Federation FMH, MEBEKO, Bern, Switzerland	Specialization / Specializzazione	Medical and Resident degree award from Swiss Federation	2010	2010
Università degli Studi di Milano, Milan, Italy	PhD	PHD in "Neurological and Pain Sciences" at the Department of Neurological Sciences. Genetics of Stroke, Thesis in ' Stroke Genetics'.	2003	2007
Università degli Studi di Milano, Milan, Italy	Specialization / Specializzazione	Medical Specialization in Neurology. Specialization in Nervous Disorders, Thesis: "disability and psycosocial outcome in Guillam-Barrè syndrome patients: a 3-5 years follow-up study"	1998	2003
Università degli Studi di Milano	Single-cycle master's degree / Laurea magistrale a ciclo unico	Master Science Degree of Medical Doctor (MD). Field of study: Medicine and Surgery. Thesis on'The role of a- MSH in Alzheimer disease'	1991	1997

Personal Statement:

The project is aimed at creating an inter center network to improve the diagnosis and care of all patients with rare cerebrovascular disease overall Italy. AB will be the PI of the project and will coordinate the overall activities, will monitor and ensure the completion of activities, will help in implementing diagnostic pathways, databases and virtual hospital platform and will contribute to data analysis and project dissemination

Positions and honors

Positions
Institution	Division / Research group	Location	Position	From year	To year
Fondazione IRCCS Istituto Neurologico Xxxxx Xxxxx,	UOC Neurologia 9 - Malattie Cerebrovascolari,	Xxx Xxxxxxx 00, 00000, Xxxxx	Complex Unit Director (provisionary) Complex Unit direction activity; human resources and budget management according to Institution objectives and guidelines; clinical activity with organization of hospitalization flows for patients with cerebrovascular diseases; organization of diagnostic and therapeutic pathways and support to multidisciplinary cooperation for patient management. Translational research supported by the Neurobiology Laboratory and the Cell Factory included in the Unit	2021	2022
MIUR Ministero dell¿Istruzione, dell¿Università e della Ricerca	MED 26/D6	XX	Qualification as Associate Professor	2017	2023
Fondazione IRCCS Istituto Neurologico Xxxxx Xxxxx,	UOC Neurologia 9 - Malattie Cerebrovascolari,	Xxx Xxxxxxx 00, 00000, Xxxxx	Medical Director of Cell Factory Unit	0000	0000
Fondazione IRCCS Istituto Neurologico Xxxxx Xxxxx	UOC Malattie Cerebrovascolari-Neurologia 9	Xxx Xxxxxxx 00, 00000, Xxxxx	Clinical and research Neurologist (permanent position) Clinical and research activity on cerebrovascular diseases with particular attention to patients with complex and rare (genetics and acquired) conditions; translational research supported by the Neurobiology Laboratory and the Cell Factory included in the Unit.	2012	2022
University of Pavia; X.Xxxxxxx IRCCS Foundation Neurological Institute	Emergency Neurologist	Pavia (italy)	Academic researcher	2011	2012
Fondazione Istituto Neurologico Nazionale Xxxxxxxx Xxxxxxx di Pavia	Emergency Department	Xxx Xxxxxxx, 0, 00000 Xxxxx (XX)	Neurologist	2011	2011
Neurocentro della Svizzera Italiana, Ospedale Regionale di Lugano, Ente Ospedaliero Cantonale (EOC)	Neurocentro della Svizzera Italiana	Xxx Xxxxxxxxx 00, 0000 Xxxxxx, Xxxxxxxx	Assistant Neurologist	2010	2010
Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Xxxxxx Xxxxx, Milano	Dipartimento di Scienze Neurologiche	Xxx X.Xxxxxx 00, 00000, Xxxxx	Neurologist (Fellowship)	2004	2010

Other awards and honors

From 2022 Co-Chair of subgroup Neurovasc of ERN on rare multisystemic vascular diseases

From 2022 Delegate and Mentor of EAN

From 2022 member of the Scientific Panel of Rare Neurological Diseases of EAN From 2022 Faculty Member of Stroke Summer School of ISA

From 2021 Member of ESO Education Commitee as Representative of EAN

From 2021 Coordinator of the European Guidelines xx Xxxxxxxx Arteriopathy of ESO

From 2020 Member of Italian SPREAD Guidelines group for pediatric, juvenile and rare stroke

Other CV informations

From 2022 Editorial Board Member of European Stroke Journal From 2021 Editorial Board of Stroke Section of Neurology (AAN) From 2021 Associated Editor of Frontiers in Neurology

From 2020 Assistant Editor of `Stroke, Journal of AHA From 2020 Associated Editor of `BMC Neurology

2020-2021 Editorial Board Member of Frontiers in Neurolog

From 2020 Associated Editor of `International Journal of Molecular Science

2020 Guest Editor of Journal of Clinical Medicine in Special Issue "Xxxxxxxx Xxxxxxxxxxxx: Recent Advances and Future Challenges"

2019 Member of the Editorial Board of International Journal of Molecular Science

2019 Guest Editor of `International Journal of Molecular Science for the Special Issue Pathophisiology and Treatment of Stroke: Present Status and Future Perspective

Selected peer-reviewed publications of the PI valid for minimum expertise level
Title	Type	Pag	Vol	Year	DOI	PMID	Cit.**	P.*
Clinical management of moyamoya patients	Review	3628	10	2021	10.3390/jcm10163628	34441923	2	L
Stroke care during the COVID-19 pandemic: experience from three large European countries	Review	1794- 1800	27	2020	10.1111/ene.14375	32492764	71	F
On being a neurologist in Italy at the time of the COVID-19 outbreak	Editorial	905-906	94	2020	10.1212/WNL.00000000 00009508	32245844	47	F
Understanding the pathophysiology of cerebral amyloid angiopathy	Article	3435	21	2020	10.3390/ijms21103435	32414028	9	L
GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease¿study protocol and preliminary results	Article	561-570	40	2019	10.1007/s10072-018- 3664-z	30604336	6	F
The role of clinical and neuroimaging features in the diagnosis of CADASIL	Article	2934- 2943	265	2018	10.1007/s00415-018- 9072-8	30311053	14	F
Takotsubo Syndrome: Clinical Features, Pathogenesis, Treatment, and Relationship with Cerebrovascular Diseases	Review	20	18	2018	10.1007/s11910-018- 0833-7	29569186	19	L
CADASIL: Treatment and Management Options	Review	31	19	2017	10.1007/s11940-017- 0468-z	28741120	16	F
Clinical pregenetic screening for stroke monogenic diseases: Results from lombardia GENS registry	Article	1702- 1709	47	2016	10.1161/STROKEAHA.1 15.012281	27245348	24	F
Fabry Disease: Recognition, Diagnosis, and Treatment of Neurological Features	Article	33	18	2016	10.1007/s11940-016- 0414-5	27225543	14	L

Title	Type	Pag	Vol	Year	DOI	PMID	Cit.**	P.*
The diagnostic challenge of Xxxxx xxx Xxxxxxx and Xxxxxxx Syndrome: Report of three cases and literature review	Article	77-83	364	2016	10.1016/j.jns.2016.03.01 1	27084221	15	F
Research progresses in understanding the pathophysiology of moyamoya disease	Review	105-118	41	2016	10.1159/000442298	26756907	52	F
Vasculogenic and angiogenic pathways in moyamoya disease	Review	315-345	23	2016	10.2174/0929867323041 60204181543	26861126	26	L
Seizure-triggered Takotsubo syndrome rarely causes SUDEP	Review	84-87	31	2015	10.1016/j.seizure.2015.0 7.015	26362382	22	L
Subarachnoid bleeding triggering Takotsubo syndrome	Article	107-109	197	2015	10.1016/j.ijcard.2015.06. 029	26142961	8	L
Next generation sequencing for systematic assessment of genetics of small-vessel disease and lacunar stroke	Article	759-765	24	2015	10.1016/j.jstrokecerebro vasdis.2014.10.019	25727672	7	F
Tako-tsubo syndrome as a consequence and cause of stroke	Article	135-137	29	2014	10.11138/FNeur/2014.29 .2.135	25306124	11	F
POLG1 mutations and stroke like episodes: A distinct clinical entity rather than an atypical MELAS syndrome	Article	8	13	2013	10.1186/1471-2377-13-8	23324391	22	L
The genetics of small-vessel disease	Article	4124- 4141	19	2012	10.2174/0929867128024 30081	22680632	9	F
Neurological features of Fabry disease: Clinical, pathophysiological aspects and therapy	Review	77-97	126	2012	10.1111/j.1600- 0404.2012.01661.x	22428782	28	F

* Position: F=First L=Last C=Correspondent O=Other N=Not applicable

** Autocertificated

Selected peer-reviewed publications of the PI for the evaluation CV
Title	Type	Pag	Vol	Year	DOI	PMID	Cit.**
Stroke care during the COVID-19 pandemic: experience from three large European countries	Review	1794- 1800	27	2020	10.1111/ene.14375	32492764	72
On being a neurologist in Italy at the time of the COVID-19 outbreak	Editorial	905-906	94	2020	10.1212/WNL.00000000 00009508	32245844	47
Research progresses in understanding the pathophysiology of moyamoya disease	Review	105-118	41	2016	10.1159/000442298	26756907	52
Epidemiology, pathophysiology, diagnosis, and management of intracranial artery dissection	Review	640-654	14	2015	10.1016/S1474- 4422(15)00009-5	25987283	208
Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection	Article	78-83	47	2014	10.1038/ng.3154	25420145	136
Familial occurrence and heritable connective tissue disorders in cervical artery dissection	Article	2023- 2031	83	2014	10.1212/WNL.00000000 00001027	25355833	45
Cervical artery dissection trauma and other potential mechanical trigger events	Article	1950- 1957	80	2013	10.1212/WNL.0b013e31 8293e2eb	23635964	120
Etiology of first-ever ischaemic stroke in European young adults: The 15 cities young stroke study	Article	1431- 1439	20	2013	10.1111/ene.12228	23837733	107

Title

Type

Pag

Vol

Year

DOI

PMID

Cit.**

Demographic and geographic vascular risk factor differences in european young adults with ischemic stroke: The 15 cities young stroke study

Article

2624-

2630

2012

10.1161/STROKEAHA.1

12.662866

22798330

Thrombolysis in Cervical Artery Dissection - Data from the Cervical Artery Dissection and Ischaemic Stroke Patients (CADISP) database

Article

1199-

1206

2012

10.1111/j.1468-

1331.2012.03704.x

22448957

** Autocertificated

Grant
Funded by Institution	Researcher inst. where xxxxx is/was performed	Year	Title	Position in Projects	Fund (euro)	Source website grant listed
Regione Lombardia	Fondazione IRCCS Istituto Neurologico Xxxxx Xxxxx	2021	Empowering progression risk of cerebral amyloid angiopathy-PRIORITY	Coordinator	270.000,00	xxxxx://xxx.xxxxxxxx- xxxxx.xx/0-x-xxxxx- anni-2018-2019
Ministero della salute	Fondazione IRCCS Istituto Neurologico Xxxxx Xxxxx	2021	Istituti Virtuali Nazionali: il network italiano delle malattie neurologiche	Collaborator	37.000,00	xxxxx://xxx.xxxxxxxx xxxxxxxx.xx/xxxxxxxx- nazionali-virtuali/
Regione Lombardia	Fondazione IRCCS Istituto Neurologico Xxxxx Xxxxx	2020	Ricerca Industriale e Sviluppo Sperimentale¿ Programma Operativo Regionale 2014-2020 Obiettivo 'Investimenti In Favore Della Crescita E Dell'occupazione' `Neuro Virtual hospital: modello di gestione multidisciplinare in remoto dei pazienti neurologici¿ (NOVHO)	Coordinator	115.000,00	xxxxx://xxx.xxxxx.xx xxxxx.xxxxxxxxx.xx/xx ocedimenti/new/band i/home
Ministero della salute	Fondazione IRCCS Istituto Neurologico Xxxxx Xxxxx	2019	Empowering the pathophysiology and prognosis of moyamoya arteriopathy, RF-2019- 12369247	Coordinator	436.000,00	xxxxx://xxx.xxxxxx.xx x.xx/xxxxxxx/xxxxxxxx/x 4_10_1_1_atti_1_1.js p?lingua=italiano&id =208
Regione Lombardia	Fondazione Istituto Neurologico Nazionale Xxxxxxxx Xxxxxxx di Pavia	2010	Progetto SVE-LA: studio dei fattori genetici associati alla malattia dei piccoli vasi e all¿ictus lacunare, DGS13465 del 22/12/2010	Collaborator	250.000,00	xxxxx://xxx.xxxxx.xx xxxxx.xxxxxxxxx.xx/xx ocedimenti/new/band i/home
Ministero della Salute	Fondazione Ospedale Maggiore Policlinico	2008	Mannose binding lectin, a potential new target for stroke therapy: biochemical, in vitro and in vivo experimental, and clinical approaches to define its role in ischemic xxxxxx, XX-0000- 1136044	Coordinator	165.000,00	xxxxx://xxx.xxxxxx.x om/search?q=GR- 2008- 1136044&rlz=1C1G CEU_itIT954IT954&o q=GR-2008- 1136044+&aqs=chro me..69i57.4381j0j7& sourceid=chrome&ie =UTF-8

Funded by Institution	Researcher inst. where xxxxx is/was performed	Year	Title	Position in Projects	Fund (euro)	Source website grant listed
Xxxxxxx Xxxxxxxxx	Xxxxxxxxxx Xxxxxxxx Xxxxxxxx Xxxxxxxxxxx	0000	Xxxxxxxx Xxxxxxxxx GENS (GENetics of Stroke), DGR no. VIII/006128-12/12/2007	Collaborator	250.000,00	xxxxx://xxx.xxxxx.xx xxxxx.xxxxxxxxx.xx/xx ocedimenti/new/band i/home

2.3 CO-PI Profile

Last Name: Xxxxx

First Name: Xxxxx

Last name at birth:

Gender: F

Title: Co-PI e ulteriore collaboratore UO1

Nationality: Italiana

Date of birth: 17/02/1970

Official H index (Scopus or Web of Science): 25.0

Country of residence: ITALY Country of Birth: ITALY Place of Birth: Monza

Scopus Author Id:57215776613 ORCID ID:0000-0001-6751-5031 RESEARCH ID:J-6016-2016

Contact address

Current organisation name: Fondazione Istituto Neurologico Xxxxx Xxxxx

Current Department / Faculty / Institute / Laboratory name: Clinical Neuroscience and Neurosurgery

Dept./Neurology IX/Neurobiology Lab

Street: Xxx Xxxxxxx 00

Postcode / Cedex: 20133 Town: Milano

Phone:x000000000000 Phone 2:

Education / training
Educational institution and location	Degree	Field of study	From year	To year
Italian Ministry of University, Education and Research (MIUR)	Specialization / Specializzazione	General Biochemistry	2020	2020
Italian Ministry of University, Education and Research (MIUR)	Specialization / Specializzazione	Applied Biology	2017	2017
Advanced School in Biotechnology, Università degli Studi of Milan (UniMI), Italy	Specialization / Specializzazione	Molecular Pharmacology of Antitumor Drugs	1998	2002
Università degli Studi of Milan (UniMI), Italy	Specialization / Specializzazione	National Board Certification	1998	1998
Università degli Studi of Milan (UniMI), Italy	Single-cycle master's degree / Laurea magistrale a ciclo unico	Biological Sciences	1990	1996

Personal Statement:

For nearly 25 years my main area of investigation has been translational research in oncology, ranging from the identification and validation of new therapeutic targets to the preclinical development of novel rationally-designed treatments. More recently I have started to work as Head of Neurobiology Laboratory in a Neuroscience Institution. My field of interest is now focused on rare cerebrovascular diseases, with particular reference to patient biomarker identification. I will be mainly devoted to the project and I will coordinate Task 2, participating in data analysis/dissemination. I have the expertise, leadership and motivation necessary to successfully carry out the proposed work, also thanks to my previous (2018-2021) role as PI of a RF-project funded by Italian MoH.

Positions and honors

Positions
Institution	Division / Research group	Location	Position	From year	To year
Fondazione IRCCS Istituto Neurologico "Xxxxx Xxxxx" of Milan, Italy	Clinical Neurosciences Department, Neurology IX - UCV Unit, Neurobiology Laboratory	Xxx Xxxxxxx 00, 00000, Xxxxx, Xxxxx	Head of Neurobiology Laboratory, Staff Scientist	2018	2022
Fondazione IRCCS Istituto Nazionale dei Tumori of Milan, Italy	Department of Experimental Oncology and Molecular Medicine, Molecular Pharmacology Unit	Xxx Xxxxxx 00, 00000, Xxxxx, Xxxxx	Senior Scientist	2010	2018
Fondazione IRCCS Istituto Nazionale dei Tumori of Milan, Italy	Experimental Oncology B, Pre-clinical Antitumor Chemotherapy and Pharmacology Unit	Xxx Xxxxxxxx 0, 00000, Xxxxx, Xxxxx	Associated Researcher	2002	2009
The Wellcome Trust Xxxxxx Institute of Cambridge	Functional Genomics Department/Transcriptomic Research Group	Xxxxxxx, XX00 0XX, Xxxxxxxxx, Xxxxxx Xxxxxxx	Visiting PhD Research Student	2001	2001
Istituto Nazionale per lo Studio e la Cura dei Tumori of Milan, Italy	Experimental Oncology B, Pre-clinical Antitumor Chemotherapy and Pharmacology Unit	Xxx Xxxxxxxx, 0, 00000, Xxxxx, Xxxxx	Junior Research Fellow	1996	2001
Università degli Studi of Milan (UniMI), Italy	Department of General Physiology and Biochemistry, Enzymology and Biochemistry Research Group	Xxx X. Xxxxxxx, 00, 00000 Xxxxx, Xxxxx	Undergraduate Fellow	1994	1996

Other awards and honors

1997-2001: winner of five Fellowships for Young Cancer Researchers 2001: winner of EMBO Award for Fellowship at the Xxxxxx Centre, UK;

Editorial Board Member of IJMS from 2020; of Frontiers in Oncology and Pharmacology from 2021 and of Frontiers in Oncology, Neuro-Oncology and Neurosurgical Oncology form 2022;

Invited Reviewer for ERA-PerMed call 2021-22;

Active member of ESN and ISN (European and International Society for Neurochemistry) and FENS (Federation of European Neurosciences Societies)

Other CV informations

I have gained considerable experience in preclinical development of antitumor agents in National Cancer Institute (Milan) specifically in tumor drug resistance, metastasis suppression and cancer biomarkers discovery in patient liquid biopsy. In 2018 I achieved a permanent Staff position as Head of Neurobiology Lab at X. Xxxxx Neurological Institute (Milan) and my research is now aimed at investigating pathogenesis of neurological diseases, including rare ones. I have been the supervisor of several undergraduate/PhD students. I am an active referee for several peer-reviewed journals and for funding agencies (Czech Science Foundation, Xxx Xxxxxxx Xxxxxxxx Foundation). Editorial Board member of IJMS/Frontiers in Oncology. Member of ESN, ISN. Invited Reviewer of ERA PerMed Joint Call 2021-2022

Selected peer-reviewed publications of the Co-PI valid for minimum expertise level
Title	Type	Pag	Vol	Year	DOI	PMID	Cit.**	P.*

Title	Type	Pag	Vol	Year	DOI	PMID	Cit.**	P.*
Novel Multifaceted Roles for RNF213 Protein	Review	4492	23	2022	10.3390/ijms23094492	35562882	0	L
The lipid asset is unbalanced in peripheral nerve sheath tumors	Article	61	23	2022	10.3390/ijms23010061	35008487	0	L
Deregulated FASN expression in BRAF inhibitor-resistant melanoma cells unveils new targets for drug combinations	Article	2284	13	2021	10.3390/cancers130922 84	34068792	0	L
Plasma lipid profiling contributes to untangle the complexity of moyamoya arteriopathy	Article	13410	22	2021	10.3390/ijms222413410	34948203	1	L
Vascular remodeling in moyamoya angiopathy: From peripheral blood mononuclear cells to endothelial cells	Article	1-22	21	2020	10.3390/ijms21165763	32796702	7	L
Understanding the pathophysiology of cerebral amyloid angiopathy	Review	3435	21	2020	10.3390/ijms21103435	32414028	9	F
Overcoming ABC transporter-mediated multidrug resistance: The dual role of tyrosine kinase inhibitors as multitargeting agents	Article	271-289	142	2017	10.1016/j.ejmech.2017.0 7.062	28851502	98	L
PKC-alpha modulation by miR-483-3p in platinum-resistant ovarian carcinoma cells	Article	9-19	310	2016	10.1016/j.taap.2016.08.0 05	27554045	21	L
Revisiting drug-DNA interaction: Novel molecules and applications in antitumor strategies	Editorial	6595	22	2016	10.2174/1381612822999 161007233232	27739367	0	F
Targeting peptidyl-prolyl isomerase pin1 to inhibit tumor cell aggressiveness	Article	144-149	102	2016	10.5301/tj.5000471	26917410	4	L
Orchestration of DSB repair: a novel BRCA2 connection	Article	1-2	14	2015	10.1080/15384101.2015. 1056614	26029962	1	F
Drug combinations with HDAC inhibitors in antitumor therapy	Article	83-117	20	2015	10.1615/XxxxXxxXxxxx.2 014012378	25746106	20	L
New mechanisms for old drugs: Insights into DNA-unrelated effects of platinum compounds and drug resistance determinants	Review	1-11	20	2015	10.1016/j.drup.2015.04.0 01	26003720	38	F
Improved apoptotic cell death in drug-resistant non-small-cell lung cancer cells by tumor necrosis factor-related apoptosis-inducing ligand-based treatments	Article	360-371	348	2014	10.1124/jpet.113.210054	24345465	24	F
Antitumor activity of a novel homodimeric SMAC mimetic in ovarian carcinoma	Article	283-293	11	2014	10.1021/mp4004578	24256025	14	F
Histone deacetylase inhibitor-temozolomide co- treatment inhibits melanoma growth through suppression of Chemokine (C-C motif) ligand 2- driven signals	Article	4516- 4528	5	2014	10.18632/oncotarget.206 5	24980831	00	X
Xxxx combinations with proteasome inhibitors in antitumor therapy	Article	4094- 4114	19	2013	10.2174/1381612811319 220015	23181571	16	F
Synergistic interaction between the novel histone deacetylase inhibitor ST2782 and the proteasome inhibitor bortezomib in platinum- sensitive and resistant ovarian carcinoma cells	Article	94-101	113	2012	10.1016/j.jinorgbio.2012. 04.007	22717676	9	F

* Position: F=First L=Last C=Correspondent O=Other N=Not applicable

** Autocertificated

Grant
Funded by Institution	Researcher inst. where xxxxx is/was performed	Year	Title	Position in Projects	Fund (euro)	Source website grant listed
Fondazione "Xxxxx Xxxxxxx", Milano, Italy	Fondazione IRCCS Istituto Neurologico Xxxxx Xxxxx	2012	Caratterizzazione/identificaz ionee validazione di nuovi bersagli terapeutici biomarcatori nel carcinoma della prostata	Collaborator	120.000,00	Fondazione "Xxxxx Xxxxxxx", Milano, Italy
Ministero della salute- cbim	Fondazione IRCCS Istituto Neurologico Xxxxx Xxxxx, Milano, Neurology 9 Unit/Italy	2021	Istituti Virtuali Nazionali: il network italiano delle malattie neurologiche¿	Collaborator	37.000,00	xxxxx://xxxxxxxxxxxx.x xxx.xx/xxxxxxxxxxxx/x reaprogetti/RCR- 2021-23671214
Ministero della salute	Fondazione IRCCS Istituto Neurologico Xxxxx Xxxxx, Milano, Neurology 9 Unit/Italy	2021	Empowering progression risk of cerebral amyloid angiopathy-PRIORITY¿	Collaborator	270.000,00	xxxxx://xxxxxxxxxxxx.x xxx.xx/xxxxxxxxxxxx/x reaprogetti/
Ministero della salute	Fondazione IRCCS Istituto Neurologico Xxxxx Xxxxx, Milano, Neurology 9 Unit/Italy	2020	Empowering the pathophysiology and prognosis of moyamoya arteriopathy¿	Collaborator	436.000,00	xxxxx://xxxxxxxxxxxx.x xxx.xx/xxxxxxxxxxxx/x reaprogetti/RF-2019- 12369247
Ministero della salute	Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori Milano, Molecular PharmacologyUnit/Italy	2018	Lipid metabolism network as a target to overcome resistance in melanoma	Coordinator	351.450,00	xxxxx://xxxxxxxxxxxx.x xxx.xx/xxxxxxxxxxxx/x reaprogetti/RF-2016- 02361091
Associazione Italiana per la Ricerca sul Cancro -AIRC	Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori Milano, Molecular PharmacologyUnit/Italy	2014	Interference with Akt- mediated drug-resistance mechanisms to target aggressive ovarian carcinoma	Collaborator	274.000,00	xxxx://xxx.xxxx.x t/finanziamenti/ Associazione Italiana per la Ricerca sul Cancro -AIRC
Fondazione X. Xxxxxxxxx, Italy	Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori Milano, Molecular PharmacologyUnit/Italy	2012	Identificazione di combinazioni per il trattamento integrato del carcinoma polmonare in modelli preclinici	Collaborator	100.000,00	xxxx://xxx.xxxx azioneberlucchi. com/premiazion i/2013/vincitori2 000_xxxxxxxx.xx ml/Fondazione X. Xxxxxxxxx, Italy
Fondazione CARIPLO Italy	Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori Milano, Molecular PharmacologyUnit/Italy	2011	Targeting pro-survival features of tumor cells by novel inhibitors of the AKT kinase	Collaborator	110.000,00	xxxx://xxx.xxxx xxxxxxxxxxxxx.xx/x t/contributi/delib ere/2011.html Fondazione CARIPLO Italy

2.3 Research Collaborators n. 2

Last Name: CAULO

First Name: XXXXXXX

Last name at birth: caulo

Gender: M

Title: Responsabile UO3 Nationality: ITALIANA Date of birth: 05/04/1972

Official H index (Scopus or Web of Science): 28.0

Country of residence: ITALY Country of Birth: ITALY Place of Birth: L'AQUILA

Scopus Author Id:6602135855 ORCID ID:0000-0002-4507-2740 RESEARCH ID:ADM-9229-2022

Contact address

Current organisation name: Azienda Sanitaria Locale ASL2 Abruzzo, Lanciano-Vasto-Chieti

Current Department / Faculty / Institute / Laboratory name: Radiology Unit

Street: via dei vestini

Postcode / Cedex: 66100 Town: CHIETI

Phone:x000000000000 Phone 2:

Education / training
Educational institution and location	Degree	Field of study	From year	To year
School of Medicine, University of L¿Aquila (Italy)	Specialization / Specializzazione	Master II level in Neuroradiology	2004	2005
Center of Biomedical Imaging of the Harvard Medical School (Boston, Massachusetts, USA)	Specialization / Specializzazione	Functional MRI visiting fellowship program	2004	2004
University ¿G. d¿Annunzio¿ Chieti- Pescara (Italy)	PhD	Biotechnologies and Functional Bioimaging	2022	2005
School of Medicine, University of L¿Aquila (Italy)	Specialization / Specializzazione	Specialization in Radiology	1997	2001
School of Medicine, University of L¿Aquila (Italy)	Specialization / Specializzazione	Medical License (Abilitazione all¿Esercizio Professionale)	1998	1998
University of L¿Aquila (Italy)	Master's Degree / Laurea Magistrale	Medicine	1991	1997

Personal Statement:

Xxxxxxx Xxxxx is a neuroradiologist with experience in diagnostic imaging, radiomics and predictive models for disease diagnosis and prognosis. His research interest includes the reorganization of the brain connectivity in patients with brain tumors, cerebrovascular disorders and epilepsy. His role in the project will be to contribute to the implementation of a clinical database, with particular attention to neuroradiological aspect and to participate to the sharing knowledge and team meetings of network and Virtual Hospital

Positions and honors

Positions
Institution	Division / Research group	Location	Position	From year	To year
University of Chieti/ASL2 Abruzzo	Department of Neuroscience, Imaging and Clinical Sciences/ Institute of Advanced Biomedical Technologies ITAB/Radiology Unit	Chieti	Full professor of Radiology ¿ Director of the Radiology Unit	2019	2022
University of Chieti/ASL2 Abruzzo	Department of Neuroscience, Imaging and Clinical Sciences/ Institute of Advanced Biomedical Technologies ¿ ITAB/Radiology Unit	Chieti	Associate professor- consultant Neuroradiologist	2015	2019
University of Chieti	Department of Neuroscience, Imaging and Clinical Sciences/Institute of Advanced Biomedical Technologies - ITAB	Chieti	Researcher ¿ Consultant consultant Neuroradiologist	2005	2015

Other awards and honors

2014-2015 Member of the executive board of AINR

2015-2021 Member of the executive board of AINR; coordinator of the ¿Functional neuroimaging¿ section 2017-2019 Coordinator of the Abruzzo local Section of SIRM

MASTER CLASSES

1999-2000 Montreal Neurological Hospital and Institute of McGill University

2004 master class in functional RM (Functional MRI visiting fellowship program), Center of Biomedical Imaging, Harvard Medical School (Boston, Massachusetts, USA)

Grant
Funded by Institution	Researcher inst. where xxxxx is/was performed	Year	Title	Position in Projects	Fund (euro)	Source website grant listed
Ministero della Salute	ASL2 Lanciano-Vasto-Chieti- Università G. x'Xxxxxxxx Xxxxxx Pescara	2013	Effects of multimodal training on cognition, biomarkers, rs-FMRI and brain structural integrity in MCI patients	Coordinator	366.368,00	xxxxx://xxx.xxxxxx.xx x.xx/xxxxxxx/xxxx/x0_ 2_1_1_1.jsp?lingua=i taliano&menu=notizi e&p=null&id=2243
Ministero dell'Università e della Ricerca	Università "G. x'Xxxxxxxx" Chieti- Pescara	2010- 2011	PRIN 2010-11, Connettività funzionale cerebrale e neuroplasticità nell¿invecchiamento fisiologico e patologico	Collaborator	75.000,00	xxxxx://xxxx.xxx.xxx.xx /

Funded by Institution	Researcher inst. where xxxxx is/was performed	Year	Title	Position in Projects	Fund (euro)	Source website grant listed
Ministero dell'Università e della Ricerca MUR	Università "G. d'Annunzio" Chieti- Pescara	2008	PRIN 2008, Installazione, test, calibrazione e validazione di un prototipo MRI a basso campo che usi sia rivelazione a temperatura ambiente che superconduttrice e sia compatibile con un sistema MEG a cabina schermata	Collaborator	120.000,00	xxxxx://xxxx.xxx.xxx.xx /
Ministero dell'università e della ricerca, MUR	Università "G. x'Xxxxxxxx" Chieti- Pescara	2006	PRIN 2006, Ritmi cerebrali a bassa frequenza ed apprendimento nel sonno e nella vegli ain soggetti normali e conpatologie neurologiche: uno studio neurofisiologico multimodale.	Collaborator	95.000,00	xxxxx://xxxx.xxx.xxx.xx /
Ministero della salute	ASL Chieti	2007	Dementia with Lewy bodies: new diagnostic markers and therapeutic implications	Collaborator	600.000,00	xxxxx://xxx.xxxxxx.xx x.xx/xxxxxxx/xxxxxxxXx nitaria/dettaglioConte nutiRicercaSanitaria.j sp?lingua=italiano&id =5751&area=Ricerca %20sanitaria&menu =finalizzata&tab=1

2.4 Research Collaborators n. 3

Last Name: Xxxxx

First Name: Xxxxxx

Last name at birth:

Gender: F

Title: Responsabile UO4

Nationality: Italiana

Date of birth: 04/07/1974

Official H index (Scopus or Web of Science): 35.0

Country of residence: ITALY Country of Birth: ITALY Place of Birth: Cassino

Scopus Author Id:55751819500 ORCID ID:0000-0003-0651-1939 RESEARCH ID:I-5253-2012

Contact address

Current organisation name: University of L'Aquila

Current Department / Faculty / Institute / Laboratory name: Biotechnological and Applied Clinical Sciences Dept

Street: Via Vetoio

Postcode / Cedex: 67100 Town: L'Aquila

Phone:x000000000000 Phone 2:

Education / training
Educational institution and location	Degree	Field of study	From year	To year
University of L¿Aquila	Specialization / Specializzazione	Master in Cerebrovascular Disease	2005	2007
University of L¿Aquila	Specialization / Specializzazione	Specialization in Neurology	1999	2004
University of L¿Aquila	Master's Degree / Laurea Magistrale	Medicine and Surgery	1993	1999

Personal Statement:

The reasercher aims at creating a hub center in the Central-South part of Italy to provide high quality of care and expertise for patients with rare causes of ischemic stroke, due to the lack of any referral center for patients with rare causes of stroke. The reseracher has already an established expertise in the field of stroke and a clinical and research collaboration with the IRCCS Besta, Neurovascular Unit. She will contribute to build a permanent clinical and research collaboration aimed to improve the care of patients with rare causes of stroke using her research and clinical networks to raise awareness on this project and collect cases with rare neurological diseases in south Italy. She already experienced telemedicine and virtual second opinions in collaboration with U1

Positions and honors

Positions
Institution	Division / Research group	Location	Position	From year	To year
University of L'Aquila	Department of Biotechnological and Applied Clinical Sciences	L'Aquila	Full professor of Neurology ¿ Director of Neurology and Stroke Unit	2018	2022
University of L'Aquila	Department of Biotechnological and Applied Clinical Sciences	L'Xxxxxx	Associate professor- consultant neurologist	2014	2018
University of L'Aquila	Neurology Clinical Unit	L'Aquila, Italy	Researcher Consultant Neurologist	2008	2014

Other awards and honors

Current positions: President elect European Stroke Organization (ESO), second vice president European Headache Federation (EHF)

Former positions: co-chair of the guideline board of the European Stroke Organization, member of the Stroke Panel of the European Academy of Neurology (EAN), Board member of the Italian Stroke association and Italian Society of Neurology.

Grant
Funded by Institution	Researcher inst. where xxxxx is/was performed	Year	Title	Position in Projects	Fund (euro)	Source website grant listed
MIUR- PRIN 2017	University of L¿Aquila	2017	Multi-center Translational Trial of Remote Ischemic Conditioning in Acute Ischemic Stroke (TRICS). A collaborative study from the Italian Stroke Organization (ISO) Basic Science network (Prot. 2017CY3J3W)	Coordinator	37.000,00	xxxxx://xxxx.xxx.xxx.xx /Iniziative/Detail?key =7MjZWWRaDOXJlt XBApiJyw%3D%3D
European Headache Federation	University of L'Aquila	2021	Real life study on resistant and refractory migraine	Coordinator	46.000,00	xxxxx://xxx.xxx- xxxxxxxx.xxx/
Novartis	University of L¿Aquila	2021	MicroRNA profile in women with migraine before and after treatment with erenumab	Coordinator	100.000,00	xxxxx://xxxxxxxxxxxxxx.xx v/ct2/show/NCT0465 9226
FISC (Fondazione Italiana per lo Studio sulle cefalee)	University of L¿Aquila	2018	Sviluppo e la validazione di uno strumento in lingua italiana per identificare pazienti con possibile emicrania cronica	Coordinator	10.000,00	xxxxx://xxxxxxxxxxxxxxx xxxxxxxxxxxxxxxx.xx/xx -cm-start-app/

2.5 Research Collaborators n. 4

Last Name: XXXXXXX

First Name: XXXXXX

Last name at birth:

Gender: M

Title: Ulteriore collaboratore UO1

Nationality: ITALIANA

Date of birth: 29/03/1962

Official H index (Scopus or Web of Science): 31.0

Country of residence: ITALY Country of Birth: ITALY Place of Birth: MILANO

Scopus Author Id:6701762120 ORCID ID:0000-0002-7285-123X RESEARCH ID:J-9822-2016

Contact address

Current organisation name: Fondazione Istituto Neurologico Xxxxx Xxxxx

Current Department / Faculty / Institute / Laboratory name: Clinical Neuroscience and Neurosurgery

Dept./Neurology IX/Neurobiology Lab

Street: xxx Xxxxxx, 00

Postcode / Cedex: 20148 Town: Milano

Phone:00393396376807 Phone 2: 0000000000

Education / training
Educational institution and location	Degree	Field of study	From year	To year
Università degli Studi di Milano	Specialization / Specializzazione	Specialization in Biotechnology. Field of study: Biotechnology and molecular biology	1991	1994
Università degli Studi di Milano	Single-cycle master's degree / Laurea magistrale a ciclo unico	Biochemistry	1981	1988

Personal Statement:

As leader of the Lab of Neurological Biochemistry and Neuropharmacology, Xxxxxx Xxxxxxx will be responsible for coordinating the development of the new methods and the analyzes on the targeted lipids. He will contribute to the recruitment of control plasma/CSF, to the optimization of the use of mass spectrometers and to the organization of laboratory activities.

Positions and honors

Positions
Institution	Division / Research group	Location	Position	From year	To year
Fondazione IRCCS Istituto Neurologico X. Xxxxx	Lab of Neurological Biochemistry and Neuropharmacology	Milan, Italy	Laboratory Director	2011	2022
Fondazione IRCCS Istituto Neurologico X. Xxxxx	Lab of Clinical investigation: Unit of high resolution electrophoresis techniques and flow cytometry	Milan, Italy	Senior Laboratory manager	2007	2011
Fondazione IRCCS Istituto Neurologico X. Xxxxx	Lab of Clinical investigation	Milan, Italy	Laboratory Manager	1992	2007
University of Xxxx	Lab of Neuroimmunology	Lund, Sweden	Postdoctoral fellow	1990	1991

Other awards and honors

Referee for Human Immunology, Tumori, Neurological Sciences, Journal of Experimental & Clinical Cancer Research, Journal of Neurooncology, Translational Neurodegeneration, Biomarkers in Medicine, Journal of Experimental & Clinical Cancer Research and Clinical Cancer Research

Adjunct professor at the School of Clinical Pathology and Clinical Biochemistry, University of Milan. 2018: grant by EISAI.

Grant
Funded by Institution	Researcher inst. where xxxxx is/was performed	Year	Title	Position in Projects	Fund (euro)	Source website grant listed
EISAI - RD28	Fondazione IRCCS Istituto	2018	Effect of perampanel in	Coordinator	21.000,00	xxxxx://xxx.xxxxxxxx-
	Neurologico Xxxxx Xxxxx		combination with ketone			xxxxx.xx/xxxxxxxxx/0
			bodies on the proliferation			47318/0/Deliberazion
			rate of human gloma cell			e+CDA+n.+25+del+1
			lines and stem cell like			+aprile+2019+_Bilan
			glioblastoma-derived cells			cio+Preventivo+Econ
						omico+Esercizio+20
						19.pdf/2cc33990-
						faa4-d4d2-1964-
						16ecbc52a6b6

2.6 Research Collaborators n. 5

Last Name: Xxxxxxxxxxx

First Name: Xxxxxxx Xxxxxxxx

Last name at birth:

Gender: M

Title: Ulteriore collaboratore UO1

Nationality: italiana

Date of birth: 02/06/1975

Official H index (Scopus or Web of Science): 25.0

Country of residence: ITALY Country of Birth: ITALY Place of Birth: Milano

Scopus Author Id:7801424407 ORCID ID:0000-0002-2551-525X RESEARCH ID:B-8647-2011

Contact address

Current organisation name: Fondazione Istituto Neurologico Xxxxx Xxxxx

Current Department / Faculty / Institute / Laboratory name: Clinical Neuroscience and Neurosurgery

Dept./Neurology IX/Neurobiology Lab

Street: xxx Xxxxxxx 00

Postcode / Cedex: 20133 Town: Milano

Phone:x000000000000 Phone 2: 0000000000

Education / training
Educational institution and location	Degree	Field of study	From year	To year
University of Milano-Bicocca, Italy	PhD	PhD Program in Neuroscience. Title thesis: 'Role of RYR3 gene in ischemic stroke'	2017	2021
University of Milan, Italy	Specialization / Specializzazione	Board Certification in Neurology. Title thesis: 'PFA-100 to detect aspirin resistance in ischemic stroke patients'	2004	2008
University of Milan, Italy	Single-cycle master's degree / Laurea magistrale a ciclo unico	Title thesis: 'A new clinical database for cerebrovascular diseases'	1994	2000

Personal Statement:

Dr Xxxxxxx Xxxxxxxxxxx is a clinical neurologist with specific competency in cerebrovascular disease. His clinical and research interests are in stroke and cerebrovascular diseases, with several publications in this field. In particular, his interests are in stroke genetics and innovative therapies. He is a member of the International Stroke Genetic Consortium. His role in the project, in accordance with his professional profile, will concern the identification and interpretation of clinical data for the implementation of the database, for the enrollment of patients and for the analysis of the results.

Positions and honors

Positions
Institution	Division / Research group	Location	Position	From year	To year
Fondazione IRCCS Istituto Neurologico Xxxxx Xxxxx	Cerebrovascular Disease Unit	Milan, Italy	Staff Neurologist	2010	2022
Bocconi University	Centre for Research on Health and Social Care Management	Milan, Italy	Clinical expert for the FP7 project "EUROHOPE"	2011	2014
University of Milan - Fondazione IRCCS Istituto Neurologico Xxxxx Xxxxx	Cerebrovascular Disease Unit	Milan, Italy	Resident in Neurology	2004	2008
Xxxxxx Neurological Institute	Acute Stroke Unit	Phoenix, Arizona, US	Clinical Observer	2004	2004
Western Infirmary General Hospital	Acute Stroke Unit	Glasgow, Scotland	Honorary Visiting Research Fellow	2003	2003

Other awards and honors

10th March 2009, International Prize Friends of Milan for Youth - Silver Plaque of the President of the Republic and the Lombardy Region, Gold Medal awarded for Neurobiology and Neurology

Grant
Funded by Institution	Researcher inst. where xxxxx is/was performed	Year	Title	Position in Projects	Fund (euro)	Source website grant listed
Ministero della Salute	Fondazione IRCCS Istituto Neurologico "Xxxxx Xxxxx" of Milan, Italy	2021	Cryptogenic ischemic stroke terapy: tailoring the approach through individual patient data and network meta-analyses	Collaborator	75.000,00	xxxxx://xxxxxxxxxxxx.x xxx.xx/xxxxxxxxxxxx/x reaprogetti/
Ministero della Salute	Fondazione IRCCS Istituto Neurologico "Xxxxx Xxxxx" of Milan, Italy	2013	The risk-benefit profile of pharmacological treatments in secondary prevention for patients with ischemic stroke: a systematic review	Collaborator	150.200,00	xxxxx://xxx.xxxxxx.xx x.xx/xxxxxxx/xxxx/x0_ 2_1_1_1.jsp?lingua=i taliano&menu=notizi e&p=null&id=2243
Ministero della Salute	Fondazione IRCCS Istituto Neurologico "Xxxxx Xxxxx" of Milan, Italy	2011	Dissecting phenotypic and genetic heterogeneity in Italian ischemic stroke patients	Coordinator	225.997,00	xxxxx://xxx.xxxxxx.xx x.xx/xxxxxxx/xxxxxxxx/x 4_10_1_1_atti_1_1.js p?lingua=italiano&id =85

2.7 Research Collaborators n. 6 - Under 40

Last Name: Xxxxxxxx

First Name: Xxxxx

Last name at birth:

Gender: F

Title: Responsabile UO2

Nationality: Italiana

Date of birth: 16/08/1983

Official H index (Scopus or Web of Science): 12.0

Country of residence: ITALY Country of Birth: ITALY Place of Birth: Busto Arsizio

Scopus Author Id:24758035400 ORCID ID:0000-0003-2370-947X RESEARCH ID:G-5249-2018

Contact address

Current organisation name: Centro Cardiologico Monzino IRCCS

Current Department / Faculty / Institute / Laboratory name: Functional proteomics, metabolomics Unit

Street: xxx Xxxxx 0

Postcode / Cedex: 20138 Town: Milano

Phone:x000000000000 Phone 2:

Education / training
Educational institution and location	Degree	Field of study	From year	To year
University of Xxxxxx Xxxxxxx, Xxxxx (XX), Xxxxx	PhD	Ph.D. in Biomedical Technologies. Field of study: Biomedical technologies, Proteomics, Mass spectrometry	2008	2010
University of Xxxxxx Xxxxxxx, Xxxxx (XX), Xxxxx	Master's Degree / Laurea Magistrale	Master of Science in Medical Biotechnologies. Field of study: Biomedical technologies, Proteomics, Experimental models in vivo and in vitro, Diagnostics, Molecular medicine	2005	2007
University of Milano, Italy	Bachelor Degree / Laurea Triennale	Degree in Science in Medical Biotechnologies. Field of studies: Biology, Genetics, Biochemistry, Anatomy, Physiology, Microbiology, Pathology and immunology, Pharmacology, Physiopathology, Genome studies techniques	2002	2005

Personal Statement:

Dr. Xxxxxxxx will lead the part of the project related to the identification of disease markers and study of the molecular mechanisms underlying the phenotypic alterations of cells and tissue in rCVD. She will perform proteomics, metabolomics and network analyses

Positions and honors

Positions
Institution	Division / Research group	Location	Position	From year	To year
Monzino Cardiologic Center IRCCS	Unit of Functional Proteomics, Metabolomics and Network Analysis	Milano (Italy)	Researcher	2013	2022
University of Milano-Bicocca	Department of Health Science, Mass Spectrometry Laboratory	Monza (Italy)	Laboratory Post-Doctoral researcher	2011	2013
Leiden University Medical Center (LUMC)	Department of Parasitology, Biomolecular Mass Spectrometry Unit	Leiden (The Netherlands)	Research Intern	2010	2010
University of Milano-Bicocca	Department of Health Science, Mass Spectrometry Laboratory	Monza (Italy)	PhD Student	2007	2010

Other awards and honors

Specialization cum laude in Experimental Medical Biotechnologies

Grant
Funded by Institution	Researcher inst. where xxxxx is/was performed	Year	Title	Position in Projects	Fund (euro)	Source website grant listed
.	.	.	.	Collaborator	0,00	.

2.8 Research Collaborators n. 7 - Under 40

Last Name: XXXXXXX

First Name: XXXXXXX XXXXXXX

Last name at birth:

Gender: M

Title: Ulteriore collaboratore UO1

Nationality: Italiana

Date of birth: 12/06/1985

Official H index (Scopus or Web of Science): 14.0

Country of residence: ITALY Country of Birth: ITALY Place of Birth: SCIACCA

Scopus Author Id:55811592900 ORCID ID:0000-0003-0664-9700 RESEARCH ID:J-1573-2017

Contact address

Current organisation name: Fondazione Istituto Neurologico Xxxxx Xxxxx

Current Department / Faculty / Institute / Laboratory name: Clinical Neuroscience and Neurosurgery

Dept./Neurology IX/Neurobiology Lab

Street: XXX XXXXXXX 00

Postcode / Cedex: 20133 Town: MILANO

Phone:x000000000000 Phone 2:

Education / training
Educational institution and location	Degree	Field of study	From year	To year
University of Milan	Specialization / Specializzazione	Residency School in Neurosurgery, Certified Neurosurgeon. Field of study: Hands-on experience and clinical management of neurosurgical diseases applied to patient clinical care, along with preclinical and laboratory researches about nervous system, completed by the discussion of the thesis entitled "Intraoperative ultrasound in spinal tumor surgery" (final marks of 70/70 cum laude).	2010	2016
University of Palermo	Single-cycle master's degree / Laurea magistrale a ciclo unico	Degree in Medicine and Surgery. Field of study: Basic preclinical and clinical studies in human biochemistry, anatomy, physiology, surgical and medical fields, completed by thesis discussion "Functional Magnetic Resonance and intraoperative electrophysiological monitoring in gliomas located in areas of language: impact on the extent of surgical resection evaluated by volumetric MRI" (final marks of 110/110 cum laude)	2003	2009

Personal Statement:

Dr.Vetrano has an experience in neurosurgical aspects of rCVD, particularly Moyamoya arteriopathy, for which he is collaborating to the ongoing registry (GENOMA project). He will contribute to the database implementation, patient recruitment, neurosurgical pathways implementation for patients who meed surgery, virtual hospital implementation and meeting organization

Positions and honors

Positions
Institution	Division / Research group	Location	Position	From year	To year
Fondazione IRCCS Istituto Neurologico "Xxxxx Xxxxx" of Milan, Italy	Department of Neurosurgery Neuro-oncological Unit	Xxx Xxxxxxx 00, 00000, Xxxxx, Xxxxx	Neurosurgeon in staff, full-time position	2021	2022
Fondazione IRCCS Istituto Neurologico "Xxxxx Xxxxx" of Milan, Italy	Department of Neurosurgery	Xxx Xxxxxxx 00, 00000, Xxxxx, Xxxxx	Neurosurgeon with research fellowship	2016	2021
Fondazione IRCCS Istituto Neurologico "Xxxxx Xxxxx" of Milan, Italy	Department of Neurosurgery, Neurosurgical Unit 1	Xxx Xxxxxxx 00, 00000, Xxxxx, Xxxxx	Resident Neurosurgeon	2013	2016
IRCCS Cà Granda Foundation Ospedale Maggiore Policlinico	Department of Neurosciences, Neurosurgery Unit	Xxx Xxxxxxxxx Xxxxxx, 00 00000 Xxxxx, Xxxxx	Resident Neurosurgeon	2010	2013

Other awards and honors

Fellowship winner "Study on pred. of outcome, disability, QoL and complications in Neurosurg." FINCB, 2017-2021 Sphingolipid Club Awrd "Sphingolipid prof. in Skull Base Chordomas", 2020

Fellowship winner "Innovative tech. for diagnostics, surgical treatment and follow-up of malformations of the nervous system" FINCB, 2016-2017

Best communication- Italian Society of Ultrasonology in Med and Biol, Rome, 2013 Travel grant European Association of Neurosurgical Societies, Tel Aviv, 2013

Grant
Funded by Institution	Researcher inst. where xxxxx is/was performed	Year	Title	Position in Projects	Fund (euro)	Source website grant listed
Regione Lombardia	Fondazione IRCCS Istituto Neurologico Xxxxx Xxxxx	2012	Project PRINTMED- 3D:Integrated platform for three-dimensional medical technologies	Collaborator	626.708,00	xxxxx://xxx.xxxxxxx.x xxxxxxxx.xx/xxx/xxxx al/istituzionale/
Regione Lombardia, Fondo Europeo di Sviluppo Regionale, POR-FERS 2014-2020	Fondazione IRCCS Istituto Neurologico Xxxxx Xxxxx, Milano	2020	Neuro Virtual Hospital: a model for the management of fragile neurological patients during the COVID- 19 emergency and any future epidemics	Collaborator	114.000,00	xxxxx://xxx.xxxx.xxxx xxx.xxxxxxxxx.xx/xxx/ portal/PROUE/FESR

2.9 Additional Research Collaborators n. 2 - Under 40 to hire

Last Name: XXXXXXXXXX

First Name: XXXXXXXX

Last name at birth:

Gender: F

Title: Additional Research Collaborators Under 40 To HIRE

Nationality: Italiana

Date of birth: 23/07/1992

Official H index (Scopus or Web of Science): 2.0

Country of residence: ITALY Country of Birth: ITALY Place of Birth: Guardiagrele

Scopus Author Id:57226344973 ORCID ID:0000-0003-3105-1292 RESEARCH ID:AHI-1883-2022

Contact address

Current organisation name: Azienda Sanitaria Locale ASL2 Abruzzo, Lanciano-Vasto-Chieti

Current Department / Faculty / Institute / Laboratory name: Radiology Unit

Street: ASL2 - Lanciano Vasto Chieti, Via dei Vestini s.n.c. - Palazzina N

Postcode / Cedex: 66100 Town: Chieti

Phone:x000000000000 Phone 2:

Education / training
Educational institution and location	Degree	Field of study	From year	To year
University of Chieti Department of Neuroscience, Imaging and Clinical Sciences Chieti, Abruzzo, ITALY	PhD	Neuroscience	2020	2023
University of Chieti Department of Radiology Department of Neuroscience, Imaging and Clinical Sciences Chieti, Abruzzo, ITALY	Specialization / Specializzazione	Radiology	2017	2021
University of Chieti, Medical School Chieti, Abruzzo, ITALY	Master's Degree / Laurea Magistrale	Medicine	2010	2016

Personal Statement:

With the present project Dr.Xxxxxxxxxx intends to collaborate in creating a hub center in the Central-South part of Italy to provide high quality of care and expertise for patients with rare cerebrovascular diseases. So far, South part of Italy lacks center for patients with rare causes of stroke. She has already a clinical expertise in the field of stroke as a stroke neuroradiologist, currently working at the Department of Neuroscience, Imaging and Clinical Sciences of University of Chieti. Within this project the reseracher hopes to gain a new position in the National Health Service (SSN), specifically in ASL2 Regione Abruzzo.

Positions and honors

Positions
Institution	Division / Research group	Location	Position	From year	To year
University of Chieti	Department of Neuroscience, Imaging and Clinical Sciences	Chieti, Abruzzo, ITALY	PhD student	2020	2023
Bambino Gesù Pediatric Hospital	Imaging Department Neuroradiology section	Rome, Lazio, ITALY	Fellow	2020	2020
New York University	New York University NYU - School of Medicine - Department of Cell Biology	XXX Xxxxxxx Xxxxxxx xxxxxx, Xxx Xxxx Xxxx, Xxx Xxxx, XXX	Student	2013	2013

Other awards and honors

PhD student at the University of Chieti - Department of Neuroscience, Imaging and Clinical Sciences from December 2020 to December 2023

Certificazione TOEFL iBT: 108/120 livello C2 (October 2012)

Reviewer for International Journals (The Neuroradiology Journal Springer; Journal of Neuroradiology Elsevier) Tutor

Appointed by AINR (Associazione Italiana di Neuroradiologia) board as member of the scientific and organizing committee of Young Topics in Neuroradiology 2020

Grant
Funded by Institution	Researcher inst. where xxxxx is/was performed	Year	Title	Position in Projects	Fund (euro)	Source website grant listed
.	.	.	.	Collaborator	0,00	.

2.10 Additional Research Collaborators n. 3 - Under 40 to hire

Last Name: Foschi

First Name: Xxxxxx

Last name at birth:

Gender: M

Title: Additional Research Collaborators Under 40 To HIRE

Nationality: Italiana

Date of birth: 29/09/1989

Official H index (Scopus or Web of Science): 7.0

Country of residence: ITALY Country of Birth: ITALY Place of Birth: Teramo

Scopus Author Id:57192255295 ORCID ID:0000-0002-0321-7155 RESEARCH ID:ABR-7231-2022

Contact address

Current organisation name: University of L'Aquila

Current Department / Faculty / Institute / Laboratory name: Biotechnological and Applied Clinical Sciences Dept

Street: Viale Xxxxxxxx Xxxxx 5

Postcode / Cedex: 48124 Town: Ravenna

Phone:x000000000000 Phone 2:

Education / training
Educational institution and location	Degree	Field of study	From year	To year
Alma Mater Studiorum - Università di Bologna	Specialization / Specializzazione	Neurology	2015	2019
Università degli studi G. x'Xxxxxxxx Xxxxxx Pescara	Single-cycle master's degree / Laurea magistrale a ciclo unico	Medicine	2009	2014

Personal Statement:

With the present project I aim to collaborate in creating a hub center in the Central-South part of Italy to provide high quality of care and expertise for patients with rare causes of ischemic stroke. So far, in the central-South part of Italy, there is not any referral center for patients with rare causes of stroke. I have already a clinical expertise in the field of stroke as a stroke neurologist, currently working at the Stroke and Neurology Unit of Ravenna. I have also a research expertise in the field of cerebrovascular diseases as member of the Bologna TIA study group (S.Xxxxxx Xxxxxxxx University Hospital of Bologna).

Positions and honors

Positions
Institution	Division / Research group	Location	Position	From year	To year
AUSL Romagna, S. Xxxxx delle Croci Hospital	Department of Neuroscience	Ravenna, Italy	Consultant Neurologist	2019	2022
Alma Mater Studiorum - University of Bologna	Neurology Clinical Unit	Bologna, Italy	Resident in Neurology	2015	2019

Other awards and honors

Xxxxx Xxxxx best scientific contribution:A prospective observational study evaluating recurrent TIA frequency, features, short and long term outcome 2019

Prize for the best scientific contribution: Ictus recidivanti del circolo posteriore: fisiopatologia di un caso clinico complesso SINSEC 2019

Xxxxx Xxxxx best scientific contribution:Giant cell arteritis with multiple intra and extracranial involvement: a combined magnetic resonance angiography and color-coded duplex ultrasonography study 2021

Grant
Funded by Institution	Researcher inst. where xxxxx is/was performed	Year	Title	Position in Projects	Fund (euro)	Source website grant listed
.	.	.	.	Collaborator	0,00	.

2.17 Expertise Research Collaborators

Selected peer-reviewed publications of the Research Group / Collaborators
Collaborato	Title	Type	Pag	Vol	Year	DOI	PMID	Cit.**	P.*
XXXXX XXXXXXX	"Small World" architecture in brain connectivity and hippocampal volume in Alzheimer¿s disease: a study via graph theory from EEG data	Article	473-485	11	2017	10.1007/s11682-016- 9528-3	26960946	63	O
XXXXX XXXXXXX	Longitudinal reproducibility of default-mode network connectivity in healthy elderly participants: A multicentric resting-state fMRI study	Article	442-454	124	2016	10.1016/j.neuroimage.00 00.00.000	26163799	60	O
XXXXX XXXXXXX	Data-driven grading of brain gliomas: A multiparametric MR imaging study	Article	494-503	272	2014	10.1148/radiol.14132040	24661247	62	F
XXXXX XXXXXXX	Multisite longitudinal reliability of tract-based spatial statistics in diffusion tensor imaging of healthy elderly subjects	Article	390-403	101	2014	10.1016/j.neuroimage.00 00.00.000	25026156	69	O
XXXXX XXXXXXX	Xxxxxxx-induced brain lesions: A wide spectrum of variably reversible MRI abnormalities	Article	1964- 1972	82	2013	10.1016/j.ejrad.2013.05. 020	23787273	120	O
XXXXXXX XXXXXXX XXXXXXX	Identification of residual tumor with intraoperative contrast- enhanced ultrasound during glioblastoma resection	Article	E7	40	2016	10.3171/2015.11.FOCU S15573	26926065	72	O
XXXXXXX XXXXXXX XXXXXXX	Preoperative magnetic resonance and intraoperative ultrasound fusion imaging for real-time neuronavigation in brain tumor surgery	Article	174-186	9	2014	10.1055/s-0034- 1385347	25429625	66	O
XXXXXXX XXXXXXX XXXXXXX	Discrete or diffuse intramedullary tumor? Contrast-enhanced intraoperative ultrasound in a case of intramedullary cervicothoracic hemangioblastomas mimicking a diffuse infiltrative glioma: Technical note and case report	Article	E17	39	2015	10.3171/2015.5.FOCUS 15162	26235015	00	X
XXXXXXX XXXXXXX XXXXXXX	Intraoperative cerebral glioma characterization with contrast enhanced ultrasound	Article	484261	2014	2014	10.1155/2014/484261	25013784	62	O
XXXXXXX XXXXXXX XXXXXXX	Fusion imaging for intra- operative ultrasound-based navigation in neurosurgery	Article	243-251	17	2014	10.1007/s40477-014- 0111-8	25177400	51	O

Collaborato	Title	Type	Pag	Vol	Year	DOI	PMID	Cit.**	P.*
Xxxxxxxx Xxxxx	Lipoxidation in cardiovascular diseases	Review	101119	23	2019	10.1016/j.redox.2019.10 1119	30833142	35	F
Xxxxxxxx Xxxxx	The selected reaction monitoring/multiple reaction monitoring-based mass spectrometry approach for the accurate quantitation of proteins: Clinical applications in the cardiovascular diseases	Review	771-788	11	2014	10.1586/14789450.2014. 947966	25400095	26	O
Xxxxxxxx Xxxxx	Urinary exosomes and diabetic nephropathy: A proteomic approach	Article	1139- 1146	9	2013	10.1039/c2mb25396h	23344851	50	O
Xxxxxxxx Xxxxx	Detection of high molecular weight proteins by MALDI imaging mass spectrometry	Article	1101- 1107	9	2013	10.1039/c2mb25296a	23340489	36	O
Xxxxxxxx Xxxxx	Alterations of the serum peptidome in renal cell carcinoma discriminating benign and malignant kidney tumors	Article	125-140	76	2012	10.1016/j.jprot.2012.07.0 32	22868251	36	F
Xxxxxxxxxxx Xxxxxxx Xxxxxxxx	Analysis of shared heritability in common disorders of the brain	Article	8757	360	2018	10.1126/science.aap875 7	29930110	784	X
Xxxxxxxxxxx Xxxxxxx Xxxxxxxx	Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes	Article	524-537	50	2018	10.1038/s41588-018- 0058-3	29531354	458	X
Xxxxxxxxxxx Xxxxxxx Xxxxxxxx	Prodromal Alzheimer's Disease Presenting as Cerebral Amyloid Angiopathy- Related Inflammation with Spontaneous Amyloid-Related Imaging Abnormalities and High Cerebrospinal Fluid Anti- A? Autoantibodies	Article	363-367	45	2015	10.3233/JAD-142376	25537009	25	F
Xxxxxxxxxxx Xxxxxxx Xxxxxxxx	Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): A meta- analysis of genome-wide association studies	Article	951-962	11	2012	10.1016/S1474- 0000(00)00000-X	00000000	345	X
Xxxxxxxxxxx Xxxxxxx Xxxxxxxx	Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke	Article	328-333	44	2012	10.1038/ng.1081	22306652	313	O
Xxxxx Xxxxxx	2021 ESC Guidelines on cardiovascular disease prevention in clinical practice	Review	3227- 3337	42	2021	10.1093/eurheartj/ehab4 84	34458905	209	O

Collaborato	Title	Type	Pag	Vol	Year	DOI	PMID	Cit.**	P.*
Xxxxx Xxxxxx	Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study	Review	2982- 3021	76	2020	10.1016/j.jacc.2020.11.0 10	33309175	683	O
Xxxxx Xxxxxx	European headache federation guideline on the use of monoclonal antibodies acting on the calcitonin gene related peptide or its receptor for migraine prevention	Article	6	20	2019	10.1186/s10194-018- 0955-y	30651064	170	F
Xxxxx Xxxxxx	Xxxxx recurrence and cerebral bleeding in patients with acute ischemic stroke and atrial fibrillation: Effect of anticoagulation and its timing: The RAF study	Article	2175- 2182	46	2015	10.1161/STROKEAHA.1 15.008891	26130094	154	O
Xxxxx Xxxxxx	Xxxxxxxx and hemorrhagic stroke: A meta-analysis	Article	3032- 3038	44	2013	10.1161/STROKEAHA.1 13.002465	24085027	114	F
XXXXXXX XXXXXX	Xxxxxxxxxx is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: A new approach for drug delivery	Article	262-270	192	2014	10.1016/j.jconrel.2014.0 7.042	25084218	473	O
XXXXXXX XXXXXX	Xxxxxxxxx and expansion of human and mouse brain microvascular endothelial cells	Article	1680- 1693	8	2013	10.1038/nprot.2013.107	23928501	59	O
XXXXXXX XXXXXX	Xxxxxxxxxxx stromal cells primed with Paclitaxel attract and kill leukaemia cells, inhibit angiogenesis and improve survival of leukaemia-bearing mice	Article	766-778	160	2013	10.1111/bjh.12196	23293837	52	O
XXXXXXX XXXXXX	A small-molecule RGD-integrin antagonist inhibits cell adhesion, cell migration and induces anoikis in glioblastoma cells	Article	83-92	42	2013	10.3892/xxx.2012.1708	23174862	51	O
XXXXXXX XXXXXX	Xxxxxxxxxxx T regulatory cells migration and phenotype in glioblastoma patients: An in vitro study	Article	353-363	115	2013	10.1007/s11060-013- 1236-x	24005771	19	L
Xxxxx Xxxxx	Global surveillance of trends in cancer survival 2000¿14 (CONCORD-3): analysis of individual records for 37?513?025 patients diagnosed with one of 18 cancers from 322 population- based registries in 71	Article	1023- 1075	391	2018	10.1016/S0140- 6736(17)33326-3	29395269	1631	O

Collaborato	Title	Type	Pag	Vol	Year	DOI	PMID	Cit.**	P.*
Xxxxx Xxxxx	Overcoming ABC transporter- mediated multidrug resistance: The dual role of tyrosine kinase inhibitors as multitargeting agents	Article	271-289	142	2017	10.1016/j.ejmech.2017.0 7.062	28851502	98	L
Xxxxx Xxxxx	Microenvironment-modulated metastatic CD133<sup>+</sup>/CXCR4 <sup>+</sup>/EpCAM<sup>- </sup>lung cancer-initiating cells sustain tumor dissemination and correlate with poor prognosis	Article	3636- 3649	75	2015	10.1158/0008- 5472.CAN-14-3781	26141860	66	O
Xxxxx Xxxxx	Targeting the akt kinase to modulate survival, invasiveness and drug resistance of cancer cells	Article	1923- 1945	20	2013	10.2174/0929867311320 9990106	23410153	80	O
Xxxxx Xxxxx	Xxxxxxxxxxxx resistance in cancer: Insights into the molecular mechanisms of a DNA-damaging drug	Article	1541- 1565	20	2013	10.2174/0929867311320 120006	23432590	56	O

* Position: F=First L=Last C=Correspondent O=Other N=Not applicable

** Autocertificated

3 - Ethics

1. HUMAN EMBRYOS/FOETUSES
Does your research involve Human Embryonic Stem Cells (hESCs)?	No
Does your research involve the use of human embryos?	No
Does your research involve the use of human foetal tissues / cells?	No
2. HUMANS
Does your research involve human participants?	Yes
Does your research involve physical interventions on the study participants?	No
3. HUMAN CELLS / TISSUES
Does your research involve human cells or tissues (other than from Human Embryos/ Foetuses?	Yes
4. PERSONAL DATA
Does your research involve personal data collection and/or processing?	Yes
Does your research involve further processing of previously collected personal data (secondary use)?	Yes

5. ANIMALS
Does your research involve animals?	No
6. ENVIRONMENT & HEALTH and SAFETY
Does your research involve the use of elements that may cause harm to the environment, to animals or plants?	No
Does your research deal with endangered fauna and/or flora and/or protected areas?	No
Does your research involve the use of elements that may cause harm to humans, including research staff?	No
7. DUAL USE
Does your research involve dual-use items in the sense of Regulation 428/2009, or other items for which an	No
8. EXCLUSIVE FOCUS ON CIVIL APPLICATIONS
Could your research raise concerns regarding the exclusive focus on civil applications?	No
9. MISUSE
Does your research have the potential for misuse of research results?	Yes
10. OTHER ETHICS ISSUES
Are there any other ethics issues that should be taken into consideration? Please specify	No

I confirm that I have taken into account all ethics issues described above and that, if any ethics issues apply, I will complete the ethics self-assessment and attach the required documents.

4 - Call-specific questions

Eligibility

I acknowledge that I am aware of the eligibility requirements for applying as specified in the Call- PNRRXXXX_M6/C2, and certify that, to the best of my knowledge my application is in compliance with all these requirements. I understand that my proposal may be declared ineligible at any point during the evaluation or granting process if it is found not to be compliant with these eligibility criteria.

I confirm that the proposal that I am about to submit draws substantially don’t repeat on an existing or recently finished GRANT funded.

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For communication purposes only, the MoH asks for your permission to publish,in whatever form and medium, your name, the proposal title, the proposal acronym, the panel, and host institution, should your proposal be retained for funding.	X
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5 – Description Project

Summary description

The management of rare cerebrovascular diseasese (rCVD) is mostly allocated in hospital with expertise, sited in the North of Italy, making difficult the patient access to the optimal care pathways. Since rare and locally dealt, also the clinical/molecular profile and clinical course of rCVD is poorLY known. By transferring knowledge and experience from referral to periheral centers and building a solid expertise in South of Italy, the project is aimed at creating a clinical and reasearch network on rCVD, offering the best diagnostic and therapeutic chances to patients overall Italy. The project will promote the development of a multidisciplinary and multi-centric model of care for rCVD patients, supported by a Virtual Hospital system. By optimizing resources and improving efficiency and quality of care ALIGNED project will ehnance the probability of understanding the rCVD clinical and molecular phenotype finally leading to lower the overall diseases burden.

Background / State of the art

Cerebrovascular diseases (CVD) are one of the leading causes of morbidity and mortality worldwide. Despite intensive investigations, more than 30% of strokes remain of undetermined origin. Rare CVD (rCVD) including heritable (i.e.

CADASIL, COL4A1 syndrome, Fabry disease) and acquired conditions (i.e. Xxxxxxx syndrome, Moyamoya arteriopathy) account for a proportion of these strokes. However, rCVD are probably misdiagnosed since clinicians are not able to recognise them. The identification of these stroke causes is important to establish appropriate management measures, including genetic counseling, and, if available, therapy. The lack of data on phenotype and clinical course of rCVD patients, given the paucity of published series, makes the diagnosis and the development of therapies challenging. Also the

molecular characterization of rCVD is still lacking, despite progresses achieved in common stroke by applying high throughput approaches as multi-omics. Actually, since the diagnosis and care of these rCVD require adequate expertise and instrumental tools, clinical and research activities on rCVD are usually reserved to few specialized centers with expertise in the field, mostly sited in the North of Italy, making difficult the patient access to the optimal diagnostic and therapeutic pathways. The creation of a clinical and research network aimed at improving the diagnostic pathways of rCVD is highly needed to fill the geographical gap affecting the Southern Italy.

Description and distribution of activities of each operating unit

U1 (FINCB, Milan) will coordinate the project and will serve as referral center of the North of Italy. The U1 will organize the collection of patient data and samples of North Italy. Favored by the presence of the Neurobiology Laboratory, the Diagnostic and Imaging Department and the Unit of Medical Genetics and Neurogenetics, U1 will coordinate together with U2 the harmonization of technologies and research procedures and will provide basic researchers with strong background in transcriptomic and lipidomic analysis and multi-omics data integration. The feasibility is guaranteed since U1 is an Italian referral centers for rare disease, is part of European Reference Network (ERN), including European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN; xxxxx://xxxxxxx.xx/) and is coordinating national and international projects on several rare and less rare diseases as Moyamoya arteriopathy (GENOMA project), cerebral amyloid angiopathy (SENECA project) and CADASIL.Therefore, part of the biological samples and neuroimaging data, planned to be used in this project, have been already collected. By the integration of a strongly phenotype-oriented approach with the use of experimental data, originated by innovative and highly sensitive/specific multi-omic techniques, U1 will maximize the chance of identifying the most critical biological disease drivers and markers, to develop patient-specific predictive models useful for tailored interventions.

U2 (CCM, Milan) is in charge of the proteomic and metabolomic analysis in search of mechanistic and diagnostic markers of

rCVD by applying mass spectrometry-based cutting-edge technologies for an unbiased identification of differentially abundant candidates (proteins or metabolites), and for their validation and simultaneous assessment in multi-marker panels. The differentially expressed mRNA/proteins/metabolites/lipids across groups with different diagnosis will be identified by cutting-edge untargeted approaches in relevant samples (i.e. cells, plasma, tissues) and validated by specific assays. In collaboration with U1, integrative approaches to study the biological phenomenon will be adopted to analyze multiple omics data and address applications such as disease subtyping, biomarker prediction, and patient stratification.

U3 (ASL2 Regione Abruzzo, Lanciano-Vasto-Chieti) will integrate conventional and advanced (perfusion-PWI, diffusion-DWI and functional connectivity-FC) MRI techniques to identify neuroradiological characteristics of rCVD to facilitate the differential diagnosis with other cerebrovascular or inflammatory disorders and to follow up the evolution of the disease and response to therapy.

U4 (University of L Aquila, L Aquila) will serve as the referral center for South Italy. The U4 will contribute, based on previous experience in stroke registries, to set-up a registry of patients with rare neurological diseases for the South Italy. U4 will coordinate the patient data as well as the biological sample collection, according to ethical rules and will contribute to the implementation of the large rCVD patient registry, favored by the experience in dealing big clinical registry on stroke. U4 is also experienced with telemedicine care and will contribute to set up this approach to provide remote consultations and follow-up to individuals with rCVD.

5.4 Specific Aims and Experimental Design

Specific aim 1

TO CREATE AN ITALIAN NETWORK OF CENTERS DEDICATED TO RCVD CARE AND TO COLLECT LARGE CASE SERIES OF PATIENTS AFFECTED BY RCVD.

TASK 1.1 TO INCREASE THE NUMBER OF CENTERS WITH EXPERTISE IN RCVD IN THE SOUTH OF ITALY.

The management of patients with rCVD is usually reserved for a few specialized centers. This uneven distribution across the territory produces high costs and inconveniences for the patient and an inevitable inequality of care. By building a solid

expertise in South Italy through the creation of a referral center and enhancing connections and sharing experience among centers, ALIGNED project will improve the care of patient in rCVD overall Italy. This strategy will also facilitate equal access to the same treatment and diagnostic pathways to rCVD Italian patients across all the national territory. Therefore, all clinical centers with interest in rCVD care and research will take part in the project. Two coordinating centers, one in the North and one in the South of Italy, supported by the project recrutiment of new young collaborators, will organize and coordinate patients collection, centralized registries/procedures implementation and will ensure quality of collected data. A panel of experts will be in charge of implementing/improving diagnostic and therapeutic pathways and organizing periodic meetings or in site visits to assess the progresses of clinical and technology transfer. The creation of a network on rCVD and the subsequent re-organization of care of rCVD patients will favour the recruitment of a large number of rCVD cases, useful for clinical and research purposes. This network will also allow a more profitable management of health care economic burden by optimizing resources and improving diagnostic and care protocols, according to European standards and ongoing protocols/guidelines.

TASK 1.2 TO DEVELOP A NEW, UNIQUE AND LARGE REGISTRY ON RCVD.

Through the network implementation, we intend to create a big dataset of clinical and neuroradiological data of rCVD patients to obtain a large and well-phenotyped cohort. Patients with a clinical, genetic and/or neuroradiological diagnosis of CADASIL, Fabry disease, COL4A1, Xxxxxxx syndrome and Moyamoya arteiopathy, will be recruited after obtaining written informed consent and according to the regulations of local ethics committees. Because of the existence of databases already started over time in the involved centers, patient recruitment will be both retrospective and prospective. In order to solve possible dissimilarities among databases, a data harmonization protocol, including strategies of data pooling and quality control will be developed and a minimum data set for patient inclusion will be established by the consortium. Patient detailed demographic, clinical (i.e risk factors, familial history, comorbidities etc.), neuroimaging and treatment data will be collected anonymously in an electronic and password-protected database. With this strategy, favoured by the previous experience in clinical registry (both on rCVD and stroke) implementation done by U1 and U4, it will be possible also to expand and adapt existing registries (i.e., the GEN-O-MA project, CADASIL, etc see preliminary data). The collection of a large database of clinical and detailed neuroradiological data is imperative for the implementation of possible future therapeutic and biological studies. In fact, the lack of enrollment in clinical trials of patients with rare diseases has always been one of the major reasons for the failure of the trial itself. Indeed, it is extremely difficult to carry out therapeutic trials in rCVD patients: the rarity of the disease makes it difficult to achieve a sufficient sample size of patients enrolled. Moreover, with a well-organised network of centers, it would be possible to optimally deal large-scale rCVD therapeutic and management interventions (i.e pharmacological) in the future.

Specific aim 2

TO DEVELOP STANDARDIZED METHODOLOGIES, SCIENTIFIC VALIDATION PROCEDURES AND TO MOLECULAR CHARACTERIZE RCVD

TASK 2.1 TO SHARE AND STANDARDISE METHODOLOGIES AND PROCEDURES AMONG NETWORK CENTERS

A survey of available techniques among participating centers will be performed at the beginning of the project to establish hospital available instruments and tools. Procedures of harmonization, standardization and technology transfer will be accomplished by the strong cooperation and data sharing among neurobiological laboratories involved in rCVD research. The network will share not only techniques but also protocols for sample collection, preparation, analysis, data sharing to get high-quality specimens, collected and handled in standardized ways to minimize potential bias or confounding factors. For this purpose, the guidelines of the Human Proteome organization will be followed when performing proteomic analysis. Further, U2 is a partner of the CA1910 -Pan-European Network in Lipidomics and EpiLipidomics, which aims to harmonize metabolomic workflows among research centers.

Task 2.2 TO CREATE AND NETWORK TWO BIOBANKS DEDICATED TO RCVD

The clinical network will favor the collection of different biological samples of rCVD patients (DNA, plasma, CSF, cells and tissue specimens). After specific informed consent, biological samples of patients with rCVD will be acquired both for diagnostic and research purposes in all centers overall Italy. According to local and national ethical rules, biological

samples will be stored in two big biobanks one in the North and one in the South of Italy. The samples will be stored anonymously according to data protection rules and all regulatory requirements for the handling and use of biological specimens, sample ownership and custody. To overcome ethical questions, communication with the individuals and involvement of agencies that will oversee the ethical, legal, and regulatory issues that are relevant to the study will be planned.

TASK 2.3 TO DEPICT RCVD MOLECULAR SIGNATURES BY UNTARGETED TRANSCRIPTOMIC, PROTEOMIC, METABOLOMIC AND LIPIDOMIC APPROACHES (DISCOVERY PHASE)

In order to highlight novel and unpredictable mechanistic and diagnostic and prognostic markers in plasma/CSF/tissue/cellular specimens of patients as compared to healthy donors (HD), an explorative analyses will be accomplished to identify key signatures and dissect relevant molecular mechanisms across omics scales addressing cellular and molecular disease features. Untargeted omics approaches will be performed by means of gene-expression arrays and quantitative label-free mass spectrometry (MS) respectively, on samples derived from rCVD patients and HD. Lipid content in plasma, CSF, tissue/cellular specimens will be analyzed by an untargeted lipidomic approach aimed at identifying different modulated lipid species/families, as preliminary performed in Moyamoya arteriopathy (see preliminary data). Uni- and multi-variate (machine learning) feature selection will be applied on identified biomarkers to devise a prognostic model by comparing clinical and neuroimaging patients phenotypes.

TASK 2.4 TO VALIDATE KEY AND RELIABLE CIRCULATING RCVD BIOMARKERS(VALIDATION PHASE)

Targeted/quantitative MS-based approaches and quantitative Real Time PCR assays will validate the key molecular features emerged in Task 2.3 to identify biomarkers for disease diagnosis/prediction/prevention. Specifically, the top candidates from the discovery phase will be: (i) validated in plasma/CSF samples from an extended rCVD patient cohort (U1-U3-U4) and controls; N=20/group (ii) analyzed in all plasma/CSF samples employed for the validation phase using ELISA or, alternatively, SIMoA technologies. For the validation phase, U2 has recently developed novel approaches for the simultaneous quantitation of multiple protein biomarkers by the selected reaction monitoring (SRM)/multiple reaction monitoring (MRM).

Specific aim 3

TO DEVELOP A MULTI-SPECIALISTIC AND MULTICENTRIC VIRTUAL MODEL OF CARE SPECIFIC FOR RCVD

The diagnostic and therapeutic pathways for patients with rCVD are often organized only in a few specialised clinical centers, limiting the access of patients coming from other Italian regions or rural areas. This uneven distribution across the territory produces high costs for the patient and an inevitable inequality of care for those who cannot afford to travel from Southern to Northern Italy for in-depth diagnosis and treatment. The idea is to develop a model that allow a multidisciplinary and multicentric "prise en charge" of patients affected by rCVD who need a second opinion or a multidisciplinary approach, optimizing the healthcare system's resources and providing a high-quality management of rCVD patients, regardless of their possibility to access to secondary or tertiary-level centers. We intend to easily establish an online connection between centers of competence and peripheral hospitals promoting also an inter-centers science exchange, useful for design/data analysis of clinical studies.

Task 3.1 TO IMPLEMENT AN IT PLATFORM TO ALLOW CLINICAL AND BIOLOGICAL DATA SHARING

A web-based platform will be developed to allow physicians to collect and anonymously share patients' data specifically created for rCVD, following the experience of NOVHO study, a pilot project coordinated by our Institute and funded by Lombardia Region, evaluating the efficacy of Virtual Hospital model on reducing the cost of health and optimizing resources of neurological and neurosurgical disease care (see preliminary data). This platform will consent to share and discuss clinical and neuroradiological data of patients as well as biological and omics data. Physicians will be trained to uniformly and anonymously report all needed anamnestic information, comorbidities, results of physical examination, diagnostic exams, and therapies. Before submitting cases, available data will be validated, to control the pertinence of the informatic data.

Task 3.2 TO CREATE MULTIDISCIPLINARY TEAMS DEDICATED TO EACH SPECIFIC RCVD

According to the expertise of the physicians, multidisciplinary teams of experts (balanced for sex and age) for each specific

rCVD will be constituted to discuss cases in order to simplify and standardize patient care and monitoring disease over time, with attention to the transition between pediatric age and adulthood.

Task 3.3 TO SUPPORT THE SCIENTIFIC EXCHANGE ACROSS CENTERS

Neurologists, neurosurgeons, neuroradiologists, genetists, biologists and other medical specialists will share the most updated research and therapeutic strategies overall Italy. The experience of physicians from tertiary centers, such as U1, will be available for all Italian patients who need second opinion. As additional expertise in South Italy, the U3 and U4 will be further exploited to serve as the Referral Center for South Italy in order to avoid overwhelmimg of the U1, and to reduce the distance for patients who need in-person evaluation and who live in South Italy. Interaction between the two referral centers will promote further improvement of care.

Experimental design aim 1

TASK 1.1 TO INCREASE THE NUMBER OF CENTERS WITH EXPERTISE IN RCVD IN THE SOUTH OF ITALY.

All the rCVD care and research centers throughout Italy interested to participate in the project will be included. Two coordinating centers, one in the North (U1) and one in the South of Italy (U4) will organize and coordinate activities for the North and South regions, respectively. A multidisciplinary panel of experts of rCVD (neurologists, bologists, neuroradiologists, geneticists, neurosurgeons) selected throughout Italy, based on their expertise in care and research on rCVD, will be created to favor the collection of well phenotyped cases, implement homogeneous registries and to guarantee the clinical, scientific and technology transfer. This activity will be supported by U3 and U4, given the expertise in multicenter registries and neuroradiological aspects [1] and by newly recruited and highly motivated young neurologists.

For each rCVD, specific diagnostic work ups as well as management and therapeutic pathways will be implemented and shared among the participating centers to improve and standardize the rCVD care. The tight collaboration among centers will also favor the recruitment of a large number of well phenotyped rCVD cases.

TASK 1.2 TO DEVELOP A NEW, UNIQUE AND LARGE REGISTRY ON RCVD.

A standardized electronic database, protected by privacy and anonymization rules, including demographic, clinical and neuroradiological data will be implemented. U1 and U4 will coordinate the recruitment of prospective and retrospective patients with a clinical, genetic and/or neuroradiological diagnosis of CADASIL, Fabry disease, COL4A1, Xxxxxxx syndrome and Moyamoya arteriopathy, after obtaining written informed consent to participate in the study, according to the local ethical committee regulation. Since some participating centers have been assembling clinical and neuroimaging data of rCVD patients for several years but collected items are heterogeneous they need to be harmonized [2-6]. A harmonization data protocol, including strategies of data pooling, quality control and a minimum data set for patient inclusion, will be implemented for the ALIGNED project, based on previous experience on national and international stroke and rCVD registries [2-10]. Patient detailed demographic, clinical neurological and systemic findings (i.e., risk factors, familial history and associated diseases/systemic symptoms or signs) as well as neuroimaging, neurophysiological and, when indicated, surgical information will be collected. Data on pharmacological treatment and psychological status, disability, quality of life will be collected too.

Experimental design aim 2

TASK 2.1 TO SHARE AND STANDARDIZE METHODOLOGIES AND PROCEDURES AMONG NETWORK CENTERS

All the participating centers will be checked by an email survey and/or by in situ visits at the beginning of the project to establish hospital assets of diagnostic/therapeutic pathways, procedures, facilities and instrument availability for rCVD. A multidisciplinary team (neurologists, neuroradiologists, biologists, geneticists), taking into account potential lack of infrastructures, will achieve an agreement on methodology and establish a common vision and action plan. By integrating individual fieldwork, local and international ethical rules, the team will implement and share guidelines to standardize procedures/methodologies, including neuroradiological pathways and diagnostic work ups. Young specialists will contribute to the fulfillment of standardization procedures to conform all the diagnostic pathways, techniques, protocols for sample collection, preparation and analysis, data sharing rules and to guarantee the high-quality of specimens, with the final goal of minimizing potential bias or confounding factors [11-12].

Task 2.2 TO CREATE AND NETWORK TWO BIOBANKS DEDICATED TO RCVD

Two biobanks, one in the North and one in the South of Italy, including different biological samples of rCVD patients (DNA, plasma, CSF, cell/tissue specimens) will be created. The biological samples will be collected after informed consent and stored anonymously according to data protection and regulatory requirements. For this purpose European Recommendations [13] on research on human biological materials will be taken into account to safeguard the fundamental rights of individuals whose biological materials are stored and intended for biomedical research.

TASK 2.3 TO DEPICT RCVD MOLECULAR SIGNATURES BY UNTARGETED TRANSCRIPTOMIC, PROTEOMIC, METABOLOMIC AND LIPIDOMIC APPROACHES (DISCOVERY PHASE)

An explorative analysis will be accomplished in different biological samples (plasma/CSF/tissues/cellular specimens) of rCVD patients as compared to healthy donors (HD), to identify relevant molecular features across omics scales.

2.3.1 qRT-PCR analyses will be performed to assess the mRNA expression levels of selected target genes. Specific RNA extraction methodology (QIAGEN RNeasy Fibrous and Lipid Tissue kits) will be uniformly adopted, due to the low abundance/particular texture of starting materials (e.g., small fragments of cerebral vessels, poorly represented cellular histotypes). TaqMan Gene Expression Array Cards (ThermoFisher Scientific) will be employed to simultaneously determine gene-expression profiles by a transcriptomic approach.

2.3.2 To explore the proteomic profiling we will employ a quantitative label free mass spectrometry (MS)-based approach, performed on a hybrid quadrupole-TOF (qTOF) instrument coupled with a 2D-LC system (Waters Corporation) [14-16].

2.3.3 Lipidomic analysis will be addressed by an untargeted lipidomic approach for identifying different modulated lipid species/families [17]

TASK 2.4 TO VALIDATE KEY AND RELIABLE CIRCULATING RCVD BIOMARKERS (VALIDATION PHASE)

Targeted/quantitative MS-based approaches and qRT-PCR assays will validate the key molecular features emerged in Task 2.3 to identify biomarkers for disease diagnosis/prediction/prevention. Replication lipidomic analysis will be carried out by quantitative targeted LC-MS/MS.

Experimental design aim 3

Task 3.1 TO IMPLEMENT AN IT PLATFORM TO ALLOW CLINICAL AND BIOLOGICAL DATA SHARING

Based on the previous experience of the pilot project [18] a specific-for-rCVD electronic platform will be created allowing clinicians throughout Italy and, if required geneticists and biologists, to share and discuss patient clinical, neuroradiological, biological and omics data. This multidisciplinary discussion will contribute to strengthen the network between centers and favor the sharing/transferring competences from referral- to peripheral-hospitals. A specific data collection form will be created, to guide referring physicians in charge of cases to report all needed anamnestic information (medical history, comorbidities, results of physical examination, diagnostic exams and therapies), neuroradiological/neurosurgical data and other relevant exams. Patient agreement will be obtained before collecting data, according to protection and privacy rules (General Data Protection Regulation -GDPR). Available data will be checked for the appropriateness and completeness by a Case Manager (a doctor or a nurse).

Task 3.2 TO CREATE MULTIDISCIPLINARY TEAMS DEDICATED TO EACH SPECIFIC RCVD

A core of expert physicians for each rCVD (neurologists, neurosurgeons, neuroradiologists, interventional radiologists, neuropsychiatrists, geneticists, neurophysiologists, and psychologists), balanced for age and gender, will be created. These expert panels will plan periodic meetings (one for month) to discuss diagnosis and provide the best diagnostic and management pathways. Residents or medical students will be allowed to attend the meetings for didactical purposes. For each participating center a Case Manager,in charge to plan meetings, will be identified to provide technical support to physicians in logging the platform and data entry and to control the completeness of patient information. U1 will coordinate the meeting organization. Meetings will be scheduled every month, in order to let maximum one month pass between the request and the discussion. A timetable of team meetings will be sent two/three months in advance to all members. In case of a very urgent case, extra virtual team meetings will be planned.

Task 3.3 TO SUPPORT THE SCIENTIFIC EXCHANGE ACROSS CENTERS

With the creation and organization of a dense network of research institutes and hospitals distributed throughout Italy, it will

be possible to achieve a solid transfer of knowledge and ensure professional growth and experience enhancement even in smaller centers. The project will enable the sharing of sensitive information, which will be conveyed in a secure mode, making it possible to conduct virtual consultations, multidisciplinary meetings, and training events, even remotely. In this way, neurologists with longer experience over time, or physicians with more specialized knowledge of rCVD will be able to spread their expertise and sow knowledge even many miles away. Clinical, biological and instrumental (i.e. MRI) data shared on the IT platform will be available for review and discussion. This will result in a significant reduction in public and private expenditures: examinations will be performed in numerous Italian hospitals without overburdening major centers, and patients will not have to pay the cost of long trips to distant, highly specialized centers. Shared data will be reviewed by multiple experts, ensuring the use of the best diagnostic and therapeutic measures, as well as the implementation of specific diagnostic pathways, to ensure equity of care. The co-partnership of centers with a strictly clinical vocation (U3, U4) with centers for research, including preclinical research (U1, U2), will enable patients who otherwise would not have been able to, to benefit from advanced analyses.

Picture to support preliminary data PNRR dati preliminari_Bersano.pptx Hypothesis and significance

The diagnosis and care of complex rCVD is challenging, due to the scarcity of data on clinical, neuroradiological and

molecular phenotype. Due to their complexity and their poor knowledge, the management of rCVD is reserved to few specialized clinical centers, with expertise in the field. These centers are mostly located in the north of Italy and therefore patients who live in rural areas, South Italy or who are in charge to peripheral hospitals have sometimes limited access to adequate diagnostic assessment or management. The principal goal of this project is to enhance and empower the infrastructures necessary to deal the diagnosis and care of a number of heritable (CADASIL, Fabry disease, COL4A1 syndrome) and not heritable (Xxxxxxx syndrome, Moyamoya arteriopathy) disease overall Italy. Through the creation of a national network for rCVD, the clinical and biological knowledge of rCVD will be easily transferred from referral centers to peripheral hospitals, localised overall Italy, overcoming inequalities in care. This network will also allow a more profitable management of health care expenditures dedicated to rCVDs: performing diagnostic examinations with the same execution protocols and quality criteria throughout Italy will save the need for requesting repetition of the same examination in another center for a so-called second opinion. In fact, it is not uncommon for a patient with rCVD to have already received an adequate diagnosis but to come to the referral center only after multiple investigations in other hospitals, often losing continuity in follow-up and with an important diagnostic and therapeutic delay. The creation of a dedicated network on rCVD is also extremely necessary to create large datasets of clinical and biological studies useful to better understand the disease clinical features, molecular phenotype and natural course and therefore, to improve rCVD diagnosis and prognosis. This large registry will be also used to recruit patients for future clinical therapeutic trials. Moreover, the molecular profile of rCVD is still poorly known and diagnostic and prognostic biomarkers of these disorders are largely lacking. The discovery of these biomarkers is developed in specialized centers, where advanced technologies support the crescent discovery of molecular disease insights. However, research activity is often conducted locally, and no standardized procedures are shared. The implementation of the Italian network of clinical and research activities of rCVD will ensure and enhance the connection among biobanks, will strengthen cooperation, relationships and experience among neurobiological laboratories involved in rCVD research. The identification of a transcriptomic, proteomic, metabolomic and lipidomic signature will be relevant to facilitate diagnostic/monitoring of rCVD. Biomarkers to identify asymptomatic rCVD patients will be very important to treat and monitor these patients. Besides, biomarkers to predict rCVD outcome will improve the management of those patients at high risk of suffer new strokes or neurovascular damage progression and could benefit of more aggressive treatments and monitoring (decrease other cardiovascular risk factors, a more intense antiaggregant therapies, more frequent clinical tests, etc). Gender dimension will be accurately considered in terms of sample selection, results analysis and personnel involved in the project.

5.5 Methodologies and statistical analyses

Methods of data collection

According to national and international privacy and anonymization rules, an electronic and password-protected database will be created including a set of patient demographic, clinical neurological and systemic findings, neuroimaging, neurophysiological and surgical data. Data on pharmacological treatments and psychological conditions, disability, and quality of life will be collected too. U1 and U4, supported by the neurologists, specifically recruited for the project, serving as North and South hub centers will manage the recruitment of rCVD cases. Cerebral MRI will be mandatory for study inclusion. After project protocol approval by the local ethics committee, all patients with a clinical, genetic and/or neuroradiological diagnosis of CADASIL, Fabry disease, COL4A1, Xxxxxxx syndrome and Moyamoya arteriopathy, will be recruited [19]. Since some participating centers already implemented databases including clinical and neuroimaging data of rCVD, both prospective and retrospective cases will be collected [2-6]. A minimal set of neuroradiological data T2/PD- Weight and/or FLAIR and/or T1 and T2*weighted sequences, Gradient Echo -GE/Susceptibility Weighted images -SWI, Diffusion Weighted Images (DWI) will be required for each MRI scan for neuroimaging standardization (U3). To provide anonymization and standardization guarantees, the database will be built by using a secure web application for building and managing databases (i.e REDCap-Research Electronic Data Capture) [20]. This database will allow the input of data from multiple institutions over a secure web connection with authentication and data logging. Automated export procedures will be also used to homogenize ongoing and already set up databases on rCVD of other informatic formats (i.e Excel, Access). A biological dataset will be created including data from different biological samples of rCVD patients (DNA, plasma, CSF, cellular and tissue specimens). It will integrate data both of existing biological datasets and of newly performed exploratory and validation analyses (mRNA expression, proteomic/metabolomic and lipidomic) on different biological samples from rCVD patients and healthy donors (HD), to identify relevant molecular features across omics scales, as foreseen by the ALIGNED project. For gene expression (GE) analyses, we will use preconfigured, off-the-shelf, 96-384-well plates microfluidic inventoried cards targeting relevant genes for specific biological pathways/processes of rCVD. The arising dataset will be deposited in the GEO repository including the transcriptional profiles of samples deriving from rCVD patients analyzed by Gene Set Enrichment Analysis [21] and by Metabolizer software [22], to define enriched hallmark gene sets and the metabolic modules in GE profiles [23]. For proteomics, as the outstanding dynamic range of plasma proteins, which covers more than 10 orders of magnitude, places substantial limits for mass spectrometry (MS)-based proteomic platforms, we will employ affinity-based proteomic technologies based on the proximity extension assay (PEA), which merges qRT- PCR with multiplex immunoassays. The basis of PEA is a dual recognition of a targeted biomarker through a matched pair of antibodies labeled with unique DNA oligonucleotides. Biomarker-specific DNA barcodes are quantified by microfluidic qPCR allowing for high-throughput relative quantification of up to 1161 human plasma proteins using a few microliters of biofluids. The identification and relative quantification of lipids will be obtained by comparing experimental data with LipidBlast spectra library and by using, for data analysis, MS-DIAL software.

A complete communication platform, plus the hands-on support of the already existing telemedicine software, including a cloud-based features for hospitals, medical practices, and other healthcare networks will be implemented to share clinical, neuroradiological and biological data, according to privacy rules (GDPR).

Statistic plan

Based on the known cohorts of patients followed by the involved centers [2-6], the number of patients expected to be enrolled in the registry (task 1.2) is estimated to be at least 500. Such a number of patients is considered sufficient in order to describe the natural history of rCVD patients.

Some indicators will be established to assess the reliability of applied procedures and guidelines as well as to assess the efficacy of the network. The number of access reduction, the medium time needed for a definite diagnosis, the number of patients achieving a diagnosis or for whom it is necessary a diagnostic revision or implementation of further investigation and/or pharmacological and/or neurosurgical intervention will be evaluated during a sample period of 14 months of the ALIGNED project and compared to 2018 and 2019 (pre-COVID-19). The number of patients lost al follow up in the the two

examined period will be also evaluated to assess the efficacy of the network implementation. The time for diagnosis or treatment for the two compared periods will be assessed based on the data taken from Regional and National Health Service System, regarding waiting list time for visits and exams.

Assuming a one-sided t-test type I error of 5% and a power of 80%, to detect a significant absolute improvement of at least 5% in the above mentioned variables (i.e. reduction of the medium time needed for a definite diagnosis from 180 days to 171 days -null hypothesis H0: Difference<9 vs alternative hypothesis H1: Difference>=9-, assuming a common standard deviation of 54), a sample of 892 patients (446 per group) is needed.

Statistical analysis

Since the rCVD are rare and the models of ALIGNED project on procedure standardization, networking and IT platform implementation have no comparative references, only descriptive statistics will be applied. Descriptive statistics will be provided in term of absolute numbers and percentages for categorical data, means with standard deviations (SDs) and medians with value ranges for continuous data. Data analyses were performed using Student -test for continuous variables, chi-square tests for categorical variables, and Xxxxxxx exact tests. A value of <0.05 was considered statistically significant. Bivariate analyses will be performed to evaluate the number of access, the medium time for a definite diagnosis, the number of patients achieving a diagnosis or needing a diagnostic revision and/or implementation of further investigation and/or treatment as well as the number of patients lost al follow up. This analysis will be performed comparing a sample period of 14 months of the study in comparison to an equal period of 2018 and 2019 (pre-COVID-19). Logistic regression models with stepwise selection were used to determine the patient factors associated with disability and/or mortality during the project time periods.

The statistical analysis of biological data will be oriented to evidence the differences in gene/protein/lipid expression between healthy and pathological phenotypes. For transcriptomics, the relative level of mRNA will be calculated by the 2- DDCt comparative method using the different specific housekeeping genes included in TaqMan Arrays. The GE analysis will be performed with BIORAD CFX Manager software (BIORAD, USA). All statistical analyses of deriving data will be performed using GraphPad Prism 5 and 8 (GraphPad Software, USA). The unpaired Student t test, one-way and two-way analysis of variance (ANOVA) followed by Bonferroni correction will be employed for evaluating significance in difference of means between groups, and values of p < 0.05 will be considered significant. For proteomics, data will be processed with Progenesis Qi for protein identification and statistical analysis. For lipidomics, the different classes will be compared by univariate tests. Then, for biomarker discovery, data will be uploaded and processed for multifactorial analysis with MetaboAnalyst. Partial least squares discriminant analysis (PLS-DA) will be performed in order to increase the group separation, and investigate the variables with a VIP score >1, which will be considered as a potential biomarker of the disease. In a second step, a quantitative targeted LC-MS/MS analysis will be directed to the determination of low abundant lipid species - such as free sphingoid base profile (sphingolipidomics) - as previously described in preliminary data xx Xxxxxxxx arteriopathy. Uni- and multi-variate (machine learning) feature selection will be applied on identified biomarkers to devise a prognostic model by comparing clinical and neuroimaging patients' phenotype.

Timing of analysis data

DURATION OF THE STUDY: 24 MONTHS

TASK 1: TO CREATE AN ITALIAN NETWORK OF CENTERS DEDICATED TO RCVD CARE AND TO COLLECT LARGE CASE SERIES OF PATIENTS AFFECTED BY RCVD.

1.1 CENTER RECRUITMENT, PROJECT ORGANIZATION 1-6 months

1.1.1 To increase the number of center with expertise in rCVD in the south of Italy 1-6 months

1.2 DEVELOPMENT A NEW, UNIQUE AND LARGE REGISTRY ON RCVD.

1.2.1 Registry implementation 1-6 months

1.2.1 Duration of patients enrollment 6-20 months

TASK 2: TO DEVELOP STANDARDIZED METHODOLOGIES, SCIENTIFIC VALIDATION PROCEDURES AND TO MOLECULAR CHARACTERIZE RCVD

2.1 SHARING AND STANDARDIZATION OF METHODOLOGIES AND PROCEDURES AMONG NETWORK CENTERS

2.1.1 Surveys and in site visit 1-8 months

2.1.1 Standardized procedures implementation 9-20 months

2.2 TO CREATE AND NETWORK TWO BIOBANKS DEDICATED TO RCVD 1-8 months

2.3 DEPICTING RCVD MOLECULAR SIGNATURES BY UNTARGETED TRANSCRIPTOMIC, PROTEOMIC, METABOLOMIC AND LIPIDOMIC APPROACHES (DISCOVERY PHASE)

2.3.1 Untargeted/targeted transcriptomics 12-20 months

2.3.2 Untargeted/targeted proteomics 12-20 months

2.3.3 Untargeted/targeted metabolomics 12-20 months

2.3.4 Untargeted/targeted lipidomics 12-20 months

2.4 VALIDATION KEY AND RELIABLE CIRCULATING RCVD BIOMARKERS (VALIDATION PHASE) 16-22 months

TASK 3: TO DEVELOP A MULTI-SPECIALISTIC AND MULTICENTRIC VIRTUAL MODEL OF CARE SPECIFIC FOR RCVD

3.1 PLATFORM FOR CLINICAL AND BIOLOGICAL DATA SHARING (VIRTUAL HOSPITAL) IMPLEMENTATION 1-8 months

3.2 CREATE MULTIDISCIPLINARY TEAMS DEDICATED TO EACH SPECIFIC RCVD

3.2.1 Center recruitment, registry implementation and project organization 1-6 months

3.2.2 Study protocol and Ethical Committee procedures 1-6 months

3.3 SUPPORT THE SCIENTIFIC EXCHANGE ACROSS CENTERS 10-23 months STATISTICAL ANALYSIS

Result statical analysis 18-23 months

MANAGEMENT OF THE OVERALL PROJECT WORK PLAN

Consortium agreement and data management plan 9-24 months Provision of periodical scientific reports: 6;12;18;24 months Organization of project (starting and kick-off) meetings: 12; 24 months

DISSEMINATION 20-24 months

5.6 Expected outcomes

Aim1: TO CREATE A NETWORK OF CENTERS WITH EXPERTISE IN RCVD throughout ITALY.

Through the ALIGNED project, we would like to make the effort to strengthen cooperation not only in research, but also at health care level to improve the diagnostic and therapeutic pathways. The project will promote the creation of a network, connecting experts and researchers from nationally dispersed hospitals, promptly ensuring the highest available quality of

care also to rural areas. It is expected to decrease patients' travels to secondary or tertiary centers, then reducing their difficulties and expenditures but also the waiting lists and costs for the National Health System. Through the ALIGNED project, peripheral hospitals would easily interact with the most experienced Italian centers. This will represent an advantage not only for healthcare professionals but, above all, for patients, who will no longer have the need to physically move to third-level healthcare facilities to obtain a diagnosis.

Aim2: TO IMPLEMENT A LARGE DATASET OF CLINICAL DATA AND MOLECULAR MARKERS OF RCVD PATIENTS.

Coordination of the activities of academic researchers and healthcare professionals throughout Italy will contribute to creating common registries and databases with extensive collection, and if required exchange, of samples, clinical data and neuroradiological pictures. This secure data exchange will include anonymized clinical, neuroradiological and molecular data. The close collaboration between all the centers involved in the ALIGNED project should both mitigate the problem of discrepancies in practiced standards, and ensure harmonized and uniform data collection. The database will facilitate the collection of data from samples and clinical history of the patients in order to accelerate the research on these diseases, to understand the clinical history of rCVD and facilitate the enrolling in clinical trials for new and more suitable treatment options. The integration of a strongly phenotype-oriented approach with experimental data originated by innovative and highly sensitive/specific multi-omic techniques will maximize the chance of identifying the most critical biological disease drivers to develop patient-specific predictive models useful for tailored interventions. Untargeted/targeted transcriptomic, proteomic, metabolomic and lipidomic profiling will contribute to discovering putative biomarkers with the ultimate goal of identifying novel therapeutic targets/new targeted molecules to limit rCVD progression.

Aim3: TO IMPROVE THE LEVEL OF CARE OF RCVD OVERALL ITALY BY STANDARDIZING METHODOLOGIES AND SHARING DATA AMONG NETWORK CENTERS

The ALIGNED project aims at standardizing the diagnostic and therapeutic protocols adopted by referral centers in Italy for rCVDs. By this project, discrepancies will be reduced and patients will be able to access highly specialized care without incurring travel expenses to reach hospitals far from their residence. A further goal is to equalize the distribution of resources and expertise throughout the territory, in order to allow equality of treatment even for patients living in more remote territories. In this regard, southern Italy has always been penalized. In ALIGNED project there is specifical interest in providing this part of Italy with a high-level center in close partnership with other centers in central northern Italy. A key contribution to uniformity will be the sharing of opinions and experience. This will be made possible through an IT platform and a shared database. The digital platform will enable the sharing of patient data, in a completely protected and secure way, and would respond to the increasingly present need for modernization and computerization of healthcare facilities.

5.7 Risk analysis, possible problems and solutions

1. Lack of adherence to the project by other centers (Task 1). The creation of this network of centers may take time to be approved and shared. Therefore, the duration of the phase to include centers interested in taking part in it will be extended.

2. Non-homogeneous diagnostic and therapeutic protocols in different centers (Task 1). Although the ALIGNED project is aimed at integrating and standardizing diagnostic and treatment pathways, procedures may remain extremely different and the methodologies transfer may be limited. To overcome this possible limit, during the entire course of the study, the coordinator center will be available for remote consultancy and in site visits to try to solve any organizational problem.

3. Reduced sample size (Task 1). rCVDs are by definition low-prevalence diseases. Therefore, the recruitment of a limited sample size population could be possible. Through an excellent partnership with other international institutes involved in rCVD care, FINCB (UO1) will make it possible to expand the pool of patients recruited and analyze data from an enlarged patient populations.

4. Heterogeneity of collected data (Task 1 and 2). Performing biological examinations in different laboratories and radiological studies in different facilities poses a potential risk of heterogeneity. To overcome this risk, periodic quality control will be carried out by the U1 and U4 centers at each stage of data collection to ensure compliance with the protocol.

The database will be periodically reviewed for completeness and accuracy by trained staff. Spot checks will be conducted throughout the duration of the study to detect any critical issues. If any acquisition or recording errors are found, the data will be verified and corrected; if this is not possible, the subject cannot be considered in the final analyses

5. Lack of suitable approaches for exploratory and validation phase (Task 2.4). If biochemical assays and/or immunoenzymatic methods are not commercially available, targeted MS approaches based on multiple reaction monitoring of proteotypic peptides/metabolites will be developed. Briefly, the selected reaction monitoring (SRM)/multiple reaction monitoring (MRM) approach used in tandem MS on a triple quadrupole mass spectrometer applied to proteins allows a fine detection of peptides, derived from a protein of interest, with a high level of specificity and sensitivity. Indeed, MRM reproducibly measures the concentration of multiple analytes when stable isotope-labeled internal standards are included in the workflow [24].

6. Inadequate performance of IT platform (Task 3). The U1 coordinating center and its IT experts will be available for remote consultation to solve any IT problems. Reports of critical issues and problems related to the use of the platform will be collected and analyzed in order to produce timely solutions. User input and suggestions will be crucial to improve the platform and database for the purpose of long-lasting data collection.

7. Lack of uniform presence of high medical and neuroradiological expertise (Task 3). The ALIGNED project will enable the sharing of expertise and technology through the use of virtual platforms and shared databases. Should it be necessary to vicariate to the lack of particular knowledge or expertise, the virtual platform will allow collegial discussion of difficult or atypical clinical cases. In this way physicians with longer experience or more specialized training will be able to contribute to the professional growth of other colleagues. Radiological images can also be shared using the same system, allowing them to be reviewed by multiple experts.

5.8 Significance and Innovation

Since rCVD are chronic and life-threatening diseases, their diagnosis and specific care is fundamental to avoid disability. However, rCVD management is often heterogeneous due to the paucity of data and the lack of expertise and is reserved in a few referral centers, mostly located in the north or center of Italy [19]. By (i) creating a network of italian centers interested in rCVD care and research (ii) implementing a big rCVD dataset of clinical, neuroimaging and biological data (iii) sharing/standardizing the existing technologies and procedures and the most advanced multi omics tools (iv) creating an IT platform for data and expertise sharing, ALIGNED project will deliver innovation and interdisciplinary exchange across centers. This widespread network will favor an equal access to diagnostic and care pathways to rCVD patients, the valorization and optimization of resources, leading to the reduction of the occurrence of devastating strokes, long-term sequelae and the rCVD burden.

5.9 Bibliography

1.Caulo 2019; doi: 10.1007/s00234-018-2139-5

2.Bersano 2016; doi: 10.1016/j.jns.2016.03.011.

3.Bersano 2019; doi: 10.1007/s10072-018-3664-z

4.Bersano 2018; doi: 10.1007/s00415-018-9072-8

5.Bersano 2016; doi: 10.1161/STROKEAHA.115.012281

6.Sacco 2022; doi: 10.1007/s10072-021-05615-2.

7.Xxxxx 2009; doi: 10.1161/STROKEAHA.108.523209

8.Xxxxx 2017; doi: 10.1161/STROKEAHA.116.015417

9.xxxxx://xxx-xxxxxxxxxxxxxx.xxx/xxxxxx-xxxxxxxx/xxxxxxx-xxxxxx-xxxxxxxx-xxxxxxx, July 6, 2022

10.xxxxx://xxx-xxx.xxx, July 6, 2022

11.xxxxx://xxx.xxxxxxxxxxxxxxxxx.xx/xx/xxxxxxxxx/xxxxxxx-xxxxxxxxx/xxxxxxxxxxx, July 6, 2022

12.xxxxx://xxxx.xx, July 6, 2022

13.COE, xxxxx://xxxxxx.xxx.xxx/xx/Xxxxx/xxxxxx_xxxxxxx.xxxx?XxxxxxXxx000000000000x000, July 6, 2022 14.Pontremoli 2018; doi: 10.1038/s41598-018-35119-7

15.Banfi doi: 10.1038/s42003-021-02630-z

16.Brioschi 2021; doi: 10.3390/ijms22020838 17.Dei Cas 2021; doi: 10.3390/ijms222413410

18.NOVHO Neuro Virtual Hospital: Modello per la gestione dei pazienti neurologici fragili durante l'emergenza COVID-19 ed eventuali epidemie future, Regione Lombardia, Fondo Europeo di Sviluppo Regionale POR-FERS 2014-2020

19.Bersano 2021; doi: 10.1007/s00415-020-09836-x

20.xxxxx://xxx.xxxxxxx-xxxxxx.xxx, July 6, 2022 21.Xxxxxxxxxxx 2005; doi: 10.1073/pnas.0506580102 22.xxxx://xxxxxxxxxxx.xxxxxxxxxx.xxx/, July 6, 2022 23.Çubuk 2019; doi: 10.1038/s41540-019-0087

24. Porro 2022; doi:10.3390/ijms23031136 25.xxxxx://xxx.xxxxx.xxx/xxxxxx-xxxxx/xx/ 26.xxxxx://xxx-xxx.xxx/xxxxxx-xxxxxxx/Xxxx 6, 2022

27.Xxxxxxxx 2021; doi: 10.1007/s10072-021-05252-9

28.Sacco 2021; doi: 10.1089/tmj.2021.0414.

29.Xxxxxxxx 2021; doi: 10.1177/0000000X000000000

30.Xxxxxxxx 2019; doi: 10.1177/1357633X19871403

31.Salami 2015; doi: 10.1200/JOP.2014.000679

32.Xxxxx 2013; doi: 10.1038/bjc.2013.231

33.Sidpra 2020; doi: 10.21037/qims-20-638 34.Xxxxxxxxxx 2022; xxx.xxx/00.0000/x00000-000-00000 35.xxxxx://xxx.xxxxxx.xxx.xx/xxxxxxx/xxxx.xxxx

5.10 Timeline / Deliverables / Payable Milestones

Step1 TO CREATE AN ITALIAN NETWORK OF RCVD CARE CENTERS

D1.1 Recruitment of center with interest in rCVD care

D1.2 Identification of experts/new neurologist for rCVD care D1.3 Preliminary results report

Step2 TO IMPLEMENT A LARGE DATASET OF CLINICAL DATA AND MOLECULAR MARKERS OF RCVD PATIENTS

D2.1 Database and bio-bank creation D2.2 Harmonization of existing data

D2.3 New patient clinical, neuroradiological and biological data collection D2.4 Statistical analysis and prediction models

D2.5: Report on clinical, neuroradiological and biological data

Step3 TO IMPROVE THE LEVEL OF CARE OF RCVD OVERALL ITALY BY STANDARDIZING METHODOLOGIES AND SHARING DATA AMONG NETWORK CENTERS

D3.1: Procedures and techniques survey result

D3.2 Procedures, techniques pathways standardization D3.3 IT platform implementation

D3.4 Case discussion report Step4: DISSEMINATION

D4.1: Meeting for dissemination of the final results

D4.2: Publication of the final results on peer reviewed international journals

Milestones 12 month

Center Recruitment, Project Organization: 1-6 months Development of a large registry of rCVD: 1-6 months

Survey of existing methodologies and procedures among network centers 1-8months To create and network two biobanks dedicated to rCVD: 1-8 months

Study protocol and Ethical Committee procedures: 1-6 months

Milestones 24 month

Standardized procedures implementation: 9-20 months

Molecular signature identification by untargeted Transcriptomic, Proteomic, Metabolomic and Lipidomic approaches (Discovery study): 12-20 months

Molecular signature validation by untargeted Transcriptomic, Proteomic, Metabolomic and Lipidomic approaches (Validation study): 12-20 months

Patients Enrollment: 6-20 months

Result of statistical analysis: 18-23 months Management of the overall project workplan

Consortium agreement and data management plan achievement:9-24 months Provision of periodical scientific reports: 6;12;18; 24 months

Organization of project (starting and kick-off) meetings: 12; 24 months

Gantt chart

gantt - PERT.pdf

5.11 Equipment and resources available

Facilities Available

FINCB is an international center of excellence in the field of rare neurological diseases and will coordinate the project (U1). Excellent diagnosis/treatment and management programs are available for rare/complex pathologies requiring expertise, diagnostic skill, advanced approaches and innovative technology. A telehealth platform, certified as class IIa medical device according to European regulamentation, is available and already used for teleconsulations [25].The Laboratory of Genetics is equipped with Illumina NextSeq500, MiSeq apparatus, Bioanalyzer 2100, ABI3130XL Automated Genetic Analyzer.

Software for data analysis (MiSeq Reporter software-Illumina), alignment and variant calling (VariantStudio software- Illumina), quality control and coverage analysis (CLC Genomics Workbench CLCbioQiagen) are available. LC-MS/MS and GC-MS and a mass spectrometry platform are available. The Neurobiology Laboratory includes cell culture (laminar flow hoods, fluorescence microscopes, incubators, FACSCalibur-cytometer), molecular biology (Qubit/Nanodrop, ThermalCyclerGradient-Eppendorf, CFX-96 qRT-PCR Biorad; 7900HT Fast RT-PCR System, QuantStudioTM 12K Flex

RT-PCR System, QuantStudio3D DigitalPCRSystem), and biochemistry instrumentations (spectrophotometer/densitometer, ELISA fluorometers, Bio-Plex 200 System, TransBlot Turbo, ChemiDoc). LC-MS/MS with a Shimadzu HPLC coupled with a Triple TOF 6600 Sciex equipped with Turbo Spray IonDrive is reserved for lipidomics.U2 includes a cell culture/histology area, direct and indirect microscopes, PALM laser microdissector, cell sorters, molecular biology tools and a mass spectrometry core lab for label-free quantitative proteomics and lipidomics (Synapt MS hybrid quadrupole TOF, 6550 iFunnel Q-TOF LC/MS) and for targeted protein and metabolite quantitation (Xevo TQS Micro, TSQ Quantum Access Quadrupole, Q-Trap 5500 system). U3 is equipped with 4 high field MR scanners, 3 helical multi-slice CT, 3 echo-doppler and 1 angiographic suite, and it has a RIS-PACS platform for storing/sharing diagnostic imaging data from centers involved in the project. U4 will serve as the referral center for patient care and for research activities in South Italy. U4, being a

founding and leading center in the Italian Stroke Research Network [9-10] and the coordinator of a national study (READAPT study) [26] involving more than 70 Stroke Units, will promote interaction with Italian stroke centers to build a network of referral for rCVD patients

Subcontract

5.12 Desc. of the complementarity and sinergy of secondary collab. researchers

U1 has a wide experience in cerebrovascular diseases and stroke genetics, implemented standardised diagnostic and therapeutic pathways for most rare diseases and developed big datasets of Moyamoya and CADASIL patients. U1 has available the facility of the Neurobiology Laboratory -with expertise in molecular biology and neurovascular biomarker identification (see preliminary data). Dr. Xxx xx Xxxxxx (Laboratory of Neurological Biochemistry and Neuropharmacology, Diagnostic and Imaging Department), and Dr. Xxxxxxx Xxxxxx (Unit of Medical Genetics and Neurogenetics) will participate as secondary collaborator researchers. Their Labs are equipped with LC-MS/MS and GS-MS instruments giving us availability and expertise of a mass spectrometry platform and of targeted exogenous and endogenous compound analyses.

U2 is a referral national Scientific and Clinical Institute highly specialized in cardiovascular diseases. U2 applies cutting- edge mass spectrometry based approaches to samples (tissue, plasma, vesicles, circulating cells, etc) to uncover new diagnostic biomarkers and therapeutic targets. UO2 has expertise in genomic, transcriptomic, proteomics, metabolomics, and lipidomics, handling, and storage of human biologic material, human genetic polymorphisms, stem cell generation, and virus vectored gene transfer. Equipment available include a cell culture area, histology equipment, direct and indirect microscopes, PALM laser microdissector, cell sorters, molecular biology tools, and a mass spectrometry core lab for label- free quantitative proteomics and lipidomics (Synapt MS hybrid quadrupole TOF, 6550 iFunnel Q-TOF LC/MS) and for targeted protein and metabolite quantitation (Xevo TQS Micro, TSQ Quantum Access Quadrupole, Q-Trap 5500 system). U3 3 has a long experience in diagnostic neuroradiology in particular in the multimodal integration of conventional and advanced MRI techniques in tumor, vascular and inflammatory disease of adult and pediatric patients. U3 is equipped with 4 high field MR scanners, 3 helical multi-slice CT, 3 echo-doppler and 1 angiographic suite and has a weekly outpatient service of MRI examinations dedicated to patients with cerebrovascular disease (approximately 500 pts/year). U3 is able to process structural and functional MR data and to use AI algorithms to assist diagnosis. U3 has a RIS-PACS platform capable of storing and sharing diagnostic imaging data from centers participating in the project.

U4 has a long-standing solid experience in stroke research and care. From 2011 U4 is dealing a large population-based

stroke registry (5187 cases), which may represent the source to select some patients who were already diagnosed with rCVD. Basing on the existing expertise developed with the stroke registry, U4 will contribute to collect patients and develop the clinical database of rCVD. U4 is also leading a national study on secondary prevention in minor stroke and TIA, involving more than 110 centers, who admit patients with stroke across all the Italian territory. This ongoing research network, including a large number of centers caring patients with stroke, will favor the development of a connection specifically dedicated to patients with rCVD.U4 has the availability of all the research infrastructure, personnel and skills to provide care for patients with rCVD and to facilitate research activities in this context.

5.13 Translational relevance and impact for the national health system (SSN)

What is already know about this topic?

Rare cerebrovascular disease are underestimated and poor studied causes of stroke. However, their diagnosis is important to avoid inappropriate and expensive diagnostic tests, to establish appropriate management measures, including presymptomatic testing, genetic counseling, and, if available, therapy (PMID: 32318851). Several reports showed how great is the economic burden of rare diseases based on direct, indirect, and mortality-related costs. For many patients with rare diseases, including rCVD, their diagnostic odyssey involves the access to multiple clinical centers, often limited by distance

problems. Therefore,the access to adequate care pathways is often limited for a number of patients. The recent pandemic experience further exacerbated difficulties in care of chronic diseases leading to the development of alternative models of care (i.e telemedicine), allowing to follow up patients avoiding contagion (PMID: 33929645).

Details on what is already know about this topic

Although rare, heritable and acquired CVD have to be considered in the differential diagnosis of stroke, since they are probably underestimated/misdiagnosed, due to the variable penetrance and expressivity. The diagnosis of rCVD is difficult, often requiring access to multiple clinical centers and expensive diagnostic examinations. Moreover, the care of these patients, who often present with associated systemic symptoms, requires a multidisciplinary and specific management, possible in few referral centers [19]. Telemedicine has grown exponentially in the last few years and its use has been accelerated by the recent COVID-19 pandemic, which challenged traditional health care delivery curtailing non-emergent care at hospitals. Evidence regarding effectiveness and safety of telemedicine were shown across a range of medical disciplines [27-28]. Virtual meetings have also been shown to break down waiting time for the complex cases diagnosis and treatment [29-33].

What this reasearch adds?

The total absence at present of a network of referral centers for rCVD produces organizational dysfunction, mismanagement of public expenditure, and haphazard patient management. ALIGNED study is innovative in two substantial areas: scientific research and health expenditure management. With regard to the first point, the management of data of all Italian patients in a single, uniform database will allow a deeper understanding of rCVD in different fields of research: clinical, neuroradiological, and biomolecular. This will undoubtedly spur the initiation of further clinical studies and open up the possibility of identifying causes and possible cures for rCVD. Regarding innovation in the management area, the creation of a national, widespread network throughout Italy will lower the costs of repeating many examinations, transfer knowledge and harmonize executive protocols overcoming the lack of expertise of some peripheral hospitals.

Details on what this reasearch adds

To date, the management of rCVDs in Italy is unevenly distributed throughout the country [34]. Not only is there a substantial gap between southern and northern Italy, but even within the same region. As the name suggests, the ALIGNED study aims to align the diagnostic and therapeutic protocols used in hospitals in our country, to ensure equity in access to medical care for all rCVD Italian patients. More evenly distributed access to care will allow substantial savings in public and private spending. Furthermore, there is to date no effective treatment for rCVDs. This is due to the rarity of the disease and the lack of homogeneous and shared databases, often managed locally, which make it impractical to perform large-scale pharmacological trials. By creating a network of reference centers, the ALIGNED study will allow the collection of numerous clinical and instrumental data, improving the understanding of rCVDs and the implementation of large clinical trials.

What are the implications for public health, clinical practice, patient care?

The uneven distribution of rCVD referral centers forces many patients to seek medical care in other regions, resulting in significant costs for the citizen and an inconsistent distribution of treatment options. This situation highlights a substantial flaw in the national public health care system, whose fundamental principles are universality, equality and equity. The project will promote the development of a multidisciplinary and multi-centric model of care for rCVD patients in Italy. With this national model the experience of secondary or tertiary centers will be promptly available for all Italian patients increasing efficiency, ensuring quality and optimizing resources of rCVD care, potentially lowering the overall disease burden and National Health System (SSN) costs.

Details on what are the implications for public health, clinical practice, patient care

The SSN is a system of facilities and services aimed at guaranteeing universal and equal health care access to all citizens without distinction of individual, social and economic conditions [35]. The ALIGNED study fits into this paradigm equalizing

access to care for patients with rCVDs, by harmonizing procedures, diagnosis and treatment protocols. This harmonization will produce significant savings in public spending and resource optimization in the country delivering uniform quality of diagnosis and treatment. The widespread availability of homogeneous advanced technologies throughout the territory will allow patients to avoid long and expensive trips far from home. In addition, the availability of the same examination in several locations in Italy will make it possible to alleviate the waiting lists of a few individual centers often located in the northern part of our peninsula. Setting-up a registry of patients with rCVD will favor national and international research collaboration.

6 - Budget

Total proposed budget ( Euro )
Costs	TOTAL BUDGET	Co-Funding	List of costs proposed for funding to the MOH	Percentage of total proposed to the MOH
1 Staff Salary	132.841,00	132.841,00	not permitted	0,00
2 Researchers' Contracts	401.000,00	0,00	401.000,00	40,10
3a.1 Equipment (Leasing -	0,00	0,00	0,00	0,00
3a.2 Equipment (buying)	10.000,00	0,00	10.000,00	1,00
3b Supplies	239.000,00	0,00	239.000,00	23,90
3c Model Costs	0,00	0,00	0,00	0,00
4 Subcontracts *	0,00	0,00	0,00	0,00
5 Patient Costs	100.000,00	0,00	100.000,00	10,00
6 IT Services and Data Bases	120.000,00	0,00	120.000,00	12,00
7 Travels	25.000,00	0,00	25.000,00	2,50
8 Publication Costs	20.000,00	0,00	20.000,00	2,00
9 Dissemination	13.000,00	0,00	13.000,00	1,30
10 Overheads *	74.298,87	9.298,87	65.000,00	6,50
11 Coordination Costs	7.000,00	0,00	7.000,00	0,70
Total	1.142.139,87	142.139,87	1.000.000,00	100,00

* percentage calculated as average value between all the Operating Units.

Report the Co-Funding Contributor:

Budget Justification
1 Staff Salary	U1 BESTA: PI 2P/M; CO-PI 4P/M; Collaborator senior neurologist 2P/M; Collaborator junior neurosurgeon 2P/M; Collaborator senior biologist 1P/M U2: PI 4P/M U3: PI 2P/M U4: PI 2P/M
2 Researchers' Contracts	U1 1 fellowship for a statistician 2y ;1 fellowship for a p. manager 2 y; 1 res collaborator for 2y U2: 1 fellowship for a biologist for 2y; U3 : 1 res contract 2 y; U4: 1 res. contract 2y; 2 fellowship for a p. manager 2 y
3a.1 Equipment (Leasing - Rent)	NA

3a.2 Equipment (buying)	U1: Fluorescence Microscope for live cell imaging; Nanophotometer
3b Supplies	U1: consumables for cell/clood/tissue/CSF cryobanking; qRT-PCR reagents; lipidomics reagents/chemicals U2:proteomic and metabolomics analysis by mass spectrometry-based and ligation approaches U3/U4:biological sample collection and storage
3c Model Costs	NA
4 Subcontracts	NA
5 Patient Costs	database-implementation and quality control; patient recruitment; neuropsychological-neuroradiological(i.e PWI, DWI, FC)neuoropthalmological evaluation; CSF, genetic and vasculitic screening
6 IT Services and Data Bases	Telehealth platform implementation allowing multidisciplinar connection and uploading different type of file, such as laboratory tests, reports, radiological images (standard Dicom supported)
7 Travels	U1: travel cost for 1 meeting/2 person/year U2: travel cost for 1 meeting in Italy-Europe/1 person U3: travel cost for 1 meeting/2 person/year U4: travel cost for 1 meeting/2 person/year
8 Publication Costs	publication costs (open access fees, language revision etc), reprints, journal subscriptions, books
9 Dissemination	U1: attendance costs for 1 meeting/2 person/year U2: attendance costs for 1 meeting/1 person/year U3: attendance costs for 1 meeting/1 person/year U4: attendance costs for 1 meeting/2 person/year
10 Overheads	project workplan and management (administrative and scientific)
11 Coordination Costs	UO meetings (kick-off meeting between the UOs) sample shipment;

Proposed total budget UO1 Institution: Fondazione Istituto Neurologico Xxxxx Xxxxx (Euro)

Costs	TOTAL BUDGET	Co-Funding	List of costs proposed for funding to the MOH	Percentage of total proposed to the MOH
1 Staff Salary	84.048,00	84.048,00	not permitted	0,00
2 Researchers' Contracts	105.000,00	0,00	105.000,00	27,03
3a.1 Equipment (Leasing - Rent)	0,00	0,00	0,00	0,00
3a.2 Equipment (buying)	10.000,00	0,00	10.000,00	2,57
3b Supplies	90.500,00	0,00	90.500,00	23,30
3c Model Costs	0,00	0,00	0,00	0,00
4 Subcontracts	0,00	0,00	0,00	0,00
5 Patient Costs	80.000,00	0,00	80.000,00	20,59
6 IT Services and Data Bases	50.000,00	0,00	50.000,00	12,87
7 Travels	10.000,00	0,00	10.000,00	2,57
8 Publication Costs	7.000,00	0,00	7.000,00	1,80
9 Dissemination	4.000,00	0,00	4.000,00	1,03
10 Overheads	30.878,36	5.883,36	24.995,00	6,43
11 Coordination Costs	7.000,00	0,00	7.000,00	1,80
Total	478.426,36	89.931,36	388.495,00	100,00

Budget Justification
1 Staff Salary	PI 2P/M; CO-PI 4P/M; Collaborator senior neurologist 2P/M; Collaborator junior neurosurgeon 2P/M; Collaborator senior biologist 1P/M
2 Researchers' Contracts	1 fellowship for a junior statistician for 2 y ; 1 fellowship for a senior project manager for 2 y; 1 research collaborator for 2 y
3a.1 Equipment (Leasing - Rent)	NA
3a.2 Equipment (buying)	Fluorescence Microscope for live cell imaging; Nanophotometer
3b Supplies	consumables for cell/clood/tissue/CSF cryobanking; qRT-PCR reagents (QIAGEN RNeasy Fibrous and Lipid Tissue extraction and retrotranscription kits, TaqMan assays, microfluidic inventoriedTaqMan array cards); lipidomics reagents/chemicals
3c Model Costs	NA
4 Subcontracts	NA
5 Patient Costs	database-implementation and quality control; patient recruitment; neuropsychological-neuroradiological (cerebral MRI, MRA, CT perfusion, NOVA-MRI, ultrasound vascular reserve study-neuoropthalmological evaluation; CSF, genetic and vasculitic screening
6 IT Services and Data Bases	Telehealth platform implementation allowing multidisciplinar connection and uploading different type of file, such as laboratory tests, reports, radiological images (standard Dicom supported)
7 Travels	travel cost for 1 meeting/2 person/year
8 Publication Costs	publication costs (open access fees, language revision etc), reprints, journal subscriptions, books
9 Dissemination	attendance costs for 1 meeting/2 person/year
10 Overheads	project workplan and management (administrative and scientific)
11 Coordination Costs	UO meetings (kick-off meeting between the UOs), sample shipment

Proposed total budget UO2 Institution: Centro Cardiologico Monzino IRCCS (Euro)

Costs	TOTAL BUDGET	Co-Funding	List of costs proposed for funding to the MOH	Percentage of total proposed to the MOH
1 Staff Salary	13.500,00	13.500,00	not permitted	0,00
2 Researchers' Contracts	40.000,00	0,00	40.000,00	20,94
3a.1 Equipment (Leasing - Rent)	0,00	0,00	0,00	0,00
3a.2 Equipment (buying)	0,00	0,00	0,00	0,00
3b Supplies	131.500,00	0,00	131.500,00	68,85
3c Model Costs	0,00	0,00	0,00	0,00
4 Subcontracts	0,00	0,00	0,00	0,00
5 Patient Costs	0,00	0,00	0,00	0,00
6 IT Services and Data Bases	0,00	0,00	0,00	0,00
7 Travels	1.000,00	0,00	1.000,00	0,52
8 Publication Costs	3.000,00	0,00	3.000,00	1,57
9 Dissemination	3.000,00	0,00	3.000,00	1,57
10 Overheads	13.440,00	945,00	12.495,00	6,54
11 Coordination Costs	not permitted	not permitted	not permitted	0,00
Total	205.440,00	14.445,00	190.995,00	100,00

Budget Justification
1 Staff Salary	PI 4P/M
2 Researchers' Contracts	1 fellowship for a junior biologist/biotechnologist for 2 y
3a.1 Equipment (Leasing - Rent)	NA
3a.2 Equipment (buying)	NA
3b Supplies	Proteomic and metabolomics analysis by mass spectrometry-based approaches (i.e. HPLC columns, solvents, vial, enzyme for digestion, standards, SPE columns) and proximity ligation assay
3c Model Costs	NA
4 Subcontracts	NA
5 Patient Costs	NA
6 IT Services and Data Bases	NA
7 Travels	travel cost for 1 meeting in Italy-Europe/1 person
8 Publication Costs	publication costs (open access fees, language revision etc), reprints, journal subscriptions, books
9 Dissemination	attendance costs for 1 meeting/1 person/year
10 Overheads	project workplan and management (administrative and scientific)
11 Coordination Costs	NA

Costs	TOTAL BUDGET	Co-Funding	List of costs proposed for funding to the MOH	Percentage of total proposed to the MOH
1 Staff Salary	23.333,00	23.333,00	not permitted	0,00
2 Researchers' Contracts	80.000,00	0,00	80.000,00	49,19
3a.1 Equipment (Leasing - Rent)	0,00	0,00	0,00	0,00
3a.2 Equipment (buying)	0,00	0,00	0,00	0,00
3b Supplies	10.000,00	0,00	10.000,00	6,15
3c Model Costs	0,00	0,00	0,00	0,00
4 Subcontracts	0,00	0,00	0,00	0,00
5 Patient Costs	20.000,00	0,00	20.000,00	12,30
6 IT Services and Data Bases	30.000,00	0,00	30.000,00	18,45
7 Travels	7.000,00	0,00	7.000,00	4,30
8 Publication Costs	3.000,00	0,00	3.000,00	1,84
9 Dissemination	2.000,00	0,00	2.000,00	1,23
10 Overheads	12.273,31	1.633,31	10.640,00	6,54
11 Coordination Costs	not permitted	not permitted	not permitted	0,00
Total	187.606,31	24.966,31	162.640,00	100,00

Proposed total budget UO3 Institution: Azienda Sanitaria Locale ASL2 Abruzzo, Lanciano-Vasto-Chieti (Euro)

Budget Justification
1 Staff Salary	PI 2P/M
2 Researchers' Contracts	1 research contract for dr. Xxxxxxxx Xxxxxxxxxx for 2y
3a.1 Equipment (Leasing - Rent)	NA
3a.2 Equipment (buying)	NA
3b Supplies	biological sample collection and storage
3c Model Costs	NA
4 Subcontracts	NA
5 Patient Costs	PWI, DWI and functional connectivity-FC; MRI techniques; Patient enrollment; clinical data-base; sample collection; virtual hospital
6 IT Services and Data Bases	Telehealth platform implementation allowing multidisciplinar connection and uploading different type of file, such as laboratory tests, reports, radiological images (standard Dicom supported)
7 Travels	travel cost for 1 meeting/2 person/year
8 Publication Costs	publication costs (open access fees, language revision etc), reprints, journal subscriptions, books
9 Dissemination	attendance costs for 1 meeting/1 p/year
10 Overheads	project workplan and management (administrative and scientific)
11 Coordination Costs	NA

Proposed total budget UO4 Institution: University of L'Aquila (Euro)

Costs	TOTAL BUDGET	Co-Funding	List of costs proposed for funding to the MOH	Percentage of total proposed to the MOH
1 Staff Salary	11.960,00	11.960,00	not permitted	0,00
2 Researchers' Contracts	176.000,00	0,00	176.000,00	68,25
3a.1 Equipment (Leasing - Rent)	0,00	0,00	0,00	0,00
3a.2 Equipment (buying)	0,00	0,00	0,00	0,00
3b Supplies	7.000,00	0,00	7.000,00	2,71
3c Model Costs	0,00	0,00	0,00	0,00
4 Subcontracts	0,00	0,00	0,00	0,00
5 Patient Costs	0,00	0,00	0,00	0,00
6 IT Services and Data Bases	40.000,00	0,00	40.000,00	15,51
7 Travels	7.000,00	0,00	7.000,00	2,71
8 Publication Costs	7.000,00	0,00	7.000,00	2,71
9 Dissemination	4.000,00	0,00	4.000,00	1,55
10 Overheads	17.707,20	837,20	16.870,00	6,54
11 Coordination Costs	not permitted	not permitted	not permitted	0,00
Total	270.667,20	12.797,20	257.870,00	100,00

Budget Justification
1 Staff Salary	PI 2P/M
2 Researchers' Contracts	1 research contract for dr. Xxxxxx Xxxxxx for 2y; 1 fellowship for a junior project manager for 2 y; 1 fellowship for a junior datamanager for 2 y
3a.1 Equipment (Leasing - Rent)	NA
3a.2 Equipment (buying)	NA
3b Supplies	biological sample collection and storage
3c Model Costs	NA
4 Subcontracts	NA
5 Patient Costs	NA
6 IT Services and Data Bases	Telehealth platform implementation allowing multidisciplinar connection and uploading different type of file, such as laboratory tests, reports, radiological images (standard Dicom supported)
7 Travels	travel cost for 1 meeting/2 person/year
8 Publication Costs	publication costs (open access fees, language revision etc), reprints, journal subscriptions, books
9 Dissemination	attendance costs for 1 meeting/2 person/year
10 Overheads	project workplan and management (administrative and scientific)
11 Coordination Costs	NA

Principal Investigator Data

Cognome: bersano Nome: Xxxx Xxxxxx: F

Codice fiscale: XXXXXX00X00X000X Documento: Carta d'identità, Numero: At4904603 Data di nascita: 14/05/1972

Luogo di nascita: GENOVA Provincia di nascita: GE

Indirizzo lavorativo: via celoria 11 Città: MILANO

CAP: 20133

Provincia: MI

Email: xxxx.xxxxxxx@xxxxx.xxx

Altra email: xxxx.xxxxxxx@xxxxxxxx-xxxxx.xx Telefono: x000000000000

Altro telefono: x000000000000 Qualifica: Dirigente Medico Neurologo Struttura: U.O malattie Cerebrovascolari

Istituzione: Fondazione Istituto Neurologico Xxxxx Xxxxx Datore/ente di lavoro? Yes

Datore/ente di lavoro SSN? Yes Nome datore/ente di lavoro non SSN:

Nome istituzione SSN: Fondazione IRCCS Istituto Neurologico Xxxxx Xxxxx Milano Tipo contratto: Lavoro Subordinato a Tempo Indeterminato

Con l'invio della presente proposta si dichiara che la stessa o parti significative di essa non sono oggetto di altri finanziamenti pubblici o privati e che di conseguenza vi è assenza del c.d. doppio finanziamento ai sensi dell'art. 9 del Regolamento (UE) 2021/241, ossia che non ci sia una duplicazione del finanziamento degli stessi costi da parte di altri programmi dell'Unione, nonché con risorse ordinarie da Bilancio statale.

By submitting this proposal, I declare that no significant part or parts of it are recipient of any other public or private funding and that consequently there isn't any so-called double financing pursuant to art. 9 of Regulation (EU) 2021/241, i.e. that there is no duplication in the financing of the same costs by other Euopean Union programs or any other ordinary resources from the State budget.

Project validation result

GANTT CHART

RAre, but not aLone: a large Italian network to empower the impervious diaGNostic pathway of rare cerEbrovascular Diseases (ALIGNED)

AIMS AND TASKS	Months
AIMS AND TASKS	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19	20	21	22	23	24

TASK 1: TO CREATE AN ITALIAN NETWORK OF CENTERS DEDICATED TO RCVD CARE AND TO COLLECT LARGE CASE SERIES OF PATIENTS AFFECTED BY RCVD.
1.1 CENTER RECRUITMENT, PROJECT ORGANIZATION
1.1.1 To increase the number of center with expertise in rCVD in the south of Italy
1.2 DEVELOPMENT OF A NEW, UNIQUE AND LARGE REGISTRY ON RCVD.
1.2.1 Registry implementation
1.2.1 Duration of patients enrollment
TASK 2: TO DEVELOP STANDARDIZED METHODOLOGIES, SCIENTIFIC VALIDATION PROCEDURES AND TO MOLECULAR CHARACTERIZE RCVD
2.1 SHARING AND STANDARDIZATION OF METHODOLOGIES AND PROCEDURES AMONG NETWORK CENTERS
2.1.1 Surveys and in site visit
2.1.1 Standardized procedures implementation
2.2 TO CREATE AND NETWORK TWO BIOBANKS DEDICATED TO RCVD
2.3 DEPICTING RCVD MOLECULAR SIGNATURES BY UNTARGETED TRANSCRIPTOMIC, PROTEOMIC, METABOLOMIC AND LIPIDOMIC APPROACHES (DISCOVERY PHASE)
2.3.1 Untargeted/targeted transcriptomic
2.3.2 Untargeted/targeted proteomic
2.3.3 Untargeted/targeted metabolomic
2.3.4 Untargeted/targeted lipidomic
2.4 VALIDATION OF KEY AND RELIABLE CIRCULATING RCVD BIOMARKERS (VALIDATION PHASE)
TASK 3: TO DEVELOP A MULTI-SPECIALISTIC AND MULTICENTRIC VIRTUAL MODEL OF CARE SPECIFIC FOR RCVD
3.1 PLATFORM FOR CLINICAL AND BIOLOGICAL DATA SHARING (Virtual Hospital) IMPLEMENTATION
3.2 CREATION OF MULTIDISCIPLINARY TEAMS DEDICATED TO EACH SPECIFIC RCVD
3.2.1 Center recruitment, registry implementation and project organization
3.2.2 Study protocol and Ethical Committee procedures
3.3 TO SUPPORT THE SCIENTIFIC EXCHANGE ACROSS CENTERS
STATISTICAL ANALYSIS
MANAGEMENT OF THE OVERALL PROJECT WORKPLAN
CONSORTIUM AGREEMENT AND DATA MANAGEMENT PLAN
PROVISION OF PERIODICAL SCIENTIFIC REPORTS FOLLOWING NATIONAL RULES
ORGANIZATION OF PROJECT (starting and kick-off) MEETINGS
DISSEMINATION

1. Plasma lipid profile of rCVD patients

Figure 1. D. Quantitative evaluation of plasma sphingoid bases in MA patients (MA, n=15) in comparison to age and sex matched healthy donors (HD, n=15). Statistical significance was evaluated by unpaired t- test. P values are schematized as follows: * <0.05; **<0.01.

Figure 1. A) Discriminant analysis (score plot) of the plasmatic lipidome in HD and Moyamoya arteriopathy (MA) patients. In the x-axis, component 1 (PC1, 23.1%) represents the maximum of the separation that can be reached within these clusters and variables, whereas, in the y-axis, component 2 (PC2, 4.6 %) represents the direction that contains the most remaining variance.

B) Heatmap of the lipids highly correlated with the disease (n=175), chosen within those with a Variance Importance in Projection (VIP) score >1.5. The concentrations were autoscaled and log-transformed for visualization. C) Boxplots represent the trends in lipid classes concentrations in HD and MA patients. The boxes represent data obtained in the range 25th-75th percentile; the line across the boxes indicates the median value; the lines above and below the boxes indicate extreme values (10th or 90th percentile). Data were reported as log-transformed and auto- scaled mass intensities (Intensity norm). Statistical significance was evaluated by unpaired t-test. P values are schematized as follows: * <0.05; **<0.01; *** < 0.001; ****<0.0001.

Intensity norm

2. CSF lipid profile of rCVD patients

18:0

Figure 2. A) Discriminant analysis (score plot) of the lipidome in CSF sample of subjects presenting unrelated atherosclerotic cerebrovascular diseases (ACVD) and MA patients. B) Heatmap of the lipids highly correlated with the disease (n=70), chosen within those with a Variance Importance in Projection (VIP) score >1.5, ordered by lipid classes, coded by different colours. C) Different lipid species and lipid class concentrations in ACVD and MA. D) CSF sphingolipids targeted analysis in MA patients (n=5) in comparison to age and sex matched controls with an unrelated disease (n=5). The boxes represent data obtained in the range 25th-75th percentile; the line across the boxes indicates the median value. Statistical significance is evaluated by unpaired t-test. P values are schematized as follows: * <0.05; **<0.01; *** < 0.001; ****<0.0001.

3. Quantitative gene expression profile in STA 4. Angiopoietin-2 concentration in plasma and CSF of rCVD patients

(superficial temporal artery) of rCVD patients

200

150 Relative mRNA quantification

100

50

20

15

10

5

20000

Ang-22 (pg/ml)

15000

10000

5000

XXXXXX

XXXX XX HD

ACVD MA HD

20000

Ang-2 (pg/ml)

15000

10000

5000

CSF

✱✱✱✱

ACVD MA

4

3

1

0.5

XXX-0 (xx00)

XXX0X (xx0)

PDGFRB (n=24)

HIF1a (n=18)

NOTCH1 (n=11)

NOTCH3 (n=16)

RNF213 (n=9)

0

Figure 4. Angiopoietin-2 (Ang-2) concentration in plasma and CSF from MA patients, HD and ACVD subjects was measured by ELISA. Data were expressed as mean ± SD, and statistical significance (**** p < 0.0001) was calculated through Student’s t-test. Values of at least three independent experiments are shown.

1100

00..55

RReelaativvee mmRRNNAA qquuaanntificcaatioonn oof AAnngg-22

5. Quantitative gene expression of Angiopoietin-2 in MCA (middle cerebral artery) of rCVD patients

XXX-0 (xx00) XXX0X ((xxx0) PDGFRB (n=24)

Figure 5. Relative mRNA quantification of

HIF1a ((n=18) RNF213 (n=9)

NOTCH3 (n=16)

NOTCH1 (n=11)

Angiopoietin-2 in MCA (middle cerebral artery) sample in MA patients by qRT-PCR. Expression level of target gene in MCA of ACVD patients is used as calibrator and

Figure 3. Relative mRNA quantification of XXX-0, XXX0X, XXXXXX, XXX0x, XXXXX0, XXXXX0 and RNF213 genes in STA (superficial temporal artery) samples of MA patients, by qRT-PCR. Expression levels of target genes in STA of ACVD patients are used as calibrator and arbitrarily set at 1. β2-microglobulin (β2M) was used as housekeeping gene.

arbitrarily set at 1. β2-microglobulin (β2M) was used as housekeeping gene.

ONGOING REGISTRY ON rCVD COORDINATED BY UO1

The paucity of centers dedicated to rCVD in the south of Italy can be inferred through the map

MOYAMOYA
Clinical features	MA patients (160)
Demographic characteristics
Age at onset (mean yrs)	33.8
Female sex	69.4%
Adults / Children	78.8%/ 21.2%
Index event characteristics
Stroke	54,4%
Ischemic	72,4 %
Heamorrhagic	27,6%
TIA	27%
Other symptoms / signs
Headache	68 (42,5%)
Seizures	40 (26,5%)
Psychiatric Disorders	36 (25%)
Cognitive Deficits	27 (18,6%)
Treatment
Revascularization	47,5%

CADASIL
Clinical features	CADASIL patients (133)
Demographic characteristics
Age at onset (mean yrs)	47.1
Index event characteristics
Stroke	40.3%
Ischemic	82.6%
Heamorrhagic	17.4%
TIA	22,2%
Other symptoms / signs
Headache	40.7%
Psychiatric Disorders	40.8%
Cognitive behaviour problems	35.5%

XXXXXXX
Clinical features	patients (9)
Demographic characteristics
Age at onset (mean yrs)	37.1
Index event characteristics
Stroke	88.8%
Ischemic	100%
Heamorrhagic	0%
TIA	44.4%
Other symptoms / signs
Headache	88.8%
Psychiatric Disorders	11.1%
Cognitive behaviour problems	22.2%

Rare Cerebrovascular Diseases(rCVD) Virtual Hospital

 A web-based platform will be developed to allow physicians to collect and anonymously share patients' data

Referring Physician

Web-based platform

Multidisciplinary Team

The results will be presented to the patient

Accesses to the Hospital

350

300

250

200

150

100

301

160

No virtual Virtual

Mean amount of face-to face consulations

No virtual Virtual

Neuro Virtual Hospital model

100.0%

90.0%

80.0%

70.0%

60.0%

50.0%

40.0%

30.0%

20.0%

10.0%

0.0%

97.5%

27.5%

72.5%

11.4%

21.5%

41.3%

21.3%

This model also gave the opportunity to Referring Physicians to directly plan the exams or surgical/radiotherapy treatments for the patients, without having them to make appointments by themselves

Time to diagnosis (days)

100

No virtual Virtual

With the virtual model, we estimated a reduction of 141 hospital accesses (47.0%)

Diagnosis

Further exams

Our virtual model allowed a reduction of hospital accesses:

Revision of the initial diagnosis

Pharmacological treatment

Non-pharmacological treat...

Exams planning

Treatment planning

The time to receive a defined diagnosis / indication for treatment in patients requiring multidisciplinary evaluation was reduced by 66%

The percentage of patients for whom the virtual discussion provided: a diagnosis, the revision of the initial diagnosis, further exams, pharmacological or non-pharmacological treatment, the organization of the exam or treatment by doctors

• The total amount of face-to-face consultations needed for the cohort of patients enrolled in the study to reach a definite diagnosis with traditional care’s model (No virtual) was 3.8 ±

0.8 for each patient.

• On the contrary with the virtual model, patient had only to be evaluated by his/her Referring Physician, resulting in a mean of 2 accesses each (the consultation before and after the virtual meeting)

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PIANO NAZIONALE DI RIPRESA E RESILIENZA (PNRR) MISSIONE 6 - COMPONENTE 2

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