4° Congresso nazionale Società Italiana Telemedicina e ... · PDF fileTelemedicina...

4° Congresso nazionale Società Italiana Telemedicina e sanità elettronica

4 novembre 1992: JAMA

What evidence-based medicine is:

The practice of EBM requires the integration of

individual clinical expertise with the

best available external clinical evidence from systematic research

patient values

Centre for Evidence-based Medicine

http://ktclearinghouse.ca/cebm/

What kind of evidence?.

Disease-related evidence



La medicina basata sulle evidenze, per sua natura, in generale ricerca e ottiene evidenze relative a malattie a definizione ontologica ben circoscritta, con studi clinici focalizzati su pazienti il più possibile privi di altre condizioni cliniche rilevanti che risulterebbero “confondenti” per le evidenze ricercate.

Dall'analisi dei singoli settori individualmente, il riduzionismo ha mosso l’approfondimento semplificativo che ha reso possibile lo sviluppo attuale delle nostre conoscenze.

In questo contesto la visione sistemica è apparsa come una pericolosa ed a tratti inquietante modalità di allontanamento dalla rassicurante e ordinata capacità di analisi dello specialismo.

Scandinavian Simvastatin Survival

Study (4S)

The Lancet, Vol 344, November 19, 1994

Coronary Death and Nonfatal MI

Years since randomization

% o

f p

atie

nts

wit

ho

ut

even

ts

34% Risk Reduction

p<0.00001


Inclusion Criteria: Prior MI and/or angina pectoris

60

70

80

90

100

0 1 2 3 4 5 6

SimvastatinPlacebo

Baseline CharacteristicsPlacebo(n=2223)

Simvastatin(n=2221)


Mean age (years)-men

58.1 58.2

Mean age (years)-women

60.5 60.5

Angina only 21% 21% MI only 62% 63% Both angina and MI 17% 16% Hypertension 26% 26% Smoker 27% 24% TC (mg/dL) 260 260 LDL (mg/dL) 180 180

Holmes 2003

Importance of co-morbidityPrevalence and age trends for selected co-morbidities

• Progressivo invecchiamento della popolazione

• Aumento dei pazienti con comorbilità multiple - multimorbilità

• Queste categorie di pazienti sono solitamente non incluse nei trial clinici

….in questi 22 anni che cosa è cambiato

LA MEDICINA CLASSICA • Concetto di malattia• La medicina ha coniato il concetto di

‘malattia’ e aderisce a questo concetto nella sua attività.

• Le malattie definite come ontologie in medicina rappresentano il risultato di un processo di consenso talora recentemente esplicito, in precedenza più frequentemente implicito, relativamente alla definizione di un’ontologia.

• Il ragionamento diagnostico assume così le caratteristiche del riconoscimento di un’impronta digitale: si ricercano i punti di identità fra malattia conosciuta e situazione clinica del paziente e, quando i punti di identità superano un certo numero, si definisce la diagnosi (approccio euristico al problema).

LA MEDICINA CLASSICA

I R

S C AB P C O

Heart Failure

E P

D M II

Aritmie

Infezioni su

device

Complicanze periprocedurali

Il fenotipo clinico complesso

HYPERTENSION

I R

LIVERCIRRHOSIS

B P C O

Heart Failure

E P

D M II

Aritmie

Infezioni su

device



HYPERTENSION

I R

ATRIALFIBRILLATION

B P C O

Heart Failure

E P

D M II


HYPERTENSION

La medicina della complessità

23

By JANE E. BRODYPublished: September 18, 2007A 78-year-old woman was found unconscious on the floor of her apartment by a neighbor who checked on her. The woman could not remember falling but told doctors that before going to bed she had abdominal pain and nausea and had produced a black stool, after which she had palpitations and felt lightheaded.

New York Times 18 sep 2007

Dr. Michael Stern reported in the June issue of Emergency Medicine.

Her medical history included

• high blood pressure, • coronary artery disease, • atrial fibrillation, • congestive heart failure and • osteoarthritis. She also had • a cold with a • productive cough.

For each condition, she had been prescribed a different drug, and she was taking a few over-the-counter remedies on her own.


PERSONAL HEALTH

The ‘Poisonous Cocktail’ of Multiple Drugs

These were the medications:• Beta-blocker to control high blood pressure.• Digitalis to help the heart pump and control its rhythm.• Coumadin to prevent a stroke caused by blood clots.• Furosemide, a potent diuretic to lower blood pressure.• Statins to lower serum cholesterol.• Baby aspirin to reduce cardiac risk from blood clots.• Cox-2 inhibitor for arthritis pain.• antidepressant for depression and anxiety.• Diazepam, as needed, to help her sleep.• Levofloxacin, an antibiotic for the cough.• Ibuprofen for body aches.• Cough medicine.



1. high blood pressure, 2. coronary artery disease, 3. atrial fibrillation, 4. congestive heart failure and 5. osteoarthritis. She also had 6. a cold with a 7. productive cough.



Comorbilità e multimorbilità

Il termine comorbilità è stato introdotto nel 1970 e si riferisce alla compresenza di una malattia aggiuntiva oltre a quella indice

(Feinstein, 1970)

Con il termine multimorbilità invece ci si riferisce alla coesistenza di vari disturbi nello stesso individuo; l’interesse si sposta pertanto da una data condizione patologica indice al soggetto che soffre di patologie multiple (patient centered)

(Batstra et al., 2002)

Clusters di multimorbilita’ (% del totale): Femmine (86.176 assicurate > 65 anni Amburgo)

Schäfer et al. 2010

Schäfer et al, 2010

Clusters di multimorbilita’ (% del totale) : Maschi (63.104 assicurati > 65 anni

Amburgo)

• Il singolo malato – potenzialmente sempre, ma in particolare oggi con il progressivo invecchiamento della popolazione – si può presentare con un quadro clinico complesso in rapporto alla coesistenza di più condizioni morbose.

• Questo complica e rende più difficile, e talora impossibile, il processo di identificazione di una di queste malattie con la condizione complessiva del paziente.

Un approccio elementare alla complessità

Holmes 2003

Importance of co-morbidityPrevalence and age trends for selected co-morbidities

• Disease Count (DC) (!!!?)• Charlson Index (CI)• Index of Co-Existent Diseases (ICEDDS)

Index of Disease Severity (IDS)

• Geriatric Index of Comorbidity (GIC)

Di Bari M, et al. J Am Geriatr Soc 2006; 54: 210

Some common measures of comorbidity

Evaluation of co-morbidityCharlson co-morbidity index (1987)

Index 2HemiplegiaKidney function disturbances (moderate/severe)Diabetes mellitus with terminal organ damageTumours: solid tumours, leukemia, lymphoma

Index 3Liver function disturbances (moderate/severe)

Index 6 AIDSMetastatic cancer

Index 1Chronic obstructive pulmonary diseases

Cardiovascular diseases: myocardial infarction, cardiac decompensation, angina pectoris, peripheral arterial disease, intermittent claudication, abdominal aneurysmCerebrovascular diseases:

cerebrovascular accidentHypertension (medically treated)

Diabetes mellitus

Auto-immune diseasePeptic ulcerationDementiaLiver function disturbances

Etimologia della complessita�

• Complesso, complicato e semplice sono termini che vengono tutti dalla stessa radice indoeuropea: plek- (parte, piega, intreccio).Da plek- derivano, in latino:

• Il verbo plicare = piegare

Il verbo plectere = intrecciare

Il suffisso –plex = parte

• La parola semplice = sine plex…

Complex Systems• A complex system is a system composed of interconnected parts that as a whole exhibit one or more properties (behavior among the possible properties) not obvious from the properties of the individual parts .

Reductionism vs System approach

• The Scientists base their research on a principle hypothesis that complex systems can be understood by seeking out its most fundamental constituents.

• Complex problems are resolved by dividing them into smaller, simpler and more tractable units.

• In the last 50 years, the reductionist approach of has been successful in revealing the chemical basis of numerous living processes.

Reductionism System approach

In order to have a better understanding of the system wide behavior, three factors need to be considered:

Context: the inclusion of all components involved in a process (and their interactions).

Time: to consider the changing characteristics of each component.

Space: to account for the topographic relationships between and among components.

The systems perspective is rooted in the assumption that

the forest cannot be explained by studying

the trees individually.

la visione sistemica è apparsa come una pericolosa ed a tratti inquietante

modalità di allontanamento dalla rassicurante e ordinata capacità di

analisi dello specialismo. La complessità pertanto è un tema sostanzialmente al momento non presente in modo organico nella formazione curriculare e post-

curriculare.

La medicina basata sulle evidenze, per sua natura, in generale ricerca e ottiene evidenze relative a malattie a definizione ontologica ben circoscritta, con studi clinici focalizzati su pazienti il più possibile privi di altre condizioni cliniche rilevanti che risulterebbero “confondenti” per le evidenze ricercate.

EVIDENZE ?

ALLHATCumulative Event Rates for the Primary Outcome

(Fatal Coronary Heart Disease or Nonfatal Myocardial Infarction)

ALLHAT Collaborative Research Group. JAMA. 2002; 288: 2981-97

Chlorthalidone (n=15,255)Amlodipine (n=9,048)Lisinopril (n=9,054)

Enrollment criteriaHypertension + 1 risk factor

(previous MI, or other CVD,LVH, type 2 diabetes,smoking, HDLChol <35 mg/dl)


ALLHAT Effects of ACE inhibitor based and Diuretic based

treatments on Blood Pressure and Outcomes

Clin Med Card Fi

Lisinopril vs ChlortalidoneOutcomes RR (95% CI)

CV mortality - All cause mortality 1.00 (0.94-1.06) Myocardial infarction 0.99 (0.91-1.08)Stroke 1.19 (1.02-1.30)*Heart failure 1.20 (1.09-1.34)*

* = p<0.01

35% of enrolled patients were blacks


Chlortalidone vs Lisinopril

stroke BP (mmHg)All patients - 15%- 2 mmHgBlacks - 40%- 4 mmHgeffect of race p<0.01


…

BI-DIL

Circulation. 2007;115:1747-1753

conclusionsThe addition of a fixed dose of isosorbide dinitrate plus hydralazine to standard therapy for heart failure including neurohormonal blockers is efficacious and increases survival among black patients with advanced heart failure.

Fino ad oggi il processo decisionale medico prevedeva una "catena di esclusioni" di quadri patologici per arrivare alla diagnosi. Ne è esempio il pensiero "euristico": il medico di elevata esperienza ricerca nella propria memoria il quadro più simile a quello che gli è di fronte, escludendo gli altri.

La complessità nella diagnosi

I percorsi (diagnostico-terapeutici) sequenziali abituali giungono alla diagnosi di malattia attraverso l’esclusione (guidate dalla evidence-based medicine) di altre. Di fronte alla complessità, al processo di esclusione gerarchica deve essere associata la capacità di includere i diversi elementi, poiché tutti contribuiscono alla genesi del quadro.

L’approccio “inclusivo” rappresenta quindi il solo approccio che rispetti l'interezza dei “descrittori” necessari per garantire l'efficacia della medicina clinica. Non è tuttavia da tralasciare un altro elemento tipico della medicina clinica: la convergenza di condizioni cliniche diverse su di un unico elemento clinico dominante.(dispnea, febbre, anemia).

La complessità di un elemento clinico:

La dispnea

DISPNEA ACUTA (ENTRO POCHI MINUTI) Cause polmonari• Pneumotorace• Embolia polmonare• Asma, broncospasmo o patologia reattiva delle vie aeree• Inalazione di un corpo estraneo• Lesione tossica delle vie aeree (p. es., inalazione di cloro, solfuro di idrogeno)Cause cardiache• Ischemia miocardica acuta o infarto• Disfunzione o rottura dei muscoli papillari• Insufficienza cardiacaAltre cause• Paralisi del diaframma• Disturbo d’ansia con iperventilazione DISPNEA SUBACUTA (ENTRO ORE O GIORNI)

Cause polmonari• Polmonite• Esacerbazione di BPCOCause cardiache• Angina o coronaropatia• Versamento pericardico o tamponamento

Oppressione toracica retrosternale con o senza irradiazione a braccio o mandibola, soprattutto nei pazienti con fattori di rischio di coronaropatiaECGValutazione degli enzimi cardiaciDisfunzione o rottura dei muscoli papillari

DISPNEA CRONICA (DA ORE AD ANNI)

Cause polmonari• Patologia polmonare ostruttiva• Patologia polmonare restrittiva• Patologia polmonare interstiziale• Versamento pleurico Cause cardiache• Insufficienza cardiaca• Angina o coronaropatiaAltre cause• Anemia• Decondizionamento fisico Oppressione toracica retrosternale con o senza irradiazione a braccio o mandibola, soprattutto nei pazienti con fattori di rischio di coronaropatiaECGValutazione degli enzimi cardiaciDisfunzione o rottura dei muscoli papillari

DISPNEA ACUTA (ENTRO POCHI MINUTI) Cause polmonari• Pneumotorace• Embolia polmonare• Asma, broncospasmo o patologia reattiva delle vie aeree• Inalazione di un corpo estraneo• Lesione tossica delle vie aeree (p. es., inalazione di cloro, solfuro di idrogeno)Cause cardiache• Ischemia miocardica acuta o infarto• Disfunzione o rottura dei muscoli papillari• Insufficienza cardiacaAltre cause• Paralisi del diaframma• Disturbo d’ansia con iperventilazione DISPNEA SUBACUTA (ENTRO ORE O GIORNI)

Cause polmonari• Polmonite• Esacerbazione di BPCOCause cardiache• Angina o coronaropatia• Versamento pericardico o tamponamento


DISPNEA CRONICA (DA ORE AD ANNI)

Cause polmonari• Patologia polmonare ostruttiva• Patologia polmonare restrittiva• Patologia polmonare interstiziale• Versamento pleurico Cause cardiache• Insufficienza cardiaca• Angina o coronaropatiaAltre cause• Anemia• Decondizionamento fisico


Paziente

Medico

Sistema sanitario

FarmacoComplessità iatrogena

TICAGRELOR

DISPNEA

Polmonite

Esacerbazione di BPCO

Insufficienza cardiaca

Embolia polmonare

Decondiziona-mento fisico

Versamento pleurico

Anemia

I R

ATRIALFIBRILLATION

B P C O

Heart Failure

E P

D M II


HYPERTENSION

4P medicinePredictive

Preventive

Participatory

An Evolving ScenarioIntegrated Care supported by ICT

Efficient patient managementModulation of disease progress

ICT as enabler of a new model of care

Personalized

GUIDELINES

MINDLINES

Construction of mindlines

BMJ 30 Oct 2004

Global Alliance against Chronic Respiratory Diseaseswww.who.int/respiratory/gard

www.who.int/chp

Pathogen

Host

Socio-economicdeterminants

Chronic disease

Life style - environmentRisk and protective factorsTobacco smoking, Pollutants

Allergens, Nutrition, InfectionsPhysical exercise, Others

Infectious disease

Ageing

Geneticdisease

Chronic diseases

Tobacco use Unhealthy diets

Physical inactivity

Harmful use of alcohol

Biomass fuel combustion

cardio-vascular diseases

X X X X X

Diabetes X X X X

Cancer X X X X X

Chronic respiratory diseases

X X X

Common risk factors of major NCDs

Comorbidities• Comorbidity is the presence of one or more disorders (or

diseases) in addition to a primary disease or disorder• or it indicates a medical condition in a patient that is

related to another condition in the same patient due to the same risk factor.

• Comorbidities are NCD characteristics and patients with a given NCD usually present several comorbidities.

• Comorbidities are associated with impaired health outcomes, complex clinical management, and increased health care costs, in particular in the elderly.

• Increased life expectancy is one of the major drivers of NCDs and comorbidities.

Life style - environmentRisk and protective factors

Tobacco smoking, PollutantsAllergens, Nutrition, Infections

Physical exercise, Others

Socioeconomic

determinants

Genes

Biological expression of chronic diseasesTranscripts, proteins, metabolitesTarget organ local inflammation

Systemic inflammationCell and tissue remodelling




Socioeconomic

determinants

Gender

Genes



Clinical expression of chronic diseasesCo-morbidities

Severity of co-morbiditiesPersistence, remission Long-term morbidity

Responsiveness - side effects to treatment




Sex

Socioeconomic

determinants

Gender

Genes

Age









Sex

Socioeconomic

determinants

Gender

Systems biology on precise phenotypes

Genes

Age









Sex

Socioeconomic

determinants

Gender

Personalized medicine- Primary prevention- Secondary prevention- Tertiary prevention- Treatment

Systems biology on precise phenotypes

Health promotionPrimary prevention

Genes

Age









Sex

Socioeconomic

determinants

Gender

Classical phenotypes

Hypothesis-driven

CVD COPD Diabetes

Classical phenotypes inpatients with severe defined diseases

and co-morbidities

Responsiveness to treatmentFollow up

Assessment of co-morbitiesand severity

Patient with chronic disease

Classical phenotypes

Hypothesis-driven Discovery driven


CVD COPD Diabetes

Classical phenotypes inpatients with severe defined diseases

and co-morbidities


Assessment of co-morbitiesand severity

Novel phenotypes in individualpatients with severe co-morbidities

of chronic diseases

Novel phenotypes

Severity of co-morbidities(standardized assessment)

Co-morbidities(standardized assessment)

Patient with chronic disease

Uniform severity of chronic diseases

Asthma Diabetes1- Underdiagnosis Risk of acute exacerbation Risk of coma and death

2- Effective treatment ICS, ß2 agonists Insulin, oral drugs

3- No treatment available/affordable

Risk of acute exacerbation Risk of coma and death

4- Incorrect diagnosis COPD (adults)CF (children)

Weight loss

5- Difficult-to-treat disease ComplianceInhaler misuseRisk factors

ComplianceComplicationsRisk factors

6- Controlled treatment dependent disease

Risk of exacerbation when treatment stopped

Risk of death when treatment stopped

7- Uncontrolled treatmentresistant disease

Treatment resistant asthma: Risks

Insulin-resistant diabetesRisks

• NCDs are multi-factorial diseases caused by: • complex gene-environment interactions (risk and protective

factors) • socio-economic determinants, • modulated by gender • and age (healthy ageing).

• Similar and differential pathways of local and systemic inflammation and bioenergetics are intertwined leading to individual-specific complex biological and clinical phenotypes.

• NCDs result from multilevel homeostatic regulatory network perturbations representing a complex interplay of common and individual-specific biological and clinical phenotypes

• NCDs cluster in co-morbidities.

NCDs are complex diseases

• Understanding NCDs cannot be achieved assessing separate mechanisms

• A management strategy using clinical and biological criteria categorizing each NCD separately has proved to be insufficient.

• Recent advances in systems biology and network analysis have opened new avenues to understand mechanisms of co-morbidities of multi-factorial NCDs.

• These tools should be integrated, deployed and validated in real life scenarios for universal adoption with implications on personalized prevention and care.

NCDs need a complex approach

• Understanding NCDs cannot be achieved assessing separate mechanisms

• A management strategy using clinical and biological criteria categorizing each NCD separately has proved to be insufficient.

• Recent advances in systems biology and network analysis have opened new avenues to understand mechanisms of co-morbidities of multi-factorial NCDs.

• These tools should be integrated, deployed and validated in real life scenarios for universal adoption with implications on personalized prevention and care.

• Perfect patient phenotyping is absolutely required for:• Comorbidities• Severity of each comorbidity

NCDs need a complex approach

« We work with the patients »

Views of patients are essentiel to:1- Engage the patient in research2- Engage the patient in treatment and propose an optimal therapeutic strategy fully accepted by the patient3- Involve patients at all stages of research in order to provide results which will meet patient’s expectations

Hypothesis-driven systems biology

Goals • One of the challenges of systems biology and functional genomics is to integrate proteomic, transcriptomic and metabolomic information to give a more complete picture of living organisms• Integration of these methods with clinical data, validation and confirmation

Methods • Proteomics (L Serrano, Barcelona)• Transcriptomics (L Serrano, Barcelona)• Metabolomics (R Balling, Luxembourg)

Integration of data in patient populations• Testing in 300 patients with extreme classical phenotypes• Validation in 200 patients with novel phenotypes• Confirmation in 200 patients from the general population

Geographical Information System System Medicine

NETWORK MEDICINE:a network based approach to human disease

Systems biology approach to medicine creates network medicine.

De Keulenaer G W , Brutsaert D L Circulation 2011;123:1996-2005

Co

ntin

uu

m

• The use of systems biology approaches to characterize disease states is just at the beginning stages.Application of systems biology to disease states will occur at multiple organizational levels with a simultaneous focus on gene network, transcriptome network, protein network and metabolic networks.

System approach to disease states

• Delineation of the systems biology of various cardiovascular diseases, including heart failure, is particularly challenging due to the involvement of multiple organ systems in these disorders, each with a particular systems biology.

• Human heart failure is a syndrome involving multiple clinical phenotypes which share an undetermined number of common pathophysiological mechanisms.

• Each of these clinical phenotypes is characterized by multiorgan derangements involving multiple biochemical pathways and numerous molecular elements in each phenotype.

• Clearly, pathophysiological changes would involve numerous biomedomic domains, each requiring detailed description.

System approach to disease states

Towards System Medicine

Genomic/Transcriptomic

Proteomic

Metabolomic

Sensoring

Social Network

7

F i g u r a ( 1 . ! La! trasformazione! dalla! medicina! di! oggi! (vecchia! e! statica)!alla! nuova! medicina! personalizzata,! resa!possibile!dalle!nuove!tecnologie!ICT!applicate!alla!persona.!!

!

!!Con!questo!approccio!sarà!possibile!adattare!nel!tempo!alle!esigenze!della!clinica!i!progressi!tecnologici!che!attualmente!si!sviluppano!con!enorme!velocità,!evitando!allo!stesso!tempo!l'eccesso!di!informazioni!e!l'incapacità!di!adattarle!alle!esigenze!del!singolo!paziente.!

!!3 . 3 ( ( I l ( p e r c o r s o ( f o r m a t i v o ( i n d i v i d u a t o (

La!proposta!che!presentiamo!si!basa!sulla!considerazione!che!nella!fase!iniziale!di!realizzazione!della!Scuola!di!Medicina!in!Trentino,!l’attività!inizi!con!il!quarto!anno,!tipicamente!destinato!alla! piena! espansione! dell’attività! clinica.! Successivamente! questa! scelta! potrà! essere!riconsiderata!se!prevarrà!l’idea!di!costruire!un!ciclo!completa.!!Il!modello!prevede!!dunque!una!suddivisione!del!tempo!di!formazione!che!6!in!modo!elastico!e!specifico!per!ciascun!insegnamento!6!possa!identificarsi!schematicamente!in!tre!segmenti:!a)!contenuti!tradizionali,!scegliendo!per!ogni!materia!un!nucleo!irrinunciabile!di!informazioni;!b)!p r o b l e m ( s o l v i n g ! relativo! alle! sindromi! e! alla! personalizzazione! dell’approccio! attraverso! la!s y s t e m ( m e d i c i n e ;!c)!insegnamento!per!processi.!!“Insegnare! la! medicina:! come! si! fa,! dove! serve! e! quando! serve”,! titolo! possibile! per! la!sperimentazione!proposta!che!contiene!già!il!senso!del!rapporto!tra!pensiero!medico!e!prassi,!il! concetto! di! medicina! non! puntiforme! (ma! che! incorpora! ! la! continuità! terapeutico6assistenziale),!il!concetto!di!appropriatezza!e!quindi!di!controllo!dei!risultati,!anche!al!fine!di!evitare!gli!sprechi.!Affidando!ad!una!rappresentazione!schematica!l’attuale!sistema!formativo!del!Corso!di!Laurea!in!Medicina!e!Chirurgia,!articolato!in!sei!anni!(vd.!Grafico!1),!se!ne!può!ipotizzare!una!divisione!verticale!in!tre!macroaree!che!abbracciano!trasversalmente!l’intero!sistema!dei!crediti!vigenti!(vd.!Grafico!2).!!!!!

Towards System Medicine

Genomic/Transcriptomic

Proteomic

Metabolomic

Sensoring

Social Network

Fenotipizzazione del comportamento• Lo studio del comportamento rappresenta una sfida particolare per la

fenomica in quanto dipende dal contesto e dal tempo ed è chiaramente molto variabile.

• Le tecnologie attualmente disponibili combinano sistemi di localizzazione basati su GPS (global position systems), accelerometri, e strumenti per il monitoraggio dell'attività neuronale. Lo studio del comportamento umano può anche essere effettuato mediante strumenti basati su web e smartphone.

to Accelerating Science and Innovation

The Mission of CERN

q Push forward the frontiers of knowledgeE.g. the secrets of the Big Bang …what was the matter like

within the first moments of the Universe’s existence?

q Develop new technologies for accelerators and detectorsInformation technology - the Web and the GRID

Medicine - diagnosis and therapy

q Train scientists and engineers of tomorrow

q Unite people from different countries and cultures

Enabling Grids for E-sciencE

EGEE-III INFSO-RI-222667

Why grids/clouds for e-Health?

Sharing computing resources and algorithmsResearch (populations studies, models design, validation, statistics)

Complex analysis (compute intensive image processing, time constraints...)

• Seq1 > dcscdssdcsdcdsc bscdsbcbjbfvbfvbvfbvbvbhvbhsvbhdvbhfdbvfd

• Seq2 > bvdfvfdvhbdfvb bhvdsvbhvbhdvrefghefgdscgdfgcsdycgdkcsqkc

• …

• Seqn > bvdfvfdvhbdfvb bhvdsvbhvbhdvrefghefgdscgdfgcsdycgdkcsqkchdsqhfduhdhdhqedezhhezldhezhfehflezfzejfv

• Data

• Algorithms

• Procedures

• Computing power• 100

The LHC data• 40 million events (pictures) per second• Select (on the fly) the ~500 interesting events per

second to write on tape• “Reconstruct” data and convert for analysis:

“physics data” [ the grid...]

(x4 experiments x15 years) Per event Per year

Raw data 1.6 MB 30 PB

Reconstructed data 1.0 MB 20 PB

Physics data 0.1 MB 2 PB

Concorde(15 km)

Balloon(30 km)

DVD stack with1 year LHC data!(~ 20 km)

Mt. Blanc(4.8 km)

102 Health-e-Child

§ 4 paediatric hospitals§ IGG - Gaslini, Genoa, Italy§ GOSH, London, UK§ NECKER, Paris, France§ OPBG, Rome, Italy

§ Strong interdisciplinary team across§ Countries and languages§ Technical and clinical fields

§ Research on three paediatric areas § Arthritis§ Cardiac Disorders§ Brain Tumours

Health-e-Child Network

• 7 technical sites• 4 clinical sites

(+1 clinical site in the US: Johns Hopkins)

103 Health-e-Child

Virtual Physiological Child

Decision Support

Disease Models

Grid InfrastructureData INTEGRATION

MEDICAL DSS

I R

S C AB P C O

Heart Failure

E P

D M II

Aritmie

Infezioni su

device



HYPERTENSION

I R

ATRIALFIBRILLATION

B P C O

Heart Failure

E P

D M II


HYPERTENSION

4P medicinePredictive

Preventive

Personalized

Participatory

An Evolving ScenarioIntegrated Care supported by ICT

Efficient patient managementModulation of disease progress

ICT as enabler of a new model of care

UNA QUINTA P : PRECISION MEDICINE

Researchers and health-care providers must have access to vary large sets of health and disease-related data linked to individual patients. These data are also critical for the development of the Information Commons, the Knowledge Network of Disease, and the development and validation of the New Taxonomy, different from the usual Disease-based Taxonomy.

D. McManus, Josée Dupuis, Patrick T. Ellinor and Emelia J. BenjaminJared W. Magnani, Michiel Rienstra, Honghuang Lin, Moritz F. Sinner, Steven A. Lubitz, David

GenomicsAtrial Fibrillation: Current Knowledge and Future Directions in Epidemiology and

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2011 American Heart Association, Inc. All rights reserved.

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January, CT et al. 2014 AHA/ACC/HRS Atrial Fibrillation Guideline

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Table of Contents Preamble ................................................................................................................................................................................... 5 1. Introduction .......................................................................................................................................................................... 9

1.1. Methodology and Evidence Review ............................................................................................................................. 9 1.2. Organization of the Writing Committee ....................................................................................................................... 9 1.3. Document Review and Approval .................................................................................................................................. 9 1.4. Scope of the Guideline ................................................................................................................................................ 10

2. Background and Pathophysiology ...................................................................................................................................... 11 2.1. Definitions and Pathophysiology of AF ...................................................................................................................... 12

2.1.1. AF—Classification .............................................................................................................................................. 13 2.1.1.1. Associated Arrhythmias ............................................................................................................................... 14 2.1.1.2. Atrial Flutter and Macro–Re-Entrant Atrial Tachycardia............................................................................. 14

2.2. Mechanisms of AF and Pathophysiology.................................................................................................................... 16 2.2.1. Atrial Structural Abnormalities ........................................................................................................................... 17 2.2.2. Electrophysiologic Mechanisms .......................................................................................................................... 18

2.2.2.1. Triggers of AF .............................................................................................................................................. 18 2.2.2.2. Maintenance of AF ....................................................................................................................................... 19 2.2.2.3. Role of the Autonomic Nervous System ...................................................................................................... 19

2.2.3. Pathophysiologic Mechanisms ............................................................................................................................ 20 2.2.3.1. Atrial Tachycardia Remodeling ................................................................................................................... 20 2.2.3.2. Inflammation and Oxidative Stress .............................................................................................................. 20 2.2.3.3. The Renin-Angiotensin-Aldosterone System ............................................................................................... 20 2.2.3.4. Risk Factors and Associated Heart Disease ................................................................................................. 21

3. Clinical Evaluation: Recommendation ............................................................................................................................... 22 3.1. Basic Evaluation of the Patient With AF .................................................................................................................... 22

3.1.1. Clinical History and Physical Examination ......................................................................................................... 22 3.1.2. Investigations ....................................................................................................................................................... 23 3.1.3. Rhythm Monitoring and Stress Testing ............................................................................................................... 23

4. Prevention of Thromboembolism ....................................................................................................................................... 24 4.1. Risk-Based Antithrombotic Therapy: Recommendations ........................................................................................... 24

4.1.1. Selecting an Antithrombotic Regimen—Balancing Risks and Benefits .............................................................. 26 4.1.1.1. Risk Stratification Schemes (CHADS2, CHA2DS2-VASc, and HAS-BLED) .............................................. 27

4.2. Antithrombotic Options .............................................................................................................................................. 29 4.2.1. Antiplatelet Agents .............................................................................................................................................. 29 4.2.2. Oral Anticoagulants ............................................................................................................................................. 31

4.2.2.1. Warfarin ....................................................................................................................................................... 31 4.2.2.2. Newer Oral Anticoagulants .......................................................................................................................... 34 4.2.2.3. Considerations in Selecting Anticoagulants ................................................................................................. 37 4.2.2.4. Silent AF and Stroke .................................................................................................................................... 39

4.3. Interruption and Bridging Anticoagulation ................................................................................................................. 40 4.4. Nonpharmacologic Stroke Prevention ........................................................................................................................ 42

4.4.1. Percutaneous Approaches to Occlude the LAA ................................................................................................... 42 4.4.2. Cardiac Surgery—LAA Occlusion/Excision: Recommendation ......................................................................... 42

5. Rate Control: Recommendations ........................................................................................................................................ 44 5.1. Specific Pharmacological Agents for Rate Control .................................................................................................... 46

5.1.1. Beta Adrenergic Receptor Blockers .................................................................................................................... 46 5.1.2. Nondihydropyridine Calcium Channel Blockers ................................................................................................. 47 5.1.3. Digoxin ................................................................................................................................................................ 47 5.1.4. Other Pharmacological Agents for Rate Control ................................................................................................. 48

5.2. AV Nodal Ablation ..................................................................................................................................................... 48 5.3. Selecting and Applying a Rate Control Strategy......................................................................................................... 49

5.3.1. Broad Considerations in Rate Control ................................................................................................................. 49 5.3.2. Individual Patient Considerations ........................................................................................................................ 50

6. Rhythm Control .................................................................................................................................................................. 51 6.1. Electrical and Pharmacological Cardioversion of AF and Atrial Flutter .................................................................... 52

6.1.1. Thromboembolism Prevention: Recommendations ............................................................................................. 52 6.1.2. Direct-Current Cardioversion: Recommendations ............................................................................................... 53 6.1.3. Pharmacological Cardioversion: Recommendations ........................................................................................... 53

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6.2. Pharmacological Agents for Preventing AF and Maintaining Sinus Rhythm ............................................................. 57 6.2.1. Antiarrhythmic Drugs to Maintain Sinus Rhythm: Recommendations ............................................................... 57

6.2.1.1. Specific Drug Therapy ................................................................................................................................. 61 6.2.1.2. Outpatient Initiation of Antiarrhythmic Drug Therapy ................................................................................ 65

6.2.2. Upstream Therapy: Recommendations ................................................................................................................ 65 6.3. AF Catheter Ablation to Maintain Sinus Rhythm: Recommendations ....................................................................... 66

6.3.1. Patient Selection .................................................................................................................................................. 67 6.3.2. Recurrence After Catheter Ablation .................................................................................................................... 69 6.3.3. Anticoagulation Therapy Periablation ................................................................................................................. 69 6.3.4. Catheter Ablation in HF ....................................................................................................................................... 69 6.3.5. Complications Following AF Catheter Ablation ................................................................................................. 70

6.4. Pacemakers and Implantable Cardioverter-Defibrillators for the Prevention of AF ................................................... 71 6.5. Surgery Maze Procedures: Recommendations ............................................................................................................ 71

7. Specific Patient Groups and AF ......................................................................................................................................... 73 7.1. Athletes ....................................................................................................................................................................... 73 7.2. Elderly ......................................................................................................................................................................... 73 7.3. Hypertrophic Cardiomyopathy: Recommendations .................................................................................................... 73 7.4. AF Complicating ACS: Recommendations ................................................................................................................ 74 7.5. Hyperthyroidism: Recommendations .......................................................................................................................... 76 7.6. Acute Noncardiac Illness ............................................................................................................................................ 76 7.7. Pulmonary Disease: Recommendations ...................................................................................................................... 77 7.8. WPW and Pre-Excitation Syndromes: Recommendations.......................................................................................... 77 7.9. Heart Failure: Recommendations ................................................................................................................................ 78 7.10. Familial (Genetic) AF: Recommendation ................................................................................................................. 80 7.11. Postoperative Cardiac and Thoracic Surgery: Recommendations ............................................................................ 81

8. Evidence Gaps and Future Research Directions ................................................................................................................. 84 Appendix 1. Author Relationships With Industry and Other Entities (Relevant) .................................................................. 86 Appendix 2. Reviewer Relationships With Industry and Other Entities (Relevant) .............................................................. 90 Appendix 3. Abbreviations ..................................................................................................................................................... 99 Appendix 4. Initial Clinical Evaluation in Patients With AF ............................................................................................... 100 References ............................................................................................................................................................................ 102


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where complex atrial fractionated electrograms are recorded. Ablation targeting these regions improved

outcomes over pulmonary vein isolation alone in some but not all studies (119-121).

In some patients with structurally normal hearts, AF is precipitated during conditions of high-

parasympathetic tone, such as during sleep and following meals, and is referred to as “vagally mediated AF”

(122). Avoidance of drugs, such as digoxin, that enhance parasympathetic tone has been suggested in these

patients, but this remains an unproven hypothesis. Catheter ablation targeting ganglion plexi involved in vagal

responses abolished AF in only 2 of 7 patients in 1 small series (120). Adrenergic stimulation, as during

exercise, can also provoke AF in some patients (123).

2.2.3. Pathophysiologic Mechanisms

2.2.3.1. Atrial Tachycardia Remodeling AF often progresses from paroxysmal to persistent over a variable period of time. Cardioversion of AF and

subsequent maintenance of sinus rhythm are more likely to be successful when AF duration is <6 months (124).

The progressive nature of AF is consistent with studies demonstrating that AF causes electrical and structural

remodeling such that “AF begets AF” (125, 126).

2.2.3.2. Inflammation and Oxidative Stress Inflammation (e.g., associated with pericarditis and cardiac surgery), may be linked to AF and can be correlated

with a rise in plasma concentrations of C-reactive protein (81). Inflammatory infiltrates consistent with

myocarditis are often present in the atria of patients with AF and in animals with atrial dilation. Plasma

concentrations of C-reactive protein and interleukin-6 are elevated in AF; increased C-reactive protein predicts

the development of AF and relapse after cardioversion; and genetic variants in the interleukin-6 promoter region

may influence the development of postoperative AF. In the canine pericarditis and atrial tachypacing models,

prednisone suppresses AF susceptibility and reduces plasma concentrations of C-reactive protein (127).

Aging, environmental stress, inflammation, and activation of the renin-angiotensin-aldosterone system

can cause oxidative damage in the atrium. Oxidative changes are present in the atrial tissue of patients with AF

and are associated with upregulation of genes involved in the production of reactive oxygen species. In human

AF and a porcine model of atrial tachypacing, atrial superoxide production increased, with an apparent

contribution of NAD(P)H oxidase (128). The antioxidant ascorbate attenuated electrical remodeling in the

canine atrial tachypacing model and reduced postoperative AF in a small study in humans (129).

2.2.3.3. The Renin-Angiotensin-Aldosterone System Stimulation of the renin-angiotensin-aldosterone system promotes structural and likely electrophysiologic

effects in the atrium and ventricle that increase arrhythmia susceptibility (130-133). In addition to adverse

hemodynamic effects, activation of multiple cell signaling cascades promotes increased intracellular calcium,

hypertrophy, apoptosis, cytokine release and inflammation, oxidative stress, and production of growth-related

factors that also stimulate fibrosis, as well as possible modulation of ion channel and gap-junction dynamics.


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mechanisms (28, 81, 82), such that AF represents a final common phenotype for multiple disease pathways and

mechanisms that are incompletely understood.

Figure 2. Mechanisms of AF

AF indicates atrial fibrillation; Ca++ ionized calcium; and RAAS, renin-angiotensin-aldosterone system.

2.2.1. Atrial Structural Abnormalities Any disturbance of atrial architecture potentially increases susceptibility to AF (83). Such changes (e.g.,

inflammation, fibrosis, hypertrophy) occur most commonly in the setting of underlying heart disease associated

with hypertension, coronary artery disease (CAD), valvular heart disease, cardiomyopathies, and HF which tend

to increase LA pressure, cause atrial dilation, and alter wall stress. Similarly, atrial ischemia from CAD and

infiltrative diseases such as amyloidosis, hemochromatosis, and sarcoidosis, can also promote AF. Additional

promoters include extracardiac factors such as hypertension, sleep apnea, obesity, alcohol/drugs, and

hyperthyroidism, which have pathophysiologic effects on atrial cellular structure and/or function. Even in

patients with paroxysmal AF without recognized structural heart disease, atrial biopsies have revealed


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*Drugs are listed alphabetically. †Beta blockers should be instituted following stabilization of patients with decompensated HF. The choice of beta blocker (cardio-selective, etc.) depends on the patient’s clinical condition. ‡Digoxin is not usually first-line therapy. It may be combined with a beta blocker and/or a nondihydropyridine calcium channel blocker when ventricular rate control is insufficient and may be useful in patients with HF. §In part because of concern over its side-effect profile, use of amiodarone for chronic control of ventricular rate should be reserved for patients who do not respond to or are intolerant of beta blockers or nondihydropyridine calcium antagonists. COPD indicates chronic obstructive pulmonary disorder; CV, cardiovascular; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; and LV, left ventricular.

6. Rhythm Control Long-term AF management may employ attempts to restore and maintain sinus rhythm, commonly referred to

as “a rhythm-control strategy”; utilizing a combination of approaches, including cardioversion, antiarrhythmic

drugs and radiofrequency catheter ablation in the setting of appropriate anticoagulation and rate control. RCTs

comparing outcomes of a rhythm-control strategy using antiarrhythmic drugs with a rate-control strategy in

patients with AF failed to show a superiority of rhythm control for either strategy on mortality (269, 313).

Furthermore, when applied in patients who are candidates for both treatment strategies (rhythm or rate control),



1. high blood pressure, 2. coronary artery disease, 3. atrial fibrillation, 4. congestive heart failure and 5. osteoarthritis. She also had 6. a cold with a 7. productive cough.



Cesario et al; A Systems Medicine Clinical Platform for the Understanding and Management of Non Communicable Diseases, Current Pharmacological Design, 2013, in press

The San Raffaele NCD platform is aims at developing tools for the analysis and interpretation of complex datasets. The availability of structured clinical platforms represents the basic condition needed to address current priorities in medicine, such as personalizing treatment and improving outcome, implementing clinical trials tailored on newly defined phenotypes and, finally, bringing P4 medicine into clinical practice, while assuring the sustainability of this approach within national health systems.

Real challenge;

Shall we improve the efficacy of rehabilitation treatment in our patients with

a System Medicine grade treatment ??

117117

Psychiatric Common information# 276 items

Clinical / Epidemiological Database (web-based – EHR)

NH / LTC

Biobank(centralised at IRCCS SR)

Diabetes

Respiratory

Cardiovascular

# 117

Alzheimer

PD

Head/Migr

# 117

# 10

# 360

# 35

# 162

# 162

# 40

Lung ca # 46

Follow up in f(t)ICT / integrated care + primary

care

San Raffaele Non Communicable Diseases Platform (SR-NCDs)

SOPs• Patient recruitment (informed consent and

questionnaires/diagnostic test administration)

• Sample collection, anonimization, and labelling

• Sample transport, processing, and storage

(-80°C or liquid N2)

Vacutainer

tubeQuantities Fractions

Number of

aliquotes

Volume of

aliquotesStorage

EDTA 3x4ml Plasma 4 ~1 ml -80°C

PBMC 2 ~0,5ml Liquid N2

Heparin 1x3 ml Whole blood 2 ~1ml -80°C

Serum separator 1x3 ml Serum 3 ~0,5-1 ml -80°C

PAXgene blood RNA tube 1x2,5ml Blood 1 ~2,5ml -80°C

Urine 10 ml Urine 2 ~5 ml -80°C

Feces - Feces 1 - -80°C

BAL (Bronchoalveolar

lavage)2-10ml cells 2 ~0,5ml Liquid N2

supernatant 2 ~10ml -80°C

Sputum 2-5ml Sputum 1 2-5ml -80°C

Sample processing and fractions aliquoting

Criostorage -80°C / N2

Casym, Lyon 25-6-13

Field of information Number of items

Domains

Demographic data 16 Hospital, ward, date of admission, age, gender, education, residence

Occupational history 12 Current and past professions, duties, workplaces

Smoking habits 23 Age of onset, type and amount of smoking, age of quitting, cohabitation with smokers

Alcohol intake 6 Type of beverage and quantity

Diet 5 Intake of fresh food and supplements

Leisure-time activities

5 amount of spare time, type of activities

Social relationships 6 Presence of relatives/friends, amount of time spent with them

Stressful life events in the previous six moths

3 Type of events

Personal medical history

161 Heart diseases, vascular diseases, blood and lymphatic system diseases, respiratory diseases, gastrointestinal diseases, liver diseases, genitor-urinary diseases, musculoskeletal systems diseases, endocrine and metabolic diseases, psychiatric diseases, neurologic diseases, other diseases.

Family medical history

39 Smoking habits, cardiovascular diseases, respiratory diseases, psychiatric diseases, headache, diabetes, memory impairment, Parkinson’s disease, Alzheimer’s disease, other diseases.

Epidemiological questionnaire Anamnestic questionnaire

Field of information Number of items

Domains


Bonassi S, et al., Omics in population studies: a molecular epidemiology perspective. Environ Mol Mutagen. 2013

Wild et al., EMM, 2013

The concept of integrative epidemiology is based on the unifying premise that the same genes (or the same pathways) that are implicated in disease risk may also be involved in a person's propensity to exposure/disease, in determining disease phenotype, and/or in modulating therapeutic outcome

Integrative epidemiology: from risk assessment to outcome prediction. JCO, 2005 Spitz MR et al.

Vineis et al., EMM, 2013

Critical events that are associated to exposure, disease progression, response to therapy.

• Genomic instability• DNA damage/Repair• Oxidative damage• Telomeres shortening

Casym, Lyon 25-6-13

Module Clinical and instrumental exams, rating scales

Common Physical examinationBlood testsUrine tests EKGPulse OximetryDrug therapy (detailed)Presence of medical devices (oxygen, mechanical ventilation)The modified Cumulative Ilness Rating Scale (MCIRS) (Linn et al., 1968; Miller et al., 1991; 1992)Mini Mental State Examination (MMSE) (Folstein et al., 1975)Rey-Osterrieth Complex Figure Test (ROCF) (Rey, 1941; Osterrieth, 1944)Montreal Cognitive Assessment (MoCA) (Nasreddine et al., 2005)Clock Drawing Test (Rouleau et al., 1992)Brief COPE (Carver, 1997)Centre for Epidemiologic Studies for Depression Scale (CES-D) (Radloff, 1977)Zung Self-Rating Anxiety Scale (SAS) (Zung, 1971)The Short Form (36) Health Survey (SF-36) (Ware and Sherbourne, 1992)Activities Of Daily Living (ADL) (Katz, 1963)Instrumental Activities Of Daily Living (IADL) (Lawton and Brody, 1969)


Casym, Lyon 25-6-13www.sanraffaele.it

Respiratory/ Cardiovascular

EchocardiogramCardiopulmonary Test24 hours ECG monitoringBlood gases analysisSpirometryExpectorate, BALNocturnal OximetrySt.George Respiratory Questionnaire (SGRQ) (Jones et al., 1991; Carone et al., 1999 )Maugeri Foundation Respiratory Failure Questionnaire (MRF26) (Carone et al., 1999 ; Vidotto et al., 2007)Modified Medical Research Council Dyspnoea Scale (MRC) (Dennis et al., 2006)6 Minute Walking Test (6MWT) (American Thoracic Society, 2002 ; Balke, 1963 ; Butland et al., 1982 ;)Bode Index for COPD (Celli et al., 2004; Cote and Celli, 2009)Modified Borg Dyspnoea Scale (Borg, 1982; Burdon, 1982)Barthel Index (Mahoney and Barthel, 1965)

Lung cancer Tumoral Markers (Cyfra 21-1, CEA, Enolasi) and miRNARadiological Findings (tumor size, H.U. value and morphological characteristics)Pathological Findings (histotype, grade, mitotic index, expression of bcl-2 and p53, immunohistochemical positivity for TTF-1)Genetic mutations on the surgical specimen (EGFR, ALK, K-RAS)


Casym, Lyon 25-6-13

Psychiatric Operational Criteria Checklist for psychotic and affective illness (OPCRIT) (McGuffin et al., 1991)Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962 )Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1960)Young Mania Rating Scale (YMRS) (Young, 1978)Hamilton Anxiety Scale (HAM-A) (Hamilton, 1959)Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987)

Headache The Migraine Disability Assessment Questionnaire (MIDAS) (Stewart et al., 1999; 2000 ;D’Amico et al., 2001) Headache Impact Test (HIT-6 TM) (Bayliss and Batenhorst, 2002; Kosinski et al., 2003)Visual Analogue Scale (VAS) (Scott and Huskisson, 1979)Neuropathic Pain Scale (Galer and Jensen, 1997; Bonezzi et al., 2000; Negri et al., 2002)

Alzheimer’s Disease Neuropsychiatric Inventory (NPI) (Cummings et al., 1994)Assessment of focal deficits (strenght, somatic sense, visive field)MDB (Mental Deterioration Battery) (Carlesimo et al., 1997): Rey’s Auditory Verbal Learning Test (RAVLT immediate and delayed recall)RAVLT RecognitionCopy of figures with and without landmarks, Digit Span Forward and Backward Stroop TestPhonological and Semantic Verbal FluencyMultiple Features Targets CancellationOral naming of nouns and actionRaven’s Colored Progressive Matrices


Casym, Lyon 25-6-13www.sanraffaele.it

Parkinson’s Disease Unified Parkinson’s Disease Rating Scale (UPDRS) (Fahn et al., 1987) Parkinson’s Disease Sleep Scale (PDSS) (Chaudhuri et al., 2002) The Epworth Sleepiness Scale (ESS) (Johns, 1991) Abnormal Involuntary Movement Scale (mAIMS) (Guy, 1976)Unified Diskinesia Rating Scale (UDysRS) (Goetz et al., 2008)MIDI Minnesota Impulsive Disorders Interview (MIDI) (Christenson et al., 1994)Progressive supranuclear Palsy Rating Scale (Golbeand Ohman-Strickland, 2007)Non Motor Symptoms scale and questionnaire (NMS) (Chaudhuri et al., 2006)Wearing Off Questionnaire (WOQ 19) (Abbruzzese et al. 2012)Unified Multiple System Atrophy Rating Scale (UMSARS) (Wenning et al. 2004)Beck Depression Inventory (BDI) (Beck et al. 1961)Parkinson’s Disease Questionnaire (PDQ-39) (Jenkinson et al., 1995; Peto et al., 1995) Neuropsychiatric Inventory (NPI) (Cummings et al., 1994)

Diabetes type 2 Specific blood testsFundus oculi examinationDoppler ultrasound of carotid and neck vessels, and of lower limbsCT angiography lower limbs Assessment of autonomy and peripheral neuropathyDiabetic foot screening


Biomedical research in the strict sense, with the characteristics of “holisticity” described, must be accompanied by a rigorous approach to the analysis of the aspects of managerial sustainability intended to optimise the utilisation of increasingly limited resources, in order to implement truly innovative and efficient best practices.

October 2013, Hon. Beatrice Lorenzin, Minister of Healthwww.quadernidellasalute.it

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