Prévia do material em texto
R O D c F J a U b U R A R 2 ev Clin Esp. 2017;217(5):252---259 www.elsevier.es/rce Revista Clínica Española RIGINAL ARTICLE iagnostic validity of hand gestures in chest pain of oronary origin� .J. Montero-Péreza,∗, F. de Borja Quero-Espinosaa, M.J. Clemente-Millána, .A. Castro-Giméneza, J. de Burgos-Marína, M.Á. Romero-Morenob Unidad de Gestión Clínica de Urgencias, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital niversitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain Unidad de Gestión Clínica de Cardiología, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital niversitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain eceived 25 October 2016; accepted 23 February 2017 vailable online 11 May 2017 KEYWORDS Emergency medicine; Chest pain; Gestures; Acute coronary syndrome Abstract Objectives: To determine the frequency of 3 hand gestures by patients with chest pain and determine the diagnostic validity of the gestures in acute coronary syndrome. Patients and methods: A prospective study was conducted on 383 adult patients treated for chest pain in an emergency department. We observed certain hand gestures, previously referred to in the medical literature as characteristic of coronary pain (gesture 1: a clenched fist held over the sternal area or Levine’s sign; gesture 2: open hand located over the same area; gesture 3: both hands placed in the center of the chest), as well as other gestures. We analyzed their association with the coronary origin of the pain. Results: We confirmed the coronary origin of the pain in 164 (43%) patients (ACS group). The other 219 patients (57%) did not have a coronary origin for the pain (nonACS group). Eighty- nine percent of the patients identified their pain with one of the 3 classical gestures. The most frequent gesture was number 2, both overall (59%) and by group (60% ACS group; 57.5% nonACS group). There was no significant association between the type of gesture and the final diagnosis (p = .172). The greater specificity corresponded to Levine’s sign (90%), followed by other gestures (86%) and gesture 3 (81%). � Please cite this article as: Montero-Pérez FJ, de Borja Quero-Espinosa F, Clemente-Millán MJ, Castro-Giménez JA, de Burgos-Marín J, omero-Moreno MÁ. Validez diagnóstica del lenguaje de las manos en el dolor torácico de origen coronario. Rev Clin Esp. 2017;217:252---259. ∗ Corresponding author. E-mail address: javiermonteroperez@gmail.com (F.J. Montero-Pérez). 254-8874/© 2016 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved. dx.doi.org/10.1016/j.rceng.2017.02.008 http://www.elsevier.es/rce http://crossmark.crossref.org/dialog/?doi=10.1016/j.rceng.2017.02.008&domain=pdf mailto:javiermonteroperez@gmail.com Diagnostic validity of hand gestures in chest pain of coronary origin 253 Conclusions: Although 89% of the patients expressed their chest pain with one of the 3 manual gestures classically associated with coronary pain, none achieved sufficient diagnostic accuracy to be used as indicative of this type of pain. © 2016 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved. PALABRAS CLAVE Medicina de urgencias; Dolor torácico; Gestos; Síndrome coronario agudo Validez diagnóstica del lenguaje de las manos en el dolor torácico de origen coronario Resumen Objetivos: Comprobar la frecuencia de 3 gestos realizados con las manos por los pacientes con dolor torácico y determinar su validez diagnóstica en el síndrome coronario agudo. Pacientes y métodos: Estudio prospectivo de 383 pacientes adultos asistidos en un servicio de urgencias por dolor torácico. Se observó la realización de determinados signos gestuales con las manos, previamente referidos en la literatura médica como característicos de dolor coronario (gesto 1: mano en puño dispuesta sobre zona esternal o signo de Levine; gesto 2: mano abierta situada en la misma localización; gesto 3: ambas manos colocadas en el centro del tórax), así como la de otros gestos. Se analizó su asociación con el origen coronario del dolor. Resultados: En 164 (43%) pacientes se confirmó el origen coronario del dolor (grupo SCA), y en 219 (57%) no se confirmó (grupo no SCA). Un 89% de pacientes identificaron su dolor con alguno de los 3 gestos clásicos. El más frecuente fue el 2, tanto globalmente (59%) como por grupos (60% grupo SCA; 57,5% grupo no SCA). No hubo asociación significativa entre el tipo de gesto realizado y el diagnóstico final (p = 0,172). La mayor especificidad correspondió al signo de Levine (90%), seguida de otros gestos (86%) y del gesto 3 (81%). Conclusiones: Aunque el 89% de los pacientes expresaron el dolor torácico con alguno de los 3 gestos manuales clásicamente asociados al dolor coronario, ninguno de ellos alcanzó suficiente precisión diagnóstica para ser utilizado como indicativo de este tipo de dolor. © 2016 Elsevier España, S.L.U. y Sociedad Española de Medicina Interna (SEMI). Todos los derechos reservados. T r p o p t o b t c i s c l t t u d p ( Background When faced with acute chest pain (ACP), the emergency physician must discern whether its origin is banal or caused by life-threatening disorders such as acute coronary syn- drome (ACS). ACP is a common symptom for consultation and repre- sents 5---15% of all emergency room care.1,2 In Spain,1,3,4 26---46% of ACP cases are initially considered an ACS but are subsequently discharged without confirming this diag- nosis. Nevertheless, 2---10% of patients who are sent home with the diagnosis of noncoronary ACP have an ACS, with a poorer prognosis than those who are correctly identified and hospitalized. The pillars for evaluating patients with ACP are the medi- cal history, physical examination, electrocardiogram and cardiac markers. Various clinical protocols, decision algo- rithms and scoring scales5---10 have subsequently attempted to improve the effectiveness and efficiency of the diagnosis of ACP but have not been validated to discern whether the origin of the ACP is coronary or not. When patients with ACP are asked questions such as ‘‘Where is the pain?’’ and ‘‘How does it feel?’’, many use hand movements to locate the pain and communi- cate its quality,11,12 graphically illustrating their symptoms. o c v herefore, important treaties on cardiology13---17 have eferred to Levine’s sign and others as suggestive or even athognomonic of the coronary origin of ACP. A closed fist ver the sternum (Levine’s sign,13 Fig. 1A) communicates a iercing quality for the pain. An extended hand describes he feeling of heaviness on the chest (Fig. 1B). A feeling f a constrictive band around the chest can be represented y the lateral movement of the palms of both hands from he center of the chest (Fig. 1C). Patients with pain of non- oronary origin could use other positions or movements to llustrate their pain, such as fingers above and below the ternum (esophageal pain) or an index finger (pain in the hest wall).18 There are scarce studies in the literature that have ana- yzed the validity of these signs in diagnosing ACS, and heir resultshttp://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0255 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0260 http://www.msssi.gob.es/estadEstudios/estadisticas/normalizacion/clasifEnferm/boletines/Codificacion_clinica_n05_96.pdf http://www.msssi.gob.es/estadEstudios/estadisticas/normalizacion/clasifEnferm/boletines/Codificacion_clinica_n05_96.pdf http://www.msssi.gob.es/estadEstudios/estadisticas/normalizacion/clasifEnferm/boletines/Codificacion_clinica_n05_96.pdf http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0270 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 y ori 2 2 2 3 3 Diagnostic validity of hand gestures in chest pain of coronar American College of Physicians, American Association for Tho- racic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60:e44---164. 24. O’Gara P, Kushner F, Ascheim D, Casey D, Chung M, de Lemos J, et al. 2013 ACC/AHA Guideline for the management of ST elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2013;61: e78---140. 25. Hamm C, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, et al. Guidelines for the management of acute coronary syn- dromes in patients presenting without persistent ST-segment elevation. The Task Force for the management of acute coro- nary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011;32:2999---3054. 26. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE, et al. 2012 ACCF/AHA focused update incorpo- rated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology 3 gin 259 Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61:e179---347. Erratum in: J Am Coll Cardiol 2013;62:1040---41. 7. Smeeth L, Skinner JS, Ashcroft J, Hemingway H, Timmis A. NICE clinical guidelines: chest pain of recent onset. Br J Gen Pract. 2010;60:7---10. 8. Catharine W, Burt E. Summary statistics for acute cardiac ischemia and chest pain visits to United States EDs 1995---96. Am J Emerg Med. 1999;17:552---9. 9. Fernández C, Fuentes M, del Prado N. Análisis e interpretación de un estudio en investigación clínica. In: Miró O, editor. Manual básico para el urgenciólogo investigador. De la idea original a la publicación final. Madrid: Ergon; 2013. p. 79---102. 0. Herbert R. Confidence Interval Calculator; 2013. Available from: http://www.pedro.org.au/spanish/downloads/confidence- interval-calculator/ [accessed 11.12.16]. 1. Doménech Massons JM. Métodos estadísticos en ciencias de la salud. Fundamentos de la teoría de la probabilidad. Prue- bas diagnósticas. Esplugues de Llobregat, Barcelona: Signo, SA; 1997. 2. Swartz MH. The heart. In: Swartz MH, editor. Textbook of phys- ical diagnosis: history and examination. Philadelphia: Elsevier Saunders; 2014. p. 343---89. http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0275 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0280 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0285 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0290 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0295 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0300 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0305 http://www.pedro.org.au/spanish/downloads/confidence-interval-calculator/ http://www.pedro.org.au/spanish/downloads/confidence-interval-calculator/ http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0315 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0320 Diagnostic validity of hand gestures in chest pain of coronary origin Background Patients and methods Design Literature search Study variables Data collection system Patient diagnosis and follow-up Statistical analysis Results Discussion Conflict of interests Referencesare not very conclusive, despite conducting he studies with patients previously selected from coronary nits.11,12 Therefore, this study analyzed the frequency and iagnostic validity of these gestures in a cohort of atients who visited the hospital emergency department HED) for ACP. The initial hypothesis was the language f hand gestures has diagnostic validity for identifying oronary ACP and distinguishing it from the noncoronary ariety. 254 F.J. Montero-Pérez et al. Figure 1 (A) Levine’s sign: clenched fist in the center of the chest. (B) Extended hand in the center of the chest. (C) Both hands p y Ed M P D T p A H P b d p w t f i a b o a L W g m c h R L ( s S T g r d o a i [ 2 h r s a g d s v laced in the center of the chest moving outwards (examined b arcus et al.12 atients and methods esign he prospective cohort study consisted of a sample of atients older than 14 years treated in an HED for CP, between June 1, 2013, and May 31, 2014. This ED treats approximately 125,000 emergency cases/year. atient selection was conducted using batch sampling. Each atch included all patients who consecutively visited for ACP uring the participating researchers’ workday. We excluded atients who refused to participate in the study, patients hose cognitive level, difficulties in communicating or func- ional limitation (apraxia, hemiparesis, etc.) impeded them rom performing the test and all patients with trauma- nduced ACP. The study was approved by the local research committee, nd all participants were asked for their informed consent. All patients underwent a case history for those varia- les included in the data collection sheet (DCS). The rest f the variables were obtained using the various computer pplications at the health center. iterature search e used the keywords ‘‘chest pain’’ and ‘‘body lan- uage’’, without a time restriction. We used the GERION etabrowser of the Virtual Library of the Public Health- are System of Andalusia, which uses the following t t A mondstone11 in 1995). (D and E) Other hand signs examined by ealth science databases: CINAHL, EMBASE, Educational esources Reported Center (ERIC), IME-Biomedicina, MED- INE, PubMed, and Scientific Electronic Library Online SciELO). We also analyzed the references included in the tudies found in the indicated bibliomedical databases. tudy variables he DCS contained the following variables: age, sex, pro- ression time of the pain, electrocardiogram-based coronary isk classification of the American Heart Association (AHA),19 iagnosis of ACP issued in the HED (cardiac, noncardiac r of uncertain origin), hospitalization in the observation rea (yes/no), patient destination (home, cardiology ward, ntensive care or other), type of hand gesture (gesture 1 clenched fist over the sternum or Levine’s sign], gesture [an open hand over the same location], gesture 3 [both ands over the center of the chest] or other signs), the esults of the coronary angiography (normal/pathological), erum troponin I readings (positive/negative), coronary ngiography by computed tomography (computed tomo- raphy angiography [CTA]) (normal/pathological), final iagnosis group (ACS/no ACS) and etiological diagno- is. The ‘‘final diagnosis group’’ was the dependent ariable. The considered gestures were represented graphically in he DCS and corresponded to the 3 most often described in he literature13,14 (Fig. 1A---C) as associated with coronary CP. y origin 255 Table 1 General characteristics of the cohort. Variables Patients Total n = 383 % Age (IQR) 66 (23) Sex Male 211 55 Female 172 45 Progression time of pain in hours (IQR) 4.56 (10) AHA classification of coronary risk according to ECG findings With ST elevation or new CLBBB 21 5.5 With ST reduction or dynamic T-wave inversion 33 8.6 Nondiagnostic ECG 329 86 Diagnosis of the pain reflected in the emergency department Cardiac 181 47 Noncardiac 134 82 Uncertain origin 68 18 Admission to observation No 191 50 Yes 192 50 Patient destination Home 228 60 Cardiology ward 117 30 ICU 19 5 Others 19 5 Final diagnosis of the pain of coronary origin (ACS group) Stable angina 28 7 Unstable angina 85 22 Acute myocardial infarction 39 10 Hemodynamic angina 12 3 Total group 164 100 Pain of noncoronary origin (nonACS group) Pericardial 19 5 Pulmonary 26 7 Gastrointestinal 6 2 Musculoskeletal 34 9 Psychogenic 14 4 ENT (pharyngolaryngeal) 1 0.30 Indeterminate 119 31 Total group 219 100 Abbreviations: ACS, acute coronary syndrome; AHA, Ameri- can Heart Association; CLBBB, complete left bundle branch block; ECG, electrocardiogram; ENT, otolaryngological origin; ICU, intensive care unit; IQR, interquartile range; ST, ST-segment Diagnostic validity of hand gestures in chest pain of coronar Data collection system Five HED physicians performed the case history and data collection for the patients included in the study. These researchers were initially trained using a correlation series on the same cases, until a kappa index of at least 80% was achieved. The interview was performed during the first contact with the patient. At that time, the evaluator was unaware of the exact diagnosis. The interview took place in the HED consultations area and, occasionally, in the obser- vation area. If there was hemodynamic instability or other condition that precluded the anamnesis in the HED, the appropriate treatment was applied and the anamnesis per- formed later, once the patient was stabilized. The type of hand sign was recorded after the researcher performed a standard introduction, ‘‘Show me where the pain is and tell me how it feels’’. The physician assigned the observed gesture to any of the drawings reflected in the DCS (Fig. 1A---C). Any other distinct sign was also recorded in the DCS. The results of the coronary angiography were considered pathological when there was a significant obstructive lesion (>50% of the lumen) in epicardial vessels larger than 2 mm in diameter.20 The laboratory data were obtained with the Nexus IT V.3.8.9.0 application (DigitasLBi Company). Serum tro- ponin I levels were determined by chemiluminescence with the Architect ci16200 analyzer (Abbott ® ), and lev- els >0.30 ng/mL were considered positive. The CTA of the coronary arteries was performed with a General Electric ® 64-slice scanner, using contrast with iopromide 370 (Ultravist ® ). Patient diagnosis and follow-up The patients were ultimately assigned to 2 diagnosis groups: the ACS group if a coronary origin was confirmed and nonACS group if there was another origin or the origin could not be confirmed. The confirmation of the coronary origin and its categorization (stable angina, unstable angina, hemody- namic angina or acute myocardial infarction) was performed according to current symptom-based criteria, peak troponin levels in the first 24 h, electrocardiogram, imaging study (CTA) and coronary angiography.21---26 The patients catego- rized with ‘‘hemodynamic angina’’ were encompassed with the nonACS group, except when there was evidence of a coronary lesion. The various types of noncoronary ACP were diagnosed according to standard criteria. To verify thefinal diagnosis of the episode, all cases were followed to discharge and for the following 12 months, reviewing the subsequent medical visits. For the patients for whom the diagnosis could not be verified, a telephone inter- view was conducted to confirm the onset of intercurrent coronary events or death by this cause. Statistical analysis The sample size calculation was performed to calculate a proportion of a finite population, considering that 5% of the patients treated in an HED2,27 are there for chest pain (in our case, 6250 cases of chest pain) and that the proportion of elevation. 2 i i l C c f s t i a r a s t t o v o s w p ( a c R W t ( a a c a c f 2 c d h ( F w e 1 t d 56 schemic heart disease is 10%.2,3,28 We accepted a maximum mprecision of ±3% and a 95% confidence level in the calcu- ation. The minimum calculated sample size was 362 cases. ases lost for any reason were replaced with the next case. The recorded data were entered into the computer appli- ation SPSS 17.0 (SPSS Inc., Released 2008. SPSS Statistics or Windows, Version 17.0, Chicago). The degree of interob- erver concordance of the interviewers on the same cases in he previous training phase was calculated using the kappa ndex. An index ≥0.80 (80%) was considered acceptable greement. We performed a univariate study using an absolute and elative frequency distribution. The quantitative variables re expressed with the arithmetic mean or median and its tandard deviation (SD) or interquartile range (IQR), respec- ively. The normal data distribution was determined using he Kolmogorov---Smirnov test. To analyze the association f the qualitative variables compared with the dependent ariable ‘‘coronary pain: yes/no’’, we employed the �2 test f bilateral significance, with Fisher’s exact test if neces- ary. We considered a por not. A diagnostic test is considered to have acceptable valid- ity if its sensitivity and specificity are ≥80%.31 In our study, the remaining signs (except gesture 2) considered in isola- tion had a specificity >80% but low sensitivity and predictive values, as well as insufficient diagnostic accuracy. In terms of likelihood ratios, which are independent of prevalence, the results show LR+ values slightly greater than 1 for ges- tures 1, 2 and 3 (1.20 for Levine’s sign), while none of the LR− were below 1. In 1995, Edmondstone11 published a brief article on the diagnostic validity of sign language in 203 patients with ACP in a coronary care unit. The ACP was coronary in 138 patients (68%) and noncoronary or indeterminate in 65 (32%), with a high proportion of patients with coronary pain compared with our study, given the origin of the patients. The author’s conclusion was that these signs are not discriminative for the diagnosis of coronary pain. Nevertheless, based on a sensitivity of 80% and a PPV of 77%, the author concluded that the performance of any of the 3 gestures could sup- t i e s rvals. ort the diagnosis of ACS. These results are not consistent ith those of our study, in which the PPV was only 45% when onsidering the performance of any of the 3 signs versus ther signs, although the sensitivity was high (93%). Never- heless, the LR+ and LR− of our study when considering, as id Edmondstone,11 the joint assessment of gestures 1, 2 nd 3 (Table 3) show the absence of diagnostic validity for hese signs. The study by Marcus et al.12 with 202 patients hospital- zed for ACP studied Levine’s sign (gesture 1), gesture 2 as in our study) and 2 other signs (Fig. 1D and E). Of the ncluded patients, 107 (53%) performed one of the 4 ges- ures: 11% performed Levine’s sign, 35% performed gesture , 16% performed gesture 3 (Fig. 1D), and 4% performed the ndex finger sign (Fig. 1E). Only the specificity of Levine’s ign (84%) was significant, which was similar to our study 89%). When comparing the results of these 2 prior studies nd the current study (Table 4), we observed that although he studies were performed in different settings, the studies ere not that different. Our study does not attempt to simplify the diagnostic act o a simple body expression. A medical diagnosis requires he integration of a variety of information, which at times s not well established, such as gestures, postures, verbal xpression and information from companions. The diagno- is is based on heuristic rules and conclusions that are 2 d n m t c p fi T g c s a e t i u p b o p d t t d v p p s g C T R 1 1 1 1 1 1 1 1 1 1 2 2 2 2 58 ifficult to identify. Therefore, a medical diagnosis (or diag- ostic hypothesis) is rarely based on a single aspect in the edical history or physical examination but rather requires he integration of complex and varied information to reach a onclusion. It is therefore not surprising that in this study the atient’s expression, considered in isolation, provides insuf- cient information to reach a secure diagnostic conclusion. he only intention was to quantify the diagnostic accuracy of estures that, in some cases such as Levine’s sign, have been onsidered useful in classical treaties13---17 and are still con- idered in some cases as having indisputable semiological32 nd even pathognomonical value for coronary artery dis- ase. It should also not be inferred from this study that he manner in which the patients express themselves has no mportance. Their expression is another link in a chain that ltimately leads to a diagnostic conclusion or hypothesis. The limitations of this study include the type of sampling erformed (by cluster), that each patient was interviewed y only one evaluator (although the previous analysis f agreement minimizes this limitation) and that not all atients underwent the same examinations to reach the final iagnosis (coronary angiography was performed on 40% of he patients, and coronary CTA was performed on 25% of he total sample). It is also possible that the patients with iabetes, due to their possible dysautonomia, could have ariations in pain intensity or location, which would mean a ossible selection bias. In conclusion, some hand signs that patients with ACP erform have a high frequency of use (89%), although the igns are not useful for determining a possible coronary ori- in. onflict of interests he authors declare that they have no conflicts of interest. eferences 1. Martínez-Sellés M, Bueno H, Sacristán A, Estévez A, Ortiz J, Gallego L, et al. Dolor torácico en urgencias. Frecuen- cia, perfil clínico y estratificación de riesgo. Rev Esp Cardiol. 2008;61:953---9. 2. García-Castrillo L, Loma-Osorio A, Recuerda Martínez E, Muñoz Cacho P. La cardiopatía isquémica en los servicios de urgencia hospitalarios. Proyecto EVICURE. Emergencias. 2000;12:183---90. 3. García-Castrillo L, Recuerda Martínez E, Loma-Osorio A, García-Camarero T, García-Cases C, Epelde Gonzalo F, et al. Características y manejo de los pacientes con dolor torácico no traumático en los servicios de urgencias hospitalarios. Resulta- dos del estudio EVICURE II. Emergencias. 2008;20:391---8. 4. Bueno H, Bardají A, Fernández-Ortiz A, Marrugat J, Martí H, Heras M. Manejo del síndrome coronario agudo sin elevación del segmento ST en España. Estudio DESCARTES (Descripción del Estado de los Síndromes Coronarios Agudos en un Registro Temporal Español). Rev Esp Cardiol. 2005;58:244---52. 5. Geleijnse ML, Elhendy A, Kasprzak JD, Rambaldi R, van Dom- burg RT, Cornel JH, et al. Safety and prognostic value of early dobutamine---atropine stress echocardiography in patients with spontaneous chest pain and a non-diagnostic electrocardio- gram. Eur Heart J. 2000;21:397---406. 6. Sanchis J, Bodí V, Núñez J, Bertomeu-González V, Gómez C, Bosch MJ, et al. New risk score for patients with acute chest F.J. Montero-Pérez et al. pain, non-ST-segment deviation, and normal troponin concen- trations: a comparison with the TIMI risk score. J Am Coll Cardiol. 2005;46:443---9. 7. Antman EM, Cohen M, Bernink PJ, McCabe CH, Horacek T, Papuchis G, et al. The TIMI risk score for unstable angina/non- ST elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2000;284:835---42. 8. Backus BE, Six AJ, Kelder JC, Mast TP, van den Akker F, Mast EG, et al. Chest pain in the emergency room: a multicenter vali- dation of the HEART Score. Crit Pathw Cardiol. 2010;9:164---9. 9. Fox KA, Dabbous OH, Goldberg RJ, Pieper KS, Eagle KA, van de Werf F, et al. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coro- nary syndrome: prospective multinational observational study (GRACE). BMJ. 2006;333:1091---4. 0. Filipiak KJ, Koltowski L, Grabowski M, Karpinski G, Glowczynska R, Huczek Z, et al. Prospective comparison of the 5 most popular risk scores in clinical use for unselected patients with acute coronary syndrome. Circ J. 2011;75:167---73. 1. Edmondstone WM. Cardiac chest pain: does body language help the diagnosis? BMJ. 1995;311:1660---1. 2. Marcus GM, Cohen J, Varosy PD, Vessey J, Rose E, Massie BM. The utility of gestures in patients with chest discomfort. Am J Med. 2007;120:83---9. 3. Levine S. Clinical heart disease. 5th ed. Philadelphia and Lon- don: WB Saunders Company; 1958. 4. Braunwald E. Thehistory. In: Braunwald E, editor. Heart disease. Philadelphia: Saunders; 1992. p. 1---13. 5. Topol EJ, editor. Textbook of cardiovascular medicine. Philadel- phia, PA: Lippincott-Raven; 1998. 6. Braunwald E, Zipes D, Libby P, editors. Heart disease. 6th ed. Philadelphia, PA: WB Saunders Company; 2001. 7. Fuster V, Alexander RW, O’Rourke RA, editors. Hurst’s the heart. 11th ed. York, PA: McGraw-Hill; 2004. 8. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment eleva- tion myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol. 2000;36:970---1062. 9. O’Connor RE, Brady W, Brooks SC, Diercks D, Egan J, Ghaem- maghami C, et al. Part 10: Acute coronary syndromes. 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122 Suppl. 3:S787---817. 0. Piers LH, Dikkers R, Willems TP, de Smet BJ, Oudkerk M, Zijlstra F, et al. Computed tomographic angiography or conventional coronary angiography in therapeutic decision-making. Eur Heart J. 2008;29:2902---7. 1. Rivero Cuadrado A. Unidad Técnica de la CIE-9-MC para el Sistema Nacional de Salud. Codificación clínica con la CIE-9-MC. Tema monográfico: cardiopatía isquémica. Boletín 5, Año II. Madrid: Ministerio de Sanidad y Consumo. Subdirección General de Recursos y Atención al Ciudadano; October 1996. Available from: http://www.msssi.gob.es/estadEstudios/estadisticas/ normalizacion/clasifEnferm/boletines/Codificacion clinica n05 96.pdf [accessed 11.12.16]. 2. Thygesen C, Alpert J, Jaffe A, Simoons L, Chaitman B, Whaite H, et al. Documento de consenso de expertos. Tercera definición universal de infarto de miocardio. Rev Esp Cardiol. 2013;66, 132.e1---e15. 3. Fihn S, Gardin J, Abrams J, Berra K, Blankenship J, Dallas A, et al. ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guide- line for the diagnosis and management of patients with stable ischemic heart disease: a report of the Ameri- can College of Cardiology Foundation/American Heart Association Task Force on practice guidelines, and the http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0165 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0170 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0175 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0180 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0185 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0190 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0195 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0200 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0205 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0210 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0215 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0215 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0215 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0215 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0215 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0215 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0215 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0215 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0215 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0215 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0215 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0215 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0215 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0215 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0215 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0215 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0215 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0220 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0225 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0225 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0225 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0225 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0225 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0225 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0225 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0225 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0225 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0225 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0225 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0225 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0225http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0225 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0225 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0225 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0230 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0235 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0235 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0235 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0235 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0235 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0235 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0235 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0235 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0235 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0235 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0235 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0235 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0235 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0235 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0235 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0235 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0235 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0240 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0245 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250 http://refhub.elsevier.com/S2254-8874(17)30054-1/sbref0250
Mais conteúdos dessa disciplina
CondutasFisioterapeuticasUtilizadas- Questões Comentadas em Fisioterapia
- PILATES_Magic Circle- OncologiaVOLL
- Mapa Mental - Fisioterapia Oncológica
- Aula 1 CIF - NEUROPEDIATRIA
- FLUJOGRAMA DE MANEJO CLINICO COVID PARAGUAY
- Mapa mental dos principais tópicos TRAUMA RAQUIMEDULAR - Resumo
- Avaliação Fisioterapêutica
- São objetivos dos exercícios para hipercifose torácica, exceto[...]. Escolha uma opção: a. Alongamento de região peitoral. b. Fortalecimento do dorso.
- Um paciente com suspeita de acidente vascular cerebral (AVC) deve ser avaliado rapidamente. Qual é a escala de avaliação neurológica utilizada para qu
- A Prática Baseada em Evidências (PBE) integra três elementos fundamentais: a melhor evidência científica disponível, a experiência clínica do profissi
- Por quanto tempo o formulário preenchido durante uma visita multidisciplinar deve permanecer na prancheta do paciente?Obrigatório
- As articulações esternoclavicular e acromioclavicular da cintura escapular permitem significativa quantidade de movimentos do membro e, combinadas ...
- O que é a Medicina Baseada em Evidências (MBE)? Nenhuma das alternativas. É um movimento de cientistas, médicos e profissionais da saúde na tentativa
- AsAs condições agudas receberam atenção em todos os modelos de atenção. Apesar disso, ainda hoje o tratamento dessas condições enfrenta diversos de...
- Um indicador de qualidade de laboratório importante para pacientes em diálise peritoneal é a taxa de peritonite. A metas recomendada é: A 1 episó...
- quais exercicios são indicados para diastase abdominal
- Quais as atividades da vida diária
- iversos fatores podem interferir no desenvolvimento infantil. Um ambiente acolhedor, boas relações familiares, estímulos adequados, herança genética e
- Com base nos fundamentos da intervenção clínica mediada por impressão 3D na Terapia Ocupacional, assinale a alternativa correta: Opções da pergunta 2:
- A drenagem linfática manual (DLM) é uma técnica amplamente utilizada na estética e na fisioterapia, visando melhorar a circulação da linfa e reduzi...
- HISTÓRIA E FUNDAMENTOS DA FISIOTERAPIA
- QUESTIONÁRIO UNIDADE I FISIO INTEGRADA
