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Pulmonary hypertension, primary, 4(PPH4)

MedGen UID:
815528
Concept ID:
C3809198
Disease or Syndrome
Synonyms: PPH4; PULMONARY HYPERTENSION, PRIMARY, 4
 
Gene (location): KCNK3 (2p23.3)
 
Monarch Initiative: MONDO:0014136
OMIM®: 615344

Definition

Primary pulmonary hypertension is a rare progressive disease characterized by increased pulmonary artery pressure in the absence of common causes of pulmonary hypertension, such as chronic heart, lung, or thromboembolic disease. There is often vascular remodeling. The clinical presentation can be nonspecific, and patients often receive a diagnosis late in their clinical course (summary by Ma et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of primary pulmonary hypertension, see PPH1 (178600). [from OMIM]

Additional description

From MedlinePlus Genetics
Signs and symptoms of pulmonary arterial hypertension occur when increased blood pressure cannot fully overcome the elevated resistance. As a result, the flow of oxygenated blood from the lungs to the rest of the body is insufficient. Shortness of breath (dyspnea) during exertion and fainting spells are the most common symptoms of pulmonary arterial hypertension. People with this disorder may experience additional symptoms, particularly as the condition worsens. Other symptoms include dizziness, swelling (edema) of the ankles or legs, chest pain, and a rapid heart rate.

Pulmonary arterial hypertension is a progressive disorder characterized by abnormally high blood pressure (hypertension) in the pulmonary artery, the blood vessel that carries blood from the heart to the lungs. Pulmonary arterial hypertension is one form of a broader condition known as pulmonary hypertension. Pulmonary hypertension occurs when most of the very small arteries throughout the lungs narrow in diameter, which increases the resistance to blood flow through the lungs. To overcome the increased resistance, blood pressure increases in the pulmonary artery and in the right ventricle of the heart, which is the chamber that pumps blood into the pulmonary artery. Ultimately, the increased blood pressure can damage the right ventricle of the heart.  https://medlineplus.gov/genetics/condition/pulmonary-arterial-hypertension

Clinical features

From HPO
Atrial flutter
MedGen UID:
13955
Concept ID:
C0004239
Pathologic Function
A type of atrial arrhythmia characterized by atrial rates of between 240 and 400 beats per minute and some degree of atrioventricular node conduction block. Typically, the ventricular rate is half the atrial rate. In the EKG; atrial flutter waves are observed as sawtooth-like atrial activity. Pathophysiologically, atrial flutter is a form of atrial reentry in which there is a premature electrical impulse creates a self-propagating circuit.
First degree atrioventricular block
MedGen UID:
43215
Concept ID:
C0085614
Disease or Syndrome
Delay of conduction through the atrioventricular node, which is manifested as prolongation of the PR interval in the electrocardiogram (EKG). All atrial impulses reach the ventricles.
Right bundle branch block
MedGen UID:
88445
Concept ID:
C0085615
Disease or Syndrome
A conduction block of the right branch of the bundle of His. This manifests as a prolongation of the QRS complex (greater than 0.12 s) with delayed activation of the right ventricle and terminal delay on the EKG.
Increased pulmonary vascular resistance
MedGen UID:
356775
Concept ID:
C1867423
Finding
Pulmonary vascular resistance (PVR) more than 3 wood units, as defined by the current definition of pulmonary hypertension. 95% of individuals have a PVR of less than 2.4 wood units.
Pulmonary arterial hypertension
MedGen UID:
425404
Concept ID:
C2973725
Disease or Syndrome
Pulmonary hypertension is defined mean pulmonary artery pressure of 25mmHg or more and pulmonary capillary wedge pressure of 15mmHg or less when measured by right heart catheterisation at rest and in a supine position.
Elevated pulmonary artery pressure
MedGen UID:
812247
Concept ID:
C3805917
Finding
An abnormally elevated blood pressure in the circulation of the pulmonary artery.
Pulmonary arterial hypertension with lack of acute response to NO challenge
MedGen UID:
1783495
Concept ID:
C5539584
Disease or Syndrome
A form of pulmonary arterial hypertension with lack of adequate hemodynamic response to NO challenge (adequate response is defined as a reduction of mean pulmonary artery pressure (mPAP) of at least 10 mmHg to reach an absolute value of mPAP 40 mmHg or less with an increased or unchanged cardiac output (CO) in response to inhaled nitric oxide at 10-20 ppm).
Thromboembolism
MedGen UID:
21532
Concept ID:
C0040038
Pathologic Function
The formation of a blood clot inside a blood vessel that subsequently travels through the blood stream from the site where it formed to another location in the body, generally leading to vascular occlusion at the distant site.

Professional guidelines

PubMed

Sánchez-de-la-Torre M, Gracia-Lavedan E, Benitez ID, Sánchez-de-la-Torre A, Moncusí-Moix A, Torres G, Loffler K, Woodman R, Adams R, Labarca G, Dreyse J, Eulenburg C, Thunström E, Glantz H, Peker Y, Anderson C, McEvoy D, Barbé F
JAMA 2023 Oct 3;330(13):1255-1265. doi: 10.1001/jama.2023.17465. PMID: 37787793Free PMC Article
Attard G, Murphy L, Clarke NW, Cross W, Jones RJ, Parker CC, Gillessen S, Cook A, Brawley C, Amos CL, Atako N, Pugh C, Buckner M, Chowdhury S, Malik Z, Russell JM, Gilson C, Rush H, Bowen J, Lydon A, Pedley I, O'Sullivan JM, Birtle A, Gale J, Srihari N, Thomas C, Tanguay J, Wagstaff J, Das P, Gray E, Alzoueb M, Parikh O, Robinson A, Syndikus I, Wylie J, Zarkar A, Thalmann G, de Bono JS, Dearnaley DP, Mason MD, Gilbert D, Langley RE, Millman R, Matheson D, Sydes MR, Brown LC, Parmar MKB, James ND; Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators
Lancet 2022 Jan 29;399(10323):447-460. Epub 2021 Dec 23 doi: 10.1016/S0140-6736(21)02437-5. PMID: 34953525Free PMC Article
Gurnani M, Birken C, Hamilton J
Pediatr Clin North Am 2015 Aug;62(4):821-40. Epub 2015 May 23 doi: 10.1016/j.pcl.2015.04.001. PMID: 26210619

Recent clinical studies

Etiology

Kovacs G, Bartolome S, Denton CP, Gatzoulis MA, Gu S, Khanna D, Badesch D, Montani D
Eur Respir J 2024 Oct;64(4) Epub 2024 Oct 31 doi: 10.1183/13993003.01324-2024. PMID: 39209475Free PMC Article
Rosenkranz S, Pausch C, Coghlan JG, Huscher D, Pittrow D, Grünig E, Staehler G, Vizza CD, Gall H, Distler O, Delcroix M, Ghofrani HA, Ewert R, Kabitz HJ, Skowasch D, Behr J, Milger K, Halank M, Wilkens H, Seyfarth HJ, Held M, Scelsi L, Neurohr C, Vonk-Noordegraaf A, Ulrich S, Klose H, Claussen M, Eisenmann S, Schmidt KH, Remppis BA, Skride A, Jureviciene E, Gumbiene L, Miliauskas S, Löffler-Ragg J, Lange TJ, Olsson KM, Hoeper MM, Opitz C
J Heart Lung Transplant 2023 Jan;42(1):102-114. Epub 2022 Oct 13 doi: 10.1016/j.healun.2022.10.003. PMID: 36333206
Chang KY, Duval S, Badesch DB, Bull TM, Chakinala MM, De Marco T, Frantz RP, Hemnes A, Mathai SC, Rosenzweig EB, Ryan JJ, Thenappan T; PHAR Investigators *
J Am Heart Assoc 2022 May 3;11(9):e024969. Epub 2022 Apr 27 doi: 10.1161/JAHA.121.024969. PMID: 35475351Free PMC Article
Poch D, Mandel J
Ann Intern Med 2021 Apr;174(4):ITC49-ITC64. Epub 2021 Apr 13 doi: 10.7326/AITC202104200. PMID: 33844574
Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani HA, Jansa P, Jing ZC, Le Brun FO, Mehta S, Mittelholzer CM, Perchenet L, Sastry BK, Sitbon O, Souza R, Torbicki A, Zeng X, Rubin LJ, Simonneau G; SERAPHIN Investigators
N Engl J Med 2013 Aug 29;369(9):809-18. doi: 10.1056/NEJMoa1213917. PMID: 23984728

Diagnosis

Kovacs G, Bartolome S, Denton CP, Gatzoulis MA, Gu S, Khanna D, Badesch D, Montani D
Eur Respir J 2024 Oct;64(4) Epub 2024 Oct 31 doi: 10.1183/13993003.01324-2024. PMID: 39209475Free PMC Article
Jone PN, Ivy DD, Hauck A, Karamlou T, Truong U, Coleman RD, Sandoval JP, Del Cerro Marín MJ, Eghtesady P, Tillman K, Krishnan US
Circ Heart Fail 2023 Jul;16(7):e00080. Epub 2023 Jun 26 doi: 10.1161/HHF.0000000000000080. PMID: 37357777
Hoeper MM, Pausch C, Grünig E, Staehler G, Huscher D, Pittrow D, Olsson KM, Vizza CD, Gall H, Distler O, Opitz C, Gibbs JSR, Delcroix M, Ghofrani HA, Rosenkranz S, Park DH, Ewert R, Kaemmerer H, Lange TJ, Kabitz HJ, Skowasch D, Skride A, Claussen M, Behr J, Milger K, Halank M, Wilkens H, Seyfarth HJ, Held M, Dumitrescu D, Tsangaris I, Vonk-Noordegraaf A, Ulrich S, Klose H
Eur Respir J 2022 Jun;59(6) Epub 2022 Jun 2 doi: 10.1183/13993003.02024-2021. PMID: 34675047Free PMC Article
Poch D, Mandel J
Ann Intern Med 2021 Apr;174(4):ITC49-ITC64. Epub 2021 Apr 13 doi: 10.7326/AITC202104200. PMID: 33844574
Cartin-Ceba R, Krowka MJ
Clin Liver Dis 2014 May;18(2):421-38. Epub 2014 Feb 25 doi: 10.1016/j.cld.2014.01.004. PMID: 24679504

Therapy

Kovacs G, Bartolome S, Denton CP, Gatzoulis MA, Gu S, Khanna D, Badesch D, Montani D
Eur Respir J 2024 Oct;64(4) Epub 2024 Oct 31 doi: 10.1183/13993003.01324-2024. PMID: 39209475Free PMC Article
Grünig E, Jansa P, Fan F, Hauser JA, Pannaux M, Morganti A, Rofael H, Chin KM
J Am Coll Cardiol 2024 Jan 30;83(4):473-484. doi: 10.1016/j.jacc.2023.10.045. PMID: 38267108
Hoeper MM, Badesch DB, Ghofrani HA, Gibbs JSR, Gomberg-Maitland M, McLaughlin VV, Preston IR, Souza R, Waxman AB, Grünig E, Kopeć G, Meyer G, Olsson KM, Rosenkranz S, Xu Y, Miller B, Fowler M, Butler J, Koglin J, de Oliveira Pena J, Humbert M; STELLAR Trial Investigators
N Engl J Med 2023 Apr 20;388(16):1478-1490. Epub 2023 Mar 6 doi: 10.1056/NEJMoa2213558. PMID: 36877098
Waxman A, Restrepo-Jaramillo R, Thenappan T, Ravichandran A, Engel P, Bajwa A, Allen R, Feldman J, Argula R, Smith P, Rollins K, Deng C, Peterson L, Bell H, Tapson V, Nathan SD
N Engl J Med 2021 Jan 28;384(4):325-334. Epub 2021 Jan 13 doi: 10.1056/NEJMoa2008470. PMID: 33440084
Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani HA, Jansa P, Jing ZC, Le Brun FO, Mehta S, Mittelholzer CM, Perchenet L, Sastry BK, Sitbon O, Souza R, Torbicki A, Zeng X, Rubin LJ, Simonneau G; SERAPHIN Investigators
N Engl J Med 2013 Aug 29;369(9):809-18. doi: 10.1056/NEJMoa1213917. PMID: 23984728

Prognosis

Rosenkranz S, Pausch C, Coghlan JG, Huscher D, Pittrow D, Grünig E, Staehler G, Vizza CD, Gall H, Distler O, Delcroix M, Ghofrani HA, Ewert R, Kabitz HJ, Skowasch D, Behr J, Milger K, Halank M, Wilkens H, Seyfarth HJ, Held M, Scelsi L, Neurohr C, Vonk-Noordegraaf A, Ulrich S, Klose H, Claussen M, Eisenmann S, Schmidt KH, Remppis BA, Skride A, Jureviciene E, Gumbiene L, Miliauskas S, Löffler-Ragg J, Lange TJ, Olsson KM, Hoeper MM, Opitz C
J Heart Lung Transplant 2023 Jan;42(1):102-114. Epub 2022 Oct 13 doi: 10.1016/j.healun.2022.10.003. PMID: 36333206
Hoeper MM, Pausch C, Grünig E, Staehler G, Huscher D, Pittrow D, Olsson KM, Vizza CD, Gall H, Distler O, Opitz C, Gibbs JSR, Delcroix M, Ghofrani HA, Rosenkranz S, Park DH, Ewert R, Kaemmerer H, Lange TJ, Kabitz HJ, Skowasch D, Skride A, Claussen M, Behr J, Milger K, Halank M, Wilkens H, Seyfarth HJ, Held M, Dumitrescu D, Tsangaris I, Vonk-Noordegraaf A, Ulrich S, Klose H
Eur Respir J 2022 Jun;59(6) Epub 2022 Jun 2 doi: 10.1183/13993003.02024-2021. PMID: 34675047Free PMC Article
Condon DF, Agarwal S, Chakraborty A, Auer N, Vazquez R, Patel H, Zamanian RT, de Jesus Perez VA
Chest 2022 Apr;161(4):1060-1072. Epub 2021 Oct 13 doi: 10.1016/j.chest.2021.10.010. PMID: 34655569Free PMC Article
Blay JY, Serrano C, Heinrich MC, Zalcberg J, Bauer S, Gelderblom H, Schöffski P, Jones RL, Attia S, D'Amato G, Chi P, Reichardt P, Meade J, Shi K, Ruiz-Soto R, George S, von Mehren M
Lancet Oncol 2020 Jul;21(7):923-934. Epub 2020 Jun 5 doi: 10.1016/S1470-2045(20)30168-6. PMID: 32511981Free PMC Article
Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M; “MOPETT” Investigators
Am J Cardiol 2013 Jan 15;111(2):273-7. Epub 2012 Oct 24 doi: 10.1016/j.amjcard.2012.09.027. PMID: 23102885

Clinical prediction guides

Rosenkranz S, Pausch C, Coghlan JG, Huscher D, Pittrow D, Grünig E, Staehler G, Vizza CD, Gall H, Distler O, Delcroix M, Ghofrani HA, Ewert R, Kabitz HJ, Skowasch D, Behr J, Milger K, Halank M, Wilkens H, Seyfarth HJ, Held M, Scelsi L, Neurohr C, Vonk-Noordegraaf A, Ulrich S, Klose H, Claussen M, Eisenmann S, Schmidt KH, Remppis BA, Skride A, Jureviciene E, Gumbiene L, Miliauskas S, Löffler-Ragg J, Lange TJ, Olsson KM, Hoeper MM, Opitz C
J Heart Lung Transplant 2023 Jan;42(1):102-114. Epub 2022 Oct 13 doi: 10.1016/j.healun.2022.10.003. PMID: 36333206
Ogo T, Shimokawahara H, Kinoshita H, Sakao S, Abe K, Matoba S, Motoki H, Takama N, Ako J, Ikeda Y, Joho S, Maki H, Saeki T, Sugano T, Tsujino I, Yoshioka K, Shiota N, Tanaka S, Yamamoto C, Tanabe N, Tatsumi K; Study Group
Eur Respir J 2022 Jul;60(1) Epub 2022 Jul 7 doi: 10.1183/13993003.01694-2021. PMID: 34824052Free PMC Article
Hoeper MM, Pausch C, Grünig E, Staehler G, Huscher D, Pittrow D, Olsson KM, Vizza CD, Gall H, Distler O, Opitz C, Gibbs JSR, Delcroix M, Ghofrani HA, Rosenkranz S, Park DH, Ewert R, Kaemmerer H, Lange TJ, Kabitz HJ, Skowasch D, Skride A, Claussen M, Behr J, Milger K, Halank M, Wilkens H, Seyfarth HJ, Held M, Dumitrescu D, Tsangaris I, Vonk-Noordegraaf A, Ulrich S, Klose H
Eur Respir J 2022 Jun;59(6) Epub 2022 Jun 2 doi: 10.1183/13993003.02024-2021. PMID: 34675047Free PMC Article
Zhang J, Gajjala S, Agrawal P, Tison GH, Hallock LA, Beussink-Nelson L, Lassen MH, Fan E, Aras MA, Jordan C, Fleischmann KE, Melisko M, Qasim A, Shah SJ, Bajcsy R, Deo RC
Circulation 2018 Oct 16;138(16):1623-1635. doi: 10.1161/CIRCULATIONAHA.118.034338. PMID: 30354459Free PMC Article
Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani HA, Jansa P, Jing ZC, Le Brun FO, Mehta S, Mittelholzer CM, Perchenet L, Sastry BK, Sitbon O, Souza R, Torbicki A, Zeng X, Rubin LJ, Simonneau G; SERAPHIN Investigators
N Engl J Med 2013 Aug 29;369(9):809-18. doi: 10.1056/NEJMoa1213917. PMID: 23984728

Recent systematic reviews

Sánchez-de-la-Torre M, Gracia-Lavedan E, Benitez ID, Sánchez-de-la-Torre A, Moncusí-Moix A, Torres G, Loffler K, Woodman R, Adams R, Labarca G, Dreyse J, Eulenburg C, Thunström E, Glantz H, Peker Y, Anderson C, McEvoy D, Barbé F
JAMA 2023 Oct 3;330(13):1255-1265. doi: 10.1001/jama.2023.17465. PMID: 37787793Free PMC Article
Morris NR, Kermeen FD, Jones AW, Lee JY, Holland AE
Cochrane Database Syst Rev 2023 Mar 22;3(3):CD011285. doi: 10.1002/14651858.CD011285.pub3. PMID: 36947725Free PMC Article
Global Burden of Disease 2019 Cancer Collaboration, Kocarnik JM, Compton K, Dean FE, Fu W, Gaw BL, Harvey JD, Henrikson HJ, Lu D, Pennini A, Xu R, Ababneh E, Abbasi-Kangevari M, Abbastabar H, Abd-Elsalam SM, Abdoli A, Abedi A, Abidi H, Abolhassani H, Adedeji IA, Adnani QES, Advani SM, Afzal MS, Aghaali M, Ahinkorah BO, Ahmad S, Ahmad T, Ahmadi A, Ahmadi S, Ahmed Rashid T, Ahmed Salih Y, Akalu GT, Aklilu A, Akram T, Akunna CJ, Al Hamad H, Alahdab F, Al-Aly Z, Ali S, Alimohamadi Y, Alipour V, Aljunid SM, Alkhayyat M, Almasi-Hashiani A, Almasri NA, Al-Maweri SAA, Almustanyir S, Alonso N, Alvis-Guzman N, Amu H, Anbesu EW, Ancuceanu R, Ansari F, Ansari-Moghaddam A, Antwi MH, Anvari D, Anyasodor AE, Aqeel M, Arabloo J, Arab-Zozani M, Aremu O, Ariffin H, Aripov T, Arshad M, Artaman A, Arulappan J, Asemi Z, Asghari Jafarabadi M, Ashraf T, Atorkey P, Aujayeb A, Ausloos M, Awedew AF, Ayala Quintanilla BP, Ayenew T, Azab MA, Azadnajafabad S, Azari Jafari A, Azarian G, Azzam AY, Badiye AD, Bahadory S, Baig AA, Baker JL, Balakrishnan S, Banach M, Bärnighausen TW, Barone-Adesi F, Barra F, Barrow A, Behzadifar M, Belgaumi UI, Bezabhe WMM, Bezabih YM, Bhagat DS, Bhagavathula AS, Bhardwaj N, Bhardwaj P, Bhaskar S, Bhattacharyya K, Bhojaraja VS, Bibi S, Bijani A, Biondi A, Bisignano C, Bjørge T, Bleyer A, Blyuss O, Bolarinwa OA, Bolla SR, Braithwaite D, Brar A, Brenner H, Bustamante-Teixeira MT, Butt NS, Butt ZA, Caetano Dos Santos FL, Cao Y, Carreras G, Catalá-López F, Cembranel F, Cerin E, Cernigliaro A, Chakinala RC, Chattu SK, Chattu VK, Chaturvedi P, Chimed-Ochir O, Cho DY, Christopher DJ, Chu DT, Chung MT, Conde J, Cortés S, Cortesi PA, Costa VM, Cunha AR, Dadras O, Dagnew AB, Dahlawi SMA, Dai X, Dandona L, Dandona R, Darwesh AM, das Neves J, De la Hoz FP, Demis AB, Denova-Gutiérrez E, Dhamnetiya D, Dhimal ML, Dhimal M, Dianatinasab M, Diaz D, Djalalinia S, Do HP, Doaei S, Dorostkar F, Dos Santos Figueiredo FW, Driscoll TR, Ebrahimi H, Eftekharzadeh S, El Tantawi M, El-Abid H, Elbarazi I, Elhabashy HR, Elhadi M, El-Jaafary SI, Eshrati B, Eskandarieh S, Esmaeilzadeh F, Etemadi A, Ezzikouri S, Faisaluddin M, Faraon EJA, Fares J, Farzadfar F, Feroze AH, Ferrero S, Ferro Desideri L, Filip I, Fischer F, Fisher JL, Foroutan M, Fukumoto T, Gaal PA, Gad MM, Gadanya MA, Gallus S, Gaspar Fonseca M, Getachew Obsa A, Ghafourifard M, Ghashghaee A, Ghith N, Gholamalizadeh M, Gilani SA, Ginindza TG, Gizaw ATT, Glasbey JC, Golechha M, Goleij P, Gomez RS, Gopalani SV, Gorini G, Goudarzi H, Grosso G, Gubari MIM, Guerra MR, Guha A, Gunasekera DS, Gupta B, Gupta VB, Gupta VK, Gutiérrez RA, Hafezi-Nejad N, Haider MR, Haj-Mirzaian A, Halwani R, Hamadeh RR, Hameed S, Hamidi S, Hanif A, Haque S, Harlianto NI, Haro JM, Hasaballah AI, Hassanipour S, Hay RJ, Hay SI, Hayat K, Heidari G, Heidari M, Herrera-Serna BY, Herteliu C, Hezam K, Holla R, Hossain MM, Hossain MBH, Hosseini MS, Hosseini M, Hosseinzadeh M, Hostiuc M, Hostiuc S, Househ M, Hsairi M, Huang J, Hugo FN, Hussain R, Hussein NR, Hwang BF, Iavicoli I, Ibitoye SE, Ida F, Ikuta KS, Ilesanmi OS, Ilic IM, Ilic MD, Irham LM, Islam JY, Islam RM, Islam SMS, Ismail NE, Isola G, Iwagami M, Jacob L, Jain V, Jakovljevic MB, Javaheri T, Jayaram S, Jazayeri SB, Jha RP, Jonas JB, Joo T, Joseph N, Joukar F, Jürisson M, Kabir A, Kahrizi D, Kalankesh LR, Kalhor R, Kaliyadan F, Kalkonde Y, Kamath A, Kameran Al-Salihi N, Kandel H, Kapoor N, Karch A, Kasa AS, Katikireddi SV, Kauppila JH, Kavetskyy T, Kebede SA, Keshavarz P, Keykhaei M, Khader YS, Khalilov R, Khan G, Khan M, Khan MN, Khan MAB, Khang YH, Khater AM, Khayamzadeh M, Kim GR, Kim YJ, Kisa A, Kisa S, Kissimova-Skarbek K, Kopec JA, Koteeswaran R, Koul PA, Koulmane Laxminarayana SL, Koyanagi A, Kucuk Bicer B, Kugbey N, Kumar GA, Kumar N, Kumar N, Kurmi OP, Kutluk T, La Vecchia C, Lami FH, Landires I, Lauriola P, Lee SW, Lee SWH, Lee WC, Lee YH, Leigh J, Leong E, Li J, Li MC, Liu X, Loureiro JA, Lunevicius R, Magdy Abd El Razek M, Majeed A, Makki A, 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