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1. Laparoscopy in children and its impact on brain oxygenation during routine inguinal hernia repair

Author

Gloria Pelizzo, Luciano Bernardi, Veronica Carlini, Noemi Pasqua, Simonetta Mencherini, Giuseppe Maggio, Annalisa De Silvestri, Lucio Bianchi, and Valeria Calcaterra

Subjects
Brain oxygenation, children, laparoscopy, near-infrared spectroscopy, Surgery, RD1-811, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background: The systemic impact of intra-abdominal pressure (IAP) and/or changes in carbon dioxide (CO2) during laparoscopy are not yet well defined. Changes in brain oxygenation have been reported as a possible cause of cerebral hypotension and perfusion. The side effects of anaesthesia could also be involved in these changes, especially in children. To date, no data have been reported on brain oxygenation during routine laparoscopy in paediatric patients. Patients and Methods: Brain and peripheral oxygenation were investigated in 10 children (8 male, 2 female) who underwent elective minimally invasive surgery for inguinal hernia repair. Intraoperative transcranial near-infrared spectroscopy to assess regional cerebral oxygen saturation (rScO2), peripheral oxygen saturation using pulse oximetry and heart rate (HR) were monitored at five surgical intervals: Induction of anaesthesia (baseline T1); before CO2insufflation induced pneumoperitoneum (PP) (T2); CO2PP insufflation (T3); cessation of CO2PP (T4); before extubation (T5). Results: rScO2decreases were recorded immediately after T1 and became significant after insufflation (P = 0.006; rScO2decreased 3.6 ± 0.38%); restoration of rScO2was achieved after PP cessation (P = 0.007). The changes in rScO2were primarily due to IAP increases (P = 0.06). The HR changes were correlated to PP pressure (P < 0.001) and CO2flow rate (P = 0.001). No significant peripheral effects were noted. Conclusions: The increase in IAP is a critical determinant in cerebral oxygenation stability during laparoscopic procedures. However, the impact of anaesthesia on adaptive changes should not be underestimated. Close monitoring and close collaboration between the members of the multidisciplinary paediatric team are essential to guarantee the patient's safety during minimally invasive surgical procedures.

Published
2017
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2. Juvenile Granulosa Cell Tumor of the Testis: Prenatal Diagnosis and Management

Author

Fabrizio Vatta, Alessandro Raffaele, Noemi Pasqua, Stefania Cesari, Piero Romano, Gian Battista Parigi, and Luigi Avolio

Subjects
prenatal ultrasound, juvenile granulosa cell tumor, testicular tumors, Pediatrics, RJ1-570, Surgery, RD1-811
Abstract

Prepubertal primary testicular tumors account for ∼1% of all pediatric solid tumors. We report a new case of prenatal diagnosis of juvenile-type granulosa cell tumor (JGCT). A fetal ultrasound performed at the 38th week of gestation for suspected nonvertex presentation identified a left multilocular septated cystic testicular mass, suggestive for JGCT. At birth, a painless left scrotal mass was detected. Ultrasound re-evaluation excluded torsion of the testis. Tumor markers and abdominal ultrasound were normal for age. Inguinal exploration revealed a cystic mass beneath the tunica albuginea that had replaced all the normal parenchyma. Since organ-sparing surgery was thus not feasible, an orchiectomy was performed and diagnosis of JGCT was confirmed. At 7-year follow-up, the child presented an uneventful outcome. Our case shows that neonatal JGCT, which has an intrauterine genesis, can be diagnosed prenatally by ultrasound in the last weeks of pregnancy.

Published
2019
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3. Intestinal Duplication and Hirschsprung's Disease: An Extremely Rare and Misleading Combination

Author

Fabrizio Vatta, Alessandro Raffaele, Noemi Pasqua, Marco Brunero, Gloria Pelizzo, and Luigi Avolio

Subjects
intestinal duplication, hirschsprung's disease, intestinal occlusion, Pediatrics, RJ1-570, Surgery, RD1-811
Abstract

Hirschsprung's disease and, more rarely, intestinal duplication can both cause intestinal obstruction in neonates. The simultaneous occurrence of these two diseases is reported in only two studies, and in both cases, intestinal duplication was an incidental finding, as it had not determined clinical intestinal occlusion. This paper reports a unique case of coexistence of the two conditions, with both causing intestinal obstruction, delayed appropriate, and definitive surgical treatment.

Published
2018
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4. Thoracoscopic Treatment of Pneumothorax in Marfan Syndrome: Hemostatic Patch to Support Lung Resection Recovery

Author

Gloria Pelizzo, Eloisa Arbustini, Noemi Pasqua, Patrizia Morbini, and Valeria Calcaterra

Subjects
Surgery, RD1-811
Abstract

Introduction. In selected patients, the absorbable fibrin patch TachoSil® is superior to standard surgical treatment in reducing air leakage after pulmonary lobectomy. Pulmonary involvement is not considered a main feature of Marfan syndrome (MFS); however, spontaneous pneumothorax (SP) with a high rate of recurrence is frequently reported. We describe the use of TachoSil® in the supportive treatment of recurrent pneumothorax in a girl with MFS. Case Report. A 12-year-old girl with a previous diagnosis of MFS and recurrent history of left spontaneous pneumothorax was submitted to thoracoscopic atypical lung resection. Two patches (9.5 × 4.8 cm) were cut from the adhesive/foam complex (TachoSil®) and were pressed against the sutured area as supportive treatment. The patient recovered with no further SP recurrences. Conclusions. The use of the TachoSil® surgical patch may be useful in pneumothorax supportive treatment, particularly in pediatric MFS by ameliorating the mechanical strength of the lung.

Published
2018
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5. Pediatric laparoscopy and adaptive oxygenation and hemodynamic changes

Author

Gloria Pelizzo, Veronica Carlini, Giulio Iacob, Noemi Pasqua, Giuseppe Maggio, Marco Brunero, Simonetta Mencherini, Annalisa De Silvestri, and Valeria Calcaterra

Subjects
laparoscopy, children, hemodinamics, changes, Medicine, Pediatrics, RJ1-570
Abstract

Adaptive changes in oxygenation and hemodynamics are evaluated during pediatric laparoscopy. The children underwent laparoscopy (LAP Group, n=20) or open surgery (Open Group, n=10). Regional cerebral (rScO2) and peripheral oxygen saturation (SpO2), heart rate (HR), diastolic (DP) and systolic pressure (SP) were monitored at different intervals: basal (T0); anesthesia induction (T1); CO2PP insufflation (T2); surgery (T3); CO2PP cessation (T4); before extubation (T5). At T1, in both the LAP and Open groups significant changes in rScO2, DP and SP were recorded compared with T0; a decrease in SatO2 was also observed at T5. In the LAP group, at T2, changes in HR related to CO2PP pressure and in DP and SP related to IAP were noted; at T4, a SP change associated with CO2PP desufflation was recorded. Open group, at T3 and T5 showed lower rScO2 values compared with T1. Pneuperitoneum and anesthesia are influent to induce hemodynamics changes during laparoscopy.

Published
2017
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6. Plunging ranula in children: case report and literature review

Author

Veronica Carlini, Valeria Calcaterra, Noemi Pasqua, Marinella Guazzotti, Mario Fusillo, and Gloria Pelizzo

Subjects
plunging ranula, children, differential diagnosis, therapy, Medicine, Pediatrics, RJ1-570
Abstract

Few cases of plunging ranulas (PRs) occur during childhood and the lesions are frequently misdiagnosed. Here, a PR in a child is reported along with a literature review. A seven-year-old female complaining of swelling in the midline neck, left-submandibular region, was evaluated. No oral cavity or major salivary glands abnormalities were detected. On palpation, a soft, painless, and fluid-containing mass was observed. The suspicion PR was performed by ultrasound. The diagnosis was confirmed with a histopathological examination. The lesion was removed with a cervical approach, without recurrence. PR is an uncommon condition in children under 10 years of age. Differential diagnosis depends on clinical examination and ultrasonography. A computed tomography-scan and magnetic resonance imaging can be performed if the diagnosis remains uncertain. In pediatrics, the key to success of the treatment may rely on the radical excision of the cyst and sublingual gland, via an intraoral or submandibular approach.

Published
2016
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7. Identification of Autophagy-Related Genes and Their Regulatory miRNAs Associated with Celiac Disease in Children

Author

Sergio Comincini, Federico Manai, Cristina Meazza, Sara Pagani, Carolina Martinelli, Noemi Pasqua, Gloria Pelizzo, Marco Biggiogera, and Mauro Bozzola

Subjects
microRNA, autophagy, celiac disease molecular markers, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Celiac disease (CD) is a severe genetic autoimmune disorder, affecting about one in 100 people, where the ingestion of gluten leads to damage in the small intestine. Diagnosing CD is quite complex and requires blood tests and intestinal biopsy examinations. Controversy exists regarding making the diagnosis without biopsy, due to the large spectrum of manifesting symptoms; furthermore, small-intestinal gastroscopy examinations have a relatively complex management in the pediatric population. To identify novel molecular markers useful to increase the sensitivity and specificity in the diagnosis of pediatric CD patients, the expression levels of two key autophagy executor genes (ATG7 and BECN1) and their regulatory validated miRNAs (miR-17 and miR-30a, respectively) were analyzed by relative quantitative real-time-PCR on a cohort of confirmed CD patients compared to age-related controls. Among the investigated targets, the non-parametric Mann–Whitney U test and ROC analysis indicated the highest significant association of BECN1 with CD status in the blood, while in intestinal biopsies, all of the investigated sequences were positively associated with CD diagnosis. Nomogram-based analysis showed nearly opposite expression trends in blood compared to intestine tissue, while hierarchical clustering dendrograms enabled identifying CD and control subgroups based on specific genes and miRNA expression signatures. Next, using an established in vitro approach, through digested gliadin administration in Caco-2 cells, we also highlighted that the modulation of miR-17 endogenous levels using enriched exosomes increased the intracellular autophagosome content, thereby altering the autophagic status. Altogether, these results highlighted novel molecular markers that might be useful to increase the accuracy in CD diagnosis and in molecular-based stratification of the patients, further reinforcing the functional involvement of the regulation of the autophagy process within a digestive and autoimmune-related disorder as CD.

Published
2017
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8. Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Author

Naomi Jane Wright, Andrew J.M. Leather, Niyi Ade-Ajayi, Nick Sevdalis, Justine Davies, Dan Poenaru, Emmanuel Ameh, Adesoji Ademuyiwa, Kokila Lakhoo, Emily Rose Smith, Abdel Douiri, Maria Elstad, Marcus Sim, Cristiana Riboni, Bruno Martinez-Leo, Melika Akhbari, Stephen Tabiri, Ashrarur Mitul, Dayang Anita Abdul Aziz, Camila Fachin, Alliance Niyukuri, Muhammad Arshad, Fowzia Ibrahim, Natalie Moitt, Mohamed Fahmy Doheim, Hannah Thompson, Harmony Ubhi, Isabelle Williams, Sophia Hashim, Godfrey Sama Philipo, Laura Herrera, Aayenah Yunus, Dominique Vervoort, Samuel Parker, Yousra-Imane Benaskeur, Osaid H. Alser, Nana Adofo-Ansong, Ahmad Alhamid, Hosni khairy Salem, Mahmoud Saleh, Safa Abdal Elrais, Sadi Abukhalaf, Patricia Shinondo, Ibrahim Nour, Emrah Aydin, Agota Vaitkiene, Kelly Naranjo, Andile Maqhawe Dube, Sodumisa Ngwenya, Mina A. Yacoub, Henang Kwasau, Gabriella Hyman, Shrouk Mahmoud Elghazaly, Ibrahim Al-Slaibi, Intisar Hisham, Helena Franco, Hana Arbab, Lubna Samad, Aqil Soomro, Muhammad Amjad Chaudhry, Safina Karim, Muhammad Adnan Khan Khattak, Shireen Anne Nah, Doris Mae Dimatatac, Candy SC Choo, Niveshni Maistry, Ashrarur Rahman Mitul, Samiul Hasan, Sabbir Karim, Hina Yousuf, Taimur Qureshi, Ibrahim Rabi Nour, Raed Nael Al-Taher, Osama Abdul Kareem Sarhan, Luis Garcia-Aparicio, Jordi Prat, Eva Blazquez-Gomez, Xavier Tarrado, Martí Iriondo, Paolo Bragagnini, Segundo Rite, Lars Hagander, Emma Svensson, Sheila Owusu, Alhassan Abdul-Mumin, Dominic Bagbio, Vijay Anand Ismavel, Ann Miriam, Shajin T, Marlene Anaya Dominguez, Monica Ivanov, Andreea Madalina Serban, Miliard Derbew, Mahmoud Elfiky, Maricarmen Olivos Perez, Marcia Abrunhosa Matias, Alexis P Arnaud, Ahmed Negida, Sebastian King, Mohamad Rafi Fazli, Nadia Hamidi, Souhem Touabti, Rossana Francisco Chipalavela, Pablo Lobos, Brendan Jones, Damir Ljuhar, Georg Singer, Annelien Cordonnier, Lorena Jáuregui, Zlatan Zvizdic, Janice Wong, Etienne St-Louis, Qiang Shu, Yang Lui, Catalina Correa, Lucie Pos, Elvyn Alcántara, Erick Féliz, Luis Enrique Zea-Salazar, Liza Ali, Matthieu Peycelon, Nzanzu Kipata Anatole, Cherno S. Jallow, Judith Lindert, Dhruv Ghosh, Cathline Freya Adhiwidjaja, Ahmad Khaleghnejad Tabari, Saran Lotfollahzadeh, Haidar Mohammad Mussein, Fabrizio Vatta, Noemi Pasqua, David Kihiko, Hetal Gohil, Ibrahim R. Nour, Muhammed Elhadi, Suad Ahmed Almada, Gilvydas Verkauskas, Toni Risteski, Alejandro Peñarrieta Daher, Oumaima Outani, James Hamill, Taiwo Lawal, Jack Mulu, Benjamin Yapo, Lily Saldaña, Beda Espineda, Krystian Toczewski, Eugene Tuyishime, Isaac Ndayishimiye, Enaam Raboe, Philip Hammond, Gregor Walker, Ivona Djordjevic, Milind Chitnis, Joonhyuk Son, Sanghoon Lee, Muaad Hussien, Sawazen Malik, Enas Musa Ismail, Ampaipan Boonthai, Nesrine Ben Hadj Dahman, Nigel Hall, Fabiola Ruth Castedo Camacho, Helena Sobrero, Marilyn Butler, Aliev Makhmud, Nathan Novotny, Ahmad G. Hammouri, Maisara Al-Rayyes, Bruce Bvulani, Qais Muraveji, Muhammad Yousuf Murzaie, Ajmal Sherzad, Sayed Aman Haidari, Abdul Baqi Monawar, Dr. Ahmad Zia Samadi, Jesh Thiessen, Ntakarutimana Venant, Sonia Inamuco Hospital, Niyonkuru Jérémie, Jean Claude Mbonicura, Butoyi Jean Marie Vianney, Amezene Tadesse, Samuel Negash, Charles A. Roberts, John N. Jabang, Abdoulie Bah, Kajali Camamra, Armandou Correa, Babucarr Sowe, A. Gai, Musa Jaiteh, Kwizera Jean Raymond, Jean Paul Mvukiyehe, Innocent Itangishaka, Emmanuel Kayibanda, Emery Manirambona, Joseph Lule, Ainhoa Costas-Chavarri, Ian Shyaka Gashugi, Albert Ndata, Georges Gasana, Yves Castar Nezerwa, Turatsinze Simeon, Jean De Dieu Muragijimana, Sakina Rashid, David Msuya, Joseph Elisante, Meghna Solanki, Emmanuel Manjira, Jay Lodhia, Mubashir Jusabani, Murad Tarmohamed, Sengua Koipapi, Touabti Souhem, Nabti Sara, Brahimi Sihem, Bouguermouh Dania, Iaiche Achour Toufik, Baghdadi Nour el islam Mounira, Alouani Habiba, Liliana Aragão, Victor Gonçalves, Marcelo Mauricio Lino Urquizo, Maria Florencia Varela, Pedro Mercado, Bonavia Horacio, Andrea Damiani, Carlos Mac, Daniel Putruele, Karen Liljesthrom, Marianela Bernaus, Cesar Jauri, Alejandrina Cripovich, Ezequiel Bianchin, Maria Gabriela Puig, Lorna Andreussi, Susana Iracelay, Dolores Marcos, Carina Herrera, Nelly Palacios, Romina Avile, Belen Serezo, Debora Montoya, Rodrigo Cepeda, Justo Vaquila, Sofficci Veronica, Liliana Pardo, Pelussi Valeria, Lapalma Julio, Aranda Diego Martin, Palazzi Lucio, Comba Gabriel, Depetrini Marianella, José Alfredo Calderón Arancibia, Enrique Huespe, Gabriela Natalia Losa, Elsa Arancibia Gutiérrez, Humberto Scherl, Daniel Emilio Gonzalez, Valentina Baistrocchi, Yanina Silva, Marcelo Galdeano, Pablo Medard, Ines Sueiras, Enrique Romero Manteola, Victor Hugo Defago, Carlos Mieres, Carlos Alberto, Fabio Cornelli, Marcelo Molina, Pablo Ravetta, Celeste Carolina Patiño Gonzalez, Maria Belen Dallegre, Maria Tatiana Szklarz, Marcos Federico Leyba, Nahuel Ignacio Rivarola, Maria Delia Charras, Adriana Morales, Paloma Caseb, Luzia Toselli, Carolina Millán, Maria del Carmen Junes, Oscar Di Siervi, Jose Gilardi, Soledad Simon, Carla Sofia Contreras, Nair Rojas, Lucia Beatriz Arnoletto, Otilia Eva Blain, Mauro Nicolas Bravo, Nancy Sanchez, Luciana Martina Herrera Pesara, Maria Eugenia Moreno, Carlos Ariel Sferco, Umama Huq, Tamanna Ferdousi, Abdullah Al-Mamun, Sadia Sultana, Refoyez Mahmud, Khalid Mahmud, Fatema Sayeed, Alexander Svirsky, Denisse Sempertegui, Amalia Negrete, Araceli Teran, Mariana Sadagurschi, Nusret Popovic, Kenan Karavdic, Emir Milisic, Asmir Jonuzi, Amira Mesic, Sabina Terzic, Nejra Dendusic, Elna Biber, Anesa Sehic, Nada Zvizdic, Emina Letic, Adna Saracevic, Ajla Hamidovic, Nejra Selak, Dzan Horozic, Lamija Hukic, Amila Muhic, Nedim Vanis, Emir Sokolovic, Adnan Sabic, Karin Becker, Elis Novochadlo Klüppel, André Iván Bradley dos Santos Dias, Miguel Angelo Agulham, Cristiano Bischoff, Stella Sabbatini, Rachel Fernandes de Souza, Ana Beatriz Souza Machado, Juliana Werneck Raposo, Maria Lucia da Silva Augusto, Bianca M.R. Martins, Mariana de Souza Santos Ferreira, Darli Fernandes de Oliveira, Carla Silva dos Santos, Fernanda Ribeiro de Fernández y Alcázar, Érika Alves Dutra da Silva, Mariana Furtado, Horácio Tamada, Marília Silva Ferreira dos Santos, Thayná Lopes de Almeida, Susy Oliveira de Andrade, Antonio Cipriano Gurgel do Amaral, Lais Sartori Giovanoni, Kamila de Deus Passos Leles, Eduardo Corrêa Costa, Leticia Feldens, Luciano Ferraz Schopf, José Carlos Soares de Fraga, Felipe Colombo de Holanda, Paola Maria Brolin Santis Isolan, Julia Loyola Ferreira, Carla Luisa Bruxel, Danielle Lopes Teixeira Ferdinando, Fabricio Zottis Barcelos, Natalia Baseggio, Nicole Knorr Brenner, Rafael Trindade Deyl, Carolina Dure, Iuri Nunes Kist, Rafael Bueno Mazzuca, Sarah Bueno Motter, Yna Ramos, Cristine Suzana Trein, Bianca Rezende Rosa, Murilo de Assis Silva, Flavio Augusto Menin, Isabela Cristina Semensato Carloni, Juliana Antinarelli Norberto da Silva, Adriano Luis Gomes, Mariana Girão Tauffer, Paulo César Bassan Gonçalves, Geraldo Magela Nogueira Marques, Eliane Moriya, Carla Labonia, Ana Lucia Carrasco, Karine Furtado Meyer, Luiz Farion-Aguiar, Fernando Amado, Amanda Antunes, Elisângela Silva, Leila Telles, Giovana Almeida, Aluísio Augusto Belmino Gadelha, Flavia de Azevedo Belesa, Acimar Gonçalves da Cunha, Jr, Beatriz Souza Barros, Josiane Bernartt Zanellato, Patricia Guimarães, Karina Ilheu da Silva, Bianca Ribas, Cristina Reuter, Francis Tanise Casado, Mila Torii Correa Leite, Daniela Testoni, Ruth Guinsburg, Simone de Campos Vieira Abib, Edson Khodor Cury, Suely Dornellas do Nascimento, Arthur Almeida Aguiar, Rodrigo Melo Gallindo, Carolina Gonçalves Borges, Yang Liu, Cai Duote, Jinhu Wang, Zhigang Gao, Liang Liang, Wenjuan Luo, Xiaoxia Zhao, Rui Chen, Peng Wang, Yijiang Han, Ting Huang, Hu Donglai, Guo Xiaodong, Chen Junjie, Libin Zhu, Guowei Wu, Xiaozhou Bao, Haijing Li, Junying Lv, Zhongrong Li, Feng Yong, Zhou Chong Gao, Qiang Bai, Weibing Tang, Hua Xie, Jethishka Motee, Jianming Zhu, Gang Wen, Weiwei Ruan, Shungen Li, Lulu Chen, Shungen Huang, Zhibao Lv, Jinjing Lu, Liuming Huang, Mengnan Yu, Wang Dajia, Yu Zuo Bai, Luis Carlos Rincon, Juliana Mancera, Edgar Alzate Gallego, Laura Torres-Canchala, Nathalia Silva Beltrán, Ghordana Osorio Fory, Daniela Castaño Avila, Angelica Maria Forero Ladino, Juanita Gomez, Martha Jaramillo, Otto Morales, Beatriz Sanchez, Nestor Julien Tinoco Guzmán, Sergio Castañeda Espinosa, Osbaldo Prieto Vargas, Lina Maria Pardo, Eliana Toral, Freud Cáceres Aucatoma, Daniel Hinostroza, Santiago Valencia, Vicente Salinas, Enrique Landivar Cino, Gabriela Yulissa Ponce Fajardo, Miguel Astudillo, Virginia Garcia, Guillermo Muñoz, Leonardo Verduga, Ivan Verduga, Ericka Murillo, Elena Bucaram, Marisol Guayelema, Monica Marmol, Janina Sanchez, Carolina Vergara, Adriana Mena, Junior Velaña, Karla Salazar, Sandra Lara, Elena Chiriboga, Julian Silva, Dalia Gad, Doaa Samy, Menan Ahmed Elsadek, Hanan Mahmoud Mohammed, Mohamed Abouheba, Karim Osamy Ali, Hayssam Rashwan, Omar Moustafa Fawzy, Tarek mohamed Kamel, Rawan Nemer, Mohamed Abada Hassan, Eyad Hassan Falah, Dina Sobhy Abdelhady, Mostafa Zain, Eman Abouzeid Abouzeid Ibrahim, Omar Ossama Elsiraffy, Ahmed Aboelela, Eman mohamed Farag, Ahmed Mohamed Oshiba, Omar Sameh Emam, Alaa Mobarak Attia, Moustafa A. Laymouna, Islam Abdelmonem Ghorab, Mansour Mkayed Mohammed, Nourhan Akram Soliman, Khaled Abd elrahman Ghaly, Kareem Sadek, Mohamed Elsherbiny, Amr Saleh, Hesham Sheir, Tamer Wafa, Mohamed Abd Elmenam, Sherif Abdelmaksoud, Ahmed Reda, Islam Mansour, Mohamed Elzohiri, Basma Waseem, Mohamed Elewaily, Mohammed El-Ghazaly, Ahmad Elhattab, Amr Shalaby, Adham Elsaied, Ahmad Adawy, Mirna Sadek, Mahmoud Abdelfattah Ahmed, Mohamed Omar Herdan, Gena Mohamed Hamed Elassall, Azhar Arabi Mohammed, Mohammed Hamada Takrouney, Tarek Mohamed Essa, Ahmed Mokhtar Mahmoud, Alshaimaa M. Saad, Mariam Albatoul Nageh Fouly, Mahmoud abdelshakour Ibrahim, Mohammad Nageh, Mahmoud M. Saad, Helmy Badr, Mohamed Fayez Fouda, Ahmed Hassan Nofal, Hisham Almohamady, Mohamed Ahmed Arafa, Mohamed Amad, Mohamed Awad Mansour, Jennifer O'Connor, Zachary O'Connor, Nzanzu Anatole, Elysé Nkunzimana, Solomon Machemedze, Lemfuka Dieudonné, William Appeadu-Mensah, Theophilus Teddy Kojo Anyomih, Priscilla Alhassan, Francis A. Abantanga, Vishal Michael, Roshine Mary Koshy, Ankit Raj, Vijay Kumar, Sundeep PT, P Santosh Prabhu, Armin Vosoughi, Ali Farooq Al-Mayoof, Muhamed Jassim Fadhle, Ali Egab Joda, Hayder Nadhim Obaid Algabri, Sultan S. Abdelhamid, Hashem M. Al-Momani, Marzouq Amarin, Louay Y. Zaghlol, Nijmeh Nasser Alsaadi, Yasmeen Z. Qwaider, Hibah Qutishat, Ahmad Hasan Aliwisat, Esraa Arabiat, Isam Bsisu, Raghad M. Murshidi, Mohammad S. Jabaiti, Ziad A. Bataineh, Husam Aldean Abuhayyeh, Thekraiat M. Al Quran, Faris J. Abu Za'nouneh, Mohanad Mutasem Alebbini, Hamzah Abullah Qudah, Omar Ghazi Hussein, Amir M.I. Murad, Justin Z. Amarin, Haya H. Suradi, Sayel H. Alzraikat, Rand Y. Omari, Bashar M. Matour, Layana Al-Halbouni, Rajai O. Zurikat, Ahmad H. Yanis, Sara Al Hussein, Ali Shoubaki, Waleed H. Ghanem, Kuria David, Soita Wycliffe Chitiavi, Moraa Mose, Robert Mugo, James Ndungu, Timothy Mwai, Swaleh Shahbal, Janan Malik, Nirav Chauhan, Francisa Syovata, Kevin Ochieng, Polycarp Omendo Liyenzero, Syeda Ra'ana Hussain, Stanley Mugambi, Roseline Ochieng, Ebtesam Othman Abdulsalam Elkhazmi, Ala Khaled, Aya Albozidi, Manal Ben Enbaya, Mala Elgammudi, Enas Soula, Wegden ibrahim almabrouk Khalel, Yasmine Ali Elhajjaji, Nouriyah Ali Alwaggaa, Sumayyah Ghayth, Dafer abdulhakim .S. Zreeg, Sara Abobaker Tantush, Fatma Bibas, Tesneem Layas, Randa Alamen M Sharif, Wesal Omar F. Saied Aljadidi, Ahmed Tarek, Hazem Ahmed, Kamila Almabrouk Mohammed Essamilghi, Mabroka Alfoghi, Ma'aly A. Abuhlega, Saddam Arrmali, Fatima Mousa Abduljawad, Hasan Mustafa Alosta, Abdulsalam Abuajaila, Fakereldeen Abdelmutalib, Fatma Bashir, Inas Almengar, Mohammad hasan Annajjar, Abdelaziz Deyab, Fathi Elzowawi, Yousef Krayem, Weam Drah, Asma Meftah, Abobaker Mohammed, Lina Ali Arrmalli, Hajir Aljaboo, Abdallah Elayeb, Mohamed Altomi, Ahmed Altaweel, Mohamed Tumi, Hana Milad Bazozi, Aisha Shaklawoon, Mohammed Meftah Alglaib, Abdullahn Abdousalam Elkaloush, Sara Trainba, Hisham Swessi, Ali Alnaeri, Aya Essam Shnishah, Hamassat Mustufa, Sondas Ali Gargum, Sara Ali Tarniba, Hawa Ahmed Shalluf, Hajer Ali Shokri, Taher L. Sarkaz, Osama Tababa, Ahmed Elhadi, Vesna Cvetanovska Naunova, Laze Jovcheski, Marjan Kamilovski, Aleksandra Gavrilovska-Brzanov, Zarina Abdul Latiff, Siti Farhan Moh Pauzi, Marjmin Osman, Felicia Lim, Ainal Huda Abu Bakar, Azrina SK Zaman, Shareena Ishak, Rufinah Teo, Dr. Tammy Teoh Han Qi, Mohd Yusran Bin Othman, Dato' Dr Zakaria bin Zahari, Zulfitri bin Md Hassan, Cheah Hui Shan, Abhirrami Lechmiannandan, Hafatin Fairos bt Tamaddun, Mohd Fitri Shukri bin Mohamed Adanan, Mohd Yusof bin Abdullah, Wang Junyi, Mohd. Tarmizi Mohd Nor, Wan Ruzaimie Noor, Mohd Razin bin Hassan, Noor Fa'izatul Rahil Ambok Dalek, Hidayah Hayati binti Hashim, Ahmad Zulhisyam bin Zarwawi, V Muthualhagi M Vellusamy, Quah Soong Yuen, Hemasutha a/p Kannessan, Najua binti Ramli, Ahmad Shafiee bin Bujarimin, Jessmine Anntinea, Anthony Dass, Hazlina Mohd. Khalid, Nur Atiqah binti Mohd Hanifah, Keily Wong Yue Jyun, Rahilah binti Abd Razak, Nur Atifah binti Mohd Naim, Siti Nur Aien binti Hamid Hamzah, Cristian R. Zalles Vidal, Eduardo Bracho Blanchet, Roberto Dávila Perez, Emilio Fernandez Portilla, Raúl Villegas Silva, Daniel Ibarra, Antonio Calderon Moore, Cesar Carrasco-Ortega, Monica Noguez Castillo, Dorihela Herappe Mellado, Guillermo Yanowsky Reyes, Luis Fernando Gonzalez Cortez, Rafael Santana Ortiz, Jamie Orozco Perez, Jorge Román Corona C.Rivera, Juan Jose Cardenas Ruiz Velasco, Moises Quiles Corona, Christian Peña Padilla, Lucina Bobadilla Morales, Alfredo Corona Rivera, Izabel Maryalexandra Rios Flores, Cristian Irela Aranda Sánchez, Gabriela Ambriz-González, Nestor Martínez Hernández Magro, Francisco Javier León Frutos, José de Jesús Cárdenas Barón, Alejandro González Ojeda, Jessica Yarza Fernández, Juan Domingo Porras, Pastor Aguirre-Lopez, Vicente Sánchez Paredes, Arturo Montalvo Marin, Jose Manuel Diaz Gomez, Lorenzo Juvencio Caamal, David Bulnes Mendizabal, Pablo Sanchez Valladares, Humberto Garcia Martinez, Opeoluwa Adesanya, Moses Olanrewaju, Rilwan Adegboyega, Nurudeen Abdulraheem, Anuoluwapo Aremo, Florence Dedeke, Anyanwu Lofty-John Chukwuemeka, Mohammad Aminu Mohammad, Abdullahi Lawalbarau, Nwokoro Collins, Ogundele Ibukunolu, Amo Shonubi, Oluwaseun Ladipo-Ajayi, Olumide Abiodun Elebute, Justina Seyi-Olajide, Felix Alakaloko, George Ihediwa, Kayode Olayade, Christopher Bode, Olakayode Ogundoyin, Dare I. Olulana, Ifeanyichukwu Kelvin Egbuchulem, Felix O. Kumolalo, Ikechukwu Ulasi, Uchechukwu Obiora Ezomike, Sebastian Okwuchukwu Ekenze, Elochukwu Perpetua Nwankwo, Emmanuel Ifeanyi Nwangwu, Isaac Chukwu, Christopher Chim Amah, Nene Elsie Obianyo, Omolara Williams, Roland Iheanyichukwu Osuoji, Omolara Moronkeji Faboya, Olalekan Temitope Ajai, Moruf Adekunle Abdulsalam, Titiloye Hannah Agboola, Bolarinwa Bolanle Temilade, Maryrose Osazuwa, Morayo Monsurat Salawu, Eze Chukwuemeka Ejinkeonye, Mariya Mukhtar Yola, Amsa B. Mairami, Adekunle T. Otuneye, Matthias Igoche, Adebayo Gbenga Tanimola, Emmanuel Akinlabi Ajao, Efeturi Agelebe, Samson Olori, Philip Mari Mshelbwala, Olabisi Osagie, Adewale Oyinloye, Auwal M Abubakar, Lateef Oyebanji, Ibrahim Shehu, Cyril Cletus, Ahmed Bamanga, Faruk Suleiman, Sani Adamu, David C.Nwosu, Yahya S.Alkali, Iliya Jalo, Aliu Rasaki, Yusuf T.Sambo, Kalakwa A.Mohammed, Abubakar M.Ballah, Victor Modekwe, Okechukwu Hyginus Ekwunife, Ugochukwu S Ezidiegwu, Andrew N Osuigwe, Jideofor O Ugwu, Chuka A Ugwunne, Nadeem Akhter, Mudassir Fayaz Gondal, Rafee Raza, Ali Raza Chaudary, Hassan Ali, Muhammad Umar Nisar, Muhammad Umer Jamal, Ghuri Shankar Pandit, Uzma Mumtaz, Muhammad Bin Amjad, Nabila Talat, Wajeeh ur Rehman, Muhammad Saleem, Muhammad Bilal Mirza, Imran Hashim, Naveed Haider, Soban Hameed, Ayesha Saleem, Sohail Dogar, Muhammad Sharif, Muhammad Kashif Bashir, Fatima Naumeri, Zarqa Rani, Muath A.M. Baniowda, Basheer Ba'baa', Majd Yousef Mohammed Hassan, Ammar Darwish, Abrar Shaheen Sehwiel, Mohammed Shehada, Abrar ghassan Balousha, Yara Ajrami, Ainaa Ata Mohammad Alzamari, Bashar Yaghi, Hasan Subhi Hasan Abu Al-saleem, Mervat Sufian Abu Farha, Mohammad Omar Mohammad Abdelhafez, Firas Anaya, Asef belal Qadomi, Abd Al-Naser Bany Odi, Muath Abdelrahem Fuad Assi, Fadwa Sharabati, Ahmad Abueideh, Doha mustafa saleh Beshtawi, Hasan Arafat, Lara Zahi Adel Khatatba, Safa' Jamal Abatli, Hiba Al-Tammam, Dania Jaber, Yara Imad Omar Kayed, Ali Abdelhay Abumunshar, Rami Anwar Misk, Asmahan Mohammad Suliman Alzeer, Mutassem Sharabati, Ihsan Ghazzawi, Osama Majed Darras, Mahmoud M.Qabaja, Ma'alem sameer Hajajreh, Yasmeen Ahmad Samarah, Dua Hasan Yaghi, Moradallah Asad Fahmi Qunaibi, Abdelrazzaq Abu Mayaleh, Sharehan Joubeh, Annan Ebeido, Samer Adawi, Ihda Adawi, Mohammad Omar Ibrahim Alqor, Ahmad Samih Arar, Hadeel Awad, Fawzi Abu-Nejmah, Osaid Shaher Shabana, Firas Alqarajeh, Tareq Z. Alzughayyar, Jomana Madieh, Mahmoud Fuad Sbaih, Raghad mohammad abdu Alkareem, Raghad abdullateef Lahlooh, Yasmeen Adly Halabi, Wisam Baker, Tasneem Fathi Hasan Almusleh, Abdulraheem Adnan Abdulraheem Tahyneh, Yazid yousef mahmoud Atatri, Najlaa Abu Jamie, Nasrallah Ashraf Al Massry, Walaa Lubbad, Ayoub A.Nemer, Mohammed Alser, Aya Azmi Shehda Salha, Khaled Alnahhal, Aya Mahmoud Elmzyyen, Amir Talat Sheda Ghabayen, Abdulwhhab Ayman Abu Alamrain, Samar H. Al-Shwaikh, Omar Adly Elshaer, Nureddin Shaheen, Jehad Fares, Hisham Dalloul, Anas Qawwash, Mustafa abu Jayyab, Dina Ayman Ashour, Ahmad Ashraf Shaheen, Samy Rafat Ramadan Naim, Eman Abu Shiha, Nagham Mohammed Al Dammagh, Walaa Almadhoun, Ashraf Ayman Al-Salhi, Abdalkarim Yhya Hammato, Jamal Mohammed Salim, Doaa Khalil Hasanain, Soha Marwan Salem Alwadia, Ismail Nassar, Hala M. Al-Attar, Haya Abdulnasser Ali Alshaikhkhalil, Yasmin Mohammed Khalil Abu Jamie, Yara shareef Ashour, Sharif S. Alijla, Mohamed Anwer El Tallaa, Adham Ashraf Abuattaya, Bisan D.M. Wishah, MOHAMMED A.M. ALDIRAWI, Ahmed S Darwish, Sulaiman T. Alzerei, Nidal Wishah, Sharif Alijla, Isidora Garcia, Marlene Diaz Echegaray, Veronica Raquel Cañapataña Sahuanay, Fernando Trigoso Mori, Jackelyne Alvarado Zelada, Juan Jose Salinas Barreto, Porfirio Rivera Altamirano, Cesar Torres Miranda, Rocio Anicama Elias, Julio Rivera Alvarez, Juan Pedro Vasquez Matos, Fernando Ayque Rosas, Jesmarina Ledesma Peraza, Andrea Gutarra Palomino, Stephany Vega Centen, Victor Casquero, María Rosa Ortiz Argomedo, Francisco Lapouble, Genaro Llap Unchón, Florangel Patricia Delgado Malaga, Luis Ortega Sotelo, Segundo Gamboa Kcomt, Araceli Villalba Villalba, Nancy Rossana Mendoza Leon, Loreley Raquel Cardenas Alva, Maria Susana Loo Neyra, Cathy Lee Alanguia Chipana, Cintya Maria de Jesus Torres Picón, Natalia Huaytalla Quiroz, Danny Dominguez, Carlos Segura Calle, Jenny Arauco, Luis Ormeño Calderón, Ximena Ghilardi Silva, Miriam Daniela Fernandez Wilson, Joan Elizabeth Gutierrez Maldonado, Cesar Diaz Leon, Waldo Berrocal Anaya, Patricia Chavez Galvez, Prince Pamela Aguilar Gargurevich, Flor de Maria Diaz Castañeda, Carmen Guisse, Erika Ramos Paredes, Jose Luis Apaza Leon, Faye Aguilar Aguilar, Raul Ramirez De La Cruz, Lenny Flores Carbajal, Carlos Mendoza Chiroque, Gladys Johana Sulca Cruzado, Natalia Tovar Gutierrez, Jennifer Sotelo Sanchez, Carolina Paz Soldan, Karina Hernández Córdova, Edgar Fernando Delgado Quinteros, Luz Mery Brito Quevedo, Juan Jose Mendoza Oviedo, Angel Samanez Obeso, Patricia Paredes Espinoza, Johann de Guzman, Raisa Yu, Vlad Cosoreanu, Sebastian Ionescu, Aurel Mironescu, Lucian Vida, Adrian Papa, Roxana Verdeata, Bogdan Gavrila, Liviu Muntean, Marija Lukac, Miona Stojanovic, Djordje Toplicic, Milan Slavkovic, Andjelka Slavkovi, Dragoljub Zivanovic, Ana Kostic, Maja Raicevic, Delphine Nkuliza, Daniel Sidler, Corné de Vos, Elmarie vd Merwe, David Tasker, Omar Khamag, Cecilia Rengura, Thozama Siyotula, Uzair Jooma, Dirk von Delft, Marion Arnold, Hansraj Mangray, Shamaman Harilal, Sanele Madziba, Naveen Wijekoon, Tharanga Gamage, Benedict Paul Bright, Alaa Abdulrahman, Ola Ahmed Abdulmjeed Mohammed, Mohammed Salah, Ahmad Elian Abu Ajwa, Mohammed Morjan, Mohammad Mohannad Batal, Vivian Faks, Mohamad Bassel Mouti, Ahmadfateh Assi, Ahmad Al-Mouakeh, Ahmad Sankari Tarabishi, Ziad Aljarad, Aos Alhamid, Jiraporn Khorana, Wannisa Poocharoen, Sirima Liukitithara, Anan Sriniworn, Wasun Nuntasunti, Monawat Ngerncham, Ratiyaporn Phannua, Kanokrat Thaiwatcharamas, Patchareeporn Tanming, Lassaad Sahnoun, Nahla Kchiche, Roua Abdelmoumen, Egemen Eroğlu, Mehmet Ali Ozen, Hatice Sonay Yalçın Cömert, Mustafa İmamoğlu, Haluk Sarıhan, Şebnem Kader, Mehmet Mutlu, Yakup Aslan, Ahmet Beşir, Şükran Geze, Bahanur Çekiç, Ali Yalcinkaya, Kaan Sönmez, Ramazan Karabulut, Zafer Türkyılmaz, Kıvanç Şeref, Merve Altın, Merve Aykut, M.Eren Akan, Melisa Erdem, Ebru Ergenekon, Canan Türkyılmaz, Elif Keleş, Ali Canözer, Aslı Öztürk Yeniay, Elif Eren, İlknur Banlı Cesur, Zerrin Özçelik, Gökmen Kurt, Mustafa Kurthan Mert, Hatice Kaya, Müge Çelik, Suleyman Cuneyt Karakus, Nazile Erturk, Alev Suzen, Nilay Hakan, Fatih Akova, Mehmet Pasaoglu, Shukurali Eshkabilov, Rustam Z. Yuldashev, Dekhkonboev Avazjon Abdunomonovich, Aliev Makhmudjan Muslimovich, Azad Patel, Chisengo Kapihya, Nicholas Ensar, Ramesh M Nataraja, Mithila Sivasubramaniam, Matthew Jones, Warwick Teague, Sharman Tan Tanny, Gordon Thomas, Kiera Roberts, Soundappan Sannappa Venkatraman, Holger Till, Manon Pigeolet, Martine Dassonville, Anas Shikha, Win Sabai Phyu Win, Zahidah Adlynee Haji Ahmad, Léamarie Meloche-Dumas, Louise Caouette-Laberge, Dickens St-Vil, Ann Aspirot, Nelson Piché, Shahrzad Joharifard, Nadia Safa, Jean-Martin Laberge, Sherif Emil, Pramod Puligandla, Kenneth Shaw, Hussein Wissanji, Eileen Duggan, Elena Guadagno, Maria Consuelo Puentes, Paola Osses Leal, Carolina Mendez Benavente, Michal Rygl, Barbora Trojanová, Klára Berková, Tereza Racková, Ladislav Planka, Jan Škvařil, Radek Štichhauer, Shahad Sabti, Alex Macdonald, Nordeen Bouhadiba, Dorothy Kufeji, Caroline Pardy, Simon Mccluney, Alireza Keshtgar, Rebecca Roberts, Hannah Rhodes, Kate Burns, Robin Garrett-Cox, Kat Ford, Hannah Cornwall, Krithi Ravi, Felicity Arthur, Paul Losty, Tony Lander, Ingo Jester, Suren Arul, Oliver Gee, Giampiero Soccorso, Michael Singh, Max Pachl, Benjamin Martin, Afnan Alzubair, Arun Kelay, Jonathan Sutcliffe, Thomas Middleton, Amy Hughes Thomas, Merina Kurian, Fraser Cameron, Jayaram Sivaraj, Mark C Thomas, Dean Rex, Ceri Jones, Kate Bradshaw, Arnaud Bonnard, Xavier Delforge, Camille Duchesne, Caroline Le Gall, Coralie Defert, Samia Laraqui Hossini, Florent Guerin, Géraldine Hery, Virginie Fouquet-Languillat, Jules Kohaut, Aline Broch, Thomas Blanc, Luke Harper, Thomas Delefortrie, Quentin Ballouhey, Laurent Fourcade, Céline Grosos, Benoit Parmentier, Guillaume Levard, Maria Giovanna Grella, Mariette Renaux Petel, Lucie Grynberg, Olivier Abbo, Sofia Mouttalib, Mélodie Juricic, Aurelien Scalabre, Elodie Haraux, Anke Rissmann, Hardy Krause, Peter Goebel, Ludwig Patzer, Udo Rolle, Andrea Schmedding, Alexandra Antunez-Mora, Bernd Tillig, Sylvester von Bismarck, Patricia Reis Barbosa, Christian Knorr, Domitille Stark, Marco Brunero, Luigi Avolio, Francesco Manni, Matilde Molinelli, Marinella Guazzotti, Alessandro Raffaele, Piero Giovanni Romano, Silvia Cavaiuolo, Gian Battista Parigi, Laszlo Juhasz, Anna Rieth, Arunas Strumila, Rūta Dagilytė, Arunas Liubsys, Pranas Gurskas, Dalius Malcius, Agne Mikneviciute, Asta Vinskaite, Vidmantas Barauskas, Liam Vierboom, Timothy Hall, Spencer Beasley, Lucy Goddard, Mark Stringer, Naveen Weeratunga, Stephen Adams, Jitoko Cama, Marilyn Wong, Sridharan Jayaratnam, Askar Kukkady, Udaya Samarakkody, Sylwester Gerus, Dariusz Patkowski, Agnieszka Wolny, Tomasz Koszutski, Szymon Tobor, Marta Osowicka, Piotr Czauderna, Dariusz Wyrzykowski, Hanna Garnier, Stefan Anzelewicz, Osowicka Marta, Agata Knurowska, Alicja Weiszewsk, Andrzej Grabowski, Wojciech Korlacki, Michal Pasierbek, Przemyslaw Wolak, Aneta Piotrowska, Anna Roszkiewicz, Piotr Kalicińsk, Agata Trypens, Grzegorz Kowalewsk, David Sigalet, Amer Alsaied, Mansour Ali, Ameen Alsaggaf, Alaa Ghallab, Yazeed Owiwi, Ali Zeinelabdeen, Mohamed Fayez, Ahmed Atta, Mazen Zidan, Asaad saleh Radwan, Hanin Shalaby, Reem Abdelbaqi, Khalid Alattas, Yar Kano, Omar Sindi, Abdullah Alshehri, Tariq Altokhais, Fahad Alturki, Mohammad Almosaibli, Dasha Krisanova, Wisam Abbas, Hee-Beom Yang, Hyun-Young Kim, Joong Kee Youn, Jae Hee Chung, Seok Hyeon Cho, In ji Hwang, Ju yeon Lee, Eung song Song, Jenny Arboleda, Mercedes Ruiz de Temiño Bravo, Alexander Siles Hinojosa, Miriam García, Isabel Casal Beloy, Detlef Oliu San Miguel, Maria Elena Molina Vazquez, Verónica Alonso, Alberto Sanchez, Oscar Gomez, Isabel Carrillo, Tomas Wester, Carmen Mesas Burgos, Martin Salö, Erik Omling, Niclas Rudolfson, Christina Granéli, Helena Arnadóttir, Emma Grottling, Kate Abrahamsson, Vladimir Gatzinsky, Michaela Dellenmark Blom, Daniel Borbonet, Paul Puglia, Vinicio Jimenez Morejon, Gaston Acuna, Mario Moraes, Jonathan Chan, Pavan Brahmamdam, Alan Tom, Karen Sherer, Brandy Gonzales, Aaron Cunningham, Sanjay Krishnaswami, Reto Baertschiger, Mary Leech, Regan Williams, Lauren Camp, Ankush Gosain, Maria Mora, Bailey D. Lyttle, Jeremy Chang, Lydia McColl Makepeace, Kathryn L Fowler, Sara Mansfield, Erica Hodgman, Chukwubinyelum Amaechi, Alana Beres, Mark N. Pernik, Luke J. Dosselman, Murad Almasri, Sunil Jain, Varun Modi, Marianelly Fernandez Ferrer, John Coon, Joann Gonzalez, Medhavi Honhar, Nensi Ruzgar, Griffin Coghill, Sarah Ullrich, Maija Cheung, Katrine Løfberg, Jodie Greenberg, Kate Davenport, Samir Gadepalli, Sarah Fox, Stephanie Johnson, Mercedes Pilkington, April Hamilton, Nicole Lin, Juan Sola, Yang Yao, Jenna Kylene Davis, Monica Langer, Jonathan Vacek, Fizan Abdullah, Julie Khlevner, William Middlesworth, Marc Levitt, Hira Ahmad, Sabina M Siddiqui, Alex Bowder, Terry Derks, Afua Amoabin Amoabin, Brooke Pinar, Frank Owusu-Sekyere, Benmanseur Saousen, Rasika Naidoo, Azra Karamustafic, Danielle Paula de Oliveira, Jerhy Andrade, Antonín Šafus, Jason Langley, Alexandra Wilke, Corazone Deya, Habib Mansour Murtadi, Mindaugas Berzanskis, Nwachukwu Calistus, Olalekan S. Ajiboye, Michael Felix, Osagie O Olabisi, Seçil Erçin, Teymursha Muradi, Stephen S. Burks, Sergio Lerma, Jillian Jacobson, Calin Calancea, Rafael Valerio-Vazquez, Guigui Sikwete, Owusu Sekyere, Akhona Mbonisweni, Shahnoor Syed, Cho Seok Hyeon, Fatemeh Pajouhandeh, Sheba Mary Pognaa Kunfah, Global PaedSurg Research Collaboration, and Tıp Fakültesi

Subjects
Male, Pediatrics, medicine.medical_specialty, Adolescent, Gastrointestinal Diseases, Psychological intervention, Disease, Global Health, Specialties, Surgical, Congenital Abnormalities, Cohort Studies, medicine, Humans, Prospective Studies, Prospective cohort study, Child, Developing Countries, business.industry, Gastroschisis, Developed Countries, Intestinal atresia, Infant, Newborn, Gestational age, Congenital diaphragmatic hernia, Infant, Articles, General Medicine, medicine.disease, Gastrointestinal Tract, Atresia, Child, Preschool, Female, business
Abstract

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p

Published
2020

9. Bronchoalveolar Lavage Fluid in Children: Comparative Proteomic Analysis in Infectious and Non-Infectious Lung Disease

Author

Valeria Calcaterra, Gloria Pelizzo, Riccardo Albertini, Carmine Tinelli, Michele Zorzetto, Noemi Pasqua, Paolo Iadarola, Maria Antonietta Avanzini, Marco Fumagalli, and Annalisa De Silvestri

Subjects
Pulmonary and Respiratory Medicine, Lung, medicine.diagnostic_test, business.industry, bronchoalveolar lavage, fluid, children, proteomics, lung, Settore MED/20 - Chirurgia Pediatrica e Infantile, Proteomics, Pediatric Disease, medicine.anatomical_structure, Bronchoalveolar lavage, Lung disease, Pediatrics, Perinatology and Child Health, Immunology, Proteome, medicine, Immunology and Allergy, business, Non infectious
Abstract

To date, relatively few studies have been specifically designed to identify the proteome profile in pulmonary pediatric disease. The aim of this study was to survey proteins present in bronchoalveo...

Published
2018

10. Intestinal Duplication and Hirschsprung's Disease: An Extremely Rare and Misleading Combination

Author

Alessandro Raffaele, Luigi Avolio, Marco Brunero, Gloria Pelizzo, Noemi Pasqua, and Fabrizio Vatta

Subjects
intestinal occlusion, medicine.medical_specialty, business.industry, lcsh:RJ1-570, lcsh:Surgery, intestinal duplication, lcsh:Pediatrics, Case Report, lcsh:RD1-811, Disease, 030230 surgery, Intestinal Duplication, medicine.disease, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Intestinal occlusion, Internal medicine, medicine, business, Surgical treatment, Hirschsprung's disease
Abstract

Hirschsprung's disease and, more rarely, intestinal duplication can both cause intestinal obstruction in neonates. The simultaneous occurrence of these two diseases is reported in only two studies, and in both cases, intestinal duplication was an incidental finding, as it had not determined clinical intestinal occlusion. This paper reports a unique case of coexistence of the two conditions, with both causing intestinal obstruction, delayed appropriate, and definitive surgical treatment.

Published
2018

11. Juvenile Granulosa Cell Tumor of the Testis: Prenatal Diagnosis and Management

Author

Stefania Cesari, Fabrizio Vatta, Gian Battista Parigi, Luigi Avolio, Alessandro Raffaele, Piero Romano, and Noemi Pasqua

Subjects
Pathology, medicine.medical_specialty, endocrine system, prenatal ultrasound, lcsh:Surgery, Case Report, Prenatal diagnosis, 03 medical and health sciences, Tunica albuginea (ovaries), 0302 clinical medicine, 030225 pediatrics, Parenchyma, medicine, Orchiectomy, juvenile granulosa cell tumor, Pregnancy, Fetus, business.industry, Ultrasound, lcsh:RJ1-570, lcsh:Pediatrics, lcsh:RD1-811, medicine.disease, testicular tumors, Gestation, 030211 gastroenterology & hepatology, business
Abstract

Prepubertal primary testicular tumors account for ∼1% of all pediatric solid tumors. We report a new case of prenatal diagnosis of juvenile-type granulosa cell tumor (JGCT). A fetal ultrasound performed at the 38th week of gestation for suspected nonvertex presentation identified a left multilocular septated cystic testicular mass, suggestive for JGCT. At birth, a painless left scrotal mass was detected. Ultrasound re-evaluation excluded torsion of the testis. Tumor markers and abdominal ultrasound were normal for age. Inguinal exploration revealed a cystic mass beneath the tunica albuginea that had replaced all the normal parenchyma. Since organ-sparing surgery was thus not feasible, an orchiectomy was performed and diagnosis of JGCT was confirmed. At 7-year follow-up, the child presented an uneventful outcome. Our case shows that neonatal JGCT, which has an intrauterine genesis, can be diagnosed prenatally by ultrasound in the last weeks of pregnancy.

Published
2019

12. Thoracoscopic Treatment of Pneumothorax in Marfan Syndrome: Hemostatic Patch to Support Lung Resection Recovery

Author

Eloisa Arbustini, Noemi Pasqua, Valeria Calcaterra, Gloria Pelizzo, and Patrizia Morbini

Subjects
Marfan syndrome, medicine.medical_specialty, Lung, biology, business.industry, lcsh:Surgery, lcsh:RD1-811, 030204 cardiovascular system & hematology, medicine.disease, Fibrin, Surgery, respiratory tract diseases, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030228 respiratory system, Pneumothorax, Surgical patch, medicine, biology.protein, Pharmacology (medical), Recurrent pneumothorax, Lung resection, business, Surgical treatment
Abstract

Introduction. In selected patients, the absorbable fibrin patch TachoSil® is superior to standard surgical treatment in reducing air leakage after pulmonary lobectomy. Pulmonary involvement is not considered a main feature of Marfan syndrome (MFS); however, spontaneous pneumothorax (SP) with a high rate of recurrence is frequently reported. We describe the use of TachoSil® in the supportive treatment of recurrent pneumothorax in a girl with MFS. Case Report. A 12-year-old girl with a previous diagnosis of MFS and recurrent history of left spontaneous pneumothorax was submitted to thoracoscopic atypical lung resection. Two patches (9.5 × 4.8 cm) were cut from the adhesive/foam complex (TachoSil®) and were pressed against the sutured area as supportive treatment. The patient recovered with no further SP recurrences. Conclusions. The use of the TachoSil® surgical patch may be useful in pneumothorax supportive treatment, particularly in pediatric MFS by ameliorating the mechanical strength of the lung.

Published
2018

13. Pediatric Laparoscopy and Adaptive Oxygenation and Hemodynamic Changes

Author

Simonetta Mencherini, Giuseppe Maggio, Valeria Calcaterra, Veronica Carlini, Giulio Iacob, Marco Brunero, Noemi Pasqua, Gloria Pelizzo, and Annalisa De Silvestri

Subjects
Insufflation, Diastole, laparoscopy, changes, Hemodynamics, lcsh:Medicine, Pediatrics, children, hemodinamics, Article, 03 medical and health sciences, Basal (phylogenetics), 0302 clinical medicine, 030202 anesthesiology, Heart rate, medicine, Laparoscopy, medicine.diagnostic_test, business.industry, lcsh:R, lcsh:RJ1-570, lcsh:Pediatrics, Oxygenation, Blood pressure, Anesthesia, 030211 gastroenterology & hepatology, sense organs, business
Abstract

Adaptive changes in oxygenation and hemodynamics are evaluated during pediatric laparoscopy. The children underwent laparoscopy (LAP Group, n=20) or open surgery (Open Group, n=10). Regional cerebral (rScO2) and peripheral oxygen saturation (SpO2), heart rate (HR), diastolic (DP) and systolic pressure (SP) were monitored at different intervals: basal (T0); anesthesia induction (T1); CO2PP insufflation (T2); surgery (T3); CO2PP cessation (T4); before extubation (T5). At T1, in both the LAP and Open groups significant changes in rScO2, DP and SP were recorded compared with T0; a decrease in SatO2 was also observed at T5. In the LAP group, at T2, changes in HR related to CO2PP pressure and in DP and SP related to IAP were noted; at T4, a SP change associated with CO2PP desufflation was recorded. Open group, at T3 and T5 showed lower rScO2 values compared with T1. Pneuperitoneum and anesthesia are influent to induce hemodynamics changes during laparoscopy.

Published
2017

14. Identification of Autophagy-Related Genes and Their Regulatory miRNAs Associated with Celiac Disease in Children

Author

Carolina Martinelli, Sara Pagani, Marco Biggiogera, Noemi Pasqua, Cristina Meazza, Gloria Pelizzo, Federico Manai, Mauro Bozzola, and Sergio Comincini

Subjects
0301 basic medicine, Male, Biopsy, Disease, lcsh:Chemistry, 0302 clinical medicine, Medicine, Intestinal Mucosa, Child, lcsh:QH301-705.5, Spectroscopy, celiac disease molecular markers, biology, medicine.diagnostic_test, microRNA, General Medicine, BECN1, Computer Science Applications, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, RNA Interference, autophagy, Models, Biological, Catalysis, Article, Cell Line, Inorganic Chemistry, 03 medical and health sciences, Humans, Physical and Theoretical Chemistry, Molecular Biology, business.industry, Gene Expression Profiling, Organic Chemistry, Autophagy, Computational Biology, Microvesicles, Small intestine, Celiac Disease, MicroRNAs, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, Gene Expression Regulation, ROC Curve, Case-Control Studies, Immunology, biology.protein, Gliadin, business, Biomarkers
Abstract

Celiac disease (CD) is a severe genetic autoimmune disorder, affecting about one in 100 people, where the ingestion of gluten leads to damage in the small intestine. Diagnosing CD is quite complex and requires blood tests and intestinal biopsy examinations. Controversy exists regarding making the diagnosis without biopsy, due to the large spectrum of manifesting symptoms; furthermore, small-intestinal gastroscopy examinations have a relatively complex management in the pediatric population. To identify novel molecular markers useful to increase the sensitivity and specificity in the diagnosis of pediatric CD patients, the expression levels of two key autophagy executor genes (ATG7 and BECN1) and their regulatory validated miRNAs (miR-17 and miR-30a, respectively) were analyzed by relative quantitative real-time-PCR on a cohort of confirmed CD patients compared to age-related controls. Among the investigated targets, the non-parametric Mann–Whitney U test and ROC analysis indicated the highest significant association of BECN1 with CD status in the blood, while in intestinal biopsies, all of the investigated sequences were positively associated with CD diagnosis. Nomogram-based analysis showed nearly opposite expression trends in blood compared to intestine tissue, while hierarchical clustering dendrograms enabled identifying CD and control subgroups based on specific genes and miRNA expression signatures. Next, using an established in vitro approach, through digested gliadin administration in Caco-2 cells, we also highlighted that the modulation of miR-17 endogenous levels using enriched exosomes increased the intracellular autophagosome content, thereby altering the autophagic status. Altogether, these results highlighted novel molecular markers that might be useful to increase the accuracy in CD diagnosis and in molecular-based stratification of the patients, further reinforcing the functional involvement of the regulation of the autophagy process within a digestive and autoimmune-related disorder as CD.

Published
2017

15. Plunging ranula in children: case report and literature review

Author

Mario Fusillo, Noemi Pasqua, Marinella Guazzotti, Gloria Pelizzo, Valeria Calcaterra, and Veronica Carlini

Subjects
medicine.medical_specialty, plunging ranula, lcsh:Medicine, Physical examination, Case Report, Pediatrics, Palpation, 03 medical and health sciences, 0302 clinical medicine, children, Major Salivary Gland, differential diagnosis, medicine, Cyst, 030223 otorhinolaryngology, therapy, medicine.diagnostic_test, business.industry, Plunging ranula, lcsh:R, Children, Differential diagnosis, Therapy, lcsh:RJ1-570, Sublingual gland, Magnetic resonance imaging, lcsh:Pediatrics, medicine.disease, Surgery, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Radiology, business
Abstract

Few cases of plunging ranulas (PRs) occur during childhood and the lesions are frequently misdiagnosed. Here, a PR in a child is reported along with a literature review. A seven-year-old female complaining of swelling in the midline neck, left-submandibular region, was evaluated. No oral cavity or major salivary glands abnormalities were detected. On palpation, a soft, painless, and fluid-containing mass was observed. The suspicion PR was performed by ultrasound. The diagnosis was confirmed with a histopathological examination. The lesion was removed with a cervical approach, without recurrence. PR is an uncommon condition in children under 10 years of age. Differential diagnosis depends on clinical examination and ultrasonography. A computed tomography-scan and magnetic resonance imaging can be performed if the diagnosis remains uncertain. In pediatrics, the key to success of the treatment may rely on the radical excision of the cyst and sublingual gland, via an intraoral or submandibular approach.

Published
2016

16. Nutritional status and metabolic profile in neurologically impaired pediatric surgical patients

Author

Riccardo Albertini, Matteo Manuelli, Noemi Pasqua, Hellas Cena, Gloria Pelizzo, Mara De Amici, Veronica Carlini, Valeria Calcaterra, Elona Luka, Mario Fusillo, and Catherine Klersy

Subjects
Adult, Male, medicine.medical_specialty, Pediatrics, Percentile, Adolescent, Endocrinology, Diabetes and Metabolism, Nutritional Status, 030209 endocrinology & metabolism, Body Mass Index, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Endocrinology, Insulin resistance, Risk Factors, Pediatric surgery, medicine, Humans, Mass index, Child, Metabolic Syndrome, Anthropometry, business.industry, medicine.disease, Prognosis, Malnutrition, Case-Control Studies, Child, Preschool, Pediatrics, Perinatology and Child Health, Body Composition, Metabolome, Female, Metabolic syndrome, Insulin Resistance, Nervous System Diseases, business, Energy Intake, Body mass index, 030217 neurology & neurosurgery, Biomarkers, Follow-Up Studies
Abstract

Background:Malnutrition is reported in pediatric neuromotor disability and impacts the child’s health. We described the nutritional and metabolic status in neurologically impaired (NI) children undergoing surgery.Methods:Anthropometry, body composition, hormonal and nutritional evaluations were performed in 44 NI subjects (13.7±8.0 years). Energy needs were calculated by Krick’s formula. Metabolic syndrome (MS) was defined applying the following criteria (≥3 defined MS): fasting blood glucose >100 mg/dL and/or homeostasis model assessment for insulin resistance (HOMA-IR) >97.5th percentile, trygliceride level >95th percentile, high-density lipoprotein (HDL)-cholesterol level 95th percentile; whilebody mass index – standard deviation score (BMI-SDS) Results:Energy intake was not adequate in 73.8% of the patients; no correlation between energy intake and BMI was noted. Undernutrition was noted in 34.1% of patients and MS in 11.36% of subjects. Fifty percent of the patients presented with insulin resistance, which was not related to BMI, body composition or other MS components.Conclusions:Nutritional and metabolic monitoring of disabled children and young adults is recommended to prevent adverse outcomes associated with malnutrition.

Published
2016

17. Laparoscopy in children and its impact on brain oxygenation during routine inguinal hernia repair

Author

Lucio Bianchi, Veronica Carlini, Valeria Calcaterra, Giuseppe Maggio, Noemi Pasqua, Simonetta Mencherini, Annalisa De Silvestri, Gloria Pelizzo, and Luciano Bernardi

Subjects
Insufflation, medicine.medical_specialty, near-infrared spectroscopy, lcsh:Surgery, laparoscopy, Brain oxygenation, Cerebral oxygen saturation, 03 medical and health sciences, 0302 clinical medicine, children, Pneumoperitoneum, 030202 anesthesiology, Heart rate, medicine, lcsh:RC799-869, Laparoscopy, brain oxygenation, medicine.diagnostic_test, business.industry, lcsh:RD1-811, Oxygenation, Settore MED/20 - Chirurgia Pediatrica e Infantile, medicine.disease, Surgery, Inguinal hernia, Pulse oximetry, 030220 oncology & carcinogenesis, Anesthesia, lcsh:Diseases of the digestive system. Gastroenterology, Original Article, business
Abstract

BACKGROUND: The systemic impact of intra-abdominal pressure (IAP) and/or changes in carbon dioxide (CO2) during laparoscopy are not yet well defined. Changes in brain oxygenation have been reported as a possible cause of cerebral hypotension and perfusion. The side effects of anaesthesia could also be involved in these changes, especially in children. To date, no data have been reported on brain oxygenation during routine laparoscopy in paediatric patients. PATIENTS AND METHODS: Brain and peripheral oxygenation were investigated in 10 children (8 male, 2 female) who underwent elective minimally invasive surgery for inguinal hernia repair. Intraoperative transcranial near-infrared spectroscopy to assess regional cerebral oxygen saturation (rScO2), peripheral oxygen saturation using pulse oximetry and heart rate (HR) were monitored at five surgical intervals: Induction of anaesthesia (baseline T1); before CO2 insufflation induced pneumoperitoneum (PP) (T2); CO2 PP insufflation (T3); cessation of CO2 PP (T4); before extubation (T5). RESULTS: rScO2 decreases were recorded immediately after T1 and became significant after insufflation (P = 0.006; rScO2 decreased 3.6 ± 0.38%); restoration of rScO2 was achieved after PP cessation (P = 0.007). The changes in rScO2 were primarily due to IAP increases (P = 0.06). The HR changes were correlated to PP pressure (P < 0.001) and CO2 flow rate (P = 0.001). No significant peripheral effects were noted. CONCLUSIONS: The increase in IAP is a critical determinant in cerebral oxygenation stability during laparoscopic procedures. However, the impact of anaesthesia on adaptive changes should not be underestimated. Close monitoring and close collaboration between the members of the multidisciplinary paediatric team are essential to guarantee the patient's safety during minimally invasive surgical procedures.

Published
2017

18. ALS-causing mutations differentially affect PGC-1α expression and function in the brain vs. peripheral tissues

Author

Hanna Bayer, Kerstin Lang, Eva Buck, Julia Higelin, Lara Barteczko, Noemi Pasquarelli, Jasmin Sprissler, Tanja Lucas, Karlheinz Holzmann, Maria Demestre, Katrin S. Lindenberg, Karin M. Danzer, Tobias Boeckers, Albert C. Ludolph, Luc Dupuis, Patrick Weydt, and Anke Witting

Subjects
Amyotrophic lateral sclerosis, Lou Gehrig disease, PGC-1α, Lactate, FUS, SOD1, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Background: Monogenetic forms of amyotrophic lateral sclerosis (ALS) offer an opportunity for unraveling the molecular mechanisms underlying this devastating neurodegenerative disorder. In order to identify a link between ALS-related metabolic changes and neurodegeneration, we investigated whether ALS-causing mutations interfere with the peripheral and brain-specific expression and signaling of the metabolic master regulator PGC (PPAR gamma coactivator)-1α (PGC-1α). Methods: We analyzed the expression of PGC-1α isoforms and target genes in two mouse models of familial ALS and validated the stimulated PGC-1α signaling in primary adipocytes and neurons of these animal models and in iPS derived motoneurons of two ALS patients harboring two different frame-shift FUS/TLS mutations. Results: Mutations in SOD1 and FUS/TLS decrease Ppargc1a levels in the CNS whereas in muscle and brown adipose tissue Ppargc1a mRNA levels were increased. Probing the underlying mechanism in neurons, we identified the monocarboxylate lactate as a previously unrecognized potent and selective inducer of the CNS-specific PGC-1α isoforms. Lactate also induced genes like brain-derived neurotrophic factor, transcription factor EB and superoxide dismutase 3 that are down-regulated in PGC-1α deficient neurons. The lactate-induced CNS-specific PGC-1α signaling system is completely silenced in motoneurons derived from induced pluripotent stem cells obtained from two ALS patients harboring two different frame-shift FUS/TLS mutations. Conclusion: ALS mutations increase the canonical PGC-1α system in the periphery while inhibiting the CNS-specific isoforms. We identify lactate as an inducer of the neuronal PGC-1α system directly linking brain metabolism and neuroprotection. Changes in the PGC-1α system might be involved in the ALS accompanied metabolic changes and in neurodegeneration.

Published
2017
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19. Comparison of Sirtuin 3 Levels in ALS and Huntington’s Disease—Differential Effects in Human Tissue Samples vs. Transgenic Mouse Models

Author

Eva Buck, Hanna Bayer, Katrin S. Lindenberg, Johannes Hanselmann, Noemi Pasquarelli, Albert C. Ludolph, Patrick Weydt, and Anke Witting

Subjects
amyotrophic lateral sclerosis, Huntington’s disease, Sirt3, PGC-1α, mitochondria, SOD(G93A), Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Neurodegenerative diseases are characterized by distinct patterns of neuronal loss. In amyotrophic lateral sclerosis (ALS) upper and lower motoneurons degenerate whereas in Huntington’s disease (HD) medium spiny neurons in the striatum are preferentially affected. Despite these differences the pathophysiological mechanisms and risk factors are remarkably similar. In addition, non-neuronal features, such as weight loss implicate a dysregulation in energy metabolism. Mammalian sirtuins, especially the mitochondrial NAD+ dependent sirtuin 3 (SIRT3), regulate mitochondrial function and aging processes. SIRT3 expression depends on the activity of the metabolic master regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a modifier of ALS and HD in patients and model organisms. This prompted us to systematically probe Sirt3 mRNA and protein levels in mouse models of ALS and HD and to correlate these with patient tissue levels. We found a selective reduction of Sirt3 mRNA levels and function in the cervical spinal cord of end-stage ALS mice (superoxide dismutase 1, SOD1G93A). In sharp contrast, a tendency to increased Sirt3 mRNA levels was found in the striatum in HD mice (R6/2). Cultured primary neurons express the highest levels of Sirt3 mRNA. In primary cells from PGC-1α knock-out (KO) mice the Sirt3 mRNA levels were highest in astrocytes. In human post mortem tissue increased mRNA and protein levels of Sirt3 were found in the spinal cord in ALS, while Sirt3 levels were unchanged in the human HD striatum. Based on these findings we conclude that SIRT3 mediates the different effects of PGC-1α during the course of transgenic (tg) ALS and HD and in the human conditions only partial aspects Sirt3 dysregulation manifest.

Published
2017
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20. Traceless bioresponsive shielding of adenovirus hexon with HPMA copolymers maintains transduction capacity in vitro and in vivo.

Author

Jan-Michael Prill, Vladimír Subr, Noemi Pasquarelli, Tatjana Engler, Andrea Hoffmeister, Stefan Kochanek, Karel Ulbrich, and Florian Kreppel

Subjects
Medicine, Science
Abstract

Capsid surface shielding of adenovirus vectors with synthetic polymers is an emerging technology to reduce unwanted interactions of the vector particles with cellular and non-cellular host components. While it has been shown that attachment of shielding polymers allows prevention of undesired interactions, it has become evident that a shield which is covalently attached to the vector surface can negatively affect gene transfer efficiency. Reasons are not only a limited receptor-binding ability of the shielded vectors but also a disturbance of intracellular trafficking processes, the latter depending on the interaction of the vector surface with the cellular transport machinery. A solution might be the development of bioresponsive shields that are stably maintained outside the host cell but released upon cell entry to allow for efficient gene delivery to the nucleus. Here we provide a systematic comparison of irreversible versus bioresponsive shields based on synthetic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers. In addition, the chemical strategy used for generation of the shield allowed for a traceless bioresponsive shielding, i.e., polymers could be released from the vector particles without leaving residual linker residues. Our data demonstrated that only a bioresponsive shield maintained the high gene transfer efficiency of adenovirus vectors both in vitro and in vivo. As an example for bioresponsive HPMA copolymer release, we analyzed the in vivo gene transfer in the liver. We demonstrated that both the copolymer's charge and the mode of shielding (irreversible versus traceless bioresponsive) profoundly affected liver gene transfer and that traceless bioresponsive shielding with positively charged HPMA copolymers mediated FX independent transduction of hepatocytes. In addition, we demonstrated that shielding with HPMA copolymers can mediate a prolonged blood circulation of vector particles in mice. Our results have significant implications for the future design of polymer-shielded Ad and provide a deeper insight into the interaction of shielded adenovirus vector particles with the host after systemic delivery.

Published
2014
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