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1. Impact of the COVID-19 Pandemic on People Living With Rare Diseases and Their Families: Results of a National Survey

Author

Maurizio Macaluso, Marc E Rothenberg, Thomas Ferkol, Pierce Kuhnell, Henry J Kaminski, David W Kimberlin, Michael Benatar, and Mirna Chehade

Subjects
Public aspects of medicine, RA1-1270
Abstract

BackgroundWith more than 103 million cases and 1.1 million deaths, the COVID-19 pandemic has had devastating consequences for the health system and the well-being of the entire US population. The Rare Diseases Clinical Research Network funded by the National Institutes of Health was strategically positioned to study the impact of the pandemic on the large, vulnerable population of people living with rare diseases (RDs). ObjectiveThis study was designed to describe the characteristics of COVID-19 in the RD population, determine whether patient subgroups experienced increased occurrence or severity of infection and whether the pandemic changed RD symptoms and treatment, and understand the broader impact on respondents and their families. MethodsUS residents who had an RD and were 9 symptoms vs none: OR 82.5, 95% CI 29-234 and 5-9: OR 44.8, 95% CI 18.7-107). Median symptom duration was 16 (IQR 9-30) days. Hospitalization (7/71, 10%) and ventilator support (4/71, 6%) were uncommon. Respondents who acquired COVID-19 reported increased occurrence and severity of RD symptoms and use or dosage of select medications; those who did not acquire COVID-19 reported decreased occurrence and severity of RD symptoms and use of medications; those who did not know had an intermediate pattern. The pandemic made it difficult to access care, receive treatment, get hospitalized, and caused mood changes for respondents and their families. ConclusionsSelf-reported COVID-19 was more frequent than expected and was associated with increased prevalence and severity of RD symptoms and greater use of medications. The pandemic negatively affected access to care and caused mood changes in the respondents and family members. Continued surveillance is necessary.

Published
2024
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2. An international survey on nasal nitric oxide measurement practices for the diagnosis of primary ciliary dyskinesia

Author

Nicole Beydon, Thomas Ferkol, Amanda Lea Harris, Murielle Colas, Stephanie D. Davis, Eric Haarman, Claire Hogg, Emma Kilbride, Panayotis Kouis, Claudia E. Kuehni, Philipp Latzin, Diana Marangu, June Marthin, Kim G. Nielsen, Phil Robinson, Nisreen Rumman, Matthew Rutter, Woolf Walker, and Jane S. Lucas

Subjects
Medicine
Abstract

Nasal nitric oxide (nNO) measurements are used in the assessment of patients suspected of having primary ciliary dyskinesia (PCD), but recommendations for performing such measurements have not focused on children and do not include all current practices. To guide the development of a European Respiratory Society-supported technical standard for nNO measurement in children, an international online survey was conducted to better understand current measurement practices among providers involved in PCD diagnostics. 78 professionals responded, representing 65 centres across 18 countries, mainly in Europe and North America. Nearly all centres measured nNO in children and more than half performed measurements before 5 years of age. The test was often postponed in children with signs of acute airway infection. In Europe, the electrochemical technique was more frequently used than chemiluminescence. A similar proportion of centres performed measurements during exhalation against a resistance (49 out of 65) or during tidal breathing (50 out of 65); 15 centres used only exhalation against a resistance and 15 used only tidal breathing. The cut-off values used to discriminate PCD were consistent across centres using chemiluminescence analysers; these centres reported results as an output (nL·min−1). Cut-off values were highly variable across centres using electrochemical devices, and nNO concentrations were typically reported as ppb. This survey is the first to determine real-world use of nNO measurements globally and revealed remarkable variability in methodology, equipment and interpretation. These findings will help standardise methods and training.

Published
2022
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3. Unfriendly Fire: How the Tobacco Industry is Destroying the Future of Our Children

Author

Andrew Bush, Thomas Ferkol, Algirdas Valiulis, Artur Mazur, Ivane Chkhaidze, Tamaz Maglakelidze, Sergey Sargsyan, Gevorg Boyajyan, Olga Cirstea, Svitlana Doan, Oleksandr Katilov, Valeriy Pokhylko, Leonid Dubey, Edita Poluziorovienė, Nina Prokopčiuk, Vaida Taminskienė, and Arūnas Valiulis

Subjects
Acute lung injury, alveolar haemorrhage, eosinophilic pneumonia, lipoid pneumonia, innate immune system, nicotine, Medicine
Abstract

Tobacco has long been known to be one of the greatest causes of morbidity and mortality in the adults, but the effects on the foetus and young children, which are lifelong, have been less well appreciated. Developing from this are electronic nicotine delivery systems or vapes, promulgated as being less harmful than tobacco. Nicotine itself is toxic to the foetus, with permanent effects on lung structure and function. Most vapes contain nicotine, but they also contain many other compounds which are inhaled and for which there are no toxicity studies. They also contain known toxic substances, whose use is banned by European Union legislation. Accelerating numbers of young people are vaping, and this does not reflect an exchange of vapes for cigarettes. The acute toxicity of e-cigarettes is greater than that of tobacco, and includes acute lung injury, pulmonary haemorrhage and eosinophilic and lipoid pneumonia. Given the worse acute toxicity, it should be impossible to be complacent about medium and long term effects of vaping. Laboratory studies have demonstrated changes in lung proteomics and the innate immune system with vaping, some but not all of which overlap with tobacco. It would be wrong to consider vapes as a weaker form of tobacco, they have their own toxicity. Children and young people are being targeted by the vaping industry (which is largely the same as the tobacco industry), including on-line, and unless an efficient legislative program is put in place, a whole new generation of nicotine addicts will result.

Published
2021
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4. Repetitive Imaging of Reporter Gene Expression in the Lung

Author

Jean-Christophe Richard, Philip Factor, Thomas Ferkol, Datta E. Ponde, Zhaohui Zhou, and Daniel P. Schuster

Subjects
Biology (General), QH301-705.5, Medical technology, R855-855.5
Abstract

Positron emission tomographic imaging is emerging as a powerful technology to monitor reporter transgene expression in the lungs and other organs. However, little information is available about its usefulness for studying gene expression over time. Therefore, we infected 20 rats with a replication-deficient adenovirus containing a fusion gene encoding for a mutant Herpes simplex virus type-1 thymidine kinase and an enhanced green fluorescent protein. Five additional rats were infected with a control virus. Pulmonary gene transfer was performed via intratracheal administration of vector using a surfactant-based method. Imaging was performed 4–6 hr, and 4, 7, and 10 days after gene transfer, using 9-(4-[ 18 F]-fluoro-3-hydroxymethylbutyl)guanine, an imaging substrate for the mutant kinase. Lung tracer uptake assessed with imaging was moderately but significantly increased 4–6 hr after gene transfer, was maximal after 4 days, and was no longer detectable by 10 days. The temporal pattern of transgene expression measured ex vivo with in vitro assays of thymidine kinase activity and green fluorescent protein was similar to imaging. In conclusion, positron emission tomography is a reliable new tool to evaluate the onset and duration of reporter gene expression noninvasively in the lungs of intact animals.

Published
2003
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5. Contributors

Author

Gathi, Abraham, primary, Sun-Young, Ahn, additional, Rasheda, Amin, additional, Anne L., Angiolillo, additional, Rami A., Ballout, additional, Khadija, Belhassan, additional, Michael J., Bennett, additional, Julie, Berg, additional, Ajay, Bhatia, additional, Janetta, Bryksin, additional, Carlos, Castillo-Pinto, additional, Amaziah, Coleman, additional, Ferdinand, Coste, additional, Jeffrey G., Dawson, additional, Edgard E., Delvin, additional, Yaser, Diab, additional, Dennis J., Dietzen, additional, Marc T., DiSabella, additional, Andrew C., Edmondson, additional, Michael, Edzards, additional, Thomas, Ferkol, additional, Gabriela (Paula), Finkielstain, additional, Mary E., Fournier, additional, Andrea, Gaedigk, additional, Uttam, Garg, additional, Sarah K., Garwood, additional, Emily L., Gill, additional, Jorge L., Granadillo, additional, Michael F., Guerrera, additional, Shannon, Haymond, additional, Paul S., Hiers, additional, Alyssa, James, additional, Janis M., Stoll, additional, Jill D., Jacobson, additional, Andrew, Janowski, additional, Smita, Jha, additional, Patricia M., Jones, additional, Jami L., Josefson, additional, Randall K., Julian, additional, Lawrence, Jung, additional, Sakil, Kulkarni, additional, Finza, Latif, additional, Courtney, Lawrence, additional, Van, Leung-Pineda, additional, Fabien, Magne, additional, Stephen R., Master, additional, Emily Riehm, Meier, additional, Deborah, Merke, additional, Asha, Moudgil, additional, Khushbu, Patel, additional, Wendy M., Paul, additional, Rowena, Punzalan, additional, Scott, Raskin, additional, Kimiyo, Raymond, additional, Alan T., Remaley, additional, Mary, Revenis, additional, Adelaide, Robb, additional, Stephen M., Roper, additional, Blachy J. Dávila, Saldaña, additional, Maryam, Salehi, additional, Tracy L., Sandritter, additional, Hemant, Sharma, additional, Troy, Tenney, additional, Silvia, Tortorelli, additional, Akshaya, Vachharajani, additional, Guy, Van Vliet, additional, Amy L., White, additional, William E., Winter, additional, and Edward C.C., Wong, additional

Published
2021
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6. Late Breaking Abstract - Nasal nitric oxide measurement in children for the diagnosis of primary ciliary dyskinesis: ERS technical standard

Author

Beydon, Nicole, primary, Kouis, Panayiotis, additional, Marthin, June, additional, Latzin, Philipp, additional, Colas, Murielle, additional, Davis, Stephanie, additional, Haarman, Eric, additional, Amanda, Harris, additional, Claire, Hogg, additional, Emma, Kilbride, additional, Claudia, Kuehni, additional, Diana, Marangu, additional, Kim, Nielsen, additional, Catherine, Pendergrast, additional, Phil, Robinson, additional, Nisreen, Rumman, additional, Matthew, Rutter, additional, Woolf, Walker, additional, Thomas, Ferkol, additional, and Lucas, Jane, additional

Published
2023
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7. Nasal nitric oxide measurement in children for the diagnosis of primary ciliary dyskinesia: European Respiratory Society technical standard

Author

Nicole Beydon, Panayiotis Kouis, June K. Marthin, Philipp Latzin, Murielle Colas, Stephanie D. Davis, Eric Haarman, Amanda Lea Harris, Claire Hogg, Emma Kilbride, Claudia E. Kuehni, Diana Marangu, Kim G. Nielsen, Catherine Pendergrast, Phil Robinson, Nisreen Rumman, Matthew Rutter, Woolf T. Walker, Thomas Ferkol, Jane S. Lucas, Beydon, Nicole, Kouis, Panayiotis, Marthin, June K, Latzin, Philipp, Colas, Murielle, Davis, Stephanie D, Haarman, Eric, Harris, Amanda Lea, Hogg, Claire, Kilbride, Emma, Kuehni, Claudia ., Marangu, Diana, Nielsen, Kim G, Pendergrast, Catherine, Robinson, Phil, Rumman, Nisreen, Rutter, Matthew, Walker, Woolf T, Ferkol, Thomas, Lucas, Jane S, Pediatrics, CCA - Cancer biology and immunology, and Amsterdam Reproduction & Development (AR&D)

Subjects
Pulmonary and Respiratory Medicine, nasal nitric oxide measurement, children, 360 Soziale Probleme, Sozialdienste, primary ciliary dyskinesia, 610 Medizin und Gesundheit
Abstract

Refereed/Peer-reviewed Nasal nitric oxide (nNO) is extremely low in most people with primary ciliary dyskinesia (PCD) and its measurement is an important contributor to making the diagnosis. Existing guidelines and technical standards focus on nNO measurements in older, cooperative children using chemiluminescence analysers. However, measurements of nNO in pre-school-age children (age 2–5 years) may facilitate early diagnosis and electrochemical rather than chemiluminescence analysers are widely used. Pre-schoolers often need different methods to be employed when measuring nNO. Hence, a European Respiratory Society Task Force has developed this technical standard as the first step towards standardising sampling, analysis and reporting of nNO measured as part of the diagnostic testing for PCD in all age groups, including pre-school-age children. Furthermore, we considered both chemiluminescence and electrochemical analysers that are in use worldwide. There was a paucity of quality evidence for electrochemical analysers and sampling methods used in young children, and the Task Force proposes future research priorities to allow updates of this technical standard.

Published
2023
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9. An Adolescent with Respiratory Distress

Author

Priya Patel and Thomas Ferkol

Subjects
Respiratory Distress Syndrome, Dyspnea, Adolescent, Cough, Immunology and Allergy, Humans
Published
2021

11. Hyperinflation is Associated with Increased Respiratory Rate and is a More Sensitive Measure of Cystic Fibrosis Lung Disease During Infancy Compared to Forced Expiratory Measures

Author

Thomas Ferkol, Sarath Ranganathan, Charles Clem, Clement Ren, Stephanie D. Davis, Heather N. Muston, James E. Slaven, and Christina Tiller

Subjects
Pulmonary and Respiratory Medicine, Vital capacity, medicine.medical_specialty, Cystic Fibrosis, Respiratory rate, Vital Capacity, Hyperinflation, Respiratory physiology, Cystic fibrosis, Article, Pulmonary function testing, 03 medical and health sciences, 0302 clinical medicine, Functional residual capacity, Respiratory Rate, Forced Expiratory Volume, 030225 pediatrics, Internal medicine, Humans, Plethysmograph, Medicine, Lung, Retrospective Studies, business.industry, Infant, Newborn, Infant, medicine.disease, Confidence interval, 030228 respiratory system, Lung disease, Pediatrics, Perinatology and Child Health, Cardiology, business
Abstract

BACKGROUND: The goal of this study was to identify clinical features associated with abnormal infant pulmonary function tests (iPFTs), specifically functional residual capacity (FRC), in infants with cystic fibrosis (CF) diagnosed via newborn screen (NBS). We hypothesized that poor nutritional status in the first 6-12 months would be associated with increased FRC at 12-24 months. METHODS: This study utilized a combination of retrospectively and prospectively collected data from ongoing research studies and iPFTs performed for clinical indications. Demographic and clinical features were obtained from the electronic medical record. Forced expiratory flows and volumes were obtained using the raised volume rapid thoracoabdominal technique (RVRTC) and FRC was measured via plethysmography. RESULTS: A total of 45 CF NBS infants had iPFTs performed between 12 and 24 months. Mean forced vital capacity, forced expiratory volume in 0.5 s, and forced expiratory flows were all within normal limits. In contrast, the mean FRC z-score was 2.18 (95% confidence interval [CI] = 1.48, 2.88) and the mean respiratory rate (RR) z-score was 1.42 (95% CI = 0.95, 1.89). There was no significant association between poor nutritional status and abnormal lung function. However, there was a significant association between higher RR and increased FRC, and a RR cutoff of 36 breaths/min resulted in 92% sensitivity to detect hyperinflation with 32% specificity. CONCLUSION: These results suggest that FRC is a more sensitive measure of early CF lung disease than RVRTC measurements and that RR may be a simple, noninvasive clinical marker to identify CF NBS infants with hyperinflation.

Published
2020
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12. Contributors

Author

Robin Abel, Steven H. Abman, Eric Alton, Daniel R. Ambruso, William Carl Anderson, Karthik Balakrishnan, Ian Michael Balfour-Lynn, Anna Bamford, Ronen Bar-Yoseph, Erika Berman-Rosenzweig, Deepika Bhatla, Joshua A. Blatter, R. Paul Boesch, Matias Bruzoni, Andrew Bush, Michael Bye, Kai Håkon Carlsen, Anne B. Chang, Stephanie D. Chao, Michelle Chatwin, Bimal Pankaj Chaudhari, Lyn Chitty, Nicola Collins, Dan M. Cooper, Jonathan Corren, Robin T. Cotton, Andrea Coverstone, Suzanne Crowley, Steve Cunningham, Garry R. Cutting, Dorottya Czovek, Charles L. Daley, Gwyneth Davies, Jane C. Davies, Alessandro de Alarcòn, Emily M. DeBoer, Marietta Morales De Guzman, Sharon D. Dell, Robin Deterding, Gail H. Deutsch, Sunalene Devadason, William Graham Fox Ditcham, Jill Dorsey, Francine M. Ducharme, John Engelhardt, Mark L. Everard, Leland L. Fan, Albert Faro, Thomas Ferkol, Louise Fleming, Angela Mary Fonceca, Hammad A. Ganatra, Amy Michelle Garcia, David Gozal, Diane Gray, Anne Greenough, Uta Griesenbach, Jonathan Grigg, James S. Hagood, Jürg Hammer, Aaron Hamvas, Jonny Harcourt, Pia J. Hauk, Ulrich Heininger, Alexander John Henderson, Marianna M. Henry, Richard J. Hewitt, Heather Young Highsmith, Noah H. Hillman, Heather Ellen Hoch, Jeong S. Hyun, Mas Suhaila Isa, Adam Jaffé, Lance C. Jennings, Alan H. Jobe, Ankur A. Kamdar, Bhushan Katira, Brian P. Kavanagh, James Kemp, Carolyn M. Kercsmar, Leila Kheirandish-Gozal, Wilson King, Paul Kingma, Jennifer Knight-Madden, Alan Paul Knutsen, Alik Kornecki, Usha Krishnan, Geoffrey Kurland, Hugh Simon Lam, Claire Langston, Ada Lee, Margaret W. Leigh, Daniel Lesser, Clare M. Lloyd, Anna Maria Mandalakas, Paulo J.C. Marostica, Stacey L. Martiniano, Jennifer Maybee, Karen M. McDowell, Peter Michelson, Aaron Samuel Miller, Claire Kane Miller, Ayesha Mirza, David R. Murdoch, Christopher J.L. Newth, Andrew Gordon Nicholson, Jerry A. Nick, Christina J. Nicolais, Terry L. Noah, Lawrence M. Nogee, Blakeslee Noyes, Andrew H. Numa, Ann-Christine Nyquist, Hugh O'Brodovich, Matthias Ochs, J. Tod Olin, Øystein Olsen, Catherine Owens, Howard B. Panitch, Hans Pasterkamp, Donald Payne, Scott Pentiuk, Jeremy Prager, Jean-Paul Praud, Andrew P. Prayle, Bernadette Prentice, Philip E. Putnam, Alexandra L. Quittner, Shlomit Radom-Aizik, Suchitra Rao, Mobeen Rathore, Gregory J. Redding, Michael Rutter, Estefany Saez-Flores, Sejal Saglani, Rayfel Schneider, Kenneth O. Schowengerdt, Marcelo C. Scotta, Thomas Semple, Laurie Sherlock, Ram N. Singh, Raymond G. Slavin, Peter Sly, Bjarne Smevik, Keely Garrett Smith, Jonathan Spahr, James M. Stark, Jeffrey R. Starke, Renato T. Stein, Paul C. Stillwell, Dennis C. Stokes, Daniel T. Swarr, Stuart Charles Sweet, Stanley James Szefler, Paul Tambyah, Christelle Xian-Ting Tan, James Temprano, Chad M. Thorson, Bruce C. Trapnell, Brian Michael Varisco, Timothy J. Vece, Harish G. Vyas, Ruth Wakeman, Colin Wallis, Jennifer Wambach, Daniel J. Weiner, Anja M. Werno, Susan E. Wert, Jeffrey A. Whitsett, Robert William Wilmott, Robert E. Wood, Christopher Todd Wootten, Marie Wright, Sarah Wright, Rae S.M. Yeung, Takeshi Yoshida, Carolyn Young, Lisa R. Young, Heather J. Zar, Pamela Leslie Zeitlin, and David Zielinski

Published
2019
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13. An Official American Thoracic Society Clinical Practice Guideline: Pediatric Chronic Home Invasive Ventilation

Author

Laura M, Sterni, Joseph M, Collaco, Christopher D, Baker, John L, Carroll, Girish D, Sharma, Jan L, Brozek, Jonathan D, Finder, Veda L, Ackerman, Raanan, Arens, Deborah S, Boroughs, Jodi, Carter, Karen L, Daigle, Joan, Dougherty, David, Gozal, Katharine, Kevill, Richard M, Kravitz, Tony, Kriseman, Ian, MacLusky, Katherine, Rivera-Spoljaric, Alvaro J, Tori, Thomas, Ferkol, and Ann C, Halbower

Subjects
Pulmonary and Respiratory Medicine, Medical home, medicine.medical_specialty, Critical Care and Intensive Care Medicine, Pediatrics, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, 030225 pediatrics, Health care, Humans, Medicine, Workgroup, Child, Intensive care medicine, Grading (education), business.industry, Community management, Guideline, Home Care Services, Respiration, Artificial, Patient Discharge, United States, ATS Clinical Practice Guideline: Summary for Clinicians, Clinical Practice, Caregivers, 030228 respiratory system, Chronic Disease, Ventilation (architecture), Societies, business
Abstract

Children with chronic invasive ventilator dependence living at home are a diverse group of children with special health care needs. Medical oversight, equipment management, and community resources vary widely. There are no clinical practice guidelines available to health care professionals for the safe hospital discharge and home management of these complex children.To develop evidence-based clinical practice guidelines for the hospital discharge and home/community management of children requiring chronic invasive ventilation.The Pediatric Assembly of the American Thoracic Society assembled an interdisciplinary workgroup with expertise in the care of children requiring chronic invasive ventilation. The experts developed four questions of clinical importance and used an evidence-based strategy to identify relevant medical evidence. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to formulate and grade recommendations.Clinical practice recommendations for the management of children with chronic ventilator dependence at home are provided, and the evidence supporting each recommendation is discussed.Collaborative generalist and subspecialist comanagement is the Medical Home model most likely to be successful for the care of children requiring chronic invasive ventilation. Standardized hospital discharge criteria are suggested. An awake, trained caregiver should be present at all times, and at least two family caregivers should be trained specifically for the child's care. Standardized equipment for monitoring, emergency preparedness, and airway clearance are outlined. The recommendations presented are based on the current evidence and expert opinion and will require an update as new evidence and/or technologies become available.

Published
2016
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14. Acute Responses to Diuretic Therapy in Extremely Low Gestational Age Newborns: Results from the Prematurity and Respiratory Outcomes Program Cohort Study

Author

Carol J. Blaisdell, James Troendle, Anne Zajicek, Claire Chougnet, James M. Greenberg, William Hardie, Alan H. Jobe, Karen McDowell, Thomas Ferkol, Mark R. Holland, James Kemp, Philip T. Levy, Phillip Tarr, Gautam K. Singh, Barbara Warner, Aaron Hamvas, Philip L. Ballard, Roberta A. Ballard, Roberta L. Keller, Amir M. Khan, Leslie Lusk, Dennis W. Nielson, Elizabeth E. Rogers, David J. Durand, Jeffrey D. Merrill, Eric C. Eichenwald, Candice Fike, Tina Hartert, Paul Moore, Judy Aschner, Scott Guthrie, Nathalie Maitre, Marshall Summar, Carl D'Angio, Vasanth Kumar, Tom Mariani, Gloria Pryhuber, Anne Marie Reynolds, Kristin Scheible, Timothy Stevens, Clement Ren, Rita M. Ryan, C. Michael Cotten, Kim Fisher, Jack Sharp, Judith A. Voynow, Stephanie Davis, Brenda Poindexter, Jonas Ellenberg, Rui Feng, Melissa Fernando, Howard Panitch, Barbara Schmidt, Pamela Shaw, Scarlett Bellamy, and Lynn M. Taussig

Subjects
Male, Pediatrics, medicine.medical_specialty, Neonatal intensive care unit, medicine.medical_treatment, Birth weight, Gestational Age, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Intensive care, Intensive Care Units, Neonatal, Medicine, Humans, 030212 general & internal medicine, Airway Management, Diuretics, Respiratory Distress Syndrome, Newborn, Respiratory distress, business.industry, Respiration, Postmenstrual Age, Infant, Newborn, Gestational age, United States, Infant, Extremely Premature, Pediatrics, Perinatology and Child Health, Female, Diuretic, business, Cohort study
Abstract

OBJECTIVE: To determine if daily respiratory status improved more in extremely low gestational age premature infants after diuretic exposure compared with those not exposed in modern neonatal intensive care units (NICU). STUDY DESIGN: The Prematurity and Respiratory Outcomes Program (PROP) was a multi-center observational cohort study of 835 extremely premature infants, gestational ages 23 0/7–28 6/7 weeks, enrolled in the first week of life from 13 U.S. tertiary NICUs. We analyzed the PROP study daily medication and respiratory support records of infants up to 34 weeks postmenstrual age. We determined whether there was a temporal association between administration of diuretics and an acute change in respiratory status in premature infants in the NICU, using an ordered categorical ranking of respiratory status. RESULTS: Infants in the diuretic exposed group of PROP were of lower mean gestational age and lower mean birth weight (p 1) for each day after the initial day of diuretic exposure. CONCLUSIONS: Our analysis did not support the ability of diuretics to substantially improve the extremely premature infant’s respiratory status. Further study of both safety and efficacy of diuretics in this setting are warranted. TRIAL REGISTRATION: Clinicaltrials.gov NCT01435187

Published
2017

15. Respiratory Medications in Infants <29 Weeks during the First Year Postdischarge: The Prematurity and Respiratory Outcomes Program (PROP) Consortium

Author

Rita M. Ryan, Roberta L. Keller, Brenda B. Poindexter, Carl T. D'Angio, Pamela A. Shaw, Scarlett L. Bellamy, Paul E. Moore, Christopher McPherson, James M. Greenberg, Barbara Alexander, Tari Gratton, Cathy Grigsby, Beth Koch, Kelly Thornton, Pamela Bates, Claudia Cleveland, Julie Hoffmann, Laura Linneman, Jayne Sicard-Su, Gina Simpson, Jeanette M. Asselin, Samantha Balan, Katrina Burson, Cheryl Chapin, Erna Josiah-Davis, Carmen Garcia, Hart Horneman, Rick Hinojosa, Christopher Johnson, Susan Kelley, Karin L. Knowles, M. Layne Lillie, Karen Martin, Sarah Martin, Julie Arldt-McAlister, Georgia E. McDavid, Lori Pacello, Shawna Rodgers, Daniel K. Sperry, Amy B. Beller, Mark O’ Hunt, Theresa J. Rogers, Odessa L. Settles, Steven Steele, Sharon Wadley, Shannon Castiglione, Aimee Horan, Deanna Maffet, Jane O'Donnell, Michael Sacilowski, Tanya Scalise, Elizabeth Werner, Jason Zayac, Heidie Huyck, Valerie Lunger, Kim Bordeaux, Pam Brown, Julia Epping, Lisa Flattery-Walsh, Donna Germuga, Nancy Jenks, Mary Platt, Eileen Popplewell, Sandra Prentice, Kim Ciccio, Charles Clem, Susan Gunn, Lauren Jewett, Maria Blanco, Denise Cifelli, Sara DeMauro, Melissa Fernando, Ann Tierney, Lynn M. Taussig, Carol J. Blaisdell, Claire Chougnet, William Hardie, Alan H. Jobe, Karen McDowell, Thomas Ferkol, Aaron Hamvas, Mark R. Holland, James Kemp, Philip T. Levy, Phillip Tarr, Gautam K. Singh, Barbara Warner, Philip L. Ballard, Roberta A. Ballard, David J. Durand, Eric C. Eichenwald, Amir M. Khan, Leslie Lusk, Jeffrey D. Merrill, Dennis W. Nielson, Elizabeth E. Rogers, Judy Aschner, Candice Fike, Scott Guthrie, Tina Hartert, Nathalie Maitre, Marshall Summar, Vasanth Kumar, Tom Mariani, Gloria Pryhuber, Clement Ren, Anne Marie Reynolds, Kristin Scheible, Timothy Stevens, C. Michael Cotten, Kim Fisher, Jack Sharp, Judith A. Voynow, Stephanie Davis, Jonas Ellenberg, Rui Feng, Howard Panitch, and Barbara Schmidt

Subjects
Male, Pediatrics, medicine.medical_specialty, Neonatal intensive care unit, medicine.drug_class, medicine.medical_treatment, Anti-Inflammatory Agents, Gestational Age, Infant, Premature, Diseases, Article, 03 medical and health sciences, 0302 clinical medicine, Prednisone, Intensive Care Units, Neonatal, Surveys and Questionnaires, 030225 pediatrics, Bronchodilator, Administration, Inhalation, medicine, Humans, Prospective Studies, 030212 general & internal medicine, Respiratory system, Diuretics, Prospective cohort study, Bronchopulmonary Dysplasia, business.industry, Infant, Newborn, Infant, Gestational age, medicine.disease, Patient Discharge, Bronchodilator Agents, Oxygen, Treatment Outcome, Bronchopulmonary dysplasia, Pediatrics, Perinatology and Child Health, Female, Steroids, Diuretic, business, Infant, Premature, medicine.drug
Abstract

OBJECTIVE: To determine patterns of respiratory medications used in neonatal intensive care unit (NICU) graduates. STUDY DESIGN: The Prematurity Respiratory Outcomes Program enrolled 835 babies

Published
2019
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16. Mutations inCCDC39andCCDC40are the Major Cause of Primary Ciliary Dyskinesia with Axonemal Disorganization and Absent Inner Dynein Arms

Author

Thomas Ferkol, Dinu Antony, Heymut Omran, Peadar G. Noone, Christopher O'Callaghan, Scott D. Sagel, Heike Olbrich, Richard D. Emes, Michael R. Knowles, Claire Hogg, Jane S. Lucas, Maimoona A. Zariwala, Whitney E. Wolf, Ann Dewar, Peter J. Scambler, Robert Wilson, M. Leigh Anne Daniels, Anita Becker-Heck, Martine Jaspers, Hannah M. Mitchison, Andrew Rutman, Niki T. Loges, Amelia Shoemark, Mark Jorissen, Theresa Taylor‐Cox, Margaret Rosenfeld, Mitra Forouhan, Patricia Goggin, Abhijit Dixit, Claire L. Jackson, Miriam Schmidts, Alexandros Onoufriadis, Margaret W. Leigh, and Eddie M. K. Chung

Subjects
Male, Axoneme, Absent inner dynein arms, Dynein, Fluorescent Antibody Technique, Biology, Article, Frameshift mutation, Radial spoke, Genetics, medicine, Humans, Exome, Cilia, Alleles, Genetics (clinical), Primary ciliary dyskinesia, Kartagener Syndrome, Cilium, Dyneins, Proteins, Inner dynein arm, medicine.disease, Pedigree, Cytoskeletal Proteins, Microscopy, Electron, Phenotype, Mutation, Female
Abstract

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by cilia and sperm dysmotility. About 12% of cases show perturbed 9+2 microtubule cilia structure and inner dynein arm (IDA) loss, historically termed ‘radial spoke defect’. We sequenced CCDC39 and CCDC40 in 54 ‘radial spoke defect’ families, as these are the two genes identified so far to cause this defect. We discovered biallelic mutations in a remarkable 69% (37/54) of families, including identification of 25 (19 novel) mutant alleles (12 in CCDC39 and 13 in CCDC40). All the mutations were nonsense, splice and frameshift predicting early protein truncation, which suggests this defect is caused by ‘null’ alleles conferring complete protein loss. Most families (73%; 27/37) had homozygous mutations, including families from outbred populations. A major putative hotspot mutation was identified, CCDC40 c.248delC, as well as several other possible hotspot mutations. Together, these findings highlight the key role of CCDC39 and CCDC40 in PCD with axonemal disorganisation and IDA loss, and these genes represent major candidates for genetic testing in families affected by this ciliary phenotype. We show that radial spoke structures are largely intact in these patients and propose this ciliary ultrastructural abnormality be referred to as ‘IDA and nexin-dynein regulatory complex (N-DRC) defect’, rather than ‘radial spoke defect’.

Published
2013
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17. Movement

Author

Thomas, Ferkol

Subjects
Pulmonary and Respiratory Medicine, Phenotype, Genotype, Microscopy, Electron, Transmission, Kartagener Syndrome, Mutation, Pediatrics, Perinatology and Child Health, Humans, Cilia, Genetic Testing
Abstract

Primary ciliary dyskinesia is an inherited disease characterized by impaired ciliary function leading to diverse clinical manifestations, including chronic sinopulmonary disease, persistent middle ear effusions, laterality defects, and infertility. Our understanding of the complex genetics and functional phenotypes of primary ciliary dyskinesia has rapidly grown, and over 35 disease-associated genes have been identified, which segregate into genes that encode axonemal motor proteins, regulatory proteins within the cilium, and cytoplasmic proteins involved in ciliary assembly. These findings have yielded unexpected insights into the clinical heterogeneity of disease and are beginning to revolutionize diagnostic testing for primary ciliary dyskinesia.

Published
2017
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18. NHLBI training workshop report: The vanishing pediatric pulmonary investigator and recommendations for recovery

Author

Hugh O'Brodovich, Pamela L. Zeitlin, Steven H. Abman, Thomas Ferkol, and Carol J. Blaisdell

Subjects
Societies, Scientific, Adult, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Biomedical Research, education, MEDLINE, Pediatrics, Accreditation, Surveys and Questionnaires, Pulmonary medicine, Pulmonary Medicine, medicine, Humans, Fellowships and Scholarships, Societies, Medical, Career Choice, Clinician scientist, business.industry, Research Personnel, United States, Education, Medical, Graduate, Family medicine, Pediatrics, Perinatology and Child Health, Workforce, National Heart, Lung, and Blood Institute (U.S.), business
Abstract

The adequacy of the pipeline of advanced pulmonary fellows to supply appropriately trained and committed researchers to enter academic careers was the major topic of a recently held National Heart Lung and Blood Institute NHLBI Workshop: Respiratory Medicine-Related Research Training for Adult and Pediatric Fellows. The special challenges and opportunities for the academic pediatric pulmonary trainee were discussed as part of this workshop and are presented as a companion article to the report by the full workshop. Surveys were conducted of pediatric chairs of academic departments and pediatric pulmonary training directors in the United States to examine the current status and opportunities for the pediatric pulmonary trainee. Strategies for recruitment and retention of talented young trainees and junior faculty are proposed.

Published
2010
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19. Airway Inflammation in Cystic Fibrosis

Author

Arnon Elizur, Thomas Ferkol, and Carolyn L. Cannon

Subjects
Pulmonary and Respiratory Medicine, Spirometry, Cystic Fibrosis, Inflammation, Critical Care and Intensive Care Medicine, Cystic fibrosis, Epithelium, Proinflammatory cytokine, medicine, Animals, Humans, Lung, Bronchiectasis, biology, medicine.diagnostic_test, business.industry, medicine.disease, Cystic fibrosis transmembrane conductance regulator, Respiratory Function Tests, medicine.anatomical_structure, Neutrophil elastase, Immunology, biology.protein, Cytokines, Inflammation Mediators, medicine.symptom, Leukocyte Elastase, Cardiology and Cardiovascular Medicine, business
Abstract

Patients with cystic fibrosis (CF) experience declining pulmonary function related to chronic airway inflammation, which results from epithelial and immune cell secretion of proinflammatory mediators that promote neutrophil influx into the airways. This inflammatory response may be disproportionate to the inciting infectious stimulus, resulting in an overly exuberant influx of neutrophils. The neutrophils release proteases, including neutrophil elastase, that eventually overwhelm the antiprotease capacity of the lung and cleave structural proteins, leading to bronchiectasis. This deleterious inflammatory process in patients with CF has become a potential therapeutic target, though the development of effective antiinflammatory therapies has been limited by the lack of sensitive outcome measures. Historically, indirect measures of lung disease, such as spirometry, have been used to assess the effect of antiinflammatory drugs. BAL remains the primary method of interrogating the inflammatory status of the airway, but the procedure is invasive and may eventually be supplanted by induced sputum. Anatomic imaging with high-resolution CT scanning is used clinically, but has unknown utility, and functional imaging, using positron emission tomography, appears promising but is still investigational. Despite the paucity of outcome measures, clinical trials of antiinflammatory agents, including corticosteroids and ibuprofen, have demonstrated benefits, though their use has been limited by adverse effects. Azithromycin is increasingly used as an immunomodulatory agent, although its mechanism of action remains unclear. Strategies for modulating the airway inflammation in patients with CF are currently under development and may offer new therapeutic options for these patients.

Published
2008
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20. Forced Expiratory Volume in 1 Second Variability Helps Identify Patients with Cystic Fibrosis at Risk of Greater Loss of Lung Function

Author

Wayne J. Morgan, Donald R. VanDevanter, David J. Pasta, Aimee J. Foreman, Jeffrey S. Wagener, Michael W. Konstan, Wayne Morgan, Michael Konstan, Ted Liou, Susanna McColley, Ann McMullen, Alexandra Quittner, Warren Regelmann, Clement Ren, Margaret Rosenfeld, Greg Sawicki, Michael Schechter, Donald VanDevanter, Jeffrey Wagener, Marlyn Woo, Dana Brasfield, Raymond Lyrene, Lawrence Sindel, Dion Roberts, John Carroll, Robert Warren, Louay Nassri, Paula Anderson, Mark Brown, Amy Silverthorn, Peggy Radford, Gerald Gong, Gregory Legris, Gerald Greene, Reddivalam Sudhakar, Arnold Platzker, Bruce Nickerson, Karen Hardy, Ivan Harwood, Gregory Shay, Bryon Quick, Allan Lieberthal, Richard Moss, Chris Landon, Yvonne Fanous, Jay Lieberman, Eugene Spiritus, Bradley Chipps, Ruth McDonald, Mark Pian, Gerd Cropp, Nancy Lewis, Dennis Nielson, Bertrand Shapiro, Jeff Wagener, Frank Accurso, Milene Saavedra, Karen Daigle, Jacob Hen, Regina Palazzo, Kathryn Dodds, Raj Pad-man, John Goodill, Glenna Winnie, Lea Davies, Tony Kriseman, Jorge Sallent, Joseph Chiaro, Martin Kubiet, Sue Goldfinger, Morton Schwartzman, Carlosenrique Diaz, Kevin Maupin, Eduardo Riff, David Geller, Floyd Livingston, Kunjana Mavunda, Jose Birriel, Luis Faverio, David Rosenberg, David Schaeffer, James Sherman, Mary Wagner, Michael Light, Bruce Schnapf, Gary Montgomery, Kevin Kirchner, Mark Weatherly, Daniel Caplan, Margaret Guill, Valera Hudson, Javeed Akhter, Donald Davison, Steven Boas, Youngran Chung, Rennee Latner, Gabriel Aljadeff, Youngran Chan, Jerome Kraut, Arvey Stone, John Lloyd Still, Girish Sharma, Lanie Eagleton, Patricia Hopkins, Umesh Chatrath, Lucille Lester, Young-Jee Kim, Veena Anthony, Howard Eigan, Michelle Howenstine, Pushpom James, Edward Gergesha, James Harris, Robert Plant, Veljko Zivkovich, Angela Collins, Edward Nassif, Richard Ahrens, Daniel Doornbos, Joseph Kanarek, Richard Leff, Pamela Shaw, Elanor Demoss, Maria Riva, Leonard Sullivan, Michael Anstead, Jamshed Kanga, Nemr Eid, Ron Morton, Bettina Hilman, Kim Jones, Scott Davis, Ralph Harder, Tom Lever, Anne Marie Cairns, Edgar Caldwell, Jonathan Zuckerman, Peter Mogayzel, Beryl Rosenstein, John McQuestion, Donna Perry, Samuel Rosenberg, Robert Gerstle, Andrew Colin, Mary Ellen Wohl, Allan Lapey, William Yee, Brian O'Sullivan, Robert Zwerdling, Ibrahim Abdulhamid, Adrian O'Hagan, John Schuen, Lawrence Kurlandsky, Richard Honicky, Douglas Homnick, John Marks, Bohdan Pichurko, Norma Maxvold, Samya Nasr, Richard Simon, Wan Tsai, Dana Kissner, John McNamara, Nancy Henry, Stephen Marker, Michael Pryor, Lynn Walker, Jim Woodward, Louis Mizell, Suzanne Miller, Daniel Rosenbluth, Philip Black, Michael McCubbin, Alan Cohen, Thomas Ferkol, George Mallory, Anthony Rejent, Bruce Rubin, Gavin Graff, Peter Konig, John Colombo, Peter Murphy, William Boyle, Worth Parker, Chandler Patton, Robert Zanni, Arthur Atlas, Nelson Turcios, Lourdes Laraya-Cuasay, Dorothy Bisberg, Helen Aguila, Sarah Allen, David James, Elizabeth Perkett, Marsha Thompson, Sonia Budhecha, Ruben Diaz, Jonathan Rosen, Robert Kaslovsky, Ronald Percciacante, Drucy Borowitz, Joseph Cronin, Colin McMahon, Lynne Quittell, Robert Giusti, Rubin Cohen, Joan DeCelie-Germana, Jack Gorvoy, Kalpan Patel, Meyer Kattan, Allen Dozor, Emily DiMango, Maria Berdella, Ran Anbar, Debra Ianuzzi, James Sexton, Catherine Tayag-Kier, John McBride, Karen Voter, Mary Dimaio, John Georgitis, Joseph Marc Majure, Maria Martinez, Clarke McIntosh, Margaret Leigh, Hugh Black, James Hughes, Anand Kantak, Robert Wilmott, Gregory Omlor, Robert Stone, Karen McCoy, James Acton, Carl Doershuk, Robert Fink, Michael Steffan, Pierre Vauthy, Patricia Joseph, Santiago Reyes, John Kramer, James Royall, Jay Eisenberg, Michael Wall, Stanley Fiel, Thomas Scanlin, Shroti Phadke, Joel Weinberg, William Sexauer, Stephen Wolf, Douglas Holsclaw, Debra Klein, Stuart Warren, Robert Kinsey, Carlos Perez, Muttiah Ganeshanathan, James Shinnick, Howard Panitch, Laurie Varlotta, Cynthia Robinson, Jose Rodriguez Santana, Mary Ann Passero, Jane Gwinn, Robert Baker, Michael Bowman, Patrick Flume, Daniel Brown, Roxanne Marville, James Wallace, Rodney Parry, Don Ellenburg, John Rogers, Ricky Mohon, Joel Ledbetter, Aram Hanissian, Robert Schoumacher, Preston Campbell, Christopher Harris, Bonnie Slovis, Dennis Stokes, Kathryn Hale, Marcia Katz, Dan Seilheimer, Marianne Sockrider, Allan Frank, James Daniel, James Cunningham, Iley Browning, John Bray, Amanda Dove, Fernando Mandujano, Larry Tremper, Martha Morse, Donna Willey-Courand, Steven Copenhaver, John Pohl, Bennie McWilliams, Marie Martine-Logvinoff, Marsh Wallace, Robert Klein, Rodolfo Amaro, Leslie Couch, Michael Brown, Claude Prestidge, Stephen Inscore, Andrew Lipton, Barbara Chatfield, Theodore Liou, Bruce Marshall, Thomas Lahiri, Donald Swartz, Laurie Whittaker, Karl Karlson, Ignacio Ropoll, Thomas Rubio, Joel Schmidt, David Thomas, John Osborn, Deborah Froh, Benjamin Gaston, Greg Elliott, Ronald Gibson, Bonnie Ramsey, Michael McCarthy, Lawrence Larson, David Ricker, Mark Robbins, Moira Aitken, Julia Emerson, Stephen Aronoff, Kathryn Moffett, Julie Biller, Mark Splaingard, Bradley Sullivan, Paul Pritchard, Stu Adair, Peter Holzwarth, Guillermo Dopico, Keith Meyer, Christopher Green, and Michael Rock

Subjects
Male, medicine.medical_specialty, Epidemiologic study, Time Factors, Cystic Fibrosis, Cystic fibrosis, Risk Assessment, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Internal medicine, Forced Expiratory Volume, medicine, Humans, In patient, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Child, Lung, Lung function, business.industry, respiratory system, medicine.disease, respiratory tract diseases, 030228 respiratory system, Multicenter study, Predictive value of tests, Pediatrics, Perinatology and Child Health, Cardiology, Physical therapy, Female, business, Risk assessment, circulatory and respiratory physiology
Abstract

Objective To evaluate several alternative measures of forced expiratory volume in 1 second percent predicted (FEV 1 %pred) variability as potential predictors of future FEV 1 %pred decline in patients with cystic fibrosis. Study design We included 13 827 patients age ≥6 years from the Epidemiologic Study of Cystic Fibrosis 1994-2002 with ≥4 FEV 1 %pred measurements spanning ≥366 days in both a 2-year baseline period and a 2-year follow-up period. We predicted change from best baseline FEV 1 %pred to best follow-up FEV 1 %pred and change from baseline to best in the second follow-up year by using multivariable regression stratified by 4 lung-disease stages. We assessed 5 measures of variability (some as deviations from the best and some as deviations from the trend line) both alone and after controlling for demographic and clinical factors and for the slope and level of FEV 1 %pred. Results All 5 measures of FEV 1 %pred variability were predictive, but the strongest predictor was median deviation from the best FEV 1 %pred in the baseline period. The contribution to explanatory power (R 2 ) was substantial and exceeded the total contribution of all other factors excluding the FEV 1 %pred rate of decline. Adding the other variability measures provided minimal additional value. Conclusions Median deviation from the best FEV 1 %pred is a simple metric that markedly improves prediction of FEV 1 %pred decline even after the inclusion of demographic and clinical characteristics and the FEV 1 %pred rate of decline. The routine calculation of this variability measure could allow clinicians to better identify patients at risk and therefore in need of increased intervention.

Published
2014

21. Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy

Author

Adam J, Shapiro, Stephanie D, Davis, Thomas, Ferkol, Sharon D, Dell, Margaret, Rosenfeld, Kenneth N, Olivier, Scott D, Sagel, Carlos, Milla, Maimoona A, Zariwala, Whitney, Wolf, Johnny L, Carson, Milan J, Hazucha, Kimberlie, Burns, Blair, Robinson, Michael R, Knowles, and Margaret W, Leigh

Subjects
Adult, Male, Adolescent, Kartagener Syndrome, Biopsy, DNA Mutational Analysis, Infant, Newborn, Infant, DNA, Middle Aged, United States, Young Adult, Microscopy, Electron, Transmission, Child, Preschool, Mutation, Prevalence, Humans, Female, Cilia, Prospective Studies, Child, Tomography, X-Ray Computed
Abstract

Motile cilia dysfunction causes primary ciliary dyskinesia (PCD), situs inversus totalis (SI), and a spectrum of laterality defects, yet the prevalence of laterality defects other than SI in PCD has not been prospectively studied.In this prospective study, participants with suspected PCD were referred to our multisite consortium. We measured nasal nitric oxide (nNO) level, examined cilia with electron microscopy, and analyzed PCD-causing gene mutations. Situs was classified as (1) situs solitus (SS), (2) SI, or (3) situs ambiguus (SA), including heterotaxy. Participants with hallmark electron microscopic defects, biallelic gene mutations, or both were considered to have classic PCD.Of 767 participants (median age, 8.1 years, range, 0.1-58 years), classic PCD was defined in 305, including 143 (46.9%), 125 (41.0%), and 37 (12.1%) with SS, SI, and SA, respectively. A spectrum of laterality defects was identified with classic PCD, including 2.6% and 2.3% with SA plus complex or simple cardiac defects, respectively; 4.6% with SA but no cardiac defect; and 2.6% with an isolated possible laterality defect. Participants with SA and classic PCD had a higher prevalence of PCD-associated respiratory symptoms vs SA control participants (year-round wet cough, P.001; year-round nasal congestion, P = .015; neonatal respiratory distress, P = .009; digital clubbing, P = .021) and lower nNO levels (median, 12 nL/min vs 252 nL/min; P.001).At least 12.1% of patients with classic PCD have SA and laterality defects ranging from classic heterotaxy to subtle laterality defects. Specific clinical features of PCD and low nNO levels help to identify PCD in patients with laterality defects.ClinicalTrials.gov; No.: NCT00323167; URL: www.clinicaltrials.gov.

Published
2014

22. Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol

Author

Leslie A. Lange, Youna Hu, He Zhang, Chenyi Xue, Ellen M. Schmidt, Zheng-Zheng Tang, Chris Bizon, Ethan M. Lange, Joshua D. Smith, Emily H. Turner, Goo Jun, Hyun Min Kang, Gina Peloso, Paul Auer, Kuo-ping Li, Jason Flannick, Ji Zhang, Christian Fuchsberger, Kyle Gaulton, Cecilia Lindgren, Adam Locke, Alisa Manning, Xueling Sim, Manuel A. Rivas, Oddgeir L. Holmen, Omri Gottesman, Yingchang Lu, Douglas Ruderfer, Eli A. Stahl, Qing Duan, Yun Li, Peter Durda, Shuo Jiao, Aaron Isaacs, Albert Hofman, Joshua C. Bis, Adolfo Correa, Michael E. Griswold, Johanna Jakobsdottir, Albert V. Smith, Pamela J. Schreiner, Mary F. Feitosa, Qunyuan Zhang, Jennifer E. Huffman, Jacy Crosby, Christina L. Wassel, Ron Do, Nora Franceschini, Lisa W. Martin, Jennifer G. Robinson, Themistocles L. Assimes, David R. Crosslin, Elisabeth A. Rosenthal, Michael Tsai, Mark J. Rieder, Deborah N. Farlow, Aaron R. Folsom, Thomas Lumley, Ervin R. Fox, Christopher S. Carlson, Ulrike Peters, Rebecca D. Jackson, Cornelia M. van Duijn, André G. Uitterlinden, Daniel Levy, Jerome I. Rotter, Herman A. Taylor, Vilmundur Gudnason, David S. Siscovick, Myriam Fornage, Ingrid B. Borecki, Caroline Hayward, Igor Rudan, Y. Eugene Chen, Erwin P. Bottinger, Ruth J.F. Loos, Pål Sætrom, Kristian Hveem, Michael Boehnke, Leif Groop, Mark McCarthy, Thomas Meitinger, Christie M. Ballantyne, Stacey B. Gabriel, Christopher J. O’Donnell, Wendy S. Post, Kari E. North, Alexander P. Reiner, Eric Boerwinkle, Bruce M. Psaty, David Altshuler, Sekar Kathiresan, Dan-Yu Lin, Gail P. Jarvik, L. Adrienne Cupples, Charles Kooperberg, James G. Wilson, Deborah A. Nickerson, Goncalo R. Abecasis, Stephen S. Rich, Russell P. Tracy, Cristen J. Willer, David M. Altshuler, Gonçalo R. Abecasis, Hooman Allayee, Sharon Cresci, Mark J. Daly, Paul I.W. de Bakker, Mark A. DePristo, Peter Donnelly, Tim Fennell, Kiran Garimella, Stanley L. Hazen, Daniel M. Jordan, Adam Kiezun, Guillaume Lettre, Bingshan Li, Mingyao Li, Christopher H. Newton-Cheh, Sandosh Padmanabhan, Sara Pulit, Daniel J. Rader, David Reich, Muredach P. Reilly, Steve Schwartz, Laura Scott, John A. Spertus, Nathaniel O. Stitziel, Nina Stoletzki, Shamil R. Sunyaev, Benjamin F. Voight, Ermeg Akylbekova, Larry D. Atwood, Maja Barbalic, R. Graham Barr, Emelia J. Benjamin, Joshua Bis, Donald W. Bowden, Jennifer Brody, Matthew Budoff, Greg Burke, Sarah Buxbaum, Jeff Carr, Donna T. Chen, Ida Y. Chen, Wei-Min Chen, Pat Concannon, Ralph D’Agostino, Anita L. DeStefano, Albert Dreisbach, Josée Dupuis, J. Peter Durda, Jaclyn Ellis, Caroline S. Fox, Ervin Fox, Vincent Funari, Santhi K. Ganesh, Julius Gardin, David Goff, Ora Gordon, Wayne Grody, Myron Gross, Xiuqing Guo, Ira M. Hall, Nancy L. Heard-Costa, Susan R. Heckbert, Nicholas Heintz, David M. Herrington, DeMarc Hickson, Jie Huang, Shih-Jen Hwang, David R. Jacobs, Nancy S. Jenny, Andrew D. Johnson, Craig W. Johnson, Steven Kawut, Richard Kronmal, Raluca Kurz, Martin G. Larson, Mark Lawson, Cora E. Lewis, Dalin Li, Honghuang Lin, Chunyu Liu, Jiankang Liu, Kiang Liu, Xiaoming Liu, Yongmei Liu, William T. Longstreth, Cay Loria, Kathryn Lunetta, Aaron J. Mackey, Rachel Mackey, Ani Manichaikul, Taylor Maxwell, Barbara McKnight, James B. Meigs, Alanna C. Morrison, Solomon K. Musani, Josyf C. Mychaleckyj, Jennifer A. Nettleton, Kari North, Daniel O’Leary, Frank Ong, Walter Palmas, James S. Pankow, Nathan D. Pankratz, Shom Paul, Marco Perez, Sharina D. Person, Joseph Polak, Aaron R. Quinlan, Leslie J. Raffel, Vasan S. Ramachandran, Kenneth Rice, Jill P. Sanders, Pamela Schreiner, Sudha Seshadri, Steve Shea, Stephen Sidney, Kevin Silverstein, Nicholas L. Smith, Nona Sotoodehnia, Asoke Srinivasan, Kent Taylor, Fridtjof Thomas, Michael Y. Tsai, Kelly A. Volcik, Chrstina L. Wassel, Karol Watson, Gina Wei, Wendy White, Kerri L. Wiggins, Jemma B. Wilk, O. Dale Williams, Gregory Wilson, Phillip Wolf, Neil A. Zakai, John Hardy, James F. Meschia, Michael Nalls, Andrew Singleton, Brad Worrall, Michael J. Bamshad, Kathleen C. Barnes, Ibrahim Abdulhamid, Frank Accurso, Ran Anbar, Terri Beaty, Abigail Bigham, Phillip Black, Eugene Bleecker, Kati Buckingham, Anne Marie Cairns, Daniel Caplan, Barbara Chatfield, Aaron Chidekel, Michael Cho, David C. Christiani, James D. Crapo, Julia Crouch, Denise Daley, Anthony Dang, Hong Dang, Alicia De Paula, Joan DeCelie-Germana, Allen DozorMitch Drumm, Maynard Dyson, Julia Emerson, Mary J. Emond, Thomas Ferkol, Robert Fink, Cassandra Foster, Deborah Froh, Li Gao, William Gershan, Ronald L. Gibson, Elizabeth Godwin, Magdalen Gondor, Hector Gutierrez, Nadia N. Hansel, Paul M. Hassoun, Peter Hiatt, John E. Hokanson, Michelle Howenstine, Laura K. Hummer, Jamshed Kanga, Yoonhee Kim, Michael R. Knowles, Michael Konstan, Thomas Lahiri, Nan Laird, Christoph Lange, Lin Lin, Xihong Lin, Tin L. Louie, David Lynch, Barry Make, Thomas R. Martin, Steve C. Mathai, Rasika A. Mathias, John McNamara, Sharon McNamara, Deborah Meyers, Susan Millard, Peter Mogayzel, Richard Moss, Tanda Murray, Dennis Nielson, Blakeslee Noyes, Wanda O’Neal, David Orenstein, Brian O’Sullivan, Rhonda Pace, Peter Pare, H. Worth Parker, Mary Ann Passero, Elizabeth Perkett, Adrienne Prestridge, Nicholas M. Rafaels, Bonnie Ramsey, Elizabeth Regan, Clement Ren, George Retsch-Bogart, Michael Rock, Antony Rosen, Margaret Rosenfeld, Ingo Ruczinski, Andrew Sanford, David Schaeffer, Cindy Sell, Daniel Sheehan, Edwin K. Silverman, Don Sin, Terry Spencer, Jackie Stonebraker, Holly K. Tabor, Laurie Varlotta, Candelaria I. Vergara, Robert Weiss, Fred Wigley, Robert A. Wise, Fred A. Wright, Mark M. Wurfel, Robert Zanni, Fei Zou, Phil Green, Jay Shendure, Joshua M. Akey, Carlos D. Bustamante, Evan E. Eichler, P. Keolu Fox, Wenqing Fu, Adam Gordon, Simon Gravel, Jill M. Johnsen, Mengyuan Kan, Eimear E. Kenny, Jeffrey M. Kidd, Fremiet Lara-Garduno, Suzanne M. Leal, Dajiang J. Liu, Sean McGee, Timothy D. O’Connor, Bryan Paeper, Peggy D. Robertson, Jeffrey C. Staples, Jacob A. Tennessen, Gao Wang, Qian Yi, Rebecca Jackson, Garnet Anderson, Hoda Anton-Culver, Paul L. Auer, Shirley Beresford, Henry Black, Robert Brunner, Robert Brzyski, Dale Burwen, Bette Caan, Cara L. Carty, Rowan Chlebowski, Steven Cummings, J. David Curb, Charles B. Eaton, Leslie Ford, Stephanie M. Fullerton, Margery Gass, Nancy Geller, Gerardo Heiss, Barbara V. Howard, Li Hsu, Carolyn M. Hutter, John Ioannidis, Karen C. Johnson, Lewis Kuller, Andrea LaCroix, Kamakshi Lakshminarayan, Dorothy Lane, Norman Lasser, Erin LeBlanc, Kuo-Ping Li, Marian Limacher, Benjamin A. Logsdon, Shari Ludlam, JoAnn E. Manson, Karen Margolis, Lisa Martin, Joan McGowan, Keri L. Monda, Jane Morley Kotchen, Lauren Nathan, Judith Ockene, Mary Jo O’Sullivan, Lawrence S. Phillips, Ross L. Prentice, John Robbins, Jacques E. Rossouw, Haleh Sangi-Haghpeykar, Gloria E. Sarto, Sally Shumaker, Michael S. Simon, Marcia L. Stefanick, Evan Stein, Hua Tang, Kira C. Taylor, Cynthia A. Thomson, Timothy A. Thornton, Linda Van Horn, Mara Vitolins, Jean Wactawski-Wende, Robert Wallace, Sylvia Wassertheil-Smoller, Donglin Zeng, Deborah Applebaum-Bowden, Michael Feolo, Weiniu Gan, Dina N. Paltoo, Phyliss Sholinsky, Anne Sturcke, Epidemiology, and Internal Medicine

Subjects
Male, Genome-wide association study, 030204 cardiovascular system & hematology, Cohort Studies, 0302 clinical medicine, Gene Frequency, Receptors, Genotype, Dyslipidemias/blood, Receptors, LDL/genetics, Genetics(clinical), Exome, Genetics (clinical), Exome sequencing, Genetics, 0303 health sciences, Serine Endopeptidases, Single Nucleotide, Middle Aged, 3. Good health, Cholesterol, Phenotype, Genetic Code, Cholesterol, LDL/genetics, Female, lipids (amino acids, peptides, and proteins), Proprotein Convertases, Proprotein Convertase 9, Sequence Analysis, Adult, Apolipoproteins E/blood, LDL/genetics, Serine Endopeptidases/genetics, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Apolipoproteins E, SDG 3 - Good Health and Well-being, Humans, Polymorphism, Allele frequency, 030304 developmental biology, Genetic association, Aged, Dyslipidemias, PCSK9, DNA, Cholesterol, LDL, Lipase, Sequence Analysis, DNA, Receptors, LDL, Lipase/genetics, Proprotein Convertases/genetics, Follow-Up Studies, Genome-Wide Association Study
Abstract

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or

Published
2014

23. Cystic fibrosis: NHLBI workshop on the primary prevention of chronic lung diseases

Author

Jessica E. Pittman, Thomas Ferkol, Richard C. Boucher, Stephanie D. Davis, and Garry R. Cutting

Subjects
Lung Diseases, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Cystic Fibrosis, Pulmonary disease, NHBLI WORKSHOP ON THE PRIMARY PREVENTION OF CHRONIC LUNG DISEASES, Disease, Cystic fibrosis, Primary prevention, medicine, Humans, Intensive care medicine, Lung, biology, business.industry, Disease progression, Congresses as Topic, medicine.disease, United States, Cystic fibrosis transmembrane conductance regulator, Primary Prevention, medicine.anatomical_structure, Lung disease, Chronic Disease, Immunology, biology.protein, National Heart, Lung, and Blood Institute (U.S.), business
Abstract

Cystic fibrosis (CF) is a life-limiting, monogenic disorder characterized by chronic sinopulmonary and gastrointestinal involvement. Progressive pulmonary disease leads to death in the majority of patients. Despite its well-defined molecular basis related to defects in the cystic fibrosis transmembrane conductance regulator anion transport channel, there are large gaps in our understanding of the origin of CF lung disease. Disease has been shown to be present in infancy, and there is mounting evidence that abnormalities begin in utero. Heterogeneity of clinical presentations and severity suggest that many factors involved in lung disease have yet to be fully elucidated. Although new advances in therapeutic treatments have shown promise in delaying disease progression, the prevention of pulmonary disease at its origin (primary prevention) should be a key goal of CF care. The objective of this workshop was to (1) review our understanding of the origins of CF lung disease, (2) determine gaps in the knowledge base that are most significant and most likely to enable prevention of CF lung disease, and (3) prioritize new research questions that will promote pulmonary health in both CF and other childhood lung diseases. The goal of this report is to provide recommendations for future research that will improve our understanding of pulmonary development in health and disease, improve outcome measures and biomarkers for early lung disease, and determine therapeutic targets and strategies to prevent the development of lung disease in children with CF.

Published
2014
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24. Primary Ciliary Dyskinesia in Amish Communities

Author

Anne M. Bowcock, Margaret W. Leigh, James W. Forsen, Maimoona A. Zariwala, Cynthia Helms, Milan J. Hazucha, David E. Brown, Michael R. Knowles, John L. Carson, David W. Molter, Hauw Lie, and Thomas Ferkol

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Mucociliary clearance, DNA Mutational Analysis, Physiology, Disease, Consanguinity, Christianity, Article, Young Adult, otorhinolaryngologic diseases, medicine, Humans, Cilia, Child, Primary ciliary dyskinesia, Extramural, Genetic heterogeneity, business.industry, Infant, Middle Aged, medicine.disease, Pedigree, Situs inversus, Mucociliary Clearance, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, Congenital disease, business, Ciliary Motility Disorders
Abstract

Primary ciliary dyskinesia is an autosomal recessive multigenic disease that results in impaired mucociliary clearance. We have diagnosed 9 subjects with primary ciliary dyskinesia from geographically dispersed Amish communities, on the basis of clinical characteristics and ciliary ultrastructural defects. Despite consanguinity, affected individuals had evidence of genetic heterogeneity.

Published
2010
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25. Airway inflammation in cystic fibrosis: molecular mechanisms and clinical implications

Author

Arnon Elizur, Thomas Ferkol, Eitan Kerem, and Malena Cohen-Cymberknoh

Subjects
Pulmonary and Respiratory Medicine, Cystic Fibrosis, Neutrophils, Cystic Fibrosis Transmembrane Conductance Regulator, Inflammation, Cystic fibrosis, Pathogenesis, Immune system, Forced Expiratory Volume, medicine, Humans, Respiratory Tract Infections, Innate immune system, Lung, Bronchiectasis, biology, business.industry, respiratory system, medicine.disease, respiratory tract diseases, medicine.anatomical_structure, Neutrophil elastase, Immunology, biology.protein, medicine.symptom, business, Signal Transduction
Abstract

Airway epithelial cells and immune cells participate in the inflammatory process responsible for much of the pathology found in the lung of patients with cystic fibrosis (CF). Intense bronchial neutrophilic inflammation and release of proteases and oxygen radicals perpetuate the vicious cycle and progressively damage the airways. In vitro studies suggest that CF transmembrane conductance regulator (CFTR)-deficient airway epithelial cells display signalling abnormalities and aberrant intracellular processes which lead to transcription of inflammatory mediators. Several transcription factors, especially nuclear factor-κB, are activated. In addition, the accumulation of abnormally processed CFTR in the endoplasmic reticulum results in unfolded protein responses that trigger 'cell stress' and apoptosis leading to dysregulation of the epithelial cells and innate immune function in the lung, resulting in exaggerated and ineffective airway inflammation. Measuring airway inflammation is crucial for initiating treatment and monitoring its effect. No inflammatory biomarker predictive for the clinical course of CF lung disease is currently known, although neutrophil elastase seems to correlate with lung function decline. CF animal models mimicking human lung disease may provide an important insight into the pathogenesis of lung inflammation in CF and identify new therapeutic targets.

Published
2013

26. Primary Ciliary Dyskinesia-Causing Mutations in Amish and Mennonite Communities

Author

Erik G. Puffenberger, Anand C. Patel, D. Holmes Morton, Maimoona A. Zariwala, Hauw Lie, Margaret W. Leigh, Milan J. Hazucha, Anne M. Bowcock, John L. Carson, Thomas Ferkol, Cynthia Helms, Michael R. Knowles, and Kevin A. Strauss

Subjects
Male, Adolescent, Population, medicine.disease_cause, Article, Wisconsin, otorhinolaryngologic diseases, medicine, Humans, Allele, education, Child, Exome sequencing, Primary ciliary dyskinesia, Genetics, Mutation, education.field_of_study, Arkansas, Genetic heterogeneity, business.industry, Kartagener Syndrome, digestive, oral, and skin physiology, Infant, Middle Aged, Pennsylvania, Disease gene identification, medicine.disease, humanities, Pedigree, Targeted Mutation, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, business, Amish
Abstract

Objective To determine whether individuals with primary ciliary dyskinesia (PCD) from unrelated Amish and Mennonite families harbor a single and unique founder mutation. Study design Subjects from Amish and Mennonite communities in several states were enrolled in the study. All subjects were clinically characterized, and nasal nitric oxide levels were measured. Nasal epithelial scrapings were collected from several subjects for ciliary ultrastructural analyses. DNA was isolated from patients with PCD and their unaffected first- and second-degree relatives. Genome-wide homozygosity mapping, linkage analyses, targeted mutation analyses, and exome sequencing were performed. Results All subjects from Old-Order Amish communities from Pennsylvania were homozygous for a nonsense mutant DNAH5 allele, c.4348C>T (p.Q1450X). Two affected siblings from an unrelated Mennonite family in Arkansas were homozygous for the same nonsense DNAH5 mutation. Children with PCD from an Amish family from Wisconsin had biallelic DNAH5 mutations, c.4348C>T (p.Q1450X) and c.10815delT (p.P3606HfsX23), and mutations in other genes associated with PCD were also identified in this community. Conclusion The Amish and Mennonite subjects from geographically dispersed and socially isolated communities had the same founder DNAH5 mutation, owing to the common heritage of these populations. However, disease-causing mutations in other PCD-associated genes were also found in affected individuals in these communities, illustrating the genetic heterogeneity in this consanguineous population.

Published
2013

27. Recurrent Pleural Effusion Without Intrathoracic Migration Of Ventriculoperitoneal Shunt Catheter: A Case Report

Author

Katherine Rivera-Spoljaric, Piyaporn Chuen-im, Bradley J. Segura, Thomas Ferkol, and Matthew D. Smyth

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Catheters, Pleural effusion, medicine.medical_treatment, Thoracentesis, Ventriculoperitoneal Shunt, Cerebrospinal fluid, Foreign-Body Migration, Recurrence, Holoprosencephaly, medicine, Humans, Radionuclide Imaging, Thoracic Surgery, Video-Assisted, business.industry, medicine.disease, Hydrocephalus, Shunt (medical), Surgery, Pleural Effusion, Radiography, Effusion, Child, Preschool, Pediatrics, Perinatology and Child Health, Hydrothorax, Female, Radiology, business, Pleurodesis
Abstract

Pleural effusion is a rare complication of ventriculoperitoneal (VP) shunting, usually due to the migration of the VP shunt catheter into the thorax. Herein we report a neurologically disadvantaged child with a lobar holoprosencephaly and hydrocephalus, initially treated with a VP shunt, who years later developed recurrent right-sided pleural effusion ultimately confirmed to be a cerebrospinal fluid (CSF) hydrothorax without intra-thoracic migration of the distal shunt catheter. Thoracentesis was compatible with a transudative effusion. Given the presence of a persistent pleural effusion, beta-2 transferrin concentrations were measured, which yielded a positive result. Plain radiographs and head computed tomography (CT) showed a normally positioned, functional VP shunt. A spine CT myelogram to look for a spinal dural-thoracic CSF fistula was negative. A radionuclide CSF shunt study demonstrated normal functioning VP shunt with radiotracer accumulation within the peritoneum, with subsequent tracer rapidly accumulating in the right hemithorax. Video-assisted thoracoscopic (VATS) exploration with drainage of the pleural effusion and pleurodesis was then performed. No diaphragmatic defect or shunt tubing within the thorax was found and the procedure failed to resolve the effusion. The patient's recurrent effusion was ultimately resolved with intracranial endoscopic choroid plexus coagulation to decrease CSF output.

Published
2011
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28. Ciliopathies: the central role of cilia in a spectrum of pediatric disorders

Author

Margaret W. Leigh and Thomas Ferkol

Subjects
Male, Pathology, medicine.medical_specialty, Respiratory Tract Diseases, Disease, Biology, Ciliopathies, Article, Bardet–Biedl syndrome, Ciliogenesis, medicine, Humans, Abnormalities, Multiple, Cilia, Child, Primary ciliary dyskinesia, Kartagener Syndrome, Cilium, Syndrome, medicine.disease, Polycystic Kidney, Autosomal Dominant, Ciliopathy, Infertility, Pediatrics, Perinatology and Child Health, Female, Neuroscience, Retinitis Pigmentosa
Abstract

Cilia are evolutionarily conserved hair-like structures with key roles in cell locomotion, fluid movement, and sexual reproduction. Recent studies have shown that cilia also sense the extracellular environment and are important signaling organelles, which direct embryonic development and organ function. Abnormal ciliary axonemal structure and function have been linked to the growing class of genetic disorders collectively known as ciliopathies. The prototypical ciliopathy, primary ciliary dyskinesia (PCD), was the first human disorder linked to ciliary dysfunction, described over a century ago, and since then, our understanding of the genetic and molecular abnormalities of this disease have greatly advanced [1-3]. The importance of cilia in other human diseases are just beginning to be elucidated, and defects have been associated with a growing number of pediatric conditions, including obesity, renal disease, hepatic fibrosis, skeletal dysplasias, endocrinopathies, neurodevelopmental defects, central nervous system (CNS) anomalies, laterality defects, and congenital heart disease (CHD) [2-5]. Research into ciliopathies has rapidly expanded, involving multidisciplinary efforts to define the complex genetics and functional phenotypes of cilia. In this review, we will describe ciliary ultrastructure and function, genetics, clinical characteristics, and overlapping features of these diverse diseases.

Published
2011

30. Contributors

Author

Jon S. Abramson, Mark J. Abzug, John J. Aiken, H. Hesham A-kader, Cezmi A. Akdis, Harold Alderman, Ramin Alemzadeh, Evaline A. Alessandrini, Omar Ali, Namasivayam Ambalavanan, Karl E. Anderson, Peter M. Anderson, Kelly K. Anthony, Alia Y. Antoon, Stacy P. Ardoin, Carola A.S. Arndt, Stephen S. Arnon, Stephen C. Aronoff, David M. Asher, Barbara L. Asselin, Joann L. Ater, Dan Atkins, Erika F. Augustine, Marilyn Augustyn, Ellis D. Avner, Parvin H. Azimi, Carlos A. Bacino, Robert N. Baldassano, Christina Bales, William F. Balistreri, Robert S. Baltimore, Manisha Balwani, Shahida Baqar, Christine E. Barron, Dorsey M. Bass, Mark L. Batshaw, Richard E. Behrman, Michael J. Bell, John W. Belmont, Daniel K. Benjamin, Michael J. Bennett, Daniel Bernstein, Jatinder Bhatia, Zulfiqar Ahmed Bhutta, Leslie G. Biesecker, James Birmingham, Samra S. Blanchard, Ronald Blanton, Archie Bleyer, C.D.R. Lynelle M. Boamah, Steven R. Boas, Thomas F. Boat, Walter Bockting, Mark Boguniewicz, Daniel J. Bonthius, Laurence A. Boxer, Amanda M. Brandow, David Branski, David T. Breault, Rebecca H. Buckley, Cynthia Etzler Budek, E. Stephen Buescher, Gale R. Burstein, Amaya Lopez Bustinduy, Mitchell S. Cairo, Bruce M. Camitta, Angela Jean Peck Campbell, Rebecca G. Carey, Waldemar A. Carlo, Robert B. Carrigan, Mary T. Caserta, Ellen Gould Chadwick, Lisa J. Chamberlain, Jennifer I. Chapman, Ira M. Cheifetz, Wassim Chemaitilly, Sharon F. Chen, Yuan-Tsong Chen, Russell W. Chesney, Jennifer A. Chiriboga, Robert D. Christensen, Andrew Chu, Michael J. Chusid, Theodore J. Cieslak, Jeff A. Clark, Thomas G. Cleary, John David Clemens, Joanna S. Cohen, Mitchell B. Cohen, Pinchas Cohen, Michael Cohen-Wolkowiez, Robert A. Colbert, F. Sessions Cole, Joanna C.M. Cole, John L. Colombo, Amber R. Cooper, Ronina A. Covar, Barbara Cromer, James E. Crowe, Natoshia Raishevich Cunningham, Steven J. Czinn, Toni Darville, Robert S. Daum, Richard S. Davidson, H. Dele Davies, Peter S. Dayan, Michael R. DeBaun, Guenet H. Degaffe, David R. DeMaso, Mark R. Denison, Arlene E. Dent, Nirupama K. DeSilva, Robert J. Desnick, Gabrielle deVeber, Esi Morgan DeWitt, Chetan Anil Dhamne, Anil Dhawan, Harry Dietz, Lydia J. Donoghue, Patricia A. Donohoue, Mary K. Donovan, John P. Dormans, Daniel A. Doyle, Jefferson Doyle, Stephen C. Dreskin, Denis S. Drummond, Howard Dubowitz, J. Stephen Dumler, Janet Duncan, Paula M. Duncan, LauraLe Dyner, Michael G. Earing, Elizabeth A. Edgerton, Marie Egan, Jack S. Elder, Sara B. Eleoff, Dianne S. Elfenbein, Stephen C. Eppes, Michele Burns Ewald, Jessica K. Fairley, Susan Feigelman, Marianne E. Felice, Eric I. Felner, Edward Fels, Thomas Ferkol, Jonathan D. Finder, Kristin N. Fiorino, David M. Fleece, Patricia M. Flynn, Joel A. Forman, Michael M. Frank, Melvin H. Freedman, Melissa Frei-Jones, Jared E. Friedman, Sheila Gahagan, Paula Gardiner, Luigi Garibaldi, Gregory M. Gauthier, Abraham Gedalia, Matthew J. Gelmini, Michael A. Gerber, K. Michael Gibson, Mark Gibson, Francis Gigliotti, Walter S. Gilliam, Janet R. Gilsdorf, Charles M. Ginsburg, Frances P. Glascoe, Donald A. Goldmann, Denise M. Goodman, Marc H. Gorelick, Gary J. Gosselin, Jane M. Gould, Olivier Goulet, Dan M. Granoff, Michael Green, Thomas P. Green, Larry A. Greenbaum, Marie Michelle Grino, Andrew B. Grossman, David C. Grossman, Alfredo Guarino, Lisa R. Hackney, Gabriel G. Haddad, Joseph Haddad, Joseph F. Hagan, Scott B. Halstead, Margaret R. Hammerschlag, Aaron Hamvas, James C. Harris, Mary E. Hartman, David B. Haslam, Fern R. Hauck, Gregory F. Hayden, Jacqueline T. Hecht, Sabrina M. Heidemann, J. Owen Hendley, Fred M. Henretig, Gloria P. Heresi, Andrew D. Hershey, Cynthia E. Herzog, Jessica Hochberg, Lauren D. Holinger, Jeffrey D. Hord, B. David Horn, William A. Horton, Harish S. Hosalkar, Hidekazu Hosono, Peter J. Hotez, Michelle S. Howenstine, Heather G. Huddleston, Vicki Huff, Denise Hug, Winston W. Huh, Carl E. Hunt, Anna Klaudia Hunter, Patricia Ibeziako, Richard F. Jacobs, Peter Jensen, Hal B. Jenson, Chandy C. John, Michael V. Johnston, Richard B. Johnston, Bridgette L. Jones, James F. Jones, Marsha Joselow, Anupama Kalaskar, Linda Kaljee, Deepak Kamat, Alvina R. Kansra, Sheldon L. Kaplan, Emily R. Katz, James W. Kazura, Virginia Keane, Gregory L. Kearns, Desmond P. Kelly, Judith Kelsen, Kathi J. Kemper, Melissa Kennedy, Eitan Kerem, Joseph E. Kerschner, Seema Khan, Young-Jee Kim, Charles H. King, Stephen L. Kinsman, Adam Kirton, Priya S. Kishnani, Nora T. Kizer, Martin B. Kleiman, Bruce L. Klein, Bruce S. Klein, Michael D. Klein, Robert M. Kliegman, William C. Koch, Patrick M. Kochanek, Eric Kodish, Stephan A. Kohlhoff, Elliot J. Krane, Peter J. Krause, Richard E. Kreipe, Steven E. Krug, John F. Kuttesch, Jennifer M. Kwon, Catherine S. Lachenauer, Stephan Ladisch, Stephen LaFranchi, Oren Lakser, Marc B. Lande, Philip J. Landrigan, Gregory L. Landry, Wendy G. Lane, Philip S. LaRussa, Brendan Lee, Chul Lee, K. Jane Lee, J. Steven Leeder, Rebecca K. Lehman, Michael J. Lentze, Norma B. Lerner, Steven Lestrud, Donald Y.M. Leung, Chris A. Liacouras, Susanne Liewer, Andrew H. Liu, Stanley F. Lo, Franco Locatelli, Sarah S. Long, Anna Lena Lopez, Steven V. Lossef, Jennifer A. Lowry, Kerith Lucco, G. Reid Lyon, Prashant V. Mahajan, Akhil Maheshwari, Joseph A. Majzoub, Asim Maqbool, Ashley M. Maranich, Mona Marin, Joan C. Marini, Morri Markowitz, Kevin P. Marks, Stacene R. Maroushek, Wilbert H. Mason, Christopher Mastropietro, Kimberlee M. Matalon, Reuben K. Matalon, Robert Mazor, Susanna A. McColley, Margaret M. McGovern, Heather S. McLean, Rima McLeod, Peter C. Melby, Joseph John Melvin, Diane F. Merritt, Ethan A. Mezoff, Marian G. Michaels, Alexander G. Miethke, Mohamad A. Mikati, Henry Milgrom, E. Kathryn Miller, Jonathan W. Mink, Grant A. Mitchell, Robert R. Montgomery, Joseph G. Morelli, Anna-Barbara Moscicki, Hugo W. Moser, Kathryn D. Moyer, James R. Murphy, Timothy F. Murphy, Thomas S. Murray, Mindo J. Natale, William A. Neal, Jayne Ness, Kathleen A. Neville, Mary A. Nevin, Jane W. Newburger, Peter E. Newburger, Linda S. Nield, Zehava Noah, Lawrence M. Nogee, Robert L. Norris, Stephen K. Obaro, Makram Obeid, Theresa J. Ochoa, Katherine A. O'Donnell, Robin K. Ohls, Jean-Marie Okwo-Bele, Keith T. Oldham, Scott E. Olitsky, John Olsson, Susan R. Orenstein, Walter A. Orenstein, Judith A. Owens, Charles H. Packman, Michael J. Painter, Priya Pais, Cynthia G. Pan, Vijay Pannikar, Diane E. Pappas, Anjali Parish, John S. Parks, Laura A. Parks, Maria Jevitz Patterson, Pallavi P. Patwari, Timothy R. Peters, Larry K. Pickering, Misha L. Pless, Laura S. Plummer, Craig C. Porter, Dwight A. Powell, David T. Price, Charles G. Prober, Linda Quan, Elisabeth H. Quint, C. Egla Rabinovich, Leslie J. Raffini, Denia Ramirez-Montealegre, Giuseppe Raviola, Ann M. Reed, Harold L. Rekate, Megan E. Reller, Gary Remafedi, Jorge D. Reyes, Geoffrey Rezvani, Iraj Rezvani, A. Kim Ritchey, Frederick P. Rivara, Angela Byun Robinson, Luise E. Rogg, Genie E. Roosevelt, David R. Rosenberg, Melissa Beth Rosenberg, David S. Rosenblatt, Cindy Ganis Roskind, Mary M. Rotar, Ranna A. Rozenfeld, Sarah Zieber Rush, Colleen A. Ryan, H.P.S. Sachdev, Ramesh C. Sachdeva, Mustafa Sahin, Robert A. Salata, Denise A. Salerno, Edsel Maurice T. Salvana, Hugh A. Sampson, Thomas J. Sandora, Tracy Sandritter, Wudbhav N. Sankar, Ajit Ashok Sarnaik, Ashok P. Sarnaik, Harvey B. Sarnat, Minnie M. Sarwal, Mary Saunders, Laura E. Schanberg, Mark R. Schleiss, Nina F. Schor, Bill J. Schroeder, Robert L. Schum, Gordon E. Schutze, Daryl A. Scott, J. Paul Scott, Theodore C. Sectish, George B. Segel, Kriti Sehgal, Ernest G. Seidman, Janet R. Serwint, Dheeraj Shah, Raanan Shamir, Bruce K. Shapiro, Richard J. Shaw, Bennett A. Shaywitz, Sally E. Shaywitz, Meera Shekar, Elena Shephard, Philip M. Sherman, Benjamin L. Shneider, Scott H. Sicherer, Richard Sills, Mark D. Simms, Eric A.F. Simões, Thomas L. Slovis, P. Brian Smith, Mary Beth F. Son, Laura Stout Sosinsky, Joseph D. Spahn, Mark A. Sperling, Robert Spicer, David A. Spiegel, Helen Spoudeas, Jürgen Spranger, Rajasree Sreedharan, Raman Sreedharan, Shawn J. Stafford, Margaret M. Stager, Sergio Stagno, Virginia A. Stallings, Lawrence R. Stanberry, Charles A. Stanley, Bonita F. Stanton, Jeffrey R. Starke, Merrill Stass-Isern, Barbara W. Stechenberg, Leonard D. Stein, William J. Steinbach, Nicolas Stettler, Barbara J. Stoll, Gregory A. Storch, Ronald G. Strauss, Frederick J. Suchy, Karen Summar, Moira Szilagyi, Norman Tinanoff, James K. Todd, Lucy S. Tompkins, Richard L. Tower, Riccardo Troncone, Amanda A. Trott, David G. Tubergen, David A. Turner, Ronald B. Turner, Christina Ullrich, George F. Van Hare, Jakko van Ingen, Heather A. Van Mater, Dick van Soolingen, Scott K. Van Why, Pankhuree Vandana, Douglas Vanderbilt, Jon A. Vanderhoof, Andrea Velardi, Elliott Vichinsky, Linda A. Waggoner-Fountain, Steven G. Waguespack, David M. Walker, Heather J. Walter, Stephanie Ware, Kimberly Danieli Watts, Ian M. Waxman, Debra E. Weese-Mayer, Kathryn Weise, Martin E. Weisse, Lawrence Wells, Jessica Wen, Steven L. Werlin, Michael R. Wessels, Ralph F. Wetmore, Randall C. Wetzel, Isaiah D. Wexler, Perrin C. White, John V. Williams, Rodney E. Willoughby, Samantha L. Wilson, Glenna B. Winnie, Paul H. Wise, Laila Woc-Colburn, Joanne Wolfe, Cynthia J. Wong, Laura L. Worth, Joseph L. Wright, Peter F. Wright, Terry W. Wright, Eveline Y. Wu, Anthony Wynshaw-Boris, Nada Yazigi, Ram Yogev, Marc Yudkoff, Peter E. Zage, Anita K.M. Zaidi, Lonnie K. Zeltzer, Maija H. Zile, Peter Zimmer, and Barry Zuckerman

Published
2011
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31. CCDC65 Mutation Causes Primary Ciliary Dyskinesia with Normal Ultrastructure and Hyperkinetic Cilia

Author

Steven L. Brody, Israel Amirav, Philip V. Bayly, Orly Elpeleg, Mollie G. Wasserman, David Shoseyov, Kate S. Wilson, Malena Cohen-Cymberknoh, Susan K. Dutcher, Eitan Kerem, Thomas Ferkol, Asaf Ta-Shma, and Amjad Horani

Subjects
Male, Pulmonology, lcsh:Medicine, medicine.disease_cause, Pediatrics, 0302 clinical medicine, lcsh:Science, Frameshift Mutation, Primary ciliary dyskinesia, Genetics, 0303 health sciences, Mutation, Multidisciplinary, Reverse Transcriptase Polymerase Chain Reaction, Cilium, Genomics, Pedigree, 3. Good health, Cell biology, Cell Motility, Medicine, Female, Ciliary Movement, Research Article, Biophysics, Pediatric Pulmonology, Biology, Frameshift mutation, Motor protein, 03 medical and health sciences, Microscopy, Electron, Transmission, Genome Analysis Tools, Ciliogenesis, otorhinolaryngologic diseases, medicine, Humans, Gene silencing, Cilia, Gene Silencing, DNA Primers, Glycoproteins, 030304 developmental biology, Linkage Maps, Base Sequence, Kartagener Syndrome, lcsh:R, Computational Biology, medicine.disease, 030228 respiratory system, Genetics of Disease, lcsh:Q, Immunostaining
Abstract

Background Primary ciliary dyskinesia (PCD) is a genetic disorder characterized by impaired ciliary function, leading to chronic sinopulmonary disease. The genetic causes of PCD are still evolving, while the diagnosis is often dependent on finding a ciliary ultrastructural abnormality and immotile cilia. Here we report a novel gene associated with PCD but without ciliary ultrastructural abnormalities evident by transmission electron microscopy, but with dyskinetic cilia beating. Methods Genetic linkage analysis was performed in a family with a PCD subject. Gene expression was studied in Chlamydomonas reinhardtii and human airway epithelial cells, using RNA assays and immunostaining. The phenotypic effects of candidate gene mutations were determined in primary culture human tracheobronchial epithelial cells transduced with gene targeted shRNA sequences. Video-microscopy was used to evaluate cilia motion. Results A single novel mutation in CCDC65, which created a termination codon at position 293, was identified in a subject with typical clinical features of PCD. CCDC65, an orthologue of the Chlamydomonas nexin-dynein regulatory complex protein DRC2, was localized to the cilia of normal nasal epithelial cells but was absent in those from the proband. CCDC65 expression was up-regulated during ciliogenesis in cultured airway epithelial cells, as was DRC2 in C. reinhardtii following deflagellation. Nasal epithelial cells from the affected individual and CCDC65-specific shRNA transduced normal airway epithelial cells had stiff and dyskinetic cilia beating patterns compared to control cells. Moreover, Gas8, a nexin-dynein regulatory complex component previously identified to associate with CCDC65, was absent in airway cells from the PCD subject and CCDC65-silenced cells. Conclusion Mutation in CCDC65, a nexin-dynein regulatory complex member, resulted in a frameshift mutation and PCD. The affected individual had altered cilia beating patterns, and no detectable ultrastructural defects of the ciliary axoneme, emphasizing the role of the nexin-dynein regulatory complex and the limitations of certain methods for PCD diagnosis.

Published
2013
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32. LRRC6 Mutation Causes Primary Ciliary Dyskinesia with Dynein Arm Defects

Author

Thomas Ferkol, Yifat S. Oren, Mollie G. Wasserman, Orly Elpeleg, Malena Cohen-Cymberknoh, Eitan Kerem, David Shoseyov, Israel Amirav, Steven L. Brody, Batsheva Kerem, Amjad Horani, and Susan K. Dutcher

Subjects
Male, Pulmonology, Genetic Linkage, Oligonucleotides, lcsh:Medicine, medicine.disease_cause, Pediatrics, 0302 clinical medicine, Autosomal Recessive, Molecular Cell Biology, RNA, Small Interfering, lcsh:Science, Primary ciliary dyskinesia, 0303 health sciences, Mutation, Microscopy, Video, Multidisciplinary, Reverse Transcriptase Polymerase Chain Reaction, Cilium, Gene Expression Regulation, Developmental, Genomics, Arabs, Pedigree, Cell Motility, Motile cilium, Medicine, Female, Ciliary Movement, Chromosomes, Human, Pair 8, Research Article, Adult, Adolescent, Molecular Sequence Data, Dynein, Biophysics, Pediatric Pulmonology, Genes, Recessive, Biology, Motor protein, 03 medical and health sciences, Genetic Mutation, Ciliogenesis, Genetics, medicine, Humans, Amino Acid Sequence, Gene Silencing, 030304 developmental biology, Analysis of Variance, Base Sequence, Kartagener Syndrome, lcsh:R, HEK 293 cells, Dyneins, Proteins, Computational Biology, Human Genetics, Sequence Analysis, DNA, medicine.disease, Molecular biology, Cytoskeletal Proteins, Microscopy, Electron, Nasal Mucosa, HEK293 Cells, Genetics of Disease, lcsh:Q, 030217 neurology & neurosurgery
Abstract

Despite recent progress in defining the ciliome, the genetic basis for many cases of primary ciliary dyskinesia (PCD) remains elusive. We evaluated five children from two unrelated, consanguineous Palestinian families who had PCD with typical clinical features, reduced nasal nitric oxide concentrations, and absent dynein arms. Linkage analyses revealed a single common homozygous region on chromosome 8 and one candidate was conserved in organisms with motile cilia. Sequencing revealed a single novel mutation in LRRC6 (Leucine-rich repeat containing protein 6) that fit the model of autosomal recessive genetic transmission, leading to a change of a highly conserved amino acid from aspartic acid to histidine (Asp146His). LRRC6 was localized to the cytoplasm and was up-regulated during ciliogenesis in human airway epithelial cells in a Foxj1-dependent fashion. Nasal epithelial cells isolated from affected individuals and shRNA-mediated silencing in human airway epithelial cells, showed reduced LRRC6 expression, absent dynein arms, and slowed cilia beat frequency. Dynein arm proteins were either absent or mislocalized to the cytoplasm in airway epithelial cells from a primary ciliary dyskinesia subject. These findings suggest that LRRC6 plays a role in dynein arm assembly or trafficking and when mutated leads to primary ciliary dyskinesia with laterality defects.

Published
2013
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37. Whole-Exome Capture and Sequencing Identifies HEATR2 Mutation as a Cause of Primary Ciliary Dyskinesia

Author

Katherine C. Thornton, Margaret W. Leigh, Emily H. Turner, Benjamin T. Levinson, Deborah A. Nickerson, Maimoona A. Zariwala, Laura G. Van Arendonk, Amjad Horani, Philip V. Bayly, Kate S. Wilson, Susan K. Dutcher, Joseph C. Giacalone, Alison J. Albee, Todd E. Druley, Steven L. Brody, Thomas Ferkol, Michael R. Knowles, Anand C. Patel, and Jay Shendure

Subjects
Adult, Male, Absent outer dynein arms, Dynein, Respiratory System, Mutation, Missense, Chromosome Disorders, Genes, Recessive, Gene mutation, Biology, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Report, medicine, Genetics, Humans, Genetics(clinical), Exome, Genetic Predisposition to Disease, Child, Genetics (clinical), Exome sequencing, 030304 developmental biology, Primary ciliary dyskinesia, 0303 health sciences, Kartagener Syndrome, Cilium, Infant, Proteins, Epithelial Cells, Axonemal Dyneins, Sequence Analysis, DNA, medicine.disease, Motile cilium, Female, 030217 neurology & neurosurgery, Chlamydomonas reinhardtii
Abstract

Motile cilia are essential components of the mucociliary escalator and are central to respiratory-tract host defenses. Abnormalities in these evolutionarily conserved organelles cause primary ciliary dyskinesia (PCD). Despite recent strides characterizing the ciliome and sensory ciliopathies through exploration of the phenotype-genotype associations in model organisms, the genetic bases of most cases of PCD remain elusive. We identified nine related subjects with PCD from geographically dispersed Amish communities and performed exome sequencing of two affected individuals and their unaffected parents. A single autosomal-recessive nonsynonymous missense mutation was identified in HEATR2, an uncharacterized gene that belongs to a family not previously associated with ciliary assembly or function. Airway epithelial cells isolated from PCD-affected individuals had markedly reduced HEATR2 levels, absent dynein arms, and loss of ciliary beating. MicroRNA-mediated silencing of the orthologous gene in Chlamydomonas reinhardtii resulted in absent outer dynein arms, reduced flagellar beat frequency, and decreased cell velocity. These findings were recapitulated by small hairpin RNA-mediated knockdown of HEATR2 in airway epithelial cells from unaffected donors. Moreover, immunohistochemistry studies in human airway epithelial cells showed that HEATR2 was localized to the cytoplasm and not in cilia, which suggests a role in either dynein arm transport or assembly. The identification of HEATR2 contributes to the growing number of genes associated with PCD identified in both individuals and model organisms and shows that exome sequencing in family studies facilitates the discovery of novel disease-causing gene mutations.

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