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1. LasR Variant Cystic Fibrosis Isolates Reveal an Adaptable Quorum-Sensing Hierarchy in Pseudomonas aeruginosa

Author

John B. Feltner, Daniel J. Wolter, Christopher E. Pope, Marie-Christine Groleau, Nicole E. Smalley, E. Peter Greenberg, Nicole Mayer-Hamblett, Jane Burns, Eric Déziel, Lucas R. Hoffman, and Ajai A. Dandekar

Subjects
Microbiology, QR1-502
Abstract

ABSTRACT Chronic Pseudomonas aeruginosa infections cause significant morbidity in patients with cystic fibrosis (CF). Over years to decades, P. aeruginosa adapts genetically as it establishes chronic lung infections. Nonsynonymous mutations in lasR, the quorum-sensing (QS) master regulator, are common in CF. In laboratory strains of P. aeruginosa, LasR activates transcription of dozens of genes, including that for another QS regulator, RhlR. Despite the frequency with which lasR coding variants have been reported to occur in P. aeruginosa CF isolates, little is known about their consequences for QS. We sequenced lasR from 2,583 P. aeruginosa CF isolates. The lasR sequences of 580 isolates (22%) coded for polypeptides that differed from the conserved LasR polypeptides of well-studied laboratory strains. This collection included 173 unique lasR coding variants, 116 of which were either missense or nonsense mutations. We studied 31 of these variants. About one-sixth of the variant LasR proteins were functional, including 3 with nonsense mutations, and in some LasR-null isolates, genes that are LasR dependent in laboratory strains were nonetheless expressed. Furthermore, about half of the LasR-null isolates retained RhlR activity. Therefore, in some CF isolates the QS hierarchy is altered such that RhlR quorum sensing is independent of LasR regulation. Our analysis challenges the view that QS-silent P. aeruginosa is selected during the course of a chronic CF lung infection. Rather, some lasR sequence variants retain functionality, and many employ an alternate QS strategy involving RhlR. IMPORTANCE Chronic Pseudomonas aeruginosa infections, such as those in patients with the genetic disease cystic fibrosis, are notable in that mutants with defects in the quorum-sensing transcription factor LasR frequently arise. In laboratory strains of P. aeruginosa, quorum sensing activates transcription of dozens of genes, many of which encode virulence factors, such as secreted proteases and hydrogen cyanide synthases. In well-studied laboratory strains, LasR-null mutants have a quorum-sensing-deficient phenotype. Therefore, the presence of LasR variants in chronic infections has been interpreted to indicate that quorum-sensing-regulated products are not important for those infections. We report that some P. aeruginosa LasR variant clinical isolates are not LasR-null mutants, and others have uncoupled a second quorum-sensing system, the RhlR system, from LasR regulation. In these uncoupled isolates, RhlR independently activates at least some quorum-sensing-dependent genes. Our findings suggest that quorum sensing plays a role in chronic P. aeruginosa infections, despite the emergence of LasR coding variants.

Published
2016
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2. Using Mobile Virtual Reality Simulation to Prepare for In-Person Helping Babies Breathe Training: Secondary Analysis of a Randomized Controlled Trial (the eHBB/mHBS Trial)

Author

Beatrice Nkolika Ezenwa, Rachel Umoren, Iretiola Bamikeolu Fajolu, Daniel S Hippe, Sherri Bucher, Saptarshi Purkayastha, Felicitas Okwako, Fabian Esamai, John B Feltner, Olubukola Olawuyi, Annet Mmboga, Mary Concepta Nafula, Chris Paton, and Veronica Chinyere Ezeaka

Subjects
Special aspects of education, LC8-6691, Medicine (General), R5-920
Abstract

BackgroundNeonatal mortality accounts for approximately 46% of global under-5 child mortality. The widespread access to mobile devices in low- and middle-income countries has enabled innovations, such as mobile virtual reality (VR), to be leveraged in simulation education for health care workers. ObjectiveThis study explores the feasibility and educational efficacy of using mobile VR for the precourse preparation of health care professionals in neonatal resuscitation training. MethodsHealth care professionals in obstetrics and newborn care units at 20 secondary and tertiary health care facilities in Lagos, Nigeria, and Busia, Western Kenya, who had not received training in Helping Babies Breathe (HBB) within the past 1 year were randomized to access the electronic HBB VR simulation and digitized HBB Provider’s Guide (VR group) or the digitized HBB Provider’s Guide only (control group). A sample size of 91 participants per group was calculated based on the main study protocol that was previously published. Participants were directed to use the electronic HBB VR simulation and digitized HBB Provider’s Guide or the digitized HBB Provider’s Guide alone for a minimum of 20 minutes. HBB knowledge and skills assessments were then conducted, which were immediately followed by a standard, in-person HBB training course that was led by study staff and used standard HBB evaluation tools and the Neonatalie Live manikin (Laerdal Medical). ResultsA total of 179 nurses and midwives participated (VR group: n=91; control group: n=88). The overall performance scores on the knowledge check (P=.29), bag and mask ventilation skills check (P=.34), and Objective Structured Clinical Examination A checklist (P=.43) were similar between groups, with low overall pass rates (6/178, 3.4% of participants). During the Objective Structured Clinical Examination A test, participants in the VR group performed better on the critical step of positioning the head and clearing the airway (VR group: 77/90, 86%; control group: 57/88, 65%; P=.002). The median percentage of ventilations that were performed via head tilt, as recorded by the Neonatalie Live manikin, was also numerically higher in the VR group (75%, IQR 9%-98%) than in the control group (62%, IQR 13%-97%), though not statistically significantly different (P=.35). Participants in the control group performed better on the identifying a helper and reviewing the emergency plan step (VR group: 7/90, 8%; control group: 16/88, 18%; P=.045) and the washing hands step (VR group: 20/90, 22%; control group: 32/88, 36%; P=.048). ConclusionsThe use of digital interventions, such as mobile VR simulations, may be a viable approach to precourse preparation in neonatal resuscitation training for health care professionals in low- and middle-income countries.

Published
2022
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3. Association between Term Equivalent Brain Magnetic Resonance Imaging and 2-Year Outcomes in Extremely Preterm Infants: A Report from the Preterm Erythropoietin Neuroprotection Trial Cohort

Author

Dennis E. Mayock, Semsa Gogcu, Mihai Puia-Dumitrescu, Dennis W.W. Shaw, Jason N. Wright, Bryan A. Comstock, Patrick J. Heagerty, Sandra E. Juul, Rajan Wadhawan, Sherry E. Courtney, Tonya Robinson, Kaashif A. Ahmad, Ellen Bendel-Stenzel, Mariana Baserga, Edmund F. LaGamma, L. Corbin Downey, Raghavendra Rao, Nancy Fahim, Andrea Lampland, Ivan D. Frantz, Janine Khan, Michael Weiss, Maureen M. Gilmore, Robin K. Ohls, Jean Lowe, Nishant Srinivasan, Jorge E. Perez, Victor McKay, Billy Thomas, Nahed Elhassan, Sarah Mulkey, Vivek K. Vijayamadhavan, Neil Mulrooney, Bradley Yoder, Jordan S. Kase, Jennifer Check, Erin Osterholm, Thomas George, Michael Georgieff, Camilia R. Martin, Deirdre O'Reilly, Raye-Ann deRegnier, Nicolas Porta, Catalina Bazacliu, Frances Northington, Raul Chavez Valdez, Patel Saurabhkumar, Magaly Diaz-Barbosa, Todd Richards, John B. Feltner, Isabella Esposito, Stephanie Hauge, Samantha Nikirk, Amy Silvia, Bailey Clopp, Debbie Ott, Ariana Franco Mora, Pamela Hedrick, Vicki Flynn, Andrea Wyatt, Emilie Loy, Natalie Sikes, Melanie Mason, Jana McConnell, Tiffany Brown, Henry Harrison, Denise Pearson, Tammy Drake, Jocelyn Wright, Debra Walden, Annette Guy, Jennifer Nason, Morgan Talbot, Kristen Lee, Sarah Penny, Terri Boles, Melanie Drummond, Katy Kohlleppel, Charmaine Kathen, Brian Kaletka, Shania Gonzales, Cathy Worwa, Molly Fisher, Tyler Richter, Alexander Ginder, Brixen Reich, Carrie Rau, Manndi Loertscher, Laura Cole, Kandace McGrath, Kimberlee Weaver Lewis, Jill Burnett, Susan Schaefer, Karie Bird, Clare Giblin, Rita Daly, Kristi Lanier, Kelly Warden, Jenna Wassenaar, Jensina Ericksen, Bridget Davern, Mary Pat Osborne, Neha Talele, Evelyn Obregon, Tiglath Ziyeh, Molly Clarke, Rachel E. Wegner, Palak Patel, Molly Schau, Annamarie Russow, Kelly Curry, Lisa Barnhart, Charlamaine Parkinson, Sandra Beauman, Mary Hanson, Elizabeth Kuan, Conra Backstrom Lacy, Edshelee M. Galvis, Susana Bombino, Denise Martinez, Suzi Bell, Corrie Long, Christopher Nefcy, Mark A. Konodi, Phuong T. Vu, Adam Hartman, T. Michael O'Shea, Roberta Ballard, Mike O'Shea, Karl Kuban, and John Widness

Subjects
Male, Pediatrics, medicine.medical_specialty, Placebo, Bayley Scales of Infant Development, Article, Double-Blind Method, Medicine, Humans, Erythropoietin, Periventricular leukomalacia, business.industry, Infant, Newborn, Gestational age, Brain, Infant, Retinopathy of prematurity, medicine.disease, Neuroprotection, Intraventricular hemorrhage, Bronchopulmonary dysplasia, Neurodevelopmental Disorders, Child, Preschool, Infant, Extremely Premature, Pediatrics, Perinatology and Child Health, Cohort, Female, business
Abstract

Objectives To compare the term equivalent brain magnetic resonance imaging (MRI) findings between erythropoietin (Epo) treated and placebo control groups in infants 240/7-276/7 weeks of gestational age and to assess the associations between MRI findings and neurodevelopmental outcomes at 2 years corrected age. Study design The association between brain abnormality scores and Bayley Scales of Infant Development, Third Edition at 2 years corrected age was explored in a subset of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial. Potential risk factors for neurodevelopmental outcomes such as treatment assignment, recruitment site, gestational age, inpatient complications, and treatments were examined using generalized estimating equation models. Results One hundred ten infants were assigned to Epo and 110 to placebo groups. 27% of MRI scans were rated as normal, and 60%, 10%, and 2% were rated as having mild, moderate, or severe abnormality. Brain abnormality scores did not significantly differ between the treatment groups. Factors that increased the risk of higher brain injury scores included intubation; bronchopulmonary dysplasia; retinopathy of prematurity; opioid, benzodiazepine, or antibiotic treatment >7 days; and periventricular leukomalacia or severe intraventricular hemorrhage diagnosed on cranial ultrasound. Increased global brain abnormality and white matter injury scores at term equivalent were associated with reductions in cognitive, motor, and language abilities at 2 years of corrected age. Conclusions Evidence of brain injury on brain MRIs obtained at term equivalent correlated with adverse neurodevelopmental outcomes as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition at 2 years corrected age. Early Epo treatment had no effect on the MRI brain injury scores compared with the placebo group.

Published
2021

4. The Impact of Erythropoietin on Short- and Long-Term Kidney-Related Outcomes in Neonates of Extremely Low Gestational Age. Results of a Multicenter, Double-Blind, Placebo-Controlled Randomized Clinical Trial

Author

David J. Askenazi, Patrick J. Heagerty, Robert H. Schmicker, Patrick Brophy, Sandra E. Juul, Stuart L. Goldstein, Sangeeta Hingorani, Bryan A. Comstock, Rajan Wadhawan, Dennis E. Mayock, Sherry E. Courtney, Tonya Robinson, Kaashif A. Ahmad, Ellen Bendel-Stenzel, Mariana Baserga, Edmund F. LaGamma, L. Corbin Downey, Raghavendra Rao, Nancy Fahim, Andrea Lampland, Ivan D. Frantz, Janine Y. Khan, Michael Weiss, Maureen M. Gilmore, Robin Ohls, Nishant Srinivasan, Jorge E. Perez, Victor McKay, Phuong T. Vu, Billy Thomas, Nahed Elhassan, Sarah Mulkey, Philip Dydynski, Vivek K. Vijayamadhavan, Neil Mulrooney, Bradley Yoder, Jordan S. Kase, Jennifer Check, Semsa Gogcu, Erin Osterholm, Sara Ramel, Catherine Bendel, Cheryl Gale, Thomas George, Michael Georgieff, Tate Gisslen, Sixto Guiang, Anne Hall, Dana Johnson, Katie Pfister, Heather Podgorski, Kari Roberts, Erin Stepka, Melissa Engel, Heidi Kamrath, Johannah Scheurer, Angela Hanson, Katherine Satrom, Susan Pfister, Ann Simones, Erin Plummer, Elizabeth Zorn, Camilia R. Martin, Deirdre O'Reilly, Nicolas Porta, Catalina Bazacliu, Jonathan Williams, Dhanashree Rajderkar, Frances Northington, Raul Chavez Valdez, Sandra Beauman, Patel Saurabhkumar, Magaly Diaz-Barbosa, Arturo Serize, Jorge Jordan, Debbie Ott, Ariana Franco Mora, Pamela Hedrick, Vicki Flynn, Amy Silvia, Bailey Clopp, John B. Feltner, Isabella Esposito, Stephanie Hauge, Samantha Nikirk, Andrea Purnell, Emilie Loy, Natalie Sikes, Melanie Mason, Jana McConnell, Tiffany Brown, Henry Harrison, Denise Pearson, Tammy Drake, Jocelyn Wright, Debra Walden, Annette Guy, Jennifer Nason, Morgan Talbot, Kristen Lee, Sarah Penny, Terri Boles, Melanie Drummond, Katy Kohlleppel, Charmaine Kathen, Brian Kaletka, Shania Gonzales, Cathy Worwa, Molly Fisher, Tyler Richter, Alexander Ginder, Brixen Reich, Carrie Rau, Manndi Loertscher, Laura Bledsoe, Kandace McGrath, Kimberlee Weaver Lewis, Jill Burnett, Susan Schaefer, Karie Bird, Clare Giblin, Rita Daly, Kristi Lanier, Kelly Warden, Jenna Wassenaar, Jensina Ericksen, Bridget Davern, Mary Pat Osborne, Brittany Gregorich, Neha Talele, Evelyn Obregon, Tiglath Ziyeh, Molly Clarke, Rachel E. Wegner, Palak Patel, Molly Schau, Annamarie Russow, Kelly Curry, Susan Sinnamon, Lisa Barnhart, Charlamaine Parkinson, Mary Hanson, Elizabeth Kuan, Conra Backstrom Lacy, Edshelee M. Galvis, Susana Bombino, Denise Martinez, Suzi Bell, Corrie Long, Cathy Longa, Michael Westerveld, Stacy McConkey, Anne Hay, Niranjana Natarajan, Shari Gaudette, Sarah Cobb, Gregory Sharp, Elizabeth Schumacher, Leslie Schuschke, Charlotte Frey, Mario Fierro, Lois Gilmore, Pamela Lundequam, Ronald Hoekstra, Anastasia Ketko, Nina Perdue, Sean Cunningham, Kelly Stout, Becky Hall, Galina Morshedzadeh, Betsy Ostrander, Sarah Winter, Lauren Cox, Matthew A. Rainaldi, Sarah Hensley, Melissa Morris, Dia Roberts, Melissa Tuttle, Christopher Boys, Solveig Hultgren, Elizabeth I. Pierpont, Tom George, Kelly E. King, Katherine Bataglia, Cathy Neis, Mark Bergeron, Cristina Miller, Cara Accomando, Jennifer Anne Gavin, Elizabeth Maczek, Susan Marakovitz, Aimee Knorr, Vincent C. Smith, Jane E. Stewart, Marie Weissbourd, Raye-Ann deRegnier, Nana Matoba, Shelly C. Heaton, Erika M. Cascio, Janet Brady, Suman Ghosh, Jessica Ditto, Mary Leppert, Jean Lowe, Janell Fuller, Tara DuPont, Pamela Kloska, Saurabh Patel, Lauren Carbonell, Anna Maria Patino-Fernandez, Carmen de Lerma, Kelly McDonough, Maiana De Cortada, Lacy Chavis, Jane Shannon, Mark A. Konodi, Christopher Nefcy, Karl C.K. Kuban, Jean R. Lowe, T. Michael O'Shea, Manjiri Dighe, Todd Richards, Dennis W.W. Shaw, Colin Studholme, Christopher M. Traudt, Roberta Ballard, Adam Hartman, Scott Janis, T. Robin Ohls, Michael O'Shea, Ronnie Guillet, M. Bethany Ball, Hannah Glass, Ben Saville, and Michael Schreiber

Subjects
Male, medicine.medical_specialty, Renal function, Gestational Age, Infant, Premature, Diseases, Placebo, Article, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Double-Blind Method, law, 030225 pediatrics, Internal medicine, medicine, Albuminuria, Humans, 030212 general & internal medicine, Renal Insufficiency, Chronic, Erythropoietin, business.industry, Acute kidney injury, Infant, Newborn, Gestational age, Acute Kidney Injury, medicine.disease, Recombinant Proteins, Blood pressure, Infant, Extremely Premature, Pediatrics, Perinatology and Child Health, Hypertension, Female, medicine.symptom, business, medicine.drug, Glomerular Filtration Rate
Abstract

OBJECTIVE: To evaluate whether extremely low gestational age neonates (ELGANs) randomized to erythropoietin have better or worse kidney-related outcomes during hospitalization and at 22–26 months corrected gestational age (cGA) compared with those randomized to placebo. STUDY DESIGN: We performed an ancillary study to a multicenter double-blind, placebo-controlled randomized clinical trial of erythropoietin in ELGANs. RESULTS: The prevalence of severe (stage 2 or 3) acute kidney injury (AKI) was 18.2%. We did not find a statistically significant difference between those randomized to erythropoietin vs. placebo for in-hospital primary (severe AKI) or secondary outcomes (any AKI and serum creatinine [SCr]/ cystatin C values at days 0, 7, 9 and 14). At 22–26 months cGA, 16% of the cohort had an estimated glomerular filtration rate (eGFR) 30 mg/g, 23% had a systolic blood pressure (SBP) >95(th) percentile for age, and 40% had a diastolic blood pressure (DBP) >95(th) percentile for age. SBP >90(th) percentile occurred less often among recipients of erythropoietin (p95(th) percentile or DBP >90(th) or >95(th) percentiles. CONCLUSIONS: ELGANs have high rates of in-hospital AKI and kidney-related problems at 22–26 months cGA. Recombinant erythropoietin (rhEpo) may protect ELGANs against long-term elevated SBP, but does not appear to protect from AKI, low eGFR, albuminuria or elevated DBP at 22–26 months cGA.

Published
2020

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