Wakabayashi-Nakao K, Yu Y, Nakakuki M, Hwang TC, Ishiguro H, Sohma Y. Characterization of Δ(G970-T1122)-CFTR, the most frequent CFTR mutant identified in Japanese cystic fibrosis patients. J Physiol Sci. 2019 Jan;69(1):103-112. doi: 10.1007/s12576-018-0626-4. Epub 2018 Jun 27. [Pubmed]
A massive deletion over three exons 16-17b in the CFTR gene was identified in Japanese CF patients with the highest frequency (about 70% of Japanese CF patients definitely diagnosed). This pathogenic mutation results in a deletion of 153 amino acids from glycine at position 970 (G970) to threonine at 1122 (T1122) in the CFTR protein without a frameshift. We name it Δ(G970-T1122)-CFTR. In the present study, we characterized the Δ(G970-T1122)-CFTR expressed in CHO cells using immunoblots and a super resolution microscopy. Δ(G970-T1122)-CFTR proteins were synthesized and core-glycosylated but not complex-glycosylated. This observation suggests that the Δ(G970-T1122) mutation can be categorized into the class II mutation like ΔF508. However, VX-809 a CFTR corrector that can help maturation of ΔF508, had no effect on Δ(G970-T1122). Interestingly C-terminal FLAG tag seems to partially rescue the trafficking defect of Δ(G970-T1122)-CFTR; however the rescued Δ(G970-T1122)-CFTR proteins do not assume channel function. Japanese, and perhaps people in other Asian nations, carry a class II mutation Δ(G970-T1122) with a higher frequency than previously appreciated. Further study of the Δ(G970-T1122)-CFTR is essential for understanding CF and CFTR-related diseases particularly in Asian countries.
K Wakabayashi-Nakao K was at the Dept. of Pharmaceutical Sciences and Center for Medical Sciences, International University of Health and Welfare Tochigi, Japan and more recently at Epsilon Molecular Engineering Inc.
Wood ME, Stockwell RE, Johnson GR, Ramsay KA, Sherrard LJ, Kidd TJ, Cheney J, Ballard EL, O’Rourke P, Jabbour N, Wainwright CE, Knibbs LD, Sly PD, Morawska , Bell SC. Cystic fibrosis pathogens survive for extended periods within cough-generated droplet nuclei. Thorax. 2019 Jan;74(1):87-90. doi: 10.1136/thoraxjnl-2018-211567. Epub 2018 Apr 7.[Pubmed]
The airborne route is a potential pathway in the person-to-person transmission of bacterial strains among cystic fibrosis (CF) populations. In this cross-sectional study, we investigate the physical properties and survival of common non-Pseudomonas aeruginosa CF pathogens generated during coughing. We conclude that Gram-negative bacteria and Staphylococcus aureus are aerosolised during coughing, can travel up to 4 m and remain viable within droplet nuclei for up to 45 min. These results suggest that airborne person-to-person transmission is plausible for the CF pathogens we measured.
Michelle E Wood is Research Assistant at the Lung Bacteria Group, QIMR Berghofer Medical Research Institute, Herston, The Adult Cystic Fibrosis Centre Prince Charles Hospital and the University of Queensland Australia. Professor Scott Bell is the Hon. Group Leader
Walicka-Serzysko K, Postek M, Milczewska J, Sands D. Change in lung clearance index with microbiological status in children with cystic fibrosis.Pediatr Pulmonol. 2019 Mar 5. doi: 10.1002/ppul.24278. [Epub ahead of print] [Pubmed]
Katarzyna Walicka- Serzysko
The impact of infections caused by bacteria, especially Gram-negative, on the progression of lung disease in cystic fibrosis is well established. Decline in pulmonary function commence already at early age. In this group of patients, the lung clearance index seems to be a better marker than FEV1 allowing non-invasive monitoring of changes in small airways.
The aim of this study was to investigate the association between the microbiological status and LCI derived from multiple breath washout (MBW) technique as well as FEV1 and FVC in children suffering from cystic fibrosis. Over the 1-year recruitment period, 136 CF patients aged 5-18 with: Staphylococcus aureus (n-27), Pseudomonas aeruginosa (first time (n-27), intermittent (n-9), and chronic (34) infection), Aspergillus fumigatus (n-6) and without pathogenic flora (n-33) were included in the study. Patients had performed a spirometry and MBW test during the visit at outpatient clinic.
The study showed that the lung clearance index in patients infected with Aspergillus fumigatus was significantly higher (P < 0.05) than in those with normal throat flora. There were also statistically significant differences in the lung clearance index obtained in subjects with chronic Pseudomonas aeruginosa infection and those with first Pseudomonas aeruginosa infection (P < 0.05). Furthermore, significant statistical differences (P < 0.05) were observed between the groups of patients with chronic Pseudomonas aeruginosa infection FEV1 > 70% and FEV1 < 70%. In conclusion, LCI was associated with microbiological status of CF patients. Chronic lung infections, especially Aspergillus fumigatus and Pseudomonas aeruginosa, were associated with increased LCI. Early eradication of pathological flora positively affects the maintenance of lower LCI.
Katarzyna Walicka-Serzysk is from Cystic Fibrosis Department Institute of Mother and Child Warsaw and Cystic Fibrosis Centre, Pediatric Hospital, Dziekandw Lesny, Poland
Walker S, Flume P, McNamara J, Solomon M, Chilvers M, Chmiel J, Harris RS, Haseltine E, Stiles D, Li C, Ahluwalia N, Zhou H, Owen CA, Sawicki G; VX15-661-113 Investigator Group. A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11 years with cystic fibrosis. J Cyst Fibros. 2019 Jun 25. pii: S1569-1993(19)30813-6. doi: 10.1016/j.jcf.2019.06.009. Free full text [Epub ahead of print] [Pubmed]
Tezacaftor/ivacaftor is a new treatment option in many regions for patients aged ≥12 years who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function (F/RF) mutation. This Phase 3, 2-part, open-label study evaluated the pharmacokinetics (PK), safety, tolerability, and efficacy of tezacaftor/ivacaftor in children aged 6 through 11 years with these mutations.
Part A informed weight-based tezacaftor/ivacaftor dosages for part B. The primary objective of part B was to evaluate the safety and tolerability of tezacaftor/ivacaftor through 24 weeks; the secondary objective was to evaluate efficacy based on changes from baseline in percentage predicted forced expiratory volume in 1 s (ppFEV1), growth parameters, sweat chloride, and the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score.
After PK analysis in part A, 70 children received ≥1 dose of tezacaftor/ivacaftor in part B; 67 children completed treatment. Exposures in children aged 6 through 11 years were within the target range for those observed in patients aged ≥12 years. The safety profile of tezacaftor/ivacaftor was generally similar to prior studies in patients aged ≥12 years. One child discontinued treatment for a serious adverse event of constipation. Tezacaftor/ivacaftor treatment improved sweat chloride levels and CFQ-R respiratory domain scores, mean ppFEV1 remained stable in the normal range, and growth parameters remained stable over 24 weeks.
Tezacaftor/ivacaftor was generally safe and well tolerated, and improved CFTR function in children aged 6 through 11 years with CF with F/F and F/RF genotypes, supporting tezacaftor/ivacaftor use in this age group. NCT02953314.Tezacaftor/ivacaftor treatment improved SwCl levels and CFQ-R respiratory domain child version scores, and lung function and normal growth were maintained over 24 weeks. These results support tezacaftor/ivacaftor as an alternative treatment option to CFTR modulators previously approved in children aged 6 through 11 years with CF and F/F and F/RF genotypes in the United States. These results also support tezacaftor/ivacaftor as a new treatment option for children aged 6 through 11 years with CF and F/RF genotypes in regions that currently lack a CFTR modulator for the treatment of this population.
Dr Seth Walker (figure) is a pulmonologist affiliated with University Hospitals of Cleveland, Cleveland Medical Center, Rainbow Babies and Children’s Hospital, Cleveland.USA
Ward N, Stiller K, Holland AE; Australian Cystic Fibrosis Exercise Survey group. Collaborators (18) Exercise is commonly used as a substitute for traditional airway clearance techniques by adults with cystic fibrosis in Australia: a survey.
J Physiother. 2019 Jan;65(1):43-50. doi: 10.1016/j.jphys.2018.11.006. Epub 2018 Dec 14. Free Full Text [Pubmed]
A cross-sectional survey at 13 CF centres in Australia, using a purpose-designed questionnaire.
More details in PubMed abstract.
The authors concluded exercise is commonly used as a substitute for traditional airway clearance techniques. Physiotherapists should advise patients that whilst there is some research suggesting a possible mechanism for exercise as a form of airway clearance, there are currently no medium-term to long-term data supporting exercise as a stand-alone form of airway clearance. These results suggest that future research to investigate the clinical effectiveness of exercise as a substitute for traditional airway clearance techniques should be a priority.
Nathan Ward is a physiotherapist in the Cystic Fibrosis Service, Royal Adelaide Hospital, Adelaide, Australia.
Warrier R, Skoric B, Vidmar S, Carzino R, Ranganathan S.The role of geographical location and climate on recurrent Pseudomonas infection in young children with Cystic Fibrosis. J Cyst Fibros. 2019 Apr 24. pii: S1569-1993(19)30072-4. doi: 10.1016/j.jcf.2019.04.013. [Epub ahead of print] [Pubmed]
A study to determine the association between residence and climate with risk of Pseudomonas aeruginosa (Pa) and other respiratory outcomes. Regular bronchoalveolar lavage and upper airway cultures were performed in young children with CF to identify Pa infection. Children were classified for residence as regional or metropolitan. Bronchiectasis was detected on periodic chest computed tomography scans. Multilocus sequence typing determined Pa genotype. Lung function was assessed using Multiple Breath Washout.
Of infants diagnosed with CF between 2006 and 2017, 129 were included in the study. There was weak evidence of a 15% increase in the rate of Pa episodes with increasing average annual maximum temperature, while the rate of Pa acquision decreased with average annual 3 pm humidity. The rate of Pa episodes was 2.1 times higher in regional participants (95%CI (1.4, 3.1); p = .001) and risk of second episode was more than five times greater (HR 5.7; 95%CI 1.9, 17); p = .002). No difference between regions in lung clearance index and presence of bronchiectasis was detected.
The authors concluded regional residence (as opposed to metropolitan) is associated with risk of acquiring recurrent infection with Pseudomonas aeruginosa in young children with CF.
Dr Ranjani Warrier is a PhD student at the Department of Respiratory Medicine, Royal Children’s Hospital, Victoria, Australia.
Prof. Sarath Ranganathan is Director of Respiratory Medicine, Royal Children’s Hospital Melbourne
Welsner M, Straßburg S, Taube C, Sutharsan S. Use of ivacaftor in late diagnosed cystic fibrosis monozygotic twins heterozygous for F508del and R117H-7T – a case report. BMC Pulm Med. 2019 Apr 11;19(1):76. doi: 10.1186/s12890-019-0840-8.[Pubmed] Free PMC Article
CFTR modulator therapy with ivacaftor is a treatment option for Cystic Fibrosis (CF) patients with at least one copy of a R117H-7T mutation in the CFTR gene. Desirable effects of this therapy are improvement of lung function, decrease in exacerbation rate, normalization or reduction of sweat chloride and weight gain. Monogenetic CF-twins carry identical genetic information, so therapy response and side effects are expected to be nearly identical under this specific therapy.
In monozygotic twins, at the age of 55, two pathogenic variants in the CFTR gene (F508del and R117H-7T) were detected. Both patients presented with a borderline sweat test (30-59 mmol/L) and despite the same genetic information and similar life circumstances the disease proceeds completely different. While one patient has severe pulmonary involvement with chronic P. aeruginosa infection, her twin sister is almost unimpaired. Liver or pancreatic involvement was not seen in either patient. Due to the presence of one copy of a R117H-7T mutation, CFTR modulator therapy with ivacaftor was initiated in both. Response and side effects were significantly different. In the less affected patient, we observed an improvement in lung function and a normalization of sweat chloride. In the severely affected patient, no functional response to treatment was seen, but stabilization of the disease state with a decrease in exacerbation and hospitalization rate and weight gain as well as a normalization of sweat chloride. There was an increase in liver enzymes in the less affected patient, which normalized after halving the dose of ivacaftor, while the therapeutic effect was maintained.
Despite nearly identical genetic information, as in monogenetic twins, therapy response and onset of side effects of CFTR modulating therapy are very different. In patients with late diagnosis and severe pulmonary involvement, ivacaftor does not seem to improve lung function, whereas in patients with late diagnosis and low disease severity a relevant therapy response was obtained. In addition to lung function, additional clinical parameters such as reduction of exacerbation and hospitalization rate and weight gain should be used to assess therapy response, especially in severely affected patients.
From the Department of Pulmonary Medicine, University Hospital Essen – Ruhrlandklinik, Adult Cystic Fibrosis Center, University of Duisburg-Essen, Tueschener Weg 40, 45329, Essen, Germany. email@example.com. Department of Pulmonary Medicine, University Hospital Essen – Ruhrlandklinik, Adult Cystic Fibrosis Center, University of Duisburg-Essen, Tueschener Weg 40, 45329, Essen, Germany.
Witters P, Libbrecht L, Roskams T, et al. Liver disease in cystic fibrosis presents as non-cirrhotic portal hypertension. J Cyst Fibros 2017;16:e11–e13. Free Full text (with figures) [Pubmed]
In the present work, we studied 8 patients with CFLD and PHT and 5 CFLD explant livers. In our patient cohort, both haemodynamic (HVPG) measurements and histological findings were identical to those in non-cirrhotic portal hypertension (NCPH). Hence, in at least a subset of CFLD patients, CFLD-related PHT is not due to the paradigmal “biliary” cirrhosis but corresponds to vascular damage as in NCPH. Although PHT clearly precedes the development of cirrhosis and end-stage liver failure in our patients, which percentage of PHT patients will go on to develop cirrhosis remains to be determined.
Prof. Dr Peter Witters. Dept Paediatric Gastroenterology and Hepatology, University Hospitals, Belgium
Wood ME, Stockwell RE, Johnson GR, Ramsay KA, Sherrard LJ, Kidd TJ, Cheney J, Ballard EL, O’Rourke P Jabbour N, Wainwright CE, Knibbs LD, Sly PD, Morawska L, Bell SC. Cystic fibrosis pathogens survive for extended periods within cough-generated droplet nuclei.Thorax. 2019 Jan;74(1):87-90. doi: 10.1136/thoraxjnl-2018-211567. Epub 2018 Apr 7. [Pubmed]
The airborne route is a potential pathway in the person-to-person transmission of bacterial strains among cystic fibrosis(CF) populations. In this cross-sectional study, we investigate the physical properties and survival of common non-Pseudomonas aeruginosa CF pathogens generated during coughing. We conclude that Gram-negative bacteria and Staphylococcus aureus are aerosolised during coughing, can travel up to 4 m and remain viable within droplet nuclei for up to 45 min. These results suggest that airborne person-to-person transmission is plausible for the CF pathogens we measured.
Wu H, Vu M, Dhingra S, Ackah R, Goss JA, Rana A, Quintanilla N, Patel K, Leung DH. Obliterative Portal Venopathy Without Cirrhosis Is Prevalent in Pediatric Cystic Fibrosis Liver Disease With Portal Hypertension. Clin Gastroenterol Hepatol. 2019 Sep;17(10):2134-2136. doi: 10.1016/j.cgh.2018.10.046. Epub 2018 Nov 4.[Pubmed]
Cystic fibrosis liver disease (CFLD) has long been postulated to be secondary to dysfunctional cystic fibrosis transmembrane conductance regulator in the apical biliary epithelium, leading to bile stasis and eventually cirrhosis with portal hypertension. However, pathologic changes in the cystic fibrosis (CF) liver are distinct from the pancreas and lungs in that fibrocystic changes are absent. Furthermore, the lack of clinically evident biliary obstruction and liver dysfunction suggest there may be alternative mechanisms that contribute to CFLD. Two recent studies (both reviewed below) in young adults described obliterative portal venopathy (OPV) and non-cirrhotic portal hypertension (NCPH) as the predominant pathophysiology in young adults (median, 22 y) with CFLD. It is unknown if OPV develops early in childhood.
The present authors report the clinical features and liver pathology in 17 explants from children and adolescents with CF. Diffuse nodularity of the capsular surfaces was seen in 76.5%, but only in 56.3% of cut surfaces of explants. No explants showed bile duct cystic dilatation or luminal inspissated material. The classic CF-associated eosinophilic granular material was seen within hepatocyte lobules of 6 explants (35.3%), all in association with neutrophilic lobulitis, but none was found within an interlobular bile duct. There was no cholate stasis or copper deposition in periportal hepatocytes.
The absence of focal biliary cirrhosis (FBC) in the majority of cases, reviewed in great detail, raises important questions about FBC as the primary driver of liver disease progression in CFLD. Their consistent observations of portal vascular compromise or paucity in a younger cohort may have important implications for both clinical management and in elucidating the complex and likely multifactorial aetiology of CF liver disease.
Dr Has Wu is in the Department of Pathology, Baylor College of Medicine, Houston, Texas.
Wu HX, Zhu M, Xiong XF, Wei J, Zhuo KQ, Cheng DY. Efficacy and Safety of CFTR Corrector and Potentiator Combination Therapy in Patients with Cystic Fibrosis for the F508del-CFTR Homozygous Mutation: A Systematic Review and Meta-analysis. Adv Ther. 2019 Feb;36(2):451-461. doi: 10.1007/s12325-018-0860-4. Epub 2018 Dec 15. [Pubmed]
The authors performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of combination therapy on lung function, nutritional status, clinical score and safety in CF for the F508del-CFTR homozygous mutation. Five RCTs, including a total of 1637 participants with the F508del-CFTR homozygous mutation who accepted CFTR corrector and potentiator combination therapy along with basic treatment were enrolled in this analysis. Primary analysis revealed that combination therapy improved the percent of predicted FEV1 (ppFEV1) (MD 2.38, 1.62-3.15, P < 0.00001), Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score (MD 2.59, 0.96-4.22, P = 0.002) and body-mass index (BMI) (MD 0.21, 0.03-0.39, P = 0.02). In the secondary analysis, combination therapy had no impact on the number of participants reporting adverse events (OR 0.88, 0.58-1.33, P = 0.53), but increased the proportion of discontinued treatments due to adverse events (OR 2.71, 1.3-5.63, P = 0.008).
The authors concluded potentiator combination therapy effectively improves lung function, nutritional status and clinical score in CF patients with the F508del-CFTR homozygous mutation, and has an acceptable safety profile.
From the Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China.
Yan J, Kevat A, Martinez E, Teese N, Johnson K, Ranganathan S, Harrison J, Massie J, Daley A. Investigating transmission of Mycobacterium abscessusamongst children in an Australian cystic fibrosis centre. J Cyst Fibros. 2019 Mar 7. pii: S1569-1993(18)30918-4. doi: 10.1016/j.jcf.2019.02.011. [Epub ahead of print] [Pubmed]
Mycobacterium abscessus is an emerging pathogen in cystic fibrosis (CF) lung disease. Hospital transmission of M. abscessus has been described. This paper details the investigation into possible cross-transmission of M. abscessus locally at our paediatric hospital CF centre, and the subsequent infection control response. Whole genome sequencing (WGS) of M. abscessus respiratory isolates with epidemiological linkage analysis using hospital electronic medical records.
6.7% (22/328) of CF patients had M. abscessus isolated from respiratory specimens. WGS revealed a cluster of three patients with genomically related isolates that differed by <7 single nucleotide polymorphisms (SNPs), suggesting a shared recent ancestor and probable cross-transmission. Epidemiological investigation revealed multiple potential crossovers between patients with genomically similar M. abscessus isolates.
The authors concluded cross-infection of NTM occurs in CF hospital patients and advise that hospital infection control practices should be upgraded to reflect this. Consensus is needed between centres.
From the Department of Microbiology, Royal Children’s Hospital, 50 Flemington Rd, Parkville, Victoria, Australia; Department of Infection Prevention and Control, Royal Children’s Hospital, 50 Flemington Rd, Parkville, Victoria, Australia.
Zhao J, Huang W, Zhang S, Xu J, Xue W, He B, Zhang Y. Efficacy of Glutathione for Patients With Cystic Fibrosis: A Meta-analysis of Randomized-Controlled Studies. Am J Rhinol Allergy. 2019 Sep 24:1945892419878315. doi: 10.1177/1945892419878315. [Epub ahead of print][Pubmed]The impact of glutathione on pulmonary function remains elusive for patients with cystic fibrosis. The aim of this systematic review and meta-analysis is to explore the influence of glutathione versus placebo on pulmonary function of cystic fibrosis.
The authors searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through May 2019, and randomized-controlled trials (RCTs) regarding the effect of glutathione on pulmonary function of cystic fibrosis are included in this meta-analysis.
Four RCTs are included. Compared with control group in patients with cystic fibrosis, glutathione treatment shows positive impact on forced expiratory volume 1 second (FEV1) (mean difference [MD] = 0.19; 95% confidence interval (CI), 0.10–0.28; P < .0001) and body mass index (MD = 0.27; 95% CI, 0.02–0.51; P = .03), but has no obvious influence on 6-minute walk test (standard MD = 0.28; 95% CI, −0.08 to 0.64; P = .13), number of exacerbations (MD = −0.10; 95% CI, −0.34 to 0.15; P = .43), abdominal pain or distal intestinal obstruction (risk ratios [RR] = 0.78; 95% CI, 0.32–1.90; P = .58), or hemoptysis (RR = 1.87; 95% CI, 0.43–8.26; P = .41).
The authors concluded glutathione treatment provides some benefits to improve pulmonary function of patients with cystic fibrosis, as evidenced by the increase in FEV1.
– Abstract not clear regarding benefits but I have described the long saga of glutathione in CF in Topics. However, their is a great deal written about glutathione and cystic fibrosis although it is still not a regular recommended component of treatment. Readers are advised to consult Medline where glutathione in cystic fibrosis retrieves no less than 349 references
Jinqiu Zhao is from the Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Bin He is from the Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Zemanick E, Burgel PR, Taccetti G, Holmes A, Ratjen F5 Byrnes CA, Waters VJ, Bell SC, VanDevanter DR, Stuart Elborn J, Flume PA; Antimicrobial Resistance International Working Group in Cystic Fibrosis. Antimicrobial resistance in cystic fibrosis: A Delphi approach to defining best practices. J Cyst Fibros. 2019 Oct 31. pii: S1569-1993(19)30919-1. doi: 10.1016/j.jcf.2019.10.006. [Epub ahead of print][Pubmed]
Antimicrobial susceptibility testing (AST) is a cornerstone of infection management in cystic fibrosis. However, there is little evidence that AST predicts the clinical outcome of CF antimicrobial treatment. It has been suggested there is a need for careful consideration of current AST use by the CF community.
The authors engaged a group of experts consisting of pulmonary (adult and pediatric) and infectious disease clinicians, microbiologists, and pharmacists representing a broad international experience. We conducted an iterative systematic survey (Delphi) to determine and quantify consensus regarding key questions facing CF clinicians in the use of respiratory culture results including what tests to order, when to obtain them, and how to act upon the results of the testing.
Consensus was reached for many questions but there was not universal agreement to the questions that were addressed. There were some differences with respect to cultures obtained for surveillance compared to when there is clinical worsening. Areas of general consensus include when and how respiratory cultures should be performed, what information should be reported, and when AST should be performed. A key finding is that clinical response to treatment is used to guide treatment decisions rather than AST results.
Recommendations are presented regarding questions related to microbiology testing for patients with CF. We have also offered recommendations for priority research questions.
– The Key Recommendations were as follows –
- Surveillance respiratory cultures should be obtained four times per yea
- Respiratory cultures should be obtained at the diagnosis of a pulmonary exacerbation
- Spontaneously or induced expectorated sputum is preferred for respiratory cultures
- Respiratory culture results should report both bacterial genus and species
- Bacterial susceptibility testing should be performed at least once annually, when a new pathogen, or at the time of a pulmonary exacerbation
- Antibiotic selection for treatment is based on bacterial species
- Changes in antibiotic treatment are based on clinical response to treatment and informed by susceptibility testing
Dr Edith Zemanick is in the Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States.