Publications by authors named "Drucy Borowitz"

65 Publications

Virtual Peer Support for People With Cystic Fibrosis and Their Family Members: A Program Evaluation.

J Patient Exp 2020 Dec 3;7(6):1748-1754. Epub 2021 Jan 3.

Cystic Fibrosis Foundation, Bethesda, MD, USA.

We sought to evaluate the feasibility, acceptability, and benefits of a virtual one-to-one peer support program for people with cystic fibrosis and their family members through a retrospective program evaluation. This peer support program was developed in collaboration with patients, health care providers, and CF Foundation program staff. Mentees were paired with a trained peer mentor for 3-month mentoring via video, phone, email, or text. We found that the peer support program was feasible and acceptable. Success factors include a range of positive benefits including practical support as well as social and emotional support. Two-thirds of mentees reported at least 4 different benefits. Mentors reported multiple benefits after providing support through mentoring. Our program evaluation demonstrates that virtual peer support based on informal sharing of life experiences is an achievable way to provide social support and enhance health and well-being in chronic disease management.
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http://dx.doi.org/10.1177/2374373520974322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786709PMC
December 2020

Designing the GALAXY study: Partnering with the cystic fibrosis community to optimize assessment of gastrointestinal symptoms.

J Cyst Fibros 2021 Jan 12. Epub 2021 Jan 12.

University of North Carolina, Atrium Health, Charlotte, NC, USA.

Background: Gastrointestinal (GI) involvement among persons with cystic fibrosis (CF) is highly prevalent, representing a significant source of morbidity. Persons with CF have identified GI concerns as a top research priority, yet universal clinical outcome measures capturing many of the GI symptoms experienced in CF are lacking. The GALAXY study was envisioned to address this unmet need.

Methods: The GALAXY study team partnered with Community Voice, a community of patients with CF and their caregivers, to identify the patient reported outcome measures that most accurately reflected their experience with GI symptoms in CF. We also surveyed CF care teams to identify the comfort level of various team members (providers, nurses and dieticians) in managing a variety of GI conditions.

Results: Members of Community Voice identified the combination of PAC-SYM, PAGI-SYM, PAC-QOL and the Bristol Stool scale with three additional symptom-specific questions as patient-reported outcome measures that comprehensively captured the CF experience with GI disease. CF care team providers reported a high level of comfort in treating GI conditions including constipation (92%), GERD (93%), and gassiness (77%), however comfort level was limited to only first-line interventions.

Conclusion: By partnering with persons with CF as well as their caregivers and medical providers, the GALAXY study is designed to uniquely capture the prevalence and severity of GI involvement among persons with CF in a manner that reflects the CF patient experience. The results of GALAXY will inform the development of future interventional trials and serve as a reproducible and objective study endpoint.
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http://dx.doi.org/10.1016/j.jcf.2020.12.021DOI Listing
January 2021

Oral Glutathione and Growth in Cystic Fibrosis: A Multicenter, Randomized, Placebo-controlled, Double-blind Trial.

J Pediatr Gastroenterol Nutr 2020 12;71(6):771-777

University of Minnesota Masonic Children's Hospital, Minneapolis, MN.

Objectives: The nutritional status of children with cystic fibrosis (CF) is associated with mortality and morbidity. Intestinal inflammation may contribute to impaired digestion, absorption, and nutrient utilization in patients with CF and oral glutathione may reduce inflammation, promoting improved nutritional status in patients with CF.

Methods: The GROW study was a prospective, multicenter, randomized, placebo-controlled, double-blind, phase II clinical trial in pancreatic insufficient patients with CF between the ages of 2 and 10 years. Patients received reduced glutathione or placebo orally daily for 24 weeks. The primary endpoint was the difference in change in weight-for-age z-scores from baseline through week 24 between treatment groups. Secondary endpoints included other anthropometrics, serum, and fecal inflammatory markers in addition to other clinical outcomes.

Results: Fifty-eight participants completed the study. No significant differences were seen between glutathione (n = 30) and placebo (n = 28) groups in the 6-month change in weight-for-age z-score (-0.08; 95% CI: -0.22 to 0.06; P = 0.25); absolute change in weight (kg) (-0.18; 95% CI: -0.55 to 0.20; P = 0.35); or absolute change in BMI kg/m (-0.06; 95% CI: -0.37 to 0.25; P = 0.69). There were no significant differences in other secondary endpoints. Overall, glutathione was safe and well tolerated.

Conclusions: Oral glutathione supplementation did not impact growth or change serum or fecal inflammatory markers in pancreatic insufficient children with CF when compared with placebo.
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http://dx.doi.org/10.1097/MPG.0000000000002948DOI Listing
December 2020

DIGEST: Developing innovative gastroenterology specialty training.

J Cyst Fibros 2020 Jul 28. Epub 2020 Jul 28.

Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.

Individuals with cystic fibrosis (CF) now have an increased life expectancy, due to advances in care provided by a multidisciplinary team. The care model has expanded over time to include multiple subspecialties. The Cystic Fibrosis Foundation conducted a survey of Care Center Directors and identified a need for pediatric and adult gastroenterologists with expertise in the diagnosis and treatment of intestinal, pancreatic and hepatic complications of CF. To address this need, the Developing Innovative GastroEnterology Specialty Training (DIGEST) program was created. The development, implementation, and early results of this training program are reported herein.
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http://dx.doi.org/10.1016/j.jcf.2020.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387932PMC
July 2020

Clinical Effectiveness of Lumacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for F508del-CFTR. A Clinical Trial.

Ann Am Thorac Soc 2021 01;18(1):75-83

Department of Medicine and the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama.

The combination of lumacaftor (LUM) and ivacaftor (IVA) is an approved CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator treatment for homozygous F508del patients with CF. To evaluate the effectiveness of LUM/IVA in children (6 yr or more) and adults (more than 18 yr) in a postapproval setting. This longitudinal cohort study, performed at 38 centers in the U.S. CF Therapeutics Development Network, enrolled homozygous F508del patients with CF ages 6 years old and older with no prior exposure to LUM/IVA. Study assessments were performed at baseline and at 1, 3, 6, and 12 months after LUM/IVA initiation. A total of 193 patients initiated LUM/IVA, and 85% completed the study through 1 year. Baseline mean percent-predicted forced expiratory volume in 1 second (ppFEV) was 85 (standard deviation, 22.4) in this cohort. No statistically significant change in ppFEV was observed from baseline to any of the follow-up time points, with a mean absolute change at 12 months of -0.3 (95% confidence interval [CI], -1.8 to 1.2). Body mass index improved from baseline to 12 months (mean change, 0.8 kg/m;  < 0.001). Sweat chloride decreased from baseline to 1 month (mean change, -18.5 mmol/L; 95% CI, -20.7 to -16.3;  < 0.001), and these reductions were sustained through the study period. There were no significant changes in hospitalization rate for pulmonary exacerbations and infection status with treatment. In this real-world multicenter cohort of children and adults, LUM/IVA treatment was associated with significant improvements in growth and reductions in sweat chloride without statistically significant or clinically meaningful changes in lung function, hospitalization rates, or infection.Clinical trial registered with www.clinicaltrials.gov (NCT02477319).
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http://dx.doi.org/10.1513/AnnalsATS.202002-144OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780982PMC
January 2021

Hemoptysis from the perspective of people with cystic fibrosis.

Clin Respir J 2020 Mar 1;14(3):299-303. Epub 2020 Jan 1.

Cystic Fibrosis Foundation, Bethesda, Maryland.

Introduction: People with cystic fibrosis (CF) are living longer, thus complications associated with age, such as hemoptysis, are increasing. The Institute of Medicine has emphasized the importance of patient-centeredness. Although guidelines about hemoptysis in people with CF are available, these focus on management of the complication and not the patient perspective.

Objective: We sought to understand hemoptysis from the point of view of those who have experienced it.

Methods: We fielded an 11-question survey to adults with CF and asked those who had hemoptysis to respond. Four questions had open-ended options: (1) the person's first experience with hemoptysis, (2) how that experience affected the way they approach their CF, (3) how they deal with hemoptysis when it occurs outside the home and (4) a free text box for general comments.

Results: Thirty-one of 132 adults with CF who were sent a survey completed it (23% response rate); 63% F), indicated that they had experienced hemoptysis and described their triggers. In response to open questioning, 77% of respondents found their first experience with hemoptysis to be 'scary,' 'frightening,' 'worrying' or 'jarring.' Half of respondents reported quality of life being negatively affected by worsening stress or anxiety, fear of bleeding in public or other life impacts.

Conclusions: Focusing on how to cope with future episodes of hemoptysis and the associated anxiety can be helpful to patients. Proactive communication and sensitivity to patient experience may deepen physician-patient rapport, increase self-efficacy to cope with future episodes and lead to more comprehensive care of hemoptysis.
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http://dx.doi.org/10.1111/crj.13132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064971PMC
March 2020

Challenging barriers to an option for improved provision of enteral nutrition.

J Cyst Fibros 2019 07;18(4):447-449

Cystic Fibrosis Foundation, Bethesda, MD, United States of America; Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, United States of America.

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http://dx.doi.org/10.1016/j.jcf.2019.06.002DOI Listing
July 2019

Pulmonary findings in infants with cystic fibrosis during the first year of life: Results from the Baby Observational and Nutrition Study (BONUS) cohort study.

Pediatr Pulmonol 2019 05 22;54(5):581-586. Epub 2019 Jan 22.

Department of Pediatrics, Division of Pediatric Pulmonology, University at Buffalo, Buffalo, New York.

Importance: Treatment recommendations for infants with CF standardize care, but most surveillance or treatment guidance of pulmonary manifestations are consensus-based due to sparse evidence.

Objective: To report observations about pulmonary correlates of growth and other clinical features in infants with CF.

Methods: We analyzed data from the prospective Baby Observational and Nutrition Study conducted in 28 centers across the US, including clinical features, medications, guardian diaries of respiratory symptoms, oropharyngeal swab cultures and chest radiographs (CXR) collected over the first year of life.

Results: Cough was reported in 84% of infants in the first year. Up to 30% had clinically important cough but only 6.3% had crackles; 16.5% had wheeze. Wisconsin CXR score was above 5 in 23% (normal = 0; maximum score = 100). Pseudomonas was recovered from at least one respiratory culture in 24% of infants and was associated with crackles/wheezes and use of proton pump inhibitors (PPI) (OR = 5.47; 95%CI = 1.36, 21.92; P = 0.02) or PPI plus histamine-2 (H2) blocker (OR = 8.2; 95%CI = 2.41, 27.93; P = 0.001), but not H2 blocker alone. Hospitalization for respiratory indications occurred in 18% of infants and was associated with crackles/wheeze and abnormal CXR but not low weight, Pseudomonas or use of acid blockade.

Conclusions: Cough is common in infants with CF, but few present with crackles/wheeze or CXR changes. Pseudomonas is associated with use of PPI or PPI plus H2 blocker, but not with respiratory hospitalization. These observations cannot prove cause and effect but add to our understanding of pulmonary manifestations of CF in infants.

Trial Registration: United States ClinicalTrials.Gov registry NCT01424696 (clinicaltrials.gov).
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http://dx.doi.org/10.1002/ppul.24261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557408PMC
May 2019

Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis-Knowledge Gaps and Research Opportunities: Overview Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

Pancreas 2018 Nov/Dec;47(10):1180-1184

Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.

A workshop was sponsored by the Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, on July 25, 2018, in Pittsburgh, Penn. The workshop was designed to bring together a multidisciplinary group of experts to accelerate the development of therapeutics for clinical application in inflammatory diseases of the exocrine pancreas. Three separate working groups (acute pancreatitis, recurrent acute pancreatitis, and chronic pancreatitis) were formed to address the needs, gaps, and opportunities. The working groups included patients with pancreatic diseases, pharmaceutical company leaders, basic scientists, clinical researchers, and representatives from the US Food and Drug Administration to assist with regulatory considerations and to identify the unmet needs, research targets, and opportunities to provide direction for successful development of therapeutic agents in these diseases. This article represents the summary of the overview presentations at the National Institute of Diabetes and Digestive and Kidney Diseases workshop including an ongoing drug trial in acute pancreatitis; a successful drug development network developed by the Cystic Fibrosis Foundation; and considerations for subject selection in drug trials, incorporating Food and Drug Administration guidelines on clinical trial design and clinical outcome measures. The summaries of each working group follow separately in accompanying articles.
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http://dx.doi.org/10.1097/MPA.0000000000001176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201320PMC
March 2019

RNA sequencing data from neutrophils of patients with cystic fibrosis reveals potential for developing biomarkers for pulmonary exacerbations.

J Cyst Fibros 2019 03 23;18(2):194-202. Epub 2018 Jun 23.

Department of Pediatrics, Pediatric Rheumatology Research, University at Buffalo, Jacobs School of Medicine and Biomedical Sciences, Clinical and Translational Research Center, 875 Ellicott St, Buffalo, NY 14203, USA. Electronic address:

Background: There is no effective way to predict cystic fibrosis (CF) pulmonary exacerbations (CFPE) before they become symptomatic or to assess satisfactory treatment responses.

Methods: RNA sequencing of peripheral blood neutrophils from CF patients before and after therapy for CFPE was used to create transcriptome profiles. Transcripts with an average transcripts per million (TPM) level > 1.0 and a false discovery rate (FDR) < 0.05 were used in a cosine K-nearest neighbor (KNN) model. Real time PCR was used to corroborate RNA sequencing expression differences in both neutrophils and whole blood samples from an independent cohort of CF patients. Furthermore, sandwich ELISA was conducted to assess plasma levels of MRP8/14 complexes in CF patients before and after therapy.

Results: We found differential expression of 136 transcripts and 83 isoforms when we compared neutrophils from CF patients before and after therapy (>1.5 fold change, FDR-adjusted P < 0.05). The model was able to successfully separate CF flare samples from those taken from the same patients in convalescence with an accuracy of 0.75 in both the training and testing cohorts. Six differently expressed genes were confirmed by real time PCR using both isolated neutrophils and whole blood from an independent cohort of CF patients before and after therapy, even though levels of myeloid related protein MRP8/14 dimers in plasma of CF patients were essentially unchanged by therapy.

Conclusions: Our findings demonstrate the potential of machine learning approaches for classifying disease states and thus developing sensitive biomarkers that can be used to monitor pulmonary disease activity in CF.
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http://dx.doi.org/10.1016/j.jcf.2018.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309595PMC
March 2019

CFTR modulator theratyping: Current status, gaps and future directions.

J Cyst Fibros 2019 01 20;18(1):22-34. Epub 2018 Jun 20.

Cystic Fibrosis Foundation, United States.

Background: New drugs that improve the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein with discreet disease-causing variants have been successfully developed for cystic fibrosis (CF) patients. Preclinical model systems have played a critical role in this process, and have the potential to inform researchers and CF healthcare providers regarding the nature of defects in rare CFTR variants, and to potentially support use of modulator therapies in new populations.

Methods: The Cystic Fibrosis Foundation (CFF) assembled a workshop of international experts to discuss the use of preclinical model systems to examine the nature of CF-causing variants in CFTR and the role of in vitro CFTR modulator testing to inform in vivo modulator use. The theme of the workshop was centered on CFTR theratyping, a term that encompasses the use of CFTR modulators to define defects in CFTR in vitro, with application to both common and rare CFTR variants.

Results: Several preclinical model systems were identified in various stages of maturity, ranging from the expression of CFTR variant cDNA in stable cell lines to examination of cells derived from CF patients, including the gastrointestinal tract, the respiratory tree, and the blood. Common themes included the ongoing need for standardization, validation, and defining the predictive capacity of data derived from model systems to estimate clinical outcomes from modulator-treated CF patients.

Conclusions: CFTR modulator theratyping is a novel and rapidly evolving field that has the potential to identify rare CFTR variants that are responsive to approved drugs or drugs in development.
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http://dx.doi.org/10.1016/j.jcf.2018.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301143PMC
January 2019

Effects of an Antioxidant-enriched Multivitamin in Cystic Fibrosis. A Randomized, Controlled, Multicenter Clinical Trial.

Am J Respir Crit Care Med 2018 09;198(5):639-647

18 Department of Statistics, University of Washington, Seattle, Washington.

Rationale: Cystic fibrosis (CF) is characterized by dietary antioxidant deficiencies, which may contribute to an oxidant-antioxidant imbalance and oxidative stress.

Objectives: Evaluate the effects of an oral antioxidant-enriched multivitamin supplement on antioxidant concentrations, markers of inflammation and oxidative stress, and clinical outcomes.

Methods: In this investigator-initiated, multicenter, randomized, double-blind, controlled trial, 73 pancreatic-insufficient subjects with CF 10 years of age and older with an FEV between 40% and 100% predicted were randomized to 16 weeks of an antioxidant-enriched multivitamin or control multivitamin without antioxidant enrichment. Endpoints included systemic antioxidant concentrations, markers of inflammation and oxidative stress, clinical outcomes (pulmonary exacerbations, anthropometric measures, pulmonary function), safety, and tolerability.

Measurements And Main Results: Change in sputum myeloperoxidase concentration over 16 weeks, the primary efficacy endpoint, was not significantly different between the treated and control groups. Systemic antioxidant (β-carotene, coenzyme Q10, γ-tocopherol, and lutein) concentrations significantly increased in the antioxidant-treated group (P < 0.001 for each), whereas circulating calprotectin and myeloperoxidase decreased in the treated group compared with the control group at Week 4. The treated group had a lower risk of first pulmonary exacerbation requiring antibiotics than the control group (adjusted hazard ratio, 0.50; P = 0.04). Lung function and growth endpoints did not differ between groups. Adverse events and tolerability were similar between groups.

Conclusions: Antioxidant supplementation was safe and well tolerated, resulting in increased systemic antioxidant concentrations and modest reductions in systemic inflammation after 4 weeks. Antioxidant treatment was also associated with a lower risk of first pulmonary exacerbation. Clinical trial registered with www.clinicaltrials.gov (NCT01859390).
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http://dx.doi.org/10.1164/rccm.201801-0105OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118015PMC
September 2018

Difficult conversations: Discussing prognosis with children with cystic fibrosis.

Pediatr Pulmonol 2018 05 12;53(5):592-598. Epub 2018 Mar 12.

Division of Pulmonology, Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.

Background Despite the chronic, progressive, and life-threatening nature of cystic fibrosis (CF), there are no guidelines for when and how to communicate prognosis to children with CF.

Methods: Semi-structured interviews with young adults with CF, parents of young adults with CF, and multidisciplinary CF health care providers assessed recall of and practices for communicating about prognosis. Recommendations for improvements were also solicited.

Results: Young adults with CF recalled learning that life expectancy is limited by CF between the ages of 8 and 16 years, and that CF is a progressive disease between the ages of 7 and 19 years. They reported that the information often came from CF physicians or from online resources. Patients and parents reported earlier knowledge of prognosis than providers assumed. While learning about prognosis caused sadness and stress for some patients and families, others denied negative feelings. Interestingly, most patients reported that disclosure of prognosis had minimal impact on their adherence and treatment goals. Patients and parents reported wanting physicians to be involved in conversations about prognosis. However, providers noted several barriers to discussing prognosis, including their own reluctance, time limitations, and uncertainty about appropriate timing and content of communication.

Conclusions: Communication about prognosis is important but also difficult for providers, patients, and families. Appropriately timed conversations, using tools to facilitate communication, could ensure patients receive timely, accurate information.
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http://dx.doi.org/10.1002/ppul.23975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904004PMC
May 2018

Pancreatic Enzyme Replacement Therapy Use in Infants With Cystic Fibrosis Diagnosed by Newborn Screening.

J Pediatr Gastroenterol Nutr 2018 04;66(4):657-663

Jacobs School of Medicine, University at Buffalo, Buffalo, NY.

Objectives: The aim of the study is to describe pancreatic enzyme practices during the first year of life in infants with cystic fibrosis (CF) and evaluate associations between dosing and outcomes, including growth and gastrointestinal (GI) symptoms.

Methods: We analyzed data from a subset of infants who were in a prospective cohort study conducted at 28 US CF centers. Anthropometric measurements and medications were recorded at each visit. Diaries with infant diet, pancreatic enzyme replacement therapy (PERT) dosing, stool frequency and consistency, and pain were completed by a parent/guardian for 3 days before each visit.

Results: Two hundred and thirty-one infants were enrolled in the main study; 205 of these met criteria for pancreatic insufficiency (PI). PERT dose between birth and 6 months was on average 1882 LU/kg per meal (range: 492-3727) and was similar between 6 and 12 months (mean: 1842 LU/kg per mean, range: 313-3612). PERT dose had a weak, negative association with weight z score at 3 and 6 months (r = -0.16, 95% confidence interval [CI] -0.29 to -0.02 and r = -0.18, 95% CI -0.31 to -0.04, respectively) but not at 12 months. There was not a clear relationship between PERT dosing and number of stools per day, stool consistency or pain. One hundred and forty-four infants (70%) were placed on acid suppression medication. Weight z score mean was 0.37 higher in infants using proton pump inhibitors (PPIs) exclusively versus those using histamine-2 blockers exclusively (95% CI -0.02 to 0.76, P = 0.06).

Conclusions: We did not observe that centers with a higher PERT dosing strategy yielded greater clinical benefit than dosing at the lower end of the recommended range.
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http://dx.doi.org/10.1097/MPG.0000000000001829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866181PMC
April 2018

Reduction of Recurrence Risk of Pancreatitis in Cystic Fibrosis With Ivacaftor: Case Series.

J Pediatr Gastroenterol Nutr 2018 03;66(3):451-454

Le Bonheur Children's Hospital, University of Tennessee Health Science Center, Memphis TN.

The effect of ivacaftor in patients with cystic fibrosis (CF) with recurrent pancreatitis is unknown. We conducted a multicenter retrospective study of patients with CF taking ivacaftor who had a history of recurrent pancreatitis. During the first 3 months of therapy, only 1 of the 6 patients had an episode of pancreatitis, which was managed on an outpatient basis. Between 3 and 12 months on ivacaftor therapy, none of the patients had recurrence of pancreatitis or required hospitalization. The use of ivacaftor was associated with a reduced frequency and recurrence rate of pancreatitis in patients with CF.
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http://dx.doi.org/10.1097/MPG.0000000000001788DOI Listing
March 2018

Effects of Diagnosis by Newborn Screening for Cystic Fibrosis on Weight and Length in the First Year of Life.

JAMA Pediatr 2017 06;171(6):546-554

Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, Seattle Children's Research Institute, Seattle, Washington3Division of Pulmonary and Sleep Medicine, Department of Pediatrics, University of Washington, Seattle.

Importance: Since the implementation of universal newborn screening (NBS) for cystic fibrosis (CF), the timing and magnitude of growth deficiency or its association with correlates of disease among infants with CF who underwent NBS has not been well described.

Objective: To examine incremental weight gain, linear growth, and clinical features in the first year of life among infants with CF who underwent NBS.

Design, Setting, And Participants: The Baby Observational and Nutrition Study (BONUS), a multicenter, longitudinal, observational cohort study, was conducted during regular CF clinic visits in the first 12 months of life at 28 US Cystic Fibrosis Foundation-accredited Care Centers from January 7, 2012, through May 31, 2015. Participants included 231 infants younger than 3.5 months who underwent NBS and had confirmed CF, with a gestational age of at least 35 weeks, birth weight of at least 2.5 kg, and toleration of full oral feeds. Of these, 222 infants (96.1%) had follow-up beyond 6 months of age and 215 (93.1%) completed 12 months of follow-up.

Exposure: Cystic fibrosis.

Main Outcome And Measures: Attained weight and length for age and World Health Organization normative z scores at ages 1 to 6 and 8, 10, and 12 months (defined a priori).

Results: Of the 231 infants enrolled, 110 infants (47.6%) were female and 121 (52.4%) were male, with a mean (SD) age of 2.58 (0.69) months. BONUS infants had lower than mean birth weights (mean z score, -0.15; 95% CI, -0.27 to -0.04) and higher birth lengths (mean z score, 0.44; 95% CI, 0.26 to 0.62). They achieved normal weight by 12 months, a significant improvement over a prescreening cohort of newborns with CF from 20 years before the contemporary cohort (mean z score increase, 0.57; 95% CI, 0.37-0.77). However, length was lower than the mean at 12 months (mean z score, -0.56; 95% CI, -0.70 to -0.42). Only 30 infants (13.6%) were at less than the 10th percentile of weight for age, whereas 53 (23.9%) were at less than the 10th percentile of length for age at more than half their visits. Male sex, pancreatic insufficiency, meconium ileus, histamine blocker use, and respiratory Pseudomonas aeruginosa infection were associated with lower weight or length during the first year. Insulinlike growth factor 1 levels were significantly lower among low-length infants. Persistently low-weight infants consumed significantly more calories, and weight and length z scores were negatively correlated with caloric intake.

Conclusions And Relevance: Since initiation of universal NBS for CF, significant improvement has occurred in nutritional status, with normalization of weight in the first year of life. However, length stunting remains common.
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http://dx.doi.org/10.1001/jamapediatrics.2017.0206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731827PMC
June 2017

Impact of CFTR Modulation on Intestinal pH, Motility, and Clinical Outcomes in Patients With Cystic Fibrosis and the G551D Mutation.

Clin Transl Gastroenterol 2017 Mar 16;8(3):e81. Epub 2017 Mar 16.

Jacobs School of Medicine and Biomedical Sciences of the University at Buffalo, Buffalo, New York, USA.

Objectives: A defect in bicarbonate secretion contributes to the pathophysiology of gastrointestinal complications in patients with cystic fibrosis (CF). We measured gastrointestinal pH, clinical outcomes, and intestinal transit profiles in patients with the G551D mutation before and after treatment with ivacaftor, a CF transmembrane regulator channel (CFTR) potentiator.

Methods: Observational studies of ivacaftor effectiveness were conducted in the United States and Canada. A subset of subjects ingested a wireless motility capsule (n=10) that measures in vivo pH, both before therapy with ivacaftor and 1 month after treatment; values obtained were compared for mean pH and area under the pH curve, and regional intestinal motility. We also queried subjects about abdominal pain and recorded body weight before and after treatment.

Results: One month after administering ivacaftor, a significant increase in mean pH was observed after gastric emptying (P<0.05). Area under the pH curve analyses indicate increased bicarbonate mass (P<0.05 for select 5 min intervals and all segments >30 min); mean weight gain was 1.1 kg (P=0.08). No difference in abdominal pain or regional transit times was seen.

Conclusions: CFTR modulation improves the proximal small intestinal pH profile in patients with the G551D CFTR mutation and we observed clinically relevant, contemporaneous weight gain, although it did not reach statistical significance. These data provide in vivo evidence that CFTR is an important regulator of bicarbonate secretion, which may be a translational link between CFTR function and clinical improvement.
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http://dx.doi.org/10.1038/ctg.2017.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387753PMC
March 2017

Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome and Cystic Fibrosis Screen Positive, Inconclusive Diagnosis.

J Pediatr 2017 02;181S:S45-S51.e1

Department for Women's and Children's Health, University of Liverpool, Institute in the Park, Alder Hey Children's Hospital, Liverpool, United Kingdom.

Objective: An unintended consequence of cystic fibrosis (CF) newborn screening (NBS) is the identification of infants with a positive NBS test but inconclusive diagnostic testing. These infants are classified as CF transmembrane conductance regulator-related metabolic syndrome (CRMS) in the US and CF screen positive, inconclusive diagnosis (CFSPID) in other countries. Diagnostic and management decisions of these infants are challenges for CF healthcare professionals and stressful situations for families. As CF NBS has become more widespread across the world, increased information about the epidemiology and outcomes of these infants is becoming available. These data were reviewed at the 2015 CF Foundation Diagnosis Consensus Conference, and a harmonized definition of CRMS and CFSPID was developed.

Study Design: At the consensus conference, participants reviewed published and unpublished studies of CRMS/CFSPID and used a modified Delphi methodology to develop a harmonized approach to the definition of CRMS/CFSPID.

Results: Several studies of CRMS/CFSPID from populations around the world have been published in the past year. Although the studies vary in the number of infants studied, study design, and outcome measures, there have been some consistent findings. CRMS/CFSPID occurs relatively frequently, with CF:CRMS that ranges from 3 to 5 cases of CF for every 1 case of CRMS/CFSPID in regions where gene sequencing is not used. The incidence varies by NBS protocol used, and in some regions more cases of CRMS/CFSPID are detected than cases of CF. The majority of individuals with CRMS/CFSPID do not develop CF disease or progress to a diagnosis of CF. However, between 10% and 20% of asymptomatic infants can develop clinical features concerning for CF, such as a respiratory culture positive for Pseudomonas aeruginosa. Most studies have only reported short-term outcomes in the first 1-3 years of life; the long-term outcomes of CRMS/CFSPID remain unknown. The European CF Society definition of CFSPID and the CF Foundation definition of CRMS differ only slightly, and the consensus conference was able to create a unified definition of CRMS/CFSPID.

Conclusions: CRMS/CFSPID is a relatively common outcome of CF NBS, and clinicians need to be prepared to counsel families whose NBS test falls into this classification. The vast majority of infants with CRMS/CFSPID will remain free from disease manifestations early in life. However, a small proportion may develop clinical features concerning for CF or demonstrate progression to a clinical phenotype compatible with a CF diagnosis, and their long-term outcomes are not known. A consistent international definition of CRMS/CFSPID will allow for better data collection for study of outcomes and result in improved patient care.
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http://dx.doi.org/10.1016/j.jpeds.2016.09.066DOI Listing
February 2017

CFTR, bicarbonate, and the pathophysiology of cystic fibrosis.

Authors:
Drucy Borowitz

Pediatr Pulmonol 2015 Oct;50 Suppl 40:S24-S30

University at Buffalo, State University of New York, Buffalo, New York.

The gene that encodes for the cystic fibrosis transmembrane regulator protein (CFTR) was identified in 1989, yet major pathophysiologic questions remain unanswered. There is emerging evidence that CFTR is a bicarbonate channel, a driver of chloride-bicarbonate exchange and through its action on local pH, a regulator of other ion channels and of proteins that function optimally in a neutral environment. In both the respiratory and gastrointestinal (GI) tracts, bicarbonate drives ionic content and fluid on epithelial surfaces, allows mucins to unfold and become slippery, and contributes to innate immunity. In the GI tract bicarbonate neutralizes gastric acid to support digestion and absorption. When CFTR is dysfunctional, lack of bicarbonate secretion disrupts these normal processes and thus leads directly to the clinical symptoms and signs of CF. This article synthesizes evidence from cell, animal, and human investigations that support these concepts. Bicarbonate secretion does not seem to be the same in all tissues and varies with physiologic demand. Thus, tissue type and whether conditions are baseline or stimulated needs to be taken into account when evaluating the evidence concerning the role of bicarbonate in the pathophysiology of CF as a regulator of local pH. Basic and applied research that focuses on the role of CFTR-mediated bicarbonate secretion helps explain many of the diverse clinical manifestations that are CF.
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http://dx.doi.org/10.1002/ppul.23247DOI Listing
October 2015

Nutritional Status Improved in Cystic Fibrosis Patients with the G551D Mutation After Treatment with Ivacaftor.

Dig Dis Sci 2016 Jan 7;61(1):198-207. Epub 2015 Aug 7.

Division of Pediatric Gastroenterology, University of Minnesota, 6th Floor East Building 8952C 2450 Riverside Ave, Minneapolis, MN, 55454, USA.

Background: The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gating mutation G551D prevents sufficient ion transport due to reduced channel-open probability. Ivacaftor, an oral CFTR potentiator, increases the channel-open probability.

Aim: To further analyze improvements in weight and body mass index (BMI) in two studies of ivacaftor in patients aged ≥6 years with CF and the G551D mutation.

Methods: Patients were randomized 1:1 to ivacaftor 150 mg or placebo every 12 h for 48 weeks. Primary end point (lung function) was reported previously. Other outcomes included weight and height measurements and CF Questionnaire-Revised (CFQ-R).

Results: Studies included 213 patients (aged ≤ 20 years, n = 105; aged > 20 years, n = 108). In patients ≤20 years, adjusted mean change from baseline to week 48 in body weight was 4.9 versus 2.2 kg (ivacaftor vs. placebo, p = 0.0008). At week 48, change from baseline in mean weight-for-age z-score was 0.29 versus -0.06 (p < 0.0001); change in mean BMI-for-age z-score was 0.26 versus -0.13 (p < 0.0001). In patients >20 years, adjusted mean change from baseline to week 48 in body weight was 2.7 versus -0.2 kg (p = 0.0003). Mean BMI change at week 48 was 0.9 versus -0.1 kg/m(2) (p = 0.0003). There was no linear correlation evident between changes in body weight and improvements in lung function or sweat chloride. Significant CFQ-R improvements were seen in perception of eating, body image, and sense of ability to gain weight.

Conclusions: Nutritional status improved following treatment with ivacaftor for 48 weeks.
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http://dx.doi.org/10.1007/s10620-015-3834-2DOI Listing
January 2016

Standardization of Research-Quality Anthropometric Measurement of Infants and Implementation in a Multicenter Study.

Clin Transl Sci 2015 Aug 5;8(4):330-3. Epub 2015 Jun 5.

Women and Children's Hospital of Buffalo, Buffalo, New York, USA.

Malnutrition is one of the earliest clinical manifestations of cystic fibrosis (CF) and is associated with poorer pulmonary and cognitive outcomes and survival later in life. Infant growth can be a responsive measure for clinical research in this age group if obtained and characterized accurately. We report here the methods to standardize and implement research-quality anthropometric measurement of infants with cystic fibrosis in the Baby Observational Nutrition Study multicenter trial.
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http://dx.doi.org/10.1111/cts.12283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351021PMC
August 2015

Outcomes of infants with indeterminate diagnosis detected by cystic fibrosis newborn screening.

Pediatrics 2015 Jun 11;135(6):e1386-92. Epub 2015 May 11.

Cystic Fibrosis Foundation, Bethesda, Maryland;

Background And Objectives: Cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS) describes asymptomatic infants with a positive cystic fibrosis (CF) newborn screen (NBS) but inconclusive diagnostic testing for CF. Little is known about the epidemiology and outcomes of CRMS. The goal of this study was to determine the prevalence, clinical features, and short-term outcomes of infants with CRMS.

Methods: We analyzed data from the US CF Foundation Patient Registry (CFFPR) from 2010 to 2012. We compared demographic, diagnostic, anthropometric, health care utilization, microbiology, and treatment characteristics between infants with CF and infants with CRMS.

Results: There were 1983 infants diagnosed via NBS between 2010 and 2012 reported to the CFFPR. By using the CF Foundation guideline definitions, 1540 and 309 infants met the criteria for CF and CRMS, respectively (CF:CRMS ratio = 5.0:1.0). Of note, 40.8% of infants with CRMS were entered into the registry with a clinical diagnosis of CF. Infants with CRMS tended to have normal nutritional indices. However, 11% of infants with CRMS had a positive Pseudomonas aeruginosa respiratory tract culture in the first year of life.

Conclusions: CRMS is a common outcome of CF NBS, and some infants with CRMS may develop features concerning for CF disease. A substantial proportion of infants with CRMS were assigned a clinical diagnosis of CF, which may reflect misclassification or clinical features not collected in the CFFPR.
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http://dx.doi.org/10.1542/peds.2014-3698DOI Listing
June 2015

Equivalent substrates enable simultaneous study of gastrointestinal pH and CF-related diabetes.

J Cyst Fibros 2015 Jul 16;14(4):e6-8. Epub 2015 Feb 16.

University of Rochester, United States.

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http://dx.doi.org/10.1016/j.jcf.2015.01.009DOI Listing
July 2015

Cystic fibrosis and the role of gastrointestinal outcome measures in the new era of therapeutic CFTR modulation.

J Cyst Fibros 2015 Mar 10;14(2):169-77. Epub 2015 Feb 10.

Pediatric Gastroenterology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

With the development of new drugs that directly affect CFTR protein function, clinical trials are being designed or initiated for a growing number of patients with cystic fibrosis. The currently available and accepted clinical endpoints, FEV1 and BMI, have limitations. The aim of this report is to draw attention to the need and the ample possibilities for the development and validation of relevant gastrointestinal clinical endpoints for scientific evaluation of CFTR modulation treatment, particularly in young children and infants. The gastrointestinal tract offers very good opportunities to measure CFTR protein function and systematically evaluate CF related clinical outcomes based on the principal clinical gastrointestinal manifestations of CF: intestinal pH, intestinal transit time, intestinal bile salt malabsorption, intestinal inflammation, exocrine pancreatic function and intestinal fat malabsorption. We present a descriptive analysis of a variety of gastrointestinal outcome measures for clinical relevance, reliability, validity, responsiveness to interventions, feasibility in particular in young children and the availability of reference values.
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http://dx.doi.org/10.1016/j.jcf.2015.01.006DOI Listing
March 2015

Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST).

Lancet Respir Med 2014 Nov 9;2(11):902-910. Epub 2014 Oct 9.

Royal Brompton Hospital, London, UK.

Background: Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, is approved for the treatment of patients with cystic fibrosis aged 6 years or older with Gly551Asp-CFTR. We assessed the safety and efficacy of ivacaftor during 96 weeks of PERSIST in patients with cystic fibrosis who completed a previous 48-week, placebo-controlled trial of the drug (STRIVE or ENVISION).

Methods: In this phase 3, open-label extension study, patients received ivacaftor 150 mg every 12 h in addition to their prescribed cystic fibrosis therapies. Patients who received placebo in their previous study initiated ivacaftor in this extension study. Patients were eligible if they had a Gly551Asp-CFTR mutation on at least one allele. The primary objective was to assess the long-term safety profile of ivacaftor as assessed by adverse events, clinical laboratory assessments, electrocardiograms, vital signs, and physical examination; secondary measures included change in forced expiratory volume in one second (FEV1), weight, and pulmonary exacerbations. This study is registered with ClinicalTrials.gov, number NCT01117012 and EudraCT, number 2009-012997-11.

Findings: Between July 8, 2010, and April 8, 2013, 144 adolescents/adults (≥12 years) from STRIVE and 48 children (6-11 years) from ENVISION were enrolled. Across both trials, 38 (20%) patients had a serious adverse event during the first 48 weeks and 44 (23%) during the subsequent 48 weeks. Two adults (1%) and one child (<1%) discontinued because of adverse events. The most common adverse events were pulmonary exacerbation, cough, and upper respiratory tract infection. Patients previously treated with ivacaftor had sustained improvements in FEV1, weight, and rate of pulmonary exacerbations for up to 144 weeks of treatment. Among adolescents/adults and children who previously received ivacaftor, absolute change in FEV1 at week 96 (144 weeks ivacaftor) was 9·4 and 10·3 % points and absolute increase in weight was 4·1 kg and 14·8 kg, respectively. For adolescents/adults only, the pulmonary exacerbation rate remained suppressed compared with that of patients who received placebo in the placebo-controlled study.

Interpretation: At 144 weeks of treatment, ivacaftor was well tolerated, with no new safety concerns. Ivacaftor also provided durable effects for 144 weeks in patients who had received active treatment in the placebo-controlled study. Those patients who previously received placebo had improvements comparable to those of patients treated with ivacaftor in the placebo-controlled study.

Funding: Vertex Pharmaceuticals Inc.
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http://dx.doi.org/10.1016/S2213-2600(14)70218-8DOI Listing
November 2014

Starting an academic career and starting a family: challenges and some potential solutions.

J Pediatr 2014 Sep;165(3):430-1

State University of New York at Buffalo, Women and Children's Hospital of Buffalo, Buffalo, NY. Electronic address:

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http://dx.doi.org/10.1016/j.jpeds.2014.05.044DOI Listing
September 2014

Study design considerations for evaluating the efficacy and safety of pancreatic enzyme replacement therapy in patients with cystic fibrosis.

Clin Investig (Lond) 2013 Aug;3(8):731-741

University of Washington, Seattle, WA, USA ; CF Therapeutics Development Network Coordinating Center, Seattle, WA, USA.

In 2006, the US FDA issued a 'Guidance for Industry' regarding submission of New Drug Applications for pancreatic enzyme replacement therapy (PERT) products. Five oral delayed-release PERT products have been approved by the FDA, and several others are under development and/ or evaluation for New Drug Application submission. We present in this paper recommendations of the Cystic Fibrosis Foundation's Cystic Fibrosis (CF) Therapeutics Development Network and Data Safety Monitoring Board regarding study design considerations for evaluating PERT products in patients with CF. Careful attention to study design and accuracy of the outcome measures has confirmed our understanding of the efficacy and safety of PERT for the treatment of exocrine pancreatic insufficiency of CF.
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http://dx.doi.org/10.4155/cli.13.63DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131768PMC
August 2013

Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis.

Am J Respir Crit Care Med 2014 Jul;190(2):175-84

1 Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.

Rationale: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation.

Objectives: To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers.

Methods: We conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, β-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m(2); P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, -53.8 mmol/L; 95% confidence interval, -57.7 to -49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor.

Conclusions: Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology.
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http://dx.doi.org/10.1164/rccm.201404-0703OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226057PMC
July 2014

Early attained weight and length predict growth faltering better than velocity measures in infants with CF.

J Cyst Fibros 2014 Dec 7;13(6):723-9. Epub 2014 Jun 7.

Cystic Fibrosis Foundation Therapeutics Development Network, Seattle Children's Hospital Research Institute, Seattle, WA 98145, United States; University of Washington School of Medicine, Department of Pediatrics, Seattle, WA 98195, United States; University of Washington, Department of Biostatistics, Seattle, WA 98195, United States.

Background: CF infants often do not grow as expected which adversely affects later clinical outcomes, thus sensitive early measures of growth deficiency are important. This study compared attained growth for age with velocity standards to determine which better predicts growth deficits at 24 months of age.

Methods: Growth deficiency in infancy based on weight and length velocity, and attained growth was calculated for 1992 infants in the US CF Foundation National Registry using the World Health Organization (WHO) and US growth standards. One, two and three month increments were used for calculating velocity and pooled for each age interval. Sensitivity and specificity of early indicators to predict growth deficiency at 24 months were calculated.

Results: Observed prevalence of weight deficiency (<10th percentile) during the first year of life was 26.8% higher (95% CI=(25.6, 28.1%), p<0.001) on average when measured by attained weight for age than velocity. Attained weight for age at four months was a more sensitive predictor of diminished weight for age (<10th percentile) at 24 months (sensitivity=100%, 95% CI=(87, 100%)) than weight velocity (sensitivity=40%, 95% CI=(23, 59%)). Attained length at four months was more sensitive to detecting subsequent stunting (<10th percentile length for age) (77%, 95% CI=(62, 87%)) than length velocity (30%, 95% CI=(19, 45%)).

Conclusions: In CF infancy, attained weight or length is more sensitive than velocity-based definitions for predicting subsequent diminished growth.
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http://dx.doi.org/10.1016/j.jcf.2014.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252713PMC
December 2014