Early Respiratory Bacterial Detection and Anti-Staphylococcal Antibiotic Prophylaxis in Young Children with Cystic Fibrosis.

Ann Am Thorac Soc. 2017 Oct 16;:

Authors: Hurley MN, Fogarty A, McKeever TM, Goss CH, Rosenfeld M, Smyth AR

Abstract
RATIONALE: Consensus is lacking regarding anti-staphylococcal antibiotic prophylaxis use for young children with cystic fibrosis. Prophylaxis is recommended in the UK, but recommended against in the US.
OBJECTIVES: To test the hypothesis that anti-staphylococcal antibiotic prophylaxis is associated with a decreased risk of Staphylococcus aureus acquisition, but no increased risk of Pseudomonas aeruginosa acquisition.
METHODS: We undertook a longitudinal observational study of children with cystic fibrosis who were recruited from birth (or their first registry entry in the period) and followed until the age of 4 years (1500 days) using UK CF Trust and US CF Foundation Registries, 2000-2009. Children were excluded if they had a culture positive for S. aureus or P. aeruginosa, or were receiving inhaled antibiotics, at first encounter. Time to first S.aureus and P. aeruginosa detection in the UK/US cohorts were compared using a Cox proportional hazards model. A UK-based analysis compared the same for those receiving flucloxacillin with those who received no prophylaxis. We included the following covariates: sex, age at registry entry, Dornase alfa use, genotype and center size.
RESULTS: The primary analysis consisted 1074 UK and 3677 US children. The risk of first detection was greater in US compared to UK for S. aureus (hazard ratio (HR) 5.79; 95% CI: 4.85, 6.90; p<0.001) and P. aeruginosa (HR 1.92; 95% CI: 1.65, 2.24; p<0.001). The UK analysis compared 278 children receiving flucloxacillin and 306 receiving no prophylaxis. Flucloxacillin was not associated with a reduced risk of S. aureus (HR 1.22; 95% CI: 0.74, 2.0; p=0.43), but was associated with an increased risk of P. eruginosa (HR 2.53; 95% CI: 1.71, 3.74; p<0.001) detection. None of the covariates significantly affected the risk estimate in either analysis.
CONCLUSIONS: Risk of first detection of S. aureus and P. aeruginosa is greater in US compared to UK. In the UK, the risk of first P. aeruginosa detection is increased among those receiving flucloxacillin compared to those who received no prophylaxis. These observational findings should be explored in a randomized controlled trial.

PMID: 29035090 [PubMed - as supplied by publisher]

Antibiotic therapy, supportive treatment and management of immunomodulation-inflammation response in community acquired pneumonia: review of recommendations.

Multidiscip Respir Med. 2017;12:26

Authors: Mantero M, Tarsia P, Gramegna A, Henchi S, Vanoni N, Di Pasquale M

Abstract
Community-acquired pneumonia is a common and serious disease, with high rates of morbidity and mortality. Management and treatment of community-acquired pneumonia are described in three main documents: the 2007 American Thoracic Society guidelines, the 2011 European Respiratory Society guidelines, and the 2009 British Thoracic Society guidelines, updated by the NICE in 2015. Despite the validity of current guidelines in improving prognosis and management of patients with community-acquired pneumonia, not all recommendations have high levels of evidence and there are still some controversial issues. In particular, there are some areas of low evidence such as the efficacy of an antibiotic molecule or scheme in patients with same risk factors; duration of antibiotic treatment, supportive therapy for acute respiratory failure and immunomodulation molecules. This review will summarize the main recommendations with high level of evidence and discuss the recommendations with lower evidence, analyzing the studies published after the guidelines' release.

PMID: 29034094 [PubMed]

Coach to cope: feasibility of a life coaching program for young adults with cystic fibrosis.

Patient Prefer Adherence. 2017;11:1613-1623

Authors: Knudsen KB, Pressler T, Mortensen LH, Jarden M, Boisen KA, Skov M, Quittner AL, Katzenstein TL

Abstract
BACKGROUND: Over the last two decades, lifespan has increased significantly for people living with cystic fibrosis (CF). However, several studies have demonstrated that many young adults with CF report mental health problems and poor adherence to their prescribed treatments, challenging their long-term physical health. Treatment guidelines recommend interventions to improve adherence and self-management. The aim of this study was to test the feasibility of a life coaching intervention for young adults with CF.
METHODS: A randomized, controlled feasibility study was conducted at the CF Center at Copenhagen University Hospital, Rigshospitalet. Participants were young adults with CF, aged 18-30 years without severe intellectual impairments. Participants were randomized to either life coaching or standard care. The intervention consisted of up to 10 individual, face-to-face or telephone coaching sessions over a period of 1 year. Primary outcomes were recruitment success, acceptability, adherence to the intervention, and retention rates. Secondary outcome measures included health-related quality of life, adherence to treatment, self-efficacy, pulmonary function, body mass index, and blood glucose values.
RESULTS: Among the 85 eligible patients approached, 40 (47%) were enrolled and randomized to the intervention or control group; two patients subsequently withdrew consent. Retention rates after 5 and 10 coaching sessions were 67% and 50%, respectively. Reasons for stopping the intervention included lack of time, poor health, perceiving coaching as not helpful, lack of motivation, and no need for further coaching. Coaching was primarily face-to-face (68%). No significant differences were found between the groups on any of the secondary outcomes.
CONCLUSION: Both telephone and face-to-face coaching were convenient for participants, with 50% receiving the maximum offered coaching sessions. However, the dropout rate early in the intervention was a concern. In future studies, eligible participants should be screened for their interest and perceived need for support and life coaching before enrollment.

PMID: 29033550 [PubMed]

Developing a model for cystic fibrosis sociomicrobiology based on antibiotic and environmental stress.

Int J Med Microbiol. 2017 Sep 28;:

Authors: Lopes SP, Azevedo NF, Pereira MO

Abstract
Cystic fibrosis (CF) infections are invariably biofilm-mediated and polymicrobial, being safe to assume that a myriad of factors affects the sociomicrobiology within the CF infection site and modulate the CF community dynamics, by shaping their social activities, overall functions, virulence, ultimately affecting disease outcome. This work aimed to assess changes in the dynamics (particularly on the microbial composition) of dual-/three-species biofilms involving CF-classical (Pseudomonas aeruginosa) and unusual species (Inquilinus limosus and Dolosigranulum pigrum), according to variable oxygen conditions and antibiotic exposure. Low fluctuations in biofilm compositions were observed across distinct oxygen environments, with dual-species biofilms exhibiting similar relative proportions and P. aeruginosa and/or D. pigrum populations dominating three-species consortia. Once exposed to antibiotics, biofilms displayed high resistance profiles, and microbial compositions, distributions, and microbial interactions significantly challenged. The antibiotic/oxygen environment supported such fluctuations, which enhanced for three-species communities. In conclusion, antibiotic therapy hugely disturbed CF communities' dynamics, inducing significant compositional changes on multispecies consortia. Clearly, multiple perturbations may disturb this dynamic, giving rise to various microbiological scenarios in vivo, and affecting disease phenotype. Therefore, an appreciation of the ecological/evolutionary nature within CF communities will be useful for the optimal use of current therapies and for newer breakthroughs on CF antibiotherapy.

PMID: 29033313 [PubMed - as supplied by publisher]

Mechanisms of humoral immune response against Pseudomonas aeruginosa biofilm infection in cystic fibrosis.

J Cyst Fibros. 2017 Oct 12;:

Authors: Mauch RM, Jensen PØ, Moser C, Levy CE, Høiby N

Abstract
P. aeruginosa chronic lung infection is the major cause of morbidity and mortality in patients with cystic fibrosis (CF), and is characterized by a biofilm mode of growth, increased levels of specific IgG antibodies and immune complex formation. However, despite being designed to combat this infection, such elevated humoral response is not associated with clinical improvement, pointing to a lack of anti-pseudomonas effectiveness. The mode of action of specific antibodies, as well as their structural features, and even the background involving B-cell production, stimulation and differentiation into antibody-producing cells in the CF airways are poorly understood. Thus, the aim of this review is to discuss studies that have addressed the intrinsic features of the humoral immune response and provide new insights regarding its insufficiency in the CF context.

PMID: 29033275 [PubMed - as supplied by publisher]

Treating resistant Pseudomonas aeruginosa lung disease in young children with cystic fibrosis.

Paediatr Respir Rev. 2017 Sep 01;:

Authors: Lim SZP, Fitzgerald DA

Abstract
Pseudomonas aeruginosa is a common bacterial pathogen in the evolution of bronchiectasis in cystic fibrosis. The appearance of resistant strains of pseudomonas is increasing with the earlier and more liberal use of a range of anti-pseudomonal antibiotics for the treatment of bacterial chest infections. The rationale for treatment and potential benefits of aggressive treatment of resistant strains of Pseudomonas aeruginosa from early in life are discussed.

PMID: 29033215 [PubMed - as supplied by publisher]

Corrigendum to "Does current reporting of lung function by the UK cystic fibrosis registry allow a fair comparison of adult centres?" [J Cyst Fibros (2017) 585-591].

J Cyst Fibros. 2017 Oct 11;:

Authors: Nightingale JA, Osmond C

PMID: 29032179 [PubMed - as supplied by publisher]

IgG avidity to Pseudomonas aeruginosa over the course of chronic lung biofilm infection in cystic fibrosis.

J Cyst Fibros. 2017 Oct 11;:

Authors: Mauch RM, Nørregaard LL, Ciofu O, Levy CE, Høiby N

Abstract
BACKGROUND AND OBJECTIVES: The mechanisms leading to low effectiveness of the humoral immune response against P. aeruginosa in cystic fibrosis (CF) are poorly understood. The aim of the present study was to assess the avidity maturation of specific antipseudomonal IgG before and during the development of chronic lung infection in a cohort of Danish CF patients.
METHODS: Avidity maturation was assessed against a pooled P. aeruginosa antigen (St-Ag) and against P. aeruginosa alginate in 10 CF patients who developed chronic lung infection and 10 patients who developed intermittent lung colonization, using an ELISA technique with the thiocyanate elution method. Avidity was quantitatively determined by calculating the avidity Constant (Kav).
RESULTS: IgG avidity to St-Ag significantly increased at the onset (Median Kav=2.47) and one year after the onset of chronic infection (Median Kav=3.27), but did not significantly changed in patients who developed intermittent colonization. IgG avidity against alginate did not significantly change over the years neither in patients who developed chronic lung infection (Median Kav=3.84 at the onset of chronic infection), nor in patients who developed intermittent colonization.
CONCLUSION: IgG avidity to P. aeruginosa alginate does not significantly enhance as chronic lung infection progresses. This probably plays a role in the difficulty to mount an effective opsonophagocytic killing to clear mucoid P. aeruginosa infection in CF.

PMID: 29032178 [PubMed - as supplied by publisher]

Exercise assessment and training in cystic fibrosis: Can less achieve more?

J Cyst Fibros. 2017 Oct 11;:

Authors: Cox NS, Holland AE

PMID: 29032177 [PubMed - as supplied by publisher]

Transformative therapies for rare CFTR missense alleles.

Curr Opin Pharmacol. 2017 Oct 12;34:76-82

Authors: Oliver KE, Han ST, Sorscher EJ, Cutting GR

Abstract
With over 1900 variants reported in the cystic fibrosis transmembrane conductance regulator (CFTR), enhanced understanding of cystic fibrosis (CF) genotype-phenotype correlation represents an important and expanding area of research. The potentiator Ivacaftor has proven an effective treatment for a subset of individuals carrying missense variants, particularly those that impact CFTR gating. Therapeutic efforts have recently focused on correcting the basic defect resulting from the common F508del variant, as well as many less frequent missense alleles. Modest enhancement of F508del-CFTR function has been achieved by combining Ivacaftor with Lumacaftor, a compound that aids maturational processing of misfolded CFTR. Continued development of in silico and in vitro models will facilitate CFTR variant characterization and drug testing, thereby elucidating heterogeneity in the molecular pathogenesis, phenotype, and modulator responsiveness of CF.

PMID: 29032041 [PubMed - as supplied by publisher]

A Closer Look at Frederic Chopin's Cause of Death.

Am J Med. 2017 Oct 11;:

Authors: Witt M, Szklener A, Kawecki J, Rużyłło W, Negrusz-Kawecka M, Jeleń M, Langfort R, Marchwica W, Dobosz T

PMID: 29031593 [PubMed - as supplied by publisher]

Type I interferon pathway activation in Copa syndrome.

Clin Immunol. 2017 Oct 10;:

Authors: Volpi S, Tsui J, Mariani M, Pastorino C, Caorsi R, Sacco O, Ravelli A, Shum AK, Gattorno M, Picco P

Abstract
Mutations of the COPA gene cause an immune dysregulatory disease characterised by polyarticular arthritis and progressive interstitial lung disease with pulmonary haemorrhages. We report the case of a young girl that presented at age 3 with polyarticular arthritis, chronic cough and high titer rheumatoid factor. Radiologic imaging showed interstitial lung disease with tree-in-a-bud nodules and air-filled cysts. Targeted genetic analysis of COPA gene showed the reported c.698G>A mutation. The patient was lost to follow up for 3years during which therapy was discontinued with the development of joint damage and deformities. Analysis of peripheral blood showed activation of type 1 interferon pathway, which was also confirmed in 4 previously reported COPA patients. Our observations underline the importance of early treatment in COPA disease to avoid loss of joint function. Furthermore, our results suggest a role for type 1 interferon in disease pathogenesis opening the possibility for targeted therapeutic approaches.

PMID: 29030294 [PubMed - as supplied by publisher]

Comparing the management of constipation and distal intestinal obstruction syndrome between paediatricians and adult physicians.

J Cyst Fibros. 2017 Oct 10;:

Authors: Green JA, Carroll WD, Gilchrist FJ

PMID: 29029973 [PubMed - as supplied by publisher]

Development and validation of an LC tandem MS assay for the quantification of β-lactam antibiotics in the sputum of cystic fibrosis patients.

J Antimicrob Chemother. 2017 Sep 27;:

Authors: Forier K, Van Heck V, Carlier M, Van Braeckel E, Van Daele S, De Baets F, Schelstraete P, Haerynck F, Stove V, Van Simaey L, Vaneechoutte M, Verstraete AG

Abstract
Objectives: Antibiotic therapy is of vital importance for the control of infectious exacerbations in cystic fibrosis (CF) patients. However, very little is known regarding the fraction of systemically administered antibiotics reaching the lower respiratory tract secretions. We developed and validated a method to measure the concentrations of piperacillin, ceftazidime, meropenem and aztreonam in CF sputum, and present the validation data.
Methods: Ultra-performance LC coupled to tandem MS was used. A single sample can be measured in 2.5 min with multiple reaction monitoring in positive electrospray ionization mode. Deuterated internal standards were used and a concentration range of 0.7-160 mg/L was covered. The method was validated according to the EMA guideline on analytical method validation.
Results: The boundaries within which a reliable measurement in CF sputum can be performed were determined. A few constraints are linked to the instability of the antibiotics in sputum. Piperacillin showed limited stability at room temperature and during freeze-thaw cycles. Autosampler instability was observed after 15 h for aztreonam at low concentrations.
Conclusions: The method allows a reliable measurement of the selected antibiotics, if precautions are taken regarding the limited stability of piperacillin at room temperature. Due to freeze-thaw instability, piperacillin should always be analysed on the day of sampling. Quick review of the analytical data and reanalysis are needed as low concentrations of aztreonam are not stable in the autosampler.

PMID: 29029070 [PubMed - as supplied by publisher]

Patient-specific modelling of regional tobramycin concentration levels in airways of patients with cystic fibrosis: can we dose once daily?

J Antimicrob Chemother. 2017 Sep 23;:

Authors: Bos AC, Mouton JW, van Westreenen M, Andrinopoulou ER, Janssens HM, Tiddens HAWM

Abstract
Background: Inhaled tobramycin is important in the treatment of Pseudomonas aeruginosa ( Pa ) infections in cystic fibrosis (CF). However, despite its use it fails to attenuate the clinical progression of CF lung disease. The bactericidal efficacy of tobramycin is known to be concentration-dependent and hence changing the dosing regimen from a twice-daily (q12h) inhalation to a once-daily (q24h) inhaled double dose could improve treatment outcomes.
Objectives: To predict local concentrations of nebulized tobramycin in the airways of patients with CF, delivered with the small airway-targeting Akita ® system or standard PARI-LC ® Plus system, with different inspiratory flow profiles.
Methods: Computational fluid dynamic (CFD) methods were applied to patient-specific airway models reconstructed from chest CT scans. The following q12h and q24h dosing regimens were evaluated: Akita ® (150 and 300 mg) and PARI-LC ® Plus (300 and 600 mg). Site-specific concentrations were calculated.
Results: Twelve CT scans from patients aged 12-17 years (median = 15.7) were selected. Small airway concentrations were 762-2999 mg/L for the q12h dosing regimen and 1523-5997 mg/L for the q24h dosing regimen, well above the MIC for WT Pa strains. Importantly, the q24h regimen appeared to be more suitable than the q12h regimen against more resistant Pa strains and the inhibitory effects of sputum on tobramycin activity.
Conclusions: CFD modelling showed that high concentrations of inhaled tobramycin are indeed delivered to the airways, with the Akita ® system being twice as efficient as the PARI-LC ® system. Ultimately, the q24h dosing regimen appears more effective against subpopulations with high MICs (i.e. more resistant strains).

PMID: 29029057 [PubMed - as supplied by publisher]

Not All Children with Cystic Fibrosis Have Abnormal Esophageal Neutralization during Chemical Clearance of Acid Reflux.

Pediatr Gastroenterol Hepatol Nutr. 2017 Sep;20(3):153-159

Authors: Woodley FW, Moore-Clingenpeel M, Machado RS, Nemastil CJ, Jadcherla SR, Hayes D, Kopp BT, Kaul A, Di Lorenzo C, Mousa H

Abstract
PURPOSE: Acid neutralization during chemical clearance is significantly prolonged in children with cystic fibrosis, compared to symptomatic children without cystic fibrosis. The absence of available reference values impeded identification of abnormal findings within individual patients with and without cystic fibrosis. The present study aimed to test the hypothesis that significantly more children with cystic fibrosis have acid neutralization durations during chemical clearance that fall outside the physiological range.
METHODS: Published reference value for acid neutralization duration during chemical clearance (determined using combined impedance/pH monitoring) was used to assess esophageal acid neutralization efficiency during chemical clearance in 16 children with cystic fibrosis (3 to <18 years) and 16 age-matched children without cystic fibrosis.
RESULTS: Duration of acid neutralization during chemical clearance exceeded the upper end of the physiological range in 9 of 16 (56.3%) children with and in 3 of 16 (18.8%) children without cystic fibrosis (p=0.0412). The likelihood ratio for duration indicated that children with cystic fibrosis are 2.1-times more likely to have abnormal acid neutralization during chemical clearance, and children with abnormal acid neutralization during chemical clearance are 1.5-times more likely to have cystic fibrosis.
CONCLUSION: Significantly more (but not all) children with cystic fibrosis have abnormally prolonged esophageal clearance of acid. Children with cystic fibrosis are more likely to have abnormal acid neutralization during chemical clearance. Additional studies involving larger sample sizes are needed to address the importance of genotype, esophageal motility, composition and volume of saliva, and gastric acidity on acid neutralization efficiency in cystic fibrosis children.

PMID: 29026731 [PubMed]

Cystic fibrosis and Silver-Russell syndrome due to a partial maternal isodisomy of chromosome 7.

Clin Case Rep. 2017 Oct;5(10):1697-1700

Authors: Gerbrands LC, Haarman EG, Hankel MA, Finken MJJ

Abstract
If an infant with cystic fibrosis exhibits failure to thrive, despite adequate disease management, Silver-Russell syndrome should be considered, given the locations of these conditions in the genome. However, an earlier clue to the diagnosis is small-for-gestational-age birth.

PMID: 29026575 [PubMed]

False-Positive Newborn Screening for Cystic Fibrosis and Health Care Use.

Pediatrics. 2017 Oct 12;:

Authors: Hayeems RZ, Miller FA, Vermeulen M, Potter BK, Chakraborty P, Davies C, Carroll JC, Ratjen F, Guttmann A

Abstract
OBJECTIVES: Evidence is mixed regarding the impact of false-positive (FP) newborn bloodspot screening (NBS) results on health care use. Using cystic fibrosis (CF) as an example, we determined the association of FP NBS results with health care use in infants and their mothers in Ontario, Canada.
METHODS: We conducted a population-based cohort study of all infants with FP CF results (N = 1564) and screen-negative matched controls (N = 6256) born between April 2008 and November 2012 using linked health administrative data. Outcomes included maternal and infant physician and emergency visits and inpatient hospitalizations from the infant's third to 15th month of age. Negative binomial regression tested associations of NBS status with outcomes, adjusting for infant and maternal characteristics.
RESULTS: A greater proportion of infants with FP results had >2 outpatient visits (16.2% vs 13.2%) and >2 hospital admissions (1.5% vs 0.7%) compared with controls; CF-related admissions and emergency department visits were not different from controls. Differences persisted after adjustment, with higher rates of outpatient visits (relative risk 1.39; 95% confidence interval 1.20-1.60) and hospital admissions (relative risk 1.67; 95% confidence interval 1.21-2.31) for FP infants. Stratified models indicated the effect of FP status was greater among those whose primary care provider was a pediatrician. No differences in health care use among mothers were detected.
CONCLUSIONS: Higher use of outpatient services among FP infants may relate to a lengthy confirmatory testing process or follow-up carrier testing. However, increased rates of hospitalization might signal heightened perceptions of vulnerability among healthy infants.

PMID: 29025964 [PubMed - as supplied by publisher]

Neutrophil elastase increases airway ceramide levels via upregulation of serine palmitoyltransferase.

Am J Physiol Lung Cell Mol Physiol. 2017 Oct 12;:ajplung.00322.2017

Authors: Karandashova S, Kummarapurugu AB, Zheng S, Chalfant C, Voynow JA

Abstract
Altered sphingolipid metabolism is associated with increased inflammation; however, the impact of inflammatory mediators, including neutrophil elastase (NE), on airway sphingolipid homeostasis remains unknown. Using a well-characterized mouse model of NE oropharyngeal aspiration, we investigated a potential link between NE-induced airway inflammation and increased synthesis of various classes of sphingolipids, including ceramide species. Sphingolipids in bronchoalveolar lavage fluids (BAL) were identified and quantified using reverse phase high-performance liquid chromatography/electrospray ionization tandem mass spectrometry analysis. BAL total and differential cell counts, CXCL1/keratinocyte chemoattractant (KC) protein levels, and high mobility group box 1 (HMGB1) protein levels were determined. NE exposure increased BAL long chain ceramides, total cell and neutrophil counts, and upregulated KC and HMGB1. The mRNA and protein levels of serine palmitoyltransferase (SPT) long chain subunits 1 and 2, the multimeric enzyme responsible for the first, rate-limiting step of de novo ceramide generation, were determined by Q/RT-PCR and western analyses, respectively. NE increased lung SPT long chain subunit 2 (SPTLC2) protein levels but not SPTLC1, and had no effect on mRNA for either subunit. To assess whether de novo ceramide synthesis was required for NE-induced inflammation, myriocin, a SPT inhibitor, or a vehicle control was administered intraperitoneally 2h prior to NE administration. Myriocin decreased BAL d18:1/22:0 and d18:1/24:1 ceramide, KC and HMGB1 induced by NE exposure. These results support a feed-forward cycle of NE-generated ceramide and ceramide-driven cytokine signaling that may be a potential target for intervention in lung disease typified by chronic neutrophilic inflammation.

PMID: 29025713 [PubMed - as supplied by publisher]

Understanding Treatment Adherence With the Health Belief Model in Children With Cystic Fibrosis.

Health Educ Behav. 2017 Oct 01;:1090198117736346

Authors: Dempster NR, Wildman BG, Masterson TL, Omlor GJ

Abstract
OBJECTIVE: Children's health beliefs are significantly related to their adherence; however, pediatric literature has rarely tested health-related theories as a whole. The goal of the present study was to evaluate the use of the health belief model (HBM) in understanding children's adherence, both globally and to individual treatment components.
METHOD: Thirty-three patient-parent dyads completed questionnaires regarding health beliefs and adherence to medical regimens.
RESULTS: Multiple linear regressions found a significant relationship among the HBM variables and reports of global adherence for children and parents. For children, the HBM variables were significantly related to adherence to aerosol medications, aerosol antibiotics, metered dose inhalers, and vitamins. For parents, the HBM variables were significantly related to children's adherence to airway clearance, oral antibiotics, and vitamins. Paired sample t tests found children and parents had significantly discrepant heath beliefs.
CONCLUSION: These findings provide further support for the HBM in evaluating pediatric adherence, with evidence that barriers and cues to action may be targets for early intervention. Future research using this model to identify a comprehensive way to assess, understand, and elicit change in the adherence to medical regimens for youth with chronic illness would be beneficial.

PMID: 29025281 [PubMed - as supplied by publisher]