Novel bioinformatics quality control metric for next-generation sequencing experiments in the clinical context.

Nucleic Acids Res. 2019 12 02;47(21):e135

Authors: Ivanov M, Ivanov M, Kasianov A, Rozhavskaya E, Musienko S, Baranova A, Mileyko V

Abstract
As the use of next-generation sequencing (NGS) for the Mendelian diseases diagnosis is expanding, the performance of this method has to be improved in order to achieve higher quality. Typically, performance measures are considered to be designed in the context of each application and, therefore, account for a spectrum of clinically relevant variants. We present EphaGen, a new computational methodology for bioinformatics quality control (QC). Given a single NGS dataset in BAM format and a pre-compiled VCF-file of targeted clinically relevant variants it associates this dataset with a single arbiter parameter. Intrinsically, EphaGen estimates the probability to miss any variant from the defined spectrum within a particular NGS dataset. Such performance measure virtually resembles the diagnostic sensitivity of given NGS dataset. Here we present case studies of the use of EphaGen in context of BRCA1/2 and CFTR sequencing in a series of 14 runs across 43 blood samples and 504 publically available NGS datasets. EphaGen is superior to conventional bioinformatics metrics such as coverage depth and coverage uniformity. We recommend using this software as a QC step in NGS studies in the clinical context. Availability: https://github.com/m4merg/EphaGen or https://hub.docker.com/r/m4merg/ephagen.

PMID: 31511888 [PubMed - indexed for MEDLINE]

Intestinal epithelial potassium channels and CFTR chloride channels activated in ErbB tyrosine kinase inhibitor diarrhea.

JCI Insight. 2019 02 21;4(4):

Authors: Duan T, Cil O, Thiagarajah JR, Verkman AS

Abstract
Diarrhea is a major side effect of ErbB receptor tyrosine kinase inhibitors (TKIs) in cancer chemotherapy. Here, we show that the primary mechanism of ErbB TKI diarrhea is activation of basolateral membrane potassium (K+) channels and apical membrane chloride (Cl-) channels in intestinal epithelia and demonstrate the efficacy of channel blockers in a rat model of TKI diarrhea. Short-circuit current in colonic epithelial cells showed that the TKIs gefitinib, lapatinib, and afatinib do not affect basal secretion but amplify carbachol-stimulated secretion by 2- to 3-fold. Mechanistic studies with the second-generation TKI afatinib showed that the amplifying effect on Cl- secretion was Ca2+ and cAMP independent, was blocked by CF transmembrane conductance regulator (CFTR) and K+ channel inhibitors, and involved EGFR binding and ERK signaling. Afatinib-amplified activation of basolateral K+ and apical Cl- channels was demonstrated by selective membrane permeabilization, ion substitution, and channel inhibitors. Rats that were administered afatinib orally at 60 mg/kg/day developed diarrhea with increased stool water from approximately 60% to greater than 80%, which was reduced by up to 75% by the K+ channel inhibitors clotrimazole or senicapoc or the CFTR inhibitor (R)-BPO-27. These results indicate a mechanism for TKI diarrhea involving K+ and Cl- channel activation and support the therapeutic efficacy of channel inhibitors.

PMID: 30668547 [PubMed - indexed for MEDLINE]

Effectiveness and Safety of Omalizumab in Patients with Allergic Bronchopulmonary Aspergillosis Complicated by Chronic Bacterial Infection in the Airways.

Int Arch Allergy Immunol. 2020 May 08;:1-8

Authors: Tomomatsu K, Oguma T, Baba T, Toyoshima M, Komase Y, Taniguchi M, Asano K, and the Japan ABPM Research Program

Abstract
BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) develops in the presence of predisposing conditions such as asthma and cystic fibrosis. Even ABPA accompanied by asthma is often complicated by chronic Pseudomonas aeruginosa or nontuberculous mycobacterial infection of the lower respiratory tract, rendering treatment with corticosteroids difficult. There have been several reports on the effectiveness of omalizumab, an anti-IgE antibody, in patients with ABPA. We analyzed the effectiveness and adverse effects of omalizumab in ABPA patients with chronic respiratory infections.
METHODS: Using our nationwide survey database and published case reports, we identified patients with severe asthma and ABPA who fulfilled the International Society for Human and Animal Mycology criteria and who had been treated with omalizumab. Exacerbation rates, control of symptoms, doses of oral corticosteroids, and pulmonary function were evaluated.
RESULTS: Among 25 patients with ABPA treated with omalizumab (median age 62 years, range 33-83 years), 12 patients had a chronic bacterial infection of the lower airways attributable to P. aeruginosa (n = 6) or nontuberculous mycobacteria (n = 6) at the initiation of omaliz-umab. Treatment with omalizumab reduced the frequency of exacerbations and systemic corticosteroid doses and improved pulmonary function. There were no significant adverse events or worsening of infection during treatment with omalizumab, except for injection-site reactions.
CONCLUSIONS: Treatment with omalizumab was effective and safe in patients with ABPA, regardless of comorbid chronic respiratory tract infections.

PMID: 32388510 [PubMed - as supplied by publisher]

Imaging of genetically-mediated pancreatitis.

Clin Imaging. 2020 Apr 18;65:113-118

Authors: O'Brien CM, O'Brien AC, Gleeson L, Conlon K, Feeney J, Malone DE

Abstract
OBJECTIVES: To review the imaging of patients with Genetically-Mediated Pancreatitis (GMP), identify common imaging findings in this cohort and assess phenotypical characteristics of specific genotypes.
MATERIALS AND METHODS: Retrospective review of the databases of the Irish National Surgical Centre for Pancreatic Cancer (NSCPC) and Cystic Fibrosis (CF) from November 2010 to January 2018. Retrospective imaging and chart review for the patients with positive genetics for GMP.
RESULTS: The NSCPC database contained 699 patients; the CF database included 352 patients. Of these 1051, 14 were identified as having GMP (age range: 20-65, M:F ratio of 1:1). 14 of 1051 patients from the database had positive genetics for GMP. 10 had imaging to support a diagnosis of hereditary pancreatitis or familial recurrent pancreatitis (1.3%) and 4 had imaging to support a diagnosis of CF-related pancreatitis. Imaging findings were considered in 3 categories, determined by genotype - PRSS1 hereditary pancreatitis, SPINK 1 autosomal recessive pancreatitis and those for CFTR - cystic fibrosis related pancreatitis. Imaging findings in PRSS1 hereditary pancreatitis patients included: pancreatic atrophy, calcification and main pancreatic duct (MPD) dilatation, referred to as the PRSS1 imaging triad. Patients with the SPINK1 gene mutation had less severe imaging manifestations (pancreatic atrophy 33%, MPD dilatation 33%, pancreatic calcification 33%). CFTR patients with imaging findings had pancreatic atrophy (100%).
CONCLUSION: GMP should be suspected when the features of 'chronic pancreatitis' are seen in young adults with no history of excess alcohol intake. Genetic testing, endocrinology review and long-term imaging follow-up for pancreatic carcinoma are indicated.

PMID: 32387800 [PubMed - as supplied by publisher]

Can lumacaftor-ivacaftor reverse glucose-tolerance abnormalities in cystic fibrosis?

J Cyst Fibros. 2020 May 05;:

Authors: Kessler L

PMID: 32387043 [PubMed - as supplied by publisher]

Anti-inflammatory effects of lenabasum, a cannabinoid receptor type 2 agonist, on macrophages from cystic fibrosis.

J Cyst Fibros. 2020 May 05;:

Authors: Tarique AA, Evron T, Zhang G, Tepper MA, Morshed MM, Andersen ISG, Begum N, Sly PD, Fantino E

Abstract
BACKGROUND: Lenabasum is an oral synthetic cannabinoid receptor type 2 agonist previously shown to reduce the production of key airway pro-inflammatory cytokines known to play a role in cystic fibrosis (CF). In a double-blinded, randomized, placebo-control phase 2 study, lenabasum lowered the rate of pulmonary exacerbation among patients with CF. The present study was undertaken to investigate anti-inflammatory mechanisms of lenabasum exhibits in CF macrophages.
METHODS: We used monocyte-derived macrophages (MDMs) from healthy donors (n = 15), MDMs with CFTR inhibited with C-172 (n = 5) and MDMs from patients with CF (n = 4). Monocytes were differentiated to macrophages and polarized into classically activated (M1) macrophages by LPS or alternatively activated (M2) macrophages by IL-13 in presence or absence of lenabasum.
RESULTS: Lenabasum had no effect on differentiation, polarization and function of macrophages from healthy individuals. However, in CF macrophages lenabasum downregulated macrophage polarization into the pro-inflammatory M1 phenotype and secretion of the pro-inflammatory cytokines IL-8 and TNF-α in a dose-dependent manner. An improvement in phagocytic activity was also observed following lenabasum treatment. Although lenabasum did not restore the impaired polarization of anti-inflammatory M2 macrophage, it reduced the levels of IL-13 and enhanced the endocytic function of CF MDMs. The effects of lenabasum on MDMs with CFTR inhibited by C-172 were not as obvious.
CONCLUSION: In CF macrophages lenabasum modulates macrophage polarization and function in vitro in a way that would reduce inflammation in vivo. Further studies are warranted to determine the link between activating the CBR2 receptor and CFTR.

PMID: 32387042 [PubMed - as supplied by publisher]

Restoration of exocrine pancreatic function in older children with cystic fibrosis on ivacaftor.

Paediatr Respir Rev. 2020 Apr 14;:

Authors: Nichols AL, Davies JC, Jones D, Carr SB

Abstract
Prior to the use of cystic fibrosis (CF) modulator therapy, exocrine pancreatic insufficiency in CF was thought to be irreversible. Improvement in pancreatic function on ivacaftor has been reported in open label studies in 1-5 year olds. The mechanism by which ivacaftor might improve exocrine pancreatic function is unclear. Although the effect of ivacaftor on pancreatic function may be more significant in younger children, evidence is mounting that there may still be potential for improvement in older children on long term therapy.

PMID: 32386958 [PubMed - as supplied by publisher]

Experience with Parent Follow-Up for Communication Outcomes after Newborn Screening Identifies Carrier Status.

J Pediatr. 2020 May 06;:

Authors: Farrell MH, La Pean Kirschner A, Tluczek A, Farrell PM

Abstract
OBJECTIVE: To conduct interviews with a multiyear sample of parents of infants found to have heterozygous status for sickle cell hemoglobinopathy or cystic fibrosis during newborn blood screening (NBS).
STUDY DESIGN: Interviewers with clinical backgrounds telephoned parents, and followed a structured script that blended follow-up and research purposes. Recruiting followed several steps to minimize recruiting bias as much as possible for a NBS study.
RESULTS: Follow-up calls were conducted with parents of 426 infant carriers of sickle cell hemoglobinopathy, and 288 parents of cystic fibrosis carriers (34.8% and 49.6% of those eligible). Among these, 27.5% and 7.8% had no recollection of being informed of NBS results. Of those who recalled a provider explanation, 8.6% and 13.0% appraised the explanation negatively. Overall, 7.4% and 13.2% were dissatisfied with the experience of learning about the NSB result. Mean anxiety levels were low but higher in the sickle cell hemoglobinopathy group (P < .001). Misconceptions that the infant might get the disease were present in 27.5% and 7.8% of parents (despite zero actual risk for disease). Several of these data were significantly predicted by NBS result, health literacy, parental age, and race/ethnicity factors.
CONCLUSIONS: Patient-centered public health follow-up can be effective after NBS identifies carrier status. Psychosocial complications were uncommon, but harms were substantial enough to justify mitigation.

PMID: 32386871 [PubMed - as supplied by publisher]

Cystic Fibrosis Transmembrane Conductance Regulator-dependent bicarbonate entry controls rat cardiomyocyte ATP release via pannexin1 through mitochondrial signalling and caspase activation.

Acta Physiol (Oxf). 2020 May 09;:

Authors: Wang Y, Zhao J, Cai Y, Ballard HJ

Abstract
AIM: Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in the heart, but its function there is unclear. CFTR regulates an ATP release pore in many tissues, but the identity and regulatory mechanism of the pore are unknown. We investigated the role of CFTR in ATP release from primary cardiomyocytes and ventricular wall in vivo.
METHODS: Proteins involved in the signaling pathway for ATP release during simulated ischaemia (lactic acid treatment) were investigated using inhibitors and siRNA; colocalization was identified by coimmunofluorescence and proximity ligation assays; changes in near-membrane pH and calcium were identified with total internal reflection microscopy; in vivo ATP release was investigated using interstitial microdialysis of rat heart.
RESULTS: Lactic acid induced CFTR-dependent ATP release from cultured cardiomyocytes and left ventricle in vivo. Lactic acid entry elevated near-membrane calcium, which involved Na/H- and Na/Ca-exchangers colocalized with CFTR. Calcium entry induced CFTR activation, which involved cAMP, PKA, FAK, Pyk2 and Src. Removal of extracellular bicarbonate abolished cardiomyocyte ATP release induced by lactic acid or CFTR activators. Bicarbonate stimulated cytochrome c expression, cytochrome c release and ATP release from isolated cardiomyocyte mitochondria. Pannexin 1 (Panx1) colocalized with CFTR. Lactic acid increased cardiomyocyte caspase activity: caspase inhibitors or Panx1 siRNA abolished cardiomyocyte ATP release, while pannexin inhibition abolished cardiac ATP release in vivo.
CONCLUSION: During simulated ischaemia, CFTR-dependent bicarbonate entry stimulated ATP and cytochrome c release from mitochondria; in the cytoplasm, cytochrome c activated caspase 3, which in turn activated Panx1, and ATP was released through the opened Panx1 channel.

PMID: 32386453 [PubMed - as supplied by publisher]

Antibiofilm activity of antifungal drugs, including the novel drug olorofim, against Lomentospora prolificans.

J Antimicrob Chemother. 2020 May 09;:

Authors: Kirchhoff L, Dittmer S, Weisner AK, Buer J, Rath PM, Steinmann J

Abstract
OBJECTIVES: Patients with immunodeficiency or cystic fibrosis frequently suffer from respiratory fungal infections. In particular, biofilm-associated fungi cause refractory infection manifestations, linked to increased resistance to anti-infective agents. One emerging filamentous fungus is Lomentospora prolificans. Here, the biofilm-formation capabilities of L. prolificans isolates were investigated and the susceptibility of biofilms to various antifungal agents was analysed.
METHODS: Biofilm formation of L. prolificans (n = 11) was estimated by crystal violet stain and antibiofilm activity was additionally determined via detection of metabolically active biofilm using an XTT assay. Amphotericin B, micafungin, voriconazole and olorofim were compared with regard to their antibiofilm effects when added prior to adhesion, after adhesion and on mature and preformed fungal biofilms. Imaging via confocal laser scanning microscopy was carried out to demonstrate the effect of drug treatment on the fungal biofilm.
RESULTS: Antibiofilm activities of the tested antifungal agents were shown to be most effective on adherent cells whilst mature biofilm was the most resistant. The most promising antibiofilm effects were detected with voriconazole and olorofim. Olorofim showed an average minimum biofilm eradication concentration (MBEC) of 0.06 mg/L, when added prior to and after adhesion. The MBECs of voriconazole were ≤4 mg/L. On mature biofilm the MBECs of olorofim and voriconazole were higher than the previously determined MICs against planktonic cultures. In contrast, amphotericin B and especially micafungin did not exhibit sufficient antibiofilm activity against L. prolificans.
CONCLUSIONS: To our knowledge, this is the first study demonstrating the antibiofilm potential of olorofim against the human pathogenic fungus L. prolificans.

PMID: 32386411 [PubMed - as supplied by publisher]

Genetic potential and height velocity during childhood and adolescence do not fully account for shorter stature in cystic fibrosis.

Pediatr Res. 2020 May 09;:

Authors: Zysman-Colman ZN, Kilberg MJ, Harrison VS, Chesi A, Grant SFA, Mitchell J, Sheikh S, Hadjiliadis D, Rickels MR, Rubenstein RC, Kelly A

Abstract
BACKGROUND: Despite improved health, shorter stature is common in cystic fibrosis (CF). We aimed to describe height velocity (HV) and contribution of height-related genetic variants to height (HT) in CF.
METHODS: HV cohort: standard deviation scores (-Z) for HT, mid-parental height-adjusted HT (MPAH), and HV were generated using our Pediatric Center's CF Foundation registry data. HV-Z was compared with population means at each age (5-17 y), the relationship of HV-Z with HT-Z assessed, and HT-Z compared with MPAH-Z. GRS cohort: HT genetic risk-Z (HT-GRS-Z) were determined for pancreatic exocrine sufficient (PS) and insufficient (PI) youth and adults from our CF center and their relationships with HT-Z assessed.
RESULTS: HV cohort: average HV-Z was normal across ages in our cohort but was 1.5× lower (p < 0.01) for each SD decrease in HT-Z. MPAH-Z was lower than HT-Z (p < 0.001). GRS cohort: HT-GRS-Z more strongly correlated with HT-Z and better explained height variance in PS (rho = 0.42; R2= 0.25) vs. PI (rho = 0.27; R2 = 0.11).
CONCLUSIONS: Despite shorter stature compared with peers and mid-parental height, youth with CF generally have normal linear growth in mid- and late childhood. PI tempered the heritability of height. These results suggest that, in CF, final height is determined early in life in CF and genetic potential is attenuated by other factors.
THIS MANUSCRIPT IS A CLINICAL STUDY: Children with CF remain shorter than their healthy peers despite advances in care.Our study demonstrates that children with CF have persistent shorter stature from an early age and fail to reach their genetic potential despite height velocities comparable to those of average maturing healthy peers and similar enrichment in known height increasing single-nucleotide polymorphisms (SNPs).Genetic risk scores better explained variability in pancreatic sufficient than in pancreatic insufficient individuals, suggesting that other modifying factors are in play for pancreatic insufficient individuals with CF.Given the CF Foundation's recommendation to target not only normal body mass index, but normal height percentiles as well, this study adds valuable insight to this discussion.

PMID: 32386398 [PubMed - as supplied by publisher]

Structural Consequences of the 1,2,3-Triazole as an Amide Bioisostere in Analogs of Cystic Fibrosis Drugs VX-809 and VX-770.

ChemMedChem. 2020 May 08;:

Authors: Doiron JE, Le CA, Bacsa J, Breton GW, Martin KL, Aller SG, Turlington M

Abstract
While the 1,2,3-triazole is a commonly utilized amide bioisostere in medicinal chemistry, the structural implications of this replacement have not been fully studied. Employing X-ray crystallography and computational studies, we report the spatial and electronic consequences of replacing the amide with the triazole in analogs of cystic fibrosis drugs in the VX-770 and VX-809 series. Crystallographic analyses quantify subtle differences in the relative positions and conformational preferences of the R1 and R2 substituents attached to the amide and triazole bioisosteres. Computational studies derived from the X-ray data highlight the improved hydrogen bonding donor and acceptor capabilities of the amide in comparison to the triazole. This analysis of the spatial and electronic differences between the amide and 1,2,3-triazole will inform medicinal chemists as they consider utilizing the triazole as an amide bioisostere.

PMID: 32385907 [PubMed - as supplied by publisher]

Oral-lung microbiome interactions in lung diseases.

Periodontol 2000. 2020 Jun;83(1):234-241

Authors: Mammen MJ, Scannapieco FA, Sethi S

Abstract
The proximity and continuity of the oral cavity and the lower respiratory tract allows the oropharyngeal microbiome to be a major determinant of the lung microbiome. In addition, host-pathogen interactions related to the oropharyngeal microbiome or its metabolites could propagate systemic inflammation or modulate host defense mechanisms that could affect other organs, including the lung. There is increasing appreciation of the pathophysiologic significance of the lung microbiome, not only in the classical infection-related diseases, pneumonia, bronchiectasis, and cystic fibrosis, but also in chronic noninfectious lung diseases, such as chronic obstructive pulmonary disease, asthma, and pulmonary fibrosis. In this review, we will explore the relationship of the oral microbiome with lung diseases, such as pneumonia, chronic obstructive pulmonary disease, asthma, and cystic fibrosis.

PMID: 32385873 [PubMed - as supplied by publisher]

Bioorthogonal non-canonical amino acid tagging reveals translationally active subpopulations of the cystic fibrosis lung microbiota.

Nat Commun. 2020 May 08;11(1):2287

Authors: Valentini TD, Lucas SK, Binder KA, Cameron LC, Motl JA, Dunitz JM, Hunter RC

Abstract
Culture-independent studies of cystic fibrosis lung microbiota have provided few mechanistic insights into the polymicrobial basis of disease. Deciphering the specific contributions of individual taxa to CF pathogenesis requires comprehensive understanding of their ecophysiology at the site of infection. We hypothesize that only a subset of CF microbiota are translationally active and that these activities vary between subjects. Here, we apply bioorthogonal non-canonical amino acid tagging (BONCAT) to visualize and quantify bacterial translational activity in expectorated sputum. We report that the percentage of BONCAT-labeled (i.e. active) bacterial cells varies substantially between subjects (6-56%). We use fluorescence-activated cell sorting (FACS) and genomic sequencing to assign taxonomy to BONCAT-labeled cells. While many abundant taxa are indeed active, most bacterial species detected by conventional molecular profiling show a mixed population of both BONCAT-labeled and unlabeled cells, suggesting heterogeneous growth rates in sputum. Differentiating translationally active subpopulations adds to our evolving understanding of CF lung disease and may help guide antibiotic therapies targeting bacteria most likely to be susceptible.

PMID: 32385294 [PubMed - as supplied by publisher]

The Detection of Bile Acids in the Lungs of Paediatric Cystic Fibrosis Patients Is Associated with Altered Inflammatory Patterns.

Diagnostics (Basel). 2020 May 06;10(5):

Authors: Caparrós-Martín JA, Flynn S, Reen FJ, Woods DF, Agudelo-Romero P, Ranganathan SC, Stick SM, O'Gara F

Abstract
Background: Cystic fibrosis (CF) is a hereditary disorder in which persistent unresolved inflammation and recurrent airway infections play major roles in the initiation and progression of the disease. Little is known about triggering factors modulating the transition to chronic microbial infection and inflammation particularly in young children. Cystic fibrosis respiratory disease starts early in life, with the detection of inflammatory markers and infection evident even before respiratory symptoms arise. Thus, identifying factors that dysregulate immune responsiveness at the earliest stages of the disease will provide novel targets for early therapeutic intervention. Methods: We evaluated the clinical significance of bile acid detection in the bronchoalveolar lavage fluid of clinically stable preschool-aged children diagnosed with CF. Results: We applied an unbiased classification strategy to categorize these specimens based on bile acid profiles. We provide clear associations linking the presence of bile acids in the lungs with alterations in the expression of inflammatory markers. Using multiple regression analysis, we also demonstrate that clustering based on bile acid profiles is a meaningful predictor of the progression of structural lung disease. Conclusions: Altogether, our work has identified a clinically relevant host-derived factor that may participate in shaping early events in the aetiology of CF respiratory disease.

PMID: 32384684 [PubMed - as supplied by publisher]

Palliative care skills in CF: Perspectives of adults with CF, caregivers, and CF care team members.

Pediatr Pulmonol. 2020 May 08;:

Authors: Trandel ET, Kavalieratos D, Basile M, Hobler MR, Georgiopoulos AM, Chen E, Goggin JL, Goss CH, Hempstead SE, Faro A, Dellon EP

Abstract
BACKGROUND: The role of cystic fibrosis (CF) care team members in delivering palliative care (PC) remains undefined. We aimed to understand the PC skills of CF care teams.
METHODS: CF care team members ("clinicians"), adults with CF ("patients"), and family caregivers ("caregivers") rated the ability of CF clinicians to provide aspects of PC using a five-point scale ("poor" to "excellent"). Median ratings were compared between groups.
RESULTS: A total of 70 patients, 100 caregivers, and 350 clinicians participated. Clinicians consistently rated their PC skills higher than patients or caregivers rated them, particularly for advanced PC skills. While clinicians, patients, and caregivers rated clinicians as "very good" at basic pain assessment and "good" at discussing prognostic uncertainty, clinicians rated themselves more highly at providing most skills, including simultaneous PC and standard CF care (P < .0001), basic depression assessment (P < .001), and discussing transplant, advance directives, end of life, code status, and hospice (all P < .0001). Respondents affiliated with adult CF care teams rated clinicians more highly than respondents affiliated with pediatric CF care teams at discussing lung transplant (P < .001), end of life (P = .006), advance directives (P < .001), code status (P = .012), and hospice (P = .016). Most patients (69%) and caregivers (60%) felt CF clinicians should receive more PC training.
CONCLUSIONS: Discrepancies exist among patient/caregiver and clinician perceptions of PC skills in CF, and skills of adult and pediatric teams may differ. Patients and caregivers feel clinicians' more advanced PC skills are lacking. CF clinicians may benefit from PC training to enhance skills and to understand how and when to utilize specialty PC services.

PMID: 32384215 [PubMed - as supplied by publisher]

Improved residual fat malabsorption and growth in children with cystic fibrosis treated with a novel oral structured lipid supplement: A randomized controlled trial.

PLoS One. 2020;15(5):e0232685

Authors: Stallings VA, Tindall AM, Mascarenhas MR, Maqbool A, Schall JI

Abstract
BACKGROUND: In the primary analysis of a 12-month double-blind randomized active placebo-controlled trial, treatment of children with cystic fibrosis (CF) and pancreatic insufficiency (PI) with a readily absorbable structured lipid (Encala™, Envara Health, Wayne, PA) was safe, well-tolerated and improved dietary fat absorption (stool coefficient of fat absorption [CFA]), growth, and plasma fatty acids (FA).
OBJECTIVE: To determine if the Encala™ treatment effect varied by severity of baseline fat malabsorption.
METHODS: Subjects (n = 66, 10.5±3.0 yrs, 39% female) with baseline CFA who completed a three-month treatment with Encala™ or a calorie and macronutrient-matched placebo were included in this subgroup analysis. Subjects were categorized by median baseline CFA: low CFA (<88%) and high CFA (≥88%). At baseline and 3-month evaluations, CFA (72-hour stool, weighed food record) and height (HAZ), weight (WAZ) and BMI (BMIZ) Z-scores were calculated. Fasting plasma fatty acid (FA) concentrations were also measured.
RESULTS: Subjects in the low CFA subgroup had significantly improved CFA (+7.5±7.2%, mean 86.3±6.7, p = 0.002), and reduced stool fat loss (-5.7±7.2 g/24 hours) following three months of EncalaTM treatment. These subjects also had increased plasma linoleic acid (+20%), α-linolenic acid (+56%), and total FA (+20%) (p≤0.005 for all) concentrations and improvements in HAZ (0.06±0.08), WAZ (0.17±0.16), and BMIZ (0.20±0.25) (p≤0.002 for all). CFA and FA were unchanged with placebo in the low CFA group, with some WAZ increases (0.14±0.24, p = 0.02). High CFA subjects (both placebo and Encala™ groups) had improvements in WAZ and some FA.
CONCLUSIONS: Subjects with CF, PI and more severe fat malabsorption experienced greater improvements in CFA, FA and growth after three months of Encala™ treatment. Encala™ was safe, well-tolerated and efficacious in patients with CF and PI with residual fat malabsorption and improved dietary energy absorption, weight gain and FA status in this at-risk group.

PMID: 32384122 [PubMed - as supplied by publisher]

Introduction to Cystic Fibrosis for Mental Health Care Coordinators and Providers: Collaborating to Promote Wellness.

Health Soc Work. 2020 May 08;:

Authors: Mueller AE, Georgiopoulos AM, Reno KL, Roach CM, Kvam CM, Quittner AL, Lomas P, Smith BA, Filigno SS

Abstract
To maximize health, individuals with cystic fibrosis (CF) follow a complex, burdensome daily care regimen. Managing CF is associated with a range of significant biopsychosocial challenges and places individuals with CF, and their caregivers, at greater risk for developing anxiety and depression. To promote wellness and address the potential barriers that affect management of this complex chronic illness, many individuals would benefit from treatment from a behavioral health provider. Social workers within multidisciplinary CF care teams are well positioned to respond to this need, and an expanding number of social workers serving as behavioral health providers in the community will be sought as a resource to provide treatment to this population. This article serves as a primer for social workers to maximize knowledge of the psychosocial and potential behavioral health needs of individuals with CF across the life span. To best support individuals with CF, authors describe the disease-specific manifestations and outline the numerous potential clinical targets for social work to promote wellness. The article concludes by highlighting the importance of communication with the medical team and considerations for effective collaborative care.

PMID: 32382728 [PubMed - as supplied by publisher]

ICER releases evidence report on elexacaftor/tezacaftor/ivacaftor for cystic fibrosis.

PharmacoEcon Outcomes News. 2020;852(1):3

Authors:

PMID: 32382247 [PubMed]

Average rate of lung function decline in adults with cystic fibrosis in the United Kingdom: Data from the UK CF registry.

J Cyst Fibros. 2020 May 04;:

Authors: Caley L, Smith L, White H, Peckham DG

Abstract
BACKGROUND: Rate of change in lung function is used as a measure of disease progression and a predictor of mortality in individuals with cystic fibrosis (CF). The aim of this study was to determine the national rate of decline in percent predicted Forced Expiratory Volume in 1 second (ppFEV1) in adults in the UK accounting for age, sex and pancreatic status.
METHODS: Data on ppFEV1 for adults with CF, excluding those post lung transplantation, was extracted from the UK CF registry between 2015 and 2017. Multilevel modelling was conducted to calculate the annual rate of change in ppFEV1 accounting for age, sex and pancreatic status.
RESULTS: Overall annual ppFEV1 decline was -1.52% (95% CI: -1.66 to -1.38%) and -0.55% (95% CI: -0.86 to -0.23%) in pancreatic insufficient (PI) and sufficient (PS) adults respectively. In PI individuals, females had a greater rate of decline in ppFEV1. There were differences between age groups. The fastest rate of decline was observed in the 18-28 years group, declining -1.76% (95% CI: -2.06 to -1.46) and -1.61% (95% CI: -1.91 to -1.31) per year in PI females and males respectively. The pattern between the sexes and age categories was more inconsistent in the PS group.
CONCLUSIONS: The average annual rates of decline in lung function in adults with CF in the UK are similar to reports from other large international cohorts. Pancreatic status has a marked impact on average rate of decline. Younger adults, especially females, have a faster rate of decline and need close monitoring.

PMID: 32381400 [PubMed - as supplied by publisher]