One-hit wonder: Late after burn injury, granulocytes can clear one bacterial infection but cannot control a subsequent infection.

Burns. 2019 Mar 01;:

Authors: Kartchner LB, Gode CJ, Dunn JLM, Glenn LI, Duncan DN, Wolfgang MC, Cairns BA, Maile R

Abstract
OBJECTIVE: Burn injury induces an acute hyperactive immune response followed by a chronic immune dysregulation that leaves those afflicted susceptible to multiple secondary infections. Many murine models are able to recapitulate the acute immune response to burn injury, yet few models are able to recapitulate long-term immune suppression and thus chronic susceptibility to bacterial infections seen in burn patients. This has hindered the field, making evaluation of the mechanisms responsible for these susceptibilities difficult to study. Herein we describe a novel mouse model of burn injury that promotes chronic immune suppression allowing for susceptibility to primary and secondary infections and thus allows for the evaluation of associated mechanisms.
METHODS: C57Bl/6 mice receiving a full-thickness contact burn were infected with Pseudomonas aeruginosa 14 days (primary infection) and/or 17 days (secondary infection) after burn or sham injury. The survival, pulmonary and systemic bacterial load as well as frequency and function of innate immune cells (neutrophils and macrophages) were evaluated.
RESULTS: Following secondary infection, burn mice were less effective in clearance of bacteria compared to sham injured or burn mice following a primary infection. Following secondary infection both neutrophils and macrophages recruited to the airways exhibited reduced production of anti-bacterial reactive oxygen and nitrogen species and the pro-inflammatory cytokineIL-12 while macrophages demonstrated increased expression of the anti-inflammatory cytokine interleukin-10 compared to those from sham burned mice and/or burn mice receiving a primary infection. In addition the BALF from these mice contained significantly higher level so of the anti-inflammatory cytokine IL-4 compared to those from sham burned mice and/or burn mice receiving a primary infection.
CONCLUSIONS: Burn-mediated protection from infection is transient, with a secondary infection inducing immune protection to collapse. Repeated infection leads to increased neutrophil and macrophage numbers in the lungs late after burn injury, with diminished innate immune cell function and an increased anti-inflammatory cytokine environment.

PMID: 30833100 [PubMed - as supplied by publisher]

Nanobody-based binding assay for the discovery of potent inhibitors of CFTR inhibitory factor (Cif).

Anal Chim Acta. 2019 May 30;1057:106-113

Authors: Vasylieva N, Kitamura S, Dong J, Barnych B, Hvorecny KL, Madden DR, Gee SJ, Wolan DW, Morisseau C, Hammock BD

Abstract
Lead identification and optimization are essential steps in the development of a new drug. It requires cost-effective, selective and sensitive chemical tools. Here, we report a novel method using nanobodies that allows the efficient screening for potent ligands. The method is illustrated with the cystic fibrosis transmembrane conductance regulator inhibitory factor (Cif), a virulence factor secreted by the opportunistic pathogen Pseudomonas aeruginosa. 18 nanobodies selective to Cif were isolated by bio-panning from nanobody-phage library constructed from immunized llama. 8 out of 18 nanobodies were identified as potent inhibitors of Cif enzymatic activity with IC50s in the range of 0.3-6.4 μM. A nanobody VHH219 showed high affinity (KD = 0.08 nM) to Cif and the highest inhibitory potency, IC50 = 0.3 μM. A displacement sandwich ELISA (dsELISA) with VHH219 was then developed for classification of synthetic small molecule inhibitors according their inhibitory potency. The developed assay allowed identification of new inhibitor with highest potency reported so far (0.16 ± 0.02 μM). The results from dsELISA assay correlates strongly with a conventional fluorogenic assay (R = 0.9998) in predicting the inhibitory potency of the tested compounds. However, the novel dsELISA is an order of magnitude more sensitive and allows the identification and ranking of potent inhibitors missed by the classic fluorogenic assay method. These data were supported with Octet biolayer interferometry measurements. The novel method described herein relies solely on the binding properties of the specific neutralizing nanobody, and thus is applicable to any pharmacological target for which such a nanobody can be found, independent of any requirement for catalytic activity.

PMID: 30832908 [PubMed - in process]

No benefit of longer eradication therapy of Pseudomonas aeruginosa primoinfections in pediatric cystic fibrosis.

BMC Res Notes. 2019 Mar 04;12(1):115

Authors: Claude F, Rochat I, Hafen GM

Abstract
OBJECTIVE: Patients with cystic fibrosis are more susceptible than members of the general population to lung infections. Infections with Pseudomonas aeruginosa require particular attention, because they may accelerate the deterioration of lung function if not adequately treated. This study assessed the eradication rate of P. aeruginosa primoinfections, with a protocol of inhaled tobramycin and oral ciprofloxacin over a 3 months' period.
RESULTS: Retrospective single-center study from June 1st, 2007 to December 31st, 2015. Inclusion of 28 pediatric patients (11 females, 17 males), with a total of 49 primoinfections. Overall success rate of 67.3%, which is similar or even inferior to figures published in the literature.

PMID: 30832714 [PubMed - in process]

Phylogenetic analysis of resistance to ceftazidime/avibactam, ceftolozane/tazobactam and carbapenems in piperacillin/tazobactam-resistant Pseudomonas aeruginosa from cystic fibrosis patients.

Int J Antimicrob Agents. 2019 Mar 01;:

Authors: Zamudio R, Hijazi K, Joshi C, Aitken E, Oggioni MR, Gould IM

Abstract
Pseudomonas aeruginosa is one of the most important pathogens in cystic fibrosis. In this study we analysed the genetic basis and phylogenetic profile of resistance to ceftazidime/avibactam and ceftolozane/tazobactam as well as carbapenems in cystic fibrosis P. aeruginosa isolates. We conducted whole genome sequence analysis of a collection of isolates resistant to piperacillin/tazobactam from seven hospitals in Scotland since the introduction of these two cephalosporin/β-lactamase inhibitor combinations. Ceftazidime resistance was primarily related to AmpC induction, as tested by cloxacillin inhibition assays, while amino acid variations in AmpC were associated with high-level ceftazidime resistance not reversed by cloxacillin. Only isolates resistant to both ceftazidime/avibactam and ceftolozane/tazobactam carried AmpD mutations, likely resulting in ampC overexpression. All isolates resistant to ceftazidime/avibactam and/or ceftolozane/tazobactam were resistant to carbapenems and showed inactivating mutations in the chromosomal oprD gene. None of the isolates bore class A, B, D plasmid-encoded carbapenemases. Critically, we show that mutational resistance emerged in phylogenetically distant lineages suggesting that the mutations occur independently without conferring a selective advantage to any phylogenetic lineage. Our findings confirm the strong contribution of mutation-driven evolution to the population structure of P. aeruginosa.

PMID: 30831233 [PubMed - as supplied by publisher]

Within-breath changes in respiratory system impedance in children with cystic fibrosis.

Pediatr Pulmonol. 2019 Mar 03;:

Authors: Zannin E, Nyilas S, Ramsey KA, Latzin P, Dellaca' RL

Abstract
BACKGROUND: The aim of this study was to assess within-breath respiratory system impedance by the forced oscillation technique (FOT) in children with cystic fibrosis (CF) and relate it to the underlying lung disease.
METHODS: Thirty-three children with CF (median [range] age 12.0 [6-17] years) underwent FOT at 8 Hz during tidal breathing, multiple breath nitrogen washout (LCI), spirometry (FEV1), body plethysmography (RV/TLC), and magnetic resonance imaging (MRI). FOT outcomes included: mean inspiratory, expiratory, and whole breath resistance (R8INSP , R8EXP , R8TOT ) and reactance (X8INSP , X8EXP , X8TOT ), and the differences between X8INSP and X8EXP (ΔX8). Morphological changes were evaluated by MRI using CF-specific morphological scores. Spearman correlation was performed to examine the correlation between FOT indices and other parameters.
RESULTS: FEV1 was negatively correlated with R8EXP (r = -0.52, P = 0.002) and ΔX8 (r = -0.55, P = 0.001), and positively correlated with and X8EXP (r = 0.56, P < 0.001). RV/TLC was positively correlated with R8EXP (r = 0.43, P = 0.013), and ΔX8 (r = 0.54, P = 0.001) and negatively correlated with X8EXP (r = -0.54, P = 0.001). We found poor correlation between FOT parameters and LCI and no correlation between FOT parameters and MRI scores.
CONCLUSION: In children with CF, changes in within-breath FOT parameters are consistent with peripheral obstruction and dynamic airway compression, while they are not associated with ventilation heterogeneities and morphological alterations.

PMID: 30828997 [PubMed - as supplied by publisher]

Impaired Health-Related Quality of Life in Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Impact of Core Symptoms.

Front Pediatr. 2019;7:26

Authors: Roma M, Marden CL, Flaherty MAK, Jasion SE, Cranston EM, Rowe PC

Abstract
Objective: The objectives of this study were to compare the health-related quality of life (HRQOL) of a North American population of adolescents and young adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to (1) healthy controls (HC), (2) adolescents with ME/CFS in other countries, and (3) other forms of pediatric chronic illness, and (4) to examine the influence of the core illness symptoms in the Institute of Medicine (IOM) case definition on impaired HRQOL. Study design: Cross-sectional study comparing individuals with ME/CFS referred to a tertiary care Chronic Fatigue clinic and HC. Eligible participants were age 10-30 years and met the Fukuda criteria for CFS. HC were eligible if they were age 10-30 years, with self-reported good, very good, or excellent general health. Pediatric HRQOL was measured using the PedsQL (Pediatric Quality of Life Inventory) and other validated instruments. Results: We enrolled 55 consecutive ME/CFS patients (46 F) aged 10-23 years. From a pool of 69 potential HC we selected 55 with similar age and gender distribution for comparison. The total and subscale scores on the PedsQL and on all other measures of HRQOL indicated significantly worse function among those with ME/CFS (all P < 0.001). The self-reported frequency of post-exertional malaise (PEM) was significantly associated with the severity of impaired HRQOL (P < 0.001). Cognitive impairment had a weaker association with the PedsQL score (P = 0.02). Orthostatic intolerance was present in 96% of the ME/CFS population. Of the 55 who satisfied the Fukuda criteria, 47 (85%) also satisfied the IOM criteria for the diagnosis. Those meeting the IOM criteria had worse PedsQL total scores than those meeting just the Fukuda criteria (P < 0.001). Conclusions: HRQOL was substantially lower in an ambulatory population of adolescents and young adults with ME/CFS than for healthy controls in North America, consistent with reports from other continents. HRQOL was also lower in ME/CFS than has been described in children with asthma, diabetes mellitus, epilepsy, eosinophilic gastroenteritis, and cystic fibrosis. The findings of this study lend further support to the inclusion of PEM, cognitive impairment, and orthostatic intolerance as core symptoms of pediatric ME/CFS.

PMID: 30828572 [PubMed]

Transition to adulthood and adult health care for patients with sickle cell disease or cystic fibrosis: Current practices and research priorities.

J Clin Transl Sci. 2018 Oct;2(5):334-342

Authors: Lanzkron S, Sawicki GS, Hassell KL, Konstan MW, Liem RI, McColley SA

Abstract
Introduction: A growing population of adults living with severe, chronic childhood-onset health conditions has created a need for specialized health care delivered by providers who have expertise both in adult medicine and in those conditions. Optimal care of these patients requires systematic approaches to healthcare transition (HCT). Guidelines for HCT exist, but gaps in care occur, and there are limited data on outcomes of HCT processes.
Methods: The Single Disease Workgroup of the Lifespan Domain Task Force of the National Center for Advancing Translational Sciences Clinical and Translational Science Award programs convened a group to review the current state of HCT and to identify gaps in research and practice. Using cystic fibrosis and sickle cell disease as models, key themes were developed. A literature search identified general and disease-specific articles. We summarized key findings.
Results: We identified literature characterizing patient, parent and healthcare provider perspectives, recommendations for transition care, and barriers to effective transition.
Conclusions: With increased survival of patients with severe childhood onset diseases, ongoing study of effective transition practices is essential as survival increases for severe childhood onset diseases. We propose pragmatic methods to enhance transition research to improve health and key outcomes.

PMID: 30828476 [PubMed]

Faecal Calprotectin.

Clin Biochem Rev. 2018 Aug;39(3):77-90

Authors: Pathirana WGW, Chubb SP, Gillett MJ, Vasikaran SD

Abstract
Calprotectin is a calcium- and zinc-binding protein of the S-100 protein family which is mainly found within neutrophils and throughout the human body. The presence of calprotectin in faeces is a consequence of neutrophil migration into the gastrointestinal tissue due to an inflammatory process. Faecal calprotectin concentrations demonstrate good correlation with intestinal inflammation and faecal calprotectin is used as a biomarker in gastrointestinal disorders. Faecal calprotectin is a very sensitive marker for inflammation in the gastrointestinal tract, and useful for the differentiation of inflammatory bowel disease (IBD) from irritable bowel syndrome (IBS). Faecal calprotectin is used for the diagnosis, monitoring disease activity, treatment guidance and prediction of disease relapse and post-operative recurrence in IBD. There may also potentially be a role for faecal calprotectin in the management of infectious gastroenteritis, acute appendicitis, peptic ulcer disease, cystic fibrosis, coeliac disease, transplant rejection and graft versus host disease. Further studies are needed to confirm its utility in these conditions. Analysis of faecal calprotectin consists of an extraction step followed by quantification by immunoassay. Over the past few decades, several assays and extraction devices including point-of-care methods have been introduced by manufacturers. The manufacturer-quoted cut-off values for different faecal calprotectin assays are generally similar. However, the sensitivities and specificities at a given cut-off, and therefore the optimum cut-off values, are different between assays. A reference standard for calprotectin is lacking. Therefore, assay standardisation is required for more accurate and traceable test results for faecal calprotectin.

PMID: 30828114 [PubMed]

Abnormal preschool Lung Clearance Index (LCI) reflects clinical status and predicts lower spirometry later in childhood in cystic fibrosis.

J Cyst Fibros. 2019 Feb 28;:

Authors: Hardaker KM, Panda H, Hulme K, Wong A, Coward E, Cooper P, Fitzgerald DA, Pandit C, Towns S, Selvadurai H, Robinson PD

Abstract
BACKGROUND: Clinical and prognostic value of preschool Multiple Breath Washout (MBW) remains unclear.
METHODS: Initial MBW results (Exhalyzer® D, EcoMedics AG) in preschool Cystic Fibrosis (CF) subjects (age 2-6 years) at a time of clinical stability were compared to (1) concurrent clinical status measures and (2) later spirometry outcomes. Abnormal Lung Clearance Index (LCI) was defined using published reference data (ULN for LCI 8.0).
RESULTS: LCI was abnormal in 56% (28/50), with mean (SD) LCI 8.61(1.85) at age 4.71(1.3) years. Abnormal LCI was associated with higher dornase alfa use, previous positive bacterial cultures and pF508.del homozygous genotype. Later spirometry (n = 44; mean (SD) 2.3(0.5) years after MBW) demonstrated that abnormal initial preschool LCI was a strong predictor of lower later spirometry outcomes.
CONCLUSION: Abnormal preschool LCI was associated with concurrent measures of clinical status and later spirometry deficits, suggesting early prognostic utility of MBW testing in this age range.

PMID: 30827846 [PubMed - as supplied by publisher]

Correlation of spirometry and body plethysmography during exercise-induced bronchial obstruction.

Respir Med. 2019 Mar;148:54-59

Authors: Schulze J, Smith HJ, Eichhorn C, Salzmann-Manrique E, Dreßler M, Zielen S

Abstract
BACKGROUND: The exercise challenge is the gold standard for diagnosing exercise-induced bronchoconstriction (EIB). Airway obstructions appear up to 30 min after the challenge, with a maximum decrease in spirometry and a maximum increase in airway resistance. There is evidence that changes in body plethysmography parameters are more sensitive to the exercise challenge and precede those in spirometry.
PURPOSE: To compare changes in body plethysmography and spirometry parameters after exercise challenges and to verify the cut-off values of sReff in EIB.
PROCEDURES: In 82 subjects with suspected EIB, a total of 473 lung function tests were measured at baseline and at 5, 10, 15, and 30 min after exercise challenges at different stages of bronchial obstruction.
FINDINGS: The maximum changes in the body plethysmography parameter sReff significantly preceded the maximum changes in the spirometry parameter FEV1 (sReff: 12.2 min ±8.8, FEV1: 15.2 min ±9.3, p < 0.005). The parameters of sReff and FEV1 had a strong negative correlation (r = -0.63, p < 0.0001) with a nonlinear, polynomial relationship. Furthermore, sReff and Reff had a strong linear correlation (r = 0.86, p < 0.001), and Reff and Rtot had a perfect linear correlation (r = 0.99, p < 0.001). Based on baseline values and on quantile regression, an increase of 0.25 kPa s in sReff was defined as significant. Using this cut-off value, FEV1 and sReff almost equally detected EIB.
CONCLUSION: The changes in sReff were more sensitive and better indicated lung impairment than did the changes in FEV1, which underestimated the degree of hyperinflation.

PMID: 30827475 [PubMed - in process]

Effects of inspiratory muscle training on postural stability, pulmonary function and functional capacity in children with cystic fibrosis: A randomised controlled trial.

Respir Med. 2019 Mar;148:24-30

Authors: Zeren M, Cakir E, Gurses HN

Abstract
BACKGROUND: Previous research has found conflictive results regarding the benefits of inspiratory muscle training (IMT) for cystic fibrosis (CF) patients. Also, involvement of postural stability is a rising concern in chronic lung diseases but its role in CF patients is poorly understood. Our aim was to investigate the effects of IMT in CF patients as well as analysing the factors which may be related to postural stability.
METHODS: Thirty-six children aged between 8 and 18 years with CF were randomly allocated to either "comprehensive chest PT" group (PT) or "IMT alongside comprehensive chest PT" group (PT+IMT). Both groups trained for 8 weeks. Dynamic and static postural stability tests on Biodex Balance system®, spirometry, respiratory muscle strength and 6-min walk distance (6MWD) was assessed at baseline and after 8 weeks of training. Determinants of postural stability was also analysed on baseline values.
RESULTS: Maximum expiratory pressure (MEP) was found to be an independent predictor for overall limits of stability (LOS) score explaining %26 of variance (R = 0.514, p = 0.003). Overall LOS score, FVC, FEV1, peak expiratory flow, MEP and 6MWD significantly improved in both groups, with no significant differences between groups. Maximum inspiratory pressure (MIP) also improved in both groups but the magnitude of improvement in MIP was greater in PT+IMT group (38 cmH2O vs 13 cmH2O; p < 0.001).
CONCLUSIONS: Combining IMT with chest PT failed to provide further improvements, except for MIP, suggesting that a comprehensive chest PT program may be individually effective in improving overall LOS score, spirometry, respiratory muscle strength and 6MWD.
TRIAL REGISTRATION: www.ClinicalTrials.gov; registration number: NCT03375684.

PMID: 30827470 [PubMed - in process]

Vitamin D and disease severity in bronchiectasis.

Respir Med. 2019 Mar;148:1-5

Authors: Ferri S, Crimi C, Heffler E, Campisi R, Noto A, Crimi N

Abstract
BACKGROUND: Bronchiectasis is a complex respiratory disease characterised by permanent dilatation of bronchi. Vitamin D plays a role in infective disease by modulating the inflammation. Patients affected by bronchiectasis are frequently Vitamin D deficient and it correlates with lung function decline. We want to understand if there is a correlation between Vitamin D and clinical and radiological severity of bronchiectasis.
METHODS: We included 57 patients (17 males/40 female with mean age 60 ± 12 years) between October 2017 and March 2018. We excluded patients with cystic fibrosis, traction bronchiectasis and reporting Vitamin D supplementation. Bronchiectasis severity index (BSI) and Bhalla score were calculated, blood inflammatory markers and Vit. D were measured and lung function tests were performed.
RESULTS: Vitamin D is deficient in 64% of patients, sufficient in 36% and normal in 7%. Mean BSI is 7.5 ± 5 and mean Bhalla score is 16 ± 4. Vitamin D levels correlate with Bhalla score (R2 = 0.68, p < 0.001) and BSI (R2 = 0.58, p < 0.0001). The correlation appears to be stronger than other markers of inflammation such as ESR and CRP [R2 = 0.33, p = 0.001 and R2 = 0.39, p = 0.001 respectively].
CONCLUSIONS: We consider Vitamin D as a good predictor of clinical and radiological severity of bronchiectasis.

PMID: 30827468 [PubMed - in process]

Airway microbiota in patients with paediatric cystic fibrosis: Relationship with clinical status.

Enferm Infecc Microbiol Clin. 2019 Mar;37(3):167-171

Authors: Sánchez-Bautista A, Rodríguez-Díaz JC, Garcia-Heredia I, Luna-Paredes C, Alcalá-Minagorre PJ

Abstract
INTRODUCTION: New massive sequencing techniques make it possible to determine the composition of airway microbiota in patients with cystic fibrosis (CF). However, the relationship between the composition of lung microbiome and the clinical status of paediatric patients is still not fully understood.
MATERIAL AND METHODS: A cross-sectional observational study was conducted on induced sputum samples from children with CF and known mutation in the CFTR gene. The bacterial sequences of the 16SrRNA gene were analyzed and their association with various clinical variables studied.
RESULTS: Analysis of the 13 samples obtained showed a core microbiome made up of Staphylococcus spp., Streptococcus spp., Rothia spp., Gemella spp. and Granulicatella spp., with a small number of Pseudomonas spp. The cluster of patients with less biodiversity were found to exhibit a greater number of sequences of Staphylococcus spp., mainly Staphylococcus aureus (p 0.009) and a greater degree of lung damage.
CONCLUSION: An airway microbiome with greater biodiversity may be an indicator of less pronounced disease progression, in which case new therapeutic interventions that prevent reduction in non-pathogenic species of the airway microbiota should be studied.

PMID: 30827333 [PubMed - in process]

Cross-infection risk in patients with bronchiectasis: a position statement from the European Bronchiectasis Network (EMBARC), EMBARC/ELF patient advisory group and European Reference Network (ERN-Lung) Bronchiectasis Network.

Eur Respir J. 2018 01;51(1):

Authors: Chalmers JD, Ringshausen FC, Harris B, Elborn JS, Posthumus A, Haworth CS, Pilkington N, Polverino E, Ruddy T, Aliberti S, Goeminne PC, Winstanley C, De Soyza A

PMID: 29326319 [PubMed - indexed for MEDLINE]

Early respiratory viral infections in infants with cystic fibrosis.

J Cyst Fibros. 2019 Feb 27;:

Authors: Deschamp AR, Hatch JE, Slaven JE, Gebregziabher N, Storch G, Hall GL, Stick S, Ranganathan S, Ferkol TW, Davis SD

Abstract
BACKGROUND: Viral infections contribute to morbidity in cystic fibrosis (CF), but the impact of respiratory viruses on the development of airway disease is poorly understood.
METHODS: Infants with CF identified by newborn screening were enrolled prior to 4 months of age to participate in a prospective observational study at 4 centers. Clinical data were collected at clinic visits and weekly phone calls. Multiplex PCR assays were performed on nasopharyngeal swabs to detect respiratory viruses during routine visits and when symptomatic. Participants underwent bronchoscopy with bronchoalveolar lavage (BAL) and a subset underwent pulmonary function testing. We present findings through 8.5 months of life.
RESULTS: Seventy infants were enrolled, mean age 3.1 ± 0.8 months. Rhinovirus was the most prevalent virus (66%), followed by parainfluenza (19%), and coronavirus (16%). Participants had a median of 1.5 viral positive swabs (range 0-10). Past viral infection was associated with elevated neutrophil concentrations and bacterial isolates in BAL fluid, including recovery of classic CF bacterial pathogens. When antibiotics were prescribed for respiratory-related indications, viruses were identified in 52% of those instances.
CONCLUSIONS: Early viral infections were associated with greater neutrophilic inflammation and bacterial pathogens. Early viral infections appear to contribute to initiation of lower airway inflammation in infants with CF. Antibiotics were commonly prescribed in the setting of a viral infection. Future investigations examining longitudinal relationships between viral infections, airway microbiome, and antibiotic use will allow us to elucidate the interplay between these factors in young children with CF.

PMID: 30826285 [PubMed - as supplied by publisher]

Adherence to medication in adults with Cystic Fibrosis: An investigation using objective adherence data and the Theoretical Domains Framework.

Br J Health Psychol. 2019 Mar 01;:

Authors: Arden MA, Drabble S, O'Cathain A, Hutchings M, Wildman M

Abstract
OBJECTIVES: Adherence to nebulizer treatment in adults with Cystic Fibrosis (CF) is poor, and interventions are needed. This research aimed to identify the factors affecting nebulizer adherence using the Theoretical Domains Framework (TDF) and to compare these for participants with different levels of adherence.
DESIGN: Data-prompted interviews using the TDF.
METHODS: Eighteen semi-structured interviews were conducted with adults with CF during which objectively measured adherence data were discussed. Framework analysis was used to code the data into TDF domains, and inductive qualitative content analysis was used to code different beliefs and experiences. Aspects of the TDF that differed between participants with different adherence levels were explored.
RESULTS: Factors influencing adherence to treatment included all 14 domains of the TDF, 10 of which appeared to vary by adherence level: Skills; Memory and decision-making; and Behavioural regulation; Environmental context and resources; Social influences; Beliefs about consequences; Beliefs about capability; Reinforcement; Social role and identify; Intentions; Optimism; and Emotions.
CONCLUSIONS: This study is the first to use objectively measured adherence data in a data-prompted interview using the TDF framework to systematically assess the full range of factors potentially influencing adherence. The results highlighted that interventions need to consider issues of capability, opportunity, and motivation. Interventions that challenge dysfunctional beliefs about adherence and which support the development of routines or habits and problem-solving may be particularly useful for adults with CF. Statement of contribution What is already known? Adherence to medication in adults with cystic fibrosis is poor. Previous research has identified a range of contributing factors in relation to subjective reports of adherence. There is a wide discrepancy between self-reported adherence and objectively measured adherence. What this study adds A data-prompted interview using objectively measured adherence data enabled the systematic assessment of potential factors that could be targeted in an intervention to increase adherence. There were some differences in the factors that were identified by high and low adherers. There is not one-size fits all intervention for adherence to medication in cystic fibrosis.

PMID: 30825258 [PubMed - as supplied by publisher]

Small molecule-facilitated anion transporters in cells for a novel cystic fibrosis therapeutic approach.

Br J Pharmacol. 2019 Mar 01;:

Authors: Fiore M, Cossu C, Capurro V, Picco C, Ludovico A, Mielczarek M, Carreira-Barral I, Caci E, Baroni D, Quesada R, Moran O

Abstract
BACKGROUND AND PURPOSE: Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease that originates from the defective function of the CFTR protein, a cAMP-dependent anion channel involved in fluid transport across epithelium. Due to their capability to replace the ion transport independently from the genetic mutation that affects the CFTR, small synthetic transmembrane anion transporters, named anionophores, are candidates as new potential CF therapeutics.
EXPERIMENTAL APPROACH: With the aim of evaluating their impact on cell physiology, we have analysed the transport properties of five compounds, three prodigiosines and two tambjamines.
KEY RESULTS: All studied compounds are capable of transporting halides and bicarbonate across the cell membrane, with a higher transport capacity at acidic pH. Interestingly, the presence of these anionophores do not interfere with the activation of CFTR, and do not modify the action of the lumacaftor and ivacaftor, a CFTR-corrector and -potentiator, respectively.
CONCLUSION AND IMPLICATIONS: Their ability to transport chloride and bicarbonate when applied at low concentration take shape as a promising starting point for the development of novel CF-therapy drug candidates.

PMID: 30825185 [PubMed - as supplied by publisher]

Associating antimicrobial susceptibility testing with clinical outcomes in cystic fibrosis: More rigor and less frequency?

J Cyst Fibros. 2019 Feb 26;:

Authors: Szczesniak RD, Cogen JD, Rosenfeld M

PMID: 30824378 [PubMed - as supplied by publisher]

Premarital Screening and Genetic Counseling Program: Studies from an Endogamous Population.

Int J Appl Basic Med Res. 2019 Jan-Mar;9(1):20-26

Authors: Bener A, Al-Mulla M, Clarke A

Abstract
Background: Studies in Arab countries have shown a significant lack of knowledge of Premarital Screening and Genetic Counseling (PMSGC) Program. PMSGC can identify and modify, through prevention and management, some behavioral, medical, and other health risk factors known to impact pregnancy outcomes.
Objective: The aim of this study was to explore the knowledge, attitudes, and practice of Qatari's toward the premarital screening program and shedding more light on a complex matter.
Materials and Methods: A cross-sectional study based on Hospitals and Primary Health Care Centers. A total sample of 1246 participants was surveyed, and 873 participants (70.0%) expressed their consent to participate in the study during January 2013-May 2014. The questionnaire based on sociodemographic data and for responses, on the PMSGC program knowledge, attitude, and practice statements. In addition, questions were asked regarding the services, activities, and how to attract and motivate the PMSGC program.
Results: The mean age and standard deviation (SD) of the males' age were 30.4 ± 6.50 and the mean and SD of females' age were 31.08 ± 5.98. There were statistically significant differences between males and females with regard to age, educational status, occupation status, household income, consanguinity, body mass index, cigarette smoking, and Shisha smoking. There were no any statistically significant differences between males and females regarding sickle cell anemia and thalassemia, glucose-6-phosphate dehydrogenase deficiency cystic fibrosis, homocystinuria, HIV, and hepatitis. The response to the ''Why proceeding through high-risk marriage?'' by gender, males and females responded statistically significant differences (P = 0.019). The step-wise multivariate regression analyses as predictors for knowledge of PMSGC program revealed that age, educational level, the lack knowledge of genetics counseling, parental interventions for cousin marriage decision, positive test results affect and change marriage decision, religious impact, household income, consanguinity, hereditary diseases knowledge, occupational status, and love factors were considered as the main factors associated with the premarriage screening and genetics counseling after adjusting for age, gender, and other variables.
Conclusion: The current study revealed that knowledge and attitude regarding PMSGC program were low in population. Motivation, enforcement, and implementation of program at the school and university educational campaigns are vital. Improved counseling and adding new topics for counseling on genetic, chronic, and mental illness; building healthy families; and reproduction and fertility are considered to be top priorities in community.

PMID: 30820415 [PubMed]

Estrogen sulfotransferase in the metabolism of estrogenic drugs and in the pathogenesis of diseases.

Expert Opin Drug Metab Toxicol. 2019 Mar 01;:

Authors: Barbosa ACS, Feng Y, Yu C, Huang M, Xie W

Abstract
INTRODUCTION: Biotransformation is important in the metabolism of endobiotics and xenobiotics. This process comprises the activity of phase I and phase II enzymes. Estrogen sulfotransferase (SULT1E1 or EST) is a phase II conjugating enzyme that belongs to the family of cytosolic sulfotransferases. The expression of SULT1E1 can be detected in many tissues, including the liver. SULT1E1 catalyzes the transfer of a sulfate group from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to any available hydroxyl group in estrogenic molecules. The substrates of SULT1E1 include the endogenous and synthetic estrogens. Upon SULT1E1-mediated sulfation, the hydrosolubility of estrogens increases, preventing the binding between the sulfated estrogens and the estrogen receptor (ER). This sulfated state of the estrogens is not irreversible, as the steroid sulfatase (STS) can convert sulfoconjugated estrogens to free estrogens. The expression of SULT1E1 is inducible by several diseases that involve tissue inflammation, such as type 2 diabetes, sepsis, and ischemia-reperfusion injury. Areas covered: This systematic literature review aims to summarize the role of SULT1E1 in the metabolism of estrogenic drugs and xenobiotics, and the role of SULT1E1 in the pathogenesis of several diseases, including cancer, metabolic disease, sepsis, liver injury, and cystic fibrosis. Meanwhile, ablation or pharmacological inhibition of SULT1E1 can affect the outcomes of the aforementioned diseases. Expert opinion: In addition to its role in metabolizing estrogenic drugs, SULT1E1 is unexpectedly being unveiled as a mediator for the disease effect on estrogen metabolism and homeostasis. Meanwhile, because the expression and activity of SULT1E1 can affect the outcome of diseases, the same sulfotransferase and the reversing enzymes STS can be potential therapeutic targets to prevent or manage diseases. Accumulating evidence suggest that the effects of SULT1E1 can be estrogen-independent and it is necessary to elucidate what other possible substrates may be recognized by the enzyme. Moreover, human studies are paramount to confirm the human relevance of the animal studies.

PMID: 30822161 [PubMed - as supplied by publisher]