Am J Physiol Lung Cell Mol Physiol. 2021 May 5. doi: 10.1152/ajplung.00538.2020. Online ahead of print.

ABSTRACT

Prolonged oxygen therapy leads to oxidative stress, epithelial dysfunction, and acute lung injury in preterm infants and adults. Heterozygous Scnn1b mice, which overexpress lung epithelial sodium channels (ENaC), and their wild type (WT) C57Bl6 littermates were utilized to study the pathogenesis of high fraction inspired oxygen (FiO2)-induced lung injury. Exposure to high FiO2 from birth to postnatal (PN) day 11 was used to model oxidative stress. Chronic exposure of newborn pups to 85% O2 increased glutathione disulfide (GSSG) and elevated the GSH/GSSG redox potential (Eh) of bronchoalveolar lavage fluid (BALF). Longitudinal X-ray imaging and Evans-blue-labeled-albumin assays showed that chronic 85% O2 and acute GSSG [400μM] exposures decreased alveolar fluid clearance (AFC) in the WT lung. Morphometric analysis of WT pups insufflated with GSSG [400μM] or amiloride [1μM] showed a reduction in alveologenesis and increased lung injury compared to age-matched control pups. The Scnn1b mouse lung phenotype was not further aggravated by chronic 85% O2 exposure. These outcomes support the hypothesis that exposure to hyperoxia increases GSSG, resulting in reduced lung fluid reabsorption due to inhibition of amiloride-sensitive ENaC. Flavin adenine dinucleotide (FADH2; 10μM) was effective in recycling GSSG in vivo and promoted alveologenesis, but did not impact AFC nor attenuate fibrosis following high FiO2 exposure. In conclusion, the data indicate that FADH2 may be pivotal for normal lung development, and show that ENaC is a key factor in promoting alveologenesis, sustaining AFC, and attenuating fibrotic lung injury caused by prolonged oxygen therapy in WT mice.

PMID:33949206 | DOI:10.1152/ajplung.00538.2020

Am J Med Genet A. 2021 May 5. doi: 10.1002/ajmg.a.62207. Online ahead of print.

ABSTRACT

Guanylate cyclase 2C (GC-C), encoded by the GUCY2C gene, is implicated in hereditary early onset chronic diarrhea. Several families with chronic diarrhea symptoms have been identified with autosomal dominant, gain-of-function mutations in GUCY2C. We have identified a Mennonite patient with a novel GUCY2C variant (c.2381A > T; p.Asp794Val) with chronic diarrhea and an extensive maternal family history of chronic diarrhea and bowel dilatation. Functional studies including co-segregation analysis showed that all family members who were heterozygous for this variant had GI-related symptoms. HEK-293 T cells expressing the Asp794Val GC-C variant showed increased cGMP production when stimulated with Escherichia coli heat-stable enterotoxin STp (HST), which was reversed when 5-(3-Bromophenyl)-5,11-dihydro-1,3-dimethyl-1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione (BPIPP; a GC-C inhibitor) was used. In addition, cystic fibrosis transmembrane conductance regulator (CFTR) activity measured with SPQ fluorescence assay was increased in these cells after treatment with HST, indicating a crucial role for CFTR activity in the pathogenesis of this disorder. These results support pathogenicity of the GC-C Asp794Val variant as a cause of chronic diarrhea in this family. Furthermore, this work identifies potential candidate drug, GC-C inhibitor BPIPP, to treat diarrhea caused by this syndrome.

PMID:33949097 | DOI:10.1002/ajmg.a.62207

Radiat Prot Dosimetry. 2021 May 5:ncab057. doi: 10.1093/rpd/ncab057. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate two chest tomosynthesis (CTS) scoring systems for cystic fibrosis (CF), one system developed by Vult von Steyern et al. (VvS) and one system based on the Brody scoring system for high-resolution computed tomography (HRCT) (modified Brody (mB)). Brody scoring of HRCT was used as reference.

METHODS: In conjunction with routine control HRCT at clinical follow-up, 10 consecutive adult CF patients underwent CTS for research purposes. Four radiologists scored the CTS examinations using the mB and VvS scoring systems. All scores were compared to the Brody HRCT scores. The agreement between the evaluated CTS scoring systems and the reference HRCT scoring system was determined using Spearman's rank correlation coefficient and the intraclass correlation coefficient (ICC).

MAJOR FINDINGS: Spearman's rank correlation coefficient showed strong correlations between HRCT score and both the mB and the VvS CTS total scores (median rs = 0.81 and 0.85, respectively). The ICC showed strong correlation between the CTS scoring systems and the reference: 0.88 for mB and 0.85 for VvS scoring. The median time for scoring was 20 and 10 minutes for the mB and VvS scoring systems, respectively.

CONCLUSIONS: Both evaluated CTS scoring systems correlate well with the reference standard Brody HRCT scoring. The VvS CTS scoring system has a shorter reading time, suggesting its advantage in clinical practice.

PMID:33948650 | DOI:10.1093/rpd/ncab057

Cell Rep Med. 2021 Apr 8;2(4):100239. doi: 10.1016/j.xcrm.2021.100239. eCollection 2021 Apr 20.

ABSTRACT

Neutrophils are often considered terminally differentiated and poised for bacterial killing. In chronic diseases such as cystic fibrosis (CF), an unexplained paradox pits massive neutrophil presence against prolonged bacterial infections. Here, we show that neutrophils recruited to CF airways in vivo and in an in vitro transmigration model display rapid and broad transcriptional firing, leading to an upregulation of anabolic genes and a downregulation of antimicrobial genes. Newly transcribed RNAs are mirrored by the appearance of corresponding proteins, confirming active translation in these cells. Treatment by the RNA polymerase II and III inhibitor α-amanitin restores the expression of key antimicrobial genes and increases the bactericidal capacity of CF airway neutrophils in vitro and in short-term sputum cultures ex vivo. Broadly, our findings show that neutrophil plasticity is regulated at the site of inflammation via RNA and protein synthesis, leading to adaptations that affect their canonical functions (i.e., bacterial clearance).

PMID:33948572 | PMC:PMC8080108 | DOI:10.1016/j.xcrm.2021.100239

Turk J Phys Med Rehabil. 2021 Mar 4;67(1):91-98. doi: 10.5606/tftrd.2021.5214. eCollection 2021 Mar.

ABSTRACT

OBJECTIVES: This study aims to investigate the effects of postural exercises as an adjunct to chest physiotherapy program on respiratory function, exercise tolerance, quality of life (QoL), and postural stability in patients with cystic fibrosis (CF).

PATIENTS AND METHODS: In this single-blind, randomized-controlled trial, 19 pediatric CF patients (11 males, 8 females; mean age: 9.36 years; range, 6 to 14 years) were randomly allocated to chest physiotherapy and postural exercise program (Group 1, n=10) or chest physiotherapy program alone (Group 2, n=9) between March 2017 and October 2017. Respiratory functions were assessed with pulmonary function tests, whereas exercise tolerance with the Modified Shuttle Test (MST), quality of life with the Cystic Fibrosis Questionnaire-Revised Child Version (CFQR), and postural stability with the Limits of Stability Test (LOS). All tests were performed before treatment and six weeks, three months, and six months after treatment.

RESULTS: Respiratory functions were improved in both groups; however, these changes were not statistically significant. The MST increased after treatment in both groups (p<0.001 and p=0.003 respectively), without a significant difference between the groups. Emotional function and treatment difficulties subdomains in CFQR were significantly increased only in the group with postural exercises (p<0.05).

CONCLUSION: The postural exercise program in addition to chest physiotherapy in pediatric CF patients whose postural changes were not taken place did not cause significant changes in respiratory function, exercise tolerance, and postural stability; however, it affected the emotional state well and improved the compliance with the treatment.

PMID:33948549 | PMC:PMC8088798 | DOI:10.5606/tftrd.2021.5214

Oxf Med Case Reports. 2021 Apr 28;2021(4):omab012. doi: 10.1093/omcr/omab012. eCollection 2021 Apr.

ABSTRACT

Coeliac disease (CD) and cystic fibrosis (CF) are well known as the most common causes of chronic intestinal malabsorption in childhood. The coexistence of coeliac disease with cystic fibrosis is uncommon. Here, we describe the case of cystic fibrosis in a patient diagnosed with coeliac disease who failed to respond clinically to a gluten-free diet and had persistent steatorrhea and failure to thrive.

PMID:33948185 | PMC:PMC8081015 | DOI:10.1093/omcr/omab012

Respir Care. 2021 May 4:respcare.08834. doi: 10.4187/respcare.08834. Online ahead of print.

ABSTRACT

BACKGROUND: Nebulized 7% hypertonic saline is used to treat patients with cystic fibrosis. Clinical trials supporting its use were conducted with breath-enhanced nebulizers (BEN). It is not uncommon for the specific nebulizer used in studies or prescribed by a physician to be unavailable to patients. The investigator compared the aerosol characteristics of hypertonic saline delivered by nebulizers of different operating principles.

METHODS: A continuous-output nebulizer (CON), a breath-actuated (BAN) jet nebulizer, and 2 brands of BEN (Pari LC Plus and Sidestream Plus) were tested. Airway delivery and aerosol characteristics of nebulizers loaded with 7% hypertonic saline were determined with 3 breathing simulations (ie, infant, child, and adult breathing patterns) and cascade impaction, respectively. Solutes were analyzed with freezing point osmometry.

RESULTS: Aerosols generated with the BEN and BAN had similar mass median aerodynamic diameters (3.43-3.67 µm), geometric standard deviations (2.12-2.34), percentage of particles < 5 µm (63.1-68.9%), and percentage of particles 1-3 µm (35.9-37%). The CON produced a larger aerosol than BEN and BAN. The 2 BENs had similar airway delivery values that were greater than those for both CON and BAN.

CONCLUSIONS: Hypertonic saline aerosols generated with the BEN and BAN devices were similar, while that generated with the CON was different. Airway delivery was similar between the BEN devices, but higher than that observed with the BAN and CON devices.

PMID:33947793 | DOI:10.4187/respcare.08834

mBio. 2021 May 4;12(3):e00458-21. doi: 10.1128/mBio.00458-21.

ABSTRACT

Bacteriocins are proteinaceous antimicrobials produced by bacteria that are active against other strains of the same species. R-type pyocins are phage tail-like bacteriocins produced by Pseudomonas aeruginosa Due to their antipseudomonal activity, R-pyocins have potential as therapeutics in infection. P. aeruginosa is a Gram-negative opportunistic pathogen and is particularly problematic for individuals with cystic fibrosis (CF). P. aeruginosa organisms from CF lung infections develop increasing resistance to antibiotics, making new treatment approaches essential. P. aeruginosa populations become phenotypically and genotypically diverse during infection; however, little is known of the efficacy of R-pyocins against heterogeneous populations. R-pyocins vary by subtype (R1 to R5), distinguished by binding to different residues on the lipopolysaccharide (LPS). Each type varies in killing spectrum, and each strain produces only one R-type. To evaluate the prevalence of different R-types, we screened P. aeruginosa strains from the International Pseudomonas Consortium Database (IPCD) and from our biobank of CF strains. We found that (i) R1-types were the most prevalent R-type among strains from respiratory sources, (ii) a large number of strains lack R-pyocin genes, and (iii) isolates collected from the same patient have the same R-type. We then assessed the impact of intrastrain diversity on R-pyocin susceptibility and found a heterogenous response to R-pyocins within populations, likely due to differences in the LPS core. Our work reveals that heterogeneous populations of microbes exhibit variable susceptibility to R-pyocins and highlights that there is likely heterogeneity in response to other types of LPS-binding antimicrobials, including phage.IMPORTANCE R-pyocins have potential as alternative therapeutics against Pseudomonas aeruginosa in chronic infection; however, little is known about the efficacy of R-pyocins in heterogeneous bacterial populations. P. aeruginosa is known to become resistant to multiple antibiotics and to evolve phenotypic and genotypic diversity over time; thus, it is particularly difficult to eradicate in chronic cystic fibrosis (CF) lung infections. In this study, we found that P. aeruginosa populations from CF lungs maintain the same R-pyocin genotype but exhibit heterogeneity in susceptibility to R-pyocins from other strains. Our findings suggest there is heterogeneity in response to other types of LPS-binding antimicrobials, such as phage, highlighting the necessity of further studying the potential of LPS-binding antimicrobial particles as alternative therapies in chronic infections.

PMID:33947755 | DOI:10.1128/mBio.00458-21

Eur J Intern Med. 2021 May 1:S0953-6205(21)00124-2. doi: 10.1016/j.ejim.2021.04.009. Online ahead of print.

ABSTRACT

BACKGROUND: Inhaled antibiotics (IA) in non-cystic fibrosis bronchiectasis (NCFB) are recommended by some clinical practice guidelines for prevention or treatment of NCFB exacerbations.

METHODS: We performed a systematic review and meta-analysis to evaluate the efficacy and safety of IA use for treatment of adults with NCFB and Pseudomonas aeruginosa chronic bronchial infection. The search was performed in the Cochrane Library, PubMed, and Web of Science databases from 2000 to 2019. Studies of IA for treatment of stable or exacerbated NCFB adults (≥18 years) with P. aeruginosa infection were considered eligible. PROSPERO Registration number: CRD42019136154.

RESULTS: Twelve trials (2476 participants) were included. IA therapy increased P. aeruginosa eradication from sputum in patients with exacerbations (OR: 3.19, 95%CI: 1.70-5.99) with similar effects on stable patients (OR: 7.22, 95%CI: 2.81-18.59), and a trend to reduced emergence of new respiratory pathogens (OR: 0.58, 95%CI: 0.28-1.18). IA achieved significant reduced exacerbation rates (RR: 0.90; 95%CI: 0.82-0.98) in stable patients, with a number needed to treat (NNT) of 59, but no significant changes in FEV1, mortality, hospitalizations or quality of life were identified. In stable patients, IA use increased antimicrobial resistance (RR: 2.10, 95%CI: 1.35-3.27) at the end of therapy, with a number needed to treat of 6.

CONCLUSIONS: IA therapy achieved a statistically significant eradication of P. aeruginosa from sputum, with a 10% reduction of exacerbations in stable patients. This effect has to be balanced with significant increases in antimicrobial resistance. Our meta-analysis failed to show a significant benefit in terms of patient-centered outcomes.

PMID:33947626 | DOI:10.1016/j.ejim.2021.04.009

Hum Gene Ther. 2021 May 5. doi: 10.1089/hum.2021.031. Online ahead of print.

ABSTRACT

A gene-addition therapy into the conducting airway epithelium is a potential cure for cystic fibrosis lung disease. Achieving sustained lung gene expression has proven difficult due to the natural barriers of the lung. The development of lentiviral (LV) vectors pseudotyped with viral envelopes that have a natural tropism to the airway has enabled persistent gene expression to be achieved in vivo. The aims of this study were to compare the yields of HA and VSV-G pseudotyped HIV-1 vectors produced under the same conditions by our standard LV vector production method. We then sought to measure gene expression in mouse airways and to determine whether LPC conditioning enhances short- and long-term gene expression. C57Bl/6 mouse airways were conditioned with 10 µl of 0.1% LPC or PBS control, followed one hour later by a 30 μl dose of a HA or VSV-G pseudotyped vector carrying either the LacZ or Luciferase reporter genes. LacZ expression was assessed by X-gal staining after 7 days, while lung luminescence was quantified regularly for up to 18 months via bioluminescent imaging. The HA pseudotyped vectors had functional titres 25 to 60 times lower than the VSV-G pseudotyped vectors. Conditioning the lung with LPC significantly increased the total number of LacZ transduced cells for both pseudotypes compared to PBS control. Regardless of LPC conditioning, the VSV-G pseudotype produced higher initial levels of gene expression compared to HA. LPC conditioning did not increase the number of transduced basal cells for either pseudotype compared to PBS, and was not required for long-term gene expression. Both pseudotyped vectors effectively transduced the upper conducting airways of wild-type mice. The use of LPC conditioning prior to vector delivery was not required in mouse lungs to produce long-term gene expression, but did improve short-term gene expression.

PMID:33947249 | DOI:10.1089/hum.2021.031

Genes (Basel). 2021 Apr 29;12(5):670. doi: 10.3390/genes12050670.

ABSTRACT

In families without a Cystic Fibrosis (CF) history, fetal ultrasound bowel abnormalities can unexpectedly reveal the disease. Isolated or in association, the signs can be fetal bowel hyperechogenicity, intestinal loop dilatation and non-visualization of fetal gallbladder. In these cases, search for CF transmembrane conductance regulator (CFTR) gene mutations is part of the recommended diagnostic practices, with a search for frequent mutations according to ethnicity, and, in case of the triad of signs, with an exhaustive study of the gene. However, the molecular diagnosis remains a challenge in populations without well-known frequent pathogenic variants. We present a multiethnic cohort of 108 pregnancies with fetal bowel abnormalities in which the parents benefited from an exhaustive study of the CFTR gene. We describe the new homozygous p.Cys1410* mutation in a fetus of African origin. We did not observe the most frequent p.Phe508del mutation in our cohort but evidenced variants undetected by our frequent mutations kit. Thanks to the progress of sequencing techniques and despite the difficulties of interpretation occasionally encountered, we discuss the need to carry out a comprehensive CFTR study in all patients in case of fetal bowel abnormalities.

PMID:33946859 | DOI:10.3390/genes12050670

Molecules. 2021 Apr 30;26(9):2639. doi: 10.3390/molecules26092639.

ABSTRACT

The cystic fibrosis transmembrane conductance regulator (CFTR) gene is influenced by the fundamental cellular processes like epithelial differentiation/polarization, regeneration and epithelial-mesenchymal transition. Defects in CFTR protein levels and/or function lead to decreased airway surface liquid layer facilitating microbial colonization and inflammation. The SERPINA1 gene, encoding alpha1-antitrypsin (AAT) protein, is one of the genes implicated in CF, however it remains unknown whether AAT has any influence on CFTR levels. In this study we assessed CFTR protein levels in primary human lung epithelial cells grown at the air-liquid-interface (ALI) alone or pre-incubated with AAT by Western blots and immunohistochemistry. Histological analysis of ALI inserts revealed CFTR- and AAT-positive cells but no AAT-CFTR co-localization. When 0.5 mg/mL of AAT was added to apical or basolateral compartments of pro-inflammatory activated ALI cultures, CFTR levels increased relative to activated ALIs. This finding suggests that AAT is CFTR-modulating protein, albeit its effects may depend on the concentration and the route of administration. Human lung epithelial ALI cultures provide a useful tool for studies in detail how AAT or other pharmaceuticals affect the levels and activity of CFTR.

PMID:33946490 | DOI:10.3390/molecules26092639

Curr Microbiol. 2021 May 4. doi: 10.1007/s00284-021-02493-x. Online ahead of print.

ABSTRACT

Burkholderia cepacia complex (Bcc) comprises 24 related species genetically distinct, associated with high mortality in cystic fibrosis (CF) patients. Due to a high level of similarity among Bcc species, accurate identification has been problematic, and most conventional and automated phenotypic tests have shown low accuracy. We evaluated accuracy of MALDI-ToF MS decreasing the cut-off score value to distinguish Bcc species compared to recA gene sequencing. A total of 145 Bcc isolates were analyzed. B. vietnamiensis (41.37%), B. cenocepacia IIIA (23.44%), B. multivorans (20%), B. cenocepacia IIIB (11.03%), and B. contaminans (2.75%) among other species were identified by recA sequencing. MALDI-ToF MS identified 100% of Bcc isolates at the genus level and 53.1% at the species level. By decreasing cut-off values for ≥1.70, the correct identification at the species level increased to 74.5%. MALDI-ToF MS proved to be useful at the genus level identification, but it still requires improvements that allow more precise identification, requiring continuous updates and addition of new spectra to its database. A review of interpretative criteria is a field to be explored with a large collection of Bcc species.

PMID:33944984 | DOI:10.1007/s00284-021-02493-x

Biochem J. 2021 May 4:BCJ20210212. doi: 10.1042/BCJ20210212. Online ahead of print.

ABSTRACT

Saliva, while often taken for granted, is indispensable for oral health and overall well-being, as inferred from the significant impairments suffered by patients with salivary gland dysfunction. Here, we show that treatment with several structurally-distinct PAN-PDE4 inhibitors, but not a PDE3 inhibitor, induces saliva secretion in mice, indicating it is a class-effect of PDE4 inhibitors. In anesthetized mice, while neuronal regulations are suppressed, PDE4 inhibition potentiates a β-adrenoceptor-induced salivation, that is ablated by the β-blocker Propranolol and is absent in homozygous ΔF508-CFTR mice lacking functional CFTR. These data suggest that PDE4 acts within salivary glands to gate saliva secretion that is contingent upon the cAMP/PKA-dependent activation of CFTR. Indeed, PDE4 contributes the majority of total cAMP-hydrolytic capacity in submandibular-, sublingual-, and parotid glands, the three major salivary glands of the mouse. In awake mice, PDE4 inhibitor-induced salivation is reduced by CFTR deficiency or β-blockers, but also by the muscarinic blocker Atropine, suggesting an additional, central/neuronal mechanism of PDE4 inhibitor action. The PDE4 family comprises four subtypes, PDE4A-D. Ablation of PDE4D, but not PDE4A-C, produced a minor effect on saliva secretion, implying that while PDE4D may play a predominant role, PDE4 inhibitor-induced salivation results from the concurrent inactivation of multiple (at least two) PDE4 subtypes. Taken together, our data reveal a critical role for PDE4/PDE4D in controlling CFTR function in an in vivo model and in inducing salivation, hinting at a therapeutic potential of PDE4 inhibition for cystic fibrosis and conditions associated with xerostomia.

PMID:33944911 | DOI:10.1042/BCJ20210212

Stem Cells Transl Med. 2021 May 4. doi: 10.1002/sctm.20-0521. Online ahead of print.

ABSTRACT

Chronic nontuberculous mycobacterial infections with Mycobacterium avium and Mycobacterium intracellulare complicate bronchiectasis, chronic obstructive airway disease, and the health of aging individuals. These insidious intracellular pathogens cause considerable morbidity and eventual mortality in individuals colonized with these bacteria. Current treatment regimens with antibiotic macrolides are both toxic and often inefficient at providing infection resolution. In this article, we demonstrate that human marrow-derived mesenchymal stem cells are antimicrobial and anti-inflammatory in vitro and in the context of an in vivo sustained infection of either M. avium and/or M. intracellulare.

PMID:33943038 | DOI:10.1002/sctm.20-0521

Stat Med. 2021 May 4. doi: 10.1002/sim.8997. Online ahead of print.

ABSTRACT

Using data from observational studies to estimate the causal effect of a time-varying exposure, repeatedly measured over time, on an outcome of interest requires careful adjustment for confounding. Standard regression adjustment for observed time-varying confounders is unsuitable, as it can eliminate part of the causal effect and induce bias. Inverse probability weighting, g-computation, and g-estimation have been proposed as being more suitable methods. G-estimation has some advantages over the other two methods, but until recently there has been a lack of flexible g-estimation methods for a survival time outcome. The recently proposed Structural Nested Cumulative Survival Time Model (SNCSTM) is such a method. Efficient estimation of the parameters of this model required bespoke software. In this article we show how the SNCSTM can be fitted efficiently via g-estimation using standard software for fitting generalised linear models. The ability to implement g-estimation for a survival outcome using standard statistical software greatly increases the potential uptake of this method. We illustrate the use of this method of fitting the SNCSTM by reanalyzing data from the UK Cystic Fibrosis Registry, and provide example R code to facilitate the use of this approach by other researchers.

PMID:33942919 | DOI:10.1002/sim.8997

Ther Drug Monit. 2021 Apr 26. doi: 10.1097/FTD.0000000000000900. Online ahead of print.

ABSTRACT

BACKGROUND: Intravenous tobramycin treatment requires therapeutic drug monitoring (TDM) to ensure safety and efficacy when used for prolonged treatment, as in infective exacerbations of cystic fibrosis (CF). The 24-h area under the concentration-time curve (AUC24) is widely used to guide dosing; however, there remains variability in practice around methods for its estimation.

OBJECTIVES: To determine the potential for a sparse sampling strategy using a single post-infusion tobramycin concentration and Bayesian forecasting to assess the AUC24 in routine practice.

METHODS: Adults with CF receiving once daily tobramycin had paired concentrations measured 2 h (c1) and 6 h (c2) following the end of infusion as routine monitoring. AUC24 exposures were estimated using Tucuxi, a Bayesian forecasting application that incorporates a validated population pharmacokinetic model. Simulations were performed to estimate AUC24 using the full dataset using c1 and c2, compared to estimates using depleted datasets (c1 or c2 only), with and without concentration data from earlier in the course. The agreement between each simulation condition and the reference was assessed graphically and numerically using the median difference ([INCREMENT]) AUC24 and (relative) root mean square error (rRMSE) as measures of bias and accuracy, respectively.

RESULTS: A total of 55 patients contributed 512 concentrations from 95 tobramycin courses and 256 TDM episodes. Single concentration methods performed well, with median [INCREMENT]AUC24 <2 mg.h.l-1 and rRMSE of <15% for sequential c1 and c2 conditions.

CONCLUSIONS: Bayesian forecasting implemented in Tucuxi, using single post-infusion concentrations taken 2-6 h following tobramycin administration, yield similar exposure estimates to more intensive (two-sample) methods, and are suitable for routine TDM practice.

PMID:33941739 | DOI:10.1097/FTD.0000000000000900

BMJ Open Qual. 2021 May;10(2):e001333. doi: 10.1136/bmjoq-2020-001333.

ABSTRACT

INTRODUCTION: Depression and anxiety are common. Rates are significantly higher in cystic fibrosis (CF), and impact health outcomes. Screening is recommended, but is difficult to implement/sustain annually in a busy CF centre. The aim was to develop an acceptable model for depression and anxiety screening in adolescents/adults with CF and their caregivers that could be sustained and shared.

METHODS: Quality improvement methodology with plan-do-study-act cycles, flow diagrams, review of data monthly with our designated 'Mental Health Team' and caregiver satisfaction surveys, were used to begin screening in clinics and to improve the process. We then piloted our process at a larger paediatric CF centre.

RESULTS: Prior to 2013, screening was not performed at our CF centre. After the first quarter of depression screening, 88% of adolescents and 69% of adults with CF were screened. The process was refined. By the second year, 99% of patients were screened. Anxiety screening began in year three; 97%-99% of patients were screened for both anxiety and depression in years 3-5. Annual caregiver screening rates were >95%. Screening was changed from Patient Health Questionnaire-2 (PHQ-2) to PHQ-9 due to better sensitivity in caregivers, and expanded to patients. Anxiety screening began in year 3 with the Generalised Anxiety Disorder-7 questionnaire. Patients and caregivers reported acceptance of screening. At the larger paediatric centre used as a pilot, 89.6% of patients were screened in year 1. Feedback included recommendations to improve tracking/follow-up of positive screens.

CONCLUSIONS: Development and implementation of a stepwise process for depression and anxiety screening was successful in a paediatric/adult CF clinic, due to constant re-evaluation by an engaged team with feedback from patients via survey. A systematic approach at a busy CF centre can serve as a model to implement screening in a clinic.

PMID:33941540 | DOI:10.1136/bmjoq-2020-001333

Antimicrob Agents Chemother. 2021 May 3:AAC.00316-21. doi: 10.1128/AAC.00316-21. Online ahead of print.

ABSTRACT

Chronic pulmonary MRSA disease in cystic fibrosis (CF) has a high probably of recurrence following treatment with standard-of-care antibiotics and represents an area of unmet need associated with reduced life expectancy. We developed a lipoglycopeptide therapy customized for pulmonary delivery that not only demonstrates potent activity against planktonic MRSA but also against protected colonies of MRSA both in biofilms and within cells, the latter of which have been linked to clinical antibiotic failure. A library of next-generation potent lipoglycopeptides were synthesized with an emphasis on attaining superior pharmacokinetics (PK) and pharmacodynamics to similar compounds of their class. Our strategy focused on hydrophobic modification of vancomycin where ester and amide functionality were included with carbonyl configuration and alkyl length as key variables. Candidates representative of each carbonyl attachment chemistry demonstrated potent activity in vitro with several compounds being 30-60 times more potent than vancomycin. Several compounds were advanced into in vivo nose-only inhalation PK evaluations in rats where RV94, a potent lipoglycopeptide that utilizes an inverted amide linker to attach a 10-carbon chain to vancomycin, demonstrated the most favorable lung residence time after inhalation. Further in vitro evaluation of RV94 showed superior activity to vancomycin against an expanded panel of gram-positive organisms, cellular accumulation and efficacy against intracellular MRSA, and MRSA biofilm killing. Moreover, in vivo efficacy of inhaled nebulized RV94 in a 48-h acute model of pulmonary MRSA (USA300) infection in neutropenic rats demonstrated statistically significant antibacterial activity that was superior to inhaled vancomycin.

PMID:33941518 | DOI:10.1128/AAC.00316-21

J Cyst Fibros. 2021 Apr 15:S1569-1993(21)00110-7. doi: 10.1016/j.jcf.2021.03.028. Online ahead of print.

NO ABSTRACT

PMID:33941502 | DOI:10.1016/j.jcf.2021.03.028