Health Qual Life Outcomes. 2022 Oct 6;20(1):141. doi: 10.1186/s12955-022-02053-2.

ABSTRACT

BACKGROUND: Cough suppression assessed by embarrassment about coughing has been shown in adolescents with cystic fibrosis (CF) and negatively affects health-related quality of life (HRQoL) and clinical indicators of disease severity in adolescent females. However, whether cough suppression exists in adults has been studied as little as its effects on clinical and psychological outcomes beyond adolescence.

METHODS: Seventy-one subjects completed the self-reported 'Cystic Fibrosis Questionnaire-Revised (CFQ-R + 14)' and a self-report questionnaire about cough suppression, health-related perspectives, and therapy adherence. The status of CF disease was quantified in terms of the percentage of predicted forced expiratory volume in one second (ppFEV1), body mass index (BMI), Pseudomonas aeruginosa, pancreatic status, and CF-related diabetes (CFRD). Additional demographic data for sex, age, graduation, employment, and marital status were assessed.

RESULTS: CS exists in adult CF and is associated with impaired HRQoL but not the overall CF disease status regarding BMI, ppFEV1, or health-related perspectives. Despite a higher prevalence of cough suppression in women, no effect of sex regarding either outcome measure was observed.

CONCLUSION: The results of this study suggest that mental health indicators have an impact on cough suppression.

PMID:36203159 | DOI:10.1186/s12955-022-02053-2

Radiol Clin North Am. 2022 Nov;60(6):1021-1032. doi: 10.1016/j.rcl.2022.06.007. Epub 2022 Sep 16.

ABSTRACT

Patients with diffuse lung diseases require thorough medical and social history and physical examinations, coupled with a multitude of laboratory tests, pulmonary function tests, and radiologic imaging to discern and manage the specific disease. This review summarizes the current state of imaging of various diffuse lung diseases by hyperpolarized MR imaging. The potential of hyperpolarized MR imaging as a clinical tool is outlined as a novel imaging approach that enables further understanding of the cause of diffuse lung diseases, permits earlier detection of disease progression before that found with pulmonary function tests, and can delineate physiologic response to lung therapies.

PMID:36202473 | DOI:10.1016/j.rcl.2022.06.007

J Pediatr. 2022 Oct 3:S0022-3476(22)00871-X. doi: 10.1016/j.jpeds.2022.09.049. Online ahead of print.

ABSTRACT

OBJECTIVES: To assess utilization of services provided by a CF Center School Specialist and evaluate relationships among student educational risk scores, family concerns for school engagement and performance, and disease severity.

STUDY DESIGN: Retrospective review of medical records for 126 children with CF in grades K-12 who were screened for educational risk or utilized school intervention services during the 2017- 2020 school years. Regression analyses were performed to identify and quantify predictors of educational risk, family concern for school performance and ability to advocate, and utilization of School Specialist services.

RESULTS: Most children with CF (62-82%) were at moderate to high educational risk. Sixteen or more school absences, family concerns for their child's school performance or inability to advocate for their school needs, child mental health visits, and greater frequency of hospitalization predicted higher educational risk scores and more encounters with the School Specialist. Better lung function and lower grade level were associated with lower educational risk. Number of encounters with the School Specialist remained high across three pre-COVID school years.

CONCLUSIONS: Our experience illustrates a need to identify educational risk and support school experiences of children and youth with cystic fibrosis as a component of the care model. Tailored support, based on identification of risk predictors, has potential to improve educational outcomes.

PMID:36202239 | DOI:10.1016/j.jpeds.2022.09.049

Obstet Gynecol. 2022 Oct 6. doi: 10.1097/AOG.0000000000004959. Online ahead of print.

ABSTRACT

OBJECTIVE: To characterize current trends and outcomes in pregnancies complicated by cystic fibrosis (CF) that resulted in delivery.

METHODS: This repeated cross-sectional study used the U.S. National Inpatient Sample to identify delivery hospitalizations of patients with CF between 2000 and 2019. Trends in delivery hospitalizations of patients with CF were assessed using joinpoint regression to determine the average annual percent change (AAPC). The risk of adverse maternal and obstetric outcomes was compared between patients with and without CF using adjusted logistic regression models accounting for demographic, clinical, and hospital characteristics, with adjusted odds ratios (aORs) with 95% CIs as measures of association. The proportion of patients with CF and other chronic conditions such as pregestational diabetes was analyzed over time.

RESULTS: From 2000 to 2019, the prevalence of CF at delivery increased from 2.1 to 10.4 per 100,000 deliveries (AAPC 6.7%, 95% CI 5.7-8.2%). The proportion of patients with CF and other chronic conditions increased from 18.0% to 37.3% (AAPC 3.1%, 95% CI 1.0-5.3%). Patients with CF were more likely to experience severe maternal morbidity (aOR 2.61, 95% CI 1.71-3.97), respiratory complications (aOR 17.45, 95% CI 11.85-25.68), venous thromboembolism (aOR 3.59, 95% CI 1.33-9.69), preterm delivery (aOR 2.15, 95% CI 1.79-2.59), abruption and antepartum hemorrhage (aOR 1.63, 95% CI 1.10-2.41), and gestational diabetes (aOR 2.47, 95% CI 2.47-3.70).

CONCLUSION: Although still infrequent (approximately 1 in 10,000), deliveries complicated by CF increased approximately fivefold over the study period. The proportion of patients with CF and other chronic conditions is increasing. Patients with CF are at increased risk for a broad range of adverse outcomes.

PMID:36201759 | DOI:10.1097/AOG.0000000000004959

Pediatr Pulmonol. 2022 Oct 6. doi: 10.1002/ppul.26191. Online ahead of print.

ABSTRACT

BACKGROUND: Health related quality of life(HRQoL) scales are now widely used in children with Cystic Fibrosis(cwCF) which reflects the course of the disease. In this cross-sectional study,our primary aim was to compare the Pediatric Oral Health-Related Quality of Life(POQL) and Oral Health Score(OHS) between cwCF and healthy group. Our secondary aim was to evaluate the association between Pseudomonas Aeruginosa(PA) colonization, pulmonary function test, OHS and POQL in cwCF.

METHODS: The study population (age ranging 6-14) included 55 cwCF followed at the Marmara University Division of Pediatric Pulmonology compared with 50 healthy peers. A survey consisted of general questions(age, sex etc.) and the POQL instrument were filled by parents.The decayed, missing and filled teeth for both primary(dft) and permanent dentition(DMFT) was detected according to WHO criteria.Data like current body mass index(BMI z score), colonization status with PA, predicted value for forced expiratory volume in one second(FEV1pp) and any hospitalizations during the previous year were obtained from their medical.Differences between the groups were evaluated using Chi-square and Mann-Whitney U test with a significance level set at 0.05 RESULTS: There was no significant difference between PA colonized cwCF and healthy controls in DMFT(p = 0.916). For all domains of POQL(emotional function, social function, role function), scores of cwCF were significantly better than healthy controls(p<0.05).There were no statistically significant differences between all domains of POQL scores in PA colonized and non-PA colonized cwCF' POQL scores(p>0.05).

CONCLUSION: Evethough POQL scores of cwCF were encouraging,dental caries prevention and regular follow-ups should be taken into consideration. This article is protected by copyright. All rights reserved.

PMID:36200396 | DOI:10.1002/ppul.26191

J Clin Transl Endocrinol. 2022 Sep 27;30:100305. doi: 10.1016/j.jcte.2022.100305. eCollection 2022 Dec.

ABSTRACT

AIMS: Increasing evidence for benefit of early detection of cystic fibrosis related diabetes (CFRD) coupled with limitations of current diagnostic investigations has led to interest and utilisation of continuous glucose monitoring (CGM). We conducted a systematic review to assess current evidence on CGM compared to reference standard oral glucose tolerance test for the detection of dysglycemia in people with cystic fibrosis without confirmed diabetes.

METHODS: MEDLINE, Embase, CENTRAL, Evidence-Based Medicine Reviews, grey literature and six relevant journals were searched for studies published after year 2000. Studies reporting contemporaneous CGM metrics and oral glucose tolerance test results were included. Outcomes on oral glucose tolerance tests were categorised into a) normal, b) abnormal (indeterminate and impaired) or c) diabetic as defined by American Diabetes Association criteria. CGM outcomes were defined as hyperglycemia (≥1 peak sensor glucose ≥ 200 mg/dL), dysglycemia (≥1 peak sensor glucose ≥ 140-199 mg/dL) or normoglycemia (all sensor glucose peaks < 140 mg/dL). CGM hyperglycemia in people with normal or abnormal glucose tolerances was used to define an arbitrary CGM-diagnosis of diabetes. The Quality Assessment of Diagnostic Accuracy Studies tool was used to assess risk of bias. Primary outcome was relative risk of an arbitrary CGM-diagnosis of diabetes compared to the oral glucose tolerance test.

RESULTS: We identified 1277 publications, of which 19 studies were eligible comprising total of 416 individuals with contemporaneous CGM and oral glucose tolerance test results. Relative risk of an arbitrary CGM-diagnosis of diabetes compared to oral glucose tolerance test was 2.92. Studies analysed were highly heterogenous, prone to bias and inadequately assessed longitudinal associations between CGM and relevant disease-specific sequela.

CONCLUSIONS: A single reading > 200 mg/dL on CGM is not appropriate for the diagnosis of CFRD. Prospective studies correlating CGM metrics to disease-specific outcomes are needed to determine appropriate cut-points.

PMID:36200022 | PMC:PMC9529501 | DOI:10.1016/j.jcte.2022.100305

Pediatr Pulmonol. 2022 Oct 5. doi: 10.1002/ppul.26196. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a genetic condition caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein that has traditionally shortened life expectancies and decreased quality of life. Recent advances in pharmacologic therapies have dramatically improved the quality and length of life for many people with CF. With this improved quality and length of life, more people with CF can expect to reach the stages of life where they need to consider their reproductive goals. Consequently, counseling people with CF, especially adolescents, on sexual and reproductive health topics has become increasingly important. We sought to evaluate the frequency of sexual health and reproductive counseling in male and female adolescent individuals within our pediatric CF center. We performed a retrospective chart review between August 2016 and July 2021. One hundred twelve individuals met inclusion criteria, and investigators found documentation related to counseling on various sexual and reproductive health topics in the medical records for 29 individuals (25.9%). Twenty individuals received counseling on a sexual health topic, 19 individuals received counseling on contraception, and 8 individuals received counseling on fertility topics. Most encounters were completed by a pediatric pulmonologist or advanced practice provider. Individuals were also infrequently referred to specialty services for reproductive health. Barriers to implementing regular and uniform counseling practices should be identified and addressed to ensure adolescent people with CF receive these crucial interventions to address individual desires for family planning, prevent unplanned pregnancies and prevent pregnancy-related CF exacerbations. This article is protected by copyright. All rights reserved.

PMID:36199260 | DOI:10.1002/ppul.26196

Trials. 2022 Oct 5;23(1):850. doi: 10.1186/s13063-022-06740-9.

ABSTRACT

BACKGROUND: Self-management support is increasingly viewed as an integral part of chronic condition management in adolescence. It is well recognized that markers of chronic illness control deteriorate during adolescence. Due to the increasing prevalence of long-term chronic health conditions in childhood and improved survival rates of previously life-limiting conditions in children and adolescents, significant numbers of adolescents are having to manage their chronic condition effectively as they transition to adult health care. Therapy adherence has been identified as a major challenge for young people living with a chronic condition such as cystic fibrosis, diabetes, or asthma requiring long-term pharmacological therapy and/or lifestyle modifications. Most systematic reviews on self-management interventions address adult populations. Very few intervention studies are directed at adolescents with a chronic condition who are transitioning to adult health services. This protocol describes a prospective randomized controlled trial of a standardized self-management intervention program delivered to adolescents aged 15-18 years prior to their transfer to adult care. This study has been designed to provide evidence regarding self-management programs for adolescents and is the first study to use the Flinders Program with this important, under-researched age group.

METHODS: A randomized controlled trial is used to investigate the effectiveness of a modified adolescent-friendly version of an adult self-management program. This program is directed at improving self-management in an adolescent cohort 15-18 years of age with a chronic condition being treated in a specialist pediatric hospital. Participants will be randomized to either usual care or the modified Flinders Program plus usual care. Data collection will include measures of specific illness control, unscheduled hospital admissions, and questionnaires to record self-management competencies, quality of life, self-efficacy, and outcome measures specific to the chronic condition at baseline, 3 months, 6 months, and 12 months after delivery.

DISCUSSION: This study will provide a better understanding of the elements required for effective self-management programs in adolescents with a chronic condition and address some important knowledge gaps in current literature. The study will be carried out in collaboration with the Discipline of Behavioural Health at Flinders University, Adelaide, Australia, in order to inform the development of an adolescent version of the successful and validated Flinders Program™.

TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12621000390886). Registered on April 8, 2021.

PMID:36199075 | DOI:10.1186/s13063-022-06740-9

Chem Biodivers. 2022 Oct 5:e202200494. doi: 10.1002/cbdv.202200494. Online ahead of print.

ABSTRACT

Biofilm-producing Staphylococcus aureus (SA) strains are frequently found in medical environments, from surgical/ wound sites, medical devices. These biofilms reduce the efficacy of applied antibiotics during the treatment of several infections, such as cystic fibrosis, endocarditis, or urinary tract infections. Thus, the development of potential therapeutic agents to destroy the extra protective biofilm layers or to inhibit the biofilm-producing enzymes is urgently needed. Advanced and cost-effective bioinformatics tools are advantageous in locating and speeding up the selection of antibiofilm candidates. Based on the potential drug characteristics, we have selected one-hundred thirty-three antibacterial peptides derived from insects to assess for their antibiofilm potency via molecular docking against five putative biofilm formation and regulated target enzymes: the staphylococcal accessory regulator A or SarA (PDB ID: 2FRH), 4,4'-diapophytoene synthase or CrtM (PDB ID: 2ZCQ), clumping factor A or ClfA (PDB ID: 1N67) and serine-aspartate repeat protein C or SdrC (PDB ID: 6LXH) and sortase A or SrtA (PDB ID: 1T2W) of SA bacterium. In this study, molecular docking was performed using HPEPDOCK and HDOCK servers, and molecular interactions were examined using BIOVIA Discovery Studio Visualizer-2019. The docking score (kcal/mol) range of five promising antibiofilm peptides against five targets was recorded as follows: diptericin A (-215.52 to -303.31), defensin (-201.11 to -301.92), imcroporin (-212.08 to -287.64), mucroporin (-228.72 to -286.76), apidaecin II (-203.90 to -280.20). Among these five, imcroporin and mucroporin were 13 % each, while defensin contained only 1 % of positive net charged residues (Arg+Lys) projected through ProtParam and NetWheels tools. Similarly, imcroporin, mucroporin and apidaecin II were 50 %, while defensin carried 21.05 % of hydrophobic residues predicted by the tool PEPTIDE. 2.0. Most of the peptides exhibited potential characteristics to inhibit S. aureus-biofilm formation via disrupting the cell membrane and cytoplasmic integrity. In summary, the proposed hypothesis can be considered a cost-effective platform for selecting the most promising bioactive drug candidates within a limited timeframe with a greater chance of success in experimental and clinical studies.

PMID:36198620 | DOI:10.1002/cbdv.202200494

Endocr J. 2022 Oct 5. doi: 10.1507/endocrj.EJ22-0260. Online ahead of print.

ABSTRACT

Metformin, an oral medication, is prescribed to patients with type 2 diabetes mellitus. Although the efficacy, safety, and low economic burden of metformin on patients have long been recognized, approximately 5% of the patients treated with this drug develop severe diarrhea and discontinue the treatment. We previously reported that 1,000 mg·kg-1·day-1 of metformin induced diarrhea in diabetic obese (db/db) mice and wood creosote (traditional medication for diarrhea) ameliorated the symptoms. In this study, we attempted to elucidate the molecular mechanisms by which metformin induces diarrhea. Cystic fibrosis transmembrane conductance regulator (CFTR) is a key ion (chloride) channel in cyclic adenosine monophosphate (cAMP)-induced diarrhea. Metformin treatment increased bile flow (bile acids and bilirubin) in the ileum of mice. In addition, the treatment was accompanied by an increase in mRNA and protein levels of CFTR in the mucosa of the ileum and colon in both wild-type (C57BL/6J) and db/db mice. Glucagon-like peptide-1 (GLP-1), as well as cholic acid, induces CFTR mRNA expression in human colon carcinoma Caco-2 cells through cAMP signaling. Although wood creosote (10 mg/kg) ameliorated diarrhea symptoms, it did not alter the mRNA levels of Glp-1 or Cftr. Similar to overeating, metformin upregulated GLP-1 and CFTR expression, which may have contributed to diarrhea symptoms in mice. Although we could not identify db/db mouse-specific factors associated with metformin-induced diarrhea, these factors may modulate colon function. Wood creosote may not interact with these factors but ameliorates diarrhea symptoms.

PMID:36198615 | DOI:10.1507/endocrj.EJ22-0260

Eur Respir Rev. 2022 Oct 5;31(166):220121. doi: 10.1183/16000617.0121-2022. Print 2022 Dec 31.

ABSTRACT

Lower respiratory tract infections lead to significant morbidity and mortality. They are increasingly caused by multidrug-resistant pathogens, notably in individuals with cystic fibrosis, hospital-acquired pneumonia and lung transplantation. The use of bacteriophages (phages) to treat bacterial infections is gaining growing attention, with numerous published cases of compassionate treatment over the last few years. Although the use of phages appears safe, the lack of standardisation, the significant heterogeneity of published studies and the paucity of robust efficacy data, alongside regulatory hurdles arising from the existing pharmaceutical legislation, are just some of the challenges phage therapy has to overcome. In this review, we discuss the lessons learned from recent clinical experiences of phage therapy for the treatment of pulmonary infections. We review the key aspects, opportunities and challenges of phage therapy regarding formulations and administration routes, interactions with antibiotics and the immune system, and phage resistance. Building upon the current knowledge base, future pre-clinical studies using emerging technologies and carefully designed clinical trials are expected to enhance our understanding and explore the therapeutic potential of phage therapy.

PMID:36198417 | DOI:10.1183/16000617.0121-2022

J Hosp Infect. 2022 Oct 2:S0195-6701(22)00312-7. doi: 10.1016/j.jhin.2022.09.017. Online ahead of print.

ABSTRACT

As the SARS-CoV-2 pandemic has proceeded, ventilation has been increasingly recognised as an important tool in infection control. Many hospitals in Ireland and the UK do not have mechanical ventilation and depend on natural ventilation. The effectiveness of natural ventilation varies with atmospheric conditions and building design. In a challenge test of a legacy design ward, we show that portable air filtration significantly increases clearance of pollutant aerosols of respirable size compared with natural ventilation and reduces spatial variation in particle persistence. Combined natural ventilation and portable air filtration are significantly more effective in particle clearance than either intervention alone.

PMID:36198345 | DOI:10.1016/j.jhin.2022.09.017

Am J Hum Genet. 2022 Sep 26:S0002-9297(22)00412-8. doi: 10.1016/j.ajhg.2022.09.009. Online ahead of print.

ABSTRACT

Whole-genome sequencing (WGS) is the gold standard for fully characterizing genetic variation but is still prohibitively expensive for large samples. To reduce costs, many studies sequence only a subset of individuals or genomic regions, and genotype imputation is used to infer genotypes for the remaining individuals or regions without sequencing data. However, not all variants can be well imputed, and the current state-of-the-art imputation quality metric, denoted as standard Rsq, is poorly calibrated for lower-frequency variants. Here, we propose MagicalRsq, a machine-learning-based method that integrates variant-level imputation and population genetics statistics, to provide a better calibrated imputation quality metric. Leveraging WGS data from the Cystic Fibrosis Genome Project (CFGP), and whole-exome sequence data from UK BioBank (UKB), we performed comprehensive experiments to evaluate the performance of MagicalRsq compared to standard Rsq for partially sequenced studies. We found that MagicalRsq aligns better with true R2 than standard Rsq in almost every situation evaluated, for both European and African ancestry samples. For example, when applying models trained from 1,992 CFGP sequenced samples to an independent 3,103 samples with no sequencing but TOPMed imputation from array genotypes, MagicalRsq, compared to standard Rsq, achieved net gains of 1.4 million rare, 117k low-frequency, and 18k common variants, where net gains were gained numbers of correctly distinguished variants by MagicalRsq over standard Rsq. MagicalRsq can serve as an improved post-imputation quality metric and will benefit downstream analysis by better distinguishing well-imputed variants from those poorly imputed. MagicalRsq is freely available on GitHub.

PMID:36198314 | DOI:10.1016/j.ajhg.2022.09.009

Sci Adv. 2022 Oct 7;8(40):eabo0522. doi: 10.1126/sciadv.abo0522. Epub 2022 Oct 5.

ABSTRACT

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. We sought to correct the multiple organ dysfunction of the F508del CF-causing mutation using systemic delivery of peptide nucleic acid gene editing technology mediated by biocompatible polymeric nanoparticles. We confirmed phenotypic and genotypic modification in vitro in primary nasal epithelial cells from F508del mice grown at air-liquid interface and in vivo in F508del mice following intravenous delivery. In vivo treatment resulted in a partial gain of CFTR function in epithelia as measured by in situ potential differences and Ussing chamber assays and correction of CFTR in both airway and GI tissues with no off-target effects above background. Our studies demonstrate that systemic gene editing is possible, and more specifically that intravenous delivery of PNA NPs designed to correct CF-causing mutations is a viable option to ameliorate CF in multiple affected organs.

PMID:36197984 | DOI:10.1126/sciadv.abo0522

Antimicrob Agents Chemother. 2022 Oct 5:e0053922. doi: 10.1128/aac.00539-22. Online ahead of print.

ABSTRACT

Mycobacterium abscessus is an emerging nontuberculous mycobacterium (NTM) pathogen infecting susceptible people with cystic fibrosis (CF) and non-CF bronchiectasis. Here, we demonstrated the activity of an FDA-approved drug, disulfiram, against drug-susceptible and drug-resistant M. abscessus strains utilizing in vitro and intracellular macrophage assays and a zebrafish embryo infection model. These data demonstrate effective antimicrobial activity of disulfiram against M. abscessus infection in vivo and strongly support further study of disulfiram in human NTM infections.

PMID:36197094 | DOI:10.1128/aac.00539-22

Eur Rev Med Pharmacol Sci. 2022 Sep;26(18):6569-6571. doi: 10.26355/eurrev_202209_29755.

ABSTRACT

INTRODUCTION: Young's syndrome (YS) is a rare, inherited syndrome commonly seen in middle-aged men with chronic rhinosinusitis, nasal polyps, decreased fertility due to azoospermia, and bronchiectasis. In this paper, we present a case of YS of unknown cause together with a literature review.

CASE PRESENTATION: A 28-year-old male patient with the complaints of cough, sputum, recurrent nasal congestion, and shortness of breath lasting for more than ten years, was admitted to our clinic after bronchiectasis was observed in the thoracic computed tomography.

CONCLUSIONS: An accurate diagnosis of YS is usually made late, which reduces patients' quality of life and leads to chronic respiratory problems. Failure to diagnose this disease may expose the patient to unnecessary and repeated hospitalizations and examinations, and result in treatment failure.

PMID:36196705 | DOI:10.26355/eurrev_202209_29755

Pediatr Pulmonol. 2022 Oct 4. doi: 10.1002/ppul.26183. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is the most common autosomal recessive disorder in the Caucasian population, with an incidence of 1:5000 live births. In 2011, the screening of CF was implemented in the Andalusian Public Health newborn screening program by using immunoreactive trypsinogen and chloride sweat test (IRT/IRT/sweat test) determinations. Since then, 79 children have been diagnosed with CF in our health area (Western Andalusia). The aim of this study was to evaluate the efficiency of this screening method and to examinate the characteristics of those CF infants who had a negative screening but who were later diagnosed. In the 2011-2021 period 462049 newborns were screened for CF using a two-step IRT determination and chloride sweat test. 63 infants were diagnosed with CF in our health area thanks to the screening, and 15 CF children had a negative screening result and were finally diagnosed by molecular sequencing of the CFTR gene. The most frequent symptoms that led to the diagnosis of those false negative (FN) patients were hyponatremic dehydration (mean age 9.75±1.5 months) and recurrent wheezing (mean age 24±14.5 months). The molecular analysis of the CFTR gene on those FN showed a diversity of genotypes, identifying more than 10 different mutations. Conclusion: The rate of FN patients obtained in this study is inadmissibly high, and the protocol used in this region has not been updated despite the advances in genetic testing in the past 10 years. An improvement on CF newborn screening should be implemented, adding molecular analysis of the CFTR gene. This article is protected by copyright. All rights reserved.

PMID:36196044 | DOI:10.1002/ppul.26183

Am J Respir Cell Mol Biol. 2022 Oct 4. doi: 10.1165/rcmb.2022-0038TR. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a multisystemic, autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene with the majority of morbidity and mortality extending from lung disease. Single-cell RNA-sequencing (scRNA-seq) has been leveraged in the lung and elsewhere in the body to articulate discrete cell populations, describing cell types, states, and lineages as well as their roles in health and disease. In this perspective translational review, we provide an overview of the current applications of scRNA-seq to the study of the normal and CF lungs, allowing for the beginning of a new cellular and molecular narrative of CF lung disease, and highlight some of the future opportunities to further leverage scRNA-seq and complementary single-cell technologies in the study of CF as we bridge from scientific understanding to clinical application.

PMID:36194688 | DOI:10.1165/rcmb.2022-0038TR

JCI Insight. 2022 Oct 4:e158879. doi: 10.1172/jci.insight.158879. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa undergoes diversification during infection of the cystic fibrosis (CF) lung. Understanding these changes requires model systems that capture the complexity of the CF lung environment. We previously identified loss-of-function mutations in the two-component regulatory system sensor kinase gene pmrB, in P. aeruginosa from CF and from experimental infection of mice. Here, we demonstrate that whilst such mutations lower in vitro MICs for multiple antimicrobial classes, this is not reflected in increased antibiotic susceptibility in vivo. Loss of PmrB impairs aminoarabinose modification of lipopolysaccharide, increasing the negative charge of the outer membrane and promoting uptake of cationic antimicrobials. However, in vivo, this can be offset by increased membrane binding of other positively charged molecules present in lungs. The polyamine spermidine readily coats the surface of PmrB-deficient P. aeruginosa, reducing susceptibility to antibiotics that rely on charge differences to bind the outer membrane and increasing biofilm formation. Spermidine is elevated in lungs during P. aeruginosa infection in mice and during episodes of antimicrobial treatment in people with CF. These findings highlight the need to study antimicrobial resistance under clinically relevant environmental conditions. Microbial mutations carrying fitness costs in vitro may be advantageous during infection, where host resources can be utilised.

PMID:36194492 | DOI:10.1172/jci.insight.158879

Microbiol Spectr. 2022 Oct 4:e0169622. doi: 10.1128/spectrum.01696-22. Online ahead of print.

ABSTRACT

Phytochemicals are promising antibacterials for the development of novel antibiofilm drugs, but their antibiofilm activity in physiologically relevant model systems is poorly characterized. As the host microenvironment can interfere with the activity of the phytochemicals, mimicking the complex environment found in biofilm associated infections is essential to predict the clinical potential of novel phytochemical-based antimicrobials. In the present study, we examined the antibiofilm activity of borneol, citral, and combinations of both as well as their Pickering emulsions against Staphylococcus aureus and Pseudomonas aeruginosa in an in vivo-like synthetic cystic fibrosis medium (SCFM2) model, an in vitro wound model (consisting of an artificial dermis and blood components at physiological levels), and an in vivo Galleria mellonella model. The Pickering emulsions demonstrated an enhanced biofilm inhibitory activity compared to both citral and the borneol/citral combination, reducing the minimum biofilm inhibitory concentration (MBIC) values up to 2 to 4 times against P. aeruginosa PAO1 and 2 to 8 times against S. aureus P8-AE1 in SCMF2. In addition, citral, the combination borneol/citral, and their Pickering emulsions can completely eliminate the established biofilm of S. aureus P8-AE1. The effectiveness of Pickering emulsions was also demonstrated in the wound model with a reduction of up to 4.8 log units in biofilm formation by S. aureus Mu50. Furthermore, citral and Pickering emulsions exhibited a significant degree of protection against S. aureus infection in the G. mellonella model. The present findings reveal the potential of citral- or borneol/citral-based Pickering emulsions as a type of alternative antibiofilm candidate to control pathogenicity in chronic infection. IMPORTANCE There is clearly an urgent need for novel formulations with antimicrobial and antibiofilm activity, but while there are plenty of studies investigating them using simple in vitro systems, there is a lack of studies in which (combinations of) phytochemicals are evaluated in relevant models that closely resemble the in vivo situation. Here, we examined the antibiofilm activity of borneol, citral, and their combination as well as Pickering emulsions (stabilized by solid particles) of these compounds. Activity was tested against Staphylococcus aureus and Pseudomonas aeruginosa in in vitro models mimicking cystic fibrosis sputum and wounds as well as in an in vivo Galleria mellonella model. The Pickering emulsions showed drastically increased antibiofilm activity compared to that of the compounds as such in both in vitro models and protected G. mellonella larvae from S. aureus-induced killing. Our data show that Pickering emulsions from phytochemicals are potentially useful for treating specific biofilm-related chronic infections.

PMID:36194139 | DOI:10.1128/spectrum.01696-22