Infect Drug Resist. 2023 Sep 6;16:5887-5898. doi: 10.2147/IDR.S426111. eCollection 2023.

ABSTRACT

BACKGROUND: Pseudomonas aeruginosa is an opportunistic pathogen involved in number of hospital-acquired infections such as catheter-associated urinary tract infections, bacteremia, septicemia, skin infections, and ventilator-associated pneumoniae. Biofilm formation is an important trait implicated in chronic infections, such as cystic fibrosis and chronic pulmonary obstruction. We evaluated effects of gentamicin, cefepime, and ciprofloxacin on biofilm of P. aeruginosa.

MATERIALS AND METHODS: A total of 266 isolates were collected from the Armed Forces Institute of Pathology (AFIP). Antibiotic susceptibility was assessed by double disk synergy testing. ESBL and carbapenemase detection was performed by phenotypic testing. Molecular screening of the genes was done by PCR. Micro-dilution broth method was used to determine minimum inhibitory concentrations of antibiotics. Biofilm formation was done by micro-titer plate assay.

RESULTS: Overall, 20% of the P. aeruginosa isolates were extensively drug-resistant (XDR-PA), and 25% were multi-drug-resistant (MDR-PA). Likewise, 43% of the isolates were ESBL producers, and carbapenemase production was detected in 40% of the isolates. Molecular analysis confirmed occurrence of different resistant factors in ESBL-positive isolates; 67% carried blaTEM, 62% blaCTXM-15, 41% blaSHV, 34% blaCTXM-14, and 33% blaOXA-1. In addition, 68% of the carbapenem-resistant isolates were positive for blaNDM-1, 25% for blaOXA-48, and 22% for blaKPC-2. Biofilm formation was assessed for 234 isolates, out of which 28% were strong biofilm formers. Moderate and weak biofilm formers constituted 46% and 23%, respectively. Overall, ciprofloxacin, levofloxacin, and cefepime showed inhibitory effects on P. aeruginosa biofilms. Antibiotics in combination showed strong synergistic effects (ciprofloxacin and cefepime), while gentamicin and cefepime resulted in complete eradication of P. aeruginosa biofilm.

CONCLUSION: We confirm strong synergistic effects of gentamicin and cefepime that completely eradicated P. aeruginosa biofilm. We further confirm inhibitory effects of ciprofloxacin, levofloxacin, and cefepime on P. aeruginosa biofilms. Hence, combination therapy can be more effective against biofilm-associated infections.

PMID:37692466 | PMC:PMC10485136 | DOI:10.2147/IDR.S426111

J Thorac Dis. 2023 Aug 31;15(8):4285-4291. doi: 10.21037/jtd-23-111. Epub 2023 Jul 31.

ABSTRACT

BACKGROUND: Chronic lung infections represent a diversity of clinical entities that combined respond to significant public health, particularly in developing countries. However, there is no data regarding the practice patterns, surgeons' preferences, and technological usage, especially among Brazilian surgeons, in the setting of the surgical treatment of chronic lung infections. We, therefore, surveyed Brazilian thoracic surgeons from the Brazilian Society of Thoracic Surgery (SBCT) about practice patterns and trends in surgical treatment for chronic lung infections.

METHODS: A cross-sectional anonymous survey of all thoracic surgeons from the Brazilian Society was conducted in 2019. As the study was purely descriptive no further statistical evaluation was performed.

RESULTS: The responsive rate was 34% (259/766) from 23 of the 26 states in Brazil. A total of 141 (54.4%) participants reported their institution as a surgical reference for chronic infection lung disease, only 13.1% of surgeons have a high-volume service (more than 11 cases operated annually). The majority (76.2%) of respondents performed 1-5 surgical resection to treat tuberculosis (TB) sequelae, but only 62 (30.1%) had performed more than one resection to treat active TB. Chronic lung infection (76%) and hemoptysis (66%) were the most common symptoms as surgical indications. A proportion of 42.2% of the respondents do not have and/or perform routine drug sensitivity tests. In addition, 19.3% of respondents were not familiar with the recommendations of surgery in the treatment of pulmonary TB. Video-assisted thoracoscopic surgery (VATS) is available for 80% of respondents, while robotic surgery is for only 10%. Most (86%) surgeons have access to surgical staplers. Among the structural resources, respiratory isolation beds in the intensive care unit (ICU) (80%) and ward (79%) are frequently available resources. However, less than 12% of surgeons have in their institution a specific operating room for sputum-positive patients.

CONCLUSIONS: Lung resection for chronic infectious disease is an essential area of activity for thoracic surgeons in Brazil, which occurs mainly in the public sphere, with no concentration of cases per surgeon or institution. The lack of adequate resources in many centers justifies the creation of reference centers for improving care for these patients.

PMID:37691680 | PMC:PMC10482616 | DOI:10.21037/jtd-23-111

Eur Respir J. 2023 Sep 9;62(3):2301354. doi: 10.1183/13993003.01354-2023. Print 2023 Sep.

NO ABSTRACT

PMID:37690789 | DOI:10.1183/13993003.01354-2023

J Biol Chem. 2023 Sep 8:105242. doi: 10.1016/j.jbc.2023.105242. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is one of the most prevalent lethal genetic diseases with over 2000 identified mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Pharmacological chaperones such as Lumacaftor (VX-809), Tezacaftor (VX-661) and Elexacaftor (VX-445) treat mutation-induced defects by stabilizing CFTR and are called correctors. These correctors improve proper folding and thus facilitate processing and trafficking to increase the amount of functional CFTR on the cell surface. Yet, CFTR variants display differential responses to each corrector. Here, we report variants P67L and L206W respond similarly to VX-809 but divergently to VX-445 with P67L exhibiting little rescue when treated with VX-445. We investigate the underlying cellular mechanisms of how CFTR biogenesis is altered by correctors in these variants. Affinity purification-mass spectrometry (AP-MS) multiplexed with isobaric Tandem Mass Tags (TMT) was used to quantify CFTR protein-protein interaction changes between variants P67L and L206W. VX-445 facilitates unique proteostasis factor interactions especially in translation, folding, and degradation pathways in a CFTR variant-dependent manner. A number of these interacting proteins knocked down by siRNA, such as ribosomal subunit proteins, moderately rescued fully glycosylated P67L. Importantly, these knockdowns sensitize P67L to VX-445 and further enhance the trafficking correction of this variant. Partial inhibition of protein translation also mildly sensitizes P67L CFTR to VX-445 correction, supporting a role for translational dynamics in the rescue mechanism of VX-445. Our results provide a better understanding of VX-445 biological mechanism of action and reveal cellular targets that may sensitize unresponsive CFTR variants to known and available correctors.

PMID:37690692 | DOI:10.1016/j.jbc.2023.105242

Respir Med. 2023 Sep 8:107406. doi: 10.1016/j.rmed.2023.107406. Online ahead of print.

ABSTRACT

BACKGROUND: The combination of cystic fibrosis transmembrane conductance regulator (CFTR) modulators elexacaftor, tezacaftor and ivacaftor (ELX/TEZ/IVA) has been approved for treatment of cystic fibrosis (CF) patients (pwCF) homozygous and heterozygous for Phe508del. We aim to assess the long-term effects of ELX/TEZ/IVA therapy on clinical outcomes in severe pwCF.

METHODS: Lung function, pulmonary exacerbation (PEx), sweat chloride concentration, body mass index (BMI) and the respiratory domain of the cystic fibrosis questionnaire-revised (CFQ-R RD) were prospectively evaluated in a cohort of pwCF who were candidates for inclusion in a compassionate program of ELX/TEZ/IVA therapy. All procedures were performed at baseline and then at 12 and 24 months after initiation of modulator therapy. The number of PExs in the year before the study enrollment was collected from our records.

RESULTS: Thirty-six adult pwCF (median age 36.7 years; BMI 19.8 kg/m2; FEV1 36.5% predicted) were recruited from 2019. At 12 and 24 months after initiation, the absolute change in ppFEV1 (percent predicted forced expiratory volume in 1 s) from baseline was +12.5% (p < 0.0001) and +13% (p < 0.0001), respectively. A median of 4.0 exacerbations per patient was reported in the preceding year, while the median number of PExs was 0.0 and 1.0 after 12 and 24 months, respectively, of modulator therapy (both p < 0.0001). After 12 and 24 months of ELX/TEZ/IVA therapy, the CFQ-R RD score improved by 22.4 points (p < 0.0001) and 16.7 points (p < 0.0001), and sweat chloride levels decreased by 65.5 mmol/L (p < 0.0001) and 60 mmol/L (p < 0.0001), respectively. BMI significantly increased.

CONCLUSIONS: Long-term ELX/TEZ/IVA combination therapy markedly impacts the clinical status of patients with severe CF, showing a sustained improvement in lung function and PEx rate.

PMID:37690570 | DOI:10.1016/j.rmed.2023.107406

J Cyst Fibros. 2023 Sep 7:S1569-1993(23)00903-7. doi: 10.1016/j.jcf.2023.08.014. Online ahead of print.

NO ABSTRACT

PMID:37689566 | DOI:10.1016/j.jcf.2023.08.014

Diabetes Metab. 2023 Sep 7:101476. doi: 10.1016/j.diabet.2023.101476. Online ahead of print.

ABSTRACT

AIM: Managing blood glucose (BG) levels during intense physical activity is challenging for elite athletes with type 1 diabetes (T1D), as it can lead to unpredictable hyper- or hypoglycemia, which can affect performance. This case study presents an 18-year-old male hockey goalie with hyperglycemia-related anxiety during competition and its impact on his T1D management.

METHODS: Mixed-methods approach, incorporating qualitative data from an unstructured interview and responses from the Hyperglycemia Avoidance Scale along with quantitative data retrieved from Diasend and laboratory results.

RESULTS: The athlete experiences physical and cognitive symptoms during hyperglycemia, affecting his performance. Hyperglycemia-related anxiety influences insulin dosage adjustments and eating habits on game days. Glycemic variability analysis reveals lower BG levels during game time.

CONCLUSION: Hyperglycemia-related anxiety leads to modified therapeutic and lifestyle regimens on competition day. Tailored treatment programs are needed for elite athletes with T1D and hyperglycemia-related anxiety.

PMID:37689238 | DOI:10.1016/j.diabet.2023.101476

Nutrients. 2023 Sep 3;15(17):3846. doi: 10.3390/nu15173846.

ABSTRACT

Cystic Fibrosis-related gut dysbiosis (CFRGD) has become a recognised complication in children with this condition, and current evidence remains insufficient to guide the selection of probiotic strains for supplementation treatments. The aim of this study was to characterise the effect of three probiotic strains on CFRGD by means of a dynamic in vitro simulation of the colonic fermentation (SHIME®). The configuration of the system included three bioreactors colonised with the faecal inoculum of a child with cystic fibrosis. For 20 days, each bioreactor was supplied daily with either Lacticaseibacillus rhamnosus GG (ATCC 53103 TM), Limosilactobacillus reuteri (DSM 17938) or Lactiplantibacillus plantarum (DSM 22266). The baseline microbiota was characterised by a high abundance of Prevotella, Faecalibacterium and Acidaminococcus genera. After 20 days of supplementation, L. rhamnosus and L. plantarum reduced Prevotella significantly, and the three strains led to increased Faecalibacterium and Bifidobacterium and decreased Acidaminococcus, with some of these changes being maintained 10 days after ceasing supplementation. The metabolic activity remained unaltered in terms of short-chain fatty acids, but branched-chain fatty acids showed a significant decrease, especially with L. plantarum. Additionally, ammonia decreased at 20 days of supplementation, and lactate continuously increased with the three strains. The effects on colonic microbiota of L. rhamnosus, L. reuteri or L. plantarum were established, including increased beneficial bacteria, such as Faecalibacterium, and beneficial metabolites such as lactate; and on the other hand, a reduction in pathogenic genera, including Prevotella or Acidaminococcus and branched-chain fatty acids, overall supported their use as probiotics in the context of CFRGD.

PMID:37686878 | DOI:10.3390/nu15173846

Cancers (Basel). 2023 Aug 24;15(17):4244. doi: 10.3390/cancers15174244.

ABSTRACT

Cystic fibrosis (CF) is a genetic disorder affecting multiple organs, primarily the lungs and digestive system. Over the years, advancements in medical care and treatments have significantly increased the life expectancy of individuals with CF. However, with this improved longevity, concerns about the potential risk of developing certain types of cancers have arisen. This narrative review aims to explore the relationship between CF, increased life expectancy, and the associated risk for cancers. We discuss the potential mechanisms underlying this risk, including chronic inflammation, immune system dysregulation, and genetic factors. Additionally, we review studies that have examined the incidence and types of cancers seen in CF patients, with a focus on gastrointestinal, breast, and respiratory malignancies. We also explore the impact of CFTR modulator therapies on cancer risk. In the gastrointestinal tract, CF patients have an elevated risk of developing colorectal cancer, pancreatic cancer, and possibly esophageal cancer. The underlying mechanisms contributing to these increased risks are not fully understood, but chronic inflammation, altered gut microbiota, and genetic factors are believed to play a role. Regular surveillance and colonoscopies are recommended for early detection and management of colorectal cancer in CF patients. Understanding the factors contributing to cancer development in CF patients is crucial for implementing appropriate surveillance strategies and improving long-term outcomes. Further research is needed to elucidate the molecular mechanisms involved and develop targeted interventions to mitigate cancer risk in individuals with CF.

PMID:37686519 | DOI:10.3390/cancers15174244

Int J Mol Sci. 2023 Aug 29;24(17):13384. doi: 10.3390/ijms241713384.

ABSTRACT

BACKGROUND: The most recent modulator combination, elexacaftor/tezacaftor/ivacaftor (Trikafta®), has been shown to improve clinical outcomes in most patients with cystic fibrosis (PwCF). Unfortunately, the clinical benefits are sometimes variable; thus, improving our knowledge of the possible causes of this variability can help reduce it.

METHODS: Circulating mononuclear cells (CMCs) and plasma were collected from 16 PwCF (including those on Trikafta® therapy) and 4 non-CF subjects. Cystic fibrosis transmembrane conductance regulator (CFTR) activity and matrix metalloprotease 9 (MMP9) expression were monitored before and after therapy, together with some clinical parameters. The relationship between MMP9 expression and the modulation of the extracellular-regulated 1/2 (ERK1/2) and nuclear factor-kB (NF-kB) pathways was also analyzed.

RESULTS: MMP9, markedly expressed in the CMCs and plasma of all the patients included in the study, was downregulated in the clinically responsive PwCF. In the non-responder, the MMP9 levels remained high. The modulation of MMP9 following treatment with Trikafta® may be controlled by the NF-kB pathway.

CONCLUSIONS: These data strongly suggest that MMP9 downregulation is a potential biomarker of therapy efficacy and that it could be useful in understanding the molecular events underlying the variable clinical responses of patients to Trikafta®. This knowledge could be helpful for future studies of personalized medicine and thereby ensure improvements in individual responses to therapies.

PMID:37686190 | DOI:10.3390/ijms241713384

Int J Mol Sci. 2023 Aug 26;24(17):13278. doi: 10.3390/ijms241713278.

ABSTRACT

The Cl--transporting proteins CFTR, SLC26A9, and anoctamin (ANO1; ANO6) appear to have more in common than initially suspected, as they all participate in the pathogenic process and clinical outcomes of airway and renal diseases. In the present review, we will therefore concentrate on recent findings concerning electrolyte transport in the airways and kidneys, and the role of CFTR, SLC26A9, and the anoctamins ANO1 and ANO6. Special emphasis will be placed on cystic fibrosis and asthma, as well as renal alkalosis and polycystic kidney disease. In essence, we will summarize recent evidence indicating that CFTR is the only relevant secretory Cl- channel in airways under basal (nonstimulated) conditions and after stimulation by secretagogues. Information is provided on the expressions of ANO1 and ANO6, which are important for the correct expression and function of CFTR. In addition, there is evidence that the Cl- transporter SLC26A9 expressed in the airways may have a reabsorptive rather than a Cl--secretory function. In the renal collecting ducts, bicarbonate secretion occurs through a synergistic action of CFTR and the Cl-/HCO3- transporter SLC26A4 (pendrin), which is probably supported by ANO1. Finally, in autosomal dominant polycystic kidney disease (ADPKD), the secretory function of CFTR in renal cyst formation may have been overestimated, whereas ANO1 and ANO6 have now been shown to be crucial in ADPKD and therefore represent new pharmacological targets for the treatment of polycystic kidney disease.

PMID:37686084 | DOI:10.3390/ijms241713278

Int J Mol Sci. 2023 Aug 25;24(17):13202. doi: 10.3390/ijms241713202.

ABSTRACT

The rapid advancements in gene therapy have opened up new possibilities for treating genetic disorders, including Duchenne muscular dystrophy, thalassemia, cystic fibrosis, hemophilia, and familial hypercholesterolemia. The utilization of the clustered, regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas) system has revolutionized the field of gene therapy by enabling precise targeting of genes. In recent years, CRISPR/Cas9 has demonstrated remarkable efficacy in treating cancer and genetic diseases. However, the susceptibility of nucleic acid drugs to degradation by nucleic acid endonucleases necessitates the development of functional vectors capable of protecting the nucleic acids from enzymatic degradation while ensuring safety and effectiveness. This review explores the biomedical potential of non-viral vector-based CRISPR/Cas9 systems for treating genetic diseases. Furthermore, it provides a comprehensive overview of recent advances in viral and non-viral vector-based gene therapy for genetic disorders, including preclinical and clinical study insights. Additionally, the review analyzes the current limitations of these delivery systems and proposes avenues for developing novel nano-delivery platforms.

PMID:37686009 | DOI:10.3390/ijms241713202

Eur J Epidemiol. 2023 Sep 8. doi: 10.1007/s10654-023-01044-x. Online ahead of print.

ABSTRACT

The impact of COVID-19 on mortality from specific causes of death remains poorly understood. This study analysed cause-of-death data provided by the World Health Organization from 2011 to 2019 to estimate excess deaths in 2020 in 30 countries. Over-dispersed Poisson regression models were used to estimate the number of deaths that would have been expected if the pandemic had not occurred, separately for men and women. The models included year and age categories to account for temporal trends and changes in size and age structure of the populations. Excess deaths were calculated by subtracting observed deaths from expected ones. Our analysis revealed significant excess deaths from ischemic heart diseases (IHD) (in 10 countries), cerebrovascular diseases (CVD) (in 10 countries), and diabetes (in 19 countries). The majority of countries experienced excess mortality greater than 10%, including Mexico (+ 38·8% for IHD, + 34·9% for diabetes), Guatemala (+ 30·0% for IHD, + 10·2% for CVD, + 39·7% for diabetes), Cuba (+ 18·8% for diabetes), Brazil (+ 12·9% for diabetes), the USA (+ 15·1% for diabetes), Slovenia (+ 33·8% for diabetes), Poland (+ 30·2% for IHD, + 19·5% for CVD, + 26 1% for diabetes), Estonia (+ 26·9% for CVD, + 34·7% for diabetes), Bulgaria (+ 22·8% for IHD, + 11·4% for diabetes), Spain (+ 19·7% for diabetes), Italy (+ 18·0% for diabetes), Lithuania (+ 17·6% for diabetes), Finland (+ 13·2% for diabetes) and Georgia (+ 10·7% for IHD, + 19·0% for diabetes). In 2020, 22 out of 30 countries had a significant increase in total mortality. Some of this excess was attributed to COVID-19, but a substantial increase was also observed in deaths attributed to cardiovascular diseases and diabetes.

PMID:37684387 | DOI:10.1007/s10654-023-01044-x

Ann Am Thorac Soc. 2023 Sep 8. doi: 10.1513/AnnalsATS.202303-245OC. Online ahead of print.

ABSTRACT

RATIONALE: Despite the high prevalence and clear morbidity of cystic fibrosis (CF) pulmonary exacerbations (PEx), there have been no published clinical trials of outpatient exacerbation management.

OBJECTIVE: To assess the feasibility of a pediatric clinical trial in which treatment of a mild PEx is assigned randomly to immediate oral antibiotics or "tailored therapy" (increased airway clearance alone with oral antibiotics added only for pre-specified criteria). The outcome on which sample size was based was the proportion of tailored therapy participants who avoided oral antibiotics during the 28 days following randomization.

METHODS: In this randomized open-label pilot feasibility study at 10 US sites, children ages 6 to 18 years with CF were enrolled at their well baseline and followed through their first randomized PEx.

RESULTS: 121 participants were enrolled, among whom 94 (78%) reported PEx symptoms at least once; among these, 81 (86%) had at least one PEx that met randomization criteria of which 63 (78%) were randomized. Feasibility goals were met, including enrollment, early detection of PEx symptoms and ability to randomize. Among the 33 participants assigned to tailored therapy, 10 (30%) received oral antibiotics, while 29/30 (97%) assigned to immediate antibiotics received oral antibiotics. The avoidance of oral antibiotics in 70 (95% CI 54, 85)% was statistically significantly different from our null hypothesis that <10% of participants assigned to the tailored therapy arm would avoid antibiotics.

CONCLUSIONS: Our pilot study demonstrates that conducting a randomized trial of oral antibiotic treatment strategies for mild pulmonary exacerbations in children with CF is feasible and that assignment to a tailored therapy arm may reduce antibiotic exposure.

CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT04608019 Primary source of funding: Cystic Fibrosis Foundation.

PMID:37683122 | DOI:10.1513/AnnalsATS.202303-245OC

J Public Health (Oxf). 2023 Sep 7:fdad164. doi: 10.1093/pubmed/fdad164. Online ahead of print.

ABSTRACT

BACKGROUND: This study provides a nationwide representative quantification of the impact of educational inequalities on cancer mortality in Italy.

METHODS: The study is based on prevalence data and mortality rate ratios according to levels of education obtained from the Italian 2011 census cohort, including >35 million individuals aged 30-74. We estimated the population attributable fraction (PAF) and the number of cancer deaths associated with low education (below university degree) in Italy by sex.

RESULTS: PAFs for low levels of education were 29.1% among men and 13.3% among women, corresponding to 22,271 cancer deaths associated with low education in men and 7456 in women in 2019. PAFs by cancer site in men were: 53.0% for upper aerodigestive tract (UADT), 44.6% for liver, 41.3% for stomach, 41.3% for lung, 37.0% for bladder, 18.5% for colorectal, 9.8% for prostate and 9.1% for pancreatic cancers. PAFs in women were: 44.5% for cervical, 36.1% for UADT, 34.9% for stomach and 13.9% for colorectal cancers. The cancer sites with the highest number of deaths associated with low education were lung among men (7902/22,271, 35.5%) and colorectum among women (780/7456, 10.5%).

CONCLUSIONS: About a quarter of cancer deaths in 2019 in Italy may be prevented by reducing the socioeconomic determinants that contribute to educational disparities in cancer mortality.

PMID:37681283 | DOI:10.1093/pubmed/fdad164

Front Cell Infect Microbiol. 2023 Aug 23;13:1196581. doi: 10.3389/fcimb.2023.1196581. eCollection 2023.

ABSTRACT

Lung infection with the fungus Aspergillus fumigatus (Af) is a common complication in cystic fibrosis (CF) and is associated with loss of pulmonary function. We established a fungal epithelial co-culture model to examine the impact of Af infection on CF bronchial epithelial barrier function using Af strains 10AF and AF293-GFP, and the CFBE41o- cell line homozygous for the F508del mutation with (CF+CFTR) and without (CF) normal CFTR expression. Following exposure of the epithelial surface to Af conidia, formation of germlings (early stages of fungal growth) was detected after 9-12 hours and hyphae (mature fungal growth) after 12-24 hours. During fungal morphogenesis, bronchial epithelial cells showed signs of damage including rounding, and partial detachment after 24 hours. Fluorescently labeled conidia were internalized after 6 hours and more internalized conidia were observed in CF compared to CF+CFTR cells. Infection of the apical surface with 10AF conidia, germlings, or hyphae was performed to determine growth stage-specific effects on tight junction protein zona occludens protein 1 (ZO-1) expression and transepithelial electrical resistance (TER). In response to infection with conidia or germlings, epithelial barrier function degraded time-dependently (based on ZO-1 immunofluorescence and TER) with a delayed onset in CF+CFTR cell monolayers and required viable fungi and apical application. Infection with hyphae caused an earlier onset and faster rate of decline in TER compared to conidia and germlings. Gliotoxin, a major Af virulence factor, caused a rapid decline in TER and induced a transient chloride secretory response in CF+CFTR but not CF cells. Our findings suggest growth and internalization of Af result in deleterious effects on bronchial epithelial barrier function that occurred more rapidly in the absence of CFTR. Bronchial epithelial barrier breakdown was time-dependent and morphotype-specific and mimicked by acute administration of gliotoxin. Our study also suggests a protective role for CFTR by turning on CFTR-dependent chloride transport in response to gliotoxin, a mechanism that will support mucociliary clearance, and could delay the loss of epithelial integrity during fungal development in vivo.

PMID:37680748 | PMC:PMC10482090 | DOI:10.3389/fcimb.2023.1196581

iScience. 2023 Aug 21;26(9):107700. doi: 10.1016/j.isci.2023.107700. eCollection 2023 Sep 15.

ABSTRACT

Pseudomonas aeruginosa (Pa) is a pathogen causing chronic pulmonary infections in patients with cystic fibrosis (CF). Manipulation of lipids is an important feature of Pa infection and on a tissue-level scale is poorly understood. Using a mouse model of acute Pa pulmonary infection, we explored the whole-lung phospholipid response using mass spectrometry imaging (MSI) and spatial lipidomics. Using a histology-driven analysis, we isolated airways and parenchyma from both mock- and Pa-infected lungs and used systems biology tools to identify enriched metabolic pathways from the differential phospholipid identities. Infection was associated with a set of 26 ions, with 11 unique to parenchyma and 6 unique to airways. Acyl remodeling was differentially enriched in infected parenchyma as the predominant biological function. These functions correlated with markers of polymorphonuclear (PMN) cell influx, a defining feature of the lung response to Pa infection, implicating enzymes active in phospholipid remodeling.

PMID:37680478 | PMC:PMC10480615 | DOI:10.1016/j.isci.2023.107700

Nat Commun. 2023 Sep 7;14(1):5495. doi: 10.1038/s41467-023-41300-y.

ABSTRACT

Bronchiolitis is the most common lower respiratory infection in infants, yet its pathobiology remains unclear. Here we present blood DNA methylation data from 625 infants hospitalized with bronchiolitis in a 17-center prospective study, and associate them with disease severity. We investigate differentially methylated CpGs (DMCs) for disease severity. We characterize the DMCs based on their association with cell and tissues types, biological pathways, and gene expression. Lastly, we also examine the relationships of severity-related DMCs with respiratory and immune traits in independent cohorts. We identify 33 DMCs associated with severity. These DMCs are differentially methylated in blood immune cells. These DMCs are also significantly enriched in multiple tissues (e.g., lung) and cells (e.g., small airway epithelial cells), and biological pathways (e.g., interleukin-1-mediated signaling). Additionally, these DMCs are associated with respiratory and immune traits (e.g., asthma, lung function, IgE levels). Our study suggests the role of DNA methylation in bronchiolitis severity.

PMID:37679381 | PMC:PMC10485022 | DOI:10.1038/s41467-023-41300-y

J Cyst Fibros. 2023 Sep 6:596-597. doi: 10.1016/j.jcf.2023.07.008. Online ahead of print.

NO ABSTRACT

PMID:37679269 | DOI:10.1016/j.jcf.2023.07.008

Chin Med J (Engl). 2023 Sep 7. doi: 10.1097/CM9.0000000000002834. Online ahead of print.

NO ABSTRACT

PMID:37678334 | DOI:10.1097/CM9.0000000000002834