Transplant Rev (Orlando). 2023 Oct 7;37(4):100800. doi: 10.1016/j.trre.2023.100800. Online ahead of print.

ABSTRACT

BACKGROUND: There is lack of consensus on non-tuberculous mycobacteria pulmonary disease (NTM-PD) treatment regimen and duration in patient listed for lung transplantation (LTx). We conducted a systematic review on treatment regimen and duration pre- and directly post-LTx, for patients with known NTM-PD pre-LTx. Additionally, we searched for risk factors for NTM disease development post-LTx and for mortality.

METHODS: Literature was reviewed on PubMed, Embase and the Cochrane Library, for articles published from inception to January 2022. Individual patient data were sought.

RESULTS: Sixteen studies were included reporting 92 patients. Most frequent used agents were aminoglycosides and macrolides for Mycobacterium abscessus (M. abscessus) and macrolides and tuberculostatic agents for Mycobacterium avium complex (M. avium complex). The median treatment duration pre-LTx was 10 months (IQR 6-17) and 2 months (IQR 2-8) directly post-LTx. Longer treatment duration pre-LTx was observed in children and in patients with M. abscessus. 46% of the patients with NTM-PD pre-LTx developed NTM disease post-LTx, related mortality rate was 10%. Longer treatment duration pre-LTx (p < 0.001) and sputum non-conversion pre-LTx (p = 0.003) were significantly associated with development of NTM-disease post-LTx. Longer treatment duration pre-LTx (p = 0.004), younger age (p < 0.001) and sputum non-conversion (p = 0.044) were risk factors for NTM related death.

CONCLUSIONS: The median treatment duration pre-LTx was 10 months (IQR 6-17) and 2 months (IQR 2-8) directly post-LTx. Patients with longer treatment duration for NTM-PD pre-LTx and with sputum non-conversion are at risk for NTM disease post-LTx and for NTM-related death. Children were particularly at risk for NTM related death.

PMID:37832509 | DOI:10.1016/j.trre.2023.100800

Cancer Epidemiol. 2023 Oct 11;87:102468. doi: 10.1016/j.canep.2023.102468. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Overweight and obesity are associated with multiple cancers. We quantified the burden of cancer attributable to overweight and obesity in Italy.

METHODS: We estimated sex- and cancer site-specific population attributable fractions (PAFs) combining relative risks (from recent meta-analyses) with national obesity prevalence data (from a large sample survey conducted in 2005, to account for a 15-year lag period). Using nationwide mortality statistics and cancer registries data, we estimated the number of cancer cases and deaths attributable to overweight and obesity in Italy in 2020, based on the counterfactual scenario of a body mass index < 25 kg/m2.

RESULTS: 3.6% of cancers in men and 4.0% in women in Italy were attributable to overweight and obesity, corresponding, respectively, to over 6900 and 7200 diagnoses in 2020. Attributable deaths were over 3600 in men and 2700 in women. PAFs (attributable cases) of overweight and obesity in men and women were, respectively, 38.1% (215 cases) and 21.8% (49 cases) for esophageal adenocarcinoma, 19.1% (1715 cases) and 14.5% (585 cases) for liver, 18.7% (1692 cases) and 16.7% (747 cases) for kidney, 13.7% (938 cases) and 10.1% (749 cases) for pancreatic, and 10.2% (2389 cases) and 3.4% (690 cases) for colorectal cancers. In women, PAFs were 22.3% (1859 cases) for endometrial and 5.7% (2556 cases) for post-menopausal breast cancer.

CONCLUSIONS: The cancer burden associated with overweight and obesity in Italy is considerable, but smaller compared to other high income countries, likely because of the lower prevalence of overweight and obesity in the Italian population.

PMID:37832242 | DOI:10.1016/j.canep.2023.102468

Cytokine. 2023 Oct 11;172:156384. doi: 10.1016/j.cyto.2023.156384. Online ahead of print.

ABSTRACT

Fungal infections caused by Scedosporium species are rising among immunocompromised and immunocompetent patients. Within the immunocompetent group, patients with cystic fibrosis (pwCF) are at high risk of developing a chronic airway colonization by these molds. While S. apiospermum is one of the major species encountered in the lungs of pwCF, S. dehoogii has rarely been reported. The innate immune response is believed to be critical for host defense against fungal infections. However, its role has only recently been elucidated and the immune mechanisms against Scedosporium species are currently unknown. In this context, we undertook a comparative investigation of macrophage-mediated immune responses toward S. apiospermum and S. dehoogii conidia. Our data showed that S. apiospermum and S. dehoogii conidia strongly stimulated the expression of a set of pro-inflammatory cytokines and chemokines such as IL-1β, IL-8, IL-6 and TNFα. We demonstrated that S. dehoogii was more potent in stimulating the early release of pro-inflammatory cytokines and chemokines while S. apiospermum induced a late inflammatory response at a higher level. Flow cytometry analysis showed that M1-like macrophages were able to internalize both S. apiospermum and S. dehoogii conidia, with a similar intracellular killing rate for both species. In conclusion, these results suggest that M1-like macrophages can rapidly initiate a strong immune response against both S. apiospermum and S. dehoogii. This response is characterized by a similar killing of internalized conidia, but a different time course of cytokine production.

PMID:37832161 | DOI:10.1016/j.cyto.2023.156384

Microbiol Spectr. 2023 Oct 13:e0283623. doi: 10.1128/spectrum.02836-23. Online ahead of print.

ABSTRACT

Mycobacterium abscessus is a multi-drug-resistant non-tuberculous mycobacterial species causing tuberculosis-like lung infections. The functional characterization of the extensive repertoire of genes encoding virulence factors and drug targets has been largely restricted by the lack of powerful genetic tools. In this study, we evaluated the performances of a Tet-OFF system, previously optimized for M. tuberculosis and M. smegmatis. Fluorescence reporter M. abscessus strains were developed where mCherry was under the control of the Tet-OFF regulatory system on an integrative plasmid. The addition of anhydrotetracycline (ATc) correlated with a decrease in fluorescence intensity not only in solid and broth medium but also in colony biofilms, for both smooth and rough variants of M. abscessus. Next, unmarked mmpL3 conditional knockdown mutants were engineered in both smooth and rough M. abscessus. Biochemical studies indicated that the addition of ATc was associated with a dose-dependent decrease in (i) the production of the MmpL3 protein, (ii) the biosynthesis of trehalose dimycolate and mycolylated arabinogalactan, (iii) bacterial viability on agar and liquid medium as well as in biofilms. Importantly, intravenous injection of ATc in zebrafish embryos infected with the rough mmpL3 conditional mutant impeded bacterial growth and correlated with a significant gain in embryo survival. These results suggest that mmpL3 is essential for M. abscessus growth in vitro and in the infected host, thus validating MmpL3 as an attractive drug target. Together, this study demonstrates the potential of ATc-dependent repression to modulate the expression of M. abscessus genes in the infected host. IMPORTANCE Mycobacterium abscessus represents the most common rapidly growing mycobacterial pathogen in cystic fibrosis and is extremely difficult to eradicate. Essential genes are required for growth, often participate in pathogenesis, and encode valid drug targets for further chemotherapeutic developments. However, assessing the function of essential genes in M. abscessus remains challenging due to the limited spectrum of efficient genetic tools. Herein, we generated a Tet-OFF-based system allowing to knock down the expression of mmpL3, encoding the mycolic acid transporter in mycobacteria. Using this conditional mutant, we confirm the essentiality of mmpL3 in planktonic cultures, in biofilms, and during infection in zebrafish embryos. Thus, in this study, we developed a robust and reliable method to silence the expression of any M. abscessus gene during host infection.

PMID:37831478 | DOI:10.1128/spectrum.02836-23

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2023 Oct 13. doi: 10.1007/s00103-023-03778-1. Online ahead of print.

ABSTRACT

BACKGROUND: In Germany, newborn screening (NGS) for cystic fibrosis (CF) was introduced on 1 September 2016. There is no legally required follow-up of abnormal screening findings, so the exact number of final diagnoses is not known. Two data sources can support the evaluation of the cystic fibrosis screening: the German Society for Newborn Screening (DGNS) collects the results of NGS and confirmatory testing for quality assurance and the German Cystic Fibrosis Registry (DMR) collects diagnostic frequencies. The aim of this manuscript is to compare the data from the DGNS and the DMR and to present limitations and strengths of each data source.

METHODS: Data from the DGNS (data as of 14 April 2023) and the DMR (data as of 12 April 2023) for children born between 2017 and 2021 were analyzed with regard to the frequencies of CF, number of patients with CF diagnosed after false-negative screening results, and ratio of CF to cases with positive cystic fibrosis screening and inconclusive diagnosis (CFSPID).

RESULTS: The DGNS has 767 datasets of newborns with CF/CFSPID and the DMR has 910 confirmed cases of CF/CFSPID. A false-negative screening was reported by the DGNS for 37/767 (4.8%) and by the DMR for 49/910 (5.4%). The ratio of CF to CFSPID is 17.4:1 (DGNS, 2017-2020) and 28.1:1 (DMR), respectively.

DISCUSSION: The DGNS and the DMR, each with different strengths in the documentation of screening (DGNS) and diagnostic data (DMR), provide important clues for the number of newly diagnosed cystic fibrosis patients after the introduction of NGS. Legal requirements for tracking those screened, recording all children with CF, and exchanging data between the DGNS and DMR could improve evaluation in the future.

PMID:37831094 | DOI:10.1007/s00103-023-03778-1

Tidsskr Nor Laegeforen. 2023 Sep 27;143(14). doi: 10.4045/tidsskr.22.0775. Print 2023 Oct 10.

ABSTRACT

BACKGROUND: Since 2009, patients with a rapidly progressing lung disease have been given a higher priority on the waiting list for a lung transplant. The purpose of our study was to examine diagnosis distribution, waiting list times, mortality and survival for patients on the waiting list in the period 1999-2020.

MATERIAL AND METHOD: We conducted a descriptive, retrospective study of patients on the waiting list for a lung transplant in the periods 1999-2008 and 2009-2020.

RESULTS: A total of 557 lung transplants were performed: 185 in 1999-2008 (median of 17.5 per year) and 372 in 2009-2020 (median of 32.5 per year). In the periods 1999-2008 and 2009-2020, the proportion of patients with chronic obstructive pulmonary disease (COPD)/emphysema was 67 % and 49 %, respectively. The corresponding figures for pulmonary fibrosis were 13 % and 23 %, and for cystic fibrosis 5 % and 11 %. Waiting list mortality was 27 % in 1999-2008 and 16 % in 2009-2020. Correspondingly for the two periods, waiting list mortality for patients with pulmonary fibrosis was 45 % and 22 %, and for cystic fibrosis 41 % and 2 %. Waiting times were shorter for all diagnoses in the period after the change in priority and longest for patients with COPD/emphysema (median of 381 days). Median survival after lung transplantation during the study period was ten years.

INTERPRETATION: For patients with pulmonary fibrosis and cystic fibrosis, the change in transplant priority in 2009 may have played a role in reducing waiting list mortality.

PMID:37830971 | DOI:10.4045/tidsskr.22.0775

mBio. 2023 Oct 13:e0151623. doi: 10.1128/mbio.01516-23. Online ahead of print.

ABSTRACT

People with cystic fibrosis (pwCF) commonly test positive for the pathogenic fungus Aspergillus fumigatus, which is associated with a decline in lung function. Trikafta is a recently approved therapy for pwCF that improves quantity and function of the CFTR protein; however, it is not known how Trikafta affects microbial communities in the lung. Therefore, the aim of this study was to determine whether Trikafta directly affects A. fumigatus growth and biology. While Trikafta did not impact the viability of A. fumigatus conidia, treatment of A. fumigatus biofilms with Trikafta reduced overall biofilm biomass. This finding was associated with increased membrane permeability, decreased viability, and reduced metabolic activity following long-term treatment of biofilms. Trikafta-induced membrane permeability, and biomass reduction was partially blocked with the calcium channel inhibitor verapamil and fully blocked by the mammalian CFTR inhibitor GlyH-101. Trikafta-induced biomass reduction and metabolic activity was shown to be regulated by the high-osmolarity glycerol pathway gene sakA. Trikafta treatment also induced resistance to the cell wall stressor calcofluor white, susceptibility to the anti-fungal drug caspofungin, and decreased inflammatory responses from murine bone marrow cells. Collectively, these results reveal that Trikafta affects infection-relevant A. fumigatus biology and host-microbial interactions. IMPORTANCE PwCF commonly test positive for pathogenic fungi, and more than 90% of the cystic fibrosis patient population is approved for the modulator treatment, Trikafta. Therefore, it is critical to understand how fungal communities, specifically A. fumigatus, respond to Trikafta exposure. Therefore, we sought to determine whether Trikafta impacted the biology of A. fumigatus biofilms. Our data demonstrate that Trikafta reduces biomass in several laboratory strains as well as clinical strains isolated from the expectorated sputum of pwCF. Furthermore, Trikafta reduces fungal viability and the capacity of biofilms to recover following treatment. Of particular importance, Trikafta affects how A. fumigatus biofilms respond to cell wall stressors, suggesting that Trikafta modulates components of the cell wall. Since the cell wall directly affects how a host immune system will respond to and effectively neutralize pathogens, our work, demonstrating that Trikafta impacts the A. fumigatus cell wall, is potentially highly relevant to fungal-induced disease pathogenesis.

PMID:37830825 | DOI:10.1128/mbio.01516-23

Cells. 2023 Sep 28;12(19):2375. doi: 10.3390/cells12192375.

ABSTRACT

(1) Background: Stereological estimations significantly contributed to our understanding of lung anatomy and physiology. Taking stereology fully 3-dimensional facilitates the estimation of novel parameters. (2) Methods: We developed a protocol for the analysis of all airspaces of an entire lung. It includes (i) high-resolution synchrotron radiation-based X-ray tomographic microscopy, (ii) image segmentation using the free machine-learning tool Ilastik and ImageJ, and (iii) calculation of the airspace diameter distribution using a diameter map function. To evaluate the new pipeline, lungs from adult mice with cystic fibrosis (CF)-like lung disease (βENaC-transgenic mice) or mice with elastase-induced emphysema were compared to healthy controls. (3) Results: We were able to show the distribution of airspace diameters throughout the entire lung, as well as separately for the conducting airways and the gas exchange area. In the pathobiological context, we observed an irregular widening of parenchymal airspaces in mice with CF-like lung disease and elastase-induced emphysema. Comparable results were obtained when analyzing lungs imaged with μCT, sugges-ting that our pipeline is applicable to different kinds of imaging modalities. (4) Conclusions: We conclude that the airspace diameter map is well suited for a detailed analysis of unevenly distri-buted structural alterations in chronic muco-obstructive lung diseases such as cystic fibrosis and COPD.

PMID:37830589 | DOI:10.3390/cells12192375

Pediatr Pulmonol. 2023 Oct 13. doi: 10.1002/ppul.26725. Online ahead of print.

NO ABSTRACT

PMID:37830526 | DOI:10.1002/ppul.26725

Rev Med Liege. 2023 Oct;78(10):558-564.

ABSTRACT

In evidence-based medicine, N-of-1 trials are increasingly attractive for rare and heterogeneous conditions. A recent French study illustrates this convincingly in the field of cystic fibrosis. A highly effective triple therapy (ETI) is currently available in Europe, which will eventually help the 85 % of Belgian patients carrying at least one copy of the F508del mutation. Most other 2.000 or so putative mutations of this gene are poorly characterised and very rare or private. To predict the efficacy of ETI at the individual level in currently ineligible patients, sophisticated tools are advocated, but they are expensive, not widely available, often partially standardised and there still remains a «grey area» concerning their reliability in this context. With-out using them, the French study suggests that more than half of these patients show clinically meaningful responses to a 4-6 weeks trial of ETI. What makes this pragmatic, cost-effective, non-invasive and simplified approach possible (type 2 N-of-1 trials) is the dramatic and rapid efficacy of a life-saving treatment without alternative and the fact that it can be assessed using simple and robust clinical and paraclinical outcomes. Here, we describe one such trial and discuss the value and limitations of this approach.

PMID:37830320

Breathe (Sheff). 2023 Sep;19(3):230152. doi: 10.1183/20734735.0152-2023. Epub 2023 Oct 10.

ABSTRACT

This article provides a brief overview of the Adult Cystic Fibrosis Conference (#ACFMilan2023) programme, which will be held on 1-2 December 2023, in Milan (Italy) and online. https://bit.ly/3sKpN6p.

PMID:37830103 | PMC:PMC10567076 | DOI:10.1183/20734735.0152-2023

Front Genet. 2023 Sep 27;14:1188472. doi: 10.3389/fgene.2023.1188472. eCollection 2023.

ABSTRACT

Introduction: Circulating fetal cells isolated from maternal blood can be used for prenatal testing, representing a safe alternative to invasive testing. The present study investigated the potential of cell-based noninvasive prenatal testing (NIPT) for diagnosing monogenic disorders dependent on the mode of inheritance. Methods: Maternal blood samples were collected from women opting for prenatal diagnostics for specific monogenic disorders (N = 7). Fetal trophoblasts were enriched and stained using magnetic activated cell sorting and isolated by fluorescens activated single-cell sorting. Individual cells were subject to whole genome amplification, and cells of fetal origin were identified by DNA-profiling using short tandem repeat markers. The amplified fetal DNA was input for genetic testing for autosomal dominant-, autosomal recessive-, X-linked and repeat expansion disorders by direct variant analysis and haplotyping. The cell-based NIPT results were compared with those of invasive testing. Results: In two cases at risk of skeletal dysplasia, caused by variants in the FGFR3 gene (autosomal dominant disorders), cell-based NIPT correctly stated an affected fetus, but allelic dropout of the normal alleles were observed in both cases. Cell-based NIPT gave an accurate result in two cases at risk of autosomal recessive disorders, where the parents carried either different diastrophic dysplasia causing variants in the SLC26A2 gene or the same cystic fibrosis disease-causing variant in the CFTR gene. Cell-based NIPT accurately identified an affected male fetus in a pregnancy at risk of Duchenne muscular dystrophy (DMD gene, X-linked recessive disorders). In two cases at risk of the myotonic dystrophy type 1 (DMPK gene, repeat expansion disorder), cell-based NIPT correctly detected an affected and an unaffected fetus, respectively. Discussion: Circulating fetal cells can be used to detect both maternally- and paternally inherited monogenic disorders irrespective of the type of variant, however, the risk of allelic dropout must be considered. We conclude that the clinical interpretation of the cell-based NIPT result thus varies depending on the disorders' mode of inheritance.

PMID:37829280 | PMC:PMC10565008 | DOI:10.3389/fgene.2023.1188472

Eur Respir J. 2023 Oct 12;62(4):2300741. doi: 10.1183/13993003.00741-2023. Print 2023 Oct.

NO ABSTRACT

PMID:37827549 | DOI:10.1183/13993003.00741-2023

Allergy Asthma Immunol Res. 2023 Sep;15(5):580-602. doi: 10.4168/aair.2023.15.5.580.

ABSTRACT

PURPOSE: The epidemiology of eosinophil-associated diseases (EADs) is not yet fully understood. While some studies have been conducted on stand-alone eosinophilic diseases, there is scarce evidence on the degree of overlap among rarer conditions.

METHODS: The retrospective Real-world inVestigation of Eosinophilic-Associated disease overLap (REVEAL) study used data from the Optum® Clinformatics® insurance claims database to describe and characterize disease overlap among 11 EADs: allergic bronchopulmonary aspergillosis, atopic dermatitis, chronic rhinosinusitis with nasal polyps, eosinophilic gastritis/gastroenteritis, eosinophilic granulomatosis with polyangiitis, eosinophilic esophagitis, bullous pemphigoid, chronic obstructive pulmonary disorder, chronic spontaneous urticaria, and non-cystic fibrosis bronchiectasis. Patient records with EADs of interest were identified between January 1, 2015, and June 30, 2018.

RESULTS: Overall, 1,326,645 patients were included; 74.4% had 1 EAD, 20.5% had ≥ 2 EADs, and 5.1% had ≥ 3 EADs. Higher rates of disease overlap were associated with older age. Higher blood eosinophil counts were also observed in patients with a greater number of overlapping conditions, suggesting a common role for eosinophilic inflammation in the pathogenesis of multiple diseases. Furthermore, greater disease overlap was associated with higher disease severity in most cohorts.

CONCLUSIONS: Results from this study have implications for quantifying unmet needs and can be used to inform treatment guidelines and raise the awareness of eosinophilic inflammation and EAD overlap among healthcare professionals from a range of disease specialties.

PMID:37827978 | DOI:10.4168/aair.2023.15.5.580

Vnitr Lek. 2023 Fall;69(5):329-334. doi: 10.36290/vnl.2023.064.

ABSTRACT

Pneumology and phthisiology (respiratory medicine) has undergone dynamic development in the last two decades. The main focus of pulmonology in the past was care for patients with tuberculosis and pneumonia. Since then, respiratory medicine evolved and the current focus is on chronic pulmonary diseases, including chronic obstructive pulmonary disease, bronchial asthma, interstitial lung diseases, but also on acute lung conditions (e.g., pneumonia, pleural diseases, respiratory failure), pneumooncology or highly specialized care for rare lung diseases (e.g., cystic fibrosis, rare interstitial diseases). Bronchology, interventional pneumology and pulmonary function testing are also important components of respiratory medicine. The importance of respiratory medicine was apparent during the COVID-19 pandemic. In this article, we provide a brief overview of the most important news to the field of respiratory medicine in the year 2022, addressing the thematic areas of bronchology, cystic fibrosis, chronic obstructive pulmonary disease, asthma, interstitial lung diseases, pleural diseases, pneumooncology, tuberculosis and non-tuberculous mycobacteria.

PMID:37827832 | DOI:10.36290/vnl.2023.064

J Membr Biol. 2023 Oct 12. doi: 10.1007/s00232-023-00294-w. Online ahead of print.

ABSTRACT

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. Structural analysis of CFTR has identified a narrow, hydrophobic region close to the extracellular end of the open channel pore that may function as a selectivity filter. The present study combines comprehensive mutagenesis of hydrophobic amino-acid side-chains within the selectivity filter with functional evaluation of channel Cl- conductance and anion selectivity. Among these hydrophobic amino-acids, one (F337) appears to play a dominant role in determining both conductance and selectivity. Anion selectivity appears to depend on both side-chain size and hydrophobicity at this position. In contrast, conductance is disrupted by all F337 mutations, suggesting that unique interactions between permeating Cl- ions and the native phenylalanine side-chain are important for conductance. Surprisingly, a positively charged lysine side-chain can be substituted for several hydrophobic residues within the selectivity filter (including F337) with only minor changes in pore function, arguing against a crucial role for overall hydrophobicity. These results suggest that localized interactions between permeating anions and amino-acid side-chains within the selectivity filter may be more important in determining pore functional properties than are global features such as overall hydrophobicity.

PMID:37823914 | DOI:10.1007/s00232-023-00294-w

mSystems. 2023 Oct 12:e0059323. doi: 10.1128/msystems.00593-23. Online ahead of print.

ABSTRACT

Chronic polymicrobial infections (cPMIs) harbor complex bacterial communities with diverse metabolic capacities, leading to competitive and cooperative interactions. Although the microbes present in cPMIs have been established through culture-dependent and culture-independent methods, the key functions that drive different cPMIs and the metabolic activities of these complex communities remain unknown. To address this knowledge gap, we analyzed 102 published metatranscriptomes collected from cystic fibrosis (CF) sputum and chronic wound infections (CW) to identify key bacterial members and functions in cPMIs. Community composition analysis identified a high prevalence of pathogens, particularly Staphylococcus and Pseudomonas, and anaerobic members of the microbiota, including Porphyromonas, Anaerococcus, and Prevotella. Functional profiling with HUMANn3 and SAMSA2 revealed that while functions involved in bacterial competition, oxidative stress response, and virulence were conserved across both chronic infection types, >40% of the functions were differentially expressed. Higher expression of antibiotic resistance and biofilm functions was observed in CF, while tissue-destructive enzymes and oxidative stress response functions were highly expressed in CW samples. Of note, strict anaerobes had negative correlations with traditional pathogens in both CW and CF samples, and they significantly contributed to the expression of these functions. Additionally, we show that microbial communities have unique expression patterns, and distinct organisms fulfill the expression of key functions in each site, indicating that the infection environment strongly influences bacterial physiology and that community structure influences function. Collectively, our findings indicate that community composition and function should guide treatment strategies for cPMIs. IMPORTANCE The microbial diversity in polymicrobial infections (PMIs) allows for community members to establish interactions with one another, which can result in enhanced disease outcomes such as increased antibiotic tolerance and chronicity. Chronic PMIs result in large burdens on health systems, as they affect a significant proportion of the population and are expensive and difficult to treat. However, investigations into physiology of microbial communities in actual human infection sites are lacking. Here, we highlight that the predominant functions in chronic PMIs differ, and anaerobes, often described as bystanders, may be significant in the progression of chronic infections. Determining the community structure and functions in PMIs is a critical step toward understanding the molecular mechanisms that increase the virulence potential of the microbial community in these environments.

PMID:37823640 | DOI:10.1128/msystems.00593-23

Eur J Dermatol. 2023 Aug 1;33(4):436-437. doi: 10.1684/ejd.2023.4519.

NO ABSTRACT

PMID:37823500 | DOI:10.1684/ejd.2023.4519

FASEB J. 2023 Nov;37(11):e23233. doi: 10.1096/fj.202301495R.

ABSTRACT

Mucus plugging and non-resolving inflammation are inherent features of cystic fibrosis (CF) that may lead to progressive lung disease and exercise intolerance, which are the main causes of morbidity and mortality for people with CF. Therefore, understanding the influence of mucus on basic mechanisms underlying the inflammatory response and identifying strategies to resolve mucus-driven airway inflammation and consequent morbidity in CF are of wide interest. Here, we investigated the effects of the proresolving lipid mediator resolvin (Rv) D1 on mucus-related inflammation as a proof-of-concept to alleviate the burden of lung disease and restore exercise intolerance in CF. We tested the effects of RvD1 on inflammatory responses of human organotypic airways and leukocytes to CF mucus and of humanized mice expressing the epithelial Na + channel (βENaC-Tg) having CF-like mucus obstruction, lung disease, and physical exercise intolerance. RvD1 reduced pathogenic phenotypes of CF-airway supernatant (ASN)-stimulated human neutrophils, including loss of L-selectin shedding and CD16. RNASeq analysis identified select transcripts and pathways regulated by RvD1 in ASN-stimulated CF bronchial epithelial cells that are involved in sugar metabolism, NF-κB activation and inflammation, and response to stress. In in vivo inflammation using βENaC TG mice, RvD1 reduced total leukocytes, PMN, and interstitial Siglec-MΦ when given at 6-8 weeks of age, and in older mice at 10-12 weeks of age, along with the decrease of pro-inflammatory chemokines and increase of anti-inflammatory IL-10. Furthermore, RvD1 treatment promoted the resolution of pulmonary exacerbation caused by Pseudomonas aeruginosa infection and significantly enhanced physical activity and energy expenditure associated with mucus obstruction, which was impaired in βENaC-Tg mice compared with wild-type. These results demonstrate that RvD1 can rectify features of CF and offer proof-of-concept for its therapeutic application in this and other muco-obstructive lung diseases.

PMID:37823221 | DOI:10.1096/fj.202301495R

Ther Adv Chronic Dis. 2023 Oct 9;14:20406223231205796. doi: 10.1177/20406223231205796. eCollection 2023.

ABSTRACT

BACKGROUND: Medication adherence in Medicare-enrolled older adults with asthma and chronic obstructive pulmonary disease (COPD) before and during the coronavirus disease 2019 (COVID-19) pandemic is unknown.

OBJECTIVES: To evaluate medication adherence and determinants of high adherence before and during the COVID-19 pandemic in this population.

DESIGN: Retrospective cohort study.

METHODS: The proportion of days covered (PDC) reflected medication adherence from January to July 2019 and from January to July 2020. Patients <65 years of age, with COPD or asthma alone, or with cystic fibrosis were excluded. Paired t tests were used to assess adherence changes. Logistic regression explored association of age, sex, diagnosis of depression, number of medications, medication-related problems, prescribers, pharmacies, controller medication classes, albuterol rescue inhaler fills, oral corticosteroid fills, and having a 90-day supply with high adherence (PDC ⩾ 80%).

RESULTS: This analysis included 989 patients. In this cohort, 61.2% of patients received oral corticosteroids. Over 60% of patients had ⩾3 rescue fills in both 2019 and 2020. Medication adherence to controller medications significantly decreased for all controller medications (p < 0.001) in 2020. In 2019 and 2020, number of controller medication classes and having a 90-day supply were associated with high adherence (p < 0.001). In 2019, variables associated with high adherence also included number of medication-related problems and having ⩾3 albuterol rescue inhalers (p < 0.001).

CONCLUSION: Medication adherence to controllers significantly decreased during the pandemic among older adults with asthma and COPD. Patients with multiple controller classes and a 90-day supply were more likely to be highly adherent. A 90-day supply of medications should be used to facilitate access to medication during the pandemic. Healthcare professionals should assess medication adherence, resolve the barriers of adherence and medication-related problems to achieve desired clinical outcomes among older adults with both asthma and COPD.

PMID:37822769 | PMC:PMC10563468 | DOI:10.1177/20406223231205796