Microb Biotechnol. 2022 Feb 8. doi: 10.1111/1751-7915.14012. Online ahead of print.

ABSTRACT

Plasmids are extrachromosomal genetic elements capable of autonomous replication within a host cell. They play a key role in bacterial ecology and evolution, facilitating the mobilization of accessory genes by horizontal gene transfer. Crucially, plasmids also serve as valuable tools in modern molecular biology. Here, we highlight recent articles aimed at implementing standardized plasmid assembly techniques and plasmid repositories to promote open science as well as to improve experimental reproducibility across laboratories. Research focused on assisting these fundamental aims is a further step towards improving standardization in molecular and synthetic biology.

PMID:35137542 | DOI:10.1111/1751-7915.14012

Nat Rev Microbiol. 2022 Feb 8. doi: 10.1038/s41579-022-00683-3. Online ahead of print.

ABSTRACT

Many microbial communities, including those involved in chronic human infections, are patterned at the micron scale. In this Review, we summarize recent work that has defined the spatial arrangement of microorganisms in infection and begun to demonstrate how changes in spatial patterning correlate with disease. Advances in microscopy have refined our understanding of microbial micron-scale biogeography in samples from humans. These findings then serve as a benchmark for studying the role of spatial patterning in preclinical models, which provide experimental versatility to investigate the interplay between biogeography and pathogenesis. Experimentation using preclinical models has begun to show how spatial patterning influences the interactions between cells, their ability to coexist, their virulence and their recalcitrance to treatment. Future work to study the role of biogeography in infection and the functional biogeography of microorganisms will further refine our understanding of the interplay of spatial patterning, pathogen virulence and disease outcomes.

PMID:35136217 | DOI:10.1038/s41579-022-00683-3

Respir Care. 2022 Feb 8:respcare.09306. doi: 10.4187/respcare.09306. Online ahead of print.

NO ABSTRACT

PMID:35135896 | DOI:10.4187/respcare.09306

Implement Sci Commun. 2022 Feb 8;3(1):12. doi: 10.1186/s43058-022-00263-9.

ABSTRACT

BACKGROUND: Preventative inhaled treatments preserve lung function and reduce exacerbations in cystic fibrosis (CF). Self-reported adherence to these treatments is over-estimated. An online platform (CFHealthHub) has been developed with patients and clinicians to display real-time objective adherence data from dose-counting nebulisers, so that clinical teams can offer informed treatment support.

METHODS: In this paper, we identify pre-implementation barriers to healthcare practitioners performing two key behaviours: accessing objective adherence data through the website CFHealthHub and discussing medication adherence with patients. We aimed to understand barriers during the pre-implementation phase, so that appropriate strategy could be developed for the scale up of implementing objective adherence data in 19 CF centres. Thirteen semi-structured interviews were conducted with healthcare practitioners working in three UK CF centres. Qualitative data were coded using the theoretical domains framework (TDF), which describes 14 validated domains to implementation behaviour change.

RESULTS: Analysis indicated that an implementation strategy should address all 14 domains of the TDF to successfully support implementation. Participants did not report routines or habits for using objective adherence data in clinical care. Examples of salient barriers included skills, beliefs in consequences, and social influence and professional roles. The results also affirmed a requirement to address organisational barriers. Relevant behaviour change techniques were selected to develop implementation strategy modules using the behaviour change wheel approach to intervention development.

CONCLUSIONS: This paper demonstrates the value of applying the TDF at pre-implementation, to understand context and to support the development of a situationally relevant implementation strategy.

PMID:35135620 | DOI:10.1186/s43058-022-00263-9

Genomics. 2022 Feb 5:110279. doi: 10.1016/j.ygeno.2022.110279. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) and cystic fibrosis transmembrane conductance regulator (CFTR) mutations have been shown to be associated with the risk of a variety of cancers. However, the clinical significance of aberrant CFTR gene expression in human tumors remains unknown. The expression profiles and prognostic landscapes of CFTR in human cancers were identified from the PubMed, OVID, CNKI, TCGA, ONCOMINE, PrognoScan, and GEPIA databases. A total of 11,005 lung adenocarcinoma (LUAD) samples from the literature, GEPIA database, and PrognoScan database were included in this study. In general, CFTR has various expression and prognostic profiles in cancers, but the results from cross-database and meta-analyses revealed that CFTR is a robust biomarker for LUAD prognosis. Collectively, this study suggests that CFTR is an important prognostic biomarker for LUAD survival, implying that it could be used as a prognostic biomarker and therapeutic target for LUAD.

PMID:35134493 | DOI:10.1016/j.ygeno.2022.110279

Am J Gastroenterol. 2021 Dec 1;116(12):2332. doi: 10.14309/ajg.0000000000001560.

ABSTRACT

Article Title: Cystic Fibrosis Transmembrane Conductance Regulator Modulator Use is Associated with Reduced Pancreatitis Hospitalizations in Subjects with Cystic Fibrosis.

PMID:35134010 | DOI:10.14309/ajg.0000000000001560

Clin Med Res. 2022 Feb 7:cmr.2022.1618. doi: 10.3121/cmr.2022.1618. Online ahead of print.

ABSTRACT

Cystic Fibrosis is a monogenic and autosomal recessive disease. It is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene responsible for encoding the CFTR protein. Involvement of the gastrointestinal and respiratory systems is the main clinical manifestation. In this case, we report a heterozygous CFTR patient harboring class I (p.Gly542*) and class V (c.2657+5G>A) mutations. The importance of this case report lies in the clinical features because the patient, aged three years old, presents early exocrine pancreatic insufficiency, which can be considered atypical, as most individuals with this genotype are pancreatic sufficient or develop pancreatic insufficiency later in life. Therefore, this study aims at presenting the tests requested that contributed to the patient's diagnosis, as well as at understanding the association between these mutations and their phenotypic presentation. Therefore, interpretation of the genotype-phenotype relationship represents a challenge, as genetic analysis alone is not sufficient to clearly predict severity of the disease. This is because the significant phenotypic heterogeneity existing among patients with the same genotype may exert socioeconomic and sociocultural influences, or by the action of CFTR modifiers, such as environmental and modifying genes, which can alter the protein's function and exert an impact on the individual's phenotype.

PMID:35131845 | DOI:10.3121/cmr.2022.1618

J Cyst Fibros. 2022 Feb 4:S1569-1993(22)00030-3. doi: 10.1016/j.jcf.2022.01.010. Online ahead of print.

NO ABSTRACT

PMID:35131172 | DOI:10.1016/j.jcf.2022.01.010

Am J Physiol Endocrinol Metab. 2022 Feb 7. doi: 10.1152/ajpendo.00234.2021. Online ahead of print.

ABSTRACT

Type 2 diabetes is associated with upregulation of neprilysin, a peptidase capable of cleaving glucoregulatory peptides such as glucagon-like peptide-1 (GLP-1). In humans, use of the neprilysin inhibitor sacubitril in combination with an angiotensin II receptor blocker was associated with increased plasma GLP-1 levels and improved glycemic control. Whether neprilysin inhibition per se is mediating these effects remains unknown. We sought to determine whether pharmacological neprilysin inhibition on its own confers beneficial effects on glycemic status and beta-cell function in a mouse model of reduced insulin secretion, and whether any such effects are dependent on GLP-1 receptor (GLP-1R) signaling. High-fat-fed male wild-type (Glp1r+/+) and GLP-1R knockout (Glp1r-/-) mice were treated with low-dose streptozotocin (STZ) to recapitulate type 2 diabetes-associated beta-cell dysfunction, or vehicle as control. Mice were continued on high fat diet alone or supplemented with the neprilysin inhibitor sacubitril for 8 weeks. At the end of the study period, beta-cell function was assessed by oral or intravenous glucose tolerance test. Fasting and fed glucose were significantly lower in wild-type mice treated with sacubitril, although active GLP-1 levels and insulin secretion during oral glucose challenge were unchanged. In contrast, insulin secretion in response to intravenous glucose was significantly enhanced in sacubitril-treated wild-type mice, and this effect was blunted in Glp1r-/-mice. Similarly, sacubitril enhanced insulin secretion in vitro in islets from STZ-treated Glp1r+/+ but not Glp1r-/-mice. Together, our data suggest the insulinotropic effects of pharmacological neprilysin inhibition in a mouse model of beta-cell dysfunction are mediated via intra-islet GLP-1R signaling.

PMID:35128957 | DOI:10.1152/ajpendo.00234.2021

Eur J Clin Invest. 2022 Feb 7:e13753. doi: 10.1111/eci.13753. Online ahead of print.

ABSTRACT

BACKGROUND: Biomarkers are used for diagnosis, risk stratification and medical decisions. Copeptin and mid-regional proadrenomedullin (MR-proADM) are markers of stress and endothelial function, respectively, which have been studied in pneumonia, sepsis and septic shock. This study aimed to assess whether copeptin and MR-proADM could predict coronavirus disease 2019 (COVID-19) in-hospital outcomes, that is multi-system complications, length of stay and mortality.

METHODS: Copeptin and MR-proADM were assessed at admission in 116 patients hospitalized with COVID-19. Data were retrospectively extracted from an online database. The primary endpoint was in-hospital mortality. The secondary endpoints were in-hospital complications, the composite outcome 'death, or admission to intensive care unit, or in-hospital complications', and length of stay. The predictive power was expressed as area under the receiver operator characteristic curve (AUROC).

RESULTS: Copeptin was increased in non-survivors (median 29.7 [interquartile range 13.0-106.2] pmol/L) compared to survivors (10.9 [5.9-25.3] pmol/L, p < 0.01). The AUROC for mortality was 0.71, with a hazard ratio of 3.67 (p < 0.01) for copeptin values > 25.3 pmol/L. MR-proADM differentiated survivors (0.8 [0.6-1.1] nmol/L) from non-survivors (1.5 [1.1-2.8] nmol/L, p < 0.001) and yielded a AUROC of 0.79 and a hazard ratio of 7.02 (p < 0.001) for MR-proADM values > 1.0 nmol/L. Copeptin and MR-proADM predicted sepsis (AUROC 0.95 and 0.96 respectively), acute kidney injury (0.87 and 0.90), the composite outcome (0.69 and 0.75) and length of stay (r = 0.42, p < 0.001, and r = 0.46, p < 0.001).

CONCLUSIONS: Admission MR-proADM and copeptin may be implemented for early risk stratification in COVID-19-hospitalized patients to help identify those eligible for closer monitoring and care intensification.

PMID:35128648 | DOI:10.1111/eci.13753

HGG Adv. 2022 Jan 11;3(2):100090. doi: 10.1016/j.xhgg.2022.100090. eCollection 2022 Apr 14.

ABSTRACT

Cystic fibrosis (CF) is a severe genetic disorder that can cause multiple comorbidities affecting the lungs, the pancreas, the luminal digestive system and beyond. In our previous genome-wide association studies (GWAS), we genotyped approximately 8,000 CF samples using a mixture of different genotyping platforms. More recently, the Cystic Fibrosis Genome Project (CFGP) performed deep (approximately 30×) whole genome sequencing (WGS) of 5,095 samples to better understand the genetic mechanisms underlying clinical heterogeneity among patients with CF. For mixtures of GWAS array and WGS data, genotype imputation has proven effective in increasing effective sample size. Therefore, we first performed imputation for the approximately 8,000 CF samples with GWAS array genotype using the Trans-Omics for Precision Medicine (TOPMed) freeze 8 reference panel. Our results demonstrate that TOPMed can provide high-quality imputation for patients with CF, boosting genomic coverage from approximately 0.3-4.2 million genotyped markers to approximately 11-43 million well-imputed markers, and significantly improving polygenic risk score (PRS) prediction accuracy. Furthermore, we built a CF-specific CFGP reference panel based on WGS data of patients with CF. We demonstrate that despite having approximately 3% the sample size of TOPMed, our CFGP reference panel can still outperform TOPMed when imputing some CF disease-causing variants, likely owing to allele and haplotype differences between patients with CF and general populations. We anticipate our imputed data for 4,656 samples without WGS data will benefit our subsequent genetic association studies, and the CFGP reference panel built from CF WGS samples will benefit other investigators studying CF.

PMID:35128485 | PMC:PMC8804187 | DOI:10.1016/j.xhgg.2022.100090

J Patient Exp. 2022 Feb 1;9:23743735221077527. doi: 10.1177/23743735221077527. eCollection 2022.

ABSTRACT

Objective: More people with cystic fibrosis (pwCF) are reaching adulthood and considering their reproductive futures. Unfortunately, many pwCF report gaps in their reproductive healthcare. We describe measures of stakeholder engagement in developing a reproductive goals decision aid for women with CF called MyVoice:CF. Methods: Stakeholders reviewed the content, design, and usability of the tool, which was informed by prior research related to CF family planning experiences and preferences as well as a conceptual understanding of reproductive decision making. We evaluated stakeholder engagement via process measures and outcomes of stakeholder involvement. We collected data via recorded stakeholder recommendations and surveys. Results: Fourteen stakeholders participated and the majority described their role on the project as "collaborator", "advisor", or "expert." Most felt their expectations for the project were met or exceeded, that they had contributed significantly, and that they received sufficient and frequent information about the process. All stakeholders provided recommen-dations and clarified aims for a CF-specific family planning tool, including its content and focus on facilitating shared decision making. Discussion: Utilizing meaningful stakeholder contributions, we developed MyVoice:CF, a novel web-based decision aid to help women with CF engage in shared decision-making regarding their reproductive goals. Practical Value: Our findings from working with stakeholders for MyVoice:CF indicate that disease-specific reproductive health resources can and should be designed with input from individuals in the relevant communities.

PMID:35128042 | PMC:PMC8814976 | DOI:10.1177/23743735221077527

Front Med (Lausanne). 2022 Jan 21;8:812775. doi: 10.3389/fmed.2021.812775. eCollection 2021.

ABSTRACT

Bronchiectasis is characterized by systemic inflammation and multiple comorbidities. This study aimed to investigate the clinical outcomes based on the bronchiectasis etiology comorbidity index (BACI) score in patients hospitalized for severe bronchiectasis exacerbations. We included non-cystic fibrosis patients hospitalized for severe bronchiectasis exacerbations between January 2008 and December 2016 from the Chang Gung Research Database (CGRD) cohort. The main outcome was the 1-year mortality rate after severe exacerbations. We used the Cox regression model to assess the risk factors of 1-year mortality. Of 1,235 patients who were hospitalized for severe bronchiectasis exacerbations, 641 were in the BACI < 6 group and 594 in the BACI ≥ 6 group. The BACI ≥ 6 group had more previous exacerbations and a lower FEV1. Pseudomonas aeruginosa (19.1%) was the most common bacterium, followed by Klebsiella pneumoniae (7.5%). Overall, 11.8% of patients had respiratory failure and the hospital mortality was 3.0%. After discharge, compared to the BACI < 6 group, the BACI ≥ 6 group had a significantly higher cumulative incidence of respiratory failure and mortality in a 1-year follow-up. The risk factors for 1-year mortality in a multivariate analysis include age [hazard ratio (HR) 4.38, p = 0.01], being male (HR 4.38, p = 0.01), and systemic corticosteroid usage (HR 6.35, p = 0.001), while airway clearance therapy (ACT) (HR 0.50, p = 0.010) was associated with a lower mortality risk. An increased risk of respiratory failure and mortality in a 1-year follow-up after severe exacerbations was observed in bronchiectasis patients with multimorbidities, particularly older age patients, male patients, and patients with a history of systemic corticosteroid use. ACT could effectively improve the risk for 1-year mortality.

PMID:35127767 | PMC:PMC8814605 | DOI:10.3389/fmed.2021.812775

Comput Math Methods Med. 2022 Jan 27;2022:8268067. doi: 10.1155/2022/8268067. eCollection 2022.

ABSTRACT

BACKGROUND: Tendon-to-bone healing is a difficult process in treatment of rotator cuff tear (RCT). In addition, diabetes is an important risk factor for poor tendon-to-bone healing. Therefore, we investigated the specific mechanisms through which diabetes affects tendon-to-bone healing by regulating the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).

METHODS: Tendon-derived stem cells (TDSCs) were extracted from rats after which their proliferative capacities were evaluated by the MTT assay. The expression levels of CFTR and tendon-related markers were determined by qRT-PCR. Then, bioinformatics analyses and dual luciferase reporter gene assays were used to identify miRNAs with the ability to bind CFTR mRNA. Finally, CFTR was overexpressed in TDSCs to validate the specific mechanisms through which the high glucose microenvironment inhibits tendon-to-bone healing.

RESULTS: The high glucose microenvironment downregulated mRNA expression levels of tendon-related markers and CFTR in TDSCs cultured with different glucose concentrations. Additionally, bioinformatics analyses revealed that let-7b-5p may be regulated by the high glucose microenvironment and can regulate CFTR levels. Moreover, a dual luciferase reporter gene assay was used to confirm that let-7b-5p targets and binds CFTR mRNA. Additional experiments also confirmed that overexpressed CFTR effectively reversed the negative effects of the hyperglycaemic microenvironment and upregulation of let-7b-5p on TDSC proliferation and differentiation. These findings imply that the hyperglycemic microenvironment inhibits CFTR transcription and, consequently, proliferation and differentiation of TDSCs in vitro by upregulating let-7b-5p.

CONCLUSIONS: A hyperglycemic microenvironment inhibits TDSC proliferation in vitro via the let-7b-5p/CFTR pathway, and this is a potential mechanism in diabetes-induced poor tendon-to-bone healing.

PMID:35126637 | PMC:PMC8813224 | DOI:10.1155/2022/8268067

Sci Total Environ. 2021 Jul 1;776:145905. doi: 10.1016/j.scitotenv.2021.145905. Epub 2021 Mar 1.

ABSTRACT

Characterizing seasonal trend in lung function in individuals with chronic lung disease may lead to timelier treatment of acute respiratory symptoms and more precise distinction between seasonal exposures and variability. Limited research has been conducted to assess localized seasonal fluctuation in lung function decline in individuals with cystic fibrosis (CF) in context with routinely collected demographic and clinical data. We conducted a longitudinal cohort study of 253 individuals aged 6-22 years with CF receiving care at a pediatric Midwestern US CF center with median (range) of follow-up time of 4.7 (0-9.95) years, implementing two distinct models to estimate seasonality effects. The outcome, lung function, was measured as percent-predicted of forced expiratory volume in 1 second (FEV1). Both models showed that older age, being male, using Medicaid insurance and having Pseudomonas aeruginosa infection corresponded to accelerated FEV1 decline. A sine wave model for seasonality had better fit to the data, compared to a linear model with categories for seasonality. Compared to international cohorts, seasonal fluctuations occurred earlier and with greater volatility, even after adjustment for ambient temperature. Average lung function peaked in February and dipped in August, and FEV1 fluctuation was 0.81 % predicted (95% CI: 0.52 to 1.1). Adjusting for temperature shifted the peak and dip to March and September, respectively, and decreased FEV1 fluctuation to 0.45 % predicted (95% CI: 0.08 to 0.82). Understanding localized seasonal variation and its impact on lung function may allow researchers to perform precision public health for lung diseases and disorders at the point-of-care level.

PMID:35125553 | PMC:PMC8813005 | DOI:10.1016/j.scitotenv.2021.145905

Dig Liver Dis. 2022 Feb 3:S1590-8658(22)00001-9. doi: 10.1016/j.dld.2021.12.018. Online ahead of print.

ABSTRACT

INTRODUCTION: The present study aimed at evaluating Italian epidemiological trends of pediatric inflammatory bowel diseases (IBD) over the period 2009-2018.

MATERIALS AND METHODS: Data from 1969 patients enrolled in the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition Registry, by 49 pediatric IBD centers throughout the country, were analyzed, comparing three different time intervals (2009-2012, 2013-2015, 2016-2018).

RESULTS: The number of new IBD diagnoses ranged from 175 to 219 per year, evenly distributed over the examined period of time. From 2009 to 2018, the minimal incidence ranged from 1.59 to 2.04 /105 inhabitants aged < 18 years, with an overall slight predominance of ulcerative colitis (UC) over Crohn's disease (CD) (ratio: 1.1). Mean diagnostic delay was 6.8 months for CD and 4.1 months for UC, with a significant reduction for CD when comparing the three-time intervals (p =0.008). The most frequent disease locations according to the Paris classification were ileocolonic for CD (41.3%) and pancolitis for UC (54.6%).

CONCLUSIONS: The minimal incidence rate in Italy seems to have stabilized over the last two decades, even if it has increased when compared to previous reports. UC is still slightly more prevalent than CD in our country. Diagnostic delay significantly decreased for CD, reflecting an improved diagnostic capacity.

PMID:35125313 | DOI:10.1016/j.dld.2021.12.018

J Cyst Fibros. 2022 Feb 3:S1569-1993(22)00031-5. doi: 10.1016/j.jcf.2022.01.009. Online ahead of print.

ABSTRACT

BACKGROUND: Time has seen management for Cystic Fibrosis (CF) advance drastically, most recently in the development of the disease-modifying triple combination therapy ivacaftor/tezacaftor/elexacaftor. There is currently limited evidence regarding both the global epidemiology of CF and access to this transformative therapy - and therefore where needs are not being met. Therefore, this study aims to define gaps in access to CF treatment.

METHODS: Patient data were extracted from established CF registries. Where these were not available, literature searches were conducted alongside an international survey of 51 CF experts to determine the diagnosed patient population. National CF prevalence estimates were combined with registry data on estimated population coverage, to extrapolate the total estimated number of undiagnosed patients. Estimates of ivacaftor/tezacaftor/elexacaftor treatment coverage were extracted from publicly available sales summaries and pricing data.

RESULTS: 162,428 [144,606-186,620] people are estimated to be living with CF across 94 countries. Of these, an estimated 105,352 (65%) are diagnosed, with 19,516 (12%) receiving triple combination therapy. We estimated 57,076 patients with undiagnosed CF. Owing to a paucity of high-quality data, estimates of undiagnosed CF in low- and middle-income countries are highly uncertain. Patient registries were available in 45 countries, and used to identify 90% of the estimated diagnosed population.

CONCLUSIONS: A significant CF patient burden exists in countries where disease-modifying drugs are unavailable, and final figures are likely underestimates. This analysis shows the potential to improve rates of diagnosis and treatment for CF, so a higher percentage of patients receive the most effective triple combination treatment.

PMID:35125294 | DOI:10.1016/j.jcf.2022.01.009

J Cyst Fibros. 2022 Feb 2:S1569-1993(22)00032-7. doi: 10.1016/j.jcf.2022.01.012. Online ahead of print.

ABSTRACT

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor induces rapid clinical improvement in patients with cystic fibrosis (CF) and advanced pulmonary disease, often leading to suspend the indication for lung transplantation. Yet no long-term data is available in lung transplant candidates.

METHODS: Lung transplant candidates (defined as being waitlisted for lung transplantation or considered for listing within 3 months) who have initiated elexacaftor-tezacaftor-ivacaftor were identified in the French cohort of patients with CF and advanced pulmonary disease. Patients were prospectively followed to evaluate treatment safety and effectiveness from initiation to July 20th, 2021.

RESULTS: Among the 331 patients with advanced CF pulmonary disease who initiated elexacaftor-tezacaftor-ivacaftor, 65 were lung transplant candidates (17 listed for transplantation, 48 considered for listing within 3 months). Median [IQR] follow-up time was 363 [329; 377] days. At the end of the follow-up period, two patients were transplanted five and 11 days following treatment initiation, two were listed for transplantation, and 61 no longer met transplantation criteria. Improvement in percent predicted forced expiratory volume in 1 s (ppFEV1) at one month was +13.4% (95% confidence interval, 10.3%-16.5%; P < 0.0001) and remained stable thereafter. Treatment burden decreased substantially, with an 86% decrease in the need for intravenous antibiotics, 59% for oxygen therapy and 62% for non-invasive ventilation.

CONCLUSION: In lung transplant candidates eligible for elexacaftor-tezacaftor-ivacaftor, the rapid improvement following initiation of treatment persisted over one year with a reduction in treatment burden and lung transplantation could be safely deferred in most patients.

PMID:35123901 | DOI:10.1016/j.jcf.2022.01.012

Chest. 2022 Feb 2:S0012-3692(22)00212-4. doi: 10.1016/j.chest.2022.01.045. Online ahead of print.

ABSTRACT

BACKGROUND: Long-term macrolide therapy has been shown to provide benefit to those with a range of chronic respiratory conditions. However, there remain concerns about the impact of macrolide exposure on the carriage and abundance of antibiotic resistance genes within the oropharynx. The potential for onward transmission of resistance from macrolide recipients to their close contacts is also poorly understood.

RESEARCH QUESTION: Does long-term macrolide use impact carriage of resistance within the oropharyngeal microbiota in people with chronic respiratory conditions and risk of onward transmission to their close contacts?

STUDY DESIGN AND METHODS: Oropharyngeal swabs were collected from 93 individuals with chronic respiratory conditions, of whom 53 were receiving long-term macrolide therapy. An oropharyngeal swab was also collected from a close co-habiting contact of each subject. Detection and abundance of ten macrolide-associated resistance genes with the potential to disseminate via horizontal gene transfer were assessed by quantitative PCR.

RESULTS: Detection of resistance genes in macrolide recipients was comparable to that in non-recipients. However, the normalised gene abundance of erm(B) was significantly higher in the macrolide recipient group (p=0.045). In the close contacts, no between-group differences in resistance gene detection or abundance were identified. Within-group analysis showed that the detection of erm(F) and mef in macrolide recipients, but not non-recipients, was significantly associated with detection in close contacts (p=0.003 and p=0.004 respectively). However, between-group analysis showed that treatment group did not predict co-carriage between patients and their close contacts (p>0.05 for each gene).

INTERPRETATION: While levels of erm(B) were higher in those receiving long-term macrolide therapy and there was evidence of gene co-carriage with close contacts, there was no evidence that macrolide use increased the onward transmission risk to their close contacts. This study therefore addresses concerns that long-term macrolide therapy could promote the dissemination of transmissible macrolide resistance.

PMID:35122749 | DOI:10.1016/j.chest.2022.01.045

Chem Phys Lipids. 2022 Feb 2:105178. doi: 10.1016/j.chemphyslip.2022.105178. Online ahead of print.

ABSTRACT

Lipid nanoparticles (LNPs) mediated mRNA delivery has gained prominence due to the success of mRNA vaccines against Covid-19, without which it would not have been possible. However, there is little clinical validation of this technology for other mRNA-based therapeutic approaches. Systemic administration of LNPs predominantly targets the liver, but delivery to other organs remains a challenge. Local approaches remain a viable option for some disease indications, such as Cystic Fibrosis, where aerosolized delivery to airway epithelium is the preferred route of administration. With this in mind, novel cationic lipids (L1-L4) have been designed, synthesized and co-formulated with a proprietary ionizable lipid. These LNPs were further nebulized, along with baseline control DOTAP-based LNP (DOTAP+), and tested in vitro for mRNA integrity and encapsulation efficiency, as well as transfection efficiency and cytotoxicity in cell cultures. Improved biodegradability and potentially superior elimination profiles of L1-L4, in part due to physicochemical characteristics of putative metabolites, are thought to be advantageous for prospective therapeutic lung delivery applications using these lipids.

PMID:35122738 | DOI:10.1016/j.chemphyslip.2022.105178