Ulster Med J. 2022 May;91(2):85-91. Epub 2022 Jun 15.

ABSTRACT

The translation of scientific evidence into guidelines and advice is a fundamental aspect of scientific communication within nutrition and dietetics. For communication to be effective for all patients, health literacy (HL) must be considered, i.e. an individual's capacity to obtain, comprehend and utilise information to empower decision-making and promote their own health. HL levels are varied and difficult to judge on an individual basis and have not been quantified, thus not giving a population mean HL competency indication. It has been evidenced that most of the working age population in England cannot comprehend healthcare materials due to complexity, thereby promoting a need for agreed readability thresholds for written healthcare information. A wide range of modalities within dietetics are used to communicate to a varied audience with the primary form written, e.g. journal articles, plain language summaries and leaflets. Audio/visual and digital communications are increasing in dietetic care and welcomed by patients; however, the effectiveness of such approaches has not been studied thoroughly and digital exclusion remains a concern. Communication considering a patient's HL level leads to empowerment which is key to effective management of chronic diseases with a high treatment burden. Therefore; this review will focus on the importance of modalities used to communicate science in nutrition to ensure they are appropriate in relation to Health Literacy.

PMID:35722219 | PMC:PMC9200103

Ulster Med J. 2022 May;91(2):118-119. Epub 2022 Jun 15.

NO ABSTRACT

PMID:35722218 | PMC:PMC9200100

Biologics. 2022 Jun 13;16:57-66. doi: 10.2147/BTT.S367032. eCollection 2022.

ABSTRACT

Biologic drugs have significantly modified the pharmacological management of several chronic conditions, including inflammatory bowel diseases (IBD). By contrast, in the last two decades, biologics have been associated with increased direct medical costs. As patents for the reference drugs have expired, the development and commercialization of biosimilars through abbreviated licensing pathways represented an affordable alternative in patients fulfilling the indication for biologics. A growing body of evidence, first in adults and then in the pediatric age group too, has provided reassuring data in terms of efficacy and safety of biosimilars both in naïve patients and in those previously on reference drugs who had to switch to the biosimilar. This review summarizes the currently available evidence for biosimilar use in IBD, with a focus on pediatric IBD. The most common practical approaches to biosimilar use in the pediatric clinical settings are also discussed.

PMID:35721798 | PMC:PMC9205321 | DOI:10.2147/BTT.S367032

Front Physiol. 2022 Jun 2;13:908230. doi: 10.3389/fphys.2022.908230. eCollection 2022.

ABSTRACT

Cystic fibrosis (CF) is a lethal and widespread autosomal recessive disorder affecting over 80,000 people worldwide. It is caused by mutations of the CFTR gene, which encodes an epithelial anion channel. CF is characterized by a great phenotypic variability which is currently not fully understood. Although CF is genetically determined, the course of the disease might also depend on multiple other factors. Air pollution, whose effects on health and contribution to respiratory diseases are well established, is one environmental factor suspected to modulate the disease severity and influence the lung phenotype of CF patients. This is of particular interest as pulmonary failure is the primary cause of death in CF. The present review discusses current knowledge on the impact of air pollution on CF pathogenesis and aims to explore the underlying cellular and biological mechanisms involved in these effects.

PMID:35721541 | PMC:PMC9202997 | DOI:10.3389/fphys.2022.908230

Front Pharmacol. 2022 Jun 3;13:877118. doi: 10.3389/fphar.2022.877118. eCollection 2022.

ABSTRACT

Background: The novel and highly effective CFTR modulator combination of elexacaftor-tezacaftor-ivacaftor (ETI) has been shown to improve lung function and body weight in people with Cystic Fibrosis (pwCF) carrying a F508del mutation. However, the impact of these modulators on gastrointestinal (GI) symptoms is relatively unknown. Therefore, the CFAbd-Score was developed and validated following FDA recommendations for development of a PROM including focus groups, multidisciplinary CF specialists, people with CF and their families. The aim of this study was to assess effects of ETI on GI symptoms using the CFAbd-Score. Methods: Gastrointestinal symptoms were prospectively assessed in pwCF using the CFAbd-Score before and up to 26 weeks during therapy. The CFAbd-Score was also administered to a healthy control (HC) group. The one-sided questionnaire includes 28 items grouped in five domains. Data analysis included calculation of scores with a weighting tool, developed according to FDA recommendations. Results: A total of 107 pwCF attended in four CF centres in Germany and four centres in the UK completed the CFAbd-Score on at least two occasions. Results were compared to those obtained from the questionnaire of 45 HCs. Despite differences in demographics, age and proportion of pancreatic insufficiency between German and UK patients, analyses based on linear mixed-effects models at week 24 of ETI therapy revealed that estimated marginal means (EMMs) of total CFAbd-Scores significantly reduced (mean ± SE: 14.9 ± 1.2→10.6 ± 1.4; p < 0.01). Also EMMs of all five domains significantly declined ("pain" 16.3 ± 1.6→10.2 ± 2.3, "GERD" 15.8 ± 1.8→8.2 ± 1.9, "disorders of bowel movement" 20.9 ± 1.5→16.0 ± 1.7, "disorders of appetite" 7.9 ± 1.1→2.6 ± 1.1 and "quality of life impairment" 10.1 ± 1.92→3.9 ± 1.9). However, during 24 weeks, CF participants' symptoms mostly still did not reach the reference levels of HCs. Discussion: Using the CFAbd-Score, the first PROM specifically developed for assessment of CF-related abdominal symptoms, we demonstrate comprehensive improvements in GI symptoms after initiation of the highly effective modulator therapy ETI.

PMID:35721187 | PMC:PMC9203829 | DOI:10.3389/fphar.2022.877118

OTO Open. 2022 Jun 13;6(2):2473974X221105277. doi: 10.1177/2473974X221105277. eCollection 2022 Apr-Jun.

ABSTRACT

OBJECTIVE: This review aimed to systematically determine the optimal nasal saline regimen for different types of sinonasal diseases.

DATA SOURCES: PubMed, Embase, SCOPUS, Cochrane Library, Web of Science, ClinicalTrials.gov. The last search was on December 6, 2021.

REVIEW METHODS: Study selection was done by 2 independent authors. Randomized controlled trials and meta-analyses were included. The effects of nasal saline treatment through various devices, saline tonicities, and buffer statuses were evaluated in patients with allergic and nonallergic rhinitis, acute and chronic rhinosinusitis (CRS), CRS with cystic fibrosis, and postoperative care, including septoplasty/turbinoplasty and endoscopic sinus surgery.

RESULTS: Sixty-nine studies were included: 10 meta-analyses and 59 randomized controlled trials. For allergic rhinitis, large-volume devices (≥60 mL) were effective for treating adults, while low-volume devices (5-59 mL) were effective for children. Isotonic saline was preferred over hypertonic saline due to fewer adverse events. For acute rhinosinusitis, saline irrigation was beneficial in children, but it was an option for adults. Large-volume devices were more effective, especially in the common cold subgroup. For CRS, large-volume devices were effective for adults, but saline drop was the only regimen that had available data in children. Buffered isotonic saline was more tolerable than nonbuffered or hypertonic saline. The data for CRS with cystic fibrosis and nonallergic rhinitis were limited. For postoperative care, buffered isotonic saline delivered by large-volume devices was effective.

CONCLUSION: Nasal saline treatment is recommended for treating most sinonasal diseases. Optimal delivery methods for each condition should be considered to achieve therapeutic effects of saline treatment.

PMID:35720767 | PMC:PMC9201324 | DOI:10.1177/2473974X221105277

Telemed Rep. 2021 Oct 12;2(1):224-232. doi: 10.1089/tmr.2021.0021. eCollection 2021.

ABSTRACT

Background: People with cystic fibrosis (PCF) have unique physical and emotional needs, which are best met through interdisciplinary care (IDC). In the midst of the pandemic, our center aimed to begin a telehealth care model with an objective to increase successful care visits from baseline of 0-95% by June 26, 2020, including meeting cystic fibrosis (CF) care standards of IDC visits that are coproduced through agenda setting with PCF. Methods: Shifting IDC for pediatric CF patients to telehealth was part of a quality improvement initiative. Our team used asynchronous virtual visits (VVs), with the IDC team members' VVs done on different days than the physician's. Multiple plan-do-study-act cycles were completed to address evolving telehealth needs, including IDC team member flow logistics, communication with PCF, and surveying PCF for the patient perspective. Rates of IDC and agenda setting were measured from March 16, 2020 to June 26, 2020. Results: IDC VVs were at 86% in March 2020 with fluctuations until mid-May when we reached 100% and achieved sustainability. Agenda setting was reached at 100% and maintained. With continued effort, an additional 46.3% of PCF registered for the patient portal, totaling 90.6% with access. Our survey revealed 100% of PCF were able to see IDC team members that they needed to, with 87% "extremely satisfied" and 13% "somewhat satisfied" with their telehealth experience. Conclusions: Successful telehealth in pediatric CF IDC can be achieved through continuous communication, optimal utilization of available technologies, and may help foster unique opportunities to help improve health outcomes.

PMID:35720757 | PMC:PMC9049801 | DOI:10.1089/tmr.2021.0021

Telemed Rep. 2022 Mar 21;3(1):93-100. doi: 10.1089/tmr.2021.0053. eCollection 2022.

ABSTRACT

INTRODUCTION: Patients with chronic health conditions are at high risk for severe COVID-19 infections, making telemedicine for patients with cystic fibrosis (CF) and cystic fibrosis-related diabetes (CFRD) particularly relevant. There are limited data regarding provider perspectives on caring for patients with CF using telemedicine, particularly for those with CFRD.

METHODS: Surveys were administered to patients with CF (with and without CFRD) and to adult and pediatric endocrinologists who specialize in CF. Data were collected using Research Electronic Data Capture; t-tests were used to compare total mean scores of Likert scale questions. The differences in responses were performed using one-way analysis of variance followed by Tukey's Honest Significant Difference test. Variables were assessed for normality and we performed the Mann-Whitney test. No change in the results of the hypothesis test was found. All results were analyzed using SPSS version 27.

RESULTS: Eighteen patients (n = 9 CFRD) and 21 providers responded. Both groups reported high satisfaction with telemedicine overall (83.3%; 71.4%), convenience (94.4%; 85.7%), and adequate time during the visit (94.4%; 76.2%), and the majority would recommend telemedicine to others (94.4%; 95.2%). Lack of in-person examination components was of more concern to providers than patients: height/weight (p < 0.001), vitals (p < 0.001), and glycated hemoglobin (p < 0.001). There was no difference in provider perception in treatment of CFRD compared to type 1 diabetes (T1D). Common themes of open-ended questions included ease in attending telemedicine appointments (patients) and decrease in "no shows" (providers).

DISCUSSION: Patient and provider satisfaction with telemedicine was high. The lack of typical components of face-to-face visits was more concerning for providers when compared to patients. Provider concern regarding lack of components specific to diabetes was similar regarding CFRD and T1D.

PMID:35720441 | PMC:PMC9049818 | DOI:10.1089/tmr.2021.0053

Front Cell Infect Microbiol. 2022 Jun 1;12:924527. doi: 10.3389/fcimb.2022.924527. eCollection 2022.

NO ABSTRACT

PMID:35719342 | PMC:PMC9199434 | DOI:10.3389/fcimb.2022.924527

J Cyst Fibros. 2022 Jun 16:S1569-1993(22)00591-4. doi: 10.1016/j.jcf.2022.06.003. Online ahead of print.

ABSTRACT

Upper gastrointestinal and upper airway disease are common in cystic fibrosis (CF) and may contribute to lower airway infection and inflammation. In a longitudinal cohort study of 32 patients (23 men; median age 32.5 years) with advanced CF lung disease (median FEV1 24.8% predicted) starting elexacaftor-tezacaftor-ivacaftor, the reflux symptom index score fell from a pre-treatment median (IQR) of 15 (11-23) to 5 (2.8-7.3) (p<0.001), the Hull airway reflux score fell from a median of 26.5 (16.3-39) to 7.5 (4-12) (p<0.001), and the sinonasal outcome score from a median of 36.5 (22-24) to 20 (10-32) (p<0.001) at 6 months on treatment. Mean FEV1% predicted rose by 9.2 points, the median respiratory domain score of the CF Questionnaire-Revised rose by 27.8 points and mean body mass index rose by 2.6 kg/m2. In addition to improving lung function and weight, CFTR modulators improve upper airway and gastro-oesophageal reflux symptoms in advanced CF.

PMID:35718668 | DOI:10.1016/j.jcf.2022.06.003

J Comp Physiol B. 2022 Jun 17. doi: 10.1007/s00360-022-01443-8. Online ahead of print.

ABSTRACT

The life history of Atlantic salmon (Salmo salar) includes an initial freshwater phase (parr) that precedes a springtime migration to marine environments as smolts. The development of osmoregulatory systems that will ultimately support the survival of juveniles upon entry into marine habitats is a key aspect of smoltification. While the acquisition of seawater tolerance in all euryhaline species demands the concerted activity of specific ion pumps, transporters, and channels, the contributions of Na+/HCO3- cotransporter 1 (Nbce1) to salinity acclimation remain unresolved. Here, we investigated the branchial and intestinal expression of three Na+/HCO3- cotransporter 1 isoforms, denoted nbce1.1, -1.2a, and -1.2b. Given the proposed role of Nbce1 in supporting the absorption of environmental Na+ by ionocytes, we first hypothesized that expression of a branchial nbce1 transcript (nbce1.2a) would be attenuated in salmon undergoing smoltification and following seawater exposure. In two separate years, we observed spring increases in branchial Na+/K+-ATPase activity, Na+/K+/2Cl- cotransporter 1, and cystic fibrosis transmembrane regulator 1 expression characteristic of smoltification, whereas there were no attendant changes in nbce1.2a expression. Nonetheless, branchial nbce1.2a levels were reduced in parr and smolts within 2 days of seawater exposure. In the intestine, gene transcript abundance for nbce1.1 increased from spring to summer in the anterior intestine, but not in the posterior intestine or pyloric caeca, and nbce1.1 and -1.2b expression in the intestine showed season-dependent transcriptional regulation by seawater exposure. Collectively, our data indicate that tissue-specific modulation of all three nbce1 isoforms underlies adaptive responses to seawater.

PMID:35715660 | DOI:10.1007/s00360-022-01443-8

J Allergy Clin Immunol. 2022 Jun 14:S0091-6749(22)00765-5. doi: 10.1016/j.jaci.2022.05.018. Online ahead of print.

ABSTRACT

BACKGROUND: A genetic defect in the epidermal barrier protein filaggrin plays a major role in the etiology of eczema and associated allergic airways diseases. However, it is still controversial to what extend loss-of-function (LOF) mutations in the filaggrin gene (FLG) contribute to the development and persistence of food allergies.

OBJECTIVE: We tested association of FLG LOF mutations with allergic reactions to diverse foods and investigated their potential effect on the persistence of early food allergies.

METHODS: We recruited 890 children with challenge-proven food allergy for the German Genetics of Food Allergy Study (GOFA). Longitudinal data were available for 684 children. All children were clinically characterized, including their allergic responses to specific foods, and genotyped for the four most common LOF mutations in FLG; R501X, 2282del4, R2447X, and S3247X. Associations between FLG mutations and food allergies were analyzed by logistic regression using the German Multicenter Allergy Study cohort as control population.

RESULTS: FLG mutations were associated with allergies to diverse foods including hen's egg (HE), cow's milk (CM), peanut, hazelnut, fish, soy, cashew, walnut, and sesame with similar risk estimates. Effects remained significant after adjusting for the eczema status. Interestingly, FLG mutations increased the risk of a persistent course of HE and CM allergy.

CONCLUSION: Using the gold standard for food allergy diagnosis, we demonstrate that FLG LOF mutations confer a risk of any food allergy independent of eczema. They predispose to the persistence of HE and CM allergy and should be considered in the assessment of tolerance development.

PMID:35714843 | DOI:10.1016/j.jaci.2022.05.018

Structure. 2022 May 31:S0969-2126(22)00185-X. doi: 10.1016/j.str.2022.05.011. Online ahead of print.

ABSTRACT

To understand mechanistically how the protein fold is shaped by therapeutics to inform precision management of disease, we developed variation-capture (VarC) mapping. VarC triangulates sparse sequence variation information found in the population using Gaussian process regression (GPR)-based machine learning to define the combined pairwise-residue interactions contributing to dynamic protein function in the individual in response to therapeutics. Using VarC mapping, we now reveal the pairwise-residue covariant relationships across the entire protein fold of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) to define the molecular mechanisms of clinically approved CF chemical modulators. We discover an energetically destabilized covariant core containing a di-acidic YKDAD endoplasmic reticulum (ER) exit code that is only weakly corrected by current therapeutics. Our results illustrate that VarC provides a generalizable tool to triangulate information from genetic variation in the population to mechanistically discover therapeutic strategies that guide precision management of the individual.

PMID:35714602 | DOI:10.1016/j.str.2022.05.011

Cell Chem Biol. 2022 Jun 16;29(6):927-929. doi: 10.1016/j.chembiol.2022.05.011.

ABSTRACT

In this issue of Cell Chemical Biology, Douglas et al. describe a potent, specific, and cell-permeable furin inhibitor that interacts with a cryptic binding site to rescue hallmarks of cystic fibrosis in human ex vivo models. BOS-318 holds promise for development of therapeutics targeting an array of furin-dependent pathologies.

PMID:35714591 | DOI:10.1016/j.chembiol.2022.05.011

Ann Am Thorac Soc. 2022 Jun 17. doi: 10.1513/AnnalsATS.202111-1266OC. Online ahead of print.

ABSTRACT

RATIONALE: The etiology of CF pulmonary exacerbations (PEx) is likely multifactorial with viral, bacterial, and non-infectious pathways contributing.

OBJECTIVES: To determine whether viral infection status and CRP can classify sub-phenotypes of PEx that differ in outcomes and biomarker profiles.

METHODS: Patients were recruited at time of admission for a PEx. Nasal swabs and sputum samples were collected and processed using the respiratory panel of the FilmArray® multiplex PCR. Serum and plasma biomarkers were measured. PEx were classified using serum CRP and viral PCR: "pauci-inflammatory" if CRP<5mg/L, "non-viral with systemic inflammation" if CRP ≥5mg/L and no viral infection detected by PCR and "viral with systemic inflammation" if CRP≥5mg/L and viral infection detected by PCR.

RESULTS: Discovery cohort (n=59) sub-phenotype frequencies were i) pauci-inflammatory (37%) ii) non-viral with systemic inflammation (41%) and iii) viral with systemic inflammation (22%). IgG, IgM, IL-10, IL-13, serum calprotectin and CRP levels differed across phenotypes. Reduction from baseline in forced expiratory volume in 1 second as percent predicted (FEV1pp) at onset of exacerbation differed between non-viral with systemic inflammation and viral with systemic inflammation (-6.73±1.78 v -13.5±2.32%; p=0.025). Non-viral with systemic inflammation PEx had a trend towards longer duration of intravenous antibiotics versus pauci-inflammation ((18.1±1.17 v 14.8±1.19 days, p=0.057). There were no differences in percent with lung function recovery to <10% of baseline FEV1pp. Similar results were seen in local and external validation cohorts comparing a pauci-inflammatory to viral/non-viral inflammatory exacerbation phenotypes.

CONCLUSIONS: Sub-phenotypes of CF PEx exist with differences in biomarker profile, clinical presentation, and outcomes.

PMID:35713619 | DOI:10.1513/AnnalsATS.202111-1266OC

Pediatr Pulmonol. 2022 Jun 16. doi: 10.1002/ppul.26040. Online ahead of print.

ABSTRACT

BACKGROUND: Because of the heterogeneity in cystic fibrosis (CF) lung disease among young children, a clinical method to identify early-onset lung disease is needed.

OBJECTIVE: To develop a CF Early-onset Lung Disease (CFELD) scoring system by utilizing prospectively collected longitudinal data on manifestations in the first 3 years of life.

DESIGN: We studied 145 infants born during 2012-2017, diagnosed through newborn screening by age 3 months, and followed to 36 months of age. Cough severity, pulmonary exacerbations (PEx), respiratory cultures, and hospitalizations were collected at each CF center visit (every 1-2 months in infancy and quarterly thereafter). These data were used to construct the CFELD system and to classify lung disease into five categories: asymptomatic, minimal, mild, moderate, and severe.

RESULTS: The most frequent manifestation of CF early lung disease was MD-reported PEx episodes, PEx hospitalizations, and positive Pseudomonas aeruginosa cultures. Parent-reported cough severity was correlated with the number of respiratory hospitalizations (r=0.48, p<0.0001). The distribution of CFELD categories was 10% asymptomatic, 17% minimal, 29% mild, 33% moderate, and 12% severe. The moderate and severe categories occurred 3-fold higher in pancreatic insufficient (PI, 49%) vs. sufficient subjects (16%), p < 0.0001. In addition to PI, gastrointestinal and nutrition-related hospitalizations, plasma cytokines IL-6 and IL-10, duration of CFTR modulator therapy, and type of health insurance were significant predictors of CFELD scores.

CONCLUSION: The CFELD scoring system is novel, allows systematic evaluation of lung disease prognosis early, and may aid in therapeutic decision-making particularly in the initiation of CFTR modulator therapy. This article is protected by copyright. All rights reserved.

PMID:35712759 | DOI:10.1002/ppul.26040

Front Pediatr. 2022 May 31;10:896439. doi: 10.3389/fped.2022.896439. eCollection 2022.

ABSTRACT

INTRODUCTION: Metabolomics is an emerging area of research and has the potential to identify clinical biomarkers for predicting or diagnosing cystic fibrosis (CF) pulmonary exacerbations (PEx).

OBJECTIVE: To identify clinically promising metabolites across different sample sources that can be used to predict or diagnose PEx in CF.

EVIDENCE REVIEW: Searches for original literature were completed through EMBASE, MEDLINE, and all databases on the Web of Science with no restrictions on language or publication date. Gray literature was collected through Google Scholar. Additional studies were obtained by contacting authors and searching reference lists of candidate papers. The patient population included individuals with CF. Studies involving patients who underwent lung transplantation were excluded. The outcome was the prediction or diagnosis of pulmonary exacerbations from metabolites directly measured from biological samples. Search results were downloaded and imported into Covidence and duplicates were removed automatically. Any remaining duplicates were manually tagged and excluded. Two independent reviewers screened each abstract for eligibility and repeated this process for full texts. Risk of bias was conducted using QUADAS-2 by two independent reviewers. A third author resolved any remaining conflicts.

RESULTS: A combined 3974 relevant abstracts were identified and 115 full texts were assessed for eligibility. The final 25 studies underwent data extraction for study design, patient demographics, studied metabolites, concentration values, and diagnostic accuracy values. Included studies differed considerably in methodologies, sample specimen types (exhaled breath condensate [EBC], sputum, saliva, plasma, urine), and disease states. We identified 19 unique metabolites that were measured by two or more studies of which 2 have the potential to predict PEx (EBC 4-hydroxycyclohexylcarboxylic acid [4-HCHC] and lactic acid) and 6 to diagnose PEx (EBC 4-HCHC and lactic acid, sputum lactic acid and nitrate, and plasma arginine and methionine).

CONCLUSION AND RELEVANCE: This systematic review has identified promising metabolites for further study in CF. Certain metabolites may provide clinical potential in predicting or diagnosing PEx, but further validation studies are required. With better tools to aid in the earlier identification of PEx, clinicians can implement preventative measures to mitigate airway damage.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/.

PMID:35712620 | PMC:PMC9192952 | DOI:10.3389/fped.2022.896439

Front Mol Biosci. 2022 May 30;9:880432. doi: 10.3389/fmolb.2022.880432. eCollection 2022.

ABSTRACT

Anti-microbial resistance is a rising global healthcare concern that needs urgent attention as growing number of infections become difficult to treat with the currently available antibiotics. This is particularly true for mycobacterial infections like tuberculosis and leprosy and those with emerging opportunistic pathogens such as Mycobacterium abscessus, where multi-drug resistance leads to increased healthcare cost and mortality. M. abscessus is a highly drug-resistant non-tuberculous mycobacterium which causes life-threatening infections in people with chronic lung conditions such as cystic fibrosis. In this study, we explore M. abscessus phosphopantetheine adenylyl transferase (PPAT), an enzyme involved in the biosynthesis of Coenzyme A, as a target for the development of new antibiotics. We provide structural insights into substrate and feedback inhibitor binding modes of M. abscessus PPAT, thereby setting the basis for further chemical exploration of the enzyme. We then utilize a multi-dimensional fragment screening approach involving biophysical and structural analysis, followed by evaluation of compounds from a previous fragment-based drug discovery campaign against M. tuberculosis PPAT ortholog. This allowed the identification of an early-stage lead molecule exhibiting low micro molar affinity against M. abscessus PPAT (Kd 3.2 ± 0.8 µM) and potential new ways to design inhibitors against this enzyme. The resulting crystal structures reveal striking conformational changes and closure of solvent channel of M. abscessus PPAT hexamer providing novel strategies of inhibition. The study thus validates the ligandability of M. abscessus PPAT as an antibiotic target and identifies crucial starting points for structure-guided drug discovery against this bacterium.

PMID:35712348 | PMC:PMC9197168 | DOI:10.3389/fmolb.2022.880432

ACS Pharmacol Transl Sci. 2022 Jun 10;5(6):419-428. doi: 10.1021/acsptsci.2c00007. eCollection 2022 Jun 10.

ABSTRACT

Background and purpose: Cystic fibrosis (CF) is associated with a myriad of respiratory complications including increased susceptibility to lung infections and inflammation. Progressive inflammatory insults lead to airway damage and remodeling, resulting in compromised lung function. Treatment with ivacaftor significantly improves respiratory function and reduces the incidence of pulmonary exacerbations; however, its effect on lung inflammation is yet to be fully elucidated. Experimental approach: This study investigates the effects of ivacaftor on lung inflammation in a lipopolysaccharide (LPS) exposure mouse model (C57BL/6). All groups received intratracheal (IT) administration of LPS (10 μg). Prophylactic treatment involved intraperitoneal injections of ivacaftor (40 mg/kg) once a day beginning 4 days prior to LPS challenge. The therapeutic group received a single intraperitoneal ivacaftor injection (40 mg/kg) directly after LPS. Mice were culled either 24 or 72 h after LPS challenge, and serum, bronchoalveolar lavage fluid (BALF), and lung tissue samples were collected. The degree of inflammation was assessed through cell infiltration, cytokine expression, and histological analysis. Key results: Ivacaftor did not decrease the total number of immune cells within the BALF; however, prophylactic treatment did significantly reduce macrophage and lymphocyte infiltration. Prophylactic treatment exhibited a significant negative correlation between the immune cell number and ivacaftor concentrations in BALF; however, no significant changes in the cytokine expression or histological parameters were determined. Conclusions and implications: Ivacaftor possesses some inherent immunomodulatory effects within the lungs following LPS inoculation; however, further analysis of larger sample sizes is required to confirm the results.

PMID:35711814 | PMC:PMC9194937 | DOI:10.1021/acsptsci.2c00007

Front Immunol. 2022 May 31;13:908010. doi: 10.3389/fimmu.2022.908010. eCollection 2022.

ABSTRACT

Respiratory diseases cause a high incidence and mortality worldwide. As a natural immunobiotic, Lactobacillus has excellent immunomodulatory ability. Administration of some Lactobacillus species can alleviate the symptoms of respiratory diseases such as respiratory tract infections, asthma, lung cancer and cystic fibrosis in animal studies and clinical trials. The beneficial effect of Lactobacillus on the respiratory tract is strain dependent. Moreover, the efficacy of Lactobacillus may be affected by many factors, such as bacteria dose, timing and host background. Here, we summarized the beneficial effect of administered Lactobacillus on common respiratory diseases with a focus on the mechanism and safety of Lactobacillus in regulating respiratory immunity.

PMID:35711436 | PMC:PMC9194447 | DOI:10.3389/fimmu.2022.908010