Sci Data. 2022 Jun 16;9(1):343. doi: 10.1038/s41597-022-01431-1.

ABSTRACT

Researchers studying cystic fibrosis (CF) pathogens have produced numerous RNA-seq datasets which are available in the gene expression omnibus (GEO). Although these studies are publicly available, substantial computational expertise and manual effort are required to compare similar studies, visualize gene expression patterns within studies, and use published data to generate new experimental hypotheses. Furthermore, it is difficult to filter available studies by domain-relevant attributes such as strain, treatment, or media, or for a researcher to assess how a specific gene responds to various experimental conditions across studies. To reduce these barriers to data re-analysis, we have developed an R Shiny application called CF-Seq, which works with a compendium of 128 studies and 1,322 individual samples from 13 clinically relevant CF pathogens. The application allows users to filter studies by experimental factors and to view complex differential gene expression analyses at the click of a button. Here we present a series of use cases that demonstrate the application is a useful and efficient tool for new hypothesis generation. (CF-Seq: http://scangeo.dartmouth.edu/CFSeq/ ).

PMID:35710652 | DOI:10.1038/s41597-022-01431-1

Eur Respir J. 2022 Jun 16:2102398. doi: 10.1183/13993003.02398-2021. Online ahead of print.

NO ABSTRACT

PMID:35710262 | DOI:10.1183/13993003.02398-2021

BMJ Open. 2022 Jun 16;12(6):e057588. doi: 10.1136/bmjopen-2021-057588.

ABSTRACT

OBJECTIVE: Describe trends in opioid plus high-risk medication coprescribing in the USA.

DESIGN: Analyses of serial, cross-sectional, nationally representative data of the National Ambulatory Medical Care Survey (NAMCS) over 2007-2016 and the National Hospital Ambulatory Medical Care Survey (NHAMCS) over 2007-2018.

SETTING: US ambulatory (NAMCS) and emergency department (ED, NHAMCS) settings.

PARTICIPANTS: Patient visits in which the patient was 18 years and older with an opioid prescription in the NAMCS or NHAMCS databases.

PRIMARY AND SECONDARY OUTCOME MEASURES: Frequency of opioid plus high-risk medication coprescribing.

RESULTS: From a combined sample of 700 499 visits over 2007-2018, there were 105 720 visits (15.1%) where opioids were prescribed. n=31 825 were from NAMCS and n=73 895 were from NHAMCS. The mean prevalence of coprescription of opioids and high-risk medications for the combined NAMCS and NHAMCS sample was 18.4% in 2007, peaked at 33.2% in 2014 and declined to 23.8% in 2016. Compared with adults receiving opioid prescriptions alone, those coprescribed opioids and high-risk medications were older, more likely female, white and using private or Medicare insurance (p<0.0001).

CONCLUSIONS: Coprescribing is more common in ambulatory than ED settings and has been declining, yet one in four patient visits where opioids were prescribed resulted in coprescribed, high-risk medications in 2016. Efforts and research to help lower the rates of high-risk prescribing are needed.

PMID:35710252 | DOI:10.1136/bmjopen-2021-057588

BMJ Open Respir Res. 2022 Jun;9(1):e001289. doi: 10.1136/bmjresp-2022-001289.

ABSTRACT

INTRODUCTION: Therapeutic advances have markedly increased life expectancy for those with cystic fibrosis (CF), resulting in a median predicted survival over 50 years. Consequently, people with CF (pwCF) are living through their reproductive years and the rate of pregnancy is rapidly rising. Despite the increased relevance of this topic, multicentre studies investigating the association between maternal health and choices made during pregnancy on maternal and fetal outcomes do not exist. Furthermore, there are very limited data on the outcomes following CF transmembrane conductance regulator (CFTR) modulator use during pregnancy and lactation.

METHODS AND ANALYSIS: Maternal and Fetal Outcomes in the Era of Modulators (MAYFLOWERS) is a prospective, multicentre observational clinical trial which will enrol approximately 285 pregnant pwCF including those who are modulator ineligible and those who choose to continue or discontinue CFTR modulator therapy during pregnancy and lactation. The primary aim of this 35-month study is to assess whether lung function changes during pregnancy differ based on the continued use of modulators or other factors such as pre-existing comorbid conditions. Secondary objectives include evaluation of pregnancy related and obstetrical complications and changes in mental health.

ETHICS AND DISSEMINATION: The design of this study required special consideration of study burden on pregnant and lactating people with chronic illness in the setting of a substantial number of unanswered questions under these conditions. MAYFLOWERS is the first prospective clinical trial examining pregnancy in CF; the outcomes will guide providers on pregnancy management in pwCF and others with chronic respiratory disease.

PMID:35710144 | DOI:10.1136/bmjresp-2022-001289

Curr Opin Pharmacol. 2022 Jun 13;65:102247. doi: 10.1016/j.coph.2022.102247. Online ahead of print.

ABSTRACT

This review provides an update on recent developments of RNA- and DNA-based methodologies and their intracellular targets in the context of cystic fibrosis (CF) lung disease. Ultimately, clinical success will require a suitable delivery system, but since the cargo for all these strategies is nucleic acid, it should hopefully be possible to exploit delivery breakthroughs from one study and apply these innovations to other experiments in order to identify the best strategy for everyone with CF. Ultimately, it may be the same approach for everyone, or possibly a number of different strategies tailored to particular mutations or classes/groups of mutations. And whilst the current focus is on CF lung disease, in the longer term the goal is to treat all affected organs in people with CF such as the pancreas, gut, and liver.

PMID:35709547 | DOI:10.1016/j.coph.2022.102247

Anesth Analg. 2022 Jul 1;135(1):e6-e7. doi: 10.1213/ANE.0000000000006031. Epub 2022 Jun 16.

NO ABSTRACT

PMID:35709460 | DOI:10.1213/ANE.0000000000006031

Biosci Rep. 2022 Jun 16:BSR20212006. doi: 10.1042/BSR20212006. Online ahead of print.

ABSTRACT

Cystic Fibrosis, the most common autosomal recessive disorder in Caucasians, is caused by mutations in the CFTR gene, which encodes a cAMP-activated chloride and bicarbonate channel that regulates ion and water transport in secretory epithelia. Although all mutations lead to the lack or reduction in channel function, the mechanisms through which this occurs are diverse - ranging from lack of full-length mRNA, reduced mRNA levels, impaired folding and trafficking, targeting to degradation, decreased gating or conductance, reduced protein levels to decreased half-life at the plasma membrane. Here, we review the different molecular mechanisms that cause cystic fibrosis and detail how these differences identify theratypes that can inform the use of directed therapies aiming at correcting the basic defect. In summary, we travel through CFTR life cycle from the gene to function, identifying what can go wrong and what can be targeted in terms of the different types of therapeutic approaches.

PMID:35707985 | DOI:10.1042/BSR20212006

Environ Microbiol. 2022 Jun 15. doi: 10.1111/1462-2920.16105. Online ahead of print.

ABSTRACT

Bacteria that successfully adapt to different substrates and environmental niches within the lung and overcome the immune defence can cause serious lung infections. Such infections are generally complex, and recognised as polymicrobial in nature. Both Pseudomonas aeruginosa and Streptococcus pneumoniae can cause chronic lung infections and were both detected in cystic fibrosis (CF) lung at different stages. In this study, single and dual species cultures of Pseudomonas aeruginosa and Streptococcus pneumoniae were studied under well controlled planktonic growth conditions. Under pH-controlled conditions, both species apparently benefited from the presence of the other. In co-culture with P. aeruginosa, S. pneumoniae grew efficiently under aerobic conditions, whereas in pure S. pneumoniae culture, growth inhibition occurred in bioreactors with dissolved oxygen concentrations above the microaerobic range. Lactic acid and acetoin that are produced by S. pneumoniae was efficiently utilised by P. aeruginosa. In pH-uncontrolled co-cultures, the low pH triggered by S. pneumoniae assimilation of glucose and lactic acid production negatively affected the growth of both strains. Nevertheless, ammonia production improved significantly, and P. aeruginosa growth dominated at later growth stages. This study revealed unreported metabolic interactions of two important pathogenic microorganisms and shed new lights into pathophysiology of bacterial lung infection. This article is protected by copyright. All rights reserved.

PMID:35706134 | DOI:10.1111/1462-2920.16105

Expert Rev Respir Med. 2022 Jun 15. doi: 10.1080/17476348.2022.2090928. Online ahead of print.

ABSTRACT

INTRODUCTION: : Great variation exists in the progression and outcomes of cystic fibrosis (CF) lung disease, due to both genetic and environmental influences. Social determinants mediate environmental exposures and treatment success; people with CF from socioeconomically disadvantaged backgrounds have worse health and die younger than those in more advantaged positions.

AREAS COVERED: : This paper reviews the literature on the mechanisms that are responsible for generating and sustaining disparities in CF health, and the ways by which social determinants translate into health advantages or disadvantages in people with CF. The authors make recommendations for addressing social risk factors in CF clinical practice.

EXPERT OPINION: : Socioeconomic factors are not dichotomous and their impact is felt at every step of the social ladder. CF care programs need to adopt a systematic protocol to screen for health-related social risk factors, and then connect patients to available resources to meet individual needs. Considerations such as daycare, schooling options, living and working conditions, and opportunities for physical exercise and recreation as well as promotion of self-efficacy are often overlooked. In addition, advocacy for changes in public policies on health insurance, environmental regulations, social welfare, and education would all help address the root causes of CF health inequities.

PMID:35705523 | DOI:10.1080/17476348.2022.2090928

Arch Pediatr. 2022 Jun 12:S0929-693X(22)00125-7. doi: 10.1016/j.arcped.2022.05.005. Online ahead of print.

ABSTRACT

BACKGROUND: Caring for a child with cystic fibrosis (CF) is challenging and stressful and even more so in a country with limited resources. Our aim was to study the impact of CF on the daily life of mothers with children who have CF in Tunisia, emphasizing the difficulties encountered.

METHODS: Overall, 20 participants were interviewed about their experiences of being caregivers and mothers of children with CF, including their knowledge about the condition, their attitude toward it, the impact of CF on their daily lives, the main difficulties they had faced, and their concerns and wishes about CF management.

RESULTS: The median age of the interviewees was 39 years. None of the mothers had known about CF before; 14 of them had difficulty accepting it at first, with suicidal thoughts in one case. Six hid the illness from the close family for fear of negative prejudices. Three mothers decided to stop having children despite availability of prenatal screening. CF also influenced the mothers' social activities (n = 13) and interfered with their jobs (n = 5). It was responsible for additional expenses in all cases. Chest physiotherapy represented a daily source of coping for all participants. Hospitalization related to Pseudomonas aeruginosa infection was considered stressful and constraining by 12 mothers. The mothers' main concern was the child's life expectancy (n = 7). Their main wish was to administer a curative treatment (n = 17).

CONCLUSION: CF was found to have deeply affected the mothers' psychosocial life stressing the need for the involvement of qualified psychologists and social workers together with the medical staff.

PMID:35705385 | DOI:10.1016/j.arcped.2022.05.005

J Immunol Methods. 2022 Jun 12:113306. doi: 10.1016/j.jim.2022.113306. Online ahead of print.

ABSTRACT

We developed a salivary assay for the detection of naturally acquired IgA antibody against Haemophilus influenzae type a (Hia) capsular polysaccharide in healthy Indigenous children from Northwestern Ontario, Canada. Hia-specific IgA antibody was detected in the saliva of 93% of Indigenous children aged 2-7 years.

PMID:35705121 | DOI:10.1016/j.jim.2022.113306

Cell Rep. 2022 Jun 14;39(11):110923. doi: 10.1016/j.celrep.2022.110923.

ABSTRACT

The uptake and digestion of host hemoglobin by malaria parasites during blood-stage growth leads to significant oxidative damage of membrane lipids. Repair of lipid peroxidation damage is crucial for parasite survival. Here, we demonstrate that Plasmodium falciparum imports a host antioxidant enzyme, peroxiredoxin 6 (PRDX6), during hemoglobin uptake from the red blood cell cytosol. PRDX6 is a lipid-peroxidation repair enzyme with phospholipase A2 (PLA2) activity. Inhibition of PRDX6 with a PLA2 inhibitor, Darapladib, increases lipid-peroxidation damage in the parasite and disrupts transport of hemoglobin-containing vesicles to the food vacuole, causing parasite death. Furthermore, inhibition of PRDX6 synergistically reduces the survival of artemisinin-resistant parasites following co-treatment of parasite cultures with artemisinin and Darapladib. Thus, PRDX6 is a host-derived drug target for development of antimalarial drugs that could help overcome artemisinin resistance.

PMID:35705035 | DOI:10.1016/j.celrep.2022.110923

Arch Bronconeumol. 2021 Oct;57(10):662-664. doi: 10.1016/j.arbr.2021.07.005. Epub 2021 Aug 13.

NO ABSTRACT

PMID:35702908 | DOI:10.1016/j.arbr.2021.07.005

J Infect. 2022 Jun 11:S0163-4453(22)00359-0. doi: 10.1016/j.jinf.2022.06.006. Online ahead of print.

ABSTRACT

COVID-19 has shown a relevant heterogeneity in spread and fatality among countries together with a significant variability in its clinical presentation, indicating that host genetic factors may influence COVID-19 pathogenicity. Indeed, subjects carrying single pathogenic variants of the Cystic Fibrosis (CF) Transmembrane Conductance Regulator (CFTR) gene - i.e. CF carriers - are more susceptible to respiratory tract infections and are more likely to undergo severe COVID-19 with higher risk of 14-day mortality. Given that CF carrier prevalence varies among ethnicities and nations, an ecological study in 37 countries was conducted, in order to determine to what extent the diverse CF carrier geographical distribution may have affected COVID-19 spread and fatality during the first pandemic wave. The CF prevalence in countries, as indicator of the geographical distribution of CF carriers, significantly correlated in a direct manner with both COVID-19 prevalence and its Case Fatality Rate (CFR). In a regression study weighted for the number of tests performed, COVID-19 prevalence positively correlated with CF prevalence, while CFR correlated with population percentage older than 65-year, cancer and CF prevalence. Multivariate regression model also confirmed COVID-19 CFR to be associated with CF prevalence, after adjusting for elderly, cancer prevalence, and weighting for the tests performed. This study suggests a putative contribution of population genetics of CFTR in understanding the spatial distribution of COVID-19 spread and fatality.

PMID:35700866 | DOI:10.1016/j.jinf.2022.06.006

Arch Bronconeumol. 2021 Aug;57(8):528-532. doi: 10.1016/j.arbr.2020.04.015.

ABSTRACT

INTRODUCTION: Bronchiectasis patients may present a reduced functional capacity due to an increase in the ventilatory demand during exercise.

OBJECTIVE: To evaluate the effects of controlled voluntary hyperinflation and increased respiratory rate on the mechanics of the respiratory system, simulating what happens during exercise, in bronchiectasis and healthy subjects.

METHODS: Bronchiectasis (n=30) and healthy (n=16) subjects were evaluated by impulse oscillometry (IOS) during a baseline condition, and in controlled conditions with baseline (b) tidal volume (V) and hyperinflation (H), with respiratory rates at 30(R30) and 40(R40) bpm, in a random order. The mixed effects and a significance level at 0.05 were used for comparisons.

RESULTS: Resistance at 5Hz (R5), and at minus 20Hz (R5-R20), in kPa/L/s, were higher in subjects with bronchiectasis in all experimental conditions (p<0.05). For the bronchiectasis group, R5 and R5-20 increased with R increase at V (VRb versus VR30 and VR40; VR30 versus VR40; R5, R20 and R5-20 increased with R increase at H (HRb versus HR40; HR30 versus HR40). For the same R, there was a decrease with H compared to V (HRb versus VR30 and VR40; and HR30 versus VR30 and VR40). For the healthy group, only R20 showed differences (HR30 versus HR40; HR40 versus VR40).

CONCLUSION: The tachypnea increases the resistance and reactance of the respiratory system in bronchiectasis patients, and the voluntary hyperinflation caused attenuates this increase. These results can guide the development of strategies to reduce the limitation of physical activity in patients with bronchiectasis.

PMID:35699030 | DOI:10.1016/j.arbr.2020.04.015

Arch Bronconeumol. 2021 Nov;57(11):708-710. doi: 10.1016/j.arbr.2020.10.016.

NO ABSTRACT

PMID:35699016 | DOI:10.1016/j.arbr.2020.10.016

Arch Bronconeumol. 2021 Jul;57(7):501-503. doi: 10.1016/j.arbr.2020.11.017.

NO ABSTRACT

PMID:35698963 | DOI:10.1016/j.arbr.2020.11.017

Arch Bronconeumol. 2021 Sep;57(9):563-564. doi: 10.1016/j.arbr.2021.06.004. Epub 2021 Jul 5.

NO ABSTRACT

PMID:35698931 | DOI:10.1016/j.arbr.2021.06.004

J Bronchology Interv Pulmonol. 2022 May 27. doi: 10.1097/LBR.0000000000000874. Online ahead of print.

ABSTRACT

BACKGROUND: Currently, no consensus guidelines recommend routine bronchoscopy procedure in cystic fibrosis (CF), as no evidence is available concerning its use as either a diagnostic or therapeutic tool. Its efficacy is controversial, and no randomized controlled prospective trials are available to check its effectiveness. The aims of the present study were to evaluate the effectiveness of bronchoscopy as a diagnostic/therapeutic tool in CF children and adolescents; and to verify the effect of serial bronchoscopy on lung disease progression in subjects with CF not responding to a single procedure.

METHODS: Data of patients who received bronchoscopy at 2 Italian CF centers were collected. Bronchoalveolar lavage was performed during the procedure including airway clearance with mucolytics, inhaled antibiotics, and/or surfactant instillation.

RESULTS: A total of 16 patients in center 1 and 17 in center 2 underwent, respectively, 28 and 23 bronchoscopic procedure in the study period. Five patients in each center underwent >1 procedure. All procedures were generally well tolerated. No patient required admission to the pediatric intensive therapy unit. In 19.6% of bronchoalveolar lavages, growth of Aspergillus fumigatus was evident, although not detected by sputum analyses. After the procedure, an increase in mean percent predicted forced expiratory volume in the 1 second >10% was observed, and a significant decrease in pulmonary exacerbations yearly was evident.

CONCLUSION: Based on the results, we suggest bronchoscopy is not to be considered an obsolete tool, and it remains useful in CF management, although in selected cases. We encourage to support longitudinal observational studies to standardize the procedure, focusing on the choice of drugs to be instilled, modalities and timing of serial bronchoscopy and subsequent follow-up in selected severe clinical conditions.

PMID:35698279 | DOI:10.1097/LBR.0000000000000874

Commun Biol. 2022 Jun 13;5(1):580. doi: 10.1038/s42003-022-03448-z.

ABSTRACT

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.

PMID:35697829 | PMC:PMC9192715 | DOI:10.1038/s42003-022-03448-z