Mycopathologia. 2021 Sep 27. doi: 10.1007/s11046-021-00582-w. Online ahead of print.

ABSTRACT

Today, the genus Scedosporium comprises at least ten species with four of them, Scedosporium apiospermum, Scedosporium boydii, Scedosporium aurantiacum and Scedosporium minutisporum capable of colonizing the lungs of patients with cystic fibrosis. Scedosporium dehoogii, which is also common in the soil, has never been reported as causing human pulmonary infections. Here we report the first genome sequence for S. dehoogii, an invaluable resource to understand the genetic bases of pathogenesis in the genus Scedosporium.

PMID:34570289 | DOI:10.1007/s11046-021-00582-w

Gerodontology. 2021 Sep 26. doi: 10.1111/ger.12592. Online ahead of print.

ABSTRACT

OBJECTIVES: The objectives of this article are to list the most commonly prescribed Oral Nutritional Supplements in the UK and Ireland and their sugar content; and to raise awareness among the dental profession regarding their uses and potential dental risks involved.

BACKGROUND: Many older patients benefit from Oral Nutritional Supplements. Prescribers may not consider dental implications of these. Patients may not think to disclose these medications to their dentist.

MATERIALS AND METHODS: A list of commonly prescribed Oral Nutritional Supplements in the UK and Ireland was compiled. Nutritional information was obtained from the manufacturers' website and arranged in order of decreasing sugar content. Potential dental implications are discussed and recommendations made for dental practitioners.

RESULTS: Pre-formed Oral Nutritional Supplements can contain between 6.6 and 27.2 g of sugar per serving. Powdered Oral Nutritional Supplements, which are to be mixed with 200 ml whole milk, contain between 16.4 and 35.0 g sugar per serving. The "shot"-type Oral Nutritional Supplements contain less sugar, ranging from 0.0 to 4.0 g per serving.

CONCLUSIONS: The sugar content of frequently prescribed Oral Nutritional Supplements can be high. While they are beneficial in assisting the patient to maintain a healthy BMI, they may increase the risk of dental caries. Dental professionals should enquire specifically about Oral Nutritional Supplements during history taking, particularly in groups who are likely to be prescribed such supplements. Consideration should also be given to increasing caries-preventive measures for patients who take these supplements.

PMID:34569084 | DOI:10.1111/ger.12592

Cureus. 2021 Aug 20;13(8):e17326. doi: 10.7759/cureus.17326. eCollection 2021 Aug.

ABSTRACT

Pseudomonas aeruginosa (PA), a gram-negative rod-shaped bacterium, is one of the most common pathogens causing colonization and infection of the respiratory tract and lungs in patients with cystic fibrosis (CF). Antibiotic therapy is the mainstay treatment for PA infection, and tobramycin is one of the widely used antibiotics in intravenous or inhalation form. This review aims to explore if there is any advantage of adding systemic antibiotics to tobramycin inhalation therapy by comparing the combination regimen to tobramycin inhalation monotherapy in CF patients with PA infection. We collected studies relevant to our review topic by doing a literature search on multiple databases. According to the currently available studies, the addition of oral antibiotics such as fluoroquinolones and azithromycin to tobramycin inhalation solution (TIS) provides no additional benefit in eradicating PA infection or producing clinical improvement in cystic fibrosis patients. However, adding intravenous antibiotics to TIS has not produced conclusive results and thus requires further research. We recommend conducting more randomized controlled trials comparing different treatment regimens, which may help discover the most beneficial treatment regimen with decreased systemic side effects.

PMID:34567873 | PMC:PMC8451513 | DOI:10.7759/cureus.17326

Front Endocrinol (Lausanne). 2021 Sep 10;12:715043. doi: 10.3389/fendo.2021.715043. eCollection 2021.

ABSTRACT

Anatomical proximity and functional correlations between the exocrine and endocrine pancreas warrant reciprocal effects between the two parts. Inflammatory diseases of the exocrine pancreas, such as acute or chronic pancreatitis, or the presence of cystic fibrosis disrupt endocrine function, resulting in diabetes of the exocrine pancreas. Although novel mechanisms are being increasingly identified, the intra- and intercellular pathways regulating exocrine-endocrine interactions are still not fully understood, making the development of new and more effective therapies difficult. Therefore, this review sought to accumulate current knowledge regarding the pathogenesis of diabetes in acute and chronic pancreatitis, as well as cystic fibrosis.

PMID:34566890 | PMC:PMC8461102 | DOI:10.3389/fendo.2021.715043

Front Pharmacol. 2021 Sep 8;12:702677. doi: 10.3389/fphar.2021.702677. eCollection 2021.

ABSTRACT

Neutrophilic inflammation is a key determinant of cystic fibrosis (CF) lung disease. Neutrophil-derived free DNA, released in the form of extracellular traps (NETs), significantly correlates with impaired lung function in patients with CF, underlying their pathogenetic role in CF lung disease. Thus, specific approaches to control NETosis of neutrophils migrated into the lungs may be clinically relevant in CF. We investigated the efficacy of phosphodiesterase (PDE) type-4 inhibitors, in vitro, on NET release by neutrophils from healthy volunteers and individuals with CF, and in vivo, on NET accumulation and lung inflammation in mice infected with Pseudomonas aeruginosa. PDE4 blockade curbed endotoxin-induced NET production and preserved cellular integrity and apoptosis in neutrophils, from healthy subjects and patients with CF, challenged with endotoxin, in vitro. The pharmacological effects of PDE4 inhibitors were significantly more evident on CF neutrophils. In a mouse model of Pseudomonas aeruginosa chronic infection, aerosol treatment with roflumilast, a selective PDE4 inhibitor, gave a significant reduction in free DNA in the BALF. This was accompanied by reduced citrullination of histone H3 in neutrophils migrated into the airways. Roflumilast-treated mice showed a significant improvement in weight recovery. Our study provides the first evidence that PDE4 blockade controls NETosis in vitro and in vivo, in CF-relevant models. Since selective PDE4 inhibitors have been recently approved for the treatment of COPD and psoriasis, our present results encourage clinical trials to test the efficacy of this class of drugs in CF.

PMID:34566635 | PMC:PMC8456009 | DOI:10.3389/fphar.2021.702677

Eur J Hum Genet. 2021 Sep 27. doi: 10.1038/s41431-021-00962-2. Online ahead of print.

ABSTRACT

Despite no consensus on the definition of 'seriousness', the concept is regularly used in policy and practice contexts to categorise conditions, determine access to genetic technologies and uses of selective pregnancy termination. Whilst attempts have been made to create taxonomies of genetic condition seriousness to inform clinical and policy decision-making, these have often relied on condition appraisals made by health and genetics professionals. The views of people with genetic conditions have been largely under-represented. This study explores the concept of seriousness through the perspectives of people with a range of 'clinically serious' conditions (fragile X conditions, spinal muscular atrophy, cystic fibrosis, haemophilia, thalassaemia). Attitudes towards suffering, quality of life (QoL) and selective pregnancy termination were elucidated from 45 in-depth qualitative interviews and 469 postal/online surveys. The majority of participants reported good health/wellbeing, and the capacity for good QoL, despite experiencing suffering with their condition. Notably, participants with later-onset conditions held more negative views of their health and QoL, and were more likely to view their condition as an illness, than those with early-onset conditions. These participants were more likely to see their condition as part of their identity. Whilst most participants supported prenatal screening, there was little support for selective termination. Moreover, social environment emerged as a critical mediator of the experience of the condition. The complex and rich insights of people living with genetic conditions might usefully be incorporated into future genetic taxonomies of 'seriousness' to ensure they more accurately reflect the lived reality of those with genetic conditions.

PMID:34565797 | DOI:10.1038/s41431-021-00962-2

J Cyst Fibros. 2021 Sep 23:S1569-1993(21)01408-9. doi: 10.1016/j.jcf.2021.09.007. Online ahead of print.

ABSTRACT

BACKGROUND: Studies in separate cohorts suggest possible discrepancies between inhaled medicines supplied (median 50-60%) and medicines used (median 30-40%). We performed the first study that directly compares CF medicine supply against use to identify the cost of excess medicines supply.

METHODS: This cross-sectional study included participants from 12 UK adult centres with ≥1 year of continuous adherence data from data-logging nebulisers. Medicine supply was measured as medication possession ratio (MPR) for a 1-year period from the first suitable supply date. Medicine use was measured as electronic data capture (EDC) adherence over the same period. The cost of excess medicines was calculated as whole excess box(es) supplied after accounting for the discrepancy between EDC adherence and MPR with 20% contingency.

RESULTS: Among 275 participants, 133 (48.4%) were females and mean age was 30 years (95% CI 29-31 years). Median EDC adherence was 57% (IQR 23-86%), median MPR was 74% (IQR 46-96%) and the discrepancy between measures was median 14% (IQR 2-29%). Even with 20% contingency, mean potential cost of excess medicines was £1,124 (95% CI £855-1,394), ranging from £183 (95% CI £29-338) for EDC adherence ≥80% to £2,017 (95% CI £1,507-2,526) for EDC adherence <50%.

CONCLUSIONS: This study provides a conservative estimate of excess inhaled medicines supply cost among adults with CF in the UK. The excess supply cost was highest among those with lowest EDC adherence, highlighting the importance of adherence support and supplying medicine according to actual use. MPR provides information about medicine supply but over-estimates actual medicine use.

PMID:34565705 | DOI:10.1016/j.jcf.2021.09.007

J Cyst Fibros. 2021 Sep 23:S1569-1993(21)01403-X. doi: 10.1016/j.jcf.2021.09.003. Online ahead of print.

NO ABSTRACT

PMID:34565704 | DOI:10.1016/j.jcf.2021.09.003

Allergy. 2021 Sep 26. doi: 10.1111/all.15109. Online ahead of print.

ABSTRACT

BACKGROUND: The European Academy of Allergy and Clinical Immunology has developed a guideline to provide evidence-based recommendations for healthcare professionals to support the transitional care of adolescents and young adults (AYA) with allergy and/or asthma. The goal of this work was to ensure that the draft recommendations are also important for patients.

METHODS: We surveyed patients aged 11-25 years with allergy and/or asthma and their parents across Europe between 17th February and 16th March 2020. The multilingual survey was distributed through national allergy and asthma patient organisations in Europe as well as through social media.

RESULTS: A total of 1210 responses from 24 European countries were collected. There were 415 (34.3%) AYA and 795 (65.7%) parents. The majority of AYA (72.3%) and parents (81.9%) were female. Patients had a history of asthma (61.1%), allergic rhinoconjunctivitis (54.1%), food allergy (53.8%), atopic eczema (42.6%), and anaphylaxis (28.8%). All recommendations achieved the median score of either 'important' or 'very important'. The least supported recommendations were the use of joint clinics with both paediatric and adult physicians attending and the use of web-based or mobile technologies for communication with the AYA. The most supported recommendation was checking that the AYA is knowledgeable and compliant with their prescribed medication. Qualitative analysis revealed conditional approval for some recommendations.

CONCLUSIONS: There was agreement from patients and parents on the importance of the draft recommendations on transitional care for adolescents and young adults with allergy and/or asthma and their parents. The recommendations now need to be implemented into clinical practice across Europe.

PMID:34564855 | DOI:10.1111/all.15109

APMIS. 2021 Sep 24. doi: 10.1111/apm.13177. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Burkholderia cenocepacia complex is associated with high transmissibility, virulence, and poor prognosis in cystic fibrosis (CF) patients. However, extrapulmonary infections are rare. We investigated the genome of a B. cenocepacia IIIA isolated from a liver abscess in a Brazilian CF patient and compared it to strain J2315.

METHODS: The whole genome was sequenced and contigs were annotated by Rapid Annotation using Subsystem Technology. The Pathosystems Resource Integration Center was used to map antimicrobial and virulence genes. The Genomic Island (GIs) analysis was performed using two prediction methods and the presence of putative plasmids and Insertion Sequences (ISs) was investigated.

RESULTS: The isolate was confirmed as B. cenocepacia IIIA to ST-28 (ET-12 lineage). A total of 64 genes for antimicrobial resistance and 47 genes related to virulence were identified. Among the Virulence Factors, there was a predominance of factors related to the invasion mechanism, to the flagellar biosynthesis protein, and to the RNA polymerase sigma factor for flagellar operon (cdpA). Two IS families (IS3 and IS5) and only one plasmid were found. On average 56 GIs were predicted by at least one of the methods applied.

CONCLUSIONS: Comparative analysis showed resistance mechanisms and virulence factors revealing invasive determinants used by B. cenocepacia IIIA (ET12) in the process of disease spread to other infection sites (extrapulmonary) of highly virulent strains in CF patients.

PMID:34561922 | DOI:10.1111/apm.13177

Cochrane Database Syst Rev. 2021 Jan 9;1:CD008394. doi: 10.1002/14651858.CD008394.pub4.

ABSTRACT

BACKGROUND: The frequency of skin ulceration makes an important contributor to the morbidity burden in people with sickle cell disease. Many treatment options are available to the healthcare professional, although it is uncertain which treatments have been assessed for effectiveness in people with sickle cell disease. This is an update of a previously published Cochrane Review.

OBJECTIVES: To assess the clinical effectiveness and harms of interventions for treating leg ulcers in people with sickle cell disease.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. We searched LILACS (1982 to January 2020), ISI Web of Knowledge (1985 to January 2020), and the Clinical Trials Search Portal of the World Health Organization (January 2020). We checked the reference lists of all the trials identified. We also contacted those groups or individuals who may have completed relevant randomised trials in this area. Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 13 January 2020; date of the last search of the Cochrane Wounds Group Trials Register: 17 February 2017.

SELECTION CRITERIA: Randomised controlled trials of interventions for treating leg ulcers in people with sickle cell disease compared to placebo or an alternative treatment.

DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion. All three authors independently assessed the risk of bias of the included studies and extracted data. We used GRADE to assess the quality of the evidence.

MAIN RESULTS: Six studies met the inclusion criteria (198 participants with 250 ulcers). Each trial investigated a different intervention and within this review we have grouped these as systemic pharmaceutical interventions (L-cartinine, arginine butyrate, isoxsuprine) and topical pharmaceutical interventions (Solcoseryl® cream, arginine-glycine-aspartic acid (RGD) peptide dressing and topical antibiotics). No trials on non-pharmaceutical interventions were included in the review. All trials had an overall unclear or high risk of bias, and drug companies sponsored four of them. We were unable to pool findings due to the heterogeneity in outcome definitions, and inconsistency between the units of randomisation and analysis. Three interventions reported on the change in ulcer size (arginine butyrate, RGD peptide, L-cartinine). Of these, only arginine butyrate showed a reduction of ulcer size compared with a control group, mean reduction -5.10 cm² (95% CI -9.65 to -0.55), but we are uncertain whether this reduces ulcer size compared to standard care alone as the certainty of the evidence has been assessed as very low. Three trials reported on complete leg ulcer closure (isoxsuprine, arginine butyrate, RGD peptide matrix; very low quality of evidence). None reported a clinical benefit. No trial reported on: the time to complete ulcer healing; ulcer-free survival following treatment for sickle cell leg ulcers; quality of life measures; incidence of amputation or harms.

AUTHORS' CONCLUSIONS: Given the very low quality of the evidence identified in this updated Cochrane Review we are uncertain whether any of the assessed pharmaceutical interventions reduce ulcer size or result in leg ulcer closure in treated participants compared to controls. However, this intervention was assessed as having a high risk of bias due to inadequacies in the single trial report. Other included studies were also assessed as having an unclear or high risk of bias. The harm profile of the all interventions remains inconclusive.

PMID:34559425 | DOI:10.1002/14651858.CD008394.pub4

Int J Mycobacteriol. 2021 Apr-Jun;10(2):166-169. doi: 10.4103/ijmy.ijmy_83_21.

ABSTRACT

BACKGROUND: The microbiology of cystic fibrosis (CF) is complicated by the presence of several species, including Mycobacterium abscessus, which are highly resistant to antibiotics. Conventional selective bacteriological methods employ antibiotics which favor the growth of one bacterial component over others in a mixed population. For in vitro studies examining multiple species, for example, in dual biofilm models, it is difficult to successfully separate M. abscessus from nontuberculous mycobacterial (NTM) species. Therefore, it was the aim of this study to develop a selective agar medium that was able to isolate M. abscessus from a pool of other highly-resistant Gram-negative organisms, which would be useful to microbiologists performing co-culture experiments and which require re-isolation of the NTM organism.

METHODS: Wylie-Stanley agar (WSA) was developed consisting of glucose, 16 g/l; yeast extract, 30 g/l; peptone, 6.8 g/l; and agar, 20 g/l along with selective supplements including chloramphenicol, 50 mg/l; ceftazidime, 32 mg/l; colistin, 24 mg/l; trimethoprim, 21.3 mg/l; sulfamethoxazole, 106.7 mg/l; and novobiocin, 50 mg/l. This medium was (i) challenged with 10 non-NTM species (27 isolates) of common Gram-negative and Gram-positive organisms associated with CF and (ii) compared to Columbia Blood Agar and Middlebrook 7H10 Agar for the isolation of M. abscessus organisms from mixed cultures of NTM organisms and Pseudomonas aeruginosa and Stenotrophomonas maltophilia.

RESULTS: This medium was highly specific for the growth of M. abscessus organisms and grew all NTM organisms. WSA medium did not allow the growth of any of the non-NTM species. When mixed cultures of M. abscessus species and P. aeruginosa and S. maltophilia were inoculated onto WSA medium, only the NTM organism could be grown successfully, highlighting the specificity of this medium. In contrast, both Columbia Blood Agar and Middlebrook 7H10 Agar allowed the growth of both NTM and non-NTM organisms.

CONCLUSION: While the specificity was high, the sensitivity of WSA was low, and therefore, we do not advocate employment of WSA medium for the primary isolation of M. abscessus organisms from CF sputum, rather for the purposes of separating M. abscessus populations of organisms from other highly-resistant organisms, including P. aeruginosa and S. maltophilia, which would be useful to microbiologists performing co-culture experiments and which require re-isolation of the pure M. abscessus organism.

PMID:34558469 | DOI:10.4103/ijmy.ijmy_83_21

Animal Model Exp Med. 2021 Sep 16;4(3):220-232. doi: 10.1002/ame2.12180. eCollection 2021 Sep.

ABSTRACT

Cystic fibrosis is an autosomal recessive disease caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Here we summarize, at the basic descriptive level, clinical and genetic characteristics of cystic fibrosis gene mutations, while emphasizing differences between CF mutations found in Chinese pediatric CF patients compared to those found in Caucasian CF patients. In addition, we describe animal models used to study human cystic fibrosis disease and highlight unique features of each model that mimic specific human CF-associated signs and symptoms. At the clinical level, we summarize CF clinical manifestations and diagnostic, treatment, and prognostic methods to provide clinicians with information toward reducing CF misdiagnosis and missed diagnosis rates.

PMID:34557648 | PMC:PMC8446696 | DOI:10.1002/ame2.12180

F1000Res. 2021 Aug 13;10:801. doi: 10.12688/f1000research.55140.1. eCollection 2021.

ABSTRACT

The airways of people with cystic fibrosis (CF) are often chronically colonised with a diverse array of bacterial and fungal species. However, little is known about the relative partitioning of species between the planktonic and biofilm modes of growth in the airways. Existing in vivo and in vitro models of CF airway infection are ill-suited for the long-term recapitulation of mixed microbial communities. Here we describe a simple, in vitro continuous-flow model for the cultivation of polymicrobial biofilms and planktonic cultures on different substrata. Our data provide evidence for inter-species antagonism and synergism in biofilm ecology. We further show that the type of substratum on which the biofilms grow has a profound influence on their species composition. This happens without any major alteration in the composition of the surrounding steady-state planktonic community. Our experimentally-tractable model enables the systematic study of planktonic and biofilm communities under conditions that are nutritionally reminiscent of the CF airway microenvironment, something not possible using any existing in vivo models of CF airway infection.

PMID:34557293 | PMC:PMC8442117 | DOI:10.12688/f1000research.55140.1

Thorax. 2021 Sep 23:thoraxjnl-2020-216265. doi: 10.1136/thoraxjnl-2020-216265. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a life-threatening genetic disease, affecting around 10 500 people in the UK. Precision medicines have been developed to treat specific CF-gene mutations. The newest, elexacaftor/tezacaftor/ivacaftor (ELEX/TEZ/IVA), has been found to be highly effective in randomised controlled trials (RCTs) and became available to a large proportion of UK CF patients in 2020. Understanding the potential health economic impacts of ELEX/TEZ/IVA is vital to planning service provision.

METHODS: We combined observational UK CF Registry data with RCT results to project the impact of ELEX/TEZ/IVA on total days of intravenous (IV) antibiotic treatment at a population level. Registry data from 2015 to 2017 were used to develop prediction models for IV days over a 1-year period using several predictors, and to estimate 1-year population total IV days based on standards of care pre-ELEX/TEZ/IVA. We considered two approaches to imposing the impact of ELEX/TEZ/IVA on projected outcomes using effect estimates from RCTs: approach 1 based on effect estimates on FEV1% and approach 2 based on effect estimates on exacerbation rate.

RESULTS: ELEX/TEZ/IVA is expected to result in significant reductions in population-level requirements for IV antibiotics of 16.1% (~17 800 days) using approach 1 and 43.6% (~39 500 days) using approach 2. The two approaches require different assumptions. Increased understanding of the mechanisms through which ELEX/TEZ/IVA acts on these outcomes would enable further refinements to our projections.

CONCLUSIONS: This work contributes to increased understanding of the changing healthcare needs of people with CF and illustrates how Registry data can be used in combination with RCT evidence to estimate population-level treatment impacts.

PMID:34556554 | DOI:10.1136/thoraxjnl-2020-216265

Thorax. 2021 Sep 23:thoraxjnl-2021-217140. doi: 10.1136/thoraxjnl-2021-217140. Online ahead of print.

ABSTRACT

Reducing treatment burden in cystic fibrosis (CF) is the top research priority for patients and clinicians. Difficulty accessing medication is one aspect of treatment burden. We investigated this with an online survey available globally for patients with CF and healthcare professionals. Almost three quarters of patients with CF in our survey report difficulty getting repeat prescriptions on time, and most community pharmacists experience interrupted supplies of CF-specific medications. These barriers affect emotional and physical health of people with CF. Two-thirds of people with CF would like to get all their CF medication from one place, their CF centre.

PMID:34556553 | DOI:10.1136/thoraxjnl-2021-217140

Thorax. 2021 Sep 23:thoraxjnl-2021-217594. doi: 10.1136/thoraxjnl-2021-217594. Online ahead of print.

ABSTRACT

INTRODUCTION: Recurrent pulmonary exacerbations lead to progressive lung damage in cystic fibrosis (CF). Inhaled medications (mucoactive agents and antibiotics) help prevent exacerbations, but objectively measured adherence is low. We investigated whether a multi-component (complex) self-management intervention to support adherence would reduce exacerbation rates over 12 months.

METHODS: Between October 2017 and May 2018, adults with CF (aged ≥16 years; 19 UK centres) were randomised to the intervention (data-logging nebulisers, a digital platform and behavioural change sessions with trained clinical interventionists) or usual care (data-logging nebulisers). Outcomes included pulmonary exacerbations (primary outcome), objectively measured adherence, body mass index (BMI), lung function (FEV1) and Cystic Fibrosis Questionnaire-Revised (CFQ-R). Analyses were by intent to treat over 12 months.

RESULTS: Among intervention (n=304) and usual care (n=303) participants (51% female, median age 31 years), 88% completed 12-month follow-up. Mean exacerbation rate was 1.63/year with intervention and 1.77/year with usual care (adjusted ratio 0.96; 95% CI 0.83 to 1.12; p=0.64). Adjusted mean differences (95% CI) were in favour of the intervention versus usual care for objectively measured adherence (9.5% (8.6% to 10.4%)) and BMI (0.3 (0.1 to 0.6) kg/m2), with no difference for %FEV1 (1.4 (-0.2 to 3.0)). Seven CFQ-R subscales showed no between-group difference, but treatment burden reduced for the intervention (3.9 (1.2 to 6.7) points). No intervention-related serious adverse events occurred.

CONCLUSIONS: While pulmonary exacerbations and FEV1 did not show statistically significant differences, the intervention achieved higher objectively measured adherence versus usual care. The adherence difference might be inadequate to influence exacerbations, though higher BMI and lower perceived CF treatment burden were observed.

PMID:34556552 | DOI:10.1136/thoraxjnl-2021-217594

BMC Med Genomics. 2021 Sep 23;14(1):234. doi: 10.1186/s12920-021-01084-w.

ABSTRACT

BACKGROUND: It is estimated that 1-13% of cases of bronchiectasis in adults globally are attributable to primary ciliary dyskinesia (PCD) but many adult patients with bronchiectasis have not been investigated for PCD. PCD is a disorder caused by mutations in genes required for motile cilium structure or function, resulting in impaired mucociliary clearance. Symptoms appear in infancy but diagnosis is often late or missed, often due to the lack of a "gold standard" diagnostic tool and non-specific symptoms. Mutations in > 50 genes account for around 70% of cases, with additional genes, and non-coding, synonymous, missense changes or structural variants (SVs) in known genes presumed to account for the missing heritability.

METHODS: UK patients with no identified genetic confirmation for the cause of their PCD or bronchiectasis were eligible for whole genome sequencing (WGS) in the Genomics England Ltd 100,000 Genomes Project. 21 PCD probands and 52 non-cystic fibrosis (CF) bronchiectasis probands were recruited in Wessex Genome Medicine Centre (GMC). We carried out analysis of single nucleotide variants (SNVs) and SVs in all families recruited in Wessex GMC.

RESULTS: 16/21 probands in the PCD cohort received confirmed (n = 9), probable (n = 4) or possible (n = 3) diagnosis from WGS, although 13/16 of these could have been picked up by current standard of care gene panel testing. In the other cases, SVs were identified which were missed by panel testing. We identified variants in novel PCD candidate genes (IFT140 and PLK4) in 2 probands in the PCD cohort. 3/52 probands in the non-CF bronchiectasis cohort received a confirmed (n = 2) or possible (n = 1) diagnosis of PCD. We identified variants in novel PCD candidate genes (CFAP53 and CEP164) in 2 further probands in the non-CF bronchiectasis cohort.

CONCLUSIONS: Genetic testing is an important component of diagnosing PCD, especially in cases of atypical disease history. WGS is effective in cases where prior gene panel testing has found no variants or only heterozygous variants. In these cases it may detect SVs and is a powerful tool for novel gene discovery.

PMID:34556108 | DOI:10.1186/s12920-021-01084-w

FASEB J. 2021 Oct;35(10):e21946. doi: 10.1096/fj.202002712RR.

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a life-threatening illness characterized by decreased alveolar-capillary barrier function, pulmonary edema consisting of proteinaceous fluid, and inhibition of net alveolar fluid transport responsible for resolution of pulmonary edema. There is currently no pharmacotherapy that has proven useful to prevent or treat ARDS, and two trials using beta-agonist therapy to treat ARDS demonstrated no effect. Prior studies indicated that IL-8-induced heterologous desensitization of the beta2-adrenergic receptor (β2 -AR) led to decreased beta-agonist-induced mobilization of cyclic adenosine monophosphate (cAMP). Interestingly, phosphodiesterase (PDE) 4 inhibitors have been used in human airway diseases characterized by low intracellular cAMP levels and increases in specific cAMP hydrolyzing activity. Therefore, we hypothesized that PDE4 would mediate IL-8-induced heterologous internalization of the β2 -AR and that PDE4 inhibition would restore beta-agonist-induced functions. We determined that CINC-1 (a functional IL-8 analog in rats) induces internalization of β2 -AR from the cell surface, and arrestin-2, PDE4, and β2 -AR form a complex during this process. Furthermore, we determined that cAMP associated with the plasma membrane was adversely affected by β2 -AR heterologous desensitization. Additionally, we determined that rolipram, a PDE4 inhibitor, reversed CINC-1-induced derangements of cAMP and also caused β2 -AR to successfully recycle back to the cell surface. Finally, we demonstrated that rolipram could reverse CINC-1-mediated inhibition of beta-agonist-induced alveolar fluid clearance in a murine model of trauma-shock. These results indicate that PDE4 plays a role in CINC-1-induced heterologous internalization of the β2 -AR; PDE4 inhibition reverses these effects and may be a useful adjunct in particular ARDS patients.

PMID:34555226 | DOI:10.1096/fj.202002712RR

PLoS One. 2021 Sep 23;16(9):e0257852. doi: 10.1371/journal.pone.0257852. eCollection 2021.

ABSTRACT

BACKGROUND: We have recently reported reduced physical activity (PA) in people with cystic fibrosis (pwCF) with and without lung transplantation (LTX) during a 6-week stringent lockdown in Switzerland. This follow-up study explores the impact of coronavirus-2019 disease (COVID-19) related pandemic restrictions on individuals' therapy regimens and health-related aspects in pwCF.

METHODS: We conducted a cross-sectional web-based national survey in Spring 2021. The survey included questions on daily PA, airway clearance and inhalation therapy, questions on COVID-19-compatible symptoms, diagnostic tests and vaccination status, and enquired health-related aspects covering the pandemic period between March 2020 to April 2021.

RESULTS: 193 individuals with CF (53% female; 25% LTX recipients) participated. Among pwCF, 10 reported COVID-19 (n = 2 LTX recipients), two subjects were hospitalized, no invasive ventilation required, no deaths. The clinical course was generally mild. Overall, 46% reported less PA during the pandemic, mostly due to closed fitness facilities (85%), lack of motivation (34%), and changes in daily structures (21%). In contrast, 32/193 (17%) pwCF were able to increase their PA levels: 12 (38%) and 11 (34%) reported undertaking home-based training and outdoor activities more frequently; 6 (19%) reported an increase in routine PA, and another 3 (9%) started new activities. Among pwCF without LTX, 5% and 4% reported to undertake less airway clearance and inhalation therapy, respectively.

CONCLUSIONS: Our study reveals unfavorable consequences of COVID-19 pandemic restrictions on PA of pwCF with unknown long-term consequences for their overall physical fitness and lung health. Strategies to overcome this undesirable situation are needed; increased uptake of telehealth PA programs and virtual exercise classes to promote PA participation might be one promising approach along with vaccination of pwCF and their close contacts.

PMID:34555108 | DOI:10.1371/journal.pone.0257852