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

Pediatr Pulmonol. 2021 Sep 23. doi: 10.1002/ppul.25693. Online ahead of print.

ABSTRACT

Miracles, like London buses, just seem to come along. The truth is, there are no miracles, just lots of hard work behind the scenes, minds open to opportunity, serendipity and possibly a little luck. In my time as a paediatric respiratory physician, I have born witness to remarkable advances in treatment that have changed patients' fortunes overnight. Examples of these include artificial surfactant replacement for premature newborns, conjugate haemophilus influenzae type b vaccination, propranolol for infants with subglottic haemangiomas, mandibular distraction for babies with micrognathia, cystic fibrosis transmembrane conductance regulator modulators therapy for patients with cystic fibrosis and antisense oligonucleotide therapy for infants with spinal muscular atrophy. There are lessons to be learned from reflection upon these life transforming treatments, and perhaps it is a good time just to pause and wonder. This article is protected by copyright. All rights reserved.

PMID:34553839 | DOI:10.1002/ppul.25693

Arab J Urol. 2021 Jul 22;19(3):206-214. doi: 10.1080/2090598X.2021.1954415. eCollection 2021.

ABSTRACT

Objectives: To provide a summary of the current evaluation of azoospermia and insights into future perspectives in the evaluation and counselling of men with azoospermia. Methods: A search of PubMed, Cochrane Reviews and Web of Science databases was performed for full-text English-language articles published between 1943 and 2020 focussing on 'future perspectives', 'azoospermia' and 'evaluation'. Results: Azoospermia represents a severe form of male infertility characterised by sperm production so impaired that there are no sperm present in the ejaculate. The current evaluation of azoospermia focusses on patient history and physical examination with selected adjunctive laboratory investigations including serum hormones, a karyotype and screening for Y chromosome microdeletions. Future diagnostics are focussed on identifying the underlying genetic aetiologies for azoospermia, as well as a greater emphasis on screening for systemic illness that men with severe infertility may be predisposed to develop. Conclusion: Azoospermia represents an extreme form of male infertility, and evaluation relies heavily on history and physical examination, as genetic evaluations for these individuals remain limited. Future evaluation will focus on next-generation sequencing and more rigorous evaluation for possible co-existing and future risk of systemic disease. ABBREVIATIONS: ADGRG2, adhesion G protein-coupled receptor G2; ASRM: American Society of Reproductive Medicine; AZF: azoospermia factor; CBAVD: congenital bilateral absence of the vas deferens; CFTR: cystic fibrosis transmembrane conductance regulator; CRKL: CRK-like proto-oncogene; E2F1: E2F transcription factor 1; HAUS7: HAUS augmin-like complex subunit 7; HR: hazard ratio; KS: Klinefelter syndrome; MAZ, MYC-associated zinc finger protein; NGS: next-generation sequencing; NOA: non-obstructive azoospermia; OA: obstructive azoospermia; RHOX: reproductive homeobox on the X chromosome; SH2: SRC homology 2; TAF7L: TATA-box binding protein associated factor 7-like; TEX11: testis-expressed 11; WES: whole-exome sequencing.

PMID:34552771 | PMC:PMC8451618 | DOI:10.1080/2090598X.2021.1954415

Sci Rep. 2021 Sep 22;11(1):18828. doi: 10.1038/s41598-021-98122-5.

ABSTRACT

Mucus clearance, a primary innate defense mechanism of airways, is defective in patients with cystic fibrosis (CF) and CF animals. In previous work, the combination of a low dose of the cholinergic agonist, carbachol with forskolin or a β adrenergic agonist, isoproterenol synergistically increased mucociliary clearance velocity (MCCV) in ferret tracheas. Importantly, the present study shows that synergistic MCCV can also be produced in CF ferrets, with increases ~ 55% of WT. Synergistic MCCV was also produced in pigs. The combined agonists increased MCCV by increasing surface fluid via multiple mechanisms: increased fluid secretion from submucosal glands, increased anion secretion across surface epithelia and decreased Na+ absorption. To avoid bronchoconstriction, the cAMP agonist was applied 30 min before carbachol. This approach to increasing mucus clearance warrants testing for safety and efficacy in humans as a potential therapeutic for muco-obstructive diseases.

PMID:34552115 | DOI:10.1038/s41598-021-98122-5

J Hosp Palliat Nurs. 2021 Sep 20. doi: 10.1097/NJH.0000000000000802. Online ahead of print.

ABSTRACT

Primary palliative care education and mentoring strengthens frontline clinicians' confidence and competence in pediatric palliative care, and potentially mitigates their moral distress. The project aims were to improve the knowledge, attitudes, and skills of frontline intradisciplinary clinicians in caring for children with serious conditions and their families. We undertook an intensive educational initiative consisting of didactic and mentoring sessions, and mentored quality improvement projects. Outcomes included the following: 93.3% of participants reported comfort in discussing death, suffering, spirituality, and hope with families, and increased comfort in end-of-life care (89.5%), increased knowledge (94.7%) and skills (100%), improved communication (100%), and being better prepared to discuss and access palliative care resources (100%). Secondary outcomes included 33% increase in specialty pediatric palliative care consults and 98% increase in the integration of specialty palliative care for patients with high-risk cancers. Specialty pediatric palliative care referral became standard for patients with cystic fibrosis, high-risk solid and brain tumors, heart failure, and patients receiving a stem cell transplant. Clinician self-reported moral distress decreased by 30%. This project improved primary palliative care knowledge, attitudes, and confidence in skills, access to care, and family satisfaction, and decreased clinician self-reported moral distress. We report on the 4-year period of project implementation and sustainability.

PMID:34550914 | DOI:10.1097/NJH.0000000000000802

Cochrane Database Syst Rev. 2021 Sep 22;9:CD010288. doi: 10.1002/14651858.CD010288.pub5.

ABSTRACT

BACKGROUND: Cystic fibrosis is an autosomal recessive multisystem disorder with an approximate prevalence of 1 in 3500 live births. Allergic bronchopulmonary aspergillosis is a lung disease caused by aspergillus-induced hypersensitivity with a prevalence of 2% to 15% in people with cystic fibrosis. The mainstay of treatment includes corticosteroids and itraconazole. The treatment with corticosteroids for prolonged periods of time, or repeatedly for exacerbations of allergic bronchopulmonary aspergillosis, may lead to many adverse effects. The monoclonal anti-IgE antibody, omalizumab, has improved asthma control in severely allergic asthmatics. The drug is given as a subcutaneous injection every two to four weeks. Since allergic bronchopulmonary aspergillosis is also a condition resulting from hypersensitivity to specific allergens, as in asthma, it may be a candidate for therapy using anti-IgE antibodies. Therefore, anti-IgE therapy, using agents like omalizumab, may be a potential therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. This is an updated version of the review.

OBJECTIVES: To evaluate the efficacy and adverse effects of anti-IgE therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Last search: 09 September 2021. We searched two ongoing trial registries (Clinicaltrials.gov and the WHO trials platform). Date of latest search: 16 August 2021.

SELECTION CRITERIA: Randomized and quasi-randomized controlled trials comparing anti-IgE therapy to placebo or other therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis.

DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias in the included study. They planned to perform data analysis using Review Manager.

MAIN RESULTS: Only one study enrolling 14 participants was eligible for inclusion in the review. The double-blind study compared a daily dose of 600 mg omalizumab or placebo along with twice daily itraconazole and oral corticosteroids, with a maximum daily dose of 400 mg. Treatment lasted six months but the study was terminated prematurely and complete data were not available. We contacted the study investigator and were told that the study was terminated due to the inability to recruit participants into the study despite all reasonable attempts. One or more serious side effects were encountered in six out of nine (66.67%) and one out of five (20%) participants in omalizumab group and placebo group respectively.

AUTHORS' CONCLUSIONS: There is lack of evidence for the efficacy and safety of anti-IgE (omalizumab) therapy in people with cystic fibrosis and allergic bronchopulmonary aspergillosis. There is a need for large prospective randomized controlled studies of anti-IgE therapy in people with cystic fibrosis and allergic bronchopulmonary aspergillosis with both clinical and laboratory outcome measures such as steroid requirement, allergic bronchopulmonary aspergillosis exacerbations and lung function.

PMID:34550603 | DOI:10.1002/14651858.CD010288.pub5

Microbiol Spectr. 2021 Sep 22:e0051921. doi: 10.1128/Spectrum.00519-21. Online ahead of print.

ABSTRACT

To combat infections, the mammalian host limits availability of essential transition metals such as iron (Fe), zinc (Zn), and manganese (Mn) in a strategy termed "nutritional immunity." The innate immune protein calprotectin (CP) contributes to nutritional immunity by sequestering these metals to exert antimicrobial activity against a broad range of microbial pathogens. One such pathogen is Pseudomonas aeruginosa, which causes opportunistic infections in vulnerable populations, including individuals with cystic fibrosis. CP was previously shown to withhold Fe(II) and Zn(II) from P. aeruginosa and induce Fe and Zn starvation responses in this pathogen. In this work, we performed quantitative, label-free proteomics to further elucidate how CP impacts metal homeostasis pathways in P. aeruginosa. We report that CP induces an incomplete Fe starvation response, as many Fe-containing proteins that are repressed by Fe limitation are not affected by CP treatment. The Zn starvation response elicited by CP seems to be more complete than the Fe starvation response and includes increases in Zn transporters and Zn-independent proteins. CP also induces the expression of membrane-modifying proteins, and metal depletion studies indicate this response results from the sequestration of multiple metals. Moreover, the increased expression of membrane-modifying enzymes upon CP treatment correlates with increased tolerance to polymyxin B. Thus, the response of P. aeruginosa to CP treatment includes both single- and multimetal starvation responses and includes many factors related to virulence potential, broadening our understanding of this pathogen's interaction with the host. IMPORTANCE Transition metal nutrients are critical for growth and infection by all pathogens, and the innate immune system withholds these metals from pathogens to limit their growth in a strategy termed "nutritional immunity." While multimetal depletion by the host is appreciated, the majority of studies have focused on individual metals. Here, we use the innate immune protein calprotectin (CP), which complexes with several metals, including iron (Fe), zinc (Zn), and manganese (Mn), and the opportunistic pathogen Pseudomonas aeruginosa to investigate multimetal starvation. Using an unbiased label-free proteomics approach, we demonstrate that multimetal withholding by CP induces a regulatory response that is not merely additive of individual metal starvation responses, including the induction of lipid A modification proteins.

PMID:34549997 | DOI:10.1128/Spectrum.00519-21

Am J Audiol. 2021 Sep 22:1-10. doi: 10.1044/2021_AJA-21-00031. Online ahead of print.

ABSTRACT

Purpose Specific classes of antibiotics, such as aminoglycosides, have well-established adverse events producing permanent hearing loss, tinnitus, and balance and/or vestibular problems (i.e., ototoxicity). Although these antibiotics are frequently used to treat pseudomonas and other bacterial infections in patients with cystic fibrosis (CF), there are no formalized recommendations describing approaches to implementation of guideline adherent ototoxicity monitoring as part of CF clinical care. Method This consensus statement was developed by the International Ototoxicity Management Working Group (IOMG) Ad Hoc Committee on Aminoglycoside Antibiotics to address the clinical need for ototoxicity management in CF patients treated with known ototoxic medications. These clinical protocol considerations were created using consensus opinion from a community of international experts and available evidence specific to patients with CF, as well as published national and international guidelines on ototoxicity monitoring. Results The IOMG advocates four clinical recommendations for implementing routine and guideline adherent ototoxicity management in patients with CF. These are (a) including questions about hearing, tinnitus, and balance/vestibular problems as part of the routine CF case history for all patients; (b) utilizing timely point-of-care measures; (c) establishing a baseline and conducting posttreatment evaluations for each course of intravenous ototoxic drug treatment; and (d) repeating annual hearing and vestibular evaluations for all patients with a history of ototoxic antibiotic exposure. Conclusion Increased efforts for implementation of an ototoxicity management program in the CF care team model will improve identification of ototoxicity signs and symptoms, allow for timely therapeutic follow-up, and provide the clinician and patient an opportunity to make an informed decision about potential treatment modifications to minimize adverse events. Supplemental Material https://doi.org/10.23641/asha.16624366.

PMID:34549989 | DOI:10.1044/2021_AJA-21-00031

Pediatr Pulmonol. 2021 Sep 22. doi: 10.1002/ppul.25683. Online ahead of print.

ABSTRACT

BACKGROUND: Reaching early and definitive diagnosis in infants with cystic fibrosis (CF) transmembrane conductance regulator-related metabolic syndrome (CRMS)/CF screen-positive, inconclusive diagnosis (CFSPID) is a priority of all CF newborn screening programs. Currently, sweat testing is the gold standard for CF diagnosis or exclusion. We assessed outcomes in a cohort of Italian CRMS/CFSPID infants who underwent repeat sweat testing in the first year of life.

METHODS: This multicentre, prospective study analysed clinical data and outcomes in CRMS/CFSPID infants born between September 1, 2018 and December 31, 2019, and followed until June 30, 2020. All subjects underwent CF transmembrane conductance regulator (CFTR) gene sequencing and the search for CFTR macrodeletions/macroduplications, and repeat sweat testing in the first year of life.

RESULTS: Fifty subjects (median age at end of follow-up, 16 months [range, 7-21 months]) were enrolled. Forty-one (82%) had the first sweat chloride in the intermediate range. During follow up, 150 sweat tests were performed (range, 1-7/infant). After a median follow-up of 8.5 months (range 1-16.2 months), 11 (22%) subjects were definitively diagnosed as follows: CF (n=2 [4%]) at 2 and 5 months, respectively; healthy carrier (n=8 [16%]), at a median age of 4 months (range 2-8 months); and healthy (n=1 [2%]) at 2 months of age. Inconclusive diagnosis remained in 39 (78%) infants.

CONCLUSIONS: Early repeat sweat testing in the first year of life can shorten the time to definitive diagnosis in screening positive subjects with initial sweat chloride levels in the intermediate range. This article is protected by copyright. All rights reserved.

PMID:34549893 | DOI:10.1002/ppul.25683