Value Health. 2021 May;24(5):744-752. doi: 10.1016/j.jval.2020.11.016. Epub 2021 Feb 18.

ABSTRACT

OBJECTIVES: Health technology assessments (HTA) rely on head-to-head comparisons. We searched for intraindividual comparisons (IIC) qualifying as head-to-head design to develop comparative evidence.

METHODS: Gemeinsamer Bundesausschuss (G-BA) appraisals between January 2011 and April 2020 were reviewed for inclusion of IIC. Identified IIC were grouped according to disease characteristics into nonprogressive, progressive, irregular, or symmetrical conditions. Evaluation of IIC by Institut für Qualität und Wirschaftlichkeit im Gesundheitswesen (IQWIG) and acceptance of IIC by G-BA were determined, and criteria for the usage and quality of IIC were developed.

RESULTS: A total of 483 appraisals finalized between January 2011 and April 2020 were reviewed. Eleven appraisals included IIC: nonacog beta (hemophilia B), turoctocog alpha (hemophilia A), emicizumab (2 appraisals: hemophilia A), pasireotide (unresectable pituitary tumor), lomitapid (homozygous familial hypercholesterolemia), glycerol phenylbutyrate (2 appraisals: urea cycle disorders), asfotase alfa (hypophosphatasia), lumacaftor (cystic fibrosis), and larotrectinib (NTRK+ solid tumors). All those appraisals related to rare genetic conditions with hemophilia and its bleeding rate are considered mainly a nonprogressive condition. All the other diseases show progressive disease characteristics. None of the identified IIC has been accepted by G-BA. Inconsistencies of before/after study design, lack of clarity on treatments prior to the switch, and different time intervals were among the most commonly cited methodological concerns.

CONCLUSIONS: IICs provide a rare opportunity to determine comparative effectiveness in distinct clinical settings that are not suitable or difficult to randomize into parallel groups. While manufacturers and researchers should aim for highest methodological standards when running an IIC, HTA bodies should accept IIC in distinct settings when determining relative effectiveness.

PMID:33933244 | DOI:10.1016/j.jval.2020.11.016

Stem Cells. 2021 May 1. doi: 10.1002/stem.3386. Online ahead of print.

ABSTRACT

The mammalian airways are lined by a continuous epithelial layer that is maintained by diverse populations of resident multipotent stem cells. These stem cells are responsible for replenishing the epithelium both at homeostasis and following injury, making them promising targets for stem cell and genetic-based therapies for a variety of respiratory diseases. However, the mechanisms that regulate when and how these stem cells proliferate, migrate, and differentiate remains incompletely understood. Here, we find that the high mobility group (HMG) domain transcription factor Lef-1 regulates proliferation and differentiation of mouse tracheal basal cells. We demonstrate that conditional deletion of Lef-1 stalls basal cell proliferation at the G1/S transition of the cell cycle, and that Lef-1 knockout cells are unable to maintain luminal tracheal cell types in long-term air-liquid interface culture. RNA sequencing analysis revealed that Lef-1 knockout (Lef-1KO) results in downregulation of key DNA damage response and cell cycle progression genes, including the kinase Chek1. Furthermore, chemical inhibition of Chek1 is sufficient to stall basal cell self-renewal in a similar fashion as Lef-1 deletion. Notably, the cell cycle block imposed by Lef-1KO in vitro is transient and basal cells eventually compensate to proliferate normally in a Chek1-independent manner. Finally, Lef-1KO cells were unable to fully regenerate tracheal epithelium following injury in vivo. These findings reveal that Lef-1 is essential for proper basal cell function. Thus, modulating Lef-1 function in airway basal cells may have applications in regenerative medicine. © AlphaMed Press 2021 SIGNIFICANCE STATEMENT: Airway basal cells (BCs) are the primary progenitor cells of the conducting airway epithelium and thus are promising targets for durable genetic- and cell-based therapies of lung diseases such as cystic fibrosis. However, the mechanisms that govern their regenerative abilities are not fully understood. The authors' show that Lef-1, an effector of Wnt signaling, is critical for BC cell cycle progression through G1/S and influences BC differentiation in vitro. Loss of Lef-1 significantly reduces the capacity of BC to regenerate the tracheal epithelium in vivo following injury. Manipulating Lef-1 expression in BCs may provide opportunities to modulate the regenerative capacity of BCs and their progeny.

PMID:33932322 | DOI:10.1002/stem.3386

Appl Environ Microbiol. 2021 Apr 30:AEM.00369-21. doi: 10.1128/AEM.00369-21. Online ahead of print.

ABSTRACT

Burkholderia cepacia complex bacteria comprises opportunistic pathogens causing chronic respiratory infections in cystic fibrosis (CF) patients. These microorganisms produce an exopolysaccharide named cepacian, which is considered a virulence determinant. To find genes implicated in the regulation of cepacian biosynthesis, we characterized an evolved nonmucoid variant (17616nmv) derived from the ancestor, Burkholderia multivorans ATCC 17616, after prolonged stationary phase. Lack of cepacian biosynthesis was correlated with downregulation of the expression of bce genes implicated in its biosynthesis. Furthermore, genome sequencing of the variant identified the transposition of the mobile element IS406 upstream the coding sequence of an hns-like gene (Bmul_0158) encoding a histone-like nucleoid structuring protein, a known global transcriptional repressor. This IS element upregulated the expression of Bmul_0158 by 4-fold. Transcriptome analysis identified the global effects of this mutation on gene expression, with major changes in genes implicated in motility, pili synthesis, type VI secretion, and chromosome associated functions. Concomitant with these differences, the nonmucoid variant displays reduced adherence to a CF lung bronchial cell line, reduced surface hydrophobicity, forms smaller cellular aggregates, but has an increase in swimming and swarming motilities. Finally, analysis of the GC content of the upstream region of differentially expressed genes led to the identification of various genomic regions, possibly acquired by horizontal gene transfer, which were transcriptionally repressed by the increased expression of Bmul_0158 gene in the 17616nmv strain. Taken together, the results revealed a significant role for this H-NS protein in the regulation of B. multivorans persistence- and virulence-associated genes.IMPORTANCEMembers of the histone-like nucleoid-structuring (H-NS) family of proteins, present in many bacteria, are important global regulators of gene expression. Many of the regulated genes were acquired horizontally and include pathogenicity islands and prophages, among others. Additionally, H-NS can play a structural role by bridging and compacting DNA, presenting a crucial role in cell physiology. Several virulence phenotypes have been frequently identified in several bacteria as dependent on H-NS activity. Here, we describe an H-NS-like protein of the opportunistic pathogen Burkholderia multivorans, a species commonly infecting the respiratory tract of cystic fibrosis patients. Our results indicate that this protein is involved in regulating virulence traits such as exopolysaccharide biosynthesis, adhesion to biotic surfaces, cellular aggregation, and motility. Furthermore, this H-NS-like protein, is one out of eight orthologs present in B. multivorans ATCC 17616 genome, posing relevant questions to be investigated on how these proteins coordinate the expression of virulence traits.

PMID:33931418 | DOI:10.1128/AEM.00369-21

J Cyst Fibros. 2021 Apr 27:S1569-1993(21)00104-1. doi: 10.1016/j.jcf.2021.03.022. Online ahead of print.

ABSTRACT

Chronic rhinosinusitis (CRS) affects nearly all individuals with cystic fibrosis (CF) and is thought to serve as a reservoir for microbiota that subsequently colonize the lung. To better understand the microbial ecology of CRS, we generated a 16S rRNA gene sequencing profile of sinus mucus from CF-CRS patients. We show that CF-CRS sinuses harbor bacterial diversity not entirely captured by clinical culture. Culture data consistently identified the dominant organism in most patients, though lower abundance bacteria were not always identified. We also demonstrate that bacterial communities dominated by Staphylococcus spp. were significantly more diverse compared to those dominated by Pseudomonas spp. Diversity was not significantly associated with clinical factors or patient age, however, younger subjects yielded a much wider range of bacterial diversity. These data mirror bacterial community dynamics in the lung and provide additional insight into the role of sinus microbiota in chronic airway disease progression.

PMID:33931358 | DOI:10.1016/j.jcf.2021.03.022

J Am Pharm Assoc (2003). 2021 Apr 20:S1544-3191(21)00160-6. doi: 10.1016/j.japh.2021.04.005. Online ahead of print.

ABSTRACT

BACKGROUND: As a result of the coronavirus disease 2019 (COVID-19) pandemic, institutions needed innovative solutions to provide care. With implementation of telehealth, a cystic fibrosis (CF) pharmacist was able to incorporate a virtual medication tour during appointments.

OBJECTIVE: The purpose of our study was to describe the uptake and impact of pharmacist-led virtual medication tours during telehealth visits in the CF clinic setting.

PRACTICE DESCRIPTION: Before the COVID-19 pandemic, a CF pharmacist participated in in-person multidisciplinary team visits to complete medication history reconciliation, assess adherence, assess efficacy and address possible adverse effects of medications, and work collaboratively with the CF care team and patient to create therapeutic plans. The virtual medication tour described in this study was completed in addition or as a complement to these pre-existing pharmacist roles and responsibilities.

PRACTICE INNOVATION: Patients seen via telehealth visit were asked to provide a virtual tour of their medications. A pharmacist completed medication history and evaluated whether storage conditions were appropriate in regard to temperature, humidity, light exposure, and accessibility to children.

EVALUATION METHODS: A pharmacist recorded findings from the virtual medication tours and made interventions when appropriate. Descriptive statistics were used for analysis.

RESULTS: Of 20 patients seen via telehealth for a quarterly visit during the first 3 months after implementation, 13 were willing to participate in a virtual medication tour. Before the visit, 25% had information missing from their medication list. Virtual medication tour allowed for resolution of this information 80% of the time. Three of the 4 participating patients with a child under 12 years old had medications stored in a location accessible to children.

CONCLUSION: A virtual medication tour led by a pharmacist can be successfully incorporated into telehealth visits and was accepted by a majority of patients. Most patients stored medications appropriately but might benefit from education on poison prevention practices.

PMID:33931355 | DOI:10.1016/j.japh.2021.04.005

J Am Pharm Assoc (2003). 2021 Apr 15:S1544-3191(21)00161-8. doi: 10.1016/j.japh.2021.04.006. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive genetic disease requiring complex, lifelong medication regimens. Given the importance of medication in CF treatment, pharmacists are vital CF care team members in the care of people living with CF (PwCF).

OBJECTIVES: This study aimed to (1) define patients' CF medication experiences and educational needs and (2) investigate the CF outpatient clinic and community pharmacist's role in addressing patient challenges.

METHODS: A work system approach informed by the Systems Engineering Initiative for Patient Safety (SEIPS) model was used to characterize knowledge and perception of CF medication regimens, educational modalities, and pharmacist interactions for PwCF. Semistructured interviews were conducted with adults living with CF at a CF center clinic. Data analyses identified relationships between the themes in the data and 4 SEIPS work system domains: tasks, tools and technology, person, and environment.

RESULTS: Thirty PwCF interviews highlighted 4 themes regarding health care experiences: (1) medication use experience, (2) medication education needs, (3) disease experience, and (4) pharmacist and pharmacy interactions. Patients reported complex medication regimens leading to challenges with medication adherence, although the benefit of treatment was recognized. Although a high level of disease-state knowledge was identified among the participants, PwCF desired to learn about CF medication benefits and adverse effects through credible sources using multiple modalities. Many reported a benefit of pharmacist involvement in their care.

CONCLUSION: Pharmacists are well-positioned to support PwCF in adherence, medication regimen management, and medication education. Opportunities exist for growth in these supportive roles of a pharmacist in both community and outpatient clinic settings.

PMID:33931354 | DOI:10.1016/j.japh.2021.04.006

PLoS One. 2021 Apr 30;16(4):e0250977. doi: 10.1371/journal.pone.0250977. eCollection 2021.

ABSTRACT

Pseudomonas aeruginosa is a ubiquitous opportunistic pathogen that causes considerable human morbidity and mortality, particularly in nosocomial infections and individuals with cystic fibrosis. P. aeruginosa can adapt to surface growth by undergoing swarming motility, a rapid multicellular movement that occurs on viscous soft surfaces with amino acids as a nitrogen source. Here we tested the small synthetic host defense peptide, innate defense regulator 1018, and found that it inhibited swarming motility at concentrations as low as 0.75 μg/ml, well below the MIC for strain PA14 planktonic cells (64 μg/ml). A screen of the PA14 transposon insertion mutant library revealed 29 mutants that were more tolerant to peptide 1018 during swarming, five of which demonstrated significantly greater swarming than the WT in the presence of peptide. Transcriptional analysis (RNA-Seq) of cells that were inoculated on swarming plates containing 1.0 μg/ml peptide revealed differential expression of 1,190 genes compared to cells swarming on plates without peptide. Furthermore, 1018 treatment distinctly altered the gene expression profile of cells when compared to that untreated cells in the centre of the swarm colonies. Peptide-treated cells exhibited changes in the expression of genes implicated in the stringent stress response including those regulated by anr, which is involved in anaerobic adaptation, indicative of a mechanism by which 1018 might inhibit swarming motility. Overall, this study illustrates potential mechanisms by which peptide 1018 inhibits swarming surface motility, an important bacterial adaptation associated with antibiotic resistance, virulence, and dissemination of P. aeruginosa.

PMID:33930077 | DOI:10.1371/journal.pone.0250977

J Paediatr Child Health. 2021 Apr 30. doi: 10.1111/jpc.15536. Online ahead of print.

NO ABSTRACT

PMID:33929764 | DOI:10.1111/jpc.15536

Turk J Pediatr. 2021;63(2):218-222. doi: 10.24953/turkjped.2021.02.005.

ABSTRACT

BACKGROUND: Burkholderia cepacia complex (Bcc) comprises multi-drug resistant, Gram-negative, motile, and aerobic bacteria. Bcc causes severe nosocomial infections particularly in patients with intravascular catheters and in those with cystic fibrosis. We studied a Bcc outbreak in non-cystic fibrosis patients.

METHODS: We analyzed data from six patients hospitalized at our center. Blood cultures identified as infectious were incubated onto 5% blood sheep agar, chocolate agar, and eosin methylene blue (EMB) agar. We examined possible sites that could be sources of infection at the clinic. We confirmed isolations with pulsed-field gel electrophoresis (PFGE) tests.

RESULTS: The first patient was hospitalized due to left renal agenesis, urinary tract infection, and renal failure. Bcc was isolated in blood cultures obtained due to high fever on the third day of hospitalization. We stopped new patient hospitalizations after detecting Bcc in blood cultures of other five patients. We did not detect further positive specimens obtained from other clinic and the patient rooms. PFGE patterns were similar in all clinical isolates of Bcc indicating that the outbreak had originated from the source.

CONCLUSIONS: Bcc infection should be considered in cases of nosocomial outbreaks of multi-drug resistant organisms that require hospitalization at intensive care units. Control measures should be taken for prevention of nosocomial infections and required investigations should be done to detect the source of infection.

PMID:33929111 | DOI:10.24953/turkjped.2021.02.005

J Child Health Care. 2021 Apr 30:13674935211013924. doi: 10.1177/13674935211013924. Online ahead of print.

ABSTRACT

Adherence to chronic pulmonary drugs in cystic fibrosis (CF) is suboptimal. We studied the feasibility and effectiveness of a multistep medication adherence-enhancing simulation intervention for pediatric CF, which was embedded in motivational interviewing and education. Product simulation experiments were performed by the children themselves, and they addressed adherence to mucolytics/hydrators and antibiotics. Dornase alfa-treated patients aged 7-13 years were included. We invited each patient and their parents to attend an interview. PowerPoint slides were presented and discussed. The final slide invited the patient to perform the simulation experiments, and, in so doing, they experienced what happens when they either do or do not take their medication. An educational film was applied as a summary tool. A patient-centered empathic counseling style was used. Two months later, the child and their parents each completed a different anonymous questionnaire. Overall, 21 patients were included. Parents rated the means of communication and improvement in their child's motivation as very satisfactory. Children highly appreciated the experiments they performed. They often answered two questions on dornase alfa correctly and associated knowledge with adherence. Our results suggest that experiential simulation-based learning is extremely appropriate, and that this multistep intervention is feasible and effective in pediatric CF.

PMID:33928824 | DOI:10.1177/13674935211013924

Am J Gastroenterol. 2021 Apr 29. doi: 10.14309/ajg.0000000000001275. Online ahead of print.

ABSTRACT

INTRODUCTION: To describe the characteristics and outcomes of children with cystic fibrosis (CF) hospitalized with cirrhosis in the United States.

METHODS: We conducted a population-based cohort study of hospitalizations among children with CF using the 2016 Kid's Inpatient Database.

RESULTS: In total, 9,615 admissions were analyzed. Diagnosis of cirrhosis was present in 509 (5.3%) and was significantly associated with increased mortality, length of stay, and hospital charges compared with those without cirrhosis. Hepatic encephalopathy was significantly associated with death in children with cirrhosis.

DISCUSSION: Future interventions should be designed to support children with CF who have cirrhosis to improve clinical outcomes.

PMID:33927124 | DOI:10.14309/ajg.0000000000001275

J Bacteriol. 2021 Apr 29:JB.00100-21. doi: 10.1128/JB.00100-21. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa induces pathways indicative of low zinc availability in the cystic fibrosis (CF) lung environment. To learn more about P. aeruginosa zinc access in CF, we grew P. aeruginosa strain PAO1 directly in expectorated CF sputum. The P. aeruginosa Zur transcriptional repressor controls the response to low intracellular zinc, and we used the NanoString methodology to monitor levels of Zur-regulated transcripts including those encoding a zincophore system, a zinc importer, and paralogs of zinc containing proteins that do not require zinc for activity. Zur-controlled transcripts were induced in sputum-grown P. aeruginosa compared to control cultures, but not if the sputum was amended with zinc. Amendment of sputum with ferrous iron did not reduce expression of Zur-regulated genes. A reporter fusion to a Zur-regulated promoter had variable activity in P. aeruginosa grown in sputum from different donors, and this variation inversely correlated with sputum zinc concentrations. Recombinant human calprotectin (CP), a divalent-metal binding protein released by neutrophils, was sufficient to induce a zinc-starvation response in P. aeruginosa grown in laboratory medium or zinc-amended CF sputum indicating that CP is functional in the sputum environment. Zinc metalloproteases comprise a large fraction of secreted zinc-binding P. aeruginosa proteins. Here we show that recombinant CP inhibited both LasB-mediated casein degradation and LasA-mediated lysis of Staphylococcus aureus, which was reversible with added zinc. These studies reveal the potential for CP-mediated zinc chelation to post-translationally inhibit zinc metalloprotease activity and thereby impact the protease-dependent physiology and/or virulence of P. aeruginosa in the CF lung environment.ImportanceThe factors that contribute to worse outcomes in individuals with cystic fibrosis (CF) with chronic Pseudomonas aeruginosa infections are not well understood. Therefore, there is a need to understand environmental factors within the CF airway that contribute to P. aeruginosa colonization and infection. We demonstrate that growing bacteria in CF sputum induces a zinc-starvation response that inversely correlates with sputum zinc levels. Additionally, both calprotectin and a chemical zinc chelator inhibit the proteolytic activities of LasA and LasB proteases suggesting that extracellular zinc chelators can influence proteolytic activity and thus P. aeruginosa virulence and nutrient acquisition in vivo.

PMID:33927050 | DOI:10.1128/JB.00100-21

Thorax. 2021 Apr 29:thoraxjnl-2020-216622. doi: 10.1136/thoraxjnl-2020-216622. Online ahead of print.

NO ABSTRACT

PMID:33927019 | DOI:10.1136/thoraxjnl-2020-216622

Thorax. 2021 Apr 29:thoraxjnl-2020-216085. doi: 10.1136/thoraxjnl-2020-216085. Online ahead of print.

ABSTRACT

Structural and functional defects within the lungs of children with cystic fibrosis (CF) are detectable soon after birth and progress throughout preschool years often without overt clinical signs or symptoms. By school age, most children have structural changes such as bronchiectasis or gas trapping/hypoperfusion and lung function abnormalities that persist into later life. Despite improved survival, gains in forced expiratory volume in one second (FEV1) achieved across successive birth cohorts during childhood have plateaued, and rates of FEV1 decline in adolescence and adulthood have not slowed. This suggests that interventions aimed at preventing lung disease should be targeted to mild disease and commence in early life. Spirometry-based classifications of 'normal' (FEV1≥90% predicted) and 'mild lung disease' (FEV1 70%-89% predicted) are inappropriate, given the failure of spirometry to detect significant structural or functional abnormalities shown by more sensitive imaging and lung function techniques. The state and readiness of two imaging (CT and MRI) and two functional (multiple breath washout and oscillometry) tools for the detection and monitoring of early lung disease in children and adults with CF are discussed in this article.Prospective research programmes and technological advances in these techniques mean that well-designed interventional trials in early lung disease, particularly in young children and infants, are possible. Age appropriate, randomised controlled trials are critical to determine the safety, efficacy and best use of new therapies in young children. Regulatory bodies continue to approve medications in young children based on safety data alone and extrapolation of efficacy results from older age groups. Harnessing the complementary information from structural and functional tools, with measures of inflammation and infection, will significantly advance our understanding of early CF lung disease pathophysiology and responses to therapy. Defining clinical utility for these novel techniques will require effective collaboration across multiple disciplines to address important remaining research questions. Future impact on existing management burden for patients with CF and their family must be considered, assessed and minimised.To address the possible role of these techniques in early lung disease, a meeting of international leaders and experts in the field was convened in August 2019 at the Australiasian Cystic Fibrosis Conference. The meeting entitiled 'Shaping imaging and functional testing for early disease detection of lung disease in Cystic Fibrosis', was attended by representatives across the range of disciplines involved in modern CF care. This document summarises the proceedings, key priorities and important research questions highlighted.

PMID:33927017 | DOI:10.1136/thoraxjnl-2020-216085

Eur Respir J. 2021 Apr 29:2000653. doi: 10.1183/13993003.00653-2020. Online ahead of print.

ABSTRACT

INTRODUCTION: A reduction in pulmonary artery (PA) relaxation is a key event in pulmonary arterial hypertension (PAH) pathogenesis. CFTR dysfunction in airway epithelial cells plays a central role in cystic fibrosis (CF); CFTR is also expressed in PAs and has been shown to control endothelium-independent relaxation.

AIM AND OBJECTIVES: We aimed to delineate the role of CFTR in PAH pathogenesis through observational and interventional experiments in human tissues and animal models.

METHODS AND RESULTS: RT-Q-PCR, confocal imaging and electron microscopy showed that CFTR expression was reduced in PAs from patients with idiopathic PAH (iPAH) and in rats with monocrotaline-induced pulmonary hypertension (PH). Moreover, using myograph on human, pig and rat PAs, we demonstrated that CFTR activation induces PAs relaxation. CFTR-mediated PA relaxation was reduced in PAs from iPAH patients and rats with monocrotaline- or chronic hypoxia-induced PH. Long-term in vivo CFTR inhibition in rats significantly increased right ventricular systolic pressure, which was related to exaggerated pulmonary vascular cell proliferation in situ and vessel neomuscularization. Pathologic assessment of lungs from patients with severe CF (F508del-CFTR) revealed severe PA remodeling with intimal fibrosis and medial hypertrophy. Lungs from homozygous F508delCftr rats exhibited pulmonary vessel neomuscularization. The elevations in right ventricular systolic pressure and end diastolic pressure in monocrotaline-exposed rats with chronic CFTR inhibition were more prominent than those in vehicle-exposed rats.

CONCLUSIONS: CFTR expression is strongly decreased in PA smooth muscle and endothelial cells in human and animal models of PH. CFTR inhibition increases vascular cell proliferation and strongly reduces PA relaxation.

PMID:33926975 | DOI:10.1183/13993003.00653-2020

Science. 2021 Apr 30;372(6541):465-466. doi: 10.1126/science.abi5695.

NO ABSTRACT

PMID:33926941 | DOI:10.1126/science.abi5695

Science. 2021 Apr 30;372(6541):eabb8699. doi: 10.1126/science.abb8699.

ABSTRACT

Although almost all mycobacterial species are saprophytic environmental organisms, a few, such as Mycobacterium tuberculosis, have evolved to cause transmissible human infection. By analyzing the recent emergence and spread of the environmental organism M. abscessus through the global cystic fibrosis population, we have defined key, generalizable steps involved in the pathogenic evolution of mycobacteria. We show that epigenetic modifiers, acquired through horizontal gene transfer, cause saltational increases in the pathogenic potential of specific environmental clones. Allopatric parallel evolution during chronic lung infection then promotes rapid increases in virulence through mutations in a discrete gene network; these mutations enhance growth within macrophages but impair fomite survival. As a consequence, we observe constrained pathogenic evolution while person-to-person transmission remains indirect, but postulate accelerated pathogenic adaptation once direct transmission is possible, as observed for M. tuberculosis Our findings indicate how key interventions, such as early treatment and cross-infection control, might restrict the spread of existing mycobacterial pathogens and prevent new, emergent ones.

PMID:33926925 | DOI:10.1126/science.abb8699

Can J Diabetes. 2021 Mar 26:S1499-2671(21)00079-4. doi: 10.1016/j.jcjd.2021.03.005. Online ahead of print.

ABSTRACT

OBJECTIVES: Our aims in this study were to document the screening rate for cystic fibrosis‒related diabetes (CFRD) in children followed at a cystic fibrosis (CF) clinic in Canada and to evaluate the accuracy of various glycated hemoglobin (A1C) cutoffs to screen for CFRD and impaired glucose tolerance (IGT) in a pediatric CF population.

METHODS: The CFRD screening rate was calculated over a follow-up period of up to 8 years among children who attended the CF clinic between 1993 and 2018. Test performance of A1C at various thresholds ranging from 5.5% to 6.2% was compared with the oral glucose tolerance test (OGTT) as the reference method. Children with CF aged ≥10 years with an OGTT performed within 120 days of A1C measurement were included in the analysis.

RESULTS: The overall CFRD screening rate was 53.0%. A total of 256 children were included for the A1C performance analysis, of whom 8.6% had an OGTT-confirmed CFRD diagnosis. An A1C threshold of 5.8% demonstrated an optimal balance between sensitivity (90.9%) and specificity (60.7%) for CFRD screening, leading to a potential reduction of 56.3% of the annual required OGTTs. A1C demonstrated poor accuracy for identifying children with IGT.

CONCLUSIONS: An A1C threshold ≥5.8% allows for identification of children requiring further CFRD investigations, which may reduce the clinical burden of children with CF without compromising the ability of early CFRD diagnosis.

PMID:33926819 | DOI:10.1016/j.jcjd.2021.03.005

Rev Mal Respir. 2021 Apr 26:S0761-8425(21)00221-7. doi: 10.1016/j.rmr.2021.04.004. Online ahead of print.

ABSTRACT

INTRODUCTION: Fungal aspergillosis colonization and allergic bronchopulmonary aspergillosis (ABPA) can have a strong impact on the prognosis in cystic fibrosis (CF). We conducted round table discussions involving French experts from pediatric and adult centers caring for patients with CF, microbiologists, radiologists and pharmacists. The aim was to explore the current state of knowledge on: the pathophysiological mechanisms of Aspergillus and other micromycetes infections in CF (such as Scedosporium sp.), and on the clinico-biological diagnosis of ABPA. In perspective, the experts explored the role of imaging in the diagnosis of APBA, specifically CT and MRI; as well as the role of bronchoscopy in the management. We also reviewed the therapeutic management, including different corticosteroid regimens, antifungals and anti-IgE antibodies.

CONCLUSION: The diagnosis of ABPA in CF should be based on more standardized biological assays and imaging to optimize treatment and follow-up.

PMID:33926779 | DOI:10.1016/j.rmr.2021.04.004

Monaldi Arch Chest Dis. 2021 Apr 15;91(2). doi: 10.4081/monaldi.2021.1619.

ABSTRACT

Inhaled therapies are relatively simple and easy to be managed however ineffective use of aerosols when self-administered may occur. We described variation of the number of clinic visits, lung function and number of antibiotic courses performed over 12 months in participants with cystic fibrosis (CF), when supervised or not by physiotherapists (PTs) at home. Participants in 8 Italian CF centers with a prescription of dry-powder antibiotic choose whether to be supervised at home (PT-FU) or not (non-PT-FU), in adjunct to routine clinic visits. PTs assisted participants with their inhaled therapies regimen and reviewed the airway clearance program in use. Mixed-effect regression models were fitted to evaluate the variation of selected endpoints over time. A total of 163 participants were included. Lung function declined over time in both groups, at higher extent in the non-PT-FU group at 6 months (-1.8, 95%CI: -4.4 to 0.7 % predicted), without reaching statistical significance, whereas in the PT-FU group only, nearly one visit less was recorded (p=0.027). Regardless the type of supervision adopted, the number of antibiotic courses did not change compared to the previous year. We counted 19/90 (21.1%) drop-out in the PT-FU, double compared to the group followed up at the clinics (p=0.065). Participants under a course of an inhaled antibiotic therapy showed a 1-year decline in lung function, whereas only the group receiving home supervision counted nearly one visit less at the CF center, whose clinical relevance should be further discussed.

PMID:33926178 | DOI:10.4081/monaldi.2021.1619