Pediatr Pulmonol. 2021 Mar 8. doi: 10.1002/ppul.25334. Online ahead of print.

NO ABSTRACT

PMID:33684256 | DOI:10.1002/ppul.25334

Environ Microbiol. 2021 Mar 8. doi: 10.1111/1462-2920.15451. Online ahead of print.

ABSTRACT

The Burkholderia cepacia complex is a group of Burkholderia species which are opportunistic pathogens causing high mortality rates in patients with cystic fibrosis. An environmental stress often encountered by these soil-dwelling and pathogenic bacteria is phosphorus limitation, an essential element for cellular processes. Here, we describe cellular and extracellular proteins differentially regulated between phosphate-deplete (0 mM, no added phosphate) and phosphate-replete (1 mM) growth conditions using a comparative proteomics (LC-MS/MS) approach. We observed a total of 128 and 65 unique proteins were down-regulated and up-regulated, respectively, in the B. cenocepacia proteome. Of those down-regulated proteins, many have functions in amino acid transport/metabolism. We have identified 24 up-regulated proteins which are directly/indirectly involved in inorganic phosphate or organic phosphorus acquisition. Also, proteins involved in virulence and antimicrobial resistance were differentially regulated, suggesting B. cenocepacia experiences a dramatic shift in metabolism under these stress conditions. Overall, this study provides a baseline for further research into the biology of Burkholderia in response to phosphorus stress. This article is protected by copyright. All rights reserved.

PMID:33684254 | DOI:10.1111/1462-2920.15451

Ir J Med Sci. 2021 Mar 8. doi: 10.1007/s11845-021-02564-9. Online ahead of print.

ABSTRACT

BACKGROUND: The 6-min walk test (6MWT) is a sub-maximal exercise test and has been widely used for evaluating of exercise capacity of patients with cystic fibrosis (CF) in recent years. Few studies have examined the relationship between 6MWT and parameters used to assess the severity of the disease in children with CF. In this study, we have examined this relationship to find out if 6MWT can be a marker of the severity of cystic fibrosis.

METHODS: A cross-sectional study was done to analyze the correlations among spirometry parameters, body mass index (BMI), chest tomography (CT), and 6MWT. CF patients, aged 7-14 years, were involved.

RESULTS: Seventy-six patients, 32F/44M, mean age 10.49 ± 3.18 years, were studied. The mean distance in 6MWT was 447 ± 84.1. The following correlations versus distance were found: FEV1 (r = 0.255, p = 0.026), FVC(r = 0.285, p = 0.013), FEF25-75% (r = 0.546, p < 0.001), BMI (r = 0.163, p = 0.160), and CT (r = 0.075, p = 0.520).The following correlations versus O2 saturation (SpO2) decline were found: FEV1 (r = -0.393, p < 0.001), FVC (r = -0.431, p < 0.001), FEF25-75% (r = -0.296, p = 0.010), BMI (r = 0.042, p = 0.721), and CT (r = -0.196, p = 0.090). There was a significant correlation between 6MWT (distance and SpO2 decline) and pulmonary function test. There was no significant correlation between BMI, chest CT, and 6MWT.

CONCLUSIONS: 6MWT can be applied beside spirometry and chest CT for CF patients follow up.

PMID:33683561 | DOI:10.1007/s11845-021-02564-9

Biotechnol Lett. 2021 Mar 8. doi: 10.1007/s10529-021-03101-5. Online ahead of print.

ABSTRACT

OBJECTIVE: Chromovert® Technology is presented as a new cell engineering technology to detect and purify living cells based on gene expression.

METHODS: The technology utilizes fluorogenic oligonucleotide signaling probes and flow cytometry to detect and isolate individual living cells expressing one or more transfected or endogenously-expressed genes.

RESULTS: Results for production of cell lines expressing a diversity of ion channel and membrane proteins are presented, including heteromultimeric epithelial sodium channel (αβγ-ENaC), sodium voltage-gated ion channel 1.7 (NaV1.7-αβ1β2), four unique γ-aminobutyric acid A (GABAA) receptor ion channel subunit combinations α1β3γ2s, α2β3γ2s, α3β3γ2s and α5β3γ2s, cystic fibrosis conductance regulator (CFTR), CFTR-Δ508 and two G-protein coupled receptors (GPCRs) without reliance on leader sequences and/or chaperones. In addition, three novel plasmid-encoded sequences used to introduce 3' untranslated RNA sequence tags in mRNA expression products and differentially-detectable fluorogenic probes directed to each are described. The tags and corresponding fluorogenic signaling probes streamline the process by enabling the multiplexed detection and isolation of cells expressing one or more genes without the need for gene-specific probes.

CONCLUSIONS: Chromovert technology is provided as a research tool for use to enrich and isolate cells engineered to express one or more desired genes.

PMID:33683511 | DOI:10.1007/s10529-021-03101-5

Radiat Prot Dosimetry. 2021 Mar 4:ncab017. doi: 10.1093/rpd/ncab017. Online ahead of print.

ABSTRACT

PURPOSE: Digital tomosynthesis (DTS) is currently undergoing validation for potential clinical implications. The aim of this study was to investigate the potential for DTS as a low-dose alternative to computed tomography (CT) in imaging of pulmonary pathology in patients with cystic fibrosis (CF).

METHODS: DTS and CT were performed as part of the routine triannual follow-up in 31 CF patients. Extent of disease was quantified according to modality-specific scoring systems. Statistical analysis included Spearman's rank correlation coefficient (r) and Krippendorff's alpha (α).

MAJOR FINDINGS: The median effective dose was 0.14 for DTS and 2.68 for CT. Intermodality correlation was very strong for total score and the subscores regarding bronchiectasis and bronchial wall-thickening (r = 0.82-0.91, P < 0.01). Interobserver reliability was high for total score, bronchiectasis and mucus plugging (α = 0.83-0.93) in DTS.

CONCLUSION: Chest tomosynthesis could be a low-dose alternative to CT in quantitative estimation of structural lung disease in CF.

PMID:33683309 | DOI:10.1093/rpd/ncab017

Rev Med Liege. 2021 Mar;76(3):202-207.

ABSTRACT

In cystic fibrosis, lung disease is early and insidious. It almost always conditions the prognosis. A pragmatic way of looking at prognostic factors is to distinguish those on which care management has little (environmental factors) or no grip (genetic factors) and those related to the quality of care, the latter being crucial. Recently, a triple-combination CFTR («Cystic Fibrosis Transmembrane conductance Regulator») modulator regimen has been shown a highly effective therapy. Ultimately, at least 90 % of Belgian patients with cystic fibrosis should benefit from this drug. However, its official price is extremely high (712 €/day), lacks transparency and illustrates problematic aspects of current orphan legislations. For the majority of citizens in Western Europe, a social ideal still prevails that healthcare should be accessible to all in an equitable fashion. Somewhere between this price and the necessity for national health systems based on solidarity to keep the costs of orphan drugs at a sustainable level, patients are looking like hostages.

PMID:33682390

J Cell Mol Med. 2021 Mar 8. doi: 10.1111/jcmm.16404. Online ahead of print.

ABSTRACT

Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) are an established risk factor for cystic fibrosis (CF) and chronic pancreatitis. Whereas patients with CF usually develop complete exocrine pancreatic insufficiency, pancreatitis patients with CFTR mutations have mostly preserved exocrine pancreatic function. We therefore used a strain of transgenic mice with significant residual CFTR function (CFTRtm1HGU ) to induce pancreatitis experimentally by serial caerulein injections. Protease activation and necrosis were investigated in isolated acini, disease severity over 24h, pancreatic function by MRI, isolated duct stimulation and faecal chymotrypsin, and leucocyte function by ex vivo lipopolysaccharide (LPS) stimulation. Pancreatic and lung injury were more severe in CFTRtm1HGU but intrapancreatic trypsin and serum enzyme activities higher than in wild-type controls only at 8h, a time interval previously attributed to leucocyte infiltration. CCK-induced trypsin activation and necrosis in acini from CFTRtm1HGU did not differ from controls. Fluid and bicarbonate secretion were greatly impaired, whereas faecal chymotrypsin remained unchanged. LPS stimulation of splenocytes from CFTRtm1HGU resulted in increased INF-γ and IL-6, but decreased IL-10 secretion. CFTR mutations that preserve residual pancreatic function significantly increase the severity of experimental pancreatitis-mostly via impairing duct cell function and a shift towards a pro-inflammatory phenotype, not by rendering acinar cells more susceptible to pathological stimuli.

PMID:33682322 | DOI:10.1111/jcmm.16404

Pediatr Int. 2021 Mar 7. doi: 10.1111/ped.14688. Online ahead of print.

ABSTRACT

BACKGROUND: Non-tuberculous mycobacteria (NTM) can cause chronic lung infection particularly in patients who have structural lung disease such as cystic fibrosis (CF). We evaluated the incidence and management of NTM infections in patients with CF in our center.

METHODS: A retrospective cohort study was carried out on CF patients having at least one positive NTM isolate between 2012-2020.

RESULTS: Ten patients (2.1 %) had at least one positive NTM culture from respiratory samples. All of them were vaccinated with Bacille Calmette-Guérin (BCG) vaccine which it is in the national vaccination program in our country. Eight patients had Mycobacterium abscessus complex (MABSC), one had Mycobacterium avium and one had Mycobacterium szulgai growth in their respiratory samples. Three patients had transient, 2 had persistent and 5 had active NTM infection (NTM pulmonary disease). Patients with NTM pulmonary disease received antibiogram directed antimycobacterial therapy. In patients with NTM pulmonary disease, the median ppFEV1 and BMI decreased by 17% and 1%, respectively, at the time of the first NTM isolation when compared with the values one year before first NTM isolation. Culture conversion was not seen in any patient infected with MABSC.

CONCLUSIONS: The NTM infection incidence is lower in our country than those countries where the BCG vaccine is not routinely applied. The BCG vaccine may be a protective factor for NTM infection. Further studies are needed about the prevalence of NTM infections, facilitating and protective factors and appropriate management of NTM infections in patients with CF.

PMID:33682254 | DOI:10.1111/ped.14688

Front Mol Biosci. 2021 Feb 18;8:634479. doi: 10.3389/fmolb.2021.634479. eCollection 2021.

ABSTRACT

The explosion of microbiome analyses has helped identify individual microorganisms and microbial communities driving human health and disease, but how these communities function is still an open question. For example, the role for the incredibly complex metabolic interactions among microbial species cannot easily be resolved by current experimental approaches such as 16S rRNA gene sequencing, metagenomics and/or metabolomics. Resolving such metabolic interactions is particularly challenging in the context of polymicrobial communities where metabolite exchange has been reported to impact key bacterial traits such as virulence and antibiotic treatment efficacy. As novel approaches are needed to pinpoint microbial determinants responsible for impacting community function in the context of human health and to facilitate the development of novel anti-infective and antimicrobial drugs, here we review, from the viewpoint of experimentalists, the latest advances in metabolic modeling, a computational method capable of predicting metabolic capabilities and interactions from individual microorganisms to complex ecological systems. We use selected examples from the literature to illustrate how metabolic modeling has been utilized, in combination with experiments, to better understand microbial community function. Finally, we propose how such combined, cross-disciplinary efforts can be utilized to drive laboratory work and drug discovery moving forward.

PMID:33681294 | PMC:PMC7930556 | DOI:10.3389/fmolb.2021.634479

Front Med (Lausanne). 2021 Feb 17;8:630209. doi: 10.3389/fmed.2021.630209. eCollection 2021.

ABSTRACT

Rationale: Coronavirus disease 2019 (COVID-19) can cause disruption of the renin-angiotensin system in the lungs, possibly contributing to pulmonary capillary leakage. Thus, angiotensin receptor blockers (ARBs) may improve respiratory failure. Objective: Assess safety of losartan for use in respiratory failure related to COVID-19 (NCT04335123). Methods: Single arm, open label trial of losartan in those hospitalized with respiratory failure related to COVID-19. Oral losartan (25 mg daily for 3 days, then 50 mg) was administered from enrollment until day 14 or hospital discharge. A post-hoc external control group with patients who met all inclusion criteria was matched 1:1 to the treatment group using propensity scores for comparison. Measures: Primary outcome was cumulative incidence of any adverse events. Secondary, explorative endpoints included measures of respiratory failure, length of stay and vital status. Results: Of the 34 participants enrolled in the trial, 30 completed the study with a mean age SD of 53.8 ± 17.7 years and 17 males (57%). On losartan, 24/30 (80%) experienced an adverse event as opposed to 29/30 (97%) of controls, with a lower average number of adverse events on losartan relative to control (2.2 vs. 3.3). Using Poisson regression and controlling for age, sex, race, date of enrollment, disease severity at enrollment, and history of high-risk comorbidities, the incidence rate ratio of adverse events on losartan relative to control was 0.69 (95% CI: 0.49-0.97) Conclusions: Losartan appeared safe for COVID-19-related acute respiratory compromise. To assess true efficacy, randomized trials are needed.

PMID:33681257 | PMC:PMC7926174 | DOI:10.3389/fmed.2021.630209

Front Cell Infect Microbiol. 2021 Feb 18;10:613774. doi: 10.3389/fcimb.2020.613774. eCollection 2020.

ABSTRACT

Azole-resistant Aspergillus fumigatus (ARAf) has emerged worldwide during the last decades. Drug pressure after long term treatments of chronically infected patients and the propagation of environmental clones selected under the pressure of imidazoles fungicides used in agriculture and farming both account for this emergence. The objectives of this study were to determine the rate of azole resistance in Aspergillus fumigatus during a 5-year period, taking into account (i) differences between underlying diseases of the patients treated, (ii) cross-resistance between azoles, and (iii) focusing on the 5-year evolution of our center's cystic fibrosis cohort. Overall, the rates of voriconazole (VRC)-resistant and itraconazole (ITC)-resistant A. fumigatus isolates were 4.1% (38/927) and 14.5% (95/656), respectively, corresponding to 21/426 (4.9%) and 44/308 (14.3%) patients, respectively. Regarding cross-resistance, among VRC-R isolates tested for ITC, nearly all were R (20/21;95%), compared to only 27% (20/74) of VRC-R among ITC-R isolates. The level of azole resistance remained somewhat stable over years but greatly varied according to the azole drug, patient origin, and clinical setting. Whereas azole resistance during invasive aspergillosis was very scarce, patients with cystic fibrosis were infected with multiple strains and presented the highest rate of resistance: 5% (27/539) isolates were VRC-R and 17.9% (78/436) were ITC-R. These results underline that the interpretation of the azole resistance level in Aspergilllus fumigatus in a routine setting may consider the huge variability depending on the azole drug, the clinical setting, the patient background and the type of infection.

PMID:33680981 | PMC:PMC7930226 | DOI:10.3389/fcimb.2020.613774

Front Immunol. 2021 Feb 19;12:587313. doi: 10.3389/fimmu.2021.587313. eCollection 2021.

ABSTRACT

Background: Pseudomonas aeruginosa (PA) infection in cystic fibrosis (CF) is associated with poor prognosis. Surfactant protein-D (SFTPD) and mannose-binding lectin (MBL) play a critical role in innate immunity and response to bacterial infections. We investigated serum levels and genetic variants of SFTPD and MBL in CF patients. Method: Thirty-five Caucasian patients homozygous for ΔF508del were genotyped for functional relevant polymorphisms within MBL2 (promoter-221 Y/X, codons 52, 54, and 57) and SFTPD genes (Met11Thr, Ala160Thr, and Ser270Thr). Serum levels of collectins, clinical characteristics, and PA status were correlated with genetic data. Results: Patients age, gender, and PA status did not affect MBL and SFTPD serum concentrations. MBL concentrations were correlated with MBL haplotypes. Patients with chronic Pseudomonas aeroginosa infection (PAC) and MBL insufficiency had a shorter interval between first PA infection and onset of PAC (0.01 vs. 4.6 years, p < 0.04) as well as a lower median age at transition to PAC (9.8 vs. 16.4 years, p < 0.03) compared to MBL sufficient patients with PAC. SFTPD serum level and FEV1% (Spearman r = -0.41, p < 0.03) showed a negative correlation irrespective of PA infection status. The hazard ratio to PA acquisition was increased in carriers of the SFTPD haplotype 11Thr-160Ala-270Ser compared to carriers of the common 11Met-160Thr-270Ser haplotype [HR 3.0 (95%CI: 1.1-8.6), p < 0.04]. Conclusion: MBL insufficiency leads to a shorter interval between first PA infection and onset of chronic infection. Susceptibility to PA acquisition is associated with SFTPD genetic variants with 11Thr-160Ala-270Ser as risk haplotype for early PA infection. This may be due to presence of threonine associated with oligomeric structure of SFTPD and binding ability to bacteria.

PMID:33679736 | PMC:PMC7933032 | DOI:10.3389/fimmu.2021.587313

Eur Respir J. 2021 Mar 7:2002288. doi: 10.1183/13993003.02288-2020. Online ahead of print.

ABSTRACT

BACKGROUND: Median survival for cystic fibrosis (CF) patients in Europe is unknown and is likely to be influenced by socioeconomic factors. Using the European Cystic Fibrosis Society Patient Registry (ECFSPR), median survival estimates were obtained for CF patients across Europe and the impact of socioeconomic status on survival was examined.

METHODS: CF subjects known to be alive and in the ECFSPR between 2010 and 2014 were included. Survival curves were estimated using the Kaplan-Meier (KM) method. Differences in the survival curves were assessed using the log rank test. Cox regression was used to estimate the association between socioeconomic factors and the age-specific hazard of death, with adjustment for sex, age at diagnosis, CFTR genotype and transplant status.

FINDINGS: The final analysis included 13 countries with 31 987 subjects (135 833 person years of follow-up) and 1435 deaths. Median survival age for these patients in the ECFSPR was 51.7 years (95% C.I. 50.0-53.4). After adjusting for potential confounders age at diagnosis, sex, CFTR genotype and transplant status, there remained strong evidence of an association between socioeconomic factors and mortality (p<0.001). Countries with higher health care spending had a 46% lower hazard of mortality (HR: 0.54, 95% CI: 0.45-0.64) than countries with lowest health care spending.

INTERPRETATION: Median survival for patients with CF in Europe is comparable to that reported in other jurisdictions and differs by socioeconomic factors.

PMID:33678607 | DOI:10.1183/13993003.02288-2020

Hear Res. 2021 Feb 19:108209. doi: 10.1016/j.heares.2021.108209. Online ahead of print.

ABSTRACT

The global impact of hearing loss and related auditory dysfunction including tinnitus and hyperacusis on human health is significant and growing. A substantial body of literature has found that these hearing diseases and disorders result from significant number of genetic variations and molecular mechanisms. Investigational new drugs have been tested and several approved drugs have been repurposed in clinical trials, but no therapeutics for any auditory related indication have been FDA approved. A unique investigational new drug called ebselen (SPI-1005), that is anti-inflammatory and neuroprotective, has been shown to reduce noise-induced and aminoglycoside-induced hearing loss in animals. Multiple phase 2 clinical trials have demonstrated the safety and efficacy of SPI-1005 treatment in Meniere's disease and acute noise-induced hearing loss. SPI-1005 is currently being tested to prevent and treat tobramycin-induced ototoxicity in cystic fibrosis patients with acute lung infections. This review summarizes the published and presented data involving SPI-1005 and other drugs being tested to prevent or treat sensorineural hearing loss. Additionally, recent clinical data showing the relationship between pure tone audiometry and words-in-noise test results in a Meniere's disease are presented, which may have larger implications for the field of hearing research.

PMID:33678494 | DOI:10.1016/j.heares.2021.108209

Chest. 2021 Mar;159(3):917-919. doi: 10.1016/j.chest.2020.10.018.

NO ABSTRACT

PMID:33678278 | DOI:10.1016/j.chest.2020.10.018

Toxicol Sci. 2021 Mar 2:kfab022. doi: 10.1093/toxsci/kfab022. Online ahead of print.

ABSTRACT

Environmental factors and gene-environment interactions modify the variable expressivity, progression, severity, and onset of some classic (monogenic) Mendelian-inherited genetic diseases. Cystic Fibrosis, Huntington Disease, Parkinson's Disease, and Sickle Cell Disease are examples of well-known Mendelian disorders that are influenced by exogenous exposures. Environmental factors may act by direct or indirect mechanisms to modify disease severity, timing, and presentation, including through epigenomic influences, protein misfolding, miRNA alterations, transporter activity, and mitochondrial effects. Since pathological features of early-onset Mendelian diseases can mimic later onset complex diseases, we propose that studies of environmental exposure vulnerabilities using monogenic model systems of rare Mendelian diseases have high potential to provide insight into complex disease phenotypes arising from multi-genetic/multi-toxicant interactions. Mendelian disorders can be modeled by homologous mutations in animal model systems with strong recapitulation of human disease etiology and natural history, providing an important advantage for study of these diseases. Monogenic high penetrant mutations are ideal for toxicant challenge studies with a wide variety of environmental stressors, since background genetic variability may be less able to alter the relatively strong phenotype driving disease-causing mutations. These models promote mechanistic understandings of gene-environment interactions and biological pathways relevant to both Mendelian and related sporadic complex disease outcomes by creating a sensitized background for relevant environmental risk factors. Additionally, rare disease communities are motivated research participants, creating the potential of strong research allies among rare Mendelian disease advocacy groups and disease registries and providing a variety of translational opportunities that are under-utilized in genetic or environmental health science.

PMID:33677604 | DOI:10.1093/toxsci/kfab022

Integr Biol (Camb). 2021 Mar 3:zyab002. doi: 10.1093/intbio/zyab002. Online ahead of print.

ABSTRACT

Culture at the air-liquid interface is broadly accepted as necessary for differentiation of cultured epithelial cells towards an in vivo-like phenotype. However, air-liquid interface cultures are expensive, laborious and challenging to scale for increased throughput applications. Deconstructing the microenvironmental parameters that drive these differentiation processes could circumvent these limitations, and here we hypothesize that reduced oxygenation due to diffusion limitations in liquid media limits differentiation in submerged cultures; and that this phenotype can be rescued by recreating normoxic conditions at the epithelial monolayer, even under submerged conditions. Guided by computational models, hyperoxygenation of atmospheric conditions was applied to manipulate oxygenation at the monolayer surface. The impact of this rescue condition was confirmed by assessing protein expression of hypoxia-sensitive markers. Differentiation of primary human bronchial epithelial cells isolated from healthy patients was then assessed in air-liquid interface, submerged and hyperoxygenated submerged culture conditions. Markers of differentiation, including epithelial layer thickness, tight junction formation, ciliated surface area and functional capacity for mucociliary clearance, were assessed and found to improve significantly in hyperoxygenated submerged cultures, beyond standard air-liquid interface or submerged culture conditions. These results demonstrate that an air-liquid interface is not necessary to produce highly differentiated epithelial structures, and that increased availability of oxygen and nutrient media can be leveraged as important strategies to improve epithelial differentiation for applications in respiratory toxicology and therapeutic development.

PMID:33677549 | DOI:10.1093/intbio/zyab002

Hear Res. 2021 Feb 21;404:108215. doi: 10.1016/j.heares.2021.108215. Online ahead of print.

ABSTRACT

Efferent innervation of the inner hair cells changes over time. At an early age in mice, inner hair cells receive efferent feedback, which helps fine-tune tonotopic maps in the brainstem. In adulthood, inner hair cell efferent innervation wanes but increases again in older animals. It is not clear, however, whether age-related inner hair cell efferents increase along the entire range of the cochlear frequencies, or if this increase is restricted to a particular frequency-region, and whether this phenomenon occurs in both sexes. Age-related hearing loss, presbycusis, affects men and women differently. In mice, this difference is also strain specific. In aging black six mice, the auditory brainstem response thresholds increase in females earlier than in males. Here, we study age-related increase of the inner hair cell efferent innervation throughout the cochlea before hearing onset, in one month old and in ten months old and older male and female black six mice. We collected confocal images of immunostained inner hair cell efferents and quantified the labeled terminals in the entire cochlea using a machine learning algorithm. The overall number of the inner hair cell efferents in both sexes did not change significantly between age-groups. The distribution of the inner hair cell efferent innervation did not differ across frequencies in the cochlea. However, in females, inner hair cells received on average up to four times more efferent innervation than in males per each of the frequency regions tested. Sex differences were also found in the oldest age-group tested (≥ 10 months) where on average inner hair cells received six times more efferents in females than in males of matching age. Our findings emphasize the importance of including both sexes in sensorineural hearing loss research.

PMID:33677192 | DOI:10.1016/j.heares.2021.108215

Drug Discov Today. 2021 Mar 3:S1359-6446(21)00111-2. doi: 10.1016/j.drudis.2021.02.026. Online ahead of print.

ABSTRACT

The Pseudomonas aeruginosa LasB elastase (elastase B, pseudolysin) is the predominant protease in the P. aeruginosa secretome. It has been shown to hydrolyse a vast array of host and pathogen proteins, degrading some, activating others, and causing damage to tissues, disrupting host immune responses, and promoting inflammation. It is a virulence factor in P. aeruginosa lung infections and has been proposed as an attractive target for the development of a novel antivirulence therapy. In this review, we summarise the activities and biological roles of LasB and focus on efforts to identify and develop specific LasB inhibitor drugs as adjuncts in the treatment of P. aeruginosa infections.

PMID:33676022 | DOI:10.1016/j.drudis.2021.02.026

Pediatr Pulmonol. 2021 Mar 6. doi: 10.1002/ppul.25361. Online ahead of print.

ABSTRACT

BACKGROUND: Treatment regimens for cystic fibrosis (CF) continue to evolve and grow in complexity. Treatment regimen burden, and associated sequelae, are incompletely understood.

OBJECTIVE: QI methods were used to investigate treatment burden of CF care, family and care team partnerships, and potential interventions to reduce burden.

METHODS: Patients 6-24 years with CF and caregivers of patients 6-13 years were surveyed. Portions of validated tools and existing surveys measured burden and family-care team partnership. An automated report calculated treatment complexity. PDSA cycles tested survey administration during CF visits and run charts tracked progress. Interventions to reduce burden were tracked, and bidirectional assessments explored partnerships among patients, families and clinicians.

RESULTS: Over 6 months, 110 patients and 62 caregivers completed assessments. Caregivers reported lower burden/higher quality of life (74.0, range 22.2-100) than patients (66.5, range 16.7-100). The mean treatment complexity score was 17.2 (range 6-34). Treatment complexity and burden increased with patient age (p<0.05 and p<0.01 respectively). Lower lung function correlated with higher patient-reported burden (p<0.01) and higher treatment complexity (p<0.0001). As burden increased, providers more often performed select interventions (discussed combining treatments, simplified regimens, or involved other team members (p<0.05 for each)). Families reported high partnership (mean scores 4.7-4.8, 5=high), and providers reported high utilization of partnership tools (tool used in 77% of encounters).

CONCLUSION: We assessed, quantified, and responded to treatment burden and complexity in real-time during outpatient CF visits. Systematic and individualized assessments of treatment complexity and burden may enhance treatment adherence while preserving quality of life. This article is protected by copyright. All rights reserved.

PMID:33675286 | DOI:10.1002/ppul.25361