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Context: Azithromycin is recommended as therapy for cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa infection, but there has not been sufficient evidence to support the benefit of azithromycin in other patients with CF.Objective: To determine if azithromycin treatment improves lung function and reduces pulmonary exacerbations in pediatric CF patients uninfected with P. aeruginosa.Design, Setting, and Participants: A multicenter, randomized, double-blind placebo-controlled trial was conducted from February 2007 to July 2009 at 40 CF care centers in the United States and Canada. Of the 324 participants screened, 260 were randomized and received study drug. Eligibility criteria included age of 6 to 18 years, a forced expiratory volume in the first second of expiration (FEV(1)) of at least 50% predicted, and negative respiratory tract cultures for P. aeruginosa for at least 1 year. Randomization was stratified by age of 6 to 12 years vs 13 to 18 years and by CF center.Intervention: The active group (n = 131) received 250 mg (weight 18-35.9 kg) or 500 mg (weight > or = 36 kg) of azithromycin 3 days per week (Monday, Wednesday, and Friday) for 168 days. The placebo group (n = 129) received identically packaged placebo tablets on the same schedule.Main Outcome Measures: The primary outcome was change in FEV(1). Exploratory outcomes included additional pulmonary function end points, pulmonary exacerbations, changes in weight and height, new use of antibiotics, and hospitalizations. Changes in microbiology and adverse events were monitored.Results: The mean (SD) age of participants was 10.7 (3.17) years. The mean (SD) FEV(1) at baseline and 168 days were 2.13 (0.85) L and 2.22 (0.86) L for the azithromycin group and 2.12 (0.85) L and 2.20 (0.88) L for the placebo group. The difference in the change in FEV(1) between the azithromycin and placebo groups was 0.02 L (95% confidence interval [CI], -0.05 to 0.08; P = .61). None of the exploratory pulmonary function end points were statistically significant. Pulmonary exacerbations occurred in 21% of the azithromycin group and 39% of the placebo group. Participants in the azithromycin group had a 50% reduction in exacerbations (95% CI, 31%-79%) and an increase in body weight of 0.58 kg (95% CI, 0.14-1.02) compared with placebo participants. There were no significant differences between groups in height, use of intravenous or inhaled antibiotics, or hospitalizations. Participants in the azithromycin group had no increased risk of adverse events, but had less cough (-23% treatment difference; 95% CI, -33% to -11%) and less productive cough (-11% treatment difference; 95% CI, -19% to -3%) compared with placebo participants.Conclusion: In children and adolescents with CF uninfected with P. aeruginosa, treatment with azithromycin for 24 weeks did not result in improved pulmonary function.Trial Registration: clinicaltrials.gov Identifier: NCT00431964. [ABSTRACT FROM AUTHOR]

Abstract Background Malignant cells in tumours of B-cell origin account for 0.1% to 98% of the total cell content, depending on disease entity. Recently, gene expression profiles (GEPs) of B-cell lymphomas based on microarray technologies have contributed significantly to improved sub-classification and diagnostics. However, the varying degrees of malignant B-cell frequencies in analysed samples influence the interpretation of the GEPs. Based on emerging next-generation sequencing technologies (NGS) like tag sequencing (tag-seq) for GEP, it is expected that the detection of mRNA transcripts from malignant B-cells can be supplemented. This study provides a quantitative assessment and comparison of the ability of microarrays and tag-seq to detect mRNA transcripts from malignant B-cells. A model system was established by eight serial dilutions of the malignant B-cell lymphoma cell line, OCI-Ly8, into the embryonic kidney cell line, HEK293, prior to parallel analysis by exon microarrays and tag-seq. Results We identified 123 and 117 differentially expressed genes between pure OCI-Ly8 and HEK293 cells by exon microarray and tag-seq, respectively. There were thirty genes in common, and of those, most were B-cell specific. Hierarchical clustering from all dilutions based on the differentially expressed genes showed that neither technology could distinguish between samples with less than 1% malignant B-cells from non-B-cells. A novel statistical concept was developed to assess the ability to detect single genes for both technologies, and used to demonstrate an inverse proportional relationship with the sample purity. Of the 30 common genes, the detection capability of a representative set of three B-cell specific genes - CD74, HLA-DRA, and BCL6 - was analysed. It was noticed that at least 5%, 13% and 22% sample purity respectively was required for detection of the three genes by exon microarray whereas at least 2%, 4% and 51% percent sample purity of malignant B-cells were required for tag-seq detection. Conclusion A sample purity-dependent loss of the ability to detect genes for both technologies was demonstrated. Taq-seq, in comparison to exon microarray, required slightly less malignant B-cells in the samples analysed in order to detect the two most abundantly expressed of the selected genes. The results show that malignant cell frequency is an important variable, with fundamental impact when interpreting GEPs from both technologies.

Abstract With cAMP signaling having a profound inhibitory effect on DNA damage-induced apoptosis in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells, understanding how this signaling pathway affects the survival capacity of the cell has important implications for cancer therapy. We have recently shown that p53 is critical for the inhibitory effect of cAMP on genotoxic agents-mediated apoptosis in BCP-ALLs. Here, we show that elevation of cAMP levels in cells exposed to DNA damage enhances the nuclear translocation and DNA binding of NF-κB by accelerating the phosphorylation of IKKβ and thereby phosphorylation and degradation of IκBα. Furthermore, we show that the ability of cAMP to potentiate the ionizing radiation-induced activation of NF-κB requires the activity of MEK. Importantly, pharmacological or genetic ablation of NF-κB reversed the inhibitory effect of cAMP on DNA damage-induced apoptosis, demonstrating that, in addition to p53, cAMP relies on the activity of NF-κB to provide cells with a survival advantage in the face of DNA damage. Collectively, our results uncover a novel and important interaction between the cAMP and NF-κB pathways that may have implications for the targeted treatment of lymphoid malignancies, such as BCP-ALL, in which aberrant NF-κB activity functions as a driving force for treatment resistance.

Rationale: Evaluating approaches to reduce treatment burden is a research priority among people with cystic fibrosis on highly effective modulators, including elexacaftor-tezacaftor-ivacaftor (ETI). Objectives: We sought to evaluate the impact of discontinuing both hypertonic saline (HS) and dornase alfa (DA) versus continuing both therapies among a subgroup of participants in the SIMPLIFY study who sequentially participated in trials evaluating the independent clinical effects of discontinuing HS and DA. Methods: SIMPLIFY participants ≥12 years old on ETI and constituting a subgroup using both HS and DA at study entry were randomized to the HS or DA trial and then randomized 1:1 to continue or discontinue the applicable therapy for 6 weeks. After completion of the first trial, eligible participants could enroll in the second trial beginning with a 2-week run-in. Study outcomes were compared across the duration of SIMPLIFY participation between a cohort remaining on both therapies during SIMPLIFY and a cohort that sequentially discontinued both as a result of trial randomizations. Multivariable regression models were used to estimate treatment differences, adjusted for time between trials, trial order, baseline age, sex at birth, and percent predicted forced expiratory volume in 1 second (ppFEV 1 ) at study entry. Results: Forty-three participants discontinued both therapies by the end of SIMPLIFY, and 63 remained on both, with overall average ppFEV 1 of 96.7% at study entry and 3.9 months as the average duration of follow-up from beginning of the first trial to completion of the second trial, including time between trials. No clinically meaningful difference in the change in ppFEV 1 from baseline to completion of the second trial was observed between those who discontinued and those who remained on both therapies (difference: 0.22% off-on; 95% confidence interval = -1.60, 2.03). Changes in lung clearance index at 2.5% starting concentration, patient-reported outcomes, and safety outcomes were also comparable. Patient-reported treatment burden, as measured by a Cystic Fibrosis Questionnaire-Revised subscale, significantly decreased in those who discontinued both therapies. Conclusions: SIMPLIFY participants who sequentially discontinued both HS and DA experienced no meaningful changes in clinical outcomes and reported decreased treatment burden as compared with those who remained on both therapies. These data continue to inform a new era of postmodulator care of people with cystic fibrosis.

Bioaerosols, such as pollen and fungal spores, are routinely monitored for agricultural, medical or urban greening practices, but sampling methodology is largely relying on techniques more than half a century old. Moreover, biomonitoring campaigns often take place in urban environments, although sources can be located outside cities' borders with ampler vegetation. Therefore, the question arises whether we are accurately picturing the biodiversity and abundance of regional bioaerosols and whether those locally detected might derive from long-distance transport, horizontally or vertically. To answer the above, we used novel, mobile monitoring devices, and aerial measurement units, like aircrafts, so as to explore bioaerosol concentrations at a variety of altitudes. An ultralight aircraft was equipped with a sampling device for bioaerosols. The device consisted of duplicate isokinetic impactors that match the physical functioning and the microscopic quantification method of the widely used ground-based Hirst-type impactors. Isokinetic airflow was realized by adjusting the air flux at the impactors' inlet to the airspeed of the aircraft. Three campaigns were made, where the comparability, efficiency and accuracy of different sampling devices were determined, namely of the abovementioned impactor, and of the mobile conventional Hirst-type pollen sampler. The campaigns involved measurements from ground level (0 m altitude) up to 900 m (above ground level (agl)) via flights. Our results showed that aircraft-based airborne pollen concentration measurements were consistently higher than those of all other devices, regardless of the altitude and sampling time. It is noteworthy that the pollen concentration exceeded 500 pollen grains/m 3 at >900 m of altitude, this concentration being 1.77 times higher than that simultaneously measured at ground level. Likewise, the diversity of pollen was also higher at higher altitude. Our results indicate the usability and superiority of small aircraft and high-flow impactors for research, achieving higher biodiversity and abundance over a shorter sampling interval compared to conventional volumetric techniques. Higher pollen amounts at higher altitudes also point at the necessity to monitor bioaerosols across the vertical dimension, especially in densely populated areas and high-traffic air space., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof. Athanasios Damialis, is the Section Editor in Heliyon Agriculture. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

The dataset presents a 43 year-long reanalysis of pollen seasons for three major allergenic genera of trees in Europe: alder (Alnus), birch (Betula), and olive (Olea). Driven by the meteorological reanalysis ERA5, the atmospheric composition model SILAM predicted the flowering period and calculated the Europe-wide dispersion pattern of pollen for the years 1980-2022. The model applied an extended 4-dimensional variational data assimilation of in-situ observations of aerobiological networks in 34 European countries to reproduce the inter-annual variability and trends of pollen production and distribution. The control variable of the assimilation procedure was the total pollen release during each flowering season, implemented as an annual correction factor to the mean pollen production. The dataset was designed as an input to studies on climate-induced and anthropogenically driven changes in the European vegetation, biodiversity monitoring, bioaerosol modelling and assessment, as well as, in combination with intra-seasonal observations, for health-related applications., (© 2024. The Author(s).)

Field observations form the basis of the majority of studies on microphytobenthic algal communities in freshwater ecosystems. Controlled mesocosm experiments data are comparatively uncommon. The few experimental mesocosm studies that have been conducted provide valuable insights into how multiple stressors affect the community structures and photosynthesis-related traits of benthic microalgae. The recovery process after the stressors have subsided, however, has received less attention in mesocosm studies. To close this gap, here we present the results of a riparian mesocosm experiment designed to investigate the effects of reduced flow velocity, increased salinity and increased temperature on microphytobenthic communities. We used a full factorial design with a semi-randomised distribution of treatments consisting of two levels of each stressor (2 × 2 × 2 treatments), with eight replicates making a total of 64 circular mesocosms, allowing a nuanced examination of their individual and combined influences. We aimed to elucidate the responses of microalgae communities seeded from stream water to the applied environmental stressors. Our results showed significant effects of reduced flow velocity and increased temperature on microphytobenthic communities. Recovery after stressor treatment led to a convergence in community composition, with priority effects (hypothesized to reflect competition for substrate between resident and newly arriving immigrant taxa) slowing down community shifts and biomass increase. Our study contributes to the growing body of literature on the ecological dynamics of microphytobenthos and emphasises the importance of rigorous experiments to validate hypotheses. These results encourage further investigation into the nuanced interactions between microphytobenthos and their environment and shed light on the complexity of ecological responses in benthic systems., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Highly effective CFTR modulator therapy (HEMT) has improved the health of many people with cystic fibrosis (pwCF), offering opportunities to discontinue burdensome therapies. SIMPLIFY included randomized, controlled trials that confirmed non-inferiority of discontinuing versus continuing dornase alfa (DA) or hypertonic saline (HS) for 6 weeks in pwCF on HEMT. In this study of post-trial treatment use by SIMPLIFY participants, we hypothesized that randomization to discontinue DA or HS during the trial would be associated with a higher likelihood of non-use of each medication during follow-up., Methods: We electronically surveyed SIMPLIFY participants every 4 weeks for 24 weeks after trial completion but before the main trial results were publicly disclosed. We asked them how often they used medications during the previous week. We estimated covariate-adjusted odds ratios (ORs) of DA or HS non-use by logistic regression with generalized estimating equations., Results: After exclusions mostly due to lack of any surveys, 472 participants were included in the analysis population, 181 from the HS trial and 291 from the DA trial. Approximately half of the analysis population completed all six surveys. At every month of follow-up in both trials, the percentage of individuals reporting non-use of DA or HS during the previous week was greater among those randomized to discontinue therapy. Among participants with responses at 24 weeks, 30/122 (24.6 %) in the HS trial and 79/222 (35.6 %) in the DA trial reported non-use of the respective study medication. After adjusting for covariates, participants randomized to discontinue DA were 8.7-times (95 % CI: 4.3-17.7) more likely to not use DA during follow-up than those randomized to continue DA, and participants randomized to discontinue HS were 5.2-times (95 % CI: 2.1-12.8) more likely to not use HS during follow-up compared to those randomized to continue., Conclusions: In healthy pwCF on ETI, randomization to discontinue DA or HS during SIMPLIFY was associated with greater odds of not using each medication after the trial compared to randomization to continue. These findings suggest that participation in a treatment discontinuation trial can influence participants' post-trial treatment decisions. This possibility may be relevant during discussions about research participation and clinical care., Competing Interests: Declaration of competing interest AHG was supported by a grant from the Cystic Fibrosis Foundation (SIMPLIFY-GIFFOR20K0-CI). KR was supported by a grant from the Cystic Fibrosis Foundation (RIEKER15PE0). NM-H was supported by a grant from the Cystic Fibrosis Foundation (HAMBLE20K0). DPN was supported by a grant from the Cystic Fibrosis Foundation (NICHOL20K0). KO-D, MK, BPO, GJO, SLM, JPC, and GSS have no financial conflict of interest to disclose related to this study., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)