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This preclinical, phase 2 report shows that VX-445, a CFTR potentiator when administered with tezacaftor and ivacaftor, improved lung function and reduced sweat chloride concentrations and symptoms in patients harboring one or two Phe508del alleles.

In cystic fibrosis (CF), lung damage is mediated by a cycle of obstruction, infection, inflammation and tissue destruction. The complement system is a major mediator of inflammation for many diseases with the effectors C5a and C3a often playing important roles. We have previously shown in a small pilot study that CF sputum soluble fraction concentrations of C5a and C3a were associated with clinical measures of CF disease. Here we report a much larger study of 34 CF subjects providing 169 testable sputum samples allowing longitudinal evaluation comparing C5a and C3a with clinical markers. Levels of the strongly pro-inflammatory C5a correlated negatively with FEV1% predicted (P < 0.001), whereas the often anti-inflammatory C3a correlated positively with FEV1% predicted (P = 0.01). C5a concentrations correlated negatively with BMI percentile (P = 0.017), positively with worsening of an acute pulmonary exacerbation score (P = 0.007) and positively with P. aeruginosa growth in sputum (P = 0.002). C5a levels also correlated positively with concentrations of other sputum markers associated with worse CF lung disease including neutrophil elastase (P < 0.001), myeloperoxidase activity (P = 0.006) and DNA concentration (P < 0.001). In contrast to C5a, C3a levels correlated negatively with worse acute pulmonary exacerbation score and correlated negatively with sputum concentrations of neutrophil elastase, myeloperoxidase activity and DNA concentration. In summary, these data suggest that in CF sputum, increased C5a is associated with increased inflammation and poorer clinical measures, whereas increased C3a appears to be associated with less inflammation and improved clinical measures.

Myeloperoxidase is the major peroxidase enzyme in neutrophil granules and implicated in contributing to inflammatory lung damage in cystic fibrosis. Free myeloperoxidase is present in cystic fibrosis lung fluid and generates hypochlorous acid. Here we report a new inhibitor of myeloperoxidase activity, Peptide Inhibitor of Complement C1 (PIC1). Using TMB as the oxidizing substrate, PIC1 inhibited myeloperoxidase activity in cystic fibrosis sputum soluble fractions by an average of a 3.4-fold decrease (P = 0.02). PIC1 also dose-dependently inhibited myeloperoxidase activity in a neutrophil lysate or purified myeloperoxidase by up to 28-fold (P < 0.001). PIC1 inhibited myeloperoxidase activity similarly, on a molar basis, as the specific myeloperoxidase inhibitor 4-Aminobenzoic acid hydrazide (ABAH) for various oxidizing substrates. PIC1 was able to protect the heme ring of myeloperoxidase from destruction by NaOCl, assayed by spectral analysis. PIC1 incubated with oxidized TMB reversed the oxidation state of TMB, as measured by absorbance at 450 nm, with a 20-fold reduction in oxidized TMB (P = 0.02). This result was consistent with an antioxidant mechanism for PIC1. In summary, PIC1 inhibits the peroxidase activity of myeloperoxidase in CF sputum likely via an antioxidant mechanism.

Aim We studied global variation in beta diversity patterns of lake macrophytes using regional data from across the world. Specifically, we examined (1) how beta diversity of aquatic macrophytes is partitioned between species turnover and nestedness within each study region, and (2) which environmental characteristics structure variation in these beta diversity components. Location Global. Methods We used presence–absence data for aquatic macrophytes from 21 regions distributed around the world. We calculated pairwise-site and multiple-site beta diversity among lakes within each region using Sørensen dissimilarity index and partitioned it into turnover and nestedness coefficients. Beta regression was used to correlate the diversity coefficients with regional environmental characteristics. Results Aquatic macrophytes showed different levels of beta diversity within each of the 21 study regions, with species turnover typically accounting for the majority of beta diversity, especially in high-diversity regions. However, nestedness contributed 30–50% of total variation in macrophyte beta diversity in low-diversity regions. The most important environmental factor explaining the three beta diversity coefficients (total, species turnover and nestedness) was elevation range, followed by relative areal extent of freshwater, latitude and water alkalinity range. Main conclusions Our findings show that global patterns in beta diversity of lake macrophytes are caused by species turnover rather than by nestedness. These patterns in beta diversity were driven by natural environmental heterogeneity, notably variability in elevation range (also related to temperature variation) among regions. In addition, a greater range in alkalinity within a region, likely amplified by human activities, was also correlated with increased macrophyte beta diversity. These findings suggest that efforts to conserve aquatic macrophyte diversity should primarily focus on regions with large numbers of lakes that exhibit broad environmental gradients.

Background: Neonatal intensive care units (NICU) are associate with a high level of antibiotic consumption. Appropriate antibiotic use is crucial to minimize the emergence of resistance and unintended consequences to the patient. Our antimicrobial stewardship program (ASP) performed a baseline review of NICU antibiotic prescribing, which revealed excessive meropenem use and inconsistent empiric antibiotic prescribing practices within the unit. Third generation cephalosporins were vastly underutilized due to concerns of increased Candida infections resulting in the unwarranted excessive use of meropenem.1 Methods: In 2023, the ASP created an institution specific empiric NICU sepsis guideline to align empiric prescribing practices with current guidelines and reduce the unwarranted use of carbapenems. After education and guideline implementation, a retrospective review, pre (April 16, 2021 to April 16, 2023) and post (April 17, 2023 to April 17, 2024) implementation was conducted. The primary objectives were to evaluate the effect of the guideline implementation on antibiotic days of therapy (DOT) per 1000 patient-days, overall meropenem and third generation cephalosporin utilization, differences in the incidence of Candida infections, and variations in antimicrobial sensitivity. Microbiologic data from sterile site cultures were obtained April 2021 to March 2023 and post-implementation (April 2023 to March 2024) to evaluate cephalosporin and meropenem resistance for each period. Results: Meropenem DOT/1000 patient-days declined from 3.9 to 2.0 (51.3%), and an associated rise in third-generation cephalosporin DOT/1000 patient-days from 15.7 to 22.9 (69.7%) occurred post-guideline implementation. There were no observed differences in the incidence of Candida infections, cephalosporin resistance in Gram-negative bacilli, or the organisms isolated over the observation period. Conclusions: Guideline implementation safely and successfully reduced the use of carbapenems by providing alternative antibiotic regimens encouraging the use of third generation cephalosporins and reduced antibiotic pressure in our NICU. There were no differences in the incidence of Candida infections, organisms, or resistance patterns. Implementation of this guideline resulted in safe decreases in antibiotic use in the NICU. Cotton CM, McDonald S, Stoll B, et al. The association of third-generation cephalosporin use and invasive candidiasis in extremely low birth-weight infants. Pediatrics. 2006;118(2):717-22.

In cystic fibrosis (CF), lung damage is mediated by a cycle of obstruction, infection, and inflammation. Here we explored complement inflammatory effectors in CF lung fluid. In this study soluble fractions (sols) from sputum samples of 15 CF patients were assayed for complement effectors and analyzed with clinical measurements. The pro-inflammatory peptide C5a was increased 4.8-fold (P = 0.04) in CF sols compared with controls. Incubation of CF sols with P. aeruginosa or S. aureus increased C5a concentration 2.3-fold (P = 0.02). A peptide inhibitor of complement C1 (PIC1) completely blocked the increase in C5a concentration from P. aeruginosa in CF sol in vitro (P = 0.001). C5a concentration in CF sol correlated inversely with body mass index (BMI) percentile in children (r = -0.77, P = 0.04). C3a, which has anti-inflammatory effects, correlated positively with FEV1% predicted (rs = 0.63, P = 0.02). These results suggest that complement effectors may significantly impact inflammation in CF lung fluid.

We studied community–environment relationships of lake macrophytes at two metacommunity scales using data from 16 regions across the world. More specifically, we examined (a) whether the lake macrophyte communities respond similar to key local environmental factors, major climate variables and lake spatial locations in each of the regions (i.e., within-region approach) and (b) how well can explained variability in the community–environment relationships across multiple lake macrophyte metacommunities be accounted for by elevation range, spatial extent, latitude, longitude, and age of the oldest lake within each metacommunity (i.e., across-region approach). In the within-region approach, we employed partial redundancy analyses together with variation partitioning to investigate the relative importance of local variables, climate variables, and spatial location on lake macrophytes among the study regions. In the across-region approach, we used adjusted R2 values of the variation partitioning to model the community–environment relationships across multiple metacommunities using linear regression and commonality analysis. We found that niche filtering related to local lake-level environmental conditions was the dominant force structuring macrophytes within metacommunities. However, our results also revealed that elevation range associated with climate (increasing temperature amplitude affecting macrophytes) and spatial location (likely due to dispersal limitation) was important for macrophytes based on the findings of the across-metacommunities analysis. These findings suggest that different determinants influence macrophyte metacommunities within different regions, thus showing context dependency. Moreover, our study emphasized that the use of a single metacommunity scale gives incomplete information on the environmental features explaining variation in macrophyte communities.

One of the most intriguing questions in current ecology is the extent to which the ecological niches of species are conserved in space and time. Niche conservatism has mostly been studied using coarse-scale data of species’ distributions, although it is at the local habitat scales where species’ responses to ecological variables primarily take place. We investigated the extent to which niches of aquatic macrophytes are conserved among four study regions (i.e. Finland, Sweden and the US states of Minnesota and Wisconsin) on two continents (i.e. Europe and North America) using data for 11 species common to all the four study areas. We studied how ecological variables (i.e. local, climate and spatial variables) explain variation in the distributions of these common species in the four areas using species distribution modelling. In addition, we examined whether species’ niche parameters vary among the study regions. Our results revealed large variation in both species’ responses to the studied ecological variables and in species’ niche parameters among the areas. We found little evidence for niche conservatism in aquatic macrophytes, though local environmental conditions among the studied areas were largely similar. This suggests that niche shifts, rather than different environmental conditions, were responsible for variable responses of aquatic macrophytes to local ecological variables. Local habitat niches of aquatic macrophytes are mainly driven by variations in local environmental conditions, whereas their climate niches are more or less conserved among regions. This highlights the need to study niche conservatism using local-scale data to better understand whether species’ niches are conserved, because different niches (e.g. local versus climate) operating at various scales may show different degrees of conservatism. The extent to which species’ niches are truly conserved has wide practical implications, including for instance, predicting changes in species’ distributions in response to global change.

The beginning years of a new teacher is a critical period and one that results in turnover 40-50% of the time (Ingersoll & Smith, 2003). This study gained insight into perceptions of induction activities of new teachers in Ohio Independent STEM schools. STEM-based pedagogies such as problem-based learning, inquiry, and student-centered approaches are core strategies in STEM schools, but can be a new skill set for beginning teachers. Through a Q-sort, thirteen participants from three Independent STEM Schools in Ohio ranked statements on a +5 to -5 scale of agreement. This along with a post-sort survey allowed themes to emerge. The areas of positive school culture and colleague collaboration and the impact of the mentor were found to be the most impactful. This research aligns with literature suggesting these areas are critical in teacher induction.

Documenting the patterns of biological diversity on Earth has always been a central challenge in macroecology and biogeography. However, we are only beginning to generate an understanding of the global patterns and determinants of macrophyte diversity. Here, we studied large-scale variation and community-environment relationships of lake macrophytes along climatic and geographical gradients using regional data from six continents. We applied statistical routines typically used in the context of metacommunity studies to provide novel insights into macrophyte community compositional patterns within regions worldwide. We found that lake macrophyte metacommunities followed clumped species replacement structures, suggesting that two or more species groups were responding similarly to the environment within regions. Underlying such general convergence, our results also provided evidence that community-environment relationships were largely context-dependent, stressing that no single mechanism is enough to account for the complex nature of compositional variation. Surprisingly, we found no general relationships between functional or phylogenetic composition and main metacommunity types, suggesting that linking multi-trait and evolutionary information to the elements of metacommunity structure is not straightforward. Our findings highlight that global conservation initiatives and biodiversity protection need to capture environmental variation at the metacommunity level, and acknowledge the highly context-dependent patterns in the community-environment relationships of lake macrophytes. Overall, we emphasize the need to embrace the potential complexity of ecological inferences in metacommunity organization across the globe.