Brexpiprazole toxicity in a paediatric patient.

Brexpiprazole is a relatively new drug that has no published research or applications within the paediatric population. Brexpiprazole targets multiple receptors and can manifest as multisystem symptoms when ingested in supratherapeutic quantities. In this report, we discuss the case of a child in early childhood who presented with delayed neurological and cardiac symptoms 24 hours after accidental ingestion of brexpiprazole. Due to delayed onset, this case highlights that a high index of suspicion and prolonged observation are necessary to appropriately manage brexpiprazole overdose or accidental ingestion.

Structural and mechanistic insights into Quinolone Synthase to address its functional promiscuity.

Quinolone synthase from Aegle marmelos (AmQNS) is a type III polyketide synthase that yields therapeutically effective quinolone and acridone compounds. Addressing the structural and molecular underpinnings of AmQNS and its substrate interaction in terms of its high selectivity and specificity can aid in the development of numerous novel compounds. This paper presents a high-resolution AmQNS crystal structure and explains its mechanistic role in synthetic selectivity. Additionally, we provide a model framework to comprehend structural constraints on ketide insertion and postulate that AmQNS's steric and electrostatic selectivity plays a role in its ability to bind to various core substrates, resulting in its synthetic diversity. AmQNS prefers quinolone synthesis and can accommodate large substrates because of its wide active site entrance. However, our research suggests that acridone is exclusively synthesized in the presence of high malonyl-CoA concentrations. Potential implications of functionally relevant residue mutations were also investigated, which will assist in harnessing the benefits of mutations for targeted polyketide production. The pharmaceutical industry stands to gain from these findings as they expand the pool of potential drug candidates, and these methodologies can also be applied to additional promising enzymes.

AZD1390, an ataxia telangiectasia mutated inhibitor, attenuates microglia-mediated neuroinflammation and ischemic brain injury.

AIMS: Excessive neuroinflammation mediated mainly by microglia plays a crucial role in ischemic stroke. AZD1390, an ataxia telangiectasia mutated (ATM) specific inhibitor, has been shown to promote radio-sensitization and survival in central nervous system malignancies, while the role of AZD1390 in ischemic stroke remains unknown. METHODS: Real-time PCR, western blot, immunofluorescence staining, flow cytometry and enzyme-linked immunosorbent assays were used to assess the activation of microglia and the release of inflammatory cytokines. Behavioral tests were performed to measure neurological deficits. 2,3,5-Triphenyltetrazolium chloride staining was conducted to assess the infarct volume. The activation of NF-κB signaling pathway was explored through immunofluorescence staining, western blot, co-immunoprecipitation and proximity ligation assay. RESULTS: The level of pro-inflammation cytokines and activation of NF-κB signaling pathway was suppressed by AZD1390 in vitro and in vivo. The behavior deficits and infarct size were partially restored with AZD1390 treatment in experimental stroke. AZD1390 restrict ubiquitylation and sumoylation of the essential regulatory subunit of NF-κB (NEMO) in an ATM-dependent and ATM-independent way respectively, which reduced the activation of the NF-κB pathway. CONCLUSION: AZD1390 suppressed NF-κB signaling pathway to alleviate ischemic brain injury in experimental stroke, and attenuated microglia activation and neuroinflammation, which indicated that AZD1390 might be an attractive agent for the treatment of ischemic stroke.

Resistance phenotype and virulence potential of Leclercia adecarboxylata strains isolated from different sources.

Introduction. Leclercia adecarboxylata is a member of Enterobacterales, often considered an opportunistic pathogen. Recent reports have highlighted L. adecarboxylata as an emerging pathogen harbouring virulence and resistance determinants.Gap statement. Little information exists on virulence and resistance determinants in L. adecarboxylata strains isolated from environmental, food, and clinical samples.Aim. To determine the presence of resistance and virulence determinants and plasmid features in L. adecarboxylata strains isolated from environmental, food, and clinical samples, as well as their phylogenetic relationship.Results. All strains tested showed resistance to ß-lactams and quinolones but were sensitive to aminoglycosides and nitrofurans. However, even though fosfomycin resistance is considered a characteristic trait of L. adecarboxylata, the resistance phenotype was only observed in 50 % of the strains; bla TEM was the most prevalent BLEE gene (70 %), while the quinolone qnrB gene was observed in 60 % of the strains. Virulence genes were differentially observed in the strains, with adhesion-related genes being the most abundant, followed by toxin genes. Finally, all strains carried one to seven plasmid bands ranging from 7 to 125 kbps and harboured several plasmid addiction systems, such as ParDE, VagCD, and CcdAB in 80 % of the strains.Conclusions. L. adecarboxylata is an important emerging pathogen that may harbour resistance and virulence genes. Additionally, it has mobilizable genetic elements that may contribute to the dissemination of genetic determinants to other bacterial genera.

Persistence and evolution of Pseudomonas aeruginosa following initiation of highly effective modulator therapy in cystic fibrosis.

Today, more than 90% of people with cystic fibrosis (pwCF) are eligible for the highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy called elexacaftor/tezacaftor/ivacaftor (ETI) and its use is widespread. Given the drastic respiratory symptom improvement experienced by many post-ETI, clinical studies are already underway to reduce the number of respiratory therapies, including antibiotic regimens, that pwCF historically relied on to combat lung disease progression. Early studies suggest that bacterial burden in the lungs is reduced post-ETI, yet it is unknown how chronic Pseudomonas aeruginosa populations are impacted by ETI. We found that pwCF remain infected throughout their upper and lower respiratory tract with their same strain of P. aeruginosa post-ETI, and these strains continue to evolve in response to the newly CFTR-corrected airway. Our work underscores the continued importance of CF airway microbiology in the new era of highly effective CFTR modulator therapy. IMPORTANCE: The highly effective cystic fibrosis transmembrane conductance regulator modulator therapy Elexakaftor/Tezacaftor/Ivacaftor (ETI) has changed cystic fibrosis (CF) disease for many people with cystic fibrosis. While respiratory symptoms are improved by ETI, we found that people with CF remain infected with Pseudomonas aeruginosa. How these persistent and evolving bacterial populations will impact the clinical manifestations of CF in the coming years remains to be seen, but the role and potentially changing face of infection in CF should not be discounted in the era of highly effective modulator therapy.

High prevalence of plasmid-mediated quinolone resistance in escherichia coli strains producing extended-spectrum beta-lactamases isolated from faeces and urine of pregnant women with acute cystitis.

BACKGROUND: Escherichia coli is the most common etiological agent of urinary tract infections (UTIs). Meanwhile, plasmid-mediated quinolone resistance (PMQR) is reported in E. coli isolates producing extended-spectrum ß-lactamases (ESBLs). Furthermore, the reservoirs and mechanisms of acquisition of uropathogenic Escherichia coli (UPEC) strains are poorly understood. On the other hand, UTIs are common in pregnant women and the treatment challenge is alarming. METHODS AND RESULTS: In the present study, 54 pregnant women with acute cystitis were included. A total of 108 E. coli isolates, 54 isolates from UTI and 54 isolates from faeces of pregnant women (same host) were collected. In the antimicrobial susceptibility test, the highest rate of antibiotic resistance was to nalidixic acid (77%, 83/108) and the lowest rate was to imipenem (9%, 10/108). Among the isolates, 44% (48/108) were ESBLs producers. A high frequency of PMQR genes was observed in the isolates. The frequency of PMQR genes qnrS, qnrB, aac(6')-Ib-cr, and qnrA was 58% (63/108), 21% (23/108), 9% (10/108), and 4% (4/108), respectively. Meanwhile, PMQR genes were not detected in 24% (20/85) of isolates resistant to nalidixic acid and/or fluoroquinolone, indicating that other mechanisms, i.e. chromosomal mutations, are involved in resistance to quinolones, which were not detected in the present study. In ESBL-producing isolates, the frequency of PMQR genes was higher than that of non-ESBL-producing isolates (81% vs. 53%). Meanwhile, UTI and faeces isolates mainly belonged to phylogenetic group B2 (36/54, 67% and 25/54, 46%, respectively) compared to other phylogenetic groups. In addition, virulence factors and multidrug-resistant (MDR) were mainly associated with phylogenetic group B2. However, predominant clones in faeces were not found in UTIs. Rep-PCR revealed the presence of 85 clones in patients. Among the clones, 40 clones were detected only in faeces (faeces-only), 35 clones only in UTI (UTI-only) and 10 clones in both faeces and UTI (faeces-UTI). We found that out of 10 faeces-UTI clones, 5 clones were present in the host's faeces flora. CONCLUSION: This study revealed a high rate of resistance to the quinolone nalidixic acid and a widespread distribution of PMQR genes in MDR E. coli strains producing ESBLs. The strains represented virulence factors and phylogenetic group B2 are closely associated with abundance in UTI and faeces. However, the predominant clones in faeces were not found in UTIs and it is possible that rep-PCR is not sufficiently discriminating clones.

Improving and controlling the drug loading capacity of seven quinolones in minced fish matrix based on microfluidics.

Traditional spiking methods for preparing matrix reference material of aquatic products is difficult to control the drug content in the matrix, especially one matrix containing multiple drugs. Minced fish is commonly used for the preparation of matrix reference materials in aquatic products, which is a relatively complex matrix with stickiness and difficult handling. Drug loading capacity is a key factor affecting the effectiveness of matrix reference materials. Here, we proposed a new spiking approach to improve the drug loading capacity of seven quinolones based on microfluidics, simultaneously. Fresh grass carp tissue underwent grinding, fine filtration, centrifugation and reconstituted in distilled water to form a liquid sample, which was subsequently mixed with a sodium alginate solution (1 %) at a ratio of 1:1.2. The mixed solution was supplemented with seven quinolones of equal concentration, followed by the preparation of uniform fish gel microspheres using microfluidic technology. The results indicated that the recoveries of seven quinolones ranged from 82.54 % to 114.17 %, demonstrating a significant improvement in the drug loading capacity of these quinolones compared to traditional methods. Moreover, the drug concentration in the matrix can be precisely controlled. A strong linear relationship was observed between the concentration of seven quinolones in the matrix and its initial concentration, which could serve as a reference for the development of other matrix reference materials.

Discovery of novel diaryl substituted isoquinolin-1(2H)-one derivatives as hypoxia-inducible factor-1 signaling inhibitors for the treatment of rheumatoid arthritis.

Since synovial hypoxic microenvironment significantly promotes the pathological progress of rheumatoid arthritis (RA), hypoxia-inducible factor 1 (HIF-1) has been emerged as a promising target for the development of novel therapeutic agents for RA treatment. In this study, we designed and synthesized a series of diaryl substituted isoquinolin-1(2H)-one derivatives as HIF-1 signaling inhibitors using scaffold-hopping strategy. By modifying the substituents on N-atom and 6-position of isoquinolin-1-one, we discovered compound 17q with the most potent activities against HIF-1 (IC50 = 0.55 µM) in a hypoxia-reactive element (HRE) luciferase reporter assay. Further pharmacological studies revealed that 17q concentration-dependently blocked hypoxia-induced HIF-1α protein accumulation, reduced inflammation response, inhibited cellular invasiveness and promoted VHL-dependent HIF-1α degradation in human RA synovial cell line. Moreover, 17q improved the pathological injury of ankle joints, decreased angiogenesis and attenuated inflammation response in the adjuvant-induced arthritis (AIA) rat model, indicating the promising therapeutic potential of compound 17q as an effective HIF-1 inhibitor for RA therapy.

Identification of CH2-linked quinolone-aminopyrimidine hybrids as potent anti-MRSA agents: Low resistance potential and lack of cross-resistance with fluoroquinolone antibiotics.

The structural optimization of B14, an antibacterial agent we previously obtained, has led to the discovery of a new class of CH2-linked quinolone-aminopyrimidine hybrids with potent anti-MRSA activities. Surprisingly, the hybrids lacking a C-6 fluoro atom at the quinolone nucleus showed equal or even stronger anti-MRSA activities than their corresponding 6-fluoro counterparts, despite the well-established structure-activity relationships (SARs) indicating that the 6-fluoro substituent enhances the antibacterial activity in conventional fluoroquinolone antibiotics. Moreover, these new hybrids, albeit structurally related to conventional fluoroquinolones, showed no cross-resistance with fluoroquinolone drugs. The most active compound, 15m, exhibited excellent activities with a MIC value of 0.39 µg/mL against both fluoroquinolone-sensitive strain USA500 and -resistant MRSA isolate Mu50. Further resistance development studies indicated MRSA is unlikely to acquire resistance against 15m. Moreover, 15m displayed favorable in vivo half-life and safety profiles. These findings suggest a rationale for further evolution of quinolone antibiotics with a high barrier to resistance.

QbD Based Formulation Development and Optimisation of Ozenoxacin Topical Nano-Emulgel and Efficacy Evaluation Using Impetigo Mice Model.

To formulate and optimize Ozenoxacin nano-emulsion using Quality by Design (QbD) concept by means of Box-Behnken Design (BBD) and converting it to a gel to form Ozenoxacin nano-emulgel followed by physico-chemical, in-vitro, ex-vivo and in-vivo evaluation. This study demonstrates the application of QbD methodology for the development and optimization of an effective topical nanoemulgel formulation for the treatment of Impetigo focusing on the selection of appropriate excipients, optimization of formulation and process variables, and characterization of critical quality attributes. BBD was used to study the effect of "% of oil, % of Smix and homogenization speed" on critical quality attributes "globule size and % entrapment efficiency" for the optimisation of Ozenoxacin Nano-emulsion. Ozenoxacin loaded nano-emulgel was characterized for "description, identification, pH, specific gravity, amplitude sweep, viscosity, assay, organic impurities, antimicrobial effectiveness testing, in-vitro release testing, ex-vivo permeation testing, skin retention and in-vivo anti-bacterial activity". In-vitro release and ex-vivo permeation, skin retention and in-vivo anti-bacterial activity were found to be significantly (p < 0.01) higher for the nano-emulgel formulation compared to the innovator formulation (OZANEX™). Antimicrobial effectiveness testing was performed and found that even at 70% label claim of benzoic acid is effective to inhibit microbial growth in the drug product. The systematic application of QbD principles facilitated the successful development and optimization of a Ozenoxacin Nano-Emulsion. Optimised Ozenoxacin Nano-Emulgel can be considered as an effective alternative and found to be stable at least for 6 months at 40 °C / 75% RH and 30 °C / 75% RH.

[Atypical antipsychotics in the treatment of depression in affective disorders and schizophrenia (using the aripiprazole model)]. / Atipichnye antipsikhotiki pri terapii depressii v ramkakh affektivnykh rasstroistv i shizofrenii (na modeli aripiprazola).

The review discusses aspects of the use of atypical antipsychotics in the treatment of depression in affective disorders and schizophrenia using the model of aripiprazole, a partial agonist of dopamine receptors. According to numerous studies, aripiprazole is the drug of choice for augmentative therapy of major depressive disorder, as well as for relieving and long-term maintenance monotherapy and combination therapy of various affective episodes of bipolar affective disorder and depression in schizophrenia.

Design, synthesis and activity evaluation of quinolinone derivatives as EZH2 inhibitors.

The enhancer of zeste homologue 2 (EZH2) is the core catalytic subunit of polycomb repressive complex 2, which catalyzes lysine 27 methylation of histone H3. Herein, a series of quinolinone derivatives were designed and synthesized based on the structure of Tazemetostat as the lead compound. Compound 9l (EZH2WT IC50 = 0.94 nM) showed stronger antiproliferative activity in HeLa cells than the lead compound. Moreover, compound 9e (EZH2WT IC50 = 1.01 nM) significantly inhibited the proliferation and induced apoptosis in A549 cells.

Alkyl quinolones mediate heterogeneous colony biofilm architecture that improves community-level survival.

Bacterial communities exhibit complex self-organization that contributes to their survival. To better understand the molecules that contribute to transforming a small number of cells into a heterogeneous surface biofilm community, we studied acellular aggregates, structures seen by light microscopy in Pseudomonas aeruginosa colony biofilms using light microscopy and chemical imaging. These structures differ from cellular aggregates, cohesive clusters of cells important for biofilm formation, in that they are visually distinct from cells using light microscopy and are reliant on metabolites for assembly. To investigate how these structures benefit a biofilm community we characterized three recurrent types of acellular aggregates with distinct geometries that were each abundant in specific areas of these biofilms. Alkyl quinolones (AQs) were essential for the formation of all aggregate types with AQ signatures outside the aggregates below the limit of detection. These acellular aggregates spatially sequester AQs and differentiate the biofilm space. However, the three types of aggregates showed differing properties in their size, associated cell death, and lipid content. The largest aggregate type co-localized with spatially confined cell death that was not mediated by Pf4 bacteriophage. Biofilms lacking AQs were absent of localized cell death but exhibited increased, homogeneously distributed cell death. Thus, these AQ-rich aggregates regulate metabolite accessibility, differentiate regions of the biofilm, and promote survival in biofilms.IMPORTANCEPseudomonas aeruginosa is an opportunistic pathogen with the ability to cause infection in the immune-compromised. It is well established that P. aeruginosa biofilms exhibit resilience that includes decreased susceptibility to antimicrobial treatment. This work examines the self-assembled heterogeneity in biofilm communities studying acellular aggregates, regions of condensed matter requiring alkyl quinolones (AQs). AQs are important to both virulence and biofilm formation. Aggregate structures described here spatially regulate the accessibility of these AQs, differentiate regions of the biofilm community, and despite their association with autolysis, correlate with improved P. aeruginosa colony biofilm survival.

Trophic transfer of antibiotics in the benthic-pelagic coupling foodweb in a macrophyte-dominated shallow lake: The importance of pelagic-benthic coupling strength and baseline organism.

In lake ecosystems, pelagic-benthic coupling strength (PBCS) is closely related to foodweb structure and pollutant transport. However, the trophic transfer of antibiotics in a benthic-pelagic coupling foodweb (BPCFW) and the manner in which PBCS influences the trophic magnification factor (TMFs) of antibiotics is still not well understood in the whole lake. Herein, the trophic transfer behavior of 12 quinolone antibiotics (QNs) in the BPCFW of Baiyangdian Lake were studied during the period of 2018-2019. It was revealed that 24 dominant species were contained in the BPCFW, and the trophic level was 0.42-2.94. Seven QNs were detected in organisms, the detection frequencies of ofloxacin (OFL), flumequine (FLU), norfloxacin (NOR), and enrofloxacin (ENR) were higher than other QNs. The ∑QN concentration in all species was 11.3-321 ng/g dw. The TMFs for ENR and NOR were trophic magnification, while for FLU/OFL it was trophic dilution. The PBCS showed spatial-temporal variation, with a range of 0.6977-0.7910. The TMFs of ENR, FLU, and OFL were significantly positively correlated with PBCS. Phytoplankton and macrophyte biomasses showed indirect impact on the TMFs of QNs by directly influencing the PBCS. Therefore, the PBCS was the direct influencing factor for the TMFs of chemicals.

Effectiveness of Two New Endochin-like Quinolones, ELQ-596 and ELQ-650, in Experimental Mouse Models of Human Babesiosis.

Endochin-like quinolones (ELQs) define a class of small molecule antimicrobials that target the mitochondrial electron transport chain of various human parasites by inhibiting their cytochrome bc1 complexes. The compounds have shown potent activity against a wide range of protozoan parasites, including the intraerythrocytic parasites Plasmodium and Babesia, the agents of human malaria and babesiosis, respectively. First-generation ELQ compounds were previously found to reduce infection by Babesia microti and Babesia duncani in animal models of human babesiosis but achieved a radical cure only in combination with atovaquone and required further optimization to address pharmacological limitations. Here, we report the identification of two second-generation 3-biaryl ELQ compounds, ELQ-596 and ELQ-650, with potent antibabesial activity in vitro and favorable pharmacological properties. In particular, ELQ-598, a prodrug of ELQ-596, demonstrated high efficacy as an orally administered monotherapy at 10 mg/kg. The compound achieved radical cure in both the chronic model of B. microti-induced babesiosis in immunocompromised mice and the lethal infection model induced by B. duncani in immunocompetent mice. Given its high potency, favorable physicochemical properties, and low toxicity profile, ELQ-596 represents a promising drug for the treatment of human babesiosis.

[Genetic characterization and drug resistance analysis of Salmonella Kentucky ST314 in Shenzhen in 2010-2021].

OBJECTIVE: To understand the prevalence, genetic characteristics and drug resistance features of Salmonella Kentucky ST314 in Shenzhen. METHODS: Whole genome sequencing of 14 strains of Salmonella Kentucky ST314 collected from 2010-2021 by the Foodborne Disease Surveillance Network of Shenzhen Center for Disease Control and Prevention for phylogenetic evolutionary analysis, drug resistance gene and plasmid detection; drug susceptibility experiments were performed by micro-broth dilution method. RESULTS: A total of 57 strains of Salmonella Kentucky were collected from the foodborne disease surveillance network, 14 of which were ST314. The Shenzhen isolates were clustered with isolates from Southeast Asian countries such as Vietnam and Thailand on clade 314.2, and the single nucleotide polymorphism distance between local strains in Shenzhen was large, indicating dissemination. In this study, a total of 17 drug resistance genes/mutations in 9 categories were detected in the genome of Salmonella Kentucky ST314, carrying 3 extended spectrum beta-lactamases(ESBLs), including bla_(CTX-M-24)(14.3%, 2/14), bla_(CTX-M-55)(7.1%, 1/14), and bla_(CTX-M-130)(14.3%, 2/14), all located on plasmids. Regarding quinolone resistance factors, two plasmid-mediated quinolone resistance(PMQR) genes were identified in the genome: qnrB6(71.4%, 10/14) and aac(6')Ib-cr(78.6%, 11/14), a quinolone resistance quinolone resistance-determining regions(QRDR) mutation T57 S(100%, 14/14). The multi-drug resistance rate of Salmonella Kentucky ST314 in Shenzhen was 92.86%(13/14)with the highest rate of resistance to tetracycline and cotrimoxazole(100%, 14/14), followed by chloramphenicol(92.86%, 13/14), cefotaxime and ampicillin(78.57%, 11/14), ciprofloxacin and nalidixic acid(71.43%, 10/14), and ampicillin-sulbactam had the lowest resistance rate(21.43%, 3/14). CONCLUSION: ST314 is the second most prevalent ST type among Salmonella Kentucky in Shenzhen, mainly isolated from food, especially poultry; phylogenetic analysis suggests that ST314 is a disseminated infection and the genome shows a highly genetically conserved phenotype. Drug resistance of Salmonella Kentucky ST314 is very serious, especially QRDR mutation, PMQR gene co-mediated quinolone resistance and plasmid-mediated cephalosporin resistance are prominent and deserve extensive attention.

Ivacaftor attenuates gentamicin-induced ototoxicity through the CFTR-Nrf2-HO1/NQO1 pathway.

OBJECTIVES: Gentamicin is one of the most common ototoxic drugs that can lower patients' quality of life. Oxidative stress is a key factors inducing sensory hair cell death during gentamicin administration. So far, there are no effective drugs to prevent or treat gentamicin- induced hearing loss. A recent study found cystic fibrosis transmembrane conductance regulator (CFTR) as a new target to modulate cellular oxidative balance. The objective of this study was to estimate the effect of the CFTR activator ivacaftor on gentamicin-induced ototoxicity and determine its mechanism. METHODS: The hair cell count was analyzed by Myosin 7a staining. Apoptosis was analyzed by TUNEL Apoptosis Kit. Cellular reactive oxygen species (ROS) level was detected by DCFH-DA probes. The Nrf2 related proteins expression levels were analyzed by western blot. RESULTS: An in vitro cochlear explant model showed that gentamicin caused ROS accumulation in sensory hair cells and induced apoptosis, and this effect was alleviated by pretreatment with ivacaftor. Western blotting showed that ivacaftor administration markedly increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO1), and NAD(P)H:quinone oxidoreductase 1 (NQO1). The protective effect of ivacaftor was abolished by the Nrf2 inhibitor ML385. DISCUSSION: Our results indicate the protective role of the CFTR-Nrf2-HO1/NQO1 pathway in gentamicin-induced ototoxicity. Ivacaftor may be repositioned or repurposed towards aminoglycosides-induced hearing loss.

Predicting lung function decline in cystic fibrosis: the impact of initiating ivacaftor therapy.

BACKGROUND: Modulator therapies that seek to correct the underlying defect in cystic fibrosis (CF) have revolutionized the clinical landscape. Given the heterogeneous nature of lung disease progression in the post-modulator era, there is a need to develop prediction models that are robust to modulator uptake. METHODS: We conducted a retrospective longitudinal cohort study of the CF Foundation Patient Registry (N = 867 patients carrying the G551D mutation who were treated with ivacaftor from 2003 to 2018). The primary outcome was lung function (percent predicted forced expiratory volume in 1 s or FEV1pp). To characterize the association between ivacaftor initiation and lung function, we developed a dynamic prediction model through covariate selection of demographic and clinical characteristics. The ability of the selected model to predict a decline in lung function, clinically known as an FEV1-indicated exacerbation signal (FIES), was evaluated both at the population level and individual level. RESULTS: Based on the final model, the estimated improvement in FEV1pp after ivacaftor initiation was 4.89% predicted (95% confidence interval [CI]: 3.90 to 5.89). The rate of decline was reduced with ivacaftor initiation by 0.14% predicted/year (95% CI: 0.01 to 0.27). More frequent outpatient visits prior to study entry and being male corresponded to a higher overall FEV1pp. Pancreatic insufficiency, older age at study entry, a history of more frequent pulmonary exacerbations, lung infections, CF-related diabetes, and use of Medicaid insurance corresponded to lower FEV1pp. The model had excellent predictive accuracy for FIES events with an area under the receiver operating characteristic curve of 0.83 (95% CI: 0.83 to 0.84) for the independent testing cohort and 0.90 (95% CI: 0.89 to 0.90) for 6-month forecasting with the masked cohort. The root-mean-square errors of the FEV1pp predictions for these cohorts were 7.31% and 6.78% predicted, respectively, with standard deviations of 0.29 and 0.20. The predictive accuracy was robust across different covariate specifications. CONCLUSIONS: The methods and applications of dynamic prediction models developed using data prior to modulator uptake have the potential to inform post-modulator projections of lung function and enhance clinical surveillance in the new era of CF care.