CoChat
Sign Up
Cited by 55Antifungal resistance and susceptibilityFungal Plant Pathogen ControlFungal and yeast genetics research

Repurposing approach identifies pitavastatin as a potent azole chemosensitizing agent effective against azole-resistant Candida species

Open access
Eldesouky, Hassan E., Salama, Ehab A., Li, Xiaoyan, Hazbun, Tony R., Mayhoub, Abdelrahman S., Seleem, Mohamed N.·2020·Scientific Reports
DOI 10.1038/s41598-020-64571-7PMC PMC7200796

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

The limited number of antifungals and the rising frequency of azole-resistant Candida species are growing challenges to human medicine. Drug repurposing signifies an appealing approach to enhance the activity of current antifungal drugs. Here, we evaluated the ability of Pharmakon 1600 drug library to sensitize an azole-resistant Candida albicans to the effect of fluconazole. The primary screen revealed 44 non-antifungal hits were able to act synergistically with fluconazole against the test strain. Of note, 21 compounds, showed aptness for systemic administration and limited toxic effects, were considered as potential fluconazole adjuvants and thus were termed as “repositionable hits”. A follow-up analysis revealed pitavastatin displaying the most potent fluconazole chemosensitizing activity against the test strain (ΣFICI 0.05) and thus was further evaluated against 18 isolates of C. albicans (n = 9), C. glabrata (n = 4), and C. auris (n = 5). Pitavastatin displayed broad-spectrum synergistic interactions with both fluconazole and voriconazole against ~89% of the tested strains (ΣFICI 0.05–0.5). Additionally, the pitavastatin-fluconazole combination significantly reduced the biofilm-forming abilities of the tested Candida species by up to 73%, and successfully reduced the fungal burdens in a Caenorhabditis elegans infection model by up to 96%. This study presents pitavastatin as a potent azole chemosensitizing agent that warrant further investigation.

AI snapshot

Written from the paper’s full text.

TL;DR

A repurposing screen of the Pharmakon 1600 library identified pitavastatin as a potent fluconazole chemosensitizer against azole-resistant Candida. Pitavastatin showed broad-spectrum synergy with azoles in vitro, reduced biofilm formation, and lowered fungal burdens in a C. elegans infection model.

Key findings

  • Screening 1,600 drugs at 16 µM against azole-resistant C. albicans NR-29448 with 8 µg/ml fluconazole yielded 44 non-antifungal hits (2.75% hit rate); 21 were classified as “repositionable” for systemic use.
  • Pitavastatin had the most potent fluconazole chemosensitizing activity among statins (ΣFICI 0.05) and at 0.25 µg/ml reduced fluconazole’s MIC by 64-fold against C. albicans NR-29448.
  • Pitavastatin synergized with fluconazole against 16/18 tested Candida strains (~89%; C. albicans n=9, C. glabrata n=4, C. auris n=5), with ΣFICI 0.05–0.5; it also synergized with voriconazole against 16 strains (ΣFICI 0.15–0.50) but with itraconazole against only 9/18 strains (50%).
  • The pitavastatin-fluconazole combination reduced biofilm-forming ability and lowered fungal burdens in infected C. elegans by ~82–96% for C. albicans NR-29448, ~84–93% for C. glabrata ATCC MYA-2950, and 14–92% for C. auris 390.

Methods

  • Primary screen: Pharmakon 1600 drug library tested by CLSI broth microdilution against C. albicans NR-29448 in the presence or absence of 8 µg/ml fluconazole; positive hits inhibited growth by >50% only with fluconazole.
  • Follow-up: checkerboard assays with statins and azoles against 18 Candida isolates; ΣFICI defined synergy as ≤0.5, additivity >0.5–1, indifference >1–4. Biofilm inhibition used crystal violet; efflux was assessed by Nile red and rhodamine 6G assays plus flow cytometry.
  • In vivo: C. elegans strain AU37 infected with C. albicans NR-29448, C. glabrata ATCC MYA-2950, or C. auris 390, then treated with pitavastatin plus fluconazole; fungal burden measured as CFU/worm. Statistics used GraphPad Prism, multiple t-tests or one-way ANOVA, P<0.05.

Limitations

  • Stated: the pitavastatin-fluconazole combination did not restore fluconazole activity in several resistant isolates; two C. albicans and four C. auris isolates maintained fluconazole resistance. It also failed to disrupt preformed/mature biofilms, and further in vivo studies in higher animals are required.
  • Stated/evident: activity depended on resistance mechanism; pitavastatin failed against strains whose efflux was solely MFS-mediated (TWO7241, SC-MRR1P683S) and did not affect MFS efflux, so synergy is not universal.
  • Evident: biofilm inhibition numbers are inconsistent between the abstract (“up to 73%”) and Results (~92%, ~70%, ~41% for the three tested strains).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41598-020-64571-7

Cites

76 of 76 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 32 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In the MFS efflux-activated strain SC-MRR1P683S, nile red fluorescence intensity was greatly diminished and comparable to the non-treated control after pitavastatin.

    “However, the nile red fluorescence intensity was greatly diminished in the MFS efflux-activated strain (SC-MRR1P683S), and the signal was comparable to the non-treated control (Fig. 3b).”
    Quote in the paperSubstantial claim
  • Findingown data

    Of the 44 primary-screen hits, 21 compounds were classified as repositionable drugs considered potential fluconazole adjuvants for treating systemic infections.

    “Of note, 21 compounds, showed aptness for systemic administration and limited toxic effects, were considered as potential fluconazole adjuvants and thus were termed as “repositionable hits”.”
    • Also stated in: § Screening of Pharmakon drug library and identification of fluconazole adjuvants hit compounds · plain
      “These initial hits were sub-grouped into seven antineoplastic agents, eight antiparasitics, eight topical agents and 21 drugs that were considered potential fluconazole adjuvants for treating systemic infections and thus were termed “repositionable drugs” (Fig. 1).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Pitavastatin-fluconazole combinations significantly reduced mean fungal CFU burdens of C. albicans NR-29448 in infected C. elegans nematodes by ~82-96% compared to untreated control (233 ± 21 CFU/worm).

    “Compared to the untreated control which accumulated 233 ± 21 CFU/worm, pitavastatin-fluconazole combinations significantly reduced the mean fungal CFU burdens of C. albicans NR-29448 in the infected nematodes by ~82–96% (Fig. 5a).”
    Quote in the paperSubstantial claim
  • Findingown data

    Pitavastatin exhibited broad-spectrum synergistic interactions with fluconazole against a variety of clinically-relevant Candida species, including emerging multi-drug resistant C. auris isolates.

    “Pitavastatin, exhibited broad-spectrum synergistic interactions with fluconazole against a variety of clinically-relevant Candida species, including emerging multi-drug resistant C. auris isolates.”
    Quote in the paperSubstantial claim
  • Findingown data

    Pitavastatin-fluconazole combinations reduced CFU burdens of C. auris 390 in infected C. elegans nematodes by 14-92% compared to untreated control (250 ± 25 CFU/ml).

    “Against C. auris 390, pitavastatin-fluconazole combinations reduced the CFU burdens in the infected nematodes by 14–92% compared to the untreated control which accumulated 250 ± 25 CFU/ml (Fig. 5c).”
    Quote in the paperSubstantial claim
  • May combine two claims. 12
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Findingown data

    Compared to single treatments, the pitavastatin-fluconazole combination significantly reduced the biofilm-forming abilities of C. albicans NR-29448 (by ~92%), C. glabrata HM-1123 (by ~70%), and C. auris 385 (by ~41%).

    “Compared to single treatments with either fluconazole or pitavastatin, incubating the tested Candida species with pitavastatin (at 0.5 × MIC) in the presence of a subinhibitory concentration of fluconazole (2 µg/ml) resulted in a significant reduction in the biofilm-forming abilities of C. albicans NR-29448 (by ~92%, Fig. 2a), C. glabrata HM-1123 (by ~70%, Fig. 2b), and C. auris 385 (by ~41%, Fig.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The primary screen identified several fluconazole chemosensitizing agents not previously reported, including aripiprazole, perhexiline, phenelzine, quinestrol, dienestrol, hexestrol, norgestimate, meclocycline, tolfenamic acid, and sulfaquinoxaline.

    “To the best of our knowledge, the primary screen revealed novel fluconazole chemosensitizing agents that have never been reported before, such as aripiprazole, perhexiline, phenelzine, quinestrol, dienestrol, hexestrol, norgestimate, meclocycline, tolfenamic acid, and sulfaquinoxaline.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Pitavastatin showed significant fluconazole chemosensitizing activity against strains with ABC-type transporter efflux mechanisms (SC-TAC1G980E and TWO7243) but failed against strains whose efflux is solely MFS-type (SC-MRR1P683S and TWO7241).

    “As shown in Table 3, pitavastatin demonstrated significant fluconazole chemosensitizing activity against strains whose efflux mechanisms involve a significant role of the ABC-type transporters (SC-TAC1G980E and TWO7243) but failed to do so against strains whose efflux mechanisms are solely mediated by the MFS-type transporters (SC-MRR1P683S and TWO7241).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Simvastatin demonstrated significant fluconazole chemosensitizing activity at 8 μM against C. albicans NR-29448, while all other repositionable hit compounds showed activity only at 16 μM.

    “Interestingly, the antihyperlipidemic agent simvastatin demonstrated a significant fluconazole chemosensitizing activity at 8 µM while all other hit compounds showed activities only at16 µM (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    C. albicans SC-MRR1P683S was indifferent to the pitavastatin effect, with nile red fluorescence intensity comparable to the non-treated control.

    “However, C. albicans SC-MRR1P683S was indifferent to the pitavastatin effect, and the nile red fluorescence intensity was comparable to the non-treated control (Fig. 4a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Pitavastatin displayed a narrow-spectrum synergistic relationship with itraconazole, with only 9 out of 18 tested Candida strains (50%) responding.

    “However, pitavastatin displayed a more narrow-spectrum synergistic relationship with itraconazole, as only 9 out of 18 of the tested Candida strains (50%) responded to the pitavastatin-itraconazole combination (Supplementary Table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Pitavastatin exhibited broad-spectrum synergistic interactions with fluconazole against 16 out of 18 tested Candida strains (~89%), resulting in 4-64 fold reductions in fluconazole MIC values.

    “Pitavastatin displayed broad-spectrum synergistic interactions with both fluconazole and voriconazole against ~89% of the tested strains (ΣFICI 0.05–0.5).”
    • Also stated in: § Pitavastatin displays a potent, broad-spectrum azole chemosensitizing activity against different Candida species · plain
      “As shown in Table 3, pitavastatin exhibited a broad-spectrum synergistic relationship with fluconazole against 16 out of 18 tested Candida strains (~89%), resulting in significant reductions in the fluconazole’s MIC values (4–64 folds).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    More potent activities were attained with pitavastatin-fluconazole combination treatments than with single fluconazole treatments against C. glabrata ATCC MYA-2950 in infected C. elegans nematodes.

    “though more potent activities were attained with combination treatments as shown earlier.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The pitavastatin-fluconazole interactions were not sufficient to restore fluconazole activity in several fluconazole-resistant isolates; two C. albicans and four C. auris isolates maintained their resistance profiles to fluconazole.

    “Of note, although pitavastatin was able to demonstrate broad-spectrum synergistic interactions with fluconazole, these interactions were not sufficient to restore the antifungal activity of fluconazole in several fluconazole-resistant isolates. Considering the current resistance breakpoints for azole drugs, two C. albicans and four C. auris isolates maintained their resistance profiles to fluconaz”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [32] Khan, Z. et al. Increasing prevalence, molecular characterization and antifungal drug susceptibility of serial Candida auris isolates in Kuwait. PLoS One 13, e0195743 (2018). source

      Not checked in the free run.

    • cites [33] Centers for Disease Control and Prevention (CDC), Candida auris: Antifungal Susceptibility Testing and Interpretation, https://www.cdc.gov/fungal/candida-auris/c-auris-antifungal.html (2019).

      Not checked in the free run.

    • cites [34] Arendrup, M.C., Prakash, A., Meletiadis, J., Sharma, C. & Chowdhary, A. Comparison of EUCAST and CLSI Reference Microdilution MICs of Eight Antifungal Compounds for Candida auris and Associated Tentative Epidemiological Cutoff Values. Antimicrob Agents Chemother 61 (2017). source

      Not checked in the free run.

    • cites [35] Sears, D. & Schwartz, B. S. Candida auris: An emerging multidrug-resistant pathogen. Int J Infect Dis 63, 95–98 (2017). source

      Not checked in the free run.

    • cites [36] Fothergill, A. W., Sutton, D. A., McCarthy, D. I. & Wiederhold, N. P. Impact of new antifungal breakpoints on antifungal resistance in Candida species. J Clin Microbiol 52, 994–7 (2014). source

      Not checked in the free run.

    • cites [37] Yenisehirli, G., Bulut, N., Yenisehirli, A. & Bulut, Y. In Vitro Susceptibilities of Candida albicans Isolates to Antifungal Agents in Tokat, Turkey. Jundishapur J Microbiol 8, e28057 (2015). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Rhodamine 6G displays substrate specificity to the ABC membrane transporters.

    “Rhodamine 6G has been shown to display a substrate specificity to the ABC membrane transporters54.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Maesaki, S., Marichal, P., Vanden Bossche, H., Sanglard, D. & Kohno, S. Rhodamine 6G efflux for the detection of CDR1-overexpressing azole-resistant Candida albicans strains. Journal of Antimicrobial Chemotherapy 44, 27–31 (1999). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Pitavastatin may enhance the antifungal activity of fluconazole through competitive interference with Candida's ABC-type membrane transporters.

    “Therefore, we postulated that pitavastatin may enhance the antifungal activity of fluconazole through a competitive interference with Candida’s ABC-type membrane transporters.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The azole chemosensitizing activity of pitavastatin is dictated by the underlying azole resistance mechanisms and suggests a possible role for membrane efflux transporters.

    “These results indicate that the azole chemosensitizing activity of pitavastatin is dictated by the underlying azole resistance mechanisms and suggest a possible role for the membrane efflux transporters.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Combining pitavastatin with voriconazole or itraconazole displayed better outcomes against isolates with lower susceptibility to either agent, suggesting potential clinical significance for treating invasive infections caused by voriconazole- or itraconazole-resistant isolates.

    “However, combining pitavastatin with either voriconazole or itraconazole displayed better outcomes against isolates displaying a lower susceptibility to either agent, suggesting a potential clinical significance for treating invasive infections caused by voriconazole (or itraconazole) resistant isolates.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: In vitro synergistic interactions between pitavastatin and azoles against Candida isolates predict potential clinical significance for treating invasive infections.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The azole chemosensitizing activity of statins has been attributed to their ability to interfere with fungal ergosterol biosynthesis.

    “Notably, the azole chemosensitizing activity of statins has been attributed to their ability to interfere with the fungal ergosterol biosynthesis26,47.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Song, J. L., Lyons, C. N., Holleman, S., Oliver, B. G. & White, T. C. Antifungal activity of fluconazole in combination with lovastatin and their effects on gene expression in the ergosterol and prenylation pathways in Candida albicans. Med Mycol 41, 417–25 (2003). source

      Not checked in the free run.

    • cites [47] Tashiro, M. et al. Pravastatin inhibits farnesol production in Candida albicans and improves survival in a mouse model of systemic candidiasis. Med Mycol 50, 353–60 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All experiments were performed in triplicates and repeated at least three times.

    “All experiments were performed in triplicates and repeated at least three times.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Nile red is a known substrate for the two major membrane transporters (ABC and MFS), which have been reported as major contributors to azole resistance in Candida.

    “Nile red is a known substrate for the two major membrane transporters (ABC and MFS) which have been reported as major contributors to azole resistance in Candida51–53.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [51] Prasad, R. & Rawal, M. K. Efflux pump proteins in antifungal resistance. Front Pharmacol 5, 202 (2014). source

      Not checked in the free run.

    • cites [52] Coste, A. T., Karababa, M., Ischer, F., Bille, J. & Sanglard, D. TAC1, transcriptional activator of CDR genes, is a new transcription factor involved in the regulation of Candida albicans ABC transporters CDR1 and CDR2. Eukaryot Cell 3, 1639–52 (2004). source

      Not checked in the free run.

    • cites [53] Morschhauser, J. et al. The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans. PLoS Pathog 3, e164 (2007). source

      Not checked in the free run.

16 of 16

  • The paper relies on this without support.

    A peak blood concentration of 0.23 µg/ml achieved after a 4 mg oral dose is sufficient for pitavastatin to act as a fluconazole adjuvant in vivo.

    “Of note, pitavastatin was shown to reach a peak blood concentration of 0.23 µg/ml following a single oral dose of 4 mg, suggesting that its indication as a fluconazole adjuvant is rationally conceivable28.”

  • The paper relies on this without support.

    In vitro synergistic interactions between pitavastatin and azoles against Candida isolates predict potential clinical significance for treating invasive infections.

    “However, combining pitavastatin with either voriconazole or itraconazole displayed better outcomes against isolates displaying a lower susceptibility to either agent, suggesting a potential clinical significance for treating invasive infections caused by voriconazole (or itraconazole) resistant isolates.”

  • The paper relies on this without support.

    The Caenorhabditis elegans infection model is predictive of efficacy against Candida infections in humans.

    “Additionally, the pitavastatin-fluconazole combination significantly reduced the biofilm-forming abilities of the tested Candida species by up to 73%, and successfully reduced the fungal burdens in a Caenorhabditis elegans infection model by up to 96%.”

  • The paper relies on this without support.

    C. elegans is a satisfactory animal model for the initial assessment of promising antimicrobial agents prior to their evaluation in mammalian models.

    “C. elegans is a satisfactory animal model for the initial assessment of promising antimicrobial agents prior to their evaluation in mammalian models.”

  • The paper relies on this without support.

    Several promising antimicrobial compounds fail when assessed in vivo in animal models, despite potent in vitro activities.

    “In the field of antimicrobial drug discovery, it is quite frequent to notice that several promising antimicrobial compounds fail when assessed in vivo in animal models, despite potent in vitro activities.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • C. auris fungal burden has conflicting units

    Minor

    The results express the C. auris control burden as CFU/ml, while the Figure 5 caption says fungal burden was determined as CFU/worm.

  • Figure 4 reports fewer repeats than the stated minimum

    Minor

    The statistical methods say all experiments were repeated at least three times, but the Figure 4 caption reports two independent replicates.

  • A ΣFICI of 1.00 is labeled indifference

    Minor

    Table 3 labels the TWO7241 interaction IND at ΣFICI 1.00, although the table's own definitions classify values greater than 0.5 and up to 1 as ADD.

  • Abstract understates the maximum biofilm reduction

    Minor

    The abstract says the combination reduced biofilm formation by up to 73%, but the results report an approximately 92% reduction for C. albicans.

  • The same strain's MICs have conflicting units

    Minor

    Tables 2 and 3 give the same four MIC numbers for C. albicans NR-29448 treated with pitavastatin and fluconazole, but Table 2 labels them μM and Table 3 labels them μg/ml. Those units cannot both describe the same numerical concentrations.

  • Nile red concentration differs by a factor of 1,000

    Minor

    The Figure 3 caption says cells were loaded with 7.5 μM nile red, whereas the corresponding assay method specifies 7.5 mM.

6 of 6

Cites

Flagged first, then by citations

1 of the 77 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Cabral, M. E., Figueroa, L. I. & Farina, J. I. Synergistic antifungal activity of statin-azole associations as witnessed by Saccharomyces cerevisiae- and Candida utilis-bioassays and ergosterol quantification. Rev Iberoam Micol 30, 31–8 (2013). · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Eldesouky, H. E., Salama, E. A., Li, X., Hazbun, T. R., Mayhoub, A. S., & Seleem, M. N.
Affiliations
  • Purdue University West Lafayette (US)
  • Zewail City of Science and Technology (EG)
Corresponding author
  • Mayhoub, Abdelrahman S.
  • Seleem, Mohamed N.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2020-05-05
Volume
10
Issue
1
Pages
7525-7525
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-020-64571-7
PMC
PMC7200796
OpenAlex
W3021393456
Semantic Scholar
680e85227f109ed8704a84bd37361bf8125b1596
Cited by
55
References
77
Citations by year
2026: 4 · 2025: 7 · 2024: 13 · 2023: 11 · 2022: 8 · 2021: 8 · 2020: 4
FWCI
1.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Purdue e-Pubs (Purdue University System) (submittedVersion)
  • VTechWorks (Virginia Tech) (submittedVersion, cc-by)
  • Greater South Information System
Funders
  • Purdue University
  • University of Missouri
  • University of Missouri-Kansas City
  • Centers for Disease Control and Prevention
  • Health Science Center, University of Tennessee
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords
pitavastatin, drug repurposing, azole resistance, Candida albicans, Candida glabrata, Candida auris, fluconazole, voriconazole, chemosensitization, antifungal synergy, combination therapy, biofilm formation, Caenorhabditis elegans infection model
MeSH terms
Antifungal Agents, Candida, Candida albicans, Microbial Sensitivity Tests, Quinolines, Drug Design, Fluconazole, Biofilms, Drug Resistance, Fungal, Candida glabrata, Drug Discovery, Drug Repositioning, Voriconazole

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review