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PMC11277577_p2
|
PMC11277577
|
sec[0]/p[2]
|
1. Introduction
| 4.207031 |
biomedical
|
Review
|
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In light of these challenges, there is significant value in promoting the development of therapeutic agents against NDM-producing bacteria. However, due to the limited research efforts in this field, progress has been modest. Nonetheless, novel antibiotics with activity against NDM producers, such as ceftazidime/avibactam plus aztreonam, aztreonam/avibactam, cefiderocol, plazomicin, and eravacycline, have recently received approval in American and European countries . However, these new drugs are not yet available globally due to issues related to drug availability and cost. Combination therapy with currently available antibiotics is one approach to combat severe NDM-producing infections , though these strategies have not fully addressed the menace. Many studies have focused on combinatory tactics to enhance antibiotic efficacy, utilizing various compounds such as β-lactamase inhibitors, outer-membrane permeabilizers, and efflux pump inhibitors . Among these, experimental and clinical investigations of combination therapy with β-lactam and β-lactamase inhibitors have been particularly explored. As a result, avibactam, relebactam, and vaborbactam have been developed and introduced to the market as serin-β-lactamase inhibitors . However, no specific NDM inhibitors have been discovered. A recent literature review on progress in the development of MBL inhibitors summarized the molecular profiles and inhibitory mechanisms of MBLs . Gu et al. have concentrated on NDM-1 inhibitors and reviewed relevant articles published after 2018, indicating chemical complexity and inconsistency .
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277577_p3
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PMC11277577
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sec[0]/p[3]
|
1. Introduction
| 3.710938 |
biomedical
|
Review
|
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Given this context, a more comprehensive evaluation of published data and a deeper discussion from a clinical applicability perspective, especially focusing on NDM inhibitors, are necessary to prepare for future crises. Therefore, our aim is to conduct a comprehensive research review of existing data on NDM inhibitors to identify promising candidates for further development.
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
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PMC11277577_p4
|
PMC11277577
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sec[1]/sec[0]/p[0]
|
2.1. Study Design and Strategy
| 4.085938 |
biomedical
|
Review
|
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We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews . After a pilot search, we conducted a systematic scoping review with the following search phrases to overview MEDLINE for all peer-reviewed publications published between 1 January 2009 and 31 December 2022: “NDM inhibitor” [All Fields] OR “NDM-1 inhibitor” [All Fields] OR “NDM-1 producing bacteria” [All Fields] OR “NDM-1-producing Escherichia coli” [All Fields] OR “beta-lactamase NDM-1” [All Fields] OR “New Delhi Metallo-β-lactamase-producing Enterobacteriaceae ” [All Fields] OR “New Delhi Metallo-β-lactamase-1” [All Fields] OR “New Delhi Metallo-β-lactamases” [All Fields] OR “MBL inhibitors” [All Fields] OR “Meropenem resistance” [All Fields] OR “In vitro Meropenem” [All Fields] OR “Overcome antibiotic resistance” [All Fields] OR “Synergistic antibacterial effects” [All Fields]. There were no language or research design filters used.
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277577_p5
|
PMC11277577
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sec[1]/sec[1]/p[0]
|
2.2. Eligibility Criteria
| 2.085938 |
biomedical
|
Study
|
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The inclusion criteria were as follows:
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277577_p6
|
PMC11277577
|
sec[1]/sec[1]/p[1]
|
2.2. Eligibility Criteria
| 3.806641 |
biomedical
|
Review
|
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Peer-reviewed articles reporting results of in vitro combination tests for potential NDM inhibitors, such as checkerboard (CB) assays, time-killing assays, kinetic assays (enzyme inhibition assays using kinetic parameters such as K i , K m , K cat , and K cat /K m values), molecular studies, in vivo animal studies, and toxicity assays.
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277577_p7
|
PMC11277577
|
sec[1]/sec[1]/p[2]
|
2.2. Eligibility Criteria
| 1.973633 |
biomedical
|
Study
|
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The exclusion criteria were as follows: (1) Articles published in languages other than English. (2) Conference or meeting abstracts, unrelated topics, review articles, guidelines, and commentaries.
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277577_p8
|
PMC11277577
|
sec[1]/sec[2]/p[0]
|
2.3. Study Selection, Data Extraction, and Definition
| 3.080078 |
biomedical
|
Study
|
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LN and MA collected, analyzed, and assessed the selected full-text articles. Articles that met the criteria for inclusion in this study underwent a comprehensive review. We extracted information regarding the inhibiting compounds, as well as the in vitro and in vivo methods employed to confirm the combination effects and safety data from each study.
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277577_p9
|
PMC11277577
|
sec[1]/sec[2]/p[1]
|
2.3. Study Selection, Data Extraction, and Definition
| 4.121094 |
biomedical
|
Study
|
[
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In this study, we focused on the results of the fractional inhibitory concentration (FIC) index based on the checkerboard (CB) assay to quantitatively measure the synergistic effects of the inhibitors. Generally, the FIC of an agent is calculated by dividing the minimum inhibitory concentration (MIC) of the agent when used in combination by the MIC of the agent when used alone. The FIC index is the sum of the FICs of the combined drugs. Interactions between the combined drugs were quantified using the FIC index as follows: an FIC index of ≤0.5 was defined as synergistic, and an FIC index of ≥0.5 to ≤4.0 was considered indifferent .
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277577_p10
|
PMC11277577
|
sec[1]/sec[2]/p[2]
|
2.3. Study Selection, Data Extraction, and Definition
| 4.09375 |
biomedical
|
Study
|
[
0.99951171875,
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The time-killing curve assay is also a fundamental approach to confirm the synergistic efficacy of two or more agents. In this study, we defined a bactericidal effect as a bacterial volume reduction of 3 log 10 CFU/mL or more at any time during incubation when the drugs were combined. Conversely, bacteriostatic activity was characterized by a reduction of less than 3 log 10 CFU/mL compared to the initial inoculum.
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277577_p11
|
PMC11277577
|
sec[1]/sec[3]/p[0]
|
2.4. Data Synthesis and Statistical Analysis
| 1.632813 |
biomedical
|
Study
|
[
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[
0.82470703125,
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] |
Data processing and aggregation were performed using Microsoft Excel ® software version 2021 (Microsoft Corporation, Redmond, WA, USA). We did not perform any statistical analysis since this is a descriptive study.
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
PMC11277577_p12
|
PMC11277577
|
sec[2]/sec[0]/p[0]
|
3.1. Search Results and Study Selection
| 4.082031 |
biomedical
|
Review
|
[
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[
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The flowchart depicting the stages of article collection is presented in Figure 1 , illustrating the process of identifying relevant reports, screening records, evaluating eligibility, and making final determinations for inclusion or exclusion in accordance with the PRISMA flow diagram. The initial search of MEDLINE databases yielded 1760 articles, which underwent further eligibility screening, resulting in the exclusion of 1628 articles. Subsequently, 132 full-text articles were assessed, and 39 articles lacking experimental data and 2 articles related to triplet agent therapy were excluded. Ultimately, 91 articles (comprising 89 original articles and 2 letter-type articles) were selected for the review.
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277577_p13
|
PMC11277577
|
sec[2]/sec[1]/p[0]
|
3.2. Description of the Review Results
| 4.105469 |
biomedical
|
Study
|
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The number of articles has significantly increased, especially in the last five years: 12 in 2018, 11 in 2019, 18 in 2020, 15 in 2021, and 22 in 2022 . A summary of 91 articles reporting 154 potential NDM inhibitors is provided in Table 1 . All 91 studies were found to have conducted CB assays. Time-killing curve assays, kinetic assays, molecular investigations, in vivo (animal- or cell-based) combination studies, and toxicity assays were carried out in 26 (28.6%), 41 (45.1%), 66 (72.5%), 30 (33.0%), and 44 (48.4%) of the studies, respectively. Various strains of NDM-producing bacteria were used in both in vitro and in vivo studies ( Supplementary Table S1 ). The two most common isolates employed were Escherichia coli and Klebsiella pneumoniae , followed by other E nterobacterales species, Pseudomonas aeruginosa , and Acinetobacter baumanii . Clinical, recombinant, standard, reference, and wild strains were used in 57 (62.6%), 27 (29.7%), 25 (27.5%), 3 (3.3%), and 2 (2.2%) of the studies, respectively, including some duplications.
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277577_p14
|
PMC11277577
|
sec[2]/sec[1]/p[1]
|
3.2. Description of the Review Results
| 4.097656 |
biomedical
|
Study
|
[
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Out of the 154 NDM inhibitors extracted from 91 eligible articles, we specifically identified 47 potential inhibitors in 37 articles, where the FIC index was determined based on the CB assay ( Table 2 ). Among these, eight compounds had already received approval from the United States FDA. Almost all of these compounds exhibited synergistic effects with an FIC index of less than 0.5. However, some cases of indifferent results were identified when various bacterial strains were tested. Out of these, 14 (37.8%) studies included data on the time-killing curve assay. Bacteriostatic effects were reported in 4 studies, while 10 studies (involving 11 inhibitors) demonstrated bactericidal effects.
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277577_p15
|
PMC11277577
|
sec[2]/sec[1]/p[2]
|
3.2. Description of the Review Results
| 4.023438 |
biomedical
|
Study
|
[
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Additionally, 12 studies (32.4%) conducted kinetic assays, in which kinetic parameters were calculated. Molecular investigations were conducted in 23 (62.2%) studies, with molecular docking and molecular dynamic simulations being commonly employed (15 out of 25 studies, 60%). To validate the efficacy of combination therapy, 10 studies (27%) presented in vivo animal data, all of which used mouse models. To assess the safety of the inhibitory drugs used, 13 (35.1%) studies reported results of toxicity assays using in vivo models. Notably, none of the compounds exhibited apparent toxic effects.
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277577_p16
|
PMC11277577
|
sec[3]/p[0]
|
4. Discussion
| 4.136719 |
biomedical
|
Review
|
[
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[
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In this scoping review, we have compiled the presently available data on NDM inhibitors published in MEDLINE. Among the various experimental methods used to evaluate the efficacy of drug combinations, we specifically focused on the FIC index calculated through the CB assay, which serves as a fundamental approach to determine the synergistic effects of two distinct drugs. Since 2014, a total of 47 compounds have been investigated as potential NDM inhibitors, with 8 of them having received approval from the United States FDA. These FDA-approved drugs include various substances such as methimazole, withaferin A, fisetin, isoliquiritin, cefmetazole, pterostilbene, cefoxitin, and tetracycline . In addition to the CB assay, bactericidal effects were observed in 10 compounds through time-killing curve assays, of which 4 substances (methimazole, fisetin, isoliquiritin, and cefmetazole) had already received FDA endorsement . No further investigations had been conducted for methimazole and cefmetazole , whereas the effectiveness and safety of combining fisetin or isoliquiritin were additionally confirmed through other approaches . Regrettably, there were no inhibiting agents that seemed readily available for clinical use, and none of these are within the reach of clinicians.
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277577_p17
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PMC11277577
|
sec[3]/p[1]
|
4. Discussion
| 4.074219 |
biomedical
|
Study
|
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Kinetic assays and molecular investigations represent more advanced methods for ascertaining combination efficacy. Comparing molecular affinities among compounds of interest using kinetic parameters such as K i , K m , K cat , and K cat /K m can provide insights into inhibitory activity from an enzymatic perspective. Molecular docking simulations of potential inhibitors are well-established computational methods for analyzing molecular binding modes. Among these two elaborated approaches, molecular docking and molecular dynamic simulations were more frequently performed (62.2% vs. 32.4%). Eleven studies did not conduct either of these methods , while nine studies evaluated both . Additionally, in vivo animal studies were performed in 10 studies , suggesting that the tested compounds, including H2dpa derivatives, sulfamoylfuran-3-carboxylic acid derivatives, peptidomimetic 4, pterostilbene, and aspergillomarasmine A, may hold promise as inhibitors.
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277577_p18
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PMC11277577
|
sec[3]/p[2]
|
4. Discussion
| 3.910156 |
biomedical
|
Review
|
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For unapproved compounds, ensuring their safety is essential for potential future clinical use. In this sense, toxicity assays provide particularly important data. In our review, 13 out of 37 studies (35.1%) conducted these assays, primarily using a mouse model. Notably, no inhibitors with apparent toxicity were reported. However, it is essential to mention that zinc-chelating agents may not be suitable for therapeutic use due to their well-documented toxicity to human cells .
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277577_p19
|
PMC11277577
|
sec[3]/p[3]
|
4. Discussion
| 4.015625 |
biomedical
|
Study
|
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[
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Our study has a few limitations that should be acknowledged. First, we conducted our search exclusively on MEDLINE due to the unavailability of access to other databases. This could potentially lead to an underestimation of relevant articles. In fact, our search approach failed to include boron-based inhibitors, such as taniborbactam, xeruborbactam, and zidebactam, which have the potential to be available in clinical settings. Possibilities of reporting bias should also be considered. Second, we only included articles in the English language, which may restrict comprehensiveness and affect generalizability. Third, our search period was up to the end of December 2022, which should have been extended to the time of drafting, because an increasing number of relevant articles have been reported in the literature. Due to time constraints, we could not afford to do so. Fourth, the presence of publication bias should be taken into consideration. Data that could be unfavorable for the inhibitors might not have been included in the articles. Fifth, clinical strains may possess various antimicrobial resistance mechanisms, and, therefore, the combination of NDM inhibitors may not necessarily exhibit synergistic effects in clinical settings. Finally, the assessment of the quality of the included studies was not fully performed, although it is a crucial aspect of the review study to ensure the validity and reliability of the conclusion.
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277577_p20
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PMC11277577
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sec[4]/p[0]
|
5. Conclusions
| 3.525391 |
biomedical
|
Review
|
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In summary, there are currently no NDM inhibitors available for therapeutic use. While previous efforts have borne fruit in identifying some potential compounds, there is still a long road ahead to discover clinically applicable and outstanding NDM inhibitors. Just as the development of serine-β-lactamase inhibitors has set an example, it is time for NDM inhibitor research to follow suit. For this purpose, the establishment of a laboratory and clinical research platform under interdisciplinary collaborations is necessary. We believe that our review work will contribute to advancing this challenging journey.
|
[
"Lutfun Nahar",
"Hideharu Hagiya",
"Kazuyoshi Gotoh",
"Md Asaduzzaman",
"Fumio Otsuka"
] |
https://doi.org/10.3390/jcm13144199
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277589_p0
|
PMC11277589
|
sec[0]/p[0]
|
1. Introduction
| 4.105469 |
biomedical
|
Review
|
[
0.998046875,
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[
0.07000732421875,
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] |
The World Health Organization (WHO), in its latest classification, categorizes individuals under 65 years old as young, those between 65 and 85 years old as young-old, and those 85 years and older as advanced-old, in parallel with the growth of the older population and their extended lifespan. Over the past few years, there has been an increasing trend in the percentage of adults aged 60 and older within the overall population . Aging leads to changes in the effectiveness of the immune system, resulting in a decline in immune function with age. These changes, also known as “immune aging”, initially involve higher levels of proinflammatory cytokine secretion and a decrease in the ability of the immune system to respond to antigens. Immunological aging also leads to chronic overstimulation of the immune system and a likely increase in the risk of an irregular systemic response to infection .
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277589_p1
|
PMC11277589
|
sec[0]/p[1]
|
1. Introduction
| 4.375 |
biomedical
|
Review
|
[
0.99609375,
0.00213623046875,
0.0016803741455078125
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[
0.139892578125,
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Medical advancements in the management of acute illnesses have indeed reduced overall hospital mortality rates, but these rates remain high in older patients. Therefore, it is an urgent and crucial need in routine clinical practice to identify prognostic indicators, especially for older patients admitted to the intensive care unit (ICU) . The Acute Physiologic Assessment and Chronic Health (APACHE)-II and the Sequential Organ Failure Assessment (SOFA) scoring systems are commonly used to assess the severity of acute illness and chronic outcomes in patients who are admitted to the ICU. These scoring systems, used to determine patient prognosis, also assist in resource allocation, continuous quality improvement, and the evaluation of a given treatment’s effectiveness . However, recent studies have drawn attention to the importance of certain inflammatory markers obtained from the complete blood count (CBC) in determining the morbidity and mortality of individuals suffering with various diseases; this is due to the ease and cost-effectiveness of assessing such markers. New inflammatory biomarkers, such as the systemic immune–inflammatory index (SII), the systemic immune response index (SIRI), the neutrophil–lymphocyte ratio (NLR), the platelet–lymphocyte ratio (PLR), the monocyte–lymphocyte ratio (MLR), the multi-inflammatory index (MII), and the pan-immune–inflammation value (PIV), have gained popularity in assessing the mortality risk resulting from various diseases . In a retrospective study by Yoldaş et al. , the effectiveness of the NLR and PLR in predicting mortality in critical patient populations was demonstrated, highlighting the ease and affordability of evaluating these markers and suggesting that high PLR and NLR in ICU patients should be closely monitored for predicting chronic outcomes. In a prospective observational study by Turan et al. , the effect of the PIV on predicting mortality and prognosis in patients with septic shock was evaluated; the authors demonstrated that it could effectively predict median survival time in patients with septic shock. In a study by Ayranci et al. that evaluated the NLR and CRP as predictors of in-hospital mortality in geriatric emergency department patients, simultaneous elevation of the CRP and NLR was found to be a more effective predictor of in-hospital mortality, suggesting that simultaneous monitoring of the CRP and NLR by emergency department physicians may help to identify older patients at high risk of mortality at an early stage.
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277589_p2
|
PMC11277589
|
sec[0]/p[2]
|
1. Introduction
| 4.109375 |
biomedical
|
Study
|
[
0.998046875,
0.0015039443969726562,
0.00028705596923828125
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[
0.9990234375,
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To the best of our knowledge, there has been no previous study evaluating the predictive value of inflammatory markers in older patients admitted to the ICU both independently of admission diagnosis and across a wide range of disease conditions and laboratory parameters. Therefore, the aim of the current study is to identify factors affecting short- and long-term prognoses and survival in patients aged 65 and over admitted to the ICU, considering the increase in the number of patients aged 65 and over and high ICU costs, and to investigate the guiding role of new inflammatory markers in patients’ survival.
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277589_p3
|
PMC11277589
|
sec[1]/sec[0]/p[0]
|
2.1. Study Location, Duration, and Ethical Approval
| 1.964844 |
biomedical
|
Study
|
[
0.9912109375,
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[
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The current study was conducted at the Internal Medicine Intensive Care Unit of the Akdeniz University Faculty of Medicine and the General Intensive Care Unit of Antalya Kepez State Hospital between June 2022 and December 2023. Ethical approval was obtained from the Akdeniz University Faculty of Medicine Ethics Committee prior to the study . This study was conducted in accordance with the principles outlined in the Helsinki Declaration.
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277589_p4
|
PMC11277589
|
sec[1]/sec[1]/p[0]
|
2.2. Study Method
| 2.908203 |
biomedical
|
Study
|
[
0.931640625,
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0.001323699951171875
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[
0.9150390625,
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0.0084381103515625
] |
This is a retrospective clinical study based on the collection of retrospective data. This research study is of an observational nature. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were followed for patient recording and allocation.
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277589_p5
|
PMC11277589
|
sec[1]/sec[2]/p[0]
|
2.3. Study Population
| 3.6875 |
biomedical
|
Study
|
[
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[
0.99658203125,
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0.0008096694946289062
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Patients aged 65 and over who were admitted to the ICU were included in this study. Patients with missing common variable data for multivariate analysis, those followed up in the postoperative ICU, those undergoing bone marrow transplantation, those who received steroid treatment, those with cirrhosis or hematologic malignancies, those developing bone marrow suppression after chemotherapy, and those who died within the first 24 h of ICU admission were excluded from this study. For patients with multiple admissions to the ICU, only data from their first admission were considered.
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277589_p6
|
PMC11277589
|
sec[1]/sec[3]/p[0]
|
2.4. Data Collection Methods
| 1.804688 |
biomedical
|
Study
|
[
0.98583984375,
0.007358551025390625,
0.00672149658203125
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[
0.93896484375,
0.057861328125,
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0.00164794921875
] |
The necessary data for the current study were obtained from ICU patient follow-up forms, hospital electronic databases, physician daily observation notes, nurses’ observation notes, test results, and pre-ICU-admission observation forms.
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277589_p7
|
PMC11277589
|
sec[1]/sec[4]/p[0]
|
2.5. Blood Measurements and Reference Values
| 3.482422 |
biomedical
|
Study
|
[
0.9931640625,
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[
0.9658203125,
0.031951904296875,
0.0005903244018554688,
0.0014867782592773438
] |
Routine blood samples were taken from all patients admitted to the ICU for hemograms and biochemistry. The patients’ neutrophil, platelet, monocyte, and lymphocyte values were routinely evaluated by taking blood samples and placing them in tubes containing ethylenediaminetetraacetic acid (EDTA), which were then sent to the hospital’s laboratory center.
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277589_p8
|
PMC11277589
|
sec[1]/sec[4]/p[1]
|
2.5. Blood Measurements and Reference Values
| 4.042969 |
biomedical
|
Study
|
[
0.9931640625,
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] |
[
0.98828125,
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0.0005888938903808594
] |
Among the parameters recorded at the time of admission to the ICU and during follow-up in the ICU at the time of the secondary endpoint, the following parameters were included: platelet count (×10 9 /L; reference range: 100–300); hemoglobin (g/L; reference range: 130.0–175.0); lymphocyte count (×10 9 /L; reference range: 1.1–3.2); neutrophil count (×10 9 /L; reference range: 42.3–77.8); monocyte count (×10 9 /L; reference range: 0.4–1.2); creatinine (μmol/L; reference range: 53.0–106.0); albumin (g/L; reference range: 35.0–55.0); and C-reactive protein (CRP) (mg/L).
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277589_p9
|
PMC11277589
|
sec[1]/sec[5]/p[0]
|
2.6. Data Recording
| 4.035156 |
biomedical
|
Study
|
[
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[
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0.005290985107421875,
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0.000762939453125
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The patients’ age, gender, comorbidities, lactate, neutrophil, monocyte, platelet, lymphocyte, NLR, PLR, MLR, PIV, SII, SIRI, MII 1-2-3, and CRP/albumin values, as well as their SOFA and APACHE-II scores at admission to the ICU, were routinely recorded. The values were calculated using the following formulas: PIV: [neutrophil count (10 3 /μL) × platelet count (10 3 /μL) × monocyte count (10 3 /μL)/lymphocyte count (10 3 /μL)]; NLR: [neutrophil count (10 3 /μL)/lymphocyte count (10 3 /μL)]; PLR: [platelet count (10 3 /μL)/lymphocyte count (10 3 /μL)]; SII: [neutrophil count (10 3 /μL) × platelet count (10 3 /μL)/lymphocyte count (10 3 /μL)]; MLR: [monocyte count (10 3 /μL)/lymphocyte count (10 3 /μL)]; SIRI: [neutrophil count (10 3 /μL) × monocyte count (10 3 /μL)/lymphocyte count (10 3 /μL)]; MII-1: [neutrophil count (10 3 /μL) × CRP]; MII-2: [PLR × CRP]; MII-3: [SII × CRP].
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277589_p10
|
PMC11277589
|
sec[1]/sec[6]/p[0]
|
2.7. Statistical Analysis
| 4.027344 |
biomedical
|
Study
|
[
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[
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0.000052809715270996094
] |
The Statistical Package for the Social Sciences (SPSS) version 26 was used to statistically analyze the data obtained from the study. The variables were evaluated using Shapiro–Wilk or Kolmogorov–Smirnov tests to determine whether the variables obtained as measurement values were suitable for normal distribution. Continuous variables were expressed as the mean ± standard deviation (SD) or the median (interquartile range) according to the normality of their distribution. Categorical variables were presented as numbers (n) and percentages (%). Pearson’s chi-square test or Fisher’s exact test was used to compare categorical variables. Student’s t-test was used for parametric variables, and the Mann–Whitney U test was used for non-parametric variables. The Wilcoxon test was used to evaluate the changes between the median values of repeated (dependent) variables. Binary logistic regression analysis or linear regression analysis was used to evaluate the relationships of statistically significant variables with outcome points independently of other factors. The goodness of fit of the models was evaluated using the Hosmer–Lemeshow test. The Kaplan–Meier test, log-rank test, and Cox regression analysis were used for survival analyses. Survival curves were drawn, and differences between the groups were evaluated using Kaplan–Meier analysis. The log-rank test was used to statistically evaluate the survival differences between groups. Cox regression analysis was used to determine the factors affecting survival. In this study, a significance level of p < 0.05 was accepted as statistically significant.
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277589_p11
|
PMC11277589
|
sec[2]/p[0]
|
3. Results
| 3.398438 |
biomedical
|
Study
|
[
0.955078125,
0.04364013671875,
0.0011053085327148438
] |
[
0.98779296875,
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0.0005784034729003906,
0.0020084381103515625
] |
After excluding 72 patients with insufficient data, those with cirrhosis, those who had undergone bone marrow transplantation, those with a hematological malignancy, those with bone marrow suppression after recent chemotherapy, postoperative patients, and deaths in the first 24 h after admission to the ICU, a total of 333 patients were finally included. The patients were divided into two groups: the deceased group ( N = 106) and the surviving group ( N = 227) .
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277589_p12
|
PMC11277589
|
sec[2]/p[1]
|
3. Results
| 4.027344 |
biomedical
|
Study
|
[
0.98291015625,
0.0165863037109375,
0.0005979537963867188
] |
[
0.9970703125,
0.0014400482177734375,
0.0005102157592773438,
0.0007963180541992188
] |
Within 28 days, 31.8% were deceased, and 68.2% survived. The mean age of the deceased group was 77.2 ± 8.5 years, and it was 78.1 ± 8.6 years in the surviving group ( p = 0.38). The distributions of sexes and chronic conditions were similar in both groups ( p = 0.25, p > 0.05, respectively). The most commonly seen chronic condition was hypertension (HT), followed by diabetes mellitus (DM) ( p = 0.40, and p = 0.64, respectively). The most common indication for admission to the ICU was acute respiratory failure ( p = 0.90). This was followed by sepsis and acute kidney failure ( p = 0.052, and p = 0.11, respectively). The baseline characteristics of the study population are summarized in Table 1 .
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277589_p13
|
PMC11277589
|
sec[2]/p[2]
|
3. Results
| 4.148438 |
biomedical
|
Study
|
[
0.98828125,
0.0111236572265625,
0.0004127025604248047
] |
[
0.99755859375,
0.001220703125,
0.0008525848388671875,
0.0005507469177246094
] |
The clinical characteristics of ICU patients according to 28-day mortality are presented in Table 2 . Variables include culture growth, steroid use, platelet and erythrocyte transfusion, progression to sepsis in the ICU, mechanical ventilation (MV) before and in the ICU, days related to MV, hospitalization stay, ICU admission, pre- and post-ICU days, and SOFA and APACHE scores. Cultural growth rate, steroid use, and progression to sepsis were significantly higher in the deceased group ( p < 0.001, p < 0.001, and p = 0.024, respectively). The need for ventilation before or during the ICU stay and a longer duration of ventilator use were also more common in the deceased group than in the surviving group ( p < 0.001, p < 0.001, and p < 0.001, respectively). The length of time spent in hospital was not different between the groups ( p = 0.68). Higher SOFA and APACHE scores were observed in the deceased group compared with the surviving group ( p < 0.001, and p < 0.001, respectively).
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277589_p14
|
PMC11277589
|
sec[2]/p[3]
|
3. Results
| 4.113281 |
biomedical
|
Study
|
[
0.9990234375,
0.0007066726684570312,
0.00025653839111328125
] |
[
0.99951171875,
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0.00031375885009765625,
0.00007611513137817383
] |
Table 3 shows the inflammatory biomarkers and ratios related to 28-day mortality, comparing values between the deceased and the surviving group. There were statistically significant differences in the NLR, SIRI, MII1, MII2, MII3, and CRP/albumin ratios between the deceased group and the surviving group ( p = 0.007, p = 0.03, p < 0.001, p < 0.001, p = 0.06, and p < 0.001, respectively). The PIV, MLR, PLR, and SII values were statistically similar between the groups ( p = 0.47, p = 0.092, p = 0.68, and p = 0.22, respectively).
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277589_p15
|
PMC11277589
|
sec[2]/p[4]
|
3. Results
| 4.113281 |
biomedical
|
Study
|
[
0.9990234375,
0.0005273818969726562,
0.00022161006927490234
] |
[
0.99951171875,
0.0002073049545288086,
0.0003762245178222656,
0.00008106231689453125
] |
Each inflammatory marker related to 28-day mortality was investigated using Cox regression univariate analysis, and the results are shown in Table 4 . The MLR, MII1, MII2, and MII3 did not show statistically significant associations with 28-day mortality ( p = 0.19, p = 0.32, p = 0.37, and p = 0.14, respectively). Meanwhile, the NLR (HR:1.022, 95% CI: 1.006–1.038, and p = 0.007), SIRI (HR:1.023, 95% CI: 1.000–1.047, and p = 0.049), and CRP/albumin ratios (HR:1.154, 95% CI: 1.086–1.226, and p < 0.001) were statistically and significantly associated with 28-day mortality.
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277589_p16
|
PMC11277589
|
sec[2]/p[5]
|
3. Results
| 4.160156 |
biomedical
|
Study
|
[
0.9990234375,
0.0005893707275390625,
0.0002472400665283203
] |
[
0.99755859375,
0.00025010108947753906,
0.0018672943115234375,
0.00010865926742553711
] |
The predictive capability of the inflammatory markers and scoring systems for 28-day mortality risk was assessed using ROC analysis, and their cutoff values with specificity and sensitivity are presented in Figure 2 and Table 5 . The NLR showed reasonable discriminatory ability in distinguishing mortality risk, with a statistically significant result (AUC: 0.593, 95% CI: 0.526–0.660, and p = 0.006). The SIRI also showed reasonably good discriminatory ability, though slightly lower than the NLR, with a statistically significant result (AUC: 0.580, 95% CI: 0.514–0.646, and p = 0.019). The CRP/albumin ratio showed moderately strong discriminatory ability and performed better than both the NLR and SIRI, with a highly statistically significant result (AUC: 0.665, 95% CI: 0.604–0.726, and p < 0.001). The CRP/albumin ratio was the most effective among the inflammatory markers in discriminating mortality risk in ICU patients. On the other hand, the APACHE score produced an AUC of 0.647, with a 95% CI of 0.579–0.714, and its predictive performance was statistically significant ( p < 0.001). The SOFA score had a higher AUC of 0.723, with a 95% CI of 0.663–0.783, and was also statistically significant ( p < 0.001). The SOFA score appeared to have the highest AUC among the predictors listed, and the CRP/albumin ratio had the highest predictive capability among the inflammatory markers.
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277589_p17
|
PMC11277589
|
sec[3]/p[0]
|
4. Discussion
| 4.136719 |
biomedical
|
Study
|
[
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[
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0.00015044212341308594
] |
According to the findings of the current study, in patients aged 65 and older who were admitted to the ICU and later died, there was a higher incidence of culture positivity, steroid use, and progression to sepsis compared with patients who survived. Additionally, patients who died before or during their stay in the ICU had greater need for ventilation, and their treatment with ventilation lasted longer. Furthermore, the SOFA and APACHE-II scores were higher in deceased patients than in survivors. Regarding 28-day mortality, the NLR, SIRI, MII 1-2-3, and CRP/albumin ratios were found to be higher in deceased patients compared to survivors. However, the values of PIV, MLR, PLR, and SII did not show a significant impact on 28-day mortality. The NLR (moderate level), SIRI (moderate level), and CRP/albumin ratio (moderate level) were identified as discriminative factors in the 28-day mortality risk assessment. The CRP/albumin ratio showed better performance than both the NLR and SIRI in predicting 28-day mortality. However, despite higher SOFA scores, both the SOFA and APACHE II scores were found to have high predictive value in determining 28-day mortality in older ICU patients.
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277589_p18
|
PMC11277589
|
sec[3]/p[1]
|
4. Discussion
| 4.136719 |
biomedical
|
Study
|
[
0.99951171875,
0.00045561790466308594,
0.00017523765563964844
] |
[
0.99853515625,
0.00023484230041503906,
0.0009927749633789062,
0.00010216236114501953
] |
Neutrophils and lymphocytes represent a significant percentage of all immune cells in the bloodstream, making the NLR a relatively simple inflammation index to calculate. In the current study, it was found that the NLR ratio was statistically higher in deceased patients compared to surviving patients, demonstrating the prognostic value of the NLR ratio in critical care patients aged 65 and older. It is assumed that systemic inflammation and stress lead to neutrophilia and lymphopenia, which causes the NLR ratio to increase . This increased NLR—as a result of an increase in the neutrophil count and secondary to an increase in the granulocyte series during inflammation, alongside a decrease in the lymphocyte count during inflammatory stress—may serve as an indicator of systemic inflammation . Additionally, increases in the NLR have been attributed to increased neutrophil production and lymphocyte apoptosis during inflammatory stress . In a prospective cohort study involving 5034 patients that aimed to predict mortality in older patients admitted to the hospital, in accordance with our study’s findings, deceased patients were found to have significantly higher NLR ratios than survivors during their hospital stay. The study also suggested that the NLR could facilitate the early identification of older patients at high risk of death because it is easily applicable and cost-effective . In another study evaluating the effect of the NLR on postoperative ICU admission and mortality in older patients undergoing hip surgery, a high NLR value was found to be a strong predictor of admission to the ICU and subsequent mortality in older patients .
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277589_p19
|
PMC11277589
|
sec[3]/p[2]
|
4. Discussion
| 4.179688 |
biomedical
|
Study
|
[
0.99951171875,
0.0004699230194091797,
0.0001766681671142578
] |
[
0.99853515625,
0.00030612945556640625,
0.0010175704956054688,
0.00011307001113891602
] |
SIRI, a novel prognostic marker based on the counts of neutrophils, monocytes, and lymphocytes, reflects the balance between the inflammatory response and immune status . It was first identified in a study involving patients with hepatocellular carcinoma (HCC) in 2014. It has been described as a strong prognostic indicator of poor outcomes and a promising marker for directing treatment strategy in HCC . Subsequently, it has been reported that SIRI elevation could be used in the diagnosis of certain cancers, particularly gastric cancer and colorectal carcinoma , indicating worsening inflammatory processes and a poor prognosis in these patients. In a study evaluating the relationship between inflammatory mechanisms and intracerebral hemorrhage in pneumonia, although the NLR showed a stronger association with the of severity pneumonia, the SIRI exhibited high predictive accuracy in the early recognition of pneumonia severity after intracranial hemorrhage as well as an association with poor neurological outcomes upon discharge . However, in the literature, data evaluating the predictive value of the SIRI for mortality and prognoses in elderly patients admitted to the ICU are scarce. In the present study, we found that although the SIRI was less effective than the CRP/albumin ratio in predicting 28-day mortality in critically ill older patients, it can still function as a strong indicator, making ours the first study to demonstrate the independent significance of the SIRI as a predictor of mortality in critically ill older patients.
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277589_p20
|
PMC11277589
|
sec[3]/p[3]
|
4. Discussion
| 4.097656 |
biomedical
|
Study
|
[
0.9990234375,
0.0006985664367675781,
0.0002143383026123047
] |
[
0.998046875,
0.0002567768096923828,
0.0014429092407226562,
0.0001208186149597168
] |
In our study, the CRP/albumin ratio was identified as an independent risk factor for 28-day mortality in critical patients, and our findings are consistent with those of previous studies. Despite the numerous scoring systems used to predict the prognosis of critical patients, the CRP/albumin ratio remains valuable. This is because it is a relatively simple marker that is easy to use in all settings. Produced in response to various cytokines after infection, ischemia, trauma and other inflammatory conditions, CRP is an acute-phase protein . Many studies have demonstrated an association between high CRP levels and low serum albumin levels and prognosis and mortality in critical patients. Additionally, it has been noted in the literature that the CRP/albumin ratio is more consistent in predicting prognosis when compared with CRP or albumin alone . In our study, we found the CRP/albumin ratio to be a biomarker with high value in predicting the survival of older patients; data to support this statement are available in the literature. The CRP/albumin ratio is an independent determinant of 28-day mortality in ICU patients, and a higher CRP/albumin ratio is associated with increased mortality in critical patients, according to a retrospective study by Par et al. . A high CRP/albumin ratio upon admission to the emergency department is an independent determinant of all-cause in-hospital mortality in patients aged 65 and older, according to another study evaluating the CRP/albumin ratio as a determinant of in-hospital mortality in geriatric patients presenting to the emergency department .
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277589_p21
|
PMC11277589
|
sec[3]/p[4]
|
4. Discussion
| 4.050781 |
biomedical
|
Study
|
[
0.99951171875,
0.00037407875061035156,
0.00019371509552001953
] |
[
0.99853515625,
0.00023436546325683594,
0.0010175704956054688,
0.00007939338684082031
] |
MIIs were initially developed by Gardini et al. . The ongoing Italian Trial in Advanced Colorectal Cancer (ITACa) study has demonstrated the usefulness of all MIIs as prognostic markers in patients with metastatic colon cancer. The MIIs allow for the evaluation of hematological parameters—such as neutrophils, platelets, and lymphocytes—along with the chronic inflammatory marker CRP, thereby acting as powerful markers of systemic conditions . They are deemed strong, easy-to-use, and practical markers for the early prediction of mortality in COVID-19 patients at high risk of mortality in the ICU . Studies in the literature have also indicated that the MIIs could function as an independent determinant in ischemic stroke patients . The results of the current study represent the first demonstration of the independent significance of all MIIs as determinants of mortality in critically ill geriatric patients. However, given the limitations of the data in the literature, we believe that more studies are needed to evaluate the prognostic importance of both SIRI and all MIIs in critical care geriatric patients.
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277589_p22
|
PMC11277589
|
sec[3]/p[5]
|
4. Discussion
| 4.0625 |
biomedical
|
Study
|
[
0.99951171875,
0.0003314018249511719,
0.0002796649932861328
] |
[
0.99658203125,
0.00017344951629638672,
0.003021240234375,
0.00007909536361694336
] |
In our study, no relationship was observed between PIV, NLR, PLR, and SII values and mortality. Various studies concerning these markers can be found in the literature. Recent studies have shown that the PIV can serve as an inflammatory marker for various diseases. In the literature, high PIV levels have been found to correlate with poor prognoses in cancer patients . A prospective study conducted on 82 septic patients in the ICU investigated the relationship between the PIV and sepsis; however, no statistically significant relationship was found between mortality and the PIV . In a study by Mangalesh et al. , the NLR, PLR, and SII were shown to be independent determinants of in-hospital mortality in septic patients, with SII performing better than both the NLR and PLR; moreover, the addition of the SII to the SOFA score led to a significant improvement in prognostic performance. A total of 5537 patients were analyzed in a study wherein the data of septic patients were examined, and a significant relationship was found between the PLR and mortality only in subgroups without vasopressor use and without AKI and those with a SOFA score of ≤10 . In a study evaluating decreased cognitive abilities in older patients after surgery, an increased SII was found to be an independently associated risk factor for decreased cognitive abilities after surgery .
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277589_p23
|
PMC11277589
|
sec[3]/sec[0]/p[0]
|
Limitation
| 3.884766 |
biomedical
|
Study
|
[
0.9990234375,
0.00051116943359375,
0.0002651214599609375
] |
[
0.99853515625,
0.0004892349243164062,
0.0006365776062011719,
0.00009828805923461914
] |
The current study has several limitations. First, the laboratory data used in the study were collected on the first day of admission to the ICU; therefore, continuous changes could not be analyzed. Second, this was a retrospective observational study, and selection bias and confounding bias are inevitable in studies of this kind. Finally, the current study was multicenter; however, a small number of patients were involved, meaning the results may not necessarily be representative of larger populations. Future larger, multicenter prospective studies are needed to confirm or refute the results of this study.
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277589_p24
|
PMC11277589
|
sec[4]/p[0]
|
5. Conclusions
| 4.070313 |
biomedical
|
Study
|
[
0.9990234375,
0.000659942626953125,
0.00024819374084472656
] |
[
0.998046875,
0.0006685256958007812,
0.0013113021850585938,
0.0001074075698852539
] |
In geriatric patients admitted to the ICU, it has been determined that (among the scoring systems used in the ICU) the SOFA score and (among the inflammatory markers) the CRP/albumin ratio have the greatest ability to predict 28-day mortality. Monitoring of the NLR, SIRI, MII 1-2-3, and CRP/albumin ratios is recommended for elderly ICU patients. Nevertheless, the effects of PIV, MLR, PLR, and SII values on predicting 28-day mortality could not be demonstrated in the current study. Therefore, we believe that further clinical studies are needed to determine the effects of the PIV, MLR, PLR, and SII on short- and long-term prognoses and survival in geriatric patients admitted to the ICU.
|
[
"Özlem Çakin",
"Arzu Karaveli",
"Melike Yüce Aktepe",
"Ayça Gümüş",
"Özlem Esra Yildirim"
] |
https://doi.org/10.3390/jcm13144011
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277601_p0
|
PMC11277601
|
sec[0]/p[0]
|
1. Introduction
| 3.863281 |
biomedical
|
Review
|
[
0.99853515625,
0.0010213851928710938,
0.0003693103790283203
] |
[
0.06927490234375,
0.307373046875,
0.61962890625,
0.003734588623046875
] |
Coeliac disease (CD) is an immune-mediated enteropathy that manifests in genetically susceptible individuals as a result of exposure to gluten . It is thought to affect around 1% of the general population worldwide, with increased prevalence seen in certain populations and families . These populations include those with concomitant autoimmune disorders, Down syndrome, and Turner syndrome, as well as those with first- and second-degree relatives with CD .
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277601_p1
|
PMC11277601
|
sec[0]/p[1]
|
1. Introduction
| 4.117188 |
biomedical
|
Review
|
[
0.9814453125,
0.01538848876953125,
0.0030689239501953125
] |
[
0.006938934326171875,
0.0748291015625,
0.9150390625,
0.003185272216796875
] |
To date, the only proven treatment for CD involves the strict, lifelong exclusion of sources of gluten from the diet . This requires avoidance of the grains wheat, barley, and rye (and their relatives), a staple of the diet in many countries . Many countries also recommend that oats are also excluded due to the high likelihood of cross-contamination, as well as a small subset of those with CD having an increased sensitivity to the similar proteins in some varieties of oats . Strict avoidance of gluten is essential in order to attenuate risk of disease-related complications, with even small amounts of gluten being harmful to some individuals . This strict avoidance can be challenging due to the risk of cross-contamination with gluten-containing foods, changes to the ingredient lists of commercial products, hidden sources of gluten in the diet, and the often-higher cost of gluten-free alternatives . Strict adherence to a gluten-free diet (GFD) requires continued vigilance, with proficient self-management the key to effective management of CD . For individuals with CD, having a sound knowledge and understanding of their condition and the importance of maintaining a GFD is essential for adherence to the diet . It is also important for the families of people with CD to understand about CD in order to support them adhering to a life-long GFD .
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277601_p2
|
PMC11277601
|
sec[0]/p[2]
|
1. Introduction
| 4.039063 |
biomedical
|
Review
|
[
0.998046875,
0.0011434555053710938,
0.0006842613220214844
] |
[
0.362060546875,
0.0019483566284179688,
0.63525390625,
0.0006194114685058594
] |
Knowledge levels of people with CD should be formally assessed in order to identify gaps in understanding and to tailor support and education to address these. This assessment should be carried out using a validated tool that is appropriate for the population to be studied. The design of the knowledge assessment tools themselves should be robust to ensure that results obtained from the tool can be confidently relied upon to develop and modify interventions. While a number of CD knowledge assessment tools have been developed and presented in the literature, their applicability to all with CD, as related to children, adults, and those in different countries, is unclear. The overall objective of this study was to undertake a systematic review to identify the different CD knowledge assessment tools that have been developed internationally. The subsequent aims were to analyse tool characteristics to determine which tools are valid, reliable, and generalisable for use with different populations with CD in the clinical and research setting. Children were also included in the target audience as knowledge of CD and the ability to self-manage is a gradual process that starts in childhood . Hence, this population could benefit from the use of validated knowledge assessment tools in supporting this process.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277601_p3
|
PMC11277601
|
sec[1]/sec[0]/p[0]
|
2.1. Process
| 3.720703 |
biomedical
|
Review
|
[
0.9833984375,
0.004627227783203125,
0.0118255615234375
] |
[
0.01012420654296875,
0.005992889404296875,
0.9833984375,
0.0004818439483642578
] |
This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA) guidelines . The protocol for this systematic review was not registered with a prospective register of systematic reviews.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277601_p4
|
PMC11277601
|
sec[1]/sec[1]/p[0]
|
2.2. Eligibility Criteria
| 2.429688 |
biomedical
|
Review
|
[
0.96875,
0.0057830810546875,
0.0254974365234375
] |
[
0.01947021484375,
0.040435791015625,
0.9384765625,
0.0014791488647460938
] |
To be included in the review, papers were required to include a written assessment tool to assess knowledge related to coeliac disease. No exclusion criteria were set for population, study type, or publication language in order to ensure identification of all available survey tools.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277601_p5
|
PMC11277601
|
sec[1]/sec[2]/p[0]
|
2.3. Information Sources and Search Strategy
| 3.583984 |
biomedical
|
Study
|
[
0.9990234375,
0.00023996829986572266,
0.0008878707885742188
] |
[
0.99560546875,
0.0024623870849609375,
0.00200653076171875,
0.00010144710540771484
] |
A search of the following databases was completed in March 2024: Medline, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsychInfo, Scopus and OpenGrey (via DANS). The search strategy included the MeSH and text word terms relating to the condition (coeliac disease), the variable to be measured (knowledge, information), the purpose of the tool (assess, measure), and how the tool may be defined (survey, questionnaire). A full breakdown of search criteria and strategies is included ( Appendix A ).
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277601_p6
|
PMC11277601
|
sec[1]/sec[3]/p[0]
|
2.4. Selection and Data Collection Process
| 3.878906 |
biomedical
|
Study
|
[
0.998046875,
0.0011453628540039062,
0.0010213851928710938
] |
[
0.99072265625,
0.0037670135498046875,
0.005321502685546875,
0.0001690387725830078
] |
The title and abstract of all papers identified under the above search terms were then collated into a database and duplicates removed. This was then independently reviewed by two assessors (SH, AVR) for relevance and inclusion for a full-text review. Any disputed papers were included for full-text review. The full-text versions of the relevant articles were again reviewed independently by two assessors and categorised for inclusion or exclusion with a clear reason for any exclusions. Disputes regarding inclusion were resolved by discussion between all authors (SH, AVR, ASD).
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
PMC11277601_p7
|
PMC11277601
|
sec[1]/sec[4]/p[0]
|
2.5. Missing Data
| 2.191406 |
biomedical
|
Review
|
[
0.791015625,
0.00791168212890625,
0.2012939453125
] |
[
0.171875,
0.1522216796875,
0.67333984375,
0.0026950836181640625
] |
In order to maximise the completeness of the data included, the authors of all papers that had not published their knowledge assessment tool questions were contacted at least twice to provide this information. If a paper included an incomplete assessment tool, the authors were contacted as above. If the full version was not provided, then the sections published were included in the review. Where papers or tools were not published in English, translations were sought from a translator with university-level qualifications in that language.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277601_p8
|
PMC11277601
|
sec[1]/sec[5]/p[0]
|
2.6. Data Items and Effect Measures
| 3.416016 |
biomedical
|
Study
|
[
0.998046875,
0.00045752525329589844,
0.0017271041870117188
] |
[
0.9892578125,
0.0015573501586914062,
0.00897979736328125,
0.00013518333435058594
] |
The details of the different studies were extracted from included papers and displayed in a comparative table. Characteristics included target cohort, country of origin, and study design. A comparative table was compiled looking at the characteristics of the tools identified and the inclusion of considerations relating to health feasibility, validity, reliability, and generalisability. Validated tools to assess these specific metrics are not available; therefore, we based our assessments using the following parameters.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277601_p9
|
PMC11277601
|
sec[1]/sec[5]/sec[0]/p[0]
|
2.6.1. Feasibility
| 4.171875 |
biomedical
|
Other
|
[
0.98095703125,
0.0081939697265625,
0.0109405517578125
] |
[
0.10540771484375,
0.56396484375,
0.328857421875,
0.0016946792602539062
] |
Health literacy: Careful consideration should be made when selecting the type and number of questions for a tool as length and complexity can influence the quality of the data obtained. Questions should be clear and written in language understandable to the target audience. Readability: Readability assessment ensures that the questions within the tool are written at a level that the targeted reader can fully comprehend. This prevents over-estimation of knowledge deficits due to user misunderstanding of the question rather than its content. It is suggested that health information, particularly when targeting a broad range of literacy levels, be written at no higher than American 6th- to 7th-grade level . This can be assessed using metrics such as the Flesch–Kincaid readability test, whereby a US 6th–7th-grade level equates to a Flesch–Kincaid score of 70–90 . Brevity: Although it is not clear how long an assessment tool should be to optimise data quality, an association has been shown between survey length and response burden, although this must be weighed against development of a questionnaire of sufficient length to answer the intended question . Format: The type of response scales used may affect the amount and type of data that are obtained. For example, Likert scales tend to be used to measure linear agreement with a question, whereas dichotomous Yes/No or multiple choice questions are more commonly used to assess knowledge levels .
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277601_p10
|
PMC11277601
|
sec[1]/sec[5]/sec[1]/p[0]
|
2.6.2. Validity and Reliability
| 2.242188 |
biomedical
|
Other
|
[
0.8515625,
0.0035762786865234375,
0.144775390625
] |
[
0.046051025390625,
0.9501953125,
0.0034275054931640625,
0.00035071372985839844
] |
Following on from feasibility assessment, validation of a tool is essential to ensure that the tool is robust, fit for purpose, and the results obtained are reflective of the function of the tool .
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277601_p11
|
PMC11277601
|
sec[1]/sec[5]/sec[1]/p[1]
|
2.6.2. Validity and Reliability
| 3.302734 |
other
|
Other
|
[
0.2391357421875,
0.0021305084228515625,
0.7587890625
] |
[
0.034881591796875,
0.94921875,
0.01551055908203125,
0.0002739429473876953
] |
Face validity is the more subjective assessment of whether the survey questions accurately measure the intended overall survey question . This can be assessed through expert review and insights based on professional judgement and from participant feedback during pilot testing. However, it is thought to be a somewhat superficial measure of validity, hence not as useful as other forms of validation . Content validity refers to ensuring the inclusion of relevant questions during the design/development phase in order to accurately and comprehensively assess the target metric . Content validity during tool development is carried out by literature review and is then structured and undergoes iterative critical analysis by experts . Construct validity ensures that the survey is effectively measuring the question .
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277601_p12
|
PMC11277601
|
sec[1]/sec[5]/sec[1]/p[2]
|
2.6.2. Validity and Reliability
| 3.060547 |
other
|
Other
|
[
0.40673828125,
0.0013370513916015625,
0.591796875
] |
[
0.0556640625,
0.9365234375,
0.007602691650390625,
0.0002853870391845703
] |
Reliability assessment may be two-fold. The first aspect assesses whether a tool can repeatedly achieve the same results from the same respondents, for example, a test/re-test . The second aspect, internal consistency/reliability, relates to how well items in a survey correlate and measure the same general construct, for example, using Cronbach’s alpha . Additionally, inter-rater reliability considers agreement between raters.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277601_p13
|
PMC11277601
|
sec[1]/sec[5]/sec[2]/p[0]
|
2.6.3. Generalisability
| 1.556641 |
other
|
Other
|
[
0.4267578125,
0.002216339111328125,
0.57080078125
] |
[
0.035919189453125,
0.9609375,
0.00252532958984375,
0.0004131793975830078
] |
The generalisability of survey questions refers to how applicable they are to other/all populations. For example, questions could be specific to regional foods, legislation, or health services and the population that they were administered in and therefore not appropriate for a broader audience.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277601_p14
|
PMC11277601
|
sec[1]/sec[6]/p[0]
|
2.7. Synthesis Methods
| 2.761719 |
biomedical
|
Study
|
[
0.9765625,
0.0026950836181640625,
0.0207977294921875
] |
[
0.98095703125,
0.01458740234375,
0.0041351318359375,
0.00035452842712402344
] |
After tool characteristics were reviewed, all questions included in the tools were extracted and collated into a spreadsheet as outlined above. These questions were reviewed by two assessors and then grouped into broad themes relating to their common knowledge themes, and duplicated questions were combined. From these broad themes, questions were categorised into knowledge domains. Data were then sought on the frequency different questions were asked in the various tools reviewed.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277601_p15
|
PMC11277601
|
sec[2]/sec[0]/p[0]
|
3.1. Study Selection
| 2.888672 |
biomedical
|
Study
|
[
0.9970703125,
0.001399993896484375,
0.0016336441040039062
] |
[
0.97900390625,
0.0080413818359375,
0.01233673095703125,
0.0005402565002441406
] |
Initial searches identified 595 publications . Following removal of duplicates (n = 271) and title/abstract review, 90 of these papers met the inclusion criteria for full-text review. Two hundred and thirty-six were excluded at this stage as they did not meet inclusion criteria, (in particular, they did not include a written assessment tool to assess knowledge related to CD).
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277601_p16
|
PMC11277601
|
sec[2]/sec[0]/p[1]
|
3.1. Study Selection
| 3.40625 |
biomedical
|
Review
|
[
0.9931640625,
0.002048492431640625,
0.00470733642578125
] |
[
0.12322998046875,
0.01206207275390625,
0.86376953125,
0.000949859619140625
] |
Of the 90 papers that satisfied criteria for full-text review, a further 65 were subsequently excluded. Twenty papers used a tool that was not looking at the assessment of knowledge in particular, while in eighteen papers a tool could not be accessed after attempting to contact the authors on two or more occasions, or the paper was pending publication. Twenty papers used a tool that had already been identified and the original paper had already been included in the review, and five papers used a tool that was not specific to CD. The remaining 25 papers were included in the systematic review of knowledge assessment tools.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277601_p17
|
PMC11277601
|
sec[2]/sec[1]/p[0]
|
3.2. Study Charatcteristics
| 2.349609 |
biomedical
|
Study
|
[
0.99267578125,
0.0015306472778320312,
0.005672454833984375
] |
[
0.9267578125,
0.0145721435546875,
0.058013916015625,
0.000888824462890625
] |
The 25 studies included in the final analysis were reviewed for their study characteristics ( Table 1 ).
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277601_p18
|
PMC11277601
|
sec[2]/sec[1]/p[1]
|
3.2. Study Charatcteristics
| 3.984375 |
biomedical
|
Study
|
[
0.99853515625,
0.0005927085876464844,
0.000766754150390625
] |
[
0.701171875,
0.0009751319885253906,
0.29736328125,
0.0003635883331298828
] |
The studies took place in 16 different countries between the years 2003 and 2024. The population sample size and study design varied considerably, from a 20-participant, single-centre study to a 3643-participant, multi-centre study. The majority of the studies were cross-sectional, with the exception of Gutowski et al. , Meyer et al. , and Vázquez-Polo et al. , which included longitudinal data collection, and Vernero et al. , who undertook an experimental study. The majority of studies (20 (80%)) looked at knowledge assessments in adults, 2 assessed parental knowledge in parents of children with CD, and 2 studies looked at knowledge in a paediatric population and in adults . Vázquez-Polo et al. planned to assess knowledge of 10–12-year-olds following nutrition education intervention. Knowledge of CD and a GFD was assessed in a range of population groups, with 13 studies among those diagnosed with CD and 7 among healthcare professionals, and 3 studies looked at general public knowledge of CD management and 5 studies among food servers and providers.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
PMC11277601_p19
|
PMC11277601
|
sec[2]/sec[2]/sec[0]/p[0]
|
3.3.1. Administration
| 2.304688 |
biomedical
|
Study
|
[
0.8671875,
0.0013341903686523438,
0.1317138671875
] |
[
0.95703125,
0.032196044921875,
0.01055908203125,
0.0003616809844970703
] |
The majority of the tools were self-administered ( Table 2 ), with Garg and Gupta et al. providing a self-completed survey but in an interview setting. Garipe et al. delivered the tool by a trained interviewer. Roma et al. also delivered their tool verbally, adjusting phraseology for age and education level of participants. Eight of the surveys were delivered electronically, with Simpson et al. offering a face-to-face option as well as the electronic survey and one via post .
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277601_p20
|
PMC11277601
|
sec[2]/sec[2]/sec[1]/p[0]
|
3.3.2. Length
| 2.660156 |
biomedical
|
Study
|
[
0.9873046875,
0.0008759498596191406,
0.01174163818359375
] |
[
0.98193359375,
0.00566864013671875,
0.01218414306640625,
0.00024962425231933594
] |
The assessment tools varied in length from 5 to 85 questions (with the 85 questions presented as four question matrices). Six of the knowledge tools sat within larger surveys also looking at other factors such as adherence and attitudes towards the GFD . Four studies did not use the same tool throughout the study . Riznik et al. , Simpson et al. , and Tan et al. used slightly different tools for the different target cohorts surveyed. Gutowski et al. administered the same tool for all participants but a different set of questions, in this case a grocery list, at the three timepoints surveyed to assess label-reading comprehension.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277601_p21
|
PMC11277601
|
sec[2]/sec[2]/sec[2]/p[0]
|
3.3.3. Format
| 2.890625 |
biomedical
|
Study
|
[
0.99658203125,
0.0015192031860351562,
0.0020046234130859375
] |
[
0.939453125,
0.030426025390625,
0.02935791015625,
0.0005469322204589844
] |
A range of different question formats were used in the tools ( Table 2 ). The majority were a dichotomous or Yes/No format with some offering a ‘maybe’ or a ‘don’t know’ option as well. Multiple choice questions were the next most common format with Likert and open-ended questions appearing less frequently. Broadly speaking, questions tended to focus on four main areas: the gluten content of foodstuffs; label reading or identifying gluten in the diet or in medications; CD and its pathophysiology; and assessing the practical daily management of CD and the GFD.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277601_p22
|
PMC11277601
|
sec[2]/sec[2]/sec[3]/p[0]
|
3.3.4. Readability
| 3.115234 |
biomedical
|
Study
|
[
0.986328125,
0.000682830810546875,
0.013214111328125
] |
[
0.9765625,
0.0067291259765625,
0.0167236328125,
0.0002263784408569336
] |
Readability was mentioned in five of the studies; however, only one provided formal assessment using Flesch–Kincaid readability scores . Howard , Silvester et al. , and Geiger et al. all included feedback on readability during pretesting and piloting of the tools in peers and neighbours, Canadian Celiac Association members (n = 3), and upper-level dietetic students (n = 16), respectively. Conversely, Roma et al. did not discuss readability assessment during the design phase; however, the questionnaire was delivered by investigators who ‘adjusted phraseology ... as and when necessary’.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277601_p23
|
PMC11277601
|
sec[2]/sec[2]/sec[4]/p[0]
|
3.3.5. Piloting
| 1.911133 |
biomedical
|
Study
|
[
0.88427734375,
0.00322723388671875,
0.11224365234375
] |
[
0.90283203125,
0.0780029296875,
0.0182647705078125,
0.001018524169921875
] |
Eleven studies reported undergoing some form of piloting of their tools prior to use. However, formal piloting was only reported in four studies, with a further six completing some form of piloting with results not reported. Garg and Gupta stated that their tool was piloted as part of a previous study.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277601_p24
|
PMC11277601
|
sec[2]/sec[2]/sec[5]/p[0]
|
3.3.6. Validity and Reliability
| 3.945313 |
biomedical
|
Study
|
[
0.998046875,
0.0004410743713378906,
0.00133514404296875
] |
[
0.91650390625,
0.00222015380859375,
0.0809326171875,
0.0001996755599975586
] |
Content Validity: Of the 25 tools included, 10 reported some form of content validity, although to varying extents. Dembiński et al. and Paganizza et al. reported development of their tool through systematic review of the literature, and although Paganizza et al. did consult two experts during development, neither study alluded to the use of structured critical analysis of findings. Most reported the support of experts in their field in the development of their tools through peer review, face validity, or expert analysis of the proposed tool questions, suggesting an informal review of the content. Vernero et al. undertook formalised content validation through expert development of the questions and review by both the lay public and volunteers with CD and a special interest in the GFD.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277601_p25
|
PMC11277601
|
sec[2]/sec[2]/sec[5]/p[1]
|
3.3.6. Validity and Reliability
| 3.126953 |
biomedical
|
Study
|
[
0.99755859375,
0.00031256675720214844,
0.0019483566284179688
] |
[
0.96142578125,
0.0296783447265625,
0.00878143310546875,
0.0003082752227783203
] |
Construct Validity: Only Vernero et al. described undertaking a full formal validation of their tools, with Garg and Gupta mentioning using a previously validated survey. Vernero et al. undertook validation using discriminant validity through the assessment of response variances between two groups: those with well-controlled CD and healthy controls.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277601_p26
|
PMC11277601
|
sec[2]/sec[2]/sec[5]/p[2]
|
3.3.6. Validity and Reliability
| 2.996094 |
biomedical
|
Study
|
[
0.93408203125,
0.00084686279296875,
0.06500244140625
] |
[
0.833984375,
0.10089111328125,
0.06451416015625,
0.0006389617919921875
] |
Reliability: Roma et al. and Zhou et al. both described formal assessment of tool reliability. The former used the Kappa statistic and test and retest percentage agreement and the latter used Cronbach’s alpha to assess tool reliability.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277601_p27
|
PMC11277601
|
sec[2]/sec[2]/sec[6]/p[0]
|
3.3.7. Generalisability
| 1.694336 |
other
|
Study
|
[
0.368408203125,
0.0017080307006835938,
0.6298828125
] |
[
0.8037109375,
0.1925048828125,
0.0030193328857421875,
0.0009245872497558594
] |
Generalisability varied between the various tools. Seven tools included local foodstuffs and brands that were specific to the region where the tool was developed, such as barley squash, faggots, Prague ham, Jelly Babies, and Vegemite, and two included local legislation such as food-labelling requirements ( Table 2 ).
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277601_p28
|
PMC11277601
|
sec[2]/sec[3]/p[0]
|
3.4. Results of Synthesis
| 3.982422 |
biomedical
|
Review
|
[
0.99853515625,
0.00092315673828125,
0.000713348388671875
] |
[
0.386962890625,
0.0015325546264648438,
0.61083984375,
0.0005474090576171875
] |
Through the systematic review process, a broad range of questions was identified for the assessment of CD knowledge. This may have been due in part to the wide range of target groups included, with knowledge assessment not limited to those with a diagnosis of CD. However, clear themes were identified in the questions asked. Most of the tools identified focused on knowledge surrounding management of a GFD, with only four studies not including an item about the identification of gluten in the diet . All of these studies looked at knowledge of healthcare professionals (HCPs). The study by Dembiński et al. was focused on knowledge among healthcare professionals of the nutritional deficiencies that people with CD may face when following a strict GFD. A general question, “My knowledge of a gluten-free diet is sufficient”, was included. This assumes that the HCPs taking part in the survey were aware of the avoidances required when following a strict GFD.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
PMC11277601_p29
|
PMC11277601
|
sec[2]/sec[3]/p[1]
|
3.4. Results of Synthesis
| 1.860352 |
biomedical
|
Other
|
[
0.98291015625,
0.003490447998046875,
0.01352691650390625
] |
[
0.2440185546875,
0.7412109375,
0.01239013671875,
0.00217437744140625
] |
Only Dembiński and Geiger , whose target audiences were HCPs, included questions regarding the nutritional concerns for those following a GFD. It is interesting that these questions were not included in more tools as they could potentially be an important knowledge requirement in effectively managing CD.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277601_p30
|
PMC11277601
|
sec[2]/sec[3]/p[2]
|
3.4. Results of Synthesis
| 3.775391 |
biomedical
|
Review
|
[
0.99658203125,
0.0015583038330078125,
0.0016918182373046875
] |
[
0.032958984375,
0.00438690185546875,
0.9619140625,
0.0006833076477050781
] |
All CD knowledge assessment questions were extracted from the 17 tools included in the review. Matrix questions identifying gluten in common food products were identified as a single question. The questions were then pooled, grouped into the four main areas mentioned above, and the following nine knowledge domains emerged: General CD knowledge Management of CD Identifying gluten in the diet and as ingredients, e.g., label reading Food labelling and legislation Nutrients and a GFD Food handling practices and training Eating out Medicines, health, and beauty Diagnosing CD
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277601_p31
|
PMC11277601
|
sec[2]/sec[3]/p[3]
|
3.4. Results of Synthesis
| 3.029297 |
biomedical
|
Study
|
[
0.99853515625,
0.0010519027709960938,
0.0005674362182617188
] |
[
0.98583984375,
0.0046234130859375,
0.009002685546875,
0.00033736228942871094
] |
The frequency of questions in each domain from the included tools was summarised ( Table 3 ). The most common questions included related to identifying gluten in the diet, either by selecting the grains that contain gluten or through label reading. The majority of the tools included asked questions regarding knowledge of CD in general, with only two tools asking about knowledge of the nutrients at risk when following a GFD/for those with CD .
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277601_p32
|
PMC11277601
|
sec[2]/sec[4]/p[0]
|
3.5. Certainty of Evidence
| 3.708984 |
biomedical
|
Review
|
[
0.93017578125,
0.0068359375,
0.06292724609375
] |
[
0.00689697265625,
0.00199127197265625,
0.99072265625,
0.0002765655517578125
] |
The studies and assessment tools included in this current review showed high levels of heterogeneity, but as the review is non-data-driven, no formal assessment could be carried out. Additionally, the focus of the review is on the survey tools included in the papers, not the study integrity itself, which leads to the certainty assessment being made according to metrics chosen to evaluate the survey tools. The objective assessment of survey tool composition, content, and format showed that most tools were lacking various important elements being considered during the development process. This limits any statement of certainty as there was no standardisation of tool development between identified studies.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277601_p33
|
PMC11277601
|
sec[3]/p[0]
|
4. Discussion
| 4 |
biomedical
|
Review
|
[
0.99560546875,
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] |
[
0.01611328125,
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] |
Through the systematic review process, 25 tools were identified to assess knowledge of CD and its management. A predetermined, structured process was used to identify the papers and assess their merit as effective tools. A range of different study types was included in the review. The studies were based in 16 different countries over a period of 21 years and assessed knowledge of CD in a variety of different populations, including health professionals, those with CD, food service workers, and the lay public. The main topics covered in the assessment tools included were general knowledge of CD and its management, including label reading, legislation, eating out, nutrients of concern, and potential non-food sources of gluten, as well as understanding the diagnostic processes for CD.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277601_p34
|
PMC11277601
|
sec[3]/p[1]
|
4. Discussion
| 4.039063 |
biomedical
|
Review
|
[
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] |
[
0.0093536376953125,
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] |
The purpose of this review was to find a knowledge assessment tool that could be used by healthcare professionals in the clinical and research setting to identify patient knowledge gaps about CD and the GFD that may affect their outcomes. For the tool to effectively satisfy this purpose, it needed to be well designed, tested, and generalisable to the intended population in order to reliably interpret findings when the tool is subsequently used . Consideration of the feasibility of assessment tools, as related to health literacy, readability, and respondent burden, is of paramount importance for both adults and children with CD. However, no formal feasibility testing was carried out in any study included in the review. Health literacy is considered to be the ability to understand, interpret, and act on health information , and reports have shown health literacy levels to be suboptimal both at school-age and continuing on in to adulthood . Hence, the language used in tools designed for the general public should reflect this in order to optimise understanding and participation , especially where children are included in the target cohort .
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277601_p35
|
PMC11277601
|
sec[3]/p[2]
|
4. Discussion
| 4.078125 |
biomedical
|
Study
|
[
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] |
[
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] |
The language used in assessment tools should be of a readability level suitable for the target population and of a length that answers the research question sufficiently while not placing undue burden on the user . While assessment tools for clinical conditions such as CD may involve some complex clinical terms and jargon, overall, a tool should not have readability assessments higher than a US grade 7-level comprehension . Davis et al. showed that level of education completed can in fact be an inaccurate estimate of reading level. They found the self-reported education level of parents surveyed in an outpatient department being up to a grade-11 level. However, when assessed, reading levels were found to be on average four grade levels lower than this, at around a US 7th- to 8th-grade level. Hence, they found that many health information resources being provided poorly correlated with actual reading level, with only 3% of resources reviewed being written below a 7th-grade level . Previous work has tried to alleviate the respondent burden of complex terms in paediatric health forms by the use of pictures, but this was not a simple fix as children still considered them as needing explanations . The known positive association between higher knowledge levels and greater adherence to GFD among both adults and children highlights how important the use of an appropriate assessment tool is to identify gaps or misconceptions in understanding . In particular, adherence to a GFD in childhood has also been associated with better growth and quality of life, so inclusion of children in the target population of such assessment tools is crucial .
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277601_p36
|
PMC11277601
|
sec[3]/p[3]
|
4. Discussion
| 4.027344 |
biomedical
|
Review
|
[
0.98291015625,
0.00360870361328125,
0.013275146484375
] |
[
0.0309600830078125,
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0.96435546875,
0.0003123283386230469
] |
Following the development of assessment tools, undertaking a pilot study allows for testing viability prior to embarking on a full validation study . This enables minor issues with the tool to be resolved prior to commencement and increases the likelihood of success . Carrying out full validity testing then determines whether the measurement tool used actually measures the proposed research concept and can quantify the variables with stable or consistent responses . Although a number of the studies in this current review reported informal pilot testing, no results were reported, and few carried out full validity testing. This thereby limits researcher or clinician confidence in using these published tools. In addition, many of the tools in the review had issues with generalisability, thereby further limiting their applicability.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277601_p37
|
PMC11277601
|
sec[3]/p[4]
|
4. Discussion
| 3.992188 |
biomedical
|
Review
|
[
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] |
[
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0.9921875,
0.0003097057342529297
] |
For an intervention to be of use outside the setting where it was originally developed/evaluated, it must be generalisable to other regions, populations, and clinical settings . In this review, generalisability was limited by the inclusion of questions regarding local food labelling and legislation, support groups, and the inclusion of regional foodstuffs, all of which may vary significantly in different countries. The cut-offs for allowable gluten traces in foods labelled gluten-free, for example, are different in different parts of the world , as well as requirements for identifying gluten and potential contamination in packaged goods . A local coeliac society was mentioned in one of the tools. Membership in a society has been associated with better adherence to a GFD, but this resource is not available in all countries and access and format may vary . Foodstuffs mentioned in some tools may not be available internationally and may, therefore, be unfamiliar to some target audiences. Consideration in the context of maintaining a GFD must be given to possible variations in recipes of commercial foodstuffs, as well as the possibility of gluten cross-contamination in different countries .
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277601_p38
|
PMC11277601
|
sec[3]/p[5]
|
4. Discussion
| 3.966797 |
biomedical
|
Review
|
[
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] |
[
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] |
No papers included in the review reported all of the pre-determined, necessary feasibility, validity/reliability, and generalisability metrics that would make it a robust and fit-for-purpose tool for the intended populations with CD in the clinical and research setting. The tool that most closely met the requirements for the study was from Vernero et al. , which presented a robust tool whose development included piloting and validation. The tool itself covered a broad range of knowledge question areas, covering six of the nine question domains that were developed in the process of data synthesis. Unfortunately, no readability assessments were described, and the tool was not generalisable to other populations due to the use of questions regarding EU-specific legislation and the inclusion of a number of local foodstuffs.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277601_p39
|
PMC11277601
|
sec[3]/sec[0]/p[0]
|
4.1. Limitations
| 3.935547 |
biomedical
|
Study
|
[
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[
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] |
Eighteen of the papers that met the basic inclusion criteria were not included as the assessment tool could not be obtained despite repeated attempts to contact authors. Inclusion of these tools would have doubled the number that could be reviewed for inclusion, and their exclusion presents a risk of bias. The lack of standardisation in the format of identified surveys forms a large part of the discussion in this current work; however, it is in itself a study limitation. Inferences as to the best format and content for a coeliac disease knowledge assessment tool are restricted due to their heterogeneity, as well as by a lack of validated assessment tools with which to assess them. Evidence-based metrics were chosen to assess survey tools, but the use of a validated, comprehensive assessment strategy would have enabled more objective summaries and inferences, as well as future comparisons.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277601_p40
|
PMC11277601
|
sec[3]/sec[1]/p[0]
|
4.2. Strengths
| 3.363281 |
biomedical
|
Review
|
[
0.990234375,
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] |
[
0.0267791748046875,
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0.0006546974182128906
] |
A robust, transparent review process was undertaken to identify tools used to assess knowledge of CD and its management internationally. Substantial efforts were made to contact the authors of papers where the tool itself was not published in the paper. The tools identified and included in the review were from a variety of centres and with varying target populations. Content synthesis of the included assessment tools allowed for generation of clear themes that may be utilised in future assessment tool development.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277601_p41
|
PMC11277601
|
sec[4]/p[0]
|
5. Conclusions
| 3.517578 |
biomedical
|
Review
|
[
0.99072265625,
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] |
[
0.005611419677734375,
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0.98974609375,
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] |
The maintenance of a strict GFD is key to effective management of CD, with better knowledge supporting autonomy in self-management and adherence . However, there are wide variations in practice for the education provided to people with CD and their wider communities . Hence, assessing knowledge of CD and its management and identifying any gaps would be essential for planning and development of future education resources. The results of this current review will inform further research to address the knowledge gap of having no suitable CD knowledge assessment tool available in the literature.
|
[
"Sophie Hall",
"Kristin Kenrick",
"Andrew S. Day",
"Angharad Vernon-Roberts"
] |
https://doi.org/10.3390/jcm13144053
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057355_p0
|
39057355
|
sec[0]/p[0]
|
1. Introduction
| 4.015625 |
biomedical
|
Study
|
[
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] |
[
0.87060546875,
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] |
Leaf microbial endophytes constitute a group of microorganisms inhabiting the leaves of plants, forming a harmonious symbiotic association with host trees after experiencing a long-term evolutionary history . Intrinsic factors such as genotype, age, plant species, and developmental stage influence their diversity and composition , as well as external factors such as soil characteristics , the hydrothermal environment , neighboring plants , phytophagous insects , and plant pathogens . The intricate environmental diversity enables leaf endophytic microbiota to demonstrate greater adaptability to environmental changes compared to inter-root microbes . Despite the undeniable influence of leaf endophytic microbiota on plants , our understanding of the underlying mechanisms, particularly under varying thinning intensities, significantly lags behind the knowledge available for inter-root microbiota .
|
[
"Beiping Liu",
"Chunhuan Li",
"Xiuhai Zhao",
"Chunyu Zhang",
"Xinyi He",
"Laiye Qu",
"Naili Zhang"
] |
https://doi.org/10.3390/jof10070470
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057355_p1
|
39057355
|
sec[0]/p[1]
|
1. Introduction
| 3.921875 |
biomedical
|
Study
|
[
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[
0.92138671875,
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] |
Thinning, the common anthropogenic disturbance being conducted prevalently in temperate forests, influences the structure and function of forest ecosystems by directly changing tree density and indirectly altering tree growth, functional traits, and composition through the modulation of sunlight penetration and precipitation . The penetration of sunlight is closely associated with the traits and functions of leaves since they are photosynthetic organs . The effects of thinning generally depend on the thinning intensity. Large-scale thinning usually leads to the excessive exploitation of forest resources, resulting in tree species loss, substantial variations in functional traits, and threats to ecosystem functions . However, when managed appropriately, it has the potential to foster tree growth, promote leaf traits and their associations with microbial endophytes, alleviate competitive pressures among tree species , and improve the stability of forest communities .
|
[
"Beiping Liu",
"Chunhuan Li",
"Xiuhai Zhao",
"Chunyu Zhang",
"Xinyi He",
"Laiye Qu",
"Naili Zhang"
] |
https://doi.org/10.3390/jof10070470
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057355_p2
|
39057355
|
sec[0]/p[2]
|
1. Introduction
| 4.277344 |
biomedical
|
Study
|
[
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[
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0.00008100271224975586
] |
The thinning-induced variations in tree spatial distribution play a crucial role in shaping ecological processes such as recruitment, growth, dispersal, and competition . According to the “moderate disturbance hypothesis” proposed by Connell , when disturbance intensity is too high, it becomes challenging for the majority of species to survive, leading to the dominance of a small number of reproductively strong or expansive colonizers. Conversely, if disturbance intensity is too low, dominant competitors may become excessively strong and outcompete disadvantaged species, resulting in reduced species diversity . Moderate thinning is deemed to stimulate the growth of specific leaf endophytic microbiota by increasing light availability, creating additional space resources, and enhancing the water use efficiency of leaves . However, excessive thinning can decrease community-level and neighbor tree diversity, resulting in a significant change in the diversity and abundance of leaf endophytic microbiota inhabiting focal tree species . Moreover, thinning-induced changes in neighbor tree richness may modulate herbivorous insects, conferring a cascading effect on leaf endophytic microbiota, a phenomenon often referred to as neighborhood effects . The neighborhood effects can trigger changes in the herbivorous insect density and their feeding activity . The extent of leaf damage by these insect herbivores has been predicted to modulate endophytic microbiota owing to the dispersal and colonization of some external microbes via the edges of damaged leaf tissues . This raises an intriguing question: what are the differences in the environmental adaptation of endophytic microbiota residing in damaged leaves compared to those in healthy leaves?
|
[
"Beiping Liu",
"Chunhuan Li",
"Xiuhai Zhao",
"Chunyu Zhang",
"Xinyi He",
"Laiye Qu",
"Naili Zhang"
] |
https://doi.org/10.3390/jof10070470
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057355_p3
|
39057355
|
sec[0]/p[3]
|
1. Introduction
| 4.171875 |
biomedical
|
Study
|
[
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] |
[
0.99951171875,
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0.000053882598876953125
] |
In this study, we aim to investigate the responses of leaf endophytic fungal and bacterial assemblages to neighbor tree species richness and herbivorous insect-caused leaf damage in temperate forests under different thinning intensities. We established three plots with different thinning intensities (i.e., control check (CK), light, and moderate thinning) in a broad-leaved Pinus koraiensis forest in Northeast China. Five dominant tree species (i.e., Pinus koraiensis , Ulmus davidiana var. japonica , Tilia amurensis , Fraxinus mandshurica , and Acer pictum subsp. mono ) were selected for the study. First, we hypothesized that thinning intensities can significantly change the diversity and composition of endophytic microflora in leaves, with a trade-off between leaf endophytic fungi and bacteria. Specifically, endophytic bacterial diversity may decrease as an enhancement of fungal diversity. Second, the intensities of thinning can significantly alter the network structure of leaf endophytes. Third, we predicted that leaf endophytes would be simultaneously regulated via the abundance of neighboring trees around the focal tree individual, via leaf functional characteristics, and via leaf damage caused by herbivorous insect feeding.
|
[
"Beiping Liu",
"Chunhuan Li",
"Xiuhai Zhao",
"Chunyu Zhang",
"Xinyi He",
"Laiye Qu",
"Naili Zhang"
] |
https://doi.org/10.3390/jof10070470
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057355_p4
|
39057355
|
sec[1]/sec[0]/p[0]
|
2.1. Study Site and Experimental Design
| 1.780273 |
other
|
Study
|
[
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] |
[
0.94482421875,
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] |
The study was carried out in a broad-leaved Pinus koraiensis forest at an altitude of 575~784 m, situated in the Jiaohe Forestry Experimental Area Administration of Jilin Province, China (127°45.287′–127°45.790′ E, 43°57.524′–43°58.042′ N). The average temperature from June to August here reaches 3.8 °C, and the average annual precipitation is 696 mm . The soil type is mountain dark brown forest soil, with a depth range of 20 to 80 cm. The vegetation belongs to Changbai Mountain flora, with common tree species such as Juglans mandshurica , Carpinus cordata , Quercus mongolica , and so on. The undergrowth consists of Syringa reticulata subsp. amurensis , Corylus mandshurica , Eleutherococcus senticosus , etc. .
|
[
"Beiping Liu",
"Chunhuan Li",
"Xiuhai Zhao",
"Chunyu Zhang",
"Xinyi He",
"Laiye Qu",
"Naili Zhang"
] |
https://doi.org/10.3390/jof10070470
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057355_p5
|
39057355
|
sec[1]/sec[0]/p[1]
|
2.1. Study Site and Experimental Design
| 2.835938 |
other
|
Study
|
[
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0.64306640625
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[
0.99609375,
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0.00011479854583740234
] |
In December 2011, three 1ha plots were established in the broad-leaved P. koraiensis forest and were logged with different thinning intensities after obtaining the approval of the Jilin Provincial Forestry Department. The thinning intensities were as follows: 0% (control check, CK), 15% (light thinning, LT), and 30% (moderate thinning, MT) . Five dominant species were selected, including P. koraiensis (PK), Ulmus davidiana var. japonica (UD), Tilia amurensis (TA), Fraxinus mandshurica (FM), and Acer pictum subsp. mono (AP). Four individual plants were randomly selected from each focal species in each plot for leaf sampling. To ensure consistency in sampling and minimize the effects of other environmental factors, we selected sample plots in forests with flat terrain and a slope of less than 5 degrees . Additionally, the forest gaps around the target tree species were essentially uniform, thereby mitigating the potential influence of light and wind speed.
|
[
"Beiping Liu",
"Chunhuan Li",
"Xiuhai Zhao",
"Chunyu Zhang",
"Xinyi He",
"Laiye Qu",
"Naili Zhang"
] |
https://doi.org/10.3390/jof10070470
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057355_p6
|
39057355
|
sec[1]/sec[1]/p[0]
|
2.2. Sample Collection and Measurement
| 3.679688 |
biomedical
|
Study
|
[
0.80224609375,
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] |
[
0.99853515625,
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0.00006568431854248047
] |
From late July to early August 2022, we collected leaves of the target tree species. Prior to this, the diameter at breast height (DBH) of each focal tree species was measured, and the neighboring trees surrounding each focal tree within a 5 m radius were recorded. Mature leaves were randomly selected from the mid-canopy layers, and their status was recorded as healthy or damaged. Leaves eaten by phytophagous insects were classified as damaged, while leaves without insect feeding were classified as healthy. The leaves were then put into sterile sealed bags and carried down the hill in a portable refrigerator. Vernier calipers were used to measure leaf thickness. The leaf thickness (LT) of each individual tree was obtained by averaging the thickness of five leaves, and all the leaves were scanned for further analysis. Image Pro Plus was used to determine the area (LA), length (LL), and width (LW) of the blade.
|
[
"Beiping Liu",
"Chunhuan Li",
"Xiuhai Zhao",
"Chunyu Zhang",
"Xinyi He",
"Laiye Qu",
"Naili Zhang"
] |
https://doi.org/10.3390/jof10070470
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057355_p7
|
39057355
|
sec[1]/sec[1]/p[1]
|
2.2. Sample Collection and Measurement
| 4.140625 |
biomedical
|
Study
|
[
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[
0.99951171875,
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] |
In the meantime, three leaves were chosen at random for each sample, and their fresh weight was determined. The leaves were then degreened at 105 °C for 15 min and dried at 65 °C to a constant weight for dry weight determination. The leaf dry matter weight (LDMC) was determined as the ratio of leaf dry weight to leaf fresh weight, and the specific leaf area (SLA) was calculated as the ratio of leaf area to leaf dry matter weight. The measurements of leaf trait variables per individual tree were taken three times, and the mean values were recorded. After grinding the leaves for 150 s with a 55 Hz grinding instrument, the nutrient content of the leaves was measured after passing through a 150-mesh screen. An elemental analyzer was used to measure the total nitrogen (N) and total carbon (C) content of the leaves (Vario EL Cube, Elementar, Germany) and to obtain the C/N ratio of the leaves. An inductively coupled plasma mass spectrometer was used to determine the content of P, K, Ca, Cu, Mg, and Zn in leaves (ICP-MS, NexION 300X, Perkin Elmre, Shelton, CT, USA), and the leaves were dissolved via the HNO 3 /HClO 4 method.
|
[
"Beiping Liu",
"Chunhuan Li",
"Xiuhai Zhao",
"Chunyu Zhang",
"Xinyi He",
"Laiye Qu",
"Naili Zhang"
] |
https://doi.org/10.3390/jof10070470
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057355_p8
|
39057355
|
sec[1]/sec[1]/p[2]
|
2.2. Sample Collection and Measurement
| 3.009766 |
other
|
Study
|
[
0.368896484375,
0.0011510848999023438,
0.6298828125
] |
[
0.99267578125,
0.007045745849609375,
0.00037288665771484375,
0.00012290477752685547
] |
Five soil cores beneath the canopy of each target tree were collected and thoroughly mixed into a composite sample, which was then placed in sterile sealed bags and transported to a lab for analysis. After removing impurities with a 2 mm sieve, the remaining soil was measured for soil moisture and pH value. Ten grams of fresh soil was weighed and dried at 105 °C to a constant mass. The dried soil was then reweighed to determine its moisture content (SWC). Soil pH was measured using a pH meter with a water-to-soil volume ratio of 1:2.5.
|
[
"Beiping Liu",
"Chunhuan Li",
"Xiuhai Zhao",
"Chunyu Zhang",
"Xinyi He",
"Laiye Qu",
"Naili Zhang"
] |
https://doi.org/10.3390/jof10070470
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057355_p9
|
39057355
|
sec[1]/sec[2]/p[0]
|
2.3. DNA Extraction, PCR Amplification, and Sequencing of Leaf Endophytic Bacterial and Fungal Communities
| 3.830078 |
biomedical
|
Study
|
[
0.99853515625,
0.00034356117248535156,
0.0009469985961914062
] |
[
0.98388671875,
0.0152435302734375,
0.0005092620849609375,
0.0001647472381591797
] |
The subsamples of leaves were washed with running water, soaked in 75% alcohol for 1 min, soaked in pure water for another 1 min, and, finally, washed with 75% alcohol again for surface sterilization. After allowing all the alcohol to evaporate, the leaves were placed in aseptic bags and stored at −80 °C to measure endophytic fungi and bacteria in the leaves.
|
[
"Beiping Liu",
"Chunhuan Li",
"Xiuhai Zhao",
"Chunyu Zhang",
"Xinyi He",
"Laiye Qu",
"Naili Zhang"
] |
https://doi.org/10.3390/jof10070470
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057355_p10
|
39057355
|
sec[1]/sec[2]/p[1]
|
2.3. DNA Extraction, PCR Amplification, and Sequencing of Leaf Endophytic Bacterial and Fungal Communities
| 4.242188 |
biomedical
|
Study
|
[
0.99951171875,
0.00032806396484375,
0.00018012523651123047
] |
[
0.99853515625,
0.0008172988891601562,
0.0003559589385986328,
0.00011599063873291016
] |
DNA extraction was carried out following the instructions of the TruSeqTM DNA Sample Prep Kit. NanoDrop 2000 and 1% agarose gel electrophoresis were utilized to analyze the concentration, purity, and quality of DNA extracted from the leaves. The extracted leaf DNA served as the template for polymerase chain reaction (PCR) amplification. The primers, 799F-AACMGGATTAGATACCCKG and 1193R-ACGTCATCCCCACCTTCC, were used to amplify endophytic bacterial variable region V3–V4 . The PCR amplification process consisted of 3 min of predenaturation at 95 °C and 27 cycles (denatured at 95 °C for 30 s, annealed at 55 °C for 30 s, and extended at 72 °C for 30 s). Finally, the reaction time was extended for 10 min at 72 °C and then stored at 4 °C. The primers, fITS7F-GTGARTCATCGAATCTTTG and ITS4R-TCCTCCGCTTATTGATATGC, were used to amplify the endophytic fungal ITS2 region . The process of PCR amplification consisted of predenaturation at 95 °C for 5 min, in 30 cycles (denaturated at 94 °C for 60 s, annealed at 58 °C for 50 s, and extended at 68 °C for 60 s), and finally an extension at 68 °C for 10 min and preservation at 10 °C. The PCR amplification system consisted of a 20 μL mixture containing 4 μL of 5 × Fast Pfu buffer, 2 μL 2.5 mM dNTPs, 0.8 μL of each primer (5 μM), 0.8 μL of Fast Pfu polymerase, 10 ng of the DNA template, and ddH2O. The AxyPrep DNA gel extraction kit (Axygen Biosciences, Union City, CA, USA) was utilized for purifying PCR products and detecting them with 2% agarose gel electrophoresis. The Illumina MiSeq platform (Illumina, San Diego, CA, USA) was used to sequence the purified PCR products following the established protocol of Megi Biopharmaceutical Co., LTD. (Shanghai, China). The original sequencing data were stored in FASTQ format.
|
[
"Beiping Liu",
"Chunhuan Li",
"Xiuhai Zhao",
"Chunyu Zhang",
"Xinyi He",
"Laiye Qu",
"Naili Zhang"
] |
https://doi.org/10.3390/jof10070470
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057355_p11
|
39057355
|
sec[1]/sec[3]/p[0]
|
2.4. Bioinformatics Analysis
| 4.132813 |
biomedical
|
Study
|
[
0.99951171875,
0.00024056434631347656,
0.0001811981201171875
] |
[
0.99755859375,
0.002002716064453125,
0.0004239082336425781,
0.0001042485237121582
] |
We selected Quantitative Insights into Microbial Ecology 2 (QIIME2) , an advanced microbiome analysis platform, for the detailed processing of all raw FASTQ data. First, the data import process was completed manually by executing the “qiime tools import” command in QIIME2. During the data cleaning and preprocessing phase, we used the “qiime dada2 denoise paired” plug-in , which incorporates advanced functions including quality pruning, noise reduction, sequence merging, and chimera detection. The approach efficiently grouped non-singleton amplified sequence variants (ASVs).
|
[
"Beiping Liu",
"Chunhuan Li",
"Xiuhai Zhao",
"Chunyu Zhang",
"Xinyi He",
"Laiye Qu",
"Naili Zhang"
] |
https://doi.org/10.3390/jof10070470
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057355_p12
|
39057355
|
sec[1]/sec[3]/p[1]
|
2.4. Bioinformatics Analysis
| 4.136719 |
biomedical
|
Study
|
[
0.99951171875,
0.0002453327178955078,
0.0001881122589111328
] |
[
0.9990234375,
0.0004353523254394531,
0.00030994415283203125,
0.00007659196853637695
] |
After quality filtering, the ASV abundance table was normalized to achieve the consistency of sampling depth using the “Interactive Sample Detail” feature within the “table. qzv” file. The “qiime feature-classifier classify-sklearn” plugin in QIIME2 was then employed to classify fungal and bacterial ASVs. The ASVs were merged and taxonomically classified by a trained Naive classifier based on the Greengenes database, clustering species with 99% similarity. Two authoritative reference databases, SILVA ( www.arb-silva.de/act ) and UNITE ( https://unite.ut.ee/ ), were used for the taxonomic assignment of endophytic fungi and bacteria, respectively. The resulting endophytic fungi amplicon sequences were validated via comparison with the NCBI database.
|
[
"Beiping Liu",
"Chunhuan Li",
"Xiuhai Zhao",
"Chunyu Zhang",
"Xinyi He",
"Laiye Qu",
"Naili Zhang"
] |
https://doi.org/10.3390/jof10070470
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057355_p13
|
39057355
|
sec[1]/sec[4]/p[0]
|
2.5. Statistical Analysis
| 4.074219 |
biomedical
|
Study
|
[
0.99755859375,
0.0003859996795654297,
0.001895904541015625
] |
[
0.99951171875,
0.00019061565399169922,
0.00027632713317871094,
0.00004482269287109375
] |
All statistical analyses and data visualizations in this study were performed using R statistical software (v.4.2.3). We conducted tests to evaluate the effects of different thinning intensities, tree species, damage, and their interactions on the assembly of endophytic bacteria and fungi. The lmer function from the lme4 package was employed to fit a mixed linear model, with the thinning intensity, tree species, and damage treated as fixed effects, and the DBH of target tree species and the composition of surrounding tree species treated as random effects. The significance of the fixed effects was assessed using the Anova function from the Car package. To examine the diversity and composition of endophytic fungi and bacteria, leaf traits, soil variables, and diversity of neighboring trees under different thinning intensities, we performed the Kruskal–Wallis nonparametric test. Differences between different thinning intensities were further analyzed using the Wilcoxon test (Wilcox.test function).
|
[
"Beiping Liu",
"Chunhuan Li",
"Xiuhai Zhao",
"Chunyu Zhang",
"Xinyi He",
"Laiye Qu",
"Naili Zhang"
] |
https://doi.org/10.3390/jof10070470
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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