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PMC11278058_p8
|
PMC11278058
|
sec[1]/sec[2]/p[0]
|
2.3. Intervention
| 4.101563 |
biomedical
|
Study
|
[
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[
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We used a Healaon taVNS device (Neurive Inc., Gimhae, Republic of Korea), which consists of an ear set with conductive ear tips placed on the auricular concha of the ears, displayed in Figure 1 . Carbon polymer electrodes were connected to a stimulator, and during active stimulation, both cymba conchae of the auricular were stimulated at 30 Hz, 200–250 us, with adjustable intensity below the pain threshold (~1.5 mA), for 60 min ( Supplementary Table S1 ). The sham intervention was applied at the same location bilaterally to the cymba conchae of the auricular, but the device did not provide stimulation during the 60 min. The active and sham devices were identical visually, and an individual not involved in data collection and analysis followed the randomization to hand the devices to the experimenter, allowing for blindness.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278058_p9
|
PMC11278058
|
sec[1]/sec[3]/p[0]
|
2.4. Outcomes
| 3.960938 |
biomedical
|
Study
|
[
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In this study, we investigated the effects of a single active taVNS session on various indices of HRV compared to a sham. A short-term HRV register (5 min in a sitting position) was recorded pre- and post-taVNS intervention.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278058_p10
|
PMC11278058
|
sec[1]/sec[3]/p[1]
|
2.4. Outcomes
| 3.685547 |
biomedical
|
Study
|
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[
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To collect heart rate variability (HRV) data, we used the H10 Polar device to make recordings through the validated HRV4Training app on an Android device; we followed the standard recommended settings . The process involved first ensuring proper placement of the H10 Polar device on the chest, securely fastening it for accurate readings. Data were transmitted in real time using Bluetooth connectivity; the device began recording HRV metrics continuously.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278058_p11
|
PMC11278058
|
sec[1]/sec[3]/p[2]
|
2.4. Outcomes
| 4.171875 |
biomedical
|
Study
|
[
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Regarding the frequency-domain metrics, which were based on divisions by the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology , we examined the high frequencies (HFs), low frequencies (LFs), and LF/HF ratio. We also explored a non-linear method to calculate the short-term detrended fluctuation exponent (DFA-alpha1). The LF captures the magnitude of heart oscillations in the range of three to nine cycles per minute (0.04 to 0.15 HZ) and is assumed, yet debatable , to have a dominant sympathetic component, while the HF captures heart rate oscillations of 9 to 24 cycles per minute (0.15 to 0.40 Hz) and is assumed to mirror the parasympathetic tonus . Their ratio is discussed elsewhere . While some sources describe it as a sympathovagal balance, there are others who argue that the LF is not exclusively representative of the sympathetic activity, together with a non-linear interaction between both autonomic systems, challenging the assumption that the LF/HF ratio accurately reflects this balance.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278058_p12
|
PMC11278058
|
sec[1]/sec[3]/p[3]
|
2.4. Outcomes
| 4.082031 |
biomedical
|
Study
|
[
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] |
The selection of time-domain metrics, which highlight variability in the interbeat interval (IBI) between successive heartbeats, is grounded in their established correlation with autonomic nervous system activity, as demonstrated by Parati et al. . We therefore assessed the following parameters: encompassed parameters such as the standard deviation of the N-N intervals (SDNN), counts of R-R intervals differing by more than 50 ms (NN50), the percentage of NN50 (pNN50), and the root mean square of the successive differences in R-R intervals (RMSSD).
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278058_p13
|
PMC11278058
|
sec[1]/sec[3]/p[4]
|
2.4. Outcomes
| 4.011719 |
biomedical
|
Study
|
[
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[
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] |
We present these results after extraction from the built-in HRV analysis module of the HRV4training app. All values were reported and used as raw metrics, except for LF and HF metrics, where normalized units were employed . It is noteworthy to mention that employing normalized units for LF and HF has distinct advantages in result interpretation. These units offer a more standardized and reliable comparison across different individuals and populations, providing insights into autonomic nervous system activity that might be obscured when using raw values alone due to high intra- and inter-subject variability .
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278058_p14
|
PMC11278058
|
sec[1]/sec[3]/p[5]
|
2.4. Outcomes
| 2.185547 |
biomedical
|
Study
|
[
0.99560546875,
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] |
[
0.99462890625,
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] |
In addition, we collected demographic data from all subjects enrolled in this study. Those variables include age (as continuous and binary, with 60 years being the cut off), biological sex, and education level, which we used as covariates.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278058_p15
|
PMC11278058
|
sec[1]/sec[4]/p[0]
|
2.5. Sample Size
| 4.117188 |
biomedical
|
Study
|
[
0.9990234375,
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[
0.998046875,
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0.00010329484939575195
] |
We planned the sample size using the available data from previous studies on taVNS and HRV . The effect sizes ranged from 1.01 (changes in total HRV power) to 13.72 (changes in HF-HRV). We could detect a variety of scenarios and different magnitudes of sample sizes, and we decided to choose a more conservative approach (effect size of 1.01). We assumed a type I error of 5% (alpha), a type II error of 20% (beta), and a power of 80% in a two-sided t -test for independent samples, and we estimated that a sample of 36 subjects would be needed. However, we expanded the sample by 20% to account for a conservative attrition rate and to increase power for secondary outcome analysis. Therefore, we included a total sample size of 44 subjects, leading to 22 subjects in each group.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278058_p16
|
PMC11278058
|
sec[1]/sec[5]/p[0]
|
2.6. Randomization and Masking
| 3.039063 |
biomedical
|
Study
|
[
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] |
[
0.5537109375,
0.43798828125,
0.0020198822021484375,
0.00614166259765625
] |
Using a web-based program ( http://randomization.com ), we created a randomization list in a 1:1 allocation ratio and kept it in sealed envelopes. An uninvolved staff member placed the randomization order in numbered sealed envelopes and maintained it throughout the study. Therefore, we could keep the blinding for participants and co-investigators, including outcome assessors.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278058_p17
|
PMC11278058
|
sec[1]/sec[6]/p[0]
|
2.7. Statistical Analysis
| 3.773438 |
biomedical
|
Study
|
[
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] |
[
0.9990234375,
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] |
The statistical analyses were carried out with STATA version 18. The differences between the metrics at baseline and after stimulation were calculated. A histogram was used to assess data distribution. Baseline characteristics were reported using descriptive statistics (e.g., mean and SD for continuous variables, frequency tabulations for categorical variables) for each group and compared using an independent t -test for continuous variables and Fisher’s exact test for categorical and binary variables.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278058_p18
|
PMC11278058
|
sec[1]/sec[6]/p[1]
|
2.7. Statistical Analysis
| 4.121094 |
biomedical
|
Study
|
[
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] |
[
0.99951171875,
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0.0002758502960205078,
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] |
The statistical analysis was focused on evaluating the impact of group assignment on various HRV outcomes, listed above. We first tested differences between groups by an independent t -test. Additionally, to calculate the adjust effects, we employed linear regression models to test for differences between the treatment and control groups across the outcome variables and to account for important covariates such as age and biological sex. The difference in scores (post-taVNS minus pre-taVNS) for each outcome was the dependent variable, and the groups (active and placebo) were the independent variable. The results for these variables were adjusted for the interaction term using the covariates mentioned above, such as group*age_group. However, only the interaction term (group*age_group) significantly altered the regression.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278058_p19
|
PMC11278058
|
sec[1]/sec[6]/p[2]
|
2.7. Statistical Analysis
| 4.066406 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.99951171875,
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0.0003287792205810547,
0.00005733966827392578
] |
For the models, we evaluated the linearity assumption by visually examining the scatterplot of each independent variable alongside a superimposed regression line plot. The assumption of homoscedasticity was verified through visual inspection of the scatterplot depicting standardized predicted values against standardized residuals . We assessed the normality of residuals through histograms and the Shapiro–Wilk normality test. Additionally, the central limit theorem was applied to distributions that approximated a normal distribution . To assess the relationships between changes (post-intervention minus baseline) in HRV indices, we conducted a Pearson correlation analysis. A significance level of p < 0.05 was set a priori to determine the statistical significance.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278058_p20
|
PMC11278058
|
sec[2]/sec[0]/p[0]
|
3.1. Healthy Participants
| 4.015625 |
biomedical
|
Study
|
[
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] |
[
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0.0003027915954589844,
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] |
The characteristics of the patients at baseline were well balanced between both groups. The mean age was 41.3 years and 61.3% of the sample were women ( Table 1 ). For the HRV metrics, there was some missing data from movement artifacts and intermittent signal loss in consecutive RR intervals, resulting in a sample ranging between 33 and 37 subjects. Independent sample t -tests for continuous variables and chi-squared tests or Fisher’s exact tests for binary and categorical variables, when comparing proportions, revealed no significant differences between baseline measures, with p -values ranging from 0.22 to 0.88.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278058_p21
|
PMC11278058
|
sec[2]/sec[1]/p[0]
|
3.2. Changes in HRV
| 4.105469 |
biomedical
|
Study
|
[
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] |
[
0.99951171875,
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0.00007164478302001953
] |
When looking at the differences between groups, there is a significant difference in the HF metric following the active stimulation of the vagus nerve as compared to sham taVNS. Active taVNS increased the HF-HRV significantly (t(36): 2.4, p = 0.02). Figure 2 and Figure 3 are a descriptive illustration of the changes in heart rate variability—HF metric—for both groups (Sham taVNS and Active taVNS) before (Pre_HF) and after (Post_HF) the stimulation, showing the pronounced increase in HF-HRV in the active group with the stimulation. This highlights the influence of taVNS on the HF component, indicating a shift in the cardiac autonomic function towards parasympathetic predominance.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278058_p22
|
PMC11278058
|
sec[2]/sec[1]/p[1]
|
3.2. Changes in HRV
| 4.183594 |
biomedical
|
Study
|
[
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[
0.9990234375,
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] |
In contrast, all other metrics of HRV measured in the trial (with their baseline values described in Table 1 ) did not reveal any significant changes between the active and sham groups in the LF/HF ratio (mean increase: sham 0.033 vs. active taVNS 0.218; t(36) = 1.25, p = 0.21) and SDNN (mean increase: sham 13.57 vs. active taVNS 6.62; t(36) = −0.77, p = 0.44). The RMSSD metric increased in the sham group (4.96) vs. a decrease in the active group (−4.79) (t(36) = −1.29, p = 0.20); PNN50 had an increase in the sham group of 2.33 vs. a decrease in active taVNS of −2.79 (t(32) = −1.23, p = 0.22); and HR had a mean decrease in sham of −2.23 vs. active taVNS of −2.77 (t(36) = −0.33, p = 0.73).
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278058_p23
|
PMC11278058
|
sec[2]/sec[2]/p[0]
|
3.3. Regression Analysis
| 4.121094 |
biomedical
|
Study
|
[
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] |
[
0.99951171875,
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0.00006669759750366211
] |
The variables mentioned in the outcome measure, such as age and sex, were tested as covariates in a linear regression model to control for their potential confounding effects on the relationship between taVNS treatment and HF_DIFF. Subsequently, a linear regression model was constructed to understand whether age or sex acted as moderators of the taVNS effect; thus, we included them as interaction terms. For context, among patients over 60 years old, males constituted 69.23% and females made up 30.77%. We found that the interaction term between age and treatment group was statistically significant ( p = 0.02), indicating that age is a significant effect modifier. This suggests that age not only influenced the outcome but enhanced the efficacy of the active taVNS as compared to the sham, with the effect becoming more pronounced in older participants . On the other hand, the interaction term involving sex was not significant ( p = 0.875), indicating that sex does not modify the taVNS effect on HF-delta ( Table 2 ).
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278058_p24
|
PMC11278058
|
sec[2]/sec[3]/p[0]
|
3.4. Correlation
| 3.927734 |
biomedical
|
Study
|
[
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[
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When performing a Pearson correlation between the changes in the HRV variables, a strong positive correlation was observed between SDNN_diff_value and RMSSD_diff_value , as well as a strong positive correlation observed between RMSSD_diff_value and PNN50_diff_value . There is no other strong positive or negative relationship highlighted by this analysis.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278058_p25
|
PMC11278058
|
sec[2]/sec[4]/p[0]
|
3.5. Adverse Effects
| 3.744141 |
biomedical
|
Study
|
[
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[
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] |
Participants were asked about side effects at the end of the stimulation period. No serious or unforeseen adverse events were documented. Only one participant in the active group reported transient tingling behind their left ear at the onset of stimulation, dissipating within the subsequent five minutes. The session concluded as planned, and no notable group distinctions were observed (sham taVNS: 0%; active taVNS: 0.04%; Pearson’s chi-squared test: χ 2 (1) = 1.0233, p = 0.312).
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278058_p26
|
PMC11278058
|
sec[2]/sec[5]/p[0]
|
3.6. Successful Blinding
| 3.007813 |
biomedical
|
Study
|
[
0.9921875,
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[
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We used a successful blinding questionnaire, where participants were queried about their assigned groups at the trial’s conclusion. Our findings revealed that 91% (40 individuals) provided incorrect responses regarding their group assignment, while only 9% (4 individuals) accurately identified their group. This clearly indicates the success of the blinding process.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278058_p27
|
PMC11278058
|
sec[3]/p[0]
|
4. Discussion
| 4.085938 |
biomedical
|
Study
|
[
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[
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Our study showed that one single session of taVNS modulates HRV, with higher changes in HF after active stimulation, indicating a shift in cardiac autonomic function toward parasympathetic predominance in healthy subjects. There was also a significant interaction with age, which suggests that older subjects showed a greater modulatory effect of taVNS on this metric.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278058_p28
|
PMC11278058
|
sec[3]/p[1]
|
4. Discussion
| 4.109375 |
biomedical
|
Study
|
[
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[
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The general consensus is that when at rest, parasympathetic outflow is mostly reflected by HRV in the time domain, and HF-HRV is frequently used as a proxy for parasympathetic activity during spontaneous breathing . Many organs and sensory areas in the outer ear and external auditory canal have been shown to interact, with the vagus nerve acting as a mediator. Examples of these interactions include the auriculo-cardiac reflex with cardiac inhibition, which can lead to syncope, and the ear-vomiting reflex . Clancy et al. found that stimulating the ear’s tragus with specific electrical pulses can shift the balance of the heart’s autonomic control toward the parasympathetic tonus. This effect was confirmed by a reduction in muscle nerve activity linked to stress, suggesting the potential of taVNS to influence heart rate and promote relaxation.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278058_p29
|
PMC11278058
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sec[3]/p[2]
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4. Discussion
| 4.332031 |
biomedical
|
Study
|
[
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The VN is the longest of the cranial nerves, made up of 80% afferent fibers and 20% efferent fibers, and has an intrinsic role in regulating the homeostatic parameters of the cardiovascular and respiratory systems . The auricular branch of the vagus nerve extends from the main bundle of the vagus nerve innervating the human ear, with most of its afferent projections to the brain located in the cymba conchae and tragus . The current fMRI evidence of the vagus afference shows that when compared to earlobe (control) stimulation, cymba conchae stimulation significantly activated the central vagal projections, including the ipsilateral NTS, the bilateral trigeminal nuclei, the dorsal raphe, the locus coeruleus, the contralateral parabrachial area, the amygdala, and the nucleus accumbens, and from there to upstream cortical projections . Based on that, stimulating the cymba conchae is able to activate brain areas which also control the vagal efferent. The insula, cingulate cortex, frontal and prefrontal cortices, hippocampus, thalamus, striatum, and amygdala showed the strongest correlations with HRV activity. Additionally, strong and mostly favorable relationships were found between HRV and brain area connectivity in the prefrontal cortex, cingulate cortex, and amygdala. Studies have shown intricate multi-level connections and support the idea that the brain and heart are connected by both structural and functional networks .
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278058_p30
|
PMC11278058
|
sec[3]/p[3]
|
4. Discussion
| 4.121094 |
biomedical
|
Study
|
[
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[
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Regarding our stimulation site, a human auricle dissection study demonstrated that the cymba conchae and tragus are the regions with the most concentrated auricular branch of the vagus nerve projections . Accordingly, we stimulated the conchae and used the HRV as one of the surrogates for measuring changes after the stimulation. We observed that the parameter that was more indicative of parasympathetic activity (HF-HRV) showed a significant increase in the active group. In our protocol, auricular vagus stimulation was performed bilaterally. Our recent meta-analysis showed that no cardiac problems were observed, and bilateral taVNS did not considerably raise the risk of unfavorable cardiovascular events , indicating that activation of the auricular vagus nerve stimulates more afferent fibers, which in turn produces an amplified effect on the central nervous system, rather than directly affecting the heart.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278058_p31
|
PMC11278058
|
sec[3]/p[4]
|
4. Discussion
| 3.951172 |
biomedical
|
Review
|
[
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[
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HRV is an accurate way to determine the health of the autonomic nervous system and offers vital information about its operation; low variation is present in sympathetic activation, such as stress conditions, with high variation in parasympathetic tonus, such as at rest or in relaxed conditions. Low HRV may indicate heart issues, whereas high HRV often means better health . It is a useful tool for measuring the nervous system’s reaction to environmental, emotional, and cognitive stimuli. Research indicates that, in healthy subjects, a higher HRV indicates better adaptability and a more favorable state of recovery, whereas a lower HRV indicates stress and a less favorable state of recovery .
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278058_p32
|
PMC11278058
|
sec[3]/p[5]
|
4. Discussion
| 4.082031 |
biomedical
|
Study
|
[
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[
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Research suggests that aging and older age are linked to reduced HRV. According to research, the 24 h average of 5 min segments, or rMSSD, decreases by about 3.6 milliseconds every ten years, reinforcing the increase in sympathetic tone with aging . Furthermore, the Cardiovascular Health Study showed that the age range between 65 and 74 years was when the frequency-domain HRV values declined the most . Our study showed that participants over 60 years old responded better to taVNS compared to younger participants, regardless of sex. This highlights that the higher sympathetic dominance that occurs with aging could be rebalanced using taVNS.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278058_p33
|
PMC11278058
|
sec[3]/p[6]
|
4. Discussion
| 4.382813 |
biomedical
|
Study
|
[
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[
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Increases in sympathetic neural activity and decreases in parasympathetic neural activity, as hallmarks of aging, are linked to modifications in autonomic nervous system function . Aging also brings about important anatomical changes in the brain . While more dorsal, lateral, and superior parts of the brain exhibit a higher loss in thickness with age, the more ventral regions, such as the ACC and the vmPFC, appear to remain generally maintained. Additionally, it has been proposed that in certain brain regions, there may be age-invariant correlations between HRV and cortical thickness . According to the findings of a study by Yoo et al. , there may be age-constant correlations between cortical thickness in more ventral brain regions, like the lateral OFC (which is less associated with age-linked declines in cortical thickness) and HRV. Recently, studies have linked vagal tone and the anatomical–molecular pathways of cellular senescence and age-related disease. For instance, according to Ask and Sütterlin , prefrontally controlled vagal neuroimmunomodulation is linked to telomere length, hence validating the Neuro-Immuno-Senescence Integrative Model and introducing a potential area of study.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278058_p34
|
PMC11278058
|
sec[3]/p[7]
|
4. Discussion
| 4.203125 |
biomedical
|
Study
|
[
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[
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In summary, autonomic alterations can have a negative impact on gut, heart, and emotional health. They may also contribute to a number of age-related illnesses that are becoming more common, such as hypertension, heart failure, and depression. In order to improve autonomic function in healthy individuals, taVNS is a promising therapeutic. For example, research found that 15 min of taVNS elevated HRV and enhanced spontaneous heart baroreflex sensitivity in young, healthy participants, increasing parasympathetic activity . Even with several studies in the area, there is still a lack of evidence regarding the acute effects of taVNS on HRV, and most of the findings are conflicting. For instance, Antonino et al. and Clancy et al. revealed a substantial decrease in the low-frequency/high-frequency ratio (LF/HF) in active taVNS compared to sham, indicating a rise in HRV. On the other hand, there were no differences in HF-HRV. taVNS also raised LF and LF/HF after extended stimulation (35 min), while short-term (10 min) stimulation had no effect on LF/HF . This suggests that the duration of stimulation can have a possible adaptation effect depending on the metric of HRV. In the study of Geng et al. , a notable shift in parasympathetic activity was seen in the high-frequency domain for brief (5 min) taVNS stimulation, with an additional improvement in the measurements of RMSSD and SDRR reported in healthy young persons in a recent work . Lately, a Bayesian random effects meta-analysis with 16 studies suggested that HRV is not a robust biomarker for acute taVNS . Interestingly, the investigations included contrasted various designs, stimulation targets, and parameters, which may impact how the findings are interpreted.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278058_p35
|
PMC11278058
|
sec[3]/p[8]
|
4. Discussion
| 4.09375 |
biomedical
|
Study
|
[
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[
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Furthermore, the correlations observed in our study, using the differences in HRV values before and after taVNS, suggest that taVNS consistently influences HRV. This is particularly evident in the enhancement of parasympathetic modulation, as indicated by the correlation between the changes in RMSSD and PNN50, and implies a broader regulatory effect on autonomic balance, reflected in the positive correlation between the changes in RMSSD and SDNN.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278058_p36
|
PMC11278058
|
sec[3]/p[9]
|
4. Discussion
| 4.046875 |
biomedical
|
Study
|
[
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[
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Another notable insight from our results is that not only taVNS was able to modulate HRV, but older subjects presented greater changes in HF after taVNS compared to young subjects. Since baseline HRV declines with age , taVNS could be more beneficial for older recipients because it causes greater increases in HRV in those with lower baseline HRV. Based on that and the fact that taVNS has a safe profile, portability, and usability, the technique shows potential to preserve function, health, and well-being as well as to avoid or lessen the impact of age-related impairments.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278058_p37
|
PMC11278058
|
sec[3]/p[10]
|
4. Discussion
| 4.027344 |
biomedical
|
Study
|
[
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[
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While our study provides critical insights into HRV metrics following taVNS, it is important to acknowledge inherent limitations, notably the homogeneity of our sample, which can limit the generalizability of our findings. A second limitation is that in our study, we conducted only one session of intervention without a longer follow-up, which makes it more difficult to measure the effect of uncontrolled factors like different session times and times of HRV measurement, menstrual cycle stages in female participants, and exercise load for each participant, all of which could affect the results. Nonetheless, it is noteworthy that it was possible to observe and measure the changes in HRV metrics following the intervention.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278058_p38
|
PMC11278058
|
sec[4]/p[0]
|
5. Conclusions
| 4.074219 |
biomedical
|
Study
|
[
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[
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Our research demonstrated that a single session of bilateral taVNS induces changes in HRV, particularly with increased HF components following active stimulation. This indicates a shift in cardiac autonomic function toward parasympathetic predominance in healthy individuals. Additionally, a noteworthy interaction with age was observed, indicating that older subjects exhibited a more pronounced modulatory effect of taVNS on this metric.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278074_p0
|
PMC11278074
|
sec[0]/p[0]
|
1. Introduction
| 4.730469 |
biomedical
|
Review
|
[
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[
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Vascular Ehlers–Danlos Syndrome is a rare autosomal dominant heritable connective tissue disorder with an estimated prevalence of 1/150,000 . It is caused by mutations in the collagen type III alpha 1 chain ( COL3A1 ) gene, which encodes the pro-alfa1 chain of type III procollagen, a fibrillary protein mainly expressed in the walls of blood vessels and hollow organs. The resulting tissue fragility increases the risk of arterial rupture, dissection, and aneurysm development, as well as rupture of the bowel and gravid uterus. Spontaneous pneumothorax, congenital hip dislocation, and talipes equinovarus can also occur. Patients may also display typical physical features such as thin nose and lips, hollow cheeks, prominent eyes, lobeless ears, translucent skin with prominent vascular pattern, acrogeria, easy bruising, atrophic scars, as well as small joint hypermobility. The diagnosis is suspected in the presence of the above clinical features or in family members of affected patients, though disease confirmation needs molecular genetic testing . Patients with vEDS exhibit high morbidity and mortality mainly from vascular events. Historically, the median life expectancy has been estimated to be around 50 years , with arterial complication rates around 1.3 events/5 years and overall organ complication rates reaching 1.6 events/5 years . Major complications occur in up to 85% of cases by the age of 43 . For instance, endovascular and surgical treatment outcomes are poor in this setting with complication rates as high as 46%, so prevention is essential . In 2010, the Beta Blocker in Ehlers–Danlos Syndrome Trial (BBEST) demonstrated a 64% reduction in the risk of arterial rupture or dissection in patients treated with celiprolol compared with controls . After this first attempt, no other medication has been clearly proven effective in preventing vascular complications in patients with vEDS, though ongoing trials are investigating other cardiovascular drugs, such as angiotensin receptor blockers (ARBs), which have yielded positive results in mouse models . The urgent need for new treatment strategies is emphasized by the fact that patients with vEDS still experience excessively high rates of serious vascular complications despite celiprolol therapy, as shown recently .
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278074_p1
|
PMC11278074
|
sec[0]/p[1]
|
1. Introduction
| 3.878906 |
biomedical
|
Review
|
[
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[
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The research has advanced greatly in recent years to overcome this gap, but there is still a long way to go. The aim of this narrative review is to summarize the current evidence on medical management of vEDS and provide future perspectives on possible novel treatment strategies , with a specific focus on vascular prevention.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278074_p2
|
PMC11278074
|
sec[1]/p[0]
|
2. Natural History of Vascular Ehlers–Danlos Syndrome: What Has Changed?
| 3.908203 |
biomedical
|
Study
|
[
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It is widely acknowledged that vEDS is an ominous condition even in young individuals. A study published in 2000 by Pepin et al. showed a median survival of 48 years, with over 80% of the patients experiencing at least one complication by the age of 40 . These data were supported by a subsequent work on more than 1200 patients, where median survival was particularly low in the male sex, mainly due to higher rates of death from vascular rupture by the age of 20 than in female counterparts .
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278074_p3
|
PMC11278074
|
sec[1]/p[1]
|
2. Natural History of Vascular Ehlers–Danlos Syndrome: What Has Changed?
| 3.966797 |
biomedical
|
Study
|
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[
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Impressively enough, the prognosis of patients with vEDS seems to have markedly improved over the last 20 years. An observational study by Frank et al. including 144 affected subjects followed in the French National Referral Center for Rare Vascular Diseases between 2000 and 2017 found an overall survival rate of 71.6% during a 5.3-year follow-up period and over 80% by the age of 50 . Comparable results were obtained in a recent multicenter observational study from the UK, where the 5-year survival was estimated around 90% .
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278074_p4
|
PMC11278074
|
sec[1]/p[2]
|
2. Natural History of Vascular Ehlers–Danlos Syndrome: What Has Changed?
| 4 |
biomedical
|
Study
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Several factors may explain this shift in the natural history of vEDS. First, vEDS management has significantly improved both in terms of the prevention and management of complications. In fact, the creation of dedicated, specialized centers in several countries has led to easier access to care while promoting patient education. Furthermore, several centers have implemented protocols to enhance vascular surveillance through regular follow-up imaging . Another relevant point is pharmacological therapy. In the above study by Frank et al., for example, about 90% of the patients were on celiprolol therapy. These subjects displayed significantly improved survival than those with no such treatment during the study period (72.4% vs. 52.2%, respectively; p < 0.001) . Similarly, in the study by Bowen et al., survival at 5 years was 96.53% for those on any cardiovascular medication (including other β-blockers and ARBs) and 42.69% for patients in the control group . Taken together, these data suggest that the systematic use of β-blockers and/or inhibitors of the renin–angiotensin–aldosterone system (RAAS) may have played a crucial role in improving outcomes of patients with vEDS in recent times. However, evidence supporting this hypothesis remains scarce, as described below.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278074_p5
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PMC11278074
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sec[2]/sec[0]/p[0]
|
3.1. The BBEST Study
| 4.371094 |
biomedical
|
Study
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Celiprolol is a third-generation β-blocker with β1-adrenoceptor antagonism and partial β2-agonism. In normotensive people, the β2-agonist properties predominate . Because of such unique characteristics, this drug may be better described as a selective adrenoreceptor modulator . Like other β-blockers, celiprolol has both antihypertensive and antianginal activity. However, the drug lacks the typical side effects of β-blockers, such as bronchoconstriction and peripheral vasoconstriction . Its blockade of β1-adrenoreceptors reduces the sympatho-adrenergic stimulation of the heart, decreasing the heart rate and myocardium contractility . Celiprolol also stimulates β2-receptors, improving vasodilatation . As evidenced by a 2013 study of porcine coronary arteries, celiprolol may also act as a β3-adrenoceptor agonist with resulting vasorelaxation . Additionally, it may induce coronary vasodilation by inducing the release of nitric oxide .
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278074_p6
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PMC11278074
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sec[2]/sec[0]/p[1]
|
3.1. The BBEST Study
| 4.136719 |
biomedical
|
Study
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In the past century, no specific medical treatment was available for patients with vEDS. In the late 90s, a group of French specialists hypothesized that a drug capable of reducing arterial wall stress while avoiding excessive vasodilatation and heart rate reduction might have improved the outcome in patients with vEDS. Celiprolol was chosen due to its unique properties. In fact, true vasodilators were unlikely to be well tolerated in subjects with vEDS, as they often have normal or even low blood pressure levels. Classical non-selective or selective β1-antagonsits were discarded as well to avoid the risk of chronic fatigue related to reduced heart rate in otherwise young and active patients . These considerations led to the BBEST, the first randomized trial on the effects of celiprolol in preventing cardiovascular events in the setting of vEDS. In this study, published in 2010, 53 patients were randomly assigned to treatment either with celiprolol with a target dose of 400 mg daily or with usual treatment and no β-blocker. The mean duration of follow-up was 47 months. The trial was stopped early for benefit, as celiprolol led to a threefold reduction in arterial ruptures or dissections in the treatment arm (hazard ratio 0.36; 95% confidence interval 0.15–0.88; p = 0.040) . Despite such encouraging results, this study has some important limitations worth mentioning and was therefore widely criticized afterwards , as discussed in the dedicated section below.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278074_p7
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|
3.2. Evidence from Experimental Models
| 4.113281 |
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Study
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Interestingly, a recent experimental study by Dubacher et al. in a mouse model of vEDS suggested that celiprolol but not losartan can improve the biomechanical integrity of the aortic wall, thereby potentially reducing the risk of dissection and rupture. Doxycycline, a tetracycline antibiotic capable of inhibiting MMPs, also positively impacted the mechanical properties of the aorta in treated mice . Targeting the balance of collagen homeostasis through inhibition of such enzymes had already proven beneficial in earlier preclinical studies on Col3a1 haplo-insufficient mouse models . However, offering doxycycline in the long term to patients with vEDS is unrealistic.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278074_p8
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|
3.2. Evidence from Experimental Models
| 4.308594 |
biomedical
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Study
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In addition to the classical β-blocker action, celiprolol stimulates nitric oxide production and thus may reduce vascular oxidative stress at the arterial wall level. The link between β adrenergic stimulation and TGFβ expression is another potential mechanism to mention in this regard . In fact, celiprolol may enhance TGFβ-mediated pro-fibrotic mechanisms through β1 antagonism while promoting collagen synthesis via β2 stimulation . This drug could therefore have a protective effect by increasing arterial stiffness. Accordingly, Boutouyrie et al. demonstrated significantly higher carotid distensibility and circumferential and pulsatile wall stress in patients with vEDS than in healthy controls , whereas celiprolol selectively increased Young’s elastic modulus by reducing carotid distensibility among BBEST participants . Importantly, a later study using another mouse model failed to demonstrate such a protective effect of celiprolol , whereas another work even suggested that the drug could accelerate rather than reduce death from aortic rupture in two different mouse models . Therefore, the precise effects of celiprolol in animal models of vEDS remain to be elucidated.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278074_p9
|
PMC11278074
|
sec[2]/sec[1]/p[2]
|
3.2. Evidence from Experimental Models
| 3.875 |
biomedical
|
Study
|
[
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In a recent case report published by Ishikawa et al., a skin biopsy was performed before and after 3 years of celiprolol administration in a patient with vEDS. Although the expression level of procollagen III did not change, the size differences in the collagen fibrils improved. Furthermore, the ER dilatation observed in skin fibroblasts before treatment, which indicated ER stress, was no longer noticed . Such preliminary data suggest an additional potential protective effect of celiprolol in patients with vEDS through these mechanisms as well, though further research should confirm this hypothesis.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278074_p10
|
PMC11278074
|
sec[2]/sec[1]/p[3]
|
3.2. Evidence from Experimental Models
| 2.78125 |
biomedical
|
Study
|
[
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Key findings from experimental models using celiprolol and other pharmacological agents in the setting of vEDS are summarized in Table 1 .
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278074_p11
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sec[2]/sec[2]/p[0]
|
3.3. Further Clinical Evidence
| 4.144531 |
biomedical
|
Study
|
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From a clinical perspective, after the BBEST, several observational studies have supported the protective role of celiprolol in vEDS. In 2019, Frank et al. published a retrospective study describing the outcomes of 144 molecularly confirmed vEDS patients followed in a French referral center between 2000 and 2017. All patients were recommended treatment with celiprolol (≤400 mg/day) on top of usual care. After a median follow-up of 5.3 years, overall patient survival rate was 71.6%, which was dependent on the COL3A1 variant, age at diagnosis, and medical treatment. In particular, patients treated with celiprolol had a better survival rate than controls and the observed reduction in mortality was dose-dependent, with the best protection being provided at the dose of 400 mg daily compared with lower doses ( p = 0.003) . In another study published in 2021 by a Swedish group, 40 patients with molecularly confirmed vEDS were offered celiprolol treatment in the period between 2011 and 2019. With a median follow up of 22 months, the annual risk of a major vascular event was 4.7%, which was comparable to that obtained in patients receiving celiprolol in the BBEST (5%) and lower than in untreated patients from the same study (12%) . Recently, Buso et al. published their personal experience with celiprolol in a cohort of 26 patients with molecularly confirmed vEDS followed at the Brescia University Hospital, Italy, from 2011 to 2023. At the last follow-up visit, all patients were on celiprolol therapy, 80% of whom were taking the maximum recommended dose of 400 mg daily. Whilst the drug was well tolerated overall, the yearly risk of symptomatic vascular events was still not negligible (8.8%), whereas the majority of the events occurred after reaching the maximum recommended dose of celiprolol .
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278074_p12
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PMC11278074
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sec[2]/sec[2]/p[1]
|
3.3. Further Clinical Evidence
| 3.732422 |
biomedical
|
Study
|
[
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In light of these data, the insufficient body of evidence supporting the efficacy and safety of celiprolol both in animal models and patients with vEDS, and the many limitations of the studies published so far, celiprolol is still not approved by the Food and Drug Administration (FDA) and is therefore not available for the treatment of vEDS in the US. A prospective, phase 3, randomized, double-blind, placebo-controlled efficacy study is ongoing and will hopefully provide some more robust data by the end of 2025.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278074_p13
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PMC11278074
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sec[2]/sec[2]/p[2]
|
3.3. Further Clinical Evidence
| 2.275391 |
biomedical
|
Study
|
[
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The clinical evidence on celiprolol and further potential drugs in the setting of vEDS is reported in Table 2 .
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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sec[3]/p[0]
|
4. Is Any Drug Better than None? Potential Role of Angiotensin II Receptor Antagonists
| 4.039063 |
biomedical
|
Study
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As celiprolol is not available in several countries and after the publication of the BBEST study and the experimental paper by Dubacher et al. , the question arose whether additional drugs acting on the cardiovascular system would elicit the same protection in the setting of vEDS. In a study using a Col3a1 m1Lsmi mouse model, Gorosabel et al. found that bisoprolol, a β1-selective antagonist, did not improve the biomechanical integrity of the thoracic aorta of treated mice compared with controls, suggesting that the beneficial effect of celiprolol may not be extrapolated to bisoprolol in humans .
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278074_p15
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PMC11278074
|
sec[3]/p[1]
|
4. Is Any Drug Better than None? Potential Role of Angiotensin II Receptor Antagonists
| 4.53125 |
biomedical
|
Study
|
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In addition to the regulation of β-adrenergic receptor function, several preclinical studies have highlighted the potential role of angiotensin II antagonism in vascular protection in the setting of vEDS. In 2013, Faugeroux et al. showed that angiotensin II infusion increased systolic blood pressure in both Col3a1 +/− and Col3a1 +/+ mice but led to a significantly higher rate of premature mortality in the former, particularly during the first week of infusion (55% vs. 0%). Remarkably, reducing angiotensin II doses significantly reduced mortality rates in this group. The authors therefore concluded that Col3a1 haplo-insufficient mice exhibit increased susceptibility to develop premature thoracic aortic rupture in response to angiotensin II and the associated increase in blood pressure levels . In a more recent French study on knock-in Col3a1 +/G182R mice leading to glycine substitution (the most common mutation observed in patients with vEDS), different antihypertensive therapies, alone or in combination, were compared in terms of effects on survival within the first 24 weeks of life . The drugs used in this study targeted heart rate and/or systolic blood pressure to decrease wall stress. In particular, mice were treated with different β-blockers such as propranolol and celiprolol, and the dihydropyridine calcium channel blockers amlodipine, losartan, and hydralazine. Among these medications, the only one that significantly reduced the risk of death from spontaneous rupture of the thoracic aorta was losartan. Of note, the discontinuation of losartan induced a return to increased mortality from aortic rupture similar to that in untreated mice, whereas initiation of losartan after weaning had the same strong beneficial effect on survival. Furthermore, administration of angiotensin II at doses with minimal effects on systolic blood pressure induced aortic rupture with a 100% mortality rate within 10 days after administration, suggesting that the deleterious effect of angiotensin II in vEDS may be at least partially unrelated to the increased blood pressure levels . In this regard, it is noteworthy that angiotensin II induces vascular remodeling through smooth muscle cell hypertrophy and secretion of extracellular matrix (ECM) proteins via multiple canonical and noncanonical signaling pathways . If altered, such mechanisms could contribute to aortic fragility in individuals with vEDS . Moreover, angiotensin 1 receptors are known to modulate sympathetic vasomotor function , which could also play a deleterious role in this setting. All these mechanisms could also be targeted by ARBs.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278074_p16
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PMC11278074
|
sec[3]/p[2]
|
4. Is Any Drug Better than None? Potential Role of Angiotensin II Receptor Antagonists
| 4.164063 |
biomedical
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Study
|
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From a clinical perspective, a recent retrospective study on 126 patients with molecularly confirmed vEDS followed in two referral centers of the UK EDS National Diagnostic Service showed that, regardless of the cardiovascular drug used, patients treated with celiprolol, other β-blockers, and/or ARBs, alone or in combination, had a significantly more favorable outcome than untreated subjects (96.53% vs. 42.67%, respectively, at 5 years). However, the small sample size, lack of randomization, and the potential presence of confounding factors are major limitations to consider. The Angiotensin II Receptor Blockade in Vascular Ehlers–Danlos Syndrome (ARCADE) study, a multicenter, double-blind, randomized, placebo-controlled, parallel group study with blind endpoint evaluation investigating the efficacy and safety of irbesartan in adult patients with vEDS , has been completed and hopefully its results will be announced soon.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278074_p17
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sec[4]/p[0]
|
5. Role of the PLC/IP3/PKC/ERK Signaling Pathway: New Hope or Nope?
| 4.503906 |
biomedical
|
Study
|
[
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Recently, dysregulation of the PLC/IP3/PKC/ERK signaling pathway emerged as a potential contributor to vEDS pathogenesis, as well as another promising therapeutic target in the near future. In physiological conditions, this complex intracellular signaling cascade is involved in various cellular processes, including cell growth, differentiation, and survival . Using two heterozygous Col3a1 mutations-carrying mouse models of vEDS ( Col3a1 G209S/+ and Col3a1 G938D/+ ), Bowen et al. demonstrated that abnormalities in this signaling pathway are likely involved in spontaneous vascular events in the setting of vEDS, as pharmacologic inhibition of PKCβ or ERK1/2 led to better outcomes in mutated mice by preventing spontaneous fatal aortic rupture. In particular, mice treated with ruboxistaurin, a PKCβ inhibitor, displayed increased survival after 45 days compared with controls (94% vs. 52%, respectively), suggesting that PKC-dependent ERK activation may be a critical driver of aortic disease in vEDS. Similarly, the administration of cobimetinib, a specific inhibitor of MEK, resulted in 90% survival after 45 days. Intriguingly, hydralazine improved survival in treated mice when initiated at birth, though protection from aortic rupture was abruptly lost around the time of sexual maturity, particularly in males. Hydralazine is an anti-hypertensive medication that acts, at least partially, by blocking the IP3-mediated calcium release from the ER and hence PKCβ activation. The above finding suggests that androgens could influence the signaling pathway by acting distally to IP3. In fact, concomitant treatment with androgen receptor antagonist bicalutamide resulted in increased survival in both sexes. Similar results were found in mice treated with both hydralazine and spironolactone .
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278074_p18
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PMC11278074
|
sec[4]/p[1]
|
5. Role of the PLC/IP3/PKC/ERK Signaling Pathway: New Hope or Nope?
| 4.109375 |
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|
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|
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Although a subsequent study using another knock-in mouse model ( Col3a1 +/G182R ) did not confirm these aspects , the above findings generated great enthusiasm in the scientific community, as they shed light after a long time on the pathophysiological mechanisms of vEDS and for the potential therapeutic repercussions. In fact, shortly after the study was published, the Prevention of Rupture with Enzastaurin in Vascular Ehlers–Danlos Syndrome (PREVEnt) trial was announced . This two-arm, multicenter, randomized, double-blind, placebo-controlled study aimed at evaluating the efficacy and safety of AR101 (enzastaurin) 500 mg once daily compared to placebo in preventing arterial events in individuals with vEDS. Enzastaurin is another PKCβ/PI3K/AKT signaling inhibitor that has shown promising results in patients with brain tumors and is commonly used in clinical practice . Unfortunately, in October 2022, the company sponsoring the PREVEnt trial announced the indefinite suspension of the study for commercial reasons , and we still do not know whether and when this avenue will be further explored in the future.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278074_p19
|
PMC11278074
|
sec[5]/p[0]
|
6. Gene Therapy: A Road Yet to Be Taken
| 3.455078 |
biomedical
|
Other
|
[
0.99755859375,
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[
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Current treatments for vEDS are only symptomatic due to our limited understanding of its pathomechanisms. In-depth molecular and cellular studies are essential to identify therapeutic targets. Beyond pharmacological approaches, gene therapy strategies hold the potential to cure the disease by addressing its root cause.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278074_p20
|
PMC11278074
|
sec[5]/p[1]
|
6. Gene Therapy: A Road Yet to Be Taken
| 4.1875 |
biomedical
|
Study
|
[
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] |
[
0.99560546875,
0.0005440711975097656,
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0.00015866756439208984
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Concerning the potential of gene therapy for treating vEDS, RNA interference (RNAi) technology has successfully targeted the expression of the mutant COL3A1 allele harboring a glycine substitution (p.Gly252Val) in patients’ dermal fibroblasts. This approach effectively targets the mutant mRNA while preserving the wild-type allele. Moreover, it has been associated with enhanced collagen fibril formation and reduced negative effects of unfolded proteins, suggesting promising therapeutic potential .
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278074_p21
|
PMC11278074
|
sec[5]/p[2]
|
6. Gene Therapy: A Road Yet to Be Taken
| 4.480469 |
biomedical
|
Review
|
[
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[
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In addition to RNAi, RNA editing represents an even more promising RNA-targeting strategy, even if the efficient delivery of RNA editing components to specific tissues, especially the vasculature, remains a significant challenge. RNA editing, particularly A-to-I editing, offers the potential to therapeutically correct pathogenic single nucleotide variants in the human transcriptome with minimal risk of creating permanent off-target edits in the genome, unlike some other editing techniques . A-to-I editing involves the hydrolytic deamination of adenosine (A) to inosine (I) and is facilitated by adenosine deaminases acting on RNA enzymes. Given that G-to-A mutations account for nearly half of all known disease-causing point mutations in humans and many clinically relevant mutations in COL3A1 involve pathogenic G-to-A mutations causing glycine substitutions , A-to-I conversion by RNA-editing systems presents significant therapeutic potential. This approach could correct disease-causing mutations, offering immense opportunities for developing targeted treatments for vEDS patients.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278074_p22
|
PMC11278074
|
sec[6]/p[0]
|
7. Recent Evidence on Non-Coding RNAs as Molecular Targets
| 4.136719 |
biomedical
|
Study
|
[
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[
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Epigenomic studies focusing on the modulation of non-coding RNA (ncRNAs) expression in cardiovascular conditions, including thoracic/abdominal aortic aneurysms and vascular connective tissue disorders like Loeys–Dietz and Marfan syndromes, have provided valuable insights into the dysregulated gene regulatory pathways linked to the underlying disease mechanisms. These research efforts have elucidated how ncRNAs, especially microRNAs (miRNAs), may influence the expression of key genes involved in maintaining vascular health and contributing to their pathogenesis .
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278074_p23
|
PMC11278074
|
sec[6]/p[1]
|
7. Recent Evidence on Non-Coding RNAs as Molecular Targets
| 4.636719 |
biomedical
|
Study
|
[
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[
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To better understand the complex vEDS pathomechanisms and identify potential molecular targets for therapeutic intervention, a recent study by Chiarelli et al. employed an integrative multi-omics approach on patient-derived dermal fibroblasts. This comprehensive transcriptomics and miRNomics analysis provided an in-depth view of the molecular alterations in vEDS. It revealed a complex pathological interplay between disrupted ECM organization, altered ER proteostasis, and defective autophagy. The detailed miRNA expression profile of patient fibroblasts offered the first disease-specific signature, underscoring the critical role of miRNAs in the vEDS pathobiology. Specifically, epigenetic changes caused by the aberrant expression of several miRNAs, including miR-15b-5p, miR-16-5p, miR-21-3p, miR-24b-3p, miR-29a-3p, miR-29b-3p, miR-138-5p, miR-145-5p, and miR-195-5p, can affect the dysregulated gene expression networks by regulating transcription of a range of targets. Among them, the upregulation of miR-29 family members, i.e., miR-29a-3p and miR-29b-3p, appears to significantly disrupt ECM turnover and cell survival processes, such as ER proteostasis and the autophagy–lysosome pathway, essential for maintaining vascular integrity. Notably, the increased expression of miR-29a/b is strongly associated with the downregulation of several genes involved in vascular ECM structure and turnover (e.g., collagens, elastin, ECM-modifying enzymes), contributing to aortic damage and aneurysm development . These miRNAs could emerge as critical molecular targets for vEDS, impacting the vascular pathogenesis. Ongoing research targeting miR-29a and miR-29b holds promise for developing tailored therapies addressing the condition’s burden and improving patient management.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278074_p24
|
PMC11278074
|
sec[7]/p[0]
|
8. Limits of Available Evidence and Challenges to Overcome
| 3.931641 |
biomedical
|
Study
|
[
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[
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Several aspects diminish the strength of the above studies and need to be mentioned. First, although celiprolol is the only drug tested in a clinical trial, evidence supporting its efficacy and safety in patients with vEDS remains very limited. In the BBEST study, investigators were not blinded with respect to the treatment, since creating a placebo with the same aspect as celiprolol tablet was excessively expensive . The small number of patients recruited and the fact that only 33 out of 53 participants had proven COL3A1 mutations constitute additional limitations worth mentioning . On the other hand, the remaining clinical evidence supporting the use of celiprolol in vEDS stems from observational studies, not designed for adequate control with placebo or further treatments .
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278074_p25
|
PMC11278074
|
sec[7]/p[1]
|
8. Limits of Available Evidence and Challenges to Overcome
| 3.984375 |
biomedical
|
Study
|
[
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Discrepancies between the results obtained by using celiprolol and other drugs in various mouse models is also noteworthy. The first models generated harbored heterozygous or homozygous null mutations, which do not capture the full spectrum of mutations responsible for the most common vEDS subtypes, like glycine substitutions or exon skips . Later, more advanced and reliable models carrying knock-in mutations similar to those known to induce vEDS in humans have partially overcome such pitfalls ; however, conflicting evidence still imposes caution in the interpretation of preclinical studies in this and other conditions, such as Marfan syndrome .
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278074_p26
|
PMC11278074
|
sec[7]/p[2]
|
8. Limits of Available Evidence and Challenges to Overcome
| 4.371094 |
biomedical
|
Review
|
[
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[
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While RNAi-based gene therapy and RNA editing show promise for vEDS, several challenges must be overcome to make these viable treatment options. Developing allelic-specific knockdown for diverse array of COL3A1 alleles is essential for ensuring precision and effectiveness. Additionally, achieving the efficient delivery of RNAi and RNA editing to treat tissues, particularly the vasculature, is crucial. The dynamic environment of the vascular system, characterized by constant movement and complex architecture, complicates the development of delivery mechanisms that can achieve precise targeting without causing adverse effects. Ensuring the long-term expression of therapeutic agents is another significant hurdle. This requires developing systems that can maintain stable and consistent gene expression over extended periods, avoiding the degradation or inactivation of therapeutic RNA. Furthermore, preventing immune responses to these therapeutic agents is critical, as the body’s natural defense mechanisms could potentially neutralize the therapy or cause harmful side effects. The specificity of RNAi technologies also presents a challenge. Off-target effects, where the therapy inadvertently affects unintended genes or cellular processes, can lead to unexpected consequences, making it vital to enhance the precision of these technologies.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278074_p27
|
PMC11278074
|
sec[7]/p[3]
|
8. Limits of Available Evidence and Challenges to Overcome
| 4.203125 |
biomedical
|
Review
|
[
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[
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The timeline for gene therapies to become available for vEDS patients is contingent on overcoming the above-mentioned challenges and navigating clinical trials. Typically, the development and approval process for new gene therapies can span a decade or more, involving preclinical studies, multiple phases of clinical trials, and regulatory review. Given the current pace of research and advancements in RNA technologies, it is conceivable that effective gene therapies for vEDS could become available within the next 10 years or less. For instance, the RNAi therapeutic agent Patisiran, used to treat hereditary transthyretin amyloidosis, has shown remarkable success and received FDA approval within a relatively short period . Regarding RNA editing, Wave Life Sciences advanced the first-ever adenosine deaminases acting on RNA (ADAR)-based RNA editor into healthy volunteers in 2023 for alpha-1 antitrypsin deficiency, with plans to treat patients soon. In parallel, a growing number of biotechs are setting their sights on similar RNA-editing opportunities for various monogenic disorders, including cardiovascular diseases . These precedents suggest that with continued research, the development of gene therapies for vEDS is feasible, albeit with its unique set of challenges.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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|
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|
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|
9. Practical Implications: How to Protect Patients with Vascular Ehlers–Danlos Syndrome in 2024?
| 3.494141 |
biomedical
|
Other
|
[
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In light of the aforementioned, one may question how the currently available evidence translates into clinical practice. Owing to the congenital, chronic, and aggressive nature of vEDS, the best preventative strategy in affected patients is likely to be a multidisciplinary approach in referral centers, so as to ensure adequate care and long-term follow-up . Drug therapy may also play a key role in disease management, though treatment options remain very limited in this setting, as extensively discussed above.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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|
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|
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|
9. Practical Implications: How to Protect Patients with Vascular Ehlers–Danlos Syndrome in 2024?
| 4.0625 |
biomedical
|
Other
|
[
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[
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In our Center for Rare Vascular Diseases at the University Hospital of Brescia (“Spedali Civili di Brescia”), Italy, individuals referred with vEDS are monitored and treated according to our local clinical protocols (“Percorsi Diagnostico Terapeutici Assistenziali”), which basically reflect the existing evidence. Once the presence of a causative mutation is confirmed, patients undergo a series of instrumental investigations to assess in particular the status of their cardiovascular system, including thorough clinical evaluation, office blood pressure measurement and 24 h ambulatory blood pressure monitoring, transthoracic echocardiography, as well as whole-body vascular imaging with computed tomography or magnetic resonance angiography. Unless contraindicated, celiprolol therapy is offered to all patients, as this remains the only drug tested so far in a clinical trial in this setting. Follow-up is generally proposed every 12 to 18 months, except in cases of intercurrent clinical conditions necessitating more closer monitoring. Celiprolol is titrated progressively up to a maximum of 400 mg per day, based on patients’ age and comorbidities, individual tolerance, as well as blood pressure and heart rate values. If blood pressure is not controlled according to current guidelines , patients are offered additional antihypertensive treatment usually consisting of an ARB. Based on the above evidence , the latter may actually be at least as effective as celiprolol in reducing the rate of vascular events, but further research is needed.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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9. Practical Implications: How to Protect Patients with Vascular Ehlers–Danlos Syndrome in 2024?
| 1.853516 |
biomedical
|
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|
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Similar protocols for clinical management are being adopted by other specialized centers across several countries . Notwithstanding this, there are currently no evidence-based guidelines for management and surveillance , and an individualized approach is likely warranted.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
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10. Conclusions
| 4.015625 |
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vEDS is a condition with a dramatic impact on affected patients. Although outcomes have significantly improved in recent years, much effort is still needed to fully understand the pathophysiological mechanisms of the disease and to provide effective treatment strategies. Beyond celiprolol, other cardiovascular drugs including ARBs may also contribute in the prevention of vascular events. Although the PREVEnt study was stopped early, inhibitors of the PLC/IP3/PKC/ERK signaling pathway could also play a role in the future. Gene therapy, particularly A-to-I conversion by RNA editing systems, is another promising curative approach in this setting. Lastly, miRNAs involved in vascular ECM structure and turnover could emerge as critical molecular targets for vEDS, providing real hope to affected patients.
|
[
"Giacomo Buso",
"Federica Corvini",
"Elena Maria Fusco",
"Massimiliano Messina",
"Fabio Cherubini",
"Nicola Laera",
"Anna Paini",
"Massimo Salvetti",
"Carolina De Ciuceis",
"Marco Ritelli",
"Marina Venturini",
"Nicola Chiarelli",
"Marina Colombi",
"Maria Lorenza Muiesan"
] |
https://doi.org/10.3390/jcm13144255
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
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|
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|
1. Introduction
| 4.730469 |
biomedical
|
Review
|
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The rising global population, climatic perturbations, and exhausting natural resources are key drivers of ecological imbalance and extinction of plants and animals. In the face of widespread damages and climatic uncertainties, existing biodiversity can support mankind and address the current challenges associated with providing bio-based resources and tackling environmental challenges, ecosystem restoration, and addressing global food demands . Microorganisms exist as integral members of the ecosystem, demonstrating ubiquitous presence. Due to their significant association with and influence on human lives, microbes demonstrate remarkable potential to adapt and thrive in climatic variations and extreme niches and promote environmental sustainability . Among other biological species, fungi comprise an integral component of our biodiversity and are estimated to include 2.2 and 3.8 million species ; however, the vast majority remain unexplored due to limited knowledge/insights about fungal biology and sophisticated technologies. The era of fungal biotechnology started with citric acid production (by controlled fermentation of Aspergillus niger ) by Pfizer in 1919 and has expanded to commercial use in food additives and the chemical and pharmaceutical sectors . Worldwide companies like Bayer, DuPont, Kerry Group, AB Enzymes, etc., are harnessing fungal resources for economic purposes. Several species of edible fungi are being extensively investigated as attractive resources of ‘high-value’ metabolites including antibiotics, food ingredients/additives, chemicals, industrial enzymes, pigments, etc. . While filamentous fungi have been widely explored and harnessed, edible mushrooms (from Ascomycota and Basidiomycota ), Saccharomyces cerevisiae , Pichia pastoris , and Yarrowia lipolytica , have been increasingly exploited for commercial use. The advances in fungal biotechnology have opened new avenues and significantly contributed to creating engineered strains with high product yields, bio-functionality, and value addition . For the discovery of new/novel transformative medicines, an insightful discussion suggested that fungi have evolved to create genetically encoded small molecules (GEMs) that can be effective against human targets, and tend to have better pharmacokinetics– brain penetration, oral bioavailability, and less off-target effects, compared to synthetic agents facilitated by advanced high-throughput technologies . With considerable progress in omics biology and their integrated use, a vast repertoire of natural products has been identified and biologically evaluated, attributed to the recent insights on the biosynthetic pathways/mechanisms. Furthermore, optimized production of these compounds can be achieved in cultures via cultivation and metabolic methods including CRISPR-Cas9-mediated gene editing, metabolic engineering, and gene silencing . The publicly available genome resources for fungal species Trichoderma spp., Aspergillus spp., Ganoderma lucidum , Penicillium spp., Rhizopus spp., and others have opened new avenues in bridging knowledge gaps in fungal biology and biotechnologies. The advanced molecular predictions have considerably expanded the metabolic pool of fungal high-value metabolites and utilization for creating a bio-based economy and achieving SDGs. Through its policies and reforms, the United Nations SDGs aim to improve people’s livelihood and facilitate sustainable practices , and it is crucial to preserve global biodiversity and bridge the gap between the microbiome and its role in global health .
|
[
"Pragya Tiwari",
"Kyeung-Il Park"
] |
https://doi.org/10.3390/jof10070506
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N/A
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https://creativecommons.org/licenses/by/4.0/
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1. Introduction
| 4.171875 |
biomedical
|
Review
|
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The rapid developments in fungal biology have facilitated the development of biomass-conversion technologies, and the production of high-value substances as food and feed components. Microbe-based sustainable innovations would likely contribute to United Nations SDGs by providing affordable energy (use of agro-industrial waste by microbial conversions), reducing economic burdens/affordable living conditions (new opportunities by the creation of bio-based industries for sustainable living), tackling climatic changes (use of sustainable alternatives fuels for reducing carbon footprints), conserving marine life (production of microbe-based bioplastics for safer marine life) and poverty reduction (microbial products/microalgae farming), among other initiatives . These objectives can be achieved via fungal biotechnologies to enhance the production of metabolites, chemicals, and proteins, microbial processing (using microbial enzymes), and advances in biorefineries to develop high-value products. Field and coworkers discussed the potential of mycorrhizal associations as a sustainable approach to achieving food security, conservation, and SDGs . It is important to mention that many mycorrhizal associations of fungi form edible mushrooms, while their collection and consumption are significant for nutrition, traditions, and the global economy . Furthermore, staple cereal crops and high-value food crops (vanilla flavors) benefit from mycorrhizas, with an important yet overlooked impact on human societies and the ecosystem.
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[
"Pragya Tiwari",
"Kyeung-Il Park"
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https://doi.org/10.3390/jof10070506
|
N/A
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https://creativecommons.org/licenses/by/4.0/
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en
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1. Introduction
| 2.529297 |
biomedical
|
Other
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Delving into how the advances in fungal biotechnologies can attain SDGs, state-of-the-art concepts, transformative approaches, achievements, and prospects/directions in the future are discussed in this paper.
|
[
"Pragya Tiwari",
"Kyeung-Il Park"
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https://doi.org/10.3390/jof10070506
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N/A
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https://creativecommons.org/licenses/by/4.0/
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en
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2. Fungal Biotechnologies and SDGs—How Far We Have Come
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other
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In the face of climate adversities and changing landscapes, human reliance on fossil fuels has impacted productivity and lifestyles and has driven increased emission rates and environmental deterioration . The increased recognition and need to prioritize sustainable practices to address and regulate the environmental impact of human activities have been the main goals of SDGs of the United Nations.
|
[
"Pragya Tiwari",
"Kyeung-Il Park"
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https://doi.org/10.3390/jof10070506
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N/A
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https://creativecommons.org/licenses/by/4.0/
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en
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2. Fungal Biotechnologies and SDGs—How Far We Have Come
| 2.568359 |
biomedical
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The enriched yet less tapped fungal biodiversity can contribute to achieving SDGs, a prospective initiative of the United Nations . Fungal species provide transformative opportunities from petroleum-based to bio-based economy opportunities attributed to converting organic substances into diverse ‘high-value’ products for addressing socio-economic concerns. The utilization of fungal bio-based products is sustainable in securing and enhancing the food supply for a growing population and limiting greenhouse emissions. In addition, the advances in fungal biotechnologies have the potential to tackle global climate change and accomplish SDG reforms ( Table 1 ).
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[
"Pragya Tiwari",
"Kyeung-Il Park"
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https://doi.org/10.3390/jof10070506
|
N/A
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https://creativecommons.org/licenses/by/4.0/
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en
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2.1. Fungal ‘High-Value’ Products to Achieve Global Food Security, Tackle Hunger and Malnutrition
| 4.023438 |
biomedical
|
Review
|
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Unlocking the road to sustainable food production is challenged by the growing world population, climate fluctuations, food prices, global catastrophes, and agricultural losses due to pathogens . The development of bio-based products via fungal biotechnologies demonstrates potential in reducing hunger and malnutrition and ensuring food security. Moreover, multiple lifestyle diseases can be tackled by functional foods and nutraceuticals of fungal origin , following balanced nutrition. Alternative food resources have gained key consensus due to their beneficial health impact and nutritional value. The multi-faceted aspects of food components are improved following microbial synthesis including bio-functionality, quality/nutritional value, peptide synthesis, antimicrobial function, and reduction in antinutritive components, etc. . Fungi-based food demonstrates potential as a high-nutritional source for addressing global hunger and malnutrition, besides demonstrating industrial importance .
|
[
"Pragya Tiwari",
"Kyeung-Il Park"
] |
https://doi.org/10.3390/jof10070506
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N/A
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https://creativecommons.org/licenses/by/4.0/
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en
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2.1. Fungal ‘High-Value’ Products to Achieve Global Food Security, Tackle Hunger and Malnutrition
| 4.535156 |
biomedical
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Review
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Among the 2–11 million fungal species in nature, only a fraction (approx. 1.5 lakh species) have been reported; furthermore, only some adhere to the acceptable guidelines of functional food. Since prehistoric times, fungal species have been used to prepare beverages and food products including cheese, bread, food flavors, etc. Only recently, the horizon has expanded to other biotechnological utilities. The prospective pharmaceutical/industrial use of economically viable strains can be attributed to the tractability and transformative potential of fungi, which lead to horizontal gene acquisition and overall plasticity . The edible mushrooms from phyla Ascomycota and Basidiomycota are widely utilized in food preparations across the globe and viewed as exquisite delicacies. The notable fungi namely Aspergillus , Penicillium , and Fusarium sp. are widely recognized for their nutraceutical/pharmacological properties. The fungal mycelium comprises dietary fiber, health-promoting lipids, and vitamins and has health benefits. Some edible fungal species are key sources of probiotics and food flavors , while certain filamentous fungi are good protein sources (high protein content) . The food derived from fungal sources has the following major advantages: amino acid profiles, high nutritional and protein content , and high concentration of fibers, vitamins, and unsaturated fats in the case of edible mushrooms . Research into harnessing the socio-economic benefits of fungi has delved into developing food components comprising nutraceuticals, functional food products, pharmaceuticals, and enzymes . Key studies have documented the bioactivities of fungal constituents. Polysaccharides from Morchella esculenta promote antioxidant enzyme function , Ganoderma enhance immune functions , Tremella relieves epidermal bleeding and Agaricus bisporus restricts the growth of cancer cells , among other examples. Health promotion effects are demonstrated by oligosaccharides from copropilous fungi and are developed as a type of functional food . With the advent of white fungal biotechnology, the quality and nutritional value of food products have remarkably improved in the flavor of bread and beverages, single-cell protein (SCP) quality and the yield and shelf life of products . Worldwide, mushrooms are considered to be major aspects of various cuisines and highly nutritional sources of carbohydrates (60%), protein (27–48%), and lipids (2–8%) , amino acids (glutamine, valine, leucine, etc.) and vitamins . The commercially cultivated mushroom species are represented by Agaricus bisporus , Pleurotus spp., Auricula auricula , Lentinus edodes , and Volvariella volvacea . The commercial market for mushrooms has witnessed a tremendous upsurge, with the value for oysters, shiitake, and champignons exceeding USD 50 billion by 2022 .
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[
"Pragya Tiwari",
"Kyeung-Il Park"
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https://doi.org/10.3390/jof10070506
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N/A
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https://creativecommons.org/licenses/by/4.0/
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en
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2.1. Fungal ‘High-Value’ Products to Achieve Global Food Security, Tackle Hunger and Malnutrition
| 4.042969 |
biomedical
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Study
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Tian and coworkers showed the beneficial effects of A. bisporus on glucose homeostasis, and the prebiotic effect on glucose homeostasis and regulation of diabetes. In C57BL/6 mice, succinate and propionate produced by Prevotella sp. signals intestinal gluconeogenesis, affects the gut–brain neural circuit, and reduces glucose in hepatic cells. The growing awareness about the nutritional components in multiple fungal species and their increased consumption has raised the demand, and sustainable methods are being employed to meet the increased demands globally. The development of novel strains via genetic engineering studies would be a prospective approach to increase the desired product yield and productivity. Fungal species are ideal resources to develop alternate food components, novel drug molecules, and maintain environmental sustainability.
|
[
"Pragya Tiwari",
"Kyeung-Il Park"
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https://doi.org/10.3390/jof10070506
|
N/A
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https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057391_p8
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2.2. Harnessing Pharmaceutical Metabolites from Fungi in Healthcare
| 2.943359 |
biomedical
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Other
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SDGs established by the United Nations aim to attain sustainable growth and holistic upliftment of human lives by 2030, utilize alternative bio-based resources, and address global issues. The transition from a fossil-based to a bio-based economy requires the integration of advanced biotechnologies with bioeconomy . The diverse yet interesting group of known fungi inhabits different ecological niches and contributes to multi-faceted roles in the environment, ranging from symbionts, and decomposers to pathogens.
|
[
"Pragya Tiwari",
"Kyeung-Il Park"
] |
https://doi.org/10.3390/jof10070506
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N/A
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https://creativecommons.org/licenses/by/4.0/
|
en
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2.2. Harnessing Pharmaceutical Metabolites from Fungi in Healthcare
| 3.982422 |
biomedical
|
Review
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Fungal species produce a plethora of diverse, ‘high-value’ compounds including therapeutics, food components, biofuels, chemicals, vegan leather, organic acids, industrial materials, etc., that can be effectively utilized for sustainable living. Fungi, as the major drivers of bio-based economy, demonstrate diverse fermentation capabilities (industrial value) attributed to their active metabolism (ecological relevance) and adaptation to wider niches (industrial applications). The commercially important high-value products, namely antibiotics and drugs, can be utilized to treat human ailments and positively impact human health and well-being. To date, thousands of pharmacologically active metabolites have been purified and characterized using fungi- demonstrating potent efficacies in treating multiple disorders .
|
[
"Pragya Tiwari",
"Kyeung-Il Park"
] |
https://doi.org/10.3390/jof10070506
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N/A
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https://creativecommons.org/licenses/by/4.0/
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en
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39057391
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2.2. Harnessing Pharmaceutical Metabolites from Fungi in Healthcare
| 4.523438 |
biomedical
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Review
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The landmark discoveries of penicillin and cephalosporin C from fungi opened new avenues and revolutionized fungi-mediated drug discovery. Constituting both classes of traditional drugs and recent landmarks, fungi-derived drugs have been effective in treating the following chronic diseases: autoimmune disorders (immunosuppressants), hypercholesterolemia (statins), and chronic infections (antifungal and antibiotics) . The representative examples include cephalosporins (antibiotic), penicillin V (antibiotic), fusidic acid (antibiotic), griseofulvin (antifungal), retapamulin and enfumafungin (antifungal), among other notable examples. The translational success of these drugs can be attributed to their validation in clinical trials (drugs for drug-resistant depression and cancer). Subsequently, fungal-derived immunosuppressants, such as cyclosporin A (from Tolypocladium inflatum ), block the calcineurin pathway (hampering T-cell activation in humans) and have been pivotal in organ transplantations . Another drug (isolated from Penicillium brevicompactum ) named mycophenolic acid hampers inosine monophosphate dehydrogenase and biosynthesis of guanine, which restricts the proliferation of lymphocyte (in organ transplantations) . The synthetic compound, fingolimod (inspired by fungi-derived myriocin), is produced by Novartis and achieved blockbuster success as an immunosuppressant for multiple sclerosis, generating USD 1 billion in 2012 . Tiwari et al. extensively discussed and highlighted the potential of plant-associated endophytes to produce potent antimicrobials and counter drug-resistant microbes, an emerging medical concern in the present era. The antimicrobials, namely hypericin, cryptocandin, leucinostatin A, colletotric acid, munumbicins, and their derivatives demonstrated clinical efficacies in treating drug-resistant pathogens; however, assessment and further trials are imperative to establish their therapeutic potential and drug development. In obstetric medicine, bromocriptine (a synthetic form of ergocryptine), is a dopamine agonist and restricts prolactin release from the pituitary gland . It is used for the treatment of hyperprolactinemia-related conditions. In therapeutic advances for treating blood cholesterol levels, fungal-derived drugs have proved pivotal in achieving key success. The discovery of mevastatin (compactin) from Penicillium citrinum by Akira Endo, a Japanese scientist, ushered in a new era . Lovastatin (the statin drug), isolated from Monascus ruber (documented as monacolin K) and subsequently from Aspergillus terreus (documented as mevinolin) , was quite successful in lowering blood cholesterol. Lovastatin was successfully marketed as a cholesterol-lowering drug in 1987, followed by mevastatin . Statins comprise one of the highest-marketed drugs worldwide, generating sales of USD 25 billion in 2005. Furthermore, several compounds of fungal origin and their derivatives are currently in clinical trials for multiple diseases and include Halimide (synthetic derivative Plinabulin) in phase III trials for cancer, Hypothemycin in phase I trials for solid tumors/melanoma, Wortmannin (synthetic derivative PX-866) in phase II clinical trials for prostate cancer, Cordycepin in phase I trials for lymphoma/solid tumors and Radicicol (synthetic derivative Ganetespib) in phase III trials for lung cancer, among other therapeutics. Gomes and coworkers have extensively discussed and highlighted the importance of marine-derived fungal metabolites for cancer treatment, including leptosins, gliotoxin, shearinine, meleagrin, neoechinulin A, and bostrycin, etc. . The biosynthetic gene clusters (BGCs) in fungal genomes synthesize bioactive, high-value metabolites and can be investigated/engineered for obtaining higher yields of the targeted metabolites.
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[
"Pragya Tiwari",
"Kyeung-Il Park"
] |
https://doi.org/10.3390/jof10070506
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N/A
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https://creativecommons.org/licenses/by/4.0/
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en
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2.3. Novel Fungal Cell Factories for the Production of Bioactive Metabolites
| 3.8125 |
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Fungal-derived metabolites exhibit enormous diversity and interesting bioactivities, namely antimicrobial, hypoglycemic, antiviral, antitumor, immunosuppressant bioactivities, etc. The increasing evidence from studies highlights the potent efficacies of fungal-derived bioactive metabolites as key therapeutics. In addition, functional food/nutraceuticals from fungi have been documented to promote human health and well-being and multiple fungal species are powerful resources used to generate ‘high-value’ substances of socio-economic relevance.
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[
"Pragya Tiwari",
"Kyeung-Il Park"
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https://doi.org/10.3390/jof10070506
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N/A
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https://creativecommons.org/licenses/by/4.0/
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en
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2.3. Novel Fungal Cell Factories for the Production of Bioactive Metabolites
| 4.195313 |
biomedical
|
Review
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Filamentous fungi are widely recognized as efficient producers of natural products, industrial substances, enzymes, proteins, organic acids, etc., and are employed as novel tools for targeted morphology engineering . In addition, fungal biomass is also important in textile industries and as a food component. Discussing industrial relevance, fungi produce key enzymes including phytases, proteases, catalases, and glucoamylases and others with wider usage . Fungal enzymes are also utilized in biofuel production to convert lignocellulosic biomass to fermentable sugars, generating an economic return of over EUR 4 billion . For large-scale cultivation (both solid-state and submerged fermentations), understanding and reprogramming fungal morphogenesis and growth are crucial. Further efforts are needed in process design to optimize fungal morphology for producing a targeted product. Multiple investigations/research in this direction have speculated that septal secretion in fungi may have industrial value and optimization of fungal morphology would improve septal junctions by genetic manipulation studies, in addition to prospective yet less-explored intercalary secretion pathways .
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[
"Pragya Tiwari",
"Kyeung-Il Park"
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https://doi.org/10.3390/jof10070506
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N/A
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https://creativecommons.org/licenses/by/4.0/
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2.3. Novel Fungal Cell Factories for the Production of Bioactive Metabolites
| 4.042969 |
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Fungal secondary metabolism and its exploration are promising, with studies suggesting that more than 60% of medicines comprise natural products . While efforts are being made for the bio-prospection of fungal resources, new techniques for the activation of silent gene clusters (BGCs) in the laboratory and pilot fermentation studies have been employed and enhanced production via targeted genome manipulation has been achieved . The advances in synthetic biology and a deeper elucidation of the filamentous life cycle for fungal genome engineering facilitate targeted strain development .
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[
"Pragya Tiwari",
"Kyeung-Il Park"
] |
https://doi.org/10.3390/jof10070506
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N/A
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https://creativecommons.org/licenses/by/4.0/
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en
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2.3. Novel Fungal Cell Factories for the Production of Bioactive Metabolites
| 4.457031 |
biomedical
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Review
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Aspergillus is fast emerging as a model for genome manipulation, attributed to the technological advances in whole genome sequencing. Engineering initiatives started in the 1950s, ranging from manipulating fungal morphologies and mutagenesis to achieving high product titers. For instance, strains of A. oryzae were subjected to nitrous acid and UV mutagenesis, resulting in less viscous broth and higher production of glucoamylase . Subsequently, mutagenesis of Trichoderma reesei with diethyl sulfite led to a highly branched and short chimeric strain showing enhanced cellulase production . Through the efforts in genome sequencing, an increased understanding of the candidate genes/metabolic pathway has been achieved for strain improvement . In addition, attempts have been made for single nucleotide polymorphism (SNP) identification in fungal genomes for better growth of fungal strains; however, studies are limited. The signaling pathways govern morphological regulation in fungi, and engineering attempts have been made to target components in the cascade for enhanced biotechnological utilities. The key signaling pathways in filamentous fungi, protein kinase A (PKA)/cyclic adenosine monophosphate (cAMP) signaling, calcium ion responses, and mitogen-activated protein kinase (MAPK) are the prime focus of targeted fungal engineering for fungal growth and morphological improvements .
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[
"Pragya Tiwari",
"Kyeung-Il Park"
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https://doi.org/10.3390/jof10070506
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https://creativecommons.org/licenses/by/4.0/
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en
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2.3. Novel Fungal Cell Factories for the Production of Bioactive Metabolites
| 4.351563 |
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In this direction, synthetic biology has made significant advances to create designer chimeras possessing minimized genomes, less complexity, and improved attributes, respectively. A reduced genome of S. cerevisiae was created, and a significant portion (14%) of chromosome 3 was deleted (tRNA, transposans, and wild-type base pairs) . The genome editing of S. cerevisiae chromosome 16 and fusion experiments resulted in chimeras with reduced genome size . In A. niger , targeting the fungal genome for minimization was achieved by deletion/inactivation of certain genes/chromosome sections by the CRISPR-Cas9 tool . The genomes of economically viable fungal species have been engineered by the CRISPR-Cas9 editing system and are as follows: available T. reesei , M. thermophila , A. oryzae and P. chrysogenum , among other notable ones, and are exploited industrially. The concept of engineering fungal genomes for size reduction relies on the deletion of non-essential genes and focuses on targeted genes/pathways for morphological changes/growth phenotype and the creation of desired fungal chimeras.
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[
"Pragya Tiwari",
"Kyeung-Il Park"
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https://doi.org/10.3390/jof10070506
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https://creativecommons.org/licenses/by/4.0/
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2.3. Novel Fungal Cell Factories for the Production of Bioactive Metabolites
| 4.417969 |
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The natural product discovery pipeline has been greatly expedited, which is attributed to the advances in the synthetic biology toolkit. In addition to CRISPR-Cas, advanced synthetic tools are promising in creating designer fungal cell factories, improving the morphological feature and high titer of the desired metabolite. The heterologous expression of key biosynthetic genes (for natural products) has been achieved in A. niger , A. nidulans , and P. chrysogenum , etc., and synthetic fungal chimeras with new/novel attributes have been created by domain swapping and fungal media optimization. Synthetic biology toolkits have expanded the horizons to facilitate polycistronic gene expression in filamentous fungi , and next-stage morphological engineering via controlled gene expression of multiple genes using a single promoter, offers interesting insights . Successful attempts in engineering and optimization of tuneable gene switches in filamentous fungi offer precise details of the strain’s morphological characteristics and gene function. It is imperative that advances in fungal imaging have provided precise information about fungal morphology; X-ray microtomography has elucidated the three-dimensional morphology of P. chrysogenum and A. niger and defined new prospects in precise quantification of hyphal number distribution in the pellet, providing future directions in understanding how pellet morphologies affect the titer of the product. These technological developments, optimized in filamentous fungi and other fungal systems (in progress), will result in novel fungal cell factories, including minimizing genomes, higher product titers, and optimized fungal morphologies, in the future.
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[
"Pragya Tiwari",
"Kyeung-Il Park"
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https://doi.org/10.3390/jof10070506
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2.4. Fungi-Based Bioremediation for Environmental Subsistence
| 4.140625 |
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The present era has witnessed an increased interest in microbial biodegradation of toxic contaminants for ecosystem restoration. Microbe-assisted bioremediation comprises a cost-effective and eco-friendly approach for the transformation of recalcitrant pollutants into environmentally degradable substances. In addition to other microbial species, fungi-mediated bioremediation is a safe and renewable strategy for mitigating contaminants/polluted locations . Fungi play a critical role as degraders and symbionts, colonizing diverse environmental niches and possessing consistent morphology and multi-faceted metabolic potential. A combination of biostimulation, bioaugmentation, natural attenuation, or individual approaches can be used as per the requirement and efficiency of the microbial strain. Mycoremediation has been a method of choice in environmental cleanups, with multiple efficient fungal species documented for their potency in mitigating heavy metal contamination, pollutants, greenhouse gases, industrial chemicals, etc. .
|
[
"Pragya Tiwari",
"Kyeung-Il Park"
] |
https://doi.org/10.3390/jof10070506
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057391_p18
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sec[1]/sec[3]/p[1]
|
2.4. Fungi-Based Bioremediation for Environmental Subsistence
| 4.722656 |
biomedical
|
Review
|
[
0.99267578125,
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[
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Mycorrhizal fungi play a key role in the ecosystem by promoting plant access to nutrients and water in soil and plant tolerance to pathogens. In addition, fungal species in mycorrhizal associations contribute to bioremediation, conservation, and ecosystem well-being . Mycorrhizal associations confer salt tolerance to the plant and promote plant growth and overall health. Bioremediation achieved in the capacities of microbial degradations minimizes the amount and harmful impact of diverse contaminants, while microbial processes aid in the mitigation of pollutants in contaminated sites. Microbe-assisted chemical and physical processes cause disintegration and structural changes in the pollutants and accelerate metabolism. In addition, microbes facilitate energy-dependent chemical reactions for the dissemination of contaminants and electron transfer via oxidation and reduction reactions. In nature, microbes acquire carbon from contaminants for growth and degrade them into simple substances. Quite interestingly, mycoremediation is effective in the removal of heavy metals and radioactive agents to be further decomposed . During pesticide degradation, fungal species obtain nitrogen, carbon, or energy for growth. Molds, e.g., Botrytis and Aspergillus, decompose sugar polymers, celluloses, starches, pectins, oils, chitin, oil components, etc. Subsequently, an environmental hazard, e.g., endosulphan, is effectively degraded by Trichoderma harzianum , Cladosporium oxysporum , Aspergillus spp., and Mucor thermohyalospora . Moreover, fungi-mediated degradation of pesticides into non-toxic substances occurs via processes namely hydroxylation, dehydrogenation, esterification, and deoxygenation . Other fungal strains are capable of bioremediating different contaminants, including textile wastewater detoxification by Zygomycetes and Aspergillus , polychlorinated biphenyl (PCB) degradation by Fusarium solani , Penicillum chrysogenum and Penicillum digitatum , biosorption of pentachlorophenol by Rhizopus oryzae CDBB-H-1877, cellulose degradation by brown rot fungi, xenobiotics degradation by Agaricus bisporus , Pleurotus ostreatus , Pleurotus pulmonarius , etc., heptachlor and heptachlor epoxide remediation by Phanerochaete ostreatus and effluents from textile industries by Ascomycetes and Basidiomycetes fungi, among other distinct examples .
|
[
"Pragya Tiwari",
"Kyeung-Il Park"
] |
https://doi.org/10.3390/jof10070506
|
N/A
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https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057391_p19
|
39057391
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sec[1]/sec[3]/p[2]
|
2.4. Fungi-Based Bioremediation for Environmental Subsistence
| 4.34375 |
biomedical
|
Review
|
[
0.99609375,
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[
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Besides the remediation of contaminants present in the environment, the restoration of polluted sites has been achieved via naturally occurring microbes. The representative examples Penicillium , and Aspergillus were effective alleviators of contaminants like textile dyes, chemicals, pesticides, industrial effluents, organic pollutants, etc. . In addition, the substantial removal of petroleum hydrocarbons and diesel contaminants in soil has been successful by short-term inoculation of Phanerochaete chrysosporium and Aspergillus niger , which facilitated bioremediation . Literature studies have shown that white rot fungi disintegrate harmful substances, namely phenols, effluent, pesticides, heavy metals, polychlorinated biphenyls, etc., and alleviate the adverse impact on soil. Studies have also established the significant potential of fungal enzymes (lipases, catalases, amylases, proteases, peroxidases, etc.) in organic waste management , highlighting their industrial value . Advanced technologies have immensely contributed to addressing limitations with fungi-mediated bioremediation. In recent times, immobilized fungi in bioreactors (fluidized bed reactors and rotating biological reactors) have been adopted for bioremediation . For the treatment of wastewater sludge from sewage plants, it is mixed with microbial inoculum in a broad-scale bioreactor and considered a sustainable approach . Furthermore, advanced practices for PAH mitigation include Trichoderma longibrachiatum -based biobarriers on nylon sponges, where high efficiency of PAH removal was achieved . An upcoming approach utilizes yeast expression systems to generate cytochrome P450 monooxygenases that can tackle hydrocarbons and aid in mitigation .
|
[
"Pragya Tiwari",
"Kyeung-Il Park"
] |
https://doi.org/10.3390/jof10070506
|
N/A
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https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057391_p20
|
39057391
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sec[1]/sec[4]/p[0]
|
2.5. Addressing Climate Changes via Fungal Biotechnologies
| 3.628906 |
biomedical
|
Study
|
[
0.59814453125,
0.0008378028869628906,
0.40087890625
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[
0.84033203125,
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For addressing climate change, it is imperative to achieve net-zero emissions by the mid-century to limit temperature rise within 1.5 °C, while adopting measures to sequester, capture, and store excess atmospheric carbon . In a recent report by the World Economic Forum, fungi can play a crucial role in addressing climate change . Fungal species inhabiting natural environments assist forests in absorbing carbon and tackling the potential impacts of climatic fluctuations. While fungi occupy diverse ecological niches and mushrooms are present in shady and damp places, mycorrhizal fungi (ectomycorrhizal fungi) assist trees and forests to absorb CO 2 faster and reduce the rate of carbon flow/return in the atmosphere. However, the rapid deforestation every year threatens the beneficial interactions, and promoting the regrowth of forests would reduce global emissions by 30%, as per the guidelines of the COP26 summit in Glasgow . Since little information is available on the role of fungal networks in combating climate change, the Society for the Protection of Underground Networks (SPUN) has devised a project to understand the role of mycorrhizal fungi in areas of climate science and map the ‘Wood Wide Web’. Thousands of fungal samples are collected to map fungal networks and utilized by SPUN (via machine learning) to create these networks and their function as carbon sinks. This information could be used to identify high-priority zones for more carbon storage and tackle extreme conditions.
|
[
"Pragya Tiwari",
"Kyeung-Il Park"
] |
https://doi.org/10.3390/jof10070506
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057391_p21
|
39057391
|
sec[1]/sec[4]/p[1]
|
2.5. Addressing Climate Changes via Fungal Biotechnologies
| 4.246094 |
biomedical
|
Review
|
[
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[
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The growing evidence from the literature suggests that fungi can contribute to farming practices and agriculture. The inoculation of seeding soil with beneficial fungi promotes soil attributes, enriches soil fertility, and decreases atmospheric CO 2 levels, crucial to environmental functioning , while pathogenic macrofungi exploit plants and animals to absorb nutrients and also contribute to biodiversity in the ecosystems. The interconnected mycelial network with the host is crucial and improves nutrient acquisition, transport, and enzyme secretion . These fungi-mediated processes are essential for sustaining biodiversity and ecosystem well-being. The translational success of arbuscular mycorrhizal fungi (AMF) as potential biofertilizers has a major impact on the global market with a value of USD 2 billion. In addition, fungi are key players and perform essential functions in the ecosystem. Globally distributed, fungi carry out processes including bioconversion, energy flow processes, and nutrient cycling and act as symbionts, pathogens, and decomposers in nature . According to a study in nature, the biodiversity of fungi determines plant biodiversity, productivity, and variation in the ecosystem and approximately 90% of plants form integral associations with fungi. In addition to other functions, fungi perform mycoremediation (as earlier discussed), degrade chemicals heavy metals, crude oils, etc., absorb heavy metals and radioactive components, and maintain ecological subsistence. However, excessive human activities and pollution levels are impacting fungal diversity/population and signaling climate change. Adequate and urgent efforts are required to stop/minimize deforestation, restore ectomycorrhizal forests, and switch from fossil fuel to renewable energy sources (as in America).
|
[
"Pragya Tiwari",
"Kyeung-Il Park"
] |
https://doi.org/10.3390/jof10070506
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057391_p22
|
39057391
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sec[2]/p[0]
|
3. Achievements and Prospects in the Present Decade: What Do We Know and What Comes Next?
| 2.917969 |
biomedical
|
Other
|
[
0.98779296875,
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[
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Recently, the United Nations General Assembly (UNGA) Science Summit stated that “understanding the world of microbes is imperative either to curb dangerous effects or to harness their power for healthier life, for sustainable energy sources, for biodiversity, for tackling climate change and for solving hunger problems”, which is one of the key objectives of the United Nations SDGs. The microbes in the environment are integrally associated and impact human lives. The increased recognition of the favorable impact of beneficial microbes on humans and the environment has contributed to their potential applications in healthcare, agriculture, and ecosystem restoration.
|
[
"Pragya Tiwari",
"Kyeung-Il Park"
] |
https://doi.org/10.3390/jof10070506
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057391_p23
|
39057391
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sec[2]/p[1]
|
3. Achievements and Prospects in the Present Decade: What Do We Know and What Comes Next?
| 3.996094 |
biomedical
|
Review
|
[
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[
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Widely exploited as a source of ‘high-value’ food ingredients (food flavors, pigments, nutritional substances, etc.), the present era has witnessed the utilization of fungi-based biofertilizers to boost crop health and productivity. Moreover, water quality and sanitation have been remarkably improved by microbe-assisted remediation of contaminated water bodies. Other achievements in microbial biotechnologies in achieving SDGs have been biofuel production as a direct source of affordable and clean energy, industrial production of high-value metabolites, potent drugs from fungi approved and marketed for disease treatment with others in different stages of drug development, environmental cleanup via bioremediation of contaminants and plastics and conferring stress tolerance to plants in times of global climate adversities.
|
[
"Pragya Tiwari",
"Kyeung-Il Park"
] |
https://doi.org/10.3390/jof10070506
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057391_p24
|
39057391
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sec[2]/p[2]
|
3. Achievements and Prospects in the Present Decade: What Do We Know and What Comes Next?
| 3.710938 |
biomedical
|
Review
|
[
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[
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Cutting-edge research has focused on deciphering and highlighting the prospects of beneficial microbes in different socio-economic contexts. With the beginning of the transition towards a bio-based economy and the efficient utilization of fungal resources, answers to the following pertinent questions are required: which species has valuable/useful traits, and how can self-sustainability be achieved by fungal production ? A better understanding can be achieved with these answers on the road towards a sustainable future. In light of the current findings, it is important to investigate/screen the vast repertoire of fungal species and validate the bioactivities, which are necessary to define the safety profiles for socio-economic applications.
|
[
"Pragya Tiwari",
"Kyeung-Il Park"
] |
https://doi.org/10.3390/jof10070506
|
N/A
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https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057391_p25
|
39057391
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sec[2]/p[3]
|
3. Achievements and Prospects in the Present Decade: What Do We Know and What Comes Next?
| 4.574219 |
biomedical
|
Review
|
[
0.99365234375,
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[
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Advanced biotechnological tools have revolutionized the exploration of natural resources. The phylogenomics-guided exploration of specific traits has been inferred from the relationship between microbial species. In addition, progress in analytical equipment and omics-assisted identification of species have contributed to bridging the knowledge gaps in metabolite biosynthesis and evaluation of their bioactive potential . Metabolomics studies have attempted to understand the fungal metabolic networks and their dynamics, providing critical insights into the taxonomic identification, fungal stress response, metabolite discovery, metabolic engineering, and plant–fungal interactions. A deeper knowledge of complex fungal interactions and their environmental responses has been attained via metabolomics . Omics biology has also contributed to research on edible fungi (cointegrated with other methods), delving into processes including stress resistance, growth and development, and its pharmaceutical value , providing in-depth information. With the advent of modern genome editing tools, like CRISPR-Cas, the production of high-value metabolites can be optimized by fungal genome engineering, heterologous expression, and gene disruption , among others. Molecular analysis of the fungal genome provides a framework to screen beneficial traits, metabolite discovery, and efficient production under laboratory conditions. The key to strengthening fungal resources and biotechnologies to achieve the sustainable goals involves obtaining extensive knowledge of fungal biology (a global effort is needed), building a global network, and providing a knowledge base platform for fungal identification, classification and collection of fungal species .
|
[
"Pragya Tiwari",
"Kyeung-Il Park"
] |
https://doi.org/10.3390/jof10070506
|
N/A
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https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057391_p26
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4. The Road Ahead: Future Directions in a Fungal Bio-Based Economy
| 3.945313 |
biomedical
|
Review
|
[
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[
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The enriched yet less tapped fungal biodiversity can contribute to realizing SDGs, a prospective initiative of the United Nations for a better world. Fungal biology and biotechnologies provide transformative opportunities from petroleum-based to bio-based economies attributed to converting organic substances into diverse ‘high-value’ products for socio-economic sustainability. Fungi have been associated with land plants during their evolutionary course, and harnessing the power of ancient players would benefit natural habitats and biodiversity . The utilization of fungal bio-based products is sustainable in securing and enhancing the food supply for a growing population and limiting greenhouse emissions. The development of alternate food products includes Quorn (meat substitute) , filamentous fungi-based biomaterials , biorefinery applications (second-generation biofuels) , biodegradation of plastics , and other notable examples. In addition, the advances in fungal biotechnologies have the potential to tackle climate change and contribute to the United Nations SDGs. The road to sustainable development is not yet reachable, and fungal resources represent prime resources in addressing sustainable livelihood and development in a global context.
|
[
"Pragya Tiwari",
"Kyeung-Il Park"
] |
https://doi.org/10.3390/jof10070506
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057383_p0
|
39057383
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sec[0]/p[0]
|
1. Introduction
| 3.945313 |
biomedical
|
Study
|
[
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[
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Children with malignancy are predisposed to invasive fungal diseases (IFD) due to severe acquired immunodeficiency as a result of the underlying disease, intensive chemotherapy, steroid treatment, or Hematopoietic Stem Cell Transplantation (HSCT) . The incidence of IFDs in these children depends upon geographical region, the underlying malignant disease, the intensity of the chemotherapy treatment, and the patient’s characteristics . Recent studies estimate the prevalence of IFDs at 5.9% among pediatric patients with cancer, varying between 2% and 28% in other studies in the field .
|
[
"Eleni Moraitaki",
"Ioannis Kyriakidis",
"Iordanis Pelagiadis",
"Nikolaos Katzilakis",
"Maria Stratigaki",
"Georgios Chamilos",
"Athanasios Tragiannidis",
"Eftichia Stiakaki"
] |
https://doi.org/10.3390/jof10070498
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057383_p1
|
39057383
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sec[0]/p[1]
|
1. Introduction
| 4 |
biomedical
|
Other
|
[
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[
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Diagnosis of IFDs is challenging due to the invasiveness of the procedure, as in the case of lung biopsy for pulmonary mycosis or due to the low yield of positive cultures, especially when the patient is under antifungal prophylaxis. Knowledge of local epidemiology and current international guidelines are crucial in deciding appropriate prophylaxis and empirical and pre-emptive treatment of IFDs. A personalized risk assessment is also warranted for the proper use of antifungals to avoid overtreatment and shift the epidemiological profile to more resistant and emerging fungi, such as those belonging to the Mucorales family .
|
[
"Eleni Moraitaki",
"Ioannis Kyriakidis",
"Iordanis Pelagiadis",
"Nikolaos Katzilakis",
"Maria Stratigaki",
"Georgios Chamilos",
"Athanasios Tragiannidis",
"Eftichia Stiakaki"
] |
https://doi.org/10.3390/jof10070498
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057383_p2
|
39057383
|
sec[0]/p[2]
|
1. Introduction
| 4.019531 |
biomedical
|
Review
|
[
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[
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Prevention, early identification, and prompt treatment are key elements affecting pediatric Hematology–Oncology patients’ IFDs course and outcome. Consensus definitions of IFDs have been recently revised and updated by the European Organisation for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium (EORTC/MSGERC). Still, their validity and application in the pediatric population require careful assessment . In the same context, the eighth European Conference on Infections in Leukaemia (ECIL-8) has updated the guidelines for the diagnosis, prevention, and treatment of IFDs in pediatric patients with cancer or post-HSCT . Guidelines on the diagnosis of invasive aspergillosis in the pediatric population have also been issued by the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and the European Confederation of Medical Mycology (ECMM) . All these publications include guidance on microbiologic, histopathologic, radiologic, and clinical identification of IFDs in neonates, children, and adolescents with malignant diseases.
|
[
"Eleni Moraitaki",
"Ioannis Kyriakidis",
"Iordanis Pelagiadis",
"Nikolaos Katzilakis",
"Maria Stratigaki",
"Georgios Chamilos",
"Athanasios Tragiannidis",
"Eftichia Stiakaki"
] |
https://doi.org/10.3390/jof10070498
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057383_p3
|
39057383
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sec[0]/p[3]
|
1. Introduction
| 3.732422 |
biomedical
|
Study
|
[
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[
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The current study intends to investigate the occurrence and epidemiology of IFDs in a single Pediatric Hematology–Oncology Department, identify predisposing factors, and describe the clinical features and outcomes in the respective cases.
|
[
"Eleni Moraitaki",
"Ioannis Kyriakidis",
"Iordanis Pelagiadis",
"Nikolaos Katzilakis",
"Maria Stratigaki",
"Georgios Chamilos",
"Athanasios Tragiannidis",
"Eftichia Stiakaki"
] |
https://doi.org/10.3390/jof10070498
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057383_p4
|
39057383
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sec[1]/p[0]
|
2. Patients and Methods
| 4.214844 |
biomedical
|
Study
|
[
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A retrospective single-center study included all children and adolescents (up to 19 years old) diagnosed and treated with neoplasia in the Pediatric Hematology–Oncology Department in Heraklion, Crete. The medical records of all patients corresponding to the period from 2013 to 2022 were registered, and relevant data were collected. The EORTC/MSGERC consensus host factors for IFDs were recorded: a recent history of prolonged neutropenia (<500 neutrophils/μL for >10 days), hematologic or not malignancy, allogeneic HSCT or solid organ transplant, prolonged use of corticosteroids (≥0.3 mg/kg for ≥three weeks in the past 60 days), treatment with B-cell or T-cell immunosuppressants, severe hereditary immunodeficiency, and graft-versus-host disease (GVHD) . Demographic data, clinical characteristics, diagnostic exams, treatment protocol, comorbidities, intensive care unit (ICU) hospitalization, neutrophils, lymphocytes, monocytes count, the duration of severe neutropenia, lymphopenia and monocytopenia, number of antimicrobials’ courses administered during the last three months before the onset of the IFD (including both antibiotics and antifungals), the antifungal prophylaxis for at least seven days before the onset of symptoms due to IFD, the clinical, laboratory and radiological characteristics of IFDs, and finally the specific treatment that followed were also recorded. The effect of each categorical variable on the development of IFD was investigated utilizing the chi-square and Fisher’s exact tests. Respectively, the Mann–Whitney U and Wilcoxon tests were used for the continuous variables. The value of p ≤ 0.05 was considered statistically significant. The statistical analysis was performed using the IBM SPSS Statistics V22 package (IBM Corp., Armonk, NY, USA). The prevalence of IFDs was calculated by dividing the number of cases by the total number of patients at risk. Definitions of IFDs (proven, probable, and possible) in this study adhered to EORTC criteria . Breakthrough IFD was defined as any invasive fungal infection occurring during exposure to an antifungal drug, according to the respective MSGERC position paper . The clinical practice guideline by the International Pediatric Fever and Neutropenia Guideline Panel was utilized for febrile neutropenia .
|
[
"Eleni Moraitaki",
"Ioannis Kyriakidis",
"Iordanis Pelagiadis",
"Nikolaos Katzilakis",
"Maria Stratigaki",
"Georgios Chamilos",
"Athanasios Tragiannidis",
"Eftichia Stiakaki"
] |
https://doi.org/10.3390/jof10070498
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057383_p5
|
39057383
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sec[1]/p[1]
|
2. Patients and Methods
| 1.064453 |
biomedical
|
Other
|
[
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The study was conducted in accordance with the Declaration of Helsinki, approved by the Institutional Review Board of the University General Hospital of Heraklion, and carried out according to its regulations .
|
[
"Eleni Moraitaki",
"Ioannis Kyriakidis",
"Iordanis Pelagiadis",
"Nikolaos Katzilakis",
"Maria Stratigaki",
"Georgios Chamilos",
"Athanasios Tragiannidis",
"Eftichia Stiakaki"
] |
https://doi.org/10.3390/jof10070498
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
39057383_p6
|
39057383
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sec[2]/p[0]
|
3. Results
| 3.617188 |
biomedical
|
Study
|
[
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In total, 154 patients’ medical records were reviewed. Of the patients aged from 32 days to 20 years, 57% were male and 43% were female. The mean age at diagnosis was 8.7 years and the most common malignancy was acute lymphoblastic leukemia (ALL; 27%), followed by lymphomas (23%), central nervous system tumors (CNS; 19%), sarcomas (9%), neuroblastoma (8%), acute myeloid leukemia (AML; 6%), kidney tumors (4%), chronic myeloid leukemia (2%), and other neoplasia (2%). Patients’ residence at a distance more than 100 km from the Department (28.8%) was not associated with IFD occurrence.
|
[
"Eleni Moraitaki",
"Ioannis Kyriakidis",
"Iordanis Pelagiadis",
"Nikolaos Katzilakis",
"Maria Stratigaki",
"Georgios Chamilos",
"Athanasios Tragiannidis",
"Eftichia Stiakaki"
] |
https://doi.org/10.3390/jof10070498
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057383_p7
|
39057383
|
sec[2]/p[1]
|
3. Results
| 4.125 |
biomedical
|
Study
|
[
0.998046875,
0.0017976760864257812,
0.00019371509552001953
] |
[
0.9990234375,
0.0003955364227294922,
0.0005545616149902344,
0.00022280216217041016
] |
The crude prevalence of IFDs was 7.8% (12/154 patients). Sixteen IFDs were recorded in 12 patients, of which eight were proven (50%), one was probable (6.3%), and seven were possible IFDs (43.7%). The IFD rates have increased by 185% during the five-year period 2018–2022 compared to 2013–2017 (10% vs. 3.5%). The mean age at IFD diagnosis was 9.8 years, and the most common IFD was possible/probable invasive pulmonary aspergillosis (IPA) in half of these cases, followed by fungemia (37.5%), Candida cellulitis (6.3%), and Pneumocystis jirovecii pneumonia (PJP; 6.3%). No sex predilection was noted (58% males vs. 42% females), and age spanned from 7 months to 19 years old (with half of patients aged >12 years old).
|
[
"Eleni Moraitaki",
"Ioannis Kyriakidis",
"Iordanis Pelagiadis",
"Nikolaos Katzilakis",
"Maria Stratigaki",
"Georgios Chamilos",
"Athanasios Tragiannidis",
"Eftichia Stiakaki"
] |
https://doi.org/10.3390/jof10070498
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057383_p8
|
39057383
|
sec[2]/p[2]
|
3. Results
| 4.140625 |
biomedical
|
Study
|
[
0.96533203125,
0.034149169921875,
0.0006155967712402344
] |
[
0.98828125,
0.0088043212890625,
0.0008802413940429688,
0.0019159317016601562
] |
One patient experienced three IFDs and was recorded three times in the datasheet; another one had two IFDs, while one patient had an IFD relapse. The two latter patients were recorded twice for the statistical analysis. Breakthrough infections accounted for 87.5% of IFDs. Most patients have been receiving micafungin as primary antifungal prophylaxis (42%), which was the most common prophylaxis administered across all chemotherapy regimens in this study, followed by liposomal amphotericin B (LAMB; 17%), and caspofungin, fluconazole, voriconazole, and pentamidine (6.7% each). Two patients have been not eligible for prophylactic antifungal treatment (20%).
|
[
"Eleni Moraitaki",
"Ioannis Kyriakidis",
"Iordanis Pelagiadis",
"Nikolaos Katzilakis",
"Maria Stratigaki",
"Georgios Chamilos",
"Athanasios Tragiannidis",
"Eftichia Stiakaki"
] |
https://doi.org/10.3390/jof10070498
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057383_p9
|
39057383
|
sec[2]/p[3]
|
3. Results
| 4.152344 |
biomedical
|
Study
|
[
0.9921875,
0.007663726806640625,
0.0002522468566894531
] |
[
0.99658203125,
0.002117156982421875,
0.0005259513854980469,
0.0008893013000488281
] |
The underlying malignancies of the patients with IFD are demonstrated in Figure 1 . AML M5, according to the FAB classification, was the most common underlying neoplasia, which was also associated with significantly higher mortality rates, as both patients who succumbed to an IFD were diagnosed with AML M5 and were over 12 years old. Interestingly, seven out of 10 AML cases in total during the observation period developed an IFD. Contrarily, only one patient out of 39 recorded ALL patients manifested an IFD (2.6%), and he was being administered with LAMB, while all other ALL patients were treated with prophylactic micafungin. All AML patients received prophylaxis with micafungin concurrent with or followed by LAMB.
|
[
"Eleni Moraitaki",
"Ioannis Kyriakidis",
"Iordanis Pelagiadis",
"Nikolaos Katzilakis",
"Maria Stratigaki",
"Georgios Chamilos",
"Athanasios Tragiannidis",
"Eftichia Stiakaki"
] |
https://doi.org/10.3390/jof10070498
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
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