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Author contributions
G.H. and F.J. collected data, analysed results, interpreted findings and drafted the manuscript. BB provided statistical support and developed the analysis plan. BH conceptualised the idea. All authors reviewed the manuscript
PMC10475034
Funding
This project received no funding.
PMC10475034
Data availability
The datasets generated during used and/or analysed during the current study available from the corresponding author on reasonable request.
PMC10475034
Competing interests
BH has a clinical partnership with Fourier Intelligence and a paid consultancy role with RecoveryVR. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
PMC10475034
References
PMC10475034
1. Introduction
inflammation, MOF, organ dysfunction, septic shock, sepsis
MULTIPLE ORGAN FAILURE, PCT, INFLAMMATION, MOF, DYSFUNCTION, SEPTIC SHOCK, SEPSIS
These authors share first authorship.Background and aim: Here, we assess the effect of adjuvant antioxidant therapies in septic shock patients with organ dysfunction and their effect on the enzymatic and non-enzymatic antioxidant systems. Methods: Randomized clinical trial run between 2018 and 2022. One hundred and thi...
PMC10177152
2. Materials and Methods
PMC10177152
2.1. Population Study
septic shock
SEPTIC SHOCK
This was a randomized and blinded longitudinal prospective clinical trial in a cohort of patients that was run between April 2018 and January 2022. The population studied included patients older than 18 years of any gender who were admitted to the intensive care unit of the ABC Medical Center, Observatory and Santa Fe ...
PMC10177152
2.2. Sample Size
The sample size was calculated considering the difference in the means of low ascorbic acid levels and improvement with the treatment using antioxidants. It suggested the inclusion of 11 patients in each group for a desired 80% power and an alpha error of
PMC10177152
2.3. Ethical Aspects
A signed informed consent form was obtained from each participant as recommended in the Declaration of Helsinki, modified in the Tokyo Congress, Japan. The research was approved by the Ethical, Biosecurity and Investigation Committees of the National Institute of Cardiology (registration number INCICh: PT 10-0-76) and ...
PMC10177152
2.4. Randomization
Electronic selection by computer was used to divide patients into blocks with a total of 5 groups with around 25 patients in each one. Group 1 received Vit C, group 2 Vit E, group 3 NAC and group 4 MT; group 5 patients remained without treatment (Tx) and formed the control group. Personnel unrelated to the study partic...
PMC10177152
2.5. Data Collection
A medical examination and a complete clinical history were performed on each patient upon admission to the ICU, and the prognostic scales of APACHE II [
PMC10177152
2.6. Description of the Intervention
In addition to the standard therapy, each group of patients received an antioxidant orally or by nasoenteral tube for 5 days. In the NAC group, 600 mg effervescent tablets were administered every 12 h; in the MT group, extended-release capsules of 50 mg in a daily dose were administered; in the Vit C group, 1 g tablets...
PMC10177152
2.7. Sample Collection and Storage
A quantity of 20 mL of blood was obtained upon admission and 48 h after treatment. Samples were identified as pre (0 h) or post sample (48 h). They were centrifuged at 3000 rpm for 20 min at 4 °C. Serum was stored in 3 or 4 Eppendorff aliquots of 1.5 mL and stored at <70° until processed.
PMC10177152
2.8. Evaluation of the Antioxidant Enzymes
PMC10177152
2.8.1. GPx Activity
A quantity of 100 μL of serum was suspended in 1.6 mL of 50 mM phosphate buffer (KH
PMC10177152
2.8.2. GST Activity
A quantity of 100 μL serum was added to 700 μL phosphate buffer (KH
PMC10177152
2.8.3. TrxR Activity
TrxR activity was assessed as previously described [
PMC10177152
2.8.4. Extracellular Super Oxide Dismutase (ecSOD) Activity
ecSOD activity was determined by electrophoresis in native 10% polyacrylamide gels. Electrophoresis was carried out at 120 V for 4 h, as previously described by Pérez-Torres et al. [
PMC10177152
2.8.5. Peroxidase Activity
Measurement of peroxidase activity was carried out by electrophoresis in native 10% polyacrylamide gels as previously described by Pérez-Torres et al. [
PMC10177152
2.8.6. GR Activity
For GR activity, 100 μL of serum were utilized according to the previously described method [
PMC10177152
2.9. Oxidative Stress Markers
PMC10177152
2.9.1. Determination of Selenium (Se)
Selenium (Se) determination was performed using 200 µL of serum according to the method described by Soto et al. and the absorbance was read at 600 nm [
PMC10177152
2.9.2. Thiols
For the measurement of thiols, to 25 mL of serum 100 μL KBH
PMC10177152
2.9.3. Total Antioxidant Capacity (TAC)
A quantity of 100 μL of serum was used for the TAC determination. The absorbance was measured at 593 nm, according to the method described by Benzie and Strain [
PMC10177152
2.9.4. Lipid Peroxidation (LPO)
A quantity of 100 μL of serum was used to determine LPO products, making them react with thiobarbituric acid as previously reported and measuring the absorbance at 532 nm [
PMC10177152
2.9.5. NO
The method reported by Griess was used for the determination of NO
PMC10177152
2.9.6. Carbonylation
A quantity of 100 μL of serum was used and protein carbonylation was detected spectrophotometrically as previously described [
PMC10177152
2.10. Statistical Analysis
Continuous variables were expressed as mean ± standard deviation or median with minimum and maximum ranges. Categorical variables such as frequencies and percentages were also reported. Normality distribution was evaluated by Shapiro–France. For the graphic analysis of the distribution of the variables, histograms and/...
PMC10177152
4. Discussion
critically ill, non-septic, hypoxia, MOF, organ damage, septic shock, sepsis, septic
PCT, SARS-COV-2 INFECTION, CRITICALLY ILL, HYPOXIA, MOF, DYSFUNCTION, SEPTIC SHOCK, SEPSIS, PATHOGENESIS, INFLAMMATORY RESPONSE
The participation of OS in septic shock and MOF has been previously reported [In this study, we found that patients with septic shock had a high SOFA score on admission to the ICU. They had high PCT and CRP levels, elevated LPO and carbonylation, and decreased TAC. These variables were compensated by the treatment with...
PMC10177152
5. Conclusions
MOF, septic shock
MOF, PCT, SEPTIC SHOCK
The addition of antioxidant therapy to standard therapy in patients with septic shock decreases MOF and regulates the inflammatory state and the OS. Vit C therapy increases its serum levels and decreases CRP, PCT and NO
PMC10177152
Author Contributions
A.A.-Á., M.E.S. Acquisition, statistical and data analysis or interpretation of data. M.E.S. Had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. A.A.-Á., I.P.-T. and M.E.S. Conceptualization and methodology. I.P.-T., R.C.-S., L.M....
PMC10177152
Institutional Review Board Statement
Biosecurity and Investigation Committees of the National Institute of Cardiology (registration number INCICh: PT 10-0-76) and Centro Medico ABC Campus Observatory number ABC-18-19, Trial Registration: ClinicalTrials.gov Identifier: NCT 03557229.
PMC10177152
Informed Consent Statement
A written informed consent for enrollment or consent to continue and use patient data was obtained from each patient or their legal surrogate.
PMC10177152
Data Availability Statement
The data in our study are available from the corresponding author upon reasonable request.
PMC10177152
Conflicts of Interest
The authors declare no conflict of interest.
PMC10177152
References
cerebral vascular disease, sepsis, Sequential organ failure, COPD, RTT
ACUTE MYOCARDIAL INFARCTION, PCT, CVD, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, COPD, OXIDATIVE STRESS, AMI, SEPSIS, PVC
Electronic selection by computer was used to divide patients into blocks with a total of 5 groups of 131 patients in total. In the group Vit C (n = 27) patients were studied, in the group with Vit E (n = 24), NAC (n = 24), MT (n = 26) and (n = 29) patients remained without treatment.PCR = C-reactive protein; Vit C = vi...
PMC10177152
Objective
post-stroke non-fluent aphasia
To explore an extension speech training program that takes Chinese idioms as context and expands them into characters, words, sentences and paragraphs and evaluate the effects of this program in patients with post-stroke non-fluent aphasia.
PMC9907817
Methods
post-stroke non-fluent aphasia
This was a randomized controlled trial. We recruited patients with post-stroke non-fluent aphasia from the Renmin Hospital of Wuhan University from January 2021 to January 2022. Participants were randomly assigned to group I and group II. Patients in group I had treatment with extension speech training based on Chinese...
PMC9907817
Results
A total of 70 patients (group I, n = 34; and group II, n = 36) completed the trial and were analyzed according to protocol. There were no significant differences in baseline values between both groups. After intervention, the scores of oral expression, comprehension, and reading in the Aphasia Battery Of Chinese scale ...
PMC9907817
Conclusion
post-stroke non-fluent aphasia
This extension speech training program based on Chinese idioms can improve the language function and daily communication ability of the patients with post-stroke non-fluent aphasia.
PMC9907817
Trial registration
Chinese Clinical Trial Registry
PMC9907817
Data Availability
The data are available at the following link: DOI:
PMC9907817
Introduction
communication disorder, stroke, Post-stroke aphasia, aphasia, cerebrovascular disease
STROKE, CEREBROVASCULAR DISEASE
Post-stroke aphasia (PSA) is an acquired communication disorder caused by cerebrovascular disease damaging the language center of the dominant hemisphere of the brain. Patients with PSA usually have difficulty remembering words or lose the ability to speak, comprehend, read, or write. PSA is one of the most common and ...
PMC9907817
Methods
PMC9907817
Design
We conducted a randomized controlled trial in the Renmin Hospital of Wuhan University from January 2021 to January 2022 to evaluate the effectiveness of speech training through Chinese idioms. This study was reviewed and approved by the ethics committee of the Renmin Hospital of Wuhan University (approval number: WDRY2...
PMC9907817
Patients
We recruited patients with non-fluent PSA in the Department of Neurology, Neurosurgery and Rehabilitation of the Renmin Hospital of Wuhan University from January 2021 to January 2022. Patients who met the inclusion and exclusion criteria, agreed to participate in the study, and signed an informed consent form were incl...
PMC9907817
Inclusion criteria
stroke, aphasia, Non-fluent aphasia, cognitive impairment
STROKE
First stroke patients with a definite clinical diagnosis by brain CT scan or MRI examination.Non-fluent aphasia diagnosed by the aphasia screening scale.Stable condition, clear consciousness, and no cognitive impairment.Native language is Chinese.Age >18 years.An education level of primary school and above.
PMC9907817
Exclusion criteria
dysarthria, hearing comprehension impairment, transcortical sensory, wernicke aphasia, Visual defect, aphasia
HEARING IMPAIRMENT, SPEECH APRAXIA, DISEASES
Suffering from other serious diseases or intolerable examination.Complete aphasia, wernicke aphasia, transcortical sensory aphasia, and transcortical mixed aphasia with severe hearing comprehension impairment.Visual defect, hearing impairment, dysarthria, and speech apraxia.Previous mental history.
PMC9907817
Sample size
The software Gpower (HHU, Germany, Dusseldorf)was used to calculate the sample size [
PMC9907817
Study groups
BLIND
After the participants signed the consent form, we randomly assigned them into group I (Chinese idioms training) and group II (routine rehabilitation training) in a 1:1 manner. We used the random envelope method for grouping concealment. After preparing the randomization plan, the sequentially-coded, opaque, and sealed...
PMC9907817
Intervention
PMC9907817
Assessment of treatment outcomes
stroke, hemiplegia, aphasia
STROKE, SECONDARY
The Aphasia Battery of Chinese (ABC) scale is the main efficacy index to evaluate the language ability of participants. The ABC scale is compiled by combining the internationally recognized Boston Diagnostic Aphasia Examination (BDAE) and Western Aphasia Battery (WAB). It has good reliability and validity [The Comprehe...
PMC9907817
Statistical analyses
SPSS version 26.0 (IBM, Armonk, NY) was used to process and analyze the data. Normally distributed data are expressed by mean (SD) and non-normally distributed data are expressed by Median(interquartile range, IQR). For the comparison of paired measurement data, the paired sample t-test was used for normally distribute...
PMC9907817
Results
From January 2021 to January 2022, a total of 124 patients were recruited, and 70 patients(group I, n = 34; and group II, n = 36) met the criteria and agreed to participate in this study. Three participants (group I, n = 1; and group II, n = 2) withdrew halfway during the intervention process, and all participants were...
PMC9907817
Flow diagram.
left hemiplegia, right hemiplegia, stroke, Transcortical motor aphasia, ischemic stroke, Broca’s aphasia, hemiplegia
STROKE, ISCHEMIC STROKE
A total of 20 women (29%) and 50 men (71%) were included in this study, with an average of 65.0 (11.3) years. The educational background mainly comprised junior middle school (n = 29, 41.4%) and senior high school (n = 22, 31.4%). The main types of stroke were ischemic stroke (n = 56, 80.0%), Broca’s aphasia (n = 41; 5...
PMC9907817
Comparison of the two groups’ general clinical data.
stroke, hemiplegia, aphasia
STROKE
Differences between groups in classify data(gender, education level, stroke type, aphasia type and hemiplegia side), age and intervention time were analysed by Chi-square test, two independent sample t-test and Wilcoxon signed rank test respectively.
PMC9907817
Language function evaluation
All participants who completed intervention were evaluated for oral expression, comprehension and reading through the ABC scale. Moreover, 28 patients (group I, n = 13; and group II, n = 15) participated in the writing evaluation. There is no significant difference between the intervention and control groups in initial...
PMC9907817
Comparison of the ABC scores before and after the intervention in both groups.
Analysed by the two independent sample t-test between groups and paired sample t-test within groups.*P <0.05
PMC9907817
Daily communication skills
aphasia
The daily communication ability of patients with aphasia was evaluated using the CADL scale. There is no significant difference between the intervention and control groups in initial CADL scores (P > 0.05). The CADL scores of both groups significantly improved following intervention compared to values before interventi...
PMC9907817
Comparison of the CADL scores before and after the intervention in both groups.
Analysed by the two independent sample t-test between groups and paired sample t-test within groups.*P <0.05
PMC9907817
Discussion
aphasia
In the present study, we found that after a 2-week intervention, both group I (Chinese idioms training) and group II (routine rehabilitation training) showed significant improvement in the scores of oral expression, comprehension and reading sections in ABC and the scores of CADL, and the improvement in group I was sig...
PMC9907817
Supporting information
PMC9907817
CONSORT 2010 checklist.
(DOC)Click here for additional data file.
PMC9907817
PLOSOne clinical studies checklist.
(DOC)Click here for additional data file.
PMC9907817
Study protocol.
(PDF)Click here for additional data file.
PMC9907817
Translation of study protocol.
(PDF)Click here for additional data file.
PMC9907817
Ethics approval.
(PDF)Click here for additional data file.
PMC9907817
Translation of ethics approval.
(PDF)Click here for additional data file.
PMC9907817
Examples of idiom materials.
post-stroke aphasia
(PDF)Click here for additional data file.We thank the Department of Neurology, Neurosurgery and Rehabilitation of the Renmin Hospital of Wuhan University for providing a platform for the development of this study. We would like to thank the speech therapist Ms. Yang HM for providing relevant training for this study. We...
PMC9907817
Supplementary Information
toxicities, high-grade gliomas, mucositis, Hypertension, hypertension, gliomas, HGGs
COLORECTAL CANCER, DISEASE, SOLID TUMORS, ADVERSE EVENT, MUCOSITIS, HYPERTENSION, HYPERTENSION, GLIOMAS
SYHA1813 is a potent multikinase inhibitor that targets vascular endothelial growth factor receptors (VEGFRs)/colony-stimulating factor 1 receptor (CSF1R). This study aimed to evaluate the safety, pharmacokinetics (PK), and antitumor activity of escalating doses of SYHA1813 in patients with recurrent high-grade gliomas...
PMC10140125
Keywords
PMC10140125
Introduction
tumor, HGG, high-grade glioma, Malignant tumors, gliomas
TUMOR, SOLID TUMORS, MALIGNANT TUMOR, INFILTRATING, NEOVASCULARIZATION, GLIOMAS, TUMOR ANGIOGENESIS
Despite advances in treating recurrent high-grade glioma (HGG, WHO grade III and IV gliomas), the prognosis remains poor, and much work still needs to be done for improvement. Malignant tumors require neovascularization for growth, invasion, and metastasis[Tumor-associated macrophages (TAMs), defined as macrophages inf...
PMC10140125
Methods
PMC10140125
Patient eligibility
myocardial infarction, unstable angina pectoris, arrhythmia, impaired cardiac function, Tumors, glioma, cardiovascular and cerebrovascular diseases, hypertension
MYOCARDIAL INFARCTION, UNSTABLE ANGINA PECTORIS, ARRHYTHMIA, TRANSIENT ISCHEMIC ATTACK, BRAIN METASTASES, CENTRAL NERVOUS SYSTEM TUMORS, SOLID TUMORS, TUMORS, CEREBROVASCULAR ACCIDENT, GLIOMA, CONGESTIVE HEART FAILURE, ONCOLOGY, HYPERTENSION, LACUNAR INFARCTION
Eligible patients were ≥ 18 years of age with recurrent or advanced solid tumors confirmed by histology or cytology refractory to standard therapy or for which no effective therapy was available. Patients had at least one measurable lesion during the baseline period (primary central nervous system tumors were assessed ...
PMC10140125
Study design and drug administration
toxicities, DLTs
DISEASE
This was a phase Ia, multicenter, open-label, dose-escalation study of SYHA1813. The overall study design is presented in Supplementary Fig. S1. The primary endpoints were the safety and tolerability of SYHA1813, including the occurrence of dose-limiting toxicities (DLTs) and the establishment of the maximum tolerated ...
PMC10140125
Safety assessments and definition of DLT
non-DLTs, Cancer
ADVERSE EVENTS, ADVERSE EVENT, CANCER
DLT was defined as the occurrence of adverse events (AEs) that the investigator judged to be related to SYHA1813 within 28 days of the first dose during the dose-escalation period (Supplementary Table S1). The MTD was defined as the maximum dose for which the probability of a DLT was ≤ 33%.An accelerated titration desi...
PMC10140125
PK evaluation
BLOOD
Blood samples for the assessment of PK parameters were collected at predefined time points during the DLT observation period as follows: Cycle 0 Day 1 (predose; 0.5, 1, 2, 4, 8, and 12 h postdose), Day 2 (24 h postdose), and Day 3 (48 h postdose); Cycle 1 Day 1 (predose), Day 8 (predose), Day 15 (predose), Day 21 (pred...
PMC10140125
Efficacy assessment
toxicity, PD, SD
DISEASE PROGRESSION, DISEASE, CENTRAL NERVOUS SYSTEM TUMORS, SOLID TUMORS
Radiographic assessments were conducted at screening and at the end of the DLT observation period and repeated every six weeks during the extended treatment period until disease progression, intolerable toxicity, or withdrawal of consent (whichever came first). The patients with central nervous system tumors were evalu...
PMC10140125
Exploratory biomarker analysis
Samples for biomarker analyses were collected on Cycle 1 Day 1 (predose), Cycle 1 Day 24 (72 h post-dose), and 14 days after the end of treatment. Soluble VEGFR2, VEGF, and CSF1 levels were measured using multiplex enzyme-link immunosorbent assay (ELISA) plates from R&D Systems (Minneapolis, MN), and placental growth f...
PMC10140125
Statistical analysis
All statistical analyses were performed using SAS® 9.4 (SAS Institute, Inc., Cary, NC, USA) except for the calculation of PK parameters using Phoenix® WinNonlin 8.1 (Pharsight Corp., Certara, Princeton, NJ, USA). Exploratory biomarker analyses were performed by a two-tailed paired t test using GraphPad Prism 9.3 (Graph...
PMC10140125
Results
PMC10140125
DLTs and MTD
anaplastic astrocytoma, bradycardia, DLTs, non-DLT, mucositis, glioblastoma, hypertension
GLIOBLASTOMA, ANAPLASTIC ASTROCYTOMA, HYPERTENSION, MUCOSITIS
According to the accelerated titration design, two patients successively completed the DLT observation period (28 days) of treatment at 5 and 15 mg. However, the patient treated with 15 mg experienced grade 3 hypertension (non-DLT), and another two patients were enrolled at 15 mg based on the study design. Of those pat...
PMC10140125
Safety and tolerability
toxicities, hypertension, mucositis, Treatment-emergent adverse
SINUS BRADYCARDIA, HYPERTENSION, MUCOSITIS, ADVERSE EVENTS
All 14 patients were evaluated for safety. Overall, 13 (92.9%) patients had treatment-emergent AEs (TEAEs) during the study (Table  Treatment-emergent adverse events (affecting ≥ 10% of patients in either treatment group)Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDH, lactate dehydro...
PMC10140125
Efficacy
tumor, colorectal cancer, HGG, RECIST, S3).For glioma, glioma, PD
GLIOMA, TUMOR, COLORECTAL CANCER, SOLID TUMOR
Ten patients were assessable for tumor response per investigator assessment, 9 with glioma (RANO criteria) and 1 with colorectal cancer (RECIST version 1.1); the other four enrolled patients withdrew from the study before the first tumor assessment. In the efficacy-evaluable population, the ORR was 20% (2/10), with all...
PMC10140125
Analysis of biomarkers
Five patients were excluded from the biomarker analysis set due to a lack of postdose measurements. After multiple-dose administration of SYHA1813, there were significant increases in the serum levels of PlGF (
PMC10140125
Discussion
tumor, DLTs, toxicities, HGG, Hypertension, hypertension
TUMOR, SINUS BRADYCARDIA, HYPERTENSION, HYPERTENSION, MALIGNANT GLIOMAS
This trial was the first to investigate the safety, PK profile, and preliminary antitumor activity of single and multiple doses of SYHA1813. The MTD of SYHA1813 was defined as 15 mg once daily.While most patients experienced at least one TRAE, most treatment-related toxicities were mild and included hypertension, plate...
PMC10140125
Acknowledgements
We would like to thank all the patients, their families, and all the investigators involved in this study.
PMC10140125
Author contributions
WL
RECRUITMENT
ZK developed the study protocol, conducted the clinical study, and coordinated with the participating hospitals. SL, YL, YL, YM, JZ, and TL were the principal researchers in each hospital and helped to contribute to participant recruitment and provide feedback about the study procedure. HW, YS, YY, and JQ performed the...
PMC10140125
Funding
The study was funded by Shanghai Runshi Medical Technology Co., Ltd, China.
PMC10140125
Statements and declarations
PMC10140125
Conflict of interest
HW, YS, YY, and JQ are employed by CSPC Pharmaceutical Group Limited. The other authors have no conflicts of interest.
PMC10140125
Ethics approval
The studies involving human participants were reviewed and approved by an institutional review board at each participating site. This study is registered at chictr.org.cn (trial registration ID: ChiCTR2100045380).
PMC10140125
Consent to participate
All patients provided written informed consent prior to the initiation of any study-related procedures.
PMC10140125
Consent to publish
The authors affirm that human research participants provided informed consent for the publication of the images in Supplementary Figures S4 and S5.
PMC10140125
References
PMC10140125
Purpose
To analyze serum estradiol (E2) and estrone (E1) during letrozole treatment and their association to Quality of Life (QoL) and side-effects.
PMC10460747
Methods
breast cancer
BREAST CANCER
Postmenopausal breast cancer patients starting adjuvant letrozole were eligible. Serum samples were taken at baseline, three, and 12 months. E2 and FSH were measured with routine chemiluminescent immunoassays. E2 and E1 were analyzed after trial completion with a highly sensitive liquid chromatography-tandem mass spect...
PMC10460747
Results
aching joints, muscle aches, vaginal dryness, Pain
Of 100 screened patients 90 completed the trial. Baseline mean LC–MS/MS E2 and E1 were 12 pmol/L (range < 5–57) and 66 pmol/L (< 5–226), respectively. E2 levels measured by immunoassay and LC–MS/MS showed no correlation. E2 and E1 were completely suppressed by letrozole except for one occasion (E1 11 pmol/L at 3 months...
PMC10460747
Conclusions
muscle pain
Letrozole supresses E2 and E1 completely below the LLOQ of the LC–MS/MS in postmenopausal women. High pre-treatment E2 levels were associated with more joint and muscle pain during letrozole. Automated immunoassays are unsuitable for E2 monitoring during letrozole therapy due to poor sensitivity.
PMC10460747