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Statistical analysis
SD
Pharmacokinetic parameters were determined by non-compartmental analysis using PK solutions software, version 2.0 (Summit Research Services). The maximum concentration of four targeted compounds (CStatistical analysis was performed using STATA statistical software (StataCorp, USA). Continuous data were illustrated as m...
PMC9924185
Data availability
The datasets generated and/or analyzed during the present study are not publicly available due to ethical concerns and confidentiality agreements but are available from the corresponding author on reasonable request that needs a consensus from colleagues.
PMC9924185
Results
PMC9924185
Screening and identification of the analyte and metabolite profiling using LC-QTOF/MS analysis
The compound profiling after oral administration of Compound screening and identification after oral administration of *The tentative conjugated of AP3 sulfate and AP6 sulfate were omitted in this table due to the detection limit of LC-QTOF/MS technique, when low concentration of untargeted metabolite was used for anal...
PMC9924185
Compound 1 (M1, t
The MS data detected a deprotonated ion [M–H]
PMC9924185
Compound 2 (M2, t
The extracted-ion chromatogram (EIC) at 507.2188 (calculated m/z 507.2236) in negative ESI of a deprotonated molecule [M-H]
PMC9924185
Compound 3 (M3, t
The MS chromatogram of M3 demonstrated the presence of the molecular structure of glucuronide. The deprotonated ion [M–H]
PMC9924185
Compound 4 (M4, t
Compound 4 (M4) at retention time 10.15 min, showed a deprotonated molecule [M–H]
PMC9924185
Selection of analytes for further quantitative determination
The WHO monograph on selected medicinal plants indicated the major compounds of
PMC9924185
Chromatographic and mass spectrometry conditions of LC-QqQ-MS/MS
PMC9924185
LC optimization
SEPARATION
Chromatographic conditions were optimized to obtain a maximum intensity, and a high sensitivity with well-quantified chromatograms of each candidate analyte (AP1, AP3, AP4 and AP6). Addition of formic acid resulted in peak distortion and a decrease in negative signal intensity of the AP1 parent compound, as described b...
PMC9924185
Mass spectrometric conditions
HEAT
The MS system, coupled with a (-)ESI ion source, was used in this analytical method due to the significant intensity observed in the negative ionization. The MS quantification was obtained by monitoring precursor/product ion transitions (m/z) at 349.1/287.2, 331.1/239.2, 479.2/161.0, 333.1/285.2 and 779.3/649.2 for AP1...
PMC9924185
Method validation results
The new validated method in this study has the ability to fully determine the four major diterpenoids in both plasma and urine, using a small volume of sample (50 µL) and only requiring a short analysis time (6 min) with the lower limit of quantification < 1.00 ng/mL.
PMC9924185
Selectivity and specificity
There was no interference effect from the endogenous matrix at the retention time of all analytes and IS. The representative chromatograms of blank plasma and urine; and the chromatograms with the retention times of the spiked four diterpenoid standards or IS in methanol, blank plasma and blank urine, are shown in Figs...
PMC9924185
Accuracy and precision
SD
The %CV for intra-day and inter-day precision of each analyte in plasma sample (Table The intra-day and inter-day accuracy and precision of four major diterpenoids: andrographolide (AP1); 14-deoxy-11, 12-didehydroandrographolide (AP3); neoandrographolide (AP4); and 14-deoxyandrographolide (AP6) in plasma (a) and in uri...
PMC9924185
Linearity, range and lower limit of quantification (LLOQ)
Three calibration curves were calculated based on data from three consecutive days using twelve concentrations for each standard in plasma and urine. The coefficients of variation of AP1, AP3, AP4, and AP6, were 0.24–9.76, 0.58–11.48, 0.20–10.64, 0.53–10.26 for plasma, and 2.71–13.43, 2.57–10.46, 2.55–10.13, 1.69–10.88...
PMC9924185
Recovery
SD
Mean extraction recovery for each analyte and IS in plasma and urine is summarized in Table Mean extraction recovery, matrix effect, and hemolyzed plasma effect for andrographolide (AP1); 14-deoxy-11, 12-didehydroandrographolide (AP3); neoandrographolide (AP4); and 14-deoxyandrographolide (AP6) in plasma (a) and in uri...
PMC9924185
Matrix effects
The matrix effects at three levels of QC concentrations are presented in Table
PMC9924185
Stability
The stability of the four major diterpenoids in biological matrices was evaluated under different conditions. The results showed that AP1, AP3, AP4 and AP6 were stable in plasma and urine during five cycles of freeze–thaw storage. The analytes were also found to be stable after 3 months of “long-term” storage at − 80 °...
PMC9924185
Hemolyzed plasma effects
There was no interference observed in the hemolyzed plasma blank at the retention time of each analyte and of IS. As indicated in Table
PMC9924185
Conclusion
This newly developed LC–MS/MS method provides a thorough analytical method for the intended purposes of quantitative determination of the four major parent compounds (andrographolide; 14-deoxy-11, 12-didehydroandrographolide; neoandrographolide; and 14-deoxyandrographolide) in both plasma and urine samples. In this way...
PMC9924185
Supplementary Information
Supplementary Information.
PMC9924185
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-023-28612-1.
PMC9924185
Acknowledgements
This study was supported in part by a grant from Thailand Science Research and Innovation (TSRI), Chulabhorn Research Institute (grant number: 36822/4274380) and a grant from Thai Traditional Medicinal Knowledge Fund, the Department of Thai Traditional and Alternative Medicine, Ministry of Public Health, Thailand. The ...
PMC9924185
Author contributions
Conceptualization and Methodology, P.S., N.P., T.S., N.R., D.P., P.P. and J.S.; Subject management and Clinical investigation, P.P.; Method validation, P.S.; Data interpretation and Statistical analysis, P.S.; Writing original draft manuscript, P.S.; Review, N.P., T.S., N.R., D.P., P.P. and J.S.; Supervision, J.S.; Fun...
PMC9924185
Competing interests
The authors declare no competing interests.
PMC9924185
References
PMC9924185
1. Introduction
intellectual impairments, neurodevelopmental disorders, intellectual disabilities, autism
DISORDERS
The purpose of this study was to examine how 14 parents of children with autism and intellectual impairments responded to an Acceptance and Commitment Therapy (ACT)-based psychological flexibility intervention programme. A randomised clinical trial was conducted. Parents were randomly assigned to the training programme...
PMC10002330
2. Materials and Methods
PMC10002330
2.1. Design
This study was approved by the European University of Madrid Ethics Committee (CIPI/20/153). The trial was registered on ClinicalTrials.gov (ID: NCT05611554). Randomisation was completed by the Principal Investigator using an online service and randomly sized, permeated blocks to each arm (ratio: 1:1). The trial was a ...
PMC10002330
2.2. Participants
neurodevelopmental disorder, neurodevelopmental disorders, intellectual disability
Convenience sampling was carried out based on the availability of participants. The eligibility requirements included being over 18 years old, not currently receiving psychological treatment, being fluent in Spanish, and having a child diagnosed with a neurodevelopmental disorder or intellectual disability. The partici...
PMC10002330
2.4. Procedure
The brief group intervention protocol for family members (9 h) followed a similar structure to the programme implemented in the previous study [
PMC10002330
2.5. Statistical Analysis
Pre-treatment, post-treatment, and follow-up (3 months) variables were analysed and described. To evaluate the effectiveness of the intervention protocol, two complementary strategies were used. On the one hand, the scores of the participants on each instrument before the intervention programme were compared to those o...
PMC10002330
4. Discussion
neurodevelopmental impairments, fatigue, neurodevelopmental disabilities, neurodevelopmental disorders, disability, intellectual disabilities, autism
EVENTS
The ACT-based intervention for parents of children with neurodevelopmental disorders and intellectual disabilities was followed by a significant reduction in perceived stress, thought suppression, and PI. Additionally, changes in the suppression of private events and PF variables were statistically significant at post-...
PMC10002330
Author Contributions
Conceptualisation, D.L. and F.M.; methodology, D.L., F.M. and E.P.; software, D.L. and F.M; validation, D.L. and F.M.; formal analysis, D.L., F.M. and E.P.; investigation, D.L. and F.M.; resources, D.L., F.M. and E.P.; data curation, D.L. and F.M.; writing—original draft preparation, D.L. and F.M.; writing—review and e...
PMC10002330
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of European University of Madrid (protocol code CIPI/20/153 and date of approval 29 July 2020).
PMC10002330
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
PMC10002330
Data Availability Statement
Not applicable.
PMC10002330
Conflicts of Interest
The authors declare no conflict of interest.
PMC10002330
Abstract
These authors contributed equally to this work and share first authorship.
PMC10321207
Purpose
breast cancer
BONE METASTASIS, BREAST CANCER
Due to the poor and unpredictable prognosis of breast cancer (BC) patients with bone metastasis, it is necessary to find convenient and available prognostic predictors. This study aimed to recognize the clinical and prognostic factors related to clinical laboratory examination and to construct a prognostic nomogram for...
PMC10321207
Methods
REGRESSION, BONE METASTASIS
We retrospectively analyzed 32 candidate indicators from clinical features and laboratory examination data of 276 BC patients with bone metastasis. Univariate and multivariate regression analyses were performed to identify significant prognostic factors related to BC with bone metastasis. Nomogram was constructed and e...
PMC10321207
Results
Patients were randomly grouped into training (
PMC10321207
Conclusion
BONE METASTASIS
This study constructed a novel prognostic nomogram for BC patients with bone metastasis. It could serve as a potential tool of survival assessment to help individual treatment decision-making for clinicians.
PMC10321207
KEY MESSAGES
breast cancer
BONE METASTASIS, BREAST CANCER
Our study investigated potential prognostic value of indicators from biochemical and blood routine examination for breast cancer patients with bone metastasis.Our study established a nomogram based on the indicators from biochemical and blood routine examination, which might enhance the ability to predict prognosis of...
PMC10321207
Keywords
PMC10321207
Introduction
cancers, tumor, malignancy, Breast cancer, cancer death
BREAST CANCER, BONE METASTASIS, CANCERS, TUMOR
Breast cancer (BC), the most frequently diagnosed malignancy, is one of the main causes of cancer death in women [Currently, the prognostic predictors of bone metastasis include the features of original tumor, tumor markers, expression of selected genes, and related clinical manifestations [Increasing studies demonstra...
PMC10321207
Materials and methods
PMC10321207
Research design and patient population
death, primary breast cancer, Cancer
BRAIN METASTASIS, PRIMARY TUMORS, LUNG METASTASIS, BLOOD, BONE METASTASIS, PRIMARY TUMOR, LIVER METASTASIS, CANCER
This was a retrospective study based on patients’ records. From 2010 to 2022, 679 BC patients with bone metastasis were treated in the Cancer Hospital of Shantou University Medical College. We applied strict inclusion and exclusion criteria during the enrollment process. Patients met the following inclusion criteria: (...
PMC10321207
Variable selection and nomogram construction
REGRESSION, BONE METASTASES
We randomly partitioned the dataset into training and validation cohorts using R programming language. According to clinical significance, we screened a total of 33 prognostic-related variables in the first step, which consisted of 10 categorical variables and 23 continuous variables. The optimal cut-off values for the...
PMC10321207
Nomogram evaluation
To evaluate the discriminative ability, we constructed a receiver operating characteristic (ROC) curve. The nomogram discrimination efficacy was assessed by concordance index (C-index) and the area under the ROC curve (AUC). They basically ranged from 0.5 (random prediction) to 1.0 (excellent prediction). In general, a...
PMC10321207
Statistical analysis
In this study, all analyses, figures and tables were performed by IBM SPSS Statistics 26 (La Jolla, CA, USA), Microsoft Excel (Redmond, WA, USA), X-tile version 3.6.1 (Version 3.6.1, Yale University) and R version 4.1.3 (
PMC10321207
Results
PMC10321207
Baseline characteristics
After patients’ enrollment, we analyzed the demographic and clinical characteristic of 276 enrolled patients (Patient characteristics in the study.IQR: interquartile range
PMC10321207
Cox proportional hazards regression analysis
breast cancer
REGRESSION, METASTASIS, BONE METASTASES, BREAST CANCER
In the training cohort, after univariate Cox regression analysis, 20 variables were significantly associated with OS, including age, ER status, other organ metastasis, and some laboratory test factors consisting of LDH, ALP, GGT, ALB, GLB, BUN, CREAT, UA, WBC, RBC, HGB, MCV, MCH, MCHC, LY%, MO%, and NE%. We drafted Kap...
PMC10321207
Construction of 1-, 3-, and 5-year OS predicting nomogram
breast cancer
BONE METASTASIS, BREAST CANCER
Based on the prognostic factors selected in the training cohort, a nomogram was developed for the prediction of OS (Nomogram for 1, 3, and 5-year OS prediction of the breast cancer patients with bone metastasis. Each prognostic factor was assigned a point on the scale, and the sum of the total points projected on the b...
PMC10321207
Evaluation of the OS predicting nomogram
ALL, breast cancer
BONE METASTASIS, BREAST CANCER
As shown in Receiver operating characteristic (ROC) curves of 1, 3, and 5-year in the training (A) and validation cohorts (B), respectively. The area under the ROC curve (AUC) was 0.797, 0.782, and 0.794 in the training cohort, and 0.723, 0.742, and 0.704 in the validation cohort, respectively.In both training and vali...
PMC10321207
Discussion
esophageal cancer, malignancies, cancer
METASTASIS, OESOPHAGEAL CANCER, INFLAMMATION, CANCER, BONE METASTASIS, MALIGNANT TUMORS, MALIGNANCIES, NASOPHARYNGEAL CARCINOMA, INFLAMMATION, REGRESSION, METASTASES
Although great progress has been made in the diagnosis and treatment of BC, the occurrence of bone metastasis still brings great challenges to the clinicians. Advanced BC is regarded as incurable with current therapeutic strategy [Among our study, the prognosis of patients with additional organ metastatic sites was usu...
PMC10321207
Author contributions
Conceptualization, Bo Huang, Fang-Cai Wu, Xin-Jia Wang and Yi-Wei Xu; Data curation, Bo Huang and Fang-Cai Wu; Formal analysis, Bo Huang and Fang-Cai Wu; Funding acquisition, Xin-Jia Wang and Yi-Wei Xu; Investigation, Wei-Dong Wang, Can-Tong Liu, Xiao-Mei Wang, Bu-Qing Shao, Ying-Miao Lin, Guo-Xing Zheng and Ming-Ming ...
PMC10321207
Disclosure statement
No potential conflict of interest was reported by the author(s).
PMC10321207
Institutional review board statement
Cancer
CANCER
This research was conducted in the Cancer Hospital of Shantou University Medical College, and this study followed the 2008 Declaration of Helsinki’s ethical guidelines and our hospital code of ethics (2022094).
PMC10321207
Data availability statement
The raw data and the R codes supporting the conclusions of this article will be made available by the corresponding authors, without undue reservation.
PMC10321207
References
PMC10321207
Abstract
PMC9977742
Objective
epilepsy
EPILEPSY
The objective of this study is to evaluate the safety and tolerability of intravenous (IV) lacosamide infusion in patients aged ≥1 month to <17 years with epilepsy.
PMC9977742
Methods
ADVERSE EVENTS
This Phase 2/3 open‐label trial (EP0060; NCT02710890) enrolled patients in two age cohorts (cohort 1: ≥8 to <17 years; cohort 2: ≥1 month to <8 years). Eligible patients were receiving oral lacosamide as adjunctive treatment or monotherapy (in an open‐label long‐term trial or by prescription) or were not receiving laco...
PMC9977742
Results
TEAEs, seizures
GENERALIZED SEIZURES, FOCAL SEIZURES
In total, 103 patients were enrolled and completed the trial; 55 patients were included in cohort 1 (≥8 to <17 years), 48 in cohort 2 (≥1 month to <8 years). During the 4 weeks before screening, 74 (71.8%) patients had focal seizures, 12 (11.7%) had generalized seizures, and two (1.9%) had unclassified seizures. Most p...
PMC9977742
Significance
epilepsy
EPILEPSY
IV lacosamide was generally well tolerated in pediatric patients (≥1 month to <17 years) with epilepsy, and no new safety concerns were identified.
PMC9977742
Key Points
epilepsy
EPILEPSY
Safety and tolerability of IV lacosamide infusions were evaluated in 103 pediatric patients (≥1 month to <17 years of age) with epilepsy.Seventy‐nine (76.7%) patients had one IV lacosamide infusion, 20 (19.4%) had two, one (1.0%) had three, and three (2.9%) had 10 infusions.The only TEAEs reported in ≥2 patients were ...
PMC9977742
INTRODUCTION
epilepsy
FOCAL SEIZURES, EPILEPSY
Lacosamide is an antiseizure medication (ASM). It is a functionalised amino acid that selectively enhances slow inactivation of neuronal voltage‐gated sodium channels.Several trials have investigated the efficacy and safety of oral formulations of lacosamide in pediatric patients. The efficacy and tolerability of adjun...
PMC9977742
METHODS
EP0060 was a Phase 2/3, multicentre, open‐label trial. The trial was conducted in accordance with the International Council for Harmonization Good Clinical Practice requirements, the ethical tenets that have their origin in the principles of the Declaration of Helsinki, and the local laws of the countries involved. Wri...
PMC9977742
Patient eligibility
epilepsy
APPENDIX, FOCAL SEIZURES, CLONIC SEIZURES, EPILEPSY
Patients could be enrolled if they were ≥1 month to <17 years of age, had a diagnosis of epilepsy with focal seizures or primary generalized tonic–clonic seizures, weighed ≥4 kg, and were considered an acceptable candidate for venipuncture and IV infusion. In addition, eligible patients were (i) receiving oral lacosami...
PMC9977742
Lacosamide dosing
epilepsy
EPILEPSY
The trial consisted of a screening and/or baseline period of up to 7 days; a treatment period; a final visit (1 day); and a safety follow‐up via telephone over a period of 1‐3 days. Patients received IV lacosamide based on clinical need or elective administration. Clinical need administration applied to patients who ne...
PMC9977742
Outcomes
ADVERSE EVENTS
The primary outcomes were treatment‐emergent adverse events (TEAEs), reported spontaneously by the patient and/or caregiver or observed by the investigator, and discontinuations due to TEAEs. Other safety outcomes included changes in 12‐lead electrocardiograms (ECGs), vital sign measurements (blood pressure and pulse r...
PMC9977742
RESULTS
PMC9977742
Patient disposition and baseline characteristics
antiseizure, seizure, Epilepsy, epilepsy
MAY, EPILEPSY, EPILEPSY
This open‐label trial was conducted between May 2017 and June 2019; 103 patients were enrolled and completed the trial (SS; 77 from Europe, 26 from North America). Most patients (96 [93.2%]) were White. Fifty‐five patients were ≥8 to <17 years of age (cohort 1) and 48 were ≥1 month to <8 years of age (cohort 2). Patien...
PMC9977742
Lacosamide exposure
Most patients (74 [71.8%]) initiated lacosamide as adjunctive IV treatment upon enrolment, 26 (25.2%) received IV lacosamide as a replacement for prescribed oral lacosamide from a commercial supply, and three (2.9%) patients received IV lacosamide as a replacement for oral lacosamide received in another open‐label, lon...
PMC9977742
Safety and tolerability of
ADVERSE EVENTS, EVENT, ADVERSE EVENT, APPENDIX
A total of seven TEAEs were reported in five (4.9%) patients following treatment with IV lacosamide (Table Treatment‐emergent adverse events (SS‐IV)Abbreviations: IV, intravenous; SS‐IV, intravenous Safety Set; TEAE, treatment‐emergent adverse event.Medical Dictionary for Regulatory Activities Version 16.1 Preferred Te...
PMC9977742
DISCUSSION
critically ill, epilepsy
CRITICALLY ILL, EPILEPSY
This open‐label, multicentre trial is the largest prospective investigation of the safety and tolerability of IV lacosamide in pediatric patients with epilepsy. IV lacosamide (2–12 mg/kg/day or 100‐600 mg/day) was generally well tolerated in patients ≥1 month to <17 years of age, and no new safety concerns were identif...
PMC9977742
Limitations
epilepsy
FOCAL SEIZURES, CLONIC SEIZURES, EPILEPSY
This trial is limited by its open‐label, uncontrolled design with no comparator or placebo group. The patient population was mostly White; the results may not be generalizable across racial groups. However, no relevant differences in the pharmacokinetics of lacosamide have been observed between healthy Asian, Black, an...
PMC9977742
AUTHOR CONTRIBUTIONS
Mark Kristof Farkas and Iryna Makedonska were involved in execution of the trial as study investigators. Cynthia Beller was involved in analysis and interpretation of the data. Ali Bozorg and Nancy Yuen were involved in study design, and analysis and interpretation of the data. Carrie McClung and Robert Roebling were i...
PMC9977742
CONFLICTS OF INTEREST
Mark Kristof Farkas and Iryna Makedonska each report no conflicts of interest. Cynthia Beller, Ali Bozorg, Carrie McClung, Robert Roebling, Tanisia Yates, and Nancy Yuen are employees of UCB Pharma.
PMC9977742
ETHICAL APPROVAL
We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
PMC9977742
Supporting information
APPENDIX
Appendix S1–S2 Click here for additional data file.
PMC9977742
ACKNOWLEDGMENTS
APPENDIX
The authors thank the patients, their caregivers, and the investigators and their teams who contributed to this trial (Appendix 
PMC9977742
DATA AVAILABILITY STATEMENT
Underlying data from this manuscript may be requested by qualified researchers 6 months after product approval in the United States and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymised individual patient‐level data and redacted trial ...
PMC9977742
REFERENCES
PMC9977742
Methods
HOA
GROUP B
Fifty-seven patients with a lipid layer thickness (LLT) ≤ 75 interferometric colour units (ICU) were included in the study. In group A (20 patients) the effect of a single drop of F6H8 or CN on HOA and LLT was assessed immediately after application and up to two hours later. For long term effects (Group B) 37 patients ...
PMC9847907
Results
HOA
CN led to an increase of the LLT from 46.8 ± 16.9 ICU to 76.3 ± 23.5 ICU (p = 0.021) and to an increase of HOA from 0.43 ± 0.06 μm to 0.48 ± 0.08 μm immediately after application (p = 0.027). There was no correlation between the increase of LLT and HOA (r = -0.04; p = 0.90). In group B an increase of LLT was observed i...
PMC9847907
Conclusion
HOA
CN leads to a short-term increase in LLT and HOA, but only immediately after application. In contrast F6H8 does lead to an increase of LLT after regular long-term use but has no effect on HOA. The regular application of lipid-based products does not seem to decrease the quality of vision as measured in HOA. Instead, CN...
PMC9847907
Data Availability
All relevant data are within the paper.
PMC9847907
Introduction
neurosensory abnormalities, inflammation, Dry Eye Disease, disease of the ocular surface, hyperosmolarity
INFLAMMATION, DRY EYE DISEASE
Dry Eye Disease (DED) is defined as a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage as well as neurosensory abnormalities play etiological ro...
PMC9847907
Materials and methods
PMC9847907
Trial design
This was a parallel-group, randomized, active-controlled trial.
PMC9847907
Participants, eligibility criteria, and settings
Eighty-two patients were included in this study. Two separate cohorts were recruited, one (A) to evaluate the immediate effect of a single application of two different lipid-based lubricants and a second (B) to assess the effect of a 12-week treatment with regular application five times per day.In cohort A (short term ...
PMC9847907
Interventions
Participants in both cohorts were randomized to either receive a cationic nanoemulsion (CN, Cationorm
PMC9847907
Outcome measurements
DISEASE
All measurements followed the same protocol: First, symptoms were assessed using the Ocular Surface Disease Index (OSDIHOA were calculated from wavefront data based on the ray tracing method and corneal front surface data obtained with a rotating Scheimpflug camera (PentacamNon-invasive measurements of the lipid layer ...
PMC9847907
Sample size consideration
Sample size calculation is obtained from previous studies.
PMC9847907
Randomization
Using a simple unrestricted system using the random generator function of Excel (Microsoft Excel 2017, Microsofta—CONSORT Flow Diagram for short-term effect group. b—CONSORT Flow Diagram for long-term effect group.
PMC9847907
Ethics approval
RECRUITMENT, EYE
This prospective interventional randomized study included patients who were referred to Dry Eye clinic of the Department of Ophthalmology, University Hospital Duesseldorf, Germany, and healthy individuals without a history of DED who served as controls. All participants gave written informed consent for pseudonymized d...
PMC9847907