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Experimental design
We used the PET neuroimaging data, responsiveness test data and structured interview data from our recently published studies (Design of the experiment. Each subject within each treatment group received a targeted ECBased on our previous studies, we estimated a target concentration which would render 50% of the subject...
PMC10312059
Anesthesia protocol
The subjects abstained from the use of alcohol and any medications for at least 48 h and from the use of caffeine-containing products for 10–12 h and fasted overnight before the experiments. Two forearm veins were cannulated for administration of study treatments and the PET radiotracer. The left radial artery was cann...
PMC10312059
Responsiveness test and classification of the state of consciousness
During the experiment, the subjects were lying on bed with custom-made response handles secured to their wrists. Responsiveness was tested with a standardized prerecorded auditory request “press the handles twice” (R-test). Responding was practiced before the anesthesia. The R-test was presented with Presentation 17.0 ...
PMC10312059
Magnetic resonance imaging (MRI)
For each subject, an anatomic MRI scan of the brain (T1, T2, FLAIR) was performed before the PET imaging session for subsequent image preprocessing and exclusion of any brain anomalies. MRI scans were obtained with a Philips Ingenuity PET-MR 3T scanner (Philips Medical Systems) with the following scan parameters: TR = ...
PMC10312059
Drug concentration measurements
Arterial blood samples for drug concentration analysis in plasma were drawn at baseline and at 20, 30, 40, and 50 min after the start of the administration of the intravenous anesthetics. High-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) was used for dexmedetomidine and S-ketamine. Propo...
PMC10312059
PET data preprocessing
deformations
Voxel-wise maps of CMRNonlinear mapping from the MRI to the MNI standard space was estimated using unified segmentation in SPM8, and the deformations were subsequently applied to the MRI and co-registered PET images. All normalized PET images were smoothed using an isotropic Gaussian kernel of 12-mm FWHM.
PMC10312059
Statistical analysis
The Kolmogorov–Smirnov test was applied to test the normality of the outcome variables. Pearson's χA flexible factorial model was constructed in SPM12 with treatment group and state (connected or disconnected) as factors. Two-way interactions between factors were modeled in the design matrix, and t-contrasts were gener...
PMC10312059
Results
PMC10312059
Behavioral state, subjective reports, and ensuing classification of the state of consciousness
The subjects were prone to fluctuation in responsiveness because of the administered ECResponsiveness state categorization and cumulative tracer uptake weightsThe final number (proportions) of subjects assigned to responsiveness state categories and median (IQR) uptake weights for respective categories in each treatmen...
PMC10312059
Drug exposure
There were no statistically significant differences between measured drug concentrations in plasma (or end-tidal air) between the connected and disconnected subjects within the treatment groups (Targeted and measured drug concentrations during the experimentMean (SD) targeted and measured drug concentrations in plasma ...
PMC10312059
State-related effects
In the propofol group, disconnectedness was associated with relatively lower glucose metabolism bilaterally in the thalamus, hippocampus, amygdala, nucleus accumbens, nucleus caudatus, and globus pallidus (State-related effects. Relationship between disconnectedness and CMRNext, we used conjunction analysis to investig...
PMC10312059
Drug-related effects
To identify nonspecified drug-induced effects on brain activity, we contrasted each connected subjects' scans within each drug group with the placebo group scans. We found that exposure to propofol, dexmedetomidine or sevoflurane was associated with relative suppression of CMRDrug-related effects. Relative rCMR
PMC10312059
Combined effects of drug and state
Contrasting each disconnected subjects' scans within each drug group with the placebo group scans, we found that propofol, dexmedetomidine and sevoflurane induced relative suppression of CMRCombined effects of drug and state. Relative CMR
PMC10312059
Discussion
amnesia
EVENTS, CORTEX
We found that decreased metabolic activity of the thalamus was specifically associated with disconnectedness during ECSeveral studies and theories of anesthetic mechanisms of action have indicated a critical role for the thalamus in regulating consciousness (Transitions between global states of consciousness during con...
PMC10312059
References
PMC10312059
1. Introduction
obesity, chronic disease
OBESITY, CHILDHOOD OBESITY, CHRONIC DISEASE
The early introduction of effective nutritional educational programs is pivotal for instilling sustainable healthy behaviors. The present work aims to present a best practice example of a nutrition and overall lifestyle school-based training program, the Nutritional Adventures (“Diatrofoperipeteies”). Conducted during ...
PMC10745706
2. Materials and Methods
PMC10745706
2.1. Study Sample and Setting
The “Nutritional Adventures” program was implemented during the school years 2020–2021 and 2021–2022 at primary schools in Greece. A random selection of schools was performed using the national list that the Greek Ministry of Education provided. Only primary schools were considered eligible for this program, since its ...
PMC10745706
2.2. Bioethics
The “Nutritional Adventures” program was approved by the Ethical Committee of Prolepsis Institute (13913-n.3, on October 2021) and is being conducted in accordance with the Declaration of Helsinki. The program was implemented in schools after the official approval of the school administrative body as well as the signed...
PMC10745706
2.3. The “Nutritional Adventures” Program
The “Nutritional Adventures” program is a synchronous, online educational intervention, tailor-made for students in primary schools and implemented by instructors with expertise in the field of nutrition and public health promotion in early life stages.
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2.3.1. The Program Objective
The Nutritional Adventures program is a 1-month school-based educational initiative that aims to promote healthy living and dietary habits in primary school children.
PMC10745706
2.3.2. The Program Framework
1-school-hour
The “Nutritional Adventures” program consists of two sections. The first section is related to a synchronous, online educational program implemented at classes of primary schools by an instructor who is specialized in the field of nutrition and public health promotion in childhood. Two 1-school-hour online sessions are...
PMC10745706
2.3.3. The Program Experimental Design
PMC10745706
Training Content
An interdisciplinary team of nutritionists/dieticians, psychologists, health promotion specialists, and pedagogues was responsible for the training content of the program. The training content was externally approved by the National Institute of Educational Policy and implemented under the auspices of the Greek Ministr...
PMC10745706
Adaptation of the Program to Educational Grade
The training content, means, and methods were adapted to the educational grade. In particular, two versions of the program were designed and tailor-made for 1st–3rd Grade and 4th–6th Grade. In younger students (i.e., 1st–3rd Grade) the story-telling educational approach was used based on a nutrition fairytale named “Th...
PMC10745706
Supportive Educational Material and Randomization of Training Methods
In all cases, students were provided with supportive educational material—tailor-made for their age—in the form of booklets and diaries. Students had the option to use it for “in-class” or “at-home” activities supervised by educators or parents, respectively. To examine the existence of superiority or equivalence in th...
PMC10745706
2.4. Pre- and Post-Intervention Assessment
A structured questionnaire was used to record the sociodemographic characteristics of students and their families, their dietary and other lifestyle habits, and overall HRQoL. The questionnaires were completed by a parent or another guardian if a parent was not available. To assess the efficacy of the program, question...
PMC10745706
2.4.1. Sociodemographic Characteristics
Sociodemographic characteristics included students’ age, sex, family structure, parents’ country of origin, level of education, and employment status. The level of education was classified as low (<9 years of education), moderate (9–12 years of education), and high (>12 years of education).
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2.4.2. Dietary Habits, Physical Activity, and Screen Time
Students’ dietary habits and overall level of adherence to Mediterranean diet were assessed using the KIDMED score [
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2.4.3. Health-Related Quality of Life
In order to assess the student’s HRQoL, the PedsQL 4.0 measurement model was utilized [
PMC10745706
2.4.4. Body Mass Index
Obesity
OBESITY, OBESE
Parents were asked to report their children’s weight and height. The revised International Obesity Task Force cut-offs according to the pooled Lambda Mu and Sigma curves were used for Body Mass Index (BMI) classification (underweight, normal, overweight, obese) [
PMC10745706
2.5. Statistical Analysis
Categorical variables are presented as relative frequencies (%), and continuous variables are presented as mean values (standard deviation). Student’s
PMC10745706
3. Results
PMC10745706
3.1. Paternal and Student Demographic Characteristics
Students’ sociodemographic characteristics according to their grades are presented in
PMC10745706
3.2. Improvement in Dietary Habits and HRQoL According to Students’ Grade
The statistical analysis of the baseline and follow-up revealed a significant improvement in the KIDMED score (mean increment = 0.25 units; An elevated HRQoL (mean increment = 1.35 units), as well as better scores in physical (mean increment = 0.99 units), emotional (mean increment = 2.15 units), social (mean increment...
PMC10745706
3.3. Improvement in Dietary Habits and HRQoL According to Intervention Group
Comparisons were also made between the parent and educator groups, as presented in As described in Intervention groups were also compared for all outcomes separately for each grade group. Parent–educator demographics were similar in both grade groups for most characteristics, except for students’ age and sex distributi...
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3.4. Improvement in Dietary Habits and HRQoL according to BMI Classification
Comparisons were also made between students with healthy and unhealthy weights, as presented in As described in
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3.5. Acceptability, Satisfaction, and Perceived Impact of the Nutritional Adventures Program
’s eating habits
When parents were asked to report on their satisfaction with the program, about 92.1% reported that the provided educational material was good/very good, 88.5% were satisfied with the educational activities, and 85.4% considered the quality of the educational activities to be good/very good. Moreover, 90.2% of parents ...
PMC10745706
4. Discussion
obesity, pandemic, overweight or obesity
OBESITY
The “Nutritional Adventures” program, presented herein, implemented during the crucial period after the COVID-19 pandemic appeared to be a successful educational approach in promoting short-term healthy nutrition during early life stages with potential long-term effects. The present work—despite the effect of low magni...
PMC10745706
5. Conclusions
The present study demonstrates that the “Food Adventures” (‘Diatrofoperipeties’) program successfully improved dietary and lifestyle habits and HRQoL in primary school children (6–12 years old). Designing a school-based virtual curriculum enabled the widespread dissemination of nutrition education across Greece, overco...
PMC10745706
Author Contributions
Conceptualization, D.V.D., K.K. and A.L.; methodology, A.S., D.V.D., K.K. and E.Z.; formal analysis, A.S., D.V.D., K.K. and M.K.; investigation, A.S., D.V.D. and K.K.; resources, A.S. and D.V.D.; data curation, A.S., D.V.D. and K.K.; writing—original draft preparation, A.S., D.V.D., K.K. and E.Z.; writing—review and ed...
PMC10745706
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Ethics Committee of Prolepsis Institute (13913-n.3-October 2021).
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Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
PMC10745706
Data Availability Statement
All data and materials are available upon reasonable request to the corresponding author.
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Conflicts of Interest
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
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Appendix A
Baseline characteristics of students in the total sample and according to intervention group (parent and teacher).Data are presented as mean (standard deviation) for normally distributed continuous variables (age) and % of the corresponding sample for categorical variables. For the normally distributed variables (age),...
PMC10745706
Appendix B
Demographic characteristics of students according to intervention group (parent and teacher), by 1st–3rd grade and 4th–6th grade students separately.Data are presented as mean (standard deviation) for normally distributed continuous variables (age) and % of the corresponding sample for categorical variables. For the no...
PMC10745706
Appendix C
Demographic characteristics of students according to their grade, by intervention group (parent and teacher).Data are presented as mean (standard deviation) for normally distributed continuous variables (age) and % of the corresponding sample for categorical variables. For the normally distributed variables (age), p’s ...
PMC10745706
Appendix D
Changes in the adherence to the Mediterranean diet, HRQoL, physical activity, and screen time between baseline and follow-up (difference), according to students’ grade, by intervention group (parent and teacher) separately.All differences were calculated as follow-up score—baseline score and are presented as mean (SD) ...
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Appendix E
Changes in the adherence to the Mediterranean diet, dietary habits, HRQoL, physical activity, and screen time between baseline and follow-up (difference), according to intervention group (parent and educator), by 1st–3rd grade and 4th–6th grade students separately.All differences were calculated as follow-up score—base...
PMC10745706
References
Baseline characteristics of students in the total sample and according to students’ grades.Data are presented as mean (standard deviation) for normally distributed continuous variables (age) and % of the corresponding sample for categorical variables. For the normally distributed variables (age), p’s were obtained usin...
PMC10745706
Background
pulmonary embolism
PULMONARY EMBOLISM, EMERGENCY
The aim of this trial-based economic evaluation was to assess the incremental costs and cost-effectiveness of the modified diagnostic strategy combining the YEARS rule and age-adjusted D-dimer threshold compared with the control (which used the age-adjusted D-dimer threshold only) for the diagnosis of pulmonary embolis...
PMC10687836
Methods
VTE, failure of the diagnostic strategy, defined as, venous thromboembolism
Economic evaluation from a healthcare system perspective alongside a non-inferiority, crossover, and cluster-randomized trial conducted in 16 EDs in France and two in Spain with three months of follow-up. The primary endpoint was the additional cost of a patient without failure of the diagnostic strategy, defined as ve...
PMC10687836
Results
VTE
Of the 1,414 included patients, 1,217 (86%) were analyzed in the per-protocol analysis (648 in the intervention group and 623 in the control group). At three months, there were no statistically significant differences in total costs (€-46; 95% CI: €-93 to €0.2), and the failure rate was non inferior in the intervention...
PMC10687836
Conclusions
VTE
Given the observed cost decrease of borderline significance, and according to the 95% confidence ellipses, the intervention strategy has a potential to lead to cost savings as a result of a reduction in the use of chest imaging and of the number of undetected VTE averted. Policy-makers should investigate how these mone...
PMC10687836
Clinicaltrials
Trial registration number ClinicalTrials.gov Identifier: NCT04032769; July 25, 2019.
PMC10687836
Supplementary Information
The online version contains supplementary material available at 10.1186/s12873-023-00910-x.
PMC10687836
Keywords
PMC10687836
Introduction
pulmonary embolism, Pulmonary embolism, VTE, venous thromboembolism
PULMONARY EMBOLISM, PULMONARY EMBOLISM
Pulmonary embolism (PE) and venous thromboembolism (VTE) are an important health and economic burden, with estimated direct and indirect costs of about 10,000€ per confirmed case of PE, and the loss of over one healthy year in Europe [The optimal diagnostic strategy for patients with suspected pulmonary embolism remain...
PMC10687836
Patients and methods
PMC10687836
Design of the MODIGLIA-NI trial and population
VTE
SECONDARY, VENOUS THROMBOEMBOLISM
This trial-based economic evaluation was based on MODIGLIA-NI, a non-inferiority, crossover, cluster-randomized trial conducted in 16 EDs in France and two in Spain. The study protocol has been previously published [The primary outcome in the efficacy trial was the percentage of failure of the diagnostic strategy (unde...
PMC10687836
Cost-effectiveness analysis
VTE, venous thromboembolism
We followed a detailed health economics analysis plan developed before the end of the trial and last modified before the freezing of the trial database. We chose a cost-effectiveness analysis instead of a cost minimization procedure, with a non-inferiority margin of 1.35%, as described in the published study protocol [...
PMC10687836
Resource use and costs
VTE
Resource use was collected prospectively in the electronic Case Record Form (eCRF) developed for the MODIGLIA-NI trial on the Cleanweb™ ® software, completed at the initial ED visit and for all hospitalizations at a three-months horizon. During the initial ED visit, data related to laboratory tests including D-dimer us...
PMC10687836
Sample size calculation
The sample size calculation was based upon clinical hypotheses, with a noninferiority margin set at 1.35%, an anticipated failure rate of 0.5% in the control group, the 2-sided α risk set at 5% and β set at 20%. The cluster design effect was estimated 1.37. Assuming that 5% of patients would not be evaluable, with 18 E...
PMC10687836
Statistical analysis
VTE
Analysis was conducted in both the per-protocol (PP) and as randomized populations. The per-protocol population excluded patients who did not meet all inclusion and non-inclusion criteria, were not treated using the strategy allocated to the ED, had a missing value for the primary end point, or had any other major prot...
PMC10687836
Missing data
VTE
EVENT
Missing data were managed differently between the two countries. For French re-hospitalization costs related to VTE, one patient out of the six with a VTE event had missing DRG information, so the cost was imputed by the mean re-hospitalization cost of the strategy group. For the Spanish centers, cost data at the index...
PMC10687836
Results
PMC10687836
Patient characteristics at baseline
VTE
Detailed information on the trial’s design, inclusion and exclusion criteria, population characteristics, and the diagnosis of VTE, results have been published. Briefly, 1,414 patients were randomized to either intervention strategy group (n = 726) or control strategy group (n = 688) in 16 emergency departments in Fran...
PMC10687836
Resource use and costs
VTE, hemoptysis
DEEP VEIN THROMBOSIS
D-dimer testing was performed in the entire the per-protocol population and 29.8% of the intervention group had a CPTA test compared to 40.1% in the control group. Data on whether or not a hospital admission occurred was unavailable for 32 (2.5%) patients. Six patients were hospitalized for VTE at three months (one in ...
PMC10687836
Cost-effectiveness analysis
VTE
In the PP population, the results of the cost-effectiveness analysis for undetected VTE averted are presented in Table The cost-effectiveness results for the as randomized population are presented in Table
PMC10687836
Discussion
pulmonary embolism, VTE
PULMONARY EMBOLISM
In this within-trial economic evaluation of the use of the YEARS criteria combined with the age-adjusted D-dimer threshold compared to the standard diagnostic strategy to rule out pulmonary embolism in the emergency department, we found a high probability that combining YEARS and age-adjusted D-dimers is less costly an...
PMC10687836
Conclusion
VTE
Cost-effectiveness analyses primarily aim to provide complementary information that can help a decision-maker to choose one strategy over another. In this context, the present study provides crucial information about the cost and cost-effectiveness of intervention strategy. Given the observed cost decrease of borderlin...
PMC10687836
Author Contributions
YF, TS, IDZ wrote the main manuscript text, with the help of MD, MM, LB, MC,ANO, NM, FBNG collected and analysed the economic data and prepared the tables and figures. All authors reviewed and approved the manuscript.
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Funding
This work was supported by a grant from Programme Hospitalier de Recherche Clinique - PHRC 2017 (French Ministry of Health). The funding body had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. The trial was sponsored by the Assistance Publique–Hopi...
PMC10687836
Data Availability
Yes.Data types: Deidentified participant data.How to access data: All the study data will be provided for review upon reasonable request to the corresponding author.When available: With publication Supporting Documents.Document types: None Additional Information Who can access the data: researchers whose proposed use o...
PMC10687836
Declarations
PMC10687836
Ethical approval
DEL
Approval of the study was obtained by the appropriate ethics committees in Spain and France (Comite de Etica de la Investigacion con Medicamentos del Hospital Clinic de Barcelona and Comite de Protection des Personnes Ile-de-France XI). Informed consent was sought for each patient before inclusion in the study: oral in...
PMC10687836
Ethical guidelines
This study is based upon a clinical trial using cluster randomization which makes individual consent unnecessary. All eligible patients were informed of the study by an information form in participating centers. The treating physician or the local investigator explained the rationale and objectives of the study. An inf...
PMC10687836
Consent for publication
Not applicable.
PMC10687836
Competing interests
Dr Simon reported receiving grants from the FrenchMinistry of Health, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline,Novartis, and Sanofi; personal fees from AstraZeneca, Ablative Solutions, Bayer, Novartis, Sanofi, and 4Living Biotech; and fees for conferences, counseling, and/or ...
PMC10687836
References
PMC10687836
Background
weight loss, gastric or gastroesophageal junction cancer
Body weight loss (BWL) is a negative prognostic factor in metastatic gastric or gastroesophageal junction cancer (mGC/GEJC). In the phase III TAGS study, trifluridine/tipiracil improved survival versus placebo in third- or later-line mGC/GEJC. These retrospective analyses examined the association of early BWL with surv...
PMC10284730
Methods
Efficacy and safety were assessed in patients who experienced < 3% or ≥ 3% BWL from treatment start until day 1 of cycle 2 (early BWL). The effect of early BWL on overall survival (OS) was assessed by univariate and multivariate analyses.
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Results
Body weight data were available for 451 of 507 (89%) patients in TAGS. In the trifluridine/tipiracil and placebo arms, respectively, 74% (224/304) and 65% (95/147) experienced < 3% BWL, whereas 26% (80/304) and 35% (52/147) experienced ≥ 3% BWL at cycle 1 end. Median OS was longer in < 3% BWL versus ≥ 3% BWL subgroups ...
PMC10284730
Conclusions
In TAGS, early BWL was a strong negative prognostic factor for OS in patients with mGC/GEJC receiving third- or later-line treatment.
PMC10284730
Supplementary Information
The online version contains supplementary material available at 10.1007/s10120-023-01393-2.
PMC10284730
Keywords
PMC10284730
Introduction
Gastric cancer, death
GASTRIC CANCER, DISEASE
Gastric cancer (GC) is the third most common cause of cancer-related death worldwide [In the third- or later-line setting, trifluridine and tipiracil (FTD/TPI; TAS-102), comprising trifluridine, a thymidine analog, and tipiracil, a thymidine phosphorylase inhibitor [As response to systemic therapy varies from individua...
PMC10284730
Methods
PMC10284730
Patients and study design
SECONDARY
The study design for the randomized, double-blind, placebo-controlled, phase III TAGS study (NCT02500043) has been reported previously [TAGS was designed and conducted in accordance with the Declaration of Helsinki and ethical principles of good clinical practice and local regulations. All protocols and amendments were...
PMC10284730
Study assessments
Tumors, Tumor, Cancer
TUMORS, TUMOR, CANCER
Tumor assessments by computer tomography of the chest and abdomen were done within 28 days before cycle 1, and every 8 weeks during study treatment and evaluated by the investigator according to Response Evaluation Criteria for Solid Tumors version 1.1 (RECIST v1.1). Safety was assessed throughout the study, and AEs we...
PMC10284730
Early BWL subgroup analysis
This retrospective, post hoc analysis examined the effect of BWL on survival and safety outcomes in patients from the TAGS study. Patients with body weight data available at the end of cycle 1 from the TAGS population were categorized into early BWL subgroups (< 3% or ≥ 3% BWL) based on weight change from start of trea...
PMC10284730
Statistical analyses
weight loss
Statistical considerations for the overall study have been previously reported. The analyses in BWL subgroups were exploratory and not powered for formal hypothesis testing, and therefore no The effect of early BWL on OS was assessed by univariate and multivariate analyses performed using Cox’s proportional hazards mod...
PMC10284730
Results
PMC10284730
Discussion
muscle gain, cancers, decreased skeletal muscle mass, weight gain, Sarcopenia, weight loss
CANCERS, SARCOPENIA
The results of these analyses in TAGS indicated that ≥ 3% BWL at the end of treatment cycle 1 was associated with unfavorable survival outcomes in patients with mGC/GEJC treated in the third- or later-line setting. The negative association of early BWL with OS was observed in both FTD/TPI and placebo treatment groups. ...
PMC10284730
Limitations
A strength of this analysis was the relatively large patient population of the TAGS trial. One key limitation was the exploratory post hoc nature of this analysis, which was not powered to investigate differences in efficacy and safety between the BWL subgroups. Imbalances in weight loss between the treatment arms prec...
PMC10284730
Conclusions
In conclusion, this analysis showed that BWL at the end of cycle 1 of treatment was associated with unfavorable survival outcomes in patients with mGC/GEJC in the TAGS trial, regardless of FTD/TPI or placebo treatment. As observed in earlier settings [
PMC10284730
Acknowledgements
ONCOLOGY
We thank all the patients and families who made this trial possible, clinical study teams and data and safety monitoring members. This trial was funded by Taiho Oncology, Inc. and Taiho Pharmaceuticals Co., Ltd. This analysis was funded by Taiho Oncology, Inc. Professional medical writing and editorial assistance were ...
PMC10284730
Author contributions
All authors had access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. MG, HH, LM, OT, KAB, and WM contributed to the study conception and design of the analysis. MG, HH, TD, EVC, and WM were responsible for data acquisition. Statistical analy...
PMC10284730
Data availability
ONCOLOGY
Data generated or analyzed during this study are on file with Taiho Oncology, Inc., and Taiho Pharmaceuticals Co., Ltd., and are not publicly available. Inquiries about data access should be sent to th-datasharing@taiho.co.jp
PMC10284730