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Results
depression
RECRUITMENT
The findings supported feasibility and acceptability, with high rates of recruitment (N=55), uptake (55/64, 86% of eligible participants), and retention (52/55, 95% at 6 weeks). Engagement was high, with 90% (26/29) and 59% (17/29) of the participants in the Mello condition still using the app during the third and sixt...
PMC10753417
Conclusions
ill
The results indicate that mechanistic, targeted, and real-time technology-based solutions may provide scalable and effective interventions that advance the treatment of youth mental ill health.
PMC10753417
Trial Registration
Australian New Zealand Clinical Trials Registry ACTRN12621001701819; http://tinyurl.com/4d3jfj9f
PMC10753417
Introduction
cognitive behavior, mental ill, anxiety, JITAIs, depression
SECONDARY, DISORDERS, EMA
Approximately one-fifth of young people worldwide are affected by mental ill health [Repetitive negative thinking (RNT) is a key transdiagnostic mechanism that accounts for the overlap between several mental disorders, particularly depression and anxiety [A key shortcoming of existing psychological treatments is the in...
PMC10753417
Methods
PMC10753417
Study Design
This study was an open label, parallel group RCT. Participants were allocated on a 1:1 ratio to the Mello app intervention group or a nonactive control group.
PMC10753417
Participants
depression, anxiety
Participants were recruited through paid web-based social media advertisements on Facebook and Instagram. Participants were young people from the general population aged between 16 and 25 years who were experiencing clinical levels of depression and anxiety (≥10 on the Patient Health Questionnaire 8 [PHQ-8] [A target s...
PMC10753417
Randomization and Blinding
Participants were randomized to the Mello or a control group using a computer-generated randomization table, with block sizes of 6 and 8, and stratified based on whether the participant was receiving psychological or other mental health treatment at the time of study participation. The randomization table was created b...
PMC10753417
Procedure
Study advertisements on social media linked to a web-based information and expression of interest page. Participants who submitted an expression of interest were sent information about the study (
PMC10753417
Interventions
PMC10753417
Intervention Development
Mello was developed based on user-centered design principles [
PMC10753417
Intervention Description
depression, anxiety
The Mello app uses real-time assessments to tailor momentary intervention strategies targeting the disruption of RNT in real time for young people with depression and anxiety (Mello app features.
PMC10753417
Outcomes
RECRUITMENT
The primary outcomes were feasibility, acceptability, and preliminary efficacy of the intervention. Feasibility was assessed through trial uptake, attrition, and engagement. A preregistered target sample of 30 participants was set to meet the aims of the study, with feasibility indicated if this sample size was met wit...
PMC10753417
Statistical Analysis
depression, anxiety
All data analyses were performed on an intention-to-treat basis. Generalized linear mixed models with a restricted maximum likelihood estimator implemented by the lme4 (version 1.1-26) package in R (version 4.0.4; R Foundation for Statistical Computing) were used to assess the associations between the condition and cha...
PMC10753417
Ethical Considerations
The study was approved by the University of Melbourne Human Research Ethics Committee (project 2021-22524-23553-5) and prospectively registered (ACTRN12621001701819). Reporting followed CONSORT (Consolidated Standards of Reporting Trials) guidelines (Participants provided written informed consent via the REDCap web app...
PMC10753417
Results
PMC10753417
Acceptability
The mean Mobile Application Rating Scale–User version scores are listed in User version of the Mobile App Rating Scale (uMARS; score range 1-5).
PMC10753417
Mechanisms
depression, anxiety
Exploratory analyses were conducted to explore whether changes in the mechanism of RNT may be associated with changes in the primary outcomes of depression and anxiety. As previously stated, a significant interaction effect was observed between groups over time for anxiety (In terms of depression, a trend toward signif...
PMC10753417
Adverse Events
pain
ADVERSE EVENTS
Two participants in the Mello group reported mild adverse events: one with worsening mental health and the other with physical pain, both deemed unrelated to the intervention or study participation. No serious or trial-related adverse events were reported during the trial.
PMC10753417
Discussion
PMC10753417
Principal Findings
JITAIs [, depression, anxiety
SECONDARY, RECRUITMENT
The aim of this pilot RCT was to evaluate the feasibility, acceptability, and estimated efficacy of a personalized, transdiagnostic, and mechanistic smartphone intervention called Mello for targeting RNT in young people with depression and anxiety. The results showed significantly greater reductions in depression, anxi...
PMC10753417
Limitations
There were several important limitations in this study. First, a fully powered trial is needed to confirm the results due to the small sample size, including the causal pathways of the intervention using formal mediation analyses across multiple time points and subgroup analysis to examine how the effects may differ be...
PMC10753417
Conclusions
depression, TG, anxiety
The results of this pilot RCT suggest that the Mello app is feasible, acceptable, and potentially clinically effective. Large and significant reductions in RNT scores were found, which may explain the effects of Mello on anxiety and depression. These findings support ongoing research and development, with a focus on en...
PMC10753417
Abbreviations
Anxiety
DISORDER
Cognitive Fusion QuestionnaireConsolidated Standards of Reporting Trialsecological momentary assessmentGeneralized Anxiety Disorder Scale 7just-in-time adaptive interventionPatient Health Questionnaire 8Perseverative Thinking Questionnairerandomized controlled trialResearch Electronic Data Capturerepetitive negative th...
PMC10753417
Data Availability
The data sets generated and analyzed in this study are available from the corresponding author upon reasonable request.
PMC10753417
2. Materials and Methods
PMC10146264
2.1. Study Design, Conduct and Treatment
hormone-sensitive prostate cancer
HORMONE-SENSITIVE PROSTATE CANCER
Five clinical trials were conducted at investigational sites in Lithuania and Latvia between 2004 and 2007 with each trial testing a different loading dose and/or regimen of teverelix DP in patients with advanced, hormone-sensitive prostate cancer (All studies were conducted in accordance with the current version of th...
PMC10146264
2.2. Patients
Tumor, cancer, adenocarcinoma of the prostate, prostate, psychiatric, alcohol abuse, Liver or renal function, N0
METASTASIS, TUMOR, CANCER, DISEASE, ADENOCARCINOMA OF THE PROSTATE, PROSTATE, METASTASIS, PROSTATE CANCER
The eligibility criteria were the same for all the trials:Inclusion criteria Histologically proven adenocarcinoma of the prostate;Androgen deprivation therapy suitable (advanced prostate cancer, i.e., with local invasion or/and metastasis);Signed written informed consent.Exclusion criteria Liver or renal function tests...
PMC10146264
2.3. Outcomes and Assessments
redness, itching, swelling, prostate, pain/tenderness, MP
ADVERSE EVENTS, SECONDARY, PROSTATE, INDURATION
The primary objective of all the trials was to assess the duration of action of an initial loading dose regimen of teverelix DP in terms of suppression of testosterone to below the castration level (0.5 ng/mL). The secondary objectives were: to assess the pharmacodynamics of teverelix DP in terms of its ability to supp...
PMC10146264
2.4. Statistical Analysis
No formal sample size calculations or between-group comparisons were performed for these explorative Phase 2 studies that were designed to obtain additional knowledge to elucidate further Phase 2/3 studies. The primary analysis was performed for the intent-to-treat (ITT) dataset, which included all patients who receive...
PMC10146264
3. Results
PMC10146264
3.1. Patients
Overall, 82 patients were enrolled and received treatment in the 5 clinical trials (
PMC10146264
3.2. Efficacy, Pharmacokinetic and Pharmacodynamic Evaluations
The mean onset of castration for the SC regimens ranged from 1.10 days (120 mg SC for 2 days) to 1.77 days (90 mg for 2 days), while it was 2.4 days with 90 mg IM administration. The mean duration of castration across the studies ranged from 32.45 days (range: 0–6 weeks for 120 mg SC for 2 consecutive days) to 68.95 da...
PMC10146264
3.3. Safety and Tolerability
INJECTION SITE REACTION
Overall, the 82 patients received 232 injections (16 via IM administration; 216 via SC administration). The most common AEs were injection site reactions (For the transrectal ultrasound (TRUS) assessment in clinical trial ARD-0301-008, a statistically significant mean change from baseline to the final assessment of −10...
PMC10146264
4. Discussion
death, non-cancer, Prostate cancer, deaths, prostate cancer
CARDIOVASCULAR DISEASE, DISEASE, PROSTATE CANCER, INJECTION SITE REACTION, INJECTION SITE INDURATION, PROSTATE CANCER
Prostate cancer is the second most common cause of cancer-related deaths in men, representing a major source of morbidity and mortality. Androgen deprivation therapy (ADT) is the primary treatment for patients with advanced prostate cancer at disease presentation, which can be achieved either with surgical or chemical ...
PMC10146264
5. Conclusions
PD
There is an unmet clinical need for a GnRH antagonist that has improved local tolerability and a sustained duration of action. Teverelix DP has the potential to address both of these points. Good local tolerability has been evidenced in numerous clinical trials, and data reported from two regimens with mean periods of ...
PMC10146264
Supplementary Materials
The following supporting information can be downloaded at: Click here for additional data file.
PMC10146264
Author Contributions
Conceptualization, C.M.M., A.U., F.J., Ž.S. and F.L.; Methodology, C.M.M., A.U., F.J., Ž.S. and F.L.; Software, C.M.M., S.v.O. and F.L.; Validation, C.M.M., S.v.O. and F.L.; Formal Analysis, C.M.M., A.U., F.J., Ž.S., S.v.O. and F.L.; Investigation, C.M.M., A.U., F.J., Ž.S., S.v.O. and F.L.; Resources, C.M.M., S.v.O. an...
PMC10146264
Institutional Review Board Statement
The studies were conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board as follows: Study EP-24332T-A013: Lithuanian Bioethics Committee: 2004-03-31 No. 30/2. Study EP-24332T-A014: Lithuanian Bioethics Committee: 2004-09-01 No. 46/1. Study ARD-0301-003: Lithu...
PMC10146264
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
PMC10146264
Data Availability Statement
Not applicable.
PMC10146264
Conflicts of Interest
C.M., S.v.O. and F.L. are employees of Antev Ltd., current Sponsor of teverelix DP. At the time the clinical trials were conducted, C.M. and F.L were employees of the Sponsor at the time, Ardana Bioscience Ltd. A.U., F.J., Z.S. declare no conflict of interest related to this research.
PMC10146264
References
PD
ADVERSE EVENTS
Teverelix DP dose and regimen and evaluation days in the Phase 2 clinical trials. Yellow box = subcutaneous (SC) injection; green box = intramuscular (IM) injection; orange box = assessment days for teverelix, testosterone and luteinizing hormone. D = day; LH = luteinizing hormone; PSA = prostate-specific antigen; Tev ...
PMC10146264
Supplementary Information
GROUP B, CHOLELITHIASIS
This study aimed to investigate the indocyanine green (ICG) dose in real‐time fluorescent cholangiography during laparoscopic cholecystectomy (LC) with a 4K fluorescent system. A randomized controlled clinical trial was conducted in patients who underwent LC for treatment of cholelithiasis. Using the OptoMedic 4K fluor...
PMC10543949
Keywords
PMC10543949
Introduction
With several decades of development in China, laparoscopic hepatobiliary surgery has been widely accepted and popularized. In recent years, a series of novel technologies, such as three-dimensional (3D) high-definition laparoscopic systems, ultra-high-definition (4K) laparoscopy, near-infrared fluorescence (NIRF) imagi...
PMC10543949
Materials and methods
PMC10543949
Patients
cholecystitis, allergies, cholecystolithiasis, liver cirrhosis
CHOLECYSTITIS, ALLERGIES, CHOLECYSTOLITHIASIS, LIVER CIRRHOSIS
Patients with cholecystolithiasis and cholecystitis who were admitted to our department for treatment with LC or common bile duct (CBD) exploration (CBDE) were evaluated for enrollment. Inclusion criteria were as follows: patients aged ≥ 18 years and undergoing LC or LC + CBDE, without signs of liver cirrhosis in compu...
PMC10543949
Study design
GROUP B
A randomized controlled trial was conducted. The primary outcome was the fluorescence intensity (FI) of the common bile duct and liver at three timepoints: before surgical dissection of the cystohepatic triangle, before clipping the cystic duct, and before closure or before CBDE. The second outcome was the cholangiogra...
PMC10543949
Imaging system
The 4K fluorescent system equipped with an NIRF imaging system (FloNavi 214K Series) was provided by Guangdong OptoMedic Technologies Inc, Guangzhou, China (web link:
PMC10543949
Sample size
G*Power [
PMC10543949
Randomization
The randomization was performed as previously reported [
PMC10543949
Intervention
ICG was intravenously administered 30 min before surgery as previously reported [
PMC10543949
FI measurements
The FI of the CBD and the liver was measured using
PMC10543949
Statistical analysis
Data are presented as the mean ± standard deviation (SD) or actual number of cases. A two-sided
PMC10543949
Results
PMC10543949
Cholangiography
As shown in Fig. Representative graphs of the three time points.
PMC10543949
FI and BLR outcomes
With increasing ICG doses, i.e., from Group A to Group D, the FIs in the liver background (Fig. Levels of the fluorescence intensity (FI) in the liver background and bile duct. Bile-to-liver ratio (BLR) and the BLR increment at the three time points.
PMC10543949
Discussion
With the clinical application of novel technologies in recent years, many standard procedures should be updated accordingly. In this study, a clinical trial was designed to investigate the optimal ICG dose suitable for use with a 4K fluorescent system for real‐time fluorescent cholangiography in LC. The data showed tha...
PMC10543949
Conclusions
In conclusion, with a 4K fluorescent system, an ICG dose ranging from 10 to 25 µg by intravenous administration within 30 min preoperatively was found to be appropriate for real‐time fluorescent cholangiography during LC.
PMC10543949
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (JPG 781 KB)Supplementary file2 (JPG 611 KB)
PMC10543949
Acknowledgements
We would like to thank the Guangdong OptoMedic Technologies Inc for providing the 4K imaging system, all participants for joining this trial, and all anesthesiologists of Guangzhou First People’s Hospital for their cooperation during surgery.
PMC10543949
Author contributions
WG
Study concept and design: YH; HL; JK; SZ and WG; Recruiting and supporting participants: HL; YX; JW; YL and ZW; Data analysis and interpretation: YH; TL; PL; ZH; FL and WG; Drafting the manuscript: YH and SZ; Critical revision of the manuscript for intellectual content: YH, SZ and WG.
PMC10543949
Funding
This work was partially supported by the Guangzhou Key Clinical Specialty Project (2019SZDZK01) and the Science and Technology Projects in Guangzhou (202102010027; 202201010623).
PMC10543949
Data availability
All data generated or analyzed during this study are included in this published article.
PMC10543949
Declarations
PMC10543949
Conflict of interest
The authors declare no conflict of interest for this article.
PMC10543949
Ethical approval and consent to participate
This study was approved by the Research Ethics Committee of the Guangzhou First People’s Hospital (approval NO: B202203101) and complied with the requirements of the Declaration of Helsinki. This study was registered in the Chinese Clinical Trial Registry (ChiCTR No: ChiCTR2200064726). The informed, written consent was...
PMC10543949
References
PMC10543949
Subject terms
Modifying behaviors, such as alcohol consumption, is difficult. Creating psychological distance between unhealthy triggers and one’s present experience can encourage change. Using two multisite, randomized experiments, we examine whether theory-driven strategies to create psychological distance—mindfulness and perspect...
PMC10368637
Introduction
DISEASE
Behaviors like alcohol use, smoking, and unhealthy eating are leading contributors to preventable disease and morbidityAlcohol use is a prevalent behaviorThe first popular strategy, mindfulness, involves creating space between a stimulus (e.g., an alcoholic drink) and a person’s natural reaction to itA second strategy ...
PMC10368637
Results
PMC10368637
Within-person effects of daily reminders on alcohol consumption
We tested the feasibility of psychological distancing reminders to reduce the number of drinking occasions and drinks per occasion on active, intervention weeks versus inactive, non-intervention weeks. To assess differences in drinking on active versus inactive weeks, we specified two separate multilevel hurdle models,...
PMC10368637
Psychological distance reminders reduce drinking frequency
Examining both distancing strategies together (i.e., collapsing across mindfulness and perspective-taking conditions), we found a directional main effect of the intervention reminders such that participants in the mindfulness and perspective-taking conditions were less likely to drink on active weeks (following active ...
PMC10368637
Psychological distance reminders do not impact drinking amount
Examining both distancing strategies together (i.e. collapsing across the two intervention conditions), we found no difference in the number of drinks consumed on alcohol use occasions on active weeks (following active intervention reminders) versus on inactive weeks (following control reminders) across both studies (S...
PMC10368637
Exploratory interaction effects of mindfulness vs. perspective-taking reminders
We next explored whether the effects of the intervention reminders varied based on distancing strategy: mindfulness vs. perspective-taking. To examine this question, we added an interaction term between active (vs. inactive) week and distancing strategy in each multilevel hurdle model, for Study 1 and Study 2 separatel...
PMC10368637
Differences in behavior change of daily reminders on drinking frequency
We conducted follow-up analyses to explore whether the within-person effects of the psychological distance intervention reminders, observed in both studies, i.e. the decrease in the drinking occasion frequency from inactive to active weeks, differed from non-intervention related changes in the absence of distancing rem...
PMC10368637
Psychological distance reminders reduce drinking frequency vs. control
Examining both distancing conditions together (i.e., collapsing across mindfulness and perspective-taking conditions), we found that individuals in the intervention groups showed a greater decrease in drinking frequency from inactive weeks to active weeks relative to the control group, both in Study 1 (Intervention rem...
PMC10368637
Additional between-person group analyses
We explored overall group differences in drinking occasions and drinks per occasion and report these results in Supplementary Analyses D. We tested whether the intervention groups drank less frequently and had fewer drinks on active weeks, and across all weeks collapsed, relative to the control group. Briefly, we found...
PMC10368637
Discussion
binge
LENS, EMA
Changing behavior is difficult. Yet changing from unhealthy to healthy choices in day-to-day life, and preventing unhealthy choices, can improve long-term quality of life and longevity. Across two studies, we leveraged smartphones to administer two theory-driven interventions to change an important health behavior—alco...
PMC10368637
Conclusion
The present study responds to calls to develop more effective, theoretically-guided behavior change interventions
PMC10368637
Methods
RECRUITMENT
We use data from two different cohorts of college students from the Social Health Impact of Network Effects (SHINE) Study which we refer to as Study 1 and Study 2. Details of recruitment, study design, and data analysis can be found in Supplement A. All research, methods, and study protocols were approved by the Human ...
PMC10368637
Sample sizes
The target sample size for Study 1 (N = 240) was determined based on a power analysis accompanying an MRI session in the original grant application (see project protocol, Ref
PMC10368637
Participants
Study 1 sample comprised 108 individuals (65 female, 42 male, and 1 other/non-binary) recruited across two urban college campuses in the Northeastern United States. Participants were aged between 18 and 28 years (
PMC10368637
Procedure
More detailed study procedures can be found in the project protocol (see Ref. Individuals who consented to take part in the intervention were randomized into three intervention conditions—mindfulness, perspective-taking, and control—, using the Qualtrics survey flow randomizer. As part of the intervention training sess...
PMC10368637
Measures
We used participant reports of drinking during the 28-day ecological momentary assessment period. Participants were asked: “Since your EVENING/MORNING survey, have you consumed any alcohol? (“No” or “Yes” response option). Participants who responded “Yes”, were asked to enter the number of standard servings of beer, li...
PMC10368637
Data preparation
Drinking was defined as the number of total alcohol servings consumed at each assessment over the 28-day period. In Study 1, the three largest, improbable values of drinks per occasion (24, 36, 60) were winsorized to the next largest value—16 drinks per occasion. This step applied to 7 signals across 3 individuals out ...
PMC10368637
Data analysis
REGRESSION
To account for the nature of the alcohol use data which are often positively skewed and include many observations at zero, we used multilevel hurdle models. Hurdle models include a logistic regression to model the zeroes in the data as well as a count regression (in this case negative binomial) to model the counts. All...
PMC10368637
Follow-up behavior change analyses
To explore whether the main findings, i.e., changes in drinking occasion frequency from active to inactive weeks differed from non intervention-related changes, we compared drinking frequency change scores among participants in the interventions and the control condition. For each person, we calculated a change score t...
PMC10368637
Author identities
Mindful that our identities can influence our approach to science, the authors wish to provide the reader with information about our backgrounds. With respect to gender, when the manuscript was drafted, nine authors self-identified as women, five as men, and one as non-binary. With respect to race, 13 authors self-iden...
PMC10368637
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-023-38478-y.
PMC10368637
Acknowledgements
P., Cancer
ABUSE, BRAIN, CANCER
Research was sponsored by the Army Research Office and was accomplished under Grant Number W911NF-18-1-0244. D.M.L and A.L.M acknowledge support from the National Institute on Drug Abuse (K01 DA047417) and the Brain & Behavior Research Foundation. D.S.B. acknowledges support from the John D. and Catherine T. MacArthur ...
PMC10368637
Author contributions
C.H.
Conceptualization: E.B.F., K.O., D.L.S., D.S.B., P.J.M.; Funding: E.B.F., K.O., D.L.S., D.S.B., P.J.M.; Methodology: E.B.F., K.O., B.D., C.H., D.L.S., O.S.; Data curation: Y.K., S.L., O.S., M.J., D.L.S., B.D.; Writing- Original draft preparation: M.J., D.L.S.; Formal analysis: M.J., D.L.S., D.C., B.D.; Project administ...
PMC10368637
Data availability
De-identified data are available on Github:
PMC10368637
Code availability
Code to reproduce the main analyses is available on Github:
PMC10368637
Competing interests
The authors declare no competing interests.
PMC10368637
References
PMC10368637
Background
inflammation
INFLAMMATION, GALLSTONE DISEASE
In addition to the reduction of symptomatic gallstone disease, ursodeoxycholic acid (UDCA) might also have beneficial metabolic effects after bariatric surgery. We examined the impact of UDCA on liver enzymes, hemoglobin A1c (HbA1c), lipids, and inflammation markers.
PMC10234851
Methods
inflammation
INFLAMMATION
Patients in the UPGRADE trial (placebo-controlled, double-blind) were randomized between UDCA 900 mg daily or placebo pills for 6 months after bariatric surgery. Patients without blood measurements pre- or 6 months postoperatively were excluded. The change in liver enzymes, Hba1c, lipids, and inflammation markers after...
PMC10234851
Results
In total, 513 patients were included (age [mean ± SD] 45.6 ± 10.7 years; 79% female). Preoperative blood values did not differ between UDCA (
PMC10234851