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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 sixth weeks, respectively. Greater reductions in depression (Cohen
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 inability to tailor interventions according to person, place, and time. Psychological problems and associated transdiagnostic processes are dynamic, showing a high degree of temporal variability as they unfold from moment to moment in interaction with the internal and external environments [RNT treatments typically involve skills and strategies aimed at disrupting the process as it is happening through techniques such as mindfulness, cognitive restructuring, or problem-solving [Researchers have looked toward smartphone apps as a medium to deliver interventions in daily life, potentially overcoming the therapy–real world gap [Smartphone apps may improve the efficacy of transdiagnostic treatments through their unique capability to detect and respond to momentary changes in transdiagnostic mechanisms in real time using personalized interventions [The opportunity to target transdiagnostic mechanisms in real time using JITAIs is an area with significant potential to improve the personalization, engagement, and effectiveness of psychological interventions. The vast majority of JITAIs have focused on health behaviors, with very little research conducted on targeting key transdiagnostic mechanisms or for application in youth populations [To the best of our knowledge, the potential for JITAIs to provide personalized interventions targeting disruption in transdiagnostic mechanisms in real time and real-world contexts for youth mental health has not yet been explored. To investigate this potential, our group developed a world-first smartphone intervention called “Mello,” a self-guided, personalized, transdiagnostic, and mechanistic smartphone intervention targeting RNT in young people with depression and anxiety. Mello is based on the JITAI model in that intervention strategies designed to disrupt RNT in the moment are tailored based on momentary assessments of relevant contextual variables. Mello does not adopt a single therapeutic modality but rather translates multiple techniques from third- and second-wave cognitive behavior therapies, which have evidence for reducing RNT into brief interventions designed to disrupt RNT in the moment. This was based on the rationale that effective intervention strategies exist across different therapeutic modalities, and consultations with young people and clinicians through the development of Mello clearly highlighted the range of techniques that were used to effectively reduce RNT in the moment. Consistent with the JITAI model of identifying and intervening in moments of need, Mello uses an algorithm that tailors a recommendation for a microintervention designed to disrupt RNT based on responses to a brief EMA check-in that captures the levels of RNT, mood, context, and location.This study was a pilot randomized controlled trial (RCT) comparing Mello with a nonactive control group over a 6-week period. The primary aim was to evaluate the feasibility, acceptability, and estimated efficacy of Mello in reducing RNT, depression, and anxiety in youth with clinical levels of depression and anxiety and increased RNT. Secondarily, the exploratory aims were to evaluate whether the effect of Mello on depression and anxiety outcomes was explained by effects on RNT, as this was the transdiagnostic target of the intervention. Further aims were to evaluate engagement with Mello and the effect of the intervention on the secondary outcomes.
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 sample size of 30 participants was initially deemed sufficient to meet the aims as a pilot study and is consistent with the guidelines in the literature for pilot trials [
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 by a researcher independent of the research team and uploaded into REDCap (Research Electronic Data Capture; Vanderbilt University). Researchers randomized participants following the completion of informed consent and baseline questionnaires using the REDCap application. Therefore, allocation was concealed from the researchers’ enrolling participants until the end of the baseline assessment. Owing to the nature of the intervention, the study participants were not blinded to the condition. As all outcomes were assessed via self-reported questionnaires, the researchers were also not blinded to the condition.
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 within the 6-month recruitment timeframe. Acceptability was assessed with the subscales (range 1-5, with higher scores indicating more positive evaluations) of the Mobile Application Rating Scale–User version [Secondary outcomes were rumination, as measured by the Ruminative Response Scale (RRS) total score (range 22-88, with higher scores indicating greater severity) [
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 changes in clinical outcome variables over time (baseline, during the intervention, and after the intervention). The models included random intercepts for each participant; a random slope for time; and fixed effects of the treatment group, time, and treatment group-by-time interactions. Generalized linear mixed models were also used to examine whether changes in the mechanism measures of RNT may be associated with changes in depression and anxiety. Pearson correlations between engagement indices and clinical measures were calculated to explore the associations between app engagement and outcomes.
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 application. All participants received a full explanation of the study, in lay terms, relating to the aims of the study, study procedures, and potential risks and benefits in taking part before providing informed consent. The participants were reminded that they can withdraw from the study at any time without prejudice. Participants were provided with a copy of the participant information and consent form and were reimbursed Aus $45 (US $29) for completing each assessment session. The participants were not reimbursed for their use of the Mello 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 significant group-by-time interaction was observed (
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, anxiety, and RNT in those who used Mello compared with an inactive control, with moderate to large effect sizes, suggesting that the app may be effective for treating depression and anxiety in youth with elevated RNT. The secondary aim was to explore whether improvements in depression and anxiety were accounted for by reductions in the target transdiagnostic mechanism of RNT, with exploratory analyses supporting this theoretical mechanism of action. Findings concerning feasibility and acceptability were positive. Recruitment targets were exceeded in the allocated trial timeframe, with 86% (55/64) of identified eligible young people participating in the trial and 95% (52/55) of participants completing all assessments. There was high endorsement of the app among users, with 96% (27/28) reporting that they would recommend the app to others and 71% (20/28) rating it as 4 or 5 stars out of 5. Finally, use statistics showed high levels of sustained engagement with Mello over the intervention period, with young people using the app on average half of all days, and 59% (17/29) of users remaining engaged at week 6. These positive results support the promise of Mello as a potentially effective, engaging, and scalable digital intervention.Systematic reviews have demonstrated generally high levels of acceptability of mental health apps in youth populations across the domains of usability, functionality, and general satisfaction [While contextualizing rates of engagement with Mello relative to the broader field is complex, given challenges in standard measurement [Although a larger trial is needed to confirm the results, the effect sizes show that using Mello led to reductions in depression and anxiety. Our findings suggest that this may occur via the hypothesized mechanism of reducing RNT. If confirmed, these findings support the theory that targeting reductions in transdiagnostic mechanisms will lead to improvements in symptoms [The pattern of effect sizes across outcome measures provides insights into the potential therapeutic mechanisms of Mello. On the basis of a recent meta-analysis [A key feature of Mello, consistent with the design of JITAIs [
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 between groups (eg, those who are and are not receiving mental health treatment). Second, it is unknown whether the effects were maintained because there was no follow-up time point. Third, the primary outcomes were measured using self-report scales during unblinded outcome assessments, raising possible sources of bias. Fourth, Mello users, but not the control group, received brief weekly phone calls, and although these were not therapeutic in content, they could not be ruled out as contributing to the effects. It is highly possible that these calls contributed to engagement, and considering this support may not be scalable, engagement would likely be lower in the “real world” [
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 enhancing personalization using machine learning, conducting a larger RCT to establish efficacy and mechanisms of action, evaluating cost-effectiveness, and ultimately scaling the intervention to ensure that all young people have permanent access to Mello.The authors would like to acknowledge the young people who dedicated their time to participating in this trial and the young people and clinicians who provided input into the design of Mello, including the MOST team at Orygen Digital. Finally, the authors would like to acknowledge the significant role of Sally Coldham, Jessi Malouf and James Gallichio, and Paul Hoskins and Nick Davis from Everyhow, in the design and development of Mello, as well as Telstra Foundation (particularly Natalie Falzon) for their generous support and guidance.The development of the Mello app and this research trial were funded by the Telstra Foundation Tech-4-Good Challenge, in support of Everyhow. This work was also supported by a Wellcome Trust Active Ingredients project on Reducing Repetitive Negative Thinking awarded to IB. IB is supported by a National Health and Medical Research Council (NHMRC) Investigator Grant (#2017876). MA-J is supported by an NHMRC Investigator Grant (#1177235) and a Dame Kate Campbell Fellowship from the University of Melbourne.Authors' Contributions: MA-J acquired funding along with TG and SD. IB led the design and development of the Mello intervention and the conceptualization and methodology of this trial. CA led project administration and investigation and supervised EC to collect the data, with oversight from MA-J. NC and SO conducted the formal analysis. IB and CA wrote the original draft of the manuscript. All authors reviewed and edited the manuscript.Conflicts of Interest: None declared.Participant information and consent form.Description of therapy activities.CONSORT-eHEALTH checklist (V 1.6.1).Ratings of therapy activity helpfulness.Digital Working Alliance Inventory results.Engagement correlations.Secondary outcome results.
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 thinkingRuminative Response ScaleWarwick-Edinburgh Mental Well-Being Scale
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 the Declaration of Helsinki and with favorable opinion from the competent authority and independent ethics committee for each investigational site (Teverelix DP was supplied as a freeze-dried powder without any excipient, which was reconstituted with 5% mannitol (
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 (ASAT/SGOT, ALAT/SGPT, total bilirubin, creatinine) exceeding twice the upper limit of the normal range, unless the elevation is attributed to hepatic metastasis;Any contraindication to the use of Teverelix DP;Life expectancy of less than 1 year;Baseline testosterone value below 2.31 ng/mL;Bilateral orchidectomy;Pre-existing hormone therapy or planned concomitant use of androgen deprivation therapy with any agent other than the investigational drug;Neurological, psychiatric disease, drug or alcohol abuse which could interfere with the subject’s proper compliance;Evidence of concurrent malignancy;Exposure to another investigational agent within the last month;Lack of ability or willingness to give informed consent;Anticipated non-availability for study visits/procedures.The subject populations were male patients with histologically proven adenocarcinoma of the prostate and for whom ADT was considered suitable (advanced prostate cancer, i.e., with local invasion and/or metastasis as staged by the Tumor, Nodes, Metastisis (TNM) scale (see below)). Patient demographics are detailed in The TNM system is a way of staging prostate cancer. It stands for Tumor, Node, Metastasis. Tumor (T) describes the size or area of the cancer. There are 4 main T stages of prostate cancer–T1 to T4.T1 means the cancer is too small to be seen on a scan or felt during an examination of the prostate.T2 means the cancer is completely inside the prostate gland.T3 means the cancer has broken through the capsule of the prostate gland.T4 means the cancer has spread into other body organs nearby, such as the back passage, bladder, or the pelvic wall.Node (N) describes whether the cancer has spread to the lymph nodes with N0 meaning that the nearby lymph nodes do not contain cancer cells and N1 means there are cancer cells in the lymph nodes near the prostate. NX means that the cancer in nearby lymph nodes cannot be measured.Metastasis (M) describes whether the cancer has spread to a different part of the body, and there are two M stages: M0 and M1. M0 means the cancer has not spread to other parts of the body. M1 means the cancer has spread to other parts of the body outside the pelvis.
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 suppress and maintain plasma testosterone levels below the castration level after 3 weeks of treatment (<0.5 ng/mL until 2 consecutive, increasing testosterone levels above the castration level with the latter recording above 2 ng/mL); to assess the effects on LH and prostate-specific antigen (PSA); and to assess the safety of teverelix DP. The safety evaluation included adverse events (AEs), clinical laboratory tests, vital signs, physical examinations. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA v7.0, Herndon, VA, USA). In addition, a formal injection site inspection was performed in 3 trials (ARD-0301-003, ARD-0301-008 and ARD-0301-010) to assess local tolerability, i.e., redness, swelling and induration (size/diameter, nature and firmness), itching and pain/tenderness. A transrectal ultrasound (TRUS) to assess total prostatic volume and the volume of peripheral and transitional zones of the prostate was conducted in the same three trials.Serum total testosterone and luteinizing hormone (LH) were measured using validated assays at MDS Pharma Services, Grossmoorbogen 25, 21,079 Hamburg, Germany. Total testosterone and LH was measured by double-antibody RIA kits from MP Biochemicals (formerly ICN Biochemicals, Santa Ana, CA, USA) after extraction of the serum with hexane and ethyl acetate using a gamma-counter Berthold 2104 with its own evaluation software. The assay kits were already validated by the producer for the standard use in human serum or plasma. Re-validation of the testosterone assay was completed by MDS Pharma Services (King of Prussia, PA, USA). The lower limit of quantification (LLoQ) for testosterone was reported as 0.0259 ng/mL. For LH, the LLoQ was 0.3 IU/L. All analyses and reporting were completed in accordance with Good Laboratory Practice (GLP).Teverelix levels were analyzed in plasma samples by HFL Ltd., Fordham, UK or by Professor Huy Ong’s laboratory at the University of Montreal, Montreal, QC, Canada. PSA measurements were performed at local laboratories. The assessment days are shown in
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 received at least one dose of study drug and at least one testosterone measurement after first administration of the study drug. The safety evaluation was based on all patients who received at least one dose of study medication. Descriptive statistics were conducted for all study variables. Categorical data were presented using counts and percentages, whilst continuous variables were presented using the mean, standard deviation (SD), standard error of the mean (SEM), median and range.
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 days (range 5–21 weeks for 180 mg SC for 3 consecutive days) (The mean pharmacokinetic (PK) results (teverelix DP concentrations (ng/mL) +SEM) for the studies are presented in
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 −10.3 (95% CI: −19.9, −0.6) cm
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 castration [In the United States, cardiovascular disease is the main cause of death for prostate cancer patients, and patients with prostate cancer have a higher risk of death from non-cancer causes than the general population [While the Phase 2 trials reported in this paper were first conducted several years ago, little progress has been made during that time in terms of injectable GnRH antagonists. Since degarelix was approved in 2008, there have been no new injectable GnRH antagonists. Data from mouse model studies suggest that the increased CV risk with GnRH agonists compared to GnRH antagonists may be attributable to FSH levels coupled with T-lymphocyte GnRH receptor activation [Therefore, the development of teverelix DP is still relevant and the development of teverelix DP is now continuing with a new sponsor with a focus on its CV safety compared to GnRH agonists and with the aim of an improved administration schedule (longer duration of action requiring fewer administrations) and local tolerability profile than degarelix.The data from these five Phase 2 clinical studies adds to the evidence from a Phase 1 clinical study that was conducted in older, healthy male subjects, showing that teverelix DP has a good safety profile and is well tolerated [The most commonly reported AE In the studies where teverelix DP is administered via SC administration was an injection site reaction, particularly injection site induration, generally of a mild intensity. In all trials, an injection site inspection was performed at every study visit post-administration (either as a formal safety endpoint in three trials or as part of analyzing AEs in two trials), and it was not up to the trial subjects to report any reactions experienced as was the case in the pivotal degarelix clinical trial [The effective loading doses of teverelix DP required injections to be administered on 3 consecutive days, which is inconvenient for the patients and may have implications for healthcare costs and resource utilization. Ideally, the loading dose would be administered at a single clinic visit, and data from this study have laid the foundations for such a regimen.An ongoing Phase 2B clinical trial (NCT04693507) with teverelix DP is testing initial loading doses of 120 mg SC plus 120 mg IM injections and 180 mg SC plus 180 mg IM injections—administered on Day 0—followed by maintenance doses of teverelix DP 120 mg SC or 180 mg SC at Day 42 and every 6 weeks up to Day 168. The establishment of an effective dosing regimen of teverelix DP in prostate cancer patients will facilitate the conduct of a Phase 3 trial in advanced prostate cancer patients at increased CV risk to test the potential CV superiority of teverelix DP versus leuprolide. The development of an ADT agent with improved CV safety will meet an unmet clinical need in this patient population.
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 castration of 55.32 days and 68.95 days, respectively, suggest that an injection interval of 6+ weeks may be a possibility. PK and PD modelling of existing data plus further clinical trials to test loading and maintenance doses will be required.
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. and F.L.; Data Curation, C.M.M., S.v.O. and F.L.; Writing–Original Draft Preparation, C.M.M.; Writing–Review and Editing, C.M.M., A.U., F.J., Ž.S., S.v.O. and F.L.; Visualization, C.M.M., S.v.O. and F.L.; Supervision, C.M.M., S.v.O. and F.L.; Project Administration, C.M.M., S.v.O. and F.L.; Funding Acquisition, C.M.M., S.v.O. and F.L. All authors have read and agreed to the published version of the manuscript.
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: Lithuanian Bioethics Committee: 2005-07-013 No. 47. Study ARD-0301-008: Lithuanian Bioethics Committee: 2006-01-26 No. 4. Study ARD-0301-010: Lithuanian Bioethics Committee: 2007-02-21 No. 10 and IEC for investigation of drugs and pharmaceutical products (Republic of Latvia): 190916-120.
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 = teverelix; T = testosterone. Mean teverelix DP concentration (ng/mL)(+SEM) vs. time (days). IM = intramuscular; SC = subcutaneous.Mean total testosterone (ng/mL), luteinizing hormone (IU/L) and PSA (ng/mL)(+SEM) vs. time (days). IM = intramuscular; LH = luteinizing hormone; PD, pharmacodynamics; PSA = prostate-specific antigen; SC = subcutaneous; T = testosterone.Patient baseline characteristics (per-protocol population).BMI = body mass index; D = day; IM = intramuscular; SC = subcutaneous; SD = standard deviation.Mean onset and duration of castration.D = day; IM = intramuscular; SC = subcutaneous. Overview of adverse events.D = day; IM = intramuscular; SC = subcutaneous.
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 fluorescent endoscopic system, we compared four different doses of ICG (1, 10, 25, and 100 µg) administered intravenously within 30 min preoperatively and evaluated the fluorescence intensity (FI) of the common bile duct and liver background and the bile-to-liver ratio (BLR) of the FI at three timepoints: before surgical dissection of the cystohepatic triangle, before clipping the cystic duct, and before closure. Forty patients were randomized into four groups, and 33 patients were fully analyzed, with 10 patients in Group A (1 µg), 7 patients in Group B (10 µg), 9 patients in Group C (25 µg), and 7 patients in Group D (100 µg). The preoperative baseline characteristics were compared among groups (The online version contains supplementary material available at 10.1007/s13304-023-01557-w.
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) imaging techniques, and telesurgery with 5G wireless system, have injected new vitality into laparoscopic surgery in a new era [Fluorescent intraoperative cholangiography using NIRF and ICG was introduced during LC [
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 computed tomography or ultrasound imaging. Exclusion criteria were as follows: allergies to iodides, iodine dyes, or ICG. All patients provided informed, written consent.
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 cholangiography effect, which was analyzed by the bile duct-to-liver ratio (BLR). Patients were randomly allocated for preoperative injection with one of the four doses of ICG (Group A: 1 µg; Group B: 10 µg; Group C: 25 µg; and Group D: 100 µg). 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).
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 [
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FI measurements
The FI of the CBD and the liver was measured using
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Statistical analysis
Data are presented as the mean ± standard deviation (SD) or actual number of cases. A two-sided
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Results
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Cholangiography
As shown in Fig. Representative graphs of the three time points.
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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.
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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 that, with a 4K fluorescent system, an ICG dose ranging from 10 to 25 µg by intravenous administration within 30 min preoperatively was appropriate for real‐time fluorescent cholangiography during LC. Compared to the dose of ICG used with 2D high-definition fluorescent systems [Dose, time interval, and the administration route of ICG are the three key factors that affect the cholangiographic effect during LC [Because of the high sensitivity of the 4K system, a lower dose of ICG than used with the HD system was proposed. The verified ICG dose (0.1 mg of ICG) used with the HD system was found unsatisfactory in the 4K system, as it showed a high background in the liver. Therefore, four different ICG doses (1, 10, 25, and 100 µg) were evaluated in this study. The data demonstrated that an ICG dose ranging from 10 to 25 µg was appropriate for real‐time fluorescent cholangiography in LC. The very-low dosage of ICG in our trail was extremely different from the previously reported studies. Most of those studies utilized dosage of 2.5 mg [According to the data of our trial, the FIs in the liver background and bile duct were ICG dose-independent, consistent with previously reported research [This study has several limitations. One of the limitations was that no follow-up data were analyzed. However, it is acceptable for this study, because we focused on fluorescent cholangiography during the surgery for navigational purposes. Furthermore, the enrolled sample size is small. We did not take the body weight factor into account in this single-center study for no significant differences of the body mass index among the four groups (Table
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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.
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Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (JPG 781 KB)Supplementary file2 (JPG 611 KB)
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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.
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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.
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Funding
This work was partially supported by the Guangzhou Key Clinical Specialty Project (2019SZDZK01) and the Science and Technology Projects in Guangzhou (202102010027; 202201010623).
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Data availability
All data generated or analyzed during this study are included in this published article.
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Declarations
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Conflict of interest
The authors declare no conflict of interest for this article.
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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 obtained from all patients.
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References
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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 perspective-taking—can change drinking behaviors among young adults without alcohol dependence via a 28-day smartphone intervention (Study 1,
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 to create psychological distance involves perspective-takingOverall, the evidence reviewed above suggests that mindfulness and perspective-taking strategies may reduce drinking by promoting different types of psychological distance. However, less is known about how to effectively integrate these strategies into individuals’ natural environments where pro-drinking influences may be presentWe randomly assigned participants to undergo a brief, in-person mindfulness, perspective-taking, or control training on how to respond to alcohol cues in their everyday life. Next, they received two smartphone reminders according to their respective condition and reported their alcohol use twice daily over the course of 28 days. We manipulated whether participants received psychological distance smartphone reminders (either mindfulness or perspective-taking) vs. control reminders, within-person over four alternating weeks, and examined changes in drinking frequency—the likelihood of having a drinking occasion, and drinking amount—the number of drinks per occasion
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Results
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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, one for Study 1 and another for Study 2. The main predictor was active week (vs. inactive week). Consistent with prior workPsychological distance reminders reduce drinking frequency but do not influence amount. a. Collapsing across experimental conditions, participants in the mindfulness and perspective-taking groups were less likely to drink following active intervention reminders relative to following control reminders in Study 1 (left) and Study 2 (right). b. We found no differences in the number of drinks consumed on alcohol use occasions following active intervention reminders, relative to following control reminders across both studies, Study 1 (left) and Study 2 (right). Note: figure presents raw data for illustration. Dots present the mean and the error bars present 95% confidence intervals.
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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 reminders) relative to inactive weeks (following control reminders) (active week vs. inactive week: OR = 1.34, 95% CI [1.01–1.77], Within-person effects of reminders on drinking on active vs. inactive weeks.Study 1: 3577 observations nested within 71 participants across 10 groups; Study 2: 6729 observations nested within 147 participants across 23 groups. The zero-inflation sub-model of the hurdle model estimates the probability of an extra zero (no alcohol use) such that a positive estimate indicates a higher chance of no alcohol use. Perspective = perspective-taking; mindful = mindfulness.
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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 (Study 1 active week vs. inactive week; OR = 0.92, 95% CI [0.69–1.23],
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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 separately. We found no significant interaction between active (vs. inactive) week and mindfulness (vs. perspective-taking) on drinking frequency (Study 1: active week vs. inactive week: OR = 0.93, 95% CI [0.62–1.41],
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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 reminders. Specifically, we compared whether changes in drinking frequency in the intervention conditions differed from changes in drinking frequency in the control condition across both samples. As part of the study protocol, the control condition received control reminders throughout the entire study period, which prompted participants to respond to alcohol naturally. Thus, we were interested in whether the observed change in drinking frequency differed from change we may expect for participants self-monitoring their own alcohol use and completing other aspects of the protocol, but without the key psychological distancing components. To test for this possibility, we randomly labeled two of the four weeks as pseudo “active” and pseudo “inactive” in the control condition, despite the protocol remaining the same throughout. This random assignment allowed us to match the control and intervention protocol as closely as possible. We repeated this randomization 100 times and compared the average pseudo-inactive-to-active-week change scores for the control group to the change scores for the intervention groups. Performing this comparison allowed us to test whether the changes in drinking frequency among participants in the intervention conditions differed from changes among participants who participated in all other aspects of the study but were not instructed to adopt psychological distance. See Follow-up behavior change analyses section of the Methods for details.
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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 reminders change drinking frequency among participants in the intervention conditions vs. control. Participants in the distancing conditions—mindfulness and perspective-taking—reported greater behavior change, i.e., drank less frequently on active vs. inactive weeks, relative to the change among participants in the control condition who received non-intervention reminders, in Study 1 (left) and Study 2 (right). Negative change scores suggest intervention consistent behavior change, or decreases in the frequency of drinking occasions.
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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 no group differences in the frequency of drinking occasions (see Tables S3 and S5). The perspective-taking group reported fewer drinks per occasion relative to the control group in Study 1. However, we did not replicate these effects in Study 2 (see Tables S4 and S6). We are cautious to make strong claims about between-person effects given the possibility that random assignment did not fully overcome baseline differences between groups. In Study 1, we observed that the perspective-taking group reported drinking less frequently at baseline relative to the control group. Since we did not collect baseline drinking information for participants in Study 2, we cannot account for potential pre-existing differences between groups in Study 2 (see Table
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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—alcohol use—among two samples of college students, as a basic science, proof of concept investigation. Within-person, we tested whether psychological distancing reminders, drawing on mindfulness and perspective-taking can decrease the frequency of alcohol occasions and the number of drinks per occasion on intervention weeks relative to non-intervention weeks over 28 days. We found that the psychological distance conditions drank directionally less frequently on active weeks, relative to inactive weeks in Study 1; and significantly less frequently on active weeks, relative to inactive weeks in Study 2, with a larger sample. Reminders, focused on creating psychological distance from alcohol cues, helped reduce the frequency of alcohol use occasions but did not impact the number of drinks consumed per occasion, within-person.On average, across both studies, the frequency of drinking occasions decreased about 2%, on weeks when participants received twice-a-day psychological distancing reminders. In Study 1, drinking occasion frequency decreased from once every 6 days to once every 8 days when intervention reminders were present. In Study 2, drinking occasion frequency reduced from once every 9 days to once every 11 days. These effects are meaningful in light of broader goals to motivate positive behavior change in daily life from a preventative lens. Decreasing the frequency of alcohol occasions is not the direct goal of most alcohol harm reduction interventions among young adults, which often target binge drinkingOur investigation builds on bodies of research that consider psychological distancing strategies, such as mindfulnessOne possibility is that repeated psychological distance reminders help offload cognitive effort when evaluating health-related optionsWith respect to intervention specificity, both the mindfulness and perspective-taking reminders reduced drinking frequency on active vs. inactive weeks to a similar degree. It is possible that different types of psychological distancing strategies, with repeated reminders, may be similarly effective in reducing the frequency of drinking occasions relative to an individual’s own baseline. Further, it is plausible that both interventions leverage a parallel psychological distance mechanism, though our data do not speak to this possibility directly. For example, neuroimaging research suggests that different forms of psychological distance are encoded similarly in the brainWhile promising, our intervention effects on reducing the frequency of drinking occasions should be interpreted with caution. We observed directional (Study 1) and significant (Study 2) within-person changes in drinking frequency from active to inactive weeks; with this change being greater than in the absence of active intervention reminders. However, participants in the intervention conditions did not necessarily drink less frequently than those assigned to the control condition, on average. One possibility is that random assignment did not completely overcome pre-existing differences in alcohol use between groups (see Intervention compliance, alcohol consumption and baseline differences in the Results section for more details). There also remains the possibility that the distancing reminders altered drinking by making individuals more reactive to being monitored, though participants also received instructions about how to approach alcohol and reported their drinking behavior daily during “inactive” weeks. Thus, our comparison likely represents a relatively conservative test of potential effects of distancing reminders on drinking behavior. Nevertheless, self-monitoring alcohol use may promote behavior changeOur results should also be interpreted considering design strengths and limitations. First, we employed theory-driven interventions within an EMA design, which allowed us to capture intervention effects in participants' natural environments and overcome common retrospective biases that ask participants to recall information about longer periods of time (e.g., amount of alcohol consumed in the previous 30 days). Next, the within-person manipulation allowed us to detect intervention effects while considering individuals’ personal drinking baselines. We employed this repeated measures design across two different samples, and across two different sites, thereby increasing the robustness of our findings. Further, we replicated these findings in a highly unusual and stressful time, the onset of the COVID-19 pandemic. Although intensive assessment often raises data compliance concerns, we observed little evidence of non-compliance in our data. The intensive sampling approach produced high response rates (approximately 95% median response rate in Study 1, with an in-person training component, and 91% median response rate in Study 2 with a fully remote delivery and a doubled sample size). These high response rates may support the feasibility of applying this approach for evaluating future interventions among college samples.It is important to note that our data cannot speak to long-term intervention effects on drinking beyond the length of 28 days, and our results may not generalize to samples beyond college students in urban college campuses in the Northeastern United States without alcohol dependence who are part of social groups. Specifically, we recruited students from pre-existing social groups (and included groups in which 80% or more expressed interest), with higher proportions of women than men. Although we controlled for non-independence of observations in statistical modeling, the non-independence may have confounded intervention effects in unmeasurable ways (e.g., spillover effects or social influence). Finally, when interpreting results, it is important to note that the psychological distancing reminders did not explicitly instruct individuals to decrease the quantity of alcohol consumed. As such, future work could test more explicit instructions to directly target the number of drinks when drinking. Finally, we used self-reported measures of drinking which may be subject to social desirability bias and may underestimate drinking levels
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Conclusion
The present study responds to calls to develop more effective, theoretically-guided behavior change interventions
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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 Subjects Electronic Research Application (HSERA) Institutional Review Board (IRB) at the University of Pennsylvania and were acknowledged by the Human Research Protection Office of the Department of Defense. All research, methods, and study protocols were conducted in accordance with the Human Subjects Institutional Review Board (IRB) at the University of Pennsylvania and the Human Research Protection Office of the Department of Defense. All participants provided informed consent before taking part in the study and were financially compensated. In Study 1, participants were compensated up to a total of $145. Compensation consisted of a $20 Amazon gift card to complete an online baseline survey; a $20 bonus Amazon gift card payment for at least 80% of the social group completing the survey; $50 for an in-person intervention training session, including an MRI scan session as part of a larger study (see Ref.
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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
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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 (
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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 session, participants underwent a brief instruction on how to respond to alcohol cues in daily life according to their respective condition. Details on the psychological distance training and the mindfulness instruction language development can be found in Supplement B. Training instructions for Study 1 and training videos for Study 2 are publicly available: The day following the in-person/online training, participants began a 28-day ecological momentary intervention and assessment protocol. Participants received twice-a-day reminders on how to respond to alcohol cues and responded to twice-a-day surveys measuring their alcohol use,  among other measures, for a total of 4 signals daily over 28 days. Intervention prompts with reminders on how to approach alcohol use, were sent at 2:00 pm and at 9:00 pm each day. Alcohol use surveys were sent at 8:00 and at 6:00 pm each day. See Fig. 
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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, liquor, and wine consumed since the previous survey using a numeric entry. Responses for each beverage category were summed to obtain the total servings of alcohol consumed for each assessment (see Ref.
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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 of 5492 observations in total. No outliers were observed in Study 2.
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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 the zeroes (not alcohol use occasions) are modeled with the logistic regression and nonzero-counts (alcohol use occasions) are modeled by a truncated negative binomial (i.e., truncated as it does not contain zero). Thus, these models allowed us to independently model whether a person drinks or not (logistic regression) at a given occasion and number of drinks when an individual drinks (count regression). We estimated hurdle modelsWe specified two models (one for Study 1 and another for Study 2) to assess whether drinking frequency and amount vary among participants in the mindfulness and perspective-taking conditions (within-person) on weeks when intervention reminders were present or absent. The main predictor of interest was active vs. inactive week and the outcomes were frequency of drinking occasions and drinking amount. To further explore if the effectiveness of the reminders varied by condition type (mindfulness vs. perspective-taking), we included an interaction term: active week (vs. inactive week) x condition type. Given that observations are nested within participants, who are in turn nested within non-independent social groups, all multilevel models accommodated the nested nature of the data, and intercepts were allowed to vary randomly across people. In models presented in the main manuscript, we controlled for the following covariates: social weekend (defined as Thursday, Friday, or Saturday), due to differences between weekend and weekday drinking among college students
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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 that captures differences in the average proportion of drinking occasions on active intervention weeks versus inactive weeks throughout the 28-day study period. First, we first calculated the average proportion of drinking occasions on active weeks and inactive weeks, separately, by dividing the number of drinks reported throughout the active and inactive intervention period by an individual’s number of responses to alcohol reminders during the same time period. Next, we subtracted the proportion of drinking occasions on active weeks from the proportion of drinking occasions on inactive weeks.To obtain change scores for participants in the control condition, who did not undergo a within-person active-to-inactive week manipulation as part of the protocol, we randomly assigned two of the four weeks in the study period as pseudo “active” and the remaining two as pseudo “inactive” weeks. To counterbalance week order, as done in the active treatment groups, we randomly split half of the participants in an ABAB design, or a BABA design, which allowed us to match the two intervention designs as closely as possible. We repeated this random assignment 100 times to stabilize the estimates. Next, we averaged the change scores in drinking frequency (from pseudo-inactive to pseudo-active weeks) for the control participants across all iterations and compared the control group’s pseudo change scores to the intervention groups’ change scores. We first checked whether the proportion of drinking occasions were significantly non-Gaussian using the Shapiro Wilk test of normality and chose to perform non-parametric Mann–Whitney–Wilcoxon tests instead of t-tests because of nonnormality. We performed this comparison using unpaired two-sided Wilcoxon tests.
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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-identified as White, one as Asian, and one as Black. With respect to engagement with college students, when this study was conducted, two were doctoral students who teach and/or mentor other students, one was a research coodinator who mentors other students, five were postdoctoral researchers or research scientists who teach and/or mentor students, and seven were professors who teach and/or mentor students.
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Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-023-38478-y.
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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 Foundation, the Swartz Foundation, the Paul G. Allen Family Foundation, the Alfred P. Sloan Foundation and the NSF (PHY-1554488, IIS-1926757). E.B.F and D.C acknowledge support from Hopelab. Y.K acknowledges support from the Mind and Life Institute. E.B.F acknowledges support from the National Cancer Institute, R01 CA229305-01A1. B.P.D acknowledges support from the Social Sciences and Humanities Research Council of Canada (Insight Grant 435-2021-0511), the Natural Sciences and Engineering Research Council of Canada (Discovery Grant RGPIN-2021-03438), Defence Research and Development Canada, and the Canada First Research Excellence Fund, awarded to the Healthy Brains Healthy Lives Initiative at McGill University. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the Army Research Office or the U.S. Government. The U.S. Government is authorized to reproduce and distribute reprints for Government purposes notwithstanding any copyright notation herein.
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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 administration: Y.K., S.L., N.C., C.H., O.S., D.L.S., E.B.F., B.D., C.H.: Validation: A.M.; D.C.; Z.B.; Supervision: E.B.F., D.L.S.: All authors: Writing—review & editing.
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Data availability
De-identified data are available on Github:
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Code availability
Code to reproduce the main analyses is available on Github:
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Competing interests
The authors declare no competing interests.
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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 surgery were compared between the UDCA and placebo group, followed by a postoperative cross-sectional comparison.
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 (
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