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Reporting summary
Further information on research design is available in the
PMC10824665
Supplementary information
Supplementary Figs. 1–4.Reporting SummarySupplementary protocols.Supplementary Tables 1–10
PMC10824665
Source data
Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Statistical Source Data.Uncropped blots.Statistical Sou...
PMC10824665
Extended data
PMC10824665
The effect of imetelstat on normal hematopoiesis.
Humanized
PMC10824665
Lipidomics analysis of imetelstat-treated
desaturation
Targeted lipidomics analysis on 593 lipid species and their desaturation levels.
PMC10824665
The effect of chemical perturbation of ferroptosis on imetelstat efficacy.
Celltiter-based cell growth analysis in a panel of
PMC10824665
Individual AML PDX responses to imetelstat.
Peripheral blood AML
Peripheral blood AML donor chimerism in the thirty individual PDX models.
PMC10824665
Extended data
is available for this paper at 10.1038/s43018-023-00653-5.
PMC10824665
Supplementary information
The online version contains supplementary material available at 10.1038/s43018-023-00653-5.
PMC10824665
Acknowledgements
Leukaemia, P.
LEUKAEMIA
We acknowledge all current and past members of the Gordon and Jessie Gilmour Leukaemia Research Laboratory, particularly E. Cooper, G. Pali, E. Duce, R. Austin, T. Vu, M. Bywater and P. Tavakoli for technical assistance and fruitful discussions; S. Chun-Wei Lee (MSKCC) for help with library preparation for HemePACT seq...
PMC10824665
Author contributions
C.B., L.J.B., L.B., F.H.H., M.M.H., G.A.K., H.A.P., O.A.W. and S.W.L. were responsible for conceptualization. The methodology was the responsibility of C.B., A.H.P., T.S., J.S., V.L., B.J., G.H. and S.W.L. Software was the responsibility of J.S. and G.H. Validation was carried out by C.B., A.H.P., A.P.S. and G.V.W. For...
PMC10824665
Peer review
PMC10824665
Data availability
RNA-sequencing data have been deposited in the Gene Expression Omnibus under accession codes
PMC10824665
Competing interests
S.W.L. has received research funding from Janssen related to imetelstat (2016–2018). For research beyond this study, S.W.L. has received funding from Celgene/Bristol Myers Squibb (2019–2022), consultancy from Abbvie (2021–2023) and advisory board fees from Abbvie and Astellas (2020–2021). The remaining authors declare ...
PMC10824665
References
PMC10824665
Background
Patient selection is key in Phase I studies, and prognosis can be difficult to estimate in heavily pre-treated patients. Previous prognostic models like the Royal Marsden Hospital (RMH) score or using the neutrophil–lymphocyte ratio (NLR) have not been validated in current novel therapies nor in the Asian Phase I popul...
PMC10070409
Methods
SOLID TUMOUR
We conducted a retrospective review of 414 patients with solid tumours participating in Phase I studies at our centre between October 2013 and December 2020.
PMC10070409
Results
The RMH model showed poorer prognosis with increasing scores [RMH score 1, HR 1.28 (95% CI: 0.96–1.70); RMH score 2, HR 2.27 (95% CI: 1.62–3.17); RMH score 3, HR 4.14 (95% CI: 2.62–6.53)]. NLR did not improve the AUC of the model. Poorer ECOG status (ECOG 1 vs. 0: HR = 1.59 (95% CI = 1.24–2.04),
PMC10070409
Conclusions
We developed a NCIS prognostic score with excellent prognostic ability for both short-term and longer-term survival (iAUC: 0.71 [95% CI 0.65–0.76]), and validated the RMH model in the largest Asian study to date.
PMC10070409
Subject terms
PMC10070409
Introduction
malignancies, tumour
MALIGNANCIES, TUMOUR, SIDE EFFECT
Our understanding of tumour biology has grown exponentially and a large number of novel molecularly targeted agents and immunotherapy have entered the clinic. Many of these agents have different side effect profiles compared to cytotoxic chemotherapy and their development plan may differ, with an emphasis on understand...
PMC10070409
Methods
PMC10070409
Study design and patient characteristics
cancer, death, tumour, Cancer
CANCER, SOLID TUMOUR, TUMOUR, CANCER
We conducted a retrospective review of patients with solid tumours participating in Phase I studies at the National University Cancer Institute, Singapore (NCIS) between October 2013 and December 2020. Patients enrolled in the studies fulfilled the eligibility criteria of the respective studies. Patient demographics, c...
PMC10070409
Statistical considerations
death
REGRESSION
Categorical variables were summarised based on counts and percentages while continuous variables were described in terms of median and interquartile range (IQR).Overall survival (OS) duration was measured from the start of therapy to the date of death. Patients who remained alive at the end of study were censored at th...
PMC10070409
Model validation
Both the RMH and RMH + NLR50 models were externally validated using the NCIS data, and their performances were evaluated using Harrell’s C-statistic and time-dependent area under the curve (AUC(
PMC10070409
Model update
tumour
TUMOUR
In addition to the RMH score, the following covariates were considered for the model update: gender, age, ECOG performance status (PS), number of co-morbidities, number of prior therapies, aspartate aminotransferase (AST), platelets, haemoglobin, NLR, tumour classification, and whether they were treated with chemothera...
PMC10070409
Results
PMC10070409
Study population
head and neck cancers, gynaecological cancer, lung cancer, Arkenau, lymphoma
LUNG CANCER, OTHER CANCER, HEPATOCELLULAR CARCINOMA, HEAD AND NECK CANCER, LYMPHOMA
There were 414 patients (157 [38%] male and 257 [62%] female) recruited in 40 Phase I studies at NCIS (Table Baseline and treatment characteristics.Note: 1. The figures are presented in terms of frequency and percentage, unless otherwise stated.2. Arkenau et al. [3. In total, 12 patients in the NCIS study population di...
PMC10070409
Development of the NCIS Prognostic Score
tumour
TUMOUR
From the updated NCIS model comprising the following significant predictors (RMH score, ECOG PS and tumour type) (Table NCIS prognostic scoring.Overall survival according to NCIS Prognostic Score for patients enrolled in Phase I trials.The three prognostic models performed similarly in predicting 90-day mortality with ...
PMC10070409
Discussion
cancers, cancer, tumour, deaths, Cancer
CANCER, CANCERS, TUMOUR, CANCER
Similar to other studies, we found the 90-day mortality rate in Phase I studies in our patient population to be ~17%, but treatment-related deaths were very rare [Compared to the original RMH score validation cohort [Our study is one of the first studies aiming to validate the RMH score in the Asian population particip...
PMC10070409
Author contributions
JL and CEC were responsible for the concept and design of the study. JL, JW and JC were involved in data collection. BCT and AC were involved in data analysis. JL, AC, BCT and CEC drafted the manuscript. All authors critically revised the manuscript for important intellectual content. CEC supervised the study. All auth...
PMC10070409
Funding
This research is supported by the Singapore Ministry of Health’s National Medical Research Council under its NMRC Centre Grant Programme, NMRC/CG/012/2013.
PMC10070409
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
PMC10070409
Competing interests
RS, Cancer
ONCOLOGY, CANCER
WPY has advisory roles for Abbvie/Genentech, Amgen, Astra Zeneca, Bristol-Myers Squibb, Ipsen and Novartis. He is part of the Speakers’ Bureau for Bayer, Eisai, Lilly, MSD Oncology, Sanofi/Aventis, Taiho Pharmaceuticals. He has received funding for travels and accommodations from Pfizer. RS (Raghav Sundar) has received...
PMC10070409
Ethics approval and consent to participate
The study was approved by the institutional review board. The need for consent was waived by the institutional review board.
PMC10070409
Consent to publish
Not applicable.
PMC10070409
References
PMC10070409
2. Materials and Methods
PMC10096552
2.1. Research Ethics and Participants
The present study adhered to the principles of the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects. Documents such as the study protocol, the investigator’s brochure, the explanation form, and the consent form were submitted to the ethics committee of the Facu...
PMC10096552
2.2. Test Food
The study used LC-Plasma capsules containing heat-killed dry LC-Plasma (Kyowa Hakko Bio CO., Ltd., Tokyo, Japan) (≥1.0 × 10
PMC10096552
2.3. Study Design
The schematic representation of the study is shown in The participants were instructed to maintain their daily habits (e.g., for diet and sleep) and to avoid foods containing a large amount of lactic acid bacteria (e.g., yogurt, fermented cheese, pickles, and lactic acid bacteria supplement) within the test period. For...
PMC10096552
2.4. Evaluation of pDC and mDC Activity
Peripheral blood mononuclear cells (PBMCs) were isolated from the blood [
PMC10096552
2.5. Evaluation of Hematological Indices
inflammation
INFLAMMATION, OXIDATIVE STRESS
To investigate the influence of exercise load and LC-Plasma intake on the objective parameters, hematological indices known to be associated with exercise-induced inflammation and oxidative stress were measured. The levels of transforming growth factor-β (TGF-β) and interleukin-6 (IL-6) were measured using an ELISA kit...
PMC10096552
2.6. Evaluation of Physiological Indices
fatigue
The low frequency to high frequency ratio (LF/HF), which is indicative of sympathetic to parasympathetic autonomic balance, was measured to assess the degree of fatigue, using the autonomic measurement device VM302 (Hitachi Systems, Tokyo, Japan) [
PMC10096552
2.7. Participant Diary and Questionnaire
fatigue, pharyngeal pain, ’ mood, pain, cough, muscle pain
Participants were asked to record the degree of each clinical symptom (physical conditions, nasal congestion/nasal discharge, pharyngeal pain, cough, joint pain, chill, fatigue, malaise, and muscle pain) daily using a five-point Likert scale modified with reference to a previous report [To evaluate the participants’ mo...
PMC10096552
2.8. Statistical Analysis
SECONDARY
The primary endpoints were pDC activity, mDC activity, participant diary records, POMS2, and TGF-β, IL-6, CPK, cathepsin L, and adrenaline levels between the PL group and the LC-Plasma group on day 15. The secondary endpoints were VAS score, LF/HF, and 8-OHdG, testosterone and leptin levels. Data were expressed as the ...
PMC10096552
3. Results
PMC10096552
3.2. Assessment for Continuous Exercise
fatigue, pain
We first analyzed the effect of LC-Plasma on continuous exercise. There was a significant decrease in pDC activity (CD86) on day 15 compared with that on day 1 in both groups, and on day 15, the level in the LC-Plasma group was significantly higher than that in the PL group (The cumulative days of fatigue in the partic...
PMC10096552
3.3. Assessment for Strenuous Single Exercise
muscle pain, listlessness
Next, we analyzed the effect of LC on a single exercise session following long-term exercise. There were no significant differences in DC activity and the POMS2 score in the intra- or intergroup comparisons. The score for the item “Are you tired?” and “Are you feeling physical listlessness?” in VAS showed a significant...
PMC10096552
4. Discussion
heart and skeletal muscle, fatigue, Fatigue
CONTRACTION
The primary aim of this study was to confirm the effects of LC-Plasma on fatigue caused by a continuous high training load. All the participants in this study belonged to the same sports club. Since the participants had had 3 days of rest without exercise before the start of the test, it is considered that the fatigue ...
PMC10096552
5. Conclusions
fatigue
The present study demonstrated that supplementation with LC-Plasma reduced the accumulation of subjective feelings of fatigue after continuous exercise in participants who routinely exercised, potentially by maintaining pDC activity. In addition, the possibilities of improvements in indices of fatigue, such as the norm...
PMC10096552
Author Contributions
H.N.
Conceptualization, Y.K., K.S. and T.F.; methodology, Y.K., K.F., Y.I. and T.F.; validation, K.S., H.N. and H.D.; investigation, Y.K., K.F., Y.I. and T.K.; writing—original draft preparation, Y.K. and T.K.; writing—review and editing, K.S., H.N., T.F. and H.D.; supervision, K.S., H.N. and H.D.; project administration, Y...
PMC10096552
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of the Faculty of Health and Sports Science, Juntendo University (approval number: 29–13). The protocol was registered in University Hospital Medical Information Network Clinical Trial Registry as UMIN000028717.
PMC10096552
Informed Consent Statement
Informed consent was obtained from all participants involved in the study.
PMC10096552
Data Availability Statement
Not applicable.
PMC10096552
Conflicts of Interest
The study was funded by Kirin Holdings Company, Limited. Y.K., T.F. and T.K. are employees of this company. Although conducted in a double-blind study, they were involved in the investigation, analyses, and writing of the manuscript. The authors declare no other conflict of interest.
PMC10096552
Background
xerostomia, LA-SCCHN, squamous cell carcinoma of the head and neck (, ototoxicity
XEROSTOMIA, ADVERSE EVENTS, DYSFUNCTION, HYPOTHYROIDISM, OTOTOXICITY
Chemoradiotherapy (CRT) with concurrent cisplatin is the standard of care as a nonsurgical definitive treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, CRT is associated with increased severe late adverse events, including swallowing dysfunction, xerostomia, ...
PMC10626703
Methods
LA-SCCHN, oropharynx cancer, tumors
TUMORS, OROPHARYNX CANCER
This study is a multicenter, two-arm, open-label, randomized phase III trial. Patients with LA-SCCHN excluding p16 positive oropharynx cancer are randomized to the standard arm or experimental arm. A total dose of 70 Gy for tumors with concurrent cisplatin at 100 mg/m
PMC10626703
Discussion
If the experimental arm is non-inferior to the standard arm in terms of TTF and superior on the safety endpoints, the 2-step40 procedure is the more useful treatment than SIB56 for definitive CRT.
PMC10626703
Trial registration
This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031210100 (
PMC10626703
Supplementary Information
The online version contains supplementary material available at 10.1186/s12885-023-11503-z.
PMC10626703
Keywords
PMC10626703
Background
dysphagia, two-step40, LA-SCCHN, squamous cell carcinoma of the head and neck (, oropharyngeal cancer
DYSPHAGIA, RECURRENCE, ADVERSE EVENTS, OROPHARYNGEAL CANCER, PRIMARY TUMOR
Chemoradiotherapy (CRT) with concurrent high-dose cisplatin (CDDP) is a standard treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) [Intensity-modulated radiation therapy (IMRT) has emerged as a current standard method for definitive CRT for LA-SCCHN. Although the advan...
PMC10626703
Methods/design
PMC10626703
Study design
ONCOLOGY, MAY
This study is a multi-institutional, two-arm, open-label, randomized phase III study. The study protocol was reviewed by the Japan Clinical Oncology Group (JCOG) Protocol Review Committee and approved by as the JCOG1912 (NEW BRIDGE) in January 2021. The certificated review board approved in March 2021, and patient accr...
PMC10626703
Endpoints
death
ADVERSE EVENTS, EVENT, EVENTS, SECONDARY, RESIDUAL DISEASE
The primary endpoint is time to treatment failure (TTF) 1 in all randomized patients. TTF1 is defined as time from randomization to the date of progression, or determination of residual disease after the completion of the protocol treatment, or death from any cause, whichever occurred first, and it is censored at the l...
PMC10626703
Eligibility criteria
Active infection, Psychiatric disorder, cancers, myocardial infarction, Tumor, head and neck cancers, head and neck surgeon, valvular disease, intramucosal tumors, human immunodeficiency virus antibody test., Fever, squamous cell carcinoma, tumors, head or neck lesions
CANCERS, UNCONTROLLED HYPERTENSION, MYOCARDIAL INFARCTION, LYMPH NODE METASTASES, TUMOR, DILATED CARDIOMYOPATHY, POSITIVE, UNSTABLE ANGINA, HYPERTROPHIC CARDIOMYOPATHY, OROPHARYNGEAL CANCER, HEAD AND NECK CANCER, ONCOLOGY, SQUAMOUS CELL CARCINOMA, TUMORS, POORLY CONTROLLED DIABETES MELLITUS
The inclusion criteria are as follows: Primary lesions are located in the oropharynx, hypopharynx, or larynx.Histologically proven squamous cell carcinoma on biopsy specimens of the primary lesion. Immunohistochemistry reveals p16 negativity in patients with oropharyngeal cancer.Clinical stage of III, IVA, or IVB (excl...
PMC10626703
Randomization
METASTASIS
After eligibility has been confirmed, registration is performed using a web-based system at the JCOG Data Center. Patients are randomized to the standard arm (SIB56) or experimental arm (2-step40). Randomization is stratified according to the institution, presence or absence of lymph nodes metastasis, and the primary s...
PMC10626703
Treatment methods
tumor, SCCHN
SQUAMOUS CELL CARCINOMA, TUMOR, PRIMARY TUMOR
Patients in both arms receive definitive CRT with CDDP at a dose of 100 mg/m Study scheme. SCCHN, squamous cell carcinoma of the head and neck; CDDP, cisplatin; SIB, simultaneous integrated boostRadiation planning is performed 2 weeks before the start of RT. The cervical computed tomography (CT) is performed using a th...
PMC10626703
Statistical analysis and evaluation criteria for the endpoints
dysphagia, dry mouth
DYSPHAGIA, ADVERSE EVENTS, HEARING IMPAIRMENT, HYPOTHYROIDISM, DRY MOUTH
A 3-year TTF1 of 50% is assumed for both arms. According to the Schoenfeld and Richter’s method [If the experimental arm is non-inferior to the standard arm in terms of TTF1 and superior in terms of safety endpoints, the 2-step40 method will be considered the more efficacious treatment. However, it is unacceptable that...
PMC10626703
Interim analysis and monitoring
Two interim analyses considering multiplicity will be conducted using the Lan and DeMets method along with the O’Brien and Fleming-type alpha spending function [In the first interim analysis, if both the non-inferiority and superiority of the experimental arm over the standard arm in terms of the primary endpoint are d...
PMC10626703
Cases review
RECURRENCES, RECURRENCE, HEAD AND NECK CANCER
Cases of patients who undergo salvage surgery after the completion of the protocol treatment will be presented at the JCOG Head and Neck Cancer Study Group conference held every 6 months to review indications for surgery and the appropriateness of the surgical procedure. Cases with regional recurrence will be reviewed ...
PMC10626703
Discussion
toxicity, toxicities, LA-SCCHN, deaths, JAVELIN, ototoxicity
ADVERSE EVENTS, DISEASE, OTOTOXICITY
The current CRT regimen for patients with LA-SCCHN is associated with severe late adverse events, decreased QOL, and increased noncancer-related deaths in long-term survivors. The ideal treatment for patients with LA-SCCHN is a modality that is satisfactory for both disease control and the patients’ daily lives. Our tr...
PMC10626703
Participating institutions
Cancer
INFECTIOUS DISEASES, SHIGA, HEAD AND NECK CANCER, CANCER
This study is a within-JCOG intersubgroup study collaborating between the Radiation Therapy Study Group and the Head and Neck Cancer Study Group. The participating institutions are those that meet the criteria for RT quality control and quality assurance and have approval from the JCOG Radiation Therapy Committee to pe...
PMC10626703
Acknowledgements
ONCOLOGY, ADVERSE EVENT, HEAD AND NECK CANCER
The authors thank in advance all the patients, investigators and institutions involved in this trial. The authors thank Ms. Shoko Todo and Ms. Naoko Otomo in JCOG Data Center for data management for this trial, and Ms. Harumi Suzuki in Data and Safety Monitoring Committee Office of the JCOG for support to adverse event...
PMC10626703
Authors' contributions
The study concept was conceived by TY, SZ, TK, and NK. The study was designed by TY, SZ, TK, NK, RT, YF, and KW. TY, SZ, TK, and NK are the primary authors of the protocol; however, all authors have contributed in this regard to some extent. TY, SZ, TK, and NK wrote the manuscript. RT, YF, NK, and KW play central roles...
PMC10626703
Funding
Cancer
CANCER
This study was supported by The Japan Agency for Medical Research and Development (AMED) (JP22ck0106751) and the National Cancer Center Research and Development Funds (2020-J-3, 2023-J-03). The funding body has peer reviewed the study design. However, the funding agencies had no influence on the study design and data c...
PMC10626703
Availability of data and materials
Not applicable.
PMC10626703
Declarations
PMC10626703
Ethics approval and consent to participate
CRB, Cancer
CANCER
The study protocol was approved by the National Cancer Center Hospital East Certified Review Committee (CRB) on January 2021 first (CRB3180009). Modifications to the study protocol will be communicated to the CRB. The CRB will revise the informed consent materials to be given to participants and adapt them in accordanc...
PMC10626703
Consent for publication
All patients will be required to provide written informed consent for the publication of the results.
PMC10626703
Competing interests
The authors declare no competing interests.
PMC10626703
References
PMC10626703
Key Points
PMC10034662
Question
depression
Is practitioner-supported mindfulness-based cognitive therapy self-help (MBCT-SH) clinically effective and cost-effective compared with practitioner-supported cognitive behavioral therapy self-help (CBT-SH) for adults experiencing mild to moderate depression?
PMC10034662
Findings
depression, depressive
In this randomized clinical trial of 410 participants with mild to moderate depression, practitioner-supported MBCT-SH led to significantly greater reductions in depressive symptom severity at 16 weeks postrandomization compared with practitioner-supported CBT-SH. The probability of MBCT-SH being cost-effective compare...
PMC10034662
Meaning
depression, depressive
Practitioner-supported MBCT-SH for mild to moderate depression was clinically effective and cost-effective compared with currently recommended practitioner-supported CBT-SH and should be made routinely available to adults experiencing mild to moderate depression.This randomized clinical trial evaluates whether practiti...
PMC10034662
Importance
depression, Depression
Depression is prevalent. Treatment guidelines recommend practitioner-supported cognitive behavioral therapy self-help (CBT-SH) for mild to moderate depression in adults; however, dropout rates are high. Alternative approaches are required.
PMC10034662
Objective
depressive, depression
To determine if practitioner-supported mindfulness-based cognitive therapy self-help (MBCT-SH) is superior to practitioner-supported CBT-SH at reducing depressive symptom severity at 16 weeks postrandomization among patients with mild to moderate depression and secondarily to examine if practitioner-supported MBCT-SH i...
PMC10034662
Design, Setting, and Participants
depression
RECRUITMENT
This was an assessor- and participant-blinded superiority randomized clinical trial with 1:1 automated online allocation stratified by center and depression severity comparing practitioner-supported MBCT-SH with practitioner-supported CBT-SH for adults experiencing mild to moderate depression. Recruitment took place be...
PMC10034662
Interventions
Participants received a copy of either an MBCT-SH or CBT-SH workbook and were offered 6 support sessions with a trained practitioner.
PMC10034662
Main Outcomes and Measures
The preregistered primary outcome was Patient Health Questionnaire (PHQ-9) score at 16 weeks postrandomization. The primary analysis was intention-to-treat with treatment arms masked.
PMC10034662
Results
depression, −2.6
Of 410 randomized participants, 255 (62.2%) were female, and the median (IQR) age was 32 (25-45) years. At 16 weeks postrandomization, practitioner-supported MBCT-SH (n = 204; mean [SD] PHQ-9 score, 7.2 [4.8]) led to significantly greater reductions in depression symptom severity compared with practitioner-supported CB...
PMC10034662
Conclusions and Relevance
depression
In this randomized clinical trial, practitioner-supported MBCT-SH was superior to standard recommended treatment (ie, practitioner-supported CBT-SH) for mild to moderate depression in terms of both clinical effectiveness and cost-effectiveness. Findings suggest that MBCT-SH for mild to moderate depression should be rou...
PMC10034662
Trial Registration
isrctn.org Identifier:
PMC10034662
Introduction
depression, Depression
Depression has a lifetime prevalence of 10.8% worldwide.To widen access, cognitive behavioral therapy self-help (CBT-SH) supported by a trained practitioner is recommended in the treatment of mild to moderate depression in national treatment guidelines.Mindfulness-based cognitive therapy (MBCT) is an in-person group pr...
PMC10034662
Method
PMC10034662
Design
depression
This was a multicenter, pragmatic, assessor- and participant-blinded (participants were unaware of which intervention was hypothesized to be superior), parallel, superiority RCT with 1:1 allocation comparing practitioner-supported MBCT-SH with CBT-SH for adults experiencing mild to moderate depression in 10 Improving A...
PMC10034662
Participants
Inclusion criteria were that participants (1) were 18 years or older; (2) met criteria on the Clinical Interview Schedule–Revised (CIS-R)
PMC10034662