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Keywords | PMC10850008 |
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Introduction | DISEASE, TYPE 2 DIABETES, COMPLICATIONS | Given the natural history of type 2 diabetes and the progressive decline in beta-cell function, most patients with the disease will undergo treatment intensification with the aim of preventing or delaying long-term complications [Simplification reduces the number of insulin injections and adapts the treatment strategy to consider each person’s circumstances [We report here the scheduled 2-year extension of BEYOND trial to assess the magnitude and the durability of the metabolic benefits of simplification. | PMC10850008 |
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Materials and methods | PMC10850008 |
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Study design | hyperglycemia, diabetes | HYPERGLYCEMIA, RECRUITMENT, TYPE 2 DIABETES, DIABETES | The three-arm trial design of BEYOND has been described previously [BEYOND was a 6-month, randomized, pragmatic, parallel group, single-center trial that evaluated the efficacy and safety of either FRC or basal insulin plus SGLT-2i to replace a full basal-bolus insulin regimen in participants with type 2 diabetes experiencing inadequate glycemic control (HbA1c > 7.5% [58 mmol/mol]), with or without metformin. The active control group consisted of patients continuing the basal-bolus regimen with their usual diabetes care. Recruitment started in July 2019 and the first part of the trial was completed in 2020 after a follow-up of 6 months. The present report consists of the data obtained up to 30 November 2022, when the last patient competed 2 years after randomization.Originally, 101 participants were randomly assigned to intensification of basal-bolus regimen, 102 to the FRC group, and 102 to the gliflo-combo group. There were 12 dropouts in the FRC group, 9 in the gliflo-combo group, and none in the basal-bolus group. In the extension phase of the trial, the investigators may suspend the medication for safety reasons or for uncontrolled hyperglycemia (i.e., HbA1c higher than the baseline value in the first assessment). Participants in both the FRC and gliflo-combo groups who withdrew from the study due to lack of treatment efficacy returned to the basal-bolus therapy but were not included in the original basal-bolus group. | PMC10850008 |
Outcomes | HYPOGLYCEMIA | The primary efficacy outcome of the extension trial was change from baseline in HbA1c at 24 months. Secondary outcomes were the proportion of participants with HbA1c < 7.0% (53 mmol/mol) or <7.5% (58 mmol/mol), total daily insulin doses, number of daily injections, percentage of participants with hypoglycemia, changes from baseline in body weight and fasting plasma glucose, and the level of satisfaction (DiabetesTreatment Satisfaction Questionnaire—DTSQ) [To limit clinical inertia, in the extension part of the trial clinicians had to improve glycemic control according to a titration algorithm for basal insulin in all three groups and for prandial insulin in the basal-bolus group (Table Titration algorithm for recommended rapid insulin analog dose adjustment in the basal-bolus groupTitration algorithm for recommended basal insulin dose adjustment in the three groups | PMC10850008 |
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Statistical analysis | SECONDARY | The efficacy population consisted of all participants randomized to study treatment (intention-to-treat). A per-protocol analysis was also performed. Categorical variables are expressed as frequencies and proportions; continuous variables are given as mean ± SD (variables normally distributed) or median and interquartile range (variables not normally distributed). Statistical differences in the primary outcome at 24 months were assessed by ANCOVA with treatment as fixed effect and baseline levels as covariates. The proportions of patients analyzed for secondary outcomes were assessed by contingency tables and χ | PMC10850008 |
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Results | PMC10850008 |
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Baseline characteristics | glifo-combo | At the start of the extension study, the original 101 participants remained in the basal-bolus group, 90 participants were in the FRC group and 93 in the gliflo-combo group. At 24 months, there were additional 32 dropouts in the FRC group and 39 in the glifo-combo group (Fig. The trial has been completed in 24 months. BBI basal-bolus insulin, FRC fixed-ratio combination (basal insulin + GLP-1RAs), GC gliflo-combo (basal insulin + gliflozin) | PMC10850008 |
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Adverse events | HYPOGLYCEMIA, EVENT, ADVERSE EVENTS, ACUTE PANCREATITIS | The proportion of patients presenting at least one episode of level 1hypoglycemia was 24.8%, 12.8%, and 9.9% in the basal-bolus, FRC, and gliflo-combo groups, respectively, with a significant difference among them (There was no event of acute pancreatitis in the fixed-combo group. Five participants in the FCR group and seven participants in the gliflo-combo group discontinued for adverse events, mostly gastrointestinal in the FRC group and genital mycotic in the gliflo-combo group. | PMC10850008 |
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Acknowledgements | Di Lorenzo, Claudia | METABOLIC DISEASES | The authors thank Lucia Digitale Selvaggio, Francesco di Maio, Michela Di Nuzzo, Daniela Forestiere, Rita Matrone, Chiara Porcellini, Alessandra Volatile (Division of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy), Silvia Angelino, Stefania Arena, Graziella Botta, Paolo Cirillo, Rosa Di Fraia, Pamela Ferrazzano, Antonietta Maio, Maria Tomasuolo, Claudia Varro, Nicole Di Martino, Concetta Di Lorenzo (Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy), Mariluce Barrasso, Mariangela Caputo, Carla Carbone, Filomena Castaldo, Alessandro Pontillo (Division of Endocrinology and Metabolic Diseases, University of Campania “Luigi Vanvitelli”, Naples, Italy) for the composition of the BEYOND study. | PMC10850008 |
Author contributions | D.G., M.L., M.I.M., and K.E. designed the research. D.G., M.L., L.S., P.C., M.G., M.P., G.B., M.I.M., and K.E. conducted the research. M.L., P.C., and L.S. collected data in the electronic database. D.G., M.L., and M.I.M. performed statistical analysis. D.G., M.L., G.B., M.I.M., and K.E. wrote the paper. D.G. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors have read and approved the final manuscript. | PMC10850008 |
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Funding | This study was funded in part by the Associazione “Salute con Stile” (no. 1.2022) (Naples, Italy). Open access funding provided by Università degli Studi della Campania Luigi Vanvitelli within the CRUI-CARE Agreement. | PMC10850008 |
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Compliance with ethical standards | PMC10850008 |
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Conflict of interest | D.G. received honoraria for speaking at meetings from Sanofi, Eli Lilly, and Company, AstraZeneca, and Novo Nordisk. M.I.M. received honoraria for speaking at meetings from Novo Nordisk, Sanof, and Eli-Lilly. K.E. received honoraria for speaking at meetings from Sanofi Aventis, Eli Lilly, and Novo Nordisk. No other potential conflicts of interest relevant to this article were reported. | PMC10850008 |
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Consent to participate | Informed consent was obtained from all individual participants included in the study. | PMC10850008 |
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Ethics approval | This study was performed in line with the principles of the Declaration of Helsinki. The study protocol was approved by the Medical Ethics Committee of University of Campania Luigi Vanvitelli (prot 731 26.11.2019) and registered at ClinicalTrial.gov NCT04196231. | PMC10850008 |
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References | PMC10850008 |
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1. Introduction | age-associated diseases, inflammation, LPS-exposure, sarcopenia | INFLAMMATION, SARCOPENIA, MUSCULOSKELETAL DISORDERS, DISEASES, INFLAMMATORY RESPONSE | These authors contributed equally to this work.Inflammaging is related to cell senescence and reflects an erratic immune system, which promotes age-associated diseases. Exercise and nutrition, particularly omega-3 fatty acids, are able to affect inflammation. Therefore, we examined the effects of an 8-week exercise and dietary intervention on the inflammatory response in community-dwelling old adults. All participants received weekly vibration and home-based resistance exercise. Furthermore, participants were randomized to either a control, high-protein (1.2–1.5 g/kg), or high-protein, omega-3-enriched (2.2 g/day) diet. Before and after treatment, inflammatory markers in fasting serum and after whole-blood ex vivo lipopolysaccharide (LPS) stimulation were assessed. Gene expression levels of inflammatory markers were quantified in peripheral blood mononuclear cells (PBMC). Sixty-one participants (age: 70.6 ± 4.7 years; 47% men) completed the study. According to generalized linear mixed models, a high-protein, omega-3-enriched diet decreased circulating anti-inflammatory interleukin (IL-) 10 and IL-1 receptor antagonist (IL-1RA). Sex-stratified analyses showed also significantly reduced pro-inflammatory markers in men with a high-protein, omega-3-enriched diet. Gene expression of IL-1RA was significantly reduced after both protein-enriched diets compared with controls. In comparison to a high-protein diet, exercise alone showed lower LPS-induced release of c-c motif chemokine ligand-2 (CCL-2), which tended to be more pronounced in men compared with women. Eight weeks of a high-protein, omega-3-enriched diet combined with exercise decreased circulating anti-inflammatory markers, and pro-inflammatory markers in men. A high-protein diet attenuated anti-inflammatory markers on gene expression level in PBMC. Exercise alone resulted in a lower pro-inflammatory response to LPS-exposure in whole-blood cultures.A persistent low-grade inflammation in higher age, also known as inflammaging, alters cell function and fuels age-related diseases such as cardio-metabolic diseases as well as musculoskeletal disorders, such as sarcopenia [The term “inflamm-aging” has recently been extended to “inflamm-inactivity”, since it is recognized that a sedentary lifestyle causes a relevant proportion of inflammatory processes [ | PMC9863449 |
2. Results | PMC9863449 |
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2.1. Baseline Characteristics | In total, 61 old adults (70.6 ± 4.7 years; 53% women) were included in the final analysis. The three groups, consisting of either a control, a high-protein (protein), or a high-protein, omega-3-enriched diet (protein + omega-3), showed similar baseline characteristics such as age, sex distribution, body composition ( | PMC9863449 |
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2.2. Adherence to Interventions and Changes in Body Composition | With regard to our exercise intervention, the participants started with overall comparable physical fitness and showed similar adherence to exercise protocols regarding vibration training as well as home-based exercises (see The high adherence rate of omega-3 supplementation resulted in a significantly increased omega-3 plasma index only in the protein + omega-3 group (see Although the body mass index (BMI) significantly increased only within the protein + omega-3 group (+0.26 ± 0.43 kg/m | PMC9863449 |
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2.3. Omega-3 Supplementation Decreased Circulating Inflammatory Markers | To investigate intervention effects on inflammatory markers in old adults, we first assessed the circulating levels of IL-6, IL-10, IL-1 receptor antagonist (IL-1RA), c-c motif chemokine ligand-2 (CCL-2), and high-mobility group box-1 (HMGB-1) in fasting serum samples. According to unadjusted within-group comparisons before and after treatment, serum concentrations of IL-6 (Subsequent sex-stratified analyses indicated that additional omega-3 supplementation led to significantly decreased IL-10 in both women ( | PMC9863449 |
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2.4. Gene Expression Levels of Inflammatory Markers in PBMC Are Reduced with Both Protein-Enriched Dietary Interventions | To better understand intervention effects on immune cells in old adults, we analyzed expression levels of genes coding cytokines/chemokines in isolated PBMC. Within-group comparison showed significant reductions in gene expression levels of IL-6 (In women, sex-stratified analyses indicated in the protein as well as the protein + omega-3 group significant reductions on gene expression levels of | PMC9863449 |
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2.5. Reduction in Ex Vivo LPS-Stimulated Cytokine/Chemokine Release after Exercise and Dietary Interventions | To investigate how exercise and dietary interventions affect the immune cell capacity of old adults, we evaluated the LPS-stimulated secretion levels of cytokines/chemokines in whole-blood cultures. Unadjusted within-group comparison indicated a significantly diminished LPS-induced production of IL-1RA in the protein group (Furthermore, within-group comparisons depicted a significant lower LPS-induced release of CCL-2 after eight weeks exclusively in the control group (In women, a significant reduced LPS-induced release of IL-1RA in the protein group ( | PMC9863449 |
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3. Discussion | To the best of our knowledge, the present sub-analysis is the first to investigate the impact of a whey protein-enriched, omega-3-supplemented diet in combination with whole-body vibration training and home-based exercise on the inflammatory status in community-dwelling old adults, using the combination of analyses in serum, in PBMC, and in ex vivo LPS-stimulated whole-blood cultures. A high-protein, omega-3-enriched diet (for 8 weeks) resulted in significantly decreased circulating anti-inflammatory IL-10 and IL-1RA. Moreover, circulating pro-inflammatory IL-6, CCL-2, and HMGB-1 decreased with omega-3 supplementation in men. Gene expression levels of | PMC9863449 |
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3.1. Isolated Effects of Exercise Intervention on LPS-Induced Chemokine Release | Details regarding the dietary compliance rates and exercise adherence of our participants were recently published [Another study performing 12 weeks of moderate strength exercises with 45 healthy old women also observed no changes in IL-2, IL-6, IL-10, TNF-α, and interferon-γ, produced by T lymphocytes [Home-based resistance exercise programs are effective in counteracting sedentariness [ | PMC9863449 |
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3.2. Decreased Inflammatory Markers in Serum after High-Protein, Omega-3 Enriched Diet | Although there is a lack of knowledge about interaction effects between exercise and omega-3 supplementation, particularly in old adults, it is assumed that omega-3 acts complementary to exercise in immunomodulatory and anti-inflammatory processes [ | PMC9863449 |
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3.3. Gene Expression Levels of Inflammatory Markers Reduced with Protein-Enriched Diets | We observed significantly lower gene expression levels of | PMC9863449 |
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3.4. Attenuated or no Change in LPS-Induced Immune Response with Dietary Interventions | In our study, we used the ex vivo whole-blood assay which is a promising method to assess the cytokine release and cell activation in response to dietary or exercise intervention. It has been demonstrated that old compared with young adults show an attenuated pro-inflammatory response to LPS exposure, possibly reflecting an impaired host defense against pathogens [ | PMC9863449 |
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3.5. Sex-Related Differences | inflammation | INFLAMMATION | Since it has been recommended to consider the impact of sex on inflammation even in higher age [ | PMC9863449 |
3.6. Strength and Limitations | INFLAMMATORY RESPONSE | One strength of this trial is the variety of assessments of inflammatory markers in serum, on gene expression level as well as in response to LPS exposure, which allowed us to have a differentiated evaluation of the inflammatory response in old adults. Furthermore, adherence to the exercise and dietary interventions was high in both the protein and the protein + omega-3 group [Limitations of our study are the small sample size and the relatively short intervention time. However, this analysis was a pilot trial using an explorative approach to determine combined effects of a dietary and exercise intervention on inflammation in community-dwelling old adults. The triple intervention of exercise, whey/protein enrichment and omega-3 supplementation, might impede the interpretation of the results, since all of them are associated with anti-inflammatory effects. However, we used a three-arm study design to distinguish the separate effects of the dietary interventions. | PMC9863449 |
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4. Materials and Methods | PMC9863449 |
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4.1. Study Design and Population Sample | This is a sub-analysis of an 8-week randomized controlled intervention trial in a 3-arm design, which has been described elsewhere in detail [ | PMC9863449 |
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4.2. Anthropometric Measurements | Weight (kg), height (cm), and waist circumference (cm) were measured to subsequently calculate BMI (kg/m | PMC9863449 |
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4.3. Dietary Assessment | Daily dietary intake was recorded using 3-day dietary protocols and calculated with the nutrition software EBISpro version 2016 (Dr. J. Erhart, Willstätt-Legelshurst, Germany). | PMC9863449 |
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4.4. Laboratory Assessments | All blood samples were collected between 8 and 10 a.m. after an overnight fast and stored at −80 °C until analysis. Commercial enzyme-linked immunosorbent assays (ELISA) were used to measure serum concentrations (pg/mL) of IL-6, IL-10, IL-1RA, CCL-2 (all BioVendor, Brno, Czech Republic), and HMGB-1 (ng/mL) (IBL International GmbH, Hamburg, Germany) according to manufacturer’s instructions. IL-6 to IL-10 was also expressed as ratio, reflecting cytokine balance. The omega-3 plasma index was measured in phospholipid fractions by gas chromatography as described elsewhere [ | PMC9863449 |
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4.5. PBMC Isolation, RNA Extraction, and Gene Expression with qPCR | To isolate PBMC, blood was collected with 8 mL BD VacutainerRibonucleic acid (RNA) was extracted from isolated PBMC using the NucleoSpin | PMC9863449 |
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4.6. Ex Vivo Whole-Blood LPS Stimulation | Ex vivo stimulation of whole-blood samples with LPS was performed to evaluate immune cell capacity as described previously [ | PMC9863449 |
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4.7. Whole-Body Vibration Training and Home-Based Resistance Exercise | All participants trained once per week under guidance at the institute on a Galileo | PMC9863449 |
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4.8. Dietary Intervention | Participants were randomly assigned to either control, high-protein (protein) or high-protein, omega-3-enriched (protein + omega-3) diet groups. While the control group continued their usual diet, both protein-enriched groups received a high-protein diet (1.2–1.5 g protein/kg body weight/day), supported with a daily 300 mL whey drink (27 g protein; including 4 g leucine). In addition, the protein + omega-3 group was supplemented daily with 3.5 mL algae oil (2195 mg omega-3 fatty acids; including 1397 mg DHA, 749 mg EPA, and 49 mg docosapentaenoic acid). To evaluate compliance, left-overs of the whey and omega-3 supplements were weighed back at the end of the study, and additionally, omega-3 index was measured in plasma. | PMC9863449 |
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4.9. Data Analysis | Statistical analyses were performed with SPSS Statistics version 25 (IBM Corp., Chicago/IL, USA). Data distribution was checked using Kolmogorov–Smirnov tests and presented as either mean ± standard deviation or median with interquartile range (IQR). Extreme outliers of relative changes after treatment, identified with boxplots and defined as cases lying 3*IQR distant, were removed from the data set. Within-group comparisons before and after treatment were tested with either paired Generalized linear mixed models with random effect on subjects were used to investigate group × time-interaction effects between groups and presented as estimated mean with 95% confidence interval (95% CI). All models were adjusted for age, sex, and FMI, since we observed significant associations with our markers of interest. Inflammatory markers were also adjusted for baseline values, when significantly different between groups at baseline. Due to skewness, inflammatory markers have been log-transformed before analyses. In addition, we performed sex-stratified analyses with mixed models adjusted for age and FMI, and compared group-specific changes between sexes with either unpaired | PMC9863449 |
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5. Conclusions | Eight weeks of a high-protein, omega-3-enriched diet combined with exercise decreased circulating anti-inflammatory markers IL-10 and IL-1RA. In men, the pro-inflammatory markers IL-6, CCL-2, and HMGB-1 were reduced following a high-protein, omega-3-supplemented diet. A high-protein diet attenuated anti-inflammatory IL-1RA on gene expression levels in PBMC. Exercise alone resulted in a lower CCL-2 response to ex vivo LPS exposure in whole-blood-cultures, which is likely attributable to the effects seen in men. | PMC9863449 |
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Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC9863449 |
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Author Contributions | C.H. | The authors’ responsibilities were as follows—conceptualization, U.H., O.P.-R. and K.N.; funding acquisition, U.H.; collection of data, U.H.; laboratory assessments, S.H., B.K. and C.H.; statistical analysis, U.H. and S.H.; writing—original draft preparation, U.H. and S.H.; writing—review and editing, B.K., C.H., O.P.-R. and K.N. O.P.-R. and K.N. contributed equally to this work: shared last authorship. All authors have read and agreed to the published version of the manuscript. | PMC9863449 |
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Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and approved by the University of Potsdam ethics committee (protocol code 58/2019 and date of approval: 21 October 2019). | PMC9863449 |
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Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC9863449 |
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Data Availability Statement | The data that support the findings of this study are available from the corresponding author upon reasonable request. | PMC9863449 |
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Conflicts of Interest | The authors declare no conflict of interest. The funders and sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. | PMC9863449 |
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Abbreviations | PMC9863449 |
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References | Fasting serum concentrations of (Gene expression levels analyzed in peripheral blood mononuclear cells of (Ex vivo whole-blood LPS-induced concentrations of (Baseline characteristics and inflammatory markers, displayed for control, high-protein (protein), and high-protein, omega-3 enriched (protein + omega-3) groups.Continuous variables are expressed as mean ± standard deviation or median (interquartile range). | PMC9863449 |
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Background | depressive, depression, psychiatric | Current psychiatric epidemiological evidence estimates that 17% of young adults (aged 18-25 years) experienced a major depressive episode in 2020, relative to 8.4% of all adults aged ≥26 years. Young adults with a major depressive episode in the past year are the least likely to receive treatment for depression compared with other age groups. | PMC10369163 |
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Objective | depression | We conducted a randomized clinical trial following our initial 4-week SMS text message–delivered cognitive behavioral therapy (CBT-txt) for depression in young adults. We sought to test mechanisms of change for CBT-txt. | PMC10369163 |
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Methods | depressive, Depression, cognitive distortions, depressive symptoms | Based on participant feedback, outcome data, and the empirical literature, we increased the treatment dosage from 4-8 weeks and tested 3 mechanisms of change with 103 young adults in the United States. Participants were from 34 states, recruited from Facebook and Instagram and presenting with at least moderate depressive symptomatology. Web-based assessments occurred at baseline prior to randomization and at 1, 2, and 3 months after enrollment. The primary outcome, the severity of depressive symptoms, was assessed using the Beck Depression Inventory II. Behavioral activation, perseverative thinking, and cognitive distortions were measured as mechanisms of change. Participants were randomized to CBT-txt or a waitlist control condition. Those assigned to the CBT-txt intervention condition received 474 fully automated SMS text messages, delivered every other day over a 64-day period and averaging 14.8 (SD 2.4) SMS text messages per treatment day. Intervention texts are delivered via TextIt, a web-based automated SMS text messaging platform. | PMC10369163 |
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Results | depressive symptoms | Across all 3 months of the study, participants in the CBT-txt group showed significantly larger decreases in depressive symptoms than those in the control group ( | PMC10369163 |
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Conclusions | depressive | Results provide evidence for the efficacy of CBT-txt to reduce young adult depressive symptoms through hypothesized mechanisms. To the best of our knowledge, CBT-txt is unique in its SMS text message–delivered modality, the strong clinical evidence supporting efficacy and mechanisms of change. | PMC10369163 |
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Trial Registration | ClinicalTrials.gov NCT05551702; https://clinicaltrials.gov/study/NCT05551702 | PMC10369163 |
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Introduction | PMC10369163 |
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Background | depressive, depression | In 2020, young adults (ages 18-25 years) in the United States experienced more major depressive episodes than other age groups and were the least likely to receive treatment for depression (eg, talking with a health provider or taking prescription medication) [Even when the rates for the treatment of depression rose nationwide, the rates for the treatment of depression for young adults rose at a significantly lower rate [ | PMC10369163 |
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Mobile Health Treatments | depression | Creative mental health treatment strategies are needed to reach young adults to address this unmet need. Digitally delivered mobile health (mHealth) treatments (or mHealth interventions) show promise for reaching young adults and serving as a clinical tool to address depression in young adults. Because mHealth interventions can increase large-scale access to evidence-based treatments, some countries such as New Zealand are integrating these approaches into their national health service infrastructure [ | PMC10369163 |
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Clinical Foundation | depressive | This study was conducted to better understand the mechanisms of SMS text message–delivered cognitive behavioral therapy (CBT-txt) as well as the acceptability of the treatment length. Our recent randomized clinical trial treating 102 young adults in the United States with at least moderate depressive symptomatology found that CBT-txt was acceptable, feasible, and efficacious compared with a waitlist control condition [ | PMC10369163 |
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This Study | depressive | Four hypotheses were tested for this follow-up study. The first hypothesis was that participants allocated to the treatment condition would show greater reductions in their depressive symptoms immediately following treatment (2 months after enrollment) and at the 3-month follow-up than participants in the waitlist control condition. Because treatment response has been linked to baseline symptom severity [ | PMC10369163 |
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Methods | PMC10369163 |
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Procedures | RECRUITMENT | In total, 103 young adults (ages 18-25 years) were recruited and enrolled in a 3-month randomized clinical trial. Participants were recruited using age-targeted advertising on Facebook and Instagram for young adults residing in the United States. Recruitment occurred over a 7-week period from July 6 to August 28, 2022. The study was advertised to all those within the study age range (18-25 years) across the United States who used Facebook and Instagram. With the aim of recruiting a geographic, racial and ethnic, and socioeconomically diverse sample, we placed no restrictions on advertisements other than age, used advertisements with a variety of images featuring people of different racial groups, and used a variety of placements (eg, feeds, stories, and reels) to reach the widest swath of potential participants. Interested individuals were directed to a study website where they would read more about the study and answer eligibility screening questions on their phones.The study was registered at ClinicalTrials.gov (identifier NCT05551702). | PMC10369163 |
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Design | The study design was a 2-arm randomized clinical trial with participants allocated to either the experimental condition or the waitlist control condition. Eligibility requirements were (1) age between 18 and 25 years; (2) a score of at least 10 on the Patient Health Questionnaire–9 (PHQ-9) [ | PMC10369163 |
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Remote Data Collection Quality Control | Data were reviewed carefully on a daily basis for quality control. Beginning July 26, 2022, we noticed increased screening activity with similar name patterns. After carefully reviewing the screening data, including the name, mailing address, IP address, phone number with area code and service carrier, and survey responses, we determined that 17 enrolled cases may have been fraudulent. We reached out via text, phone, and email to these 17 cases to confirm their identity but none of the participants responded. All 17 cases were administratively removed from the study on July 28, 2022. We enacted other procedures, such as using Qualtrics (Qualtrics), the web-based survey program that flags responses likely to be from bots, attempts to prevent multiple submissions from a single respondent, and assigns a fraud score indicating the likelihood of a response being fraudulent [Eligible individuals were instructed to complete the baseline survey on their phones, where upon completion, they were randomized to either the treatment or waitlist control condition. Randomization was automated by Qualtrics as part of the baseline survey. Randomization was stratified by sex using block randomization with a fixed block size of 10 to reduce bias during randomization and to ensure equal representation of sex across both conditions. The participants completed follow-up assessments at the 1-, 2-, and 3-month follow-ups. Waitlist condition participants were eligible to receive the treatment texts upon the completion of the 3-month follow-up survey. Participants who completed the screening, baseline, and all follow-up assessments received US $150 in Amazon eGift cards. | PMC10369163 |
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Text-Delivered Treatment: CBT-txt | PMC10369163 |
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Overview | CBT-txt was adapted from an evidenced-based, in-person CBT treatment manual [ | PMC10369163 |
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Theoretical Underpinnings of CBT-txt | depression | DISORDERS | The theory underlying CBT-txt is the Generic Cognitive Model, which specifies common cognitive and behavioral processes associated with disorders such as depression [ | PMC10369163 |
Clinical Structure of CBT-txt | adult abuse | ABUSE, ADULT ABUSE | We expanded our initial 4-week CBT-txt treatment [SMS text message–delivered cognitive behavioral therapy (CBT) content and structure (474 texts over 8 weeks; mean 14.8 texts per day, every other day).Participants assigned to the CBT-txt intervention condition received 474 texts delivered every other day over a 64-day period, averaging 14.8 texts per treatment day. Participants indicated the time of day they would like to receive the intervention texts. Intervention texts were delivered via a web-based automated SMS text messaging platform called TextIt. Project staff programmed TextIt to deliver intervention texts and extract data from the web-based survey platform Qualtrics to automatically personalize intervention texts. Texts were individualized based on data provided by participants in the baseline survey as well as throughout the treatment period.In addition to the scheduled intervention messages, participants could access automated booster messaging to provide on-demand supportive messages by texting “4MOOD” at any time, as needed. The “4MOOD” messages are organized around topics (eg, cognitive techniques and positive activities) such that participants select a category of message to receive each time they text “4MOOD” for additional support. All text messages end with the response, “If this is a crisis call 911.” If participants want to find out about receiving professional help, they choose option 4 and the program texts them a link to a list of national mental health services, suicide prevention hotlines, and a child and adult abuse hotline. This list includes a link to access Substance Abuse and Mental Health Services Administration’s treatment locator, which offers a database of treatment providers that can be filtered by location. | PMC10369163 |
Example of a texting conversation over 1 day. (The italicized text is autopopulated by programming and is programming logic; it is not shown to the participant. This limited example of SMS text message–delivered cognitive behavioral therapy does not provide the context of previous texting conversations or subsequent conversations that are built on past conversations.) | depressed, bad feelings | Hi Let’s look at how thoughts, what we tell ourselves, affect our mood. We are usually not aware of these negative thinking patterns that influence our moodText We actually fool ourselves and create more bad feelings about things that are *simply not true.* Our depressed thinking keeps us in this cycle.Study the list carefully, see which patterns you use. We will refer to these often as these serve as a guide to identify and change our thinking and mood. Text OKLooking at the list, identify at least 1 of the thinking patterns that you’ve used recently. Text back the number of the pattern. Text 1-10 or UNSURE
Good job identifying a pattern. So, what was the situation that led you to use
Ok, Look at the list again & think about this some more: http://selftalk.mjmood.com Text READY when you’re ready to discuss. Text UNSURE if you’re still unsure.
Ok, we know it can be hard to look at the way we talk to ourselves honestly. Remember that the more you put into this program the more you will get out of it.Carefully observe your automatic thoughts the next few days. Try to challenge them as not accurate or facts, but a result of your being in a depressed moodThis is a critical skill for you to learn. It seems simple, but when you practice this you’ll be surprised at how much this can change how you feel.Thanks | PMC10369163 |
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Fidelity of CBT-txt | We followed previous successful research in developing text-delivered interventions derived from in-person treatments [ | PMC10369163 |
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Participant Safety Protocol | Depression | We instituted a participant safety protocol that reviewed all incoming texts for crisis-related words both automatically (ie, autotext review) and with staff reading every text from all participants at least once per day. If participants indicated SI on the Beck Depression Inventory-II (BDI-II) or if their follow-up BDI-II (see the | PMC10369163 |
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Measures | PMC10369163 |
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Demographics | depression | Participant age, sex, race and ethnicity, socioeconomic status, family history of depression, and current use of antidepressant medication were collected at the baseline assessment. | PMC10369163 |
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Acceptability and Engagement | Participants’ acceptability of the intervention was measured via participant-reported satisfaction with the intervention as well as passively collected engagement with the intervention content and features. Satisfaction was assessed using a measure developed in our past work [ | PMC10369163 |
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Screen of Depression Symptoms | The PHQ-9 was used to determine eligibility [ | PMC10369163 |
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Depression Symptoms and Severity | depression | Baseline and follow-up assessment of depression severity was assessed with BDI-II [ | PMC10369163 |
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Behavioral Activation | Depression | Behavioral activation was measured using the Behavioral Activation for Depression Scale, Short Form [ | PMC10369163 |
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Perseverative Thinking | Repetitive negative thinking was measured using the Perseverative Thinking Questionnaire (PTQ) [ | PMC10369163 |
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Cognitive Distortion | Cognitive distortion | Cognitive distortion was measured using the Cognitive Distortions Scale (CDS) [ | PMC10369163 |
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Statistical Analyses | PMC10369163 |
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Latent Change Score Modeling | Latent change score (LCS) analyses were conducted in a structural equation modeling framework using the | PMC10369163 |
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Mediation Analysis | Depression | Mediation was also tested in LCS models. LCSs were created for (1) the baseline to 3-month change in the mediator (Behavioral Activation for Depression Scale, CDS, and PTQ in separate models) and (2) the baseline to 3-month change in the outcome (BDI-II). Pretreatment mediator and BDI-II scores at baseline were included as covariates in the model. The change in mediators was regressed on CBT-txt (and baseline covariates) to create the | PMC10369163 |
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Ethics Approval | All procedures were approved by the institutional review board of The University of Tennessee (approval UTK IRB-20-06164-FB). | PMC10369163 |
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Results | PMC10369163 |
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Demographic Results | Our sample size was 103. The participants’ mean age was 22 (SD 2.2) years and 84.5% (87/103) were female, and they resided in 34 different states in the United States and the District of Columbia. The sample comprised 15.5% (16/103) Asian, 3.9% (4/103) Black or African American, 7.8% (8/103) Hispanic or Latino, 8.7% (9/103) more than 1 race, and 63.1% (65/103) White participants. While not used analytically, college student status, childhood socioeconomic status (“Has your family ever received food assistance, such as free or reduced lunch, or SNAP benefits?”), and past and current use of antidepression medication were described to characterize the sample. Slightly more than half (55/103, 54.5%) were not enrolled in college part time or full time. Approximately one-third (35/103, 34%) of the participants endorsed a family history of government food assistance, and 42.7% (44/103) of participants had been prescribed antidepressant medication at some time in their life but only 20.4% (21/103) were currently prescribed antidepressant medication. CONSORT diagram for study participant flow and condition allocation. | PMC10369163 |
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Acceptability and Engagement | depression | Participants endorsed levels of acceptability and engagement similar to our previous pilot of CBT-txt for young adult depression. Two-thirds (69/103, 67%) of the participants completed the intervention (responding to ≥95% of intervention texts), although somewhat lower than in our previous pilot (85%) [ | PMC10369163 |
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LCS Results | PMC10369163 |
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Clinical Significance | Depression | We used 2 measures of clinical significance. First, the number of participants at the end of the trial with high-end state functioning as defined by Jacobson and Truax [Depression severity level (BDI-II categories) percentages at 3 months by condition. | PMC10369163 |
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Discussion | PMC10369163 |
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Principal Findings | depression, depressive symptoms | RECRUITMENT | The findings from this investigation contribute to the mHealth literature by providing convincing evidence that text-delivered CBT treatment can significantly and consistently reduce depressive symptoms in young adults. These findings also specify 3 treatment mechanisms that each explain a significant portion of the treatment effect when separately introduced into the mediation analysis models and even larger effects when combined. These results support the specification of 3 candidate therapeutic mechanisms of change within CBT-txt.All 4 of our hypotheses were supported in this trial’s findings. Our primary hypothesis tested the efficacy of CBT-txt to reduce depressive symptoms, relative to the control condition. The results supported this hypothesis across all 3 months of the study, revealing a strong treatment effect. The mediation analyses also supported our hypotheses regarding the mechanisms of change within the CBT-txt treatment structure. Separate models showed that each mediator accounted for a substantial proportion of the CBT-txt treatment effect on depression. Models with all mediators included showed that, combined, these mechanisms explained 63% of the CBT-txt treatment effect, with changes in perseverative thinking showing the strongest independent indirect effect.Although we did not experimentally test dosage effects in this trial, this study was a follow-up to our initial CBT-txt trial [Finally, these findings provide further support for recruiting young adults with depression via Facebook and Instagram, providing an efficient pathway toward engaging this hard-to-reach and underserved population. We recruited a sample of 103 participants in 7 weeks with excellent rates of retention, satisfaction, and engagement. These findings also support the use of CBT-txt as part of a continuum of care. For example, CBT-txt could serve as a form of pretreatment while individuals are placed on waitlists to be seen by clinicians. This approach could quickly reduce the severity of symptoms, particularly for individuals who are experiencing moderate to severe depressive symptoms. Targeting those with the most severe depression with CBT-txt may provide rapid symptom relief, which could then be followed up by a clinician. For some, CBT-txt may be enough; for others, it may serve as a jump start to their treatment and others may find it useful to combine CBT-txt while seeing a clinician for therapy. Supporting this latter idea, it is noteworthy that 278 participants were excluded from the study for reporting current or recent treatment for depression, suggesting that some young adults may recognize a need for supplemental options to traditional depression treatment. Social media recruitment may also reach young adults seeking preventive or early intervention services. Of note, 110 participants were not eligible for the study, as they reported only minimal (25/110, 22.7%) or mild (85/110, 77.3%) depression symptoms on the PHQ-9. | PMC10369163 |
Limitations | depressive | The study results should be considered in light of the following limitations. First, although this study was structured as a follow-up pilot study, having a larger sample size and longer follow-up periods may strengthen confidence in the findings. Second, the sample was 84% female, limiting the generalization across biological sexes. Although the rates of major depressive episodes are double for female young adults compared with male young adults (22.9% vs 11.1%) [The results of this trial provide further support for CBT-txt as an efficacious, efficient, and reliable form of treatment to address depressive symptomatology among young adults. To the best of our knowledge, CBT-txt is unique in its SMS text message–delivered modality and in its strong clinical evidence supporting efficacy. While acknowledging the study limitations and the potential treatment effect fluctuations due to the sample size, these results build upon our first trial’s promising findings and provide more empirical evidence for the treatment format, delivery modality, and clinical possibilities of using CBT-txt at scale.This research was funded by the Betsey R Bush endowment for Children and Families at Risk and Behavioral Health Research, Center for Behavioral Health Research, College of Social Work, University of Tennessee.Conflicts of Interest: None declared.Full model results for latent change score mediations.CONSORT eHEALTH checklist (V 1.6.2). | PMC10369163 |
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Abbreviations | depressive, Depression | Beck Depression Inventory-IIcognitive behavioral therapySMS text message–delivered cognitive behavioral therapyCognitive Distortions ScaleConsolidated Standards of Reporting Trialslatent change scoremajor depressive disordermobile healthPatient Health Questionnaire–9Perseverative Thinking Questionnairereliable change indexsuicidal ideation | PMC10369163 |
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Introduction | children)Additional, myopic | MYOPIA, PCT | Sufficient outdoor time is a widely accepted method for preventing myopiaFortunately, some clinical trials have discovered a novel and intriguing intervention—which has many different names, e.g., low-level laser therapy (LLLT)The first well-designed randomized controlled study also reported that this special red light therapy could shorten the AL to a mean value of − 0.06 mm (74 children)Additional evidence regarding the effect of PBM therapy on shortening the AL in myopia came from the authorized PCT patent WO2020244675A112 with a disclosure date of 2020. In the patent, a similar phenomenon was observed, including a decrease in AL for 84 myopic children (6–23 years old) for several months (one child underwent therapy for 3 months, the other 83 children underwent therapy for 6 months) after PBM therapy twice a day.Previously, we published a retrospective cohort study | PMC9969012 |
Methods | PMC9969012 |
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Study design | EYE | This 12-month clinical trial was designed to be a randomized, controlled, parallel study with follow-up visits every 3 months. Potentially eligible children were recruited from the hospital after a screening visit.The trial was designed to begin in February 2021 and end in June 2023. All subjects were enrolled at the Optometry Center of Ningbo Eye Hospital. Our study and protocol conformed to the principles of the Declaration of Helsinki and were approved by the ethical committee of Ningbo Eye Hospital (Number: 2020xjx-012). | PMC9969012 |
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Eligibility criteria | optic nerve dysfunction, astigmatism, amblyopia, optic media lesions, cataract, glaucoma, retinal lesions | ASTIGMATISM, AMBLYOPIA, EYE DISEASES, CATARACT, GLAUCOMA | The inclusion criteria were as follows: (1) the subject's guardian agreed to participate in the study and signed a written informed consent form; if the subject could express his or her willingness to participate in the trial, the subject's consent was also obtained; (2) age 3–16 years old (including the boundary values); there were no restrictions regarding gender; (3) the cycloplegic refraction with either spherical equivalent refractive (SER) was ≤ − 0.50 D ~ − 8.00 D (including the boundary values), and the total astigmatism was ≤ 2.50; (4) spectacle-corrected monocular VA was 0.0 logMAR or better; and (5) willing to wear SVS throughout the trial.The exclusion criteria were as follows: (1) patients who intended to use atropine (including 1% high concentration or 0.01% low concentration); (2) patients wearing peripheral defocus spectacles or duo-focal soft contact lenses; (3) patients with eye diseases such as glaucoma or retinal lesions; (4) optic media lesions (e.g., central thick corneal scars, cataract); (5) patients with optic nerve dysfunction; (6) patients with amblyopia; (7) research physicians determined that the subject was not eligible for other reasons. After screening, the participants were selected based on professional inquiry and baseline examination. The participants and their parents or legal guardians were informed about the benefits and risks of this study before providing signed informed consent on behalf of their children. | PMC9969012 |
Interventions and visits | SFChT, diopter | CYCLOPLEGIA, ACD | All spectacle lenses were made for single focus with full correction for each subject as the first intervention throughout the whole procedure for both groups. PBM therapy was performed with a low-intensity laser (LD-A, Jilin Londa Optoelectronics Technology, Jilin, China) with an irradiance of 0.35 ± 0.02 mW/cmDuring the baseline visit, eligibility was evaluated, and baseline measures were conducted. The dates of all subsequent visits were determined based on completion of the baseline examinations. Cycloplegic refraction using an automatic refractometer (Topcon KR-800, Topcon Corporation, Tokyo, Japan) and 100% subjective trial lenses were recorded at baseline and 12 months, respectively. Cycloplegia was achieved using 3 drops of 1% cyclopentolate hydrochloride eyedrop (CYCLOGYL, Alcon Laboratories, Inc., USA), and the spherical equivalent refraction (SER) was determined (obtained with the following formula: SER = spherical diopter + astigmatism/2). The follow-ups were conducted at 3 months, 6 months, 9 months and 12 months. The values of AL (IOLMaster 500, Carl Zeiss Meditec AG, Germany), CCP (Pentacam 70700, Oculus, Inc., Germany), SFChT (Spectralis OCT, Heidelberg Engineering GmbH, Germany) and ACD (Pentacam 70700, Oculus, Inc., Germany) were all recorded and evaluated at each visit in addition to the baseline visit.Other ophthalmologic examinations included slit-lamp examination (HS-5000(HLG), Huvitz Co. Ltd, Korea), noncontact tonometry (Topcon CT-80, Topcon Inc., Japan), and fundus scan with optical coherent tomography (Spectralis OCT, Heidelberg Engineering GmbH, Germany). | PMC9969012 |
Evaluated parameters | SFChT, myopia | MYOPIA, SECONDARY, ACD | The primary outcome variables were changes in AL and SER compared to baseline. SER (sphere plus half cylinder) from the pattern of five measurements was measured at least 30 min after instillation of 2 drops of 1% cyclopentolate administered every 5 min. AL was measured by calculating the average of five measurements obtained from the same IOLMaster. The secondary outcome variables included SFChT (Spectralis OCT, Herdingberg, Germany), ACD (from IOLmaster 500) and CCP (from Pentacam). PBM therapy was administered twice a day for 3 min per session with an interval of ≥ 4 h between sessions based on the self-report of participants or their supervision. We also evaluated the subjects’ social context, such as schools, and lifestyle (e.g., outdoor time) via questionnaires.Due to the small sample size, we aimed to avoid the influence of age on different growth rates of AL. Therefore, the eligibility criteria for age were set from 8 to 12 years old. In addition, we also removed the limitation on baseline AL ≥ 24.40 mm because the myopia suppression effect is unknown for axial lengths greater than 24.40 mm. | PMC9969012 |
Sample size calculation | Power Analysis and Sample Size Software (PASS 2022) (NCSS, LLC. Kaysville, Utah, USA) was used to determine that the minimum sample size was 24. A previous study found that the rate of AL change was approximately 0.25 mm/year (0.13 mm/year vs. 0.38 mm/year) slower in participants treated with repeated low-level red light than in controls | PMC9969012 |
Subsets and Splits