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Internalization | The LMM with baseline internalization as a covariate, randomized group as a between-subjects factor, study phase (T2 and T3) as a within-subjects factor, three 2-way interactions, and one 3-way interaction found a nonsignificant effect of group (The preplanned ANCOVAs showed a significant effect of randomized group on internalization both at T2 (In line with previous results, the post hoc repeated measures ANOVAs showed no significant effect of time in the control group (Trait internalization over time for both groups. *Significant analysis of covariance effect of the randomized group at a specific time point. | PMC10131926 | ||
Skin Shade Dissatisfaction | The complete LMM conducted on skin shade dissatisfaction showed a nonsignificant effect of group (The preplanned ANCOVAs showed a significant effect of randomized group on skin shade dissatisfaction at T2 (The post hoc repeated measures ANOVAs showed no significant effect of time in the control group (Trait skin shade dissatisfaction over time for both groups. *Significant analysis of covariance effect of the randomized group at a specific time point. | PMC10131926 | ||
Negative Mood | The LMM with baseline negative mood as a covariate, randomized group as a 2-level between-subjects factor, study phase (T2 and T3) as a 2-level repeated measures factor, three 2-way interactions, and one 3-way interaction showed a nonsignificant effect of group (The preplanned ANCOVAs confirmed the previous results, finding a nonsignificant effect of randomized group on negative mood at T2 (The post hoc repeated measures ANOVAs showed a significant effect of time in the control group ( | PMC10131926 | ||
Positive Mood | The LMM conducted on positive mood showed a nonsignificant effect of group (The preplanned ANCOVAs confirmed these results, finding a nonsignificant effect of randomized group on positive mood at both T2 ( | PMC10131926 | ||
Dose-Response Analyses | REGRESSION | Dose-response effects on trait outcomes at T2 and T3 in the intervention group were examined by running multiple regression analyses with Helmert-coded engagement scores (ie, the number of videos watched) as independent variables. The analyses showed no dose-response for all trait outcomes at any time point: body satisfaction at T2 ( | PMC10131926 | |
State Outcomes | PMC10131926 | |||
State Mood | Six dependent sample Cumulative analyses showed a significant interaction effect (The repeated measures ANOVA on prevideo scores was significant (Plotted means for state mood in the intervention group with prevideo and postvideo means for each video. | PMC10131926 | ||
Exploratory Analyses | On the basis of these findings, exploratory analyses were conducted to test whether the observed delayed effect on trait body satisfaction could be mediated by the immediate effect that the intervention had on internalization. Such a finding would provide support for the relationship between these variables as defined in the Tripartite Influence Model [Randomized group was significantly associated with the mediator (The model resulted in complete mediation, with the indirect effect of randomized group on body satisfaction at T3 being positive and significant (β=.03, 95% CI 0.017-0.041), and the direct effect was nonsignificant (β=.03, Exploratory mediation analysis. *Significant effect ( | PMC10131926 | ||
Discussion | PMC10131926 | |||
Intervention Effectiveness on Trait Outcomes | CURB | Scalable, cost-effective, and evidence-based interventions to curb body dissatisfaction are necessary and in demand among adolescent girls and young Indonesian women [In this study, we found Interestingly, the impact of In addition to the role that internalization played as a mediator of body satisfaction, our hypothesis that internalization as an outcome would decrease at 1 day and 1 month after the intervention was confirmed, reinforcing that the intervention successfully targets this key risk factor. Similarly, skin shade dissatisfaction decreased at 1 day after the intervention, as predicted; however, these effects were not maintained at 1-month follow-up. This might be attributed to the purpose-built measure we used, given the lack of an appropriate validated measure of skin shade dissatisfaction. In addition, it could be that our intervention did not have sufficient potency to deliver sustained change given how deeply embedded skin shade dissatisfaction is among girls and women in Indonesian society.Contrary to the hypotheses, the intervention had no significant impact on positive or negative trait mood. This may be because Finally, some exploratory post hoc analyses (see | PMC10131926 | |
Dose-Response Effects | Intervention adherence was excellent, with intervention participants having watched an average of 5 out of the 6 videos and completed, on average, 14 of the 18 activities. These adherence results are much higher than those often observed in web-based psychological interventions [ | PMC10131926 | ||
Intervention Effectiveness on State Outcomes | Overall, the effectiveness of Gain score comparisons within cumulative analyses showed that state-based improvements in body satisfaction were particularly strong for videos 1 (setting the scene), 3 (targeting appearance-based comparisons), 5 (targeting self-body talk), and 6 (concluding the story), and for state mood, video 6. Interestingly, of the 4 videos targeting specific risk factors for body dissatisfaction (videos 2-5), the 2 that targeted internal cognitive changes were the most effective at generating state change in body satisfaction. This may be because participants felt they could take immediate control of their thought processes to combat these risk factors for body dissatisfaction (ie, they had learned how to stop the chain of comparisons and view their body more compassionately in the moment), whereas the skills learned in videos 2 (targeting media literacy) and 4 (targeting appearance-based teasing) may take longer to put into practice and benefit from. Video 6 was also particularly effective in improving body satisfaction and mood. This final video presents an alternative world to the dystopian future seen in video 1, where society lives free from appearance pressures owing to the everyday positive changes made by just one individual (ie, Putri). Therefore, it is perhaps unsurprising that this new reality boosts both body satisfaction and mood among the audience, as it showcases the impact of individual-level changes.It is noteworthy that we also found significant and progressive improvements in pre- and poststate body satisfaction scores for videos 1 to 6 (with a plateau between videos 4 and 5 for prevideo scores and a plateau between videos 3 and 4 for postvideo scores). Similarly, we observed a progressive increase in pre- and poststate mood scores, specifically between videos 1 and 3 for prevideo scores, which were maintained until video 6, and between videos 1 and 6, with a plateau between videos 3 and 5 for postvideo scores. A possible reason for the state score increases before each video could be that after watching the first video, participants felt progressively more invested in the narrative of | PMC10131926 | ||
Strengths | Notable strengths of our study include excellent participant retention and intervention adherence, which are unusual for eHealth intervention trials [ | PMC10131926 | ||
Limitations | There are a few key areas that future research could explore. First, funding constraints prevented us from evaluating the independent impact of the intervention’s videos versus the combined impact of videos and activities. This is an area for future research. Second, although social comparisons are a potentially important change mechanism in this work, as per the Tripartite Influence Model [ | PMC10131926 | ||
Conclusions | PCD | This parallel randomized controlled trial showed that This study was funded by a research grant from the Dove Self-Esteem Project (Unilever). The funder had no role in the data analysis, decision to publish, or manuscript preparation.We would like to especially thank Laura Baines (Girl Effect) and Samantha Jackson (Percolate Galactic) for their invaluable efforts in creating Authors' Contributions: KMG was responsible for conceptualization, methodology, writing the original draft, project administration, data curation, and funding acquisition. SH was responsible for writing the original draft, project administration, data curation, and resources. NC was responsible for conceptualization, methodology, reviewing and editing, and funding acquisition. CG was responsible for methodology, formal analysis, and writing the original draft. KN was responsible for resources, project administration, and reviewing and editing. LAS was responsible for resources and reviewing and editing. BEM was responsible for resources and reviewing and editing. PW was responsible for methodology, formal analysis, and reviewing and editing. PCD was responsible for supervision, conceptualization, reviewing and editing, and funding acquisition (lead). HW was responsible for supervision, methodology, and reviewing and editing.Conflicts of Interest: PCD is an independent consultant for the Dove Self-Esteem Project global education initiative. SH was an independent consultant for Dove (Unilever) in 2021. PCD and SH were on the Dove Self-Esteem Project Global Advisory Board from 2013 to 2016. PCD is an independent consultant for Instagram owned by Meta (the parent company of Facebook). The intervention evaluated is owned by the nonprofit organization Girl Effect. The Dove Self-Esteem Project (Unilever) was permitted to review the manuscript and suggest changes; however, the authors exclusively retained the final decision on content. The views expressed are those of the authors and not necessarily those of Unilever. It should be noted that Unilever did not suggest any changes.Bahasa Indonesia translation of “Evaluating the Efficacy of a Social Media–Based Intervention (Warna-Warni Waktu) to Improve Body Image Among Young Indonesian Women: Parallel Randomized Controlled Trial”.Missing items for each trait outcome per condition at each time point.The number of participants who completed at least 80% of the items on each trait measure.Retention rates for state outcomes in the intervention group (n=924).Complete participant ethnicity data.Number of minutes to complete each time point survey.Intervention adherence: videos viewed and activities completed.Trait outcomes as per linear mixed models executed with 21 dimensions and an unstructured covariance structure.Cumulative analyses for state outcomes.Exploratory post hoc analyses tested the differential effect of the intervention on participants with higher and lower levels of body satisfaction at baseline.CONSORT-eHEALTH checklist V 1.6.1. | PMC10131926 | |
Abbreviations | analysis of covarianceBody Esteem Scale for Adolescents and Adultslog likelihoodlower- and middle-income countrylinear mixed modelPositive and Negative Affect Schedule for Childrenparticipant identification numberSociocultural Attitudes Towards Appearance Questionnairetime 1, baselinetime 2, 1 day after the interventiontime 3, 1 month after the intervention | PMC10131926 | ||
Background | TNBC | TRIPLE-NEGATIVE BREAST CANCER | Neoadjuvant chemotherapy (NACT) is the mainstay of treatment of stages II and III triple-negative breast cancer (TNBC). This study aims to evaluate if the addition of carboplatin to NACT is associated with an increase in the pathological complete response (pCR) rates in TNBC. | PMC10504209 |
Methods | TNBC | We conducted an open-label phase II randomized clinical trial in a single center in Brazil. Patients with stage II and III TNBC were randomized to receive standard NACT with or without carboplatin. All the patients received doxorubicin (60 mg/m | PMC10504209 | |
Results | tumors, Germline BRCA status | DISEASE, TUMORS | Between 2017 and 2021, 146 patients were randomized, 73 on each arm. The median age was 45 years. Most patients (66.4%) had locally advanced stage III disease, 67.1% had T3/T4 tumors, and 56.2% had clinically positive axillary lymph nodes. Germline BRCA status was available for all patients, and 19.9% had pathogenic | PMC10504209 |
Conclusion | TNBC | The addition of carboplatin to standard NACT in stages II and III TNBC was associated with a non-statistically significant numerical increase in the pCR rate. Follow-up for survival outcomes and translational research initiatives are ongoing. | PMC10504209 | |
Supplementary Information | The online version contains supplementary material available at 10.1007/s10549-023-07011-0. | PMC10504209 | ||
Keywords | PMC10504209 | |||
Introduction | TNBC, tumor, death, breast cancer | TRIPLE-NEGATIVE BREAST CANCER, TUMOR, BREAST CANCER, DISEASE, DYSFUNCTION | Triple-negative breast cancer (TNBC) is a subtype that accounts for approximately 15–20% of all breast cancer diagnoses. Clinically defined as lacking ER, PR, and HER2 expression, TNBC is characterized by an aggressive natural history and worse survival outcomes compared with other breast cancer subtypes [Neoadjuvant chemotherapy (NACT) remains the mainstay of early-stage and locally advanced disease treatment, and pathological complete response (pCR) as a surrogate endpoint is well-established in TNBC [Over the past years, there has been considerable interest in using platinum salts in treating TNBC because homologous recombination DNA repair dysfunction sensitizes tumor cells to these agents and induces cell death [Therefore, we conducted a phase II randomized clinical trial to evaluate if adding carboplatin to standard NACT could increase the pCR rate in patients with known BRCA status presenting with early-stage and locally advanced TNBC in Brazil. | PMC10504209 |
Methods | Cancer | CANCER | NACATRINE is an open-label phase II randomized trial conducted in a single center in Brazil. The study was conducted in compliance with the guidelines of the Declaration of Helsinki, International Conference on Harmonization and Good Clinical Practice. All patients gave informed consent for using tissue and biomarker evaluation for research purposes. The NACATRINE trial was approved by the Medical Ethics Committee of Barretos Cancer Hospital (1.796.766) and was registered at ClinicalTrials.gov under the number NCT02978495. All patients signed voluntary informed consent before study entry. | PMC10504209 |
Patient population | TNBC | Key eligibility criteria included patients more than 18 years old, with ECOG PS 0 or 1, adequate organ function with newly diagnosed stage II–III TNBC (ER < 1%, PR < 1%, and HER2 negative according to ASCO/CAP Guidelines [ | PMC10504209 | |
Randomization and stratification | All eligible patients were randomized in a 1:1 ratio to receive standard NACT with or without carboplatin. Treatment was allocated by computerized local randomization using the REDCAP (Research Electronic Data Capture) software. Randomization was stratified according to | PMC10504209 | ||
Procedures | neutropenia, toxicity, toxicities, clinically node-negative disease, anemia, Cancer | ADVERSE EVENT, METASTASIS, NEUTROPENIA, FEBRILE NEUTROPENIA, ADVERSE EVENT, THROMBOCYTOPENIA, DISEASE, ANEMIA, SENTINEL NODE, BLOOD, CANCER | All women were screened at baseline for distant metastasis with chest and abdomen tomography and bone scintigraphy. Blood samples were collected from all women at baseline to define BRCA1 and BRCA2 mutational status and storage at the BioBank of Barretos Cancer Hospital [According to the investigator's choice, a sentinel node procedure was done in patients with clinically node-negative disease before or after NACT.As summarized in Fig. S1 (supplementary material), the chemotherapy protocol consisted of doxorubicin (60 mg/mAn assessment of toxicity and laboratory tests preceded each chemotherapy cycle. Adverse events (AEs) were assessed according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Dose adjustment criteria followed the protocol. In brief, in the case of grade 2 neutropenia, chemotherapy was allowed with granulocyte-colony-stimulating factor (G-CSF) prophylaxis at the investigator’s discretion. In the case of grade 3 or 4 neutropenia, or febrile neutropenia, chemotherapy was delayed and postponed until grade 1 with dose reduction according to local protocol. For anemia, thrombocytopenia, and non-hematological toxicities grade 3 or worse, chemotherapy was postponed and reinitiated with dose reduction when toxicity recovered to grade 1. Toxicity-based dose adjustments were carried out according to drug-specific standard guidelines. In the experimental arm, if necessary, carboplatin was discontinued after two dose reductions, and paclitaxel was continued as monotherapy.Patients underwent surgery within 3–6 weeks after the last chemotherapy cycle. The decision about performing breast-conserving surgery (BCS) or mastectomy depended on the patient’s and surgeon’s preferences and followed institutional guidelines. In patients with clinically node-positive disease after chemotherapy, axillary dissection was required. In patients with clinically node-negative disease, the timing (before or after neoadjuvant therapy) of sentinel node biopsy was at the investigator's local practice. Adjuvant radiotherapy was given according to local practice. All randomized patients remained in the study and follow-up. | PMC10504209 |
Outcomes | tumor | TUMOR | The primary endpoint was the pathologic complete response (pCR) rate. pCR was defined as no invasive tumor in the breast and lymph nodes (ypT0ypN0) and followed international guidelines [Additionally, biological samples were collected during the study to conduct molecular and clinical analyses to assess the presence of prognostic and predictive markers of benefit or resistance to the study regimens. | PMC10504209 |
Statistical analysis | We hypothesized that the carboplatin-containing neoadjuvant regimen could increase the pCR rate from 20 to 35% compared with the non-carboplatin neoadjuvant-containing regimen. Safety data were summarized descriptively for all patients who received at least one dose of study treatment. TEAEs leading to treatment interruption, dose reduction, or discontinuation of study drugs are reported.For the sample description, the frequency was used for the qualitative variables and average and standard deviation for the quantitative ones. Comparison between groups was performed using the | PMC10504209 | ||
Role of the funding source | The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. | PMC10504209 | ||
Discussion | neutropenia, toxicity, TNBC, hereditary mutations, tumors | RECURRENCE, NEUTROPENIA, DNA STRAND BREAK, DISEASE, ADVERSE EFFECTS, TUMORS | In the NACATRINE study, a phase II randomized clinical trial conducted at a single center in Brazil, the addition of carboplatin to an anthracycline and taxane-based NACT regimen was associated with a numerical but not statistically significant increase in the pCR rate. Survival data are immature and, so far, do not show differences between groups. The toxicity profile was favorable and comparable to previous data, with increased neutropenia rate and dose reductions. However, the incidence of severe adverse effects was low, and there was no difference in treatment interruption between the two groups.NACT remains the standard treatment for early-stage and locally advanced TNBC. Platinum cytotoxic agents (such as carboplatin) cause DNA strand breaks via cross-linkage of DNA strands, increasing their effectiveness in tumors with impaired DNA repair pathways, a finding commonly seen in TNBC as well as in patients with hereditary mutations such as BRCA or other homologous recombination pathways genes [Benefits in terms of pCR and survival outcomes have placed the Keynote-522 study protocol, containing polychemotherapy with carboplatin associated with the immunotherapy pembrolizumab, as the preferred regimen for the neoadjuvant treatment of stages II and III TNBC [Genetic diversity of germline variants in TNBC predisposition genes is unexplored in miscegenated populations, such as those living in Latin America [Our findings are comparable to the published literature in the field, considering that various randomized clinical trials consistently demonstrated increased clinical response and pCR rates using neoadjuvant carboplatin in TNBC. The relationship between the use of neoadjuvant carboplatin and long-term survival benefits has been considered a controversial issue in breast oncology, considering that many studies that demonstrated pCR gain did not show significant benefits in terms of DFS and OS. However, recently the BRIGHTNESS study was published [The present study adds to the growing body of evidence supporting carboplatin as a component of NACT in stage II–III TNBC. We acknowledge that our study has several limitations, including the absence of dose-dense chemotherapy given the lack of access to colony-stimulating factors (G-CSF) in the public health system of LMIC, the relatively small sample size and difficulties inherent to the lack of statistical power in a phase II study. Despite not crossing the threshold for statistical significance of 15%, we believe the increase in the pCR rate observed in this study can be considered clinically significant and congruent with other randomized clinical trials. Since carboplatin is a widely accessible treatment even in LMIC, with low cost and a known and manageable toxicity profile, we consider that it can be regarded as in most cases of patients with TNBC with an indication for NACT in current clinical practice.Our study has several qualities and opportunities, such as an adequate clinical-epidemiological description of the profile of patients with TNBC treated in a public health institution in a LMIC, in addition to providing results in terms of pathological response and survival outcomes that have diverse applicability, including for planning new clinical research initiatives. All patients included had samples collected for a well-structured biobank that will serve for translational research initiatives, given that identifying predictive biomarkers to better define subsets of TNBC patients who benefit from the addition of carboplatin remains an unmet need. Additionally, the study aimed to identify biomarkers associated with pCR, residual invasive disease after NACT, and recurrence, and we intend to publish these exploratory analyses in the future. | PMC10504209 |
Conclusion | TNBC | The addition of carboplatin to standard NACT in stages II and III TNBC was associated with a non-statistically significant numerical increase in the pCR rate of 13.7%, consistent with other similar clinical trials. Follow-up for survival outcomes and translational research initiatives are ongoing. Given the consistent results with previous studies, the addition of carboplatin appears to have a favorable risk-to-benefit profile. It might be considered a potential NACT component for patients with high-risk TNBC in LMIC. | PMC10504209 | |
Acknowledgements | Cancer | RECRUITMENT, CANCER | The authors would like to thank the BioBank of the Barretos Cancer Hospital for the technical support in handling biological samples from the patients, the Researcher Support Center (NAP) for the support with the recruitment of clinical trial participants, and the Barretos Cancer Hospital Research Incentive Program (PAIP). The authors also thank Dr. Carlos Henrique Barrios for his contribution and critical reading of the manuscript. | PMC10504209 |
Author contributions | DCL | CPS | ASBC recruited the patients and participated in the study design. ACOL participated in the study design. DCL recruited the patients. CEP recruited patients and participated in the study design, preparation, and critical reading of the manuscript. MMCZ recruited the patients. AJAF participated in the manuscript preparation and critical reading of the manuscript. IVVS assisted with case selection and sample review. MAO participated in the data analysis. EIP participated in the manuscript preparation and critical reading of the manuscript. MMCM participated in the manuscript preparation and critical reading of the manuscript. TR data interpretation and manuscript writing. CPS participated in the study design, conceived, and guided the development of the study, and participated in the manuscript preparation and critical reading of the manuscript. All authors have substantially revised the manuscript and approved the submitted version. | PMC10504209 |
Funding | This clinical trial received funding from the Department of Science and Technology—DECIT, Brazilian Ministry of Health (Grant No. 879848/2018). | PMC10504209 | ||
Data availability | The data generated in this study are available upon request from the corresponding author. | PMC10504209 | ||
Declarations | PMC10504209 | |||
Conflict of interest | The authors declare no potential conflicts of interest. | PMC10504209 | ||
References | PMC10504209 | |||
Background | GASTROINTESTINAL DISORDERS | Oral microbial therapy has been studied as an intervention for a range of gastrointestinal disorders. Though research suggests that microbial exposure may affect the gastrointestinal system, motility, and host immunity in a pediatric population, data have been inconsistent, with most prior studies being in neither a randomized nor placebo-controlled setting. The aim of this randomized, placebo-controlled study was to evaluate the efficacy of a synbiotic on increasing weekly bowel movements (WBMs) in constipated children. | PMC10313516 | |
Methods | Sixty-four children (3–17 years of age) were randomized to receive a synbiotic ( | PMC10313516 | ||
Results | Treatment increased ( | PMC10313516 | ||
Conclusions | These findings suggest the potential for (i) multi-species-synbiotic interventions to improve digestive health in a pediatric population and (ii) bioinformatics-based methods to predict response to microbial interventions in children. | PMC10313516 | ||
Impact |
Synbiotic microbial treatment improved the number of spontaneous weekly bowel movements in children compared to placebo.Intervention induced an increased abundance of bifidobacteria in children, compared to placebo.All administered probiotic species were enriched in the gut microbiome of the intervention group compared to placebo.Baseline microbial richness demonstrated potential as a predictive biomarker for response to intervention. | PMC10313516 | ||
Background | nine-strain, constipation | Recent advances in microbiome tools (e.g., culturing, bioinformatics) have enabled a deeper understanding of microbial ecology and the gut microbiome’s role in human health. Gastrointestinal microbes exert functional influence on the host through a range of metabolic and immunological mechanisms, and the host shapes resident microbial communities through diet, nutrition, lifestyle, and medication.Gut microbiota are suggested to influence bowel movement frequency through multiple mechanisms. These include ligand-receptor type interactions with the competitive exclusion of pathogens, generation of antibacterial substances, setting an anti-inflammatory tone to the gut environment, signaling effects that influence the enteric nervous system, and breakdown of fiber to generate short-chain fatty acids that improve gut function.A number of pilot studies have been conducted to identify if microbial therapies can improve the quantity and quality of weekly bowel movements (WBMs). These have included supplementation of live bacteria (i.e., candidate probiotics), ingredients to support the growth of beneficial organisms (i.e., prebiotics), or a combination of the two (i.e., synbiotics). In children, an intake of inulin-type fructans has been associated with softer stool consistencyFor specific strains, there have been statistically significant, beneficial outcomes in human trials.Consequently, there is a need to test in placebo-controlled trials the efficacy of microbial therapies in reducing pediatric constipation and its associated symptoms. Here, we do so in a pilot study to determine the impact of a nine-strain (eight species) synbiotic (a prebiotic and defined microbial consortium) formulation (with the prebiotic comprising mixed-chain length oligosaccharides) on ameliorating constipation. | PMC10313516 | |
Methods | PMC10313516 | |||
Study design and primary objective | The clinical trial was IRB-approved, multicenter, randomized, double-blind, and placebo-controlled with two parallel arms (ClinicalTrials.gov identifier NCT04534036). Following a run-in period of 14 days, subjects were randomly assigned to an intervention and placebo arm for a duration of 84 days. “Constipated” was defined as having fewer than four WBMs, whereas “low WBMs” was a superset of this group, defined as having fewer than five WBMs. The primary objective of the study was to assess the change from baseline to day 84 in the weekly frequency of spontaneous bowel movements between subjects receiving placebo and those receiving a multistrain synbiotic. | PMC10313516 | ||
Randomization and patient selection | A standardized treatment effect of 0.6 in Bristol Stool Form Scale change was estimated. Based on this anticipated treatment effect, a sample size of 43 per arm was needed to achieve 85% power. This number was increased to >100 to account for attrition. In total, 121 healthy male/female subjects were assessed for eligibility (Fig. | PMC10313516 | ||
Randomized, placebo-controlled clinical design. | ADVERSE EVENTS | CONSORT diagram indicating clinical trial design and execution.Cohort characteristics.Allocation, randomization, blocking, and blinding were executed by a Contract Research Organization. 1:1 randomization was done via a computer-generated sequence (with the expectation of normal age distribution in the active and placebo groups) using two strata (male vs. female) and block sizes of 2, 4, and 6. The randomization resulted in 43 subjects in the synbiotic arm and 48 receiving placebo. Parents reported in a logbook the daily frequency and consistency of their child’s stool and any adverse events or use of medications. The subjects were asked to not consume any additional probiotic supplements or foods during the study period. WBMs were reported to the study coordinators twice weekly throughout the 84-day intervention period. While first-dosing was administered in 91 children, 27 children did not complete through day 84. These study participants or their legal guardian(s) received a termination notice upon which clinical product or placebo was returned to the study coordinator for prompt disposal. All data for these non-completing 27 children at baseline were dropped from the analysis and baseline microbiome samples were destroyed. | PMC10313516 | |
Intervention | The interventional composition consisted of 6.2 g of mixed-chain length prebiotic substrates suspended in a single sachet with nine microbial strains (>10 | PMC10313516 | ||
Statistical analysis of clinical data | ADVERSE REACTIONS, REGRESSION | Analyses of clinical outcomes were performed using SASIn relation to WBM frequency, we considered two sub-cohorts as presenting with clinically relevant bowel movement patterns at baseline, defined as children with <4 WBMs and children with <5 WBMs. This second cohort is a superset of the first. In other words, the population of children with baseline WBMs up to 4 WBMs (e.g., including 0, 1, 2, or 3) is referred to as “<4 WBMs” in accordance with the protocol primary outcome definition. The population of children with baseline WBMs up to 5 WBMs (e.g., including 0, 1, 2, 3, or 4) is referred to as “<5 WBMs.”Endpoints assessed were (i) increase of ≥1 WBM from baseline to day 84, (ii) increase of ≥2 WBMs from baseline to day 84, (iii) increase of ≥3 WBMs from baseline to day 84, and (iv) KINDLE quality of life (QOL questionnaire) as a standardized tool to assess adverse reactions and tolerability. We additionally measured if children with >4 WBMs experienced a change in WBM frequency as a function of treatment.Binary endpoints (1, 2, and 3) were analyzed by logistic regression, with adjustment for age and baseline number of WBM. The continuous endpoint 4 was analyzed with covariance (ANCOVA), with adjustment for baseline and age. Cross-tabulations of the three responder endpoints with the treatment provided counts and percentages. Summary statistics were provided for a change in number of WBMs by subject groupings. | PMC10313516 | |
Metagenomic sequencing | HT | Fecal samples were extracted by Diversigen with PowerSoil Pro (Qiagen) automated for high throughput on the QiaCube HT (Qiagen), using Powerbead Pro Plates (Qiagen) with 0.5 and 0.1 mm ceramic beads. Samples were quantified with Quant-iT PicoGreen dsDNA Assay (Invitrogen). Libraries were prepared with a procedure adapted from the Illumina DNA Prep kit (Illumina) and sequenced on an Illumina NovaSeq using paired-end 2×150 reads (Illumina) targeting a mean read depth of at least 4 million reads per sample. | PMC10313516 | |
Diversity and microbiome feature abundance quantification | All shotgun metagenomic sequencing was quality-controlled prior to analysis. We executed all quality control with a combination of bbtoolsAnnotation of microbial taxa, pathways, and gene family abundances was performed using MetaPhlAn3 and HUMAnN3 running the default settings.Shannon and Simpson diversity were computed for each phylogenetic level with the vegan package in R. | PMC10313516 | ||
Quantification and comparisons of bifidogenic and probiotic strain abundance | We next aimed to compute the relative abundances of particular strains of interest in our active versus treatment metagenomes at baseline and endpoint. Specifically, these organisms were (i) microbial strains administered in the active formulation, and, (ii) all members of the We used a portion of Anvi’o’s metapangenomic workflowSpecifically for the | PMC10313516 | ||
Metagenome association study (MAS) on microbiome feature abundances | bloating, pain | REGRESSION, REGRESSIONS | We executed a MAS between microbial feature (i.e., taxon/pathway) abundance and responder status, treatment, bloating, pain, and weekly/change in bowel movements. We looked at associations between these clinical variables and microbial feature abundances at baseline/endpoint where relevant (e.g., we did not compute the association between endpoint microbiome abundances and baseline WBMs). Prior to running the analysis, we took the natural log of all microbiome features and added a fudge factor of 0.00001. We additionally removed features that occurred in fewer than three samples.For binary outcome variables, we used logistic regression adjusted for baseline WBMs and age. For all other regressions (with continuous dependent variables), we used linear regression with a Gaussian link function. The only exception to our adjusting strategy was when baseline weekly WBMs were the outcome variable, in which case we did not include it as an independent variable as well. For each dependent variable, we adjusted for multiple hypothesis correction using the Benjamini–Yekutieli procedure. | PMC10313516 |
Results | PMC10313516 | |||
Synbiotic use increases weekly bowel movements in constipated children compared to placebo | non-constipated | We aimed to estimate the increase in WBMs across the entire cohort, including both constipated and non-constipated individuals. We recruited 121 individuals, 30 of which were excluded prior to the study beginning (see Methods). A total of 64 (33 active and 31 placebo) returned for the day 84 timepoint (Fig. Response rate and analyses of clinical outcomes.* | PMC10313516 | |
Increased abundance of the administered probiotic species in the treatment arm | constipation | We next aimed to investigate microbiome changes as a function of treatment and response to treatment. We received stool samples from 52 individuals at both the baseline and day 84 timepoints. We carried out shotgun sequencing on these samples in an effort to estimate their microbiome composition as a function of treatment and changes in constipation.We queried if the eight microbial species present in the intervention were detectable at greater abundances in the treatment versus the placebo group at the trial endpoint (Fig. | PMC10313516 | |
Limited features are significantly altered in treatment or constipation-associated phenotypes in this study | bloating, pain | REGRESSION | Via a discovery-driven MAS, we aimed to determine if the abundance of specific taxonomies or pathways was altered at baseline versus the endpoint as a function of treatment, bloating, pain, and WBMs. Adjusting for age and baseline WBMs, we used logistic regression to evaluate the association between baseline abundance of each microbiome taxonomic group across phylogenies as well as pathways identified in our sequencing data. We identified substantial heterogeneity in our cohort in these microbial feature abundances, so we only analyzed pathways and taxa that occurred in ten or more samples, yielding a total of 185 taxa and 2213 pathways. Within these, we identified one statistically significant relationship after correcting for multiple hypothesis testing: a decreased abundance of We additionally computed beta diversity between individuals in the treatment group at all phylogenetic levels (using MetaPhlAn3 output) and did not observe clear stratification by treatment status (Supplementary Fig. | PMC10313516 |
Response rate to probiotic treatment is contingent upon species richness | REGRESSION | We next computed alpha diversity using Shannon, Simpson, and taxonomic richness metrics at the phylum, class, order, family, genus, and species levels for all samples. This was done using Wilcoxon tests to compare variation in each of these three metrics between baseline and endpoint for non-responders and responders as well as individuals in the placebo group who both did or did not improve without treatment. Responders were defined as all individuals who received treatment and experienced an increase in WBMs of ≥1. We did not see any association between response to treatment and Shannon or Simpson diversity.However, we found that baseline richness of multiple phylogenetic levels (family, order, class, and phylum, We next stress-tested the ability of richness to discriminate between responders and non-responders using both alternative modeling approaches and a different method for quantifying taxonomic abundance within metagenomes (Kraken2/Bracken as opposed to MetaPhlAn3). We defined responders as individuals who received treatment and experienced an increase in WBMs of ≥1. In addition, to account for potential confounding factors, we tested the association between richness at each phylogenetic level and responder status using a logistic regression approach adjusted for baseline WBMs, sex, and age. The association between responder status and richness was still either significant or trending for all groups ( | PMC10313516 | |
Discussion | constipation | ADVERSE EFFECTS, DISEASE | This placebo-controlled, randomized clinical trial demonstrated that a novel synbiotic formulation increased weekly WBMs in children who had low-frequency WBMs at baseline. We additionally characterized the microbiome in individuals who received and responded to treatment versus those who did not, identifying microbial richness as an indicator of a high likelihood of response to treatment. Only a fraction of studies that evaluate the impact of microbial therapy on human health is executed in a placebo-controlled or randomized setting. While useful in many ways, non-randomized study designs are not able to test a fundamental causal link between treatment and disease. Moreover, high placebo response rates are typically observed in gastrointestinal trials with subjective endpoints due to the potential effects of stress, belief, and other psychosomatic influences on the gastrointestinal system and symptomology.Children with low WBMs at baseline (defined as <4 WBMs) taking the synbiotic experienced a response rate comparable to trials testing the impact of fiber-based and laxative interventions on pediatric constipation. For example, a placebo-controlled recent study on polyethylene glycol reported a response rate of up to 77% and a placebo response rate of 42%.Our cohort had two major drawbacks: (i) like other recent efforts in this field,We also note that defining constipation as <4 WBMs is specific to this study and the clinical trial it represents. While we claim WBMs at frequencies of <4 WBMs are clinically relevant, other definitions of constipation, which include even lower WBMs, do exist.In addition, one further limitation is that our analysis is based on a single nine-strain synbiotic composition administered to children. Patterns of microbial persistence upon use of other probiotic strains, or by populations not present in our study, such as infants, adults, and individuals with preexisting medical conditions warrant further prospective human research. Also, bifidobacterial growth, strain persistence, and correlation with richness cannot be tied to individual strains, dosages, methods of delivery, or any other single feature of microbial therapy.This study expands our knowledge by employing several bioinformatics-based techniques to evaluate the effect of a rationally defined multi-species, multistrain synbiotic in a pediatric population. We found no indication that the intervention adversely affected children and there were no reported adverse effects, increases in symptom severity, or dropouts related to tolerability. Due to the impact of constipation on the overall quality of life, it is encouraging that statistically significant improvements in ≥2 and ≥3 WBMs were found in constipated children, a response that we believe a medical practitioner would consider clinically relevant.We also were able to show that treatment affected individuals’ microbial gene composition. Specifically, in those who received treatment, we observed an increase in specific bifidobacteria, including the persistence of all probiotic species over time. This was observed despite substantial heterogeneity in taxonomic signatures at baseline, and we did not see the same effect in the placebo group.Furthermore, despite limited individual microbial taxa being associated with clinical phenotypes check large, we observed the ability of microbial richness to potentially predict response to treatment across multiple phylogenetic levels, modeling approaches, and taxonomic characterization methods. Shannon and Simpson diversity were not indicative of response. This yields implications for designing future trials related to personalized response based on an individual’s baseline microbiota. We hypothesize that the greater species richness is likely to translate directly into a greater variation of functional traits and depletion of available resources, resulting in the competitive exclusion of exogenous bacteria. Although other groups have reported personalized responses and resistance to microbial therapy, the problem of identifying those individuals with a tractable set of indicators who are most likely to benefit remains open. | PMC10313516 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41390-022-02289-0. | PMC10313516 | ||
Author contributions | B.T.T. led bioinformatic analysis and manuscript drafting without involvement in trial design. C.E.M. and R.D. designed the bioinformatic strategy and participated in data analysis and manuscript drafting. B.P.C. contributed to the manuscript review from a functional assessment and clinical perspective. J.V. contributed to trial conception and text review. E.K. performed bioinformatics data analyses and visualization. G.S. assisted with statistical analysis. M.P. and P.A.B. contributed to data analysis and manuscript review from a prebiotic and probiotic perspective. S.G.P. and N.V. contributed to data interpretation and manuscript review. J.F.P. contributed to the manuscript review with an emphasis on bioinformatic analysis and computational techniques related to microbiome analysis. A.F. contributed to the manuscript review from a pediatric and clinical perspective. G.A.A. contributed to the manuscript review from an informatics perspective. E.A.M. contributed to the manuscript review including pediatric and gastroenterological perspectives. J.B. provided clinical trial operations management and sample processing support. G.R. assisted with study design and manuscript writing. | PMC10313516 | ||
Funding | This work was funded by Seed Health (SH). SH funding contributed towards study design, microbiome sequencing, bioinformatics, and manuscript preparation. | PMC10313516 | ||
Data availability | All software used in this project is available at | PMC10313516 | ||
Competing interests | FOUNDER, APC, BLOOM | B.T.T. and G.S. led data analysis and were not involved in study design or trial execution. R.D. is a co-founder and CEO of Seed Health (SH) and Luca Biologics. J.V., A.F., E.A.M., C.E.M., and J.F.P. are members of the SH Scientific board. SH Scientific board members and employees hold equity positions in SH unless otherwise stated. B.T.T., G.S., N.V., P.A.B., G.R., and E.K. are consultants for SH and were not involved in the microbial synbiotic or clinical trial design. B.T.T. additionally consults for Enzymetrics Bioscience and holds an equity position in SH. S.G.P. and G.A.G. are employed by SH and were not involved in microbial synbiotic or clinical trial design. B.P.C. receives potential royalties from the Rome Foundation for the usage of the modified Bristol Stool Form Scale for Children, which is not used in this study. A.F. is additionally a cofounder and stockholder of Alba Therapeutics, a company developing treatments complementary to the gluten-free diet by exploiting gut permeability. E.A.M. is additionally on the Scientific Advisory Board of Axial Biotherapeutics, Pendulum Therapeutics, Bloom Science, Mahana Therapeutics, APC Ireland, Danone, and Amare. J.F.P. is the Founder and Chief Scientific Officer of Diversigen, Inc. and is on the Scientific Advisory Board for 4D Pharma, PLC. C.E.M. is cofounder of Biotia and Onegevity Health. J.V. is on the scientific advisory boards for Biomica and Plexus Worldwide. | PMC10313516 | |
Consent for publication | Patient consent was required and received for this clinical trial and publication. | PMC10313516 | ||
References | PMC10313516 | |||
Background | migraine, Migraine, migraine-related | DISABLING DISEASE, MIGRAINE, IRON DEPOSITION, MIGRAINE | Migraine is one of the world’s most prevalent and disabling diseases. Despite huge advances in neuroimaging research, more valuable neuroimaging markers are still urgently needed to provide important insights into the brain mechanisms that underlie migraine symptoms. We therefore aim to investigate the regional iron deposition in subcortical nuclei of migraineurs as compared to controls and its association with migraine-related pathophysiological assessments. | PMC10080952 |
Methods | migraine, Headache, Migraine, CM | MIGRAINE, MIGRAINE, IRON DEPOSITION | A total of 200 migraineurs (56 chronic migraine [CM], 144 episodic migraine [EM]) and 41 matched controls were recruited. All subjects underwent MRI and clinical variables including frequency/duration of migraine, intensity of migraine, 6-item Headache Impact Test (HIT-6), Migraine Disability Assessment (MIDAS), and Pittsburgh Sleep Quality Index (PSQI) were recorded. Quantitative susceptibility mapping was employed to quantify the regional iron content in subcortical regions. Associations between clinical variables and regional iron deposition were studied as well. | PMC10080952 |
Results | CM | DISEASE PROGRESSION, IRON DEPOSITION | Increased iron deposition in the putamen, caudate, and nucleus accumbens (NAC) was observed in migraineurs more than controls. Meanwhile, patients with CM had a significantly higher volume of iron deposits compared to EM in multiple subcortical nuclei, especially in NAC. Volume of iron in NAC can be used to distinguish patients with CM from EM with a sensitivity of 85.45% and specificity of 71.53%. As the most valuable neuroimaging markers in all of the subcortical nuclei, higher iron deposition in NAC was significantly associated with disease progression, and higher HIT-6, MIDAS, and PSQI. | PMC10080952 |
Conclusions | migraine, migraine-related dysfunctions | MIGRAINE, IRON DEPOSITION | These findings provide evidence that iron deposition in NAC may be a biomarker for migraine chronicity and migraine-related dysfunctions, thus may help to understand the underlying vascular and neural mechanisms of migraine. | PMC10080952 |
Trial registration | ClinicalTrials.gov, number NCT04939922. | PMC10080952 | ||
Keywords | PMC10080952 | |||
Background
| migraine, Migraine, CM | DISORDER, DISEASE COURSE, PATHOPHYSIOLOGY, MIGRAINE, MIGRAINE, IRON DEPOSITION | Migraine is a highly prevalent disorder that imposes an enormous socioeconomic burden. While patients with chronic migraine (CM) only account for 1.4–2.2% of the general population globally [The pathophysiology of migraine involves both vascular and neural mechanisms [Using non-invasive techniques such as T2-weighted and T2*-weighted MR imaging, the signal reduction caused by iron provides us with an indirect way to visualize iron content. In migraineurs, increased iron deposition has been found in the PAG [With the recent development, quantitative susceptibility mapping (QSM) is a novel post-processing technique to quantitatively assess the magnetic susceptibility of the tissue thus may provide improved image quality for the visualization of the subcortical nucleus [This study aims to use the QSM to comprehensively investigate the brain iron concentration of subcortical brain nuclei in patients with CM and EM as compared to healthy controls. The relationships between iron deposition and disease course as well as functional disabilities were also investigated. | PMC10080952 |
Methods | PMC10080952 | |||
Participants | migraine, obesity, CM | INFECTIOUS DISEASES, OBESITY, HEADACHE DISORDERS, HYPERCHOLESTEROLEMIA, SYSTEMIC DISEASE, CORONARY DISEASE, DIABETES MELLITUS, MIGRAINE, HIGH BLOOD PRESSURE | This study was approved by the local Institutional Review Board, and written informed consents were obtained from all participants. From September 2021 to January 2023, individuals diagnosed with EM or CM according to the International Classification of Headache Disorders, 3rd edition criteria were selected.Patients were recruited based on the following inclusion criteria: (1) age: 18–70 years; (2) confirmed diagnosis is EM or CM; (3) history of migraine greater than 1 year. Subjects were excluded if they were (1) high blood pressure; (2) coronary disease; (3) diabetes mellitus; (4) hypercholesterolemia; (5) infectious diseases; (6) chronic inflammatory conditions and other autoimmune conditions; (7) severe systemic diseases; (8) pregnancy or lactation; (9) obesity (body mass index > 30 kg/m | PMC10080952 |
Clinical assessment | Headache, migraine-related functional disability, headache pain, migraine, Migraine | MIGRAINE, MIGRAINE | All subjects underwent a medical interview including demographic data (age, sex) and personal family histories. For migraineurs, disease duration (measured in years from first symptoms), frequency of migraine attacks per month, migraine days per month, and peak headache pain intensity (measured by visual analog scale (VAS) were registered. The 6-item Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) were performed to measure the degree of migraine-related functional disability, and Pittsburgh Sleep Quality Index (PSQI) was also performed to assess the sleep quality of migraineurs over the past month. | PMC10080952 |
Image Acquisition | All the MR images were acquired using a United Imaging MR790 3.0 T scanner (Shanghai, China). T1 weighted images were acquired with a 3D fast spoiled gradient-echo sequence; the parameters were: TR = 6.9 ms, TE = 2.9 ms, flip angle = 9°, inversion time = 1000 ms, field of view = 256 × 240 mm, voxel size = 1 × 1 × 1 mm | PMC10080952 | ||
Image processing | The QSM images were reconstructed from GRE data using the SEPIA (SuscEptibility mapping PIpeline tool for phAse images) toolbox [The magnitude image, in the same space as the QSM image, was used for registration and was obtained by summing the squares of magnitude images among different TEs. 3D T1, T2, and magnitude images were skull-stripped using BET in FSL. By using citatlaskit (Summarized steps of the pipeline for image preprocessing. The phase images were unwrapped, and the background field was removed with the regularisation-enabled SHARP filtering method. Magnetic susceptibility was quantitatively calculated using MEDI and quantitative susceptibility map (QSM) images were generated. T1, T2, and magnitude images were skull-stripped. By using Advanced Normalization Tool (ANTs), SyN multimodal warping was performed using joint T1 and T2 cost function to transform the high-resolution probabilistic subcortical brain nuclei atlas in CIT168 space to individual space. Eventually, the QSM value of each subcortical nuclei was extracted from each manually refined region of interest (ROI) based on the subcortical nuclei atlas | PMC10080952 | ||
Statistical analysis | migraine, CM | MIGRAINE, DISEASE | Sex was recorded as binary variables. Age, disease duration, migraine attacks per month, disease duration, migraine days per month, VAS, HIT-6, MIDAS, and PSQI were recorded as continuous variables, and one-sample Kolmogorov–Smirnov test was used to check the normality of all continuous variables. Demographics and clinical variable were compared between controls and migraineurs, and between CM and EM using independent samples Analysis of variance (ANOVA) was performed to evaluate the regional difference in iron-related metrics among the three groups. Subsequently, Bonferroni post hoc analysis was applied to analyze the difference between each of the two groups. Partial correlation analysis was conducted to detect the potential relationship between regional iron-related metric and clinical variables in migraine patients, and in patients with CM and EM, respectively. All analyses were adjusted for age and sex. Bonferroni correction for the problem of multiple comparisons in multiple-region level, and to further control for the type I error was performed. A significance level of | PMC10080952 |
Results | PMC10080952 | |||
Regional comparisons of iron-related metric between groups | Significantly higher QSM value was observed in Pu (Iron content (measured by QSM value) distributions in the putamen, caudate, and nucleus accumbens among three groups. * indicates the significant difference ( | PMC10080952 | ||
ROC analysis of the QSM value | After calculation of receiver operating characteristic curves (Fig. Receiver operating characteristic (ROC) curves for iron deposits in nucleus accumbens (NAC). | PMC10080952 | ||
Relationship between iron-related metric and clinical variables | Headache, Migraine | DISEASE, MIGRAINE | In migraineurs, the QSM values of NAC were significantly associated with longer disease duration (Correlation between iron deposits in nucleus accumbens (NAC) and clinical variables in migraineurs. HIT-6, The 6-item Headache Impact Test; MIDAS, Migraine Disability Assessment; PSQI, Pittsburgh Sleep Quality Index | PMC10080952 |
Discussion | neuroinflammation, central pain, migraine-related functional disability, pain, CM, headache-related disability, migraine | MIGRAINE, DISEASE, IRON DEPOSITION | Our study demonstrated that migraineurs had increased iron deposition in Pu, Ca, and NAC than healthy controls. Meanwhile, patients with CM had a significantly higher volume of iron deposits in multiple subcortical brain nuclei including Pu, Ca, NAC, SNc, PBP, and HN compared to EM. Volume of iron in NAC can be used to distinguish patients with migraine from controls with a sensitivity of 72.9% and specificity of 86.8, and CM from EM with a sensitivity of 85.45% and specificity of 71.53%. Moreover, greater iron deposition in NAC was significantly associated with greater migraine burden, as measured by longer disease duration, higher frequency of attacks, more migraine days per month, and higher scores in HIT-6, MIDAS, and PSQI.Although increased iron deposition of subcortical nuclei has been reported in migraine patients, there is a lack of comprehensive subcortical nucleus and systematic comparison. Welch et al. [Repetitive episodes of neuroinflammation and hyperoxia lead to iron redistribution and iron unbalance in migraine patients [Our correlation analysis showed that greater iron deposition in NAC was significantly associated with greater migraine burden, as measured by longer disease duration, higher frequency of attacks, and more migraine days per month, suggesting a relationship between recurring attacks and accumulation of iron [If increased iron concentrations in NAC would play a role in the migraine chronicity, this might theoretically reflect a defective central pain processing system related to dysfunctions in several domains. NAC is located at the junction of the basal nucleus and the marginal system. The outer part of the septum and the inner and lower part of the caudate nucleus are connected to the pre-olfactory nucleus, and the ventral side is the ventral pale sphere and olfactory nodules. NAC plays important role in reward and punishment mechanisms, but studies on NAC and migraine are limited. The current study found that increased iron deposits in NAC were also associated with a higher level of migraine-related functional disability, as measured by HIT-6 and MIDAS, which are both widely accepted measures to assess headache-related disability and its impact on quality of life. As a key node of neural circuits projecting to multiple pain structures and mediating motivated behaviors [In addition, increased regional iron deposits of NAC were associated with worse sleep quality in migraineurs. Migraineurs usually have worse sleep quality than non-migraineurs [ | PMC10080952 |
Limitations | depression | Despite the novelty of the current study, this prospective study is still prone to several limitations. One important limitation is the fact that our results are based on cross-sectional observation, longitudinal data are needed to justify a such conclusion. Second, the current study included patients across a wide age range. While this approach allowed us to observe for a diverse sample of migraineurs regardless of age, it also limited our ability to draw conclusions about age-specific effects and their associated comorbidities. For instance, elderly patients are usually more prone to depression [ | PMC10080952 | |
Conclusions | migraine, disability, migraine-related disability, CM | PATHOPHYSIOLOGY, DISEASE, MIGRAINE, IRON DEPOSITION | In conclusion, we have successfully demonstrated that there is an increased iron deposition in multiple subcortical nuclei, especially NAC, in patients with CM, and the regional iron accumulation level in NAC could be used to distinguish CM patients from EM. More importantly, the increased iron deposition in NAC was associated with higher disease burden, higher migraine-related disability, and worse sleep quality, suggesting a potential role as a neuroimaging marker to track patient disability and aid in the monitoring of treatment regime. These results provided further evidence for future research efforts to understand the underlying vascular and neural mechanisms behind the pathophysiology of migraine. | PMC10080952 |
Acknowledgements | We thank all migraineurs and their families who were involved in this study. | PMC10080952 | ||
Authors’ contributions | RECRUITMENT | XXP and LKM designed the study. XXP wrote the first draft of the manuscript. XXP, ZMT, and WX collected the clinical and MRI data. ZFL, HJH, and CHR assisted with patient recruitment. LX, LKC, ZQZ, GXJ, HPY, ZMM, and LKM assisted with the research design. All authors contributed to the final manuscript. All authors read and approved the final manuscript. | PMC10080952 | |
Funding | This study was supported by the National Natural Science Foundation of China (Grant No. 82001766). | PMC10080952 | ||
Availability of data and materials | The data that support the findings of this study are not publicly available due to privacy or ethical restrictions. Data are however available from the corresponding authors upon reasonable request and with permission after the completion of the study. | PMC10080952 | ||
Declarations | PMC10080952 | |||
Ethics approval and consent to participate | The experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Human Research Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine (IRB2021001248). Written informed consent was obtained from individual or guardian participants. | PMC10080952 | ||
Consent for publication | Not applicable. | PMC10080952 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10080952 | ||
References | PMC10080952 | |||
Background | depression, anxiety | Repetitive negative thinking (RNT) is a key transdiagnostic mechanism underpinning depression and anxiety. Using “just-in-time adaptive interventions” via smartphones may disrupt RNT in real time, providing targeted and personalized intervention. | PMC10753417 | |
Objective | depression, anxiety | This pilot randomized controlled trial evaluates the feasibility, acceptability, and preliminary clinical outcomes and mechanisms of Mello—a fully automated, personalized, transdiagnostic, and mechanistic smartphone intervention targeting RNT in young people with depression and anxiety. | PMC10753417 | |
Methods | heightened depression, anxiety | Participants with heightened depression, anxiety, and RNT were recruited via social media and randomized to receive Mello or a nonactive control over a 6-week intervention period. Assessments were completed via Zoom sessions at baseline and at 3 and 6 weeks after baseline. | PMC10753417 |
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