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5. Conclusions | ADHD | VASCULAR INFLAMMATION | This exploratory study revealed that persons with ADHD, especially children on ADHD medication, have higher-than-normal pro-inflammatory sICAM-1 and sVCAM-1 and lower SCFA levels in plasma and that children with ADHD also have higher levels of additional pro-inflammatory markers, e.g., IL-12/IL-23p40 and IL-2Rα. Treatm... | PMC10004766 |
Supplementary Materials | The supporting information can be downloaded at: Click here for additional data file. | PMC10004766 | ||
Author Contributions | Conceptualization, C.L. and L.L.Y.; Methodology, L.L.Y., M.S. (Miranda Stiernborg) and C.L.; Software, L.L.Y. and M.S. (Miranda Stiernborg); Validation, L.L.Y., J.X., Y.W., I.A.N. and R.L.; Formal Analysis, L.L.Y. and M.S. (Miranda Stiernborg); Investigation, L.L.Y., J.X., Y.W., R.L. and C.L.; Resources, E.S., K.K., S.... | PMC10004766 | ||
Institutional Review Board Statement | The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Review Board in Stockholm (protocol code 2015/884-31 and 2017/91-31 and date of approval 24 July 2015 and 23 February 2017). | PMC10004766 | ||
Informed Consent Statement | Written informed consent was obtained from all subjects involved in the study. | PMC10004766 | ||
Data Availability Statement | Restrictions apply to the availability of these data. Data are available from the corresponding author with the permission of the Swedish Ethical Review Authority. | PMC10004766 | ||
Conflicts of Interest | The authors declare no conflict of interest in relation to the work described. | PMC10004766 | ||
References | inflammation, ADHD | ACUTE INFECTIONS, INFLAMMATION | Immune activity marker level comparisons between adult healthy controls and adult ADHD patients: Y-axes represent analyte levels. The differences between groups were analyzed using nonparametric Mann–Whitney U test, and FDR-adjusted Differences in immune activity marker level between children and adults with ADHD at ba... | PMC10004766 |
Background | Breastfeeding should begin as soon as possible after birth and continue exclusively to 6 months of age. In Vietnam, as in many other countries, breastfeeding is decreasing because of modern lifestyles and the promotion of infant formula. It is important to provide mothers, family members, and the community with the kno... | PMC9854088 | ||
Methods | We used a four-step mixed methods approach with a literature review, formative research (22 in-depth interviews and 49 self-administered online questionnaires), and testing of prototype apps (3 focus groups discussion and external experts). Formative research and focus group discussion involved 99 participants. Finally... | PMC9854088 | ||
Results | Mothers were mostly concerned about the initiation of breastfeeding, preventing and reducing difficulties encountered during breastfeeding, and nutrition for breastfeeding mothers. Mental health and well-being in the postnatal period are also concerns. Three key features to be included in the app were identified from t... | PMC9854088 | ||
Conclusion | The development of the app followed a best practice approach, including the involvement of stakeholders and grounding in behavior change theory. The next step is to evaluate the effectiveness of the BeBo mobile app in a well-conducted randomized controlled trial. | PMC9854088 | ||
Trial registration | ACTRN12619000531112. | PMC9854088 | ||
Keywords | PMC9854088 | |||
Background | Vietnam is a middle-income country in Southeast Asia with a population estimated at 96.9 million inhabitants, with 35% living in urban areas [Breastfeeding rates are influenced by many factors related to both the family and the community. Mothers are central to breastfeeding and their decisions have the most influence ... | PMC9854088 | ||
Methods | PMC9854088 | |||
Study overview | MAY | We developed a prototype mHealth app, which we named BeBo, which is targeted toward Vietnamese mothers to increase breastfeeding rates. The name “BeBo” was selected as it mimicked infant babbling and baby jargon. We then designed a two-arm, parallel triple-blinded randomized controlled trial to evaluate the effectivene... | PMC9854088 | |
App development process | MOHR | The BeBo team was composed of researchers and practitioners in health promotion, breastfeeding, infant nutrition, and maternal and child health care with experience in developing infant feeding guidelines from both Vietnam and Australia together with a software developer and a designer. The team had weekly meetings ove... | PMC9854088 | |
Step 1. Identify the determinants of breastfeeding and expectation on the app | PMC9854088 | |||
Online survey on app features and contents | We sent an online survey link through a Facebook page to the contacts of a young researcher aged in her 30s, who was likely to have contact with the infant’s mothers. A total of 49 mothers and fathers responded to the survey. A questionnaire included information on the characteristics of respondents, time for installin... | PMC9854088 | ||
In-depth interviews with mothers | We conducted 22 in-depth interviews with mothers to explore the facilitators and barriers of breastfeeding. Mothers were asked to describe their feeding experience since they delivered the child. The interview’s guidelines were about what kind of food they feed to the child since birth, how they selected the feeding me... | PMC9854088 | ||
Step 2. Prototype development | We began the prototype development after completing the analysis of the results from the online survey and the 22 in-depth interviews. Regarding the app functions, we outlined desired functions which included pushed notifications, library content, and the mechanism for a triple–blinded controlled trial. We also created... | PMC9854088 | ||
Messages or push notifications | BSE | We applied self-efficacy theories for developing behavior change messages because the intervention of the mobile app was more focused on individual approaches. Maternal breastfeeding self-efficacy (BSE) is reflective of a mother’s confidence in breastfeeding and is a modifiable factor [ | PMC9854088 | |
Library information | BSE | Library information was developed based on the framework for messages and the Dennis BSE Scale [ | PMC9854088 | |
Step 3. Pre-test the designs, notifications, and library contents | PMC9854088 | |||
Focus group discussions | After developing the prototype, we conducted three focus group discussions to elicit feedback regarding the designs, push notifications, and library contents and made modifications accordingly before usability testing.The three focus group discussions with mothers at 24–36 weeks gestation (18 mothers) were held for tes... | PMC9854088 | ||
Experts review library contents | The library contents were internally reviewed by three Vietnamese researchers who were the team members. We also invited five external reviewers who were health promoters and counselors on nutrition and breastfeeding to comment on the library content. Two of them were from the two hospitals, one from an international n... | PMC9854088 | ||
Step 4. Prototype testing | Among people who had a smartphone in Vietnam, 41.1% use the iOS platform, and 57.5% use the Android platform. BeBo was developed to work on the iOS platform version 11 and Android platform version 7 or upper which covered 92.4% of iOS and 77.3% of Android users, respectively [ | PMC9854088 | ||
Statistical analysis | PMC9854088 | |||
Quantitative data | A descriptive analysis was conducted using SPSS software (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp). The percentage was used to summarize binary variables and mean ± standard deviation to summarize the score variables. All variables were internally consistent in scale... | PMC9854088 | ||
Qualitative data | All interviews and discussions were recorded and transcribed to text using Word. Two researchers coded the transcripts independently and sought a mutual agreement on the main themes used in the content analysis. | PMC9854088 | ||
Results | PMC9854088 | |||
Step 1. Determinants of breastfeeding and expectation on the app | PMC9854088 | |||
Online survey on app features and contents | The majority of 49 respondents (7 fathers and 42 mothers) were from Hanoi (74%), where the study was conducted. They all had children under 5 years old. | PMC9854088 | ||
Time to install the app | 81% wanted to install the app during pregnancy, and 17% wanted to have it after delivery. | PMC9854088 | ||
Desired app functions | EVENTS | Respondents preferred the app which helped to monitor child development, send notifications, and remind of upcoming events, had information on maternal and child care, and the ability to search for needed information. Posting questions, sharing information, discussing, or receiving notifications on those posts were les... | PMC9854088 | |
Frequencies of receiving push notifications | Equal proportions (33%) of participants wanted to receive push notifications daily or 2–3 times per week and only less than a quarter of participants would prefer to receive push notifications once a week (22%). | PMC9854088 | ||
Content of push notifications | Each notification should contain a piece of information, the more information the better (63%). Receiving repeated messages every 4 weeks was selected by nearly one-third of the participants (33%).After discussion within the research group, we decided to design and install the app for mothers during a pregnancy instead... | PMC9854088 | ||
Information preferences | weight gain, breast milk | The preferred information was divided into three groups: maternal care, child care, and breastfeeding. For maternal care, participants were keen to receive information on mental health, birth preparation, nutrition, and living with their parents-in-law rather than monitor the gestational weight gain during pregnancy or... | PMC9854088 | |
Qualitative research findings | Among 22 participants, three mothers were pregnant with their second child, 5 had a child aged under 6 months, 5 had a child aged 6–12 months, and 9 had a child over 12 months. About 7 of 22 mothers had exclusively breastfed, 12 had both breastfeeding with additional formula feeding and three had used infant formula on... | PMC9854088 | ||
From mothers | milk, fever, breast milk, panic, pain, tiredness, mastitis, shivering | MASTITIS | Early initiation of breastfeeding was the most difficult for mothers, particularly among those who had a cesarean delivery. Someone else (grandparents, fathers, health care workers) took care of their newborn while mothers often found the milk did not “come in” in the first days.
“I had a cesarean section. There was no... | PMC9854088 |
From family members | SAID | The husband could help his wife in preparing food, cooking, and clean for the baby. However, most of them did not have a preference for either breastfeeding or infant formula and seemed to follow the mother’s or grandparent’s decision. Messages which focused on, or emphasized the love between the father–newborn and hus... | PMC9854088 | |
Step2. The design, function, and content of the app | We used results from the literature review and the formative research above to identify and design the app functions. | PMC9854088 | ||
2a. App function and design | Being simple and easy to use and the ability to function without internet access were important criteria for the app functions.The app function included (a) push notifications: a short message service (SMS) system to continue delivering information to mothers about target behaviors and encourage them to use the app; (b... | PMC9854088 | ||
Interface design | This theme refers to the design and layout, including consistency, location of icons, functions on each screen, font, color, density, placement, and images [Home screen and notifications log | PMC9854088 | ||
Push notifications | tetanus | TETANUS | The notifications conveyed messages on targeted behaviors. Users could tap the messages to open the related thread in the library information. Messages were designed to be re-readable at any time in the app [During pregnancy, the notifications were re-sent after every 4 weeks to make sure participants received a full s... | PMC9854088 |
Library information | Each message was linked with one piece of information in the library (a thread). They were repeated every 4 weeks but the information in threads was different to provide more information and keep the mother reading. Each thread contained the message, the title of the thread related to the messages, a picture to illustr... | PMC9854088 | ||
The design of the triple–blinded controlled trial | The design of the triple–blinded controlled trial is shown in Fig. The data collector interviewed mothers using Research Electronic Data Capture (REDCap) and each mother was given a unique identifying number.RegistrationThe data collector team downloaded and installed the app and then launched the app for the first tim... | PMC9854088 | ||
2b. Design content of the app | PMC9854088 | |||
Messages or push notifications | BSE | We first identified target behaviors, then key determinants, and applied BSE theories for developing the messages and library content (Table Example of the framework for developing messages | PMC9854088 | |
Library information | Findings from the literature review and formative research were used as a guide to identify the content needed in the library. For example, we included information on managing a crying child [Most of the messages and library content highlighted the ability to have early initiation of breastfeeding and exclusive breastf... | PMC9854088 | ||
Step 4. Internal review, prototype testing, and revision of the app | MINOR | Modifications were made based on focus group feedback. Prototype testing to detect errors was conducted before the app went live. A total of eight iOS and five Android beta versions had been tested and revised. Some major errors were fixed including unable to install the app, unable to activate the app, search the algo... | PMC9854088 | |
Discussion | We developed the BeBo App using both the behavioral intervention technology model for developing the app and the steps for developing and pretesting a text messaging program for health behavior change. | PMC9854088 | ||
App function | The app is relatively simple with text messages and library information. Another app developed for increasing breastfeeding among African Americans had almost the same technological components and had above-average usability [We understand that the interactive app feature is of interest and may increase engagement. How... | PMC9854088 | ||
App content | A recent study found that the majority of the websites and apps on infant feeding were of poor quality and lacked evidence-based content [ | PMC9854088 | ||
Messages to promote exclusive breastfeeding | depression, anxiety | Our findings on the determinants of breastfeeding were similar to previous studies in Vietnam. Mothers are aware of the need for breastfeeding [The desire to breastfeed and be a ‘good mother’ could create anxiety and stress for mothers who have found it difficult. A study in Vietnam reported that a mother who had highe... | PMC9854088 | |
Limitations | There are several limitations to be considered with this project. The link to the online survey provided a sample of mothers who had a higher level of education and who lived in an urban environment. These respondents may not be typical of the general population. We used semi-structured questions to guide focus group d... | PMC9854088 | ||
Authors’ contributions | Conceptualization, C.B., and A.L.; methodology, C.B., A.L., Y.Z., T.P.H.D., T.T.H.B, T.T.D.D, and N.M.P.; app development, T.T.C., X.H.N., T.T.D.D., and N.M.P; randomization, C.B., A.L., Y.Z., and N.M.P; investigation, C.B. T.P.H.D.; writing—original draft preparation, review and editing T.T.D.D.; writing—review and ed... | PMC9854088 | ||
Funding | This research was funded by a grant from the Vietnam National Foundation for Science and Technology Development (NAFOSTED) and the National Health and Medical Research Council of Australia under grant number NHMRC.108.03–2018.09. | PMC9854088 | ||
Availability of data and materials | The datasets used are available from the corresponding author upon reasonable request. | PMC9854088 | ||
Declarations | PMC9854088 | |||
Ethics approvals and consent to participate | The study protocol has been approved by the Curtin Human Research Ethics Committee (Ref: HRE2019–0143-03) and the Ethical Review Board for Biomedical Research, Hanoi University of Public Health (Ref: 28/2019/YTCC-HD3). The trial’s registration number is ACTRN12619000531112. We obtained a written consent form from all p... | PMC9854088 | ||
Consent for publication | Not applicable. | PMC9854088 | ||
Competing interests | The authors declare that they have no competing interests. | PMC9854088 | ||
References | PMC9854088 | |||
Subject terms | Alzheimer’s disease | DISEASE | In Alzheimer’s disease, the spread of aberrantly phosphorylated tau is an important criterion in the Braak staging of disease severity and correlates with disease symptomatology. Here, we report the results of TANGO (The authors present the results of a phase 2 study of gosuranemab, a monoclonal antibody targeting N-te... | PMC10724064 |
Main | Alzheimer’s disease, AD, primary tauopathies, neurodegenerative disease | NEURODEGENERATIVE DISEASE | Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a high unmet needGosuranemab is a humanized immunoglobulin G4 monoclonal antibody to N-terminal tauThe safety, efficacy, pharmacokinetics and pharmacodynamics of gosuranemab have been evaluated in previous clinical trialsHowever, because AD is pat... | PMC10724064 |
Results | PMC10724064 | |||
Participants | RECRUITMENT | A total of 654 participants were randomized (updated from the preplanned 528 participants due to overenrollment caused by fast recruitment) to one of four groups (650 participants were dosed): placebo ( | PMC10724064 | |
Secondary endpoint results for cognitive and functional measurements (CDR-SB) | SECONDARY | No significant difference in the CDR-SB score (a secondary endpoint) was observed between the gosuranemab groups and the placebo group. The difference between the treated groups and the placebo group at week 78 was –0.01 ( | PMC10724064 | |
Secondary endpoint results for immunogenicity | The incidence of treatment-emergent anti-gosuranemab antibody responses was low at all time points and similar between all gosuranemab dose groups and the placebo group. One participant in the intermediate-dose group (1.0%) and four participants in the placebo group (1.9%) had a positive treatment-emergent anti-gosuran... | PMC10724064 | ||
Exploratory endpoints: other key efficacy outcomes (cognitive and functional analyses) | In one exploratory endpoint, the change from baseline in the 13-item Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog13) score at week 78, patients in the high-dose gosuranemab group performed statistically significantly worse than those in the placebo group (Extended Data Fig. | PMC10724064 | ||
Exploratory endpoints: CSF biomarkers | A robust decrease in the CSF levels of unbound N-terminal tau compared to baseline was observed in all gosuranemab groups but not in the placebo group, confirming target engagement of gosuranemab (Fig. | PMC10724064 | ||
Exploratory endpoint: tau PET neuroimaging | No significant differences were observed between the gosuranemab and placebo groups ( | PMC10724064 | ||
Post hoc analysis of the aborted LTE period | SAEs | The LTE period of the study was terminated early owing to the lack of efficacy demonstrated upon readout after the placebo-controlled period. Data from the LTE period were analyzed up to week 104, during which the sample size was still substantial (the Long-term exposure to gosuranemab was well tolerated by the partici... | PMC10724064 | |
Effect of COVID-19 | Despite the COVID-19 pandemic, most participants received 16–20 of 20 infusions during the placebo-controlled period ( | PMC10724064 | ||
Discussion | AD | SEPARATION, SECONDARY, PATHOLOGY, DISEASE PROGRESSION | The TANGO study evaluated the safety and efficacy of gosuranemab in patients with AD. The participants tolerated gosuranemab well at all doses evaluated, and the safety outcomes were consistent with those reported in previous studies. However, no dose produced a favorable separation from placebo on a secondary endpoint... | PMC10724064 |
Methods | The full trial protocol and statistical analysis plan can be downloaded at | PMC10724064 | ||
Study overview | AD, MCI | DISEASE | This randomized, parallel-group study consisted of a 78-week double-blind, placebo-controlled phase and a subsequent dose-blind LTE phase. Enrolled participants were randomized (1:1:2:2) to one of four treatment arms: (1) low-dose gosuranemab (participants in this group were subsequently randomized 1:1 to receive eithe... | PMC10724064 |
Eligibility criteria | Alzheimer’s Association criteriaThis study, decline in memory function, MCI, AD dementia | DER, POLAND | Participants were adults aged 50–80 years who had exhibited a progressive decline in memory function for >6 months before screening and had been diagnosed with either MCI due to AD or mild AD dementia according to National Institute on Aging–Alzheimer’s Association criteriaThis study was conducted in accordance with th... | PMC10724064 |
Biomarker substudies | Participants were assigned to either a tau PET substudy (based on the geographical availability of the tau PET radioligand) or a CSF substudy. Participants assigned to the tau PET substudy were provided the option to also participate in the CSF substudy (participants enrolled in both substudies were considered enrolled... | PMC10724064 | ||
Primary and secondary endpoints | SECONDARY | For the placebo-controlled period of this study, the primary endpoint was the incidence of AEs and SAEs. The secondary endpoints were (1) the change in the CDR-SB score from baseline over time at week 78, and (2) the incidence of anti-gosuranemab serum antibody responses over time up to week 90. | PMC10724064 | |
Exploratory endpoints | Key exploratory endpoints included (1) the change from baseline at week 78 in the ADAS-Cog13, MMSE, ADCS-ADL and FAQ scores; (2) the change from baseline in the CSF levels of unbound N-terminal tau; (3) the change from baseline in tau levels as measured by CSF testing (that is, t-tau, p-tau181) and tau PET; and (4) the... | PMC10724064 | ||
Post hoc analyses for the LTE period | The primary endpoint for the LTE period in this study was the incidence of AEs and SAEs over the placebo-controlled and LTE periods. Analyses of key exploratory endpoints included continued assessment of the efficacy endpoints from the placebo-controlled period, such as CDR-SB, ADAS-Cog13, MMSE, ADCS-ADL and FAQ scores... | PMC10724064 | ||
Sample size | AD, MCI | SECONDARY | No formal sample size calculation was performed for the primary safety endpoint. Sample size calculation was based on the multiple comparison procedure—modeling approach. A sample size of 528 participants was planned to provide approximately 80% power to detect a dose–response relationship in the change from the baseli... | PMC10724064 |
Statistics and reproducibility | DISEASE, INFUSION REACTION, SECONDARY | Statistical analyses were performed using SAS version 9.4. The analyses were performed by one statistical programmer, and the results were independently programmatically checked by a second statistical programmer and reviewed by two statisticians. The prespecified unblinded analysis was performed at the completion of t... | PMC10724064 | |
COVID-19 | Measures were taken to mitigate risks caused by the COVID-19 pandemic and to circumvent issues related to site closures. Flexibility in site-visit scheduling was allowed, and all resulting protocol deviations had to be reported under the specific category of COVID-19-associated deviations. When in-person visits were no... | PMC10724064 | ||
Reporting summary | Further information on research design is available in the | PMC10724064 | ||
Supplementary information |
Study protocol and statistical analysis plans for the placebo-controlled and LTE periods.Reporting SummaryADAS-Cog13 results in the placebo-controlled and LTE periods. Analysis was performed using a mixed model for repeated measures with data from the placebo-controlled and LTE periods. Analyses were two-sided at a 5%... | PMC10724064 | ||
Source data |
Statistical source data.Statistical source data.Statistical source data.Statistical source data.Statistical source data.Statistical source data.Statistical source data.Statistical source data. | PMC10724064 | ||
Extended data | PMC10724064 | |||
Longitudinal changes on secondary efficacy assessments from baseline to week 78. | Adjusted mean change from baseline (±SE) up to week 78 on the (
| PMC10724064 | ||
Longitudinal changes in the FAQ score from baseline to week 78. | Adjusted mean change from baseline (±SE) up to week 78 on FAQ score. A greater positive change indicates worsening of symptoms. Sample sizes for each group at each time point are listed for each panel. Analyses were two-sided at 5% significance level. No adjustments were made for multiple comparisons.
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Adjusted mean change in tau PET SUVR from baseline to week 78. | Adjusted mean change from baseline (±SE) in tau PET SUVR in brain regions corresponding to (
| PMC10724064 | ||
Extended data | is available for this paper at 10.1038/s43587-023-00523-w. | PMC10724064 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s43587-023-00523-w. | PMC10724064 | ||
Acknowledgements | We thank all participants and their companions who participated in the TANGO study, as well as the investigators and their staff who conducted the trial. This study was sponsored and funded by Biogen Inc. Medical writing and editorial support was funded by Biogen Inc. and provided by Nucleus Global in accordance with t... | PMC10724064 | ||
Author contributions | M.S., J.K. and J.O’G. had full access to all study data and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: D.G., E.R., R.R., E.H. and S.B.H. Study supervision and oversight: M.S., J.K., J.O’G., E.R., R.R., L.V., E.H., A.M.R., J.C., Y.L., H.H. and S.B.H. Acqu... | PMC10724064 | ||
Peer review | PMC10724064 | |||
Data availability | The trial results are publicly available at ClinicalTrials.gov ( | PMC10724064 |
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