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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. Treatment with Synbiotic 2000, compared to placebo, reduced IL-12/IL-23p40 levels and suggestively reduced sICAM-1 and IL-2Rα levels in children. Synbiotic 2000 also suggestively increased propionic acid levels, which, together with highly associated formic and acetic acid levels, in turn, correlated negatively with sICAM-1 and sVCAM-1 in the children and protected against IL-1β-induced sICAM-1 expression in vitro. This suggests that Synbiotic 2000, in children with ADHD, reduces markers of intestinal and vascular inflammation, the latter in part through increasing SCFA levels. The findings warrant further studies to determine if persons with ADHD would benefit inflammation-wise from dietary intake of Synbiotic 2000 or a similar synbiotic. | 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.A., R.L., M.G. and C.L.; Data Curation, L.L.Y., R.L. and C.L.; Writing—Original Draft Preparation, L.L.Y.; Writing—Review and Editing, primarily L.L.Y. and C.L.; and all authors revised a late version; Visualization, L.L.Y. and C.L.; Supervision, V.M. and C.L.; Project Administration, C.L.; Funding Acquisition, C.L. and L.L.Y. All authors have read and agreed to the published version of the manuscript. | 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 baseline. Confidence intervals (CIs) for treatment effects of Synbiotic 2000, compared to placebo and adjusted by sex, on immune activity marker levels. CIs were from analysis of covariance models for (SCFA level comparisons at baseline (Confidence intervals (CIs) for treatment effects of Synbiotic 2000, compared to placebo and adjusted by sex, on SCFAs. CIs were from analysis of covariance models among (Correlation analysis between levels of immune activity markers and SCFAs in ADHD. Spearman’s rank correlation coefficients for (Summary of the findings.Characteristics at baseline of participants with ADHD.Two persons were excluded from the study because of suspected acute infections based on high CRP (above 15 mg/mL) or SAA (above 10 mg/L) levels. No other person analyzed in this study had an obvious acute inflammation (their CRP levels were <15 mg/L). Results are given as median (25 | 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 knowledge and strategies to improve breastfeeding rates. Smartphones are almost ubiquitous in Vietnam and of the potential to provide information about breastfeeding. This study aimed to document the process of designing and developing a mobile app to increase breastfeeding rates in Vietnamese women. | 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, the revisions of the app were tested. All of the formative research was undertaken in Hanoi in 2019–2020. Target behaviors followed by key determinants, to improve breastfeeding self-efficacy were studied and this information was then applied in developing the messages and library content. Barriers and facilitators to breastfeeding were identified from literature reviews and qualitative research. The messages were targeted at not only mothers but also included fathers, mothers-in-law, or families. | 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 the formative research: (1) notifications; (2) an information library; and (3) a searching function. The research found that the app should be installed during pregnancy rather than after delivery (81% vs 17%, respectively). Notifications that convey breastfeeding messages should be sent 2–3 times per week. | 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 on initiating and maintaining breastfeeding [Recent successful interventions using mobile technologies have been shown to improve exclusive breastfeeding through appropriate mobile Health (mHealth) applications in high-income and other Asian countries [The popularity of smartphones in Vietnam provides an opportunity for implementing mHealth interventions, particularly in urban areas with 146 million mobile phone connections (150% of the population), and 68 million internet users (70% of the population) [In this paper, we describe the development of a mHealth app optimized to improve breastfeeding rates in urban areas in Vietnam. Based on our research and results, we suggest processes and recommendations for developing and evaluating mHealth apps adapted for use in low- and middle-income countries. | 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 effectiveness of the “BeBo” app. Details of the study protocol have been published [Data were collected in Hanoi from May 2019 to March 2020. | 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 over the internet to review the development of the intervention.The development process was adapted from the behavioral intervention technology model to ensure replicability [Establishing the intervention aims (WHY): (a) to increase breastfeeding rates (b) be able to evaluate its effectiveness in improving breastfeeding rates through a randomized controlled trial.Selecting behavioral strategies to improve knowledge of mothers and aid shared decision (HOW): (a) to improve knowledge and enhance breastfeeding self-efficacy among mothers, (b) to promote shared information and involvement in decision-making on exclusive breastfeeding to family members and healthcare providers.Designing app elements to deliver selected behavioral strategies (WHAT): We identified the main messages delivered in form of push notifications. This element was the most important part of the success of the intervention [Defining when and under what conditions the app would be used (WHEN): time for installing the app, frequency and timing for generating push notifications, and expected information in the library content.Combining both the behavioral intervention technology model for developing the app [Process for developing BeBo mobile app, adapted from Mohr and Abroms [ | 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 installing the app, desires for app functions, information on maternal and child health care, and breastfeeding. The preferences for information on maternal and child health care were scored from 1 to 3, in which, 1 was the lowest and 3 was the highest. Data were collected using the Qualtrics system (Qualtrics, Provo, UT). | 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 method, what made them select or change, their perception of the benefits of breastmilk and breastfeeding, challenges they meet during breastfeeding, and kind of supports they received during breastfeeding. The belief and practices on post-birth rituals to infant feeding which included solid food introduced were also asked.Mothers who visited the two hospitals involved in the study were invited to participate in the interviews. To capture the widest range of perspectives possible, mothers were screened using a set of questions on the age of the child (less than one or more than 1 year old), experience with breastfeeding (exclusive breastfeeding or mixed with formula feeding), and mode of delivery (vaginal or cesarean while they waited for a health check-up in the hospital. Mothers were selected to ensure a variety of socio-economic groups and experiences and were invited for in-depth interviews after finishing their health check-ups. Interviews were undertaken either in the hospitals or the cafeteria nearby, the location chosen by the mothers. Each in-depth interview lasted 45–60 minutes. Selection processes and interviews were conducted by a researcher who had public health background and was experienced in qualitative study. After every four to five interviews, the researcher summarized the main themes and discussed with the team for selecting new mothers and revising questions’ guidelines until the information was saturated. | 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 visual mock-ups with interface design reviewed by team members and revised. We selected target behaviors, identified key determinants of the behavior, and then mapped the push notifications to develop library content. | 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 testing the app designs and messages for the intervention group in both hospitals, both primiparas and multiparous mothers. We asked mothers to score each message from 1 (the lowest) to five (the highest) in terms of their preferences. The messages were categorized into four groups (1) Believing breastmilk is the best option for newborns until 6 months (benefits of breastmilk/colostrum to newborn, to mothers, (2) belief in having enough breastmilk for the baby; (3) involving husband, grandmothers, and healthcare providers support for exclusive breastfeeding, and (4) planning for breastfeeding exclusively.User-friendliness of the messages, perceived relevance of messages, trust in messages, understanding of messages, and new information learned were guided for discussion after ranking [Focus group discussions were undertaken in person by a Vietnamese team member who was working on maternal and child health with experience in both quantitative and qualitative research. | 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 non-government health organization, one from the Ministry of Health, and one from the Hanoi University of Public Health. All of them had at least 5 years of experience in their work. | 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 directions, e.g., 1 = lowest, 3 or 5 = highest. A higher mean indicates a more accentuated level of concern or preference. | 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 less preferred. Some other functions were suggested such as liking the app with clinics/hospitals for pregnant care or child care or searching nearby pediatrics hospitals, receiving counseling from experts, music for mothers and newborns, etc. | 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 of after delivery as originally planned. Push notifications were auto-generated three times per week during pregnancy and two times per week after delivery. Notifications were repeated every 4 weeks to make sure all mothers received the messages before delivery. | 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 have sex during pregnancy. For child care, participants liked the information on the management of child health during illness, immunization, and monitoring an infant’s progress rather than on feedings. During breastfeeding, mothers asked about nutrition for mothers, issues related to breastfeeding, and difficulties rather than expressing and storing breast milk or infant formula. | 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 only. Ten mothers had a vaginal delivery and the remainder had a cesarean delivery. | 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 skin-to-skin contact. The doctors took the baby out of the operating room and bring to her grandmother. After the operation, I was alone in a postnatal room for the whole day. On the second day, I was in pain and could not move, I did not have any drops of milk, and I could not sit up. So, grandmothers took care of her and gave her only bottles”. (0304Text2).When milk had “come in”, mothers had a lack of knowledge and experience in dealing with difficulties during breastfeeding and often turned to an easier option of formula feeding with support from family members.“On day 10th, I had a fever, I didn’t know it was mastitis at that time. I could not express milk much. It was so painful. I clicked my tongue: “let’s feed her with formula, I don’t have much milk, she is hungry and crying. Pumping causes soreness in nipples, tiredness, shivering, and fever but not much milk is extracted”. So, I did not eat much, and ran out of milk after 20 days. I fed my baby with formula completely since then”. (0904Text4).Some examples of difficulties during breastfeeding were their infant not focusing on breastfeeding, both playing and sucking at the same time, prolonged time taken for breastfeeding compared with bottle feeding; a child sleeping while breastfeeding, which did not happen with bottle feeds; a child ‘demanding’ feeds too often and the mother didn’t get enough sleep at night and breastfeed refusal. Mothers were also stressed and blamed themselves as “bad mom” when breastmilk was not yet ejected or not enough, newborns gained no weight, etc. Good preparation and planning for breastfeeding during pregnancy would help to adapt to breastfeeding.“On the third day, there was still no milk as full as I thought. I began to panic and was afraid of not having enough breast milk. I remember when I attended an antenatal class, the counselor repeated again and again that “if you think you don’t have enough milk for the baby, you won’t have enough milk for real! You must be relaxed and comfortable!”. I called my sister for support and reassurance. I tried to reassure myself and not to feed with formula. In the evening of the third day after giving birth, the milk came in a lot”. (0904Text3). | 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 husband-wife would involve the husband in helping with breastfeeding.
“My husband said nothing, but he seemed to follow grandparents who supported stopping breastfeeding. He thought I would be tired from being woken -up many times to breastfeed the baby at night”. (0904Text1).The mother-in-law is the most influential person. She was very helpful in caring for newborns and mothers as local birthing traditions did not support new moms doing housework in their first month after delivery. However, the differences in lifestyles and caring could create more stress for first-time mothers.“After giving birth, I was very tired. My son was the first grandchild of a big family. His grandmother hugged and carried him almost all day. I was even not allowed to hold him. I could not have skin-to-skin contact for the first 12 hours as I wanted. When he cried, I told the grandmother to let me breastfeed him, however, she scolded me: “He′s hungry! How can you feed him when you have no milk!” (0904Text3).Grandmothers often turned to use infant formula to enable them to feed a child whenever he/she cries, a preference for a “chubby” baby. They had also been exposed to infant formula advertisements on television. Involving family members in the preparation and planning for breastfeeding during pregnancy would support their breastfeeding decision and practice. | 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) library information which contains threads explaining the short messages. Two versions of the app were available, one for the intervention and the other for the control app. In the intervention version, the mother received messages and library information on breastfeeding and maternal and child health care. In the control one, no information on breastfeeding was given, the mother received messages and library contents on maternal and child health care only. In the trial, the researchers randomized the mothers into either of the version based on age, educational level, and parity [The app Bebo allowed mothers to (1) Register; (2) Receive messages at a desired day and time in a week; (3) Reread the messages; (5) Touch the messages to open the related thread in the library content; (6) Read and search information in the library content. During the trial, the app needed to register with a password provided by the researcher for a randomized controlled trial study. This password was removed after the project ended. | 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 set of 12 messages before delivery. After delivery, the messages were released according to key development milestones of the baby Users could tap messages on the home screen to access expanded content in the libraries.Messages could be reread at any time in the app. They were about tetanus vaccination, weight control during pregnancy, maternal nutrition, folic acid supplementation, other micronutrient supplementation, physical activities, and smoking. | 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 illustrate messages or information in the thread, references, and links for further reading. The thread could be opened and read at any time without internet access. The library content for the control group also appeared in the intervention version. Library content for the intervention group did not appear in the control version (Fig. Library content of the intervention (left side) and control (right side) group | 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 time to subscribe to push notifications with firebase cloud messaging or apple push notification service.The app registered the device to firebase cloud messaging or the apple push notification service.The firebase cloud messaging or apple push notification service accepted the app and sent it to the app as a device token.The data collection team updated the mother’s profile including the mother’s name, identifying number, phone number, and the desired date of the week’s notifications.The app sent the mother’s profile including the device token to the Webapp (the app was now waiting for activation of the version).RandomizationThe administrator used information from REDCap (mother age, educational level, and parity) for randomizing the mother into either the control or intervention group. He then updated the mother’s group in their profile on Webapp to assign them either a control or intervention version.The administrator sent an alert to the mother to open the app for activation.The Webapp sent the notification to the mother app via firebase cloud messaging or apple push notification service based on the device token.The firebase cloud messaging or apple push notification service sent the notification to the mother app based on the device token.ActivationMother touched or opened the notification to activate the app without notice of the app’s version.The app requested the mother’s group from Webapp to create the scheduled local notifications and finished the app registration and activation.Architecture diagramsOnly the administrator could extract information from REDCap and Webapp. In the follow-up phone call, the admin provided data collectors with name, identity number, phone number, and expected birthdate which were extracted from the Webapp. Data analysts would be provided with a data set without information on the control/intervention group. | 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 breastfeeding among all mothers regardless of delivery mode. | 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 algorithm, and update the mother’s profile. Some minor errors were fixed including larger font size, higher contrast color filters designed, mixed English and Vietnamese, spelling mistakes, and adjusting pictures in the app to fit with the screen. After prototype testing and adjustments, BeBo is being currently evaluated in a randomized clinical trial with the target population described. | 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. However, we decided to not develop an app for monitoring the child’s growth, albeit it was one of the most preferred features reported by mothers. There are additional privacy considerations with receiving detailed information of this type. As we targeted to improve exclusive breastfeeding rates, the app was designed for mothers’ use until 6 months after birth. At this stage of development, attention to the increasing weight of an infant may drive a mother to formula feeding, whereas the public health emphasis is on overall development [Often mothers do not manage exclusive breastfeeding due to unsolved difficulties in breastfeeding. Therefore, emotional support along with providing appropriate knowledge is very important for lactating mothers. A function of mutual communication between a mother and lactation counselors built into the app is ideal. However, there is a lack of lactation counseling services in Vietnam so we cannot build this function. | 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 higher breastfeeding self-efficacy was less likely to have postpartum depression [The support of partners and grandparents was important to mothers. A mother was more likely to continue exclusive breastfeeding at 4 and 6 months with a father’s support [However, those messages received low preferences compared with the other messages. Mothers were reluctant to ask healthcare providers for support on breastfeeding. Healthcare providers thought they were for treatment, and health information was delivered in a one-way style, with reliance on writing rather than counseling [The effectiveness of the app had been evaluated in a randomized controlled trial and resulted in the significance of improving early initiation of breastfeeding within 2 h and exclusive breastfeeding during the hospital stays among mothers who have a cesarean section [ | 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 discussions and in-depth interviews. However, divergent views may have been missed and we may receive possibly feedback from respondents than in the general population. Self-selection bias could have been possible given convenience sampling was used. Those who were interested in obtaining maternal and child care information and technological interventions may be more likely to participate in our study than the others. They may have a better knowledge of maternal and child health care as well as the ability in using smartphones. We considered all these aspects in developing the app. | 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 editing, C.B.; visualization, T.T.D.D.; supervision, C.B., A.L., Y.Z., T.P.H.D., and T.T.H.B; project administration, T.T.D.D. All authors have read and agreed to the published version of the manuscript. | 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 participants before the interviews. | 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-terminal tau, in patients with early Alzheimer’s disease. Gosuranemab was safe and well tolerated, but the clinical efficacy endpoint was not met. | 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 pathologically and clinically distinct from primary tauopathies | 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-gosuranemab antibody response at any time point after baseline and within the week 76 visit. Persistent responses were observed in two participants in the placebo group (0.9%); no participants in the gosuranemab-treated groups showed a persistent response. Transient responses were observed in two participants in the placebo group (0.9%) and one participant in the intermediate-dose group (1.0%). | 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 participants. The safety profiles during the LTE period were similar to those during the placebo-controlled period, and no additional safety concerns were observed with the limited exposure to gosuranemab in the LTE period. The overall incidence of AEs and SAEs in the LTE period was similar between the early-start ( | 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: the change in the CDR-SB score from baseline at 78 weeks. Furthermore, none of the treatment groups exhibited an improvement over the placebo group in any of the exploratory efficacy endpoints. In one such assessment (ADAS-Cog13 scale), the high-dose group performed statistically significantly worse than the placebo group at week 78; however, this difference was not statistically significant in the LTE period. The lack of clinical efficacy observed in TANGO is consistent with the results of recent clinical trials investigating the N-terminal anti-tau antibodies semorinemab and tilavonemab in early ADTreatment with gosuranemab was associated with a robust reduction in the CSF levels of unbound N-terminal tau, confirming the target engagement of this antibody. In the treatment groups, the CSF levels of p-tau181 and total tau were lower at week 76 than at baseline. However, differences in p-tau181 and total tau levels among the treatment and placebo groups were significant only for some dose groups, and no dose–response was observed for either measure. Analysis of the tau PET substudy—the largest [Preclinical models of AD to date leave room for improved clinical translation. In several preclinical tau transgenic mouse models, the anti-tau antibodies tilavonemab, zagotenemab and semorinemab, which target N-terminal or conformational epitopes of tau, have demonstrated efficacy in reducing tau pathology and, in some cases, providing functional or behavioral improvementsAll groups exhibited comparable reductions in hippocampal and total brain volumes, consistent with disease progression. A statistically significant increase in the lateral ventricular volume, with unclear clinical significance, was observed in the high-dose treatment group relative to the placebo group.The pharmacodynamic data from the TANGO study are consistent with those from previous trials investigating gosuranemab. In a single-ascending-dose trial, gosuranemab doses of 70–4,200 mg decreased the CSF levels of unbound N-terminal tau by 67–97% at 4 weeksIn the TANGO study, gosuranemab was tested based on the hypothesis that extracellular seeding-competent tau species propagate tau pathology throughout the brain. This study is supported by preclinical data demonstrating the high binding affinity of gosuranemab to monomeric and aggregated forms of tau and its ability to remove seeding-competent forms of tau from AD brain lysate and interstitial fluid derived from tau transgenic miceIn addition to the biological and technical limitations discussed above, operational limitations should be considered when interpreting the study results. This study was affected by the COVID-19 pandemic. Many efforts were made to minimize the effect of the pandemic on the study participants. As a measure against study withdrawals, participants were allowed flexibility in scheduling their site visits. This flexibility made possible the low discontinuation rate observed in the study, at the expense of increased protocol deviations. However, these deviations were generally balanced across treatment groups, mitigating the potential effect of this limitation on the interpretation of the results. Limited data were collected during the LTE period due to the early termination of the study. | 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 either 125 mg gosuranemab q4w or 375 mg gosuranemab q12w), (2) intermediate-dose gosuranemab (600 mg q4w), (3) high-dose gosuranemab (2,000 mg q4w) or (4) placebo (0.9% NaCl q4w). Randomization was conducted by interactive response technology (IRT); the IRT vendor generated the randomization sequence. Randomization was stratified by region, disease stage (MCI or mild AD), baseline AD medication use and tau PET and/or CSF substudy enrollment (see the ‘ | 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 the Declaration of Helsinki and all applicable International Council for Harmonisation and Good Clinical Practice guidelines. Investigators were required to obtain ethics committee approval before beginning the study. For study sites in the USA, the study protocol was approved by Advarra’s central IRB or one of the following local ethics committees: BioMed IRB, San Diego, CA; Biomedical Research Alliance of New York, Lake Success, NY; Western IRB, Puyallup, WA; University of California, Los Angeles, Office of the Human Research Protection Program, Los Angeles, CA; Tufts Health Sciences IRB, Boston, MA; Stanford University Research Compliance Office, Palo Alto, CA; Houston Methodist IRB, Houston, TX; and Human Investigation Committee, Yale University IRB, New Haven, CT. For sites in other countries, the study protocol was approved within each respective country by the following local IRBs or ethics committees: Melbourne Health Human Research Ethics Committee (Australia); Alfred Hospital Ethics Committee (Australia); Eastern Health Research and Ethics Committee (Australia); Austin Health Human Research Ethics Committee (Australia); Comité de Protection des Personnes Ouest I (France); Ethikkommission des Fachbereichs Medizin der Ludwig-Maximilians-Universität München (Germany); Comitato Etico dell’Azienda Ospedaliero Universitaria Policlinico Paolo Giaccone, Palermo (Italy); Comitato Etico Istituzioni Ospedaliere Cattoliche (Italy); Azienda Ospedaliera Universitaria Policlinico Umberto I–Università di Roma La Sapienza (Italy); Comitato Etico IRCCS Ospedale S. Raffaele di Milano (Italy); Comitato Etico per le Sperimentazioni Cliniche della Provincia di Vicenza (Italy); Adachi Kyosai Hospital IRB (Japan); Teikyo University Hospital, Mizonokuchi IRB (Japan); Tokyo Medical University Hospital IRB (Japan); Takeda Hospital Group IRB (Japan); Koseikai Sone Clinic IRB (Japan); National Center for Geriatrics and Gerontology IRB (Japan); Osaka University Hospital IRB (Japan); Bioetyczna przy Okregowej Izbie Lekarskiej w Gdansku (Poland); Hospital Universitari i Politecnic La Fe (Spain); and Etikprövningsmyndigheten (Sweden). All participants provided written informed consent before participating in any study-related activities. An independent data monitoring committee reviewed safety data on an ongoing basis. | 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 in the tau PET substudy for randomization purposes).PET imaging was performed using [Participants in the tau PET substudy underwent tau PET scans at baseline, 52 weeks and 78 weeks. Participants in the CSF substudy had CSF samples collected at baseline, 48 weeks and 76 weeks. A small subset of participants ( | 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 change from baseline in brain volume as measured by MRI. | 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 baseline CDR-SB score (secondary objective) at 78 weeks, assuming a maximal 40% reduction with the highest gosuranemab dose compared to placebo and an estimated 20% dropout rate at 18 months (week 78) in this study. This calculation assumed an estimated mean change of 1.99 from the baseline CDR-SB score at 78 weeks in the placebo group and a common s.d. of 2.38, based on available data from Alzheimer’s Disease Neuroimaging Initiative (ADNI1, ADNI2 and ADNI GO) studies (amyloid positive from amyloid PET or CSF testing, MMSE score of ≥22, CDR global score of 0.5 for MCI and 0.5 or 1 for mild AD). All analyses were two-sided at a 5% significance level. | 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 the placebo-controlled period. Efficacy analyses were performed on the full analysis set (that is, all randomized participants who received the study treatment (gosuranemab or placebo)). Four participants were randomized but not dosed and excluded from the analysis. Secondary objective (CDR-SB) and key exploratory endpoints were analyzed using a mixed model for repeated measures (MMRM), with fixed effects of treatment, time, interaction between treatment and time, baseline value of the parameter of interest, interaction between the baseline value of the parameter of interest and time, baseline MMSE score, region, disease stage and baseline use of AD symptomatic medications. Model diagnostics were performed to evaluate the normality of data distribution and the impact of outliers. Missing data were assumed to be missing at random. Similar models were used for key secondary and exploratory endpoints. Additional analyses of efficacy endpoints from the LTE period were performed using data from the placebo-controlled and LTE periods.Biomarker analyses (CSF testing, tau PET and structural MRI) were performed on either the evaluable set or the modified evaluable set for each type of analysis, in which the evaluable set consisted of all participants in the full analysis set who underwent the relevant procedure (lumbar puncture, PET or MRI) and the modified evaluable set consisted of the subset of the evaluable set with at least one postbaseline measurement of the specific parameter being analyzed. Biomarker analyses used an MMRM similar to that used for efficacy analyses; however, age was also used as a covariate for tau PET and MRI analyses, and region was not used as a covariate for CSF and tau PET analyses.All safety analyses, except MRI safety analyses, were performed using data from all randomized participants who received at least one dose of the study treatment. MRI safety analyses were performed using data from all participants who received the study treatment and had at least one safety MRI scan after the baseline visit. Infusion reactions were defined as AEs that occurred on the day of or up to 2 days after an infusion. | 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 not possible, safety surveillance and selected clinical assessments (CDR, ADCS-ADL, ISLT, Category Fluency Test and Letter Fluency Test from the Delis–Kaplan Executive Function System, and Columbia Suicide Severity Rating Scale) were allowed to be performed by telephone. Infusions at home or alternative sites and home-nursing options were permitted in some instances. Visits or procedures missed due to reasons related to the COVID-19 pandemic had to be completed as soon as possible and reported as delayed or missed with appropriate reasons provided. | 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% significance level. No adjustments were made for multiple comparisons. | 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.
| PMC10724064 | ||
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 the Good Publication Practice guidelines ( | 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. Acquisition, analysis or interpretation of data: M.S., J.K., J.O’G., L.V., E.R., R.R., L.V., E.H., S.S., A.M.R., J.C., D.G., Y.L., H.H. and S.B.H. Drafting of the manuscript: M.S., J.K., J.O’G., E.H., A.M.R., J.C., D.G., Y.L., H.H. and S.B.H. Statistical analysis: J.K., J.O’G. and Y.L. | PMC10724064 | ||
Peer review | PMC10724064 | |||
Data availability | The trial results are publicly available at ClinicalTrials.gov ( | PMC10724064 |
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