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Supporting information | PMC10619799 | |||
Protocol of the study. | (DOCX)Click here for additional data file. | PMC10619799 | ||
CONSORT checklist. | (DOC)Click here for additional data file. | PMC10619799 | ||
S1-S4 Tables. | (DOCX)Click here for additional data file.We wish to thank all the participants for generously contributing their time and experience to this study. We are grateful for the support received from all the members of the Obstetrics and Gynecology Department and Bahar clinic in Baharlou hospital. | PMC10619799 | ||
Background | SECONDARY | Primiparous women experience various challenges if not provided with social support in the early postpartum period. Support in form of postpartum education programs is needed to improve mental well-being in primiparous women. The aim of this study was to determine the effect of a postnatal supportive education program for husbands on the perceived social support (primary outcome), and stress and maternal self-efficacy (secondary outcome) of their primiparous wives. | PMC10045875 | |
Methods | This randomized clinical trial was performed on pregnant women referring to healthcare centers for routine care from September to November 2021 in Kermanshah, Iran. One hundred pregnant women were randomly divided in to intervention and control groups. Four 45–90 min online training sessions were held weekly for the husbands of the intervention group. The primiparous women completed the Postpartum Partner Support Scale, Perceived Stress Scale, and Postpartum Parental Expectations Survey before (third day after delivery, immediately and one month after completing the intervention. Data were analyzed using Fisher's exact test, Chi-square test, independent t-test, and repeated measures analysis of variance in SPSS version 24, and | PMC10045875 | ||
Results | In the control and intervention groups before the intervention, socio-demographic characteristics ( | PMC10045875 | ||
Conclusion | The postpartum supportive education program for husbands was effective in promoting social support for primiparous women. Thus it can be introduced as routine care in the postpartum period. | PMC10045875 | ||
Trial registration | Clinical trial registration Iranian Registry of Clinical Trials; | PMC10045875 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12905-023-02270-x. | PMC10045875 | ||
Keywords | PMC10045875 | |||
Introduction | depression, fatigue | SECONDARY | The early postpartum period is an exciting and joyful time for many parents, yet it is a stressful transient period during which most primiparous women face a variety of physical and emotional challenges, including fatigue and difficult responsibilities of caring for the baby and profound changes in the couple's roles and responsibilities [The postpartum period is characterized by the vulnerability of primiparous women to stress. Postpartum stress not only impairs the health of primiparous women but also reduces their self-esteem, impedes adaptation to the role of mother, and impairs maternal bond with the baby [Maternal self-efficacy refers to the mother’s belief in her abilities as an efficient mother and is greatly influenced by the sense of motherhood, self-confidence and perception of empowerment [Barnard (1994) emphasizes the importance of social support in the first year after childbirth [The results of a randomized controlled trial demonstrated the effectiveness of the postnatal psychoeducation program in improving maternal parental self-efficacy, social support and reducing postnatal depression of primiparous women [In some Western countries, mothers and their infants are discharged early to facilitate family-centered postnatal care and encourage a sense of parental involvement. [Given the importance of primiparous women’s mental health in facilitating adaptation to changes and new roles in the during the postpartum period, many husbands have a vital and decisive role in supporting their wives during this period. However, there is no sufficient time to provide all the necessary information in a short period of hospitalization, and according to a conducted survey, no study was found on the effectiveness of a postnatal supportive education program for husbands on perceived social support, stress and maternal self-efficacy of their primiparous wives. Therefore, the present study was conducted to determine the effect of a postnatal supportive education program for husbands on perceived social support (primary outcome), and stress and maternal self-efficacy (secondary outcome) of their primiparous wives. | PMC10045875 |
Hypothesis of study | Education to the husbands of primiparous women will lead increased perceived social support and maternal self-efficacy and reduced stress of these women in the postpartum period. | PMC10045875 | ||
Primary aim | Determine the effect of a postnatal supportive education program for husbands on perceived social support of their primiparous wives. | PMC10045875 | ||
Secondary aim | Determine the effect of a postnatal supportive education program for husbands on stress and maternal self-efficacy of their primiparous wives. | PMC10045875 | ||
Methods | PMC10045875 | |||
Study design and participants | This randomized, controlled clinical trial study using two parallel groups was performed on 100 pregnant women referring to health centers in Kermanshah, Iran from September to November 2021. Figure CONSORT flowchart of the study | PMC10045875 | ||
Sample size calculation | The sample size was calculated based on the main variable of the study (social support) according to Khanzadeh and Moghaddam Tabrizi [
μ1: mean difference of the social support in the intervention group (11.25), μ2: mean difference of the social support in the control group (4.95), SD1: standard deviation of the social support before intervention (14.21), and SD2: standard deviation of the social support after intervention ( | PMC10045875 | ||
Sampling and random allocation method | BLIND | The present study was approved by the committee of ethics of Ahvaz Jundishapur University of Medical Sciences (IR.AJUMS.REC.1399.401) and was registered in Iranian Registry of Clinical Trials (IRCT20160427027633N8). First, According to the information of Kermanshah health center, Kermanshah city was divided into 4 geographical regions (or 4 classes) based on socio-economic status of the residents. These four regions included 76 healthcare centers, and from the healthcare centers of each region, one was selected by simple random method (drawing lots). These centers were Taleghani, Hafezieh, Shahid Souri, and Haj Daei, from which 28, 34, 22, and 16 women were selected by convenience sampling method (based on the share of each center). After making the necessary arrangements and obtaining a permit, the researcher went to these centers and selected eligible women. In this way, by referring to the Sib system, information about the women who were covered by the center and met the study entry criteria was extracted and they were contacted by phone to come to the health center to participate in the study. The study aims and method were explained to pregnant women and their husbands in a face-to-face meeting and informed written consent was gained from them (pregnant women and their husbands). The telephone numbers of the women and their husbands were taken, and the researcher gave her telephone number to them, and they were advised to inform the researcher when the mother gave birth to the baby. After the women completed the questionnaires online on the third day after delivery, the educational content was offered to the intervention group. It should be noted that the membership of the husbands in the virtual (Skype) group was monitored by checking whether or not they had installed Skype on their cellphones, and in case they had not, it was installed on their cellphones. Necessary training on how to use Skype was given to them.The women were randomly divided into 6 blocks with an allocation ratio of 1:1 to the intervention and control groups. Blocked randomization was performed by a person who was not involved in data collection, and in order to conceal random allocation, opaque sealed packets in random sequence were used. To this aim, first, a random sequence was created by a table of random numbers and recorded on a card and the cards were placed in packets according to the random sequence. Packets were opened in the order of woman entry in the study and they were allocated into either the intervention or control group. Data analysis was performed by a statistician who was unaware of the nature of the codes. Due to the nature of the intervention, it was not possible to blind neither the participants nor the researchers. | PMC10045875 | |
Intervention | Training was performed for intervention group in Skype. While the control group received only routine care. Training involved 4 online sessions of 45 to 90 min in Skype, held weekly (one session per week) by the researcher. Due to the different nature of education on natural childbirth and cesarean section, the women in the intervention group were divided according to the type of delivery (32 women who were supposed to have a normal delivery were in 4 groups of 8, and 18 women who were going to deliver their baby by a cesarean section were in 3 groups of 6). Topics of training sessions included: first session: the importance of maternal health in the postpartum period and the importance of social support for the mother in this period, second session: anatomical and physiological changes in the postpartum period, the impact of these changes on the mothers mental state, and the way she should be cared for, third session: baby care, the principles of breastfeeding and how to deal with its challenges, fourth session: the father’s responsibilities in the postpartum period and his supportive role in helping mothers adapt to changes (Interventional group educational content sessions are available in Additional file Socio-demographic characteristics of the intervention and control groups*Independent t-test, ** Fisher’s exact test, *** chi-square testThe educational content was prepared by referring to the available library resources and with the guidance of supervisors and consultants and also based on the instructions and guidelines of the Iranian Ministry of Health. The validity of the educational content was evaluated qualitatively and approved by 10 relevant experts and faculty members related to the subject under study, including four reproductive health specialists, one midwifery specialists, three gynecologists and two psychologists. Each week after the review session, the content was presented in text, video and audio formats to the intervention group until the next session. Meetings were held upon agreement of the husbands. Each week, the researcher reminded the audience of the time of the training sessions by phone and text messages. In addition, the intervention group provided access to the researcher to ask questions via WhatsApp. Immediately and one month after completing the intervention (i.e., the fourth and eighth weeks after delivery), the questionnaire was completed by primiparous women online. In the end, in order to observe the ethical considerations, the educational materials were provided to the control group. | PMC10045875 | ||
Study outcomes | SECONDARY | In this study, the study outcomes (primary outcome: social support and secondary outcome: maternal self-efficacy and stress) were measured at three time intervals: baseline or before intervention (third day after delivery), immediately after the intervention (fourth week after delivery), and one month after the intervention (eighth week after delivery). The outcome measures were completed by primiparous women online. | PMC10045875 | |
Data collection tools | Data collection tools included socio-demographic questionnaire, Postpartum Partner Support Scale, Perceived Stress Scale, and Postpartum Parental Expectations Survey. | PMC10045875 | ||
Socio-demographic questionnaire | ’s disease | This questionnaire includes questions related to age, husband’s age, age gap with husband, educational of the woman and her husband, employment status of the woman and her husband, economic status, husband’s disease, weight at birth, type of baby feeding, breastfeeding problems, delivery method, pregnancy status, and baby’s gender and parental satisfaction with. | PMC10045875 | |
Primary outcome | PMC10045875 | |||
Postpartum Partner Support Scale (PPSS) | This scale was developed in 2017 by Dennis et al. This questionnaire has a four-point Likert scale (from | PMC10045875 | ||
Secondary outcome | PMC10045875 | |||
Postpartum Parental Expectations Survey (PPES) | This scale designed by Reese in 1992, was used to measure maternal self-efficacy. This questionnaire has 25 affirmatively worded items scored based on a 10-point Likert scale (from | PMC10045875 | ||
Perceived Stress Scale (PSS) | STRESSFUL EVENTS | Perceived Stress Scale was developed in 1983 by Cohen et al. to measure general perceived stress over the past month. Thoughts and feelings about stressful events, as well as controlling, overcoming, coping with stress. In the present study, the 14-item version was used which is answered based on a 5-point Likert scale (from | PMC10045875 | |
Data analysis | The collected data were analyzed using descriptive statistics (frequency, percentage, mean and standard deviation) and inferential statistics using SPSS version 24. | PMC10045875 | ||
Discussion | depression, depressed | DISEASES, BLIND | The results of this study showed that the postnatal supportive education program for husbands enhanced the understanding of social support for their primiparous women in the fourth and eighth weeks after delivery. It can be argued that providing education and consultation services to husbands in order to increase their awareness about the characteristics and issues of women in the postpartum period is one of the tools for promoting husbands’ social support to their wives, which has a positive effect on the couple’s knowledge, attitude and practice with respect to postpartum health [To the best of our knowledge, no study has yet been conducted on the effect of husband education or counseling on social support, maternal self-efficacy, and stress in postpartum women. However, previous studies have shown the overall impact of participation and counseling of pregnant women's husbands, primiparous women and couples in this respect. Mohammadpour et al. (2020), for instance, conducted a randomized clinical trial to determine the effect of husband counseling on social support perceived by their pregnant wives. Their intervention involved four 60-min sessions of group counseling (each group consisting of 7 to 10 people) once a week for four consecutive weeks. The results showed that the mean score of social support 4 weeks after the intervention in the intervention group increased significantly compared to the control group [The results of the present study showed that the postnatal supportive education program for husbands of primiparous women promoted maternal self-efficacy in these women in the fourth and eighth weeks after delivery. It can be argued that educating men to promote support for their primiparous wives can play an effective role in reinforcing the mother’s abilities and her interpretation of the competence she has to play the role of a mother, thus increasing her self-efficacy [Salonen et al. (2010) investigated the effect of an online educational intervention on increasing maternal satisfaction and self-efficacy. Mothers in the intervention group had access to an educational website offering infant care training content from the 20th week of pregnancy whereas the control group received only the routine training. No statistically significant difference was observed between the two groups 6 to 8 weeks after delivery in terms of self-efficacy and parental satisfaction compared to before the intervention [In the present study, participants had access to information through education. This useful information helped the men to acquire the right knowledge independently and, by providing support to the mother, they managed to perform the challenging parenting tasks and increase the mother’s self-efficacy. The helpful feedback given to the husbands served as verbal encouragement, thus allaying their concerns and increasing their self-confidence and motivation to promote maternal self-efficacy.The results of the present study showed that the postnatal supportive education program for husbands of primiparous women reduced the perceived stress in these women in the fourth and eighth weeks after delivery. This can be attributed to the fact that educating husbands on providing emotional, informational, and instrumental support to the mother reduces her physical and psychological stress. Therefore, among the available support sources, the support provided by sexual partners is very important [Also, study of Alio et al. (2013) showed that the primary benefits of male partner involved during pregnancy were the reduction of maternal stress levels and the encouragement of positive maternal behaviors [One of the limitations of this study was that women in this study had no neuropsychiatric diseases. This may affect the generalizability of the results to women who are depressed. The second limitation was that data collection was based solely on participants’ own reports, and the researchers did not use other sources of data collection such as observation. The third limitation was that due to the nature of the intervention, the researchers were not blind to data collection after the intervention. Also, no data was collected from husbands. The last limitation was the cultural component. This prevents generalization to other realities. There is no homosexual culture in Iran, and families made up of a man and a woman and who are married. Other family models (single parent, mixed families, not married, formed by people of the same sex), which are not considered here and could be considered in other studies. These limitations notwithstanding, this study is worthwhile considering the following: Random allocation, concealment of allocation, random selection of women from health centers in 4 districts of the city, long-term follow-up, providing telephone numbers to answer participants’ questions, and providing educational content to the control group at the end of the study. Also, the intervention was designed around the planned delivery method. Therefore, we suggest that a similar study be done in women with a history of depression or suffering from that with more sophisticated statistical analysis. | PMC10045875 |
Conclusion | This study demonstrated the effectiveness of a postnatal supportive education program for husbands (male partners) in improving perceived social support, maternal self-efficacy, and stress in primiparous women. Therefore, policymakers in postpartum care are advised to consider the participation of husbands in the postpartum care process and to devise plans to increase the awareness of husbands and their role in promoting maternal and infant health. Also, to confirm the results of this study, a randomized controlled trial with a larger sample size from the whole population is suggested. | PMC10045875 | ||
Acknowledgements | The authors would like to thank all the participants in this study. | PMC10045875 | ||
Authors’ contributions | All authors contributed to this study; F-SH, and ZA designed the study. F-SH, MJ, ZB and MN provided the training. F-SH and ZA collected the data, B-CH analyzed the data analysis, F-SH drafted the manuscript. All authors read and approved the final manuscript. | PMC10045875 | ||
Funding | The study is part of the results of the PhD dissertation of the first author in midwifery, which was financially supported by Ahvaz Jundishapur University of Medical Sciences (AJUMS) in Iran. | PMC10045875 | ||
Availability of data and materials | The data that support the findings of this study are available from the corresponding author upon reasonable request. | PMC10045875 | ||
Declarations | PMC10045875 | |||
Ethics approval and consent to participate | Ethical approval for this study was obtained from the research ethics committee of Ahvaz Jundishapur University of Medical Sciences with the ethics code of IR.AJUMS.REC.1399.401. In addition, this trial registered in Iranian registry of clinical trials; | PMC10045875 | ||
Consent for publication | Not applicable. | PMC10045875 | ||
Competing interests | The authors have no conflicts of interest to disclose. | PMC10045875 | ||
References | PMC10045875 | |||
1. Introduction | sepsis, groin, early-life | SKIN, SEPSIS, ADVERSE EFFECTS | The structure and function of infant skin is not fully developed until 34 weeks of gestation, and this immaturity is associated with risk of late-onset sepsis (LOS). Topical coconut oil improves preterm-infant skin integrity and may reduce LOS. However, data on early-life skin-microbiome succession and potential effects of emollient skin care in preterm infants are scarce. We therefore collected skin-microbiome samples from the ear, axilla, and groin on days 1, 7, 14, and 21 from preterm infants born <30 weeks of gestation as part of a randomized clinical trial of standard skin care vs. topical coconut oil. We found that within-sample microbiome diversity was highest on day 1 after birth, with a subsequent decline and emergence of Human skin hosts a diverse, low-density microbiome of bacteria and fungi [Skin colonisation begins immediately at, or even before, birth; however, the factors influencing the succession of the skin microbiota are not completely understood. For example, the effect of the mode of delivery on skin-microbiome composition remains controversial [Infant skin at birth is initially rich in Firmicutes, followed by Actinobacteria, Proteobacteria, and Emollients used for neonatal skin care, both mineral-oil-derived and natural oils, aim to reduce TEWL and improve skin integrity [Our previously described, randomized, controlled trial of topical coconut oil in very (born <30 weeks GA) preterm infants resulted in improved skin integrity, without adverse effects [ | PMC10706365 |
2. Results | groin | We collected skin swabs from 72 very preterm infants from the axilla, ear, and groin on days 1, 7, 14, and 21 after birth. Microbiome analysis was performed on samples with sufficient DNA content from 672 swab samples, from a total of 56 infants (28 infants each in intervention and control arms, respectively). The demographics of participants are described in For skin-microbiome analysis, a total of 52,972,312 reads were obtained from 672 swab samples. A total of 14,912 ASVs were assigned to reads after denoising with the DADA2 pipeline. The ASVs were assigned to 34 phyla, 81 classes, 209 orders, 354 families, 819 genera, and 540 species. We identified 40 ASVs as potential contaminants, using the Decontam pipeline [ | PMC10706365 | |
2.1. Succession of the Skin Microbiota of Preterm Infants in Both Control and Intervention Infants | There were substantial changes in the composition of the skin microbiome over the first three weeks of life (The dissimilarity between microbial communities at different body sites and ages at sampling was assessed with non-metric multidimensional scaling (NMDS) using the Bray–Curtis dissimilarity index. Between-body-site distances were greater than within-site distances (PERMANOVA, Using qPCR for | PMC10706365 | ||
2.2. Factors Associated with Diversity of the Preterm-Infant Skin Microbiome | We tested the association between various participant-level factors and alpha diversity (within sample diversity) using linear mixed models. Bacterial richness (Chao1) in axilla samples was lower than that in groin samples (Bacterial richness was lower on day 7 (We also analyzed the association between the total duration of antibiotic therapy, prior to each sampling time point, and alpha diversity. Lower Shannon diversity index was similar to prior antibiotic treatment ( | PMC10706365 | ||
2.3. Effect of Topical Coconut Oil on the Skin Microbiome | We analyzed the effect of coconut oil emollient on within-sample diversity using a linear mixed model with participant ID as a random effect and with site and age as fixed effects. Compared to the control arm, there was a trend towards reduced microbiome richness in the intervention arm (beta = −9.97, 95% CI [−22.68, 2.74], Using qPCR, we analyzed the number of genome copies of CoNS and CoNS DNA was detected by qPCR in 66.8% of all samples. On day 1, CoNS DNA was detected in 40 participants (55.56%) from at least one site. By day 7, 70 participants (97.2%) had detectable levels of CoNS DNA from at least one site, with a concurrent increase in copy number. The CoNS load remained stable from day 7 onwards (For the axilla and ear sites, the median number of CoNS genomes detected was similar between the intervention and control arms at all time points (When all sites were combined, the number of CoNS genomes per swab increased from day 1 to day 7 for both the control and intervention arms ( | PMC10706365 | ||
3. Discussion | We investigated the effect of topical coconut oil emollient on the skin microbiome in preterm infants born <30 weeks of gestational age. Microbiome data were collected longitudinally from three body sites up to 21 days after birth. Overall, within-sample diversity was highest on day 1 after birth, with a subsequent decline and emergence of the The reduction in diversity with age is likely due to a combination of host and environmental factors [Alpha diversity of the skin microbiome was significantly lower in the intervention arm than in the control arm, perhaps related to the higher absolute abundance of CoNS observed in children receiving coconut oil. In contrast, coconut oil application had no effect on the prevalence and absolute quantity of We have previously reported that the implementation of topical coconut oil skin care in our NICU was associated with a lower frequency of LOS, without a change in the pattern of causative organisms [Antibiotics decrease skin-microbiome alpha diversity in preterm infants [Strengths of this study include its prospective integration into a randomized clinical trial comparing preterm infants’ skin care with and without topical coconut oil, including serial sampling of three body sites. However, this study was underpowered to make conclusive findings about associations between the microbiome and antibiotic administration and clinical outcomes such as LOS. This study highlights the rapid succession of the skin microbiome, especially during the first week of life, and the potential modifying effects of topical coconut oil therapy. | PMC10706365 | ||
4. Materials and Methods | PMC10706365 | |||
4.1. Participant Recruitment and Sample Collection | congenital malformations | SKIN, SKIN CONDITION | This trial, conducted in the NICU at Edward Memorial Hospital, Perth, was approved by the institutional human research ethics committee (HREC2015191EW) and registered with the Australian Clinical Trial Registry (ACTRN12616000042448). Infants born <30 weeks’ gestational age without major congenital malformations or congenital skin conditions were enrolled. Virgin coconut oil (Nature Pacific, Varsity Lakes, QLD, Australia) was provided in individually sealed 5 mL sachets for each application. Coconut oil (5 mL/kg) was applied by trained nursing staff to neonates in the intervention arm every 12 h for 21 days, commencing within 24 h of birth. The control arm was given standard neonatal care as per NICU guidelines without topical coconut oil [Skin swabs (eNAT FLOQ Swabs | PMC10706365 |
4.2. DNA Extraction, PCR, and Amplicon Sequencing | BLOOD, STERILE | DNA was extracted from the eNAT tubes using the Qiagen Blood Mini Kit with several modifications. Briefly, 1 mL of sample was aliquoted in sterile 2 mL tubes containing 1.0 mm and 0.1 mm sized silicon beads. The tube was centrifuged at 10,000× The 16S rRNA gene V4 region was amplified using 515F and 806R primers with 50 ng of DNA in final volume of 50 µL. Several negative controls were amplified using water as a template. The amplification and amplicon size were confirmed by running samples on 1% ( | PMC10706365 | |
4.3. Bioinformatics and Statistical Analysis | Demultiplexed sequences were quality filtered using QIIME (Quantitative Insights into Microbial Ecology) version 2.2020.2 [To remove contaminants that were seen in sequenced controls, we used an in silico approach using the Decontam package in R software (v 4.3.2) [All univariate statistical analysis was carried out in the R software using the Vegan package version 2.5.7 [ | PMC10706365 | ||
4.5. Quantification and Detection of Bifidobacterium | As per the NICU standard protocol at KEMH, all infants received oral supplementation with | PMC10706365 | ||
Supplementary Materials | The following supporting information can be downloaded at Click here for additional data file. | PMC10706365 | ||
Author Contributions | Conceptualization, T.S., A.C., M.P.N. and S.P.; Methodology, T.S., M.P.N., M.S.P. and N.-U.-H.G.; Formal analysis, N.-U.-H.G., C.A.M. and J.H.; Investigation, T.S., S.P. and J.H.; Resources, M.S.P., A.C. and T.S.; Data curation, T.S., S.P. and J.H.; Writing—original draft preparation, N.-U.-H.G., C.A.M. and M.P.N.; Writing—review and editing, A.C., T.S., M.S.P. and J.H.; Visualization, N.-U.-H.G. and C.A.M.; Supervision, T.S., A.C. and M.P.N.; Funding acquisition, T.S., A.C. and S.P. All authors have read and agreed to the published version of the manuscript. | PMC10706365 | ||
Institutional Review Board Statement | This study was approved by the institutional human research ethics committee (HREC2015191EW) of King Edward Memorial Hospital, Perth. | PMC10706365 | ||
Informed Consent Statement | Informed consent was obtained from the parents of all participants involved in the study prior to participation. | PMC10706365 | ||
Data Availability Statement | Data are unavailable due to privacy and ethical restrictions. | PMC10706365 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC10706365 | ||
References | groin | Relative abundance of bacterial taxa in individual participants. Compositional bar plot shows the mean relative abundance at the genus level for each individual participant at axilla, ear, and groin sites for samples collected on days 1, 7, 14, and 21. Genera that had a relative abundance of <10% are listed as “other”.(Quantitative PCR data for Alpha-diversity metrics for body site: axilla, ear, and groin. (Alpha-diversity metrics for age at sampling: day 1, day 7, day 14, and day 21. (Alpha-diversity metrics for control and intervention arms at each body site. (Beta-diversity NMDS plot for (Quantitative PCR data for coagulase-negative staphylococci from participants at all time points for (Quantitative PCR data for coagulase-negative staphylococci from participants with combined sites and time points. DNA in ng was measured using a standard curve and converted to total genomes per swab. The median for each arm/time point is represented by a black bar (when a median value is 0, the bar is not shown). Each time point was compared between the intervention and control arms using a Mann–Whitney test. Comparisons with significant differences are denoted in each figure (* = Demographic characteristics of very preterm infants in control and intervention arms *.* Data are expressed in medians.Bacterial genera with relative abundances that differed between body sites or with age at sampling. Differential abundance testing was performed with a mixed effects model in MaAsLin2, using Sample ID as a random effect and body site and age at sampling as fixed effects. | PMC10706365 | |
Background and aims | multiorgan failure, inflammation, death, ARDS | INFLAMMATION, CORONAVIRUS, MULTIORGAN FAILURE, ARDS, ACUTE RESPIRATORY DISTRESS SYNDROME | The main causes of death in patients with severe Coronavirus disease-2019 (COVID-19) are acute respiratory distress syndrome (ARDS) and multiorgan failure caused by a severe inflammatory cascade. Novel treatment strategies, such as stem-cell-based therapy and their derivatives can be used to relieve inflammation in these cases. In this study, we aimed to evaluate the safety and efficacy of therapy using mesenchymal stromal cells (MSCs) and their derived extracellular vesicles in COVID-19 patients. | PMC10294333 |
Materials and methods | ARDS | ARDS | COVID-19 patients with ARDS were included in this study and allocated into two study and control groups using block randomization. While all patients received recommended treatment based on guidelines from the national advisory committee for COVID-19 pandemic, the two intervention groups received two consecutive injections of MSCs (100 × 10 | PMC10294333 |
Results | A total number of 43 patients (the MSC alone group = 11, MSC plus EV group = 8, and control group = 24) were included in the final analysis. Mortality was reported in three patients in the MSC alone group (RR: 0.49; 95% CI 0.14–1.11; | PMC10294333 | ||
Keywords | PMC10294333 | |||
Introduction | CORONAVIRUS | Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), was first observed in December 2019 in Wuhan, Hubei province, China [SARS-CoV-2 could infect many organs, mainly through angiotensin-converting enzyme-2 receptor (ACE-2), and other potential receptors like glucose-regulated protein-78 (GRP-78), causing several symptoms in affected individuals [In late 2020, vaccines were developed to prevent COVID-19 [ | PMC10294333 | |
Materials and methods | PMC10294333 | |||
Study design | acute respiratory distress syndrome, ARDS | ARDS, SARS-COV-2 INFECTION, ACUTE RESPIRATORY DISTRESS SYNDROME | This phase II randomized, multicentric clinical trial was conducted on COVID-19 patients with acute respiratory distress syndrome referred to Masih Daneshvari and Shariati hospitals, two major referral centers for COVID-19 hospitalization in Tehran, Iran, during 2020. The inclusion criteria were: age between 18 and 65, confirmation of SARS-CoV-2 infection by qRT-PCR, diagnosis of ARDS according to the Berlin criteria [ | PMC10294333 |
MSC and MSC-derived EVs | We used good manufacturing practice (GMP)-certified MSCs for this study, which underwent a panel of quality control tests as part of their certificate of analysis. The cell preparation protocol was previously described in our study [ | PMC10294333 | ||
Study endpoints | ADVERSE EVENTS | The primary endpoint in this study was assessment of adverse events, based on common terminology criteria for adverse events (CTCAE) version 4 [ | PMC10294333 | |
Statistical analysis | For statistical analysis, the data was entered into version 26 of the Statistical Package for the Social Sciences (SPSS | PMC10294333 | ||
Results | PMC10294333 | |||
General information | At baseline, 43 patients were enrolled in this study, of whom 24 were randomly placed in the control group, 11 were placed in the MSC alone group, and 8 were placed in the MSC plus EV group. The flowchart of the study is presented in Fig. Flowchart of the study | PMC10294333 | ||
Adverse events | ADVERSE EVENT | There was no adverse event (AE) or serious adverse event (SAE) linked to either type of intervention. Collectively, mortality occurred in three patients of the intervention groups (15.87%) and eight patients of the control group (33.4%). Mortality was reported in three patients of the MSC alone group (RR: 0.49; 95% CI 0.14–1.11; | PMC10294333 | |
Clinical symptoms | cough, dyspnea, ARDS | ARDS | In this study, various clinical symptoms were evaluated before and after the intervention. Specifically, symptoms closely associated with ARDS were examined in detail. The cough symptom showed improvement in both intervention groups compared to the control group. Additionally, all patients in the MSC group and nearly 90% of patients in the MSCs plus EVs group and control group had dyspnea at baseline, which decreased to below 10% in each group after the intervention ( | PMC10294333 |
Inflammatory markers | The serum levels of inflammatory markers before and after intervention are presented in Table The inflammatory markers change in study groups. Red: MSC group; blue: MSC + EV group. Data is presented based on median and interquartile range and compared to the control group. *Refers to | PMC10294333 | ||
Discussion | Multiorgan failure, CRS, ARDS, extensive lung damage | SYSTEMIC INFLAMMATORY RESPONSE, SARS-COV-2 INFECTION, ADVERSE EVENTS, CYTOKINE RELEASE SYNDROME, MULTIORGAN FAILURE, ARDS, PATHOGENESIS | In this study, we administered allogenic MSCs to COVID-19 patients who were in the progressive phase of ARDS. We observed that systemic administration of MSC and local administration of MSC-EVs in COVID-19 patients is safe, with minimal adverse events. Furthermore, MSCs had significant effects on inflammatory markers compared to the control group.Evaluating laboratory outcomes of COVID-19 patients after administering MSCs was one of the goals of this study. The unpredictable clinical course of SARS-CoV-2 infection presents a challenging issue in managing COVID-19 [Assessing the laboratory markers of coagulation was another goal of this study. Multiorgan failure due to cytokine storm is usually reported in severe cases of COVID-19 patients, particularly in patients with ARDS [In this study, we also evaluated the impact of MSCs on inflammatory markers. We observed that MSCs significantly decreased the concentration of inflammatory markers in COVID-19 patients. Cytokine release syndrome (CRS), which is a rigorous systemic inflammatory response, may be responsible for severe COVID-19 pathogenesis and extensive lung damage [The decrement of inflammatory cytokines was more pronounced in the case of IL-6, which was reduced by both MSCs and MSCs plus EV administration. However, routine treatment according to national guidelines for COVID-19 did not change IL-6 values in the control group. This finding is particularly valuable considering that IL-6 is a key mediator of cytokine storm and strongly correlates with complicated COVID-19 patients with adverse clinical outcomes [Our study suggested that the administration of MSCs is safe in COVID-19 patients. We observed lower rates of mortality in intervention groups compared to the control group, although this difference was not significant. Previous studies have also demonstrated no adverse events of MSCs in COVID-19 patients [In summary, stem cell therapy, particularly the use of MSCs has emerged as a promising treatment option for severe COVID-19 cases. Several clinical studies have been conducted so far in this regard. Clinical studies have demonstrated that MSC therapy is generally safe and well-tolerated in severe COVID-19 patients, associated with no significant adverse events [This study has certain remarkable advantages. It has one of the largest sample sizes in the national population, providing a suitable view of MSCs administration in Iranian COVID-19 patients. In addition, we assessed basic laboratory parameters and reported their improvement in the MSC treated COVID-19 patients. Another positive aspect of this study is the administration of MSC-EVs through a nebulizing device, which can be an accessible method for COVID-19 patients. However, the current study has some limitations. Many COVID-19 patients with ARDS had been treated with corticosteroids and antiviral drugs before MSCs transfusion, according to the national guideline for treating COVID-19 induced ARDS. This is a confounding variable in assessing the inflammatory markers. Besides, the levels of routine laboratory outcomes in many patients had some abnormality due to the severe condition and we couldn’t assess the exact impact of MSC or MSC-EV on laboratory outcomes. Our medical records did not include any other critical laboratory parameters to include in the study and also, we cannot assess advance laboratory parameters, such as flow cytometric analysis of lymphocytes due to high costs. Furthermore, given the pandemic situation, we could not register their complete laboratory data and this issue was one of the pitfalls of this study. We started the MSC-based at the critical stage of COVID-19 and earlier infusion of MSCs might be associated with better outcomes. Besides, lower sample size of the intervention group was challenging for subgroup analysis. These issues should be addressed in the future studies. In addition, many other molecules and signaling pathways that are essential in the pathogenesis of COVID-19 were not evaluated in this study. | PMC10294333 |
Conclusion | The systemic administration of MSCs and respiratory inhalation of MSC-EVs in COVID-19 patients are safe and associated with improvement in inflammatory markers. The immune modulatory impact of MSCs and MSC-EVs can alleviate cytokine storm and its related consequences in COVID-19 patients. However, further studies with larger sample sizes should be conducted to verify and validate these results. | PMC10294333 | ||
Acknowledgements | The authors deeply appreciate the efforts by their collaborators at Royan ATMP Technology Development Center (ATMP-TDC), Regenerative Medicine Department at Royan institute, QA, QC, and production departments at Cell Tech Pharmed Co., Royan Stem Cell Technology Co., and Royan Ati Tech Pharmed Co., clinicians and nurses at Shariati and Masih Daneshvari hospitals. | PMC10294333 | ||
Author contributions | RA | MZ, MAS, MN, FS, and SHE contributed in drafting manuscript, data collection, and performing follow-up of the patients. SMH, RA, HJ, NK, HA, and HM contributed in the patient’s selection, conducting medical practice and follow-up. AN, AA, SNH, FA, NJ, NF, LT, and MG contributed in quality assurance, quality control, and production. EHS, MV, and HB contributed to the study design, analyzing data, editing the manuscript and final approval of the manuscript. | PMC10294333 | |
Funding | Grants from the Royesh Venture Capital Fund and CellTech Pharmed supported this work. The funding resources provided cell products and covered the costs of hospitalization and laboratory parameters of patients. The funding sources had no responsibilities in the study design, data collection, analysis, and interpretation, manuscript writing, or in the decision to submit this paper for publication. | PMC10294333 | ||
Availability of data and materials | The datasets generated and analyzed during the current study are available upon reasonable request from the corresponding author, after obtaining permission from the national institutional review board of COVID-19 in Iran. All materials used in this study are either commercially available or can be obtained from the corresponding author upon reasonable request. | PMC10294333 | ||
Declarations | PMC10294333 | |||
Ethics approval and consent to participate | We conducted this study in accordance with the Helsinki declaration [ | PMC10294333 | ||
Consent for publication | Not applicable. | PMC10294333 | ||
Competing interests | EHS and MV were collaborating for the industrial manufacturing of the products used in this work, and they declare no financial interest that could have appeared to influence the data reported in this paper. The remaining authors have no conflicts of interest to declare. | PMC10294333 | ||
References | PMC10294333 | |||
1. Introduction | Attention deficit hyperactivity disorder, ADHD, attention deficit hyperactivity disorder | SECONDARY | Synbiotic 2000, a pre + probiotic, reduced comorbid autistic traits and emotion dysregulation in attention deficit hyperactivity disorder (ADHD) patients. Immune activity and bacteria-derived short-chain fatty acids (SCFAs) are microbiota–gut–brain axis mediators. The aim was to investigate Synbiotic 2000 effects on plasma levels of immune activity markers and SCFAs in children and adults with ADHD. ADHD patients (n = 182) completed the 9-week intervention with Synbiotic 2000 or placebo and 156 provided blood samples. Healthy adult controls (n = 57) provided baseline samples. At baseline, adults with ADHD had higher pro-inflammatory sICAM-1 and sVCAM-1 and lower SCFA levels than controls. Children with ADHD had higher baseline sICAM-1, sVCAM-1, IL-12/IL-23p40, IL-2Rα, and lower formic, acetic, and propionic acid levels than adults with ADHD. sICAM-1, sVCAM-1, and propionic acid levels were more abnormal in children on medication. Synbiotic 2000, compared to placebo, reduced IL-12/IL-23p40 and sICAM-1 and increased propionic acid levels in children on medication. SCFAs correlated negatively with sICAM-1 and sVCAM-1. Preliminary human aortic smooth-muscle-cell experiments indicated that SCFAs protected against IL-1β-induced ICAM-1 expression. These findings suggest that treatment with Synbiotic 2000 reduces IL12/IL-23p40 and sICAM-1 and increases propionic acid levels in children with ADHD. Propionic acid, together with formic and acetic acid, may contribute to the lowering of the higher-than-normal sICAM-1 levels.Attention deficit hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental psychiatric disorder with about 5% worldwide prevalence among children and adolescents and 3% in adults [Preclinical studies from germ-free and antibiotic drug-treated mouse models have shown that the absence or alteration of normal gut microbiota early in life has significant effects on immune activity [Short-chain fatty acids (SCFAs) have been proposed to be messengers for microbiota–gut–brain communication. They are fatty acids with less than six carbon atoms, which are mainly generated by anaerobic colonic bacteria via fermentation of dietary fibers or branched-chain amino acids [Immune activity is also considered to be an important mediator in the microbiota–gut–brain axis [The aim of this study was to explore the effects of Synbiotic 2000 on concentrations of plasma immune activity markers and SCFAs in ADHD. These analyte concentrations constitute secondary outcome measures in the placebo-controlled randomized trial ISRCTN57795429 ( | PMC10004766 |
2. Materials and Methods | PMC10004766 | |||
2.1. Participants | psychiatric, ADHD | All participants in this study, including ADHD patients and healthy controls, were recruited through a double-blind randomized controlled trial (ISRCTN57795429) of Synbiotic 2000 intervention performed between January 2016 and June 2018 at psychiatric clinics in Stockholm, Sweden, as previously described [ | PMC10004766 | |
2.2. Interventions | Synbiotic 2000, the active treatment provided by Synbiotics AB Sweden for free, consisted of lyophilized 4 × 10 | PMC10004766 | ||
2.3. Analysis of Plasma Immune Activity Markers | Peripheral blood was collected in tubes containing EDTA. Immediately after collection, the tubes were centrifuged at 1700× | PMC10004766 | ||
2.4. Analysis of Plasma Short-Chain Fatty Acids (SCFAs) | SCFAs (formic, acetic, propionic, butyric, isobutyric, succinic, valeric, isovaleric, and caproic acid) were analyzed in EDTA plasma by liquid chromatography–mass spectrometry (LC-MS) according to a method described previously [ | PMC10004766 | ||
2.5. Cell Culture | Human aortic vascular smooth muscle cell line (hAVSMCs), developed from a 23 years old African American healthy female, was purchased from (ATCC, Manassas, VA, USA, | PMC10004766 | ||
2.6. Statistical Analysis | ADHD | Analysis of differences in analyte levels between diagnosis groups (control versus ADHD patient), age groups (child versus adult), medication groups (yes versus no), and sexes (males versus females) was performed using Mann–Whitney U tests. Statistical relationships between two analytes were assessed by applying Spearman’s rank correlation tests. Descriptive statistics are presented with median levels and IQR. To correct for multiple testing, false discovery rate (FDR)-adjusted | PMC10004766 | |
3. Results | PMC10004766 | |||
3.1. Baseline Levels of Immune Activity Markers in ADHD Patients | ADHD | Clinical characteristics of the study participants, being pediatric and adult ADHD patients and adult healthy controls, are summarized in The healthy controls included were from two categories, healthy family members and unrelated individuals. The baseline levels of eotaxin-1, fractalkine, MCP-1, TGF-β3, and TRAIL differed between these two groups of controls ( | PMC10004766 | |
3.2. Effects of Synbiotic 2000 on Immune Activity Markers | ADHD | Children treated with Synbiotic 2000 showed a significant reduction of levels of IL-12/IL23p40, sICAM-1, and TGF-β3 from baseline to 9-week follow-up, while children treated with placebo did not show any level change of any immune activity marker over time (Among children with ADHD, pro-inflammatory cytokine IL-12/IL-23p40 was reduced by Synbiotic 2000 compared to by placebo, at α = 0.05, defined as the suggestive difference (95% CI: −0.158, −0.014, | PMC10004766 | |
3.3. Baseline Levels of Short-Chain Fatty Acids (SCFAs) in ADHD Patients | ADHD | Plasma concentrations of six SCFAs were analyzed in the ADHD patients and the healthy controls. We found that the shorter SCFAs (formic acid, acetic acid, propionic acid, and succinic acid) were significantly correlated with each other in both controls and patients (Comparing levels between pediatric and adult ADHD patients, concentrations of formic acid ( | PMC10004766 | |
3.4. Effects of Synbiotic 2000 on SCFAs | No significant changes in SCFA concentrations from baseline to follow-up were found neither for those on placebo nor those treated with Synbiotic 2000 for neither children nor adults (As shown in | PMC10004766 | ||
3.5. Associations between Immune Activity Markers and SCFAs | ADHD | Immune activity markers and SCFAs are both important components in the microbiota–gut–brain axis, and a small number of cellular in vitro studies have reported the effects of butyrate on a few immune activity markers. We performed a correlation analysis between plasma levels of the immune activity markers and concentrations of the SCFAs, which we, in the aforementioned analyses, found to be different in ADHD compared to controls (all controls for immune activity markers and family controls for SCFAs). In children with ADHD, baseline acetic acid levels were significantly negatively correlated with pro-inflammatory sICAM-1 and sVCAM-1 ( | PMC10004766 | |
3.6. Effects of SCFAs on ICAM-1 Expression in Human Aortic Vascular Smooth Muscle Cells In Vitro | human aortic vascular smooth muscle | To further validate the negative correlations between SCFAs and sICAM-1, we did three independent in vitro experiments in human aortic vascular smooth muscle cells. Our results showed lower IL-1β-induced ICAM-1 expression when the cells were pre-incubated with formic acid, acetic acid, or propionic acid of the concentrations found in plasma ( | PMC10004766 | |
4. Discussion | autistic traits, IBD, ADHD | PATHOLOGY, INFLAMMATORY BOWEL DISEASE | This study is the first to report the effects of a synbiotic intervention on plasma levels of immune activity markers and SCFAs in children and adults with ADHD. We previously reported that this intervention in an RCT design reduced autistic traits in children and improved emotion regulation in adults with ADHD [IL-12 and IL-23 are heterodimers and share the p40 subunit called IL-12/IL-23p40. IL-12 and IL-23 promote Th1 and Th17 expansion, respectively, and are reported to be involved in the pathology of inflammatory bowel disease (IBD). The p40 subunit is a therapeutic target in IBD [Notably, the pattern of correlations between levels of immune activity markers and SCFAs detected in ADHD patients was not found in controls, suggesting that the associations between immune activity analytes and SCFAs are not generalizable beyond ADHD but depend on a complex regulation at physiological conditions (To our knowledge, we are the first to report plasma levels of fractalkine, GRO-α, IL-12/IL-23p40, IL-18, IL-2Rα, TGF-β1, TGF-β2, TGF-β3, TRAIL, and VEFG-A in individuals with ADHD. The adult ADHD patients displayed at baseline different levels only of pro-inflammatory sICAM-1 and sVCAM-1 compared to the whole control group. Compared to the adults with ADHD, the children with ADHD had different baseline levels of eight of the immune activity markers and were hence analyzed separately. Most of these differences in marker levels between children and adults are not previously reported, neither in ADHD patients nor healthy individuals. Levels at baseline of eotaxin-1, fractalkine, MCP-1, TGF-β3, and TRAIL were higher in healthy family members of the ADHD patients than among healthy unrelated controls. Both genetic and environmental underpinnings may explain this, although there is no report showing that these markers are higher in persons with ADHD. The plasma SCFA concentrations at baseline of the patients and family controls of this study were previously reported to show lower levels of plasma formic and propionic acid in adults with ADHD compared to family controls after controlling for antibiotic drug exposure and other potential influencing factors [The sample size of our RCT was relatively large, including 182 children and adults. An additional main strength is that the conducted in vitro experiments of SCFAs possible anti-inflammatory effect was at physiological SCFA levels. There are limitations to this study. First, there were only four healthy controls for children, and hence, we could not analyze this group. Therefore, we were unable to adequately relate the analyte levels in children with ADHD to reference values. Second, our data on medications with anti-inflammatory effects (melatonin, antidepressants, antipsychotics, anxiolytics, sleeping pills, proton-pump inhibitors, and statins) or medications with gut microbiome effects (melatonin, antipsychotics, or antidepressants) ( | PMC10004766 |
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