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Project information and funding | This trial was executed under the model project of Social Impact Bond—one of the styles of Pay for Success policy constructed by the City of Yokohama—with a business contract between the City of Yokohama, Kids Public, Inc., the University of Tokyo, and other stakeholders. Kids Public, Inc. collected personal information, such as names and e-mail addresses, as part of their services and shared this data with the research team under the participants’ agreement. The research team was solely responsible for constructing the questionnaire, collecting baseline and outcome data, conducting the analyses, and drafting the manuscript. Details of the Pay for Success project are described in Additional file | PMC10294407 | ||
Discussion | depression, depressive symptoms | Compared to the participants assigned to the usual care group, those assigned to the mHealth group—where they could use mHealth consultation services according to their needs free of charge—had a lower risk of elevated postpartum depressive symptoms three months after delivery. Women assigned to the mHealth group tended to display higher parenting self-efficacy, lower levels of loneliness, and fewer perceived barriers to healthcare access. No differences were observed in the number of medical facilities used between the groups. Among the participants in the mHealth group, those who consulted with midwives and those who used the chat consultations tended to have a decreased risk of elevated postpartum depressive symptoms. Importantly, despite the general concerns that new technology may expand the socioeconomic disparity in health and healthcare use [The difference between our findings and those of a recent study indicating mixed results on the effect of mHealth-based prevention for PPD may be attributed to the features of timeliness [Compared to these studies, the most remarkable advantage of our intervention was the timeliness and appropriateness of the consultation, as the services provided technology-based interactive, synchronous communication. Although reservations were necessary for consultations, women could consult even after a few minutes when they needed help if a professional was available. After childbirth, women could consult with midwives through text-based chatting without reservation or time limitations. A participant in the mHealth group commented in an open-ended questionnaire asking about the study participation, at three months post-delivery, that, “When I had concerns or something I did not know about childcare, I researched these things by myself, but I could not judge whether the results I found suited me or determine what I should do. At that time, it was very reassuring to be able to consult with healthcare professionals immediately through mHealth service.” (All comments related to the intervention were listed in Additional file Removing psychological barriers to healthcare may be another critical mechanism for preventing postpartum depressive symptoms. Using the mHealth app can be a strategy to overcome fear of stigma or judgment in vulnerable populations [Other potential mechanisms include enhanced parenting self-efficacy [This study has several limitations. First, the generalizability of our findings is limited given that our study participants were only Japanese speakers having Internet access and almost all participants were over 20 years of age with a partner. The lack of clear standardized procedures during consultations also limits generalizability. When implementing similar services that this study evaluated, the content should be arranged according to the setting in which they are implemented. We also note that the effect size of the service shown in this study may vary depending on the setting. As our study participants had a higher percentage of elevated depressive symptoms at baseline compared to the previous review, partially due to the COVID-19 pandemic, the intervention effect may differ in situations outside the pandemic. Second, the attrition rate (13%) may lead to biased results, although sensitivity analysis with multiple imputations showed nearly the same results. Third, we did not use a formal clinical diagnosis of PPD as the primary outcome; however, the EPDS is a well-validated scale for the diagnostic interview for depression around the world [ | PMC10294407 | |
Conclusions | This was the first randomized controlled trial to investigate the effectiveness of mHealth consultation services in preventing PPD during the COVID-19 pandemic. Our study showed the considerable potential of mHealth interventions and possible mechanisms to prevent PPD and ensure equity in services in real-world settings. Removing physical and psychosocial barriers to healthcare through mHealth can be a valuable option to improve perinatal mental health in local government policies. Future studies should explore the effective components of mHealth consultation and detailed mechanisms for preventing PPD and evaluate whether these services reduce the disparity in PPD onset across socioeconomic statuses [ | PMC10294407 | ||
Acknowledgements | Hashimoto | HASHIMOTO, RECRUITMENT | Mitsuru Nakao, Co-Governance and Creation Division, Policy Bureau, the City of Yokohama; Naoya Hashimoto, Kids Public, Inc.; and Daisuke Shigemi, Kids Public, Inc., discussed how to implement this study in a real-world setting with our study team. Yuji Watanabe, the City of Yokohama; Kenta Tamura, the City of Yokohama; and Toru Nagami, the City of Yokohama, assisted with recruitment and birthday confirmation. Hanae Nagata, MD, MPH; Kaori Sumino, MPH; Keiko Ueno, MD, MPH, PhD; Minami Koda, MPH; Saki Nakamura, MPH; and Hisako Ogasawara, MD, MPH, supported the improvement of the online questionnaires. | PMC10294407 |
Authors’ contributions | YA and NK had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. | PMC10294407 | ||
Funding | This trial was funded by the City of Yokohama. The service provider, Kids Public, Inc. offered the mobile health consultation service funded by the City of Yokohama. This work was supported by the Japan Society for the Promotion of Science (No. 26670306, 18H04071). Before the study was constructed, the University of Tokyo, the City of Yokohama, and Kids Public Inc. discussed the study design. The research team coordinated with members of the City of Yokohama to recruit participants. Kids Public Inc. collected participants’ personal information and shared it with the research team (with participants’ consent). Only the research team created the study protocol, collected data at baseline, and three months after delivery, analyzed the data, and edited the manuscript. The City of Yokohama and Kids Public Inc. had the opportunity to conduct a fact-check of the manuscript before submission; however, the authors had full editorial control of the manuscript and provided final approval for all content. | PMC10294407 | ||
Availability of data and materials | The data are available from the corresponding author on reasonable request. | PMC10294407 | ||
Declarations | PMC10294407 | |||
Ethics approval and consent to participate | The study was conducted in accordance with the principles of the Declaration of Helsinki and relevant local/international guidelines. The study protocol was approved by the ethical review board of the University of Tokyo (no. 2019347NI). All participants provided informed consent to participate in this study by submitting an online form. | PMC10294407 | ||
Consent for publication | Not applicable. | PMC10294407 | ||
Competing interests | DN2 reports personal fees from Startia, Inc.; en-power, Inc.; MD.net; and AIG General Insurance Company, Ltd. outside the submitted work. | PMC10294407 | ||
References | PMC10294407 | |||
Methods | anemia, birth anomalies | ADVERSE EVENTS, PRETERM LABOR, PRETERM RUPTURE OF MEMBRANES, ANEMIA | A pilot open-label randomized clinical trial. Participants with confirmed diagnosis of anemia in three tertiary hospitals in Nigeria were studied. Eligible participants were randomized 1:1 to either Mojeaga syrups 50 mls (200mg/50mls) administered three times daily in conjunction with conventional iron therapy (Mojeaga group) for 2 weeks or conventional iron therapy alone without Mojeaga (standard-of-care group) for 2 weeks. Repeat hematocrit level were done 2 weeks post-initial therapy. Primary outcome measures were changes in hematocrit level and median hematocrit level at two weeks post therapy. Maternal adverse events and neonatal outcomes (birth anomalies, low birthweight, preterm rupture of membranes and preterm labor) were considered the safety outcome measures. Analysis was by intention-to-treat. | PMC10166496 |
Results | deaths, congenital anomalies | ADVERSE EVENTS | Ninety five participants were enrolled and randomly assigned to the Mojeaga group (n = 48) or standard-of-care group (n = 47). The baseline socio-demographic and clinical characteristics of the study participants were similar. At two weeks follow-up the median rise in hematocrit values from baseline (10.00±7.00% vs 6.00±4.00%;p<0.001) and median hematocrit values (31.00±2.00% vs 27.00±3.00%;p<0.001) were significantly higher in the Mojeaga group. There were no treatment-related serious adverse events, congenital anomalies or deaths in the Mojeaga group and incidence of other neonatal outcomes were similar (p>0.05). | PMC10166496 |
Conclusion | congenital anomalies, anemia | ANEMIA DURING PREGNANCY, ANEMIA | Mojeaga represents a new adjuvants for standard-of-care option for patients with anemia. Mojeaga remedy is safe for treating anemia during pregnancy and puerperium without increasing the incidence of congenital anomalies, or adverse neonatal outcomes. | PMC10166496 |
Data Availability | All relevant data are within the paper and its | PMC10166496 | ||
Introduction | anemia, constipation, Anemia, IDA, nausea, vomiting | IRON DEFICIENCY ANEMIA, ANEMIA, IRON DEFICIENCY, ANEMIA | Anemia in women is a major public health burden worldwide, particularly in low- and middle-income countries [Iron deficiency anemia (IDA) is often treated with oral iron supplements even in pregnancy. However, due to gastrointestinal side effects such as nausea, vomiting, and constipation, compliance is often poor and results in subsequent discontinuation [Mojeaga herbal remedy (produced by Mojeaga International Ventures Ltd, Nigeria) is a natural preparation containing a combined Therapy with Mojeaga herbal remedy has emerged as one of the adjuncts to conventional therapy for the treatment of anemia in the obstetric population. It is uncertain the benefits and safety of the therapy in the obstetric population, and whether the two weeks’ duration of therapy should suffice for clinical practice. According to current UK guidelines on the management of iron deficiency in pregnancy by Pavord et al., it was revealed that for anemic women, a trial of oral iron should be considered as the first line diagnostic test, whereby an increment demonstrated at two weeks is a positive result [To the best of our knowledge, this is the first randomized trial on the efficacy and safety of combined Mojeaga and oral iron therapy schedule. Therefore, this study determined the efficacy, safety and tolerability of mojeaga remedy as an adjunct to conventional oral iron therapy (standard-of-care) for correcting anemia in the obstetric population. | PMC10166496 |
Methods | PMC10166496 | |||
Study setting | The study was carried out at the antenatal (obstetrics) clinics of Nnamdi Azikiwe University Teaching Hospital (NAUTH), Nnewi, Enugu State University of Science and Technology Teaching hospital, Parklane, Enugu and Chukwuemeka Odumegwu Ojukwu University Teaching Hospital, Awka, all are tertiary hospitals in South-east Nigeria. | PMC10166496 | ||
Study design | This was an open-label randomized clinical trial. | PMC10166496 | ||
Study population | anemia | RECRUITMENT, ANEMIA | The participants comprised obstetrics participants with clinical and laboratory diagnosis of anemia and gave written informed consent before recruitment. The participants were recruited at the antenatal clinics or referred for treatment of their anemia from other hospitals. Participants were recruited before to commencing the intervention and control agents. | PMC10166496 |
Inclusion criteria | Anemia, anemia | ANEMIA, ANEMIA IN PREGNANCY, ANEMIA | Inclusion criteria included obstetrics adult participants with confirmed clinical and laboratory diagnosis of anemia (hematocrit of <31.5%) and with normal liver and renal function markers or profiles. Anemia was confirmed by prospective expert hematology review. In this study, significant anemia in pregnancy is defined as a hemoglobin concentration <11 g/dL (or hematocrit <33.0%) in the first trimester or <10.5 g/dL (or hematocrit <31.5%) in the second and third trimesters [ | PMC10166496 |
Exclusion criteria | nausea and vomiting, anemia, cancers, chronic medical disorders | CANCERS, ANEMIA | Pregnant women in the first trimester of pregnancy (because of nausea and vomiting during this period), chronic medical disorders including HIV/AIDS, cancers, etc. and women on chronic medications that cause anemia were excluded. | PMC10166496 |
Randomization and allocation sequence | Following consent, patients at the selected hospitals were screened for eligibility. The participants, eligible for the study, were randomized into two groups (blocks of 4, 1:1 ratio) using block randomization using a randomization table created by a computer software program by a person not involved in the study and available at | PMC10166496 | ||
Blinding of participants, personnel and outcome assessors | Only the outcome assessors were blinded. The study was open-label, with both participants and investigators aware of treatment assignment. | PMC10166496 | ||
Study procedure/Drug administration | anemia | ANEMIA | Participants with a clinical and laboratory diagnosis of anemia presenting in Outpatient Clinic or antenatal clinic of the study hospitals for symptoms or signs of anemia were screened consecutively. All participants underwent routine medical examination that included pulse rate, body weight, blood pressure determination and general examination to ascertain the presence of and severity of anemia. All consenting participants were diagnosed to have either anemia or not after undergoing the hematological test. Only patients with confirmed clinical and laboratory diagnosis of anemia were randomized. Eligible participants were sequentially allocated using an opaque sealed envelope to receive either Mojeaga and conventional oral Therapy, or the conventional oral iron Therapy alone. Therapies were given for two weeks. | PMC10166496 |
Intervention therapy | Standard doses of 50 mls (200mg/50mls) of Mojeaga were administered three times daily in conjunction with conventional iron therapy (standard-of-care) two times a day (breakfast and dinner) for 2 weeks. | PMC10166496 | ||
Control therapy | Standard/conventional doses of iron therapy (standard-of-care) were administered two times a day (breakfast and dinner) for 2 weeks. The standard-of-care consist of standard doses of one capsule of Astyfer (a supplement with Ferrous fumarate 150mg, Glycine 10mg, L-Histidine hydrochloride H | PMC10166496 | ||
Follow-up | anemia, nausea, vomiting, bowel disturbances | SIDE EFFECT, ADVERSE EVENTS, ANEMIA, ADVERSE EFFECTS, EVENTS, COMPLICATIONS | All participants were followed up in outpatient settings. During each follow-up weekly visit, participants were contacted on phone on weekly basis to assess the level of compliance with the trial drugs. Participants were informed about the usual side effect of hematinic preparations and were told to report nausea, vomiting, bowel disturbances, or any other complications. Where possible, the participants were also encouraged to record any side effects or adverse events in a paper that was reviewed at each follow-up visit, and they were explicitly asked about such events during each interview. Where possible, the drug compliance was checked before follow-up test and at follow-up visit by checking the used drug packets. Any participants found to be developing complications such as worsening of the symptoms from the study were given appropriate treatment. Repeat hematocrit level was done 2 weeks post initiation of treatment in all the participants to confirm or refute success of the treatment (correction of anemia and levels of hematocrit) and absence/presence of adverse effects. All the pre and post (repeat) hematocrit level were carried out by a Hematologist, while the liver function test (LFT) and serum electrolytes, urea and creatinine (SEUCR) were carried out by the senior laboratory Scientist of Chemical Pathology in Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria laboratory and the other two collaborating hospitals. | PMC10166496 |
Outcome measures | PMC10166496 | |||
Primary | The primary endpoint included changes in the hematocrit level and mean or median hematocrit level at two weeks after initial therapy. | PMC10166496 | ||
Secondary | diarrhea, birth anomaly, pain, dizziness, nausea,, colitis | ADVERSE EVENTS, PRETERM PREMATURE RUPTURE OF MEMBRANES, ADVERSE EFFECTS, SECONDARY, PRETERM LABOR, COLITIS | The secondary endpoints included the proportion of patients with persisting anemic symptoms (epigastric pain, weakness, dizziness) at two weeks after initial therapy, incidence of any maternal adverse events (such as diarrhea, nausea, vomiting, colitis and drop-out from adverse effects) following commencement of therapy, incidence of any fetal adverse events (such as preterm labor, preterm premature rupture of membranes, low birthweight or birth anomaly) following commencement of therapy, mean levels of renal function parameters (serum electrolyte, urea and creatinine) at two weeks after initial therapy and mean levels of liver function parameters (aspartate transaminase (AST); alkaline phosphatase (ALP); and alanine transaminase (ALT)) at two weeks after initial therapy. As safety variables, adverse events were monitored throughout the whole study period from the signature of the informed consent form up to the last visit. | PMC10166496 |
Sample size determination | Since this is a pilot study, we assumed a mean hematocrit level of 29.1% in the control group, mean hematocrit level of 31.5% in the intervention group after the intervention [ | PMC10166496 | ||
Sampling approach | All individuals during the period from February 27, 2020 to February 20, 2022, after satisfying the inclusion and the exclusion criteria were randomly allocated. | PMC10166496 | ||
Drug active dose validation/standardization | The cover of the Mojeaga remedy bottle has a measuring cap which is of 25 mls capacity for uniform administration and validation. Each 500mls of Mojeaga remedy contains 2069.57 mg of active Mojeaga remedy [ | PMC10166496 | ||
Statistical analysis | Data was analyzed using SPSS version 23, IBM Company, USA. The data were expressed as the number (percentage), mean (standard deviation [SD]) or median (±interquartile range), and 95% confidence interval [95% CI] as appropriate. Categorical variables were compared using the Chi-squared test and Fisher’s exact test, as necessary and relationship expressed using relative risks and 95% confidence intervals. Independent t-test or Mann-Whitney U-test was used to compare mean (±standard deviation) or median (±interquartile range) of continuous variables between treatment groups, depending on their normality of distribution. The intention-to-treat efficacy analysis was based on all the patients who received the study medication and had completed the follow-up visit. Interim analyses were done after 30 participants have been recruited. Participants with no observed outcome were considered as treatment failures. When possible, subgroup analysis were also done, where applicable. A p value of <0.05 was considered to be significant. Interim analyses of principal safety and efficacy outcomes were performed on behalf of the data and safety monitoring committee by the trial statistician (who remained unaware of the treatment assignments). The authors acknowledge the slip in planning the statistical analysis as both the interim analysis and the final analysis were performed (without attempting to make any adjustments, with respect to maintaining Type I error overall or for the final analysis). The result of interim analysis was presented as an abstract/E-poster in the XXIII World Congress of Gynecology and Obstetrics (FIGO) held virtually in Australia in October 2021, and is available at | PMC10166496 | ||
Ethical consideration | The study adhered to CONSORT guidelines [ | PMC10166496 | ||
Certification of analysis | To ensure a high quality standardized formulations, the raw material was authenticated and the product was laboratory tested and certified by Prof JU Iyasele of Chemistry Department, University of Benin, Nigeria in accordance with Institute of Public analyst of Nigeria Decree no 100 of 1992. | PMC10166496 | ||
Results | PMC10166496 | |||
Baseline characteristics | Between February 27, 2020, and February 20, 2022, two hundred and sixty seven participants were assessed for eligibility, 72 participants were excluded for different reasons (58 did not meet the inclusion criteria: HIV/AIDS (25); first trimester pregnancy (17) and declined to participate (16)), while 95 eligible participants were enrolled and randomly assigned to the Mojeaga group (n = 48) or the standard-of-care group (n = 47; | PMC10166496 | ||
Flowchart of the participants. | Of the 95 participants, 85 were pregnant: Mojeaga group (n = 42) and standard-of-care group (n = 43), while 10 were puerperal women (Mojeaga group (n = 6) and standard-of-care group (n = 4). So far, all 95 participants completed the treatment and were included in analysis.As shown in | PMC10166496 | ||
Distribution of sociodemographic variables across research groups. | Abbreviations: BMI = Body mass index; SSCE = Senior school certificate examination; OND = Ordinary National diploma; HND = Higher national diploma; BSC = Bachelor of science; SD = Standard deviationAdditionally, the baseline pre-therapy hematocrit level, pre-therapy serum electrolyte, urea and creatinine level and liver function test parameters were similar in both groups (p>0.05). The details are as shown in | PMC10166496 | ||
Comparison of pre-treatment serum variables between research groups. | Abbreviations: Na (NR) = Sodium (Normal range: 135–145); K = Potassium (NR 3.5–5.5); Cl = Chloride (NR 96–106); Bicarbonate (NR 21–31); Urea (NR 1.7–9.1); Creatinine (NR 53–106); AST = Aspartase transaminase (NR 1–40); ALP = Alkaline phosphatase (NR 60–170); ALT = Alanine transaminase (NR 1–40); Hematocrit (NR 30–54); IR = Interquartile range. | PMC10166496 | ||
Primary endpoints | PMC10166496 | |||
Median rise in hematocrit values | The median rise in hematocrit values at two weeks follow-up was significantly higher in Mojeaga group (10.00±7.00% vs 6.00±4.00%; p<0.001). Similarly, the median hematocrit values at two weeks follow-up were significantly higher in Mojeaga group (31.00±2.00% vs 27.700±3.00%; p<0.001). This is shown in | PMC10166496 | ||
Comparison of hematocrit parameters (primary outcome) among research groups after treatment. | Abbreviations: IR = interquartile range | PMC10166496 | ||
Comparison of symptom resolution between research groups pre and post-therapy. | PMC10166496 | |||
Proportion of participants with persisting anemic symptoms (epigastric pain, weakness, dizziness) at two weeks after initial therapy | Persistent anemic symptoms were reported in 4.2% of the Mojeaga group and 8.5% of the control group (p = 0.329). There were no cases of treatment failure. | PMC10166496 | ||
Comparison of incidence of fetal adverse events among research groups. | PROM, Premature rupture | Abbreviations: PROM = Premature rupture of fetal membranes;Not available* = Those that was recruited at puerperal period. | PMC10166496 | |
Frequency of adverse effects in research groups during treatment. | PMC10166496 | |||
Comparison of serum electrolyte and function tests of all research participants at post-therapy. | Abbreviations: Na (NR) = Sodium (Normal range: 135–145); K = Potassium (NR 3.5–5.5); Cl = Chloride (NR 96–106); Bicarbonate (NR 21–31); Urea (NR 1.7–9.1); Creatinine (NR 53–106); AST = Aspartase transaminase (NR 1–40); ALP = Alkaline phosphatase (NR 60–170); ALT = Alanine transaminase (NR 1–40); Hematocrit (NR 30–54); IR = Interquartile range. | PMC10166496 | ||
Median levels of liver function parameters (AST, ALT and ALP) at two weeks after initial therapy | As shown in | PMC10166496 | ||
Discussion | toxicity, congenital anomalies, hepatic and renal functions, anemia | ANEMIA IN PREGNANCY, STILL, ADVERSE EVENTS, RECRUITMENT, ANEMIA, WORMS, PRETERM LABOR, DISEASES | This trial which is the first positive randomized trial involving Mojeaga therapy in women with anemia shows that Mojeaga therapy improves anemia compared with the use of standard of care alone. Until now, treatment recommendations for moderate and severe anemia in pregnancy and gynecological patients were based on the use of parenteral therapy and blood transfusion and occasionally oral therapy. The findings of this study suggest that concomitant use of standard iron therapy with Mojeaga improves efficacy with significant rise in hematocrit and higher hematocrit level.In this study, the median rise in hematocrit values at two weeks follow-up was significantly higher in Mojeaga group compared to the standard-of-care group (10.00±7.00% vs 6.00±4.00%; p<0.001). Also, the mean hematocrit values at two weeks follow-up were significantly higher in Mojeaga group (p<0.001). The apparent anemia recovery benefit of Mojeaga regardless of pregnant or no-pregnant status suggests that Mojeaga is promising adjuvant therapy for anemia. This benefit could be due to high amount of natural iron in the Mojeaga formulations. Similarly, the previous case report by Eleje et al on the use of Mojeaga re-counted improvements in anemia symptoms in women that received Mojeaga remedy [The findings of our study raise the question of the mechanism of action of Mojeaga in the treatment of anemia in obstetrics population. Although the exact mechanism of action is not known, Mojeaga may work by accelerating a rapid turn-over of the bone-marrow erythropoiesis. This possible mechanisms was revealed by the findings of Idu et al that showed that the histo-architectural structure of the bone marrow of the experimental animals showed a stimulating effect of myeloid/erythroid cell ratio > 60 in the treatment (Mojeaga) groups when compared with control groups [Our randomized controlled clinical trial showed that Mojeaga has a favorable safety profile, and also when combined with the conventional oral iron therapy. The frequency of adverse events, abnormal laboratory analysis, vital signs, and physical findings was similar across the two treatment groups. Although serum bicarbonate level was different in both study groups, the overall bicarbonate levels were within the normal limits. Similarly, in a recent preclinical study by Idu et al that evaluated the toxicological profile of Mojeaga herbal remedy on male and female animal models, acute and chronic toxicity of Mojeaga herbal remedy in male and female Wistar rats were investigated through thorough examination of mortality rate, body and organ weight changes, hematological indexes, biomarkers of hepatic and renal functions and histopathological study across all treatment groups using standard protocol [One clinical implications of our study findings was that in the study, we adopted the two weeks assessment for efficacy of intervention of anemia because, a prior case report reported a two week therapy [Additionally, our protocol for assessing efficacy of intervention of anemia in two weeks was similar to a French study by Broche et al on iron use in pregnancy [It is noteworthy of the issues related to the clinical benefit and risks of adding a product during pregnancy that has unknown mechanism of action and which was associated with a greater hematocrit improvement at two weeks but little difference in clinical symptoms. Anecdotal report has revealed that the majority of pregnant women use the Mojeaga medication during pregnancy despite the unavailability of evidence-based information about its teratogenic risks. Still, this medication use during pregnancy will continue to raise uncertainty and concern among pregnant women and their health care providers. This is one of the impetus for this present study.Whilst interpreting the results of this study, several strengths and shortcomings arose which required consideration. The strengths of the study include the good uptake and inclusion of a representative sample of participants from obstetrics units across a range of socioeconomic groups and hospitals, the near-complete follow-up period allowing complete case analysis, and limiting bias in the results. Therapeutic options for women with anemia especially those who refuse blood transfusion have been scarce, in part because recruitment challenges have made randomized controlled trials in cases with anemia requiring oral therapy infeasible. Our study has overcome this challenge. This study was the first randomized trial to evaluate the effectiveness, safety and tolerability of Mojeaga as adjunct to conventional oral iron therapy for correction of anemia in obstetrics population. One potential weakness of this study was the bias of individual investigators to open label nature of the trial. To control this, the protocol required blinded intervention sequence and computer-generated random numbers. Additionally, the intention-to-treat analysis was employed with resultant marked benefit associated with Mojeaga, supporting the evidence for improvement in anemia symptoms. This study did not control for worms or helminthic diseases which could be attributable as one of the causes of anemia in pregnancy, as the participants did not routinely receive antihelminthic therapy such as mebendazole during pregnancy. Although during the study, the two groups experienced comparable decrease in fetal adverse events, there were no recorded congenital anomalies and no changes in incidence of preterm labor, and low birth weight in either group. This finding should be interpreted with caution because our study is a very small study with only 44 women given the investigational product in pregnancy. Therefore, an absence of adverse events in such a small cohort does not establish safety. There are also some limitations of prior safety and mechanistic data and the limitations of the study design and outcomes. For example, the present study is an open label trial as phase I and phase II trials are often open label [ | PMC10166496 |
Conclusion | congenital anomalies, anemia | ADVERSE EVENTS, ANEMIA DURING PREGNANCY, ANEMIA | In conclusion, based on the findings of our study, Mojeaga should be considered a new adjuvants to standard-of-care option for pregnant and puerperal women with anemia. Mojeaga remedy is safe for treating anemia during pregnancy and puerperium without increasing the incidence of congenital anomalies, low birthweight, preterm labor/rupture of membranes or other adverse events. These findings, therefore, suggest the potential benefit of Mojeaga for treating patients with anemia and support for further adequately powered confirmatory trials investigating the efficacy and safety of Mojeaga remedy. | PMC10166496 |
Supporting information | PMC10166496 | |||
CONSORT 2010 checklist of information to include when reporting a randomised trial*. | (DOC)Click here for additional data file.(DOCX)Click here for additional data file.(XLSX)Click here for additional data file.The study was coordinated by the Effective Care Research Unit at Nnamdi Azikiwe University University, Awka, Nigeria. The authors appreciate the help of the staff of Nnamdi Azikiwe University University Teaching Hospital (NAUTH), Nnewi, Nigeria; Enugu State University of Science and Technology Teaching hospital, Parklane, Enugu, Nigeria and Chukwuemeka Odumegwu Ojukwu University Teaching Hospital, Awka, Nigeria and participants involved in the trial. Publication of these results should not be considered an endorsement of any product used in this study by the Nnamdi Azikiwe University or any of the organizations where the authors are affiliated. | PMC10166496 | ||
Background and purpose | cardioembolic stroke, cardioembolic ischemic stroke | The efficacy and safety of tirofiban in endovascular therapy for cardioembolic ischemic stroke patients remain controversial. This study aimed to evaluate the role of intravenous tirofiban before endovascular therapy in cardioembolic stroke. | PMC10621173 | |
Methods | sICH, stroke, cardioembolism, Vessel Occlusion Stroke, disability | INTRACRANIAL HEMORRHAGE, STROKE | This post hoc analysis utilized data from the RESCUE BT (Endovascular Treatment With versus Without Tirofiban for Patients with Large Vessel Occlusion Stroke) trial, which was an investigator-initiated, randomized, double-blind, placebo-controlled trial. Participants were randomized to receive either tirofiban or a placebo in a 1:1 ratio before undergoing endovascular therapy. The study included patients aged 18 years or older, presenting with occlusion of the internal carotid artery or middle cerebral artery (MCA) M1/M2 within 24 h of the last known well time, and with a stroke etiology of cardioembolism. The primary efficacy outcome was global disability at 90 days, assessed using the modified Rankin Scale (mRS). The safety outcome included symptomatic intracranial hemorrhage (sICH) within 48 h and mortality within 90 days. | PMC10621173 |
Results | cardioembolic stroke | A total of 406 cardioembolic stroke patients were included in this study, with 212 assigned to the tirofiban group and 194 assigned to the placebo group. Tirofiban treatment did not correlate with a favorable shift towards a lower 90-day mRS score (adjusted common odds ratio [OR], 0.91; 95% CI 0.64–1.3; | PMC10621173 | |
Conclusions | sICH, disability, cardioembolic stroke | Tirofiban treatment was not associated with a lower level of disability and increased the incidence of sICH after endovascular therapy in cardioembolic stroke patients. | PMC10621173 | |
Keywords | PMC10621173 | |||
Introduction | Ischemic stroke, cardioembolic stroke | SECONDARY, ISCHEMIC STROKE | Ischemic stroke remains a significant global health burden, contributing to substantial morbidity and mortality rates [Tirofiban, a glycoprotein IIb/IIIa receptor inhibitor, has gained attention as a potential adjunctive therapy in the context of EVT for cardioembolic stroke [In this secondary analysis of the RESCUE BT trial [ | PMC10621173 |
Methods | PMC10621173 | |||
Study design and participants | stroke, vessel occlusion, acute ischemic stroke, cardio-embolism | STROKE | The RESCUE BT trial was a prospective, investigator-initiated, double-blind, randomized, placebo-controlled trial aimed at assessing the safety and efficacy of intravenous tirofiban versus placebo prior to EVT in acute ischemic stroke with large vessel occlusion from 55 hospitals in China between October 2018 and October 2021. The trial protocol and primary results had been published [Patients who were aged 18 years old or more, presenting with occlusion of the internal carotid artery (ICA) or middle cerebral artery (MCA) -M1/M2 within 24 h of time last known well, and with a stroke etiology of cardio-embolism were included in the present study. For patients who experienced a stroke within 48 h of Direct Oral Anticoagulant (DOAC) intake, they did not receive thrombolytic treatment. In patients with a history of warfarin anticoagulation therapy, intravenous thrombolysis was considered if INR ≤ 1.7 or a PT < 15 s, with the informed consent of patients or their family members. | PMC10621173 |
Etiological identification of Cardiac embolism | cardioembolic stroke | ACUTE STROKE | In this study, we implemented a meticulous and comprehensive approach for the etiological identification of cardioembolic stroke. Data were collected from various sources, including case report forms and source documents, encompassing comprehensive medical history, clinical features, laboratory tests, 24-h electrocardiograms, echocardiography, non-invasive brain imaging, and DICOM format angiography. Two experienced neurologists, blinded to treatment allocation, centrally assessed the data. The criteria for cardioembolic-related LVO were optimized based on the Trial of Org 10172 in Acute Stroke Treatment [ | PMC10621173 |
Treatments | stroke, angioplasty | STROKE, DEEP VEIN THROMBOSIS | Eligible subjects were randomly assigned to the tirofiban group or the control group. The tirofiban group received intravenous bolus and continuous infusion of tirofiban, while the control group received saline placebo. Tirofiban was administered as a 10 μg/kg bolus, followed by a maintenance infusion of 0.15 μg/kg/min for up to 24 h. The specific endovascular treatment techniques, such as stent-retrieval, local aspiration, angioplasty, and stenting, were performed based on the neurointerventionalists' discretion. However, the use of intra-arterial thrombolytics (e.g., alteplase or urokinase), tirofiban, rescue drug, or other glycoprotein IIb/IIIa inhibitors was not recommended. The rescue drug, available in the study kits, could be used if antegrade blood flow could not be maintained after angioplasty and/or stenting, following the same administration protocol as the study drug. Patients experiencing deteriorating symptoms underwent an immediate repeat of the routine or dual-source head CT scan. For those patients whose condition remained stable, a routine or dual-source head CT scan was conducted 20 h post-procedure. At the 20th hour, all patients without contraindications received oral antiplatelet therapy with aspirin and/or clopidogrel tablets. Patients undergoing angioplasty/stenting received dual-antiplatelet therapy with aspirin and clopidogrel, while others received mono-antiplatelet therapy. The study drug was discontinued at the 24th hour, and subsequent patient management followed the current stroke management guidelines. Intravenous heparin could be used during the thrombectomy procedure, as determined by the operator. Additionally, subcutaneous heparin or low-molecular-weight heparin could be administered post-procedure for deep vein thrombosis prophylaxis. However, the use of other anticoagulants or antiplatelet agents was prohibited within the first 24 h post-randomization. | PMC10621173 |
Variables and imaging assessment | ischemic injury, Thrombolysis, Stroke, Cerebral Ischemia | CEREBRAL ISCHEMIA, STROKE | During the enrollment process, demographic variables, vascular risk factors, baseline NIHSS score, treatment information, and workflow measures were recorded. To ensure consistency and reliability in the evaluation process, all imaging data were reviewed by the imaging core laboratory of the RESCUE BT. The determination of the occlusion site was made based on the findings from CT or MR angiography conducted upon admission, with specific classification into distinct categories including internal carotid artery (ICA), middle cerebral artery M1 segment (M1 MCA), or middle cerebral artery M2 segment (M2 MCA). The extent of ischemic injury was quantified by employing the widely recognized Alberta Stroke Program Early CT Score (ASPECTS). The evaluation of reperfusion status during the final angiography utilized the expanded Thrombolysis in Cerebral Ischemia (eTICI) score [ | PMC10621173 |
Outcomes | The primary outcome of this study was to assess the proportion of patients achieving functional independence after 90 days, defined as a modified Rankin Scale (mRS) score of 0–2 [ | PMC10621173 | ||
Statistical analysis | Patient characteristics and clinical outcomes in the two groups were reported using descriptive statistics, including number (percentage) or median and interquartile range. Categorical variables were analyzed using the χ [ | PMC10621173 | ||
Results | PMC10621173 | |||
Discussion | bleeding, sICH, cardioembolic, cardioembolic stroke, platelet aggregation | BLEEDING | This paper reports on a post hoc analysis of the RESCUE BT randomized trial, which aimed to investigate the efficacy of tirofiban for patients presenting with cardioembolic LVO within 24 h of onset. The results demonstrated that the administration of intravenous tirofiban prior to EVT didn’t improve the rate of functional independence at 90 days. However, the use of tirofiban in cardioembolic stroke patients undergoing endovascular therapy was associated with an increased risk of sICH compared to placebo. These findings suggest that tirofiban may be a harmful adjunct to endovascular therapy for patients with cardioembolic LVO.The occurrence of sICH associated with antithrombotic drugs in endovascular therapy is a well-known concern [The increased risk of sICH associated with tirofiban administration in cardioembolic stroke patients undergoing endovascular therapy can be attributed to several factors. Firstly, tirofiban's mechanism of action involves inhibiting platelet aggregation, which can lead to prolonged bleeding time and impaired hemostasis [This study possesses several limitations that should be considered when interpreting the findings. Firstly, the analysis was conducted as a post hoc analysis within the RESCUE BT trial, which may introduce inherent limitations and potential biases. This study might have been underpowered to detect a significant treatment effect within the specific subgroup of patients with cardioembolic stroke. Larger-scale randomized controlled trials specifically focusing on this patient population are essential to further validate our findings. Secondly, the tirofiban group exhibited a significantly longer time from symptom onset to randomization, leading to a delayed time to reperfusion, although the difference in the time from symptom onset to reperfusion did not reach statistical significance. Previous studies have shown that a prolonged time from symptom onset to reperfusion in patients undergoing endovascular therapy within 6 h is associated with unfavorable outcomes [ | PMC10621173 |
Conclusion | bleeding, sICH, cardio-embolism, cardioembolic stroke | SECONDARY, BLEEDING | The secondary analysis conducted in the RESCUE BT trial, with a specific focus on the cardio-embolism subgroup, has provided concerning insights into the concomitant administration of tirofiban and EVT. Our analysis has revealed a significant association between tirofiban usage and an increased risk of sICH among patients with cardioembolic stroke. These findings emphasize the potential harm and heightened bleeding risk associated with tirofiban administration in this population. To confirm and further explore these observations, additional studies are warranted, aiming to validate these findings and investigate alternative strategies for optimizing outcomes in patients with cardioembolic stroke. | PMC10621173 |
Acknowledgements | We are grateful to all patients and investigators in the RESCUE BT trial. | PMC10621173 | ||
Author contributions | BR and ZY: the conception and design of the study. WZ, ZQ, XY and FL: acquisition of data. LG, YY, RM and ZL: analysis and interpretation of data. YL, JZ and HZ drafting the article or revising it critically for important intellectual content. ZY, TL, JF and GT: final approval of the version to be submitted. | PMC10621173 | ||
Funding | This study was supported by the Sichuan Provincial Central Leading Local Science and Technology Development Special Project. No.2021ZYD0106. | PMC10621173 | ||
Availability of data and materials | All data relevant to the study are included in the article or supplement. Further inquiries on data availability can be directed to the corresponding authors. | PMC10621173 | ||
Declarations | PMC10621173 | |||
Ethics approval and consent to participate | The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The study protocol received approval from the ethics committee of Xinqiao Hospital, Army Medical University, as well as the relevant ethics committees at all participating centers. | PMC10621173 | ||
Competing interests | All authors declare that they have no competing interests in the study. | PMC10621173 | ||
References | PMC10621173 | |||
Background | MH, opioid use disorder | Considering different factors, such as high withdrawal rates in methadone maintenance treatment (MMT) programs alongside mental health (MH) problems appearing in patients with opioid use disorder and the lack of prior research on the effect of zinc supplementation in this respect, the present study aimed to investigate the effect of zinc supplementation on the probability of relapse (PoR) and MH problems in patients with opioid use disorder undergoing MMT. | PMC9817328 | |
Methods | opioid use disorder, Depression, Anxiety | RELAPSE | For this purpose, a randomized controlled trial with a clinical basis was fulfilled on a total of 68 patients with opioid use disorder receiving MMT, allocated to two groups, viz. intervention, and control (each one consisting of 34 individuals). Then, the participants in the intervention group were given zinc supplements combined with methadone for three months, and the controls only took methadone, according to the treatment plan. The data were collected using the Relapse Prediction Scale (RPS) and the Depression, Anxiety, and Stress Scale 21 (DASS-21) before, one month after, and at the end of the intervention program. | PMC9817328 |
Findings | Compared to the control group, the likelihood of drug use ( | PMC9817328 | ||
Conclusion | MH, opioid use disorder | Accordingly, it was concluded that zinc supplementation could reduce the PoR and improve MH problems in patients with opioid use disorder experiencing MMT. However, further research is recommended to fill the gaps. | PMC9817328 | |
Trial registration | The research protocol has also been listed on the Iranian Registry of Clinical Trials (IRCT) with code no. IRCT2020050904736N1. | PMC9817328 | ||
Keywords | PMC9817328 | |||
Background | anxiety, MH, Behavioral impairments, aggression, opioid use disorder, depression, irritability, affective dysregulation | DISORDER, ZINC DEFICIENCY, DYSFUNCTION, DISORDERS | As one of the first-line treatments for opioid use disorder, methadone maintenance treatment (MMT) seems to be a long-acting or permanent therapy that replaces opioids with other safe alternatives to control physical and mental problems facing patients with opioid use disorder [The evidence further suggests that many patients with opioid use disorder undergoing MMT suffer from mental health (MH) problems, including depression and anxiety [A noteworthy achievement in such programs is sustainability. Higher relapse rates in this respect mean that a large number of patients with opioid use disorder discontinue treatment and start drug use; therefore, therapy is not effective [Of note, a healthy, balanced diet containing essential micronutrients supports effective treatment for patients with opioid use disorder undergoing MMT [Behavioral impairments, depression, affective dysregulation, anxiety, aggression, and irritability, as the disorders that are predominantly associated with CNS dysfunction, often occur due to zinc deficiency, as evidenced in human and animal specimens [ | PMC9817328 |
Aim | MH, opioid use disorder | Considering the high withdrawal rate in methadone maintenance treatment (MMT) programs alongside mental health (MH) problems appearing in patients with opioid use disorder and the lack of prior research on the effect of zinc supplementation on PoR and MH status in patients with opioid use disorder undergoing MMT, the present study aimed at:Investigating the effect of zinc supplementation on PoR in patients with opioid use disorder undergoing MMTInvestigating the effect of zinc supplementation on MH status in patients with opioid use disorder undergoing MMT | PMC9817328 | |
Methodology | PMC9817328 | |||
Research design | opioid use disorder | This study was a randomized, single-blind, parallel, two-arm clinical trial on patients with opioid use disorder receiving MMT in an addiction treatment clinic in an urban area of Iran from April 2021, lasting three months. The research protocol was also listed on the Iranian Registry of Clinical Trials (IRCT) with code no. IRCT2020050904736N1. | PMC9817328 | |
Participants | schizophrenia, opioid use disorder, bipolar disorder, psychosis | The statistical population included adult patients with opioid use disorder undergoing MMT. The inclusion criteria in this study were the willingness to participate, age over 18, literacy, drug use confirmed by positive urine tests, taking methadone as supervised by a physician for at least three months, and no chronic mental illnesses, such as psychosis, bipolar disorder, and schizophrenia. As well the exclusion criteria were the participants’ decline to continue the study for any reason, changes to the treatment plan, and the use of zinc-containing compounds prior to the intervention program.The sample size was thus estimated at 32 individuals in each group, with reference to a similar study with 80% test power and a 95% confidence interval. Considering the 20% sample loss, the final sample size in each group was determined to be 40. The researcher then referred to the selected addiction treatment clinic for the sampling of the convenience type. For this purpose, first, the patients with opioid use disorder undergoing MMT were examined in terms of meeting the inclusion criteria. Next, the study objectives and phases, data confidentiality, and the voluntary basis of entering into and withdrawing from the research process were presented by holding face-to-face meetings with the eligible individuals. Afterward, those who agreed to participate in the study signed an informed consent form. Finally, out of 140 patients with opioid use disorder referred to the addiction treatment clinic concerned, 100 individuals with a history of at least three months of receiving methadone met the inclusion criteria, of which 80 ones agreed to participate in the study. A randomized block design was further utilized to allocate the samples to the intervention and control groups. The random allocation sequence (with 20 blocks of four) was accordingly established using the Random Allocation Software. For the act of concealment, some closed envelopes containing cards with the letters A (for the intervention group) and B (for the control group) were prepared according to an encoded allocation sequence. An envelope was then opened by an outsider who had no role in the study and did not know about the card inside for each individual. Based on the card inside, the patients with opioid use disorder were allocated to one of the intervention or control groups. Of note, only the data analyst was blinded to the allocation of the participants to the groups in this study to ensure that all the analytical decisions were made without bias. The CONSORT flow diagram of the study is illustrated in Fig. The research process according to the CONSORT flow diagram (2010) | PMC9817328 | |
Data collection | Depression, Anxiety | RELAPSE | The study data were collected using the Demographic Survey Form (DSF), the Relapse Prediction Scale (RPS), and the Depression, Anxiety, and Stress Scale 21 (DASS-21) before, one month after, and three months after the intervention (i.e., the completion of the intervention program). | PMC9817328 |
DSF | The DSF consisted of items focused on the participants’ age, gender, marital status, living conditions (single or with family), smoking status (cigarettes or hookahs), education level, and occupation. | PMC9817328 | ||
RPS | The 45-item RPS was administered to assess the PoR. Each item included a situation in which the respondent could rate the likelihood of drug use and drug craving [ | PMC9817328 | ||
DASS-21 | MH | The DASS-21 was implemented to measure the MH status of the study participants. Lovibond and Lovibond [ | PMC9817328 | |
Intervention program | The participants allocated to the intervention group were visited by a physician every two weeks, and then received a two-week supplement of zinc combined with methadone as planned. The daily dosage of the zinc supplement was about 12 mg. The supplement used in this study was Suzin Zinc Sulfate, made by Alhawi Pharmaceutical Co., Iran (of note, each capsule of 110 mg of zinc sulfate was equivalent to 25 mg of zinc). To check the participants’ cooperation in the intervention group, as well as their regular zinc supplement intake, their families were contacted three times a week. The researcher also welcomed their questions and ambiguities.On the other hand, the participants in the control group only received methadone, according to the treatment plan, and their visits were fixed every two weeks to check their methadone use by a physician or a nurse. Of note, no placebo was given to this group. All the study participants were also asked not to change their diet and type of medication at the end of the study. The methadone dose was registered in both intervention and control groups. | PMC9817328 | ||
Data analysis | MH | The SPSS Statistics software package (ver. 23) was used for the data analysis. To this end, the data from the intervention and control groups were summarized descriptively, using frequency and percentage for the categorical variables and mean and standard deviation (SD) for the continuous ones. The Kolmogorov–Smirnov test was further implemented to examine the normal distribution of data. To evaluate the homogeneity of the study groups, independent-samples t-test, Chi-square test, and Fisher’s exact test were utilized. Moreover, repeated measures analysis of variance (ANOVA) was performed to compare the predictive scores of the PoR and MH in the study groups. All the inferential tests were completed at the significance level of 0.05. | PMC9817328 | |
Discussion | gastrointestinal tract function, anxiety, abdominal pain, MH, vomiting, constipation, opioid use disorder, malnutrition, depression, anorexia | INFLAMMATION, MALNUTRITION, ZINC DEFICIENCY, OXIDATIVE STRESS, GASTROESOPHAGEAL REFLUX DISEASE, ANOREXIA, COMPLICATIONS | This study aimed to investigate the effect of zinc supplementation on the PoR and MH in patients with opioid use disorder undergoing MMT, wherein the results indicated that zinc supplementation could reduce the PoR and improve the MH status in such individuals. As no studies had so far assessed the effect of zinc supplements on the PoR and MH among patients with opioid use disorder going through MMT, to the best of the authors’ knowledge, the results of the present study were reviewed based on the research outcomes in other populations and groups.In this line, previous research had reported that the complications of opioid analgesics use, such as anorexia, constipation, gastroesophageal reflux disease, vomiting, and abdominal pain, could affect the gastrointestinal tract function and induce malnutrition as well as the deficiency of various minerals in the body, including zinc [Moreover, zinc deficiency is able to have a significant effect on other mechanisms involved in relapses and even be associated with depression and anxiety [The related literature also shows that a large number of patients with opioid use disorder subjected to MMT suffer from MH conditions, especially depression and anxiety [Even if the possible biological mechanisms that help improve MH (mainly the symptoms of depression and anxiety) via zinc supplementation are not yet fully understood, previous research has shown that zinc regulates neurotransmission, neurogenesis, the endocrine system, inflammation, and oxidative stress in signaling pathways is of utmost importance [ | PMC9817328 |
Limitations | MH, opioid use disorder | BLIND | To interpret the findings, there are some limitations in the present study that should be considered. First, this clinical trial was conducted in only one addiction treatment clinic located in an urban area of Iran, which could reduce the generalizations to all patients with opioid use disorder undergoing MMT. Second, the PoR and MH here were assessed using self-report scales; however, the implementation of objective methods could be more beneficial in better assessing the impact of such intervention programs. Third, the effect of zinc supplementation in the present study on the PoR and MH status was not measured at long intervals after the completion of the intervention program (of note, the intervention lasted three months). Finally, the nature of the intervention in this study made it difficult to blind the participants. | PMC9817328 |
Implications for clinical practice | MH, opioid use disorder | This study has some implications for clinical practice. In view of that, the findings highlight the effect of zinc supplementation on reducing the PoR and improving MH in patients with opioid use disorder experiencing MMT. Therefore, healthcare providers can introduce zinc supplements into the treatment plans for such individuals to help diminish their PoR and enhance their MH. However, further research is needed to replicate such outcomes. In addition, more studies are recommended to reflect on the challenges facing zinc administration in clinical practice from the perspective of healthcare providers and patients with opioid use disorder undergoing MMT, which can aid in making decisions for the inclusion of zinc supplements into the treatment plan of this group. | PMC9817328 |
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