The clinical value of the relationship between gastrointestinal microbiome imbalance and its corresponding interventions with kidney disease is emerging. This study describes the hotspots and evolution of gastrointestinal microbiome and kidney disease research over the past three decades by scientific collaboration networks and finally predicts future trends in the field through bibliometric analysis and visualization studies. CiteSpace was used to explore the original articles from January 1990 to August 2021 to visualize the knowledge network of journals, countries, institutions, authors, references, and keywords in this field. Publications were extracted from Web of Science Core Collection database using the terms “gastrointestinal microbiome” and “kidney disease” (and their synonyms in MeSH). A total of 2145 publications with 93880 references in 102 journals were included in the analyses. The number of studies combining gastrointestinal microbiomes with kidney diseases has increased significantly over the past two decades. The United States is the leading country in the number of documents, and the leading institution is the Cleveland Clinic. The most landmark articles in the field are on chronic renal failure, L-Carnitin, and cardiovascular disease. The pathogenesis of uremia toxin is an emerging trend in gastrointestinal microbiomes and kidney diseases. In addition, probiotic or synbiotic supplements have strong clinical value in adjusting abnormal intestinal symbiotic environments. This study demonstrates a growing understanding of the interaction between gut microbiota and kidney disease over time. Using microbial supplements to improve the living conditions of kidney disease patients is a promising and hot research focus. Based on publications extracted from the database, this study may provide clinicians and researchers with valuable information to identify potential collaborators and partner institutions and better predict their dynamic progression. Chronic kidney disease (CKD) has become one of the chronic diseases with the heaviest economic burden globally, and the number of CKD patients is increasing rapidly . AccordiThe human gastrointestinal tract is home to tens of thousands of microbial communities, mainly composed of bacteria . There aThe analysis and summary of the structure of knowledge, the evolution of research centers and frontiers are important contributions of information science (IS) for researchers . There iCiteSpace is one of the representative bibliometric analysis applications based on citation analysis theory . It is uWe used the terms “gastrointestinal microbiomes” and “kidney diseases” and all of their hyponyms in Medical Subject Headings (MeSHs) provided by the National Library of Medicine (NLM)/PubMed. We search Web of Science Core Collection (WoSCC) completely and loaded all literature in the field from 1990-2021 , and the literature type was set as “articles”.CiteSpace is a Java-based data analysis and document visualization application with outstanding functions, including co-citations, co-authors, and co-occurring keyword analyses, which helps to provide instant directions for analysis progression in a certain research field . Three cAccording to the Web of Science database, we retrieved 2262 studies among which 2154 are originals and reviews containing 93880 references. In 102 journals, 899 keywords were extracted by 973 main authors from 110 countries.The earliest article in the field of gastrointestinal microbiomes and kidney diseases was published in English by Ramosalvarez, M, who used monkey kidney tissue to cultivate the intestinal flora collected from healthy children to determine whether there were poliovirus or other viruses in the children’s intestines .In the next two decades, the research in the field of gastrointestinal microbiomes and kidney diseases is relatively scattered and marginal in the preliminary exploration without a representative research cluster, and in-depth analyses of the specific relationship between gastrointestinal microbiomes and kidney diseases were ignored, with only 6 articles published from 1956 to 1989. It was not until 1990 that the number of articles in this field began to accumulate steadily, surging from 5 to 2139 manuscripts exponentially.Co-country analysis by the CiteSpace algorithm can reveal the regionality of the research cooperation net in this field, which is displayed in CiteSpace software mainly judges cooperation between two institutions when their names appear in one publication through the co-occurrence frequency matrix. We list the top ten authors with the highest productivity in this field and conclude their key contributions in this field Table 1.The most productive authors in the research field of gastrointestinal microbiomes and kidney diseases is Denise Mafra, with 32 articles appearing in more than one article’s citation, focusing on renal nutrition and inflammation in CKD patients . The secAll articles in the research field of gastrointestinal microbiomes and kidney diseases have been published in a total of 1,105 journals. We identified the top 10 most productive journals in this field Table 2.butyrate, with a strength of 5.31, active from 2019 and continuing until 2021.Co-cited keyword analysis offers the focus, research trends, and knowledge structure in this research field, extracting the topics that scholars in this field pay attention to. The analysis functions on word frequency, trend, burstiness and network attributes. A document co-citation network map is displayed in The third-largest cluster is “trimetlylamine oxide (TMAO)”(ranked #2), consisting of 101 members and having a mean year of publication in 2016. TMAO is a typical uremic toxin produced by the intestinal flora’s metabolism, which means that research into the mechanism of kidney disease has been profound . The mosThere are many burst-edge nodes of the organ and red color on the right side of The co-citation analysis of gastrointestinal microbiomes and kidney diseases research produced 239 co-citation clusters marked with the index words in the respective citations. To describe the nature of this clustering, CiteSpace extracts noun phrases from article titles that cite clusters based on three specialized metrics: latent semantic indexing, log-likelihood ratio, and mutual information. The log-likelihood ratio usually provides the best results in terms of uniqueness and coverage of topics related to the cluster. The tendency of research interests is highlighted through citation bursts with the measure of the innovativeness of research results and a frontier “footprint” of this study field . The larThe following six references highlight the emerging trend that began in 2013. The main content of these studies is the changes in the intestinal flora of patients in disease states and their role in disease progression . The lasTang, W H Wilson et al. study the clinical prognostic value of TMAO in chronic kidney disease (CKD) patients and non-CKD patients and to verify the hypothesis that TMAO plays a direct role in the occurrence and development of renal dysfunction. They found that elevated plasma TMAO levels in patients with CKD predicted poor long-term survival .Vaziri ND et al. proves that diet and drug intervention for uremia and/or chronic kidney disease would profoundly change the intestinal microbiome, though the specific mechanism was remained unclear at that time . RamezanWong, Jakk et al. found that the bacterial family with urease, uricase, indole, and p-cresol forming enzyme in the End Stage Renal Disease patients significantly expand and contribute to the toxicity and inflammation of uremia in intestinal microbial metabolis .Rossi, Megan et al. found that synbiotics do not significantly reduce serum is, but do reduce serum PCs, which is conducive to improving fecal microbiome in patients with CKD .The relationship between gut microbiota imbalance and its corresponding interventions and kidney disease is becoming a research focus of scholars . Our stuDerived from the document co-citation cluster markers, it can be noticed that scholars and experts are interested in the influence of metabolic activities in the intestine and the subsequent reaction brought by its metabolic interaction on patients . AccordiBurst detection and keyword visualizes the research hotspots intuitively. The core knowledge domains in gastrointestinal microbiomes and kidney diseases research are chronic renal failure, L-Carnitin, and cardiovascular disease. It could be speculated from the citation bursts that the pathogenesis of uremica toxin is an emerging trend in gastrointestinal microbiomes and kidney diseases. Probiotic or synbiotic supplements are being studied to adjust abnormal intestinal symbiotic environments, delaying or halting the progression of the disease .Synthesizing the evolution of citation clusters and burst detection, the footprint in the field of gastrointestinal microbiomes and kidney diseases is present clearly. Intestinal flora imbalance refers to abnormalities in the abundance, uniformity, and composition of microbial communities that are prevalent in chronic kidney disease, including a marked decrease in probiotics and a significant increase in potentially pathogenic bacteria . Gut dysThe analysis of co-authors shows that researchers make outstanding contributions to the field. The earliest reference with a strong citation burst is Wang, Zeneng, et al., 2011. Their discovery of a relationship between gut flora-dependent metabolism of dietary phosphatidylcholine and cardiovascular disease pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease and can be regarded as the milestone finding that inspired subsequent research . Aronov There are some strengths of this study. The combination of knowledge maps and visual analysis could simultaneously reflect the current status of research quantitatively present the distribution of collaboration among countries, institutions and authors. Secondly, this study summarizes the key contribution and turning points in this fields. Third, this study reports the latest progress in the research field visual through co-cited reference analysis and keyword analysis. We admit this bibliometrics study has some inherent limitations. First, only WoSCC database was analyzed in this study due to the inherent algorithm of CiteSpace. Some articles published in other databases may be omitted. Second, the non-English article may be underestimated according to the evaluated system of CiteSpace.Over the past two decades, the scientific collaboration network showed that collaboration between different countries and institutions has been adequate, with a gradual expansion of research scope and depth over time. The core contributors in the field of research on intestinal flora and kidney disease are the United States and China. Research in recent years has focused on the effects of imbalanced gastrointestinal microbiome metabolites on various human systems and the clinical value provided by probiotic and synbiotic supplementation. The interaction between gastrointestinal microbiomes and kidney diseases is expected to be a promising perspective for the treatment of chronic kidney disease. However, these mechanisms have not yet been clearly investigated, and further studies are needed to corroborate them.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.WQ conceived the study and performed critical revision of the manuscript. JT designed the study, drafted the manuscript and supervised the study. MC designed the study, performed statistical analyses and wrote the manuscript. YW processed statistical data and developed the analyses. YT performed the article retrieval and data interpretation. All authors read and approved the final manuscript.This work was supported by National Natural Science Foundation of China No. 81970612.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The data were continued with the Logistics Regression test and the dominant variables related to stunting were underweight , under-five age , and premature birth (p = 0.027 with an OR of 2187). The conclusion of this study is that the most important factor in the incidence of stunting in South Kalimantan is underweight nutritional status.Stunting prevalence in South Kalimantan has been higher than the national figure and is the sixth highest in Indonesia. Not many studies in South Kalimantan have analysed the risk factors for stunting comprehensively that combine sociodemographic factors, utilization of maternal health services, and characteristics of children. Therefore, the purpose of this study was to analyse sociodemographic factors, utilization of maternal health services, and characteristics of children under 5 as determinants of stunting in South Kalimantan Province. This study used an analytic observational method with a cross-sectional design. Data collection used secondary data from the results of South Kalimantan Baseline Health Research 2018. The total population of toddlers obtained from South Kalimantan Baseline Health Research 2018 data was 1218 toddlers, and all of them were taken as samples. Data analysis used a chi square test for bivariate test and Logistic Regression for multivariate test. There is a relationship between mother’s education level ( Stunting in Indonesia is still a nutritional problem that needs serious treatment. The Indonesian Ministry of Health’s data and information centre 2018) states that stunting is a condition in children who have shorter body length/height compared to their peers. This category is based on WHO child growth standards. Stunting is the impaired growth and development that children experience from poor nutrition, repeated infection, and inadequate psychosocial stimulation. Children are defined as stunted if their height-for-age is more than two standard deviations below the WHO Child Growth Standards median. Stunting adversely affects both short- and long-term consequences, including poor child growth and development. The WHO states Indonesia as the country with the third-highest stunting prevalence in Southeast Asia, with a prevalence of 36.4% from 2005 to 2017 [8 states The Indonesia Nutrition Status Survey in 2021 reports that the stunting prevalence in Indonesia is 24.4%, while the stunting prevalence target for 2024 is 14% . South KStunting can interfere with the physical and cognitive development of children . In addiResearch by Wicaksono and Hartanti (2020) found that the factors associated with the incidence of stunting were individual, household, and community factors. Individual factors consist of gender and immunization status. Household factors consist of the educational status of the father and mother, household welfare, and slum settlements. In addition, there are also factors of influence from the community, namely the place of residence (village or city) .Similar research has also been conducted by Ardiansyah et al. (2018) which states that stunting is caused by age, gender, parental education, parental income, number of household members, early initiation of breastfeeding, exclusive breastfeeding, and maternal height. The results of multivariate analysis showed that the most dominant factor was father’s education .Adolescent pregnancy is also associated with the incidence of stunting as in the research of Larasati et al. (2018). This study shows that the younger a person’s gestational age will increase the incidence of stunting . Until nThis study used observational analytic with a cross-sectional design with secondary data from the 2018 Baseline Health Research . The population of this study was 1218 children aged 0–59 months who were included as the 2018 Baseline Health Research sample in South Kalimantan Province. The secondary analysis for this research was conducted from May to August 2022. Children less than 5 years old in this research were called ‘toddler’.For the primary data collection of Riskesdas 2018, the Ethical Committee of Health Research, NIHRD, the Ministry of Health of Indonesia gave their approval with the reference number LB.02.01/2/KE.267/2017. All participants were asked for their consent and signed the informed consent form in the survey.The dependent variable of the study was the incidence of stunting, which is characterized by height-for-age less than -2 SD from the WHO child growth standard. The independent variables of the study were classified into sociodemographic characteristics, utilization of maternal health services, and toddler’s characteristics.Sociodemographic data as well as history of pregnancy, delivery, and toddler’s feeding practices were collected by trained interviewers with a validated questionnaires. Occupational status of each of the parents were classified into working and not working. Classification of the area of residence into rural and urban follows the classification from Statistics Indonesia, which is the official statistics agency in the country. Household members were numbers of people belonging to the subject’s household.Variables regarding the utilization of maternal health services include Ante Natal Care (ANC) visits, consumed Iron and Folic Acid (IFA) tablets, childbirth location, and birth attendants. ANC visits were defined as the number of antenatal visits during pregnancy. Consumed IFA tablets refer to the number of IFA supplement tablets consumed by the mother during pregnancy of the child(ren) under 5 years old. A question on childbirth location was asked to know whether or not the child was born in a healthcare facility. Meanwhile, birth attendants of the child were classified into skilled or healthcare worker and non-healthcare worker.Toddler’s characteristics include age, gender, gestational age, birthweight, immunization status, status of prelacteal feeding, exclusive breastfeeding, underweight, wasting, and age of mother when giving birth to the child. Data from the maternal and child health book  were used to observe the child immunization status. The anthropometric measurements were performed by trained enumerators. Premature birth was defined if the gestational age at delivery was less than 20 weeks. Low birth weight was defined when the birth weight of the baby was less than 2500 g. Prelacteal feeding refers to the presence of any other food/drink given to the baby before starting to be breastfed. Additionally, status of adolescent mother is defined if the mother age when giving birth to the baby was 19 years old or younger.Univariate analysis was performed by looking at the distribution and percentage of each variable. Bivariate analysis was conducted by looking at the relationship of each independent variables with the dependent variable . Variables having significant relationships with the stunting status were then entered into the next stage which was the multivariate analysis. Those analyses were performed with a complex samples design using SPSS Version 25.p 0.001) and father (p 0.002) education and stunting in children under 5. Being born to parents who have completed high school can reduce the odds of stunting. The risk of stunting was almost the same in both urban and rural residents as well as in households with less and more than four members.Bivariate analysis  was carrThe results of bivariate analysis showed that babies born in healthcare facilities had a lower risk  of being stunted than those whose birth locations were not in health facilities. However, there is no statistically significant relationship between all of the variables about the utilization of maternal health services to the risk of child stunting in this population.p-value < 0.001), as can be seen from the large OR value shown in the age category. This risk tends to increase until the toddler is aged 24–35 months, and then decreases again in toddlers aged 36–60 months.Toddler’s age is a factor that may determine stunting status . Babies whose birth weight were less than 2500 g have a 2.1 times risk of becoming stunted toddlers than babies with normal birth weight (≥ 2500 g).Another variable that was statistically significant in influencing stunting was the status of low birth weight (p = 0.008), but those who received exclusive breastmilk were still at risk of suffering from stunting.The variable of exclusive breastfeeding history was associated with the incidence of stunting .The multivariate analysis conducted in this study resulted in four variables related to the incidence of stunting in children under five in South Kalimantan, namely age range, history of premature birth, as well as status of underweight and wasted. These results were obtained after adjusting for other variables, namely the mother’s age at delivery, the father’s education level, and a history of low birth weight.The underweight status is the main determinant of the incidence of stunting in children under 5 in South Kalimantan with an OR value of 18.241 (95% CI 8.054–41.312).The age of the toddler is also a determining factor in the incidence of stunting, where the risk begins to appear after the toddler is over the age of 6 months. After the age of 6 months, toddlers begin to be given complementary foods and the process of parenting related to diet becomes very influential on the nutritional status of children. Thus, it can be concluded that the incidence of stunting in the province of South Kalimantan is more influenced by factors of parenting and quality of complementary feeding. The trend of increasing risk was seen in toddler aged 6–11 months , then increased in later toddler and the risk was highest in toddler aged 24–35 months . Furthermore, the risk began to decrease in toddler aged 36–59 months.Another determinant of stunting was a history of preterm birth . Toddlers with a history of premature birth have a higher risk of stunting than toddlers born at term. However, the wasting variable showed OR 0.129 (95% CI 0.049–0.339). Wasting is a condition when a toddler is underweight in relation to his or her height. A thin toddler has a low body weight but is quite tall. The R-square value obtained is 24.5%.Thus, it can be interpreted that the incidence of stunting in children under five in South Kalimantan can be explained by 24.5% because of the determinants of underweight, toddler’s age, history of premature birth, and wasting. Meanwhile, 76.5% of stunting risk among this population is influenced by other variables.The results of the study in Education can stimulate nutritional status both directly and indirectly through influencing the awareness and cultural preferences that may shape the habit of food consumption. Ultimately, good dietary habit leads to good nutritional status. Education also affects hygiene and sanitation including sources of drinking water, drainage system, and housing conditions. Good hygiene and sanitation practices will build health by decreasing infection cases .The level of education can play a role in understanding health problems that will have a major impact on nutritional status, in this case stunting. A person’s level of education will affect family income. The higher the level of education, the better the family income, so that it will have an impact on family food security. In addition, the level of parental education is also assumed to affect the level of knowledge, including knowledge about family health and nutrition. This will increase efforts in parenting for children, utilization of health services, sanitation hygiene, and other behaviours .p value < 0.01), with a minimum high school education can reduce the risk of stunting [p value of 0.000 [This study is in line with the research of Wicaksono and Hartanti (2020) which states that the education of fathers and mothers is related to the incidence of stunting , so there were other factors that caused stunting besides family members.The characteristics of the area of residence  are not a determinant of the cause of stunting in this study.The variables of the use of maternal health services in this study were ANC visits, consumption of IFA tablets during pregnancy, delivery in health facilities, and birth attendants. All of these variables are not related to the incidence of stunting in the results of the bivariate statistical analysis of this study. However, descriptive data still illustrate the tendency to cause stunting. The descriptive data in Health services for pregnant women (ANC) are crucial for the health of the mother and her womb where it was found that mothers who had ANC visits less than four times during pregnancy were more likely to have stunted children at the age of 0–23 months compared to mothers who made ANC visits as many as four times or more .The antenatal phase is an important period to prevent stunting. In this phase, foetal growth occurs and is the optimal period for child development up to the first 1000 days of life. Environmental and nutritional factors in this phase will affect foetal growth, brain development, gastrointestinal tract, metabolism, and immune system. Nutrient intake is very important to support this phase of the first 1000 days of life, including amino acids, iron, iodine, calcium, zinc, magnesium, and vitamins .Based on this explanation, the results of this study which show that ANC is not associated with stunting can be caused by maternal nutritional intake during pregnancy which is the main factor. The nutritional intake was not identified in this study, so even though ANC was carried out, if the nutritional intake was not good, it would still increase the risk of stunting.Number of consumed IFA supplement tablets during pregnancy was also not associated with the incidence of stunting in this study. However, Consumption of IFA supplement tablets during pregnancy has a linear correlation with child growth. However, in general, growth failure in toddlers is influenced by lack of nutrient intake. In addition to iron, this includes folic acid, calcium, amino acids, and other nutrients ,11. ConsOther nutrients beside iron and folic acid were not identified in this study. Because the IFA supplementation is not the only one that affects the incidence of stunting, the factor of consuming IFA tablets during pregnancy is not associated with the incidence of stunting in this study. In addition, the mechanism that causes growth disorders is the condition of anaemia in pregnant women, where Hb levels were not identified in the study so that it has not been able to describe the condition of anaemia as the cause of growth disorders.In this study, childbirth location and presence of skilled birth attendant(s) was not associated with stunting. This is shown by mothers who gave birth in health facilities having stunted children by 73.4% . TorlessThis unrelated variable can be assumed because the location of delivery and birth attendants are related to the management for delivery assistance, so there is still an advanced phase that has a long impact on the occurrence of stunting, namely nutritional intake in toddlers.This study analysed several characteristics in children under five that were associated with stunting. Variables that were significantly related were age, birth weight, exclusive breastfeeding, and underweight.Toddler’s age is a determinant of stunting, as can be seen from the large OR value shown in the toddler age category . ChildreToddler’s age is a risk factor for stunting because it is related to the growth period. We found that toddlers aged > 6 months have a higher risk of stunting than children aged < 6 months. At this age, they having experienced interactions with environmental factors and feeding patterns . Childrep value = 0.000, where age < 6 months has a risk of becoming stunted by 14–22%, which then along with increasing age also increases the risk of stunting [This study is in line with Mulu et al. (2022) who explained that age is related to the incidence of stunting . Das andstunting .p-value 0.05). Babies whose birth weight is less than 2500 g have a 2.1-fold risk of becoming stunted compared to babies with normal birth weight (≥2500 g).Another variable that was statistically significant in influencing stunting was low birth weight (Low birth weight (<2500 g) will have an impact in the first 6 months of life. Then the impact will decrease until the child is 24 months old. If the baby can achieve appropriate growth in the first 6 months, then it is possible that the baby has a normal body length. A history of low birth weight indicates growth retardation in the womb that occurs acutely and chronically .p value of 0.006 associated with stunting. Low birth weight increases the risk of stunting by 12,429 times compared to normal birth weight [This study is in line with the research of Lestari, Hasanah, and Nugroho (2018), which states that low birth weight has a h weight .Exclusive breastfeeding is also a determinant factor for stunting, although we found more stunting cases from children who did not receive exclusive breastfeeding. Our data suggest that the period after 6 months of the completion of exclusive breastfeeding can play a crucial role, especially in terms of the child’s dietary intake. Theoretically, exclusive breastfeeding reduces the risk of stunting. Introducing liquid/solid foods other than breast milk to children aged < 4 months will increase the risk of gastrointestinal disease, which will result in growth disorders, nutritional deficiencies, and susceptibility to infectious diseases until the age of 2 years. Exposure to infectious diseases such as diarrhoea and fever can increase the risk of stunting, where the incidence of this disease is more commonly found in children who are not exclusively breastfed .Early initiation of breastfeeding is also necessary to increase the success of exclusive breastfeeding. The first milk that issues during breastfeeding contains colostrum which is rich in nutrients and antibodies. Colostrum is essential for the growth of the gut microbiota and the immune system. Colostrum is only released in the first 2–3 days after delivery .Our findings about exposure to prelacteal feeding are in line with Kuchenbeker et al. 2015) who shows that early initiation of breastfeeding as one of the practices of exclusive breastfeeding is significantly related to the growth of toddlers. Giving food before the age of 6 months also has an impact on infant growth retardation [ who showAnother variable that is statistically significant is underweight. We found that underweight in children under 5 years olds can increase the risk of stunting up to 18.241 times. Underweight conditions can be caused by birth weight, birth length, frequency and quality of maternal ANC, and quality of food consumed by children. Dietary intake of the children must provide sufficient nutrients for their growth and development. However, a culture of dietary restrictions or abstinence can hinder the fulfilment of children’s nutritional needs .The research of Syeda et al. (2021) reported similar finding, where underweight in the second and third years will increase the risk of stunting greater than the age of <1 year. These data are related to the diet given to children by parents .Other characteristics of children under 5 such as gender, history of premature birth, history of prelacteal feeding, nutritional wasting status, and status adolescent mothers were not statistically associated with the incidence of stunting in children under five in South Kalimantan. These data show that stunting can occur in both male and female sexes so that gender differences in parenting patterns can begin to change.In addition, immunization status is not related to stunting because immunization is already a mandatory program that has been implemented by population, so that it has been received by both stunted and non-stunted toddlers. This is shown by the data in Wasting is also not related to stunting in this study, because weight in wasting is a short-term (acute) nutrition indicator, thus it can change quickly. While stunting has length/height as a long-term (chronic) nutrition indicator, accordingly the factors that influence stunting should already pass on long-lasting impact.In this study, being born to an adolescent mother was not a risk factor for stunting. This is possibly due to the fact that the number of adolescent mothers who were sampled was relatively too small. Although not significantly related, descriptive data show that from the 1218 toddlers who were sampled, the percentage of stunting in adolescent mothers was 41.7%, which is around 10% higher than the percentage among adult mothers. This percentage can indicate a trend towards the risk of stunting in adolescent mothers.Almost half of the female population in South Kalimantan married before the age of 19 years old , suggestHowever, our study does not confirm adolescent pregnancy as a risk factor for stunting in South Kalimantan. This study is in line with the research of Fonseka et al. (2022) which states that there is no relationship between maternal age and the incidence of stunting. The most important determinant is nutritional intake during childhood .The results of the multivariate analysis in Toddler who are underweight, and within age range of 24–35 months old are at higher risk of stunting. These variables are related to child’s dietary intake, while premature birth can be related to mother’s age and health conditions during pregnancy including the maternal nutritional status. Thus, the results of the analysis of this study illustrate that nutritional intake is more dominant in increasing the risk of stunting compared to other variables. Those variables  are simultaneously associated to stunting risk with the magnitude of the association was 24.5%.Factors that also affect the incidence of stunting beyond those investigated in our study are sensitive factors, such as agriculture and food security, mental health, child protection, water, and sanitation that come from multisector .The basic factors that must be strengthened are the level of community knowledge and education, government policies, budget sources and leadership patterns, social, economic, and political environmental conditions. These basic factors can act as inputs for stunting management .Stunting can be manifested after chronic undernourishment with causes that are multifactorial. Stunting puts children at high risk of infection with delayed recovery as well as growth retardation .From these basic factors, it will affect food security which consists of the availability, access, and utilization of foods. In addition, parenting and eating patterns at the home level, access and use of health facilities, as well as a healthy and safe environment will also be affected. These factors will play a role in the process of tackling stunting. The expected outcome is that the nutritional status and development of the foetus and child will be optimal .Due to the multifactorial nature of the cause of stunting, both sensitive and specific interventions need to be carried out to tackle the problem. Additionally, management and policy reviews can be strengthened as a basis for linking processes to optimize the outputs .This study concludes that the educational level of both parents, toddler’s age, birth weight, status of exclusive breastfeeding, and underweight are associated with the increased risk of stunting among toddlers in South Kalimantan, Indonesia. The main contributing factors to the risk of stunting is underweight.


The concept of social entrepreneurship emerged as a significant factor that contributes toward public welfare and prosperity. Recent studies showed that social entrepreneurship influences the economic growth and sustainability of the state. Therefore, the underlying aim of this study was to investigate the impact of social entrepreneurship on sustainable economic growth and value creation. This study also undertook to observe the mediating role of innovation in the relationship between social entrepreneurship and sustainable economic growth and between social entrepreneurship and value creation. A questionnaire technique was adopted to obtain data from 343 tour operators in China. The Smart-PLS software was used to analyze the data through the aid of a structural equation modelling (SEM) technique. The results revealed that social entrepreneurship has an effect on sustainable economic growth and value creation. The results also demonstrated that innovation has an effect on sustainable economic growth and value creation. Moreover, it was also observed that innovation mediated the relationship between social entrepreneurship and sustainable economic growth and between social entrepreneurship and value creation. Theoretically, this study made a valuable contribution by examining the impact of social entrepreneurship on sustainable economic growth and value creation and innovation as a mediator. In terms of practical implications, this study would certainly aid the policymakers to devise policies and strategies aim to encourage and promote social entrepreneurship. Moreover, future studies can introduce other mediating and moderating variables in order to gain a deeper insight into the phenomenon. Recently, the concept of entrepreneurship has been explored and viewed from different perspectives . One of Specifically, social entrepreneurship has recently grabbed the attention of researchers and practitioners and this concept has emerged as a prominent factor that contributes to the betterment of society . BusinesImportant contributions have also been seen in the field of entrepreneurship by the psychologists for providing clear understanding of the behavioral factors that drive the career choices of the entrepreneurs and their success . As a reEntrepreneurial activities are conducted to solve societal problems and boost sustainable development in the country. Thus, social value is created through innovation, progressiveness, social responsibility, and competitiveness . InnovatSustainable economic development and economic stability are crucial for the country’s growth . The socThe Global Entrepreneurship Monitor defined the social entrepreneurial variable as the activities initiatives or organizations that have a certain objective regarding environmental, social, or community aspects . These fSocial entrepreneurship is a novel concept that needs attention as fewer studies have been conducted to understand this concept . Al-QudaThis study also developed the research questions that have been answered in the study. The research questions are the following: What is the relationship between social entrepreneurship and sustainable economic development? What is the effect of social entrepreneurship on value creation? What is the influence of social entrepreneurship on innovation? What is the relationship between innovation and sustainable economic growth? and What is the effect of innovation on value creation? The research questions that were also developed to address the mediating role of innovation have also been established and the questions are the following: Does innovation mediate the relationship between social entrepreneurship and sustainable economic growth? and Does innovation mediate the relationship between social entrepreneurship and value creation?This study intends to examine the impact of social entrepreneurship on sustainable economic growth and value creation among tourist operators in China. The study also aimed to analyze the mediating role of innovation between social entrepreneurship and sustainable economic growth and also between social entrepreneurship and value creation. The framework of the study was supported by the theory of social entrepreneurship, which has been explained below.via viable models and economic sustainability . Such studies aimed to unravel behavioral processes, such as investigating the role of active information seeking, entrepreneurial experience, and divergent thinking in the process of opportunity identification . StudiesSocial entrepreneurship and sustainable economic growth together benefit society and assure future development and prosperity . HoweverSustainable economic growth is inspired by social entrepreneurship . EntreprH1: Social entrepreneurship has an effect on sustainable economic development.Entrepreneurship deals with creating new businesses by taking advantage of the opportunities that emerge in the market . This phA lack of evidence exists with regard to social entrepreneurship and its impact on value creation. Few studies have shown a positive relationship between these constructs. For instance, H2: Social entrepreneurship has an effect on value creation.Entrepreneurs, in general, are regarded as innovators as they seek opportunities in the market and develop new innovative products or services . In the H3: Social entrepreneurship has an effect on innovation.Studies have argued that policies related to sustainable economic growth accelerate through innovation; as a result, a win-win situation is created for the public and organizations . RegardiBoth social entrepreneurship and innovation play an important role in boosting economic growth and development in the country . OrganizInnovation has a positive and significant relationship with economic sustainability. Innovation and sustainability together help to boost economic, environment, and social development . SustainH4: Innovation has an effect on sustainable economic growth.Value creation is a process that is closely associated with innovation and innovative activities . InnovatInnovation from the social economics perspective is a complex phenomenon because innovation requires time and effort. Nonetheless, innovation for the whole society creates value creation to a greater degree. For example, H5: Innovation has an effect on value creation.via innovation.Based on various studies innovation is related to social entrepreneurship and sustainable economic growth. For instance, social entrepreneurs are agents that foster innovation through their entrepreneurial behavior . ConsequSocial entrepreneurship and sustainable development mainly focus on the quality of life by reconciling the sustainability aspects with social factors. Additionally, social entrepreneurship and innovation have been regarded as key indicators that fuel sustainable economic growth . In thisThe mediating role of innovation has been studied from different perspectives. For example, Calic and H6: Innovation has a mediating role between the relationship of social entrepreneurship and sustainable economic growth.H7: Innovation has a mediating role between the relationship of social entrepreneurship and value creation.This section presents the methodology that was adopted to examine and investigate the effect of social entrepreneurship on sustainable economic growth and value creation. Moreover, the mediating role of innovation was also studied. This study adopted a quantitative design and a deductive approach to analyze and examine the proposed hypotheses. These hypotheses were formulated to aid the researcher to examine the effect of the predictor variables on the outcome variables. The adoption of a quantitative design aided in eliminating the biases present within the study, so that the reliability of the results may be ensured . The proThe process of data collection was completed in 2 weeks and a total of 343 forms were obtained. After a thorough screening of the survey forms, 57 forms were discarded as they were either incomplete or improperly filled. Hence, the overall usable response rate was 86%. The data from the usable survey forms were later examined through the aid of statistical software. The target population of this study was comprised of tour operators located in various regions of China. A non-probabilistic convenience sampling approach was used to draw a sample from the population. The adoption of a convenience sampling technique significantly facilitated the researcher to obtain data from readily available respondents in a timely and cost-effective manner . The unip-values (This study adopted the structured equation modelling (SEM) technique to analyze the data that were obtained from the respondents. For this purpose, the Smart-PLS 3.3.3 statistical tool was used. p-values .The data for this study were gathered through the aid of a five-point Likert scale . A detailed description of the measurement scales is given below. There were eight items in the measurement scale of social entrepreneurship, and it was adopted from The demographic profile of the respondents of the study can be viewed in The output of the measurement model can be seen in The assessment of the direct model can be viewed in The composite reliability values higher than 0.70 are considered to be satisfactory . It can The R-square and Q-square values can be viewed in The output of the structural model can be viewed in p-values. The desirable t-statistic values should be above 1.96 . The t-statistic and p-values were 8.953 and 0.000, respectively, and therefore, H2 was also accepted. The effect size of 0.397 indicated weak to moderate model strength. H3 stated that SE had an effect on innovation. The t-statistic and p-values are 10.481 and 0.000, respectively, and therefore, H3 was also accepted. The effect size was recorded at 0.322 indicating weak model strength. H4 predicted that innovation had an effect on sustainable economic growth (SEG). The t-statistic and p-values are 5.360 and 0.000, respectively, and thus, H4 was accepted. The effect size was 0.138 indicating weak model strength. H5 proposed that innovation had an effect on VC. The t-statistic and p-values were 2.852 and 0.005, respectively, and therefore, H5 was also accepted.The analyses of the five direct hypotheses, i.e., H1, H2, H3, H4, and H5, are shown in p-values were 5.123 and 0.000, respectively, and therefore, H6 was accepted. H7 proposed that innovation mediated the relationship between SE and value creation (VC). The t-statistic and p-values were 2.853 and 0.005, respectively, and therefore, H7 was also accepted.The results of the indirect effects can be viewed in via innovation.The existing social and economics literature had a few gaps which have been addressed in the current study by examining the role of social entrepreneurship on sustainable economic growth and value creation. To carry out the research, the data were acquired from tour operators in China. The study also examined the indirect or mediating role of innovation in the relationship between social entrepreneurship and sustainable economic growth. The present investigation also analyzed the relationship between social entrepreneurship and value creation The intensive review of literature showcases the significant participation of psychology and psychologists in the field of entrepreneurship and social entrepreneurship. There is a potential for the psychologists in engaging with entrepreneurship and instigate novel topics in the research that facilitates and strengthens the psychological approaches in theory, practice and methodology to better understand the facets of entrepreneurship . EntreprThe second hypothesis (H2) of this study posited that social entrepreneurship has an effect on value creation. This hypothesis was accepted. The results are in synchrony with the results of the study conducted by The results of the mediating role of innovation showed that innovation mediates the relationship between social entrepreneurship and sustainable economic growth. Thus, the sixth hypothesis (H6) was also accepted which posited that innovation has a mediating role in the relationship between social entrepreneurship and sustainable economic growth. These results are in harmony with the findings of The current study incorporates some theoretical implications. First, the study aimed to examine the role of social entrepreneurship on sustainable economic growth and value creation. The findings greatly contribute to the literature on social economics and sustainability because few studies were conducted in this regard. Moreover, the study also improved the literature by analyzing the role played by innovation as a mediator. The reader could understand how innovation facilitates the relationship between social entrepreneurship and sustainable economic growth and between social entrepreneurship and value creation. Moreover, other researchers can enhance their knowledge with regard to the importance of social entrepreneurship and how it contributes to sustainable economic growth. The researchers can also understand the significant role played by innovation to enhance both sustainable economic growth and value creation.Taking the results of the study into account, it becomes imperative to provide practical guidelines for the policymakers and tour operators. Therefore, the present study proposed some practical implications. The results obtained depict that social entrepreneurship has a significant relationship with sustainable economic growth and value creation. This implies that policymakers must devise strategies and policies to encourage social entrepreneurship. This can be done by showing social entrepreneurs the kind of impact they can have on society. In this way, they would be motivated to serve society and work for public well-being. Another way that can be adopted by policymakers or government at the state level to boost social entrepreneurship is by giving them recognition. Moreover, social entrepreneurs must be encouraged by supporting the notion of social entrepreneurial activities. Social entrepreneurs work for society without expecting anything tangible in return; however, support from the government can boost their morale. Furthermore, the study found that innovation is a significant factor that facilitates the relationship between social entrepreneurship, sustainable economic growth, and value creation. Therefore, the management of tour operators must enhance the process of social entrepreneurship in order to accelerate innovation. Innovation acts as a catalyst that can boost value creation and economic development. Also, policy-makers and social entrepreneurs together can take advantage of the opportunities in terms of environmental aspects, economic aspects, and social aspects so that they can bring prosperity to society.Like other studies, this study also includes a few limitations. First, this study has been conducted in China, therefore, future researchers can conduct the study in other Asian or western countries. The small sample size was another limitation of the study, and thus, a larger sample can be taken in future studies for data generalization. To carry out this study, the data were obtained from tour operators, so other industries or companies can also be considered in the future. This would enhance the understanding of the framework in other contexts as well. Another limitation of the study was the study design. The study was cross-sectional as the data were taken at one point in time. Future studies can use longitudinal data to examine how social entrepreneurship evolves. This study was quantitative; therefore, in the future, researchers can examine the same theoretical framework using qualitative data. Social entrepreneurship is a subjective phenomenon, so obtaining qualitative data would provide deep insights into the subject matter. Future studies can add new mediators or moderators to the current framework, for example, social change can be used as a mediator and good governance can be used as a moderator.Social entrepreneurship is a phenomenon that affects the economic growth of the country. Higher economic growth leads to a higher rate of employment and better living standards for the people in the society. To understand the impact of social entrepreneurship, this study examined the role of social entrepreneurship on sustainable economic growth and value creation among tour operators in China. The study also determined the mediating effect of innovation in the relationship between social entrepreneurship and sustainable economic growth and between social entrepreneurship and value creation. This investigation revealed that social entrepreneurship has an impact on sustainable economic growth, value creation, and innovation. The results obtained also showed that innovation impacts sustainable economic growth and value creation. The study found that innovation mediates the relationship between social entrepreneurship and sustainable economic growth and between social entrepreneurship and value creation among tour operators in China.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved Shandong University of Arts, China. The patients/participants provided their written informed consent to participate in this study. The study was conducted in accordance with the Declaration of Helsinki.WW conceptualized the concept, collected the data, analyzed the data, wrote the draft, and approved the submitted version.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cardiorenal syndrome (CRS) is a complex disease in which the heart and kidneys are simultaneously affected, and subsequently, the malfunction of one organ promotes the deterioration of the other. Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF. The pathophysiology of CRS is not well known and several mechanisms have been proposed. An elevation of central venous pressure seems to be one of the key points to consider, among others such as an increase in intraabdominal pressure. Several diagnostic tools have been identified to establish the diagnosis of CRS in patients with HFpEF. Currently, the availability of biomarkers of renal and cardiac injury, the use of pulmonary ultrasound, the monitoring of the size of the inferior vena cava and the study of the renal venous pattern offer a new dimension in accurately diagnosing and quantifying organ damage in CRS. Beyond the symptomatic treatment of congestion, until recently specific therapeutic tools for patients with CRS and HFpEF were not available. Interestingly, the development of new drugs such as the angiotensin/neprilysin inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors offer new therapeutic strategies with potential benefits in reduction of cardiorenal adverse outcomes in this population. Randomized clinical trials that focus on patients with HFpEF are currently ongoing to delineate optimal new treatments that may be able to modify their prognosis. In addition, multidisciplinary teamwork  is expected to decrease the number of visits and the rate of hospitalizations, with a subsequent patient benefit. Taking  < .001] . Other l < .001] .Cardiovascular disease, especially HF, is a common thread between nephrologists and cardiologists. This relationship was for the first time described by Robert Bright in 1836 when he observed cardiac structural changes in patients with advanced kidney disease . Since tMechanisms involved in the kidney–heart cross-talk are complex, involving different haemodynamic and non-haemodynamic pathways, which allows targeting different therapeutic strategies. In this regard, a multidisciplinary approach is fundamental. A strong ‘marriage’ of cardiologists and nephrologists enhances patient-tailored decisions with a wide vision based on the characteristics of each case. A close working relationship between nephrologists and cardiologists is the key to successfully managing symptoms and prolonging life where possible; treating with diuretics, angiotensin-converting enzyme inhibitors and mineralocorticoid receptor antagonists, while avoiding electrolyte abnormalities and AKI; and multidisciplinary team decisions for dialysis and device therapy, altogether, maybe the key for the CRS treatment . It has HF is a major clinical and public health problem and HFpEF is the most common form of HF. CKD has also a high global prevalence, and renal dysfunction is one of the most important risk factors predicting mortality and poor outcomes in HF patients. Therefore, understanding the interrelation between the heart and kidneys in the clinical scenario of CRS is essential. We currently have new tools that help us in the diagnosis, such as biomarkers and imaging techniques. Altogether this allows the early identification of these patients, with the aim of offering them the best treatment. The appearance of new drugs, such as SGLT2 inhibitors, represents a start for the prognostic improvement of CRS. The complexity of these patients requires multidisciplinary management and the implementation of cardiorenal units, which are expected to reduce the number of visits as well as the hospitalization rate, with a positive impact not only on the patient but also on the health system.


Microorganisms are closely related to skin diseases, and microbiological imbalances or invasions of exogenous pathogens can be a source of various skin diseases. The development and prognosis of such skin diseases are also closely related to the type and composition ratio of microorganisms present. Therefore, through detection of the characteristics and changes in microorganisms, the possibility for diagnosis and prediction of skin diseases can be markedly improved. The abundance of microorganisms and an understanding of the vast amount of biological information associated with these microorganisms has been a formidable task. However, with advances in large-scale sequencing, artificial intelligence (AI)-related machine learning can serve as a means to analyze large-scales of data related to microorganisms along with determinations regarding the type and status of diseases. In this review, we describe some uses of this exciting, new emerging field. In specific, we described the recognition of fungi with convolutional neural networks (CNN), the combined application of microbial genome sequencing and machine learning and applications of AI in the diagnosis of skin diseases as related to the gut-skin axis. A tremendous array of microorganisms widely exist in nature and the human body. In healthy humans various types of microorganisms and dominant microbiota are present within different parts of the body and a stable number and ratio of microorganisms are maintained through competition or synergy . With chConvolutional Neural Network (CNN) is a special type of machine learning that can assimilate both isolated topographies as well as entire images and classify these images according to their unique features . DermatoThe differences in diagnosing onychomycosis using CNN vs. manual microscopic examinations have been compared and analyzed. Results from one report found that the accuracy of CNN diagnosis was 10% greater than that of traditional diagnostic methods . In thatIn addition to nails, fungal infections within other regions, such as the skin and hair, can also be diagnosed using CNN. However, due to the expansive areas involving skin and hair, the lesions are not concentrated. As a result, the low fungal content in an individual lesion hinders the recognition of mycelial characteristics by CNN, which can then decrease the diagnostic accuracy in these regions . One appMachine learning can provide the means for identifying patterns in the sequencing data of a pathogen to generate a system for subdividing that pathogen. In this way, it can be used to determine which branch of the pathogen is infected to provide a basis for administration of the most appropriate medication. This method can be applied for the diagnosis of syphilis, as the internal structure of treponema is like that of bacteria with five genera, among which treponema is the pathogenic bacteria resulting in syphilis. In contrast, the clinical diagnosis of syphilis requires serological tests including TPPA and TPHA, which lack the ability to determine which branch of the pathogen is infecting the patient, thus precluding decisions regarding the most effective medication . One exavia its ability to detect partial fragments of microbial ribosomal DNA. This fragment includes 9 variable and 10 conserved regions, with the former determining relationships between species and the latter providing an understanding of differences between species. Diversity information of microorganisms in a sample can be obtained by amplifying and sequencing partial regions of the rRNA DNA sequence in the extracted sample , three machine learning methods – random forest (RF), XGBoost, and LightGBM were used to analyze these samples. In addition, samples from the legs of 278 British women were also obtained for analysis using machine learning. The results from this study revealed that skin moisture levels were higher and a better skin condition was observed as a function of increased levels of lactobacilli. With an abundance of Bergeyella, the skin was dehydrated and the probability for dermatitis was relatively high .Metagenomics, which differs from that of 16S sequencing, directly extracts DNA from all microorganisms of environmental samples, with the detection object including all microbial genomes, due to its more prolific genome database . The diaGut microbiota play an important role in maintaining human health. The host and microbiota maintain a state of homeostasis within the body through subtle interactions, with disruptions in this balance affecting the entire organism, even within organs far removed from the gut, such as the integumentary system . In factResults from previous studies have shown that microbes on the skin surface are highly related to the occurrence and development of vitiligo, and the progression of this disease can be estimated by observing changes in skin microbes. For example, increased levels of streptomycin and streptococci are observed in active vs. stable vitiligo as detected by the Novaseq sequencer; and differences in Beta diversity  are present between patients with active vs. stable vitiligo . While tE. coli, fewer bifidobacteria, bacteroides and lower levels of alpha-diversity (Atopic dermatitis (AD) is a chronic inflammatory disease that may result from a complex interaction among genetic predisposition, immune dysfunction, environmental allergens and skin barrier abnormalities. Interestingly, results from previous studies have suggested that AD patients show abnormal gut microbiomes prior to the onset of this disease. Infants (2 months of age) whose fecal calprotectin was greater than normal showed an increased risk of developing AD at 6 years of age . In addiiversity . Such fiiversity . In thativersity . FinallyThe human microbiome is closely related to skin diseases. Accordingly, an understanding of the microbial community composition, structure, function and its changes within the skin can serve as critical indices for the diagnosis of skin diseases. With this method, different machine learning models can be used to analyze changes in the abundance, type, and composition ratio of microorganisms in different aspects of the disease state versus that of healthy people, which can then enhance the accuracy of diagnosing skin diseases. Moreover, as compared with that of traditional methods, this procedure can also serve to predict the occurrence and progression of diseases.As this new technology currently resides in developmental stages, many limitations remain. For example, sequencing data have low rates of representation and insignificant features as well as easy under-segmentation caused by the image characteristic which can result in a reduction in the accuracy of conclusions derived with this technique . In addiTS: searched and analyzed the published literature and drafted the manuscript. XN and QH: searched and analyzed the published literature. R-QQ and FC: reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.This study was funded and supported by National Natural Science Foundation of China (82173401 and U1908206).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Several strategies and interventions have been implemented to improve male partner involvement (MI) in Sub-Saharan Africa, but evidence on successful interventions is scarce. This controlled before-and-after intervention study aims to evaluate the impact of three interventions on male partners' involvement in HIV+ women's care in Malawi. We piloted these three interventions: the organization of a special day for men, the deployment of male champions in communities to increase awareness on MI, and the delivery of an incentive (food package) for couples attending the facility. We observed a significant increase in the number of women accompanied by their partners (from 48.5 to 81.4%) and the number of women feeling safe at home (from 63.5 to 95.2%) after the special day intervention. This outcome increased after the deployment of male champions in communities (from 44.0 to 75.0%). No significant improvement was observed in the site where we delivered the incentive to couples. Our findings showed that the special day for men and the use of male champions might effectively increase the male involvement in the health of their female partners. Male involvement (MI) is a critical issue, especially in maternal and child health (MCH) and in the Prevention of Mother to Child Transmission (PMTCT) of HIV in Sub-Saharan Africa (SSA). In this continent, men plays an relevant role in the decision-making process within the household and this often impacts women's access to healthcare, contraception, food, and work, and, as a consequence, pregnancy outcomes –4. Low mQualitative studies suggest that women are not supported enough by their male partners in many aspects; some of the barriers reported are access to transport to the clinic, lack of accompaniment to appointments, sometimes men are even reported to hinder female access to the clinic and female retention in care itself –16. GendIn 2020, an estimated 990,000 Malawians were living with HIV, and 12,000 Malawians died from AIDS-related illnesses in the same year. More than 98% of pregnant women were tested for HIV, and more than 95% of those testing positive were on treatment , 22. PreIn Malawi, male involvement in MCH and PMTCT ranges from 3.2 to 74% . One stuSimilar data are reported in other SSA countries: a Ugandan study reported a high prevalence (74%) of low male involvement, and only 5% of men escorted their partners to the Antenatal Care (ANC) clinic . In KenySeveral health interventions and strategies have been implemented in Sub-Saharan Africa and Malawi. However, most of these programs have not shown success. Few studies and with variegate study design were conducted as shown by a recent systematic review . A previOur research aims to assess the impact of three different interventions on male partners' involvement in HIV+ women's care in Malawi .We conducted a controlled before-and-after intervention study in Malawi in 3 clinics managed by the DREAM program (Disease Relief through Excellence and Advanced Means) in Kapire, Kapeni and Balaka. Each clinic piloted a different intervention: Kapire, the use of male champions; in Balaka, the introduction of a special day for male patients; in Kapeni incentives  for male partners attending the clinic. The study protocol originally included a control center where no intervention was performed. This center was later removed from the study as we encountered some technical problems that affected the collection of data.DREAM is a health program run by the Community of Sant'Egidio aimed at addressing a wide range of health challenges according to the needs of different contexts –40. The ClinicalTrials.gov .The paper is the first output of a pilot project, called “WeMen,” that aims to evaluate the impact of three different interventions on adherence and the retention to Antiretroviral therapy (ART) of HIV-positive women . The metThe baseline analysis was conducted from July 2019 to March 2020; the interventions took place from August 2020 to January 2021 and the post-intervention from October 2020 to March 2021. We included HIV+ women in both the pre-and post-intervention periods who agreed to join the study. Women younger than 18 years and with no stable partner were excluded.In the healthcare centers where we carried out the interventions, we asked women to invite their male partners to the health center for HIV testing and counseling, and we administered a questionnaire to the woman at the subsequent visit . The queBox 1Main outcomesDid your partner accept to come with you to the clinic (Yes/No)Has your partner accepted to be tested for HIV? (Yes/No)In general, how satisfied are you with the overall support you get from your partner? (Very dissatisfied/dissatisfied/neither/satisfied/very satisfied)Do/did you generally feel physically or emotionally unsafe in your relationship with your partner? (Yes/No/Sometimes/I prefer not to respond)Other outcomes (Yes/No)Does your partner approve of using a contraceptive method to prevent pregnancy?Does your partner agree that you attended antenatal clinics when you were/are pregnant?Does your partner support transportation cost for you to get to the healthcare center/PMTCT clinic?Did your partner help you remember to take your HIV medication during the past year?As described in the protocol paper, the primary outcomes evaluated in the WeMen project are women's retention in care and adherence to treatment at 6 months, 1 and 2 years. These are still under evaluation and will be published in a following paper.Did your partner accept to come with you to the clinic?” over the number of women included in the study. The second outcome (ii) is calculated as the proportion of affirmative responses to the question “Has your partner accepted to be tested for HIV?” over the number of women whose partner agreed to accompany her to the clinic. The third outcome (iii) was measured with a Likert scale with values from 1 (very dissatisfied) to 5 (very satisfied) to the question “In general, how satisfied are you with the overall support you get from your partner?” The fourth intermediate outcome (iv) was measured by the proportion of negative responses to the question “Do/did you generally feel physically or emotionally unsafe in your relationship with your partner?” over the total number of women included in the study. Other outcomes related to male involvement were measured with dichotomic questions where the affirmative response indicated a positive attitude from the male partner. The questions related to the four “main outcomes” and the 5 “other outcomes” are reported in We performed statistical analysis with software “R” version 4.1.2  [packageThe same data were collected in the pre-and post-analysis using specific software, respecting patient privacy and data security rules. We used a two-sample test of proportions to test the difference between outcomes expressed by rates at baseline and post-intervention, and we calculated a 95% confidence interval for differences in proportions. We used the Kruskal-Wallis test to test the difference in the distribution of responses to indicator three expressed with a Likert scale.The study protocol has been reviewed and approved by the College of Medicine Research and Ethics Committee (COMREC) under Malawi's National Health Science Research Committee (NHSRC) with approval number 2021.In total, 324 women were included at the baseline and 381 in the post-intervention evaluation, as shown in As reported in p < 0.001), the number of women feeling safe at home  and the level of satisfaction of female partners about male support . On the other hand, the proportion of men who accepted Voluntary Counseling and Testing (VCT) when they accompanied their female partner to the clinic decreased (from 86.7 to 64.4%).In the site where the special day intervention was implemented, we observed a significant increase in male involvement from baseline to post-intervention in terms of the number of women accompanied from their partners after delivering an invitation card  and in some other outcomes, such as the proportion of men approving the access of their partners to healthcare services  and antenatal care .In the center where the male champions intervention was implemented, an increment was observed in the proportion of women feeling safe at home  are promising interventions in the uptake of maternal antiretroviral therapy and male support , 35. ComHowever, since these are multi-component interventions, it is difficult to attribute the effect of an intervention to one component both in our study and in previous studies where the effect of every single component was not reported , 52.Some limitations of this study are related to the design adopted and the local context, and we have reported them in the published protocol of the study . These iIn order to produce more reliable results, it would have been necessary to include a more significant number of facilities, randomize the selection of facilities, calculate a sample size capable of limiting systematic errors, and prolonging both the enrollment period and the duration of the interventions tested. However, these activities would have entailed unaffordable costs, and longer study duration was not allowed in this research project. Furthermore, during the study, difficulties emerged in data collection caused by a high workload and a high turnover for the health personnel involved, also because of the COVID-19 outbreak after the start of the study. Due to these difficulties, it was impossible to collect data of sufficient quality in the control center that would have allowed us to assess whether the results derived from temporal trends or unmeasured events.In addition to these limits, a social desirability response bias may be a confounder and lead to inaccurate self-report conclusion: some women may have had privacy concerns; they may not want to reveal unsupportive behaviors of their male partner since they do not want to endanger their relationship and preferred to preserve their relationship avoiding possible interferences and conflicts within the couple . These bOne of the strengths of this study is having adopted an ecological approach with interventions aimed at individuals but targeting facilities or communities , 55. On A further limitation of the study that limits its reproducibility and comparison with other studies on the subject is the absence of a validated standard tool for measuring male involvement. However, using several indicators allows us to interpret the results from multiple points of view and compare them with studies that have used the same indicators.Special days and Male champions were the interventions able to consistently increment the studied variables, while nudges were feebly impacting male involvement; this could mean that the social and context aspects, rather than the individual/material ones, should be considered when planning specific programs to increase male involvement. The management of health care units and the design of services is strongly implicated in male partners' possible involvement. Hence, the delivery of male-friendly services should be considered a responsibility of the policymakers and service providers, both at the local and national levels. Further studies could be helpful to evaluate more in detail some aspects. In particular, the possible effect of confounders factors not considered in our analysis , the specific aspects of the special days' intervention that could be more effective in the male involvement increment, and others.Our results have important implications from a public health perspective that support the feasibility and effectiveness of specific interventions aimed at male involvement. As a general consideration, our findings highlight the need for a comprehensive intervention aimed at a multi-level impact  on the social context related to the male-female interaction. In our study, However, in our opinion, the study can significantly contribute to the design of more male-friendly services to enhance both male- and female-health status. Local and international guidelines on HIV care should consider more clearly MI and include specific interventions aimed at its improvement.Complex public health interventions acting on multiple levels could effectively increase the male involvement in the health of their female partners, as reported by the same women. In particular, the realization of special opening days of clinics reserved for men with health education services and awareness campaigns in the communities with male champions proved to be the most promising interventions. The ecological approach used in these interventions, which also act on the environment/context and not only on individuals, and having acted both at the clinical facility level and at community and social network level, are the aspects that probably have increased the effectiveness of the interventions. However, the ecological approach does not elicit the direct causal mechanisms and the effectiveness of the individual components of the interventions. Moreover, it is necessary to adopt standard and validated criteria to measure male involvement in health services. It is recommended to replicate interventions of this type in other contexts to produce more evidence of their effectiveness and observe the impact on final health outcomes such as adherence and retention in care in programs for the treatment of chronic diseases. Given the limitations of the context and the availability of time and resources, the results should be interpreted with caution. They should be intended as a first step in order to test the most promising interventions in more extensive studies to verify their validity.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by College of Medicine Research and Ethics Committee (COMREC) under Malawi's National Health Science Research Committee (NHSRC) with approval number 2021. The patients/participants provided their written informed consent to participate in this study.IT, FC, IP, and SO: conceptualization, methodology, and writing—original draft. BM and DT: data curation. BM and SO: formal analysis. SO: funding acquisition and visualization. IT and SO: investigation. FC: project administration. FC and SO: resources. LP and SO: supervision. MM, LP, and GT: validation and writing—review & editing. All authors have read and agreed to the published version of the manuscript.This research was funded by the Italian Ministry of Foreign Affairs through the Italian Agency for International Cooperation within the Global Fund 5% program aimed at providing evidence on how to improve the interventions of the Global Fund against tuberculosis, HIV, and malaria in the countries where the fund operates. Grant WeMen! Improving womens access to health care system through mens inclusion AID 011587/08/05.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


It is unknown if changes have been made to the original participant’s information sheet/informed consent form (PIS/ICF) provided by the WHO Solidarity Plus team when it was transferred to participating countries.National principal investigators from 30 countries were asked if the original PIS/ICF was edited in their countries and, if so, to share with us the one used to recruit participants. We assessed whether the 25 different elements of information from the good clinical practice guidelines and the Declaration of Helsinki were present in, deficiently described, or absent from the PIS/ICFs.Nineteen national principal investigators responded: eight  stated that no edits were introduced to the original PIS/ICF; eight  added some elements of information in the national PIS/ICF; and three  reported not participating in the trial. None of the elements included in the original PIS/ICF were omitted from the edited PIS/IFC. Six elements of information were omitted and five deficiently described in the original PIS/ICF. The number of elements omitted from the edited PIS/ICFs varied (range = 2-5). Nine PIS/ICFs incompletely described or omitted the informing of study participants about the study results, while five deficiently described or omitted the anticipated expenses for trial participation. Information concerning whom to contact for more information or in case of injury was deficient in six PIS/ICFs. Unlike the original PIS/ICF, all edited PIS/ICFs informed participants about the existence of compensation or treatment for any injury related to the trial.WHO should consider adding three of the omitted elements in PIS/ICFs of future multinational similar trials. In 2020 the World Health Organization (WHO) sponsored the Solidarity trial, an open, adaptive trial that assessed four repurposed medications on top of standard of care vs standard of care in hospitalised COVID-19 patients. In August 2021, the WHO announced a second open, large, adaptive trial to assess three new drugs with the same design and in the same patient population, the Solidarity Plus trial. These drugs are artesunate, imatinib and infliximab, already authorized for other indications. Solidarity Plus was to be conducted in 600 hospitals in 52 countries on four continents. Unlike the Solidarity trial, the WHO made the Solidarity Plus trial protocol and other documents (including the participant’s information sheet/informed consent form (PIS/ICF)) freely available from the beginning [There are three basic ethical principles to be fulfilled by any human subject research: respect for persons (or autonomy), beneficence, and justice. Autonomy stands for self-determination and requires protection of those with diminished autonomy. A research study fulfils the principle of beneficence by aiming to produce generalisable knowledge that would be valuable for society and by attempting to maximize benefits and minimize risks for research participants. Finally, justice, in general, requires fairness in participant selection and in the distribution of the study’s benefits and burdens . To fulfThe PIS/ICFs of the Solidarity and the Solidarity Plus trials are short (four pages) and simple. How these documents are tailored to the context and requirements of clinical research in each participating country is, however, unknown. To our knowledge, the changes introduced to the PIS/ICF by any of the 36 countries participating in the Solidarity trial have not been published. Since the original PIS/ICF of the Solidarity Plus trial was publicly available, we considered that the analysis of the nature and extent of the modifications introduced in the original PIS/ICF in the participating countries would be of interest for future multinational trials sponsored by the WHO or other non-commercial organizations aiming to conduct RCTs in numerous countries across all continents.To date, the national principal investigators (PIs) of the participating countries in the Solidarity Plus trial have not been disclosed publicly. In June 2022, however, the national PIs of the 36 countries participating in the Solidarity trial became publicly available [On June 8, 2021, we asked the national PIs of 30 countries whether the original PIS/ICF provided by the Solidarity Plus WHO team was edited when the trial was implemented in their countries, and if so, to share with us the edited version that was being used to recruit participants. The addition of the national/site information was not considered to be an edit of the original text. Three of these 30 PIs asked us to write to the WHO as the global sponsor of the trial. On June 29, the WHO Solidarity Plus team expressed support for our study but made it clear that, although they had the information we were interested in, the information for each country should be provided by the national PIs themselves. On June 29/ 30 and, if necessary, on July 10, we sent reminders to the national PIs of the 30 countries for the requested information noting that the WHO supported our study ─one member of the WHO Solidarity Plus team was copied into all emails sent from June 29 onwards.The Solidarity Plus trial protocol states that it would be conducted in accordance with the International Conference on Harmonization good clinical practice (GCP) . CompliaWe first reviewed the original PIS/ICF provided by the WHO team and then assessed the PIS/ICF provided by the national PIs who informed us that the document was edited in their countries before starting to recruit participants. Two authors (RDR and TCV) independently reviewed the edited PIS/ICFs included in our analysis to assess whether the 20 elements of information specified in the GCP and the 10 mentioned in the DoH were also mentioned in these PIS/ICFs  stated that the PIS/ICF used in their countries were translated to the local language, without adding elements of information not already present in the original PIS/ICF provided by the WHO team. The other eight countries , stated the local PIS/ICF were edited and provided us with a copy; all of these were in English except those of Colombia (in Spanish), Portugal (in Portuguese), and Switzerland (in French). The national PIs of Italy, Peru, and Spain informed us that their countries decided not to participate in Solidarity Plus.Among the eight countries that edited their PIS/ICFs, five  assessed the three medications , infliximab (single IV infusion), imatinib ) along with standard of care vs standard of care . Canada The eight edited PIS/ICFs had between two and 12 more pages than the original PIS/ICF  were also incorporated in the eight edited versions included in this analysis. Existing informed consent regulations applicable to countries involved in a multinational trial may not be optimal for helping potential participants make good decisions . This isTo our knowledge, this is the first time that the information provided in PIS/ICFs used to recruit participants in many countries in a WHO-sponsored trial is assessed. We found that in countries from all four continents involved in Solidarity Plus, the original PIS/ICF provided by the WHO was either used without introducing any new element of information or was edited to follow the regulatory or REC requirements of the participating country.Our assessment of the WHO study team’s original PIS/ICF showed that 24% (6/25) of the elements of information included in the GCP and the DoH were absent; an additional 20% (5/25) were deficiently described. Although eight countries did not edit the original PIS/ICF, the other eight did. Among the latter, the edited PIS/ICFs added several elements of information to reduce the percentage of missing elements to 8%-20% (range = 2-5 of 25). However, not all 25 evaluated elements of information should be considered as relevant to all protocols. Relevant RECs should decide which elements should be included and how they should be described in the PIS/ICFs given the nature of the research and the potential participants’ characteristics.Although there are several guidance documents on categories of information that should be provided to trial participants ,11,12, oOf most relevance, the original PIS/ICF did not contain information about the WHO establishing a global liability insurance for participants suffering serious adverse reactions from exposure to the investigational medications, covering all participating countries . This waThe PIS/ICFs of only two countries (Canada and Switzerland) informed the participant that he/she will receive any new information that becomes available that could affect his/her interest to continue in the trial. Since the investigational medications were to be given between one and 14 days, it is unlikely that any new information could impact the course of these treatments. This could be the reason why this information was omitted from most of the PIS/ICFs. However, this cannot be applicable to all participants that are receiving the standard of care, in case an additional medication is incorporated into usual care.Information on the funding source was deficient in all countries except in Canada and Switzerland. This could be explained by the way the WHO provided this information in the original PIS/ICF, which only mentions co-sponsorship , without mentioning any funding source. It is well-known that there is some ambiguity between the meanings of “sponsor” and “funder” . In factStrictly speaking, conflicts of interest were deficiently described or absent in all but one PIS/ICF (Canada). Nevertheless, mentioning only that the medical staff would not receive any payment as a form of disclosure of conflict of interest could be considered as sufficient information for participants in countries with limited clinical trial experience, even though receiving income from industry to conduct other studies are of concern in developing countries that usually have low salaries for health care professionals . We undeNot a single PIS/ICF informed participants on post-study provisions. Since participation in the trial ends at hospital discharge, it could be reasonable to omit this element as it would add no relevant information to potential participants.Finally, it is difficult to understand why the number of participants to be recruited  is not mentioned in the original PIS/ICF or in four of the eight edited documents. Similarly, it is hard to explain that the PIS/ICF in some countries did not mention how the trial results would be provided to participants. We understand that this could be difficult in certain participating countries, but should not be the case in developed countries like Argentina, Canada, Lithuania, and Switzerland.This study has two main limitations. First, the limited number (n = 16) of participating countries and of those that provided the edited PIS/ICF (n = 8). However, it is difficult to know what percentage it represents of the total number of countries participating in the Solidarity Plus trial. Hence, among the 51 participating countries included on the registry (ISRCTN18066414) as of July 2022, at least three  are not actually participating. We believe that assessing a larger number of edited PIS/ICF is key to determining the actual status of edits introduced worldwide; however, we believe they are unlikely to be different from what we obtained with the eight countries in our study, which include both countries with developed clinical research system and others lacking it. Second, our assessment may differ from other investigators, particularly on those elements of information that we regard as deficiently described. Yet, this is not relevant, as our main focus is on those elements absent from the assessed PIS/ICFs.Although the WHO Research Ethics Review Committee issued an informed consent form template for clinical trials  (with a No elements included in the original PIS/ICF were omitted from the edited ones in the countries, which strongly suggests that, if the WHO team had included one or more of the omitted elements, they very likely would have also been included in the edited ones. We suggest that the original PIS/ICF should have included information on compensation or treatment for injuries that result from exposure to the investigational medicines, the lack of trial-related expenses for participants, and the target number of participants, which would mean adding just a few sentences (