Many studies have explored the link between the gut microbiota and schizophrenia. To date, there have been no bibliometric analyses to summarize the association between the gut microbiota and schizophrenia. We aimed to conduct a bibliometric study of this association to determine the current status and areas for advancement in this field.Publications related to the gut microbiota and schizophrenia were retrieved from the Web of Science Core Collection (WoSCC). The WoSCC literature analysis wire and VOSviewer 1.6.16 were used to conduct the analysis.In total, 162 publications were included in our study. The publications generally showed an upward trend from 2014. A total of 873 authors from 355 organizations and 40 countries/regions contributed to this field. The leading authors were Timothy Dinan, John F Cryan, and Emily Severance. The leading institutions were Johns Hopkins University, the University College Cork, and the University of Toronto. The most productive countries were the United States (US), China, and Canada. In total, 95 journals contributed to this field. Among them, the top three productive journals were Schizophrenia Research, Progress in Neuro Psychopharmacology Biological Psychiatry, and Frontiers in Psychiatry. The important keywords in the clusters were gut microbiome, bipolar disorder, schizophrenia, antipsychotics, weight gain, metabolic syndrome, gut-brain axis, autism, depression, inflammation, and brain.The main research hotspots involving the connection between schizophrenia and the gut microbiota were the characteristics of the microbiota composition in schizophrenia patients, the gut-brain axis, and microbial-based interventions for schizophrenia. The studies about the association between gut microbiota and schizophrenia are limited, and more studies are needed to provide new insights into the gut microbiota in the pathogenesis and treatment of schizophrenia. Schizophrenia is a serious psychiatric illness that affects approximately one in a hundred people worldwide –5. The rIn recent years, the link between schizophrenia and the gut microbiota has received increasing attention. Recent studies have shown that the gut microbiota can modulate brain function through the gut-brain axis –19. The In our study, publications about schizophrenia and the gut microbiota were downloaded from the WoSCC. The following search terms were used: TS = (microbiome* OR flora microbiot* OR bacteria OR microflora) AND TS = (intestin* OR gut OR gastro-intestin* OR gastrointestin*) AND TS = (schizophrenia OR “schizoaffective disorder” OR “schizophreniform disorder” OR “first episode psychosis” OR “schizophrenia spectrum disorder”). The search results were confined by the publication date from the inception of the study to 30 May 2022; types of publications, including articles and reviews; and English language. In our study, we conducted a literature search and screening according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .h-index was used to evaluate the citations of the researcher’s publications. The WoSCC literature analysis wire and VOSviewer 1.6.16 were used to conduct the analysis. The WoSCC literature analysis wire was used to analyze the publication years, categories, document types, the distribution of authors, institutions, countries/regions, and h-index. VOSviewer1.6.16 software was used to conduct assessments of the coauthorship of authors, keywords, countries/regions, and institutions. The total link strength (TLS) was used to evaluate the cooperation relationship. In the keyword co-occurrence analysis, we merged the synonyms of “induced weight-gain,” weight-gain and “weight gain” to the term “weight gain”; “probiotic supplementation” and “probiotics” into “probiotics”; “autism spectrum disorders,” “autism spectrum disorder,” and “autism” into the term “autism”; and “microbiome,” “microbiota,” “intestinal microbiota,” “gut microbiome,” “gut microbiota,” and “fecal microbiota” into the term “gut microbiota.”The A total of 162 publications containing 78 reviews and 84 articles were included, as shown in h-index of 12, followed by John F Cryan who had 12 publications with 1,929 citations and an h-index of 12, Emily Severance who had 11 publications with 580 citations and an h-index of 9, Robert Yolken who had 11 publications with 580 citations and an h-index of 9, and Michael Maes who had 7 publications with 160 citations and an h-index of 7. In total, 873 authors contributed to this field. Timothy Dinan was the leading author who had 13 publications with 1,933 citations and an All publications were from 355 organizations and 40 countries/regions. The top three most productive institutions were Johns Hopkins University with 14 publications and 931 citations, University College Cork with 14 publications and 1,942 citations, and the University of Toronto with 10 publications and 341 citations. In total, 95 journals contributed to this field. Among them, the top three productive journals were Schizophrenia Research with 14 documents and 809 citations, Progress in Neuro Psychopharmacology Biological Psychiatry with 9 documents and 115 citations, and Frontiers in Psychiatry with 6 documents and 51 citations. Aerococcaceae, Rikenellaceae, Pasteurellaceae, Brucellaceae, and Bifidobacteriaceae, decreased in patients with schizophrenia. Their results demonstrated that the microbiome may alter neurologic function and neurochemistry, which is related to the pathology of schizophrenia. The fourth most-cited article, with 155 citations, was published in Schizophrenia research and authored by Schwarz et al. in 2018. They found that Lactobacillus abundance was elevated in patients with first-episode psychosis (FEP) and was related to the severity of schizophrenia. Their results showed that microbiota alterations benefited remission and treatment response in schizophrenia patients. h-index of 12, John F Cryan who had 12 publications with 1,929 citations and an h-index of 12, and Emily Severance who had 11 publications with 580 citations and an h-index of 9. The Severance Emily and Yolken Robert participated in the most collaborations with other authors. The leading institutions were Johns Hopkins University with 14 publications, the University College Cork with 14 publications, and the University of Toronto with 10 publications. The most productive countries were the US with 59 documents, China with 37 documents, and Canada with 18 documents. In total, 95 journals contributed to this field. Among them, the top three productive journals were Schizophrenia Research with 14 documents, Progress in Neuro Psychopharmacology Biological Psychiatry with 9 documents, and Frontiers in Psychiatry with 6 documents. There are four research directions in the clusters. The cluster represented in green includes the important keywords of gut microbiome and bipolar disorder. The cluster represented in blue includes the important keywords of schizophrenia, antipsychotics, weight gain, and metabolic syndrome. The cluster represented in red includes the important keywords of gut-brain axis, autism, and depression. The cluster represented in yellow includes the important keywords of inflammation and brain.To the best of our knowledge, this is the first bibliometric study to explore the link between schizophrenia and the gut microbiota. In total, 162 publications were included in our study. The publications generally showed an upward trend from 2014. The most top subject categories were psychiatry with 70 publications. A total of 873 authors from 355 organizations and 40 countries/regions contributed to this field. The leading authors were Timothy Dinan who had 13 publications with 1,933 citations and an In the field of schizophrenia and gut microbiota, most of the articles were published in the US, and the percentage of articles from the US was 38% (155/388). Among the top ten institutions, six were located in the US. Among the top ten productive authors, five were from the US. The prominent country in this field was the US. The number of studies from other countries/regions should be improved.Veillonella abundance was significantly higher while Ruminococcus and Roseburia abundances were significantly lower in patients with schizophrenia. Germ-free mice that received fecal microbiota transplantation (FMT) from the microbiota of schizophrenia patients had higher glutamine and GABA levels and lower glutamate levels in the hippocampus. There was considerable discord between these results due to factors including small sample sizes, potential confounders, and the measurement methods. More large-scale prospective studies should be conducted to identify whether specific microbiome compositions are associated with an increased risk of developing schizophrenia. (2) The role of the gut-brain axis. In the top 20 most-cited references, 7 publications explored the gut-brain axis and its role in the association between schizophrenia and the gut microbiota, and the important keywords gut-brain axis, inflammation, and brain were in the cluster represented in blue. The gut microbiota was found to be associated with schizophrenia via processes involved in the gut-brain axis, including immune-regulating pathways, neurotransmitter synthesis, the production of bioactive microbial metabolites, and tryptophan metabolism  The characteristics of the microbiota composition in schizophrenia. In the top 20 most-cited references, 5 publications explored the characteristics of the microbiota composition in schizophrenia patients. A systematic review  demonstrtabolism , 45–48. tabolism –53. Gasttabolism –56. (3) tabolism , 57–60. tabolism –67. MoreThere are some limitations to our study. First, all publications were from the WoSCC database because it was the best citation-based database and was the most widely used in bibliometric and visual analysis. Second, only publications in English were included in our study. Additionally, the literature produced in 2022 was not fully assessed because of the study cut-off time.The studies about the association between gut microbiota and schizophrenia are limited although the gut microbiota may play an important role in the pathogenesis and treatment of schizophrenia. More studies are needed in the future. Most of existing studies are of cross-sectional design, so it is challenging to establish the causality. Further researches should focus on the role of gut microbiota in the pathogenesis of schizophrenia and the effective treatment for schizophrenia using data analysis approaches that deal more effectively to avoid confounding factors.The main research hotspots regarding the connection between schizophrenia and the gut microbiota were the characteristics of the microbiota composition in schizophrenia patients, the gut-brain axis, and microbial-based interventions for schizophrenia. The studies about the association between gut microbiota and schizophrenia are limited, and more studies are needed to provide new insights into the gut microbiota in the pathogenesis and treatment of schizophrenia.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.CY, XW, HL, and XL were responsible for the data collection, investigation, figures and tables construction and writing the original draft. SW and JH contributed to the discussion and final review and editing. All authors reviewed and edited the final manuscript.


Nitrofurantoin is a commonly prescribed antibiotic for uncomplicated urinary tract infections. Despite a number of side effects, it is increasingly prescribed due to its low cost, high efficacy, and minimal antimicrobial resistance. One of the rare, however significant side effects of nitrofurantoin is idiosyncratic drug-induced liver toxicity. It commonly presents with abdominal pain and elevated liver enzymes. Interestingly, it can cause either an acute or a chronic hepatitis-like syndrome that can be severe and lead to liver failure or cirrhosis. We present a case of a healthy 24-year-old female who presented with epigastric abdominal pain, which was found to be drug-induced liver injury (DILI) secondary to her recent nitrofurantoin use. Nitrofurantoin is an antibacterial drug of the nitrofuran family that is commonly prescribed for urinary tract infections (UTIs). Nitrofurantoin is prescribed both for short-term use against acute UTIs as well as long-term use as a prophylactic in patients that are prone to recurrent UTIs . NitrofuA 24-year-old obese female urgent care worker with a past medical history of gastroesophageal reflux disease (GERD) presented to the emergency department complaining of epigastric pain that started a few hours before admission. She described the pain as burning with no radiation. It was associated with nausea and two episodes of non-bloody, non-bilious vomiting. She denied fever, chills, rash, joint pain, dysuria, frequency, urgency, recent trauma, herbal medicine use, or associated symptoms. Medication history included famotidine for GERD as needed and ibuprofen as needed for menstrual pain. Additionally, she was recently diagnosed with a urinary tract infection and had been taking nitrofurantoin (50 mg every six hours) for the past three days. Family history was significant for pancreatic cancer in her father. Her social history included occasional alcohol use (one to two drinks) about two to four times a month, last use was two weeks ago. She denied any tobacco use or drug use. On admission, the patient was afebrile with normal vital signs. The physical exam was unremarkable. An abdominal exam revealed a non-tender, non-distended abdomen with no signs of organomegaly. The blood tests were significant for direct bilirubin of 0.7 mg/dL, total bilirubin of 1.9 mg/dL, aspartate aminotransferase (AST) of >717 U/L, and alanine aminotransferase (ALT) of 476 U/L. Additionally, serum sodium, potassium, chloride, blood urea nitrogen (BUN), creatinine, glucose, albumin, international normalized rate (INR), and alkaline phosphatase levels were all within normal limits  cells, hypoalbuminemia, and hypergammaglobulinemia ,12. ThesMost cases of acute DILI due to nitrofurantoin will resolve on their own after discontinuation of the drug but should be monitored in case chronic liver injury develops . In chroAfter developing nitrofurantoin-induced DILI, patients can become sensitized to the drug and have a high probability of relapse if the patient uses nitrofurantoin again ,16. ContNitrofurantoin is an uncommon cause of DILI associated with various clinical phenotypes, natural histories, and treatments. Patient demographic  and laboratory features  at DILI onset have been associated with the severity and outcomes of liver injury in patients with DILI. Early withdrawal of the medication nearly always results in rapid normalization of the liver biochemistry. Given the wide use of nitrofurantoin, it is important for clinicians to consider this adverse effect. Many studies suggest that medical interventions such as the use of NAC and corticosteroids may provide benefits to some patients, but additional studies are needed. Follow-up with hepatic function tests can be considered as a preventive measure after starting nitrofurantoin.


The theoretical stress-strain model for compressed composite cement materials’ behavior without empirical coefficients was proposed by Iskhakov in 2018. This model includes the following main parameters describing concrete behavior: stresses and strains corresponding to the border between the elastic and non-elastic behavior stages of a concrete specimen, ultimate elastic strains, and stresses and strains at the end of the post-peak region. Particular attention is focused on the descending branch of the stress-strain diagram, as well as on the analysis of concrete elastic and plastic potentials. These potentials are important for assessing the dynamic response of the concrete element section, as well as for concrete creep analysis. The present research is aimed at experimental verification of the above-mentioned theoretical model. The obtained experimental results are in good agreement with the theoretical ones, which confirms the model’s accuracy and enables a significant reduction in the empirical coefficients number in compressed reinforced concrete elements design. This, in turn, represents the scientific novelty of this study. The stress-strain relationship is the fundamental feature of concrete response under external loads in the entire range of its behavior. Currently, available models describing this relationship are mainly based on experimental data. This approach is also reflected in modern design codes ,2.One of the first attempts to investigate the compressed concrete stress-strain .Another issue related to the descending branch investigation is considering the joint work of a testing machine and a compressed specimen. The influence of a testing machine’s insufficient stiffness on the obtained deformations in the compressed concrete specimen was identified ,17. As aThe present research is devoted to in-depth experimental investigations of the above-mentioned problems, including new methods for their implementation. In particular, this investigation is based on the previous theoretical results and on generalizing the εc model , as wellεc model , the Quaεc model , and theεc model .–Experimental verification of the theoretical stress-strain model for compressed concrete;–Analysis of the model post-peak stage and comparison of experimental results with theoretical ones.The main objectives of the study are:–Exact border between elastic and inelastic concrete behavior;–Ultimate elastic deformation and elastic potential of compressed specimen section;–Limit stress of the The novelty of this study is in experimental justification of the above-mentioned theoretical model and its following parameters:The results of this study provide a basis for updating the above-mentioned parameters.The theoretical stress-strain model for compressed concrete is based on the following three known principles: the Mini-Max Principle , Quasi-iThe Mini-Max Principle idea is determined by obtaining the real load-bearing capacity of the structure, avoiding under- or over-estimation . This beThe essence of the Quasi-isotropy idea is that a bent reinforced concrete element section at ULS is calculated assuming that it is made of a non-linear isotropic material . This apThe Structural Phenomenon was proposed as a result of extensive experimental and theoretical data analysis of reinforced concrete structures’ behavior at three levels: the material level and levels of static and dynamic loadings . The pheIt can be summarized that using the above-described principles allows to obtain theoretical solutions to many new and existing problems, which could be previously solved by using empirical coefficients. Thus, further development of the limit equilibrium method and the general theory of reinforced concrete elements became possible.The three above-described principles enabled the formulation of the main provisions for the theoretical model of the compressed concrete stress-strain relationship  13]. Th. Th13]. –The maximum value of elastic deformations –The limit concrete elastic potential determined by the deformation nalysis) ;–The ultimate elastic stress reaching half of the concrete strength, i.e., –The boundary of the diagram descending branch is determined by the stress equal to In the present study, six cylindrical specimens with 15 cm diameter and 30 cm height subjected to axial loading were tested in order to obtain the experimental stress-strain relationship for normal-strength concrete, including the descending branch. The research included two test series with three specimens in each of them, marked as Sp1.1, Sp1.2, Sp1.3 and Sp2.1, Sp2.2, and Sp2.3, respectively. The concrete strength, corresponding to C20/25 and C35/45 concrete classes, was determined using three 15 × 15 × 15 cm cubic specimens for each test series, respectively . The lowCylindrical specimens were chosen to avoid local stress concentration problem, which is pronounced, for example, in the corners of the prismatic ones . Thus, t–Locally produced composite 52.5N CEM II/AM-SLV Portland cement with portions of granulated blast furnace slag (S) and siliceous fly ash (V) from 18 to 30% ;–3;Water-reducing and retarding admixture (G100X) with a density of 1.212 kg/dm–3;Retarding and water-reducing admixture (HGP) with a density of 1.188 kg/dm–Mix of three different types of locally available quarry sand with a fraction size of 0–1.2 mm, 0–2.5 mm, and 0–5 mm;–Locally available quarry crushed dolomite limestone with a coarse aggregate fraction of 9–16 mm according to .–The materials for preparing the second test series’ concrete mixture were:–Locally produced composite 42.5N CEM II/B-LL Portland cement with portions of limestone between 21 and 35% ;–Locally available quarry sand with a fraction size of 0–4.75 mm;–Locally available quarry crushed dolomite limestone with a coarse aggregate fraction of 19/14 mm according to .Ready-mix concrete and concrete produced in laboratory conditions were used in the first and second test series. Concrete mixture for the first series was prepared using the following materials:3 rotating pan mixer was used for concrete mixture preparation, and the calculated mixture volume was 0.043 m3.A 0.045 mThe final concrete mixture compositions for dry aggregates are presented in The concrete mixture was cast into steel molds and compacted by tamping and rodding in 2 and 3 layers for cubic and cylindrical specimens, respectively, following ,31. All rding to .A servo-hydraulic closed-loop class 1 testing machine (with a maximum error of 1% FS) and a maximum load of 3000 kN was used to carry out concrete cylinders under axial compression . The rigThe following measurement equipment was used to obtain the compressed concrete stress-strain experimental relationship. Eight strain-gauges (SG) with 30 and 60 mm bases were used in the specimen longitudinal direction to investigate the behavior in the ascending branch range. SGs were placed in pairs  to duplicate the obtained experimental results. Both sensor types had a resolution of up to 0.1 micro-strains  with a 50 mm measurement base, sensitivity of 0.02 microns, and a Four linear displacement transducers (LDT) with a 50 mm stroke and a high resolution , based on standard deviations, for the experimental data presented in Typical failure schemes of experimental specimens are presented in As mentioned above, the main parameters for concrete behavior under compressive load are stresses and strains, determined by points 1–4 in The analysis of the data presented in  concept : the ela–Stresses and strains define the border between the elastic and inelastic compressed concrete behavior;–The elastic potential of compressed concrete is important for dynamic analysis and investigations of reinforced concrete structure creep.The experimental results fully confirm the following main parameters of the theoretical stress-strain model for compressed concrete:In the frame of the present research, geometrical correspondence between the descending branch in the compressed concrete stress-strain diagram and the ascending one was verified. It was also confirmed that the experimentally-obtained value of the descending branch limit stress is The present experimental investigations fully confirm the theoretical stress-strain diagram of compressed concrete. As a result, this diagram can be called the “Law of Concrete” and included in the modern concrete theory. This law ensures the proper and accurate design of compressed reinforced concrete elements without empirical coefficients, which is important for the further development of structural concrete theory.


Background: Antimicrobial resistance is a public health problem that threatens the efficacy of antibiotics. Incorrect knowledge of antibiotics may lead to their inappropriate use, hinder their effectiveness, and cause antibiotic resistance. Population-based educational campaigns have been found to have either mixed or no effect on improving knowledge and appropriate antibiotic practices, suggesting the need for more targeted approaches in tailoring education for specific subpopulations. Women are the primary caregivers of their families and are more willing to contact healthcare providers. They had greater knowledge of antibiotics and better adherence to the completion of the antibiotic regimen. Therefore, they are suitable for prioritization in a campaign program.Objective: This study examined the knowledge and practices of female visitors to health centers in Malang, Indonesia with respect to antibiotic use.Methods: This cross-sectional study was conducted in Malang, Indonesia, in July and August 2018. Data were collected from 677 women. Multivariate logistic regression was performed to identify the potential factors associated with antibiotic knowledge, self-medication, and completion of antibiotic regimens.Results: Overall, 82.7% of respondents were aware that antibiotics are used against bacteria, while 38.4% reported self-medication with antibiotics and 51.7% reported completing antibiotic regimens. Women with higher education, previous antibiotic use experience, and very easy accessibility to primary doctors were more likely to have high antibiotic knowledge than those with primary education, no antibiotic use in the previous year, and easy/other level of accessibility to primary doctors. Subjects residing in urban areas and with less accessibility to primary doctors were more likely to self-medicate with antibiotics. Additionally, the completion of antibiotic regimens was positively associated with access to a primary care doctor and high antibiotic knowledge.Conclusion: IF Policymakers tend to reduce inappropriate antibiotic use among women. Priority advocates are recommended for urban residents who have experiences of antibiotic use in the previous year. It is therefore important to increase their awareness, particularly regarding diseases against which antibiotics are effective, and activities such as unnecessary use of antibiotics in healthy animals, which may affect their overall effectiveness among humans. More communication channels should be included in the overall scheme to improve the public awareness and accessibility of health professionals. Antibiotic resistance (ABR) is a global threat that leads to treatment failure, longer hospital stays, increased cost of care, morbidity, and mortality . The stuInappropriate antibiotic use is reportedly higher in low- and middle-income countries . A studySeveral studies have attempted to determine the factors that may affect these key points to prevent ABR problems. However, population-based educational campaigns were found to have either mixed or no effects on improving knowledge and appropriate antibiotic practices, suggesting the need for more targeted approaches in tailoring education for specific subpopulations . Previou. There is widespread existence of pharmacies and kiosks, which subsequently improve access to medicines and facilitate self-medication  , which are allowed to be used for self-medication. A common dispensing pattern was the direct request of antibiotics by clients, who walked into pharmacies or drug stores and asked for antibiotics without prescription, either by their generic/brand name or by showing an empty package or sample . There dication . Most stTherefore, determining the potential factors that may affect women’s attitudes or behaviors toward antibiotics is an important task to address the research gap and for future policy planning. This study aimed to assess the knowledge levels regarding antibiotics and factors associated with antibiotic knowledge level, completion of antibiotic regimens, and practice of self-medication for women in Malang, Indonesia.The study was conducted in Malang, Indonesia. Malang is part of East Java Province, which lies on Java Island. The population of Malang is the second highest in East Java, with approximately 3.35 million inhabitants. This cross-sectional survey was conducted in July and August 2018 at four primary healthcare centers called puskesmas. Prior to the study, primary healthcare centers in Malang were contacted to inquire about their availability for participation and to assist with data collection. Finally, four primary healthcare centers, two located in the city center and two in rural areas, were selected for their locations and willingness to collaborate. Convenience sampling was used in this study. Female visitors aged 18–49 years and who were able to communicate  in Bahasa Indonesia  were invited to participate in this study. If both patients and companions were present, only one participant was asked to participate. In total, 677 visitors were contacted and 583 completed the questionnaire.After conducting a review of comparable studies, we developed a structured questionnaire to collect data . The queWe developed the questionnaire in English. Two Indonesian master students from Taipei Medical University who were familiar with Bahasa Indonesia were invited to translate and back-translate the questionnaire before and after the pretesting to ensure consistency with the original questions and contextual applicability in terms of cultural differences. The developed questionnaire was pretested once by 10 local residents. The pretesting results indicated that the questionnaire is clearly understandable, following which we used it for data collection.Trained assistants collected data through standardized interviews. They explained the aim and content of this study as well as informed consent to potential respondents. If the respondents were unable to read, the questionnaire was read to them.Knowledge of antibiotics was assessed using the 11 questions listed in Antibiotic usage behaviors were assessed using the following two questions: for antibiotic self-medication, “Do you purchase antibiotics without a medical prescription?” (yes/no), while for the completion of antibiotic regimens, “Do you always complete the course of treatment with antibiotics even if you feel better?” (yes/no).Other independent factors included sociodemographic and health-related variables. The participants’ sociodemographic characteristics included residence , age , marital status, and educational level. Marital status was a dichotomous variable categorized as single (including divorced and widowed) or married. Educational level was categorized as low (junior high school or less), middle (senior high school), or high (college or above).Health-related variables included having health insurance (yes or no), previous use of antibiotics in the past year (yes or no), self-rated health , access to a primary care doctor , and source of antibiotic information. The source of information indicated whether respondents had received antibiotic information from either of two professional sources—a doctor or pharmacist. Those who had received antibiotic information from both a doctor and pharmacist, either a doctor or pharmacist, and none were respectively coded as “2,” “1,” and “0.”The completed questionnaire was checked and coded before being entered into Excel. The data were digitally stored and analyzed using SPSS version 18.0 . Descriptive data are presented as frequency and percentage or mean and standard deviation (SD), as appropriate. Bivariate associations between the independent and dependent variables were assessed using the chi-squared test. Multivariate logistic regression models were used to assess factors independently associated with antibiotic knowledge, antibiotic self-medication, and completion of antibiotic courses. The strength of the association was reported using adjusted odds ratio (aOR) and 95% confidence interval (CI).Before conducting the study, an informed consent form and other related documents were reviewed and approved by the ethical clearance committee of the University of Muhammadiyah Malang (reference no.: E.5.a/226b/KEPK-UMM/VII/2018). Additionally, the written informed consent form was obtained from the participants before they responded to the questionnaire.In total, data from 583 participants were analyzed, of which 33.5% reported self-medication with antibiotics and 52.8% reported completing antibiotic regimens. Information on the knowledge of antibiotics among the respondents is summarized in The multivariate analytical results also revealed that participants from urban areas  were more likely to report antibiotic self-medication compared with those from rural areas. Moreover, individuals who had not used antibiotics in the past year  were less likely to report antibiotic self-medication. Respondents with a lower ease of access to a primary care doctor  were likely to report antibiotic self-medication compared with people with easy access.Easy and unregulated access to antibiotics in Indonesia, coupled with poor knowledge of antibiotic usage, is a combination that will likely lead to inappropriate use and worsen the antibiotic-resistance problem.This is the first study in Malang, Indonesia to assess the knowledge and practices of women in a primary healthcare setting. This study demonstrated that women with higher education, more sources of antibiotic information, previous antibiotic experience, and easy access to primary care physicians scored higher in antibiotic knowledge. However, living in urban areas or using antibiotics in the past year may have made them prone to self-medication. Further, difficulty accessing a primary care doctor and low antibiotic knowledge may cause them to not complete antibiotic regimens.Consistent with studies conducted in Italy and Sweden , higher This study found that people with experience of antibiotic use performed better in terms of antibiotic knowledge. Consistent with Salm et al.’s findings, respondents who had received antimicrobial treatment in the past 12 months had more correct responses regarding antibiotic knowledge . AnotherWe found that women who had easy access to primary care physicians had higher antibiotic knowledge. According to a previous study, those who reported that they had access to a formal health care provider were almost three times as likely to have adequate health literacy compared with those without formal health care provider access . AdditioOur results showed that living in an urban area is associated with antibiotic self-medication. Urban areas may have greater access to antibiotics than rural areas; considering multiple outlets such as pharmacies, general stores, friends, relatives, and kiosks , urban dFurthermore, a Southern European study reported that a lack of proper antibiotic use knowledge was associated with a higher risk of self-medication . Self-meOur study found that individuals who had not used antibiotics in the past year  were less likely to report antibiotic self-medication. Some studies reported that previous experience related to the efficacy of antibiotic treatments may be a reason for self-medication . A studyFor the first time of antibiotic use, patients usually seek medical care from care workers such as pharmacists. When they re-experience symptoms that they have experienced before, they may seek treatment that had been successful for them in the past . FurtherOur findings indicate that half of the participants did not complete antibiotic regimens. Consistent with a previous study, 45% of respondents expressed a negative attitude regarding stopping antibiotic use before completing the course once they felt better . This miOur findings suggest that completion of the antibiotic regimen was associated with a higher knowledge level and more information sources. A study in Lithuania indicated that two-thirds of the participants had insufficient knowledge regarding antibiotics, which may lead to increased non-adherence and self-medication .Previous studies have showed that adherence to antibiotic therapy and appropriate antibiotic use are strongly associated with better public awareness and knowledge of antibiotics . RegardiThe authors included the statement, “When I get a cold, I take antibiotics to help me get better more quickly” to determine the attitude scores of antibiotic use . AccordiThis was a cross-sectional study that utilized convenience sampling; hence, causal inferences cannot be drawn and the results’ generalizability is limited. Convenience sampling may have led to selection bias. Other potential confounding factors such as financial status, details concerning medication reimbursement, attitudinal variables, and the frequency of antibiotic-use were not collected, and thus, our results should be interpreted with caution.Several studies have suggested that women have higher knowledge levels and better compliance to complete treatment . FurtherWhile establishing a tailor-made national antibiotic communication strategy, it is essential to understand the levels of knowledge regarding antibiotics and potential factors associated with antibiotic knowledge, completion of antibiotic regimens, and practicing self-medication in women.The behavior of buying antibiotics not included in the OWA list without prescription still exists. The drivers of inappropriate antibiotic dispensing included poor knowledge of antibiotics and AMR, incentives to elevate medicine sales, and insufficient regulatory enforcement . In IndoThe key findings of our study will help policymakers in Indonesia to establish future interventions for women to improve their antibiotic use.More stringent regulation of the dissemination of antibiotics is the first step in combating their misuse. If Policymakers tend to reduce inappropriate antibiotic use in women. Priority advocates are recommended for urban residents who have experience of antibiotic use in the previous year. Additionally, increasing public awareness and knowledge is essential for changing antibiotic usage behaviors. There seem to be knowledge gaps in women in terms of the effectiveness of antibiotics against different types of pathogens and activities, which can compromise antibiotic effectiveness. It is therefore important to increase their awareness, particularly regarding diseases against which antibiotics are effective, and activities such as unnecessary use of antibiotics in healthy animals may affect their overall effectiveness among humans. More communication channels should be included in the overall scheme to improve public awareness regarding antibiotics and accessibility of health professionals.


Lactobacillus, Escherichia-Shigella, and Dubosiella, while the mucosal microbiota showed a significant increase in Bifidobacterium, Akkermansia, Albaculum, Bilophila, and Coriobacteriaceae_UCG-002 and a lower abundance of Enterococcus, Helicobacter, Dubosiella, and Collinsella. Furthermore, the treatments enhanced lactose fermentation and SCFA production, which may be related to the modulation of the luminal microbial community. A lower ratio of phosphorylation Na/H exchanger3/Na/H exchanger3 (pNHE3/NHE3) and a higher sodium monocarboxylate1 (sMCT1) expression were found in the treatment group than in the model group, which may be related to the changes in the mucosal microbial community. Also, the treatments may restore the impacted metabolic pathways of gut microbiota. These results provide an important foundation for mechanism of SL action and developing PL-based treatment for lactose-induced diarrhea.In our previous study, we demonstrated that Shen-ling-bai-zhu-san (SL), a classical Chinese herbal formula, could alleviate lactose-induced diarrhea. However, little is known about the mechanism underlying SL action or the efficacy of the polysaccharide (PL) derived from SL. In this study, we investigated the effect of SL and PL on improving the dysregulated luminal and mucosal microbiota in rats with high lactose diet using 16S rRNA analysis. The concentrations of lactose, lactic acid in cecum and short-chain fatty acids (SCFAs) in cecum and portal vein were measured, meanwhile the expression of ion transporters were ascertained. Our data suggest that the SL, PL and cecal microbiota transplantation (CMT) significantly decreased fecal water content and water intake. In the luminal microbiota there was a significant increase in Akkermansia, Bifidobacterium and Blautia and a lower abundance of  It is generally accepted that electroneutral NaCl absorption by the intestine largely reflects the tandem operation of apical Na/H exchange and Cl/HCO3 exchange processes, primarily involving the Na/H exchanger3 (NHE3) and the Cl/HCO3 exchanger solute carrier family 26 member 3(SLC26A3)  .14 microorganisms in the gut, encoding more than three million genotypes   . Since iet (HLD) . It is oTraditional Chinese medicine (TCM) has been used for several millennia to treat diarrheal diseases in China and other developing countries, and now, an increasing number of countries have gradually come to accept it as an effective approach . Shen-liIndeed, emerging data suggest that the gut microbiota is a vital “organ” for the absorption and metabolism of drugs, especially herbal medicine formulae. SL contain many tonifying herbs, such as ginseng, Poria cocos, Rhizoma Atractylodis and Chinese yam, which are largely composed of polysaccharides and considered to be prebiotics in modulating the gut microbiota. Increasing evidences have shown that herbals, including SL, that contain fiber, polysaccharide (PL), phenol, and other substances, have been reported to yield anti-obese, anti-diabetic and anti-inflammatory effects through the modulation of diverse gut microorganisms . Therefoad libitum and had free access to water for 4 days prior to the induction of diarrhea.The experimental procedures followed the guidelines and practices of the Animal Care Ethics Committee of Xiyuan Hospital (Permission code: 2020XLC014). The procedures were conducted in accordance with the Beijing Administration Office Committee of Laboratory Animals. Male SD rats (200–220 g) were housed under an artificial 12 h light-12 dark cycle (lights on at 08:00 h). Forty rats were fed a standard chow diet Dioscorea opposita Thunb (400 g), Dolichos lablab L (300 g), Nelumbo nucifera Gaertn (200 g), Coix lacryma-jobi L. var. mayuen (200 g), Platycodon grandiflorum (Jacq.) A. DC (200 g), and Glycyrrhiza glabra L (400 g), were decocted in water three times. Then, the SL extract was filtered and concentrated to 1.20 g/ml. The mixture of ten herbs was refluxed with 10-fold distilled water at 100°C for 2 h. The extraction was repeated twice and the extracted solutions were concentrated and precipitated with 95% ethanol. The generated precipitate was then statically settled overnight and dried under vacuum, yielding the crude polysaccharide. The ratio of crude PL/SL was approximately 13%  with Amomum kernel (200 g). The residue of that extraction and eight others herbs, including Panax ginseng C. A. Mey (400 g), Poria cocos (Schw.) Wolf (400 g), tely 13% .−1. The mobile phase was acetonitrile (A) and water (B) for detecting atractylenolide. A gradient program was used as follows: 18–22% A at 0–24 min, 22–29% A at 24–30 min, 29–33% A at 30–40 min, and 33–38% A at 40–50 min.The chemical components of SL were analyzed using an Agilent 1,200 high-performance liquid chromatography (HPLC) system (Agilent USA). SL components were separated by a CAPCELL PAK C18 MG II . Three grams of SL powder was added to 30 ml of water-saturated n-butanol solution and incubated overnight. After 30 min of ultrasonic treatment, the filtrate was filtered again. After the filtrate was dried, 10 ml of 80% methanol was added to dissolve the residue, which was filtered with a 0.45 μm microporous filter membrane to yield the test solution. Ginsenoside Re , ginsenoside Rg1 , ginsenoside Rb1 , and atractylenolide Ⅰ . The mobile phase consisted of acetonitrile (A) and 0.5% Trifluoroacetic Acid (TFA) water (B) for detecting ginsenoside Re, Rg1 and Rb1 at a flow rate of 1.0 ml min-derived from SL on lactose induced diarrhea, 48 rats were randomly divided into seven groups (n = 6-8 for each group): a blank control group with normal chow diet , a model group with high lactose diet (HLD), an SL-treated group with high lactose diet (SL), an SL-treated group with normal diet (SN), a polysaccharide-treated diarrheal group with high lactose (PL), a polysaccharide-treated diarrheal group with normal diet (PN), and an SL-treated antibiotic group (STA). Chronic diarrhea was induced by supplementing the diet with an incremental high lactose diet (30%-40%–50%) lactose for 21 days, which consisted of 30% lactose for the first week, 40% lactose for the second week and 50% lactose for the third week, as described previously. The SL and PL groups were fed with incremental high lactose diet by oral gavage of SL (1 g/kg) and PL (0.13 g/kg) for 21 days once a day. The SN and PN group was fed with normal diet by intragastric administration of SL (1 g/kg) and PL (0.13 g/kg) for 21 days once a day, respectively. The STA group was fed with incremental high lactose diet and a cocktail of broad spectrum antibiotics (ABX) by oral gavage of SL (1 g/kg) for 21 days once a day. The detailed experimental procedure is shown in I To evaluate the effect of SL and PLn = 6-8 for each group) according to different donor rats as follows: Lactose-SL-PL-, or L-S-P-; Lactose + SL-PL-, or L + S-P-; Lactose + SL + PL-, or L + S + P-; Lactose + SL-PL+, or L + S-P+; Lactose-SL + PL-, or L-S + P-; and Lactose- SL-PL+, or L-S-P+. The L + S-P-, L + S + P-, L + S-P+ groups were fed by high lactose diet to induce chronic diarrhea whereas the L-S + P-, L-S-P+ and L-S-P- groups received normal diet. Rats in the L + S + P- and L-S + P- groups were treated with SL (1 g/kg), rats in the L + S-P+ and L-S-P+ groups were administered with PL (0.13 g/kg), rats in the L-S-P- group was treated with 1 ml normal saline orally once per day.II To evaluate the role of the gut microbiota in the anti-diarrheal effects of SL and PL, 46 rats were randomly divided into six groups , and following transplantation, the cecal contents of each group were collected. A cocktail of antibiotics, including ampicillin (1 g/L), vancomycin (500 mg/L), ciprofloxacin HCl (20 mg/L), metronidazole (1 g/L), and neomycin (1 g/L) was added to the drinking water of rats in the antibiotic group and CMT groups for 18 days . After tThe donor rats were from all six groups, including N + S-P-(N-HLD), L + S-P-(L-HLD), L + S + P-(LS-HLD), L + S-P+ (LP-HLD), L-S + P- (S-HLD) and L-S-P+ (P-HLD). The cecal and colon contents were collected, and 2 g samples were stored in a sterile cryotube for the detection of the microbiota. The remaining samples were diluted in pre-reduced phosphate buffered saline (PBS) (1:2 volume [contents]/volume [PBS]) and centrifuged at 2,000 rpm for 5 min under a laminar flow hood in sterile conditions, and the supernatant was collected and used as transplant material and quickly stored at -80°C until use in oral gavage .TransStart FastPfu buffer, 2.5 mM dNTPs 2 μl, 0.8 μl of forward primer (5 μM), 0.8 μl of reverse primer (5 μM), 0.4 μL of TransStart FastPfu DNA polysaccharide, 10 ng of template DNA, and ddH2O up to 20 μl. PCRs were performed in triplicate. The PCR product was extracted from a 2% agarose gel, purified using the AxyPrep DNA Gel Extraction Kit  according to the manufacturer’s instructions and quantified using a Quantus™ Fluorometer .Microbial community genomic DNA was extracted from luminal and mucosal microbiota using the E. Z.N.A.® Soil DNA Kit  according to the manufacturer’s instructions. The DNA extract was checked on a 1% agarose gel, and DNA concentration and purity were determined with a NanoDrop 2000 UV–vis spectrophotometer . The hypervariable region V3-V4 of the bacterial 16S rRNA gene was amplified with the primer pairs 338F (5′-ACTCCTACGGGAGGCAGCAG-3′) and 806R (5′-GGACTACHVGGGTWTCTAAT-3′) by an ABI GeneAmp® 9700 PCR thermocycler . PCR amplification of the 16S rRNA gene was performed as follows: initial denaturation at 95°C for 3 min, followed by 27 cycles of denaturing at 95°C for 30 s, annealing at 55°C for 30 s and extension at 72°C for 45 s, with a single extension at 72°C for 10 min, ending at 4°C. The PCR mixtures contained 4 μL of 5 × The V3-V4 region was amplified with the 16S rDNA gene universal primers 338 F (5′-ACTCCTACGGGAGGCAGC-3′) and 806R (5′-GGACTACHVGGGTWTCTAAT-3′). The PCR products were then purified, and the concentrations were adjusted. Sequencing was performed on an Illumina MiSeq PE300 system . The raw data were deposited into the NCBI Sequence Read Archive (SRA). The accession number is SUB11116044.The raw 16S rRNA gene sequencing reads were demultiplexed, quality-filtered by fastp version 0.20.0 and mergeOperational taxonomic units (OTUs) with a 97% similarity cut off  were cluPortal blood (2 ml) was sampled directly from the hepatic vein using a heparinized syringe. Blood samples were centrifuged for 4 min at 4°C at 600 x g. A volume of 500 µl of the plasma fraction was stored at -80°C. The colonic tissues were washed in ice-cold 0.9% (w/v) NaCl (pH 7.0), and the mucosa were scraped off using a glass slide before immediate freezing in liquid N2 and storage at -80°C until microbiota analysis and Western blotting. The cecal contents were sampled in sterile tubes. Samples were stored frozen at -80°C until analysis. Thawed feces (0.5 g) were mixed with 100 ml distilled water and stirred until dissolved. The samples were then soaked for 30 min at room temperature. The supernatant was used for pH examination by a pH meter .The sample (∼50 mg) was removed from the freezer after being thawed at 4°C for 30 min, placed into a 1.5 ml centrifuge tube and accurately weighed. Then, 1 ml of 50% methanol aqueous solution was added to the tube and mixed for 30 min. The tube was then centrifuged at 4°C and 12,000 rpm for 5 min. The supernatant (50 μL), propionic acid isotope standard solution , 3-nitrophenylhydrazine  methanol/water  solution and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride /methanol/water/pyridine (69.375:23.125:7.5) solution were charged into a 1.5 ml centrifuge tube and mixed at 30°C for 30 min. After that, butylated hydroxytoluene methanol solution  and methanol/water  solution were added to the tube and mixed. The tube was centrifuged at 4°C and 12,000 rpm for 5 min. The supernatant (200 μL) was transferred into a vial for MS detection. A Waters ACQUITY UPLC I-CLASS chromatography (Waters USA) unit equipped with a Waters UPLC BEH C8 column (2.1 mm (inner diameter) ×100 mm (length), 1.7 μm (particle dimension) was used for separation with a column temperature at 45°C. The mobile phase consisted of 0.01% formic acid aqueous solution (phase A) and methanol/isopropanol  with a flow rate of 0.3 ml/min, and the elution gradient used as follows: 95% A,5% B at 0–2 min; 85% A,15%B at 2–9 min; 0% A,100% B at 9–11 min; and 95% A, 5% B at 11–13 min. The injection volume was 5.0 µL. The MS data were collected by a Waters XEVO TQ-S Micro system. The parameters were set as follows: an ion source voltage of 3.0 kV, ion source temperature of 150°C, desolvation temperature of 350°C, desolvation gas flow of 1,000 L/h, and cone gas flow of 10 L/h.g for 10 min at 4°C. The supernatant was eluted from HLB cartridges and evaporated to dryness under a nitrogen stream. Then, 50 ml of deionized water was added to the tube and redissolved.Lactose and lactate were detected by corresponding assay kits  according to the instructions. An aliquot of 50 mg of cecal and proximal colon content was dissolved in deionized water, vortexed for 20 s and centrifuged at 12,000 × Proximal colonic mucosa was collected from the colon mucosa of diverse groups. Tissues were homogenized and sonicated in cold lysis buffer with protein inhibitors and phosphatase inhibitors . After 30 min of standing at 4°C, the samples were centrifuged at 12,000 x g for 30 min at 4°C. The pellets were discarded, and the supernatant was used for blotting. The proteins (30 µg) were separated via eight or 10% SDS/PAGE. The blot was washed with Tris-buffered saline containing Tween-20 and incubated overnight at 4°C with polyclonal primary antibodies against MCT1, sMCT1, slc26a3, NHE3, and pNHE3  and the t-test.All data are presented as the mean ± SEM. Differences among multiple groups were evaluated using ANOVA with Prism software , and those between two groups were assessed using the Four chemicals were identified by HPLC as primary components of SL. The typical HPLC chromatogram of SL is shown in A diarrhea rat model was induced by the administration of a 30%/40%/50% lactose diet for 21 days, according to our previous study . During Since mucosa-associated bacteria live in closer proximity to the intestinal epithelium, they likely execute contrasting functions within the GI ecosystem compared with luminal microbiota. Therefore, the luminal and mucosal microbiota of rats were investigated by sequencing the bacterial 16S rRNA V3-V4 region. A total of 6-8 samples from each of the nine groups were analyzed by high-throughput pyrosequencing, which generated 5,286,598 useable reads, and 1,503 OTUs were collected. After treatment, the Sobs and Shannon indices of the luminal microbiota were higher in the SL and normal groups than in the HLD group . Furtherp = 0.001). The bacterial communities in the lumen microbiota and the HLD and SL groups had a higher degree of separation, suggesting that the overall structures of the bacterial communities in the groups were significantly different. In comparison, the SL and PL groups showed a partially overlapping microbiota, and the bacterial communities from two samples of the PL group overlapped with the HLD group  based on unweighted UniFrac showed a distinct clustering of bacterial types for each experimental group, suggesting that the SL, PL, and HLD groups caused major changes in gut microbiome profiles   , and Escsus 27%) .Lactobacillus in the SL, PL, and P-HLD groups was lower than that in the HLD group by 45%, 23% and 45%, respectively, but was subsequently restored to normal levels to a substantial extent , which is a supervised analysis suitable for high-dimensional data, was performed . The mucl extent . Meanwhil extent . In addil extent .Bacillus, Facklamia, g__norank_f__Muribaculaceae, g__norank_f__Rhizobiales_Incertae_Sedis, Exiguobacterium, Morganella, Veillonella, and Anaerostipes were enriched in SL rats. In the PL group, the genera Pediococcus, Dubosiella, Adlercreutzia, Weissella, Ruminococcus_ torques_group, Klebsiella, Bilophila, Enterobacter, unclassified_p__Firmicutes, and unclassified_o__Lactobacillales were enriched  to identify the specific bacterial taxa associated with the SL and PL. As shown in enriched . In the enriched  left. Thionaceae  right.could not be reversed to normal levels, it was significantly lower than that in the model group. In the STA group, the concentration of lactose did not decrease, suggesting that the gut microbiota would be influenced by the treatment of SL.Due to natural lactase deficiency in adult rats, a large amount of undigested lactose accumulates in cecal luminal contents, which would elevate the osmotic load. The colonic microbiota, which ferment lactose and lactic acid, play a vital role in colonic processing of lactose. Higher amounts of lactose and lactic acid were mainly encountered in the cecum of the model group . After SSCFAs were quantified in intestinal contents and portal vein blood among distinct groups, including ND, HLD, PL, SL, S-HLD, and P-HLD treatments. The total SCFA in intestinal contents was 54% lower in the model group than in the normal group , which wNo significant difference in SCFAs was noticed in intestinal contents between the CMT and model groups. A slight increase in SCFA (acetate) was observed in the S-HLD group, and butyrate was significantly increased in the P-HLD group compared to the HLD group . FinallyMCT1 and sMCT1 are the most likely major contributors to SCFA entry into the colonic epithelium. Both NHE3 and slca6a3 are prominently expressed in colonic epithelial cells and participate in the tandem operation of apical Na/H exchange and Cl/HCO3 exchange processes and electroneutral NaCl absorption. Bacteroides, Parabacteroides, norank_f__Erysipelotrichaceae, Akkermansia, Ruminococcus_gnavus_group, Allobaculum and Bilophila, showed a negative correlation with lactose and/or lactate and/or a positive correlation with SCFA and pH value. Cluster 2, including Lactobacillus, Bifidobacterium, Lactobacillus, Pediococcus, Coriobacteriaceae_UCG-002, Escherichia-Shigella, Enterococcus, Collinsella, Dubosiella, Megamonas and Veillonella, was negatively correlated with the SCFA concentration and pH value but positively correlated with the lactose and lactate concentrations.The therapeutic effect of SL and PL on luminal microbial communities may primarily be mediated by the metabolites of lactose, such as lactate and SCFAs. The change in the protein expression of SCFA transporters and NHE3 may play a key role in the therapeutic effect of SL and PL on mucosa microbiota. To confirm the relationship between the altered gut luminal microbiota composition and lactose metabolism and between the altered mucosa microbiota composition and relevant transporter expression, we conducted Spearman’s correlation analysis displayed by a heatmap, as shown in As shown in o investigate the influence of SL, PL and CMT treatment on potential metabolic pathways of luminal and mucosal microbiota in HLD rats, we conducted phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) analysis based on the luminal and mucosal microbiota composition of each group.As indicated in In the HLD group, fatty acid metabolism and biosynthesis, biosynthesis of amino acids and secondary metabolites were all significantly decreased; carbohydrate metabolism , Two-component system, ABC transporters and Microbial metabolism in diverse environments were significantly increased. SL restored 12 pathways, including fatty acid and carbohydrate metabolism and biosynthesis of fatty acid, amino acids and secondary metabolites, as shown in S-HLD resulted in upregulation of glycosphingolipid biosynthesis, N- glycan biosynthesis and other glycan degradation in the luminal microbiota . In the in vivo. The results demonstrated that SL improves the symptoms of diarrhea, as evidenced by a reduction in watery stool, fecal water content via the regulation of gut luminal microbiota fermentation and mucosa-associated bacterial populations, which may dramatically change in a setting of altered host ion transporters.In the present study, the effect of SL and SL-derived polysaccharide on high lactose-induced diarrhea was studied + transporter expression and phosphorylation levels with and without SL and polysaccharide treatment.Our previous study indicated that SL ameliorated HLD-induced diarrhea associated with ion transport . It has We also sought to assess the effects of manipulation of the gut microbiota by chronic antibiotic administration on an HLD model with SL treatment and to investigate whether cecal microbiota of SL or PL treatment transfer could ameliorate the effects in ABX rats induced by HLD. Our results showed that after antibiotic administration, the effect of SL on HLD was not observed. The body weight decrease, water stool and fecal water increase in SL-treated ABX-rats, as compared to those of the HLD model without SL, suggests that the gut microbiota play a key role in the therapeutic effect of SL on the HLD model. Our study found that recipient rats receiving fecal transplantation from SL- and PL-treated HLD rats also showed a significant remission of HLD-induced diarrhea, which supports the beneficial effects of SL and PL that can be partially mediated by gut microbiota.Bacteroides spp., Corynebacteriaceae, Lactobacillaceae, Paraprevotellaceae, Veillonellaceae, Prevotellaceae, Clostridiaceae, and others. In our study, after SL treatment, the abundances of the phyla Firmicutes and Proteobacteria were remarkably decreased. At the genus level, SL obviously increased the abundance of Bifidobacterium, Blautia, Megamonas and Akkermansia and greatly decreased the relative abundance of Lactobacillus and Escherichia/Shigella. It has been demonstrated that Bifidobacterium  and Lactobacillus  have become the most widely used species as probiotics. Lactobacillus spp. is evidently the most prominent probiotic agents among lactic acid bacteria (E. coli in the large intestine of piglets (Lactobacillus and Bifidobacterium being significantly increased in the HLD group compared to the control group.The effects of SL, PL and CMT on the composition of the luminal and mucosal microbiota of mice were investigated via high-throughput MiSeq sequencing. As reflected by the Sobs and Shannon indices, we observed that HLD reduces the alpha diversity of the gut microbial community. Although SL treatment could not recover the richness of gut microbiota to normal, the alpha diversity was significantly improved after SL treatment compared to that of the HLD model, suggesting that SL reverses the diarrhea-induced reduction in the species richness of gut microbiota. Previous studies demonstrated that SL could improve functional dyspepsia , antibiobacteria . It is g piglets . Further piglets , which a piglets . In our Escherichia/Shigella. In addition, the mucosal genera Pediococcus, Subdoligranulum, Bilophila, Rhodococcus, Blautia, Adlercreutzia, Coriobacteriaceae_UCG-002, and norank_f__Muribaculaceae were enriched in S-HLD compared to HLD group. Although the relative abundance of Lactobacillus in S-HLD group is not significantly different from the HLD group, the relative abundance of Bifidobacterium decrease from 15% to 10%, which also might be the consequence of the effect of S-HLD treatment on the gut microbiota. Further, according to our observation, the effect of SL on high-lactose induced diarrhea is better than that of S-HLD indicating the relative lower abundance of Lactobacillus in SL group compared to S-HLD group. Although the PL treatment cannot reverse the richness of gut luminal microbiota and few genera were restored, the richness of gut mucosa microbiota was higher and upregulated mucosal microorganisms such as g_Pediococcus, g_dubosella, Adlercreutzia, Ruminococcus_torques_group, Allobaculum, Weissella, Subdoligranulum, which are considered as the lactic acid bacteria or SCFA-producing bacteria. After transplantation, it is interesting that PL-HLD significantly reduced the relative abundance of Lactobacillus and increased the relative abundance of Akkermansia, Bifidobacterium, Allobaculum, and Ruminococcus gnavus compared to that of the HLD group.We considered that the relative abundance of Lactobacilli was lower in the luminal microbiota after SL treatment because the concentration of luminal lactose was significantly reduced due to being hydrolyzed into lactate and SCFA, resulting in a decrease in lactose-fermenting bacteria, which is the consequence of the effect of SL on the gut microbiota. This led us to question how lactose is hydrolyzed by the microbiota. A possible explanation could be that SL induced a high proportion of Bifidobacteria, Blautia, Akkermansia and Ruminococcus gnavus, as carbohydrate bacteria . Like SLBifidobacteria can utilize a diverse range of dietary carbohydrates that escape degradation in the upper parts of the intestine and are believed to play a key role in carbohydrate fermentation in the colon . A recenFurthermore, the relative abundance of Akkermansia, as a potentially beneficial bacterium, was significantly increased after SL and CMT treatment. Many previous reports have shown that traditional Chinese medicine, including rhein , Rhizomain vitro (In our study, the concentration of cecal lactate was significantly decreased after SL and PL treatment compared to that in the HLD model, and it is interesting that the concentrations of cecal acetate and propionate were significantly increased and that their concentrations in serum were decreased. In contrast, the concentrations of cecal and serum butyrate were significantly increased. Although the relative abundance of lactic acid bacteria is high, meanwhile SL and PL also induced a high proportion of SCFA-producing bacteria such as Bifidobacteria, Megamonas, Blautia, Romboutsia, Allobaculum, Akkermansia which could promote lactic acid further converting to SCFA. So the lactic acid concentration is not high but SCFA is high in cecal content. Meanwhile, previous study in vitro  has showBacteroides showed a strong negative correlation with luminal lactose, indicating that these genera might play an important role in lactose fermentation.The altered gut microbial composition is closely related to lactose fermentation, including lactate and SCFA production. SL increases luminal Bifidobacteria, Megamonas, Blautia, Romboutsia, Akkermansia and mucosal Pediococcus, Rhodococcus, and Coriobacteriaceae UCG-002, which are involved in carbohydrate metabolism and SCFA production. In agreement with the results from the literature  and our + transporting epithelia. It has been demonstrated that luminal SCFAs stimulate NHE3 activity (NHE3 activity has been shown to be regulated by dietary and humoral factors in a variety of Naactivity . In the activity . In our Alterations in dietary carbohydrates have important effects on the composition and function of the gut microbiota. While the gut microbial community can be modified by dietary carbohydrates, it can also affect carbohydrates by playing a role in their metabolism . Many stEnterococcus, Helicobacter, Dubosiella, and Collinsella in the mucosal microbiota.We transferred fecal microbes from SL- and PL-treated normal rats to non-treated diarrheal rats, which showed a significant delay in diarrheal onset and obvious remission of the severity of diarrhea. The results of 16S rRNA sequencing showed that the gut luminal and mucosal microbiotas were rejuvenated, with a significant increase in Akkermansia, Bifidobacterium, Ruminococcus gnavus, and Bilophila and a lower abundance of Lactobacilli and Dubosiella in the luminal microbiota, with a significant increase in Bilophila and Coriobacteriaceae_UCG-002, Escherichia-Shigella and a lower abundance of In the present study, we want to investigate the effect of PL derived from SL in order to verify whether PL is one of an important effective constituent of SL. There are no differences in fecal water and cecal pH value after SL and PL treatment. However, PL showed a strong effect on food intake and weight gain than that of SL. Although the Sobs and Shannon indices was higher in SL treatment than that of PL treatment group, there is no difference in S-HLD and P-HLD. Both SL and PL could induce lactose fermentation and SCFA production. So we think PL play an important role in alleviating HLD-induced diarrhea, as an important effective constituent of SL.In addition, SL and PL treatment effectively enhanced luminal lactose fermentation and SCFA production, which may be strongly associated with modulation of the gut luminal microbial community. A lower ratio of pNHE3/NHE3 and higher sMCT1 expression were found in the treatment group than in the model group, which may be closely related to the modulation of the mucosal microbial community. The regulatory mechanism partly contributed to the reshaping of the negatively impacted gut microbiota community by restoring their damaged metabolic pathways. This study demonstrated that SL and PL treatments alleviated the deterioration of high lactose-induced diarrheal symptoms, improved cecal lactose fermentation, regulated colonic luminal and mucosal microbiota, and restored intestinal ion transport .Collectively, our findings demonstrate that SL and SL-derived crude polysaccharide had a positive therapeutic effect on HLD-induced diarrhea and its relationship with the luminal and mucosal microbiotas, which provides an important foundation for mechanism of SL action and developing PL-based treatment for lactose-induced diarrhea.


Serrated lesions (SLs), including sessile serrated lesions (SSL) and traditional serrated adenomas (TSA) have become subject of increased interest for their role as CRC precursors.Study aim was to evaluate the risk to develop total metachronous advanced neoplasia (T-MAN) at follow-up in patients with index SL compared to a matched cohort without SL.Patients 45-74y with SLs were identified through pathology database search. SL patients were matched 2:1 by sex; age; synchronous polyps ; timing of index, to patients without SL. Primary outcome was risk of T-MAN (advanced adenoma or high-risk SL) at follow-up. Secondary outcomes included risk of T-MAN stratified by synchronous polyps and SL characteristics.1425 patients were included . The SL group had greater risk of T-MAN compared to the non-SL group [Hazard-ratio (HR)=6.12 3.91-9.58)]. Patients with SL+HRA had higher risk of T-MAN compared to HRA alone [HR=2.62 (95%CI 1.45-4.71)], as well as patients with SL+LRA compared to LRA alone [HR=7.03 (95%CI 2.78-18.44)], and SL without adenoma compared to no-adenoma [HR=14.87 (95%CI 6.51-33.95)]. Presence of proximal SSL (HR=9.30), large SSL (HR=17.87) and proximal large SSL (HR=24.99), but not distal SSL, was associated with greater risk for T-MAN.Patients with SLs are at greater risk for developing T-MAN regardless of synchronous adenomas. Patients with SL and HRA, and those with large or proximal SSLs appear to be at greatest risk for T-MAN.OtherACGR. Djinbachian Grant / Research support from: Grant from the American College of Gastroenterology for the conduction of this project, M.-L. Lafontaine: None Declared, J. Anderson: None Declared, H. Pohl: None Declared, T. Dufault: None Declared, M. Boivin: None Declared, M. Bouin: None Declared, D. von Renteln Grant / Research support from: Daniel von Renteln is supported by a “Fonds de Recherche du Québec Santé” (FRQS) career development award and has received research funding from ERBE, Ventage, Pendopharm, Fujifilm, and Pentax., Consultant of: Boston Scientific and Pendopharm,


Watch group. Amoxicillin–clavulanic acid (50%), azithromycin (29%), ciprofloxacin (28%), metronidazole (21%), and cefuroxime (20%) were the most prescribed antibiotics. Antibiotic prescribing parameters  were documented in almost all prescriptions. Conclusions: Extending antimicrobial stewardship to the out-patient settings by developing standard treatment guidelines, an out-patient specific drug formulary, and antibiograms can promote rational antibiotic use at the hospital. The EMR system of the hospital is a valuable tool for monitoring prescriptions that can be leveraged for future audits.Background: Monitoring of antibiotic prescription practices in hospitals is essential to assess and facilitate appropriate use. This is relevant to halt the progression of antimicrobial resistance. Methods: Assessment of antibiotic prescribing patterns and completeness of antibiotic prescriptions among out-patients in 2021 was conducted at the University Hospital of Kwame Nkrumah University of Science and Technology in the Ashanti region of Ghana. We reviewed electronic medical records (EMR) of 49,660 patients who had 110,280 encounters in the year. Results: The patient encounters yielded 350,149 prescriptions. Every month, 33–36% of patient encounters resulted in antibiotic prescription, higher than the World Health Organization’s (WHO) recommended optimum of 27%. Almost half of the antibiotics prescribed belonged to WHO’s  Antibiotics are life-saving drugs commonly used in clinical practice worldwide ,2. HowevAWaRe—Access, Watch, and Reserve [According to the World Health Organization (WHO), the rate of antibiotic prescribing in general practice should be less than 27% of all prescriptions ,10,11. H Reserve . The Acc Reserve ,16. Coun Reserve . Therefo Reserve ,19. Such Reserve . In 2017, Ghana developed a national action plan to combat AMR based on the principles of WHO GAP ,21. SeveAWaRe classification, and (c) completeness of antibiotic prescriptions.We conducted a study on antibiotic prescribing patterns and completeness of documentation among out-patients of the University Hospital, KNUST, in the Ashanti Region of Ghana in 2021. The specific objectives were to assess (a) demographic and clinical characteristics of patients who received antibiotics, (b) the monthly trend of antibiotic prescribing per WHO This was a cross-sectional study using routinely collected electronic data from outpatient medical records of the University Hospital, KNUST.Ghana is a West African country with a population size of 30.8 million as of 2021. Administratively, the country is divided into 16 regions with Accra being the capital city . The heaThe University Hospital, KNUST, is a quasi-government district-level hospital with 135 beds and has patient footfall of at least 100 patients a day at the out-patient department (OPD). The hospital is located in the second largest administrative region, the Ashanti Region . The hosThe OPD of the University Hospital is the first port of call for patients presenting to the hospital. When a patient visits the hospital for the first time, an account is created for them by the Records Department and a unique identification number is assigned. During subsequent visits, patients go through a data clerk from the Records Department who retrieves their account from the electronic medical record (EMR). Following this, the patient is evaluated by a physician/physician assistant and the relevant clinical findings are updated on the EMR. Following consultation at the OPD, the patient’s prescription is entered by the physician/physician assistant directly into the EMR. Information on the prescribed treatment is, thus, transferred electronically to the pharmacy department for dispensing to the patient. In case the prescribed antibiotics are not available at the hospital pharmacy, a paper-based prescription is generated at the pharmacy for the patient to purchase from outside the hospital.For documentation and maintenance of records and reports, the hospital relies on the EMR system developed in-house connecting the various departments of the hospital. It is largely a local area network (LAN)-based system with some components being web-based. Demographic information such as age and sex of patients attending the outpatient department (OPD) are recorded in the EMR at the time of first visit to the hospital. Clinical information pertaining to the patient is updated on the EMR by the physician/physician assistant at the time of consultation. This includes medical history, comorbidities, diagnosis, as well as the prescribed treatment.The study included prescriptions of all patients treated at the OPD of the University Hospital between January and December 2021.Data on demographic and clinical characteristics and drug prescriptions of patients was retrieved from the EMR system of the OPD.® . Antibiotics prescribed were categorised according to the WHO AWaRe classification into Access, Watch, or Reserve group. A patient was considered to have received an antibiotic if any of the prescriptions retrieved against their unique identifier contained an antibiotic. A patient encounter referred to a consultation on the same day in a department of the OPD. Each medicine prescribed during a patient encounter was considered as a separate prescription. Frequencies and proportions of prescriptions of antibiotics were analysed with different units of analysis: patient encounters and prescriptions. Completeness of antibiotic prescriptions was assessed in terms of six quality indicators: (1) indication for treatment, (2) name of antibiotic prescribed, (3) duration, (4) dose of antibiotic prescribed, (5) route of administration, and (6) frequency of administration. Data from the EMR was retrieved in a MS Excel CSV format, cleaned, and processed using Python in Jupyter Notebook, a web-based interactive computing platform , and anaBetween January and December 2021, 49,660 patients had visited the OPD of the KNUST Hospital resulting in 110,280 patient encounters. Data review and cleaning yielded 350,149 prescriptions that were analyzed further.More than half of the patients were male (53.9%) with over 45% being between the ages of 15 and 24 years. The mean age was 29 ± 18 years and ranged between 0 to 105 years. Of all those with recorded chronic conditions (5242), 68.4% had hypertension which was the most common .A higher proportion of patient encounters involving children under 15 years more often included prescribed antibiotics (54.5%) compared to the older age groups. Antibiotics were uniformly prescribed in encounters with females (35%) and males (36%). The majority of encounters (54%) in the dental clinic more often had prescribed antibiotics .During the study period, 110,280 patient encounters occurred in the OPD, out of which 39,339 (36%) resulted in the prescription of an antibiotic. The trends of antibiotic prescriptions varied from 32–40% during the year 2021. The hospital found increased prescriptions in the months of February, July, and December. Across all months, the percentage of encounters with antibiotics prescribed exceeded the desired optimal value of 20% as recommended and in line with WHO prescribing indicators .Access category contributed to 45–52% of all antibiotic prescriptions every month. Similarly, antibiotics belonging to the Watch category contributed to 43–51% of all antibiotic prescriptions every month. The prescription of Reserve antibiotics was found to be minimal, contributing to less than 3% of all antibiotic prescriptions every month  with a monthly range between 15–18%. Antibiotics belonging to the ry month .Among the Access group of antibiotics, amoxicillin–clavulanic acid was the most commonly (50%) prescribed followed by metronidazole (21%). Among the Watch group of antibiotics, azithromycin (29%) and ciprofloxacin (28%) were the most commonly prescribed .All antibiotic prescribing parameters  were documented in all 58,885 prescriptions with the exception of 44 prescriptions where the names of a few specific antibiotics were not documented. The documented names of antibiotics were not uniform in the hospital; there were discrepancies in terms of their spellings and the marketing brands to which they belonged. Though indications were captured, they did not follow the standard classification system.Reserve antibiotics across the year. The practice of completing documentation of prescription parameters was followed in almost all antibiotic prescriptions. In the following paragraphs, we discuss the implications of our findings.To our knowledge, this is the first study that assessed outpatient antibiotic prescribing practices from a district hospital in the Ashanti region of Ghana. Our study findings reveal that more than a third of patient encounters in the OPD had antibiotics. There was a low prescription of WHO (a) Antibiotic prescriptions: Of all patient encounters in the study, antibiotics were prescribed in over 36% of encounters throughout the year, which is higher than the WHO recommended levels of 27% of encounters . HoweverAWaRe antibiotics: Antibiotics belonging to the Watch group were prescribed in almost half of the antibiotic prescriptions every month. Watch antibiotic use in this study is higher than that found in Finland (23%) but lower than in Iran (77%) [Watch group are at higher risk of developing AMR compared to Access antibiotics. Reserve antibiotic use was, however, low across the year, which is encouraging. To optimize prescribing, an antibiotic treatment formulary focused around the WHO AWaRe categories is needed to increase Access group use, reduce Watch antibiotics, and keep Reserve use low. Routine review meetings at the hospital to monitor the appropriateness of antibiotic usage based on clinical conditions of the patients will help ensure guideline compliance.(b) an (77%) . Antibio(c) Completeness of antibiotic prescriptions: We observed that almost all of the prescriptions had adhered to good documentation, which includes mentioning the drug, dose, duration, route, frequency, and diagnosis. The hospital EMR system included a module for prescribing, which ensured efficient documentation. The availability of this system is a valuable resource that will facilitate future audits. There is scope for further strengthening of this mechanism wherein a few of the variables must be entered in a standard format and not as open-ended fields. For instance, the diagnosis did not follow any standard disease classification, and therefore could not be included in the analyses. Using WHO’s International Classification of Diseases (ICD) ,44 couldAccess group were amoxicillin–clavulanic acid, metronidazole, and tetracycline, while for the Watch group azithromycin, ciprofloxacin, and cefuroxime were the most prescribed. Similar results were reported from other studies from Ghana and Vietnam [(d) Types of antibiotic prescription: The common types of antibiotics prescribed included amoxicillin–clavulanic acid, azithromycin, ciprofloxacin, metronidazole, and cefuroxime. The most prescribed antibiotics among the  Vietnam ,45. GoinThe study has the following strengths. First, is the large dataset from the EMR which was available and used for analyses. Second, the completeness of study variables opted for this study was up to 98%. Third, the study was conducted and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines statement . There aWatch group was widespread. The antibiotic prescription parameters were well-documented. Extending antimicrobial stewardship to the OPD settings by developing standard guidelines, an OPD specific drug formulary and antibiograms can promote rational antibiotic use and improve patient outcomes in the hospital.There was high antibiotic usage in the hospital when compared to WHO standards. The use of antibiotics from the