Short-bowel syndrome (SBS) results from the loss of a significant portion of the small intestine leading to a state of malabsorption. After an intestinal loss, there is a process of adaptation involving the Glucagon-Like Peptide-2 (GLP-2), an enteroendocrine peptide also involved in nutrient absorption. Teduglutide is a recombinant analog of GLP-2 approved in 2016 to treat selected SBS pediatric patients who are dependent on parenteral support. The present systematic review aims to evaluate the efficacy of Teduglutide in pediatric patients with SBS in reducing the need for parenteral nutrition (PN).We performed a literature search on MEDLINE and Embase to include articles up to November 2021. We included articles that involved using Teduglutide in the SBS pediatric population to define its efficacy in reducing the need for PN. The key words used were GLP-2, teduglutide, child.Fourteen studies completely fulfilled the inclusion criteria. Two hundred 23 patients were treated with Teduglutide, and the median duration of treatment was 45 weeks (IQR: 36–52.5 weeks). One-hundred and fifty-two patients were treated with 0.05 mg/Kg/d of subcutaneous Teduglutide, 38 received 0.025 mg/Kg/d and 8 received either 0.125 mg/Kg/d or 0.20 mg/Kg/d. A total of 36 patients achieved enteral autonomy (EA) after a median of 24 weeks of treatment (IQR: 24–48 weeks) and 149 patients showed a reduction in PN needs in terms of volume, calories, or hours per day. Eleven studies reported complications: gastrointestinal were the most common, with 89 cases reported in treated patients and 11 in non-treated patients.Teduglutide appears safe and effective in reducing PN requirements and improving EA in the pediatric population. However, more studies are needed to understand its efficacy in the long term and after discontinuation and possible complications.https://www.crd.york.ac.uk/prospero/], identifier [CRD42022301593].[ Intestinal Failure (IF) is caused by loss of a significant portion of the small intestine following congenital disease, acquired causes or surgical resection. With the inability to maintain protein, electrolyte, and micronutrient balance due to malabsorption the body may fail to sustain growth in affected children.Short Bowel Syndrome (SBS) is a complex condition that requires specialized care to prevent complications: for these reasons, treatment should be carried out by multidisciplinary intestinal rehabilitation teams. Such a team will help combine medical approaches and surgical techniques to achieve enteral autonomy (EA) and prevent IF-associated complications. SBS patients require PN to get nutrients and fluids that cannot be obtained through enteral nutrition. It is of the utmost importance to find ways to help them achieve EA and weaning from PN since this will improve their overall quality of life and psychological status . MoreoveAfter a significant intestinal loss, the remaining intestine will undergo adaptation. Gradually, changes will take place to maximize the absorptive area and provide the body with an adequate quantity of fluids, macro-, and micronutrients. This event is particularly true in pediatric patients, especially under 5 years of age, because bowel length increases in the first 5 years of life , 3. In tThe adaptation process involves several hormones, such as endothelial growth factor (EGF), growth hormone (GH), and Glucagon-like peptide-2 (GLP-2); among these, GLP-2 is a crucial component. GLP-2 is a 33-amino-acid peptide derived from a proglucagon precursor that also carries the sequence of glucagon and GLP-1. This peptide is secreted by enteroendocrine L cells, which can be found in the basal aspect of the intestinal mucosa in the distal ileum and proximal colon; nutrients induce its secretion in the intestinal lumen and then the peptide acts through second effectors such as IGF-1. GLP-2 improves nutrient absorption and gut-barrier function and slows motility in the short term. Thus, it promotes contact of nutrients with the intestinal mucosa, and it may also act as a regulator of blood supply to the gut . GLP-2 aFor this reason, researchers studied the formation of an analog recombinant form of this peptide with a longer lifespan, Teduglutide. In 2016 the European Medicines Agency approved the use of Teduglutide in pediatric patients (ages 1–17 years old); Teduglutide is resistant to the action of dipeptidyl peptidase IV, and it has a longer half-life compared to human GLP-2 , 12. AftWe conducted a literature search using MEDLINE and Embase to include articles up to November 2021 using the following keywords: glucagon-like peptide, teduglutide, child. We included studies with an English abstract available.Inclusion criteria for this systematic review were original articles including pediatric patients (aged < 18 years old) affected by SBS and IF and dependent on PN, treated with a recombinant analog of GLP-2 Teduglutide. The primary endpoint was the efficacy of Teduglutide in reducing the dependence of PN. Secondary endpoints included evaluating plasmatic citrulline levels and stool frequency and consistency improvement.The search strategy was done according to the PRISMA statement, and the present systematic review analysis was registered on the PROSPERO database (registration number: CRD42022301593) .After excluding duplicates, two authors (F.G. and MC.C) reviewed the articles independently and in a blind manner and articles were first screened for inclusion by title and abstract. Any disagreement was resolved by consensus.When two articles were published by the same research group or in case of potential patients’ overlap, we considered the study that included a higher number of patients to avoid duplication of data.Data were extracted using an internal spreadsheet, and the following information was extracted: (1) Study characteristics; title, first author, year of publication, country of the hospital in which the study was conducted, study design, number of patients enrolled, and number of patients treated; (2) characteristics of participants and treatment; (3) outcome of treatment; (4) complications.Given the paucity of available studies and patients identified with our selection criteria, data are reported as a narrative review.https://methods.cochrane.org/methods-cochrane/robins-i-tool  tool available at s-i-tool . Any disn = 8), study design (n = 2) and inclusion of non-pediatric patients (n = 1). The complete screening process is detailed in The literature search identified 313 studies . After removing 39 duplicates, 274 studies were screened for inclusion based on title and abstract review. Given the lack of records and the condition’s rarity, we considered eligible abstracts and posters when they included relevant information regarding treatment efficacy and fulfilled inclusion criteria. The abstract or the complete text, when available, were then examined in detail. Fourteen studies fulfilled the inclusion criteria and were finally included in our review –26. PrinThe main characteristics of those studies are summarized in The 14 selected studies included 248 patients, of which 223 were treated with Teduglutide. Duration of treatment went from 42 days to 60 weeks with a median of 45 weeks (IQR: 36–52.5 weeks). Seven studies were single center studies, while five were multicentric. Two papers did not report the country or the center of the study. Nine were prospective, three were retrospective analyses, and two were case reports in the included studies.All but one study included patients aged 1–17; one study included children < 1 year of age . The ageGender was specified in 8 studies, out of 122 patients for which it was known 81 (67%) were male, and 41 (33%) were female.n = 44, 31%), followed by volvulus , necrotizing enterocolitis  and intestinal atresia . The causes of resection are summarized in Ten studies specified the underlying diagnosis that led to SBS-IF, with a total number of 144 patients, while four studies did not mention the primary diagnosis. The most common diagnosis was gastroschisis , while in 98 patients it was absent (72%) , 24, 26.Length of the colon was reported in 8 papers, mainly as a percentage of the remaining colon, ranging from 8% of total length to the presence of the whole colon.Of the 223 treated patients 152 (61%) were treated with 0.05 mg/Kg/d of subcutaneous Teduglutide, 38 (16%) received 0.025 mg/Kg/d, 8 (3%) received 0.125 mg/Kg/d and 8 (3%) were treated with 0.20 mg/Kg/d. In 17 patients (7%) the dose was not specified. Twenty-five patients (10%) were in the Standard of Care (SOC) arm and did not receive Teduglutide. Characteristics of Teduglutide administration are summarized in After treatment, a total of 36 patients (16%) achieved EA after a median of 24 weeks of treatment (IQR: 24–48 weeks), and 149 patients (67%) showed a reduction in PN needs in terms of volume, calories, or hours per day. Thirty-eight patients who reduced PN requirements were in the 0.025 mg/kg/day group, 105 were in the 0,05 mg/kg/day group, one patient was in the 0.02 mg/kg/day group, and five patients the dose was not known. Study results are reported in In 7 studies , 20, 25,Eight studies out of 14 evaluated changes in stool’s quality and all of them showed an improvement in patients’ stool either in reducing the number of evacuations per day or in better quality of stool , 20, 25.Seven studies evaluated plasmatic levels of citrulline, showing higher plasmatic levels if compared to baseline , 24, 25.Eleven studies reported complications on treatment: gastrointestinal complications were the most common event, with 87 cases reported in treated patients and 10 in non-treated patients. Other complications (more than two events) were upper respiratory tract infections, CVC related complications, pyrexia, hepatobiliary or pancreatic disorder, dehydration, or electrolyte dysfunctions or injections site bruises. One study reported insurgence of abdominal distensions, loss of appetite, and worsening diarrhea in one patient after 2 weeks of treatment discontinuation due to unexpected drug supply issues . The mosSBS is a complex condition that affects around 24.5 children every 100,000 live births . AchieviIn the last 40 years, treatment of SBS has changed dramatically since the introduction of Autologous Gastrointestinal Reconstruction procedures (AGIR) pioneered by Adrian Bianchi in the ‘80s . Non-traTeduglutide was approved in 2016 to treat patients older than 1 year of age affected by IF. It has proven to be safe in this population and adults, and the studies included in our review confirm the safety of the treatment. Side effects and possible adverse reactions reported in the drug leaflet are respiratory tract infections, anxiety and insomnia, headache, gastrointestinal disorders, congestive heart failure, hepatobiliary, and pancreatic disorders, injections site reactions and stoma complications. The findings in our study are primarily consistent with what was already known of adverse effects based on adults’ studies. At the same time, anxiety and insomnia were not reported as typical (more than two events) in any of the studies included.This study aimed to evaluate the efficacy of Teduglutide in reducing the need for PN in children affected by SBS-IF. Six studies among inclusion criteria specified that patients should be stable at baseline with no changes in PN support in the last 3 months at least , 24, 25.Seven studies included showed augmentation of plasmatic Citrulline levels along with Teduglutide treatment. Citrulline can be used as a marker of intestinal function in situations where there is a significant loss of enterocytes’ mass and function, its levels appear to be strongly correlated with small bowel length and intestinal absorption in patients affected by SBS , 33. ThePatients suffering from IF still have a high mortality rate that ranges from 30 to 50% . SurvivaThis review has different limitations that should be recognized. Data are extracted from both prospective and retrospective studies, and we included clinical trials and case reports. Only a limited number of studies was available at this systematic review, and only 14 studies completely fulfilled the inclusion criteria. Given the paucity of records, we decided to include abstracts without a full article available: this could impact the overall quality of included studies. Limitations concerning the availability of data and information were previously reported in the quality assessment in the results section: small sample size and short follow up , 19, 26,In many studies, we did not find the intestinal size, previous surgery or height and weight before and after treatment. In some cases, PN and EN regimens before or after treatment were not described. Another limiting factor is the different doses at which Teduglutide was administered; the exact amount was also not specified in three papers , 15, 23.Despite limiting factors, our work could contribute to the scientific community: this is the first systematic review ever conducted on the use of Teduglutide in the pediatric population. SBS is a rare disease that has a high impact on the lives of affected patients and their families. It is fundamental to give these children more options for treatment possibilities. Teduglutide seems to be a promising opportunity in selected SBS patients that must be considered when thinking of a multidisciplinary approach to this complex condition. It should be proposed for treatment in patients over 1 year of age affected by SBS who are stable following a period of intestinal adaptation after surgery. The recommended dose is 0.05 mg/kg body weight once daily.Since its approval in 2016, different studies have been conducted on the pediatric population, but more data on the long-term efficacy of Teduglutide and complications related to treatment are needed. Moreover, it still must be studied and understood if the improvement in achieving EA and reducing PN requirements persists in the long-term, especially after treatment discontinuation. Only four studies out of the 14 included in this systematic review analyzed the PN requirement after treatment discontinuation , 18, 24.This study represents the first systematic review on the efficacy of Teduglutide in the pediatric population. Our work shows that teduglutide appears safe in treating patients under 18 years of age and effectively reduces PN requirements and improves EA in pediatric patients affected by SBS. Teduglutide is a valuable tool in the hands of professionals who treat these patients, and it should be considered when creating a multidisciplinary treatment plan for these children. However, more studies are needed to fully understand the complications related to long term treatment and the efficacy of Teduglutide, especially after discontinuation of treatment.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.FG, RCi, RCo, and AM contributed to conception and design of the study. FG and RCi organized the database. FG, RCi, and MDR performed data extraction. MCC and MCR performed the quality assessment. FG wrote the first draft of the manuscript. MCR, RCo, RCi, MCC, MDR, and AM wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.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.


Although probiotics have been shown to improve constipation-related symptoms, a clear consensus on the use of probiotics as a constipation-relieving agent has not been reached, which is attributed to the limited available evidence and inconsistent protocols used in existing studies. Lactobacillus plantarum P9 probiotic powder, 100 billion colony-forming units (CFUs)/day) or a placebo group. Volunteers, treatment distributors, data collectors, and data analysts will be blinded. The primary outcome is the weekly mean frequency of complete spontaneous bowel movements (CSBMs), and secondary outcomes include weekly mean frequency of CSBMs ≥3, weekly mean frequency of spontaneous bowel movements (SBMs), weekly mean stool appearance score, weekly mean difficulty of passing stool score, weekly percentage of volunteers who use auxiliary measures to assist with defecation (WPUAMA), quality-of-life (QOL) score, emotional status score, gut microbiome, and faecal metabolome. Each outcome measure will be assessed at the time points of preadministration (day 0), administration (day 14 and/or 28), and postadministration (day 42) to identify inter- and intragroup differences. Adverse events will be recorded to evaluate the safety of L. plantarum P9. Discussion. The protocol will provide methodological guidance for other similar studies, avoiding methodological bias and ultimately facilitating the formulation of consensus on the use of probiotics as a constipation-relieving agent. In addition, the results are more comprehensive than those of existing studies and may objectively and scientifically reflect the effectiveness of L. plantarum P9 on constipation. If the expected study findings are obtained, L. plantarum P9, taken as a probiotic, may become a complementary choice for chronically constipated patients. This trial is registered with Chinese Clinical Trial Registry (ChiCTR) (no. ChiCTR2000038396) registered on November 22, 2020, https://www.chictr.org.cn/showproj.aspx?proj=54024. A randomized, double-blind, placebo-controlled clinical trial is designed to study the efficiency and possible mechanism of action of probiotics for chronic constipation, in which 200 eligible volunteers with chronic constipation will be randomly assigned to a probiotic group (oral  Constipation is a common diagnosis made by gastroenterologists based on the assessment of infrequent bowel movements <3 per week) and difficult stool passage, while patients may report multiple symptoms, including a sense of incomplete defecation, abdominal pain, bloating, excessive straining accompanied by a sensation of anorectal blockage during stool passage, and requiring manual assistance to release the stool. Acute (or nonchronic) constipation either results in blockage of the intestinal tract that requires surgery  or tends per weekThe global prevalence of constipation ranges from 10% to 30% –7. The vOnly one-fifth of patients with constipation seek medical advice , and laxHowever, although many studies have reported that probiotics are potentially beneficial for constipated individuals –43, a clL. plantarum P9 on chronic constipation and to guide other studies assessing the effectiveness of probiotics. The correlation between the clinical improvement of symptoms and changes in intestinal flora was also analysed.Thus, we designed this protocol to study the effectiveness of This study is a randomized, double-blind, placebo-controlled clinical trial conducted in Nanchang, China, and volunteers may receive the intervention  in their own homes. The protocol was prospectively registered at the Chinese Clinical Trial Registry (ChiCTR) (NO. ChiCTR2000038396)  and appr(1)Two or more of the following symptoms: (a.) difficulty passing stool, at least 25% of defecations; (b.) lumpy or hard stool, at least 25% of defecations  types 1 or 2  53]); ; (53]);Loose stool rarely occurs without the use of laxatives.Insufficient stools are rarely present without the use of laxatives.Onset of the following symptoms for at least 6 months before enrolment and symptoms within the past 3 months that meet the following criteria , 52:Two (2)Willing to sign the informed consent form (3)The volunteers involved in this study will be patients with chronic constipation aged 18–65 years. For patients aged from 18 (exclusive) to 50 (inclusive) years, the result of stool tests (including occult blood) conducted during the screening period must be normal or abnormal but determined to be clinically irrelevant by the investigators. For patients aged 50 (exclusive) to 65 (inclusive) years, the result of a colonoscopy performed at a tertiary or higher-level hospital within the past 6 months must be normal or abnormal but determined clinically irrelevant by the investigators.Eligible patients should fully meet the Rome IV criteria :(1)OnsetPersonal or family history of colon cancer, celiac disease, or inflammatory bowel diseaseIntestinal organic diseases confirmed on a previous colonoscopyPlans to become pregnant or father a child in the next 3 months, or pregnant, or breastfeedingAllergies to samples or ingredientsUse of antibiotics or probiotics within the past two weeksUse of antianxiety, antidepressant, or other psychotropic drugs within the past monthNeed for long-term use of medications for constipationHistory of severe diseases, such as myocardial infarction, cerebral infarction, and malignant tumour, judged by the investigators as disqualifying conditionsMajor mental illnesses, inability to control one's actions, or inability to cooperateIlliteracy, inability to understand the informed consent form, or inability to independently sign the informed consent formVolunteers with any of the following conditions will be excluded:The investigators will recruit volunteers from the public through in-person communication, posters, and WeChat promotions. Volunteers can scan a WeChat two-dimensional (QR) code to register for enrolment, submit their personal information, and answer questions related to inclusion and exclusion criteria. Volunteers will undergo a procedure that includes three rounds of screening. First, the investigators will collect and collate the volunteers' registration information and, according to the information provided by registrants, invite potentially eligible candidates to participate in a central consultation with clinical specialists for further screening and selection of eligible volunteers. Second, during the central consultation, trained study implementers will introduce the trial to volunteers in the form of a video and information sheets describing the main aspects of the trial and discuss the information provided in the video and information sheets. Then, volunteers will meet with the clinical specialist to confirm their registration information, especially regarding inclusion and exclusion criteria. Third, volunteers will sign an informed consent form in the presence of a member of the data management team (DMT). Then, volunteers will undergo a 14-day screening period when they will not be allowed to take any medicines or health products to improve their constipation symptoms. Each volunteer will be asked to collect one stool sample and complete an online diary entry daily . At the R 4.1.0 and used to randomly assign the unique number (participant) to the probiotic group or the placebo group. During the study, the volunteer's treatment distributors, data collectors, and data analysts will be blinded to the randomization sequence. The randomization sequence will be maintained by an independent project administrator and will only be unblinded in the case of major safety issues or when performing the interim and final data analyses. Moreover, an independent project administrator will label the probiotics or placebo packages with unique numbers corresponding to random sequences in advance to achieve allocation concealment. During the period of administration, the distributor will distribute the treatment packages according to the unique number that corresponds to each participant.Eligible volunteers will be assigned a unique serial number . The unique number will be used as the volunteers' ID throughout the study period to guarantee anonymity and confidentiality. For each of these unique numbers, a random sequence will be generated by the computer software L. plantarum P9 and placebo powders will be manufactured in parallel and independently by Research and Development Department, Jiangzhong Pharmaceutical Company Limited . Briefly, the preparation procedure consists of three steps: weighing, mixing, and packaging. L. plantarum P9 powder is composed of 20% maltodextrin, 20% orange powder, 20% maltitol, and 40% L. plantarum P9, while placebo powder consists of 60% maltodextrin, 20% orange powder, and 20% maltitol. Raw materials for L. plantarum P9 and placebo powders are mixed using a Hopper mixer (hit-400) and sealed into 2 g packages. The temperature is controlled at 25 ± 2°C, and the relative humidity is less than 65% during the three steps. In the study, when the product of L. plantarum P9 powder is manufactured, a randomized sample is sent to Jinhua Yinhe Biotechnology Co., Ltd. (https://yinhewdy168.foodmate.net/) for quality inspection. The activity of probiotics is greater than 67 billion colony-forming units (CFUs)/g.The Period of screening (preadministration observation period) (days 14 to 0): in this phase, volunteers will not receive the intended interventions, i.e., probiotics and placebo. Eligibility screening will be performed as described during volunteer recruitment .L. plantarum P9 powder directly or with warm water (below 40°C) on a full stomach at a dose of 100 billion CFUs per day; if antibiotics must be taken, probiotics should be taken 2 hours later. (2) Placebo group: volunteers will take the placebo in the same manner as the probiotics group. The placebo contains no probiotics but has the same appearance, packaging, and taste as the L. plantarum P9 powder.Observation period during administration (days 0 to 28): (1) Probiotics group: volunteers will take 1 package of All remaining probiotics or placebo (unused) and empty (used) packages will be collected at the end of this period to monitor compliance. During the study, both probiotics and placebo will be stored in a cool, dry place away from direct sunlight.Postadministration observation period (days 29 to 42): no probiotics or placebo will be taken.The study will include three phases , includiLactobacillus plantarum used in this study; (2) antianxiety, antidepressants, and other psychotropic drugs; and (3) other substances designed to improve intestinal symptoms.The following treatments are prohibited during the study: (1) probiotics, prebiotics, and foods containing probiotics (such as yoghurt) other than the In addition, antibiotics will be monitored during the study, and normal dietary habits will be recommended. All concomitantly used substances/drugs related to defecation should be recorded daily in the online defecation diary , and expThe primary outcome measure is the weekly mean frequency of complete spontaneous bowel movements (CSBMs) , 54, 55.A defecation diary developed with reference to the literature , 53–56 wA CSBM is defined as the ability to achieve a complete bowel movement without the use of any drugs or other auxiliary measures during the previous 24 hours. Based on the diary , the weeBased on the diary , the chaThe Patient Assessment of Constipation Quality-of-Life (PAC-QOL) questionnaire  , 59 App will be For the indicator of the gut microbiome, DNA will be extracted from the stool samples with the QIAamp Fast DNA Stool Mini Kit  according to the manufacturer's instructions, and the quality of DNA will be examined using agarose gel electrophoresis and a NanoDrop spectrophotometer. Shotgun metagenomic sequencing will be performed on all samples using an Illumina HiSeq 2500 instrument. Libraries will be constructed from DNA fragments with a length of ∼300 bp; paired-end reads will be generated by sequencing 150 bp in the forward and reverse directions. Meanwhile, the metagenomic analysis will include several parts: the analysis of alpha diversity and beta diversity in each group to understand whether the differences in the microbiota compositions of groups are significant and a comparison of the taxonomic characteristics of the study group and the control group at the level of phylum, genus, and species to identify specific genes related to the individual differences of constipation. Metagenomic biological pathway analysis will be used to evaluate the effect of probiotics on the function of gut metagenomics in patients with constipation and to explore the metagenomic biological pathways contributing to the mechanism underlying the effect of probiotics on the treatment of constipation.For the indicator of the faecal metabolome, stool samples will be extracted using the protein precipitation method, and the supernatant will be transferred to sample vials for LC-MS/MS analysis. The original data will be subjected to peak alignment, retention time correction, and peak area extraction using the XCMS-Plus program. The structure of metabolites will be identified by accurate mass matching (<5 ppm) and two-level spectrum matching, and the METLIN database will be retrieved. We will then delete data with missing values > 50% in the group, normalize the data, and conduct multidimensional statistical analysis, including unsupervised principal component analysis (PCA), supervised partial least squares discriminant analysis (PLS-DA), and potential differentially abundant metabolite analysis. The metabolomic analysis might further identify the potential differentially abundant metabolites of probiotics in the treatment of constipation, and a correlation analysis between the gut microbiota and metabolites will be performed.All related clinical trials have reported that probiotics are safe and do not induce significant adverse events compared with the placebo group. However, four types of adverse reactions related to probiotics should be considered, including symptoms that may be attributed to systemic infections, deleterious metabolic activities, excessive immune stimulation, and gastrointestinal side effects , which wDemographic profiles, special situations related to defecation during the study, including changes in dietary habits , taking antibiotics, and any other reported situation will be recorded and assessed as needed.S = 6, α = 0.05, and β = 0.20, the sample size should be at least 63 volunteers per group, as calculated with the formula for statistically significant effectiveness. After considering the drop-out rate (20% or lower), the sample size should be 76 or more participants per group. The final sample size will be 100 participants per group for a total of 200 volunteers.This study is a clinical trial during which volunteers will consume a sample medication or placebo for 28 days and will be followed up for 42 days. The primary outcome measure is the weekly frequency of CSBMs. The expected weekly frequencies of CSBMs on day 28 are 1.1 in the control group and 4.1 in the probiotic group, with a between-group difference of 3. Given a standard deviation The probiotics and placebo will be supplied as packages distributed in boxes. At the start of the administration period, the appropriate number of probiotic and placebo packages will be distributed to the participants. All used (empty) and unused packaging will be kept by volunteers. At the end of the administration period, these packages will be collected to verify the number of remaining packages and calculate the dosing rate. A dosing rate ≥80% indicates good compliance. A WeChat group will be established for the participants to improve compliance. The study personnel will post messages in the WeChat group to remind participants to take the samples as scheduled and complete the questionnaire. In addition, each participant will receive a reward of 300 RMB once they complete the follow-up.Volunteers will be withdrawn from the trial for the following reasons: (1) continuous adverse reactions involving systemic infections that cannot be resolved after certain measures are taken, deleterious metabolic activities, excessive immune stimulation, gene transfer, and gastrointestinal side effects, which may be attributed to probiotics ; and (2)https://www.longseemed.com).The defecation diary  completeAn independent data management team (DMT) will be established to maintain and monitor study quality and safety. The data of individual characteristics, defecation diary entries , and DASThe intention-to-treat (ITT) analysis will be conducted between the two groups. Then, the following four data sets will be used for the per-protocol (PP) analysis: (1) the data from all participants who completed the follow-up and (2) a subgroup analysis regarding levels of compliance  to validate the robustness of the results. The hypothesis will be tested using the methods described below during the ITT and PP analyses.χ2) test will be used for the outcome measures, namely, the percentage of volunteers with a weekly mean frequency of CSBMs ≥3 and WPUAMA, at each observation point. In the analyses, the P value indicating statistical significance will be set to 0.05.First, the Wilcoxon signed-rank sum test will be used for the outcome measures, including the weekly mean frequency of CSBMs, weekly mean stool appearance score, weekly mean difficulty of passing stool score, weekly mean frequency of SBMs, QOL score, and emotional status score, at each observation point to analyse the intergroup differences in each outcome measure. The chi-square /2], where k is the number of sample groups included in the comparison.Then, the Kruskal–Wallis rank sum test will be used for multiple comparisons of outcome measures, including the weekly mean frequency of CSBMs, weekly mean stool appearance score, weekly mean difficulty of passing stool score, weekly mean frequency of SBMs, QOL score, and emotional status score, and the R software (v.4.0.2) and Adobe Illustrator. PCA and PLS-DA will be performed and visualized using the R packages vegan, ggplot, and ggpubr, and the adonis P value will be generated based on 999 permutations. The t-test, Wilcoxon test, and Kruskal–Wallis test will be used to evaluate differences in variables between and within groups; P values will be corrected for multiple testing using the Benjamini–Hochberg procedure. Meanwhile, Pearson's and Spearman's correlation coefficients will be calculated to analyse the correlations between different indicators in clinical, metagenomic, and metabolomic data.In addition, the statistical analyses of metagenomic and metabolomic data will be performed using Interest in using probiotics as a constipation-relieving agent is increasing, as approximately half of patients have been disappointed with their current treatments. Probiotics hold great promise as a complementary treatment. However, a clear consensus on its recommendation for a patient with constipation is still unavailable because the existing evidence is limited and the methodology used by the existing studies lacks consistency, precluding a comparison of the results. In this context, we developed the protocol for this study.8 [10 [The key parameters of the methodology used in the previous RCTs and the present RCT are shown and compared in 8  to 1010 8 [10  CFUs; imWe optimize the methodology from the following aspects: ① The general principle for a high-quality RCT is strictly obeyed through the participation of third-party independent companies or the DMT, including randomization, parallel control, blinding, allocation concealment, combination of ITT and PP analyses, consideration of withdrawals or dropouts, replication (enough observed study subjects), and other factors. ② The sample size (100 for each group) is obtained based on the expected difference in weekly frequency of CSBMs between the treatment group and control group, which is sufficient to ensure the reliability and accuracy of the results. The sample sizes in 33 of the 35 previous RCTs are dozens or even several participants, which is probably not sufficient to obtain an accurate result. ③ The latest Rome criteria (Rome IV for the present RCT) are suggested for the diagnosis of chronic constipation to avoid any other self-definition by researchers. ④ Multidimensional outcomes have been observed in the present RCT, including improvements in clinical symptoms, QOL score, emotional status score, and modifications in the gut microbiome and faecal metabolome, to produce a chain of evidence from causal improvements in metagenomic and metabolomic data to clinical symptoms and then to the emotional state and QOL. The outcomes are measured using accepted methods, e.g., BSFS , PAC-QOLL. plantarum P9 on chronic constipation. The study is articulated with a clear testable hypothesis stating that L. plantarum P9 improves the clinical symptoms and patient QOL by modifying the intestinal flora. Additionally, the safety of L. plantarum P9 will be assessed.In addition, the protocol is conducted to prove its feasibility and scientificity by studying the effects of L. plantarum P9 on constipation. In addition, the protocol will provide methodological guidance for similar studies, avoiding methodological bias and ultimately facilitating the formulation of a consensus on the use of probiotics as a constipation-relieving agent.Thus, we believe the study will be a high-quality RCT. The results will be more comprehensive than those of existing studies and will objectively and scientifically reflect the effectiveness of This study started recruiting patients on October 1, 2020. To date, 130 patients have been enrolled. Enrolment is expected to be completed by May 31, 2022, and all follow-up visits are expected to be completed by July 31, 2022. The protocol is version 2.0, and the date of the edition is 10 September 2020.


The key interest of this research is to identify the causes of the ongoing increasing trends in caesarean section or C-section (CS) deliveries in both urban and rural areas of Bangladesh.This study analyzed all Bangladesh Demographic and Health Survey (BDHS) datasets through Chi-square and z tests and the multivariable logistic regression model.CS deliveries were found to be more prevalent in urban than in rural areas of Bangladesh. Mothers above 19 years, above 16 years at first birth, overweight mothers, those with higher educational levels, those who received more than one antenatal care (ANC) visit, fathers having secondary/higher education degrees and employed as workers or in business, and mothers living in wealthy households in the cities of Dhaka, Khulna, Mymensingh, Rajshahi, and Rangpur divisions had a significantly higher likelihood of CS deliveries in urban areas. Contrastingly, mothers with ages between 20 and 39 years, above 20 years at first birth, normal weight/overweight mothers, those with primary to higher level of education, those in the business profession, fathers who also received primary to higher education, mothers who received more than one ANC visit, and those living in wealthy households in Dhaka, Khulna, Mymensingh, Rajshahi, and Rangpur divisions were more likely to have CS deliveries in rural areas. The 45–49 age group mothers had a five times higher likelihood of CS deliveries [odds ratio (OR): 5.39] in urban areas than in rural areas. Wealthy mothers were more likely to be CS-delivered in urban (OR: 4.84) than in rural areas (OR: 3.67).The findings reveal a gradual upward alarming trend in CS deliveries with an unequal contribution of significant determinants in urban and rural areas of Bangladesh. Therefore, integrated community-level awareness programs are an urgent need in accordance with the findings on the risks of CS and the benefits of vaginal deliveries in this country. A caesarean section can be a life-saving intervention when medically indicated, but it can also trigger many short-term and long-term adverse health complications for both mother and baby –4. CS shA study showed that the global average CS rate increased by 12.4% in the period between 1990 and 2014, with the maximum average annual rate of increase happening in Asia . MoreoveVarious studies conducted in South Asian countries, including Bangladesh, have pointed out to increased concerns about the higher rate of CS and predict that the national increase in the CS rate could be partially motivated by private health facilities that are mainly driven by profit maximization , 33, 34.This study considered all published BDHS datasets  to examine the trends in CS delivery rates. However, an assessment of the association of CS deliveries with different socioeconomic and demographic characteristics and subsequent analysis is based on the most recent secondary data collected from BDHS-2017/18. The sampling frame of this survey was the list of enumeration areas (EAs) of the 2011 Population and Housing Census of the People's Republic of Bangladesh. The primary sampling unit of the survey was an EA. The survey used a two-stage stratified sampling technique. In the first stage, 675 EAs were chosen, with 227 and 448 EAs from urban and rural areas. However, data could not be collected from three EAs because of the occurrence of natural disaster. These clusters were in Dhaka (one urban cluster), Rajshahi , and Rangpur . In the second stage, a systematic sample of 30 households was selected from each EA. A total of 20,250 residential households were selected in four phases. Among the 20,376 ever-married women aged 15–49 years and eligible for interviews, 20,127 were interviewed, yielding a response rate of approximately 99%. The detailed sampling procedure is available in the report of BDHS-2017/18  No or (ii) Yes. This variable was measured by asking a question to the participants, “Did you ever give birth by CS?”.In this study, the mother's age in years , age at 1st birth , body mass index (BMI) , educational level , occupation , the father’s education level , the father's occupation , birth order , number of antenatal visits during pregnancy , religion , place of residence, wealth index , and division  were all considered covariates.Yi is a binary variable that takes a value of “1” if the respondent received CS delivery and “0” otherwise; Xi is a vector of independent variables and p-th independent variable in the study.In this study, initially, bivariate analysis (Chi-square test) was performed to determine significant associations between mode of birth (caesarean vs. non-caesarean) and select sociodemographic factors. These associated variables were considered independent variables for the logistic regression model (unadjusted and adjusted), which was implemented to find the most influential factors for CS delivery. The logistic regression model can be expressed asThe percentage of delivery by CS based on ever-married women aged 15–49 years, separated by location, namely, rural and urban regions, is presented in CS deliveries are widespread in the urban areas of Khulna, Dhaka, and Rajshahi divisions. In contrast, such deliveries are less common in Barisal division's rural and urban areas, followed by the Chittagong division. However, in the Sylhet division, CS was popular initially, but after 2014, the prevalence is less observable. Overall, for the entire survey period, an increasing trend in the percentage of CS is observed in all parts of the country’s urban and rural regions.The bar chart portrayed in p-value < 0.001 in urban areas, the association is also significant in rural areas with a p-value of 0.085. On the other hand, religion shows a significant association in only rural areas with a p-value of 0.001. Because the difference between the proportions of CS in urban–rural areas can be explicitly visualized, the significance of this difference can also be justified by using the z-test in terms of every covariate considered in this study. The results of the test statistic, along with the p-value, are presented in p-values are less than 0.001 in all levels of the considered variables, except in the wealth index, which is categorized as a middle-class parameter, which denotes that the father does not engage in any work. However, the difference between the two variables of urban and rural areas is also significant, in that there is a 10% level of significance, since the p-values of the wealth index (middle) denoting that the father does not work are 0.002 and 0.075, respectively -related variables were investigated by using the chi-square test, and the results are given in ectively .Then, the multivariable logistic regression model with CS as the dependent variable and the identified significant covariates as the independent variables was used to measure the impact of the covariates on CS. The results are presented in Mothers who received a higher number of antenatal care visits during pregnancy also had higher odds of undergoing CS delivery in both urban and rural areas, for example, 1–4 visits , 1–4 visits , and 8 or more  compared with 0 visits. Rural mothers who were employed had less odds of CS done on them (OR = 0.5) than those who were not. The likelihood of CS deliveries was higher among mothers at first birth in the age group of (24 + years) in urban (OR: 2.6) and rural areas (OR: 2.0) compared with the ≤16 year age group. The possibility of CS decreased with a higher birth order in both urban and rural areas; for example, a birth order of more than 3 in urban (OR = 0.5) and rural areas (OR = 0.4) was lower than that of first birth. The mother's age, religion, and the father’s occupation were not significantly associated with CS deliveries in both areas .One of the key findings of this study is that the CS delivery rate is continuously increasing over time in urban and rural residents. In a study by Khan et al., it is reported that the prevalence rate of CS has been increasing in Bangladesh over the last few decades . HoweverNevertheless, CS deliveries are increasing in both areas, but in urban areas, the popular appeal of such deliveries is more than two times that in rural areas over the past decade, and it was much higher in the previous decade. These findings indicate that a large number of urban mothers prefer CS compared with their rural counterparts. Many studies have identified urbanization as a significant contributing factor to CS practices in several countries , 44–51. Another finding shows that “other complications during delivery (31.9%)” is the leading indication for CS, followed by malpresentation (23.4%), failure to progress in labor (23.2%), previous CS (22.9%), convenience (9.3%), and unwillingness to bear labor pain (6%). A study conducted in the Thakurgaon district of Bangladesh reported that the most typical indications for CS were previous CS (29.4%), fetal distress (15.7%), cephalopelvic disc proportion (10.2%), prolonged obstructed labor (8.3%), and post-term dates (7.0%) . AnotherThese findings also indicate that the pregnant mother's age, age at first birth, BMI, education, occupation of the mother and her partner, birth order, ANC visits, wealth index, and geographic region (division) are the significant leading factors of CS deliveries in both urban and rural areas. Interestingly, religion is a significant leading factor of CS in rural areas. The factors mentioned above were also identified as potential significant predictors of CS deliveries in many previous studies , 53–55. Moreover, this study measured the risk of pregnant mothers’ CS deliveries from a different viewpoint of the significant leading factors. It found that older mothers were more likely to experience different complications during pregnancy and delivery , 59–61, Our findings indicate that mothers with higher education are more likely to undergo CS. This finding is similar to previous studies’ results , 54, 55.Furthermore, mothers whose husbands are also better educated are more likely to accept CS than those whose husbands are less educated, with the likelihood being slightly greater in urban areas. Working mothers are the least likely to opt for CS compared to non-working mothers in both areas. This may be due to the fact that working mothers have less chances of receiving ANC services because of time constraints . LikewisThe main strength of this study is its novelty. Second, this study was carried out with country representative data. Third, methodological robustness increased the acceptability of the findings. The main limitation of this study is that it was conducted with cross-sectional data, and therefore, causal inferences could not be derived. Second, there may be other contributing factors to CS delivery that were not considered in this study.The increasing trends in CS deliveries in urban areas is approximately two- to sixfold higher than in rural areas between the years 1993 and 1994 and between 2017 and 2018, and this indicates an undesirable situation in the context of Bangladeshi healthcare. Many factors have already been identified previously for the increasing number of CS deliveries in the country. However, this study focused on the urban–rural variations in CS deliveries. It is suggested that policymakers should design community-based maternal healthcare programs to reduce the prevalence rates of CS and also the economic burden placed on both urban and rural settings in light of the findings of this research.This study has been conducted in the urban and rural areas of Bangladesh with the principal aim of examining the CS delivery pattern over time and to identify its causes and influential factors. The trend analysis showed that CS delivery prevalence has increased over the past two decades in both areas with apparent differences. Moreover, the increasing trends and the urban–rural divide have also manifested in Bangladesh's geographic divisions. Furthermore, extraneous complications during delivery have been the leading indications for CS, followed by malpresentation, failure to progress in labor, previous CS, convenience, and unwillingness to bear labor pain in both urban and rural areas, however, with a slight difference. However, among these causative factors, CS delivery due to only malpresentation is higher in rural areas than in urban areas, while the prevalence of the remaining factors is higher in urban areas. The analysis confirmed that CS delivery is significantly influenced by the pregnant mother's age, age at first birth, BMI, education, occupation of both mother and husband, birth order, ANC visits, wealth index, and geographic division in both urban and rural areas; religion is an important covariate in rural areas. These findings reveal that the aforementioned influential factors of CS vary in terms of the resident settings  of pregnant mothers.This study found that urban mothers were more likely to undergo CS deliveries than their rural counterparts. This was mainly the case of those who were more than 19 years old, overweight, had higher education levels, received more than one ANC visit, were aged greater than 16 years at first birth and whose husbands were secondary or higher educated and professionals or businessmen, and lived in wealthy households in Dhaka, Khulna, Mymensingh, Rajshahi, and Rangpur divisions. On the other hand, mothers with age between 20 and 39 years, age at first birth >20 years, normal or overweight, received primary to higher education, business professionals, whose husbands were also primary to higher educated, received more than one ANC visit, and belonged to wealthy families in Dhaka, Khulna, Mymensingh, Rajshahi, and Rangpur divisions were more likely to undergo CS deliveries in rural areas. However, the increasing practice of CS delivery is posing a threat to traditional and normal deliveries, and for a low- and middle-income country like Bangladesh, CS can place a heavy financial burden on the healthcare system and family economic status. Therefore, the government of Bangladesh needs to act fast by developing new policies and regulations to make sure that CS is carried out only when it is medically appropriate to do so and not for the sole purpose of deriving financial benefits.


We aimed to evaluate the relationship between the proportion of Android to Gynoid ratio and the incidence of kidney stones among US adults.Participants aged 20-59 years from the 2011-2018 National Health and Nutrition Examination Survey (NHANES) database were selected to assess the association between Android to Gynoid ratio and kidney stone prevalence using logistic regression analysis, subgroup analysis and calculation of dose-response curves.This study ultimately included 10858 participants, of whom 859 self-reported a history of kidney stones. And after adjusting for all confounders, an increased Android to Gynoid ratio was associated with an increased prevalence of kidney stones . And subgroup analysis showed an increased prevalence of kidney stones in women , non-diabetic , 60 > age ≥ 40 years , Mexican-American  and white  groups, there was a significant positive association between A/G ratio and kidney stones. In contrast, in the hypertensive subgroup, the A/G ratio was associated with kidney stones in all groups.Higher Android to Gynoid ratio is associated with a high prevalence of kidney stone disease. Kidney stones disease (KSD) are among the most common and common diseases in urology and are caused by the abnormal accumulation of certain crystalline substances  in the kidney and are characterized by high prevalence and easy recurrence –3. A stuObesity has now become one of the serious health problems affecting the health of the global population , 12. ObeFor measuring body fat content and distribution, computed tomography (CT) and magnetic resonance imaging (MRI) are often considered the gold standard. However, the high radiation produced by CT, the lengthy acquisition and analysis times associated with MRI, and the higher costs of both techniques have limited their use in clinical and research settings. Dual-energy X-ray absorptiometry (DXA), on the other hand, is also sufficiently accurate and involves less radiation exposure, a shorter scan time, and a lower cost –21. FurtAn Android to Gynoid ratio (A/G ratio) is a DXA-based fat distribution index. Numerous studies have shown that the A/G ratio is strongly associated with insulin resistance and cardiovascular disease , 25, botData for the evaluation of this study were obtained from NHANES from 2011 to 2018. This is a survey conducted by the Centers for Disease Control and Prevention (CDC) every two years for public health surveillance in the U.S. The NHANES study protocol was reviewed and approved by the Institutional Review Board of the National Center for Health Statistics (NCHS), and all participants provided written informed consent. All methods were conducted in accordance with relevant guidelines and regulations. Our study examined data from four consecutive two-year survey cycles. All participants were evaluated with the KIQ026 survey (Do you have kidney stones) and a total of 39,156 people participated in the questionnaire. The exclusion criteria are shown in the figure Figure 1https://wwwn.cdc.gov/Nchs/Nhanes/2017-2018/DXXAG_J.htm. The occurrence of kidney stones (Variable Name: KIQ026) was designed as an outcome variable. The questionnaire KIQ026 (ever had kidney stones)? was used to assess kidney stones; if the participant answered “yes,” he was considered to have kidney stones.A/G ratios (Variable Name: DXXAGRAT) were designed as exposure variables. Relevant data were obtained by performing DXA measurements on subjects. DXA examinations were obtained by trained and certified radiologic technologists using a Hologic Discovery Model A densitometer . The examination excluded subjects who were pregnant (urine pregnancy test and/or self-reported positive at the time of the DXA examination), self-reported a history of X-ray contrast (barium) use within the past seven days, or measured more than 450 pounds or more than 6’5” (DXA table limit). Whole-body scans were obtained on a Hologic Discovery A densitometer  using software version Apex 3.2. The Android and Gynoid regions were determined by the HOGIC APEX software used in the scan analysis for automatic delineation . Finallywww.cdc.gov/nchs/nhanes/.In order to summarize potential confounders that could confound the relationship between A/G ratio and KSD, adjusted multivariate models were used. The following covariates were selected: age, gender, race, education level, poverty to income ratio (PIR), marital status, alcohol consumption, smoking status, physical activity, METS-IR, BMI, diabetes, hypertension, asthma, laboratory tests  and some dietary intake factors . A 24-hour dietary recall was completed by all participants, and the average intake of the two recalls will be used in the analysis. The dietary intake factors had a high number of missing values, which we converted to categorical variables. We assessed these variables in tertile, with the lowest tertile serving as the reference group and missing values set as dummy variables. These covariates were determined using self-report questionnaires, interviews, physical examinations, and laboratory measurements. Information on age, gender, race/ethnicity, PIR, smoking, alcohol consumption, history of hypertension, and history of diabetes were determined by questionnaire. Information on the dietary intake of the participants was obtained through interviews. Participants’ BMI and waist circumference were obtained by physical examination, and laboratory measurements were used for the remaining covariates. Cholesterol, triglyceride, and uric acid concentrations in serum or plasma were measured using the timed-endpoint method. The timed rate biuret method was used to measure phosphorus in blood, and the indirect (or diluted) I.S.E. (ion selective electrode) method was used to measure calcium concentrations in serum, plasma, or urine (uses indirect (or diluted) I.S.E. (ion selective electrode) methodology to measure calcium concentration, the modular chemistry side uses the Jaffe rate method  to determine serum, plasma, or urine Creatinine concentrations in creatinine, Tosoh Automated Glycohemoglobin Analyzer HLC-723G8 was used to measure glycosylated hemoglobin in patients, HDL data were obtained using Roche/Hitachi Cobas 6000 Analyzer, patients with excess LDL deficiency, we used Friedewald formula to recalculate the patient’s LDL. Details of the study variables used are all publicly available at www.empowerstats.com; X&Y Solutions, Inc., Boston, MA, USA) and R version 3.4.3 .To illustrate the complex, multi-stage sampling design used to select a representative non-institutionalized U.S. population, the sampling weights, strata, and subgroups provided in the NHANES study were applied to all statistical analyses. Continuous variables are expressed as weighted means and 95% CIs, and categorical variables are expressed as weighted proportions and 95% CI. We first did a VIF covariate screening of all covariates and removed the covariate if the VIF value was greater than five, considered to have sharedness. Based on the guidelines , three dThe analysis involved 11327 participants, including 895 patients with kidney stones Table 1.VIF values for all covariates for covariate screening were less than 5, so all covariates were included in the final model. A multifactorial logistic regression analysis was performed showing a 1.75-fold increase in the prevalence of kidney stones for each unit increase in the A/G ratio  Table 2.To assess the robustness of the association between the A/G ratio and the prevalence of kidney stones, a subgroup analysis was performed Table 3.Using a generalized additive model and smoothed curve fitting, a relationship between A/G ratio and kidney stones was further investigated. Our results show that the A/G ratio is linearly and positively correlated with the KSD Figure 2KSD has a complex etiology, a high recurrence rate, and a wide range of individual variations. Therefore, examining KSD’s risk factors is essential for both prevention and treatment. According to our knowledge, this is the first study to investigate the association between A/G ratios and the prevalence of nephrolithiasis. According to our analysis of four consecutive NHANES two-year cycles (2011–2018) of a nationally representative population, the A/G ratio is predictive of kidney stone occurrence, and the higher the A/G ratio, the higher the risk.This correlation may be due to a number of reasons. First, an increase in the A/G ratio generally represents an abnormal increase in fat content in the Android region. Android region contains the liver, pancreas, and kidneys. There have been numerous studies demonstrating that fat accumulation in these structures can have harmful effects both directly and indirectly on the body –33. An aWe also stratified the variables by age, sex, race, hypertension, and diabetes status in this study. There was a positive correlation between the prevalence of the A/G ratio and the KSD in all subgroups when unadjusted. After adjusting for all variables, this correlation was statistically significant in all groups only if they were grouped according to hypertension. However, the correlation between A/G ratio and KSD was more significant in the hypertensive group. This may be because hypertension itself is a risk factor for KSD , so it eHowever, after adjusting for all confounding variables. This correlation was only significant among Caucasians and Mexican-Americans in stratification by race. It may be due to the fact that black groups appear to be less affected by obesity than other races . FurtherThe study has several advantages. First of all, this is the first comprehensive analysis of the correlation between the A/G ratio and KSD. Second, NHANES follows a well-designed study protocol with extensive quality assurance and quality control. In addition, the large representative sample size makes our results more reliable and generalizable to the entire US multi-ethnic adult population. Furthermore, the wide range of covariates used for adjustment enhances the accuracy of statistical inferences.Of course, our study has some limitations. First, our study was based on the NHANES database, which is a cross-sectional study, and we were unable to obtain a causal relationship between the A/G ratio and kidney stones. Second, out of the DXA test results, many of our data were based on self-reporting, which may have some recall and reporting bias, such that a small number of asymptomatic urinary stones may be excluded. Third, the database did not provide more detailed information, such as medication history and stone composition. It is therefore necessary to conduct further research in order to confirm our results and explore in more detail the correlation between the A/G ratio and KSD.Based on a cross-sectional study of a US population, we found that a high A/G ratio was associated with an increased prevalence of kidney stones. This may have significant implications for the prevention and treatment of kidney stones. Therefore, this needs to be validated by further studies and the potential mechanisms explored.https://www.cdc.gov/nchs/nhanes/index.htm.Publicly available datasets were analyzed in this study. This data can be found here: GL, HL, and YH: Conceptualization, Methodology, Software. QH, XS, and YC: Visuali-zation, Investigation. MC, JX, and ZH: Writing - review & editing. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China .The authors are grateful for the invaluable support and useful discussions with other members of the urological department. We are also grateful to all participants and research teams in the National Health and Nutrition Examination Survey.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.


Callithrix sp.) wild mammals, which are distributed into 14 families and seven orders, in addition to the presence of free-ranging domestic dogs and cats. Four species are in some category of threat of extinction at national or global levels. Amongst them, Leontopithecusrosalia (first record for the Rio de Janeiro City in more than a century) and Leopardusguttulus are classified as Vulnerable by IUCN. Most wild native species were registered in the three habitat types, but with differences in the frequency of records. Our results indicate that the presence of domestic dogs and cats influenced the species composition in each area, with Nasuanasua, Dasyproctaleporina and Didelphisaurita less frequent in places where domestic dogs and cats are more frequent. This is the first systematic effort to understand the occurrence and distribution of mid- and large-sized mammals in the Pedra Branca Forest.The Pedra Branca Forest is in a highly urbanised region of the central portion of Rio de Janeiro City and comprises the largest urban forest in the world . The local flora and fauna are protected by three conservation units and the Estação Biológica Fiocruz Mata Atlântica (EFMA), which comprises 462 hectares on the east side of the remnant. The local biodiversity is still little known compared to other Atlantic Forest remnants from the Rio de Janeiro State. Here, we provide results of a survey of medium- and large-sized terrestrial mammals from the EFMA. In addition, we analysed the distribution of this fauna along three habitat types defined as Peridomicile, Transitional Forest and Forest Core. Sampling was performed from 2017 to 2020 and comprised a camera-trap survey, interviews with residents and local workers and occasional records. Results include occurrence records for 16 autochthonous and one allochthonous ( Three Atlantic Forest remnants—Pedra Branca, Tijuca and Gericinó-Mendanha—are present in Rio de Janeiro City. The Pedra Branca Forest is the largest remnant of urban forest in the world and is located in a highly urbanised region of the central portion of the City. This remnant is partially connected to the Tijuca Forest by small forest fragments separated by highways and both are isolated from the Gericinó-Mendanha Forest by a matrix of urban densification. The flora and fauna of Pedra Branca are protected by the Parque Estadual da Pedra Branca , Parque Natural Municipal da Prainha, Reserva Biológica de Guaratiba and the Estação Biológica Fiocruz Mata Atlântica . Most of the territory is preserved by the PEPB, which comprises areas above 100 m a.s.l. . The EFMA is on the east side of the remnant, in an area under high human pressure, whose biological diversity, including mammals, is still poorly known compared to other localities in the Municipality and in the State of Rio de Janeiro—for example, Tijuca Forest  and SerrThe EFMA is adjacent to six communities with high social vulnerability and precarious sanitation conditions. These communities extend through the forest edge, putting domestic and wild animals, insect vectors and humans in potential contact, which constitutes a favourable environment for the circulation of zoonotic and non-zoonotic pathogens . From thStudies with mammals in the Pedra Branca Forest that used systematised sampling were only conducted for the small-sized species, including bats, rodents and marsupials . Thus, tIndividualised records of medium- and large-sized mammals from Fiocruz Atlantic Forest Biological Station, Rio de Janeiro, south-eastern Brazil, registered by camera trap, are available in Suppl. material 22°56'25" S, 43°24'18" W, Fig. The study was carried out at the Estação Biológica Fiocruz Mata Atlântica  Peridomicile, which consists of areas up to 100 m adjacent to the communities (ca. 30–35 m a.s.l.) and is characterised by the presence of backyards and orchards, with vegetation dominated by exotic species; (ii) Transitional Forest, which extends from the end of the peridomicile area to 100 m.a.s.l., with a prevalence of native plants, but with dense understorey and low canopy; and (iii) Forest Core, including all areas above 100 m a.s.l. and comprising preserved areas, without human constructions, with little human activities, more open understorey, high canopy and great presence of epiphytic plants, streams and rock formations on a sloping topography.Didelphis, Sylvilagus). The nomenclature used for xenarthrans and marsupials followed different authors in The species survey was conducted using three different methods: (i) sampling with camera-traps; (ii) interviews with residents who live around the EFMA; and (iii) occasional records made directly by researchers during field activities. Only mammals whose species-level identification can be performed, based on external morphology, were considered in the results. This procedure allowed the inclusion of all mammals with a body weight of > 1.0 kg , as wellFor the camera trap survey, Trophy Cam trail cameras  were distributed at 19 points along the areas defined as peridomicile, transitional forest and forest core  and the Red Book of Threatened Brazilian Fauna . We alsoCallithrix sp.) wild mammals, which are organised into 14 families and seven orders  and allochthonous . Amongst them, the following six were included in our list: B.variegatus, Leontopithecusrosalia, S.nigritus and T.tetradactyla, which were confirmed by direct observation; and C.tatouay and E.sexcinctus, whose occurrence is confirmed for Tijuca Forest—an Atlantic Forest remnant geographically close to EFMA. Although the occurrence of D.tajacu has been confirmed for the Mendanha Forest—another Atlantic Forest remnant geographically close to EFMA—we chose not to include it in our list due to the rarity of the species in the Municipality of Rio de Janeiro. Thus, the records of Eirabarbara, Galictiscuja, Dicotylestajacu and Dasypusseptemcinctus obtained from interviews were considered dubious. Eight species were recorded by direct observation, none exclusively.The sampling effort with camera-traps provided 1,189 records of 12 species of wild mammals and domestic dogs and cats. Eighteen species were recorded by interviews, of which nine were not recorded by camera traps , followed by the forest core  and transitional forest , followed by Cuniculuspaca , Canislupusfamiliaris  and Dasyproctaleporina , Didelphisaurita  and Canislupusfamiliaris ; in the transitional forest, were Didelphisaurita , Dasyproctaleporina  and Canislupusfamiliaris ; while in the forest core, the predominant species were Cuniculuspaca , Dasyproctaleporina  and Didelphisaurita . The rarefaction curve (Mao Tao) of the accumulated richness by the sampling days reached its asymptote with 12 species recorded between 100 and 150 sampling days  as independent populations, we did not find significant differences between the averages of camera-day records for these areas  and differed significantly in relation to the similarity of the records  and domestic cats  influenced species composition, with Nasuanasua, Dasyproctaleporina and Didelphisaurita less frequently registered in the points where domestic dogs and cats were most frequent. Additionally, records of domestic animals were important to differentiate Peridomicile from Transitional Forest and Forest Core . Peridomicile records clearly differentiate this area from the other two  as all sample points defined as Peridomicile were grouped into a single cluster Fig. . The othNasuanasua, Didelphisaurita and Cuniculuspaca. Some species, registered in the Tijuca Forest using camera traps, such as Cabassoustatouay and Sapajusnigritus, were not recorded by this method in the EFMA, but were included in the list, based on the results of interviews (Cabassoustatouay and Sapajusnigritus) and subsequent observation (Sapajusnigritus). Recently, Pumaconcolor on the west side of Pedra Branca Forest and surroundings. Despite the rarity of the species in the metropolitan region of Rio de Janeiro, we do not rule out the possibility of its occurrence within the limits of the EFMA, considering its connectivity with the rest of the remnant.About 60 spp. of mammals from different orders are known to occur in the region of the Pedra Branca Forest . HoweverDespite differences in habitat structure and composition amongst the Peridomicile area, Transitional Forest and Forest Core, differences were not observed in the abundance of medium and large mammals amongst these areas in the EFMA. The survey focused mainly on the use of camera traps because they favour records of species that are difficult to detect through active search and because the method requires less effort when compared to active search or capture . SurveysPumayagouaroundi, Pumaconcolor, Dicotylestajacu and Tayassupecari , is also a threat due to possible niche overlap  and Parque Nacional Iguazú (Argentina) where this species is commonly observed near areas with high human activity (Domestic dogs and cats exert different types of pressure on local biodiversity. Amongst the 17 wild species recorded in the EFMA, there are predation records by dogs for eight species, competition records for six and pathogen transmission reports for two . In the tic dogs . Our resre feral . The sha overlap . Domesti overlap . Our resturbance . Our res species . High fr species , potentiactivity . Thus, dprimates, it is also worth mentioning the record of the golden-lion-tamarin, Leontopithecusrosalia, in the EFMA and adjacent areas. One individual of this species was recorded by direct observation in 2017, living with a group of Callithrix. Subsequently, the species was also reported by residents and Fiocruz employees, who reported the presence of more than one individual, with at least one female and a juvenile. We have records of at least three individuals that co-exist with Callithrix in the surroundings of EFMA. The species is endemic to the southeast Atlantic Forest, originally occurring in coastal lowland forests of the States of Rio de Janeiro and southern Espírito Santo (In relation to to Santo . Apparento Santo . Recentlto Santo . The oriSporothrix spp., which causes sporotrichosis, a zoonotic disease that mainly affects cats, but can also affect humans (Peridomicile is a distinct area inside EFMA’s territory concerning medium- large-sized mammal communities, probably by the effects of the high level of anthropogenic disturbances. Habitat loss, introduction of exotic species and poaching are the main threats to mammals in the Pedra Branca Forest . These pt humans . RegardiDB57CE05-0072-5167-BCF0-134EC6AAB36210.3897/BDJ.10.e86756.suppl1Supplementary material 1Individualised records of mammals from Fiocruz Atlantic ForestData typeOccurrence recordsFile: oo_717025.xlsxhttps://binary.pensoft.net/file/717025Iuri Veríssimo, Beatriz Maria da Silva Jorge7D6553EE-2139-596B-BF9A-2C317F7D4F1D10.3897/BDJ.10.e86756.suppl2Supplementary material 2SIMPER analysis resultsData typeaverage between-group Bray-Curtis dissimilarityBrief descriptionSIMPER analysis results: Contribution of each species to overall dissimilarities amongst sampling areas.File: oo_711742.xlsxhttps://binary.pensoft.net/file/711742Cecília Andreazzi


Diabetic cardiomyopathy, secondary to diabetes, is the main cause of death in patients with diabetes. In China, traditional Chinese medicine has achieved good performance in treating diabetic cardiomyopathy. However, to date, no systematic review or meta-analysis has been published on the treatment of diabetic cardiomyopathy by traditional Chinese medicine.This study strictly followed the preferred guidelines for systematic review. Two researchers searched seven databases: EMbase, PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journal Database, and WANFANG Database. The retrieval time limit ranged from the establishment of the database to August 2022. All clinical randomized controlled trials that met the inclusion and exclusion criteria were included in this study. Statistical analysis was performed using RevMan 5.3.This study analyzed the clinical efficacy and safety of traditional Chinese medicine in the treatment of diabetic cardiomyopathy.The results of this study provide evidence-based medical evidence for the clinical use of traditional Chinese medicine in the treatment of diabetic heart disease in the future. The onset of DC is insidious, and only manifests as molecular-level damage to myocardial cells at the early stage, without obvious clinical manifestations. In the middle and late stages of the disease, DC can manifest as continuous aggravation of myocardial cell damage, extensive necrosis of small myocardial cells, and myocardial fibrosis, eventually leading to irreversible myocardial structural remodeling and cardiac function decline. The main clinical manifestations include angina pectoris, arrhythmia, cardiogenic shock, and heart failure.,10Diabetic cardiomyopathy (DC) is a heart disease with abnormal myocardial structure and function caused by diabetes in the absence of cardiac risk factors such as hypertension, coronary artery disease, and heart valve disease. accounting for 10.5% of the global population. It is proved that 19% to 26% of DM patients will develop heart failure, and 50% to 80% of DM patients will die from cardiovascular complications. Current treatment measures for DC are relatively limited, and no antidiabetic drugs except sodium glucose cotransporter 2 inhibitors have obvious cardiovascular benefits. Intensive hypoglycemia cannot effectively prevent the occurrence of cardiovascular events in DM patients but increases the risk of heart failure. In addition, effective treatment measures for DC cardiotoxicity have not been established, and there are no specific drug recommendations in the guidelines. The search for effective therapeutic targets for DC remains an urgent issue. In recent years, traditional Chinese medicine compounds and proprietary Chinese medicines have shown advantages in the treatment of DC because of their multichannel, multitarget, and slight side effects. A large amount evidence suggests that traditional Chinese medicine may be a potential drug for the treatment of DC.Epidemiological studies showed that by 2021, diabetic patients in the world reached 537 million,Randomized controlled trials published in journals were selected for this study. The aim of this study was to conduct a high-quality systematic evaluation of the clinical efficacy and safety of traditional Chinese medicine combined with Western medicine in the treatment of DC in order to provide more credible evidence-based medical evidence for the clinical application of traditional Chinese medicine in the treatment of DC.https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022352653). The protocol was carried out strictly in accordance with the preferred guidelines for systematic reviews. All data in this study were derived from published studies and therefore do not require ethical approval.The protocol was registered with PROSPERO , while the experimental group was given traditional Chinese medicine  on the basis of the control group.The primary outcome is clinical effectiveness rate.Other outcomes included left ventricular ejection fraction, the ratio of peak early diastolic blood flow velocity to peak late diastolic blood flow velocity (E/A), fasting blood glucose, 2h postprandial blood glucose, glycosylated hemoglobin, total cholesterol, triglyceride, low-density lipoprotein cholesterol, and incidence of adverse events.Duplicate publications. Incomplete or incorrect experimental data. The outcome observation indicators formulated in this study were extracted. Intervention measures did not meet these requirements.Seven databases, including EMbase, PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journal Database, and WANFANG Database, were searched using a computer. The retrieval time limit was set from the establishment of the database to October 2022.Search terms include: “traditional Chinese medicine,” “Chinese herbal medicine,” “prescription,” “soup,” “powder,” “drink,” “injection,” “capsule,” “pill,” “granule,” “diabetic cardiomyopathy,” and “DC”.A detailed example of the PubMed search strategy is shown in Table Two independent researchers (HS and HY) searched and filtered the literature. By reading the title, abstract, and full text, combined with the inclusion and exclusion criteria, the literature that could be included in this meta-analysis will be determined, and the inclusion results will be cross-checked. If there is any disagreement, a third researcher (LHM) will assist with the judgment. The selection process for the studies is shown in the flowchart Fig. .A data extraction table was designed using Microsoft Excel after filtering the data. The data were extracted by two researchers (HS and HY), and then the data characteristics of the final included literature were sorted out, mainly including: study characteristics , characteristics of the research subjects , clinical trial methods , clinical trial methods , and outcome observation indicators . If the information is incomplete, the original author of the article will be contacted by email or phone. Disagreements were resolved through consultation with a third researcher.If data were missing from the included studies, we contacted the corresponding authors for missing data and additional information. If the corresponding author does not reply after one month, we will consider deleting the data, or analyzing the available information and perform a sensitivity analysis to reduce the potential impact of the data on the results of this study.Cochrane collaboration’s tool will be utilized for assessing risk of bias provided by the Cochrane Handbook for Systematic Reviews of Interventions to assess the risk of bias in the included literature; the literature will be rated as High risk of bias, Unclear risk of bias, Low risk of bias. The assessment included six domain-based evaluations, and the details are listed in Table Statistical processing was performed using Review Manager software (version 5.3), and the results are displayed as a forest plot.P < .05 was considered statistically significant.The count data were expressed as odds ratios, and the measurement data were expressed as weighted mean differences. All effect sizes were expressed with 95% confidence intervals, and I2 test was used for statistical heterogeneity tests. If P ≥ .1, I2 ≤ 50%, it indicated that the heterogeneity of each study was small, and a fixed effect model was used for analysis; if P < .1, I2 > 50%, indicating that the heterogeneity was large, and a random effect model was selected.When there is large heterogeneity, subgroup analysis  can be used to analyze the source of heterogeneity.Sensitivity analyses will be performed if low-quality studies are included. In addition, sensitivity analysis was performed when there was large heterogeneity between the studies.A funnel plot was used to assess the presence of reporting bias. Breviscapine can interfere with the Nrf2 signaling pathway to improve the cardiac function of the DC mouse model; Andrographis paniculata Ester protects the DC myocardium by down-regulating the expression of signaling pathways such as IL-6 and NF-κB; bakuchiol can inhibit cardiomyocyte fibrosis. A large number of clinical trials of traditional Chinese medicine in the treatment of DC have been carried out, and the effectiveness of traditional Chinese medicine in the treatment of DC has been confirmed. However, no high-quality systematic reviews and meta-analyses related to DC have been published, and their efficacy and safety have not been widely recognized. This study aimed to comprehensively summarize the clinical evidence of various traditional Chinese medicines in the treatment of DC, to explore their clinical efficacy and safety, and to explore the efficacy of traditional Chinese medicine formulations  in the treatment of DC through subgroup analysis. This study provides high-quality evidence-based medical evidence for clinical diagnosis and treatment to help clinicians choose the best treatment plan.DC is a major adverse factor that affects the prognosis and survival of patients with diabetes. Owing to the complex pathogenesis and non-obvious early stage symptoms, the diagnosis and treatment of DC have brought great difficulties. In recent years, with the extensive development of basic research on Chinese herbal medicine, the mechanism of action of Chinese medicine in DC treatment has been scientifically confirmed.Conceptualization: Shuo Han.Data curation: Shuo Han, Yuan Hou, Huaman Liu.Funding acquisition: Huaman Liu, Quanlin Zhao.Methodology: Shuo Han, Yuan Hou.Software: Shuo Han, Yuan Hou.Supervision: Huaman Liu, Quanlin Zhao.Writing – original draft: Shuo Han.


This study aims to investigate the indirect effect of impulsiveness on suicidal ideation through depression and the moderating effect of impulsiveness on the indirect effect in an integrated path model.Self-rating depression scale (SDS), Barratt impulsiveness scale-11th version (BIS-11), and self-rating idea of suicide scale (SIOSS) were applied. A moderated mediation path model was established including impulsiveness, depression, and suicidal ideation as observed variables.The main results revealed that the moderated mediation path model fit well in describing the relationships among impulsiveness, depression, and suicidal ideation. The indirect effect of impulsiveness mediated by depression and the moderating effect of impulsiveness on suicidal ideation was significant. Multiple comparisons showed that the indirect effects under different conditions of impulsiveness had statistical differences. The higher the impulsiveness was, the stronger the predictive effect of depression on suicidal ideation was.The present study confirms that people who have impulsive traits are riskier to generate suicidal thoughts because they are more likely to suffer from depression and that people who are depressive have even higher risk to develop suicidal thoughts when they simultaneously have impulsive traits. In clinical and health care work, when considering depression to prevent suicidal ideation, impulsiveness needs to be monitored throughout the process of premorbid and onset stages of depression. According to the newest worldwide statistics , about 9As described in the diathesis-stress-model , vulneraIn some studies, impulsiveness and depression are two independent variables related to suicidal ideation –12. AnotThe integrated motivational-volitional model holds that impulsiveness is an interacting variable with suicidal ideation in predicting suicide behavior, while does not mention the effect of impulsiveness on suicidal ideation nor its interaction with any psychopaths . One stuState impulsiveness is a process of fast decision or behavior without thinking . HoweverCombining these two hypotheses, we construct a moderated mediation path model (MODMEDPM). The whole hypothesis of this study is that impulsiveness indirectly affects suicidal ideation through depression and simultaneously moderates the indirect effect. To be more reliable, we take the simple moderation path model (SMODPM) as the alternative model for comparison. The conceptual diagrams of MODMEDPM and SMODPM are shown in We applied cluster sampling method to select a cohort who was healthy in mentality. To control the confounding effects, we only recruited two grades of students, including 196 freshman (40.8%) and 284 sophomore (59.2%). Because the junior, senior and interns studied in different hospitals, who were faced with mixed stressors which could be confounding variables. The psychological tests were conducted within one month. All the 480 participants were examined. The cohort included 245 females (51.0%) and 235 males (49.0%) aged 16–21 (18.66 ± 0.80). Other demographic characteristics, including grade, residence, only child status, and family structure, as well as descriptive statistics of variables were shown in Suicidal ideation was assessed by the twenty-six-item Self-rating idea of suicide scale (SIOSS). This scale was developed in Chinese by Xia . The parThe Barratt impulsiveness scale (SIOSS) consists of 30 items. It was originally developed by Ernest S. Barratt in 1959 . The 11tThe Self-rating depression scale (SDS) was initially developed by William W. K. Zung in 1965 for evaluating depression in patients with depressive disorder . The scaThe internal consistency reliability coefficients and the correlation coefficients of the variables were calculated in SPSS 20.0 . We alsoFirstly, we constructed a baseline model, which was a saturated model with all variables  linked by paths , Bayesian information criterion (BIC), comparative fit index (CFI), Tucker & Lewis index (TLI) and root mean square error of approximation (RMSEA) were used to compare the model fits. The level of significant tests for the paths was set to 0.05. The mediating effect was examined with the bootstrap method with a sampling size of 5,000. The scores of the three variables, including impulsiveness, depression, and suicidal ideation, were mean centered before modeling.Z = 2.770, p < 0.001), we performed correlation matrix with spearman coefficients. The results showed that all the three variables were correlated with each other significantly, as shown in r = 0.726, p < 0.001), as well as between impulsiveness and depression . From the perspective of psychometrics, there are several items as observed indicators of the three variables presenting similar meanings, which may result in strong correlations of depression with impulsiveness and suicidal ideation. Considering the possible serious common method biases, we conducted a test and got the first common factor's explained variation as 24.31% , and the indirect effect of impulsiveness on suicidal ideation was significant . The indirect effect here could be explained as mediating effect because all the significant coefficients were positive.As shown in moderation =0.115, SE = 0.027, 95%CI = ]. However, this coefficient really represented the moderating effect on the path from depression to suicidal ideation. To test the moderating effect of impulsiveness on the indirect effect from impulsiveness to suicidal ideation, the conditional indirect effect analysis  was conducted. Firstly, impulsiveness was divided into three conditions: low impulsiveness (mean-1SD), medium impulsiveness (mean), and high impulsiveness (mean + 1SD). Secondly, we calculated the simple slopes, which represented the moderated mediating effects, under the three conditions, respectively. Thirdly, we compared the three slopes to define whether they were statistically different. As these were multiple comparisons, the significant level was set to be 0.05/3 = 0.017. The results showed that the slope under the condition of high impulsiveness was higher than that under the condition of medium and low impulsiveness , and the slope under the condition of medium impulsiveness was higher than that under the condition of low impulsiveness .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.