Moringa oleifera has been used for centuries due to its medicinal properties and health benefits. The plant has antifungal, anti-viral, and anti-inflammatory properties. We aimed to evaluate the effect of consumption of Moringa leaves, along with a regular diet on serum hemoglobin and retinol and underweight status among rural Bangladeshi adolescent girls.n = 113) received a meal comprising rice, concentrated dal, and fried potato with Moringa pakora (oil-fried snack); the control group (at a different school in an adjacent area with similar population demographics) received calorie-matched meal without Moringa pakora for 6 months. We used generalized liner regression (GLM) analysis, to explore the effect of the intervention among the groups between baseline and endline.This school-based quasi-experimental study involved 226 adolescent girls (12–14 years-old). Intervention group (P = 0.010) and serum retinol . No significant changes in weight was observed between groups.Mean age of the intervention and control groups were 12.7 ± 0.7 and 13.3 ± 0.8 years, respectively. After adjusting for maternal education, absenteeism, asset index, BMI-for-age Z-score, GLM regression showed significant positive changes in hemoglobin (intervention vs. control: coef = 0.41, Consumption of Moringa leaves has the potential to improving hemoglobin and serum retinol level and should be encouraged as regular diet. Adolescence, a unique period of human growth linking childhood and adulthood, includes 10–19 year-olds and is further divided into early adolescence (10–14-years-old) and late adolescence (15–19-years-old) . AdolescBangladeshi adolescents aged 10–19-years-old account for over one-fifth of the country's total population, including 14.4 million girls , 7. Two Moringa oleifera leaves have been found to contain the majority of essential nutrients required to maintain good health  on the micronutrient status of adolescent girls in rural Bangladesh. To implement the study in a school-based setting, random assignment of students was not possible as it would be unethical to include some children from one class and not include other children.The study was conducted in Muktarpur union  of Kaliganj sub-district, a semi-urban area located near to Dhaka, the capital of Bangladesh.We listed the schools in the region, consulted with the headmasters and school committee members, visited the facilities, and obtained the student's list. Of the six high schools in Muktarpur Union, three were excluded as only limited numbers of adolescent girls attended there. We discussed the purpose and objectives of the study with the local stakeholders and chairman. After getting their approval, we randomly selected one school for the intervention and another school as a control group.Our intervention was focused on the early adolescent period, when the rate of human growth is the highest outside early infancy. In Bangladesh, children in our target age group of 12–14 years usually study at class VI-VIII. After the selection of participating schools, list of female students in these classes were obtained from the schools. Age of the students was verified through birth certificate/immunization cards (if available) or admission information from the school archives. All female students in classes VI-VIII were screened. A total of 180 girls from intervention schools and 156 girls from control schools was screened and 226 adolescent girls (113 in each schools) completed the trial and returned follow-up questionnaires . Before Unmarried adolescent girls aged 12–14-years-old who attended the selected high schools were eligible for the study. Participants were excluded if they were taking any other nutritional supplements , as this may affect the levels of hemoglobin and other micronutrients that we intended to measure. Adolescent girls with documented medical records of chronic disease were also excluded. However, we provided the meal to every girl due to ethical reason but collected data from only the recruited participants.We assumed a mean hemoglobin level of 12.0 g/dL in the control group , mean heThe intervention package included (1) a school-based mid-morning meal containing Moringa leaves (150 g) cooked traditionally as pakora (oil-fried snack), and (2) behavior change communication (BCC) on nutrition and dietary habits, personal health, and hygiene issues that magnify the risk of malnutrition for 6 months.aluvaji), once daily for 5 days/week. Each tiffin box was numbered so that leftover food could be measured daily for each participant. A standard food record form was used to measure food compliance. The tiffin meals provided to both arms supplied 411 kilocalories.Each adolescent girl from the intervention group received Moringa leaves cooked as pakora along with 30 g rice and 25 g concentrated dal, once daily, for 5 days/week at tiffin time. The control group received 30 g rice, 25 g concentrated dal and 25 g fried potato (sajna (Moringa) leaves were mixed with mashed lentils, and then onion, chili and salt were added and mixed to make a paste. A portion of ~50 g paste was fried as pakora. Each student received 3 pakora/ day. Three pakoras provided 282 kilocalories/person/day.We recruited two local cooks who were responsible for preparing the meals daily under direct supervision of the field staff. Two field staff monitored and measured the cooking procedure and placed the meals in the food boxes using measuring cups to measure 30 g of rice and 25 g of concentrated dhal. To prepare Moringa pakora, 150 g granules of fresh Two locally recruited health workers conducted bi-monthly counseling on nutrition and dietary habits, personal health, and menstrual hygiene, targeting the female adolescents from both arms in small groups after the school day had ended. The duration of each session was usually 30–40 min.A team of field staff was responsible for implementing the study under the guidance of the Investigator(s). Before starting the field activities, 5 days of intensive training was provided to the field staff. The emphasis of the training was interview techniques and understanding the questionnaire. Field staff also received training on anthropometric measurements following the standard WHO guidelines .Before the survey, the questionnaire was thoroughly discussed, extensive field-testing was conducted, and necessary modifications were made. The structured questionnaire was used to collect information on socioeconomic status and demographics, health and morbidity, food consumption patterns, and other relevant information.Information on ethnicity, religion, level of education of household head, occupation of household head, number of family members, ownership of the house, number of dwelling rooms, household construction materials, toilet facilities, sources of drinking water, household assets, land ownership, and household monthly expenditure were collected as key indicators of socioeconomic status.Data on food items were collected using an adapted version of FANTA's Minimum Dietary Diversity for Women. The categories are: (1) grains, white roots, tubers, and plantains; (2) pulses ; (3) nuts and seeds; (4) dairy; (5) meat, poultry, and fish; (6) eggs; (7) oils and fats; (8) fruits; (9) vegetables; and (10) condiments and seasonings, etc. .Consumption of the provided mid-morning meals was measured daily using a standard food record form to measure compliance to the food.Trained field staff was collected anthropometric measurements (weight and height) monthly using established methods  and recoTrained field staff asked all participants standard questions about recent morbidity within the previous 15 days using pre-coded questionnaires designed for recording specific morbidity symptoms. The morbidity recall period was 2 weeks. Urinary tract infections and symptoms of menstrual problems and experiences regarding school absenteeism was also collected monthly.Anemia assessment was done by considering the hemoglobin concentration of capillary blood using HemoCue 301 device . Trained research staff was conducted the assessments. After asepsis by chlorhexidine gluconate at 0.5%, the disposable lancet on the fingertip (middle or ring or index) made a puncture. The first drop of blood was discarded. The second drop made to form by gentle pressure. Once the sample is formed, the micro cuvette was dipped into it to fill it up with the blood sample by capillary action.Peripheral blood samples were collected from all participants in the intervention and control groups at baseline, 3 months and endline. The blood samples were labeled using bar-coded identification labels specifically created for this study that correspond to the subject's identification number. Thus, the laboratory had easily identified which particular cluster scan been tested in a batch and thus minimize repeated freeze/thaw cycles. A sample record/handover form, including the name of the participant, ID number, sample ID number and type of analysis, was completed. Samples were transported to the nutritional biochemistry laboratory in Dhaka in a temperature-controlled cool box and stored in a −70°C freezer at the laboratory until blood parameters were quantified by high-performance liquid chromatography (HPLC).Trained staff were responsible for delivering the food in the classrooms with the help of two locally recruited field staff. They went to the classroom during tiffin time, provided the meals to the students, and informed the students not to throw food out as the leftover food was measured. Each tiffin box had an identifier number for each participant to measure the remaining food. Every class also had male students, and we also offered them the food, if they wanted it. However, their intake was not measured or monitored. Total intervention period was 6 months.This study (PR-19060) was approved by the Research Review Committee and Ethical Review Committee, the two compulsory components of the institutional review board of the International Center for Diarrhoeal Disease Research, Bangladesh . Written informed consent was obtained from all study participants (>18-years-old) and/or assent (<18-years-old) from their parents/guardians prior to enrolment.The primary outcomes were the differences in the mean changes in the adolescent girls' hemoglobin and retinol levels from baseline to endline between the intervention group and control group. The secondary outcome was the difference in weight gain between the intervention group and the control group.A senior research officer was responsible for regular observations at the schools and checking the data for validity and completeness. The staff independently repeated the data collection for 3–5% of the study participants on the same day using a field-tested format.After completion of data collection, data were entered into Microsoft (MS) Access software. Maximum validation rules were set in the data system to prevent errors during data entry. After completing the entry, data were transferred to Stata  software.Statistical plots such as histograms, scatter plots were used for data visualization. Descriptive statistics were used to compare frequencies and proportions for categorical variables, and means and standard deviations for symmetric quantitative variables.t-test and the chi-square test to compare means and explore the associations among categorical variables. Coefficients were generated by generalized linear regression modeling (GLM), in which a dependent variable is regressed on the set of hemoglobin and retinol levels. Effect of intervention was adjusted for variables those were associated with the outcome during univariate regression such as maternal age, sex of household head, maternal education, BMI for age, wealth index and absentism of school. P-values < 0.05 were considered significant for all tests.We used the Student's The mean age of the adolescent girls in the intervention and control groups was 12.7 and 13.3 years, respectively; this difference was not statistically significant. The mean weight and height of the girls were similar in both groups. The mean hemoglobin level was 12.0 and 11.8 g/dL for the intervention and control groups, respectively. Serum retinol was similar in both groups (1.3 μmol/l).At baseline, the girls in the intervention group (148.85 cm) were marginally shorter than the girls in control group (149.70 cm). However, at the end of the follow-up, the height of the girls in the intervention group had increased more than the height of the girls in the control group (153.43 vs. 152.87 cm). On average, participants in the intervention group became 0.56 cm taller than the girls in the control group, however, the association was not statistically significant.Z-score, GLM analysis showed a significant positive change in the hemoglobin level . A significant positive change in the retinol level was also observed between the intervention group compared to the control group . We did not observe any significant impact of the intervention on weight gain among the study participants.The primary outcomes were mean hemoglobin and serum retinol levels, as presented in This study aimed to assess the effect of consumption of Moringa leaves  on the nutritional status of adolescent girls in Bangladesh. To our best knowledge, this is the first study to assess the nutritional effects of Moringa in Bangladesh, which is widely available in the country and traditionally used to treat fever and diarrhea. However, there is limited scientific evidence to confirm the benefits of this potential plant-based food. Our school-based, quasi-experimental study demonstrates the beneficial effects of regular consumption of Moringa leaves on Bangladeshi female adolescents. Consumption of Moringa leaves as part of a daily nutritious snack, combined with nutrition BCC, significantly improved the average hemoglobin and retinol levels of the female adolescents aged 12–14 years.The measurement of average hemoglobin level from our study echoes with the result of school-going children from the last National Micronutrient Survey done in 2011–12. At baseline, average hemoglobin level was higher in the intervention group compared to the control group, though, the differences were not statistically significant. In our study, although both groups had an increment of the hemoglobin level at endline, the intervention group experienced a significant improvement. These results are in agreement with previous studies that showed consumption of Moringa leaves increased the mean hemoglobin level from 11.43 to 12.36 g/dL  and 10.4Moringa leaves have a total carotene content of 40,000 μg and beta carotene content of 19,000 μg/100g, thus having equivalent bioavailability as synthetic vitamin A  in each group, which enabled a fair statistical comparison. The Hemocue devices used to measure hemoglobin level were calibrated every day; the retinol samples were transported to the nutritional biochemistry laboratory at the icddr,b and analyzed in a blinded manner. Nevertheless, our work has some limitations. A limitation of the study was its quasi-experimental design, as it was not possible to mask the fieldworkers responsible for delivering the meals to the participants and recoding the data, or the participants to their group allocation.Our school-based intervention showed that addition of Moringa leaves to the diet significantly improved the hemoglobin and retinol levels, among adolescent girls in Bangladesh. Incorporating recipes with Moringa leaves in the daily diet may provide a simple preventive and maintenance strategy to ameliorate micronutrient deficiency during this critical period of female growth and development, in achieving better health outcomes.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This study (PR-19060) was approved by the Research Review Committee and Ethical Review Committee, the two compulsory components of the Institutional Review Board of the International Center for Diarrhoeal Disease Research, Bangladesh . Written informed consent was obtained from all study participants (>18-years-old) and/or assent (<18-years-old) from their parents/guardians prior to enrolment. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.MK and KIS conceptualized the study, drafted the original manuscript, and revised the final version of the manuscript. KIS contributed to drafting the manuscript and result interpretation. MK, KIS, GA, RSR, ABB, FDF, MAH, and TA had contributed to data analyses, interpretation, and write-up of the manuscript. All authors contributed to the article and approved the submitted version.This research study was funded by icddr,b's core donors and Swedish International development Cooperation Agency (Sida), Sweden, grant number GR:01455.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.


No treatments are approved for Becker muscular dystrophy (BMD). This study investigated the efficacy and safety of givinostat, a histone deacetylase pan-inhibitor, in adults with BMD.Males aged 18–65 years with a diagnosis of BMD confirmed by genetic testing were randomized 2:1 to 12 months treatment with givinostat or placebo. The primary objective was to demonstrate statistical superiority of givinostat over placebo for mean change from baseline in total fibrosis after 12 months. Secondary efficacy endpoints included other histological parameters, magnetic resonance imaging and spectroscopy (MRI and MRS) measures, and functional evaluations.p = 0.8282). Secondary histology parameters, MRS, and functional evaluations were consistent with the primary. MRI fat fraction in whole thigh and quadriceps did not change from baseline in the givinostat group, but values increased with placebo, with LSM givinostat–placebo differences at Month 12 of −1.35% (p = 0.0149) and −1.96% (p = 0.0022), respectively. Adverse events, most mild or moderate, were reported by 88.2% and 52.9% patients receiving givinostat and placebo.Of 51 patients enrolled, 44 completed treatment. At baseline, there was greater disease involvement in the placebo group than givinostat, based on total fibrosis (mean 30.8 vs. 22.8%) and functional endpoints. Mean total fibrosis did not change from baseline in either group, and the two groups did not differ at Month 12  BMD disease progression. Becker muscular dystrophy (BMD) is a heterogeneous muscle disease, with substantial variability in age of onset and clinical presentation . In the via S-nitrosylation of a cysteine residue , resulting in a reduced amount or truncated size of the dystrophin protein . Dystrop residue . This me residue . A poten residue .In this manuscript, we report the results of a study that investigated the efficacy and safety of givinostat, a HDAC pan-inhibitor, in adults with BMD.This was a Phase II, randomized, double-blind, placebo-controlled study that aimed to evaluate the effects of givinostat on micro- and macroscopic muscle morphology and function. The study was conducted in two centers: University of Milan, Italy, and Leiden University Medical Center, the Netherlands, with the University of Florida (ImagingDMD) serving as the central data management and processing center for magnetic resonance imaging (MRI) and spectroscopy (MRS). Following a four-week screening period, patients were randomized to receive givinostat or placebo for 12 months, attending study visits every 2 weeks for the first 2 months, then every 12 weeks for the remainder of the study.ClinicalTrials.gov (NCT03238235).Eligible patients were males aged 18–65 years, inclusive, with a clinical diagnosis of BMD confirmed by genetic testing (based on patient records), and who were able to walk between 200 and 450 m in the 6 min walk test (6MWT). If patients were receiving a systemic corticosteroid, angiotensin converting enzyme inhibitor, or α- or β-adrenergic receptor blocker they were expected to have no significant change in dose or regimen immediately prior to the start of study treatment. Among the reasons for exclusion were: Use of any pharmacologic treatment, other than corticosteroids, or surgery in the 3 months prior to study entry that might have an effect on muscle strength or function; symptomatic cardiomyopathy or heart failure (New York Heart Association Class III or IV) or left ventricular ejection fraction <50% at screening or with heart transplant; and contraindications to muscle biopsy or magnetic resonance scans. All patients provided written informed consent prior to any study-related procedure. Full inclusion and exclusion criteria are listed in the During the screening period and after 12 months, chemical shift encoded MRI and MRS of the right lower leg, thigh and gluteus maximus, and an open muscle biopsy of the brachial biceps were performed see . They thThe protocol was amended four times. The main changes in the first amendment were the addition of MRI evaluations of the lower leg and an increase in maximum age from 60 to 65 years. Amendment 2 resulted from a blinded evaluation of data from the first 21 patients, in which 11 patients required dose reduction due to thrombocytopenia, and four patients had high plasma triglyceride levels. The givinostat starting dose was therefore reduced . Patients, investigators, and site and sponsor staff were blinded to treatment assignment. Given platelet count reductions are observed after administration of givinostat, personnel who performed the various efficacy analyses were different from those who recorded the safety results.Patients were randomized 2:1 9/L that did not meet the stopping criteria, the dosage was reduced by 20% of the current dose.Givinostat (10 mg/mL) or placebo oral suspension were administered using a graduated dosing syringe as two daily doses (morning and evening) after a meal. The starting dose was selected according to body weight as shown in The primary objective was to demonstrate statistical superiority of givinostat over placebo in terms of the mean change from baseline in total fibrosis after 12 months of treatment. Secondary efficacy endpoints included change from baseline after 12 months of treatment in: other histological parameters ; MRI measures of muscle fat fraction, MRI CSA and contractile area in the gluteus maximus, thigh and lower leg muscles; MRS fat fraction of the vastus lateralis and soleus; MFM ; timed-function tests ; 6MWT; and muscle strength of the knee extension and elbow flexion measured by hand-held myometry. Additional details on the histology, MRI, MRS, and functional endpoints are in the t-test with alpha level of 5% and assuming a common standard deviation (SD) of 10% (based on blinded interim data from the first 20 patients). Allowing for 5% of patients with unevaluable biopsies, the total number of patients to be randomized was 51 .It was calculated that 48 patients with evaluable baseline biopsies , would provide 80% power to test the null hypothesis of no treatment effect on total fibrosis vs. the alternative hypothesis that the treatment effect was ≥9%, using a two-sided Since the blinded data at the time of the sample size re-estimation indicated non-normal distribution of the primary efficacy variable, mean fibrosis at baseline and Month 12 were log transformed prior to analysis, and then back-transformed. An analysis of covariance (ANCOVA) model was fitted to the data with the difference between log Month 12 and log baseline values as the dependent variable, log baseline value as covariate, and treatment and concomitant steroid use at baseline as independent class variables, and the results were presented as least squares means (LSM). The secondary histology, MRI and MRS endpoints were analyzed using a similar method to the primary objective, although without log transformation. The functional endpoint objectives were analyzed using a mixed model for repeated measures, with fixed effect class terms included for treatment, visit, visit by treatment interaction, and concomitant steroid use at baseline, and the baseline value included as a covariate. An unstructured covariance matrix was used to model the within-patient error.The intent-to-treat (ITT) set was used for all efficacy analyses, and comprised all patients randomized to treatment and who received at least one dose of study medication. The safety set comprised all patients who received at least one dose of study medication, and was used for all safety analyses.The study was conducted between January 2018 and March 2021. Of 70 patients screened, 51 were enrolled, 44 of whom completed study treatment . The ITTFor the primary endpoint, total fibrosis, the mean value at baseline was higher in the placebo group than the givinostat group, suggesting a greater degree of disease involvement . Over thp = 0.0149) and −1.96% (p = 0.0022), respectively  from baseline at Month 12 in the placebo group for fat fraction in both the whole thigh and quadriceps, with resultant LSM differences between the two groups of −1.35% , and approached a difference in the quadriceps assessment . There were no differences between groups for the MRI CSA endpoints  from baseline in the placebo group, but no change with givinostat . The twondpoints , or for ndpoints .As with the histology endpoints, baseline functional endpoint values were consistent with greater disease involvement in the placebo group, with lower MFM score, longer times required to complete the timed-function tests, a shorter distance covered in the 6MWT, and lower values in the hand-held myometry assessments . ChangesA total of 17 patients commenced the study on high-dose givinostat, 17 on low-dose givinostat, and 17 on placebo. Subsequently, 26 patients (82.4%) in the givinostat group had their dose reduced due to an adverse event (either decreased platelet count or hypertriglyceridemia). Three patients (8.8%) in the givinostat group and one patient (5.9%) in the placebo group permanently discontinued treatment due to adverse events, one as a result of decreased platelet count (in the givinostat group) and three for hypertriglyceridemia .All of the patients receiving high-dose givinostat experienced at least one adverse event, most commonly decreased platelet counts and diarrhea . HoweverThe mean platelet count was lower at baseline in the givinostat group than the placebo group . There wThis was the first clinical trial to evaluate the effects of givinostat in BMD. The study aimed to evaluate givinostat effects on muscle morphology (by histology and magnetic resonance), and on muscle function and strength, as well as evaluating tolerability. The primary objective was to demonstrate superiority of givinostat over placebo in terms of the mean change from baseline in total fibrosis after 12 months of treatment. This was not met. This was also true for the other histological parameters. In contrast, whole thigh and quadriceps MRI measures showed muscle deterioration in the placebo group (increased fat replacement and decline in contractile area), but no change from baseline over the 12 month follow-up period in the givinostat group. This resulted in differences between the two groups at Month 12, providing a potential signal that the use of givinostat was associated with stabilization of disease progression.The contrasting study results, with no difference between the two groups in the histological and functional assessments but differences in the whole thigh and quadriceps MRI assessments may, of course, indicate that givinostat is not effective in this BMD population. However, givinostat has previously demonstrated efficacy in mouse DMD models , 16, andp = 0.01]  and high inter-patient variability in the various outcome measures , suggests caution in the interpretation of the overall findings. In addition, it is clear that total fibrosis is not the best primary endpoint for a study in BMD, given the minimal changes over the follow-up period , and other measures such as MRI-based quantification of fat fraction may be better suited. Furthermore, a large number of patients did not meet the eligibility criteria , mainly Overall, the efficacy results from the current study highlight the challenges of conducting a study in BMD, a relatively slowly-progressing disorder where the main aim is to prevent (or at least delay) disease progression, rather than cure. Although the study failed to achieve the primary endpoint, there was a potential signal from the MRI assessments that suggests givinostat could prevent (or at least slow down) disease progression in BMD, slowing fat replacement in the whole thigh and quadriceps muscles. This study also provides additional support to the use of MRI as an assessment tool in future BMD studies.The raw data supporting the conclusions of this article are available on reasonable request from the sponsor, following submission of a valid research protocol to the corresponding author.The studies involving human participants were reviewed and approved by an Independent Ethics Committee for each institution. The patients/participants provided their written informed consent to participate in this study.GC, EN, KV, RW, and MR: conceptualization, methodology, investigation, writing—review and editing, and visualization. CC, HK, DV, FM, JB, NV, SN, and LA: methodology, investigation, writing—review and editing, and visualization. SC and PB: conceptualization, methodology, supervision, writing—review and editing, and visualization. All authors approved the submitted version of the manuscript.


Of them, six corresponding genes were new to CRC metastasis. In addition, a metastasis resister variant was also identified. Based on these eleven variants, we constructed a logistic regression model for rapid risk assessment of early metastasis, which was also deployed as an online server, AmetaRisk (http://www.bio-add.org/AmetaRisk). In summary, we made a valuable attempt in this study to exome-wide explore the genetic driving force to local invasion, which provides new insights into the mechanistic understanding of metastasis. Furthermore, the risk assessment model can assist in prioritizing therapeutic regimens in clinics and discovering new drug targets, and thus substantially increase the survival rate of CRC patients.Metastasis is the main fatal cause of colorectal cancer (CRC). Although enormous efforts have been made to date to identify biomarkers associated with metastasis, there is still a huge gap to translate these efforts into effective clinical applications due to the poor consistency of biomarkers in dealing with the genetic heterogeneity of CRCs. In this study, a small cohort of eight CRC patients was recruited, from whom we collected cancer, paracancer, and normal tissues simultaneously and performed whole-exome sequencing. Given the exomes, a novel statistical parameter LIP was introduced to quantitatively measure the local invasion power for every somatic and germline mutation, whereby we affirmed that the innate germline mutations instead of somatic mutations might serve as the major driving force in promoting local invasion. Furthermore,  Colorectal cancer (CRC) is one of the most frequent cancers worldwide and has the highest mortality after lung cancer , 2. The Accumulating lines of evidence indicate that genetic factors may play a crucial role in CRC metastasis . HoweverIn recent years, several prediction models were developed for tumor metastasis assessment. Some used conventional clinical pathological characteristics, such as age, race, gender, tumor site, and tumor size, to establish the Cox regression models  to assess metastasis and survival outcomes for CRC patients –20. SomeTumor metastasis is an invasive action of tumor cells, which refers to the process of tumor cells spread to other parts of the body. In principle, metastasis usually progresses in four steps: local invasion, intravasation into the blood circulation system, extravasation into the surrounding tissues, and colonization and proliferation in new locations . Local ivia mining multiple omics data derived from different CRC sources. Lastly, we developed a machine learning model for rapid assessment of early CRC metastasis.In this work, we attempted to mine driver genes/mutations in early CRC metastasis. For this purpose, we elaborately designed an experiment to profile genomic alternation landscapes of cancer, paracancer, and normal tissues simultaneously in a CRC cohort. Upon the genomic mutation profiles, a new statistical parameter was introduced to quantitatively evaluate the contribution of every mutation to local invasion. Subsequently, we identified metastasis driver mutations This study was approved by the Ethics Committee of the Xiamen Xianyue Hospital and was performed in accordance with the Helsinki Declaration. All patients provided written informed consent prior to inclusion in the study. A total of eight CRC inpatients from the Zhongshan Hospital, affiliated to Xiamen University, Fujian Province, China were recruited in this study. They were selected from more than 248 CRC inpatients on the basis of the following criteria: (1) the patients have no blood kinship by medical background review; (2) the patients were diagnosed with rectal differentiated adenocarcinoma of stage II or III; and (3) the patients received a similar chemotherapy regimen and the prognoses were benign. These eight patients were further divided into two groups: the NM group of four patients who had no metastasis till surgery excision, and the LM group of four patients who had local lymphatic metastasis but no distal metastasis. The medical details of the patients are briefly summarized in For every patient in the cohort, three tissue samples were collected from the tumor removal surgery under authorization in advance: the tumor sample was collected at the near edge of the tumor, and the paracancer and normal samples were taken 2 cm and 5 cm away from the tumor, respectively . The DNA concentration was measured by a Qubit Fluorometer and diluted to 50–300 ng/µl. For each sample, 3–5 µg of DNA was applied for quality control, and its integrity was checked by the agarose electrophoresis. The whole exome was captured using the MGIEasy Exome Library Prep Kit  and the library for sequencing was prepared according to the manufacturer’s instruction. The whole-exome sequencing (WES) was performed by the Beijing Genome Institute  using the BGISEQ-500 platform in a 100-base pair (bp) paired-end mode.Before variant calling, quality control was conducted to the sequencing raw data using Trimmomatic  . The cleFor every tumor and paracancer samples, the tissue purity and ploidy were estimated on the basis of genome-wide somatic mutation profiles with Sclust  , taking i if the driving potential outmatches the resisting potential, Mi is considered as the driver mutation to metastasis; otherwise, Mi is the resister mutation. To measure the summarized potential of Mi to local invasion, a novel parameter, namely, local invasion power (LIP), was introduced:Every mutation likely plays dilemmatic roles in metastasis, promotion, or resistance. For a gene mutation, MMi and Mi and where RMTi , VMPi and VMNi stand for the variant allele fraction (VAF) of variant Mi in tumor, paracancer, and normal tissues, respectively. They were determined by dividing reads of alternate allele Mi by total reads at this locus and further normalized by all reads count. LIP > 0 indicated that the variant Mi was prone to promoting invasion than resistance. A larger LIP suggested that the mutation had more power to drive local invasion.where VMoreover, we assume that the tumor invasion is the accumulated consequence of all mutations. Some mutations likely promote tumor cells invading into nearby tissue (paracancer tissue), while some intend to resist the invasion. If the overall promotion effects at the paracancer tissue overwhelm the resistance effects, local invasion is prone to progress; otherwise, invasion unlikely happens  at the selected allele in the metastasis group, respectively. Nm and Nn stand for the number of mutations and non-mutations at the selected allele in the non-metastasis group, respectively. As a result, a list of metastasis-associated variants with OR >5 was determined. (3) The genetic predisposition of metastasis-associated variants to patient survival was examined. For this, the gene expression level interfered by mutation was first determined according to the expression quantitative trait loci (eQTL) information derived from the Genotype-Tissue Expression (GTEx) (p <0.01) variants to either sigmoid or transverse colons were included in the analysis, which were 1,185,110 variants in the GTEx. Having the information of mutations on gene expression levels, we then performed survival analysis subject to high or low gene expression on the basis of 763 CRC patients (including 571 colon and 192 rectum patients) from The Cancer Genome Atlas (TCGA) using the R packages survival (v3.2-3) and survminer (v0.4.8) with default parameters. As a result, we screened out eleven effective variants that could change the host gene expressions and subsequently affect the survival of patients (p < 0.01). These eleven effective variants included ten potential metastasis driver variants that may reduce the survival rate of CRC patients and one resister variant on the opposite.where Mn (GTEx) . Only thTo aid risk assessment of early metastasis, we built a determinant classifier. The core component of classifier was a logistic regression model. The model was constructed on the basis of four exome datasets of this study and three independent CRC cohorts , covering a total 61 CRC patients. The datasets were split into a training set and a testing set in a combinational way Table 3.V, corresponding to the eleven metastasis-associated variants, in which carrying the mutation was defined as 1, otherwise 0.The model took the mutation profiles of eleven metastasis-associated driver variants identified in this study as the input, and output the estimated probability of metastatic risk. In model construction, the input genetic mutation profile was converted into a one-dimension 11-feature binary vector L was prepared for V ,which contained the average LIPs of the eleven metastasis-associated variants determined on the basis of the training dataset.Meanwhile, a weighted vector V and L (V·L) as the accumulated driving force of metastasis contributed by the eleven variants for the patient. For the metastasis issue (y = 1) . the probability of occurrence P (y = 1) can then be determined by the logistic regression:Accordingly, we calculated the dot product of iw is the regression coefficient for the variant and b is the intercept. The regression coefficient iw and intercept b were estimated using the Maximum Likelihood Estimation (MLE) with the glm function of the R package stats (v3.6.0).where The model performance was evaluated by the conventional parameters of accuracy, sensitivity, and specificity, which were calculated with the R function confusionMatrix from the package Caret (v6.0-86) as follows:P and N stand for the positives and the negatives, respectively. The values of TP (true positives), TN (true negatives), FN , and FP  were calculated on the basis of the confusion matrices of the classification model. The area under the receiver operating characteristic curve (AUC) was also determined with the R package pROC (v1.16.2). For evaluation of all models, the leave-one-out cross-validation (LOOCV) strategy was applied to attain unbiased estimation of training. For this purpose, the training dataset was divided 51-fold (corresponding to 51 patients), of which 50 were used for model construction and the remaining one was used for internal evaluation. The LOOCV process was repeated 51 times, and the average parameters were used to evaluate the model performance of the training set.where t-test, p = 7.97e-4). The average purity of tumors and paracancer tissues was 0.52 and 0.33, respectively  produced an average on-target coverage of about 197×, indicating that the sequencing was substantially deep enough for reliable variant calling. Using the matched normal samples as reference, we determined the purities of tumor and paracancer tissue for every patient based on the genome-wide somatic mutation profiles. On average, the purity of tumor samples was significantly higher than that of matched paracancer samples  and 8,275 indels (inserts and deletions). For every mutation, we calculated the LIP; meanwhile, we determined the summation of all mutation LIPs  for every cohort member. Regretfully, both the LIP distribution and sLIPs were unable to differentiate the lymphatic metastasis group (LM) from the non-metastasis group (NM) (p = 0.039) . In the end, we obtained ten potential driver variants to metastasis. These variants can enhance (six variants) or suppress (four variant) their parental gene expression, and all would consequently shorten the lifetime of half survivals for an average of 31.5 months  instead of the whole germline mutation profiles that would be much more costly in practice. The model performance was internally evaluated in a manner of LOOCV, which obtained an average result: accuracy = 0.788, specificity = 0.800, sensitivity = 0.769, and AUC = 0.839. Additional external evaluation also achieved a fairly good performance: accuracy = 0.766, specificity = 0.567, sensitivity = 0.767, and AUC = 0.709. These results affirm that the model is substantially effective for early metastatic assessment.http://www.bio-add.org/AmetaRisk. The AmetaRisk was built upon an architecture of Linux + Tomcat + JSP. To initiate the assessment, the user is required to check the status (yes or no) of eleven metastasis driver/resister variants detected in the tissue samples, which can be determined on tumor, paracancer tissue, or peripheral blood. Upon submission of variant status profile, the server will return a probability value of metastatic risk, ranging from 0 to 1.0 , a surrogate measure of the proportion of DNA molecules in the tissue specimen carrying the variant . The VAFHowever, using sLIP value directly to assess metastatic risk may not be a good solution; many mutations actually contributed little to metastasis . The trevia participation in “phospholipase C signaling”  with a similar experiment design were reported , 78. UnfIn summary, we made a valuable attempt in this study to explore the genetic basis underlying CRC metastasis. Our efforts will provide new insights into the mechanistic understanding of early metastasis, as a complement to current metastasis hypotheses such as “seed and soil”, “big-bang”, and “tumor self-seeding”. Moreover, we constructed a machine learning model for metastatic risk assessment at the early stage of local invasion. This model and its online tool, AmetaRisk, provide a rapid and economic way to assist in prioritizing a precise therapeutic regimen in advance and increasing the survival rate of CRC patients in clinics.https://ngdc.cncb.ac.cn/gvm/ (accession number: GVM000184).The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found at: The studies involving human participants were reviewed and approved by the Ethics Committee of Xiamen Xianyue Hospital. The patients/participants provided their written informed consent to participate in this study.Z-LJ and PY designed and supervised the study. PY, Z-XF, Z-YL, and Z-YZ collected the samples, performed the clinical diagnosis, and prepared the samples for sequencing. R-FD, YZ, and L-YW analyzed the data, and drafted and revised the manuscript. Z-LJ and PY commented on and revised the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the National Key Research & Developmental Program of China (2018YFC1003601).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 interestAll 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.


Material and Method. This retrospective study included 322 patients followed up in ICU with a diagnosis of COVID-19. A record was made of demographic data, laboratory values, clinical results, and mortality status. All the data of the patients were compared between high and low variations of the NUTRIC score and the mNUTRIC score.  The NUTRIC  score and the modified NUTRIC score are two scoring systems that show the nutritional risk status and severity of acute disease of patients. The only difference between them is the examination of interleukin-6 (IL-6) level. The aim of this study was to investigate whether or not the NUTRIC score is superior to the mNUTRIC score in the prediction of mortality of patients with COVID-19 followed up in the Intensive Care Unit (ICU). p = 0.0001 for all). The AUC values were 0.791 for high NUTRIC score and 0.786 for high mNUTRIC score (p = 0.0001 for both). No statistically significant difference was determined between the two scoring systems.  A high NUTRIC score was determined in 62 patients and a high mNUTRIC score in 86 patients. The need for invasive mechanical ventilation, the use of vasopressors in ICU, the development of acute kidney injury, and mortality rates were statistically significantly higher in the patients with high NUTRIC and high mNUTRIC scores than in those with low scores ( Although the NUTRIC score was seen to be superior to the mNUTRIC score, no statistically significant difference was determined. Therefore, when IL-6 cannot be examined, the mNUTRIC score can be considered safe and effective for the prediction of mortality in COVID-19 patients. On the same day, the first case of COVID-19 was recorded in Turkey [At the end of December 2019, a new coronavirus  was identified in a case series of pneumonia with rapid person-to-person infection in the city of Wuhan, Hubei Province, China [n Turkey . As thern Turkey .2) ≤93%, and a ratio of partial arterial oxygen pressure to fractioned oxygen saturation (pO2/FiO2) of <300, and critical disease is defined as respiratory failure, septic shock, and multiple organ dysfunction/failure [The virus is spread through aerosol droplets in COVID-19 infection and most patients can have a mild disease course with symptoms such as fever, listlessness, muscle and joint pains, loss of appetite, headache, nausea, vomiting, loss of taste and smell, and cough . In more/failure . These t/failure .There is still no appropriate method or clinical scoring system to show the severity of COVID-19 and predict disease course. To date, several scoring systems have been used to predict the severity of COVID-19 and show prognosis, including the Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Function Assessment (SOFA), Pneumonia Severity Index (PSI), Combination of Confusion, Urea, Respiratory Rate, Blood Pressure, and Age ≥65 (CURB-65), and Modified Early Warning Score (MEWS) , 9. In aHeyland et al. developed the Nutrition Risk in the Critically Ill (NUTRIC) score as a scoring system specific to ICU patients for the evaluation of the nutritional risk of patients. This scoring system is formed from age, APACHE II score, SOFA score, the number of comorbidities, the length of hospital stay before admittance to ICU, and serum interleukin-6 (IL-6) level. The NUTRIC score not only evaluates the nutritional status of the patient but also helps to determine the severity of acute disease . PatientThere is extremely limited information related to the nutritional risk status, clinical outcomes, and disease course of COVID-19 patients followed up in ICU. Different studies have used the NUTRIC score and the mNUTRIC score to evaluate the nutritional status of COVID-19 patients, but no study could be found in the literature that has compared these two scores.Therefore, the aim of this retrospective study was to compare the efficacy of the NUTRIC score and the mNUTRIC score in the evaluation of the nutrition risk and the prediction of the clinical outcomes and mortality in COVID-19 patients followed up in ICU.Approval for this retrospective study was granted by the Clinical Research Ethics Committee of Ankara City Hospital No. 1  and/or thorax computed tomography (CT) findings consistent with COVID-19. The patients followed up in ICU were severe pneumonia cases and critical patients.This retrospective study included the data of patients aged 18 years who were followed up in three COVID-19 ICUs in Ankara City Hospital between June 1The nutritional requirements and support of the patients were planned with the general consensus of the ICU team. For those who could not have oral intake with no contraindication for enteral nutrition, a nasogastric tube was attached within the first 24 hours and enteral nutrition was started. For patients who could not receive enteral nutrition, parenteral nutrition support was applied.Patients were excluded from the study if they remained in ICU for less than 24 hours or if the medical data were incomplete.Data of the patients were retrieved from the hospital information management system and the patient observation forms in respect of age, gender, history of chronic diseases, comorbidities, laboratory values, length of stay in ICU, length of stay in hospital before admittance to ICU, total length of stay in hospital, disease outcome , disease severity , Glasgow Coma Score (GCS), noninvasive oxygen treatments , the requirement for invasive mechanical ventilation, the duration of invasive mechanical ventilation, the nutritional route , the requirement for vasopressors, development of acute kidney injury, and the requirement for renal replacement therapy.Evaluation of acute kidney injury was made using the KDIGO classification  . Evaluatt-test was used for data showing normal distribution and the Mann–Whitney U test for data not conforming to normal distribution. In the determination of cutoff values for the scoring systems used in the study, sensitivity and specificity values were calculated and the area under the ROC curve (AUC) was evaluated with ROC analysis. In all the tests, a value of p < 0.05 was accepted as the level of statistical significance.Data obtained in the study were analyzed statistically using SPSS vn. 25.0 software. Categorical variables were stated as number and percentage and continuous variables as mean ± standard deviation (SD) values, or if not conforming to normal distribution, as median, minimum, and maximum values. In the comparisons of categorical variables, the chi-square test or the Fisher test was used. In the comparisons of continuous measurements between groups, according to the number of variables, the Student's Evaluation was made of a total of 322 COVID-19 patients, comprising 62.1% males and 37.9% females with a mean age of 69.1 ± 14.4 years (interquartile range (IQR): 19–99 years). No comorbidities were determined in 15.2% of the patients. The most common comorbidities were hypertension (63%), diabetes mellitus (39.4%), and coronary artery disease (29.2%). According to the CDC criteria, the majority of the patients (79.2%) were admitted to ICU with severe pneumonia and the remainder (20.8%) were critical patients. Mortality developed in 57.5% of the patients.The median APACHE II score was 11 IQR: 2–39), the median SOFA score was 3 (IQR: 1–16), and the median Glasgow Coma Score was 15 (IQR: 3–15). A total of 189 (58.7%) patients required invasive mechanical ventilation and vasopressor drugs were required by 145 (45%) patients. Acute kidney injury developed in 105 (32.6%) patients, and intermittent dialysis or continuous renal replacement therapy (CRRT) was applied to 71 (22%). The median length of stay in ICU and total length of stay in hospital were 9 days (IQR: 2–43) and 14 days (IQR: 2–69), respectively. The demographic and clinical data and the laboratory test results of the patients are shown in Tables –39, the p = 0.0001). In patients with a high NUTRIC score, heart failure, chronic renal failure, and a history of cerebrovascular event were determined more than in patients with a low score . The length of stay in ICU and total length of stay in hospital were determined to be significantly shorter in those with a high NUTRIC score compared to those with a low score . The GCS of patients with a high NUTRIC score were determined to be significantly lower than those of the patients with low NUTRIC scores (p = 0.0001).A high NUTRIC score (≥6) was determined in 62 patients and a high mNUTRIC score (≥5) in 86 patients. The median age was determined to be statistically significantly older in the patients with a high NUTRIC score compared to those with a low score . Critical disease was seen more together with a high NUTRIC score compared to those with a low NUTRIC score (p = 0.0001). The requirement for invasive mechanical ventilation, requirement for vasopressors on admittance to ICU, the use of vasopressors in ICU, development of acute kidney injury, the need for dialysis or CRRT, and mortality rates were determined to be higher in those with a high NUTRIC score compared to those with a low score .Statistically significantly higher median APACHE II and SOFA scores were determined in patients with high NUTRIC scores compared to those with low scores , and albumin, lymphocyte, and haemoglobin values were significantly lower  in patients with a high NUTRIC score.In the laboratory test results, levels of creatinine, total bilirubin, procalcitonin, ferritin, WBC, NLR, lactate, and IL-6 were determined to be significantly higher (p = 0.0001). In patients with a high mNUTRIC score, heart failure, arrhythmia, chronic renal failure, history of cerebrovascular event, and Alzheimer's disease were determined more than in patients with a low score . The total length of stay in hospital was determined to be significantly shorter in those with a high mNUTRIC score compared to those with a low score (p = 0.001). The GCS of patients with a high mNUTRIC score were determined to be significantly lower (p = 0.0001).In the patients with a high mNUTRIC score, age was determined to be statistically significantly older compared to those with a low score . Critical disease was seen more in patients with a high mNUTRIC score than in those with a low mNUTRIC score (p = 0.0001). The requirement for invasive mechanical ventilation, requirement for vasopressors on admittance to ICU, the use of vasopressors in ICU, development of acute kidney injury, the need for dialysis or CRRT, and mortality rates were determined to be higher in those with a high mNUTRIC score compared to those with a low score .Statistically significantly higher median APACHE II and SOFA scores were determined in patients with high mNUTRIC scores compared to those with low scores , and albumin, haemoglobin, and thrombocyte values were significantly lower  in patients with a high mNUTRIC score. The comparisons of the NUTRIC scores and mNUTRIC scores are shown in In the laboratory test results, levels of creatinine, D-dimer, procalcitonin, ferritin, WBC, neutrophils, NLR, lactate, and IL-6 were determined to be significantly higher (The area under the curve (AUC) values were found to be 0.791 (95% CI: 0.743–0.840) for the NUTRIC score and 0.786 (95% CI: 0.737–0.835) for the mNUTRIC score for the prediction of mortality, with no statistically significant difference . In the COVID-19 disease, which caused the death of millions of people, has become a destructive pandemic . As therThe NUTRIC score, which was developed by Heyland et al. and later modified by Rahman et al., not only evaluates the nutritional status of patients but also helps in determining the severity of acute disease , 14. Altp = 0.0001), the length of stay in ICU and total hospital stays were shorter, and the APACHE II and SOFA scores were determined to be higher compared to patients with low scores (p = 0.0001). It has been reported that according to the CDC criteria, 80% of COVID-19 patients are asymptomatic, 15% have severe pneumonia, and 5% are critical patients [Values of ≥6 for the NUTRIC score and ≥5 for the mNUTRIC score have been defined as high scores. Just as patients with high scores require more active and effective nutritional support, they are also associated with more negative clinical outcomes , 14. Of p = 0.0001). The mortality rates of patients, the requirement for invasive mechanical ventilation, the use of vasopressors on admittance to ICU, the use of vasopressors while in ICU, the development of acute kidney injury, and the requirement for dialysis or CRRT were significantly higher in patients with high NUTRIC and mNUTRIC scores compared to those with low scores (p = 0.0001). The IL-6 levels were also found to be significantly higher in patients with high NUTRIC and mNUTRIC scores.The patients followed up in ICU in the current study were those with severe pneumonia or critical patients. The rate of critical disease seen in patients with high NUTRIC and mNUTRIC scores was significantly greater  [p < 0.001) [p = 0.03) [In a study by Zhang et al. of 136 COVID-19 patients, those with a high mNUTRIC score were compared with those with a low score, and similar to the current study, a statistically significant difference was reported in respect of age, APACHE II score, SOFA score, GCS, the use of vasopressors, and mortality  . Li et a< 0.001) . In a stp < 0.001) [p = 0.036 and p = 0.142). This could have been due to there being no proven treatment for COVID-19 and that the disease course led more rapidly to mortality in critical patients with severe pneumonia or who developed organ failure. The COVID-19 pandemic has affected the whole healthcare system and so for associated reasons such as delays in transferring patients to ICU, shortcomings in the availability of invasive or noninvasive oxygen support systems, and insufficient numbers of healthcare personnel, which shortened the time to mortality, there may have been a shorter length of stay in ICU. In addition, the longer period of hypoxemia and the need for oxygen of patients with low scores and delays in discharge from ICU because of following the defined quarantine periods could have prolonged the length of stay in ICU of patients with low scores. In a study by Mayr et al., 114 patients with end-stage liver disease were evaluated in respect of NUTRIC and mNUTRIC scores. Age, IL-6, APACHE II score, SOFA score, and mortality rates were determined to be higher in patients with high NUTRIC and mNUTRIC scores compared to those with low scores (p < 0.001) [Jeong et al. examined both the NUTRIC and mNUTRIC scores in sepsis patients and reported that advanced age, APACHE II score, SOFA score, the use of vasopressors, the need for CRRT, and mortality rates were statistically significantly different in patients with high NUTRIC and mNUTRIC scores compared to those with low scores, and the total length of stay in hospital was longer (< 0.001) . Those f< 0.001) . The finThe AUCs of the NUTRIC and mNUTRIC scores predicting mortality were 0.791 and 0.786, respectively, with no significant difference determined between the two scores. The AUCs of the APACHE II score and SOFA score were 0.880 and 0.829, respectively. In the ROC curve of the NUTRIC and mNUTRIC scores, the best cutoff value was 3.5.In the study by Mayr et al. of patients with end-stage liver disease, the AUC for prognostic value of the NUTRIC score was 0.806, and for the mNUTRIC score, 0.788. The highest combined sensitivity and specificity was found with a cutoff value of ≥7. Both the scores were determined to perform better than APACHE II (AUC = 0.745) and SOFA (AUC = 0.778) . In the p = 0.45). The best cutoff value of the ROC curve for the mNUTRIC score was 6 with sensitivity of 75% and specificity of 65% [Jeong et al. examined 482 sepsis patients and reported AUC of 0.762 (95% CI: 0.718–0.806) for the NUTRIC score and 0.757 (95% CI: 0.713–0.801) for the mNUTRIC score in showing 28-day mortality, with no statistically significant difference (y of 65% . In anoty of 65% . Braschey of 65% . The AUCIL-6 is an important marker of inflammation, and just as its relationship with many other diseases has been investigated, so there are also many recent studies showing an association with COVID-19 –26. ThosAs this was a retrospective study, the potential effect of the medical condition on height, weight, and body mass index was not taken into consideration from the medical records. As the records may have not been complete during the intense period of the pandemic, the effects of nutritional support on clinical course and mortality could not be clearly evaluated.The results of this study demonstrated that after the APACHE II and SOFA scores, the NUTRIC and mNUTRIC scores were effective scoring systems in COVID-19 patients in ICU, and due to the lower cost and ease of calculation of the mNUTRIC score, it could be considered in preference to the NUTRIC score.


To investigate the potential prognostic role of C-reactive protein to albumin ratio (CAR) in patients with urinary cancers, including renal cell carcinoma (RCC), bladder cancer (BC), and prostate cancer (PC).We searched and screened literatures with PubMed, Embase, Cochrane Library, and Web of Science in January 2022. We applied combined hazard ratios (HRs) and 95% confidence intervals (CIs) to assess the associations.Thirteen studies including 2,941 cases were analyzed in our study. Merged results indicated that highly pretreated CAR was associated with inferior overall survival  and progression-free survival  for urinary cancers. In a subgroup analysis of OS by tumor type, CAR can be a predictor in RCC , BC , and PC . In a subgroup analysis of PFS by tumor type, CAR can be a predictor in BC , and RCC . The reliability and robustness of results were confirmed.High pretreated CAR was effective predictor of poor survival in patients with urinary cancers and can act as prognostic factor for these cases.PROSPERO (CRD42022306414). Urinary neoplasms, including renal cell carcinoma (RCC), bladder cancer (BC) and prostate cancer (PC), are usual cancers with increased morbidity and mortality. These three tumors were among the 10 most common malignancies in the United States in 2019  and immuThere was increasing evidence of a link between tumor-caused inflammatory response and tumorigenesis and disease progression . Kinds oOur study was performed and presented following the PRISMA guidelines. The protocol has been presented on PROSPERO (No. CRD42022306414). A comprehensive literature search was conducted with MEDLINE, Embase, Cochrane Library, and Web of Science electronic databases. We searched and screened the potential literatures up to January 2022. The key words embraced: “C-reactive protein to albumin ratio” , “urinary cancer”  and “prognosis” . A manual screen of study references was also conducted to obtain possibly relevant literatures. The language of included studies was restricted to English.To be eligible for inclusion, studies must meet the following criteria: (1) studies focusing on the association between pretreated CAR and prognosis of urological cancers, including renal cell carcinoma (RCC), bladder cancer (BC), prostate cancer (PC); (2) studies reported the correlation of pretreated CAR with overall survival (OS), and progression-free survival (PFS); (3) studies directly offered hazard ratios (HRs) with 95% confidence intervals (CIs) in the multivariable cox analyses; (4) studies published in peer-reviewed journals. Exclusion studies according to exclusion criteria: (1) studies didn’t provided HRs with 95% CIs for pretreated CAR in the multivariable cox analyses; (2) duplicated studies; (3) not original articles, such as conference abstracts, reviews, letters or case reports. Two researchers  screened and assessed the literatures independently. The dispute was settled through discussion.In the light of a pre-designed standardized form, data were extracted by two researchers  as following: study features ; patient and tumor characteristics ; characteristics of study methodology ; the detailed HRs with 95% CIs of each study and endpoint.The New-castle-Ottawa Scale (NOS) was applied to assess the quality of the included studies. There were 9 items in total . The val2 > 50% and/or P<0.1 were believed as measures of significant heterogeneity. In the case of significant heterogeneity, the random-effects model was applied to calculate the aggregate HRs and 95% CI. Otherwise, the fixed effects model was applied. Subgroup analyses of overall survival and progression-free survival were also conducted. Publication bias was evaluated by funnel plots, checked by Egger’s and Begg’s tests. We also conducted sensitivity analysis to examine the stability of the findings. Stata 12.0  was applied for all statistical analyses.HRs with related 95% CI in each qualified study were combined to assess the prognostic role of pretreated CAR in cases with urinary tumors. In each meta-analysis, Higgins I-Squared statistics and Cochran’s Q test were used to evaluate heterogeneity among the enrolled literature. ILiterature search identified 242 studies, and no article was discovered through reference screening. As shown in the flow chart of the literature searching Figure 1Only data on RCC, BC and PC was identified, studies about the prognostic role of CAR in other urinary cancers were lacking. 2 = 28.6%, p = 0.165), a fixed model was used for analysis. Pooled results showed that higher levels of CAR were associated with poorer OS for urological cancers . Subgroup analysis by cancer type showed that higher CAR levels were associated with poorer OS in RCC , BC , and PC   Table 4.There were 7 literatures on PFS of urological cancers , 22–24. The funnel diagram of OS and PFS was shown in Sensitivity analysis was further conducted to examine the effect of a single study on the overall results. There was no significant change in HRs associated with CAR and OS or PFS in patients with urinary cancers Figure 4The present study attempted to systematically review the available literatures and to evaluate the prognostic significance of CAR in urogenital malignancies using a meta-analysis. Based on high-quality studies, high level of pretreated CAR was found to be significantly correlated to poorer OS and PFS after combining the data. Subgroup analysis by cancer type remained significant for RCC, BC, and PC. Subgroup analyses of several variables of OS and PFS did not alter the direction of the findings. Publication bias checks and sensitivity analyses also confirmed the reliability and robustness of our findings. CRP and albumin are common hematologic indexes in clinic, which are easy to measure and low cost. Thus, CAR can be applied as a competent prognostic indicator for urinary tumors.For urological tumors, a comprehensive meta-analysis initially examined CAR as a prognostic factor in cases with RCC. They identify that high pretreated CAR was correlated to poorer OS and PFS . The assInflammatory reactions promote the development of tumors by influencing the microenvironment of urinary tumors. Cancer cell proliferation, necrosis, invasion, and hypoxia trigger immune responses in the tumor microenvironment, and in turn trigger the generation of various of inflammatory factors . Serum CThere was increasing evidence of a link between tumor-caused inflammatory response and tumorigenesis and disease progression . Kinds oHowever, some of the limitations of this systematic review should be explained. First of all, only 13 studies have been enrolled in the meta-analysis, which may lack statistical power, especially for BC and PC. Second, all enrolled studies were performed in Asia. Therefore, we should be careful to apply the results of the present study in patients from western countries. Third, all the included studies were cohort studies with retrospective design, which may result in selection bias. Fourthly, different cut-off values of CAR in different studies may lead to inconsistent outcome thresholds. Lastly, due to inadequate literatures, other urinary cancers were not analyzed in our study, and the endpoint cancer-specific survival was not studied.Taken together, the present study identified that pretreatment CAR level could be a likely predictor for cases with urinary tumors. Nevertheless, well-designed prospective studies also are wanted to validate these results.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.Protocol/project development: MW and YZ. Data collection or management: QC, ZY, and HG. Data analysis: PL, YL, and CL. Manuscript writing/editing: MW and YZ. All authors read and approved the final manuscript.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.