Anemia is a problem of both the developed and developing world, which occurs in all age groups of the population. Half of the anemia cases are due to iron deficiency and affects physical growth and mental development. Nevertheless, there is a scarcity of information about anemia and associated factors among infants and young children aged 6 to 23 months in low-income countries like Ethiopia.  The aim of this study was to assess the prevalence of anemia and associated factors among infants and young children aged 6–23 months. P < 0.05.  A community-based cross-sectional study design was used among 531 mothers/caregivers-children pairs in Debre Berhan Town, North Shewa, Ethiopia, from February 1 to March 2, 2018. The cluster sampling technique was used to select the study participants. Sociodemographic data were collected from mothers/caregivers using pretested structured questionnaires. Hemoglobin levels were measured using a HemoCue analyzer machine . All relevant data were described using descriptive statistics such as frequencies, proportions, mean, and standard deviation. Odds ratio and 95% CI were estimated using binary logistic regression to measure the strength of the association between anemia and explanatory variables. The level of statistical significance was declared at  The overall prevalence of anemia was 47.5% (95% CI: 43.1–51.4%) of which 18.3% were mildly anemic, 25% were moderately anemic, and 4.1% were severely anemic. In multivariable logistic regression analysis, household food insecurity , unmet minimum dietary diversity , stunting , and underweight  positively associated with anemia while having ≥4 antenatal care visits  and met minimum meal frequency  had a protective effect against anemia.  Generally, the study showed that anemia was a severe public health problem among infants and young children in the study setting. Antenatal care visit, meal frequency, dietary diversity, underweight, stunting, and food insecurity significantly associated with anemia. Therefore, efforts should be made to strengthen infant and young child feeding practices and antenatal care utilization and ensure household food security, thereby improving the nutritional status of children. Nutrition during the first 1000 days is very critical for child health, growth, cognitive development, and productivity in later life , 3.Anemia is defined as a low hemoglobin concentration in the blood leading to poor oxygenation of body tissue. It occurs at all age groups at one point in the life cycle but mostly affects reproductive age women and under-five children , 5. AnemAnemia reflects overall population health and nutritional status. Anemia can result in different health consequences such as maternal and child mortality, poor motor and cognitive development, high school absenteeism, poor school performance, and reduced working capacity among adults , 15. WorAnemia arises from multifaceted factors and is classified as nutritional, nonnutritional, and genetic bases . Low iroAlthough the prevalence of anemia and associated factors among mothers and under-five children was identified in Ethiopia, it has been noticed that there could be variations across settings in the country , 21–26. A community-based cross-sectional study was conducted from 1 February to 2 March, 2018, in Debre Berhan Town, North Shewa Zone, Amhara, Regional State, Ethiopia. Emperor Zara Yaqob founded the town and served as the capital of the North Shewa Zone. The town is located 130 km from Addis Ababa, the capital city of Ethiopia, and 690 km from Bahir Dar, the capital of the Amhara Region. The town has an altitude of 2840 meters above sea level. The area practices a mixed farming system: crop production with animal husbandry. The main crop production in the area is barley, wheat, peas, lentils, and linseed. Cattle, sheep, horses, donkeys, and mules are the main live stocks.According to the 2017 Town Health Administrative Office report, the town has a total population of 88369, of whom 14011 are under-five children and 6707 are children under two years. The town has nine kebeles  in Ethiopia, one referral hospital, three health centers, and 14 health posts.The source population of the study was all infants and young children aged 6–23 months and their mothers or caregivers in Debre Berhan Town. The study population was all infants and young children aged 6–23 months and their mothers/caretakers living in three randomly selected kebeles/clusters. All mother/caregiver-child pairs living for at least six months in the study were included in the study. Mothers or caregivers who were unable to respond to the interview due to their child's or their own illness and infants and children who had taken iron or vitamin A supplements or subjected to deworming or blood loss due to injury in the past three months were excluded from the study. The cluster sampling technique was used to select mother/caregiver-child pairs. Debre Berhan Town has 9 kebeles and three randomly selected kebeles are considered as clusters. The total number of children in each selected cluster was obtained from health extension workers (HEWs) family folder documentation. Based on the records of HEWs, 577 infants and young children aged 6–23 months were found in the selected clusters.The sample size was determined using a single population proportion formula with the following assumptions: prevalence of anemia among children aged 6–23 months to be 66.6% (22), 5% margin of error, 95% confidence level, design effect of 1.5, and 10% for nonresponse, which gave rise to 564 samples. In the case of more than one child being available in a given household, both children were included in the study. Due to the nature of cluster sampling, 577 infants and young children-mothers pairs living in selected clusters were included in the study.Socioeconomic and demographic data of mothers or caregivers and their children were collected through home-to-home visits using a pretested structured interviewing-administered questionnaire which was adapted from similar studies , 22. TheThe child's dietary diversity score was assessed using the dietary diversity assessment tool adapted from the WHO standardized questionnaire for infant and young child feeding practices. It was based on the mother's or caregiver's recall of all foods given to her child in the past twenty-four hours prior to the survey. The dietary diversity score was based on seven food groups consumed by the child: grains, roots and tubers, legumes and nuts, dairy products, flesh foods, eggs, vitamin A-rich fruits and vegetables, and other fruits and vegetables . HousehoAnthropometric data, such as the child's height and weight, were also collected. The child's length was measured to the nearest 0.1 centimeters using the United Nation Children's Fund (UNICEF) horizontal wooden length board with a movable headpiece on a flat surface. Children were kept in a recumbent position and the five contact points, including the head, shoulders, buttocks, calves, and heels, were maintained against the length of the board in a straight direction. The child's weight was measured to the nearest 0.1 kg. The weight of a child was estimated by subtracting the mother's/caregiver's weight record from the weight record of both mother and child obtained together. Each anthropometric measurement was measured after removing shoes, heavy clothes, and capes. Each participant was measured twice and the average value was taken when there were variations between two consecutive measurements. The weight scale was adjusted to zero level and calibrated using a standard 2 kg weight object before weighing each study participant.Hemoglobin level was measured with a HemoCue analyzer machine . The HemoCue HB 301 analyzer has internal quality control, the self-test. Every time the analyzer is turned on, the analyzer automatically verifies the measurement performance. This test is performed at regular intervals if the analyzer remains switched on. Upon passing the self-test, the display will show the HemoCue system and three dashes showing that the analyzer is ready to perform the measurement . When anA separate lancet was used for each child's finger pricking. After wiping off the first two drops of the blood sample, a third drop was collected and completely filled to a cuvette in one continuous motion. Hemoglobin data were adjusted during analysis at an altitude of 2840 meters above sea level and hemoglobin adjustment was done according to the WHO 2011 recommendation . The hem  Anemia: In this study, anemia among children aged 6–23 months was the outcome variable, and it was understood as hemoglobin level <11 g/dL after adjustment for individual hemoglobin value by subtracting 1.9 g/dL for an altitude of 2840 meters above sea level .  Food-secure household: If the household head responds no to all questions items 1–9 or responds yes to question item 1 and experiences rarely in the past four weeks .  Food-insecure household: If the household head responds at least yes to question item 1 and experiences sometimes in the past four weeks .  Minimum dietary diversity was achieved: The proportion of children aged 6–23 months who received 4 or more food items among the seven food groups .  Minimum meal frequency was achieved: The minimum number of times a child aged 6–23 months received solid, semisolid, or soft foods. If a child is breastfed, aged 6–8 months, s/he should receive two times and if aged 9–23 months, s/he should receive three times while a nonbreastfed child aged 6–23 months should receive four times during the previous day .  Stunting: Length for age <−2SD of the WHO growth standard .  Underweight: Weight for age less than −2SD of the WHO growth standard .  Wasting: Weight for length <−2SD of the WHO growth standard .  Household wealth index: The proxy measure of household living standards based on the sum of available assets of the owner like productive assets, durable assets, domestic animals, and housing characteristics .  Diarrhea: Children with a history of ≥3 times loose stool or watery diarrhea per day for two weeks prior to the study .  Timely introduction of complementary feeding: The child starts to receive solid, semisolid, or soft foods at the age of six months in addition to continued breastfeeding .  Early initiation of breastfeeding: The proportion of children born in the last 24 months who were put to the breast within one hour of birth .Data collection tools were prepared in English and translated into Amharic and then translated back into English to check for its consistency. Pretest was done on 5% of the study sample in the nonselected kebele. Two days of training was given to data collectors and supervisors on the objectives and context of the study, content of the questionnaire, how to fill the questionnaire in the field, interview technique, household selection procedure, respondent approaching technique, hemoglobin, and anthropometric measurement. The relative technical error of measurement (%TEM) was calculated to minimize intra- and interobserver variability . Data coFirst, data were checked for completeness, accuracy, and consistency before entering the computer. Data were then coded and entered into Epi-Data version 3.1 and exported to IBM-SPSS version 22 statistical software for analysis. The household wealth index was computed using principal component analysis (PCA) with all its assumptions, after which it was categorized into five quintiles: lowest, second, middle, fourth, and highest.Nutritional indices of infants and young children, such as height-for-age Z-score (HAZ), weight-for-age Z-score (WAZ), and weight-for-height Z-score (WHZ), were calculated according to the WHO 2006 multicenter growth reference . WHO AntP value <0.25 during bivariate logistic regression analyses such as maternal education, wealth index, child's sex and age, food security status, antenatal care follow-up, birth interval, introduction of complementary foods, dietary diversity, meal frequency, undernutrition , and presence of fever and diarrhea were retained for multivariable logistic regression analysis to control for all possible confounders and to identify predictors of anemia. Multicollinearity between independent variables was checked using the value of standard error (SE), whereby all variables with SE less than 2 were considered. Model fitness was checked with the Hosmer–Lemeshow test and its P value was greater than 0.05. In a multivariable analysis, adjusted odds ratio (AOR) and 95% confidence interval were estimated to measure the strength of association between the dependent variable and covariates. The level of statistical significance was declared at P value <0.05.Bivariate logistic regression was done to see the association between each independent variable and the outcome variable, anemia. Covariates with Before the commencement of data collection, Haramaya University Institutional Health Research Ethics Review Committee (IHRERC) reviewed and approved the study with reference number C/Ac/R/D/01/878/18. Each study participant was informed, and voluntary, written, and signed consent was secured. Children who were found to be anemic during data collection were linked to the nearest health facility for treatment.Of five hundred seventy-seven mothers/caregivers of infants and young children aged 6–23 months, a total of 531 participated in the study and making a response rate of 92.0%. Seven mother-child pairs were excluded according to the exclusion criteria and 39 were nonrespondents. The mean (±SD) age of the mother was 27 (±4) years. The majority, 467 (87.9%) mothers, had formal education. The mean (±SD) age of children was (14.7 ± 5.1) months. Slightly more than half, 271 (51%), of them were females. More than two-thirds, 356 (67%), of children were in the age range of 12–23 months .In our study, 526 (99.1%) infants and young children are ever breastfed. The majority, 482 (91.6%) children, initiated breastfeeding within one hour after delivery and 326 (61.4%) started complementary foods at 6 months. Nearly two-thirds, 348 (65.5%), and three-fifths, 324 (61%), achieved minimum meal frequency and minimum dietary diversity (≥4) food groups, respectively .The majority, 519 (97.7%), mothers had at least one antenatal care (ANC) visit for the index child. Nearly all, 522 (98.3%), mothers delivered the index child at a health institution. All households had access to safe drinking water or pipe water .Of the 531 interviewed mother-child pairs, the prevalence of stunting was 19.2% (95 CI: 16.2–24.2), of which 9.8% was severely stunted. Similarly, the prevalence of wasting was 12.6% (95 CI: 9.8%–15.8%), of which 4.3% was severely wasted, while 17.5% (95% CI: 14.1%–21%) were underweight with 7% severely underweight .In the present study, the mean (±SD) hemoglobin level was 10.8 (±1.87) g/dL with a maximum hemoglobin value of 16.8 g/dL and a minimum of 5.6 g/dL. The overall prevalence of anemia was 47.5% (252) (95% CI: 43.1%–51.4%) of which 18.3% (97) were mildly anemic, 25% (133) moderately anemic, and 4.1% (22) severely anemic .The prevalence of anemia among children of mothers who had no education and had primary education was 64.1% and 66.1%, respectively, and the prevalence decreased as mothers/caregivers attained secondary education and above (36.4%). Anemia varies with the child's sex and age. More than half, 53.8% (140), of males and 41.3% (112) of females were anemic, but the prevalence decreased as the child age increased .In bivariable logistic regression analyses, maternal education, household's wealth index, child's sex and age, food security status, minimum dietary diversity, met minimum meal frequency, antenatal follow-up, history of diarrhea, fever two weeks prior to data collection, stunting, underweight, birth interval, and age at the commencement of complementary feeding were significantly associated with anemia.In multivariable logistic regression analysis, food insecurity, ANC follow-up, minimum dietary diversity, met minimum meal frequency, underweight, and stunting were significantly associated with anemia.Children from food-insecure households had 2.7 times  higher odds of being anemic than those children from food-secure households. The odds of anemia were reduced by 50%  among children born to mothers who had four or more ANC visits compared with children born to mothers who had fewer than four ANC visits. The odds of anemia were reduced by 75% among children who met their minimum meal frequency  compared with those children with unmet meal frequency. Similarly, children with less minimum dietary diversity were 2.5 times  more likely to be anemic than those children with achieved minimum dietary diversity. Stunted children were 2.3 times  more likely anemic, while the underweight children had 2.7 times  higher odds of anemia .The present study assessed the prevalence of anemia and associated factors among infant young children aged 6–23 months. The World Health Assembly set a fifty percent reduction of anemia among pregnant women by the year 2025 as a global nutrition target. But the magnitude of anemia remains a significant public health concern across the globe . Anemia The study findings showed that 47.5% of infants and young children aged 6–23 months were anemic. The magnitude is unacceptably high, which needs a strong effort to reduce where the level is not more a public health problem. This finding is similar to the studies reported in China (51.3%)  and RomaIn this study, there was a significant association between ANC follow-up and anemia. This is in line with a study done in Ethiopia . ChildreChildren from food-insecure households were 2.7 times more likely to be anemic compared to children in food-secure households. This is consistent with a study done in the US . This coDietary diversity and meal frequency were also significantly associated with anemia. This is consistent with studies done in China  and EthiMoreover, undernutrition was found to be a significant predictor of anemia. This finding is consistent with the studies done in Rwanda  and nortThis study has the following limitations. First, due to the nature of the design, the study might not show causal relationships between predictors and anemia. Second, the study did not assess other risk factors for anemia such as intestinal parasites, HIV, genetic disorders, folate, vitamin B12, and vitamin A deficiencies. Third, the study used only hemoglobin level to define anemia, which does not reveal the body's level of iron stores. Fourth, household food security was assessed for the past four week's period. This could subject the study to recall and social desirability bias. Lastly, there could be possibilities for anthropometric and hemoglobin measurement errors, but all possible efforts were made to minimize all forms of errors. Despite all the aforementioned limitations, the study tried to assess the prevalence of anemia and associated factors among infants and young children aged 6–23 months at the population level. Nevertheless, the interpretation of the findings of the study needs to be carefully made as measurement error in anthropometry and hemoglobin level determination can either underestimate or overestimate the results of the study.Based on the WHO cutoff point, the prevalence of anemia observed among children aged 6–23 months in the study area is a severe public health problem. Household food insecurity, less frequent antenatal care follow-up, dietary diversity, meal frequency, and undernutrition were significantly associated with anemia. Therefore, integrated efforts need to be made to improve infant and young appropriate feeding practices and maternal ANC service utilization. Similarly, multisectorial work needs to be emphasized to ensure household food security in the study community.


In this study, the objective was to develop a new and highly-accurate artificial intelligence model for slope failure prediction in open-pit mines. For this purpose, the M5Rules algorithm was combined with a genetic algorithm (GA) in a novel hybrid technique, named M5Rules–GA model, for slope stability estimation and analysis and 450-slope observations in an open-pit mine in Vietnam were modeled using the Geo-Studio software based on essential parameters. The factor of safety was used as the model outcome. Artificial neural networks (ANN), support vector regression (SVR), and previously introduced models  were also developed for evaluating the proposed M5Rules–GA model. The evaluation of the model performance involved applying and computing the determination coefficient, variance account for, and root mean square error, as well as a general ranking and color scale. The results confirmed that the proposed M5Rules–GA model is a robust tool for analyzing slope stability. The other investigated models yielded less robust performance under the evaluation metrics. Slope collapse is a critical hazard in open-pit mines as it can be of any scale, small or large, and directly affect people, equipment, and production processes Fig. . Therefo2 and three-dimensional techniques3 for slope stability analysis were applied to various geological structures,. Wei, et al.4 combined the generalized Hoek-Brown and strength reduction method to evaluate the stability of slopes in rock mass. Many types of seismic actions were also investigated and assessed for the stability of slopes in different conditions9. However, owing to the complexity of geological structures, slope stability is a challenging aspect for large open-pit mining projects10.Numerical methods12. The random finite element method (RFEM) and limit equilibrium method (LEM), as well as other modeling methods based on finite elements and stochastic simulation, were typically applied to calculate slope stability16.Furthermore, as soil layers exhibit heterogeneous characteristics, geotechnical and geological uncertainties can worsen the poor estimation of slope stability20, particularly in the prediction of landslides including slope stability23. Artificial intelligence (AI) is a powerful tool capable of replacing traditional methods such as slope stability and landslide26, blast-induced problems 32, optimization in mine planning34, and geology and geophysics37. For slope stability prediction, Qi and Tang38 developed six different soft computing models based on a meta-heuristic algorithm  and machine learning algorithms . A promising result was found in their study for predicting slope stability when the area under the receiver operating characteristic curve reached up to 0.967. Sakellariou and Ferentinou39 introduced an artificial neural network (ANN) model that used geometrical and geotechnical parameters to predict the factor of safety (FOS) based on their database of experiments. In another study, Samui40 applied support-vector machine (SVM) for slope stability analysis using a database of practical investigations. Choobbasti, et al.41 also conducted similar work with ANN models. Despite the high appreciation from researchers for the effectiveness of AI techniques in predicting slope stability, experimental data are often insufficient because of time and cost constraints.In recent years, more advanced computational techniques have been widely applied in many fields43. Based on these tools, slope stability prediction was analyzed and accurately evaluated for many models. Moreover, scientists have applied a big-data approach to AI for slope stability analysis46. Chakraborty and Goswami47 simulated 200 cases with different shear strengths and geometric parameters to evaluate slope stability using ANN and multiple linear regression (MLR). Jellali and Frikha48 used OptumG2 to generate 30,000 elements and predicted slope stability using the particle swarm optimization (PSO) algorithm with promising results. Mojtahedi, et al.49 applied the Monte Carlo technique using Geo-Studio software with 224 datasets. Saleh50 applied ANN to a database of 2,180 simulated slope cases using Geo-Studio software. Qi and Tang38 attempted to develop six soft computing models using optimization approaches based on firefly algorithms (FFA), concluding that an FFA–SVM model was the best. Koopialipoor, et al.51 applied various hybrid AI models, such as ANN-PSO, ANN-ICA , ANN-GA , and ANN-ABC , based on OptumG2 software analysis results. They found that the ANN-PSO model provided better performance than the other models. Gao, et al.52 successfully developed a promising hybrid model called ICA–ANN based on the combination of ANN and ICA with 400 OptumG2 simulations. Qian, et al.53 also performed similar work for forecasting slope stability based on OptumG2 software.To overcome the abovementioned limitations, various simulation software based on RFEM and LEM methods, among others, were introduced (such as OptumG2 and Geo-Studio)54. However, it is not taking into account to predict and evaluate the stability of slopes. Furthermore, the performance, as well as the parameters of the M5Rules-GA model, are different based on different databases. Therefore, the M5Rules-GA model was investigated to predict slope stability herein and it is considered as a novel model in this field. Besides, several ANNs, support-vector regression (SVR), and previously introduced slope stability prediction models  were also implemented for a comprehensive comparison of the proposed M5Rules–GA model. There were 450 simulations of open-pit mine slopes in Vietnam, as a database for predicting slope stability.The review of previous works reveals that AI techniques are widely applied in slope stability prediction and analysis. However, such methods are not applied in all areas/regions. Furthermore, many AI models and techniques are yet to be investigated. To promote continued improvements in safety, development of knowledge, and enhancing slope stability, prediction performance in other areas is necessary. Therefore, a novel hybrid model, namely M5Rules–GA, for predicting slope stability  using a genetic algorithm (GA) and M5Rules was proposed and investigated in this study. It is worth mentioning that the team of authors developed the M5Rules-GA model for predicting the energy efficiency of buildings  with high accuracy60. Therefore, these details are not included in the present study. This section highlights the background of M5Rules and GA for developing the new hybrid M5Rules–GA model.In this study, eight AI techniques were used to develop slope failure predictive models, including ANN, SVR, M5Rules, PSO, FFA, ICA, ABC, and GA. However, the details for ANN, PSO, FFA, ICA, ABC, and SVR techniques were presented in many previous works61. It is a type of decision tree algorithm in machine learning that can be applied for regression and classification problems63. In regression, M5Rules is based on a combination of regression tree models64. In addition, the partial and regression tree (PART) algorithm is applied to generate the rules for the M5 tree model65. These rules can improve the performance of the M5 tree model rather than the regression tree models, and it is called M5Rules. In M5Rules, the tree can be developed based on the four following options: pruned/unpruned tree; smoothed/unsmoothed predictions; build regression tree/rule; and define the minimum number of instances per leaf66. The workflow for the development of the M5Rules model is shown in Fig. M5Rules is well-known as an enhanced model of the M5 model with rules68. Four steps are conducted in GA for finding an optimal function: genetics, mutation, natural selection, and crossover. Before implementing an optimization of an objective function, GA needs an initial population and their fitness are calculated70. Note that the number of population of individuals is generated heuristically or randomly71. In GA, the quality of the population can be improved by the selection operator. Subsequently, two individuals are generated with higher fitness using the crossover operator. Mutation operators can create a new generation with better performance in the population by randomly modifying some genes72. It is worth mentioning that replacement strategies can be applied to replace the current generation by newly generated offsprings. There are two main types of replacement: generational and steady-state replacements73. In addition, other related replacement strategies, such as elitism, delete n-last, delete n, random replacement, weak parent replacement, and both parents replacement, can be applied for replacement of generation in GA74. The structure and the framework of the GA are simulated in Fig. Meta-heuristic algorithms are well-known as robust algorithms for optimization problems. Among those, the GA has one of the dominant performances in optimization based on the theory of DarwinTcn the structure of the chromosome.The change in fitness from newly generated offsprings is less than a specified constant.In GA, the cycle of operators  is employed and looped. To end the algorithm, two stopping conditions can be applied as follows:pruned, smoothed, rules, and the number of instances per leaf. Note that the PART algorithm generates rules for the M5 tree model. With each round, GA searches the M5Rules model parameter values with the M5Rules model performance evaluated using a fitness function ). The search process is performed until the optimal M5Rules model is found, i.e., the model with the most extreme fitness function value. The framework of the M5Rules–GA model is illustrated in Fig. In this section, the M5Rules–GA model, which is the slope stability prediction model proposed in this study, is presented and highlighted. The performance of the M5Rules model is determined by its parameters. Pruning and smoothing tasks can be applied during the development of the M5 tree model. Additionally, rules and the number of instances per leaf are important parameters affecting the performance of the M5Rules model. Therefore, the GA is applied to optimize the parameters of the M5Rules model: 2), variance account for (VAF), and color intensity were applied based on the measured and predicted values on both training and testing phases. They were calculated according to Eqs. , angle of internal friction (φ), and slope angles  for the computations of FOS values. According to Zhou, et al.76, the slope is stable at FOS > 1. However, according to Sakellariou and Ferentinou39, the slope is stable only at FOS As recommended by previous researchers, mentclass2pt{minim78, 80% of the database was used for the training of the models; the remaining 20% was used to assess the models’ performance. The training dataset was randomly selected, and all the abovementioned models were developed based on the same training phase and tested using the same testing phase.To develop the models, the FOS database needs to be prepared and normalized. Accordingly, the dataset used should be split into two phases. As recommended in previous studiesPm), crossover probability (Pc), number variable (n), and number of populations (p). Pm, Pc, and n were set to 0.1, 0.8, and 5, respectively, and the values for p were set to 50, 100, 150, 200, 250, and 300. Additionally, the steady-state replacement method79 was applied in GA. RMSE was used as the fitness function, according to Eq. p = 200 at the iteration of 412 (RMSE = 0.0218).For the development of the M5Rules–GA model, the step-by-step approach shown in Fig. σ and C used as the main parameters for controlling SVR model performance. A 10-fold cross-validation80 was applied to increase the accuracy while preventing overfitting or underfitting of the SVR model. Furthermore, the Box-Cox transformation technique81 was applied to reduce the skewness of the data. A trial and error approach with various SVR models was conducted to determine the best SVR model for this study. The best SVR model for analyzing slope stability was found at C = 276.385.For SVR modeling, a kernel function was applied  with 84, ANNs with one or two hidden layer(s) can solve most problems. Therefore, a trial and error approach was conducted to find the best ANN models with one or two hidden layer(s). The min-max scale technique  was used as a normalization method for the dataset to avoid overfitting of the ANN models. Eventually, four ANN models were established: ANN 5-8-1, ANN 5-11-1, ANN 5-8-11-1, and ANN 5-12-16-1, called ANN 1, ANN 2, ANN 3, and ANN 4, respectively. Their structures can be seen in Fig. For ANN models, hidden model layers resist definition or explicit explanation. However, according to previous works2, VAF, a general ranking, and color range). The purpose of using multiple metrics, ranking, and color intensity methods is to recognize the best model in those of the developed models. Furthermore, the testing dataset is taken into account as the new dataset in practical; thus, evaluating the performance of the models on the testing dataset will provide an overview of the reliability of the models in practice. Also, to evaluate the performance of the models through the training time (runtime), the total time of training of the models was calculated in Table Based on Table Based on Table Regarding the accuracy of the models, a color range can preliminarily provide a performance evaluation of the models. Green and white represent the best and worst performances, respectively. Table Considering further evaluation criteria, such as standard deviation, centered root mean square (RMS) difference, and correlation coefficient, a Taylor diagram was drawn to visualize and comprehensively assess the developed models, as shown in Fig. Based on the results of this study, the proposed M5Rules–GA model provided the best accuracy among all the investigated models for slope stability forecasting. The M5Rules model was substantially enhanced using GA optimization, thereby achieving outstanding performance. We expect M5Rules–GA model to be useful in evaluating and predicting slope stability at mines, thus preventing and minimizing slope collapse damage. In addition, the other models also showed positive results, and they might be considered in other instances. Although the performance of the proposed M5Rules–GA model was interpreted in the context of the present study’s dataset, we suggest its broader application to other regions with extended datasets.


A good prediction model plays an important role in determining the progression to diabetic kidney disease. We aimed to create a model to predict progression to kidney failure in patients with diabetic kidney disease.We retrospectively assessed 641 patients with type 2 diabetic kidney disease as derivation cohort and 280 patients as external out time validation cohort. We used a combination of clinical guidance and univariate logistic regression to select the relevant variables. We calculated the discrimination and calibration of different models. The best model was selected according to the optimal combination of discrimination and calibration.p value of the Hosmer–Lemeshow, .817). There was no significant difference in NRI among laboratory model, lab-medication model, and full model (p > .05). So, we chose the laboratory model as the optimal model.During the 3 years follow up, there were 272 outcomes (42%) in derivation cohort and 138 outcomes (49%) in external validation cohort. The final variables selected in the multivariate logistics regression were age, gender, hemoglobin, NLR, serum cystatin C, eGFR, 24-h urine protein, and the use of oral hypoglycemic drugs. We developed four different models as clinical, laboratory, lab-medication, and full models according to these independent risk factors. Laboratory model performed well in both discrimination and calibration among all the models (C-statistics: external validation 0.863; We constructed a nomogram which contained hemoglobin, NLR, serum cystatin C, eGFR, and 24-h urine protein to predict the risk of patients with diabetic kidney disease initiating renal replacement in 3 years. Tangri et al. developed the kidney failure risk equation (KFRE) to identify a high-risk population of CKD 3-5 patients who are likely to developing ESRD based on demographic, clinical, and laboratory variables [c values . Howeverc values . It has c values . But thec values . HoweverTherefore, we aimed to develop and validate a model to predict the 3-year risk of progression to kidney failure that could be easily implemented in clinical practice, using the variables routinely measured in patients with DKD.2.2.1.In this population-based retrospective cohort study, patients with type 2 DKD who were hospitalized in the First Hospital Affiliated with Zhengzhou University were screened. A total of 641 patients who were hospitalized from December 2012 to December 2015 were enrolled as derivation cohort, while 280 patients hospitalized from January 2016 to December 2017 were enrolled as external out time validation cohort. The DKD diagnosis was based on the guidelines created by the Kidney Disease: Improving Global Outcomes [2.2.Clinical characteristics, including age, sex, duration of diabetes mellitus (DM), systolic blood pressure, diastolic blood pressure, the main medical history of hypertension, coronary heart disease and cancer, body mass index (BMI) and the use as the drugs such as the oral hypoglycemic drugs, insulin, renin-angiotensin system blocker, and statin were collected. Laboratory parameters, including hemoglobin, neutrophil: lymphocyte ratio (NLR), serum creatinine level, serum urea level, serum uric acid level, serum total protein level, serum albumin level, serum calcium level, total cholesterol level, triglyceride level, serum cystatin C level, serum β 2 microglobulin level, glycated hemoglobin (HbA1c) level, blood glucose level, C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), estimated glomerular filtration rate , 24-h urine protein level, bicarbonate level and the PH value of urine were initially collected at the time of diagnosis with DKD.2.3.The primary endpoint was kidney failure, as defined by the initiation of dialysis and renal transplantation.2.4.SD) or medians  to express the continuous data, while the categorical data are expressed as the absolute values and percentages. Then, we used the univariate logistic regression to select the potential variables. Before the multiple logistic regression, we calculated the collinearity of the variables and remove the factors, serum urea level and serum creatine level, that exist in collinearity. Then, we used a combination of clinical guidance and univariate logistic regression with the enter method to select the relevant variables and conduct multiple logistic regression. The clinical characteristics, including age, sex and the use of oral hypoglycemic drugs, and the statistically significant biochemical measures, including the hemoglobin level, NLR, serum cystatin C level, eGFR, and 24-h urine protein level, were selected to construct the sequential models. Next, the area under the receiver operating characteristic curve, which is referred to as the C-statistic, was used to assess the discriminatory ability of the models. The calibration was assessed by the Hosmer–Lemeshow (H-L) test and calibration curves. The goodness of fit of the models was evaluated by the Akaike information criterion (AIC). We divided all the derivation patients into five groups and selected one group as the internal validation cohort and the other four groups as the training cohort. We used the training cohort to develop the models and the internal validation cohort to validate the models. We repeated the process 5 times to assess the discriminatory ability and calibration of the models. The C-statistic, the AIC, and the p value of the Hosmer–Lemeshow (H-L) test shown were the averages of 5 repetitions, and the detailed values for each individuals repetition are displayed in the Supplementary Materials. The best model was selected according to the optimal combination of the discrimination and calibration calculated by the fivefold crossvalidation and external validation which is ‘Bootstrapping’. The net reclassification improvement and integrated discrimination improvement of models were also used to evaluate the discriminatory ability of the models. Last, we constructed a nomogram to predict the risk of a patient with DKD initiating renal replacement in 3 years. All analyses involved in the development and validation of the model were conducted with R software, version 3.5.3 .There were some missing data in several variables. Variables that indicated the renal function, such as serum creatine, serum urea, serum cystatin C, serum β2 microglobulin, and serum uric acid, had 3.9% missing values. There were 2.9% missing data in hemoglobin and NLR and 6.1% in serum total protein and serum albumin. The 24-h urine protein had 3.1% missing values and CRP and ESR had 8.4% missing data. We used multivariate multiple imputation with chained equations to impute missing values to maximize the statistical power and diminish bias . First, 3.3.1.The baseline clinical characteristics and laboratory parameters of the derivation cohort and external validation cohort are shown in 3.2.p value of univariate logistic regression were shown in p < .001), higher β2 microglobulin levels , higher 24-h urine protein levels  and higher NLRs  had a higher risk of undergoing renal replacement. In addition, patients who had higher serum calcium levels  and higher serum albumin levels  had a lower risk of renal replacement. There are also other indicators that are statistically significant in univariate analysis (p < .05). We conducted the collinear analysis in p, .007), gender , hemoglobin , NLR , serum cystatin C , eGFR , 24-h urine protein  and the use of oral hypoglycemic drugs  test, and calibration curves were used to depict the discriminatory ability and calibration of the models. A higher C-statistic reflected a good discriminatory ability, while a p value of the Hosmer–Lemeshow (H-L) test close to 1 and a relatively lower AIC suggested that the predicted probability was not significantly different from the observed probability in the models. Clinical model, including age, gender and the use of oral hypoglycemic drugs only, performed poorly in both the training cohort  and the validation cohort . The remaining three models, laboratory model, lab-medication model, and full model, had similar C statistics in both internal and external validation  improvement in full model compared with laboratory model, while the NRI of the two model was not statistically significant . The IDI between the comparison of full model and lab-medication model showed a 1.4%  improvement, but NRI was not significant .To further evaluate the discriminatory ability of the models, we considered the following categories of the risk kidney failure within 3 years: 0% to 24.9% was low, 25.0% to 74.9% was intermediate, and 75.0% or more was high. The cutoff values used to calculate the net reclassification were 25% and 75%. The net reclassification improvement (NRI) and integrated discrimination improvement (IDI) of laboratory, lab-medication, and full models were shown in 3.5.2), higher serum cystatin C level (2.1 mg/L), lower NLR (2.83), and very high urine protein level (7.8 g/d) would have a total of 186 points, indicating a predicted 3-year probability of the onset of renal replacement of 58.6%.Based on the above analysis, laboratory model performed well in terms of both discrimination and calibration. Therefore, we regarded laboratory model, which contained hemoglobin, NLR, serum cystatin C, eGFR, 24-h urine protein as the optimal model. The nomogram to predict the probability of DKD initiating renal replacement in 3 years is shown in 4.p = .817. Our study demonstrated that lower eGFR, higher cystatin C levels, lower hemoglobin, higher NLR level and higher 24-h urine protein significantly increased the risk of renal replacement therapy in patients with DKD.We have developed and validated a set of risk prediction models using laboratory data that are obtained routinely in patients with DKD and could be easily integrated into a laboratory information system to predict the progression to kidney failure among patients with DKD. The laboratory model behaved good performance among the sequential models. The C-statistic for laboratory model was 0.986 in the training cohort, 0.983 in the internal validation cohort and 0.863 in the external validation cohort, showing good discriminatory performance, and the calibration was good, with K-fold crossvalidation is one of the most commonly used methods of evaluating the predictive performances of a model [K-fold crossvalidation, (K − 1) fold is allocated to model development, and the residual fold is adopted for the model validation. Jung suggested the nearest integer value of log(n) as a rule for choosing K [ a model . In K-fooosing K , while Zoosing K . ConsequIn recent decades, risk prediction has gained increasing attention, and several prediction models have been developed to predict CKD in the general population ,11,16–18Proteinuria is a strong prognostic factor for the progression of DKD to kidney failure. In some studies, proteinuria was demonstrated to be a predictor of kidney failure ,11,19. SCystatin C, a cysteine protease inhibitor, has been demonstrated to be an early renal marker in diabetic patients . Our stuIn patients with DKD, the NLR was demonstrated to be associated with the 24-h urine protein level and albumin excretion in 80 Turkish patients with newly diagnosed type 2 diabetes . WheelocHowever, a number of limitations of this study should be considered. DKD was mostly clinically diagnosed from the presence of macroalbuminuria and renal impairment in patients with diabetes. Therefore, there might be other types of kidney disease that were included. It is possible that adding pathological information may have improved the predictive ability of the models. In addition, our study population was limited to Chinese patients with type 2 diabetes and advanced CKD, so our findings may not be widely generalizable. What’s more, the time of follow-up is short. A long term prospective cohort study of multicenter is required in future.Future studies into the prognostication of DKD should aim to optimize the inclusion criteria and stratify renal function to improve the precision of the prediction model. External validation through multicenter studies is also necessary.All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee at which the studies were conducted, and were approved by the Clinical Research Ethics Committee of the First Affiliated Hospital of Zhengzhou University (2018-KY-82) and conform to the 1964 Helsinki declaration and its later amendments or comparable ethical standards.Participant consent was waived because of the retrospective nature of the study and the anonymous nature of clinical data.Click here for additional data file.


Indomethacin, naproxen, and ibuprofen inhibited nociceptive trigeminocervical neurons activated by stimulation of the dura mater, whereas only indomethacin inhibited responses activated by a nitric oxide donor. −1), ibuprofen (30 mg·kg−1), or naproxen (30 mg·kg−1) inhibited dural-evoked firing within the trigeminocervical complex with different temporal profiles. Similarly, both indomethacin and naproxen inhibited L-glutamate-evoked cell firing suggesting a common action. By contrast, only indomethacin was able to inhibit NO-induced firing. The differences in profile of effect of indomethacin may be fundamental to its ability to treat paroxysmal hemicrania and hemicrania continua. The data implicate NO-related signaling as a potential therapeutic approach to these disorders.Nonsteroidal anti-inflammatory drugs, cyclooxygenase inhibitors, are used routinely in the treatment of primary headache disorders. Indomethacin is unique in its use in the diagnosis and treatment of hemicrania continua and paroxysmal hemicrania. The mechanism of this specific action is not fully understood, although an interaction with nitric oxide (NO) signaling pathways has been suggested. Trigeminovascular neurons were activated by dural electrical stimulation, systemic administration of an NO donor, or local microiontophoresis of L-glutamate. Using electrophysiological techniques, we subsequently recorded the activation of trigeminovascular neurons and their responses to intravenous indomethacin, naproxen, and ibuprofen. Administration of indomethacin (5 mg·kg One important group is indomethacin-sensitive headaches, notably paroxysmal hemicrania and hemicrania continua.26 in addition to their use in pain more broadly. They are distinguished by different chemical structures, eg, indomethacin is an acetic acid derivative, whereas ibuprofen is a propionic acid derivative; and by their profiles of absorption, metabolism, and excretion. Remarkably, NSAIDs do not act equally in all headache disorders. A particularly striking example is the indomethacin-sensitive trigeminal-autonomic cephalalgias: paroxysmal hemcrania57 and hemicrania continua.58 Indeed, the current diagnostic criteria for these disorders use an indomethacin response as a defining characteristic.27 An animal model recapitulating aspects of the trigeminal-autonomic cephalalgias has reported that indomethacin was significantly more effective than naproxen,1 suggesting an alternate mechanism of action from that previously demonstrated in animal models of migraine mechanisms.6 Taken together, it seems likely that indomethacin has a unique action that is not yet clarified.Nonsteroidal anti-inflammatory drugs, which are cyclooxygenase (COX) inhibitors, are used in headache therapy, such as in migraine,25 This model has proven effective at predicting antimigraine clinical efficacy.6 We also compared the local effects of microiontophoretically applied indomethacin and naproxen on iontophoresed glutamate-activated dural-responsive second-order neurons in the TCC. It has been suggested that indomethacin may modulate nitric oxide (NO) signaling pathways. Nitric oxide is known to induce headache and delayed migraine in patients.32 In preclinical studies, indomethacin is able to inhibit NO-induced dural vasodilation,3 and this effect is unique because naproxen or ibuprofen were ineffective in this regard.61 Nitrergic mechanisms may be involved in the pathophysiology of headache disorders and therefore indomethacin may target pathways of NO metabolism and signaling as its therapeutic action. We thus hypothesized that indomethacin may demonstrate differential modulation of second-order neurons with trigeminovascular nociceptive inputs and further that indomethacin may be differentially responsive at inhibiting NO-induced neuronal activity compared to naproxen or ibuprofen.Here, the effects of indomethacin, naproxen, and ibuprofen were compared in an established animal model of trigeminovascular nociception, which uses activation of dural nociceptive inputs in the trigeminocervical complex (TCC), believed to be important in the pathophysiology of a range of primary headache disorders.49 Experiments adhered to the guidelines of the Committee for Research and Ethical Issues of the International Association for the Study of Pain68 and the ARRIVE guidelines.35All experiments were conducted under license of the University of California, San Francisco Institutional Animal Care and Use Committee and conforming to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.4 Anesthesia was induced by intraperitoneal application of sodium pentobarbital . After reaching a sufficient level of anesthesia, the animal was then placed on a thermostatically controlled homeothermic blanket and kept within physiological ranges. The femoral veins and left femoral artery were cannulated for intravenous administration of subsequent anesthesia, experimental drugs, and blood pressure monitoring . Anesthesia was maintained by intravenous application of sodium pentobarbital (25-30 mg·kg−1·h−1). The trachea was cannulated for mechanical ventilation with oxygen-enriched air . Adequate ventilation was monitored through end-tidal CO2 analysis . For further procedures, animals were positioned in a stereotactic frame. The blood pressure, end-tidal CO2, and temperature were electronically displayed online, and together with the repeated observation of the animal's corneal and noxious withdrawal reflexes, used for monitoring suitable depth of anesthesia, and dose of sodium pentobarbitone was adjusted accordingly within the given range. Upon conclusion of electrophysiological recording protocols, all animals were euthanized by an i.v. dose of pentobarbital followed by central nervous tissue collection.Male Sprague-Dawley rats  were used in all experiments, randomized to experimental groups, and analyzed by an observer blinded to their grouping. The selection was limited to male animals so that no interference of the estrous cycle was obtained and the number of animals used could be minimized for ethical reasons, while offering the opportunity of observing the effects of the tested drugs in steady conditions.7 For microiontophoretic experiments, the cells had to show stable baselines of increased firing rate in response to microiontophoretic L-glutamate ejections and stable baselines of increased firing rate in response to electrical stimulation of the MMA. The criteria for intravenous experiments did not include microiontophoretic L-glutamate ejections. Poststimulus histograms (PSTH) were established for sequences of 20 stimulations. A mean firing rate of 30% above baseline was required,48 within a 7 to 10 ms period of the main firing episode, corresponding to Aδ fibers. Poststimulus histograms were collected with 1-ms bin sizes over a poststimulus period of 100 ms. The action potential firing of the neurons recorded in response to microiontophoresis of L-glutamate were collected in successive 1-second bins and analyzed as cumulative rate histograms.For all electrophysiological recordings, a midline incision was made to expose the skull above the middle meningeal artery (MMA), and the appropriate area of the spine above the first and second cervical (C1/C2) levels. A small craniotomy above the MMA was then performed using a saline cooled dental drill, and a hemilaminectomy of C1 was performed, followed by a small incision of the dura mater so the recording electrode  could be lowered  into the dorsal horn (5 µm steps) of the exposed TCC. Wide-dynamic-range neurons, identified by noxious pinch, and innocuous brush, responding to electrical stimulation of the MMA/dura mater , were identified and recorded as described.2O for injection, pH 8-8.3) 1 ml·kg−1 was then administered intravenously. In all electrophysiological studies, animals received only a single dose of an NSAID intravenously. Further PSTHs were collected 5, 10, 15, 20, 25, 30, and 45 minutes after administration.To study the intravenous effect of indomethacin, naproxen, and ibuprofen on electrical stimulation of the MMA, a baseline response was evaluated before administration of the drug/control baseline (mean out of 4 stimulation series of 20 sweeps). One of the tested drugs or the vehicle control .All experimental and physiological data were acquired, displayed, and saved on a personal computer using an online data analysis system .52At the end of the experiment, the recording site was electrically lesioned or marked by microiontophoretic ejection of pontamine sky blue (PSB), and tissue collected for further histological processing. Topological localization of lesion sites was then identified according to the Paxinos and Watson brain atlas.60 Ejection currents of the same polarity as the molecule's polarity were used for ejection of indomethacin and naproxen, and the charges ranged from 70 to 100 nA. The negative ejection currents for L-glutamate microiontophoresis ranged from 30 to 80 nA. To receive a response similar to receptive field stimulation of the first and second trigeminal dermatomes, the ejection current for L-glutamate was established individually for each recorded cell.By application of holding currents between 5 and 7 nA, with a polarity opposite to the charge of the respective ion, all ions were retained in the barrels.−) were coejected over a period of 3 to 5 minutes of L-glutamate ejection, followed by recovery. For statistics, the first 5 cycles after the ejection of the test-compound ceased were analyzed , in ejection/retaining cycles with ejection period of 7 to 9 seconds and retaining period of 30 seconds of the ejection time to avoid desensitization of the L-glutamate response. Once 5 stable baseline responses were achieved, the testing compounds or control  of one of the drugs and a PSTH at the end of the microiontophoresis episode after further 5 minutes of recovery. After full recovery, this process was repeated with the other substances used  at the end of the experiment for later localization of the recording sites, and for reconstruction of further recording sites in compliance with the microdrive readings. After termination of each experiment, the brain tissue was collected and fixed in 10% formalin for histological processing.−1·min−1 dissolved in 0.9% saline solution, over 5 minutes. After a recovery period of 15 minutes, SNP infusion was repeated and the recorded firing rates of the duration of SNP infusion were averaged; the calculated value equals the SNP-induced activity at baseline. After a resting period of 3 minutes' control, indomethacin (5 mg·kg−1), naproxen (30 mg·kg−1), or ibuprofen (30 mg·kg−1) was slowly infused intravenously. Ten minutes after infusion, SNP injection cycles of 5-minute infusion time and recovery periods of 15 minutes were started. Sodium nitroprusside infusions were repeated at 10, 30, 50, and 70 minutes after drug administration.In a separate group, all the animals received additional cannulation of the carotid artery, ipsilateral to the TCC recording site, for NO donor infusion. Having identified stable cells fulfilling the criteria for electrophysiological measurements: stable dural responsiveness and receptive field in the V1 branch of the trigeminal nerve, we observed the response of wide-dynamic-range neurons to intra-arterial administration of sodium nitroprusside (SNP), 2 µg·kg20), pH 8 to 8.5 as control; and 2.5% PSB  in 100 mM sodium acetate and 200 mM NaCl for current balance.8 L-glutamate, indomethacin, naproxen, and PSB were ionized as anions. OH anions were microiontophoresed as control.Microiontophoresis barrels of the combination electrode were filled with 200 mM L-glutamate monosodium, , pH 8.0; 15 mM indomethacin (Sigma), pH 8.0 to 8.3; 50 mM naproxen (Sigma), pH 8.0 to 8.3; distilled Water . The data sets of intravenous experiments and the effect of electrical stimulation and SNP, as well as microiontophoresis experiments (background and elicited activity) were analyzed by performing a mixed-model repeated-measures analysis of variance. Greenhouse–Geisser corrections were applied if the assumption of sphericity was violated. For all multiple comparisons, Bonferroni correction was applied. In the case of 2). The cells recorded in the experiments were identified being located within the TCC located in the dorsal horn within layers III-V at the level of C1.Slow intravenous administration of vehicle control, indomethacin, naproxen, and ibuprofen had no effect on any physiological parameter recorded  led to a 17 ± 3% inhibition of cell response 10 minutes after administration  when compared to baseline. Naproxen (n = 8) demonstrated a slower profile, significantly inhibiting cell firing  after 20 to 30 minutes with a maximum inhibition of 26 ± 6% after 30 minutes . Neuronal activation was also inhibited by ibuprofen  over a prolonged period (10-30 minutes), with a maximum of 20 ± 5% 30 minutes after administration .The effect of intravenously administered drugs on PSTHs recorded in the TCC was tested in 33 animals. Administration of indomethacin  and were highly reliable . Application of control currents (cells n = 8) had no effect on L-glutamate-evoked cell firing in the TCC . Indomethacin (cells n = 9) significantly inhibited neuronal activity  by 22 ± 8%  compared to control. After ejection ceased, L-glutamate cycles continued to be inhibited by 27 ± 10% . This effect lasted for up to 15 minutes. Naproxen (cells n = 7) also showed an effect on L-glutamate-evoked cell firing in the TCC . However, the onset of the effect was not significant during the ejection of the drug but during the recovery period, displaying a 21 ± 9%  inhibition .The current for microiontophoresis ranged from 60 to 80 nA, and drugs were microiontophoresed for 5 to 6 cycles with ejection periods of 5 to 10 seconds and retaining periods of 15 to 22 seconds. The baseline responses did not show significant differences (FP ≥ 0.27).The microiontophoresis of control ions, indomethacin, or naproxen had no effect on neuronal firing due to electrical stimulation of the dura mater  by 26 ± 3%, returning to baseline levels within 2 minutes after each SNP infusion , naproxen , or ibuprofen  did not alter the increase of background activity in response to SNP infusions  in macrophages in vitro,30 a mechanism that is most likely due to decreased PGE2 production through COX2, as it has been shown that PGE2 is able to upregulate iNOS expression in macrophages in vitro.51 Yet, this mechanism is unlikely to be essential for our results because SNP is a direct donor of NO without iNOS involvement and the selective iNOS inhibitor GW274150 failed in prophylactic treatment of migraine.28 The NO donor glyceryl trinitrate has been known to trigger migraine for some time.29 The delayed headache has the typical clinical phenotype of a migraine attack.55 Glyceryl trinitrate is also capable of triggering a cluster headache attack with a delay of about 10 minutes after infusion, if it is used during an active cluster period.20 Given this context, the modulation of NO-induced early activation of trigeminal activity, as demonstrated here, suggests that NO might play a significant role in the pathophysiology of paroxysmal hemicrania and hemicrania continua. Interestingly, NO also demonstrated modulatory effects through activation of Nav1.9 channels in a mouse model of triptan-induced medication overuse headache,9 and indeed indomethacin has been reported to produce a migraine-like headache when used in hemicrania continua.33Investigating the interaction of indomethacin with NO and NO-mediated mechanisms, indomethacin has been shown to reduce NO production from rat microglia.24 as one key structure within the pathophysiological pathway of trigeminal autonomic cephalagias.44 Nitric oxide donors have previously been described to cause activation of neurons within the spinal trigeminal nucleus, midbrain, and forebrain structures when tested in animal studies.62 Direct activation of trigeminovascular neurons as well as sensitization was found performing electrophysiological work using GTN in an animal in vivo study.39 This suggests the activation, driven by SNP infusion, may be at least partly caused by local NO effects in the TCC or other central structures with modulatory connectivity to the TCC. This includes cervical inputs5 and structures feeding the downstream modulatory pathway to the TCC such as the periaqueductal gray,36 rostral ventromedial medulla,19 and hypothalamic nuclei such as the A11.59 Nitric oxide is known to activate cells through indirect elevation of cyclic guanosine-monophosphate (cGMP) levels,46 causing vasodilation through subsequent decrease of Ca2+. Independent from cGMP levels, it is also capable of modulating the level of CGRP release within the trigeminal ganglion.18 In addition to these effects, the microiontophoresis of an NOS inhibitor at the level of the TCC showed inhibitory effects on L-glutamate and electrical-induced activity of second-order neurons, thereby demonstrating a direct effect on second-order neurons.40 Nitric oxide/nNOS activity has also been suggestive of antinociceptive capabilities in chronic inflammation,63 yet these effects are limited to chronic pain and rely on nNOS activity.Nitric oxide release facilitates the parasympathetic craniofacial pathways37 Nitric oxide is a highly volatile molecule with a very short half-life46; so, we may have achieved higher levels of NO at relevant structures, although the dose of SNP per injection period was lower in our experimental setup (10 vs 50 µg·kg−1), when compared to that of Koulchitsky et al,37 and higher than in their study where they investigated sensitization at the level of trigeminal nucleus.38 A comparison of these studies is, however, challenging because SNP was infused into the carotid artery ipsilateral to the electrophysiological recording sites, with similar direct action to what has been reported.39 Studies of the effect of NO donors on neuronal activity in the trigeminal ganglion, but not the TCC, found a delayed activation.66 This might also be attributed to an increase in local CGRP levels, as well as the receptor activity modulating protein 1 (RAMP-1) component of the CGRP receptor because it was immunohistochemically demonstrated after i.v. administration of GTN to rats.56 Application of CGRP itself on trigeminal ganglia cultures, however, demonstrated increased iNOS expression and NO release.43In our experiments, there was no sensitization as determined by altered baseline activity, change of dural, or cutaneous receptive fields. Although NO has been described to induce central sensitization in a rat model, infusion of SNP intravenously did not produce a significant immediate facilitation of trigeminal firing.In summary, the data, taken with previous work, suggest a possible central action of the NSAIDs indomethacin and naproxen. An inhibitory effect on electrically induced trigeminal firing is demonstrated for indomethacin, ibuprofen, and naproxen; by contrast, the effect on NO-evoked trigeminal firing can be seen for only indomethacin. The results offer new insights into NSAID mechanisms in primary headache disorders and highlight alternative signaling pathways involved in the particular pathophysiology of hemicrania continua and paroxysmal hemicrania. Moreover, the data are consistent with the substantially central nervous system pathogenesis of paroxysmal hemicrania and hemicrania continua. Taken together with our previous studies, perhaps therapies directed at nitrergic mechanisms may be a promising target for the treatment of paroxysmal hemicrania and hemicrania continua.O. Summ has no conflicts of interest to declare; and reports a fellowship from MSD Sharp & Dohme GmbH not related to the work. A.P. Andreou declares no direct conflicts; and reports equipment grant from eNeura, honoraria and travel expenses from Eli Lilly and eNeura, in relation to educational duties and advisory boards, as well as sponsorships for educational purposes from Autonomic Technologies, eNeura, Allergan, Eli Lilly, and Novartis. S. Akerman declares no conflicts; and reports personal fees from Allergan, Amgen, GSK, Novartis, and A&O unrelated to the submitted work. P.R. Holland declares no direct conflicts; and reports research grants from Amgen, Celgene, and Eli Lilly, as well as honoraria and travel expenses in relation to educational duties and advisory boards from Allergan, Novartis, and Almirall. J. Hoffmann declares no direct conflicts and reports honoraria for consulting activities and/or serving on advisory boards from Allergan, Autonomic Technologies Inc, Chordate Medical AB, Eli Lilly, Hormosan Pharma, Novartis, and Teva. He received personal fees for medicolegal work as well as from Sage Publishing, Springer Healthcare, and Quintessence Publishing. All these activities are unrelated to the submitted work. J. Hoffmann reports a research grant from Celgene. P.J. Goadsby declares no direct conflicts, and reports, over the last 36 months, grants and personal fees from Amgen and Eli-Lilly and Company, grant from Celgene, and personal fees from Alder Biopharmaceuticals, Allergan, Aeon Bopharma, Biohaven Pharmaceuticals Inc, Clexio, Electrocore LLC, eNeura, Epalex, Impel Neuropharma, MundiPharma, Novartis, Santara Therapeutics, Teva Pharmaceuticals, Trigemina Inc, and WL Gore, and personal fees from medicolegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee.


Individuals with vigorous physical activity appeared to have a better emotional state and less screen time than those with light physical activity. During this nationwide lockdown, more than half of Chinese adults temporarily adopted a sedentary lifestyle with insufficient physical activity, more screen time, and poor emotional state, which may carry considerable health risks. Promotion of home-based self-exercise can potentially help improve health and wellness.We aimed to evaluate the effects of the COVID-19 lock down on lifestyle in China during the initial stage of the pandemic. A questionnaire was distributed to Chinese adults living in 31 provinces of China via the internet using a snowball sampling strategy. Information on 7-day physical activity recall, screen time, and emotional state were collected between January 24 and February 2, 2020. ANOVA, χ² test, and Spearman’s correlation coefficients were used for statistical analysis. 12,107 participants aged 18–80 years were included. During the initial phase of the COVID-19 outbreak, nearly 60% of Chinese adults had inadequate physical activity (95% CI 56.6%–58.3%), which was more than twice the global prevalence . Their mean screen time was more than 4 hours per day while staying at home (261.3 ± 189.8 min per day), and the longest screen time was found in young adults (305.6 ± 217.5 min per day). We found a positive and significant correlation between provincial proportions of confirmed COVID-19 cases and negative affect scores (r = 0.501,  In late 2019, new cases of Corona Virus Disease-19 (COVID-19) were reported in Wuhan, Hubei province, China . In response, beginning from 23 January 2020, the Chinese government initiated a series of prevention and control strategies to curb the spread of the virus, such as locking down entire cities, and travel warnings, home-based medical observation, and home quarantine ,5. FurthIt is well known that insufficient physical activity is a key risk factor for cardiovascular disease, hypertension, diabetes, and prostate and colon cancer ,10. SincResearch published since the COVID-19 outbreak has focused on epidemiological prediction , clinicaThis is a nationwide cross-sectional study, which aimed to survey changes in activity and daily routine among Chinese citizens during home quarantine. We recruited Chinese adults living in 31 provinces of China during Chinese New Year public holiday (24 January through 2 February 2020), which coincided with the initial stages and outbreak peak of the COVID-19 epidemic. The questionnaire was distributed using a snowball sampling strategy through contactless distribution on the internet. Individuals were asked to recall their physical activity and emotional state over the past 7 days, within an overall collection period between 31 January and 9 February 2020. Instructors in social sports in various provinces participated in questionnaire distribution via their working platforms. In addition, the WeChat Subscription and social media platforms with high click-through rates also reprinted our questionnaire. The sample size of each province with quotas based on the sampling plan of the sixth national physical fitness monitoring, and the sample size of all provinces, was divided into four levels according to population density . Data anPhysical activity data and sedentary time were collected using the Chinese validated version of the International Physical Activity Questionnaire (IPAQ)-Short form , and traMood was assessed using the Positive and Negative Affect Schedule (PANAS) questionnaire of two 10-item scales . Ten iteWe considered four relevant sociodemographic factors in our analysis: place , sex (men and women), age group, and geographical location (province). Age was divided into ten groups: <20 years, 20–24 years, 25–29 years, 30–34 years, 35–39 years, 40–44 years, 45–49 years, 50–54 years, 55–59 years, and ≥60 years. Furthermore, in order to clarify the correlations of physical activity, screen time, and mood of individuals during the epidemic, the three physical activity levels were analyzed with screen time and mood state. p < 0.05 was defined as statistical significance. Our overall prevalence estimates were compared with the global age-standardized prevalence of insufficient physical activity and China’s prevalence of insufficient physical activity (non-epidemic period) from WHO [Descriptive statistics such as percentages, 95% CIs, means, and standard deviations, were calculated for categorical variables and continuous variables, respectively. The χ² test was used to assess statistical difference in the prevalence of insufficient physical activity according to region of residence , sex (men and women), and age subgroups. The normality of continuous variables was checked by the Kolmogorov–Smirnov test. The differences in screen time, positive affect scores, and negative affect scores among region of residence , sex (men and women), age subgroups, and three intensity levels of physical activity were tested using ANOVA. The level of from WHO . Given tfrom WHO , we wereDuring the home quarantine required by the COVID-19 outbreak, 12,107 participants (5633 men and 6474 women) were included in the final analysis . Across 2 = 13,088.10, p < 0.0001; 2 = 12,700.00, p < 0.0001; Compared with the global level reported by WHO, the prevalence of insufficient physical activity more than doubled during the initial stage of COVID-19 epidemic in China  was significantly lower than among women  during home quarantine (χp < 0.0001) and 25–29 group , while negative affect scores of men were somewhat lower , while there was a downward trend of negative affect scores from vigorous physical activity to light physical activity  were Hubei 54.8%), Guangdong (55.7%), Henan (60.7%), Zhejiang (60.3%), and Hunan (59.9%). Three of those provinces fell below the average in prevalence of insufficient activity in China during the epidemic. For the Hubei province, the area of most serious viral spread, the prevalence of insufficient physical activity was not as high as we expected. However, focusing on Wuhan city, the epicenter of the outbreak, the prevalence of insufficient physical activity was nearly 9% higher compared with that in the Hubei province. Meanwhile, another city seriously affected by the epidemic, Wenzhou, had a similar trend in the prevalence of insufficient physical activity compared with that in Zhejiang province (an increase of 3.5%). Hence, with the growing coronavirus crisis, people in outbreak areas are likely to experience fear of becoming sick, feelings of helplessness, and panic [%, GuangdThe prevalence of insufficient physical activity in first-tier cities of China less affected by COVID-19 such as Beijing (48.9%) and Shanghai (50.2%) were obviously lower than the average level of China during initial stages of the outbreak, and Beijing is the least affected area. This phenomenon may be associated with high economic and educational levels in Beijing ,24. It iUnexpectedly, several provinces that were less strongly affected by COVID-19, but had strict home quarantine and travel restrictions, showed a high prevalence of insufficient physical activity: Qinghai (73.7%), Xinjiang (69.3%), Jilin (68.8%), Heilongjiang (68.6%), and Tibet (67.0%). Because Jilin and Heilongjiang are located in the cold northeast regions of China, the closure of winter sports facilities because of the outbreak may explain the high prevalence of insufficient physical activity. Qinghai, Xinjiang, and Tibet are in western areas, with relatively underdeveloped economies and low health educational levels. Facing a public health emergency, residents in these provinces may place limited value on exercise, or their exercise habits may be easily changed. One similar study reported that compared to regular school days, children and adolescents in Tibet engaged in significantly less physical activity on the weekend . MoreoveScreen time among adults is a significant factor in assessing health behaviors. Screen time among Chinese residents was more than 4 hours per day during home stay. Several epidemiological studies indicated that 2 h/day on screen-based entertainment was associated with a 48% increased risk of all-cause mortality while 4 h/day with an approximately 125% increase in risk of cardiovascular disease (CVD) events . Screen Finally, there was a positive correlation between the proportion of confirmed COVID-19 cases with provincial negative affect scores, with the highest negative affect scores reported in Hubei province. During the initial stage of the COVID-19 outbreak, the higher negative affect scores may be associated with the fear of falling sick ,38 or dyOur study has several limitations. First, because of the limited resources available and the rapid onset of the COVID-19 outbreak, the snowball sampling strategy was adopted. Although our respondents are not nationally representative samples of Chinese adults, we made efforts to utilize the social platforms used by instructors in social sports in various provinces to ensure the diversity and demographic representativeness of participants. Second, there seems to be an oversampling of younger participants (aged ≤ 30 years), especially students in our surveyed population, due to the relatively high participation in social networks, finally diminishing the study generalizability. Third, self-reported data on physical activity may not be as accurate as assessment using accelerometers, although we chose a WHO-approved physical activity questionnaire (IPAQ-S) with high reliability and validity for the investigation. Fourth, we only had available data of global age-standardized prevalence of insufficient physical activity and prevalence of insufficient physical activity in China from WHO to assess the differences between the epidemic period and a non-epidemic period. Lastly, it would be necessary to conduct a prospective study on the same group of participants after the epidemic period to capture trends in physical activity over time. Notwithstanding the aforementioned limitations, this study provides invaluable information on physical activity status across 31 provinces in China during the initial stage of the COVID-19 epidemic. Most significantly, our findings indicate the necessity of early health promotion and fitness guidance during home quarantine. This could guide future policy and programmed planning for health promotion during future health emergencies.In summary, during the initial phase of the COVID-19 outbreak, nearly 60% of Chinese citizens engaged in inadequate physical activity, while the prevalence of insufficient physical activity was more than double the global level. Screen time among Chinese residents was more than 4 hours per day during the quarantine, and the longest screen times were found in young adults. Women, young adults, and the residents of remote regions had a higher prevalence of insufficient physical activity. During home quarantine, there was a positive correlation between the proportion of confirmed COVID-19 cases with provincial negative affect scores, and individuals engaging in vigorous physical activity had better emotional states and less screen time while the group engaging in only light activity showed the opposite trend. If the trends noted during the outbreak continue, the risk of chronic diseases in Chinese residents may be increased.


The objective of this paper is to demonstrate, considering the experiences from Chinese people, if slow transit constipation (STC) can be accurately diagnosed, choosing patients qualifying for surgery, subtotal colectomy with antiperistaltic cecosigmoidal anastomosis (STC-Anti-CSA) may come with more acceptable short and long-term outcomes.A retrospective study was performed at a department of colorectal and anal surgery. A cohort of 29 patients were coming with up to 5 years’ follow-up care, who were in a diverse range of age, BMI, laxative medicine histories, including both males and females. Pre-surgery work-up strictly followed a protocol designed to rule out the patients who were not suitable for surgery treatments. Classification of STC was followed after diagnosis. STC-Anti-CSA was performed in all cases. The operative time, blood loss, average post-operative length of stay (LOS), frequency of BMs, stool consistency and patients satisfaction, by using Wexner constipation score (WCS), numerical rating scale (NRS), and abdominal bloating score (ABS), over the study period were recorded.2. The period of laxative medicine history was 4.8 years (2–13 years). The mean operative time was 152 ± 34 min, and the mean perioperative blood loss was 123 ± 51 mL. Average post-operative LOS (LOS) was 8 days. There were no severe post-operative complications, peri-operative mortality, anastomotic leaks, or revisions of the original surgery. Initial post-operative BMs averaged 6 times/day. During the period of 1 month to 12 months follow-up care, BMs fell down to 2 or 3 times/day. By the 1st to 3rd year follow-up care, BMs averaged 5 to 7 times/week. However, from the 4th year to 5th year, constipations recurred somehow. However, most patients were satisfied with their bowel patterns.In this study, there were 14 males and 15 females, with mean age 51, and BMI from 20.14 to 31.62 kg/mSTC-Anti-CSA can receive acceptable postoperative outcomes as long as the patients can be accurately diagnosed and classified as severe STC. Among the surgical procedures for STC, this procedure may be another suitable option, especially for Chinese people. Normally such patients would all have a laxative taking-history, including osmotic laxatives, prescription medications, supplemental medicine of higher fiber intake. Some patients have surpassed dietary changes but no obvious improvements. In the initial period of STC, patients can have a limited benefit from laxatives, fiber intaking, and dietary changes.,4 However, usually over years and even decades, these treatments would become less and less efficient, and less benefits can be received from such kinds of medicines, and there usually coming with progressive worsening abdominal distention and less BMs. To defecate and relieve this constipation, patients have to resort to a higher dose of laxative, which can cause a higher volume capacity of colon such as dilation, elongation, and redundancy. Such changes of colon reversely can cause more severe constipation, which may require acute hospitalization for abdominal distention and obstructive symptoms, such as nausea, vomiting, and pain. Unfortunately, even after acute hospital treatment, including a placement of a nasogastric tube for gastric decompressing, enema from anus, some STC patients still need an acute emergent surgery of colostomy due to some of colon wall necrosis from heavy stool burden.Approximately 15% of the adult Chinese population are suffered from chronic constipation.To avoid such severe outcomes happened, along with selecting a surgical timepoint which can receive a better postoperative recover, as a surgeon, how to accurately diagnose and classify the STC severity becomes a top thing. A tailored selection of surgery process before life-threatening complications occurring is indispensable. The objectives of this study are:1.to classify the STC patients who need a surgical treatment and then2.to demonstrate the outcomes and benefits of a subtotal colectomy with antiperistaltic cecosigmoidal anastomosis procedure, comparing with other surgical treatments, among Chinese people.2A written informed consent was obtained from the patient, and institutional Ethics Committee of the Second Hospital of Jilin University approved this study.From April 2010 to May 2014, in the Second Hospital of Jilin University, 29 patients were selected and followed up until now. For the safety and effectiveness of the treatment plan chosen, before the surgeries involved, the surgical indications are strictly followed as: all the patients to receive a surgery should be qualified for1.the Rome III diagnosis criteria for constipation;2.at least two positive Sitz Mark Colon Transit Studies to confirm the exist of STC;3.laxative medicine-taking history is more than 2 years;4.Wexner constipation score  is more than 15;5.age range is from 18 years old to 70 years old;6.surgical involvement is strongly desired by the patient.Meanwhile, there are also exclusion criteria:1.some sever comorbid conditions, such as liver dysfunction, and aspiration dysfunction, not suitable for a surgical procedure;2.evidence of psychological symptoms or history of mental illness;3.diagnosis of outlet obstruction;4.combined with life-threatening diseases;5.evidence of organic colon disease.Finally, all the patients underwent surgery.,7 which was also mentioned above in the exclusion criteria. These examinations were necessary and indispensable, because if ruled out, the patients meant to should been underwent another different surgical procedure involving. A key diagnostic maneuver used is Sitz Mark Colon Transit Study, which is not only been used to diagnose but also to classify the severe degree of STC. All the candidates in this study showed a value of 5 or more out of 20 radio-opaque markers present on abdominal X-ray on the 5th day after the initial, which were considered to be a positive result.The patients’ characteristics are listed in Table Subtotal colectomy with antiperistaltic cecosigmoidal anastomosis was performed on all the patients. The ascending colon was dissected at around 10 cm from ileocecal valve. At the meantime, the ileocolic mesentery, where the ileocecal vessels were, and cecum were carefully preserved in every case. The distal margin was at sigmoid colon, around 10 to 15 cm up from peritoneal reflection. The distance from peritoneal reflection reserved depended on the individual situation about the colon margin vessel supplying and the length of ileocolic and sigmoid colonic mesentery. Close the left ascending colon. An end to end anastomosis was performed by a circular stapler approximating the cecal stump  to the sigmoid colonic stump. Considering the blood supply, rotation of the ileocolic mesentery should be avoided when creating the anastomosis. During hospitalization, the operative time, blood loss, complications, if occurred, and post-operative length of stay (LOS) were recorded. Post-discharge from the hospital, frequency of BMs, stool consistency, and patients satisfaction at the time set point of 1 week post-surgery, 1 month, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years were recorded. Long-time complications should also be recorded, such as abdominal pain and distention, constipation, incisional hernia, and anastomosis leak, if there happened. All the data were collected through out telephone calls after discharge from hospital.Two figures were designed to evaluate the outcome of treatment pre- and post-operation. One of them is an efficacy endpoint which has recorded the overall symptom improvement score given by the patients at the timepoint of the 6th month, the 1st year, the 2nd year, the 3rd year, the 4th year, and the 5th year post-operation, with the standard following statement: “The treatment helped to improve my bowel problems,” using a 5-point Likert Scale . Meanwhile, another efficacy endpoint was also applied to each patient. In that figure, improvements of severity of individual constipation symptom were assessed by 10-cm Visual Analogue Scale ("nothing” to “extremely intense”). Furthermore, a thorough table was used to assess to functional recovery compared at different time points , by using the scores of WCS, abdominal pain intensity assessed by the numerical rating scale , and the abdominal bloating score .32, with a mean of 26.18 kg/m2, which suggested obese for Chinese people. All the candidates involved in this study had a chronic constipation history over 2 years (2 years to 15 years), with the WCS ranging from 18.4 to 24.1. All the patients had had a laxative-taking history through the STC, from 2 years to 14 years. No patients had received a major abdominal surgery before this one. The operative data and hospital LOS have been shown in Table As shown in Table Surgery related complications are shown in Table Post-operative frequency of BMs is tabulated in Figure The improvements of overall STC symptom assessment post-operationally are shown in Figure Pre- and post-operational functional recovery results were shown in Table 4 Although the pathogenesis of STC is still unknown quite clearly, increasing doctors tend to believe that STC is a functional disorder, charactering by continuing colonic smooth muscle activity decreasing, intrinsic colonic nerves decreasing, and the number of cells of Cajal reducing. Until now, no effective non-surgery approaches have been recommended toward the entire nervous system degeneration. Therefore, the colon with STC adapts to becoming a non-functional pouch or reservoir. At this view, a surgery involvement would become the only approach eventually. However, the timepoint of surgery involvement is top crucial, as is shown in Figure The STC has a high morbidity in China. Nowadays, two surgical approaches are acceptable worldwidely, one is total colectomy with ileorectal anastomosis, the other is subtotal colectomy with ceco-rectal anastomosis. The former is widely used especially by the surgeons from Europe and the United States, because of its high cure rate and low recurrence. However, the patients receiving this such surgery are tend to suffer from refractory diarrhea, abdominal pain, and distention.–13 The latter preserves the ileocecal valve, which can remain the pressure difference between ilium and cecum. The patients who receive this term of treatment can have a lower morbidity of refractory diarrhea, which would definitely bring with a higher quality of post-surgery life.In terms of treatments for STC, surgery is a common and usually the final approach, especially for the patients with poor responses to conservative treatment, such as laxative, and diet changes.Our institute performed some subtotal colectomies with ceco-rectal anastomosis on the patients of STC. The patients were found that also tend to suffer from unacceptable increased BMs. We compared the anatomy between the Chinese people and European people, and then came to a hypothesis that Chinese patients having more refractory diarrhea rates due to the reason that the Chinese people had a longer sigmoid colon and shorter rectum than the Europeans. So when the sigmoid colon was removed from abdomen, there were not enough organ to deal with the water ingredients in stools for Chinese, which would definitely lead to a diarrhea. Due to this fact, our institute began to perform the surgery of subtotal colectomy with antiperistaltic cecosigmoidal anastomosis, which preserved more length of colon than that of the ceco-rectal anastomosis.In fact, the type of surgery for the STC to perform, such as whether total or subtotal colectomy, whether ileocecal valve sparing or not, whether isoperistaltic or antiperistaltic cecorectal anastomosis, have been discussed for many years. For every type of surgery, there were successful cases with high cure rate and more BMs than before, meanwhile usually with several failure cases with recurrence of constipation. What should be more meaningful to analysis is the reasons of causing the failure cases than others. In our opinion, the key point of surgery efficacy is different surgical design depending upon different individual situation. Considering this viewpoint, we highlight the type of surgery for the Chinese STC patients is subtotal colectomy with antiperistaltic cecosigmoidal anastomosis, which is different from other surgeries, due to the reasons as follows:1.the Chinese people tend to have a longer sigmoid colon than European and American people, so such procedure can bring an easier process for surgeons which is not require a rotation of the ileocecal junction and could avoid causing blood vessel torsion, and is more easier to anastomosis than ileo- or ceco-rectal anastomosis. Furthermore, the longer sigmoid colon preserved can lead less tension around anastomosis, which can decrease the incidence of anastomosis leak.2.A longer sigmoid colon preserved can absorb more water ingredients from stool, which can be helpful to alleviate morbidity of refractory diarrhea after the surgery, and the bacterium in the sigmoid colon can also be preserved, which can provide the benefit to maintain the hemostasis of micro-environment around.3. An additional benefit is the ileocecal valve can provide a sphincter-like function, which can decrease the pressure with ileum distention, meanwhile maintain the pressure in cecum and ascending colon. That sphincter-like function of ileocecal valve can prevent the back flow of bacterial content from the cecum to ileum.The preservation of the ileocecal valve during this surgery has been proved to have an advantage accepted widely. With the function of ileocecal valve, the food ingredients can stay a longer time in the terminal ileum, as a result, electrolyte, bile salt, and vitamin B12 can have a better absorption.4.The antiperitaltic anastomosis can make a pouch-like organ, which can delay the intestinal content emptying, avoiding the refractory diarrhea post-surgery.As shown in Figure  Wang has a score of 5.4 ± 1.6 in 41 cases of total colectomy with ileorectal anastomosis. Zhang has a score of 3.2 ± 1.8 in 23 cases of total colectomy with ileorectal anastomosis, a score of 3.7 ± 1.6 in 22 cases of subtotal colectomy with ileosigmoidal anastomosis. Yu has a score of 5.0 ± 1.0 in 31 cases of open-abdominal both total colectomy with ileorectal anastomosis and subtotal colectomy with antiperistaltic cecorectal anastomosis. Song has a score of 6.11 ± 2.09 in 41 cases of subtotal colectomy with cecorectal anastomosis, a score of 4.51 ± 1.8 in 41 cases of total colectomy with ileosigmoidal anastomosis. Finally, our study has score of 4.12 ± 1.10 in 29 cases with subtotal colectomy with antiperistaltic cecosigmoidal anastomosis, which has a better result than most surgery groups. Among the antiperistaltic anastomosis groups, our study has the best score result, comparing with the Xu's, Yu's, and Song's group. It shows us that sigmoid colon reserved does not lead to constipation as long as the length of sigmoid colon remaining is proper. In our study, the distal margin of sigmoid colon is around 10 to 15 cm up from peritoneal reflection, which means the location of anastomosis is very near to the junction of sigmoid colon and rectum. That anastomosis can have the benefits of avoiding the refractory diarrhea along with the ileocecal valve existing, preserving the function of colon as much as possible, and making the surgery more easier than the ileorectal anastomosis.As shown in Table 5This study demonstrates that, following algorithm of workup of STC, the surgical indications criteria and excluding criteria, it is feasible to perform this surgery of subtotal colectomy with antiperistaltic cecosigmoidal anastomosis with optimal short- and long-term results for severe STC as compared with other Chinese surgical groups, who performed subtotal and/or total colectomy. Meanwhile implications of this study long-term results suggest that, considering the constipation would recur ultimately, a minimally invasive surgery could be recommended as a better choice, such as subtotal colectomy with antiperistaltic cecosigmoidal anastomosis, comparing with total colectomy. Finally, subtotal colectomy with antipeirstaltic cecosigmoidal anastomosis can be another suitable surgical procedure, especially for Chinese people.I would like to thank Dr. Jian Shi for assistance in preparation of the manuscript.Conceptualization: yongping yang, Tongjun Liu.Data curation: yongping yang, Jian Shi, Zeyun Zhao, Lingyun Yu.Formal analysis: yongping yang, Jian Shi, Zeyun Zhao.Methodology: yongping yang, Jian Shi, Tongjun Liu.Resources: Zeyun Zhao.Supervision: Lingyun Yu, Tongjun Liu.Writing – original draft: yongping yang, Lingyun Yu.Writing – review & editing: Lingyun Yu, Tongjun Liu.