Establishment of an unbiased association between gestational weight gain (GWG) and perinatal health is urgently needed in China, which has the largest population in the world. Our study aimed to create weight-gain-for-gestational-age charts using early pregnancy body mass index (BMI) to present selected percentiles of GWG in China.A population-based follow-up study was conducted based on the Maternal and Newborn Health Monitoring System, which recruited 132,835 pregnant women between October 2013 and September 2016 in 12 districts/counties of 6 provinces in China. Multilevel analyses and restricted cubic splines were performed to model the longitudinal repeated maternal weight gain measurements and obtain smoothed curves for GWG. The internal and external validation of each model was also assessed.To develop models of GWG, 34,288 women were included. Smoothed percentiles of GWG in the 3rd, 10th, 50th, 90th, and 97th percentiles were estimated for each week of gestation. The median figures for GWG were 15.0 kg, 14.4 kg, 13.5 kg, and 12.1 kg in underweight, normal weight, overweight, and obese women, respectively, at 40 weeks. Of all the weight measurements, more than 70% and 95% fell within the expected 1 to 2 standard deviations, respectively. To accomplish external validation of the models, 20,458 women were included. The specificities of measurements in the 5th, 10th, 15th, 25th, 75th, 85th, 90th, and 95th percentiles in four BMI categories were between 90% and 100%.The population-based gestational weight gain Z-score charts performed well in providing guidance regarding expected gestational weight gain in Chinese women. The Institute of Medicine (IOM) proposed guidelines for the rate of GWG and total GWG by a woman’s pre-pregnancy body mass index (BMI) in 2009.12 Z-score charts can provide mean values and standard deviations (SDs) for weight gain throughout gestation, specific to gestational week, which would be used to calculate Z-scores and percentiles for GWG by GA. New measures have been developed in the United Kingdom,13 the United States,12,14 Sweden,15 and Malawi.16 However, most of these were established with small sample sizes and were not population based, not stratified by pre-pregnancy BMI values, and/or not verified for validity. The only standard that was based on population and stratified by pre-pregnancy BMI values was created in Sweden; however, external validation was not provided,15 which is necessary for clinical application. In addition, all of these Z-score charts are based on the World Health Organization (WHO) BMI categories, which are not available specifically for Asians, who have a higher body fat ratio and risk of obesity-related diseases than Europeans with the same BMI.17,18 Thus, there are different cut-offs for BMI categories for people of Asian and European descent.Z-score charts of average maternal weight gain by GA can be created just as the growth standards for children aged 0 to 5 years were created, which have now been applied in many countries worldwide.19Because China has the largest population in the world, there is an urgent need to establish Z-scores for GWG in Chinese women by GA. Therefore, we performed this study to create Z-score charts based on Chinese BMI categories in a population-based follow-up study of Chinese women. In addition, we assessed the internal and external validation of the new charts. We investigated healthy pregnant women with good pregnancy outcomes, according to recommendations by the WHO.Data on the study population were obtained from the Maternal and Newborn Health Monitoring System (MNHMS) at the National Center for Women and Children’s Health, Chinese Centers for Disease Control and Prevention. The MNHMS was established to comprehensively monitor the prenatal health care and pregnancy outcomes information of pregnancy women. Participants resided in 12 districts/counties of 6 provinces: Liaoning, Hebei, Fujian, Guangdong, Sichuan, and Yunnan. A total of 132,835 pregnant women had been recruited between October 2013 and September 2016. One city from each province was selected randomly, and then two districts/counties from each city were selected randomly via three-stage cluster sampling. All pregnant women in 12 districts/counties were included if they had resided for at least 6 months at one of the 12 study sites and had been recruited at their first prenatal care visit. The data of MNHMS contained all maternal information obtained prior to pregnancy, at all prenatal care visits, at delivery, and during neonatal care . Women were excluded if any weight observations that were 2). The Chinese BMI category standards of the Working Group on Obesity in China20 were used to categorize women as underweight (<18.50 kg/m2), normal weight (18.50–23.99 kg/m2), overweight (24.00–27.99 kg/m2), or obese (2). Maternal weight should be assessed at every routine prenatal visit. Gestational weight gain (in kilograms) was calculated as the difference between the measured weight at the time of a prenatal care visit or at delivery and the measured weight at the first prenatal visit. Gestational age was estimated based on the last menstrual period and ultrasound.Maternal height (in centimeters) and weight (in kilograms) were measured at the first prenatal care visit (<13 completed weeks) to calculate an early pregnancy BMI (kg/m11 The number and location of the spline knots were chosen according to the Akaike information criterion (AIC), and a minimum AIC value for the model meant that the goodness of fit is optimal.We created four separate models for each BMI category  and applied multilevel (random-effects) analysis to model the longitudinal repeated maternal weight gain measurements as a function of GA. Weight gain measurements were log transformed  before modeling to ensure homoscedasticity of any residual errors and normality of distribution of the data. To prevent negative values on the charts, a constant was added to all weight measurements to shift the minimum value of the distribution to 1 before we modeled the data on the log scale. The models were specified with two levels (measurements within and between women) and random intercepts and random slopes, which provided more flexible estimates of weight gain patterns. To obtain an equation for week-specific SDs, an unstructured covariance matrix was ensured from the multilevel model. We modeled GA using restricted cubic splines to obtain smoothed curves for GWG.8,12 . After regrouping, the data were modeled with the same strategy, and the new Z-score charts were compared with those obtained from original classification.A sensitivity analysis was performed to explore the possibility of misclassification bias that might have occurred through for the use of early pregnancy BMI rather than pre-pregnancy BMI. We performed a post hoc analysis to estimate the proportion of women that might have been misclassified because of a weight gain of 2 kg during the first trimesterWe assessed the internal validation of the model with the training sample set by visually comparing the fit of the predicted means and SDs to the crude data and calculating the percentages of crude weight gain measurements that fell within the predicted limits for 1 and 2 SDs . Moreover, we assessed the external validation of the model using the validation sample set that was collected during the third study year. We assessed the external validation of the model with two methods. First, we use the same method as internal verification to compare the fit of the models that developed by training set to the crude weight gain data of validation set. Then to further explore the external validation, the sensitivity and specificity of each BMI category model were calculated to identify selected percentiles for GWG and the Youden index (Youden index = sensitivity + specificity − 1) was also calculated. Because no optimal cut-offs of GWG Z-score charts were available, we selected 5th, 10th, 15th, 25th, 75th, 85th, 90th, and 95th percentiles to assess. In order to obtain the sensitivity and specificity, the Z-scores of the validation samples were calculated with the developed GWG models . The “gold standard positive” was defined as the calculated Z-score < the expect x-th percentile (estimated by the model), and “test positive” was defined as the calculated Z-score < observed x-th percentile . Taking the 10th percentile as an example, “gold standard positive” was that if the calculated Z-score was less than the expected 10th percentile, and “test positive” was that if the calculated Z-score was less than observed 10th percentile. All analyses were performed using STATA Software, version 13.0 .A total of 88,319 pregnant women were recruited between October 2013 and September 2015 in the MNHMS. We excluded women with multiple births, preterm births, or stillbirths; those whose early pregnancy BMI and plausible weight gain data were missing; and those with pre-existing hypertension or type 1 or 2 diabetes mellitus. This left 44,399 women in the sample. We then excluded women who had newborns without records of birth weight or with abnormal birth weight . Finally, we excluded women with implausible weight observations. We therefore included 34,288 women and 253,026 weight observations in the analysis  had a normal BMI during early pregnancy, 6,486 (18.9%) were underweight, 3,817 (11.1%) were overweight, and 894 (2.6%) were obese. Corresponding numbers of weight measurements were 48,397, 167,924, 29,502, and 7,203, respectively. Overall, the median number of weight measurements was 8  per pregnant woman, and the mean GA at first prenatal visit was 9.5  weeks. The characteristics of the 34,288 women and infants who participated in the study are detailed in Table Equations for the smoothed mean values and SDs of weight gain by GA in each BMI category  are shown in Table Table n = 10,448, 77,311 weight measurements); 82.8% of the women  remained in the normal weight group. In the overweight group, 32.0% of the women  were added to the normal weight group to form a reclassified normal weight group . Then, 32.0% of overweight women  were excluded from the overweight group and 29.2% of women from the obese group (261/894) were added to the overweight group to form a reclassified overweight group . Finally, 29.2% of women in the obese group (261/894) were excluded to form a reclassified obese group . The percentile values on the GWG Z-score charts were indistinguishable after we reclassified these groups.The result of sensitivity analyses showed that 17.2% of women in the normal weight group  were excluded and added to the underweight group to form a reclassified group of underweight women , 72.3% , 71.3% , and 70.8%  of crude weight measurements fell within the expected 1 SD (68% expected) of the mean, respectively, and 95.8% , 95.9% , 96.0% , and 95.6%  of weight measurements fell within the expected 2 SDs (95% expected) of the mean, respectively. The estimated lines for means, 1 SD, and 2 SDs and crude weight measurements are shown in Figure The population used to assess the external validity  included 20,458 pregnant women with 146,994 weight observations. Baseline demographic characteristics are shown in In our study, we developed percentiles and Z-score charts that described GWG by GA of healthy Chinese women with BMI categories based on Chinese population norms. These models for weight gain by GA performed well for Chinese women in internal and external validation analyses, which showed that the sensitivities, specificities, and Youden indexes of the Z-scores were acceptable. Our Z-score charts could, therefore, be used for epidemiologic studies within the Chinese population to estimate the unbiased association between GWG and maternal and offspring outcomes. However, because optimal Z-scores and percentile ranges remain to be established with more sufficient clinical evidence, these charts should be used only to encourage clinicians to closely monitor a woman with a very low or very high Z-score, rather than recommending immediate behavioral alterations.15,21 In other words, the IOM recommended ranges fell within the 25th and 75th percentiles of our Z-score charts for underweight and normal weight women and fell below the 50th percentile for overweight and obese women. The common reference that is currently used in China to recommend GWG in clinical practice and epidemiological studies is the IOM recommendations. However, total GWG recommendations proposed by the IOM are linked to pregnancy duration, and the application of a single standard during the whole pregnancy would introduce bias for weight management. Therefore, compared with IOM recommendations, our Z-score charts may be most suited for guidance in monitoring GWG in pregnant women in China.In our study, median weight gains at 40 weeks were within the ranges of the IOM recommendations for underweight and normal weight categories and were higher than the IOM recommendations for overweight and obese categories, which was consistent with other studies.12–16 A study based at the Magee-Womens Hospital in Pittsburgh reported mean singleton GWG at 40 weeks of 16.4 kg for normal weight women12 and 15.8 kg for overweight women14; these figures are higher than those observed in our study . A cohort study, the INTERGROWTH-21st Project, reported a standard GWG at 40 weeks of 13.7 kg in normal weight women who came from eight countries, including China13; this is about 0.7 kg less than the average GWG seen in our study. The INTERGROWTH study did not develop Z-score charts for women who were underweight, overweight, and obese. In addition, in this cohort study, 5 GA windows were selected for 8 countries to obtain 40 comparisons to assess variations in GWG across countries. Only the data from China showed high (>0.5) standardized site differences , which indicated that Chinese women might be different from other study populations; this can probably be attributed not only to socioeconomic and cultural factors, but also to actual biological differences. Thus, it remains debatable whether this international standard is suitable for Chinese women. Most previous studies used populations with a small sample size , were not population-based, and did not obtain Z-score charts for women in different BMI categories. A population-based cohort study performed in Sweden obtained GWG values at 40 weeks that differed from ours by 0.2 to 1.4 kg for different BMI categories.15 However, it is difficult to compare our charts with previous charts because study designs, methods, and populations are different.Previous studies have provided few relative GWG Z-score charts.22 Temporal validation is one category of external validation,23 which is better than internal validation.22 In our study, we assessed the temporal validation of our GWG Z-score charts. After we developed the GWG models with a first sample of pregnant women, we assessed the models’ external validation among pregnant women who delivered in different years. Because no optimal cut-offs of GWG Z-score charts were available, we selected several percentiles to assess external validation by means of calculating the sensitivity, specificity, and Youden index. The analysis of external validation showed that our GWG Z-score charts had high sensitivities and specificities for Chinese underweight, normal weight, and overweight women.To date, no GWG Z-score charts have been externally validated, although it is essential for practical use to validate and calibrate new models. Whether the models can be applied to populations other than the one studied depends on their performance outside the training sample, that is, external validation.19 with a large sample size of healthy pregnant women who had good maternal and perinatal outcomes. Compared with total GWG recommendations, Z-score charts could provide means and SDs throughout most of the pregnancy for clinicians or pregnant women to monitor the progress in GWG. Although a single low or high Z-score might be uninformative, more concern could be taken when low or high Z-scores occur repeatedly or if a very low or very high Z-score appears, so that clinicians could give their patients advice or treatment.In this population-based study, we developed Chinese GWG Z-score charts, according to WHO recommendations,8 which also caused flat weight gain curve lines and the less reliable results in the early period (<13 weeks). However, the weight of the first prenatal care in early pregnancy is used by obstetric clinicians as individual-specific baseline to monitor GWG in second and third trimester, which may mean that our study has more practical application value.One limitation of our study is that the early pregnancy BMI, rather than pre-pregnancy BMI, was used to classify women. This introduces the possibility of misclassification bias. However, it is not feasible to measure the pre-pregnancy weight of women in large population studies, especially in low-risk women, and self-reported pre-pregnancy weight is generally unreliable due to its ability to introduce error or recall bias. The results of the sensitivity analyses indicated that the possibility of misclassification was small and acceptable. Early pregnancy BMI was used as the baseline, in fact, pregnant women have 0–2 kg weight gain in the first trimester,n = 894]). The small sample size did not allow us to classify obese women into different classes and resulted in lower specificities for validity of Z-scores of obese women within the 5th and 10th percentiles in comparison with other BMI categories. Further study is needed in a larger sample of obese pregnant women to ensure the robustness of GWG model. In addition, the failure to identify and remove pregnant women who have some pregnancy complications that are reportedly associated with excessive or insufficient GWG is one of the limitations of our study. We do not have sufficient evidence to exclude pregnant women, because the diagnostic evidence associated with these complications was not collected, such as medication records and surgery records. Therefore, further comprehensive study design and information collection needs to be done.Another limitation is that the sample size of obese pregnant women in our study was comparatively small, because the rate of obesity is low in Chinese pregnant women (the rate of obesity in our study was 2.6% [In conclusion, we have described Z-score charts for GWG in a population-based follow-up study of Chinese women with healthy pregnancy outcomes, which provides a tool for epidemiological studies to explore the association between GWG and adverse pregnancy outcomes. Moreover, these Z-score charts provide greater sensitivity for monitoring a woman’s GWG than measurements such as total GWG or the rate of GWG. The Z-score charts were developed using Chinese women with healthy pregnancy outcomes; however, they are not necessarily equal to the optimal GWG. Further epidemiological studies are needed to make the associations of Z-scores and long-term outcomes, such as maternal weight retention and childhood and adolescent obesity, and to establish thresholds for optimal weight gain.


The usefulness, safety and oncological validity of laparoscopic gastrectomy (LG) for remnant gastric cancer (RGC) have not been widely reported.A total of 38 patients who underwent gastrectomy for RGC were enrolled at Wakayama Medical University Hospital between April 2008 and December 2018. All consecutive patients were included in this retrospective study; the patients were divided into the open gastrectomy group and the laparoscopic group according to the sequential nature of their operation. Fifteen patients underwent open gastrectomy for RGC (OGR) between April 2008 and December 2013, and 23 patients underwent LG for RGC (LGR) after 2014.P = .002), 3 patients of which (25%) converted to open gastrectomy. There was no significant difference in the number of lymph node dissections or in operative time between the 2 groups, but blood loss was significantly lower in the LGR group than that in the OGR group (P = .002). Furthermore, although there was no difference between the 2 groups in C-reactive protein value on postoperative day 1, C-reactive protein value on postoperative day 3 was significantly lower in the LGR group than in the OGR group (P = .012). There were no differences in postoperative complications or long-term outcomes, including recurrence-free survival and overall survival.In the OGR group, all initial operations were performed by open surgery, whereas in the LGR group, 11 patients (47%) initially underwent laparoscopic surgery and 12 patients (53%) initially underwent open surgery (LGy is suitable in cases in which the initial surgery is performed by laparoscopic surgery. Even if the initial surgery is open surgery, it is oncologically equivalent to open gastrectomy and can be performed safely with less blood loss. It is often diagnosed as advanced gastric cancer that is revealed after completion of standard surveillance for the initial disease. We previously reported that a periodic endoscopic follow up after prior gastrectomy was an important factor affecting the curative resection of RGC. Meanwhile, laparoscopic gastrectomy (LG) has become widespread, with advances in endoscopic surgical instruments and understanding of microanatomy.,5 LG for early gastric cancer has been proven to be non-inferior in terms of safety and long-term prognosis compared with open gastrectomy (OG).–8 Moreover, among patients with locally advanced gastric cancer, laparoscopic distal gastrectomy did have an inferior rate of disease-free survival at 3 years compared with open distal gastrectomy in a randomized clinical trial.Gastric cancer is an important health problem, which is the fourth most common cancer and the second leading cause of cancer death worldwide. Since then, it has been reported in several reports, but they have been limited to short-term results, and without focus on the oncological feasibility and long-term results.–16 This retrospective study therefore compares short-term clinical outcomes regarding safety and effectiveness, and the long-term outcomes of LGR with those of open gastrectomy for RGC (OGR) in our institute.LG for RGC (LGR) was first reported in 2005.22.1 and the residual tumor status was defined using the standard R-classification . The severity of the postoperative complications within 30 days after operation was estimated according to Clavien-Dindo classification.This retrospective cohort study was conducted at the Wakayama Medical University Hospital, Wakayama, Japan. This study was in agreement with the guidelines of the institutional ethics committee and was conducted in accordance with the Declaration of Helsinki. A total of 38 patients underwent gastrectomy for RGC at Wakayama Medical University Hospital between April 2008 and December 2018. All consecutive patients were included in this retrospective study; the patients were divided into 2 groups according to the sequential nature of their operation. Fifteen patients underwent OGR between 2008 and 2013, and 23 patients underwent LGR between 2014 and 2018. We began a prospective cohort study of LG for advanced gastric cancer in 2012 (UMIN000025029). In both the OGR group and the LGR group, clinicopathologic factors were evaluated retrospectively based on the hospital records including age, sex, initial gastric disease, type of initial gastrectomy, approach of initial operation, interval to surgery for RGC, symptom at diagnosis, tumor location, histologic type and tumor size, and surgical factors including operation time and blood loss. The clinical and pathological stages were determined according to the TNM classification (UICC 8th edition),2.2In both OGR and LGR, a common indication for the surgical treatment of RGC is complete resection of the carcinoma with radical lymphadenectomy. The surgery of each group of patients were performed by the same surgical teams. In principle, total gastrectomy of the remnant stomach is intended for surgically indicated RGC, but partial gastrectomy has been permitted for the elderly or high-risk cases with tumor located at the site of the anastomosis. When the initial operation was distal gastrectomy, lymph node dissection around the celiac axis, proximal splenic artery and paracardial nodes was routinely performed, and the left gastric artery was ligated at its base if it had been left undivided. Reconstruction was performed by the Roux-en-Y method. When the initial operation was proximal gastrectomy, however, the lymph node dissection around the celiac axis, infrapyloric and suprapyloric areas were routinely performed.2.3P < .05.All statistical analyses were carried out using JMP Pro 14.1 . Categorical variables were assessed using Chi square method. Continuous variables were evaluated using the Wilcoxon signed-rank test. Recurrence-free survival (RFS) was calculated from the time of operation to the first documented recurrence of disease, or until death from any cause. Overall survival (OS) was defined as the time from the gastrectomy to the date of death from any cause. Survival curves were plotted according to the Kaplan-Meier method, which were subsequently compared using log-rank test. Statistical significance was defined as 33.1P = .023). There was no difference between the 2 groups in initial gastric disease, type of initial gastrectomy, reconstruction method, or interval to the surgery for RGC from the initial operation. In the OGR group, all initial operations were performed by open surgery, whereas in the LGR group, 11 patients (47%) initially underwent laparoscopic surgery and 12 patients (53%) initially underwent open surgery (P = .002). There were no differences between the 2 groups in terms of the tumor location, histologic type, tumor size, pathological stage, or curability.Table 3.2P = .009). There was no difference in the number of lymph node dissections between the 2 groups, but the number of metastatic lymph nodes was higher in the OGR group than in the LGR group (P =.014). There was no difference in operation time between the 2 groups, but blood loss was significantly lower in the LGR group than in the OGR group, with median blood loss of 115 ml in the LGR group and 290 mL in the OGR group (P = .002). Furthermore, although there was no difference between the 2 groups in C-reactive protein (CRP) value on the postoperative day (POD) 1, CRP value on POD3 was significantly lower in the LGR group than in the OGR group (P = .012). There were no differences in postoperative complication rates or hospital stay between the 2 groups, but the start time of postoperative food intake was significantly shorter in the LGR group than in the OGR group (P = .002). Even if the initial surgery was limited to open surgery, there was no difference in the operation time (P = .786) and postoperative complication rates (P = .721) between the OGR and LGR groups. Additionally, the blood loss was significantly smaller in the LGR group than in the OGR group (P = .014). There was no mortality in the OGR group and the LGR Group.Surgical outcomes and postoperative complications are shown in Table 3.3In the LGR group, 12 patients 53%) underwent initial operation by open surgery, 3 (25%) of which converted to open gastrectomy due to intra-abdominal adhesions (Table % underwe3.4P = .466). Two cases of recurrence were observed in both the OGR and LGR groups, respectively. In the OGR group, 1 case had peritoneal and lymph node metastasis and 1 case had peritoneal metastasis, and otherwise in the LGR group, 1 case had peritoneal metastasis and 1 case had liver metastasis. In OS, the median follow-up period was 46 months. As shown in Fig. P = .654).We examined the RFS and the OS period of patients who underwent R0 resection. In RFS, the median follow-up period was 44 months. As shown Fig. 4–16 An outstanding advantage of laparoscopic surgery is that CO2 gas of the pneumoperitoneum enters the layer to be divided, making it possible to easily and accurately confirm the separative layer, even in the patients with RGC. According to our case series, laparoscopic surgery is recommended because all operations for RGC were completed laparoscopically when the initial operation was performed laparoscopically. The total conversion rate to OGR was 13%. In each of these cases, open gastrectomy was the initial surgical approach. The rate of open conversion has been reported to be 5.6 to 47.1% in the previously published some case series. ,14,15 The median operation time was reported 362 minutes by Nagai et al and 324 minutes by Tsunoda et al, while it was reported around 200 minutes by Kim et al and Qian et al ,13,15,16 Even if the initial surgery was limited to open surgery, because there was an advantage in the short-term results of LGR, we make LGR the first choice as our surgical criteria for RGC.Surgical treatment for RGC is considered to have a high degree of difficulty due to the extensive adhesion associated with the initial surgery and the fibrosis around the dissected blood vessels and tissues, especially when the initial surgery for a malignant disease.,20 Although the number of metastatic lymph nodes was higher in the OGR group than in the LGR group, there was no difference in the number of lymph node dissections between the 2 groups. The frequency of postoperative complications between the 2 groups was not significantly different between the groups, and LGR could be safely performed. The postoperative complication rate and the length of postoperative hospital stay was similar to the previous report.–16 The CRP value on POD3 was significantly lower in the LGR group than in the OGR group, indicating that LGR was minimally invasive. The reason why the amount of blood loss was significantly smaller in the LGR group was considered to be that it was possible to identify blood vessels and layers to be dissected by magnified view of laparoscopic surgery. The prognosis of advanced RGC has been reported to be worse than that of advanced primary gastric cancer. No difference was found in long-term outcomes in the RFS and the OS between the 2 groups, suggesting that LGR is an oncologically appropriate surgical procedure. This study showed for the first time that laparoscopic surgery for RGC has equivalent long-term oncological outcomes compared with open surgery.When the depth of RGC is T3 or T4 with invasion to the greater curvature, we perform splenic hilum lymph node dissection with splenectomy. However, in the elderly and in patients with poor performance status, the spleen was preserved except when lymph node metastasis was obvious in prior imaging examination.Several limitations associated with this retrospective study warrant mention. The first issue is the different historical background, that OGR was performed at the beginning of the research period, whereas LGR was performed after 2014. In this study, the patients were divided into 2 groups according to sequential nature of the operation. This design could introduce bias in the statistical analysis and reduce the power of the study. In the LGR group, median age was significantly higher than in the OGR group, and in the OGR group, the approach for the initial surgery was biased to open surgery. Secondly, the number of patients included in this study was relatively small, even though the incidence of RGC was very low. Multi-center large cohort studies evaluating short- and long-term outcomes in patients with RGC treated with LGR are required. In addition, a prospective study could overcome the limitations of the retrospective design and selection bias. Future multicenter randomized clinical trials should be designed and performed to compare the surgical approaches.In conclusion, LGR is suitable in cases in which the initial surgery is performed by laparoscopic surgery. Even if the initial surgery is open surgery, LGR is oncologically equivalent to OGR and can be performed safely with less blood loss.We thank proofreading and editing by Benjamin Phillis from the Clinical Study Support Center at Wakayama Medical University.Study concept and design: Junya Kitadani, Toshiyasu Ojima.Acquisition of data: Junya Kitadani, Masaki Nakamura, Keiji Hayata, Naoki Fukuda. Analysis and interpretation of data: Junya Kitadani, Toshiyasu Ojima, MasakiNakamura, Masahiro Katsuda. Drafting of the manuscript: Junya Kitadani, Toshiyasu Ojima, Masaki Nakamura, Masahiro Katsuda. Critical revision of the manuscript for important intellectual content: Hiroki Yamaue.Statistical analysis: Junya Kitadani, Toshiyasu Ojima, Keiji Hayata, Hiroki Yamaue. Administrative, technical, and material support: Masaki Nakamura, Keiji Hayata, Masahiro Katsuda, Hiroki Yamaue. Conceptualization: Junya Kitadani, Toshiyasu Ojima.Data curation: Junya Kitadani, Toshiyasu Ojima, Akihiro Takeuchi, Shinta Tominaga, Hideki Motobayashi, Tomoki Nakai. Formal analysis: Junya Kitadani, Toshiyasu Ojima, Masaki Nakamura. Investigation: Junya Kitadani, Toshiyasu Ojima, Masaki Nakamura, Keiji Hayata, Masahiro Katsuda.Methodology: Masaki Nakamura. Project administration: Masahiro Katsuda, Hiroki Yamaue.Supervision: Hiroki Yamaue. Visualization: Junya Kitadani. Writing – Original Draft: Junya Kitadani. Writing – Review & Editing: Toshiyasu Ojima.Conceptualization: Junya Kitadani, Toshiyasu Ojima, Hiroki Yamaue.Data curation: Junya Kitadani, Keiji Hayata, Masahiro Katsuda, Akihiro Takeuchi, Shinta Tominaga, Naoki Fukuda, Hideki Motobayashi, Tomoki Nakai.Formal analysis: Junya Kitadani, Toshiyasu Ojima.Methodology: Junya Kitadani, Toshiyasu Ojima, Masaki Nakamura, Keiji Hayata, Naoki Fukuda.Project administration: Junya Kitadani, Toshiyasu Ojima, Hiroki Yamaue.Supervision: Toshiyasu Ojima, Masaki Nakamura, Hiroki Yamaue.Visualization: Masahiro Katsuda.Writing – original draft: Junya Kitadani.Writing – review & editing: Toshiyasu Ojima, Hiroki Yamaue.


The objectives of this study were to describe a novel statewide registry for cardiac surgery in Brazil (REPLICCAR), to compare a regional risk model (SPScore) with EuroSCORE II and STS, and to understand where quality improvement and safety initiatives can be implemented.A total of 11 sites in the state of São Paulo, Brazil, formed an online registry platform to capture information on risk factors and outcomes after cardiac surgery procedures for all consecutive patients. EuroSCORE II and STS values were calculated for each patient. An SPScore model was designed and compared with EuroSCORE II and STS to predict 30-day outcomes: death, reoperation, readmission, and any morbidity.p<0.001).A total of 5222 patients were enrolled in this study between November 2013 and December 2017. The observed 30-day mortality rate was 7.6%. Most patients were older, overweight, and classified as New York Heart Association (NYHA) functional class III; 14.5% of the patient population had a positive diagnosis of rheumatic heart disease, 10.9% had insulin-dependent diabetes, and 19 individuals had a positive diagnosis of Chagas disease. When evaluating the prediction performance, we found that SPScore outperformed EuroSCORE II and STS in the prediction of mortality (0.90 vs. 0.76 and 0.77), reoperation (0.84 vs. 0.60 and 0.56), readmission (0.84 vs. 0.55 and 0.51), and any morbidity (0.80 vs. 0.65 and 0.64), respectively (The REPLICCAR registry might stimulate the creation of other cardiac surgery registries in developing countries, ultimately improving the regional quality of care provided to patients. Multicenter registries in cardiac surgery constitute the basis for most of the progress achieved in the United States and the European Union , 2. HoweIn a state where up to 80% of all cardiac surgery procedures are reimbursed by the federal Unified Health System (SUS), development of regional data collection mechanisms for QI and safety is essential to serve as a basis for clinical guidelines and healthcare policies. Of importance, increasing international literature with regional data allows researchers and policy makers to fine-tune guidelines and policies to better align clinical practice with regional clinical and socioeconomic reality.EuroSCORE II was published in 2012  and was The São Paulo Cardiovascular Surgery Registry (REPLICCAR) was created in 2013 with the goal of improving patient safety and implementing quality improvements in the São Paulo state network . Funnel Regarding the quality issues faced by developing countries for cardiac surgery procedures, the objective of this article is threefold: (1) to describe the REPLICCAR statewide registry, (2) to create the SPScore model for validation and comparison with EuroSCORE II and STS, and (3) to describe a novel web application that allows research peers, providers, policy makers, and patients to dynamically and directly explore REPLICCAR data to establish QI and safety initiatives.The REPLICCAR registry was funded through a partnership between the Secretary of Health of the State of São Paulo and the São Paulo Research Foundation (FAPESP).REPLICCAR is a mandatory prospective registry currently involving 11 different centers around the state of São Paulo, Brazil. REPLICCAR included all consecutive adult patients undergoing cardiac surgical procedures involving Coronary artery bypass grafting (CABG) and/or heart valve surgery. No patients who met these criteria were excluded. The EuroSCORE II and STS variables were also prospectively collected for each patient, in each center, and the calculation was performed by researchers trained for this purpose at the coordinating center. SPScore was constructed so that it could be incorporated into regional data collection and management systems. To this end, REPLICCAR was divided into a developmental data set and a validation data set using random sampling from a binomial distribution. In the validation data, the performance of SPScore was compared with the performance of EuroSCORE II and STS. This study is described according to the applicable components of the SQUIRE statement .The REPLICCAR project (SDC: 3853/12/109) was approved by the Research Ethics Committee of the University of São Paulo, Heart Institute, Hospital das Clínicas, University of São Paulo Medical School, Brazil. The Brazilian Platform for Health Research and the Institutional Review Board of each of the 11 currently participating sites approved the data collection for REPLICCAR registry.Data were collected at 11 different centers across the state of São Paulo, Brazil. These sites included the Beneficência Portuguesa de São Paulo, Santa Casa de Marília, Heart Institute (InCor) at the University of São Paulo, Santa Casa de São Paulo, the State University of Campinas, São José do Rio Preto Hospital, Santa Casa de Piracicaba, São Paulo Federal University, SOBAM Group, Hospital das Clínicas of the University of São Paulo at Ribeirão Preto and the Paulo Sacramento Hospital.http://bdcardio.incor.usp.br/). Data quality checks were performed on a regular basis, with feedback provided to individual centers when necessary.REPLICCAR participants were recruited from locations within the São Paulo Health Technology Assessment Network (HTA-NATSs/SES-SP). Perioperative patient data, including observed mortality data and follow-up until 30 days after surgery were collected on an online platform  and a subsequent web application (http://repliccar.incor.usp.br:3838/exploratory/) to enable the network of participants to experience QI and safety initiatives to reduce morbidity and mortality after cardiac surgery in the state of São Paulo.We developed a SPScore model , education, gender, body mass index (weight in kilograms divided by height squared in meters), previous myocardial infarction, time since infarction (in days), previous coronary stent, time from stent implantation to surgery, previous heart surgery, NYHA functional class, rheumatic heart disease, glycated hemoglobin levels, hematocrit, atrial fibrillation, ejection fraction, pulmonary artery systolic pressure, walking speed, insulin-dependent diabetes, creatinine clearance levels, urgency/emergency admission, presence of Chagas disease, isolated coronary artery bypass graft surgery, types of arterial grafts, presence of left ventricular aneurysm, procedures for mechanical complications, replacement or repair of aortic/mitral/tricuspid and/or pulmonary heart valve, concomitant ascending aortic procedure, and level of blood cell transfusion.A full data dictionary for the REPLICCAR registry in its current version is provided on the website In-hospital death was defined as death during hospital stay or up to 30 days after surgery if hospital discharge occurs. In addition, the other outcome variables up to 30 days after surgery included: (1) reoperation, defined as any type of reoperation, including reoperation for bleeding; (2) readmission within 30 days after surgery; (3) any morbidity, defined as the presence of cardiac complications , acute renal failure, any infection , and other complications, including systemic inflammatory response syndrome and stroke.Our exploratory analysis started by evaluating distributions, frequencies, and percentages for each of the continuous and categorical variables. Categorical variables were evaluated for near-zero variation . ExtensiWe modeled outcomes and predictors in the format described in the previous sections. To create a good predictive model, we evaluated a series of different machine learning classification models for predicting categorical variables, including Neural Network, Boosting, Multivariate Adaptive Regression Splines, Generalized Linear Model, Bagging, Nearest Neighbors, Support Vector Machines, Random Forest, Decision Tree, Linear Discriminant Analysis, Penalized Discriminant Analysis, Shrinkage Discriminant Analysis, Naive Bayes and Generalized Partial Least Squares. The validation followed a nested resampling strategy, in which the outer resampling is used to reduce overfitting, adopting a 5-fold cross-validation; the inner resampling was used for hyperparameter tuning using a 3-fold cross-validation strategy.In situations where the outcome measures were imbalanced and, therefore, led the models to overestimate the class more often, we used the Synthetic Minority Over-sampling Technique (SMOTE). SMOTE creates synthetic data points for the minority class using a k-nearest neighbor approach. The number of synthetic data points was limited to avoid overestimating the minority class. Comparisons across models were performed using metrics for the area under the curve. The area under the curve ranges from 0 to 1, with 1 corresponding to perfect accuracy and 0.5 corresponding to random chance. The final model, named SPScore, was chosen based on a simultaneous combination of clinical face validity (reflecting current knowledge in the field of cardiac surgery) and predictive accuracy (maintaining the area under the ROC curve at 80% or more). Our modeling strategy involved the comparison only the test data, as multiple comparisons would increase the odds of model overfitting. For STS and EuroSCORE II models, we used simple Generalized Linear Models. The performance of the SPScore model was then compared to EuroSCORE II and STS in the validation data set for plotting calibration curves  and for discrimination (using the area under the ROC curve).Calibration plots were constructed using Friedman’s super-smoother methodology on ungrouped data, while displaying the observed versus expected mortality trend . Based oEleven Brazilian centers participated in the study. The final REPLICCAR registry contained records from 5222 patients. Data of the prevalence of risk factors and predictive variables are shown in As our registry provides data that directly reflects the daily practice of each of the participating institutions, it was also important to provide a mechanism that would allow each center to simulate potential Quality Improvement and Safety interventions. Thus, we generated a machine learning model with an interrelated set of potential causes for all postoperative complications .The calibration curves for SPScore, STS, and EuroSCORE II are presented in p values < 0.001 , readmission (0.84 vs. 0.55), and any morbidity (0.80 vs. 0.65). All SPScore model outcomes were significantly greater than EuroSCORE II, with  vs. 0.60001 Figs .To the best of our knowledge, this is the first report of a state-wide Quality Improvement and Safety registry in cardiac surgery created in a developing country. We have outlined its main data collection infrastructure, along with a graphical interface for data exploration. In addition, we have presented SPScore, a machine learning model in which simulated Data Quality and Safety initiatives can be conducted, allowing prioritization over future interventions.Initial efforts in Quality Improvement and Safety are traditionally attributed to Ernest Codman, using concepts borrowed from the technology industry . As a coCardiac surgery procedures in developing countries have been consistently reported to have higher mortality rates than those in developed countries . For insDespite these issues, some studies have demonstrated that cardiac surgery outcomes in developing countries can be reduced over time through systematic team interventions , 25. TheWe evaluated the SPScore, EuroSCORE II, and the STS models as tools for risk prediction in cardiac surgery procedures. In our study, the SPScore outperformed EuroSCORE II and STS in predicting mortality, readmissions, reoperations, and any morbidity among Brazilian patients. Due to different population mixes and risk factors, there are significant differences in the prevalence of conditions and types of procedures between our study sample, EuroSCORE II, and the STS population. For example, rheumatic heart disease is a frequent condition in Brazil, with a prevalence of 14.5%. In contrast, in most European and North American countries the most frequent condition is degenerative heart disease. Therefore, it was actually expected that, given these differences, EuroSCORE II and STS would result in a poor calibration and discriminative power for the Brazilian population. We also found that, depending on the selected statistical model, EuroSCORE II can both overpredict or underpredict mortality among Brazilian patients. Even when overpredicting mortality, SPScore demonstrated a better calibration curve than the EuroSCORE II. Our findings suggest that the application of the REPLICCAR multicenter database and the creation of the SPScore model could help the quality improvement efforts to enhance surgical procedures.Despite adding an important component to the Quality Improvement literature, our study does have limitations. First, given that our hospital network is geographically distributed, it is difficult to ensure reliability of the coding pattern of our procedures and outcomes. This limitation is currently being addressed through a measurement program related to inter-observer reliability followed by extensive site training, ultimately improving the consistency across our coders. Second, we opted for not including self-reported measures of quality of life or dysfunction. Although these measures constitute a critical piece in an assessment aimed at obtaining patient perspectives, it also increases the time required to evaluate individual patients. Third, despite our best efforts in controlling for missing rates, some of our variables had particularly high rates, specifically walking speed as a proxy for frailty. To control this limitation, we made use of imputation algorithms followed by sensitivity analyses to ensure that our conclusions were valid under different assumptions. Finally, given that our sample was not randomly drawn from a larger patient population, its external validity can be questioned. This limitation is currently being addressed through the inclusion of additional sites to the REPLICCAR registry, potentially reaching a third of all surgical procedures in the State of São Paulo. Finally, although social determinants of health have a significant effect on hospital readmissions and mortality , our datWe have described the internal structure of REPLICCAR, a novel registry for cardiac procedures in Brazil, with the aim of providing a model for similar centers in other developing countries. A regional risk assessment model, the SPScore, provided more precise estimates of death, readmission, reoperation, and any morbidity compared to EuroSCORE II and STS. A specific emphasis was placed on establishing mechanisms that enable scientific peers, health care providers, policymakers, and the general public to not only explore our data, but also to virtually simulate predictions to guide the choice of future quality improvement and safety interventions.


Total serum IS reduction was observed in a subgroup of participants  versus UBF: 62.5 μmol/L (31–133), p = 0.009) who had a daily UBF intake closer to that proposed in the study. No changes were observed in other secondary outcomes. UBF did not promote changes in serum levels of IS or pCS and IAA; a decrease in IS was only found in the subgroup of participants who were able to take 21g/day of the UBF. In chronic kidney disease (CKD), the accumulation of gut-derived metabolites, such as indoxyl sulfate (IS), p-cresyl sulfate (pCS), and indole 3-acetic acid (IAA), has been associated with the burden of the disease. In this context, prebiotics emerge as a strategy to mitigate the accumulation of such compounds, by modulating the gut microbiota and production of their metabolites. The aim of this study was to evaluate the effect of unripe banana flour  on serum concentrations of IS, pCS, and IAA in individuals undergoing peritoneal dialysis (PD). A randomized, double-blind, placebo-controlled, crossover trial was conducted. Forty-three individuals on PD were randomized to sequential treatment with UBF (21 g/day) and placebo (waxy corn starch—12 g/day) for 4 weeks, or vice versa (4-week washout). The primary outcomes were total and free serum levels of IS, pCS, and IAA. Secondary outcomes were 24 h urine excretion and dialysis removal of IS, pCS, and IAA, serum inflammatory markers , serum lipopolysaccharide LPS, and dietary intake. Of the 43 individuals randomized, 26 completed the follow-up . UBF did not promote changes in serum levels of IS ( Numerous metabolites that normally are part of the mammalian serum metabolome are derived from the metabolism of the gut microbiota ,2. AmongStudies have shown that CKD is associated with altered colonic microbiota composition ,19,20,21Diet seems to be the main determinant of gut microbial metabolism . The typIn this context, prebiotics emerge as a strategy to mitigate the accumulation of these compounds, by modulating the gut microbiota and production of metabolites towards lower amino acids fermentation. Prebiotics are substrates selectively utilized by host microorganisms, providing health benefits. Among them are fermentable dietary fibers, such as inulin, fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), and resistant starch (RS). When these undigested carbohydrates reach the colon, they are fermented by specific colon bacteria, which leads to changes in the composition and metabolic activity of the gut microbiota, benefiting the health of the host ,33. To dIn this sense, we tested for the first time whether providing UBF to individuals with CKD undergoing peritoneal dialysis would reduce the serum gut-derived uremic toxins .www.ensaiosclinicos.gov.br, ID number: RBR-4xxwwj). Written informed consent was obtained from each participant.This is a randomized, double-blind, placebo-controlled, crossover trial. The study was approved by the Ethics Committee of Universidade Federal de São Paulo  and registered at the Brazilian Clinical Trials Registry  from Fundação Oswaldo Ramos outpatient clinic , aged 18–80 years, with a dialysis vintage of at least three months and adherent to dialysis treatment were invited to participate in the study. The exclusion criteria were the use of prebiotics, probiotics, synbiotics, and antibiotics one month before the beginning of the study, the presence of inflammatory bowel diseases, stomach, or bowel resection, liver cirrhosis, cancer, human immunodeficiency virus, peritonitis in the last month, pregnancy, and breastfeeding.Participants were discontinued from the study if they presented any gastrointestinal intolerance even after dose adjustments, were hospitalized, started antibiotic therapy, underwent kidney transplant, or wished to be withdrawn.Musa acuminata (group AAA), subgroup Cavendish, at the first stage of maturation (unripe), not subjected to a maturation chamber, and purchased at a local market. The production of UBF was performed in accordance with the patented process (PI 0705778-4) proposed by Tribess et al. [The UBF was prepared in the Food Research Center (FoRC) of the Universidade de São Paulo (USP) with the unripe banana pulp, s et al.  to preses et al.  and the s et al. , respects et al. . RegardiSupplements were packaged in identical sachets and identified by the numbers 225 and 653 in a handling pharmacy, under the responsibility of a pharmacist . Each UBF sachet contained 10.5 g of flour (5 g of RS) and the placebo sachets contained 6 g waxy corn starch. The amount of placebo was defined in order to provide a similar amount of energy in relation to UBF .The initial dose of both interventions was one sachet per day. After the three initial days, in the absence of adverse effects, participants were advised to double the daily amount of each supplement. In the presence of difficulties to take the proposed final dose (two sachets daily), such as any adverse gastrointestinal symptom, the participant was maintained in the study with the tolerable dose. Participants were advised to take the supplements during meals, mixed in any drink or food at low to moderate temperature in order to preserve the resistant starch.The participants were assigned to sequential treatment with UBF and placebo, or vice versa, after a blocked randomization procedure using a random block of 4 participants in a 1:1 ratio. A computerized random list was generated by an independent researcher. The list was handed over to another independent researcher who was responsible for separating and allocating supplements to participants. The duration of each intervention was 4 weeks with a washout period (4 weeks) between them. Before and after each intervention, venous blood, 24 h dialysate, and 24 h urine of participants with daily urinary volume ≥200 mL were collected. The majority of the participants had been previously advised by a renal dietitian, according to the nutritional guidelines for patients undergoing peritoneal dialysis ,42, in tThe primary outcomes were serum levels of IS, pCS, and IAA. The secondary outcomes were 24 h urine excretion and dialysis removal of IS, pCS, and IAA, serum inflammatory markers (high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α)), serum lipopolysaccharide (LPS), dietary intake, and gastrointestinal symptoms.Demographic and clinical data were collected from medical records. Venous blood samples were collected in the morning and under fasting conditions (12 hours). Aliquots were immediately centrifuged and the serum was stored at −80 °C. Aliquots of urine and dialysate were also stored at −80 °C.exc = 283 nm and λem = 380 nm for IS and IAA and λexc = 265 nm and λem = 290 nm for pCS.Serum, urinary, and dialysate concentrations of IS, pCS, and IAA were quantified by high-performance liquid chromatography (HPLC) with fluorescent detection. Samples were diluted with the exception of dialysate, heated at 95 °C for 30 minutes and centrifuged at 13,000 rpm for 10 minutes at room temperature. Then, the samples were cooled on ice for 10 minutes, filtered through 0.22 mm filter, and injected into the system of HPLC. To quantify the free fractions, the serum samples without dilution were only centrifuged and filtered (0.22 mm). The chromatographic system was the one described by Rodrigues et al. . During Serum IL-6, IL-10, and TNF-α were measured using a kit of 3-cytokine Milliplex MAP Human Cytokine/Chemokine Magnetic Bead Panel  following the specific protocol provided by the manufacturer. Serum LPS was determined using the Hycult Biotech Limulus Amebocyte Lysate assay . Serum levels of urea, creatinine, sodium, potassium, ionized calcium, phosphorus, glucose, albumin, glycated hemoglobin, and high-sensitivity C-reactive protein were measured by standard techniques. Residual renal function (RRF) was calculated by the mean of creatinine and urea clearance corrected for body surface area . Dialysi®  was used to calculate the average nutrient intake.A food record of three alternate days, including the day before blood collection, was used to estimate energy, protein, and fiber intake. Participants completed the records at the beginning and at the end of each intervention. All records were checked in a face-to-face interview by the same dietitian, using food models and household utensils to improve the accuracy of the recorded data. The software NutwinProtein intake was also estimated by the protein equivalent of nitrogen appearance (PNA), normalized by desirable or adjusted body weight .Gastrointestinal symptoms were monitored using the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire, translated and validated into Brazilian Portuguese. This questionnaire consists of 15 questions comprising the following symptoms: abdominal pain, reflux, nausea, borborygmi, abdominal distension, belching, flatulence, diarrhea, and constipation. The intensity and/or frequency of each symptom are scored according to a seven-level Likert scale. The total GSRS score ranged from 15 to 105 points. The higher the score, the higher the intensity and/or frequency of the symptom .The sample size was calculated using, as a reference, the study of Sirich et al. . A total® software version 18.0 for Windows .The data are presented as the mean and standard deviation (SD), median and interquartile range, or frequency and percentage, as appropriate. Student’s t-test or Mann–Whitney test and Pearson's Chi-square or Fisher’s exact test were used to compare the baseline characteristics between the patients who discontinued and patients who completed the follow-up. Generalized estimating equations (GEE) were used to analyze the effect of intervention on the variables. Statistical significance was established at p values < 0.05. All statistical analyses were performed using the SPSSParticipants were recruited between May 2018 and September 2018 from a single peritoneal dialysis center. Forty-three participants were recruited and randomly allocated to sequential treatment with UBF and placebo, or vice versa. Twenty-six participants concluded both arms of the trial, as depicted in the Consolidated Standards of Reporting Trials (CONSORT) flow diagram .In the study population, the causes of CKD were diabetic nephropathy (19.2%), hypertensive nephropathy (3.8%), glomerulonephritis (7.7%), polycystic kidney disease (15.4%), other causes (11.5%), and unknown causes (42.3%). The majority of participants were men (53.8%), 34.6% had diabetes, 84.6% had residual diuresis, and 92.3% were undergoing nocturnal intermittent peritoneal dialysis (NIPD). The most common dialysis prescription was 5 cycles per 9 hour cycling session with 10L of total volume infusion using a glucose-based solution. The participants were on antihypertensive medication (96%), insulin (31%), statins (73%), and phosphate binders (65.5%). p = 0.67). The median daily intake of placebo was 9.6 g (6.6–10.4) and UBF 14 g (11.4–18). Therefore, the daily intake of resistant starch in the UBF arm was about 6.8 ± 2.1 g (48% of UBF).Seven patients (26.9%) in the UBF arm and four patients (15.4%) in the placebo arm did not tolerate taking two sachets per day; therefore, they were maintained with the tolerable dose (one sachet/day). The reasons for the intolerance to the initially proposed dose were the large volume of flour , intolerable increase in flatulence (UBF: two patients), and hardening of stools . Taking these dose adjustments into account, the overall adherence was good in both arms (placebo: median adherence 86.7% (67.3–92.6) versus UBF: 83% (64.6–94.5), p = 0.30).With regard to gastrointestinal symptoms, no change was observed in the GSRS score between the interventions (As shown in As can be seen in p > 0.05). 2) slightly reduced in the placebo arm . Despite this, the urinary and dialysate excretion of uremic toxins did not differ between the arms during the follow-up (Eleven participants (42.3%) were able to take the two sachets during the entire follow-up with adherence greater than 80%. These participants had a median daily intake of placebo of 10.4 g (10–11.6) and UBF of 18.7 g (17.2–19.7) corresponding to about 8.8 g ± 0.6 of resistant starch daily. In this subgroup, 54.5% were women, 54 ± 15 years old, 36.4% had diabetes, 90.9% had residual diuresis, and 90.9% were undergoing nocturnal intermittent peritoneal dialysis (NIPD). These characteristics were not different from the group of participants with adherence less than 80%  with RS representing approximately 87% of the total fiber. The beneficial effect of RS on uremic toxins has not been clearly demonstrated. In HD patients, while a decrease in serum total IS was found in two studies with the administration of 16–18 g/day of RS ,36, in aDespite its importance, adherence to the intervention has not always been carefully assessed or monitored in studies. In the present study, even though strategies were adopted to favor the regular use of two sachets of UBF, some participants had low adherence, and others did not tolerate the proposed dose, which corresponded to 10 g of RS, and were then maintained in the study with their tolerable dose. Separately analyzing the participants who were able to take more than 80% of the proposed dose (8.8 g ± 0.6 of RS daily), serum levels of total IS decreased after UBF compared to placebo. It is important to highlight that the reduction was not due to increased urinary excretion, dialysis removal of IS, or changes in usual dietary intake. This finding suggests that the impact of UBF on the serum IS may be dependent on the dose of UBF and probably the amount of RS.Bacteroidetes-to-Firmicutes ratio and in the Ruminococcus bromii, which seems to be the keystone species for the degradation of RS [Faecalibacterium prausnitzii [The type and amount of substrate that reach the human colon are key modulators of bacterial composition and metabolism. An increase in carbohydrates available for fermentation in the colon seems to favor carbohydrates fermentation over nitrogenous compounds, leading to a reduction in specific metabolites such as indole, which is the precursor of IS ,26. It hon of RS ,49,50. Ausnitzii , a butyrusnitzii ,53, whicusnitzii  and is fusnitzii . HoweverRegarding the other two gut-derived uremic toxins evaluated (pCS and IAA), no impact of UBF was observed. Similarly, no difference in the serum total pCS was observed in other RS intervention studies with HD patients ,36. In hDespite the findings mentioned above, well-designed prebiotic intervention studies in CKD and particularly in PD are scarce. Recently, no changes were also observed in the serum levels of pCS and IS in a well-designed cross-over study in PD, with 10 g of inulin . It is pIn the present study, the use of UBF did not result in changes in the inflammatory markers evaluated , nor in the serum levels of LPS (marker of gut permeability). The slight increase observed in IL-6 after UBF does not appear to be an effect of the intervention, since no difference was found between UBF and placebo. In addition, no difference was observed in the levels of IL-6 in the subgroup that showed greater adherence to the intervention. Several factors contribute to the inflammatory state in CKD, including the uremic toxins . FurtherSome limitations and strengths of the present study should be acknowledged. The loss of a significant number of participants during the follow-up resulted in a relatively small sample size, which may have limited the statistical power for detection of changes in the outcomes. The long duration of the study required in a crossover design may have contributed to the withdrawals. The low tolerability to the UBF may have prevented finding more consistent results. Indeed, a decrease in serum IS was found in the subgroup of participants who ingested the total dose proposed. Although plausible, this subgroup analysis should be viewed with caution due to potential selection bias introduction. The gut microbiota and their metabolites were not assessed, limiting in-depth understanding of the impact of UBF on the composition and metabolism of gut microbiota and consequently, on the uremic toxins. The strengths are the study design and especially, the control of known confounders such as dietary intake (protein and fiber), urinary excretion, and dialysis removal of the uremic toxins.In conclusion, we found that the UBF did not affect either the serum levels of IS or pCS and IAA. A reduction in serum total IS was observed, when about 20 g of UBF was used daily. This finding was independent of dietary intake and urinary excretion and dialysis removal of uremic toxins. No effect of UBF was observed in inflammatory markers and intestinal permeability. Our results highlight the difficulty of implementing the regular use of flours with prebiotics in clinical practice, since a large amount of the supplement seems to be required to promote a significant reduction in uremic toxins. This factor should be considered when developing strategies to target the gut microbiota in CKD, since the potential benefits depend on the continuous use of the supplement. Further studies evaluating different doses of prebiotics and especially, the combination of prebiotic types may be required for a better understanding of their effect on the production of gut-derived metabolites and consequently, on the accumulation of uremic toxins in CKD.


The gold standard treatment for end-stage heart failure is heart transplantation; however, the rate of transplantation remains inadequate because of the paucity of organ donation. The left ventricular assist device (LVAD) has been used as a bridge therapy before transplantation. The LVAD is being used increasingly because it reduces mortality despite the accompanying morbidities. Therefore, the anesthetic management of LVAD-related morbidities is important and requires experience and knowledge. Herein, we describe a 60-year-old male patient with an LVAD with complaints of right hemiparesis, dysphasia, and facial paralysis. We aim to present the anesthetic management of a patient with intracranial hemorrhage who underwent LVAD exchange due to thrombosis. A 60-year-old  patient was admitted to our emergency department with right hemiparesis, dysphasia, and facial paralysis. The patient had a history of HeartWare  implantation via left anterolateral thoracotomy 1 year previously due to ischemic heart failure.3 /uL. The neurological examination revealed that the patient was confused, with no cooperation and orientation. He had weakness in the right arm and leg (2+/5), dysphasia, loss of blinking control on the right side, decreased tearing, drooping of the mouth to the right side, and a Glasgow Coma Score of 10. Cranial computed tomography (CT) was planned for the patient upon consultation by the neurosurgery department. In the cranial CT, hematoma accompanied by edema in the left parietal lobe and linear densities compatible with SAH in the left superior central sulcus and left ventricular minimal compression were observed, which showed intracranial hemorrhage progression  of 3.23, a prothrombin time of 36%, a hemoglobin level of 12.6 g/dL, and a platelet level of 150×10gression . The LVAThe neurosurgery department did not plan emergency surgery; anti-edema therapy was administered with dexamethasone and furosemide as suggested. Anticoagulant and antiaggregant therapy was stopped. Subsequently, left ventricular heart failure with pulmonary edema and hemodynamic instability developed in the patient. Pump thrombosis was suspected, and this diagnosis was confirmed by transthoracic echocardiography. Sixteen days after admission to the hospital, emergency HeartWare Ventricular Assist Device  exchange was planned.2) of 89.2 mmHg, and partial pressure of carbon dioxide (pCO2) of 37.5 mmHg. In addition to cardiac anesthesia monitorization , neurological monitoring with near-infrared spectroscopy (NIRS), Pulse index Continuous Cardiac Output (PiCCO) , and the bispectral index was performed. Due to left heart failure, low-dose inotropic support (0.5 μg/kg/min of dobutamine) was started preoperatively. The patient was taken to the operating room with arterial pressure of 87/42 mmHg, heart rate of 120/min, oxygen saturation , and 50% oxygen/air mixture. Anesthesia was maintained with bolus doses of 1 µg/kg of fentanyl, and infusion dosages of 0.05 mg/kg/h of midazolam, and 0.5 mg/kg/min of ketamine to keep the bispectral index values between 40 and 50. At the beginning of the operation, the NIRS values were 52/50 (R/L) and they were maintained at 50/51±10. During the operation, a 0.5-mg adrenaline bolus was administered because of hypotension due to cardiac manipulation and cannulation; the NIRS values dropped to 38/39 for 10 minutes and 1 mg/kg of pentothal was administered for cerebral protection. Afterward, the patient’s blood pressure returned to normal levels, and his NIRS values returned to baseline. Respectively, 0.1 μg/kg/min of noradrenaline and 0.05 μg/kg/min of adrenaline infusions were initiated due to hypotension. Subsequently, the adrenaline infusion was stopped, and a noradrenaline infusion was increased gradually. Because the contractility was adequate, adrenaline was discontinued and noradrenaline was continued for vasoconstriction.Anesthesia induction of the patient was performed with 2 mg/kg of ketamine, 0.2 mg/kg of midazolam, 1 µg/kg of fentanyl, and 0.6 mg/kg of rocuronium. A 40-F left-sided double-lumen endobronchial tube was used for intubation. Thereafter, the bronchial cuff was collapsed, and mechanical ventilation was started with a tidal volume of 4–6 mL/kg, 10–12/min  support was commenced for 1-lung ventilation; conventional cardiopulmonary bypass was not preferred on account of the higher dose of heparin. Heparin (5000 U) was applied, and the activated clotting time value was kept as twice the input value. The patient was given 5 packs of erythrocyte suspension, 7 packs of fresh frozen plasma, and 2 packs of pooled platelet suspension. In addition, 250–300 μg/kg of vitamin K and 10 mg/kg of boluses and then 1 mg/kg/h of tranexamic acid infusion were administered to avoid postoperative bleeding. After the LVAD exchange, the patient was weaned from ECMO with 0.3 μg/kg/min of noradrenaline and 3 μg/kg/min of dobutamine infusions. The pulmonary evaluation of the patient revealed bilateral crepitant rales, and the initial arterial blood gas analysis revealed an SpOAt the end of the operation, the patient’s double-lumen endobronchial tube was replaced with a single-lumen endobronchial tube and he was transferred to the intensive care unit (ICU). During a postoperative period of 14 days, the hematoma began to resolve and the ventricles were normal . The INR2 Pump thrombosis may present in a wide spectrum, varying from minimal hemolysis/minimal changes in pump parameters to acute hemodynamic collapse, multiorgan failure, massive hemolysis, or critical thromboembolic complications.2 In our patient, pump thrombosis caused hemodynamic instability, necessitating inotropic support and an urgent pump exchange.The incidence rate of pump thrombosis varies between 0.04% and 0.09%.2 The treatment options for pump thrombosis are pump exchange and thrombolysis. Due to SAH in our patient, thrombolysis was not an appropriate treatment option and pump exchange was performed. Consequently, resorptions of hemorrhage due to thrombolysis treatment and kidney/multiorgan failure, which can develop secondary to thrombolytic treatment, were also avoided.The treatment of pump thrombosis depends on the localization of the thrombus and the clinical status of the patient.5 We, therefore, opted for midazolam and ketamine in our patient for the induction and maintenance of anesthesia to ensure adequate anesthesia depth  and to avoid hemodynamic lability. We also tried to reduce the intracranial pressure-enhancing effect of ketamine by providing low-dose use with anesthesia depth control and the combination with midazolam and fentanyl.A major problem in patients with the LVAD is the difficulty in anesthesia management because of end-stage heart failure; the transition of drugs to the circulation and the distribution of the drugs are decreased when compared with healthy patients owing to the low ejection fraction. Accordingly, more attention should be paid to drug doses and titration. The monitorization of the bispectral index helps to protect cerebral autoregulation by allowing adjustment for adequate blood pressure and anesthetic drug titration.6 However, given our patient’s abnormal bleeding parameters, we used continuous cardiac output measurement with a PiCCO system. We also utilized the activated clotting time instead of thromboelastography/rotational thromboelastometry, which is recommended for coagulation follow-up,6 because it is not available in our hospital.Transesophageal echocardiography and pulmonary artery catheterization are recommended for monitoring hemodynamic data in LVAD intraoperative anesthetic management.5 We preferred ECMO support to maintain low intracranial pressure in our patient by preventing hypoventilation and hypercarbia, treated his hypotension with inotropic agents, and performed soft intubation. Additionally, we administered an osmotic diuretic agent (2 mg/kg of 20% mannitol intravenously) to increase the intracranial pressure reduction. In patients with intracranial hemorrhage, major precautions that need to be taken include soft intubation, avoidance of hyper/hypotension, mild hyperventilation, head elevation, and avoidance of high concentrations of inhalation agents and nitrous oxide in order not to increase intracranial pressure.5 Hence, we aimed to use thiopental for cerebral protection, especially in the period when our patient’s NIRS values were reduced. We also administered corticosteroids during the prolonged hypotension periods as is suggested in the literature.5 It is known that steroids have many adverse effects including hyperglycemia, but they decrease the proinflammatory response, act as an antioxidant in the ischemic tissue, and allow the regulation of serum sodium and plasma osmolarity.7Although there is no clinically relevant evidence, pharmacological protective agents  are recommended in ischemia.5 Accordingly, we transfused blood products to provide both normovolemia and normal oxygenation (Hb~10 g/dL) and to prevent adverse effects on cerebral oxygenation due to anemia.5 As a result, our patient’s intracranial pressure was reduced and his perfusion pressure was improved.7 Following the patient’s hypotensive period, we maintained his mean arterial pressure as high as possible to prevent the adverse effects of ischemia.Excessive blood loss due to high INR values and reoperation can cause hemodynamic instability and ischemia in neurons.5 In our patient, the blood glucose concentration was maintained between 100 and 180 mg/dL with an insulin infusion.Hyperglycemia worsens and prolongs healing in patients with SAH; blood glucose concentrations should, therefore, be treated over 180 mg/dL and maintained between 80 and 200 mg/dL.Postoperative intracranial hemorrhage is a complication that significantly reduces survival expectancy in patients with the LVAD. Moreover, during pump exchange procedures of patients with intracranial hemorrhage, the method of cerebral protection, the maintenance of hemodynamic stability, and the titration of anesthetic agents may complicate the management of anesthesia and, thus, need experience. In such cases, the treatment and follow-up of multiple parameters, avoidance of hypotension, and the use of neuroprotective methods can prevent possible neurological complications.


At present nearly half of the world’s population is under some form of government restriction to curb the spread of COVID-19, an extremely contagious disease. In Bangladesh, in the wake of five deaths and 48 infections from COVID-19, between March 24 and May 30, 2020, the government imposed a nationwide lockdown. While this lockdown restricted the spread of COVID-19, in the absence of effective support, it can generate severe food and nutrition insecurity for daily wage-based workers. Of the 61 million employed labor force in Bangladesh, nearly 35% of them are paid on a daily basis. This study examines the food security and welfare impacts of the COVID-19 induced lockdown on daily wage workers both in the farm and nonfarm sectors in Bangladesh. Using information from more than 50,000 respondents complied with the 2016–17 Household Income and Expenditure Survey (HIES) in Bangladesh, this study estimates daily wage rates as Bangladesh Taka (BDT) 272.2 in the farm sector and BDT 361.5 in the nonfarm sector. Using the estimated daily wage earnings, this study estimates that a one-day complete lockdown generates a US$64.2 million equivalent economic loss only considering the wage loss of the daily wage workers. After estimating the daily per capita food expenditure separately for farm and nonfarm households, this study estimates a minimum compensation package for the daily wage-based farm and nonfarm households around the US $ 1 per day per household to ensure minimum food security for the daily wage-based worker households. UntilThe present study uses information from 50,000 economically active workers in Bangladesh, collected by the Bangladesh Bureau of Statistics (BBS), to quantify the economic loss due to the COVID-19 lockdown based on the lost wage earnings of the daily wage workers in the farm and nonfarm sectors of Bangladesh. Then, applying simple econometric estimation processes, this study estimates the minimum compensation packages for the daily wage-based farm and nonfarm households of Bangladesh that ensure their minimum food security during the lockdown. The rest of the study is organized as follows. The next section describes the current poverty situation and the COVID-19 induced restricted movement and lockdown in the world and Bangladesh. Section 3 explains materials and methods, and section 4 presents major findings. Section 5 provides conclusions and policy implications.To control the spread of COVID-19, at least 157 countries and territories in the world imposed varying levels of movement restrictions [Despite the extraordinary success in alleviating abject hunger and extreme poverty since the 1990s , 21. In It is projected that COVID-19 will further exacerbate the poverty and abject hunger in the world in a number of ways. It is argued that the overburden on the health sector causes the reallocation of resources to the health sector to save lives, which may reduce resource allocation to the agriculture and industrial sectors, thereby hampering the food production and input supply chains . More imIt is observed that during epidemics like HIV/AIDS and Ebola, food prices in affected countries increased significantly, with severe impacts on food security, especially for vulnerable populations including women, children, and marginal people . For exaGiven the COVID-19 induced chaos, if major food and cereal exporting countries restrict their exports, a severe crisis may be generated in the food and cereal import-dependent countries , 33. In In 2019, a total of 135 million people in the world were severely food insecure . Food inIn Bangladesh, on March 23, 2020, in the wake of three deaths and 25 infections of COVID-19 , the Banrd out of 113 countries on the Global Food Security Index [nd out of 119 countries in 2006 [Since 2000, Bangladesh has continued to achieve stunning economic progress. After independence in 1971, the per capita GDP of Bangladesh was $133.6, which had increased to $418.1 in 2000, and $1688 in 2018 . Despitety Index , whereas in 2006 .The COVID-19 induced turmoil, however, could substantially undermine the economic achievement of Bangladesh by affecting trade and the garment industry of Bangladesh. Bangladesh is the second largest garment exporting country in the world after China, where, in more than 4,000 garment factories, more than 4.4 million workers are employed, the majority of whom are female . More thboro rice (dry-season irrigate rice crop) in 2020 has not only spoiled farmers’ harvest, but also curbed income opportunity of the casual labor, who earn a major portion of their yearly from harvesting boro rice. Consequently, among the different groups, daily wage laborers are the most food vulnerable group during this COVID-19 induced lockdown in Bangladesh [The nationwide lockdown and movement restriction can also severely undermine the economic achievement of Bangladesh by directly curbing the wage earning opportunity of the economically employed labor force. In 2016–17, the economically active employed labor force (15 years and above) of the country was 60.8 million, of which 85.1% were informal workers . The shangladesh .In 2000, 48.9% of the total population of 127.7 million, were classified as poor, which reduced to 31.5% in 2010 . HoweverWhat is missing in the existing literature is an estimate of the magnitude of the economic loss associated directly with the lockdown measure taken by the government to curb the spread of the coronavirus, as opposed to the estimate of overall negative impacts. Using Bangladesh as a case, this study quantifies the daily economic loss due to wage earning forgone of daily wage-based workers both in farm and nonfarm sectors. As to food security, it has already been suggested to expand the public support system . The preth series. The monetary poverty of the country is measured mainly based on the HIES, which is a nationally representative comprehensive survey [This study relies on Bangladesh’s 2016–17 Household Income and Expenditure Survey (HIES) data collected by the Bangladesh Bureau of Statistics (BBS). Since 1971, BBS has conducted 15 rounds of surveys, with the HIES 2016–17 survey being the 16e survey . To enhaThe 2016–17 HIES survey is a multipurpose survey, with nine sections detailing information on household level demographics, food consumption, farm and nonfarm economic activities, and labor allocation. This study uses data on labor allocation, daily wage earnings, and food consumption. As each household was comprised of 4.0 persons on average, information on age, education, marital status, rural-urban affiliation, and job status in the sampled seven days were given for all 184,320 members of the sampled 46,080 households. In this study, however, we have only considered the economically employed respondents, who were more than 15 or less than 60 years old. Thus, this study uses the sub-sample consisting of 50,671 individuals, of which 34,152 (67.4%) were from rural areas, 16,519 (32.6%) from urban areas, 6,522 (12.9%) female and 44,149 (87.1%) male.si) of a respondent i, working in sector s , and cereal price is the price of cereals per kg in Bangladesh Taka (BDT/kg). This variable is included in the regression to control for a possible association between cereal price and wage payment of the daily wage workers. The ILCis is a vector of variables, which includes respondent-level characteristics, such as:To calculate the economic loss associated with the COVID-19 induced lockdown, we estimate the daily wage earnings  ;marital status ;age in years;a dummy for age group 15–24 years (Age 15–24);a dummy for age group 25–34 years (Age 25–34);a dummy for age group 35–44 years (Age 35–44);a multiplicative dummy consisting of Age 15–24 × FM;a multiplicative dummy consisting of Age 25–34 × FM; anda multiplicative dummy consisting of Age 35–44 × FM.RLCis includes a rural dummy that assumes a value of 1, if a respondent is from a rural area, and 0 otherwise, and 63 dummies for 64 districts of Bangladesh. In addition, in estimating daily wage income, we include inverse Mill’s ratio calculated after estimating The vector of variables i  in sector s, as follows:lnEDFXis the natural log of the household level daily total expenditure on all food (in terms of BDT); wage earnings, i calculated as:ILCis and RLCis are the same as explained in HLCis includes:By multiplying the estimated per head average daily wage earnings (in BDT) in the farm sector household level income from rent of land and other properties, insurance income, profit and dividend income, lottery and prize money, charity, gift, royalty and assistance both in cash and kind, remittance income, gratuity and retirement benefits, interest received and other income in cash or kind. To make it daily, we divided by 365;household level receipt from social safety nets, including any positive income from any social safety net programs by any member of the household. To make it daily, we divided it by 365; andland owned (acres).lnEDFXis), and the estimated household level total daily wage earnings s.In estimating θ than the normal time, where 0 < θ < 1. It means, in the lockdown time, the total wage earnings of a daily wage-based household will be θ = 1. Consequently, the logarithm of the household level daily total food expenditure with this lost income (θ is the lockdown induced wage earning fraction (0< θ < 1), and lnEDFXis specified in Eq (3)In reality, however even under a stringent lockdown measure, daily wage earners may desperately search for any miscellaneous work, and thus can earn some positive income (>0). The earnings of a daily wage worker during lockdown time, however, can be lower by a fraction by s as follows:MSs is the minimum required daily support to a household, θ is the estimated coefficient. θ, the value of θ = 0.1) in the COVID-19 induced lockdown time compared to the daily wage earning in the normal time, then the household level daily total food expenditure will become fraction 0.1^ , setting the non-daily wage workers as the base (= 0) and assigning a value of 1 for daily wage-based farm workers (Nf), and a value of 2 for daily wage nonfarm workers (Nnf) as follows:HLCis, ILCis, and RLCis are the same as in Homesteadis is the size of the homestead land owned (acres).In estimating the wage function , we haveSome basic background information of the sampled respondents is presented in A closer scrutiny of More than one-fifth of the sampled respondents were from Dhaka Division, followed by Chattogram (18.3%) and Khulna Divisions (15.2%) . Dhaka aAs per The average daily household level total food expenditure was BDT 213.5, of which the expenditure only on cereals accounted for 30% (BDT 64.7). The daily per household level consumption of cereals was 1.8kg . This inTables In 2016–17, there were 24.7 million workers in the farm sector and 36.1 million in the nonfarm sector . There iIn the estimated functions, we have included the natural log (ln) of the estimated daily total wage earnings of a sampled household in explaining the daily household level total food expenditure of the sampled daily wage-based farm and nonfarm households . The estθ = 0.1, 0.2 and 0.3) compared to the normal time daily wage earnings, the estimated daily minimum supports are presented in f2 = 0.34 and γnf2 = 0.41 and θ) for the daily wage-based farm households, and it ranged between BDT63-104 in the case of the daily wage-based household in the nonfarm sector under the assumptions of 70%, 80% and 90% income loss  due to COVID-19 induced lockdown time  are directly engaged in the farm sector, of which 44.4% are paid on daily basis, and 36.1 million are engaged in the nonfarm sector, of which 18.4% are paid on daily basis. This study stressed that, compared to others, the daily wage-based workers in both farm and nonfarm sectors are comparatively more resource poor in terms of land ownership and education. Based on the estimated daily wage earnings, this study found that under the assumption of complete lockdown, the daily economic loss due to prohibiting daily wage-based workers to work would be US$ 64.2 million.θ = 0.1, 0.2 and 0.3) compared to the normal time income, we have estimated that on average it is necessary to provide daily BDT 51–104 or around US $ 1 per daily wage-based households during the COVID-19 induced lockdown time. It is important to mention here is that, the suggested minimum support US$ 1/day/household is calculated based on considering only food expenditure. The suggested minimum support package is thus only suitable for the short-term. In the case of a long-term lockdown situation, it is necessary to include the costs of health, education, clothing and housing.This study also demonstrated that the average wage elasticity in explaining the daily food expenditure at the household level ranged from 0.20 to 0.34, and the daily household food expenditure ranged from BDT 149.5–152.5 for the daily wage-based farm households. For the daily wage-based nonfarm households, the average wage elasticity in explaining the daily food expenditure at the household level ranged from 0.29 to 0.41, and the daily household food expenditure ranged from BDT 167–171. Assuming 10%, 20% and 30% of the daily earnings of the daily wage-based households in the farm and nonfarm sectors Click here for additional data file.S2 TableBase district: Bagerhat = 0.(DOCX)Click here for additional data file.S3 TableBase district: Bagerhat.(DOCX)Click here for additional data file.S1 File(DO)Click here for additional data file.S2 File(DTA)Click here for additional data file.