Curcumalonga and Boswelliaserrata share anti-inflammatory and antimicrobial effects that could be useful in the management of these clinical conditions. The aim of this study was to evaluate the efficacy of curcumin and boswellia extracts  and LFD on the relief of abdominal bloating in IBS subjects with small bowel dysbiosis, in comparison to LFD alone, in a 30-day supplementation, randomized trial. IBS participants were randomized to either the intervention (500 mg bid of CBP and LFD) or control arm (LFD). Small bowel dysbiosis has been defined by an increase of urinary indican with normal urinary skatole. A total of 67 subjects were recruited. The intervention group (33 subjects) showed a significant decrease (p < 0.0001) of bloating, abdominal pain, and indican values at the end of the study, when compared to the control group (34 subjects). Moreover, the subjects of the intervention group showed a significantly better (p < 0.0001) global assessment of efficacy (GAE) as compared to controls. In conclusion, in subjects with IBS and small bowel dysbiosis, abdominal bloating can be successfully reduced with a supplementation with CBP and LFD.Bloating is a symptom frequently reported by subjects with irritable bowel syndrome (IBS) and small bowel dysbiosis, and Low FODMAP’s diet (LFD) has been used to treat them. Extracts of  Bloating is one of the most frequent symptoms reported by patients with gastrointestinal functional disorders ,2,3,4. IGrowing interest is currently dedicated to the potential correlation between abdominal bloating, irritable bowel syndrome, small bowel bacterial overgrowth (SIBO), and dysbiosis. IBS is characterized by gut microbial dysbiosis, and gut microbiota could play a key role in the pathogenesis of this syndrome . BloatinThe antibiotic treatment of IBS is generally linked to Rome criteria amelioration in 48% of subjects . DysbiosWith regard to botanicals, recent literature shows that curcumin and Boswellia extracts share interesting anti-inflammatory and gut antimicrobial effects ,25,26,27Based on these data, the aim of this study was to evaluate the efficacy of curcumin and boswellia extracts  and low FODMAP’s diet (LFD) on the relief of abdominal bloating in IBS subjects with small bowel dysbiosis, in comparison to low FODMAP’s diet alone.This is a one-month (30 days) supplementation, randomized trial in which participants were randomized to either the supplement or control arm, performed at the Department of Public Health of the University of Pavia, Italy. The objective of the study was to evaluate the efficacy and safety of CBP in subjects with abdominal bloating, IBS, and small bowel dysbiosis. The study was conducted in accordance with the Declaration of Helsinki and the ICH Guidelines for Good Clinical Practice, following approval from the Local Independent Ethics Committee (Ethic code number: 0612/22052019). Written informed consent was obtained from each participant. The study was conducted from 5 February 2021, to 3 October 2021.Male and female subjects, with a diagnosis of IBS and small bowel dysbiosis who complained of bloating, were potential candidates for the study. The inclusion criteria were as follows: age 18–70 years; bloating reported as the main symptom; and a diagnosis of moderate IBS according to Rome III criteria, as abdominal pain for at least 1 day per week in the last 3 months that is associated with two or more of the following: related to defecation, associated with a change in stool form, or associated with a change in stool frequency ,31; or sExclusion criteria were: normal urinary indican values or increased urinary skatole values; subjects already on a LFD or other dietary restriction, such as gluten free diet or lactose free diet within the past 6 months; soy, nuts, or seafood allergies or insulin-dependent diabetes; known history of celiac disease, symptomatic diverticular disease, or inflammatory bowel disease or microscopic colitis; prior small bowel or colonic surgery or cholecystectomy; use of antibiotics, excluding topical, in the past 3 months; bloody diarrhea or severe vomiting; and a medical history of severe renal disease (defined as serum creatinine >1.5 mg/dL), or liver disease .Subjects included in the study received CBP 500 mg bid for 30 days. The choice of dose was based on previous clinical experience with CBP . The posSupplementation compliance was calculated as the ratio between the administered supplement (as determined by returned tablets) and the expected intake during the actual treatment period for each patient. All subjects (cases supplemented with CBP and controls) were instructed to follow nutritional recommendations, according to the low FODMAP’s diet by the same dietician . The con(1)The score of abdominal bloating. On the questionnaire, participants were asked whether they felt “bloating/uncomfortably full”. There were four options that participants could choose: none (symptom did not occur), mild , moderate , or severe  .(2)The score of the abdominal pain intensity. The score was defined using a validated visual analog scale score for pain (0 for ‘no pain’ to 10 for ‘most severe pain’) ,38.Study visits were scheduled at baseline (day 0) and at day 30. On both occasions all participants filled a questionnaire on the following:For all subjects the assessment of intestinal dysbiosis was performed by evaluating the urinary indican and skatole within 7 days prior to study inclusion and at the end of study. Urinary indican and skatole were considered normal at values lower than 10 mg/L and 10 µg/L, respectively .At the end of the study, according to Kruis et al., a global assessment of efficacy (GAE) using a 4-point scale was fulfilled by each subject  ,41.At each of the two visits, vital signs were checked and serum samples were collected. At the end of study urine samples were collected. Laboratory assessments were performed and analyzed with reference to the normal ranges. Participants were instructed to promptly report during the 30-day supplementation on any unwanted discomfort, intended as adverse event. Adverse events were likewise checked at the final visit.Curcuma longa L. and Boswellia serrata standardized extracts  was prepared by Indena S.p.A., Milan, Italy, as oblong-shaped, film-coated tablets, corresponding to a content of 17.0–23.0% w/w of curcumin and 7.0–11.0% w/w of boswellia extracts, respectively, by high performance liquid chromatography (HPLC) assay [®, Emmerthal, Germany), polyvinylpolypyrrolidone E1202 , sodium croscarmellose E468 , silicon dioxide E551 , talc E553b , magnesium stearate E470b , and hydroxypropyl methylcellulose E463-based film-coating . Before releasing, the film-coated tablets containing the food-grade lecithin formulation were tested for appearance, average mass, uniformity of mass, HPLC-content of curcumin and boswellia extracts, disintegration time, and microbiological quality.For the clinical study, the sunflower lecithin-based formulation of C) assay . The actThe primary endpoint was the decrease in intensity of abdominal bloating. Secondary endpoints included (1) the change of urinary indican values, (2) the change in intensity of abdominal pain, (3) the number of subjects with complete bloating relief, and (4) the GAE as assessed by the subject at the end of the study. Safety endpoints included adverse events, laboratory results, and vital signs.The sample size was estimated for the primary endpoint bloating using Zhao’s formula for Wilcoxon Mann–Whitney test . With ant-tests for continuous variables and chi-squared test for categorical ones. Differences between baseline variables in the two groups were investigated using First, the Wilcoxon Mann–Whitney test was used to assess if there were pre–post differences between the supplemented cases and control group in the bloating and on abdominal pain that are measured by a numerical rating scale from 0 to 3 and from 0 to 10, respectively. Secondly, a Cumulative Link Model (CLM), implemented in the ordinal R package, was performed in order to estimate the effect of the supplementation on bloating and on abdominal pain  ,44,45. 1 for the pre-measurement, 𝛽2 for the treatment group, 𝛽3 for age, and 𝛽4 for sex, according to the following equation:In the fitted model, the outcome Y represented the post-measurement, while the effect of the explanatory variables were 𝛽As for the secondary endpoint indican, measured on a continuous scale, after log-transforming and checking for normality both graphically and numerically, a linear model as in the above equation was fitted on the log-transformed variable. All the analysis was performed using R 3.5.1 statistical software . DescripSeventy-four patients with bloating and IBS were screened, and 67 (90.5%), 51 females and 16 males, with mean (±SD) age of 43.09 (±15.10), were recruited and analyzed .Six out of seven subjects were excluded because they did not meet the inclusion criteria: all of them had a urinary indican value within normal limits. One subject declined to participate.p-values for groups comparisons are reported. No statistically significant differences were observed between the two groups at baseline.Of the 67 enrolled subjects, 34 were randomly assigned to the control group, and 33 to the supplemented group. In p < 0.0001) and for abdominal pain (secondary endpoint) (p < 0.0001). In p-value for CLM or LM are reported. The estimate according to CLM should be interpreted as log odds of being in the higher level versus the combined middle and low categories of the outcome after supplementation in the treated group taking all the other variables in the model held constant. Both for bloating and abdominal pain, in the CBP group as compared to the control group a statistically significant effect of the proposed supplementation was observed, with a log odd respectively of 𝛽 = −6.11  and 𝛽 = −5.23  of being in the higher categories of score . Results of the paired Wilcoxon Mann–Whitney test indicated a statistically significant pre–post difference between the two groups both for bloating (primary endpoint) (p < 0.0001), which corresponded to a decreasing of indican of 40% as compared to control group. As for indican, the result of the linear model on the log-transformed variable indicated a statistically significant effect of treatment in the CBP group (𝛽 = −0.52 and p < 0.0001) was observed between the two groups.In Curcuma longa and Boswellia serrata are not available and these results indicate a new potential option for the relief of bloating in IBS and small bowel dysbiosis subjects.This study clearly shows that the supplementation of CBP and LFD is associated with a significant decrease of bloating in subjects with IBS and small bowel dysbiosis as compared to controls treated with LFD alone. This finding demonstrates the crucial and positive role of CBP in achieving this primary outcome. At the end of the study, 33 subjects of the intervention group reported no or a mild degree of bloating, in comparison to only 10 subjects in the control group. According to our knowledge, previous clinical data on this effect of extracts of LFD has been utilized to ameliorate bloating discomforts, as well as IBS and SIBO in various studies, with promising results ,20,21. IA retrospective study published by Gibson et al.  and otheA similarity with our outcomes comes from the study of Pedersen et al. . In thatIn our trial positive effects of the addition of CBP to LFD have been obtained when abdominal pain was considered. As a matter of fact, abdominal pain decreased significantly only in that group. LFD alone was not efficacious to reduce abdominal pain in IBS subjects with small bowel dysbiosis, thus, underlining the positive and fundamental role of CBP. Takamura and Pimentel showed that, as a consequence of intestinal dysbiosis, subjects with IBS symptoms, including bloating, may have increased intestinal permeability, dysmotility, chronic inflammation, autoimmunity, decreased absorption of bile salts, and even altered enteral and central neuronal activity . Thus, fAntibiotics are widely used to treat bloating in order to counteract intestinal dysbiosis that could be responsible for increasing gas production. In various trials rifaximin has been reported to be significantly better than placebo in reducing bloating in patients with IBS, thus, confirming the efficacy of anti-bacterial therapy ,52,53. ACurcuma longa and Boswellia serrata appears to be useful for abdominal bloating in subjects with IBS and small bowel dysbiosis following a LFD. Up to now there has been no evidence-based algorithm for treating subjects with bloating. The treatment options are diet, exercise, pharmacological medications, probiotics, antibiotics, smooth muscle antispasmodics, osmotic laxatives, prokinetic agents, chloride channel activators, and tricyclic antidepressants. This new, natural approach based on supplementation with extracts of The positive outcome of this botanical management is confirmed by the participants’ global assessment of efficacy (GAE) that showed a significant difference when cases and controls were compared. At the end of the study, 93.9% of the CBP group were classified in grade 3 (‘effective-marked improvement in symptoms’) or in grade 4 (‘very effective-as good as no symptoms’) of GAE, while this result was obtained only by 14.7% of controls. The phytosome technology is a 100% food-grade technology applied to natural products in order to obtain a solid dispersion by mixing a carrier like phospholipids  and the active principles, in order to increase the exposure area of natural molecules or extracts to the gastrointestinal layer. Recently, Del Rio et al. demonstrated that phytosome formulation notably influenced the biotransformation of curcuminoids since the fermentation of lecithin-curcuminoids by fecal human microbiota led to more efficient production of curcuminoid catabolites .Some limitations of our study need to be taken into account. The subjects have been randomized to the two different treatment choices, but there was lack of blinding. Furthermore, the control group did not receive placebo but LFD and this constitutes a weakness of the study, when referring to the large placebo responses in IBS revealed in other studies. A final limitation of the study is that the adherence with LFD has not been checked in both the intervention and control groups.Curcuma longa and Boswellia serrata (as curcumin boswellia phytosome) and LFD. Moreover, this is one of the few studies in which abdominal bloating has been evaluated as a primary endpoint in IBS patients and one of the few studies in which LFD has been tested to treat IBS in a Mediterranean country.In conclusion, the strength of our study is that, to the best of our knowledge, this is the first controlled clinical research project in which abdominal bloating in IBS subjects with small bowel dysbiosis has been successfully treated with a concomitant supplementation with extracts of Our results should be confirmed by larger trials, with longer duration of supplementation.


A growing body of evidence suggests that preadmission metformin use could decrease the mortality of septic patients with diabetes mellitus (DM); however, the findings remain controversial. Therefore, this meta-analysis was conducted on available studies to confirm the relationship between preadmission metformin use and mortality in patients with sepsis and DM.CIs) were analyzed using the inverse variance method with random effects modeling.A comprehensive search of the PubMed, Embase, and Cochrane Library databases was performed for studies published before August 8, 2021. Observational studies assessing the correlation between metformin use and mortality in patients with sepsis and DM were considered eligible studies. We used the Newcastle–Ottawa Scale (NOS) to assess the outcome quality of each included article. Furthermore, the odds ratios (ORs) and 95% confidence intervals  in patients with sepsis and DM. Surprisingly, there was no statistically significant difference in the levels of serum creatinine (weighted mean difference (WMD), 0.36; 95% CIs, −0.03–0.75; P = 0.84) and lactic acid  between preadmission metformin use and non-metformin use.Eleven articles including 8195 patients were analyzed in this meta-analysis. All the included articles were scored as low risk of bias. Our results showed that preadmission metformin use had a lower mortality rate (OR, 0.74; 95% This study is the most comprehensive meta-analysis at present, which shows that preadmission metformin use may reduce mortality and not increase the levels of serum creatinine and lactic acid in adult patients with sepsis and DM. Therefore, these data suggest that the potential efficacy of metformin could be assessed in future clinical studies.https://inplasy.com/?s=INPLASY2021100113, identifier INPLASY2021100113. Sepsis is a life-threatening systemic inflammation characterized by host immune dysfunction and multiple organ damage . An estiMetformin, a classic oral antidiabetes drug, is extensively recommended as a first-line treatment of type 2 DM , 7. In aRecent studies demonstrated the positive effects of metformin in patients with sepsis. Doenyas-Barak et al.  and JochThis systematic review and meta-analysis protocol was registered on INPLASY (ID: INPLASY2021100113). This study was conducted according to the guidance of the meta-analysis of observational studies in the epidemiological guidelines. The PRISMA 2020 checklist is shown as We comprehensively searched the PubMed, Cochrane, and Embase databases for English language studies published before August 08, 2021. We used a combination of MeSH/Emtree, title, abstract, and keyword terms to search for relevant studies. The search terms were “metformin”, “sepsis”, and “critically ill”. Endnote x9 software was used for literature screening. We reviewed the eligible articles to identify other potentially relevant studies. Literature retrieval was conducted by two researchers. The search process is shown in Studies were included in this meta-analysis if: the patients with sepsis and DM who used metformin before admission were enrolled; the control group was DM complicated with sepsis but not treated with metformin; mortality in metformin and non-metformin users was measured; the patients were adults; the articles were observational studies; and the articles were published in English. Articles lacking relevant outcomes or patients with sepsis complicated with other illnesses were excluded. Commentaries, reviews, and studies for which full articles could not be retrieved were excluded.The relevant articles and eligible data were assessed and extracted by two authors, respectively. If a disagreement occurred, which was discussed and the consensus with a third author was reached. The following data were collected from each study: first author name, publication date, the type of studied design and center, number of patients, study period, sex and mean age between groups and primary outcome.Using the Newcastle–Ottawa Scale (NOS) for cohort studies, the risk of bias was assessed for each outcome in all included studies. According to the selection of cohort (up to 4 points), the comparability of cohort design and analysis (up to 2 points) and the adequacy of result measurement (up to 3 points), a maximum of 9 points will be obtained. Seven to nine points are considered high quality (low risk of bias) .CIs) for each result using a random effects model to explore the heterogeneity between studies.The interesting outcomes were mortality in sepsis patients with or without metformin before admission. Furthermore, the meta-analysis used the combined effects of each result. We calculated odds ratios (ORs) and 95% confidence intervals .The outcome of interest was the mortality, serum creatinine and lactic acid levels of septic patients with or without preadmission metformin use. The meta-analysis used the pooled effects of each outcome. The random effects models were used to evaluate ORs and 95% nel plot  was used854 studies were determined and 16 studies were eliminated because of duplication. After assessing the full-text eligibility, only 32 articles that addressed reasons potentially associated with the original study question remained. Eleven studies , 21–25 eCIs were missing, the data were calculated based on the original data reported from the original studies. The eligible studies were observational studies that included septic patients with DM who used preadmission metformin. Furthermore, three articles , 17, 21 Ten studies were observational studies, and one was a prospective cohort study. The risk of bias assessment scores for all studies was greater than or equal to six points, indicating a low risk of bias based on the NOS. CIs, 0.62–0.88; P < 0.01; CIs, −0.03–0.75; P = 0.84; CIs, −0.49–0.18; P = 0.07; The preadmission use of metformin in septic patients significantly lowered mortality when compared with the mortality in patients who were not treated with metformin .We performed the Funnel plots 4 and BeThis meta-analysis included 8195 patients and demonstrated that the mortality rate of preadmission metformin users was lower than that of non-metformin users in adults with DM and sepsis. Our findings suggest that metformin could have a therapeutic potential for septic patients with DM.The relationship between metformin use and mortality in patients with infectious diabetes remains controversial. Therefore, some studies –19 demonvia decreased pro-inflammatory factors, such as NF-κB and tumor necrosis factor alpha (TNF-α)  . Moreove (TNF-α) , improve (TNF-α) . Notably (TNF-α) , 34, whi (TNF-α) . Further (TNF-α) . Finally (TNF-α) , improviMeta-analysis is a comprehensive statistical analysis method for multiple studies on a subject. When the difference between the results of each study is greater than expected, there is statistical heterogeneity in the summary results of the meta-analysis. The high heterogeneity of the included studies of this study reflects the differences of these studies. Because of the low publication bias, we consider the heterogeneity was not significant. The heterogeneity may originate from differences in sample sizes, lactate concentrations, and the combined application of other antidiabetes drugs.CIs were extracted to compute the effect of metformin on mortality.This meta-analysis has several strengths. Firstly, the sample size was large, making the results more convincing. Secondly, the risk of bias was low for all included studies. Finally, the random effects model with generic inverse variance was used, and the adjusted ORs and 95% Our study has several limitations. Despite the comprehensive search, only eleven studies met the inclusion standards and ten were observational studies; therefore, the conclusion should be confirmed in future clinical studies. Furthermore, most original studies did not report the dose of metformin and whether other kinds of hypoglycemic agents were used. Hence, this study did not determine whether different doses of preadmission metformin use and other hypoglycemic agents would influence the effect of metformin on septic patients with DM. Thirdly, this study was constrained to studies published in English. Thus, publication bias cannot be excluded.This meta-analysis suggests that we should continue perform the large sample observational and clinical study to confirm the effect of metformin on septic patients with DM, and thereby to searche the mechanism of metformin in reducing the mortality on septi patients with DM. Additionally, the does and time of metformin use in septic patients with DM should be researched in the future clinical studies.This is the most comprehensive meta-analysis to investigate the association of metformin use with mortality in septic patients with DM. The findings suggest that preadmission metformin use may reduce the mortality of septic patients with DM, and without increasing the levels of serum creatinine and lactic acid. However, stronger support from more high-quality research is still needed.All the authors contributed equally to the work presented in this article. YL, HZ, YjG, and XD conceived the idea of this study. YlG and YD contributed to the data extraction. YL and HZ computed and evaluated the pooled outcomes. YjG and XD contributed to the study protocol and wrote the article. YjG and XD revised the article. All authors contributed to the article and approved the submitted version.This study was supported by the 2021 youth talent promotion project in Henan Province (Grant No.2021HYTP053), 2021 joint construction project of Henan Medical Science and technology breakthrough plan (Grant No. LHGJ20210299), and Henan Provincial Ministry Co-construction Project (2018010040).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


New methods of dietary assessment are increasingly making use of online technologies. The development of a new online food frequency questionnaire warranted investigation of its feasibility and the reproducibility of its results.To investigate the feasibility and reproducibility of a newly developed online FFQ (WebFFQ).n = 229) filled in the WebFFQ and answered questions about its feasibility, and in two subsequent focus group meetings, participants (n = 9) discussed and gave feedback about the feasibility of the WebFFQ. In the second study, the WebFFQ’s reproducibility was assessed by asking participants (n = 164) to fill it in on two separate occasions, 12 weeks apart. Moreover, in the second study, participants were offered personal dietary feedback, a monetary gift certificate, or both, as incentives to complete the study.The semiquantitative WebFFQ was designed to assess the habitual diet the previous year, with questions about frequency of intake and portion sizes. Estimations of portion sizes include both pictures and household measures, depending on the type of food in question. In two independent cross-sectional studies conducted in 2015 and 2016, adults were recruited by post following random selection from the general population. In the first study, participants (p = 0.001), fiber showed the least difference at 1.6% (p = 0.007), and sugar intake differed the most at −6.8% . Percentage energy obtained from macronutrients did not differ significantly between the first and second WebFFQs.In the feasibility study, evaluation form results showed that participants raised issues regarding the estimation of portion size and the intake of seasonal foods as being particularly challenging; furthermore, in the focus group discussions, personal feedback on diet was perceived to be a more motivating factor than monetary reward. In the reproducibility study, total food intake was lower in the second WebFFQ; however, 63% of the food groups were not significantly different from those in the first WebFFQ. Correlations of food intake ranged from 0.62 to 0.90, >86% of the participants were classified into the same or adjacent quartiles, and misclassification ranged from 0 to 3%. Average energy intake was 3.5% lower (Our results suggest that at group level, the WebFFQ showed good reproducibility for the estimations of intake of food groups, energy, and nutrients. The feasibility of the WebFFQ is good; however, revisions to further improve portion size estimations should be included in future versions. The WebFFQ is considered suitable for dietary assessments for healthy adults in the Norwegian population. New dietary assessment methods are increasingly making use of online technologies.This study investigated the feasibility and reproducibility of a new online food frequency questionnaire (WebFFQ).Estimating portion sizes and intake of seasonal foods were regarded as challenging by the participants.Portion size pictures were regarded by some as helpful.Reproducibility was overall good.The WebFFQ was shown to adequately reproduce intakes of food and nutrients in a general adult Norwegian population.”Self-report instruments are used frequently in research on nutrition. All methods used to assess long-term or short-term diet, either prospectively or retrospectively, have associated measurement errors ,2. Self-The use of online computer technology does not obviate all limitations of an FFQ , howeverTo gain access to the WebFFQ, participants had to log in to the secure governmental login system (MinID) to ensure their secure identification. An informed consent was also obtained via the WebFFQ.The WebFFQ was designed to assess habitual diet, food and nutrient intakes at group level, as well as to rank individuals according to their intakes. The WebFFQ consisted of 279 questions about the types, frequency of consumption, and portion sizes of food and beverages that participants had consumed the previous year. The questions were grouped according to the following main categories: bread; spread and butter/margarine; breakfast cereals; yoghurt; cold (including milk), warm, and alcoholic beverages; dinner meals; vegetables and legumes; fruits, berries, spices, nuts, and seeds; cakes and desserts; snacks; and dietary supplements. The WebFFQ included pictures of different portion sizes for food items, for which portion size may be difficult to estimate, such as composite dishes or when the food items do not come in natural units such as slices, spoons, or cups. Frequency of consumption of each food or beverage ranged from never to several times per month, week, or day. If participants did not fill in certain questions, an automated prompt would make them aware of this. All questions were mandatory. To reduce the burden of participants, categories of food or beverage (i.e. yoghurt) could be bypassed for products never consumed . Anthropometric and demographic questions were placed at the end of the questionnaire. The WebFFQ is designed for use on PCs, tablets, and mobile phones. Depending on which device the participants use, an adaptive web-design changes the screen appearance of the WebFFQ.Data from the WebFFQ were saved in the secure storage facility TSD (Services for Sensitive Data) at UiO, and the dietary data transferred to the food and nutrient calculation system KBS, version 7.3, at the Department of Nutrition, UiO . EstimatIn January 2015, 2,000 adults between 18 and 75 years, selected randomly from the Norwegian National Population Registry, received invitations by post to take part in a study to evaluate the feasibility of the WebFFQ. The feasibility study included filling in the WebFFQ once and subsequently answering the feasibility evaluation form , which wn = 89) were invited via email. Two focus group meetings were organized a few weeks after the last participant had filled in the feasibility evaluation form, with three and six participants, respectively. The meetings were held at the Department of Nutrition, UiO, and conducted as semi-structured focus group interviews with one moderator and one assistant present in addition to the participants. During the focus group discussions, the participants were asked about the procedures of invitation and login; how they experienced the ease of use and structure of the WebFFQ; the use of incentives and reminders by SMS or telephone; the associated text with guidelines and information about the WebFFQ; and any other comments. The discussions were recorded, and the data were processed manually and summarized.In the feasibility evaluation form, participants were asked to indicate if they would like to be invited to focus group meetings. Those who indicated positively . The participants filled in the same WebFFQ twice, approximately 12 weeks apart, during January to March  and April to June  2016 .The feasibility and reproducibility studies were conducted according to the Declaration of Helsinki, and a written informed consent was obtained from all participants. No data were collected about the persons who were invited but chose not to participate.t-test and Wilcoxon signed-rank test were used to test for differences in intakes between WebFFQ1 and WebFFQ2, when data were normally and non-normally distributed, respectively. Correlations between estimates from WebFFQ1 and WebFFQ2 were performed using Pearson and Spearman correlations on normally and non-normally distributed data, respectively. For cross-classification analyses, intake estimates were ranked and classified into quartiles of intake. Misclassification was defined as classification into the opposite quartile. Differences in intakes estimated from WebFFQ1 and WebFFQ2, presented as absolute (g/day) and percentage, were calculated for each participant, and the group mean was calculated for each variable. Sample size calculations were based on a correlation coefficient of ≥0.5, with a significance level of 5% and a power of 90%, which resulted in a sample size of 76  from all macronutrients except alcohol were normally distributed and presented as mean and standard deviation (SD) or 95% confidence intervals (CIs). Estimated intakes of alcohol, energy from alcohol, and intakes of food and micronutrients showed skewed distributions and are presented as median and 25th and 75th percentiles. One exception was the intake of vegetables, which was normally distributed. Paired-sample ze of 76 . To estize of 76 . Previouze of 76 –13. Sign2, and 10% were smokers. More than 50% had completed higher education, and 70% were married or cohabiting  filled in the WebFFQ. The study population consisted of 112 men and 148 women, mean age 46.2 years (range 18–75), the mean BMI was 25.2 kg/mhabiting . Of the habiting . Mean tin = 156) did not answer the question ‘Were there any unclear questions in the WebFFQ?’, 10% (n = 29) answered ‘no’ and 20% (n = 44) answered ‘yes’. The following issues were registered by participants who answered ‘yes’, in descending order: estimation of portion sizes; estimation of consumption frequency for foods associated with season; the WebFFQ was too long; filling in the WebFFQ took too much time; and the list of foods and beverages had too few alternatives for those on diets or who were vegetarians.As many as 70% (n = 7), and the WebFFQ was easy to understand and use . The majority of the participants who made positive comments found the WebFFQ to be either ‘very easy’ or ‘quite easy’ to fill in (n = 19), while two of them found it ‘a little difficult’.Twenty-one participants (9%) made positive comments; the pictures were helpful in estimating portion sizes  gave written consent and filled in the WebFFQ once (WebFFQ1). After 3 months, 71% of the 232 participants filled in the WebFFQ a second time (WebFFQ2). Thus, the final study population consisted of 164 participants, of whom 59% were women  and reflEstimated intake of food groups is presented in p = 0.001). The mean difference in energy intake at group level was 3.5% (p = 0.03) to 18.7 g/day for carbohydrates (p = 0.002). Fiber showed the least difference, with 1.6% (p = 0.007), and sugar intake differed the most with −6.8%, however, borderline significant (p = 0.08) between the first and second administrations of the WebFFQ . Eight of 10 macronutrients, in addition to alcohol, showed high correlation (>0.7). Correct classification ranged from 51% for fiber to 68% for alcohol. Misclassifications into opposite quartiles were low for the absolute intakes of macronutrients .p = 0.01), protein , and fiber , in addition to carbohydrates  and saturated fats . Correlations between absolute intakes of energy and macronutrients ranged from 0.73 for sugar to 0.87 for alcohol   .p = 0.02), protein , and carbohydrates . The correlations ranged from 0.62 for the intake of fiber to 0.91 for the intake of alcohol   .Estimated proportions of energy from energy-providing nutrients were not significantly different in WebFFQ1 and WebFFQ2 . The corp-values ranging from <0.001 to 0.03. The intakes of vitamins A and E showed no significant differences, p = 0.3 and p = 0.2, respectively . The correlations found in our study were in the same range or higher than those presented in other reproducibility studies of online FFQs , 28. HowTotal energy intakes in the present reproducibility study were high, and using the Goldberg evaluation of energy intake  indicateThe participation rate in the reproducibility study was low, which was a limitation to the study. Results from a biased study sample may not be representative of a wider national population. Additionally, the number of men in the reproducibility study was low, which may have influenced the correlation analyses in men. One strength of the reproducibility study was the long time between the first and second administrations of the WebFFQ, which limited the learning effect .In an earlier validation study, we evaluated the WebFFQ with regard to intakes of nutrients and food groups using doubly labeled water and 24-h recall . At grouThe self-administered online WebFFQ demonstrates good feasibility and reproducibility for estimations of food groups, energy, and nutrients at group level. Therefore, together with the results of the earlier validation study, the WebFFQ may be considered suitable for dietary assessments in healthy adults in the Norwegian population.


At t1, the sale of absolute vegetable components did not change , but more per main component were sold at t1 . In addition, the sale of fruit  increased after the intervention. The total consumption of vegetables  and fruit , however, did not change. To effectively change daily consumption, the intervention needs to be expanded.The purpose of the study was to evaluate whether an environmental intervention in a university canteen changes the sale and daily consumption of vegetables and fruit among canteen users. The intervention focused on decision guidance, including a positive incentive and nudging. In a pretest−posttest-design, daily sales data of pieces (pcs) of vegetable components and fruit, as well as the sale per main component (pcs/mc), were assessed. Here, 20 opening days were analyzed, each after the intervention (t1) and in the same period of the previous year (t0). Vegetable and fruit consumption were assessed in a controlled pretest−posttest design . The intervention group (IG;  Vegetables and fruit are of particular importance in a healthy diet. An adequate consumption of these foods reduces the risk of disease adjusted life years and premature mortality  ,2. But iChanges in the food environment are appropriate to initiate improvements in dietary behavior . To promInterventions in order to increase the vegetable and fruit consumption in canteens are often based on the principles of decision guidance. In terms of intervention depth and effectiveness, Jürkenbeck et al. rank decision guidance between decision support (low intervention depth) and decision restriction (highest intervention depth) . Two impTherefore, the present study aimed to analyze whether a mainly decision guiding environmental intervention in a university canteen impacts the sale and daily consumption of vegetables and fruit. The present intervention study applied different nudging strategies, a positive incentive, and some elements of decision support. It was the hypothesis that the sale of vegetables and fruit would increase. In addition, it was assumed that there were no compensation effects. Consequently, an increase in vegetables and fruit consumption was hypothesized.The daily lunch offered in the university canteen comprised four main components. Additional side dishes could be selected, e.g., vegetable components  and fruit pieces (piece of fresh fruit and fresh fruit cup). Vegetable and fruit side dishes were already available daily at t0.The intervention consisted of different measures, according to Jürkenbeck et al. , with a Sales data (electronic cash: Toshiba IBM SurePOS 500) regarding vegetable components  and fruit (piece of fresh fruit and fresh fruit cup), as well as vegetable components and fruit sold per main component, were assessed. The analysis covered 20 opening days, beginning one week after the intervention started (t1: 17 November–12 December 2014) and in the same period of the previous year (t0: 18 November–13 December 2013).The assessment took place before (t0: 20 January–28 February 2014) and at least ten weeks after (t1: 15 January–17 April 2015) the intervention started. All university members (students and employees ~2800) were invited to participate in the study by e-mail, via the learning management system, by flyer, during lectures, or by personal contact. A minimum of 34 participants was planned according to the tables of Bortz and Döring  for repeThe dietary assessment was conducted by a validated food record. Participants recorded their food consumption over three days by estimating the amounts via typical household measures  and documented it in a closed form .Additional items were collected by questionnaire (online/paper−pencil). These were gender, age, weight, height, personal presence at university, the use of the canteen for lunch, and the canteen’s health-promoting lunch option. Body mass index (BMI) was calculated via dividing weight (kg) by height in meters-squared.2-tests for categorical variables.Statistical analyses were performed using SPSS Statistics version 27 . Comparisons between groups  were conducted using Mann–Whitney U-tests for continuous variables and Pearson’s Chip-values were < 0.05.To detect possible changes in the vegetable and fruit consumption over time, an analysis of variance (ANOVA) with repeated measures was performed and the intervention status (intervention group vs. control group) was applied as a covariable. Differences were considered as statistically significant when The study was performed in accordance with the guidelines of the Declaration of Helsinki. It was approved by the Ethics Committee of the University of Education Schwäbisch Gmünd. Only data of participants who had given their written informed consent were analyzed.In total, 95 university members participated in Substudy B. The characteristics of the participants according to group are shown in The hypotheses were partially confirmed. The intervention resulted in higher sales of vegetable components per main component, as well as more fruit in absolute terms and per main component. The hypothesis regarding the consumption behavior could not be confirmed. Unfortunately, the effects on vegetable and fruit sales were relatively small. These effects were hardly measurable or compensated in regard to daily vegetable and fruit consumption.The present study confirms other studies on the selection behavior/sale or on-site consumption of vegetables and fruit. Apparently, the selection/sale ,22,26 orParticularly high price reductions >30%) ,21 or th% ,21 or Another strategy used in the present study, increasing the vegetable content in the main component (reformulation), seems to be very promising, at least in the laboratory. Increasing the proportion of vegetables in a main component is often not noticed by test persons ,44, yet Regarding the daily vegetables and fruit consumption, no effects were confirmed. Reasons for this can only be speculated. Whether the differences between the intervention group and control group play a role remains unclear. It seems unlikely that this is a possible reason, as vegetable and fruit consumption increased slightly in the control group while remaining at a similar level in the intervention group. The measures were not effective enough, possibly because they covered too few of the meals offered. In addition, the study included a relatively small number of participants, and the methods could have been slightly more precise.The outcome parameter of the total daily vegetable and fruit consumption has only been used in a few intervention studies in canteens ,35,36,37One limitation of the present study is that the analysis of the sales data (Substudy A) is unfortunately only based on a pretest−posttest design. However, this is also the predominantly used design in other studies ,22,23,26On a positive note, Substudy B provides the controlled study design mentioned above. Although there are some differences between the intervention group and control group, both groups came from the same social environment of a university. Ideally, a long-term RCT with simultaneous measurement of sales or on-site consumption and total daily consumption would have been conducted.Admittedly, the number of participants in this study was relatively small, and the drop-out rate did not meet the optimal maximum of 20% for nutrition-related intervention studies in general . HoweverThe intervention group in this study had relatively low exposure to the intervention (2.3 ± 1.2 canteen visits/week), which represented below-average canteen use among students , the larThrough the intervention, the sales of vegetables (per main component) and fruit (absolute and per main component) increased to a small extent. This seems easier to achieve for fruit than for vegetables. However, for vegetables, there is a greater requirement (greater consumption deficit compared to the recommendation) and less clear study evidence. Nevertheless, the total daily consumption of vegetables and fruit could not be increased.In the present study, the measures were centered on the marketing of a health-promoting menu. Expanding reformulation, nudging, and pricing incentives to a broader range of products is recommended. The more courageous application of these measures also offers the opportunity to bring about changes in overall daily consumption. It can be assumed that only the exclusive application of the measures to the entire lunch offer will have a relevant impact on daily vegetable and fruit consumption. Moreover, the effect could unfold across social differences in all social groups . This sh


Background: Budget impact analysis (BIA) is an economic assessment that estimates the financial consequences of adopting a new intervention. BIA is used to make informed reimbursement decisions, as a supplement to cost-effectiveness analyses (CEAs).Objectives: We systematically reviewed BIA studies associated with anti-diabetic drugs and assessed the extent to which international BIA guidelines were followed in these studies.Methods: We conducted a literature search on PubMed, Web of Science, Econlit, Medline, China National Knowledge Infrastructure (CNKI), Wanfang Data knowledge Service platform from database inception to June 30, 2021. ISPOR good practice guidelines were used as a methodological standard for assessing BIAs. We extracted and compared the study characteristics outlined by the ISPOR BIA Task Force to evaluate the guideline compliance of the included BIA.Results: A total of eighteen studies on the BIA for anti-diabetic drugs were identified. More than half studies were from developed countries. Seventeen studies were based on model and one study was based on real-world data. Overall, analysis considered a payer perspective, reported potential budget impacts over 1–5 years. Assumptions were mainly made about target population size, market share uptake of new interventions, and scope of cost. The data used for analysis varied among studies and was rarely justified. Model validation and sensitivity analysis were lacking in the current BIA studies. Rebate analysis was conducted in a few studies to explore the price discount that was required for new interventions to demonstrate cost equivalence to comparators.Conclusion: Existing studies evaluating budget impact for anti-diabetic drugs vary greatly in methodology, some of which showed low compliance to good practice guidelines. In order for the BIA to be useful for assisting in health plan decision-making, it is important for future studies to optimize compliance to national or ISPOR good practice guidelines on BIA. Model validation and sensitivity analysis should also be improved in future BIA studies. Continued improvement of BIA using real-world data is necessary to ensure high-quality analyses and to provide reliable results. Diabetes is one of the fastest-growing global health emergencies of the twenty-first century and has reached alarming levels, which is associated with significant clinical and economic burdens on society and people with diabetes . AccordiDiet and exercise are first line treatments along with metformin to achieve the goal of improving glycemic control and preventing both microvascular and macrovascular complications . In ordeBudget impact analysis (BIA) addresses the expected changes in the expenditure of a healthcare system after the adoption of a new intervention. It estimates the financial consequences of adoption and diffusion of a new healthcare intervention within a specific healthcare setting given budget constraints. The structure of BIA can be adjusted according to different needs for different countries as well as for time horizons, perspective and underlying diseases . Budget As far as we know, there has been no review examined BIA studies in the field of diabetes. Since the high prevalence of diabetes and high treatment costs have a significant impact on drug availability and the sustainability of the reimbursement fund, it is important to study the financial budget for diabetes drugs. Therefore, focusing on the BIA of antidiabetic drugs, this study aimed to review the findings of the current BIA studies and assess the extent to which international BIA guidelines were followed in these studies.This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.* OR budgetary impact* OR budget impact analy* OR budgetary impact analy* OR budget impact stud* OR budgetary impact stud*) OR [ AND budget*]} AND (diabetes OR diabetes mellitus OR DM OR diabetic). Targeted keyword search was also conducted in two Chinese databases  and Wanfang Data knowledge Service platform) to identify studies which were published between 1994 and June 30, 2021 and reported estimates of the budget impact of the introduction of a new drug to the treatment.Based on published guidelines for BIA and other published methodological studies, we conducted a literature search in four English databases  to identify studies on BIA of antidiabetic drugs published in English or Chinese from 1980 to June 30, 2021. The key concepts used for the search were “budget impact analysis” AND “diabetes mellitus” see . The folWe included studies reporting results of an original BIA pertaining to antidiabetic drugs. Comments, letters, editorials, and meeting abstracts were excluded. We also excluded studies that were not related to diabetes or anti-diabetic drugs, or studies that conducted only cost-effectiveness analyses, reviews, and BIAs of other non-drug interventions for diabetic patients.We conducted the duplicate removal and filtering of studies first. Then two reviewers screened the title and abstracts followed by a second round of examining abstracts and full texts independently. A third author resolved any disagreement. This selection process was documented in a PRISMA flowchart see .Based on the ISPOR Task Force guidelines, we developed evidence tables which presented a summary of how each study addressed the key items of the study, including population size and characteristics, budget holder's perspective, budget time horizon, intervention and comparators, market share, model structure, clinical and cost data, cost calculation, and sensitivity analysis. We then systematically extracted data and summarized the findings from all included studies in the evidence tables.Assessment of guideline compliance of the included studies was conducted to check the extent to which the ISPOR Task Force guideline of BIA were followed in these studies . The assn = 139), and by screening of title and abstract (n = 298) and full text (n = 28), 18 BIA studies ( studies –27 were n = 11) were from Europe and the U.S., of which five studies were conducted in US (n = 11) were conducted from a payer's perspective and a few studies (n = 5) from the perspective of health care system, while one study (n = 15) focused on BIA only, while the other studies (n = 3) combined the BIA with cost-effectiveness analysis.ed in US , 24–27, ed in US , 22, oneed in US , one in ed in US , one in ed in US and one ied in US . Apart fed in US –12, two ed in US , 23, oneed in US  and one ed in US . Among tne study  was condne study . All thene study  that wasn = 8) evaluated the budget impact of insulin, including basal insulin (n = 5) (n = 1) (n = 1)    (n = 1)  –22, 26,  (n = 1) , bolus i (n = 1) . One stu (n = 1) . Among t (n = 1) . The resglutide) , 25, 27,gliptin) , 15, 23,iflozin) , 17 and  (n = 1) .n = 13) (n = 2) (n = 2) (n = 13) calculated the size based on local epidemiological data, while the other two studies calculated the size based on real world evidence (The eligible population were mainly chosen according to the indication of intervention and the coverage of the payer's plan. The majority of studies n = 13) –25, 27 r (n = 2) , 21, or  (n = 2) , 26, and –25, 27  (n = 2) , 23–27,  (n = 2) , 21, 22. (n = 2) . Among tevidence , 22. It evidence . Two othevidence , 26, 27 evidence , 22–27 revidence –12 contan = 6) (n = 6) (n = 4) (n = 2)  , 19, 23  (n = 6) , 25, 27, (n = 4) , 24, 26  (n = 2) , 18. Not (n = 2) , 24. The (n = 2) , 23–25,  (n = 2) –21, 27 d (n = 2) , 22, 26 n = 10) compared research drug used in two treatment strategies under different scenarios  reported the hypothetical market shares of the new interventions within the time horizon of the study. Among the 17 studies, 11 assumed that the market share of the new intervention increased gradually  (n = 6) (n = 8) (n = 4)  , 26, 27  (n = 6) , 23, 25  , 26, 27 (n = 8) , 24–26 a (n = 4) , 22–26 r (n = 4) , 21, 27  (n = 4) , 27 cond (n = 4)  also repIn this study, we systematically reviewed 18 BIA studies for anti-diabetic drugs for diabetes mellitus, which were conducted in various countries and regions including Europe, the U.S., Asia and South America. The methodological characteristics according to the ISPOR guidelines for BIA  and reseMajor deviations in the study design from the recommendations in the ISPOR Task Force guidelines  were theAn important recommendation from the ISPOR Task Force guideline  is to adSome critical study characteristics were difficult to determine, including the estimation of the population size of the new intervention, the determination of comparators, the market share and the selection of model structure. These items are critical because they determine the size of target population for the new intervention, which are the important factors influencing the results of the BIA. Target population are usually estimated by two ways: based on epidemiological data or based on real world evidence. In our review, most studies (72.22%) were conducted based on local epidemiological data. In some countries, such as China, epidemiological data related to diseases and drug treatments are also required for the NRDL submission. In addition, the guidelines of BIA indicated that the target population is not a static group, but a dynamic one that varies with incidence, cure, prognosis, and death. But most studies in this review did not appropriately account for a dynamically changing population while only six studies , 21, 23 Another difficulty in conducting BIA is making the assumption of intervention/comparator market uptake. When a new drug is introduced, there are many factors influencing the change in the market share of the new drug and the comparators. It is difficult for budget holders to evaluate the accuracy of these assumptions based on the available evidence and data. So far, many published BIA studies did not take market uptake into account, but assumed the extreme cases instead where the comparator drug was 100% replaced by a new drug. There are three types of market change according to the ISPOR guidelines, including substitution, combination, expansion . Our revOur review corroborates precedent findings , 33 on lThe features of health care systems should be taken into account when conducting BIA. For example, in China, the reimbursement rate for outpatient and inpatient is different. The reimbursement rate of inpatients (65%) is significantly higher than that of outpatients (50%), which should be taken into account when submitting the BIA for NRDL negotiation. Furthermore, the characteristics of the medical system are also related to the selection of cost range. We found that the studies included in this review varied in terms of treatment-related costs. Some studies not only included the drug acquisition costs, but also analyzed the associated costs, such as needle costs, self-measured blood glucose (SMBG) costs. This might not be applicable in all healthcare settings. For instance, in China, the needle and SMBG related expenses are not reimbursed in most provinces and cities. Therefore, such costs should not be included when a BIA is conducting from the perspective of payer.The conflict of interest and the funding sources cannot be ignored when considering the quality of BIAs. It should be noted that the vast majority were sponsored by the pharmaceutical companies, and as expected, the authors' conclusions of all sponsored studies were in favor of these drugs. In this way, BIAs have deviated from the intended goal of providing short-term economic consequences from a health system perspective and appeared to be tailored to show short-term savings. In 2016, Faleiros et al.  reportedAnother contributor to improper quality might be that there have been counterarguments on the usefulness of BIAs due to the close proximity of the technique to CEA . HoweverUnlike rare disease, diabetes is a chronic progressive disease with a high prevalence and a large patient population, especially in patients with type 2 diabetes. Moreover, the incidence and mortality of type 2 diabetes are equivalent, which should be negligible. Therefore, it is acceptable to consider the total population as a static group instead of taking short-term population changes into account when calculating the target population in BIA study.Chronic complications are the main cause of the heavy economic burden of diabetes. Research showed that 81% of the total medical expenses for T2DM were used for the treatment of diabetes-related complications . In addiThe key analytical process and input parameters should be validated when conducting a BIA according to the ISPOR guidelines and the economic evaluation guidelines. Validation could be done by consulting budget holders and corroborating model parameters. All inputs and formulas should be validated by a second budget impact expert. After the new intervention is introduced, it is recommended to continue data collection and compare it with the estimates obtained from the BIA. This will provide important reference for future decision-making and studies. Furthermore, it is suggested to conduct analysis from multiple perspectives including payer, healthcare system for the complete consideration of related costs.This review is the first to assess the methodology and the guideline compliance of BIAs specifically for anti-diabetic drugs. We have summarized the key elements to ensure the quality of BIA research comprehensively. In addition, we concluded the budget results of the included studies to provide a comprehensive reference for BIA studies of antidiabetic drugs. A potential limitation of this review is that we only included studies published in English and Chinese due to the language capacity limitation of the research team. References were retrieved from four international databases and two Chinese databases. . Moreover, it should be noted that BIAs directly submitted to reimbursement agencies were not studied.BIA is an important tool to assess the affordability of adopting a new antidiabetic drug in a certain health setting amid the rise of many new diabetes drugs. Our systematic review finds that there seems to be great variability in the study design and some studies had low compliance to the ISPOR guidelines. In order to provide useful and high-quality evidence to assist the decision-making process, researcher should ensure their BIA studies were conducted in compliance with the recommended guidelines or the requirements according to the decision makers. Besides, continued improvement of the validity of the model and sensitivity analysis are necessary. Furthermore, the accuracy of parameters in the BIA needs to be more rigorously demonstrated to indicate the quality of the findings. Finally, more BIA studies for antidiabetic drugs based on real-world data should be conducted in future research.The original contributions presented in the study are included in the article/ZL, ZR, and HH conceptualized this study. ZL, ZR, and DY collected the materials. ZL, ZR, and HH conducted analysis. ZL, ZR, CU, YL, and HH drafted the manuscript. All authors reviewed and approved the final vision. All authors contributed to the article and approved the submitted version.This research is partially supported by the grants from the University of Macau (MYRG2020-00230-ICMS).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Objectives: Data and data visualization are integral parts of  decision-making in general and stewardship  in particular. However, systematic research on the use of data visualization in stewardship is lacking. This study aimed at filling this gap by creating a visual dictionary of stewardship through an assessment of data visualization  in stewardship research.Methods: A random sample of 150 data visualizations from published research articles on stewardship were assessed . The visualization vocabulary (content) and design space (design elements) were combined to create a visual dictionary. Additionally, visualization errors, chart junk, and quality were assessed to identify problems in current visualizations and to provide improvement recommendations.Results: Despite a heterogeneous use of data visualization, distinct combinations of graphical elements to reflect stewardship data were identified. In general, bar  and line charts  were preferred visualization types. Visualization problems comprised color scheme mismatches, double y-axis, hidden data points through overlaps, and chart junk. Recommendations were derived that can help to clarify visual communication, improve color use for grouping/stratifying, improve the display of magnitude, and match visualizations to scientific standards.Conclusion: Results of this study can be used to guide data visualization creators in designing visualizations that fit the data and visual habits of the stewardship target audience. Additionally, the results can provide the basis to further expand the visual dictionary of stewardship toward more effective visualizations that improve data insights, knowledge, and clinical decision-making. The amount of and reliance on data increases with the increase of scientific publications and information technologies in healthcare . These bData visualization is an active (research) field in itself and is generally part of statistical software for data analysis processes . Information on the data visualization process is numerous and can be transferred between research fields . HoweverData and data visualization play important parts in the field of infectious diseases and antimicrobial resistance (AMR) for the reporting on the growing burden on health and healthcare systems . ComprehIt has been shown how important it is to study data and data visualization experiences and perceptions in the medical domain and how these can influence the interpretation of data ,b. IdentIn this study, we aim to fill these gaps by assessing and defining the design space of data visualization in stewardship and to create a visual dictionary. The results of this study can help data visualization creators, such as AMR-/data-professionals and scientists, to anticipate the visual domain context of the target audience and link it with existing recommendations for the data visualization process. This could benefit both research and clinical decision-making in the translation and communication of data to understandable and actionable information needed to tackle the AMR challenge, thereby improving the quality and safety of health and healthcare.stewardship , infection control , and institutional surveillance . These three topics reflect the core components of an integrated, comprehensive stewardship concept in institutional healthcare : the underlying data labeled as categorical, ordered, or quantitative-Marks: the basic geometric element -Channel: channels control the visual appearance of marks-Position: horizontal, vertical, both-Color-Shape-Tilt-Size: length, area, volume-Channel effectiveness-Magnitude: the effectiveness to express ordered attributes can be ranked: position on common scale (most effective) > position on unaligned scale > length > tile/angle > area > depth > color luminance/saturation > curvature/volume (least effective)-Identity: the effectiveness to express categorical attributes can also be ordered: color hue >shapeIn addition, data visualizations were labeled with the visualization type used  and the use of faceting . Each visualization was assessed upon its interpretability without additional text .Visualization quality was captured by rating the first and last impression during the analysis process on a scale form 1 (poor) to 5 (good). The choice of the visualization type given the underlying data was rated on a scale from 1 (poor) to 5 (good). In addition, free, written text was recorded to capture comments and remarks about the data visualization.A structured assessment form  was deveAttributes were analyzed for pairwise co-occurrence and presented if a combination occurred more than twice in total.Descriptive statistics were calculated for visualization type, number of attributes, faceting, rating, and visualization type choice. attributes and grouping the attribute names using inductive coding. Next, quantitative analyses of visual characteristics  were performed stratified per attribute, thereby adding the visual design space to the vocabulary. Linking the vocabulary and design space enabled the creation of a visual dictionary to help identify attributes  with associated channels .The visual dictionary was created based on the visual vocabulary (stewardship-related content) and visual design space . The vocabulary was analyzed by identifying Comments about the visualizations were coded in Microsoft Excel by two researchers (CL and JK). An open coding round was followed by axial coding to discover related concepts in the sub-codes. Differences were discussed until consensus was reached, which increased the internal validity . Next toattributes. These sections are followed by visualization ratings, identified visualization problems, and suggested recommendations for visualization creators.In total, 150 visualizations were analyzed (IRR: 87% joint probability of agreement). The following sections are separated into visual vocabulary (content) and dictionary with results stratified by identified time , setting , antimicrobial consumption , resistance , antimicrobials , percentage , count , incidence , numeric value , and bacteria . Attributes could be grouped into objects  and measurements . However, the following analysis focuses on attribute combinations and attributes are thus kept ungrouped.In total, 48 different attributes were coded. The 10 most used attributes were time and antimicrobial consumption (n = 21), time and incidence (n = 18), antimicrobial consumption and antimicrobials (n = 12), antimicrobials and resistance (n = 12), time and resistance (n = 12), time and antimicrobials (n = 11), antimicrobial consumption and setting (n = 10), resistance and setting (n = 9), time and setting (n = 9), and percentage and setting (n = 8).Attributes showed different co-occurrence patterns . The 10 n = 54, 36.0%) and line charts  were predominantly used. Bar charts were most frequently associated with attributes antimicrobials, bacteria, cohorts, compliance, counts, diagnosis, errors, percentages, resistance, setting, and survey answers. Line charts were predominantly associated with antimicrobial consumption, costs, cut-off, incidence, numeric values, regression, statistics, and time  of all visualizations. In these, visualization types that were combined more than once were bar charts with line charts  and stacked bar charts with line charts . In 41 visualizations (27.3%) facets were used, i.e., one visualization split into a matrix of visualizations using the same axes.Different visualization types combined in one visualization were used in 10.7% .Size: Size was most often visually reflected through length. Area to reflect size was used for 4.Magnitude/ordering: Position on a common scale was mostly used in quantitative and ordered attributes reflecting the best channel effectiveness for these attribute types. Categorical attributes mostly used color hue, which is preferred over the less effective use of shapes. A detailed channel effectiveness analysis is available in the n = 83) of all visualizations were interpretable without additional text (in caption or in the manuscript text). The overall choice of visualization type was rated with a mean of 4.62 (SD: 0.9) on a scale from 1 (poor) to 5 (good). The assessment of the visualization quality  was rated with a mean of 3.6 (SD:1.2).Overall, 55.3% (The coding of the identified problems are presented in the coding scheme in n = 8), for example with redundant direct labels for each data point. Other chart junk was found in visualizations using unnecessary 3D (n = 8), background colors (n = 6), shadow (n = 4), and color/shape filling (n = 4).Most chart junk represented text that cluttered the visualization  bar or line charts; quite homogenous design choices. We argue that the visualization type choice is based on tradition and habits as a systematic approach to data visualization in the field was missing until now . A lack However, given the wide variety of data in the field and the increased complexity that big data will add , more “visual variability” might be expected and even needed in the future . A firstOf note, academic journals play an important part in this process by providing the platform for data visualizations and should be encouraged to promote high quality data visualization practices. Furthermore, it could be worth considering standardizing data visualization for often used data types and contents in the field, given the prominent patterns in the visual dictionary  within the large variety of content  observed in this study. For time series specifically, an overview of data visualization methods exist , and sima priori excluded geographical data, these complex data require dedicated research and visualization techniques which are provided in great detail by others  . This alThis study has several limitations. Despite sampling from a comprehensive set of articles that cover the stewardship field, only a limited number of data visualizations were included. Moreover, only data visualizations from scientific publications and not from other sources relevant to stewardship data visualization creators [e.g., data systems used in practice  and AMR visual language of the diverse field of stewardship. As data-driven solutions for stewardship are of increasing importance, effective processes of transforming this data to insights and knowledge is essential. Data visualization supports and enables this transformation and our results can guide the optimal visualization design choices that are grounded on expectations and habits in the field. In the future, our study can provide the basis to further expand the visual dictionary of antimicrobial stewardship toward more effective data visualizations that improve data insights, knowledge, and decision-making.In this study, we analyzed the visual domain context of stewardship . We successfully created a visual dictionary that can support the process of creating and using tailor-made data visualizations in the field. Thereby, our results allow data visualization creators to learn the The original contributions presented in the study are included in the article/JK and CL: conceptualization, data analysis, and writing – original draft. CL: visualization. JK, CL, NB-dJ, and CG: discussing assessment form and results. NB-dJ, BS, LG-P, CA, and CG: supervision. All authors: writing – review and editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


As one of the key factors, postoperative recurrence of hepatocellular carcinoma (HCC) influences the therapeutic effects and survival period of patients. Therefore, the early diagnosis of postoperative recurrence of HCC plays an important role in improving the therapeutic effects and prognosis. Contrast-enhanced ultrasound (CEUS) plays an important role in the early diagnosis of postoperative recurrence of HCC. However, the accuracy of CEUS in predicting postoperative recurrence of HCC is still controversial. Therefore, in this study, a meta-analysis was carried out to further evaluate the accuracy of CEUS in predicting postoperative recurrence of HCC, thus providing evidence support for the early diagnosis of HCC.The literatures on the CEUS diagnosis of postoperative recurrence of HCC were collected by searching China National Knowledge Infrastructure, Wanfang, China Biology Medicine disc, PubMed, EMBASE, Cochrane Library, and Web of Science on computer. The retrieval time is set from the start of the database until April 2021. The meta-analysis of the literatures that meet the quality standards was conducted by Stata 16.0 software.The results of this meta-analysis will be submitted to a peer-reviewed journal for publication.This study will provide evidence support for the accuracy of CEUS in the diagnosis of postoperative recurrence of HCC.The private information from individuals will not be published. This systematic review also should not damage participants’ rights. Ethical approval is not available. The results may be published in a peer-reviewed journal or disseminated in relevant conferences.DOI 10.17605/OSF.IO/HB46W. In recent years, with the development of economy and the change of people's living habits, the incidence and mortality of the disease are increasing year by year. Postoperative recurrence of HCC is one of the key factors affecting the therapeutic effects and survival period of patients. Therefore, the early diagnosis of postoperative recurrence of HCC plays an important role in improving the therapeutic effects and prognosis.Hepatocellular carcinoma (HCC) is one of the most common cancers in China.,6 The former is simple to be operated and is widely used in clinic, with high value in the diagnosis of HCC. The latter includes ordinary ultrasound, contrast-enhanced ultrasound (CEUS), computed tomography (CT), magnetic resonance imaging, and so on.–10 In recent years, with the continuous improvement of CEUS technology and the application of ultrasound contrast agent, it displays more and more obvious advantages in the diagnosis of liver space-occupying lesions.At present, the clinical methods adopted to determine the recurrence of HCC include AFP detection and imaging examination.–18 The purpose of this study is to perform meta-analysis to explore the value of CEUS in predicting the postoperative recurrence of HCC, thus providing reference basis for early clinical diagnosis.The diagnostic performance of CEUS for postoperative recurrence of HCC has been continuously evaluated and confirmed as well. However, there exist inconsistencies in the effects in various literatures.22.1The protocol of the systematic review has been registered on Open Science Framework (registration number: DOI 10.17605/OSF.IO/HB46W). It was reported by following the guideline of preferred reporting items for systematic reviews and meta-analysis protocol statement.2.2Inclusion criteria:(1)To explore the diagnostic value of CEUS in the diagnosis of postoperative recurrence of HCC.(2)All patients who accepted the operation of HCC were included.(3)The gold standard was clinicopathological diagnosis, comprehensive imaging examination , and long-term clinical follow-up results.(4)The data of the 4 tables of diagnostic tests can be obtained directly or indirectly.Exclusion criteria:(1)Literatures with incorrect data sources, incomplete data, and incorrect statistical methods.(2)Literatures with repeated research data.(3)Case reports, reviews, cell, or animal studies.2.3This study conducted a literature search in the China National Knowledge Infrastructure, Wanfang, China Biology Medicine disc, PubMed, EMBASE, Cochrane Library, and Web of Science. The retrieval time is set from the build of the database until April 2021. The language restrictions are Chinese and English. The search strategy for PubMed is displayed in Table 2.42.4.1All literatures were screened independently by 2 researchers based on the inclusion and exclusion criteria. In case of disagreement, a decision is made through discussion or consultation with relevant experts. The screening flow chart of this study is demonstrated in Figure 2.4.2The following information was extracted: first author, year of publication, type of study, language, sample size, average age, gold standard, as well as true positive, false positive, true negative, and false negative. When the data collected by the 2 researchers are inappropriate, an agreement is reached through consultation. If the disagreement still exists after consultation, a third party (not the researcher) should be asked to make a decision.2.4.3If there are insufficient or missing data in the literature, the authors will be contacted via email. If the data are still not available, only the current available data will be analyzed and the potential impacts will be discussed.2.5 including 11 evaluation criteria. Each standard is evaluated by “yes,” “no,” and “unclear.” “Yes” refers to that it meets this standard, “No” means that it does not meet this standard or is not mentioned, and “unclear” is partially consistent or unable to obtain sufficient information for evaluation. If the 11 standards are met, the quality of the literature will be rated as “A;” if more than 1 item is “unclear,” it will be rated as “B;” if “no” occurs, it will be rated as “C.”The methodological quality of the included studies was assessed by following quality assessment of diagnostic accuracy studies-2 criteria,2.6Q and I2 values. Meanwhile, a fixed effect model (without obvious inhomogeneity) or a random effect model (with significant heterogeneity) was employed to merge the data. The statistical test level was α = 0.05.All of the above statistical analyses were performed with Stata 16.0 . We calculated pooled sensitivity (SEN), specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, area under the curve, and their 95% confidence interval. What's more, the pooled diagnostic value of CEUS through the summary receiver operating characteristic curve, and area under the curve was tested. The threshold effects were detected by applying spearman correlation coefficient. The calculation of heterogeneity was caused by the nonthreshold effects of Cochrane-2.7A subgroup analysis will be made on the basis of gold standard type, study type, surgery type, and threshold.2.8We will adopt the one-by-one exclusion method to analyze the SEN of the results.2.9The publication bias was determined by conducting Deeks’ funnel plot asymmetry test.2.10Since the program does not include the recruitment of patients and the collection of personal information, it does not require the approval of the Ethics Committee.3 At present, ultrasound and enhanced CT are routinely used for regular follow-up. CEUS technology is also applied more and more widely. The neovascularization of recurrent and metastatic foci after HCC is abundant, and it is mainly supplied by hepatic artery. When the contrast medium reached the hepatic artery, the lesion developed immediately, the intensity was higher than that of the surrounding normal liver tissue, homogeneity or inhomogeneity is enhanced, and the portal vein phase disappeared rapidly. Under the background of liver cirrhosis, CEUS can judge HCC and atypical hyperplastic nodules by contrast-enhanced imaging, because CEUS can observe every moment from the development of the hepatic artery to the complete disappearance of the contrast medium. Furthermore, liver can be completely scanned in the portal phase and delayed phase, and it is easier to detect small lesions in liver. With high SEN and accuracy, CEUS can be considered as a reliable method for follow-up after HCC. Many studies have confirmed that CEUS is of great value in predicting the recurrence after HCC. We performed a meta-analysis to determine the accuracy of CEUS in the prediction of the postoperative recurrence of HCC, so as to resolve the dispute.The postoperative recurrence of HCC is high.Conceptualization: Wencui Wu, Jieying Fu.Data collection: Jia Tang.Funding acquisition: Wencui Wu.Investigation: Wencui Wu.Methodology: Huan Luo.Project administration: Wencui Wu.Resources: Huan Luo, Jia Tang.Software: Jia Tang, Huan Luo.Supervision: Wencui Wu, Jia Tang.Validation: Jia Tang.Visualization: Jia Tang.Writing – original draft: Wencui Wu, Jieying Fu.Writing – review & editing: Wencui Wu, Jieying Fu.


To explore the factors that affect the prognosis of overall survival (OS) and cancer-specific survival (CSS) of patients with stage IIIC1 cervical cancer and establish nomogram models to predict this prognosis.Data from patients in the Surveil-lance, Epidemiology, and End Results (SEER) programme meeting the inclusion criteria were classified into a training group, and validation data were obtained from the First Affiliated Hospital of Anhui Medical University from 2010 to 2019. The incidence, Kaplan-Meier curves, OS and CSS of patients with stage IIIC1 cervical cancer in the training group were evaluated. Nomograms were established according to the results of univariate and multivariate Cox regression models. Harrell’s C-index, calibration plots, receiver operating characteristic (ROC) curves and decision-curve analysis (DCA) were calculated to validate the prediction models.The incidence of pelvic lymph node metastasis, a high-risk factor for the prognosis of cervical cancer, decreased slightly over time. Eight independent prognostic variables were identified for OS, including age, race, marriage status, histology, extension range, tumour size, radiotherapy and surgery, but only seven were identified for CSS, with marriage status excluded. Nomograms of OS and CSS were established based on the results. The C-indexes for the nomograms of OS and CSS were 0.687 and 0.692, respectively, using random sampling of SEER data sets and 0.701 and 0.735, respectively, using random sampling of external data sets. The AUCs for the nomogram of OS were 0.708 and 0.705 for the SEER data sets and 0.750 and 0.750 for the external data sets, respectively. In addition, AUCs of 0.707 and 0.709 were obtained for the nomogram of CSS when validated using SEER data sets, and 0.788 and 0.785 when validated using external data sets. Calibration plots for the nomograms were almost identical to the actual observations. The DCA also indicated the value of the two models.Eight independent prognostic variables were identified for OS. The same factors predicted CSS, with the exception of the marriage status. Both OS and CSS nomograms had good predictive and clinical application value after validation. Notably, tumour size had the largest contribution to the OS and CSS nomograms. Cervical cancer is the most common malignant tumour of the female reproductive system, and the fourth most common malignant tumour in women, after breast cancer, colorectal cancer and lung cancer . In 2018The International Federation of Obstetrics and Gynecology (FIGO) stage is a systematic staging system based on a clinical examination . In 2018The FIGO staging system is most frequently used to assess the prognosis of patients with cervical cancer. The new FIGO stage reflects the important effect of lymph node metastasis on the prognosis of cervical cancer patients . HoweverA trend is to use nomograms to build cancer prediction models, because nomograms simplify a large number of complex factors into a single simple numerical estimation model to predict the probability of events . CurrentThe purpose of this study was to explore the factors that affect the prognosis of patients with stage IIIC1 cervical cancer and establish nomogram models to predict the prognosis of stage IIIC1 cervical cancer.This retrospective observational study was conducted with data from the Surveil-lance, Epidemiology, and End Results (SEER) programme. The SEER database is a publicly available, federally funded cancer reporting system . No caseOne external validation set was generated to validate the nomogram in the present analysis, and the data were obtained from the First Affiliated Hospital of Anhui Medical University from 2010 to 2019; all patients in this dataset were pathologically diagnosed with cervical cancer. All patients under closed follow-up, every 3 months for the first 2 years, every 6 months for the next 3 years, and annually thereafter. This study was approved by Anhui Medical University Ethics Committee.Inclusion criteria were patients with a pathological cervical cancer diagnosis who were included in the SEER database from 2004 to 2015; cervical cancer was the first primary tumour; no stage IV disease; all patients underwent surgery and were evaluated positive for pelvic lymph node metastasis; age ≥ 18 years; patients who died within 1 month; information about race, differentiation, surgery, marriage status, tumour size, extension range was complete; and the histopathological diagnosis was squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma utilizing ICD-O-3 codes, with poor / moderate / well differentiation  curves and cancer-specific survival (CSS) curves in groups with different lymph nodes metastasis statuses. Additionally, univariate and multivariate Cox regression models were employed to estimate hazard ratios (HRs) and exact 95% confidence intervals (CIs) to analyse the prognostic factors for stage IIIC1 cervical cancer. OS was the primary endpoint outcome from the date of diagnosis to the date of death or the latest follow-up. CSS was the special endpoint outcome from the date of diagnosis to the date of death from cervical cancer or the latest follow-up.http://www.R-projectct.org/). P values < 0.05 were considered significant. All methods were performed in accordance with the relevant guidelines and regulations.Significant prognostic factors of OS and CSS in the Cox proportional hazards regression model were used to build the nomograms to predict the 3- and 5-year OS and CSS rates. Harrell’s C-index and receiver operating characteristic (ROC) curves were calculated to measure the accuracy of the prediction models. Calibration plots show the relationship between the predicted probability and the actual outcome. Finally, decision-curve analysis (DCA) was applied to evaluate the clinical applicability of the constructed nomogram by quantifying the net improved benefits at various threshold probabilities. All statistical analyses and plots were performed using SPSS 23.0  and R version 3.6.2 (p < 0.001), and Kaplan-Meier survival curves also confirmed the effect of lymph node metastasis on the prognosis, as shown in Fig. From 2004 to 2015, 1638 patients with cervical cancer exhibited pelvic lymph node metastasis (21.17%). First, the incidence of lymph node metastasis in patients with cervical cancer decreased slightly from 2004 to 2015, as shown in Fig. The training cohort included, a total of 1683 patients diagnosed with cervical cancer between 2004 and 2015. For the validation cohort, 148 patients met the criteria in the First Affiliated Hospital of Anhui Medical University between 2009 and 2019, 125 of whom were in active follow-up, and 15.54% were lost to follow-up. The majority of patients in the training cohort were middle-aged women (57.80%), and patients in the validation cohort were middle-aged women, similar to the training cohort. Regarding tumour characteristics, squamous cell carcinoma, confined to the cervix uteri / uterus and with tumour size ≥4 was the main diagnosis in both cohorts. However, the distributions of poor differentiated tumours distributions were 52.70, and 22.40% respectively in training and validation cohorts, respectively. Details are provided in Table Univariate and multivariate Cox proportional hazard regression analyses were used to calculate the prognostic factors for OS and CSS. The results of the univariate Cox proportional hazard regression analysis are shown in Table Based on the prognostic factors for OS and CSS derived from the Cox proportional hazard regression analyses, OS and CSS nomograms were established and are shown in Fig. , and tumour size, extension range, and other factors exert significant effects on the prognosis of stage IIIC1 cervical cancer [Researchers have discovered that pelvic lymph node metastasis is a high-risk factor for patients with cervical cancer, which has been confirmed in many studies , 14. Untl cancer . Therefol cancer –17.Then, we established OS and CSS nomograms based on the results of the multivariate Cox proportional hazard regression analysis. The factors in the OS nomogram included age, race, marriage status, tumour size, histology, extension range, surgery, and radiotherapy. For the CSS nomogram, only marriage status was excluded. Previous studies of the effect of marital status on cancer have shown that married patients have advantages in terms of the early diagnosis of cancer, which included cervical cancer . In addiOur nomograms are highly innovative and practical. First, although nomograms for cervical cancer have been widely used , 21, a nThe C-indexes of the nomograms of random sampling of SEER and external data sets were all range from 0.65 to 0.75, which were acceptable and indicating that our nomograms have favourable discrimination ability , 24. In Notably, tumour size had the largest contribution to the OS and CSS nomograms.. In cervical cancer, the effect of tumor size on prognosis in stage IB and stage II has been confirmed and shown in the FIGO staging system , 28. AccAlthough the nomograms were verified using an external data set, our study still has some limitations. First, as a retrospective study, this research filtered data from data sets and excluded patients with missing data for the collected variables, leading to selection bias. Second, some key indicators are lacking, especially the dosage of radiotherapy and details of chemotherapy regimens. For example, only “Yes” and “No” were shown in the SEER database for chemotherapy, leading to a weaken effect of chemotherapy on survival. Third, the insufficient sample size of the external data set and some missing data caused inadequate verification.In conclusion, age, race, marriage status, histology, extension range, tumour size, radiotherapy and surgery were all independent prognostic factors for OS. The same factors predicted CSS, with the exception of the marriage status. In addition, OS and CSS nomograms were established in our study based on the results of a multivariate Cox proportional hazard regression analysis, and both had good predictive and clinical application value after validation. Notably, tumour size had the largest contribution to the OS and CSS nomograms.