The North and Northeast region presented the lowest mean income in Brazil, statistically different from the South (p < 0.01) and the Southeast (p < 0.01). The North region presented the lowest sugar intake from industrialized products—different from the Northeast (p = 0.007), the Southeast (p = 0.010), and the South (p = 0.043). Also, the North presented the lowest consumption for food prepared at home among other regions (p < 0.001). Total sugar (sucrose) intake did not differ according to body mass index (p = 0.321). There was no significant difference in sugar (sucrose) consumption among the three days (p = 0.078). The addition of sugar (sucrose) contributed to 36.7% of all sugar (sucrose), and sweetened beverages with 22.53%. Food prepared at home contributed 20.06% and industrialized products 22.53% of the sugar (sucrose) intake. Therefore, free sugar (sucrose) consumption is still the largest contributor to the total consumption of sugar (sucrose), followed by sweetened drinks, especially during the weekend. The average percentage of sugar (sucrose) intake is above the World Health Organization recommendation to consume less than 5% of the total energy that comes from sugars. Since this population presents a high percentage of overweight and obese, the sugar (sucrose) consumption could increase health implications, increasing the costs for public health.Non-communicable diseases are increasing worldwide, and it has been known that sugar intake is associated with health implications. Studies show that sugar consumption is high among the low-income population. In Brazil, there is a Food Assistance Program to offer inexpensive and healthy meals to the low-income population, aiming to improve their health. However, no study has evaluated either the amount of sugar consumption by the Brazilian low-income population or its distribution among the consumed products. This work aimed to analyze the sugar (sucrose) consumption by the Brazilian low-income population. We carried out a cross-sectional and descriptive study to evaluate the typical customers of a popular restaurant (PR) in Brazil (a Brazilian Food Assistance Program for low-income people). In the final sample, 1232 adult PR customers were surveyed. The exclusion criteria were pregnant women, diabetics, or people following any special diet with sucrose restrictions. Individuals were selected at lunchtime while they were in line waiting to collect their meal. Invitations to participate occurred to the first person in line, then the 15th person, and this pattern was used until the sample was completed. Three-day 24 h recall was used to evaluate sugar consumption. Sociodemographic and anthropometric data were collected to allow profiling of the customers. A statistical analysis of the data with descriptive nature  was performed to characterize the sample. For all the analyses, statistical normality tests were performed (Kolmogorov–Smirnov) to verify the statistical test assumptions. The mean total energy value (TEV) over the evaluated three-day period was 1980.23 ± 726.75 kcal. A statistically significant difference was found between income groups ( Pesquisa de orçamento familiar—POF) [There is a consensus in public health that sugar (sucrose) needs to be reduced from desserts, snacks, and sugar (sucrose)-sweetened beverages . Sugar-siar—POF) .Non-communicable diseases are increasing worldwide, and the association between sugar intake and health implications is known ,5,6. A sSome studies show that sugar consumption is high among the low-income population in some countries ,16,17. IThe cultivation of sugar cane in Brazil contributes to its wide availability and low cost, strongly influencing its use as an ingredient in several bakery and confectionary products  in addition to sugar-sweetened beverages. It is hypothesized that there is high sugar consumption among low-income Brazilian populations through the consumption of different types of products. However, no study has evaluated either the amount of sugar consumption by low-income populations or its distribution among consumed products. Studies usually focus on evaluating soft drink consumption and not the pattern of sugar intake. In this context, this study aimed to analyze the consumption of sugar (sucrose) in low-income populations of Brazil.Ministério do Desenvolvimento Social e Combate à Fome, MDS) [This cross-sectional study is a result of the cooperation agreement signed between the Department for Social Development and Hunger Fighting   with theme, MDS) . A simplEach PR was required to have a minimum sample of 37 customers. The PRs included in this study were located in urban centers where there is considerable human traffic, which facilitates people´s access to the PRs . The estOn the first day (Monday), participants were recruited, and they signed the acknowledgment and agreement terms, and the evaluation occurred for three days at the PRs. While in line waiting to collect their food, each participant received information about the research, the need to have lunch at the PR for at least two more days, the advice to introduce themselves on the consecutive days of the study, and the procedures for weight and height measurements on Tuesday. Participants were not excluded if they were illiterate, but they needed to sign the acknowledgment and agreement terms which was read by the researcher. After the recruitment, the same participant continued the evaluation for the rest of the study. For this study, participants had to complete the three days of consumption evaluation to qualify. The same individual was interviewed at the restaurant to complete the three-day 24 h recall, in which they were asked about their relevant activities during the whole of the previous day. According to the Institute of Medicine, Food, and Nutrition Board, the evaluation of at least three consecutive days of food consumption is representative of an individual’s diet . For eacThe evaluation of sociodemographic data was developed by a structured questionnaire with standard questions by a trained researcher. The evaluated variables were gender, age, level of education, and income. The anthropometric measurements of weight and height were taken on the second day of the study in each PR before participants had their lunch and, from this data, the body mass index (BMI) was calculated. The questionnaire also contained questions regarding diet-related diseases and non-communicable diseases.The customers that had not presented 24 h recall data for all of the three days were excluded from the sample. From the 1750 recruited participants, a total of 1232 people that had been randomly and systematically assessed completed the whole protocol. The sampling error for national representativeness was less than 3% . It is important to mention that PRs only offer lunch to Brazilian low-income people on weekdays. The summary of the study stages is displayed in The customers were interviewed on consecutive three days, and in each day, 24 h recall was applied. On Monday, customers were asked about their consumption at each meal held on Sunday, to characterize the weekend consumption, and the other two days (Tuesday and Wednesday) regarded the weekday consumption. For this analysis, a 24 h recall [®, Porto Alegre, Brazil).The only meal participants consumed at the PR was lunch composed of a meat source, rice, beans, salads, and one side dish. Fruits as desserts were not served in all the PRs, and sweet desserts were not offered in any of them. Based on the recorded data, the nutritional values were calculated using the information available in the Brazilian Food Composition Table . When thOn Monday (the first day), sociodemographic information was also collected, such as gender, age, family income, as well as the anthropometric variables  of the individual . All datIn the assessment of the nutritional composition of meals, the total energy value (TEV) of the day of each participant was analyzed, along with their consumption of sugar (sucrose) in each preparation at each evaluation date. For the sugar (sucrose) consumption analysis of each participant, all 24 h recalls were evaluated to identify four consumption groups: (1) added sugar; (2) sweetened drinks; (3) industrialized foods; and (4) sweet food prepared at home.For added sugar (sucrose), all sugar (sucrose) used by the participant to sweeten coffee, tea, milk, smoothie, porridge, and juice ) were measured. The amount of sugar (sucrose) reported by the individual and recorded in the 24 h recall for each type of liquid was considered. For the sucrose from deserts prepared at home , the typical amount of sucrose used for these recipes in Brazil was considered.The third assessed item was the consumption of sucrose present in industrialized products, such as sweet biscuits, jellies, sweet pastries, sweet tablets, chocolate, candies, ice cream, popsicles, breakfast cereal, granola, condensed milk, sweetened yoghurt, ketchup, and cereal bars, among others. For sucrose in each of these products, label information, product websites, and data provided by Proteste  were useThus, for each of the three days, four groups of sugar (sucrose) were evaluated. The percentage of energy provided was estimated by these four groups concerning the consumption of TEV of each participant to allow for comparison with WHO recommendations, i.e., up to 10% of the energy intake from consumption of sucrose and preferably below 5% .® software, using descriptive variables, correlations, parametric tests, and the t-test and Tukey test for ANOVA to verify statistical differences in the data between regions. It was established that p < 0.05 was statistically significant. Outliers (participants with disparate high sugar intake) were removed after analyzing data.Nutritional information was corrected by variability among people and within each person using MSM software to estimate the usual intake of nutrients by the population. The statistical analysis of this study was processed by SPSS 24.0The Statistical Package Program for Science—SPSS, version 24.0, was used in statistical analyses. A statistical analysis of the data with descriptive nature  was performed to characterize the sample. For all the analyses, statistical normality tests were performed (Kolmogorov–Smirnov) to verify statistical test assumptions. Nonparametric tests were used for variables that did not confirm the normality assumptions, such as Kruskal–Wallis, chi-square, Wilcoxon, and Mann–Whitney. For the quartiles, when necessary, the Bonferroni test was used.This research was approved by the Research Ethics Committee of the Health School of the University of Brasilia, under No. 0372/2010, and followed the guidelines established by the Declaration of Helsinki. Each participant signed a free consent form agreeing to participate in the study. If necessary, researchers read the terms for the participant and if they did not feel comfortable to continue with the research, the next participant in line was invited to join the study.n = 706) were evaluated in three days using 24 h recalls. The most frequent per capita income reported was between ½ to 1 minimum wage (p < 0.01). The North and Northeast region presented the lowest mean income in Brazil, being statistically different from the South (p < 0.01) and the Southeast (p < 0.01). The data resulting from the measurements for the customers revealed a population mostly above weight   .p < 0.05). The differences occur between food prepared at home and sweetened drinks (p < 0.05), and between food prepared at home and added sucrose (0.005). For males, there was also a statistical difference among the groups of sucrose intake (p < 0.05), and only food prepared at home was similar to industrialized products (p = 1.00). There were no statistical differences among male and female for all the sugar (sucrose) groups , there is a statistical difference between the four different groups of sugars analyzed  groups .p = 0.321). However, the consumption of sugar (sucrose) for each classification group was different among the diverse types of sucrose intake (p < 0.01). For income, the only group without statistical difference among the types of sucrose intake was the no income group (p = 3.00). As for regions, only the Midwest presented a similar consumption of sucrose among the diverse sucrose intake groups (p = 2.00).Total sucrose intake did not differ according to BMI (p < 0.001), and products prepared at home (p = 0.005) were checked. For added sugar (sucrose) in liquids and sweetened drinks, there were no differences .The differences between the five Brazilian regions for the intake of sucrose from industrialized products (p = 0.007), the Southeast (p = 0.010), and the South (p = 0.043). Also, the north presented the lowest consumption for food prepared at home, being different from the Northeast (p < 0.001), the South (p < 0.001), and the Southeast (p < 0.001).Evaluating these groups of sugar (sucrose) intake and regions, the North presented the lowest intake from industrialized products and it was different from the Northeast (2), the EER was 1891.76 ± 388.76, and for normal weight (BMI: 18.5–24.9 kg/m2), the EER was 2157.05 ± 399.71. A significant difference in the EER between the two groups (p < 0.01 and F = 2.518) was verified. The mean of the total energy expenditure (TEE) obtained for the overweight (BMI: 25.0–29.9 kg/m2) was 2379.96 kcal ± 410.93 (n = 310), and for obese (BMI ≥ 30 kg/m2) 2498.36 kcal ± 468.22 (n = 167).With the data obtained in this study, it was possible to calculate an average estimated energy requirement (EER)  of 2118.The TEV average consumption over 24 h was 1980.23 kcal ± 726.75, ranging from 369.23 to 5878.10 kcal for the three days of the week. The lowest TEV consumption occurred among females and represented individuals with only lunch consumption at the PR. The outliers of sucrose intake were removed to perform the analysis, and TEV was not considered for this removal. Such average TEV consumption represents a lower energy intake than needed for individuals, for both normal weights and those with overweight and obesity, corresponding to 91.3% of the normal weight needs.p = 0.078). When assessing the contribution of each item on the average of the three days, it was observed that the addition of sugar contributed to 36.7% of all sugar (sucrose) and sweetened beverages with 22.53%. Food prepared at home contributed 20.06% and industrialized products 22.53%.There was no significant difference in sugar (sucrose) consumption among each of the three days  intake, while the addition of sugar consumption was constant throughout the week, representing 1/3 of the sugar ingested by the individuals. The average percentual contribution of sugar in the 24 h recall was 6.6%, with a minimum of 0% and a maximum of 59.2%.The average consumption per capita/day of soft drink, according to POF, was 94.7 g . Using tAs for juices, powdered juices, and nectars, the Brazilian consumption according to POF was 146 g . Using tThe North region presented the lowest income among the evaluated population of this study and probably explains the lowest sugar (sucrose) intake from industrialized products and sweetened drinks.According to the UN food balance sheet data, the New Zealanders, on average, consume about 147 g/day (37 teaspoons) of sugar . Souza eMarriott et al.  examinedIn the present study, the average percentage is within the WHO recommendations to consume less than 10% of the total energy that comes from sugars , with thA British study showed that ageing men (19–64 years) consume 15.2% (82 g/day) of non-milk extrinsic sugars (NMES) and women 13.5% (57.2 g/day). The NMES included all added sugars in processed and manufactured foods and drinks, and sugars in fresh fruit juices, honey, and syrups . In the In this study, the sugar (sucrose) intake from beverages on Sunday was higher than during the weekdays. Other studies found, similarly, that diet on weekends was less healthy than that on weekdays, and that diet quality on Saturday was the poorest. Compared with average weekday consumption, consumption on Saturday was associated with an increase in the daily intakes of total energy by 181.04 kcal , and by 18.34 kcal (10.07–26.62) for the energy from sugar (sucrose)-sweetened beverages . This fiIt is necessary to change the high sugar (sucrose) intake worldwide, but this cannot be imposed by either politicians or the public. A consensus must be built to change this large sugar (sucrose) intake . It is iAs previously mentioned, in Brazil, the food culture is heavily influenced by the culture of sugar cane because of the immigration of several populations who brought a taste for cakes and sugary desserts, mainly from Portuguese colonization.This study, however, has inferential limitations. Pregnant women and children were excluded from the sample due to their specific needs and methods for assessing nutritional status, or due to legal restrictions. Another limitation was the exclusion of diabetic customers, because this pathology restricts the consumption of sugars.Data was collected using 24 h recall, and this method presents limitations because it depends on the participant’s memory and a well-trained interviewer to get detailed information, especially regarding sugar (sucrose) addition. A gold method would be a direct weighing of each item consumed. Another limitation of this study is the use of mean values to represent the sugar (sucrose) composition in industrialized products, food prepared at home, and sweetened drinks. Not all products present the same amount of sugar (sucrose), and there is variance among different available types.Since this research study encompasses a population with low per capita income, the free sugar (sucrose) consumption is still the most significant contributor to the total consumption of sugar (sucrose), followed by sweetened drinks, especially during the weekend. This study was conducted using adults participating in a social program of great importance in Brazil. This social program uses simple and cheap ingredients for food preparation at lunchtime, the main meal consumed by Brazilians. Therefore, elaborated desserts using sugar (sucrose) in their preparation did not contribute to the sugar (sucrose) intake, since they are more expensive and more workers are required for their preparation. Also, these popular restaurants do not serve sweetened drinks at lunch as this would make the meals more expensive. These characteristics from PRs are positive for their customers, and do not encourage them to eat more sugary products.Sugar intake of the participants did not follow the recommendations of WHO, of a maximum of 5% of TEV from sugar in the diet. Even though it was a low-income population, the sugar and sugary products consumed were above these limits. Since this population presents a high percentage of overweight and obese participants, new diseases associated with excessive sugar intake could easily appear.Sweetened drinks are responsible for a high consumption of sugar (sucrose) during the weekends, but for weekdays, this low-income population adds free sugar (sucrose) to other kinds of drinks, leading to a pattern of high need of sugar (sucrose) content in other forms of consumption.Evidently, in the Brazilian case, the progress of the social programs that drew thousands of people out of poverty must become associated with nutrition education programs and encouragement of a healthy lifestyle, seeking to prevent a situation whereby a change in social class could also be accompanied by the consumption of products rich in free sugars.


Background: Epidemiological evidences regarding the association between the use of non-steroidal anti-inflammatory drugs (NSAIDs) and the risk of prostate cancer (PC) is still controversial. Therefore, we conducted a meta-analysis to explore the controversy that exists.Methods: Electronic databases including Medline, EMBASE, Web of Science, Cochrane Library, BIOSIS, Scopus, CBM, CNKI, WANFANG, and CQVIP were used to search for and identify eligible studies published until December 31, 2017. Pooled effect estimates for the relative risk (RR) were computed through fixed-effects or random-effects models as appropriate. Publication bias was evaluated by Egger's and Begg's tests and potential sources of heterogeneity were investigated in subgroup analyses.Results: A total of 43 observational studies were eligible for this meta-analysis. A protective effect was identified for the intake of any NSAIDs on the risk of PC . Moreover, the long-term intake of NSAIDs (≥5 years rather than ≥4 years) was associated with reduced PC incidence . Aspirin intake was also associated with a 7.0% risk reduction of PC . The inverse association became stronger for advanced PC and PC with a Gleason score ≥7 compared to the association with total PC. Interestingly, it was the daily dose (≥1 pill/day) rather than, long-term aspirin intake (≥4 or ≥5 years) that was associated with reduced PC incidence . The pooled effects for non-aspirin NSAIDs demonstrated no significantly adverse or beneficial effects on total PC, advanced PC, or PC with Gleason score ≥7, though all pooled RRs were >1.Conclusions: Our findings suggested a protective effect of the intake of any NSAIDs on the risk of PC, especially in those who took the NSAIDs for a long period. Moreover, aspirin intake was also associated with a decreased risk of PC, and there was a dose related association between aspirin intake and the risk of PC, while no significant effects of long-term aspirin intake were found on the PC incidence. PC is the most prevalent cancer in male and the third leading cause of cancer-related death worldwide . It has Experimental studies suggested that chronic inflammation is involved in the carcinogenesis of PC, especially high-grade PC –8. It waEpidemiological studies reported an inverse association between the intake of NSAIDs and the risk of colorectal cancer, gastric cancer, and breast cancer –15. NeveGiven the widespread use of NSAIDs, more information is needed to carefully weigh their role in the incidence of PC. Therefore, we performed this meta-analysis to clarify the potential association between the use of NSAIDs and the risk of PC to investigate the sources of variability between studies, which may highlight the importance of considering methods of preventing PC.This meta-analysis aimed to explore the association between the use of NSAIDs and the risk of total PC, advanced PC and PC with Gleason score ≥7.Does the intake of NSAIDs reduce the risk of total PC, advanced PC and PC with Gleason score ≥7?This study was conducted in accordance with the 2015 Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines , 25.We included retrieved articles whose design was a case-control, cohort or cross-sectional study evaluating the association between the use of NSAIDs and the incidence of PC. No restrictions were imposed regarding language.We included the participants who were exposed to any single NSAID or a mixture of NSAIDs.We included studies whose results included odds ratios (ORs), relative risks (RRs), hazard ratios (HRs), standardized incidence ratios (SIRs), or incidence rate ratios (IRRs) and 95% confidence intervals (95% CIs), or provided the available raw data needed to calculate the RRs, wherever possible.This meta-analysis is registered with the International Prospective Register of Systematic Reviews (PROSPERO registration number: CRD42018090475).Ten computerized literature databases were searched systematically by a professional librarian for relevant studies up to December 31, 2017. Medical subject headings (MeSH) in combination with free text searches were used. The full search strategy is presented in Table Reviews, case reports, letters, commentaries, and animal experimental studies were all excluded. If overlapping study populations were identified, the study with the larger population or greater amount of information was selected for inclusion, but relevant articles with required information were also included. The identification of relevant studies was performed independently by two different authors (JW and XW), and disagreements were resolved through consultation with a third reviewer (HY).The methodological quality of the included articles was assessed by two independent authors (QW and XW) according to the Newcastle–Ottawa scale (NOS) (for case-control and cohort study) and a modified version of the NOS , participants, geographic location, dose or duration of drug intake, the sources of drugs, adjusted confounders (numbers of the three main factors and whether they were adjusted for comorbidity or the simultaneous use of other medications), types of effect measures , information source, and study period. Given that PSA-based screening for PC may be more popular after 2000 than that before 2000. Thus, studies were stratified by study period after 2000 or that before 2000. Publication bias was evaluated by Egger's and Begg's tests. A sensitivity analysis was subsequently conducted to explore whether the pooled result was influenced by individual studies . The Cochrane articles , 28. Whe studies , 30.Figure A total of 10,604 articles were identified according to the keywords. One article was identified through references and included. After screening titles or abstracts, we identified 47 articles for full-text review. Two articles were excluded due to the lack of complete data needed to evaluate the estimates of the effect of the intake of NSAIDs on PC incidence, and 2 articles were excluded because they had less data than that of another 2 articles from the same populations. Finally, a total of 43 articles were included.Among the identified articles, there were 19 case-control studies , 31–47, I2 = 94.00%, P < 0.001). Possible reasons for that heterogeneity were explored in the subgroup analyses. In addition, a non-significant decreased risk was detected for advanced PC or PC with Gleason score ≥7, though the pooled RRs were <1.Unlike previously conducted meta-analyses, this meta-analysis found a protective effect of the intake of any NSAIDs on PC risk due to the inclusion of recent research  Figure . HoweverI2 = 0.00%; pooled RR 0.797, 95% CI = 0.698–0.910, I2 = 72.10%, respectively). Interestingly, long-term intake of NSAIDs (≥5 years rather than ≥4 years) was associated with an 11.8% reduction in PC incidence, with little evidence of heterogeneity . Notably, no significantly beneficial effects were found in the “High-quality studies” on total PC. However, when we restricted our analysis to studies adjusting for comorbidities, the association did not remain and there was no significance when the studies were stratified by the numbers of the three main factors, though the pooled RR was also <1  .Considering the pharmacology of aspirin differ from that of other NSAIDs, the meta-analyses for aspirin and non-aspirin NSAIDs (NA-NSAIDs) were also conducted, respectively. The 34 studies that evaluated aspirin intake and total PC risk showed a 7.0% risk reduction of PC with aspirin intake  and displayed considerable heterogeneity , quality of studies , geographic region , information source , comorbidities, the source of aspirin, and the number of the three main adjusted factors. Contrary to a recent study, it was the daily dose (≥1 pill/day) not the long-term intake of aspirin (≥4 years or ≥5 years) that was associated with reduced PC incidence . In addition, we summarized the final pooled effects of aspirin intake from 16 studies which have adjusted for the concomitant use of other medications and found a lower risk of PC , compared with the 7.0% risk reduction of PC among all aspirin users. Interestingly, studies performed after the year 2000 showed a negative association unlike those performed before 2000 , and the subgroup analysis on ORs also demonstrated a similar negative trend  . Moreover, a non-significant decreased risk was detected in “high quality studies,” though an adverse effect of non-aspirin NSAIDs on total PC was observed in “poor quality studies.” The detailed data are shown in Table The pooled effects for non-aspirin NSAIDs demonstrated no significantly adverse or beneficial effects on total PC, advanced PC, or PC with Gleason score ≥7. However, all pooled RRs were >1 Figure . Notablyp = 0.185; for the intake of aspirin, p = 0.537; for the intake of non-aspirin NSAIDs, p = 0.953, respectively)  Figure . Age, raTo the best of our knowledge, this is the first meta-analysis that attempted to explore the association between PC incidence and the dose and duration of the intake of NSAIDs, which could be the most important factors affecting the effect of NSAIDs on PC and which have not been addressed by previous meta-analyses. In our meta-analysis of 43 studies, we observed that the intake of any NSAIDs and the intake of aspirin were inversely related to PC incidence. Aspirin use was also associated with a 9.1 and 8.2% reduction in advanced PC risk and the risk of PC with Gleason score ≥7, respectively. Particularly, long-term intake of NSAIDs (≥5 years rather than ≥4 years) was associated with an 11.8% reduction in total PC incidence, while it was the daily dose of aspirin (≥1 pill/day) not the long-term aspirin intake (≥4 years or ≥5 years) that was associated with reduced total PC incidence.Inconsistent with previous meta-analyses, this meta-analysis found a protective effect of any NSAIDs intake on total PC risk. A recent meta-analysis suggested a positive relation between the intake of any NSAIDs and the risk of PC , while nCompared to that in all aspirin users (7.0%), our finding of a larger (12.5%) PC risk reduction among those who took at least 1 aspirin tablet daily may indicate a dose related association between the intake of aspirin and the risk of total PC, although we could not pool the data to investigate the association between aspirin intake of less than 1 pill/day and the risk of PC. The above dose related association was reported in several studies , 35, 53.Regarding long-term intake of NSAIDs or aspirin, the association became less consistent. We found that long-term intake of NSAIDs (≥5 years rather than ≥4 years) and non-aspirin NSAIDs (≥4 or ≥5 years) was associated with reduced PC incidence. The results for NSAIDs or non-aspirin NSAIDs may be valid due to little evidence of heterogeneity. However, no significantly beneficial effects were found between long-term intake of aspirin (≥4 or ≥5 years) and the risk of total PC, though the pooled RRs were <1. Previously, a modest 12–18% reduction in total PC risk was reported among long-term aspirin users (≥4 years) , 70. MorAs for the geographic difference, we observed that the intake of NSAIDs or aspirin was associated with a decreased PC risk in both Europe and North America, though there was no statistical difference in PC risk due to the intake of NSAIDs in Europe. Additionally, a negative association was also observed between PC incidence and the intake of non-aspirin NSAIDs in North America, while there was an insignificant positive relation between PC incidence and the intake of non-aspirin NSAIDs in Europe. Some previous studies indicated that the effect of the intake of NSAIDs on PC incidence seemed to vary by geographic region, which may result from a potential bias. For example, studies of European men reported that the use of NSAIDs was associated with an increased risk of total PC , 17, 44,Furthermore, we detected that there was no remaining association between the intake of NSAIDs and PC incidence when we restricted our analysis to studies adjusting for comorbidities. The final pooled effects of aspirin intake seemed to be influenced by the concomitant use of other medications. Comorbidity and the concomitant use of other medications could influence the risk of PC and introduce an indication bias due to the fact that several comorbidities (cardiovascular and rheumatologic diseases) were the main reasons for their intake of NSAIDs. In addition, cardiovascular events and PC shared several common risk factors, such as smoking, alcohol, obesity, and low levels of physical activity. Thus, PC may be more prevalent in those with certain risk factors than in the general population . It shouI2 = 16.20 and 28.40%, respectively). Although the final pooled effect of aspirin intake on the incidence of advanced PC was consistent with the results of previous studies, the degree of risk reduction in those studies varied from 11 to 30% . Moreover, aspirin intake was also associated with a decreased risk of PC, and it was the daily dose (≥1 pill/day) not the long-term intake of aspirin (≥4 or ≥5 years) that was associated with the reduced incidence of PC. No significantly adverse or beneficial effects were found between the intake of non-aspirin NSAIDs and the risk of total PC, advanced PC, or PC with Gleason score ≥7. It is necessary to perform further well-designed large-scale randomized controlled trials to draw a definitive conclusion, which could adjust for the potential known and unknown confounders.ZS and TO conceived and designed the study. ZS, XW, KY, JW, HY, and QW contributed to the extraction of data and analysis of the results. All the authors contributed in writing and editing the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: DLBCL is the most commonly occurring type of non-Hodgkin's lymphoma, which may be found at various extranodal sites. But little is known about the particular trends of extranodal DLBCL.Methods: A total of 15,882 extranodal DLBCL patients were included in incidence analysis from the Surveillance, Epidemiology, and End Results (SEER) database (1973–2015). The joinpoint regression software was used to calculate the annual percent change (APC) in rates. Nomograms were established by R software to predict overall survival (OS).Results: The extranodal DLBCL incidence continued to rise at a rate of 1.6%  per year over the study period, until it declined around 2003. The incidence-based mortality trend of extranodal DLBCL had a similar pattern, with a decrease happening around 1993. Five-year survival rates improved dramatically from the 1970s to 2010s (44.15 vs. 63.7%), and the most obvious increase occurred in DLBCL patients with primary site in the head/neck. The C-index showed a value for OS of 0.708, which validated the nomograms performed well and were able to forecast the prognosis of patients with extranodal DLBCL. The calibration curves showed satisfactory consistency between true values and predicted values for 1-, 5-, and 10-year overall survival, respectively.Conclusions: The incidence and incidence-based mortality of extranodal DLBCL had been increasing for decades, followed by a promising downward trend in recent years. These findings may help scientists identify disease-related risk factors and better manage the disease. The prediction signature cloud identifies high-risk patients who should receive effective therapies to prevent the fatal nature of this disease, and low-risk patients to reduce over-treatment. Non-Hodgkin lymphoma (NHL) is the tenth most common cancer in the world in 2018 . In the In recent years, the most of DLBCL patients' survival rate have been dramatically increased since R-CHOP  was introduced as a first-line therapy . HoweverThe present study aimed to explore the incidence and mortality trends of extranodal DLBCL by primary site involved and patient demographic characteristics from the Surveillance, Epidemiology, and End Results (SEER) cancer registry during 1973–2015. The results may help scientists identify disease-related risk factors and better manage the disease. In addition, we have developed a new prediction model specifically for patients with extranodal DLBCL in the rituximab era that may provide an accurate risk stratification of individual and guide the treatment.The incidence cases come from the registries of the SEER-9 cancer incidence file of the US National Cancer Institute from 1973 to 2015. For the SEER database has only been recorded on the Ann Arbor Stage since 1983, we limited the analysis of the impact of the Ann Arbor Stage on the incidence from 1983.The incidence-based mortality (IBM) cases were different from traditional mortality cases, which linked mortality records to incident cancer cases. The IBM cases were only included from 1988 to 2015 to ensure maximum majority of the deaths occurring after 1973 and IBM rates was not underestimated in the first few years. This interval was chosen, because the mean survival time for patients with DLBCL is 10 years.The patients diagnosed from 1973 to 2015 were enrolled from the SEER 18 registries with 28% of the US population in the survival analysis.The patients diagnosed from 2002 to 2015 were selected out from the SEER 18 registries for construction of nomogram. The patients diagnosed before 2002 were excluded, because we aimed to build a prediction model for the rituximab era and 79% of DLBCL patients have received rituximab as first-line treatment from 2002 .n = 66 and n = 7, respectively) analysis. In addition, those who survived for less than a month were excluded in survival analysis and construction the nomogram, because their survival time were recorded as 0 in SEER database. We excluded the patients whose Ann Arbor Stage and race was unknown when constructing the nomogram.Eligible patients were diagnosed with lymphoma with the International Classification of Diseases for Oncology, third edition, ICD-O-3 histology code 9680 . These patients were excluded: (1) DLBCL wasn't primary malignancy; (2) the patients were not active follow-up; (3) the primary site of the lymphoma was central nervous system, mediastinum or unknown. Patients with primary CNS DLBCL and primary mediastinal DLBCL were excluded, because they have unique clinical features, prognosis, and the treatment that differ from other sites. The sparse number of patients whose race was unknown were excluded for further evaluation in the incidence and Incidence-Based Mortality  children: ≤14 years; (2) AYAs: 15–39 years; (3) adults: 40–64 years; (4) the elderly: ≥65 years, according to the National Cancer Institute Progress Review Group on AYA Oncology and the National Comprehensive Cancer Network guidelines. Autologous stem cell transplantation (ASCT) is an effective method to treat recurrent patients, but ASCT was most commonly offered to patients <65 years. Survival rates change dramatically with age for those older than 65 due to geriatric syndromes and comorbid diseases. Therefore, the elderly were further divided into groups every 5 years in the process of survival analysis and modeling. The stage was divided into early (Ann Arbor Stage I/II) or advanced (III/IV) stage. Based on the ICD-O-3 topography code published by SEER, primary sites were classified into 10 sites: Skin/soft tissue ; Gastrointestinal tract ; Head/Neck ; Genitourinary tract (C51-68.9); Skeletal tissue ; Respiratory system ; Hematologic system (C42-42.4); Liver/pancreas (C22-25.9); Breast tissue (C50-50.9); and Other .*Stat version 8.3.2 was used to calculate incidence and IBM rates. All rates were age adjusted to the 2000 US standard population and expressed per 100,000 person-years. Joinpoint regression analysis program, version 4.5.0.1, was used to analyze the incidence and mortality trends of extranodal DLBCL, and annual percentage change (APC) and average annual percentage change (AAPC) were used to assess rate changes. We use the rms package in R Bioconductor to calculate 1-year, 5- and 10-year overall survival (OS). In order to determine how different variable levels were associated relatively, as well as individually, with survival, Univariable and multivariable Cox proportional hazards regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). SPSS used for survival analyses. P < 0.5 was a statistically significant standard.SEERThe steps to construct the nomogram are as follows. Firstly, the primary outcome was set to be OS. Secondly, variables  which may determine the outcome were selected on basis of priori clinical hypotheses. Thirdly, the survival related factors were determined via Cox proportional hazards regression model. Finally, a prognostic nomogram for OS was built through R Bioconductor based on multivariate analysis above.As for the application of the nomogram, firstly, the point for each trait of the patient was allocated via a vertical line from the corresponding variable to the point scale. Then, all the points were summed up and a vertical line was drawn from the total point scale to obtain different probability of 1-, 5-, and 10-year OS.Concordance index (C-index) and calibration curve are used to assess the performance of the model. C-index >0.5 is considered statistically significant, and a larger value indicates a stronger predictive ability of the model. The closer the predicted value is to the diagonal line on the calibration plot, the stronger the model prediction ability. The model experienced 1,000 bootstrap reiterations.A total of 15,882 patients with extranodal DLBCL as the first malignancy diagnosed were included in the incidence analysis from SEER database from 1973 to 2015. Patient characteristics are outlined in p < 0.001) per year over study period, until it declined around 2003 , and then it stabilized from 1991 to 2005 , followed by a sharp decrease from 2005 to 2015  . The incBoth the incidence and incidence-based mortality of early stage patients showed an initial significant increase and then turn to decrease. The incidence increased steeply during 1983–1990  and more slowly from 1990 to 2003 , then it went down during 2003–2015  . In termFor advanced stage patients, the incidence and incidence-based mortality rates started from a rapid increase, with a change occurring 2007 and 1990, respectively, that the incidence rate turned to decrease and mortality rates leveled off.There was no joinpoint in the trend of incidence and incidence-based mortality in the children over the study periods, which rose at a rate of 1.5%  and fell at a rate of −1.6%  per year, respectively. For the AYA and the elderly, the incidence showed an initial increase, followed by declines at a rate of −1.1%  and −2.3%  around 1991 and 2003, respectively . The incThere was a continued increase in both incidence and incidence-based mortality of white patients, with a decrease happening 2003 and 2002, respectively. The incidence of white patients increased steeply during 1980–1990  and 1997–2003 , then it went down during 2003–2015  . In termWe observed two different patterns in incidence analysis by sites : (1) AftOverall median survival for patients with extranodal DLBCL was 93 months, with 1-, 5-, and 10- year survival rates of 75.767, 57.937, and 44.021%, respectively. Five-year survival rates improved dramatically from the 1970s to 2010s , and primary sites in the skin and soft tissue, gastrointestinal tract, genitourinary tract, respiratory system, liver/pancreas, breast tissue, and other were associated with decreased survival .Next, the factors closely related to survival on multivariate analysis were used to construct nomograms by the R Bioconductor . The proAs far as we know, this is the first ever study based on large population to uncover trend of the incidence and mortality for extranodal DLBCL by clinical features, and to systematically compare them based on these characteristics, which may help scientists identify disease-related risk factors and better manage the disease. The appropriate management of extranodal DLBCL should be able to stratify patients into distinct prognostic groups. Therefore, we have developed a new prediction model in the rituximab era that may provide an accurate risk stratification of individual to determine the best treatment options for the individual. We demonstrate that the incidence and incidence-based mortality of extranodal DLBCL have been increasing for decades, but it has shown a promising downward trend in recent years. This phenomenon may be partly explained by our survival analysis. The 5-year survival rates have improved dramatically from the 1970s to 2010s (44.15 vs. 63.7%), and the most obvious increase occurred in patients with primary site in the head/neck.The overall mortality trend of extranodal DLBCL began to decline in 1993, which was 10 years earlier than incidence, indicating that the main reason for the decline of extranodal DLBCL mortality is the improvement of survival rate. We hypothesize that improvements in management and treatment of patients may lead to improved survival. One of the most significant improvements was the introduction of the IPI index as the gold standard for classifying high-risk and low-risk patients and guiding treatment . AnotherIt is worth noting that the mortality trend of early stage patients has been declining since 2007, and the mortality rate of advanced stage patients has only stabilized from the initial rapid growth since 1993, but it has not shown a downward trend. This phenomenon may suggest that new, more effective and systemic treatments, in addition to R-CHOP schemes, are needed to prevent the fatal nature of patients at advanced stage. Chimeric antigen receptor modified T (CAR-T) cell therapy by targeting the CD19 antigen has made breakthroughs in the treatment of NHL at advanced stage, and showed the possibility of cure . AxicabtHelicobacter pylori (H. pylori) and Campylobacter jejuni was closely related to primary gastrointestinal DLBCL  The differences were in occupational exposure factors, health awareness, and lifestyle  Theifestyle , and womifestyle . (4) Horifestyle . (5) Menlymphoma .In our article, we showed that the incidence of extranodal DLBCL increased with age, which was consistent with the theory that the incidence increased exponentially with age in the multi-step carcinogenic model of solid tumors . Two facThe death rate for white patients has declined significantly since 2002, while that for black and other ethnic groups has remained virtually unchanged. One possible explanation for this was reported by an article showing that the black and other race people had less access to rituximab than white people in 2002, when rituximab was first used . AnotherWe here showed that extranodal DLBCL patients with primary site in the head/neck had the most obvious increase of 5-year survival rate from the 1970s to 2010s (48.82 vs. 72.76%), which is consistent with previous studies –47. The At present, the most routine prognostic system in DLBCL patients is the International Prognostic Index (IPI). However, there is multiple variables and prognosis heterogeneity in some defined risk groups according to the IPI guidelines. As a graphic expression of a mathematical model, the nomogram helps to determine the possibility of clinical event by combing biological and clinical variables. Nomograms are widely used in various types of cancers , 51. TheSome limitations due to information availability in the SEER database should be noticed when interpreting our findings. First, information regarding therapy is limited. In SEER, there is no information about chemotherapy, which is a major modality of treatment for DLBCL. Therefore, we couldn't explore the effect of treatment on survival and the trend of incidence and mortality. We partially addressed this issue by dividing the time of diagnosis into 1970s, 1980s, 1990s, 2000s, and 2010s. Second, the incidence-based mortality rates by Ann Arbor Stage may be underestimated, because the SEER database has recorded the information of Ann Arbor Stage since 1983, which shortened the incubation period between diagnosis and death. Third, the information about radiation exposure, environmental exposures and individual life style and family history, which may be associated with the rates of incidence and mortality, was not available. Fourth, there was no record of baseline performance status, B-symptoms, bulky disease, and lactate dehydrogenase levels. Therefore, we couldn't include these potential prognostic factors in the prediction model.Our study shows that the incidence and incidence-based mortality of extranodal DLBCL had been increasing for decades, but have shown a promising downward trend in recent years. The findings may provide new insight into better healthcare quality and better manage extranodal DLBCL. Moreover, the 5-year survival rates have improved dramatically from the 1970s to 2010s (44.15 vs. 63.7%), and the most obvious increase occurred in patients with primary site in the head/neck. We also constructed the nomogram, a robust, and clinically practical risk stratification, in the rituximab era, which may help guide treatment and develop individual-specific tracking programs.Publicly available datasets were analyzed in this study. This data can be found here: the Surveillance, Epidemiology and End Results database.This study was conducted in full compliance with the publication guidelines provided by SEER. The data were obtained from SEER, so the approval of an ethics committee was not needed.XY collected and analyzed the data and wrote the paper. AX, FF, ZH, QC, and LZ research literature, edit the paper, and revise the paper. CS and YH conceived and designed this study, analyzed the data, and wrote the paper. All authors reviewed the paper, and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The aim was to explore contraceptive uptake, associated factors and satisfaction among post abortion-care (PAC) seeking women in Kenya. Due to unsafe abortions, almost 120 000 Kenyan women received PAC in 2012, and of these women, 70% did not use contraception before pregnancy.This study was nested in a larger randomised controlled trial, where 859 women sought PAC at two public hospitals in Kisumu, in June 2013–May 2016. The women were randomly assigned to a midwife or a physician for PAC, including contraceptive counselling, and followed up at 7–10 days and three months. Associated factors for contraceptive uptake were analysed with binary logistic regression, and contraceptive method choice, adherence and satisfaction level were examined by descriptive statistics, using IBM SPSS Statistics for Windows, Version 22.0.Out of the 810 PAC-seeking women, 76% (n = 609) accepted the use of contraception. Age groups of 21–25  and 26–30 , and previous experience of 1–2 gravidities  were independent factors associated with the up-take. Methods used: injections 39% (n = 236); pills 27% (n = 166); condoms 25% (n = 151); implant 7% (n = 45) and intrauterine device (IUD) 1% (n = 8). At 3-month follow-up of the women , 354 (75%) women still used contraception, and most  were satisfied with the method. Reasons for discontinuation were side-effects , partner refusal , planned pregnancy  and lack of resupplies .PAC-seeking women seem highly motivated to use contraceptives, yet a quarter decline the use, and at 3-month follow-up a further quarter among the users had discontinued. Implant, IUD and permanent method are rarely used. Strategies to improve contraceptive counselling, particularly to adolescent girls, and to increase access to a wide range of methods, as well as provider training and supervision may help to improve contraceptive acceptance and compliance among PAC-seeking women in Kisumu, Kenya. Many regions of the world have high numbers of unwanted pregnancies and unmet contraceptive needs –5. An esAccess to contraception supports people’s rights to determine the number and spacing of children and reduces the need for induced abortions, especially unsafe abortions , 6, 7. TKenya’s total fertility rate is 3.9 children during a woman’s lifetime [An estimated 465,000 induced abortions, mostly using unsafe procedures were performed in Kenya in 2012, a rate of 48 per 1,000 women of reproductive age , 10. UnsPAC is widely recognized as a critical practice to address complications related to miscarriage and incomplete abortion and reduce repeat abortions by the provision of contraception services , 13–17. This paper is based on analyses of secondary outcomes from a randomised controlled trial with the aim to assess the effectiveness of midwives administering misoprostol to women with incomplete abortion seeking PAC, compared with physicians . The proCounselling space was provided in a secluded room and to securely store the large number of protocol records. The study was designed and coordinated by researchers at the Department of Public Health Sciences, Global Health (IHCAR), and Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden; Kisumu Medical Education Trust; University of Nairobi, Kenya; Moi University, Eldoret, Kenya; and Jaramogi Oginga Odinga Teaching and Referral Hospital and Kisumu County Hospital, Kisumu, Kenya. The research questions and outcome measures were developed by researchers and health care providers experienced in PAC at the studied facilities.The Jaramogi Oginga Odinga Teaching and Referral Hospital Ethical Review Committee (diary number ERC42/13) and the Swedish regional Ethics Committee in Stockholm (2013/902-31/1) gave ethical approval for the study. All the patients provided written, informed consent and could withdraw from the study at any time without consequences .The inclusion criteria were women presenting with vaginal bleeding in the first trimester of pregnancy and diagnosed to have incomplete abortion, and the exclusion criteria were omen with unstable hemodynamic status and shock, signs of sepsis .Eligible women who consented to participate were randomly assigned to a midwife (intervention) or standard care with a physician (control) for diagnosis and treatment . Data maFrom 1 June 2013 to 31 May 2016, women seeking PAC were recruited (n = 859), by midwives and physicians involved in PAC at two facilities in Kisumu. The health care providers took part in a 5-day theoretical and practical training program which followed the Kenyan and the World Health Organization’s standardised PAC training module and medical eligibility criteria for contraceptive use , 23. On-Four midwives per facility were trained as research assistants and were responsible for screening and enrolment of participants. The midwives role was also to monitor the supply stock . The research assistants conducted the follow-up visits, including assessing abortion status and the contraceptive uptake.Women admitted with signs of incomplete abortion were screened based on self-reported last menstrual period, pregnancy test, symptoms and clinical assessments. Eligible women who consented to participate were randomly assigned to the midwife or the physician group for the clinical assessment . Each paThe women were offered reimbursement for travel costs as an incentive to attend the follow-up appointment. All the women received an SMS reminder two days before their scheduled appointments. Women who did not show up were contacted by a research assistant using a cell phone provided by the project, and the women was given new appointments and encouraged to attend. No serious adverse events were recorded.The outcome for this paper was the contraceptive uptake among the PAC-seeking women who were followed up (n = 810/859) as assessed by background characteristics  and six Did you receive contraceptive counselling? (7–10-day follow-up)Did you accept to start a contraceptive method? (7–10-day follow-up)What method did you chose to start? (7–10 day follow-up)Are you still using the method? (3-month follow-up)What is your satisfaction level with the chosen method? (3-month follow-up)What is your reason for interrupting the method? (3-month follow-up)The sample size calculation was based on the main outcome, assuming that the rate of incomplete abortions was 4% . The paracceptance to start a contraceptive method. The variables in the bivariate analysis that had a p value < 0.05 were used as explanatory variables . To adjust for possible interactions between the variables, each variable was controlled against the others, and correlations of less than 0.70 were used. The associations were presented as odds ratios (OR) with a 95% confidence interval (CI). IBM SPSS Statistics for Windows, Version 22.0 was used for all the analyses. All the authors had full access to the data, and the first author regularly reported the preliminary results to the entire research team. The corresponding author had final responsibility for the decision to submit the manuscript for publication.To determine the factors associated with women’s acceptance of starting to use a contraceptive method and the adherence at three months, Pearson’s chi-squared test was used, and the significance level was set at < 0.05. The same method was used to investigate possible differences between the two provider groups (midwife and physicians). In addition, a binary logistic regression model was used to identify the factors associated with the dependent variable Out of the 859 women, a total of 49 (6%) women were lost to follow-up (24 in the midwife group and 25 in the physician group). Finally, a total of 810 women, 409 in the midwife group and 401 in the physician group, received PAC due to first-trimester incomplete abortion and were included in the per-protocol analysis. p = 0.249).Among 810 women who were followed-up at 7–10 days, most  reported that they had received contraceptive counselling at the first visit, and 609 women (75%) had accepted starting the contraceptive method of their choice. There were no differences in the acceptance rate between the midwife and the physician groups (p = 0.021), previous gravidity experience (p = < 0.01), parity (p = 0.01) and to be accompanied by partner at the clinic (p = 0.02). A nonlinear correlation between age and contraceptive acceptance was identified, showing the largest proportion of acceptance among women aged 21–25 years  and 26–30 years , but falling off in age groups of 31–35 years  and 35–45 years . The proportion of acceptance was lowest in the age group 14–20 years . With regard to previous gravidity experience, the largest proportions of acceptance were among women with previous experience of 1–2 gravidities  and 3–12 gravidities , compare to nulligravidity  (p = 0.007).acceptance of starting a contraceptive method, presented as OR with a 95% CI  and 26–30 years  and to have experienced 1–2 previous gravidities . The Hosmer and Lemeshow Test showed a non-significant chi2 (p = 0.947) and indicated that the model fits the data well.A binary logistic regression (n = 792/810 women) was used to assess the independent factors associated with the dependent variable the a 95% CI . The varAmong the 609 women who started contraceptive methods, 470 (77%) were followed up at three months. At that time, 354/470 (75%) were still using the method, and 94% (n = 332/470) of these women were highly satisfied or satisfied with the method. Nine women were not satisfied, and 13 women wanted to stop using their method , and one women were never provided the requested permanent method.Among the 115 women (25%) who had interrupted continuation of their contraception were distributed by following methods: pills = 35/126 (28%); injection = 33/188 (18%); condoms = 31/112 (28%); implant = 9/32 (28%), and IUD = 5/6 (83%). The interruption rate was similar for both the midwife group  and the physician group . The contraceptive method chosen was not reported for two women.p < 0.05) with adherence to the chosen method at the 3-month follow-up.The most common reasons for interruption were side-effects, mainly bleeding problems , partner refusal , desire for pregnancy  and lack of resupplies . None of the associated background factors  had a siThe aim of this study was to investigate contraception up-take, associated factors and satisfaction among women who received post abortion contraceptive counselling from midwives and physicians in a low-resource setting in Kenya. The results show high uptake and satisfaction of post abortion contraception, in particular among women in the age of 21–30 years and among women with previous gravidity experience. However, a quarter of the women declined to start a contraceptive method, and a further quarter of the women had interrupted the use of the method at 3-month follow up. The most common reasons were side-effects such as bleeding problems, partner refusal and desire for a pregnancy, aligning with other studies , 24, 25.The most commonly chosen contraceptive method among the PAC-seeking women were injection, followed by pills and condoms, similar to national rates of methods used in Kenya . AlthougThe second most common reason for contraceptive discontinuation was the refusal of male partners to use the method, which was as common as the desire for a new pregnancy. In line with this finding, there was also an association between the woman’s contraceptive acceptance and male partner accompany to the clinic. Improving male involvement in the prevention of unintended pregnancies, which ought to be a shared responsibility, should be encouraged , 28. HowAge (21–30 years) and previous pregnancy experience were found to be predictors of acceptance of starting a contraceptive method among PAC-seeking women. The participating women origin from Western Kenya, a poor and low-income region, which may have introduced bias to identify association between contraception and acceptance with regard to socioeconomics . However, such association is expected as these variables are theoretically connected  and alsoThe association between contraception acceptance, and being married (or cohabiting) and to be accompanied by partner to the clinic were eliminated when adjusted for age and gravidity in the regression model . This caThe results of this study show that implementation of systematic provision of contraceptive counselling and provision of contraceptives in PAC are feasible and has great potential for future quality development. However, the facilities in this setting were challenged by limited resources, shortages of staffs, skills and inadequate supply chain management. Injection was the most commonly chosen method and may have been caused by heavy workload due to shortage of staffs, as injections are the easiest method to provide. Nevertheless, injections are known to have higher risks for side-effects than other contraceptives, especially IUDs and implants . In thisAdd to the problem that sporadic stock-outs of contraceptive methods occurred throughout the study period (supply chain management and financing). The limited capacity to offer a full choice of methods as they did not always have readily assembled IUDs and implant kits, added to the weakness of this study. These obstacles were not identified as an issue that needed to be addressed during the baseline assessment, because all contraceptives were available at that time, and all providers were trained. When these issues were identified later, it was difficult to catch up, solve and prevent them. Moreover, it precluded rigorous statistical analysis on these methods.In addition, the questionnaire was not designed to measure contraception uptake as a primary outcome as the main outcome was the use of misoprostol to treat incomplete abortion . NeverthThe high discontinuation rate for the IUD use indicates insufficient continued follow-up and staff training on IUD, and must be further explored and improved. Moreover, the proportion of non-acceptance of a contraceptive method and the proportion of discontinuation points to several barriers to obtain and provide post abortion contraception. Obstacles among PAC-seeking women include side effects, lack of resupplies and partner disapproval of contraceptive use. Barriers at the provider level may reflect lack of skills, denial of certain methods, and disapproval of contraception to adolescents or women who have not yet delivered a child. To develop strategies mitigating these barriers are urgent, such may include provider training and supervision on contraceptive counselling, timing of return to fertility, side-effects and health concerns. In addition, timely informed method-switching needs to be better recognised in PAC to avoid discontinuation and the risk of sub-sequent unintended pregnancies, unsafe abortion and unwanted or mistimed births.At the facility and policy level further development is need to improve contraceptive services so that women can make informed choices among a wide range of methods, and obtain the chosen method before discharge from the facility. In addition, more research is required to understand underlying reasons for contraceptive use and non-use among young women. Such as better understanding of the impact that socio-cultural stigma, negative gender norms, and male-involvement may have on the woman’s contraceptive acceptance, choices and compliance.The findings show that systematic provision of post abortion contraception is feasible in a low-resource setting in a country with restrictive abortion regulations, but need further development. The PAC-seeking women in this study seem highly motivated to use contraceptive methods, and associated factors were to be in the age of 21–30 years and to have had previous gravidity experience. Yet, a quarter decline contraceptive use and at three month follow up an additional quarter had discontinued among the users. Injection was the most common choice, while implant and IUD, were rarely used. None received permanent methods. Moreover, these facilities should place priority on provider training and supervision on a wide range of methods, and to make them affordable to increase women’s access to a full range of contraceptives, comprehensive and accurate information, in particular to adolescent girls.S1 File(PDF)Click here for additional data file.


Approximately 40% of new chemical entities (NCEs), including anticancer drugs, have been reported as poorly water-soluble compounds. Anticancer drugs are classified into biologic drugs  and small molecule drugs (nonbiologic anticancer drugs) based on effectiveness and safety profile. Biologic drugs are administered by intravenous (IV) injection due to their large molecular weight, while small molecule drugs are preferentially administered by gastrointestinal route. Even though IV injection is the fastest route of administration and ensures complete bioavailability, this route of administration causes patient inconvenience to visit a hospital for anticancer treatments. In addition, IV administration can cause several side effects such as severe hypersensitivity, myelosuppression, neutropenia, and neurotoxicity. Oral administration is the preferred route for drug delivery due to several advantages such as low cost, pain avoidance, and safety. The main problem of NCEs is a limited aqueous solubility, resulting in poor absorption and low bioavailability. Therefore, improving oral bioavailability of poorly water-soluble drugs is a great challenge in the development of pharmaceutical dosage forms. Several methods such as solid dispersion, complexation, lipid-based systems, micronization, nanonization, and co-crystals were developed to improve the solubility of hydrophobic drugs. Recently, solid dispersion is one of the most widely used and successful techniques in formulation development. This review mainly discusses classification, methods for preparation of solid dispersions, and use of solid dispersion for improving solubility of poorly soluble anticancer drugs. Cancer is one of the leading causes of death worldwide, and treatment remains a great challenge. Currently, there are three major cancer treatment strategies of surgery , chemotherapy (use of anticancer drugs), and radiotherapy (delivered by a radiooncologist) . The objw/w) and high-loading efficiency (>75%) drug delivery system. In another study, trastuzumab, a monoclonal antibody with specific targeting to human epidermal growth factor receptor 2 (HER2) protein, was used in combination with cisplatin for treatment of HER2-overexpressing breast cancer . A . A 22]. In the clinic, there are many insoluble drugs with small dose administration such as risperidone (0.25–4 mg), lorazepam (0.5–2 mg), diazepam (2–10 mg), and clonazepam (0.5–2 mg), which do not require increased solubility. However, the solubility of these drugs is usually affected by pH due to physicochemical properties resulting in a decrease in the effective treatment. For example, risperidone is indicated for treatment of schizophrenia at a small dose  in oral administration. It is a weak base that is practically insoluble in water. Its solubility is pH dependent, with high solubility in acidic pH, and decreasing solubility as pH increases (range from >200 mg/mL at pH 2.1 down to 0.29 mg/mL at pH 7.6 and reaches 0.08 mg/mL at pH 8). After oral administration, risperidone is rapidly absorbed, and approximately 80% of drugs will be absorbed in the GI tract, where the solubility significantly drops. Moreover, risperidone is a metabolized drug, in which approximately 70% and 14% of the dose is excreted in urine and feces, respectively. Therefore, enhancing solubility in simulated intestinal pH to ensure higher drug concentrations at the main absorption site and improve BA is a challenge in drug development.To improve the solubility and BA of poorly water-soluble drugs, several methods have been developed such as solid dispersion (SD) ,24,25, cAn SD is defined as a group of solid products consisting of a hydrophobic drug dispersed in at least one hydrophilic carrier, resulting in increased surface area and, enhanced drug solubility and dissolution rate. They are classified as follows.Many carriers are used in SD. These carriers determine the final formulation properties and can be categorized into first, second, and third classes .d-mannitol, d-fructose, d-dextrose, and d-maltose as carriers at a different weight ratios to the drug. The results showed that a 100% solution of mannitol showed an 806-fold increase in solubility compared to the conventional drug in water. The dissolution profile of clotrimazole SD was improved at 1:3 drug to mannitol ratio. In conclusion, urea and sugars were first used as crystalline carriers for production of SD. These formulations were thermodynamically unstable, resulting in slow drug release.The first study of SD was conducted by Sekiguchi and Obi in 1961 . They stBecause of thermodynamic instability of first class SD , second w/w fenofibrate/ poloxamer 407. Surfactants are also used in preparation of SD of poorly soluble anticancer drugs such as docetaxel [The third class of SD was recently developed. In this class, surfactant can be used alone or in the combination with other hydrophilic carriers in the preparation of SD . Surfactocetaxel , flutamiocetaxel , and lapocetaxel . A eutectic mixture is a mixture of two components that melt at a single temperature. Components A and B were co-melted at the eutectic point (E) , where tHerein, SD is a mixture of the drug and a carrier . Solid sA glass solution is a homogeneous system in which the drug molecule is dissolved in a glassy solvent ,82. GlasOne of the most important advantages of SD is drugs interacting with hydrophilic carriers can decrease agglomeration and release in a supersaturation state, resulting in rapid absorption and improved BA .SD can improve drug wettability and increase the surface area, resulting in enhanced aqueous solubility of drugs.SD can be produced as a solid oral dosage form, which is more convenient for patients than other forms like liquid products.In addition, SD showed an advantage compared to salt formulation, cocrystallization, and other methods. For example, salt formulations use ionized active pharmaceutical ingredients (APIs) (cationic or anionic form) and are widely used in the pharmaceutical industry due to the broad capacity of design according to desired drug properties. However, not all drugs can ionize with all cations/anions, and phase dissociation or stability issue is inherent in salt formation or cocrystallization. Salt formulation showed several disadvantages such as reduced solubility and dissolution rate, resulting in decreased relative BA ; greater regulatory scrutiny for strong acid salts isolated from alkyl alcohols; and increased hygroscopicity, e.g., for Na and, K salts, spray-drying/lyophilization can dissociate strong acid salts. The disadvantages of salt formulation can be resolved when the formulation is produced using an SD.Practically, dissolution of drugs is a prerequisite for complete absorption to have the desired therapeutic effect of anticancer drugs after oral administration. Most of the anticancer drugs exhibit poor aqueous solubility causes of dissolution limit resulting low BA and high variability in blood concentration. The limitation of drug dissolution can improve by SD, a technique that induces supersaturated drug dissolution and with that it enhances in vivo absorption.SD was widely used for enhancing dissolvability in water of poorly water-soluble drugs with several advantages as follows: Physical instability.SDs show changes in crystallinity and decreased dissolution rate with aging.Tg) or disrupting interactions between the drug and carrier, resulting in a decreased solubility and dissolution rate of the drug.Due to their thermodynamic instability, SD is sensitive to temperature and humidity during storage. These factors can promote phase separation and crystallization of SD by increasing the overall molecular mobility, decreasing the glass transition temperature  technology . The lisThe melting method was first used in 1961 by Sekiguchi and Obi . The basmax (13.1-fold). The solvent evaporation method has often been used to improve solubility of poorly water-soluble anticancer drugs such as paclitaxel [The solvent evaporation method is one of the most commonly used methods in the pharmaceutical industry for improving solubility of poorly water-soluble drugs. This method was developed mainly for heat unstable components because drug and carrier are mixed by a solvent instead of heat as in melting method. Therefore, this method allows use of carriers with an excessively high melting point. The basic principle of this method is that drug and carrier are dissolved in a volatile solvent for homogeneous mixing. SD is obtained by evaporating the solvent under constant agitation. Then, the solid SD is crushed and sieved. This method was first applied by Tachibana and Nakamura in 1965 . The forclitaxel , docetaxclitaxel , and othclitaxel . In the clitaxel , azithroThe melting solvent method was first studied by Goldberg el al. . In theiMelt agglomeration is a process in which a binder acts as a carrier. In this method, the drug, binder, and other excipients are heated to above the melting point of the binder. Alternatively, a dispersion of the drug is sprayed onto the heated binder ,149,150.0–24h (1840 ± 381.8 ng·h/mL) and Cmax (498.7 ng/mL) of the drug from the SD were enhanced 2.4 times and 5.6 times compared with those of pure drug . In another study by Sathigari el al., [Hot-melt extrusion is a common method for improving solubility and oral BA of poorly water-soluble drugs, in which the amorphous SD is formed without solvent, thereby avoiding residual solvents in the formulation . This me el al., , efavire0–72h of the drug in the SD was 2.3-fold greater than that of the drug alone. In another study on a flutamide SD prepared by lyophilization to enhance the dissolution rate [Lyophilization is an alternative process to the solvent evaporation method in which the drug and carrier are dissolved in a solvent and then the solution is frozen in liquid nitrogen to form a lyophilized molecular dispersion . This meion rate , PVP K30w/w) was prepared by the electrospinning method [p < 0.05) greater than that of ketoprofen alone. In another study, an amorphous formulation of indomethacin and griseofulvin was prepared by the electrospinning method using PVP as the carrier. This formulation was stable for 8 months in a desiccator [The electrospinning method is a combination of SD technology and nanotechnology. In this method, solid fibers are produced from a polymeric fluid stream or melt delivered through a millimeter-scale nozzle . The advg method . Dissolusiccator .p < 0.05) enhanced dissolution compared with the other two methods. Furthermore, the solubility of silymarin from the SD prepared by co-precipitation improved 2.5-fold in comparison with that of the conventional drug. In this method, the carrier is first dissolved in solvent to prepare a solution, and the drug is incorporated into the solution with stirring to form a homogeneous mixture. Then, water is added dropwise to the homogenous mixture to induce precipitation. Finally, the precipitate is filtered and dried. In a study by Sonali et al. , a silym2) and sprayed through a nozzle into an expansion vessel with lower pressure. The rapid expansion induces rapid nucleation of the dissolved drugs and carriers, leading to the formation of SD particles with a desirable size distribution in a very short time. To date, SCF can be performed by several methods such as rapid expansion from supercritical solution (RESS) [2 is a suitable solvent for preparation of SD of insoluble drugs, primarily due to its low critical temperature (31.04 °C) and low critical pressure (7.38 MPa), lack of toxicity, lack of inflammability, and environmental safety [max and AUC of the final formulation increased 3.6-fold and 3.4-fold, respectively, in comparison with that of the drug alone, demonstrating improved BA. In drug development, SCF technology is a potential method for enhancing solubility and BA of poorly water-soluble drugs. One limitation of this method is that most drugs are not soluble in CO2. SCF was introduced in late 1980s and early 1990s. SCF produces a formulation with a narrow particle size range (microparticles or nanoparticles) without solvent and was reported by Hannay and Hogarth in 1897 as a medium for particle production . A substn (RESS) , gas antn (RESS) , supercrn (RESS) , and soln (RESS) . The RESl safety . To imprl safety  preparedl safety . The resSpray-drying is one of the oldest methods for drying materials, especially thermally-sensitive materials such as foods and pharmaceuticals. In this method, the drug is dissolved in a suitable solvent, and the carrier is dissolved in water to prepare the feed solution. Then, the two solutions are mixed by sonication or other suitable methods until the solution is clear. In the procedure, the feed solutions were firstly sprayed in a drying chamber via a high-pressure nozzle to form fine droplets. The formed droplets are composed of drying fluid (hot gas) and form particles of nano or micro size . ClinicaIn this method, the carrier is dispersed in water and processed into a paste. Then, the drug is added and kneaded thoroughly. The final kneaded formulation is dried and passed through a sieve if necessary. In a previous study by Dhandapani and El-gied , cefiximAnticancer drugs are classified into biologic drugs  and small molecule drugs (nonbiologic anticancer drugs) based on effectiveness and safety profile. Biologic drugs are administered by intravenous (IV) injection due to their large molecular weight, while small molecule drugs are preferentially administered by gastrointestinal route. Oral administration is currently preferred for treatment of cancer in comparison with IV route because it is convenient, painless, safe, and economic. Oral drugs can be administered at home, do not induce the same discomfort as an IV infusion, and the drug concentration can be maintained for long time periods in cancerous cells. In addition, oral dosage forms are easy to store and transport. Therefore, oral administration has received increasing attention, leading to increased numbers of anticancer drugs being developed for oral dosing. To date, SD technology is widely used to improve the solubility and BA of anticancer drugs due to its simplicity, economy, and high effectiveness. Most methods are suitable for making SD, in which melting method, solvent evaporation method, SCF technology, and freeze-drying are common for production of SD formulation of anticancer drugs in comparison with other methods. The selected method will be based on physicochemical properties of anticancer drugs.Several manufacturing methods were used to produce SD. However, not all methods are available for commercial processes. Practically, the melting method and solvent evaporation method are two distinct processes that are widely used on lab and industrial scale. On the lab scale, for the solvent evaporation method, a rotary evaporator was mostly used to produce SD. Recently, SCF and freeze-drying are also employed. Due to its simplicity and economy, the melting method is popularly used. Currently, several types of equipment from many manufacturers such as Brabender Technologies, Coperion GmbH, Thermo Fisher Scientific, and Leistritz Advanced Technologies Corp are available in the laboratory, in which SD amount can be produced from a few grams to a kilogram. On the industrial scale, production of SD is not as simple as at the lab scale because it involves a large amount of product from a few to several hundred kilograms. In addition, processes need to be robust, reproducible, and follow good manufacturing practices (GMP). These are difficult to ensure for processes such as solvent cast evaporation or water bath melting process. Spray-drying and freeze-drying are the most representative of the solvent evaporation methods used for manufacturing SD. Moreover, the spray-drying process is easy to scale up from lab scale to industrial scale. Melt agglomeration and hot-melt extrusion are two types of melting processes available on the industrial scale. For instance, hot-melt extrusion is one of the most common methods used on an industrial scale to produce SD using twin-screw extruder with a large diameter of the screw (16–50 mm) compared with small diameter of the screw at lab scale (11–16 mm). In summary, the selected method for manufacturing process plays an important role in the success of a formulation. On the lab scale, the criteria for selecting the melting method are based on the melting point and thermal stability. For selecting the solvent evaporation method, important factors to consider are properties of the drug, carrier, and an organic solvent. On the industrial scale, the production of SD is limited to only a few manufacturing processes. Hot-melt extrusion is the most common among the melting processes to produce SD. For the evaporation method, the selection criteria are based on solvent toxicity and loading capacity.v/v), is associated with serious side effects due to Cremophor EL such as severe hypersensitivity, myelosuppression, neutropenia, and neurotoxicity [Cancer is one of the leading causes of death worldwide and is defined as a group of diseases involving abnormal cell growth with potential to invade or spread to other parts of the body. The World Health Organization predicted that the burden of cancer will increase to 23.6 million new cases each year by 2030 . In 2018toxicity ,17,18. Ttoxicity  prepared® Roche), regorafenib , and everolimus  are three commercial anticancer drugs that were prepared by SD [® was prepared from vemurafenib and hypromellose acetate succinate carrier at a weight ratio of 30/70 (w/w). Dissolution of the SD formulation was approximately 30 times higher compared to the crude powder. Stivarga, which contains regorafenib and PVP-25 as the carrier, showed a 4.5-fold increase in dissolution rate compared to that of the drug mixture. In addition, the BA of the drug from the SD was approximately 7 times higher than that of the conventional drug. Afinitor is an SD prepared with drug and HPMC at a weight ratio of 1:40 in which the dissolution rate from the SD was improved about 4-fold in comparison with the pure drug. The anticancer drugs investigated for SD are shown in In the past few decades, many oral formulations of anticancer drugs have been developed. Oral administration is currently the desired route for treatment of cancer because it is convenient, painless, safe, and economic. In addition, oral dosage forms are easy to store and transport. The prerequisite for oral administration is complete and predictable absorption. To achieve this, drugs have to dissolve in water to absorb in GI tract to be effectively taken up in the circulatory system. However, nearly all anticancer drugs are poorly water-soluble, which can lead to incomplete absorption and poor BA, resulting in large inter- and intra-individual variability in drug concentrations in vivo. Thus, improving the solubility of anticancer drugs is a great challenge in development of improved cancer therapies in the pharmaceutical industry . Among sed by SD . ZelboraSD is currently considered one of the most effective methods for enhancing the solubility and BA of poorly water-soluble drugs. Even though the issues related to preparation, stability, and storage formulation of drugs may limit the numbers of commercial SD products on the market, SD products are still steadily increasing in clinical settings based on improved manufacturing methods and carriers to solve the above problems.®, Gelucire®, Pluronic®, and Soluplus®. In recent years, carriers used in the preparation of SD have been developed. Some studies used new carriers, while other studies used more than one carrier for production of SD formulation. Using more than one carrier in the formulation of SD, many effective methods were designed, recrystallization was decreased, and the stability of SD was improved. Some carriers used recently are InulinIn the manufacturing process, Kinetisol Dispersing (KSD) ,167,168 In this review, we focused on classification of SD, methods for preparation of SD, and current trends in SD for improving the solubility of poorly water-soluble drugs, including anticancer drugs. IV administration is preferred for anticancer treatment. However, patients are inconvenienced by this route because they have to visit a hospital to receive treatment. Therefore, scientists are working to develop oral dosage forms of anticancer drugs. Oral administration is currently the most common route of administration of drugs because it is convenient for patients. A prerequisite for oral administration is dissolution of the drug in water to allow absorption in the GI tract; however, approximately 40% of NCEs including anticancer drugs are insoluble in water which leads to poor absorption, poor BA, and high intra- and inter-individual variability in blood concentrations. Therefore, improving the solubility of poorly water-soluble drugs is a large challenge in the pharmaceutical industry. To overcome this problem, various methods such as complexation, lipid-based systems, SD, micronization, nanonization, and cocrystallization were developed for clinical use. Among these, SD is one of the most successful methods and is widely used for development of drugs. It is considered a promising technique to overcome problems related to poor aqueous solubility and poor BA. By improving wettability of drugs and surface area, drug solubility and dissolution were increased. In the preparation of SD, understanding the properties of the carrier and drug, and selecting a suitable method play crucial roles in the success of the formulation.