Prevention and treatment of colorectal adenoma (CRA) are great significant to reduce morbidity and mortality of colorectal cancer. Although there have been numerous studies on CRA recently, few publications utilized the bibliometrics to evaluate this field. The objective of current study was to provide a comprehensive analysis of the current state and frontier progress of CRA over the past 20 years.The Web of Science Core Collection was utilized to extracted all studies of CRA during 2002-2022. Bibliometric tools including CiteSpace, VOSviewer, and the Online Analysis Platform of Literature Metrology were used for statistical analysis. CiteSpace and the Online Analysis Platform were used to evaluate the contributions of various countries/regions, institutions, authors, and journals in this field. Research hotspots and trends were identified through keywords and references analysis by VOSviewer and CiteSpace.Cancer Epidemiology Biomarkers & Prevention had the highest number of publications and Gastroenterology was the most co-cited journals. Analysis of keywords clusters showed that “mechanism/pathophysiology”, “risk factors and prevention”, “colonoscopy screening and treatment”, “metabolism”, and “microbiota” were the major frontier topics and the main research directions.2,268 publications from 2002 to 2022 in total were identified. The number of global publications in this field has increased annually. The USA was the most productive country, contributing nearly 30% of global publications. But in recent years, China’s publications grew rapidly and had the highest citation strength. The most productive institutions was the National Cancer Institute. Baron JA from the USA was the most productive and the one of most co-cited authors. CRA publications have shown a gradual upward trend in recent years, most of which have been published by developed countries. Developing countries should further focus on CRA research and transnational cooperation with developed countries in the future, in order to better improve the situation of the increasing morbidity and mortality of CRC. Baron JA was the most outstanding researcher in this field. More attention should be devoted to “pathogenesis of CRA”, “less invasive diagnostic methods”, “chemoprevention”, and “screening and risk prediction of CRA including gut microbiome and metabolism”, which will be frontiers in the future. Thus, iEndoscopic detection and removal of CRA are the main methods of diagnosis and treatment respectively, which could reduce the risk of CRC incidence and mortality , 8. NeveBibliometrics, based on mathematics and statistics, is one way to analyze massive heterogeneous literature. So far, there has been no systematic global research trends in CRA, so it is necessary to investigate the entire position of CRA study to help scholars in tracking research development. The present research problem is that the diagnosis and treatment of CRA are in a period of quick transformation; however, there is a research gap in the lack of scientific analysis to sum up this trend. In case of a scientific study is conducted by bibliometrics, it will promote scholars’ comprehending of the CRA research fields and increase the efficiency of scientific research , 15. Hen22.1The Web of Science Core Collection (WoSCC) was selected to conduct a bibliometric analysis for the following reasons (1): WoSCC is the most authoritative, comprehensive, and widely used global database; (2) WoSCC provided the detailed literature information needed for software including CiteSpace, VOSviewer, and Biblioshiny; (3) Our choice of WoSCC was also based on previous studies and researches of Chaomei Chen, the developer of CiteSpace –18. Ther2.2http://bibliometric.com/) were employed to construct visualized maps of scientific literature.Two researchers (Xue Li and Xueqian Wang) independently screened the abstracts individually and reached a consensus on the qualifying papers. Data including the titles, countries/regions, institutions, journals, authors, and keywords was subsequently exported and saved as TXT. format. CiteSpace software 5.7.R3 , VOSviewer software 1.6.18 , Biblioshiny software, and the Online Analysis Platform of Literature Metrology (2.3All publication characteristics were well recorded and described. We got access to the impact factors (IF) of the relevant journals by the current edition of JCR , which is a basic criterion for the assessment of academic influences. The H-index acquired from WoSCC has been widely accepted for evaluating the scientific contribution, which is defined as the number of papers with citation number ≥h (the ranking position where the number of publications is greater than the number of citations). The number of annual publications and growth trends were analyzed by the Online Analysis Platform of Literature Metrology and Microsoft Excel.CiteSpace V5.8 R3 was mainly employed to create citation analysis mapping, co-citation analysis mapping, co-authorship analysis mapping, citation bursts mapping, journal dual-map, and keyword timeline mapping, most of which consisted of nodes and links, with different meanings in different analysis methods. In citation/co-citation/co-authorship analysis, the nodes represented an item, and the size represented frequency. Moreover, the line between the two nodes represented the relationship between the research items; darker color and thicker line represented the greater cooperation intensity between nodes. The centrality was an index, which could reflect the significance of nodes in the cooperation networks. Nodes with a centrality value of more than 0.1 occupied the pivotal locations connecting nodes, and were regarded as central nodes displayed in purple rings. Bursts detection could reflect emerging academic trends and new topics, predicted frontier research directions, and revealed potential hotspots in a field; the blue line was timeline, whereas citation bursts detection was shown as a red segment on the blue timeline, which indicated the start year, end year, and duration of the bursts. Z-score and F-score were used to re-adjust or standardize the citation data and could be used to identify major citation paths in the dual-map. The details on CiteSpace settings were as follows: time span(2002-2022), years slices (1 or 3), pruning (Minimum Spanning Tree and Pruning Sliced Networks), and selection criteria (Top N=50). Other parameters were set to the default settings.VOSviewer 1.6.18 was mainly conducted keyword cluster analysis in this study. The nodes and lines in the VOSviewer maps stood for the weights and associations of the study objectives, where the scientific mapping generated by the VOSviewer automatically groups the nodes into different colors by clusters. The settings of the VOSviewer were as follows: Created a map based on bibliographic data (WOS files), Type of analysis (co-occurrence), Unit of analysis (keywords), Chose threshold .Biblioshiny software, bibliometrix package in R version 4.3.0 was performed to visualize a three-filed plot to show the relationship between authors, institutes, countries, and keywords. In addition, Biblioshiny software was also conducted a thematic map to show the classification based on keywords.3A total of 4,413 publications were extracted, and 2,268 publications were finally confirmed, including 2,193(97%) original articles and 75(3%) reviews. The total number of citations for the retrieved articles was 87,331, and the mean citations per article was 35. The H-index was 115. The volume of publications related to CRA in the past 20 years was shown in 3.1A total of 63 countries/regions performed research in this field. CiteSpace software was conducted to analyze the research of each country, and the top 10 most productive countries/regions were shown in 3.2The results of the collaborative relationship between different institutions showed 582 nodes and 643 links Table 2.A three-filed plot that showed the relationship between institutions, authors, and keywords was displayed in 3.3Cancer Epidemiology Biomarkers & Prevention (n=107) ranked first, followed by International Journal of Cancer(n=59), Cancer Prevention Research(n=54), Gastrointestinal Endoscopy(n=50); And six had an Impact Factor(IF) of more than five. Among the top 10 most productive journals, Gut had the highest IF of 23.06. In addition, the co-citation analysis of journals was presented as a network map with 792 nodes and 7,909 links (Gastroenterology(n=1474), followed by The New England Journal of Medicine, and Gut  Table 4;The dual-map overlay could well show the distribution of journals and the relationship between journals and cited journals (the color path represented the cited relationship). 3.4In most cases, numerous researchers are needed to cooperate on a study, and their contributions are described as a ranking of authors. We could assess the key authors and their collaboration in a research field by analyzing the characteristics of authors’ cooperative networks through CiteSpace. In co-authorship analysis, results included 742 nodes and 1838 links Table 5.3.5Keywords reflected the core of the article, which could be used to analyze the frontiers of knowledge related to the research field. 6,483 keywords were extracted by VOSviewer. As shown in Timeline view reflected the time of a topic in this field and showed this field’s evolutionary trajectory  and co-cited journals (90%). Therefore, we considered that high-quality journals have maintained close contact with the CRA research field. Besides, in recent years, more and more journals have shown great interest in CRA-related papers, which also indicated the vigorous development in this research field  in 2005, and its corresponding author was Bresalier RS from University of Texas M.D. Anderson Cancer Center. This study explored cardiovascular risk of a chemoprevention agent of CRA, rofecoxib. In this randomized, placebo-controlled, double-blind trial, Bresalier RS et al. found that among patients with a history of CRA, the use of rofecoxib, a selective COX-2 inhibitor, was associated with an increased cardiovascular risk, including myocardial infarctions and ischemic cerebrovascular events, and the increased relative risk of thrombotic events was first observed after approximately 18 months of treatment  by bibliometric methods. The USA published the most publications and the highest H-index, Australia cooperated extensively with other countries, while China performed well and developed rapidly in recent years. The USA had most outstanding institutions and scholars in this field. Updates on the latest research or advances can be found in The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.XW and HL conceived the study and supervised the manuscript. XL and WZ drafted the manuscript, and prepared the figures and tables. XL and XW extracted all data and performed the bibliometric analyses. SY, QM, CZ, and RC revised the manuscript. All authors contributed to the article and approved the submitted version.


The COVID-19 pandemic has impacted children and adolescents’ physical activity (PA), sleeping patterns, and psychological and behavioral health. Yet, little is known about the differences between those in countries with various economic statuses.Articles published from database inception through 16 March 2022 were retrieved using CINAHL Complete, Cochrane Library, EMBASE, Medline, PubMed, and PsycINFO. High-quality studies that reported the number of participants with parameters associated with PA, sleeping patterns, and psychological and behavioral problems in young people aged under 18 years during the pandemic were included. We referenced the Canadian 24-Hour Movement Guidelines for PA and sleep duration to provide the event rate for young people who were not compliant with the guidelines. The event rate of young people who had decreased sleep quality and experienced psychological and behavioral problems were also investigated. A subgroup analysis was conducted to identify the differences in those in countries with diverse economic statuses. Funnel plot analysis and Egger's test were also conducted to identify any risk of publication bias.I2 = 96.62) and 43%  of young people did not meet the PA and sleep duration recommendation guidelines. In addition, 31%  of young people had decreased their sleep quality. Yet, no significant difference was found across countries with different economic statuses. However, the event rates of participants with psychological and behavioral problems were 32%  and 19% , respectively. In addition, the rate of psychological problems was more severe in those who live in lower middle-income countries (p < 0.001), while the rate of behavioral problems was more severe in those who live in high-income countries (p = 0.001).A total of 66 studies with 1,371,168 participants aged between 0 and 18 years, involving 27 countries, were included. During the pandemic, we identified that 41% (95% CI: 39%, 43%; During the pandemic, the discouragement of PA, poor sleep quality, and high risk of psychological and behavioral problems are concerning. A large number of young people did not comply with the recommendation guidelines. Timely implementation of recovery plans is critical to address the adverse effects on young people.https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=309209, identifier CRD42022309209. The emeThere are a growing number of studies examining the impact of the pandemic on physical activity (PA) and mental health among children and adolescents. A scoping review reported that a reduction in PA was reported in 57 (out of 74) studies in children and adolescents during the pandemic . A decreSeveral studies investigated the changes in PA and psychological health during the pandemic , 12–15. We also noticed that health inequities between different countries have undermined the efforts to bring the pandemic under control, including therapeutics, diagnostics, and distribution of vaccines. Historically, the infection and mortality rates were high among the most disadvantaged communities during the health crisis . A regreThis meta-analysis aimed to identify the event rate of children and adolescents who were not meeting the Canadian 24-Hour Movement Guidelines in PA and sleep duration, as well as the changes in PA levels, sleeping patterns, and psychological and behavioral problems in countries with different economic statuses during the pandemic. Alike to distinctions in infection rate and socioeconomic status, we hypothesized that there would be differences in all the outcomes across countries with different economic statuses. Particularly, the event rate of children and adolescents who were unable to meet the Canadian 24-Hour Movement Guidelines in PA and sleep duration were high during the pandemic. We also hypothesized that the event rates of decreased PA, sleep duration, and poor sleep quality were different among countries with different economic statuses and the event rates of psychological and behavioral problems during the pandemic were different among countries with different economic statuses.2.2.1.This meta-analysis adhered to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines. The protocol of this meta-analysis was published in the PROSPERO database (registration number: CRD42022309209). We systematically searched on CINAHL Complete, Cochrane Library, EMBASE, Medline, PubMed, and PsycINFO from database inception to 16 March 2022 without language restrictions for studies with quantitative data involving level of PA, sleeping patterns, and psychological and behavioral problems in children and adolescents (age ≤18 years) during the pandemic. For non-English articles, “Google Translate” was used, followed by a consultation of professional translations by native speakers. To ensure minimal missing data, we manually searched the reference list of all relevant studies. The search history is available in Studies that reported the number of participants with parameters associated with PA, sleeping patterns, and psychological and behavioral problems in young people aged under 18 years during the pandemic were included in this meta-analysis. Studies that involved participants who were not representable for the general young people population, such as studies that exclusively involved participants with pre-existing physiological or psychological health problems or student-athletes, were excluded. Abstracts, editorial comments, and unpublished studies were also excluded.2.2.The quality of the included articles was assessed by two independent reviewers with reference to the following six items from the Downs and Black assessment tool adopted by the literature –29: (1) 2.3.With reference to the inclusion and exclusion criteria, the titles and abstracts for potential studies were screened by two independent reviewers, and the full texts of the remaining articles were evaluated. Disagreements were resolved by a third reviewer. The relevant data were extracted in the included studies by the same reviewers using a standardized data retrieval sheet. The number of participants was extracted and separated into two groups based on their responses to the level of PA, sleeping patterns, and psychological and behavioral problems during the pandemic.PA level: We followed the Canadian 24-Hour Movement Guidelines to separate participants into either a “meeting recommendation” group or “not meeting recommendation” group if appropriate . The guiSleeping pattern: For sleep duration, we followed the Canadian 24-Hour Movement Guidelines . The guiPsychological and behavioral problems: We separated participants who were at risk or had an increase of psychological or behavioral problems into one group and who were at no risk or had a decrease of or no change in psychological or behavioral problems into another group. The number of participants with psychological or behavioral problems was compared to the number of those without psychological or behavioral problems.In addition, confounding variables including countries’ economic status were assessed by a subgroup analysis. With reference to World Bank (2020), countries’ economic statuses were separated into four income groups: low-, lower middle-, upper middle-, and high-income countries . The claI2, and a random effect model was selected if heterogeneity was 50% or above. The subgroup analysis was performed and compared by countries’ income levels. Funnel plot analysis was implemented to assess the risk of publication bias. Egger's test was conducted to identify any risk of publication bias, with p ≤ 0.05 considered a potential publication bias. If publication bias was indicated, the trim-and-fill method was used to recompute the combined effect. A sensitivity analysis was implemented to assess the robustness of all outcomes.Comprehensive Meta-Analysis version 3.0  was used for statistical analysis. The targeted outcomes were presented as event rates with 95% confidence intervals (CIs) and presented in forest plots. Heterogeneity was reported as 3.3.1.A total of 12,731 studies were retrieved from the databases. After excluding 5,415 duplicated studies, another 7,027 studies were excluded by screening the titles and abstracts. Furthermore, 227 studies were removed after assessing the full tests based on the inclusion and exclusion criteria. Finally, a total of 66 studies were included in our meta-analysis , 32–94. 3.2.A total of 1,371,168 participants aged between 0 and 18 years, involving 27 countries, were included, most of which had the data collection period conducted in 2020. The characteristics of the included studies are described in 3.3.I2 > 90% and a moderate risk of bias. The Downs and Black assessment of all included studies and the GRADE score of all outcomes are presented in The overall quality grading of included studies was moderate to high based on the six items in the Downs and Black assessment tool. Most studies failed to score on item 4, which was related to failure to attempt to adjust for confounding. Some studies did not use validated questionnaires for data collection, therefore failed to score on item 5. As for the certainty of outcomes, all outcomes were graded as moderate, which was mostly due to high inconsistency with 3.4.I2 = 96.62) and 43% , respectively. In the subgroup analysis, we could only retrieve data for high- and upper middle-income countries. The event rates of participants not meeting PA recommendation guidelines were 40%  for high-income countries and 44%  for upper middle-income countries. Likewise, the event rates of participants not meeting the sleep duration recommendation guidelines were 53%  for high-income countries and 31%  for upper middle-income countries. No significant difference was observed between the income level countries in meeting the recommendation guidelines of PA level (p = 0.063) and sleep duration (p = 0.172).The event rates of participants not meeting the recommendation guidelines of PA level and sleep duration during the pandemic are presented in forest plots in 3.5.I2 = 99.64) for participants with decreased PA, 34%  for participants with changes in sleep duration, and 31%  for participants with poorer sleep quality. We were able to conduct the subgroup analysis for high-, upper middle-, and lower middle-income countries for the pooled PA level. The event rates of participants with decreased PA levels were 60%  for high-income countries, 63%  for upper middle-income countries, and 79%  for lower middle-income countries. No significant difference was seen among the three income levels (p = 0.769). As for the pooled sleep duration and sleep quality, the event rate of participants with changes in sleep duration was 40%  for high-income countries and 25%  for upper middle-income countries, and that of participants with poorer sleep quality was 37%  for high-income countries and 31%  for upper middle-income countries. No significant difference was seen among income level countries in sleep duration (p = 0.059) and sleep quality (p = 0.397).The pooled event rates of participants with decreased PA, with no participation in PA, or who are not meeting the PA recommendation guidelines and with changes in sleep duration and sleep quality during the pandemic are presented in forest plots in 3.6.I2 = 99.85) and 19% , respectively. In the subgroup analysis, the event rates of participants with psychological problems were 45%  for high-income countries, 24%  for upper middle-income countries, and 70%  for lower middle-income countries. We observed a significant difference among all three income levels (p < 0.001), between high-income and upper middle-income countries (p < 0.001), and between upper middle- and lower middle-income countries (p = 0.001). However, there was no significant difference between high-income and lower middle-income countries (p = 0.087). For behavioral problems, the event rates of participants with behavioral problems were 27%  for high-income countries and 9%  for upper middle-income countries. Similarly, we identified a significant difference between both income level countries (p = 0.001).The event rates of participants with psychological and behavioral problems during the pandemic are presented in a forest plot , S5. The3.7.p = 0.008), changes in sleep duration (p = 0.001), and psychological problems during the pandemic (p < 0.001). However, other outcomes resided in symmetric funnel plots shape and results of Egger's test showed no significant publication bias . After adjustment using the trim-and-fill method, the event rates were 61%  instead of 61%  for participants with decreased PA level and 27%  instead of 32%  for participants with psychological problems. However, the event rate for changes in sleep duration remained unchanged after the trim-and-fill method.Publication bias was evaluated by funnel plot and Egger's test. The funnel plots of all outcomes are presented in 3.8.The robustness of our results was examined by the leave-out-one sensitivity analysis. Our results were not modified with the stepwise exclusion of each study. More details are displayed in Supplementary Table S14.The current systematic review and meta-analysis explored the effects of the pandemic on PA, sleep duration, and sleep quality, as well as psychological and behavioral problems among children and adolescents in countries with different economic statuses. We have identified the event rate of children and adolescents who were not compliant with the Canadian 24-Hour Movement Guidelines in PA and sleep duration in countries during the pandemic. We have also provided the event rate of children and adolescents with discouraging PA performance including decreased PA, no participation in PA, or not meeting the recommendation guidelines, changes in sleeping patterns, and psychological and behavioral problems in countries with different economic statuses during the pandemic. To the best of our knowledge, this is the first meta-analysis that objectively examines the effect of the pandemic on these parameters for young people living in different countries with different economic statuses.I2 = 96.62) of children and adolescents who did not meet the PA recommendation guidelines during the pandemic. However, no significant difference was found among countries with high-, upper middle-, and lower middle-income groups for the pooled PA (p = 0.769) and compliance with PA recommendation guidelines (p = 0.063).Our results supported the hypothesis that the event rates of children and adolescents who were unable to meet the Canadian 24-Hour Movement Guidelines in PA and sleep duration were high during the pandemic. However, although we hypothesized there would be differences in those across countries with different economic statuses, our results had shown otherwise. Decreased PA during the pandemic and failure to comply with the PA recommendation guidelines were reported during the pandemic , 95. ThiI2 = 99.42) of children and adolescents did not meet the guidelines for sleep duration, and 34%  of them had changed, either increased or decreased, their sleep duration during the pandemic. However, there was no significant difference in sleep duration among countries with different economic statuses (p = 0.432). These findings were in line with a previous systematic review that reported sleep duration did not change in 43% of participants on weekdays and in 46.2% on weekends (I2 = 99.66). Similarly, there was no significant difference among the countries with different incomes (p = 0.307). The results supported that the decrease in PA, sleep duration, and sleep quality in young people is not associated with the incomes of the countries that they are living in. Contrariwise, our results may be biased because there were scanty studies included from lower middle-income countries, and no studies could be found from low-income countries.In addition, 43% . Our results also partially supported the hypothesis that the event rates of psychological and behavioral problems were different among countries with different economic statuses (p < 0.001). However, there was no significant difference in the event rate between high-income and lower middle-income countries for psychological problems. Although the inconsistency might be due to the limited number of studies for lower middle-income countries, the event rate for children and adolescents in middle lower-income countries remains the highest at 70%  among the event rates of those in high- and upper middle-income countries. As a result, this meta-analysis provides evidence that the socioeconomic context can influence psychological problems among young people and the mental health needs of children and adolescents were high, especially in middle lower-income countries  of children and adolescents had behavioral problems during the pandemic. Although most countries applied restrictive measures to control the spread of the virus, we found that the influence on behavioral problems among young people in high- and upper middle-income countries differ significantly (p = 0.001). Household income is an important part of the family socioeconomic status that is associated with behavior problems of young people (I2 = 99.75) than those among young people in upper middle-income countries with 9% . This may result from the influence of this pandemic and its measures on parents and young people. The diversity of infection rates and different protective measures may contribute more impacts on behavioral problems among young people in high-income countries than in lower-income countries. However, a recent study reported that an increase in income is unrelated to behavioral problems in children and adolescents during the pandemic . This is expected as the outcome measures used to measure PA, sleeping patterns, and psychological and behavioral problems were diversified. We attempted to control the influences of high heterogenicity by using a random effect model and assessed the publication bias with funnel plots and Egger's test. Moreover, potential publication bias is a factor that should be taken seriously, as it could easily exaggerate the effects when none exists. We have adjusted the results with the trim-and-fill method to lessen the publication bias, but the potential influence of publication bias should, nevertheless, be cautious when interpreting the results, especially for the event rate for changes in sleep duration.The studies included in this meta-analysis only represented high-, upper middle-, and lower middle-income countries. No study reported our targeted outcomes in low-income countries. The impacts of poverty and inequality induced by the pandemic on the PA, sleeping patterns, psychological wellbeings, and behavioral changes in children and adolescents in low-income countries are unknown. This could be attributed to the limited data retrieved in the included studies that met our inclusion criteria. In addition, although we searched six scientific databases with no language restriction, we expected that the findings may cover nearly all relevant published articles. There was an inevitable possibility that additional relevant articles might have been missed due to the restriction of our search to these six databases. However, we minimized the possibility of missing data by manually searching the reference lists of all relevant studies. Therefore, we believed that the number of studies missing from our meta-analysis was likely small and would have a limited impact on our results. Lastly, our outcomes showed high heterogenicity (6.The discouragement of PA during the pandemic has affected young people negatively. Changes in PA levels, sleep duration, poorer sleep quality, and psychological and behavioral problems were seen among young people in countries with different economic statuses. Moreover, 41% of the young population did not meet the recommendations for PA, and 43% of the young population did not meet the recommendations for sleep duration during the pandemic. In addition, the rate of psychological problems was more severe in those who live in lower middle-income countries, while the rate of behavioral problems was more severe in those who live in high-income countries. Also, studies on the changes in PA, sleep duration, sleep quality, and psychological and behavioral problems in lower middle- and low-income countries were scanty. Further studies are necessary to investigate the impacts of the pandemic on children and adolescents, especially in lower middle- and low-income countries.


Undifferentiated pleomorphic sarcoma (UPS) is a highly malignant soft tissue sarcoma with a poor prognosis and no clear effective clinical means for treatment, and there has been no significant progress in research within this field in recent years. This study aimed to investigate the epidemiology, etiology, clinical features, diagnostic modalities, various treatment modalities, and prognosis of retroperitoneal undifferentiated pleomorphic sarcoma and to contribute to the clinical management of this type of disease. In this study, we report a case of undifferentiated pleomorphic sarcoma with a primary origin in the retroperitoneum. Undifferentiated pleomorphic sarcoma occurring in the retroperitoneum is rarely reported.A 59-year-old man with abdominal distension and pain for 4 months presented to our hospital after the failure of conservative treatment. A 9.6 cm by 7.4 cm mass in the left retroperitoneum was found on a CT scan of the whole abdomen with three degrees of enhancement. After surgical treatment, the tumor and the left kidney were completely removed, and pathological examination and genetic sequencing showed an apparent undifferentiated pleomorphic sarcoma. The patient subsequently declined follow-up treatment and is currently alive and well.At the current level of clinical technology, the treatment of undifferentiated pleomorphic sarcoma is still in the exploratory stage, and the scarcity of clinical cases of this disease may have hindered the acquisition of clinical trials and research data for this disease. At present, the first choice of treatment for undifferentiated pleomorphic sarcoma is still radical resection. In the existing clinical studies, there are no strong data to support the effect of preoperative neoadjuvant chemoradiotherapy and adjuvant chemoradiotherapy in clinical practice. Similar to other diseases, the use of radiotherapy and chemotherapy before and after surgery may be a potential treatment for this disease in the future. Targeted therapy for this disease still needs further exploration, and we need more reports on related diseases to promote future treatment and research on this disease. Undifferentiated pleomorphic sarcoma (UPS), a malignant soft tissue tumor of mesenchymal origin, occurs in middle-aged and elderly people, more often in men than in women. The disease occurs mainly in the extremities and only rarely in the retroperitoneum , 2, and The patient, 59 years old, had pain in the left upper abdomen after eating before April and lost 15 kg in the past 2 months, with no relief after taking oral gastric medication. In order to seek further treatment, he consulted our outpatient clinic.A mass-like, dense soft tissue shadow was seen in the left upper abdomen, measuring approximately 9.6 cm by 7.4 cm, with a CT value of about 41 HU. On enhancement scan, the mass was inconsistent enhancement and poorly demarcated from the tail of the pancreas, the left adrenal gland, and the left kidney, and the pancreatic duct was not dilated. Intraoperatively, the patient's mass was found to be located on the dorsal side of the pancreas, adjacent to the abdominal aorta and to the right of the splenic hilum, with unclear demarcation from the left kidney, as shown in The patient's preoperative imaging tended to indicate malignancy, and the tumor had certain boundaries with the kidney, but the anatomical location of the tumor was complicated, and the physician suggested a puncture biopsy. However, the family refused, considering factors such as possible kidney injury and bleeding, so this preoperative procedure was not performed. The general appearance of the tumor was observed intraoperatively, and it was found to be soft and irregular in shape, adhering more closely to the renal vessels, which made separation difficult. To achieve a complete resection of the tumor and to reduce the possibility of tumor recurrence after surgery, it was therefore decided to remove the ipsilateral kidney intraoperatively. The patient was preoperatively diagnosed with a retroperitoneal mass and underwent a combined left nephrectomy, left adrenalectomy, and mass removal. The tumor was solid, bloody yellowish, and the visible perirenal fat capsule was largely visible as shown in The pathological findings were undifferentiated pleomorphic sarcoma, not excluding dedifferentiated liposarcoma, as jointly diagnosed by two senior pathologists at our hospital. The left kidney and retroperitoneal mass had a total weight of 816.5 g. The volume of the mass was 12.0 cm by 9.5 cm by 6.5 cm, the surface was slightly stringy, the cut surface was grayish white, firm, and hard, and two tough nodules, both 0.3 cm in diameter, were palpated in the adipose tissue around the mass. The renal pelvis and ureteral mucosa were not abnormal. No lymph nodes were seen in the renal hilum. The adrenal gland was 4.5 cm by 1.0 cm by 0.8 cm in size, golden yellow in color, firm, and tough in texture. The tumor volume was 12 cm by 9.5 cm by 6.5 cm, and the nuclear schizophrenia was about 10 nuclei/10 HPF. Local tumors necrosis, local invasion of the adrenal parenchyma, and renal peritoneal adhesions did not invade the renal parenchymal vasculature and nerves, tumor infiltration of the ureter and blood vessels were visible, and tumor infiltration was visible at the end of the cut edge. A metastasis was visible in the lymph nodes around the tumor (3/3), as shown in Immunohistochemistry: CD34(−), Desmin(−), Ki-67(+40%), SMA, S-100(scattered +), CD117(−), Dog-1(−), HMB45(−). TFE3(+), CK-pan(−), H-caldesmon(−), β-catenin(membrane +). STAT6(−), CK-pan(−), Vimentin(+), CK5/6(−), WT-1(weak+), Calretinin(−), D2-40(−).Diagnosis: retroperitoneal (including left kidney) malignant tumor of mesenchymal origin consistent with undifferentiated pleomorphic sarcoma; it was recommended that genetic testing was attempted to further exclude dedifferentiated liposarcoma, as shown in The tumor mutational burden (TMB) was 2.922.92 Muts/Mb (ModerateModerate), microsatellite instability (MSI) was detected as microsatellite stable (MSS), positive gene (1): TP53 p.I332M; negative gene (1): PTEN copy number was decreased in tumor tissues. The HLA-I-like molecular genotype was detected as HLA-I ; heterozygous secondary variants were detected as PTEN copy number reduction only; the evidence level was C, which may be sensitive to platinum-based chemotherapy modalities; and no hereditary tumor-related genetic variants were detected. The genetic diagnosis also excluded the possibility of dedifferentiated liposarcoma.The patient recovered well after surgery with only transient renal insufficiency. After consultation with the Department of Nephrology and the Department of Urology I, relevant symptomatic treatment was performed, and the patient was discharged 7 days after the surgical intervention, with the renal function returning to normal at the time of discharge. After the postoperative joint consultation with several specialists, the combination of the targeted therapy drug anlotinib and the immunotherapy drug pablizumab was recommended. The patient was informed about his condition but did not indicate his attitude toward the next treatment. However, according to the current follow-up results, the patient is currently in good health with no significant abnormalities, and we are continuing to follow up with him.p < 0.01) (Soft tissue sarcomas (STSs) are rare malignant tumors of mesenchymal origin that account for approximately 1% of adult malignancies , with a  < 0.01) , and mor < 0.01) , 19. App < 0.01) , 21.Patients with undifferentiated pleomorphic sarcoma usually have no obvious specific symptoms, and clinical symptoms are usually related to the location and size of the tumor.Patients typically present with clinical indications that are signs of tumor compression. In this case, the patient presented with gastritis because the mass was located in the posterior peritoneum and pressed forward on the stomach, and some patients may report to the clinic with respiratory symptoms due to tumor metastasis in the lungs. In similar cases and this case report, common symptoms included abdominal pain (lumbago) in five cases 83.3%) , 6, 8, 93.3% , 6,Radiological details about UPS are scarce in the literature because of how uncommon it is. Imaging of this disease is usually non-specific, and exclusionary diagnostic methods are mostly used . The majDue to the rarity of UPS, standard management guidelines have not yet been established. Despite a multimodal approach including surgery, radiotherapy, and chemotherapy, targeted therapy is the predominant therapy. In addition, surgical resection is the leading treatment for performing gross tumor resection (GTR), and the achievement of negative surgical margins due to the extension of the resection is one of the most frequently reported predictors of recurrence and survival. Surgical treatment has removed the gross tumor cells, but potentially smaller lesions or tumor cells in circulating cells are still alive, and a combination of other treatments is needed to effectively control tumor recurrence.Regarding the effect of radiation therapy, most researchers believe that local radiotherapy is more effective in tumors that have not infiltrated. Especially in undifferentiated pleomorphic sarcomas located in the extremities and superficial occurrences , radiothAs for the timing of radiation therapy application, some studies have shown that radiation therapy in the perioperative period, preoperatively, can prolong the patient's survival time . With reFor the treatment of deep tumors in several parenchymal organs and RA-UPS, chemotherapy performs better compared to radiation therapy . The effp < 0.001) and AXL overexpression (p = 0.015) were associated with reduced disease-specific survival (DSS) (Undifferentiated pleomorphic sarcoma (UPS) is an aggressive adult soft tissue sarcoma characterized by low tumor mutational burden (TMB) and high copy number alterations . In receal (DSS) . In addial (DSS) , anti-hual (DSS) , and varThe survival rate of this condition is related to the site of disease onset, with a 5-year survival rate of more than 70% for tumors in the trunk and extremities and less than 50% for tumors in the head and neck , which mIn the patient described here, the tumor adhered to the renal hilum and adhered more tightly to the renal vessels, making separation more difficult and showing obvious infiltration. There were some surrounding lymph node metastases, but no distant metastases for the time being. The tumor, left kidney, and left adrenal gland were completely removed during surgery. After follow-up, the patient is in good mental and physical condition but did not express a clear opinion on the future treatment.In conclusion, retroperitoneal undifferentiated pleomorphic sarcoma is rare and difficult to diagnose. There are no obvious specific signs in the early clinical stage, and most patients come to the hospital with non-specific symptoms such as tumor compression. For this disease, we should classify and summarize the imaging manifestations and actively perform tumor puncture biopsy if the benign and malignant tumors cannot be clearly determined. In accordance with the pathological results of tumor puncture, relevant radiotherapy and chemotherapy should be performed during the perioperative period to reduce the risk of surgery and postoperative recurrence. Currently, there are no clear guidelines for the treatment of this disease, and more in-depth research is needed regarding chemotherapy and comprehensive treatment.


This study investigated the influence of parenting and grandparenting caregiving styles on fundamental motor skills (FMS) of preschool children.A total of 1,326 preschool children  aged 4–6 years were recruited from the kindergartens of Jinhua City, China. Locomotor skills (LM), ball skills (BS), and total fundamental movement skills (TS) of children were assessed by the Test of Gross Motor Development-3rd edition (TGMD-3).p < 0.001) increased with age (irrespective of sex or caregiving style). For the sex comparisons, BS scores of boys were significantly higher than girls (p < 0.001), while LM and TS scores were not different between boys and girls. For the caregiving style comparison, parenting is superior to grandparenting in developing of children's FMS. Parenting boys of 4-, 5-, and 6-years old showed better BS compared to age-matched parenting girls, whereas boys of 5-years old in grandparenting only showed better BS compared to same-age grandparenting girls (p < 0.05). Furthermore, parenting boys of 6-years reported higher LM (p < 0.01), BS (p < 0.001), and TS (p < 0.001) scores compared to grandparenting boys, but girls' FMS at all ages were not significantly different between the caregiving styles.There were 978 children in parenting and 348 children in grandparenting caregiving styles. The LM, BS and TS scores of children were considerably (Parenting caregiving style is positively associated with proper development of FMS among children. Girl children with poor FMS in grandparenting may need a special care or intervention programs to promote their FMS. Fundamental movement or motor skills (FMS) are defined as basic learning movement patterns in preschool children. Preschool age is a crucial period for developing and practicing of FMS that are essential for more complex physical and sporting activities . The itePrevious studies have shown that family environment, particularly parenting, or caregiving style is involved in improving of physical activity, academic performance and motor skills among children , 11, 12.According to the social-ecological model and theoretical frameworks, parenting (by parents or grandparents) plays a fundamental role in shaping their children's behavior and personality , 26. ParAlthough parenting and grandparenting is advantageous on various outcomes of children, the child caring values and benefits of caregiving styles are contradictory between parents and grandparents . The outIn this study, we aimed to monitor the FMS development in kindergarten children (aged 4–6 year), and compare the influence of parenting and grandparenting caregiving styles on FMS competence. We then examined the age-specific and sex-specific changes in FMS competence among children with both caregiving styles. Since authoritative parenting is favor to promote several outcomes in children , 41, we This cross-sectional study was conducted in Jinhua, a city with ~1 M population in Zhejiang Province of Eastern China. A total of 1,343 healthy children  from two large-scale kindergartens  were recruited by a random cluster sampling method. The study was conducted from March to June 2021. During the study period, 17 children were dropped due to incomplete assessment scores, resulting 1,326 children as the final sample size. The basic characteristics of children, including age, height, weight, body mass index (BMI) and sex were recorded at their respective kindergartens. There were a total of 698 boys and 628 girls. The caregiving style of each child either parenting or grandparenting was recorded with the help of their teacher or caregiver. Other variables, like family economy status and sex of caregivers were not analyzed. Children in a family with a combination of caregivers (parents and grandparents) were not enrolled, and the ideal parenting type in this study was “authoritative.”The details of this study were provided with the Chinese version of the written informed consent form and also explained verbally to the directors of the kindergarten, teachers, parents, or grandparents, and students before their voluntary participation. The study design and all assessment procedures were reviewed and approved by the Institutional Ethical Committee of Zhejiang Normal University, and the approval number is ZSDR2019013.2]. These assessments were performed in the empty hall of each kindergarten during the school hours. Meanwhile, demographic data (age and gender) of children provided by their teachers were recorded for the analysis. Caregivers provided the caregiving details of their children. Based on the caregiving type, we categorized the children into two groups namely, grandparenting and parenting. In “grandparenting caregiving style” grandparents are the main caregivers, while in “parenting caregiving style” parents are the main caregivers. The main caregiver means the person, who looks after the child's daily activities at least from 6 months prior to the study. Taking care of children by relatives, guardians or babysitters were excluded from our study.The basic characteristics, including bodyweight (kg) and height (m) of children were measured using a weight and height scale to the nearest 0.1 kg and 0.1 cm, respectively. Then BMI was calculated using the weight and height of children at respective ages [weight (kg)/height (m)rd edition [TGMD-3, . For the purpose of analysis, children were grouped on the basis of sex (two groups), caregiving styles (two groups), and age (three groups). For the age comparisons, all children were arbitrarily categorized into three age groups, including 4, 5, and 6 years. One-way ANOVA was performed (separately) among the FMS scores and caregiving styles, age, and sex to explore the influence of each of these three variables. In order to examine any significant difference across caregiving styles according to age groups and sex classes, across age groups according to caregiving styles and sex, and across sex classes according to caregiving styles and age groups, one-way ANOVA was subsequently performed. The results of the one-way ANOVA displayed through the F-values and level of significance was set at p < 0.05.Obtained data were analyzed using the IBM SPSS Statistics . Descriptive statistics for participant characteristics were displayed as Means ± SD or In this study, a total of 1,326 kindergarten children aged 4, 5, and 6 years with parenting and grandparenting caregiving styles were participated. There were 522 boys and 456 girls in parenting, and 176 boys and 172 girls in grandparenting caregiving style. The average height of boys and girls in parenting and grandparenting caregiving styles was not different . Similarp < 0.001). For the gender comparison, the scores of LM and TS were not significantly different between boys and girls, whereas the BS scores were significantly higher in boys compared with girls (p < 0.001). For caregiving styles, children with parenting showed superior FMS scores  than that of children with grandparenting caregiving style  than girls at the same age (p < 0.05) compared to girls at the same age, which is different from the boys in parenting , BS (p < 0.001), and TS (p < 0.001) scores compared with that of same age of boys in grandparenting  could influence the fundamental motor skills of preschool age children. We studied the changes in FMS among children (4–6 years) from Zhejiang province of China, and the changes were compared with their age, sex, and caregiving styles. Our findings showed that caregiving styles influence preschool children's FMS, and this influence is associated with age (4–6 years) and sex of children. Parenting caregiving style significantly improved FMS of boys at 6-year, while FMS of girls  remained unchanged with parenting and grandparenting caregiving styles. To be specific, the ball skills of boys at all ages  were better than girls of respective ages with parenting caregiving style. Our findings revealed that authoritative parenting type is important to promote various motor skills of preschool children. However, the influence of parental sex, and the role of other parenting types  on children's FMS competence is yet to be elucidated.Increasing age is the most consistent key variable of all subsets of FMS among children . In our Exploring of sex-specific responses of FMS among children with parenting and grandparenting is an important perspective to understand whether caregiving style affects FMS differently in boys and girls. In this context, we found that boys scored higher than girls in BS but not in LM and TS. We then identified that boys of all ages , particularly in parenting caregiving style, possess better ball skills than girls. Similar to our findings, a study from Australia reported that the boys had better object-control skills than the girls . Other sAccording to Clark , it is aThere are several reasons to explain the differences in children's FMS scores between parenting and grandparenting caregiving styles. The selected parenting type in this study was authoritative, in which parents maintain a positive and warmth relationship with their child, and child tend to gain confidence, self-efficacy, and positive emotions , 35. TheDue to the rapid migration of young parents from rural to urban areas in China (for better career or business opportunities), taking care of their child is a major concern in many families , 70. As Preschool children participated in this study are Chinese, and our findings can be generalized to children in the Chinese society, where most caregivers are biological parents. Further studies are necessary to demonstrate the influence of similar caregiving styles on FMS of children from Western countries. The differences between biological parenting and non-biological parenting on motor skills can be studied in future to emphasize the importance of biological parenting. Our findings primarily addressed the influence of caregiving styles on children's FMS, however, the influence of other variables, including parental sex and household income on motor competence of children needs to be investigated. Furthermore, parenting type in this study was authoritative, and the influence of other parenting types, such as authoritative, permissive, and uninvolved on children's FMS is also need to be demonstrated. Finally, children in this study were from one caregiving style (parents or grandparents), and the effect of combination of two caregiving styles (both parents and grandparents) on children's FMS is also yet to be elucidated.Poor motor competence observed in girl preschoolers with grandparenting implies that some practical interventions are necessary to promote their motor skills. Based on our findings, it is encouraged to practice positive parenting, particularly authoritative type to build a strong bonding between child and parent and to promote FMS proficiency. Furthermore, young parents should strive to balance their career and family, ensuring that they offer adequate care, facilities and support for their children.Parenting caregiving style is strongly associated with proper development of FMS competence among kindergarten children. Improved FMS proficiency in children helps to enhance cognitive skills, academic performance, health-related outcomes and physical fitness. Therefore, parenting is highly encouraged for preschoolers, especially for girls, who reported poor motor skills with grandparenting caregiving style.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.The studies involving humans were approved by Institutional Ethical Committee of Zhejiang Normal University (ZSDR2019013). The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants' legal guardians/next of kin.JH, SZ, and WY: data collection. JH and SZ: data analysis and original draft preparation. YZ, HZ, and LL: data interpretation and validation. WY, MK, and QC: supervision, project administration, review, and editing and finalize the manuscript. WY: funding acquisition. All authors have read and approved the final version of the manuscript.


In this way, we assessed the potential risks that pharmaceutical excipients, generally considered safe, might pose to the aquatic environment. We investigated both their individual ecotoxicity and their interactions with tablet ingredients using concentration addition (CA) and independent action (IA) models to shed light on the often-overlooked ecotoxicological consequences of these substances. The CA model gave a more accurate prediction of toxicity and should be recommended for modeling the toxicity of combinations of drugs with different effects. A challenge when studying the ecotoxicological impact of some pharmaceutical excipients is their poor water solubility, which hinders the use of standard aquatic ecotoxicity testing techniques. Therefore, we used a modification of the Microtox® Basic Solid Phase protocol developed for poorly soluble substances. The results obtained suggest the high toxicity of some excipients, i.e., SLS and meglumine, and confirm the occurrence of interactions between APIs and excipients. Through this research, we hope to foster a better understanding of the ecological impact of pharmaceutical excipients, prompting the development of risk assessment strategies within the pharmaceutical industry.The ecotoxicological impact of pharmaceuticals has received considerable attention, primarily focusing on active pharmaceutical ingredients (APIs) while largely neglecting the potential hazards posed by pharmaceutical excipients. Therefore, we analyzed the ecotoxicity of 16 commonly used pharmaceutical excipients, as well as 26 API–excipient and excipient–excipient mixtures utilizing the Microtox Most research on pharmaceuticals in the environment concerns active pharmaceuticals ingredients (APIs); however, it should be remembered that, in order to produce a pharmaceutical product with the desired physicochemical properties, a number of auxiliary substances  have to be used, i.e., surfactants, lubricants, emulsifiers, and preservatives. Many of these substances are also used in foods and cosmetics. Considering the number of drugs taken and the fact that each pharmaceutical preparation contains, on average, from a few to a dozen or even more excipients, an assessment of the risks associated with the presence of these substances in the environment seems reasonable . CurrentFor example, in Sweden, for the 7600 pharmaceutical products available for sale, there are as many as 1300 different excipients . AccordiSome of the excipients, such as sugars, starch, cellulose, proteins, or glycerol, are generally considered safe for the environment. Other substances, such as preservatives, cause more concern due to their anti-microbial properties . Similar® test to evaluate ecotoxicity of various drug formulations  of 10 popular APIs . It. It2 nant tested . They she et al.  for its D. magna . Other a in rats . Howeverf silica .A. fischeri increased in the series crospovidone < povidone K25 < povidone K30, with EC50, 30 min values 49,855 mg/L < 1599 mg/L < 1130 mg/L, respectively  and are characterized by complexing properties.It is worth paying attention to the toxicity of three compounds in the povidone group—povidone K25, povidone K30, and crospovidone (type A) . These aectively . The lowThe compositions of the three pharmaceutical formulations of ARBs , studied in our previous work , were an50 values (as non-toxic), such as sorbitol, pregelatinized maize starch, magnesium stearate, crospovidone, and sodium stearyl fumarate, were not tested. In this study, the ecotoxicity of two-component excipient–excipient mixtures was investigated using excipients that showed interactions with APIs. The ecotoxicity of three-component mixtures (3× excipient or API + 2× excipient) was also analyzed. The ecotoxicological results for these mixtures are shown in Due to the large number of possible combinations, mixtures of compounds with very high EC50, 30 min values which were calculated using the CA and IA models together with the calculated MDR coefficients allowing to characterize the antagonistic, additive, or synergistic effects. In this study, five binary VAL mixtures with excipients, present in the Valtap (ZENTIVA A.S.) pharmaceutical formulation, were tested.The experimental ecotoxicity values for mixtures containing valsartan (VAL) are presented in 50, 30 min = 56.97 mg/L) lower than the predicted toxicity ; 122.3 mg/L (IA)). It is worth recalling that the EC50, 30 min values for the individual components of this mixture of VAL and colloidal anhydrous silica are 150.5 mg/L  are presented in In the case of LOS-K, four binary mixtures with various excipients were tested. The smaller number of mixtures than for VAL was due to the fact that the pharmaceutical formulation of Lozap (active ingredient: LOS-K) contained fewer excipients than, for example, the formulation of Valtap (active ingredient: VAL). Interestingly, according to the assumptions of the CA model, all OS-K mixtures showed an additive effect, i.e., no increase or decrease in the mixture toxicity compared to the expected value. This was probably due to the fact that LOS-K, as the only tested ARB, was used in the form of potassium salt. This form showed better solubility and lower hydrophobicity; hence, the second component of the mixture did not significantly change the toxicity or availability of LOS-K for bacteria.For the series of VAL and LOS-K mixtures, the values predicted using the IA model were significantly lower than the experimental values, suggesting the presence of antagonistic effects.50, 30 min values calculated using the CA and IA models together with the calculated MDR coefficients, allowing a characterization of the antagonistic, additive, or synergistic effects.The experimental ecotoxicity values for mixtures containing telmisartan (TEL) are presented in 50 values using this model were again significantly lower. As with VAL, TEL also exhibited an antagonistic effect when combined with povidone K25, possibly for the same reason, i.e., agglomeration that reduced the availability of TEL to bacteria. Both TEL and VAL have hydroxyl groups in their chemical structures that can interact with the carbonyl groups of povidone K25, facilitating aggregation; such interactions are known for povidone and polyphenols [50 value for the mixture of TEL with mannitol was surprising. While the EC50, 30 min values of the individual components were 77.31 mg/L  is a slightly toxic compound with an acidic pH of approximately 4. Meglumine predominated in the tested mixture (30% in the mixture) with a pH close to 11; hence, the pH of the mixture was alkaline, which caused cross-linking of povidone K25 and, consequently, its lower solubility. Thus, the contribution of povidone K25 to the final toxicity of the mixture was negligible [In mixtures containing meglumine , according to calculations using the CA model, no antagonistic/synergistic effects were observed. On the other hand, in the mixture of two excipients, meglumine + povidone K25, strong synergistic interactions were observed . This effect could be explained by the change in pH value of the mixture in relation to the pH value of the individual substances . Meglumigligible .A. fischeri, where the CA model was found to give a more accurate prediction of toxicity and should be recommended for modeling toxicity of a combination of drugs with different effects [A. fischeri, the molecular targets of the investigated drugs were unified, and their mechanisms of toxic action were similar, usually focused on the bacterial membrane; hence, a higher precision associated with the CA model was observed.In conclusion, for all tested ARB mixtures , the use of the CA model allowed calculating the toxicity of the mixtures with a greater accuracy, whereas the IA model significantly overstated or underestimated the predicted toxicity values . The sam effects . However effects . It is wIn continuation of our studies, the ecotoxicity of artificially composed multicomponent mixtures was tested for all ARBs to reflect their actual pharmaceutical formulation, i.e., a mixture of all excipients, and then the same mixture with the addition of APIs (ecotoxicity of the whole tablet) . The res® Acute Reagent, Reconstitution Solution and Solid Phase Test Diluent) used in ecotoxicological tests were purchased from Modern Water, Inc.  via the Polish distributor, Tigret LLC . Pharmaceutical excipients used in this study were obtained as a gift from Polpharma SA  . Pure ARAliivibrio fischeri (strain NRRL B-11177) was used to evaluate the acute toxicity of individual excipients, as well as the API–excipient and excipient–excipient mixtures . The modified Microtox® Basic Solid Phase Test protocol was applied, which was described in detail in our previous work [A. fischeri was measured after 5, 15, and 30 min of exposure of the bacterium to each sample and then compared with the light output of a control sample. The EC50 values, corresponding 95% confidence intervals, and confidence factors were estimated using the Microtox Omni 4.2. Software™.The bioluminescent marine bacterium mixtures . The inhous work ; a schemThe toxicity of the investigated mixtures was predicted using the concentration addition (CA) and independent action (IA) models and compared with experimental values . The preThe prediction of the combined effect based on the IA approach was modeled using the following formula:The composition of the mixtures corresponded to the composition declared by the manufacturer of a given pharmaceutical preparation; however, as pharmaceutical manufacturers reserve the right not to define the quantitative content of individual excipients, these amounts were selected in accordance with the recommendations regarding the percentage of individual excipients in the formulation.50 value calculated using the CA/IA model (Equations (1) and (2)), and 50 value recorded using the Microtox® test. The effects were further classified as synergistic (MDR ≥ 2), additive (0.5 < MDR < 2), or antagonistic (MDR ≤ 0.5) [The model deviation ratio (MDR), defined as follows, was calculated to evaluate the synergic or antagonistic effects of the tested compounds in the pharmaceutical mixtures:R ≤ 0.5) .Answering the question raised in the title, it can be concluded from the research conducted in this study that pharmaceutical excipients, generally considered as safe, can threaten the aquatic environment. However, it is possible to reduce the risk. Firstly, intensive studies should be initiated into the ecotoxicity of commercial and newly marketed pharmaceutical formulations, taking into account the increase in toxicity as a result of interactions between components. Secondly, studies should be aimed at discovering new excipients, which are non-toxic to the environment. Thirdly, excipients with known, high ecotoxicity should be replaced by less toxic substitutes. Fourthly, the pharmaceutical and cosmetic industries should reduce the levels of toxic excipients in the final products. Lastly, new studies should lead to a situation where active substances can be applied in a different pharmaceutical form, omitting ecotoxic excipients, e.g., tablets containing harmful excipients could be replaced by excipient-free capsules.® test allowed estimating the ecotoxicity associated with pharmaceutical substances that can be dissolved/suspended in a liquid medium or adsorbed onto a solid environmental matrix. While some excipients may present a high risk to aquatic organisms, such as SLS and meglumine, it is essential to note that some excipients, including commonly used magnesium stearate, were found to be safe for the aquatic environment (Our study highlights the potential ecotoxicological hazards posed by pharmaceutical excipients, an area that has been largely overlooked. The tests carried out using bioluminescent bacteria and a recently developed modification of the Microtoxironment . ImportaIn conclusion, addressing the unnoticed problem of ecotoxicological hazard from pharmaceutical excipients demands concerted efforts from researchers, regulators, and pharmaceutical industries. Understanding how pharmaceutical excipients affect different organisms within the ecosystem will enable us to develop better risk assessment strategies and ensure the protection of aquatic life and the environment as a whole.


Malnutrition - comprising both undernutrition and overweight - has to be addressed in the medical follow-up of older adults due to the negative consequences for the functional state and general health. Still, little is known about the nutritional state of nursing home (NH) residents, especially with respect to weight gain or weight loss after NH admission. Therefore, this study aims to evaluate changes in the body mass index (BMI) during the first year following NH admission, and to explore demographic and clinical characteristics related to BMI changes.Data from two prospective studies that recruited participants at NH admission were combined. Demographic and clinical characteristics including the BMI were assessed at baseline and after one year. A linear regression model was estimated to explore the impact of demographic and clinical characteristics on the change in BMI.2 , while weight changes were either very small or not significant in the other BMI groups. Characteristics related to weight gain were younger age and less agitation.The study cohort consisted of 1,044 participants with a mean age of 84.3 years (SD7.6) at baseline; 64.2% were female. At baseline, 33% of the NH residents had severe to moderate undernutrition, while 10% were obese. During the first year of their NH stay, residents with severe to moderate undernutrition had an average increase in BMI of 1.3 kg/mMalnutrition is a common health challenge at NH admission, with one third of NH residents being moderately to severely underweight and 10% being obese. However, during the first year of NH stay, there was a favourable development for underweight NH residents, as they increased their BMI, and 43.6% changed to a higher weight classification, while we observed no changes in the BMI in residents with obesity. As NH residents are in the last phase of their lives, interventions to prevent malnutrition or overweight should be initiated while still home-dwelling, and then continued in the nursing homes. Feed me, feed me, Simon, feed me all night long!” sings the bloodthirsty Venus flytrap in the Little Shop of Horrors. In contrast to the man-eating plant in the musical, most humans are content with standard food, and their main inclination is that it satisfies their nutritional needs, taste, and eating habits. However, malnutrition is a global challenge, with undernutrition denoting insufficient intake of energy and nutrients to meet an individual’s needs to maintain good health, and overweight as abnormal or excessive fat accumulation that presents a risk to health, and it has to be addressed in the care and medical follow-up of older adults [“r adults , 2. The r adults . Additior adults .Norwegian NHs are designed for people in need of continuous care and supervision. Mean age at admission is 84 years, and 84% of the long-term residents suffer from dementia , 6. ManyStill, little is known about the nutritional state of residents at NH admission, especially with respect to weight gain or loss, and demographic and clinical characteristics related to weight changes. Therefore, this study aims to evaluate changes in the body mass index (BMI) during the first year following the NH admission, and to explore demographic and clinical characteristics related to BMI changes.We combined data from two prospective clinical studies that recruited participants from 71 NHs in 45 municipalities in Norway at NH admission. The demographic and clinical characteristics from both cohorts were similar. These studies were:Resource Use and Disease Course in Dementia - Nursing Home (REDIC-NH) including 696 persons. Inclusion took place between 2012 and 2014 .Cooperation between The Department of Old Age Psychiatry, Innlandet Hospital Trust, and municipal nursing homes in the Innlandet County (SAM-AKS III). SAM-AKS III is an ongoing study that started in 2014 .Inclusion criteria were: (i) 65 years of age or older in REDIC-NH and 60 years of age or older in SAM-AKS III or (ii) having dementia irrespective of age. (iii) In addition, expected survival should be six weeks or more for REDIC-NH and four weeks or more for SAM-AKS III. Only residents that completed baseline assessment (BL) were included in the studies.For the present study additional inclusion criteria were: (a) Participants had completed BL within 90 days after NH admission, (b) participants had completed the 12-months follow-up examination (FU12) within one year and 90 days after BL or had died before FU12, and (c) BMI recorded at all assessments.Data collection was performed by trained healthcare workers at the NH, mainly registered nurses, under supervision of research nurses from the Research Centre for Age-Related Functional Decline and Disease. The research nurses completed a five-day training prior to study start, while the data collectors completed a two-day training. Data were collected through structured interviews with participants and a caregiver .All rating scales and inventories were applied using validated, Norwegian versions. The following demographic and clinical data were collected:Gender, age, and living arrangements before admission to NH, were collected by reviewing patients’ journals.2). The height was assessed at BL by either measuring the resident or by asking the residents or their proxies when the resident was unable to stand erect. The weight was established by weighing the residents at BL and at FU12.relates a person’s weight to the height , moderate undernutrition , normal weight  and overweight . In addition, participants with a BMI of 30 or higher were classified as obese [was applied to assess the severity of dementia. The rating scale comprises six items, where the total CDR score is obtained based on an algorithm . For staassesses neuropsychiatric symptoms. The instrument contains 12 items and is conducted as an interview with a caregiver. Severity (scored 0–3) is multiplied by frequency (scored 0–4), giving an item score from 0 to 12, where higher scores indicate more severe symptoms , 22. Basconsists of six items (scored 1–5) and assesses personal activities of daily living (PADL) function. The overall score ranges from 6 to 30, where higher scores indicate higher PADL dependency .rates physical health and was assessed by the health care workers performing the examinations. It consists of one item comprising four categories: excellent, good, moderate, or poor .was applied to assess pain. For this study, we only included the overall proxy rating ranging from 0 to 10, where a higher score indicates more severe pain. The residents’ capacity to consent to participation in the study was considered by the NH staff, including the NH physician. Written informed consent was obtained by the participants with full capacity to consent, or by next of kin on behalf of the participants in case of reduced capacity to consent. The Regional Ethics Committee for Medical research in South-Eastern Norway approval for the two studies (2011/1378a and 2014/917) includes the analysis for the present study.2-test for categorical variables. The analyses comparing participants with severe undernutrition, moderate undernutrition, normal weight, overweight, and obesity according to pre-specified BMI cut-offs were considered exploratory. For some of the exploratory analyses the sub-cohorts of participants with severe and moderate undernutrition were combined. The BMI change between BL and FU12 was assessed by paired samples t-test. A linear regression model was estimated to explore the impact of demographic and clinical characteristics at BL on the change in BMI between BL and FU12. The following characteristics were included: age, gender, living alone before NH admission, GMHR, PSMS, CDR-SoB, the NPI sub-syndromes Agitation, Psychosis and Affective, the overall proxy rating of MOBID-2, and BMI at BL. Due to mathematical coupling and regression to the mean, a straightforward regression analysis between change in BMI and BL BMI might provide biased results. To obtain an accurate estimate of the association between the BMI at BL and the change in BMI, Blomqvist’s method adjusting the estimated coefficient and its standard error for measurement error variance, was applied [Demographic factors and clinical characteristics were presented as means and standard deviations (SDs), or frequencies and percentages. The group differences were assessed by Student’s t-test for continuous variables and χ applied , 27. MeaAs shown in Fig. Table 2  between BL and FU12. Persons with severe to moderate undernutrition had the highest increase in BMI, with 1.3 kg/m2  and 43.6% of residents in these weight classifications changed to a higher weight classification during their first year of NH stay.Table Table 2, while weight changes were either very small or not significant in the other BMI groups. Weight gain was associated with younger age and less agitation.At NH admission we observed that about 33% of the NH residents had severe to moderate undernutrition, while 10% were obese. Residents with undernutrition were older, living more often alone before NH admission, had more symptoms of agitation, and a higher mortality rate. Residents with obesity where younger, experienced more pain, had a lower general health state and less cognitive impairment. During the first year of their NH stay, persons with severe to moderate undernutrition had an average increase in BMI of 1.3 kg/mOur findings regarding undernutrition are in line with previous research that reports a prevalence of undernutrition of 30% in Swedish NHs . The finHowever, our findings contradict quite frequent reports in Norwegian media about insufficient nutrition of NH residents and patients supposedly “starving to death” –32. RathIn residents with overweight, we see that almost one third is classified as obese after one year of NH stay, increasing the share of residents with obesity from 10 to 14%. Additionally, we observed that residents who suffered from obesity at BL, were the group with no significant change in BMI. A previous study reported a prevalence for obesity of 18% in a French NH population, with no weight change during the two-month observation period, despite dietary regimes. As in our study, pain was more frequently reported in residents with obesity as compared to the other BMI groups . As descWe followed a cohort of 1,044 participants in a longitudinal study from NH admission and during the first year of their long-term NH stay, with clinical examinations at BL and after 12 months. For clinical, prospective studies in the NH setting cohorts of about a thousand participants are scarce. The study cohort consisted of NH residents from both urban and rural municipalities. High quality of the data collection was secured by a standardized interview carried out by healthcare workers with adequate training under the supervision of research nurses. Furthermore, the Norwegian health and social system provides a rather homogenous environment for health service research as there are hardly any private sector healthcare providers on the market. The decision of NH admission is made by care workers in the municipality administration, mainly based on the patients’ functional status and with comparable thresholds for admission.Still, the main weakness of this study is that our sample might not be representative of the general NH population in Norway, as less than half of all eligible residents participated in REDIC-NH and SAM-AKS III, and as the stricter inclusion criteria of the present study resulted in an additional attrition of study participants. Further, the BMI was only assessed at two time points one year apart. Thus, we know nothing about the changes in BMI of the deceased participants. The nutritional state was solely assessed by BMI, as we lacked information about comorbidities or possible problems with food intake. The BMI does not always represent the full nutritional status of an older person, as it does not necessarily reflect changes in a person’s percentage of muscle mass and body fat. This might have led to an underestimation of malnutrition.Malnutrition is a common health challenge at NH admission, with one third of NH residents being moderately to severely underweight and 10% being obese. However, during the first year of NH stay, there was a favourable development for underweight NH residents, as they increased their BMI, and 43.6% changed to a higher weight classification, while we observed no changes in the BMI in residents with obesity. As NH residents are in the last phase of their lives, interventions to prevent malnutrition or overweight should be initiated while still home-dwelling, and then continued in the nursing homes.