Adherence to statins in real-world practice settings is known to be suboptimal. However, less is known about how adherence changes over time and whether changes in adherence are associated with adverse cardiovascular (CV) outcomes.To (a) characterize yearly changes in adherence among initially adherent patients taking statins for primary prevention and (b) assess the association between changes in statin adherence with subsequent risk of CV events.A 10% random sample of the IMS LifeLink Health Plan Claims Database covering the time period from July 1, 1997, to December 31, 2008, was used to identify a cohort of primary prevention statin users. Adherence was estimated in yearly segments beginning with the index statin prescription using proportion of days covered (PDC). PDC was categorized into 3 levels: PDC ≥ 0.80, 0.20 ≤ PDC  less than  0.80, PDC  less than  0.20. Patients were excluded if they experienced CV events or had PDC  less than  0.80 in their first year of statin exposure. Descriptive statistics were used to explore proportions of the cohort in each PDC category during each year. Cox-proportional hazards models were used to estimate the 5-year CV event risk associated with yearly adherence transitions.Of the 11,126 patients beginning at the highest level of adherence (PDC ≥ 0.80) in year 1, 70% remained at this level in year 2. Of those in this level during year 2, 73% remained at this level in year 3. 828 (7.44%) experienced a CV event during their observable follow-up time. It was found that those who transitioned from the highest to the lowest level of adherence in year 2 (PDC  less than  0.20) experienced 2.26 greater CV event hazard (P  less than  0.0001). Adjusting for year 2 adherence, patients at the lowest level in year 3 experienced a 271% increase in CV hazard (P  less than  0.0001), as compared with the highest level of adherence.This study found that patients’ adherence levels tend to decline over time, and a transition to levels of adherence lower than a PDC of 80% was associated with increased risk of CV events. These results are useful in the context of targeting interventions that aim to improve patients’ adherence.


ABCG2 (BCRP), increase breast cancer stem cells drug resistance, and epithelial mesenchymal transition.multidrug resistance (MDR) is One of the foremost challenges in overcoming breast cancer. Various molecular processes are involved in the development of MDR in breast cancer cells, including over expression of ABC transporters such as ABCG2, in MDR breast cancer cells.In the present study, we used bioinformatics and experimental analysis to investigate the role of miR‐548 K, in the modulating of ABCG2 gene in MCF7‐MX cell lines was significantly more than MCF7 cell lines. On the other hand, we increased the expression of miR‐548 K in MCF7‐MX and MCF7 cell lines through its transfection, which dramatically coincided with decreasion in the ABCG2 transcripts level. Additional studies on patient samples revealed that the expression of ABCG2 showed an increase in ABCG2 level in neoadjuvant chemotherapy drugs resistance (NCDR) patients compared to primary pre‐operative chemotherapy drugs response (PCDR) patients. Also, a reduction in the expression of miR‐548 K in NCDR patients was revealed.In silico inspections introduce 14 microRNAs targeting 3′‐UTR region of ABCG2 transcripts, which are probably involved in breast cancer drug resistance. An association was highlighted between miR‐548 k with ABC transporter family. The expression level of ABCG2 in MDR breast cancer cells.The results of our study suggest that miR‐548 K may be involved in modulating the expression of  This condition is a multifactorial disease which various factors involved in its development.ABCG2 gene expression increases, which leads to a more frequent appearance of this protein on the cell membrane. This rise in the level of ABCG2 protein helps pump out the chemotherapy drugs from the cancer cells thereby causing drug resistance. Although ABCG2 role in the development of drug resistance in cancer cells is known, the regulatory mechanisms that enhance the expression of this protein in cancer cells and create a growth advantage have not yet been identified.Cancer cells acquire various properties that cause cell growth and proliferation as well as resistance to stresses in later stages. Some principal problems in cancer treatment are the transformation of cancer cells and adaptation to the conditions and stresses imposed on them. Multi‐drug resistance (MDR) is a challenge in overcoming cancer cells. In breast cancer, chemotherapy is a treatment strategy employed before surgery to limit the tumor cells (neoadjuvant therapy) or after surgery to prevent the recurring growth of cancer cells (adjuvant therapy). Drug resistance may be observed at any of these steps. Various mechanisms are involved in the development of drug resistance; the most well‐known is the overexpression of drug transporters like the ATP‐binding cassette (ABC), which are located on the cytoplasmic membrane.MicroRNAs are small non‐coding RNAs that have been shown to play a role in various cellular and pathogenic processes. Changes in the miRNAs expression patterns in different diseases, including cancer, are tracable; this feature introduces the miRNAs as a potential biomarker.ABCG2 gene expression in breast cancer cells.In the present study, we aimed to investigate the role of miR‐548 k on 2MicroRNA selection MicroRNAs that have a protected target site on ABCG2 mRNA were identified using the miRTarBase (https://mirtarbase.cuhk.edu.cn/), TargescanHuman8.0 database (www.targetscan.org) and, miRWalk . MicroRNAs tissue expressions were checked by the GTEx database . Pubmed (https://pubmed.ncbi.nlm.nih.gov), Scopus (https://www.scopus.com), COREMINE (https://www.coremine.com), and google scholar (http://scholar.google.com) were used to scrutinize the published studies. Basic Local Alignment Search Tool (BLAST) (https://blast.ncbi.nlm.nih.gov/) was used to align the sequences. A network designed by performed by Cytoscape v3.9.0.2.12 at 37°C.Human breast cancer cells MCF‐7 and the multidrug‐resistant cell line MCF7‐MX obtained from American Type Culture Collection , were provided from the cell bank at the Pasteur Institute . These cells were cultured in Dulbecco's Modified Eagle Medium  containing 10% fetal bovine serum (GIBCO), 1% Antibiotic‐Antimycotic (100×) (Gibco), and MX only to the culture media for MCF‐7/MX cells in an atmosphere with 5% CO2.25/well), incubated for 24 h, and then transfected with 25 nM miR‐548 K mimic, 25 nM miR‐NC using iN‐fect™ , according to the manufacturer's instructions. Briefly, the reagent and FBS were diluted in a 1:30 ratio then adding the target (miR‐548 K or scramble oligonucleotides) was incubated for 15 min at room temperature. Finally, the iN‐fect/oligonucleotide complex was poured gently on the cells and returned to the incubator for 24–48 h. The transfection efficiency was set up by scramble oligonucleotide labeled with FITC, and results were observed using a fluorescent microscope . Forty‐eight hours after transfection, the cells were used for RNA extraction.MCF‐7 and MCF‐7/MX cells were seeded into 6‐well plates  including 10 patients with stage III breast tumors and pre‐operative neoadjuvant chemotherapy drugs resistance (NCDR) (including mitoxantrone/doxorubicin/cyclophosphamide) along with 9 patients with stage I breast tumors and primary pre‐operative chemotherapy drugs response (PCDR). Normal breast tissue was obtained from areas adjacent to the tumor tissue as control. Patients who did not receive pre‐operative chemotherapy or suffered from other malignancies were excluded from this study. According to The protocols of the Ethics committee of SKUMS (IR.SKUMS.REC.1399.197 and IR.SKUMS.REC.1399.142), after achiving informed consent, clinicopathological data were received from all the patients. The study protocol also complied with the Declaration of Helsinki . Tissue biopsies were snap‐frozen and stored at −80°C until RNA extraction.2.4ABCG2 and miR‐548 K. Total RNA was extracted from cultured MCF‐7 and MCF‐7/MX cells and patient samples with triazole  method. Total RNA quality and concentration were evaluated by electrophoresis in a 1.5% agarose gel, and D260/D280 and D260/D230 absorbance by Thermo Scientific™ NanoDrop 2000. DNase I  was used to remove DNA.Quantitative Real‐Time PCR was performed to detect the expression levels of the ABCG2 cDNA synthesis was performed using Oligo dT primers, according to the manufacturer's protocol for the Geneall Kit. QRT‐PCR was performed by Rotor‐Gene Q  using 2X QPCR Master Mix Syber Green . The GAPDH was used as an internal control for data normalization. The following PCR amplification primers were used for ABCG2 and GAPDH:ABCG2: Forward, 5′‐ GTTTCAGCCGTGGAAC‐3′; and Reverse, 5′‐ CTGCCTTTGGCTTCAAT‐3′.GAPDH: Forward, 5′‐ TTCACCACCATGGAGAAGGC‐3′; and Reverse, 5′‐CCCTTTTGGCTCCACCCT‐3′.For miR‐548 K cDNA synthesis, miRNAs polyadenylation was done and subjected to reverse transcription using BON‐miR 1st‐strand cDNA synthesis kit and then QRT‐PCR was performed using BON‐miR QPCR , according to the manufacturer's protocol. Small Nucleolar RNA, C/D Box 47 (SNORD47) was used as an internal control for data normalization. The Pfaffl method was used to report fold changes.2.5GAPDH mRNA and SNORD47 respectivly. Comparation between tumor or treatment mimic and adjacent normal breast tissues or treatment scrambles cell lines were done respectivly. Futhermore, for explain the association between genes or miRNA expressions in a certain sample, the results were stated as the ratio of target genes over GAPDH or SNORD47 expression (relative expression [REx]) respectivly. QRT‐PCR were performed in triplicate for each sample, and the results were averaged. The statistical analyses of the expression data were performed by Graph Pad prism 8.0. The t‐test was used to obtain the rate of change of expression data. P‐value < .05 was considered significant.The REST 2009 software  was used for relative expression analysis.The quantities of mRNA and miRNA in the tissues or cell lines were standardized to the 33.1ABCG2‐related microRNAs from miRTarBase, TargescanHuman8.0 and miRWalk databases showed that 1100 microRNAs have target sites on the 3′‐UTR region of the transcripts of this gene. Tissue expressions were checked by the GTEx database ; the microRNAs that did not have expression in the breast tissue were excluded from the study. In the next step, we checked the filtered microRNAs in terms of their expression in breast tissue, in the published documents, and in terms of their role in drug resistance in breast cancer. Fourteen microRNAs were determined, which may probably be involved in breast cancer drug resistance mediated by ABCG2  fold greater than in MCF7 cell lines. Also, it was highlighted that the expressions of ABCG2 gene in treatment mimic MCF7 cell lines was 0.407 (P = 0.003) fold and in MCF7‐MX was 0.573 (P = 0.001) fold fewer in comparison with treatment scrambles respectively  and in MCF7‐MX cell lines was 3.046 (P = 0.003) times more than treatment scrambles respectively  more than in the adjacent normal tissues but the expression changes of ABCG2 gene in tumor tissues in PCDR patients were not significant in comparison with adjacent normal tissues  lower in comparison with adjacent normal tissues, but the expression of miR‐548 k in tumor tissues in PCDR patients was 1.727 times (P = 0.019) more in comparison with adjacent normal tissues ; formal analysis ; writing – review and editing . Zahra Ghasemi: Data curation ; visualization ; writing – review and editing . Hajar Yaghoobi: Conceptualization ; funding acquisition ; writing – review and editing .This study was financially supported by the Shahrekord University of Medical Sciences (grant no: 3417 and 3529).The authors have stated explicitly that there are no conflicts of interest in connection with this article.According to The protocols of the Ethics committee of SKUMS (IR.SKUMS.REC.1399.197 and IR.SKUMS.REC.1399.142), clinicopathological data were received from all the patients. The study protocol was also complied with Declaration of Helsinki .


Although resistance to persuasion has been of interest in psychology, relatively little research has examined how different resistance strategies can affect the strength-related features of attitudes. The current research presents a metacognitive account of two resistance strategies and their effect on attitude certainty and intentions. Specifically, we examine how the strategies of counterarguing and bolstering can differentially affect attitude certainty and intentions to act on the attitude under attack.In two experiments, we implemented a 2(Perceived Thought Type: bolster vs. counterargue) x 2 between-participants design. Participants read weak or strong arguments about a counterattitudinal topic. After reporting their thoughts in response to the message topic, participants received bogus feedback regarding the nature of their thoughts . Following the feedback, participants reported their attitudes and attitude certainty.N =241), participants’ thoughts perceived as counterarguments elicited attitude certainty that was more sensitive to the quality of the attacking information than when thoughts were perceived as bolstering one’s opinion. Experiment 2 (N  = 287) replicated the effect with a different topic and demonstrated a similar pattern on intentions to act on the attacked attitude.In Experiment 1 (The research demonstrates that two relatively thoughtful strategies, bolstering and counterarguing, can play an important role in attitude certainty and intentions following a persuasion attempt. For example, resistance has been examined as a process . This type of thought . It is expected that, despite similar levels of effort in generating thoughts, thoughts perceived as bolstering would yield attitude certainty that is less affected by quality of the attacking information, relative to thoughts framed as counterarguments, where exposure to strong arguments would yield greater attitude certainty than exposure to weak arguments. Such a finding would be the first evidence to show the limiting effect of argument quality on certainty across the different types of thought-based resistance strategies one could potentially have.f = 0.17 can be detected with 80% power. Data and materials are available here: https://osf.io/jc5n3/?view_only=a772c2458e884137805491450f115a28.To test these hypotheses, we based our sample size on previous research. For Experiment 1, we aimed for at least 50 participants per condition, which is consistent with previous research on attitude certainty and counterarguing . For botIn Experiment 1, we provide an initial test of the moderating role of perceived resistance strategy type on perceived argument quality and certainty. Specifically, we expect that participants’ attitude certainty would be more sensitive to the quality of an attacking message when participants are told that their post-message thoughts counterargue the message rather than bolster their initial attitude. When participants are told that their thoughts bolster their initial attitude, however, it is expected that participants will report similar levels of certainty across the argument quality conditions. To test this, participants who support drug testing for welfare recipients were exposed to a counterattitudinal message . In order to manipulate the perceived resistance strategy, we adapted a bogus feedback paradigm , such thageM = 19.73, ageSD = 1.81) constituted the study sample for the 2(Perceived Thought Type: bolster vs. counterargue) × 2 between-participants design.The study sample came from a larger data collection effort, where 524 students were recruited from a social science pool at a large Midwestern university. Of these, 246 reported favorable opinions toward the target issue of drug testing for welfare participants. Five additional participants were excluded from analyses because they did not write any thoughts following exposure to the message. The remaining 241  were exposed to the research materials. After reporting their opinions, participants read a counterattitudinal message that opposed drug testing for welfare recipients. Just before reading the message, participants were exposed to the argument quality manipulation such that half of participants were told that the message contained strong arguments whereas half were told that the message contained weak arguments . As previously mentioned, because we were interested in resistance to persuasion, only participants who reported favoring drug testing for welfare recipients  most welfare recipients spend the welfare money on necessities, (b) drug use is no more a problem for individuals receiving welfare than people who do not, and (c) such laws discriminate based on socioeconomic status. The arguments were presented on separate screens in that order. After reading all three arguments, participants were given an opportunity to write up to four thoughts about the information. Participants were then told that the computer would analyze their thoughts and the analysis would indicate (via bogus feedback) the nature of their thoughts . Specifically, participants in the bolstering conditions were provided information indicating their thoughts supported their initial opinion, whereas participants in the counterarguing conditions were given information indicating their thoughts refuted the message content. Participants across both conditions received positive feedback such that their thoughts provided a great deal of support for their opinions (bolstering), or that their thoughts counterargued the message very well.Following the feedback, participants reported their attitudes, attitude certainty, perceived engagement with the issue, and an argument quality manipulation check. Participants were then debriefed as to the fictitious nature of the message and the purpose of the research.… the computer will measure the extent to which your thoughts support your initial position toward drug testing for welfare recipients.” In the counterarguing conditions, participants read: “… the computer will measure the extent to which your thoughts refute the claims in the message.” Participants were told that the index could range from 1 to 10, with higher scores indicating greater bolster or counterarguing, depending on their assigned condition.After reporting their thoughts, participants received feedback regarding the nature of their thoughts . In the bolstering conditions, participants read “thought bolstering index” or “counterarguing index.” The number was provided along with corresponding information about the level of bolstering or counterarguing. All participants received a 9 (out of 10) and told that their thoughts provided a great deal of support for their initial opinion (bolster conditions) or counterargued the message very well (counterargue conditions).After an 8-s delay used to simulate the basis calculation, the computer provided participants with a number, labeled as either a “All participants received the same message. Prior to reading the message, however, participants were told that the study was interested in getting reactions to all types of reasons that oppose drug testing for welfare recipients. Participants in the weak argument conditions were told that they will read the weakest reasons opposing drug testing, whereas participants in the strong conditions were told that they will read the strongest reasons .Following the feedback manipulation, participants reported their attitudes toward drug testing welfare recipients on five 9-point scales  and three attitude correctness items  adapted by not certain at all, 9 = very certain). Items were presented randomly; both clarity (α = 0.96) and correctness (α = 0.83) demonstrated adequate reliability. All seven items were combined to create a single index of attitude certainty (α = 0.93).Participants completed the four attitude clarity , how deeply they thought about the message , how much effort they put into reading the message , and how personally involved they felt with the topic . Responses were combined to create a single index of issue engagement . This served as a manipulation check.Participants were asked to report how persuasive the message arguments were  = 4.71, p = 0.03, d = 0.28, with participants in the strong argument conditions rating the arguments as more persuasive  than the arguments in the weak argument conditions . No other effects were significant (ps > 0.73).A 2(Perceived Thought Type: bolster vs. counterargue) × 2 ANOVA on the argument quality manipulation check revealed a main effect of Perceived Argument Quality SD = 1.02) after reading the proposal. A research assistant blind to the study’s purpose and experimental conditions rated whether each thought was in favor (coded as +1), against (coded as −1), or neutral/irrelevant (coded as 0) toward the message. Thought favorability was calculated by subtracting the number of thoughts against the proposal from the thoughts favoring the proposal, divided by the total number of thoughts generated .Overall, participants generated an average of 2.68 thoughts (ated see . Negativps > 0.14), suggesting any effect on attitude certainty is unlikely to be due to differences in thought favorability across the conditions.A 2(Perceived Thought Type: bolster vs. counterargue) × 2 ANOVA on the thought favorability measure revealed no significant effects  = 3.93, p = 0.05, d = 0.26, such that participants in the bolstering feedback conditions had more favorable attitudes  than the counterargument feedback conditions . No other effects were significant (ps > 0.20).The same analysis on participants’ attitudes revealed a marginal effect of Perceived Thought Type, Consistent with previous research on argument quality and attitude certainty, we expected that participants would be less certain in their attitude after reading the weak message . ImportaF = 3.15, p = 0.08, d = 0.22, with participants reporting greater certainty following exposure to the message labeled as strong  rather than weak . Of greater importance was the significant Perceived Thought Type × Perceived Argument Quality interaction F = 5.71, p = 0.02, pn2 = 0.02  or strong , F = 0.02, p = 0.66, d = 0.08. However, in the counterarguing conditions, participants were more certain when the message was labeled as strong  rather than weak , F = 8.48, p = 0.004, d = 0.53. Thus, as predicted, perceived resistance strategy moderated the influence of argument quality on attitude certainty.To test this, we submitted the attitude certainty measure to a 2(Perceived Thought Type) × 2 ANOVA. A marginal main effect of Perceived Argument Quality emerged 0.02 see . SpecifiM = 6.54, SD = 1.52; t(240) = 15.79, p < 0.001]. Nonetheless, we sought to rule out the possibility that any differences in attitude certainty may be due to differences in participants’ perceptions that they effortfully processed the message.Both bolstering and counterarguing have been speculated to be relatively high effort processes . Indeed,F = 5.70, p = 0.02, d = 0.31, with participants reporting greater issue engagement following exposure to the message labeled as strong  rather than weak . No other effects were significant (ps > 0.48).A 2(Perceived Thought Type) × 2 ANOVA on the composite subjective elaboration measure revealed a main effect of Perceived Argument Quality To recap, Experiment 1 demonstrated that attitude certainty resulting from thoughts perceived as counterarguments are affected by the quality of the attacking message, such that attitude certainty in response to a strong attack was higher than in response to a weak attack. However (and more novel), argument quality did not affect attitude certainty when thoughts were framed as bolstering thoughts. Moreover, similarly high levels of issue engagement were found across the thought framing conditions, suggesting that participants’ amount of processing was not responsible for these effects.Having demonstrated the general finding, Experiment 2 built upon Experiment 1 in two ways. First, we sought to conceptually replicate Experiment 1 in a laboratory setting where experimental control is higher than in online-administered studies . We alsoWe also examined the implications of thought type and argument quality on the relationship between attitudes and behavioral intentions. A common finding in the attitudes literature is that attitudes are more strongly related  to behavioral intentions to the extent that they are held with greater certainty . Thus, wageM = 19.49, ageSD = 1.7) constituted the study sample for the 2(Perceived Thought Type: bolster vs. counterargue) × 2 between-participants design.Participants were 292 students recruited from a social science participant pool at a large Midwestern university. Five participants were excluded from analyses because they did not write any thoughts following exposure to the message. The remaining 287 .thought bolstering index” or “thought counterarguing index.” The number was provided along with corresponding information about the level of bolstering or counterarguing. All participants received a 9 (out of 10) and told that their thoughts provided a great deal of support for their opinion (bolster conditions) or counterargued the message very well (counterargue conditions).After a 10-s delay used to simulate the basis calculation, the computer provided participants with a number, labeled as either a “Similar to Experiment 1, participants in the weak argument conditions were told that they will read the weakest reasons that support the program, whereas participants in the strong conditions were told that they will read the strongest reasons.As with Experiment 1, participants were given up to four boxes and were instructed to type one thought per box. Importantly, the thought listing instructions simply asked participants to list their thoughts; the instructions did not guide participants to list either bolstering our counterarguing thoughts.α = 0.96).Following the bogus feedback manipulation, participants reported their attitudes toward the university service proposal using the same scales as in Experiment 1 . In addition, participants also completed the attitude clarity and attitude correctness items on the same 9-point scales from Experiment 1. Both clarity (α = 0.93) and correctness (α = 0.85) demonstrated adequate reliability. All eight items were combined to create a single index of attitude certainty (α = 0.93).After reporting their attitudes, participants first reported their global attitude certainty on a 9-point scale . The two items were combined to create an index of knowledge .Attitude-relevant knowledge refers to the extent to which one has information related to the attitude object of interest . Regardlα = 0.85).Following the knowledge items, participants completed the subjective elaboration items using the same 9-point scales from Experiment 1 .After reporting their issue engagement, participants reported their willingness to discuss their attitude toward the program (a) with someone who has an opposing viewpoint, (b) in public, and (c) their willingness to sign a petition that supports their attitude toward the university service program .Following the knowledge measures, participants were asked to report how persuasive the message arguments were  = 7.79, p = 0.006, d = 0.33, with participants in the strong argument conditions rating the arguments as more persuasive  than the arguments in the weak argument conditions . No other effects were significant (ps > 0.21).A 2(Perceived Thought Type: bolster vs. counterargue) × 2 ANOVA on the argument quality manipulation check revealed a main effect of Perceived Argument Quality SD = 0.94) after reading the proposal. Following all of the critical dependent measures, participants rated each of their own thoughts in terms of its favorability toward the message. Specifically, participants rated whether each thought was in favor (coded as +1), against (coded as −1), or neutral/irrelevant (coded as 0) toward the proposal. Thought favorability was calculated by subtracting the number of thoughts against the proposal from the thoughts favoring the proposal, divided by the total number of thoughts generated .Overall, participants generated an average of 3.08 thoughts , suggesting any effect on attitude certainty is unlikely to be due to differences in thought favorability across the conditions.A 2(Perceived Thought Type: bolster vs. counterargue) × 2 ANOVA on the thought favorability measure revealed no significant effects (ps > 0.36) suggesting that attitudes were not affected by the manipulations. Thus, any differences in attitude certainty are not likely due to changes in attitude favorability.The same analysis on participants’ attitudes revealed no significant effects  = 3.84, p = 0.05, d = 0.23, with participants reporting greater certainty following exposure to the message labeled as strong  rather than weak . Of greater importance was the significant Perceived Thought Type × Perceived Argument Quality interaction F = 4.61, p = 0.03, pn2 = 0.02  or strong , F = 0.02, p = 0.91, d = 0.02. However, in the counterarguing conditions, participants were more certain when the message was labeled as strong  rather than weak , F = 8.52, p = 0.004, d = 0.53.We submitted the combined attitude certainty measure to a 2(Perceived Thought Type) × 2 ANOVA. A marginal main effect of Perceived Argument Quality emerged 0.02 see . SpecifiF = 6.70, p = 0.01, d = 0.30, with participants reporting greater knowledge of the policy following exposure to the message labeled as strong  rather than weak . The Perceived Thought Type × Perceived Argument Quality interaction was also significant F = 5.35, p = 0.02, p2n = 0.02. Specifically, in the bolstering conditions, there was no difference in perceived knowledge when the message was labeled as weak  or strong , F = 0.04, p = 0.85, d = 0.03. However, in the counterarguing conditions, participants reported greater knowledge about the program when the message was labeled as strong  rather than weak , F = 12.14, p < 0.001, d = 0.58. Thus, similar to attitude certainty, perceived resistance strategy moderated the influence of argument quality on knowledge.A 2(Perceived Thought Type) × 2 ANOVA on the knowledge measure revealed a main effect of Perceived Argument Quality M = 6.92, SD = 1.47, t(286) = 22.11, p < 0.001). A 2(Perceived Thought Type) × 2 ANOVA on the issue engagement measure revealed no significant effects (ps > 0.09), suggesting that any differences in attitude certainty are not likely the result of differences in issue engagement of the message.Similar to Experiment 1, participants reported a relatively high level of issue engagement and that was above the scale midpoint of 500  = 6.29, p = 0.01, pn2 = 0.02  or strong , F = 1.11, p = 0.29, d = 0.17. However, in the counterarguing conditions, participants reported greater intentions to act on their attitude when the message was labeled as strong  rather than weak , F = 6.27, p = 0.01, d = 0.45. Thus, similar to attitude certainty and perceived knowledge, perceived resistance strategy moderated the influence of argument quality on intentions to act.A 2(Perceived Thought Type) × 2 ANOVA on intentions revealed the predicted Perceived Thought Type × Perceived Argument Quality interaction 0.02 see . SpecifiAs noted earlier, the Perceived Thought Type × Perceived Argument Quality interaction affected attitude certainty and intentions. These results set up a test to examine whether, consistent with previous research, increases in attitude certainty from being exposed to a message labeled as strong perceived would lead to increases in intentions to act on one’s attitude . SpecifiM = 0.25, SE = 0.12) mediated the effect of the Perceived Thought Type × Perceived Argument Quality on the intention measure, 95% BS CI:   = 1.71, p = 0.1, 95% CI: . Thus, attitude certainty mediated the effect of the interaction between Perceived Thought Type and Perceived Argument Quality.,M = 0.24, SE = 0.08 95% CI: ). When thoughts were perceived as bolstering, however, no such mediation was evident .Examination of the index of moderated mediation revealed that the higher order indirect effect of the attitude certainty term , argument quality did not affect attitude certainty when thoughts were framed as bolstering thoughts. Moreover, participants’ attitudes were not affected by the feedback manipulation, suggesting that similar amounts of resistance (or lack of change) occurred across the conditions.Experiment 2 also demonstrated that framing thoughts as counterarguments or bolstering thoughts has consequences for behavioral intentions. Specifically, when thoughts were perceived as counterarguments, attitudes became more predictive of behavioral intentions after participants had resisted a message believed to be strong, but not after they had resisted a message believed to be weak. Mediation analyses revealed that, consistent with previous research on certainty and intentions  certaintThoughts in response to a persuasive appeal can be integral to persuasion and resistance processes . DespiteThe current experiments extend the work on resistance strategies  from a mSecond, the current experiments suggest that not all thought-based resistance strategies are equal with respect to their relation to an attack. When resisting an attack via counterarguing, the strength of the message seems to have a greater influence on attitude certainty than when resisting by bolstering.Of course, we do not mean to suggest a bolstering strategy should be the preferred or even default defense in fending off an attack. The current experiments do not speak to the limiting conditions of bolstering, where such a strategy may be undermined. Future work should examine the boundary conditions for bolstering as a successful strategy. One possibility may be to consider situations where expressing one’s thoughts may be affected by other variables in a persuasion context that are not directly associated with the content of the attack. For example, sharing or advocating for a particular position to perceived experts may yield less certainty in bolstering thoughts than advocating to a less expert source, perhaps because they would be more open-minded to change their opinion .We believe that one unexpected result from Experiment 1 related to attitude bolstering merits mention. Specifically, participants in the bolstering feedback conditions had more favorable attitudes than in the counterargument feedback conditions. It could be that relative to perceiving thoughts as counterarguments, perceiving them as bolstering increased the perception that the thoughts were supportive of the initial position, thus making subsequent attitudes more extreme . Such a finding is consistent with mere thought effects in self-persuasion . While tOne of the advantages of using the strategy manipulations in the current experiments is the experimental nature of the data to argue for causal effects of bolstering versus counterarguing effects on certainty. Specifically, we adapted a bogus feedback manipulation that targets participants’ perceptions of their thoughts on order to create a desired resistance strategy. While similar manipulations have been successful in affecting resistance success  and attiMoreover, additional support for bolstering versus counterarguing effects on certainty and related attitude attributes could be gained by documenting relations between natural variations in the type of preferred resistance strategy on attitude certainty. That is, there are individual differences in the type of resistance strategy one prefers to use when defending an attitude , and theFuture work could also examine various attitude-related features of resistance strategies. That is, in addition to attitude certainty, features such as issue importance and attitude-relevant knowledge may be associated with various strategies. For example, successfully generating counterarguments may require a relatively high amount of issue-relevant knowledge , which may serve as ammunition in fending off an attack . Indeed,type of knowledge may be more closely associated with a counterarguing strategy. Because the majority of attitude-relevant knowledge is congenial to one’s opinions  can be found: The studies involving human participants were reviewed and approved by the Iowa State University Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Helicobacter pylori (H. pylori) remains a significant cause for upper gastrointestinal diseases globally. Eradicating H. pylori facilitates the reduction of gastric cancer,Despite a declining prevalence in the last few decades, H. pylori has recommended increasing the duration of first‐line therapy with amoxicillin, clarithromycin, and a PPI to 2 weeks, with randomized controlled studies in both Malaysia and globally showing an increased H. pylori eradication rate in recent times.H. pylori sensitivity to Amoxycillin. A recent study from Malaysia had shown that the eradication for H. pylori was 92.8% with a high‐dose dual‐therapy regimen compared with 86.2% with a standard clarithromycin‐based triple‐therapy regimen for 2 weeks.The recent Malaysian consensus report on H. pylori culture based methods to determine antibiotic susceptibility lack precision and are often affected by common use of PPIs and antibiotics. Molecular‐based techniques are the most reliable method to detect H. pylori antibiotic resistance currently. However, there is a lack of laboratory facilities for molecular‐based testing in regions with limited healthcare resources.Despite these well‐proven first‐line eradication regimes, there is still a 10%–15% failure rate. Antibiotic treatment regimens for cases refractory to first‐line therapy should ideally be guided by antibiotic susceptibility testing, to minimize further resistance. H. pylori cases in adults with dyspepsia from Thailand.H. pylori positive dyspeptics, their first‐line regime (predominantly clarithromycin‐based triple therapy) eradication rate was 85.08%. Empirical based second‐line therapy consisted mainly of higher doses of clarithromycin‐based triple therapy, bismuth‐based quadruple therapy, or levofloxacin‐based triple therapy. The eradication rate for empirical based therapy was 69.87%. Twenty six patients received a third‐line regime with a 53.85% eradication rate and 10 patients received a fourth‐line regime with a 50% success rate. The low eradication rates for refractory H. pylori cases in this study are believed to be multifactorial. The authors report that their retrospective study did not capture data on treatment adherence, which would have considerably influenced the efficacy of multiple courses of antibiotics. Furthermore, more effective salvage regimens recommended in the guidelines, such as triple therapy with rifabutin, high‐dose dual‐therapy, or furazolidone‐containing regimens,In this issue of JGH OPEN, Rattanachaisit et al. report on the efficacy of empirical based therapy for refractory H. pylori infection can be challenging to treat in resource‐limited settings. Although molecular techniques for antibiotic susceptibility testing are ideal, these are not readily available. Most guidelines continue to recommend empirical based treatment regimes, but provided a careful medication history is obtained. Finally, re‐treatment with clarithromycin‐based regimes tends to lead to more resistance and should be avoided.In summary, refractory


Obstructive sleep apnea (OSA) is one of the most common chronic diseases. Trefoil factor family 3 (TFF3) peptides are secreted by major and minor salivary glands and may be involved in the pathogenesis of OSA. This study aimed to evaluate salivary TFF3 and flow rate between those with and without OSA.This was a prospective experimental study that enrolled patients with OSA and non‐OSA. Total unstimulated saliva was collected, the salivary flow rate was measured, and the TFF3 level was analyzed by using a modified sandwich enzyme‐linked immunosorbent assay. Baseline characteristics, TFF3 level, and salivary flow rate were compared between both groups. Factors associated with the TFF3 level and flow rate were computed by using multivariate linear regression analysis.p = .276 and flow rate non‐OSA 0.40 vs. OSA 0.35 mL/min; p = .320). Factors associated with the TFF3 level were neck circumference with a negative coefficient of −16.419 (p =  .042). For the salivary flow rate, only age was a significant factor with the coefficient of −0.013 (p = .044).Twenty‐eight participants were recruited in the study: 20 patients with OSA (71.42%) and 8 non‐OSA as control. The TFF3 and salivary flow rates between both groups of non‐OSA versus OSA were comparable (TFF3 non‐OSA 61.06 vs. OSA 96.00 ng/mg; TFF3 and salivary flow rate were comparable between patients with OSA and non‐OSA. The factor associated with TFF3 level was neck circumference, while age was negatively associated with the salivary flow rate in patients with OSA. Healthy subjects presented a significantly higher level of TFF3 than snoring and other combined OSA groups. Logistic regression confirmed a correlation between TFF3 concentration and OSA level. Thus, they suggest the involvement of TFF3 in the pathogenesis of OSA . All subjects provided written informed consent before recruitment and their anonymity was maintained throughout the duration of the study. This study was conducted between March and October 2019.Patients with OSA and non‐OSA were enrolled to the study. OSA patients aged between 25 and 80 years old, diagnosed by the presence of an apnea–hypopnea index (AHI) of five times/h or more by polysomnography, were recruited before starting any treatment modalities from an outpatient Sleep clinic of the university hospital. A non‐OSA group of healthy participants with an AHI of <5 times/h served as a control group. The control group was recruited actively by the study advertisement. Participants with previous OSA treatment, oral lesions, or salivary gland dysfunction were excluded from both the non‐OSA and OSA groups.Eligible participants were assessed for baseline characteristics, physical signs, and laboratory results, including TFF3, and salivary flow rate. Baseline characteristics include age, gender, OSA risk assessment using the Berlin questionnaire, Epworth Sleepiness Scale (ESS), history of snoring, comorbid conditions, and periodontal condition. History of snoring was self‐reported, while comorbid conditions were collected from medical charts. OSA patients with comorbid diseases were allowed to take regular medication. The Berlin questionnaire was used to classify OSA risk as low and high risk, while ESS indicated a sleepiness score ranging from 0 to 24. Physical signs were blood pressure, body mass index (BMI), and neck/wrist/waist circumferences. The periodontal condition was evaluated by probing depth measurement in all remaining teeth. Pocket depth ≥4 mm indicates periodontitis. An AHI score was also recorded by polysomnography. Those with an AHI of five events/h or more were defined as OSA and categorized as mild, moderate, and severe with the AHI of 5–14, 15–29, and 30 times/h or more, respectively. The unstimulated whole‐saliva samples were collected and subsequently measured salivary flow rate and analyzed for the TFF3 level.2.2g under 4°C for 5 min. The supernatant was aliquoted into a 2 mL tube and stored at −80°C until TFF3 concentration (ng/mg) was measured using modified sandwich ELISA . We measured the unstimulated salivary flow rate by using the technique recommended by Navazesh . The cen2.3To quantify salivary TFF3 levels, we used our previously generated monoclonal antibody (mAb) clones 286 and 116 for a modified sandwich ELISA technique , while those with non‐normally distributed, data were presented as median (range). The inferential statistics were used to calculate differences between those with and without OSA. An independent p value of less than 0.20 by a univariate linear regression analysis were entered into the model and factors with a p value of less than 0.25 in the multivariate linear regression analysis were remaining in the final model. Results were reported as unadjusted/adjusted coefficients by linear regression analysis with p values. All statistical analyses were performed by using STATA software.Factors associated with TFF3 level and flow rate in patients with OSA were computed by using multivariate linear regression analysis: stepwise approach. Those with multicollinearity were excluded from the model. Factors with a 3p = .038) than the non‐OSA group. The OSA group also had more proportion of Berlin high‐risk category, snoring, body mass index, neck/wrist/waist circumferences, and AHI than the non‐OSA group. The OSA group had a median AHI of 18.6 events/hour and was categorized as mild , moderate , and severe . Besides, as the OSA group was elder than non‐OSA, 63% of them had periodontal disease with a pocket depth of 4–5 mm or more than 6 mm. The TFF3 and salivary flow rates between both groups were comparable . There was no significant difference of TFF3 and flow rate among OSA severities and control groups (Table p =  .276).There were 28 participants who were screened, recruited, and met the study criteria: 20 patients with OSA 71.42%) and 8 non‐OSA subjects. The OSA group was significantly different from the non‐OSA group in terms of OSA‐related factors except ESS (Table .42% and p = .042). For flow rate, there were three factors remaining in the final model (Table p = .044).Multivariate linear regression analysis showed that there were two factors remaining to be associated with TFF3 level: age and neck circumference    as shown in Table The strength of our study was enhanced by the multivariate model analyses. However, there are some limitations in this study. First, the sample size was small indicating preliminary results. However, significant predictors for TFF3 and salivary flow rate were present. Factors related to OSA and its treatment were not evaluated. Further larger studies are required to confirm the results of this study as this study population was collected from the university hospital setting. The results may not be generalized for the general population. Finally, there was no sample size calculation. With respect to the nonsignificant results, the study may not have enough statistical power to test its hypothesis.5TFF3 and salivary flow rate were comparable between patients with OSA and non‐OSA controls. The factor associated with TFF3 level was neck circumference, while age was negatively associated with the salivary flow rate in patients with OSA.Conception and design of study: Supanigar Ruangsri. Acquisition of data: Supanigar Ruangsri, Gintawat Doolgindachbaporn, Worrapon Chokwatwikul, and Kanchanaporn Wattanawareekul. Analysis and/or interpretation of data: Supanigar Ruangsri, Gintawat Doolgindachbaporn, Worrapon Chokwatwikul, Kanchanaporn Wattanawareekul, Subin Puasiri, and Kittisak Sawanyawisuth. Drafting the manuscript: Supanigar Ruangsri. Revising the manuscript critically for important intellectual content: Kittisak Sawanyawisuth. Approval of the version of the manuscript to be published: Supanigar Ruangsri, Gintawat Doolgindachbaporn, Worrapon Chokwatwikul, Kanchanaporn Wattanawareekul, Subin Puasiri, and Kittisak Sawanyawisuth.The authors declare no conflict of interest.


The efficacy of breast reconstruction for patients with N2‐3M0 stage female breast cancer (FBC) remained unclear due to the lack of randomized clinical trials. This retrospective study aimed to explore the efficacy of breast reconstruction for patients with N2‐3M0 stage FBC.Two thousand five hundred forty‐five subjects with FBC staged by N2‐3M0 from 2010 to 2016 were retrieved from the Surveillance, Epidemiology, and End Results database. Generalized boosted model (GBM) and propensity score matching (PSM) analyses and multivariable Cox analyses were employed to assess the clinical prognostic effect of postmastectomy reconstruction for patients with N2‐3M0 stage FBC in breast cancer‐specific survival (BCSS).p = 0.400) and GBM cohort . In the multivariate analyses, there was no difference in the effect of PMbR and mastectomy on BCSS in the original cohort , PSM cohort , and GBM cohort . Triple‐negative breast cancer (TNBC) was a detrimental factor affecting BCSS for patients in the PMbR group.Totally, 1784 candidates underwent mastectomy alone (mastectomy group), and 761 candidates underwent postmastectomy reconstruction (PMbR group), with 418 breast‐specific deaths after a median follow‐up time of 57 months (ranging from 7 to 227 months). BCSS in the mastectomy group showed no statistical difference from that in the PMbR group in the PSM cohort (HR = 0.93, 95% CI: 0.70–1.25, Our study demonstrated that PMbR is an oncologically safe surgical treatment and can be widely recommended in clinics for females with non‐TNBC staged by T0‐3N2‐3M0. Patients with FBC diagnosed from 2010 to 2016 were recruited with the criteria as follows: (1) primary tumor diagnosis of breast cancer; (2) Breast‐Adjusted American Joint Committee on Cancer (AJCC) 6th N2‐3 and M0 stage; (3) cancer‐directed surgery recode mastectomy with or without reconstruction.Data for this study were generated with the SEER*Stat program  unknown age at diagnosis, marital status, AJCC stage, survival time, estrogen receptor (ER) status, progesterone receptor (PR) status, or human epidermal growth factor receptor 2 (HER2) status; (2) the diagnosis methods of autopsy only or death certificate; (3) AJCC stage IV or N0‐1 and M0 stage; (4) missing surgical records or surgery not performed. Figure  unknown Subjects were followed up with a median follow‐up time of 3.50 years . The endpoint of this study was breast cancer‐specific survival (BCSS), defined as the time from the date of diagnosis until death related to breast cancer.2.2PSM and GBM analyses were performed to balance the baseline features between mastectomy and PMbR groups. Logistic regression analysis was established to calculate propensity scores by study variables. In the PSM analysis, the clinicopathological parameters were matched according to propensity scores with the ratio of 1:1 through the nearest neighbor matching with the caliper of 0.2 in mastectomy and PMbR groups.êx) into analytic weights and assessed the treatment effects of PMbR. The weight of the average treatment effect (ATE) was estimated as follows:Observations were weighted by the inverse of the calculated probability of receiving the observed sequence of treatments the individual received, referred to as an inverse probability of treatment weight (IPTW) analysis. As a machine‐learning method of implementing IPTW and based on a decision‐tree model, the GBM analysis could create complex models by combining multiple simple models through an iterative algorithm to produce a better predictive performance than any simple model, with no loss of sample size.For objects in the PMbR group:For objects in the mastectomy group:Each research object was given a corresponding weight for weighting through the propensity score value by the principle of the standardization method. Then, the distribution of the propensity score and confounding factors was consistent in each group. Pearson's chi‐square test, Fisher's exact test, and standardized mean difference (SMD) were applied to compare the differences between mastectomy and PMbR groups. SMD less than 0.1 indicated an excellent balance effect.p < 0.05 was considered to have statistical significance. Statistical analyses were conducted in software package R version 4.1.2. GBM was fitted using the TWANG R package (https://www.rand.org/statistics/twang.html).Hazard ratios (HR) with 95% confidence intervals (CIs) were calculated by the Cox proportional hazards model to estimate risk factors affecting BCSS. The Cox proportional hazards models were tested by the likelihood ratio and Wald test. Survival curves were plotted through the Kaplan–Meier analyses. Two‐sided 33.1p‐value  patients had undergone postmastectomy breast reconstruction (PMbR group), and 1784 (70.0%) patients had undergone mastectomy only (mastectomy group). The rate of PMbR increased from 26.1% in 2010 to 34.2% in 2016, with an absolute increase of 6.1% Figure  indicatee Figure , as welle Figure , indicat3.2p < 0.001; Figure p = 0.400) and GBM cohort . The cumulative incidence of 5‐year BCSS in the PMbR and mastectomy groups was 82.5% and 78.1% in the PSM cohort, 81.0% and 74.1% in the GBM cohort, and 79.2% and 72.0% in the original cohort, respectively.Subjects of the PMbR group tended to show more favorable BCSS in all the original cohort , GBM cohort , and original cohort  , T4 stage (p < 0.05), N3 stage (p < 0.05), triple‐negative subtype (p < 0.001), and two beneficial predictors of BCSS, radiotherapy (p < 0.05) and chemotherapy (p < 0.05), were revealed in the Cox analyses in all the PSM, GBM, and original cohorts.To ensure more robust results, the multivariate Cox analysis was conducted in the PSM, GBM, and original cohorts Table . There w3.4p = 0.039), T4 stage , N3 stage , and triple‐negative subtype  were still detrimental factors of BCSS. In addition, radiotherapy  was a protective factor of prognosis for patients who underwent mastectomy with reconstruction.To further estimate the unfavorable factors of PMbR, a multivariate Cox analysis was conducted in the PMbR group of the original cohort. As shown in Figure 3.5p = 0.010), T4 stage , N3 stage , and triple‐negative breast cancer (TNBC)  were unfavorable factors of BCSS for FBC patients with N2‐3 stage. The cumulative incidence of 5‐year BCSS was 73.3% in the grade III–IV subgroup, 67.3% in the T4 stage subgroup, 78.1% in the N3 subgroup, and 53.2% in the TNBC subgroup.Survival analyses were performed to explore the impact of histopathological grade, T stage, N stage, and molecular subtype on BCSS of patients in the PMbR group. As shown in Figure 3.6p = 0.377; PSM cohort: HR = 1.25, p = 0.169; GBM cohort: HR = 1.18, p = 0.176), histological type , and LN examined  had no independent impact on BCSS. In the sensitivity analysis, the HR of PMbR for BCSS was similar in the original cohort , PSM cohort , and GBM cohort  compared to the previous analysis.In order to examine whether there were other potential confounding factors not included in the PS calculation, sensitivity analysis was conducted by including three variables: tumor laterality, histological type, and the number of resected lymph nodes (LN). Table 4Owing to the deepening regarding of FBC, rapid development in oncological therapeutic areas, and establishment of its oncological safety profile in breast cancer treatment, the acquaintances and innovations in theories and reconstructive techniques of PMbR have evolved in recent years.As previously mentioned, the reconstructive technique of PMbR has been recommended to be eligible for all FBC patients with mammectomy by NCCN and ESMO guidelines.Clinical and pathological characteristics, such as age, histologic grade, marital status, stage, and so on, have always been regarded as essential criteria that help to establish reasonable clinical protocols in patients with FBC. This research revealed significant differences in the clinicopathological characteristics, such as age, married status, and chemotherapy status between the PMbR and mastectomy groups. To balance the differences between groups and supplement the lack of RCTs, both PSM and GBM analyses were performed. As a novel method of propensity scoring applied to medical research, the performance of GBM analysis played a vital role in balancing the clinicopathological features. It could overcome the disadvantage of wasting the sample size by PSM analysis, which was often used to make characteristics between groups balanced and comparable in observational studies.Kaplan–Meier analyses and multivariate Cox models are utilized to further estimate the effectiveness of PMbR for subjects with N2‐3M0 stage FBC. According to our survival analyses, the reconstructive technique of PMbR is safe for patients with N2‐3M0 stage FBC in comparison with those with mastectomy. This finding coincides with those reported in the literature that the reconstructive technique of PMbR is oncologically safe for patients with advanced nodal stage FBC.To further estimate the factors affecting BCSS and identify the patient suitable for PMbR surgery, a multivariate Cox analysis is performed on the clinicopathological features of patients in the PMbR group. In our study, grade III–IV in the degree of cell differentiation, T4 stage, and triple‐negative subtype FBC are adversely independent factors affecting BCSS for patients with N2‐3M0 stage FBC. Such results demonstrated that the assessment of appropriate patients suitable for PMbR should be carefully made. The surgery of PMbR could not be chosen for patients with T4N2‐3M0 stage or N2‐3M0 stage triple‐negative breast cancer as the standard treatment because they provide decreased BCSS. And PMbR could be recommended for females with non‐triple‐negative FBC staged by T0‐3N2‐3M0.There were some limitations in this study, so conclusions should be explained carefully. First, the retrospective design would suffer from potential biases, including selection bias, confounding bias, and so on. Second, potential confounding biases led by unmeasured factors, which were not available in the SEER database or we could not access, such as insurance status, socioeconomic status, education level, BMI, comorbidity, smoking status, etc.5In conclusion, this study found an increasing tendency for modern female patients with breast cancer of advanced nodal stage to choose breast reconstruction. And the reconstructive technique of postmastectomy reconstruction is a safe and efficient option of operative therapy and could be recommended for non‐triple‐negative FBC patients staged by T0‐3N2‐3M0.Yuting Zhao: Conceptualization ; formal analysis ; methodology (lead); software (lead); writing – original draft (lead). Lutong Yan: Formal analysis ; methodology ; writing – original draft . Shouyu Li: Data curation (lead); methodology ; visualization (lead). Zejian Yang: Software ; validation . Na Chai: Investigation ; software . pei qiu: Investigation . Huimin Zhang: Resources (lead). Jianjun He: Project administration (lead); supervision (lead); writing – review and editing . Can Zhou: Conceptualization ; funding acquisition (lead); writing – review and editing (lead).The authors declare that they have no competing interests.This study was approved by the Ethical Committee of the First Affiliated Hospital of Xi'an Jiaotong University. The SEER data erase the identity information of patients, so there is no need for informed consent from the patients.Supplementary InformationClick here for additional data file.


To assess seizure semiology and disease evolution in a large number of hypothalamic hamartoma (HH) patients.Seizure semiology and associated medical records for 78 patients with HH‐related epilepsy were retrospectively reviewed. Potential predictors of seizure types were assessed through univariate and binary logistic regression analyses.r = −0.445, p = 0.009). A significantly higher rate of patients with automatism in the DF‐II group relative to the DF‐III group was found in both χ2  and logistic regression analyses .57 (73.1%) patients presented with gelastic seizures at the onset of epilepsy, of whole 39 (68.4%) experienced additional seizure types with a mean latency interval of 4.59 years. Automatism, version, and sGTCs were increasingly common with disease evolution. The intraventricular size of HH was significantly negatively correlated with the disease evolution interval (Gelastic seizures are the most common initial seizure type in HH patients, but variable semiologies occur with disease evolution. The intraventricular HH lesion size is an important determinant of epilepsy evolution. DF‐II HH lesions contribute to a higher chance of automatism evolution. The present study furthers our understanding of the dynamic organization of the seizure network affected by HH. Hypothalamic hamartomas (HH) are benign brain lesions comprised of ectopic glial and neural tissue that are an important cause of treatment‐resistant epilepsy, especially in pediatric patients.In total, 78 patients that were evaluated at the epilepsy centers of Beijing Fengtai Hospital and Beijing Tiantan Hospital from August 2015–April 2022 were retrospectively analyzed for this study. HH was usually characterized by a T1 signal similar to that of the cortex and increased T2 signal strength in magnetic resonance imaging (MRI).Disease evolution was assessed based on detailed clinical recordings. All patients underwent video‐electroencephalography (VEEG) monitoring and the recording of habitual seizure events, with seizure types being determined based on a combination of this monitoring and clinical interviews. The following semiology components included in this study were selected based on our clinical experience and prior semiology reportsHigh‐resolution whole brain MRI scanning was performed for each patient with a 3T Siemens Verio scanner  via a 3D T1 sagittal magnetization prepared rapid gradient echo sequence , T2 axial , FLAIR axial , FLAIR sagittal , FLAIR coronal , T2 STIR axial , T2 STIR sagittal , and T2 STIR coronal  sequences.The Delalande and Fohlen (DF) classification system was then used to characterize these HH lesionsN = 5). MB involvement was considered evident when the interruption of the halo of T1 hyperenhancement surrounding these structures in contact with the HH mass was evidentThree primary zones along the mediolateral axis from the midline of the third ventricle were considered: the thin periventricular, medial, and lateral zones, with the latter two being separated by a sagittal plane passing through the anterior pillar of the fornix.t‐tests and ANOVAs. p < 0.05 was the significance level. Predictors of ictal seizure semiology were identified through binary logistic regression analysis.Semiologic elements for each patient were analyzed, with the semiology frequency being determined based on the number of patients with each element as a fraction of the total patient population. Given that DF‐I cases exhibit atypical clinical presentations and DF‐IV cases are rare, analyses of the relationship between anatomical characteristics and epilepsy evolution were conducted for patients in groups DF‐II and DF‐III. Evolution analyses were conducted for patients that exhibited GS as the initial seizure event and additional seizure types during disease evolution. The disease evolution period (DEP) was calculated as the interval between the onset of gelastic and non‐gelastic seizures. Categorical data were compared with Fisher's exact test, while continuous data were compared with p < 0.001). GS were present at the onset of epilepsy in 57 (73.1%) patients, with a mean age of 2.10 ± 2.46 years (range: 0.1–11 years) at seizure onset. With respect to the percentage of patients in these different groups presenting with GS at the time of initial epilepsy onset, significantly more patients in groups DF‐II , III , and IV  experienced GS during their first ictal event relative to group DF‐I  . Additionally, 39 of these patients (68.4%) exhibited other seizure types over the course of epilepsy evolution with a mean latency interval of 4.35 ± 3.89 years (range 0.1–13 years) and mean onset age of 7.22 ± 5.07 years (range: 0.9–21 years)  with a mean age of 3.8 ± 5.4 years (range: 0.1–29.0 years) at seizure onset and a mean age of 9.9 ± 8.7 years (range: 1.7–38.0 years) at time of VEEG evaluation. The mean disease duration for this patient cohort was 6.1 ± 6.5 years (range: 0.1–30 years). Precocious puberty was observed in 16 patients. Of these patients, 15, 30, 28, and 5 were classified into the DF‐I, DF‐II, DF‐III, and DF‐IV groups, respectively, with corresponding mean ages of seizure onset of 12.12 ± 7.17, 2.29 ± 2.34, 1.54 ± 1.53, and 0.75 ± 0.78 years old. Disease onset in group DF‐I was significantly later than in the three other groups  and 28.21% (22/78) of patients exhibited GS and GS+ semiology, respectively, while 7.69% (6/78) exhibited dacrystic seizures. Vegetative signs such as facial flush, elevated heart rate, and elevated respiratory rate often occur during the early phases of GS or GS+ and were observed in 33.33% (23/69) of these patients. GS frequency in group DF‐I  was lower than that in groups II , III , and IV .Ictal version occurred in 23 patients (29.49%), with similar prevalence rates in the DF‐I , II , III , and IV groups , exhibiting lateralization in 18 patients (78.3%). Automatism (29.49%), including manual and oral automatism, was also common in HH‐related epilepsy patients. Seizures with automatism were more common in the DF‐I  and II  groups relative to groups III  and IV . Of these patients, 32.05% exhibited sGTCs, with these rates being highest in group DF‐I (53.3%).Tonic seizures, including those involving the unilateral or bilateral extremities or axial tonic seizures, affected 14.10% of these patients. The prevalence rates for other seizure signs including blinking, clonic, spasms, and behavioral arrest were 14.10%, 3.85%, 16.67%, and 17.95%, respectively. For further details regarding the rates of these semiologic signs in each of these DF subgroups, see Fig. When analyzing disease duration, semiologic changes were grouped into short (<2 years), intermediate (2–5 years), and long disease duration (≥5 years) groups. GS percentages did not change significantly over the course of disease evolution, whereas the frequencies of semiologic signs, including autonomic signs , GS+ , automatism , ictal version , and sGTCs  rose with the prolongation of disease duration , children (3–12 years), and adolescent‐adult (≥12 years) groups. Automatism , ictal version  and sGTCs  frequencies rose with age of surgical evaluation. Epileptic spasms, in contrast, were most common in the infant group, with respective frequencies of 33.3%, 16.7%, and 3.7% in the infant, children, and adolescent‐adult groups . The mean volume of both the total HH lesions (1862.5 ± 1191.1 mm3) and the intraventricular portion of these lesions (652.5 ± 255.1 mm3) in DF‐III patients were significantly increased as compared to the mean total lesion volume in the DF‐II group . Pearson correlation analyses of group DF‐III patients revealed that the volume of the intraventricular portion of the HH lesion  rather than total lesion volume , was negatively correlated with DEP. Moreover, the volume of the intraventricular portion of the HH lesions in the DF‐II and DF‐III groups was significantly negatively correlated with DEP . Other topographical measurements, including the depth of invasion in the hypothalamus and the length along the anteroposterior axis of the hypothalamus, were also not significantly correlated with DEP.To analyze the relationship between anatomical dimensions and epilepsy evolution, 33 patients, including 17/30 and 16/28 in the DF‐II and DF‐III groups, respectively, were selected. The mean DEP in the DF‐II group (6.06 ± 3.98 years) was significantly longer than in the DF‐III group (2.78 ± 2.98 years) . Total HH volume , the volume of the intraventricular part of the HH lesion , MB completeness  were also significantly associated with the onset of ictal automatism.None of the analyzed predictors were significantly correlated with the onset of autonomic signs, version, dacrystic, blinking, tonic, clonic, spams, or sGTCs. Univariate analyses revealed DF classification to be a predictor of the onset of ictal automatism, with these rates being higher in group DF‐II relative to group DF‐III . As such, a binary logistic regression analysis of DF classification, disease duration, age at surgical evaluation, onset age, gender, and MB completeness was conducted to identify predictors of ictal automatism. This approach revealed that DF classification was a significant predictor of the onset of ictal automatism , which indicates that patients in group DF‐II are more prone to have ictal automatism than those in group DF‐III.Given that DF classification and HH volume were significantly correlated with one another, the total and intraventricular volumes of HH lesions were both excluded from logistic analyses. MB completeness did not differ significantly between patients in the DF‐II and DF‐III subgroups  GS was the most common seizure type at onset in this patient population (73.1%), with 68.4% of patients ultimately developing additional seizure types following a mean 4.35‐year latency period; (2) Ictal automatism, version, and sGTCs were all common seizure semiologies associated with the evolution of HH‐related epilepsy; (3) the volume of HH lesions, and particularly the volume of the intraventricular portion of these lesions, was closely associated with disease evolution such that smaller lesions were related to more gradual epilepsy evolution; and (4) patients with DF‐I HH lesions generally exhibited atypical seizure manifestations, including later disease onset and lower rates of GS at the time of epilepsy onset. In addition, DF‐II patients were at a higher risk of developing ictal automatism over the course of disease evolution as compared to DF‐III patients.Gelastic seizures are the characteristic seizure type in HH‐related epilepsy patients, often occurring initially during infancy or early childhood at a high frequency, occurring in clusters in some cases.Over the course of epilepsy evolution, many other seizure types generally develop in patients following initial GS presentation after a delay,DF type I HH lesions, also referred to as parahypothalamic hamartomas, can often result in central precocious puberty and, more rarely, can cause late‐onset epilepsy.There are multiple limitations to this study. For one, the age of seizure semiology onset was determined based on clinical interviews and medical records, and as a result, mild GS or other mild events occurring at an early age may have been overlooked. Secondly, seizure events associated with sGTCs incidence were determined based on medical records and could not be confirmed through objective video evidence. Third, neurodevelopmental evaluation and endocrine function were not incorporated into this study.In summary, the results of this large cohort study provide insight into seizure semiology and disease evolution in HH‐related epilepsy patients. The most characteristic semiology in these patients was GS, which frequently occurred during early childhood, followed by other seizure semiologies including ictal version and automatism with a mean 4.35‐year duration of onset. DF type II HH patients were also more likely to develop automatism over time. These results also suggest that the size of the intraventricular portion of an HH lesion is a key determinant of disease evolution, which indicates that the intraventricular part of HH is more important when intraoperatively targeting the lesion with ablation techniques, such as radiofrequency thermotherapy and laser interstitial thermotherapy. However, the preliminary results of the present study raise several issues for further research, including how the epilepsy network altered and evolved during DEP and network mechanism for the epileptogenesis of ictal automatism.Conception and design of study—Kai Zhang, Jian‐guo Zhang, Xiaoqiu Shao and Xiu Wang. Acquisition and analysis of data—Xiu Wang, Chang Liu, Zhong Zheng, Wenhan Hu, Chao Zhang, Xiaoli Yang. Drafting a significant portion of the manuscript or figures—Xiu Wang, Chang Liu, Zhong Zheng, Wenhan Hu.The present study was supported by National Natural Science Foundation of China , National Key R&D Program of China (2021YFC2401201) and Capital's Funds for Health Improvement and Research .The authors have stated that they had no interests which might be perceived as posing a conflict or bias.Figure S1 Diagram showing the anatomical relationship between the hypothalamus and an HH lesion, including the depth of lateral invasion (A) and the anterior–posterior dimension along the hypothalamus (B). In A, alphabet a represents the line between the fornix (arrow) and the mammillothalamic tract (asterisk) while line b corresponds to the lateral invading depth based on line a. In B, line a corresponds to the vertical line at the midpoint of the mammillary body based on the AC–PC line, while lines b and c correspond to the anterior and posterior dimensions along the hypothalamus.Figure S2. MB involvement was detected based on the completeness of a halo of T1 signal hyperenhancement on MRI images. (A–C) Respectively demonstrate a complete MB without any evidence of the interruption of the halo of signal hyperenhancement in the axial, sagittal, and coronal planes. (D–F) Demonstrate an incomplete MB signal in the axial, sagittal, and coronal planes, respectively. MB, mammillary body.Click here for additional data file.


Previous studies have linked gut microbiota with cancer etiology, but the associations for specific gut microbiota are causal or owing to bias remain to be elucidated.We performed a two‐sample Mendelian randomization (MR) analysis to assess the causal effect of gut microbiota on cancer risk. Five common cancers, including breast, endometrial, lung, ovarian, and prostate cancer as well as their subtypes  were included as the outcomes. Genetic information for gut microbiota was obtained from a genome‐wide association study (GWAS) comprising 18,340 participants. In univariable MR (UVMR) analysis, the inverse variance weighted (IVW) method was conducted as the primary method, with the robust adjusted profile scores, weighted median, and MR Egger used as supplementary methods for causal inference. Sensitivity analyses including the Cochran Q test, Egger intercept test, and leave‐one‐out analysis were performed to verify the robustness of the MR results. Multivariable MR (MVMR) was performed to evaluate the direct causal effects of gut microbiota on the risk of cancers.Sellimonas predicted a higher risk of estrogen receptor‐positive breast cancer , and a higher abundance of class Alphaproteobacteria was associated with a lower risk of prostate cancer . Sensitivity analysis found little evidence of bias in the current study. MVMR further confirmed that genus Sellimonas exerted a direct effect on breast cancer, while the effect of class Alphaproteobacteria on prostate cancer was driven by the common risk factors of prostate cancer.UVMR detected a higher abundance of genus Our study implies the involvement of gut microbiota in cancer development, which provides a novel potential target for cancer screening and prevention, and might have an implication for future functional analysis. We found that sarcopenia and cachexia have different effects on OS for PDAC patients undergoing radical excision by studying the data of 614 PDAC patients. To comprehensively investigate the role of gut microbiota in the issue of cancer incidence, the MR analyses were conducted at five distinct feature levels, including phylum, class, order, family, and genus. The study design accompanied by the fundamental MR assumptions was presented in Figure 2.2https://mibiogen.gcc.rug.nl/.The genetic information of gut microbiota was accessed from a largest GWAS conducted by the MiBioGen consortium, comprising 18,340 participants from 24 cohorts (~78% Europeans).The summary GWAS data for BC was obtained from the Breast Cancer Association Consortium (BCAC) consisting of 122,977 cases and 105,974 controls, and all the participants were of European ancestry.Summary data for EC and its histologic subtypes (endometrioid and non‐endometrioid subtypes) were obtained from a large‐scale GWAS consisting of the Endometrial Cancer Association Consortium (ECAC), the Epidemiology of Endometrial Cancer Consortium (E2C2), and the UK Biobank, involving up to 12,906 cases and 108,979 health controls from European ancestry.We obtained summary‐level statistics of LC from the International Lung Cancer Consortium (ILCCO) comprising 11,348 patients with lung cancer and 15,861 controls .For overall invasive epithelial ovarian cancer, we used the GWAS statistics from the Ovarian Cancer Association Consortium (OCAC), comprising up to 25,509 cases and 40,941 controls of European ancestry.The associations of SNPs with PC were obtained from the GWAS study from the Prostate Cancer Association Group to Investigate Cancer‐Associated Alterations in the Genome (PRACTICAL) Consortium, consisting of 79,148 cases diagnosed with prostate cancer and 61,106 controls of European descent.https://gwas.mrcieu.ac.uk/).Specifically, the GWAS data for these cancers were deposited at the Integrative Epidemiology Unit (IEU) Open GWAS Project  were eliminated. If SNPs could not be found in the outcome datasets, proxies at the threshold of LD r2 > 0.8 were used if applicable. Finally, we aligned the effect alleles of the exposure‐ and outcome‐SNPs through harmonization, and excluded those with incompatible alleles  or being palindromic with intermediate allele frequency.211 bacterial taxa were grouped into five taxonomic levels . Fifteen bacterial taxa were unknown and thereby were excluded from our study, making 196 bacterial taxa remained. Considering the limited number of SNPs available, we used the SNPs at a lenient 2.4For Univariable MR analysis (UVMR), the random‐effects inverse‐variance weighted (IVW) method was performed as the primary analysis for causality inference, for which the Wald ratio estimates were combined to elicit a pooled effect on the outcome.p < 0.05/n, where n is the number of bacterial taxa included in each feature level). Hence, the multiple‐testing significance was 5.56 × 10−3, 3.13× 10−3, 2.5 × 10−3, 1.56 × 10−3, and 4.20 × 10−4, respectively, for phylum, class, order, family, and genus. We also considered a nominal significance level for the MR estimates at p < 0.05.For the primary MR results, multiple‐testing significance was determined at each feature level using Bonferroni correction  analysis was undertaken to appraise whether the pooled estimation was biased by any high‐influence point.Given that the composition of gut microbiota could be influenced by endocrine factors and diet habits, UVMR could not reflect a direct effect of gut microbiota on cancer incidence as these endocrine factors or diet habits could also influence cancer risk. To determine whether the observed significant effect of bacterial taxa on cancer was a direct or indirect impact, we further conducted multivariable MR analysis (MVMR) accounting for the traditional risk factors of the cancers.All analyses were performed based on the R program (version 4.0.0) using the “TwoSampleMR” package (version 0.5.4) and the “Mendelian Randomization” package (version 0.5.1).3In total, 196 bacterial taxa  were included for MR analysis Table . After r3.1The preliminary associations between bacterial taxa at distinct taxonomic levels and the five common cancers derived from IVW were presented in Figure Sellimonas was significantly associated with an increased risk of ER+ BC . We also observed that a genetically predicted higher abundance of class Alphaproteobacteria was causally associated with a decreased risk of PC . The consistent direction and magnitude of the estimates from other MR models, including RAPS, WM, and MR‐Egger regression, further supported the causal inferences , orders , families , and genera  on at least one of the cancers ; formal analysis ; methodology ; software ; validation ; writing – original draft ; writing – review and editing . Biying Yang: Conceptualization ; methodology ; writing – original draft ; writing – review and editing . Tiantian Tang: Investigation ; methodology ; software ; supervision ; validation ; writing – review and editing . Zijing Xiao: Validation ; visualization ; writing – review and editing . Fengzhan Ye: Visualization ; writing – review and editing . Xiaoyu Li: Validation ; writing – review and editing . Shangbin Wu: Supervision ; validation ; writing – review and editing . Jin‐gang Huang: Supervision ; writing – review and editing . Shanping Jiang: Conceptualization ; data curation ; project administration (lead); writing – review and editing .The authors declare no conflicts of interest.In the present study, we only utilized publicly available summary data, and the Ethics approval and consent to participants could be obtained in the original GWAS.Figure S1.Click here for additional data file.Table S1–S2.Click here for additional data file.


Several groups proved kidney‐sparing surgery (KSS) had equivalent oncological outcomes compared with radical nephroureterectomy (RNU) for the low‐risk upper urinary tract urothelial carcinoma (UTUC) patients. Whereas, the clinical efficacy of KSS for high‐risk UTUC, especially for distal high‐risk ureteral carcinoma, remains unclear.To evaluate the feasibility of KSS for patients with distal high‐risk ureter cancer.Our study included 22 patients who diagnose the distal high‐risk ureter cancer and underwent KSS between May 2012 and July 2021 in the First Affiliated Hospital of Chongqing Medical University. Overall survival (OS), confirmed as the primary endpoint of present study, was assessed by a blinded independent review committee (BIRC). The secondary endpoints included the postoperative SF‐36  score, progression‐free survival (PFS), postoperative complications, and so on.Overall, 17 (77.3%) and 5 (22.7%) patients underwent segmental ureterectomy (SU) and endoscopic ablation (EA), respectively. By the cut‐off date, the mean OS was 76.3 months (95% Cl: 51.3–101.1 months) and the mean PFS was 47.0 months (95% Cl: 31.1–62.8 months), respectively. And the SF‐36 score in a majority of patients was >300 (90.9%).This is a daring endeavor to explore the clinical efficacy of KSS in distal high‐risk ureter cancer based on the high‐risk UTUC criteria, which shows satisfactory results in the long‐term prognosis and operation‐associated outcomes. However, future randomized or prospective multicenter studies are necessary to validate our conclusions. We explored the clinical efficacy of kidney‐sparing surgery (KSS) in distal high‐risk ureter cancer based on the high‐risk UTUC criteria, which was a daring endeavor. In present study, the long‐term prognosis and operation‐associated outcomes were all satisfactory, even in patients with relatively advanced TNM stage. Future randomized or prospective multicenter large‐scale researches remains necessary for further validation. Upper urinary tract urothelial carcinoma (UTUC) accounts for approximately 5–10% of urothelial cancers, while ureteral cancer represents only a third.KSS, known as a series of surgery, includes ureteroscopy, ureteral resection, and so on. Several researchers have demonstrated patients with low‐risk UTUC undergoing KSS showed a similar survival to who undergoing RNU. Thomas S et al. reported a large‐sample study recruiting 2,299 patients which showed KSS, comparing with RNU, for low‐risk UTUC reduced the morbidity such as renal dysfunction, without sacrificing oncological outcomes.Although KSS is not preferred for high‐risk ureter cancer in each guideline, in daily clinical work, some patients with high‐risk ureter cancer and relatively poor physical fitness desire KSS, largely due to the slighter adverse reaction of postoperative adjuvant chemotherapy and less complications after surgery. Accordingly, KSS has been gaining more and more attention in the evaluation before surgery. And we found that the patients underwent KSS had well life qualities, with a similar survival to those underwent RNU. Meanwhile, more hemorrhage and longer operation time of RNU,In summary, we conducted this study to assess the safety and feasibility of KSS in distal high‐risk ureter cancer patients. And we wished that present study could provide a reference for the selection of patients better suited to undergo KSS.22.1The study was approved by the Institutional Ethics Board of the First Affiliated Hospital of Chongqing Medical University. We retrospectively collected data on patients who underwent KSS at the First Affiliated Hospital of Chongqing Medical University between May 2012 and July 2021. Diagnosis of ureter cancer could be confirmed by biopsy, cytology with a mass on cross‐sectional imaging, or cytology with ureteroscopic mass visualization. All the patients were assessed as high‐risk UTUC according to EAU guidelines (version 2021). Patients who followed up less than 6 months or those receiving neoadjuvant therapies were excluded. Meanwhile, the ones with end‐stage renal disease or solitary kidney were also counted out.In our study, the clinicopathologic characters, collected from the computerized medical records, of all the participants were retrospectively reviewed. The study was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice guidelines. All data were anonymized before accession and thus the requirement for informed consent was waived by the ethical committee, considering the retrospective nature of this study.2.2SU was performed according to the standard criteria: extrafascial dissection of the lesion with wide margins and complete bladder cuff excision. Complete tumor resection or destruction was assessed by individual surgeons in the EA. Specifically, in our medical center, all the KSSs were undergone in distal ureter cancer in consideration of the increasing operative difficulty and risk in upper ureter cancer. Most importantly, surgeons stress emphasized the primary standard therapy of high‐risk UTUC. Each patient was informed of the risk of recurrence and those underwent EA were informed that it's of vital importance to conduct an early second‐look ureteroscopic and stringent surveillance. All patients followed up every 12 weeks after surgery. Otherwise, the relations would receive a follow‐up call. Blood losses were estimated during operation by the surgeon. All postoperative complications were monitored and graded according to the Clavien–Dindo classification.2.3p values are two‐sided and statistical significance was set at <0.05. The Kaplan–Meier estimate was employed to calculate and plot survival curves. Our primary clinical outcome was overall survival (OS) which was assessed by the blinded independent review committee (BIRC). The secondary endpoints included QOL, progression‐free survival (PFS), and postoperative complications. All analyses were performed with SPSS 25.0 software.All reported 33.1Between May 2012 and July 2021, 22 KSSs were performed, of which 17 (77.3%) were SU while 5 (22.7%) were EA, including 15 (68.2%) male and 7 (31.8%) female patients. The median age was 68 years (range: 38–91 years). At baseline, most patients (72.7%) showed hydronephrosis on computerized tomography (CT), and 17 (77.3%) were demonstrated high‐grade pathology. Four patients had BCa histories, which were all diagnosed as high‐grade UC and had undergone transurethral resection of the bladder (TURB). Four (18.2%) patients underwent cystoscopies while other six (27.3%) patients underwent ureteroscopies before surgery in order to confirm the feasibility of KSSs. None of the participants suffered from upper or middle ureter cancer. Demographic and perioperative parameters are listed in Table 3.2By the cut‐off date of February 10, 2022, the mean OS was 76.3 months (95% Cl: 51.3–101.1 months) and the mean PFS was 47.0 months (95% Cl: 31.1–62.8 months), respectively. The median PFS was 60 months (95% Cl: 0.0–144.3 months) while the median OS was not reached , 1 in 11 patients (50.0%), 2 in 7 patients (31.8%), and 4 in 2 patient (9.1%). Meanwhile, the SF‐36 score in a majority of patients was >300 (90.9%). The QOL and the adverse events were listed in Table 3.4The mean operative time was 101.9 ± 47.8 min, and the median estimated blood loss was 50.0 ml (range: 10.0–360.0 ml). Mean hospitalization duration was 8.9 ± 7.0 days, where none of the patients was transferred to the intensive care. The major intraoperative complications were intestinal injuries and major vascular injuries, each seen in one patient . Pathologic and operation‐associated outcomes are given in Table Intuitively, the brief characters and outcomes were showed in Table 4Compared with RNU, which excises the entire section of ureter and the ipsilateral kidney, KSS straightly removes or extirpates the tumor and retains the ipsilateral kidney. As we all know, it's a broad trend to improve minimally invasive operation for surgical diseases. And increasingly patients demand of KSS because of psychological factors or other reasons. Importantly, based on less loss of kidney function, KSS might become an alternative on account of it providing more choices for subsequent care such as probably postoperative adjuvant chemotherapy. Besides, continually updated disease risk stratification also led to a favorable rise in KSS for selected patients like those with localized, unifocal, and distal ureter tumors.KSS and RNU, in patients with low‐risk UTUC, showed comparable oncologic outcomes, which was proved in several articles. Simhan J et al. evaluated 1,227 patients with low‐ or moderate‐grade, localized non‐invasive UTUC, which showed similar cancer‐specific mortality rates between RNU group and KSS group.In our study, KSS showed a median PFS of 60 months and a mean OS of over 6 years, not worse than that of patients underwent RNU in most of articles. Based on our experience, maybe distal ureter cancer, relatively small sized tumor, and no distant metastasis gave the main assists. And we collected nearly all the high‐risk ureter cancer patients in our medicine center, who had undergone KSS, according to the EAU guidelines without excessive exclusive criteria, avoiding missing any high‐risk patients. Thus, our study is still valuable for analyzing the feasibility of KSS among distal high‐risk patients.Regrettably, the rate of bladder recurrence is 22–47%, even though undergoing RNU for UTUC.SF‐36 sore was rarely reported in researches for KSS even in those for low‐risk ureter cancer. Almost all of the participants have a score of >300, which were similar or even better than those before operation. Surprisingly, a patient whose preoperative ECOG was 1 and tumor confined within the mucosal layer had a SF‐36 score of 767.9. In current clinical practice, KSS brought satisfactory QOL to most of the patients, even though to the patients that had disease relapses within 6 months. Nearly half of them were willing to undergo adjuvant chemotherapy and all of them survived over 12 months except a stage‐T3 patient. Furthermore, KSS had showed consistent benefit to the QOL across all the subgroups, including patients with recurrence or metastasis. Of the 8 patients who had determined disease progression, only 1 patient had a relatively lower SF‐36 score less than 300, probably because of the pre‐operative poor ECOG of 3 and the relatively advanced TNM staging(T3N2M0). For this patient, who had a preoperative ECOG score of 3, the families of that patient chose KSS even though we informed them the lymph node metastases during the operation, large due to the probable severe complications of RNU.KSS was well tolerated in our study. Only one patient suffered from Clavien II complications which were treated by total parenteral nutrition. And more than half of the patients were discharged within 1 week. At 1 month after surgery, 11 patients complained of frequent urination, e8 of them complained of gross hematuria, and 2 of them complained of occasional pain. After further investigation of the case data, 8 of the 11 patients with frequent urination were all male patients over 60 years old, with full prostate on pre‐operative CT, so the symptoms of frequent urination may be associated with prostate hyperplasia. Among the eight patients with gross hematuria, two still had intermittently gross hematuria after 3 months, which was considered to be due to their advanced staging , larger wound area in the surgical area and older age. This single‐arm study did not compare KSS with RNU because nearly all the patients with localized distal ureter tumor underwent KSS. And due to the lack of cases with ureteral cancer in the particular location, the sample size was too small to demonstrate the superiority of KSS exactly. Besides, this study based on Chinese resident have not explored therapeutic effects by ethnicity or race.5In conclusion, we conducted daring endeavors in KSS for distal high‐risk ureter cancer. In present study, KSS performed well in the long‐term prognosis and operation‐associated outcomes. The KSS cohort had a satisfactory QOL without compromising oncological outcomes, even among the patients with relatively advanced staging, indicating that KSS has the potential to become a treatment option for several selected patients with distal high‐risk distal ureter cancer. However, whether KSS is appropriate for upper ureter cancer is still a controversial problem. And KSS needs to be carried out in patients with high compliance due to the possible underlying risks. Future randomized or prospective multicenter large‐scale researches are necessary for validation of the value of KSS for patients with high‐risk ureter cancer.Yu Jiang: Conceptualization ; formal analysis (lead); methodology ; software (lead); writing – original draft (lead); writing – review and editing . Yueqiang Peng: Data curation (lead); investigation ; validation (lead); writing – review and editing . Siwei Ding: Investigation ; visualization ; writing – review and editing . Yongbo Zheng: Methodology ; supervision ; visualization ; writing – review and editing . Yunfeng He: Project administration . Jiayu Liu: Conceptualization (lead); funding acquisition (lead); methodology ; project administration ; supervision .The authors declare that they have no competing interest.