Despite the growing body of research concerning affective relationships between teachers and ethnic minority students, very little is known about student‐teacher relationship (STR) quality for religious minority students. Many Islamic schools have a mixed workforce consisting of both Muslim and non‐Muslim teachers. This means that the quality of religiously congruent and religiously incongruent STRs can be directly compared.We investigated whether the quality of the STR experienced by Dutch Islamic school students depended on the religious background of their teacher (Muslim vs. non‐Muslim). We also examined the role of teachers’ implicitly measured attitudes towards Muslims as a possible explanation for differences in relationship quality.Mage = 10.02 years, SD = 1.25) and their 35 teachers .Participants were 707 students  from 35 classes (Grade 3–6) , and teachers’ implicit attitude towards Muslims (vs. non‐Muslims) was measured with an Implicit Association Test.Students reported relatively high levels of closeness and low levels of conflict and negative expectations for both Muslim and non‐Muslim teachers. Conflict was slightly higher in religiously incongruent STRs, but only when teachers’ implicitly measured attitude towards Muslims (vs. non‐Muslims) was included in our model.Results of this study indicate that religious incongruence does not play a major role in STR quality in Islamic primary education. The affective relationships between primary school students and their teachers have been studied with increasing interest in the last decades  also belong to religious minority groups , there is a lack of research on STRs quality in religious minority students. In Western Europe, Muslims constitute a salient minority group that faces much prejudice and discrimination , and less conflict (H2) and negative expectations (H3) in the STR if their teacher was Muslim versus non‐Muslim. Additionally, we hypothesized that teachers’ implicitly measured attitude towards Muslims (vs. non‐Muslims) would be positively associated with closeness and negatively with conflict and negative expectations, and – given the difference in this attitude between Muslim and non‐Muslim teachers in our previous study (masked reference) – partly mediate the relationship between teachers’ religious background and students’ perceptions of closeness (H4), conflict (H5), and negative expectations (H6) in the STR. We controlled for children’s gender, grade level, and teachers’ gender and years of teaching experience, as previous studies indicate that boys and older children tend to have less positive relationships with their teachers Baker,  and thatIn total, 43 Islamic primary schools were approached to participate. At the time of the data collection (spring 2017) there were 49 Islamic primary schools in the Netherlands. Six of these schools had Muslim teachers only and were not approached to take part in this study. Fifteen schools did not respond or declined participation, 14 schools could not be contacted, and four schools agreed to participate but responded too late. Ten schools agreed to participate. After the school boards agreed to participation, teachers were asked for their active consent to participate in the study. Parents received an informed consent letter and had the opportunity to object to participation of their child. The participation rate of the students was 98.3%. Data were collected during school hours. Children filled out the questionnaires anonymously, while teachers filled out a questionnaire on their background characteristics and took an implicit association test (IAT). Children were able to ask one of the researchers for help when they did not understand a question properly.SD = 1.25; range 8–14 years). All students were Muslim but from different ethnic backgrounds. Most children identified themselves as Moroccan (43.0%), Turkish (28.4%), or other (23.5%), 1.4% self‐identified as Dutch, and 3.6% of the students did not report their ethnicity. The 35 participating teachers  had a mean age of 32.94 years (SD = 6.37). Twenty teachers identified themselves as Muslim and 15 teachers as non‐Muslim. Most teachers had a Dutch origin (42.9%) of which 57.14% identified themselves as non‐believers, 28.57% as Christian, and 14.28% as Muslim. Followed by Moroccan , Turkish , and other (8.7%) of which 50% were Christian, 25% Muslim, and 25% had no religion. On average, the teachers had 7.51 years (SD = 5.77) teaching experience, and 4.83 years (SD = 4.43) in Islamic schools specifically.The final sample consisted of 707 students  from 35 classes (Grade 3 to 6). Students’ mean age was 10.02 years , conflict  and negative expectations  All items had a five‐point Likert‐type scale with the following response options; 1 (No!), 2 , 3 (Sometimes), 4 , and 5 (Yes!). Previous research has provided support for the validity and reliability of the measure among a representative sample of primary school students in the Netherlands  = 388.74, p <.001, CFI = .91, TLI = .90, RMSEA = .052. Cronbach’s was α = .84 for closeness, α = .83 for conflict, and α = .69 for negative expectations.The Dutch version of the Student Perception of Relationship with Teacher Scale  and the valence of words . Prior research has established that IAT measures have satisfactory internal consistency and test‐retest reliability for use in correlational studies  was then taken to be an indicator of a teacher’s implicit attitude towards Muslims versus non‐Muslims. Higher scores indicated a greater preference for Muslims over non‐Muslims. The internal consistency of this IAT, calculated by the method described by Bosson, Swann, and Pennebaker  were taken into account as covariates. There were no missing values for the teacher data. There were few missing data at the student level (<2.5%), which were handled by the full information maximum‐likelihood (FIML) method , multilevel analyses were performed in MPlus  level and a within (student) level. The relations of interest were all situated at the between level, as the independent variable and mediating variable (teacher religion and implicitly measured attitude) were assessed at the class level and contained no variance at the within level. Likewise, the covariates teachers’ gender, age, years of teaching experience, years of experience in Islamic schools, and students’ grade were between level variables. At the within level, student gender was included as a covariate. All categorical predictors were entered as dummy variables. Continuous variables were grand‐mean centreed before they were entered in the models. In a first step, all predictors, including the covariates, were included in the model, Next, non‐significant relations were set to zero to obtain the most parsimonious models .The multilevel model included a s Kline, . The sigz tests). The set level of significance was 5%. Model fit was evaluated based on the Akaike Information Criterion (AIC), root‐mean‐square error of approximation (RMSEA), the comparative fit index (CFI), and the chi‐square. Smaller values of the AIC indicate better fit, an RMSEA below.05 indicates good fit of a model, and values between.05 and.08 indicate reasonable fit. Values above.10 indicate poor fit. A CFI above .90 indicates acceptable fit and above.95 indicates good fit of a model  = 0.214, p = .831) or conflict (t(460.12) = −1.70, p = .090)), but there was a significant difference in negative expectations, t(498) = 2.71, p = .006, with higher scores for Turkish versus Moroccan students . Therefore, student ethnicity was added as a covariate (dummies) in subsequent analyses. In addition, we tested whether students’ STR reports differed based on whether they had the same ethnicity as their teacher. Most students had a different ethnicity than their teacher  and for N = 178 students (26.4%) there was an ethnic match. Ethnic match (yes/no) was not significantly related to TSR quality.Although the focus of this study is on religion rather than ethnicity, we explored whether the TSR differed between students with different ethnic background, by comparing the two largest ethnic groups, that is, students with Turkish and Moroccan backgrounds. The other groups were too small to include in this comparison. Results of t(19.85) = −3.81, p = .005, d = 1.13. For the Muslim teachers, it was significantly higher than zero, t(19) = 6.12, p <.001, suggesting a preference for Muslim over non‐Muslims, but for the non‐Muslim teachers, it did not differ significantly from zero, t(14) = −0.70, p = .497, suggesting a neutral attitude. Table Table X2(23) = 47.777, p = .002; AIC = 5049.603; RMSEA = .039; CFI = .960. Results are shown in Table A multilevel model was specified to test the hypotheses simultaneously. This model fitted the data well, X22 = 47.777b = −.14, p = .028, indicating that students of Muslim teachers reported less conflict compared with students of non‐Muslim teachers, when the other effects were controlled for. The corresponding standardized coefficient indicated a medium‐sized effect for this difference, b* = −.38. The indirect relation between teacher religion and conflict via teachers’ implicitly measured attitude was statistically significant. However, contrary to our expectations (H5), this effect was positive, as teachers’ implicitly measured attitudes towards Muslim children were related to more conflict. Moreover, the direct effect of teacher religion on conflict was significant and negative. Together, these findings indicate that teacher religion had two opposite effects that counteracted each other, resulting in a small total effect. Additionally, we tested a model in which we excluded implicitly measured attitudes. In this model, there was no significant relation between teacher religion and conflict, b = −.07, p = .395.1Overall, we obtained little support for our hypotheses. Teacher religion was not significantly associated with closeness (H1) and negative expectations (H3) in the STR, and the indirect effects of teachers’ religion on both variables (H4 and H6) via their implicitly measured attitude were not significant. Still, in line with H2, a significant total effect was found of teacher religion on conflict, With regard to the covariates (not shown in the figure), it was found that female students reported more closeness, less conflict, and more negative expectations compared with male students. Additionally, it was found that students in higher grades reported less negative expectations. Students furthermore reported more closeness with female teachers compared with male teachers and less conflict with more experienced teachers.Prior research has shown that minority students can be at risk for developing less favourable affective relationships with their teachers  in relationship quality with Muslim versus non‐Muslim teachers. Contrary to expectations, teachers’ attitude was related to more rather than less conflict – something that we will further discuss below – and this relation suppressed the direct effect of teacher religion. Thus, the lower rates of conflict in religiously congruent STRs emerged under the rather unlikely condition that Muslim and non‐Muslim teachers had a similar attitude.We examined three aspects of student‐reported STR quality  in Islamic primary school children, and we tested whether their teacher’s implicitly measured attitude towards Muslims (vs. non‐Muslims) mediated the relations between the teacher’s religious background and these three relationship aspects. We expected that the quality of the perceived STR would be better for Muslim students with a Muslim versus a non‐Muslim teacher. This was the case for conflict, but not for closeness or negative expectations. Consistent with previous findings on ethnically incongruent STRs  with their teacher, regardless of religious background. Moreover, although we did not use the exact same items, these relationship reports seem to be better than those obtained in similar research among ethnic minority students (mostly Turkish and Moroccan) at regular primary schools , teachers’ implicit attitudes toward Muslim students’ may be confounded with their attitudes towards ethnic minority students as most Muslim students also have an ethnic minority background. By combining implicit measures towards religious and ethnic minority groups, future research could examine the possible overlap between both types of attitude targets. Despite its shortcomings, our research has two strengths beyond those already mentioned. To our knowledge, it is the first study to examine affective STRs in the context of religious instead of ethnic differences. In addition to this, it responds to the need for more studies on the effects of implicitly measured teacher attitudes on real students, rather than hypothetical ones in experimental or vignette research ; Data curation ; Formal analysis ; Investigation ; Methodology ; Project administration ; Writing – original draft ; Writing – review & editing . Lisette Hornstra: Conceptualization ; Formal analysis ; Methodology ; Supervision ; Writing – review & editing . Jochem Thijs: Conceptualization ; Methodology ; Supervision ; Writing – review & editing .


When handover is conducted at the patient's bedside, active patient participation can be encouraged, which may improve the safety and quality of care. There is a need for valid and reliable tools to measure patient perceptions of participation in bedside handover, to ensure the rising number of implementation and improvement efforts are consistently and effectively evaluated. The aim of this study is to systematically develop and evaluate the psychometric properties of a self‐report survey to measure patients' perceptions of participation in bedside handover.n = 130). In Phase 2, content validity was assessed with four health consumers, four nurses and four researchers. Next, 10 current hospital inpatients tested the survey for end‐user satisfaction. In Phase 3, 326 inpatients completed the survey, allowing exploratory factor analysis, reliability analyses and convergent/divergent validity analyses to occur.In Phase 1, our team developed a conceptual framework and item pool (Phase 1 and 2 resulted in a 42‐item survey. In Phase 3, 321 surveys were available for analysis. Exploratory factor analysis revealed a three‐factor solution, with 24 items, which matched our conceptual framework. The three factors were: ‘Conditions for patient participation in bedside handover’, ‘Level of patient participation in bedside handover’ and ‘Evaluation of patient participation in bedside handover’. There was strong evidence for factor reliability and validity. Additionally, the correlation between factors was strong.This study furthers our conceptual understanding by showing that nurse facilitating behaviours are a strong precursor for patient participation and perceived handover outcomes, justifying the need for nursing training. A robust survey has been developed to measure patient perceptions of participation in bedside handover, which can effectively evaluate this approach to care. Engaging consumers and nurses as research team members was invaluable in ensuring that the survey is acceptable for end‐users.A health consumer and nurse partnered as members of the research team from study inception to dissemination. There are various ways that patients can participate in bedside handover, such as listening to, adding, clarifying, asking or answering questions and/or identifying missed information.Invariably, nurses determine handover location without consultation with the patient.Publications about implementing, improving and sustaining bedside handover are sharply increasing.1.2The aim of this study was to systematically develop and psychometrically evaluate a self‐report survey to measure patients' perceptions of participation in bedside handover. To achieve our aim, we: (1) inductively and deductively generated a conceptual framework to underpin survey development and an item pool; (2) pilot‐tested the survey for end‐user satisfaction and evaluated content validity and (3) fully evaluated the survey by undertaking exploratory factor analysis (EFA), reliability analyses and convergent/divergent validity analyses.22.1In Phase 1, a conceptual framework was developed based on theory and our systematic review. Next, items were developed based on our conceptual framework, existing measures, our systematic review and previous qualitative and quantitative work. Phase 2 followed an exploratory cross‐sectional approach involving pilot testing of the item pool for content validity and end‐user satisfaction. Phase 3 was an evaluative cross‐sectional design adopting a correlational analytic approach to evaluate the psychometric quality of the instrument. All phases of the research had human research ethics approval from Gold Coast Hospital and Health Service (HREC/2019/QGC/50604) and Griffith University (2019/414). All participants were provided verbal and written ethics‐approved information and return of survey implied consent.2.22.2.11.Conditions for patient participation in bedside handover: A state where both patients and nurses have met the conditions for active patient participation in bedside handover. Nurse conditions include their interpersonal style and behaviours that encourage patient participation and their information‐sharing behaviours that need to be adapted to the individual. Patient conditions include their individual characteristics such as their capacity to participate in bedside handover.2.Level of patient participation in bedside handover: An evaluation of levels of patient behaviour and preferences. For behaviour, it is the extent of participation a patient undertakes in bedside handover. Patient participation includes nurse–patient communication about health information, and the levels range from passive to active patient participation. Health information includes topics like patient symptoms, capabilities or usual regimens, and patients may communicate by sharing information and asking questions. Patients may also participate nonverbally, for example by listening to nurse communication. For preference, it is an assessment of their preferred levels of participation.3.Evaluation of patient participation in bedside handover: An assessment of whether the level of participation a patient experienced was what they desired and resulted in positive outcomes like perceived quality of the interaction, the nurse–patient relationship, adaptation to the individual, patient understanding and patient satisfaction.Our team developed a conceptual framework based on theory and empirical literature to guide item development. Nurse–patient communication conceptual models by Fleischer et al.2.2.2An initial list of 130 items was generated that were believed to appropriately map the conceptual framework we developed. Two surveys were found related to patient participation in bedside handover, which were developed in a robust manner.2.3Next, content experts established content validity over two rounds. The content expertize of consumers, nurses and researchers was sought due to their experience, practice or research relating to bedside handover. In Round 1, four consumers, four nurses and four researchers participated, and in Round 2, one consumer, one nurse and one researcher from Round 1 participated. Eighteen items were removed based on Polit and Beck'sstrongly disagree, 2 = disagree, 3 = agree and 4 = strongly agree).Next, the list of items was formatted into a survey. We followed Pett et al.'sThe survey was tested with current hospital inpatients for final end‐user satisfaction. Full details are provided in Supporting Information: File 2.42.4.1This study was conducted on five wards in one Australian metropolitan tertiary hospital, including (1) gastrointestinal medicine and surgery; (2) cardiology medicine; (3) neurology medicine; (4) vascular medicine and surgery and (5) head and neck, urology and gynaecology surgery.2.4.2Inclusion criteria were inpatients aged ≥18 years who had experienced ≥1 bedside handover. Exclusion criteria were patients physiologically unstable or not mentally capable of participation , or patients unable to read English. Research Assistants screened all patients on the ward on a given day of data collection and met with the Nurse Unit Manager or their delegate to determine participants who met the inclusion and exclusion criteria. Once eligible participants were identified, the Research Assistant approached the patient providing a written (ethics‐approved information sheet) and verbal description of the project. The survey was provided to the patient in paper format with a pen. Participants had the option to complete the survey independently. The Research Assistant returned at an agreed upon time to collect the survey. Some participants required assistance completing the survey, such as patients who were unable to write due to their injuries, the Research Assistant completed responses for these participants as required.The minimum number of cases required for a ‘good’ sample and EFA is 300.N = 40 nurses (who were involved in the same bedside handover patient participants most recently experienced) completed the process section of the ‘Quality improvement and audit tool for nurse‐to‐nurse bedside clinical handover in ward settings’.To support validity analyses, a sample of 2.4.3Contextual and demographic informationParticipants were asked to report their age, gender and number of nights spent in the hospital during the current admission. Additionally, participants were asked questions about the bedside handover they were reflecting on when completing this survey including: ‘when did your most recent bedside handover happen?’ ‘handover was close to my bedside, so I could participate’, ‘a family/friend/carer/significant other was present during the most recent bedside handover’, ‘I felt well enough to participate during the most recent bedside handover’, ‘this was my first bedside handover ’ and ‘did you share your room with another patient during your most recent bedside handover?’.Patient participation in bedside handovern = 42) generated and refined in Phase 1 and 2 of this study were presented to patients on a paper‐based survey. The survey had three sections relating to the three constructs in our conceptual framework. Participants were asked to think about a recent bedside handover they had experienced when completing the entire survey. To match the style of the items, two sections had the response options: 1 = strongly disagree, 2 = disagree, 3 = neutral, 4 = agree and 5 = strongly agree and one section had the response options: 1 = not at all, 2 = slightly, 3 = moderately, 4 = considerably and 5 = a great deal (see Supporting Information: File Items (2.4.4The FACTOR programme and Mplus (v8) packages were used for all analyses. To explore the internal structural validity of the 42 items, EFA was conducted. EFA was appropriate since the instrument is new and its dimensional structure and therefore, the optimal scoring approach is unknown. The analyses adopted three foci: (1) evaluation of overall model fit for the factor solutions; (2) evaluation of item performance and (3) evaluation of the performance of each extracted factor. Please see Supporting Information: File h2 < 0.30) with weak primary loadings (<0.63 using the benchmark of 0.63 as ‘very good’)An intentionally large item pool was generated to maximize content domain coverage. Therefore, strict item retention criteria were adopted to eliminate poorly performing items and ultimately, minimize respondent burden when completing the final instrument. After extracting the most accommodating factor solution (seven‐factor) solution, item adequacy was appraised using multiple indicators. Items with low overall communality , which is an assessment of the reliability of the factor scores. ORION values >0.80 indicate the precision of the factor score estimates.Finally, evidence for the construct validity of the factors was assessed with convergent correlation coefficients between patient and nurse reports, and converging patient demographics, such as age, gender, closeness of handover to bedside and patient rating of feeling ‘well’ enough to participate.2.5Recently, a systematic review of patient engagement in survey development studies identified that no surveys were coconstructed with patients from item development through to the validation phase.‘The Partnership Analysis Tool’ was delivered to the consumer (M. S.), nurse (K. J.) and lead researcher (G. T.) every 6 months to monitor their partnership.3n = 185, 57.8%). The handover that patients reflected on when completing the survey was close to the bedside to enable participation  and in private rooms . For 266 (85.3%) patients, it was not their first handover and they felt well enough to participate . A family/friend/carer/significant other was only present for 19 (6.1%) handovers.From November 2020 to January 2021, 354 patients were approached for participation and provided with a survey, of those 326 returned completed surveys, representing a 92.1% response rate. Due to ethical requirements at the hospital, we were unable to ask patients why they declined, but patients that voluntarily provided this information indicated reasons, such as feeling too unwell, had visitors present, were not interested in participation or were frustrated with being in hospital. Participants had a mean age of 61.3 years (SD = 17.2 years), were in the hospital for a median of three nights (interquartile range = 4) and were mostly males  = 2884.19, p < .001. Upon investigation, it appeared that participants were more likely to complete questions earlier in the survey than later, providing a possible reason for a significant MCAR test. To address missing data, a hot‐deck multiple imputation approach designed for use in EFA was used.Of the surveys returned, five were removed as they had ≥50% missing data. Of the 321 surveys retained in the final analyses, the missing values were 2.26%. Little's missing completely at random (MCAR) test was significant, indicating missing data was systematic 3.1Horn's parallel analysis and Schwarz's (BIC) dimensionality text suggested a three‐factor solution, while the Hull method supported a unidimensional solution. Using all 42 items, Kaiser's criterion, which is known to over‐estimate the number of factors,Decisions about a number of factors to extract were coincident with the analysis of item performance. Beginning with the most accommodating factor solution (seven factors), an iterative approach was taken to evaluate item performance using the criteria specified above. Items were removed one at a time, before re‐estimating the EFA to further interrogate items.p < .05) onto three factors represented a statistically and theoretically sound solution. Keiser's criterion, Horn's parallel analysis and Schwarz's (BIC) dimensionality text converged in supporting the three‐factor solution. The Hull method, once again, favoured a unidimensional solution.In the final solution, 26 items loading strongly and significantly (adjustedχ2 (200) = 91.58, p = 999, χ2/df = 0.44, root mean square error of approximation < 0.01 , comparative fit index > 0.99, Tucker–Lewis index = 0.1.01, standardized root mean squared error = 0.04. The three factors combined explained 80.6% of variance in the 24 items. Table Following this item‐removal process, model fit for the three‐factor solution was excellent, The three factors closely aligned with our initial conceptual framework of patient participation in bedside handover, and thus labels used in our conceptual framework were used to name factors. Based on an interpretation of the content of the highest loading items, Factor 1 represents conditions for patient participation in bedside handover. Factor 2 represents the level of patient participation in handover, particularly with respect to the communication. Finally, Factor 3 represents the evaluation of patient participation in bedside handover.3.2α estimates are good to excellent as follows: Factor 1 = 0.96 , Factor 2 = 87  and Factor 3 = 96 .Table 3.3r = .53, 95% CI: . Factors 2 and 3 were very strongly correlated, r = .78, 95% CI: . Finally, Factors 1 and 3 were strongly correlated, r = .63, 95% CI: . As these three dimensions are theoretically linked, these strong associations provide evidence for the convergent validity of the scales. Discriminant validity for each factor is evidenced by the larger average item‐factor loading  relative to the average interfactor correlations .The interfactor correlations were significant and strong, corroborating the use of an oblique rotation approach. Factors 1 and 2 were strongly correlated, R2 = .94, p < .001), ‘level of patient participation in bedside handover’  and ‘evaluation of patient participation in bedside handover’  and nurse observer reports.Patient reports on the three extracted factors were regressed onto a group of nurse respondent questions to determine if patient reports could be externally corroborated. These results show very high and significant overlap between patient report of ‘conditions for patient participation in bedside handover’  and moderately higher ratings of ‘level of patient participation in bedside handover’  when they reported they were well enough to participate compared with participants who reported they were not well enough to participate . As might be expected, the evaluations of benefits from bedside handover did not vary as a function of patients self‐rated health status , F = −1.76, p = .080, d = −0.50.Participants provided much higher ratings of ‘conditions for patient participation in bedside handover’ . The number of nights the patient had stayed in the hospital correlated weakly with ‘conditions for patient participation in bedside handover’ , however, did not correlate with ‘level of patient participation in bedside handover’ or ‘evaluation of patient participation in bedside handover’ .As displayed in Table 4We developed the patient participation in bedside handover survey, a 24‐item survey, comprising three reliable factors, which supports our initial conceptual framework of patient participation in bedside handover (see Supporting Information: File In our study, many nurse disposition items were retained in ‘conditions for patient participation in bedside handover’, and whether patients' perceived nurses were close to the bedside strongly influenced this factor. This confirms the importance of nurses' facilitating behaviours as critical to the success of patient participation in handover. Other researchers have shown that nurses can control patient participation by displaying or not displaying inviting actions,Notably, fewer items about patient conditions loaded on all factors. Researchers have demonstrated that patients have a strong preference for handover to occur at the bedside,Retained items for ‘level of patient participation in bedside handover’ related to patient information‐exchanging behaviours. This is consistent with evidence from other Australian and Swedish patients who rank being able to speak as one of the most important features of bedside handover.All items that we generated for the construct ‘evaluation of the benefits of patient participation in bedside handover’ were retained. This confirms that the perceived outcomes that were developed sufficiently covary and represent the variation in patient perceptions of outcomes of handover. As systematic review findings suggest, both individual benefits for patients, like feeling involved and confident, and relational benefits, like having improved relationships and trust with nurses, were items retained in our survey.4.1As per the GRIPP2 checklist, the consumer, nurse and lead researcher reflected on the process of consumer and clinician engagement.4.2Our study highlights that nurses' behaviours are a core condition for active patient participation in handover and patients' perceived outcomes. Educators for undergraduate nurses and nurses in the clinical workforce should provide training for nurses to provide them with the skills to promote patient engagement. Items in ‘conditions for patient participation in bedside handover’ could guide training on important facilitating behaviours to entrench in nurses, while ‘level of patient participation in bedside handover’ could guide training on ways to engage patients in handover. In novel work by Barello et al.,There are many future directions for the survey. We know that routine communication encounters like handover are not always used to their full potential to promote meaningful patient participation.5Our team of consumers, nurses and researchers rigorously developed a survey to measure patient perceptions of participation in bedside handover. This survey has the potential to increase the quality of evaluation of bedside handover implementation and improvement efforts. Using a systematic and partnership design, we reduced the items from 130 to a more precise set of 24 that represent three valid and highly reliable constructs. Our understanding of the concept of patient participation in bedside handover has been clarified as a result of the factors that have emerged. For example, we found less value in measuring patient conditions for bedside handover, while the importance of nurses' facilitating behaviours for reaping handover benefits cannot be understated. Additionally, there is variation in how patients engage in handover, including sharing information, asking questions and planning care, an important consideration for tailoring care to the individual patient. Involving consumers and nurses in all phases of this research study strengthened the survey developed; we recommend that research teams monitor consumer and clinician engagement throughout the research study to ensure true engagement in the research process occurs.The conception and design of the study: Georgia Tobiano, Andrea P. Marshall, Kim Jenkinson, Margaret Shapiro, Michael Ireland. Acquisition of data: Therese Gardiner. Analysis and interpretation of data: Georgia Tobiano, Andrea P. Marshall, Therese Gardiner, Kim Jenkinson, Margaret Shapiro, Michael Ireland. Drafting the article or revising it critically for important intellectual content: Georgia Tobiano, Andrea P. Marshall, Therese Gardiner, Kim Jenkinson, Margaret Shapiro, Michael Ireland. Final approval of the version to be submitted: Georgia Tobiano, Andrea P. Marshall, Therese Gardiner, Kim Jenkinson, Margaret Shapiro, Michael Ireland.The authors declare no conflict of interest.Supplementary information.Click here for additional data file.


Statistically significant correlations were found between 5‐International Index of Erectile Function and age, hypertension, diabetes, Epworth sleepiness scale, apnoea‐hypopnea index score, O2 saturation‐nadir, and oxygen desaturation index. Age, diabetes and O2 saturation‐nadir were independent predictors of erectile function. Epworth sleepiness scale, apnoea‐hypopnea index score, O2 saturation‐nadir, oxygen desaturation index and albumin were higher compared to patients without erectile dysfunction. No statistically significant differences were reported for drug‐induced sleep endoscopy patterns and erectile dysfunction. Patients with obstructive sleep apnoea were at significant risk of having erectile dysfunction. Males with obstructive sleep apnoea should be investigated for erectile dysfunction.This cross‐sectional study aimed to investigate the prevalence and clinical characteristics of erectile dysfunction in patients with obstructive sleep apnoea. We enrolled 133 male patients with suspected obstructive sleep apnoea. Ear, nose and throat evaluation, laboratory tests, body mass index, Epworth sleepiness scale, 5‐international index of erectile function, overnight ambulatory polygraphy and drug‐induced sleep endoscopy patterns were assessed. Eighty patients reported obstructive sleep apnoea. 60% ( The estimated prevalence in the general population ranges from 9% to 38%, with over 100 million people affected worldwide , with erectile function scores, in order to evaluate the potential impact of those parameters.2This prospective cross‐sectional study was approved by the Research Ethics Board of the University of Naples “Federico II” (n. 316/20) and was conducted according to the World Medical Association Declaration of Helsinki Guidelines. All patients gave their written informed consent to the study. From January 2018 to November 2019, we evaluated 133 consecutive male patients complaining snoring, sleepiness, morning dry mouth and tiredness compatible with suspected OSA  and the 5‐International Index of Erectile Function (IIEF‐5) questionnaires. The ESS (range 0–24), is an eight‐item questionnaire used to assess the propensity to fall asleep in various circumstances, with a cut‐off of ≥10 points indicating excessive daytime sleepiness , prolactin (PRL), luteinizing hormone (LH), and follicle‐stimulating hormone (FSH) —were obtained from all subjects at the time of the enrolment in the study. C‐reactive protein (CRP), albumin, total cholesterol, low‐density lipoprotein (LDL), high‐density lipoprotein (HDL) cholesterol and triglycerides were assessed as well. The height and weight of all patients were measured, obtaining Body Mass Index (BMI) according to the formula weight (Kg)/height (m)2.2All subjects underwent overnight ambulatory RP  according to the American Academy of Sleep Medicine Guidelines  was performed, in order to evaluate potential surgical treatment candidates and clinical mismatches.DISE was performed employing a flexible rhinopharyngolaryngoscope  in the operating theatre using a propofol target‐controlled infusion (TCI) to achieve a complete evaluation of the upper airways (UA) collapse. Bispectral Index (BIS) was used to check the level of sedation during DISE. Blinded VOTE classification scoring was used for classifying the type of obstruction detected at DISE. The VOTE classification represents a method to assess the type of obstruction, based on the collapse and closure of the airway of different oropharyngeal structures . Descriptive statistics were obtained and reported as means and standard deviations for continuous variables while frequencies and percentages were reported for categorical variables. Normality of data was tested with the Kolmogorov–Smirnov test and parametric tests were used accordingly. Power analysis for sample size assessment was conducted considering, according to current literature, a 50% of prevalence of erectile dysfunction among OSA patients, accordingly to alpha = 0.005 and beta = 0.2 , were diagnosed with ED. Laboratory data and RP parameters are reported in Table According to polygraphic parameters, 80 male patients were diagnosed with OSA, met inclusion criteria and were enrolled in the study Figure . 16 . Multiple linear regression analysis showed that age, diabetes, and SaO2‐nadir statistically significantly predicted IIEF‐5   = −2.646; p = 0.010]. Similarly, the mean AHI score in ED subjects was 32.1 ± 16 whereas in non‐ED subjects was 24.5 ± 12.8 ; with analogous results for ODI  and SaO2‐nadir (%) . Age was also significantly different between ED and non‐ED patients with a mean 57.94 ± 8.96 versus 50.56 ± 7.75 respectively .Among 48 ED patients, 45.8% reported mild ED (IIEF‐5 score: 17–21), 27.1% mild to moderate ED (IIEF‐5 score: 12–16), 20.8% moderate ED (IIEF‐5 score: 8–11) and 6.3% severe ED (IIEF‐5 score: 5–7). The main EES score was 9.13 ± 5.2 compared with 6.63 ± 3.24 in non‐ED patients . In addition, a higher prevalence of diabetes was, reasonably, found in ED patients  . Among possible causative factors linking ED and OSA, increased oxidative stress with reduced vasodilation and bioavailability of nitric oxide (NO), increased levels of catecholamines and endothelin, sleep fragmentation, reduced amounts of REM sleep, daytime sleepiness, impaired vigilance, prolonged bulbocavernosus reflex latency and decreased level of testosterone are considered the most important . In our study, we found a slightly higher level of albumin in OSA patients with ED. This data is in contrast with different studies reported in the literature that correlates hypoalbuminemia and ED in patients with chronic hepatitis and cirrhosis  and IIEF‐5. In addition, to our univariate results and the mean differences in values among OSA patients with and without ED, multiple logistic regression analysis showed that age, diabetes and SaO2‐nadir were independent predictors of IIEF‐5  and consequently of ED. Our model showed a worsened IIEF‐5 score of −0.164 points for every year of age and −3.33 points for the presence of diabetes, whereas, for every 1% increase in SatO2‐nadir, IIEF‐5 score improved by 0.558 points. Despite the relatively small sample size, these data pointed out that the treatment and prevention of diabetes is essential to prevent ED, especially in patients with OSA, where diabetes itself represents an important comorbidity and a predictor of the ineffectiveness of phosphodiesterase‐5 inhibitors (PDE5‐I) therapy  clinic with OSA are at significant risk of having ED. Therefore, males with OSA should be investigated for ED.Elena Cantone, Matteo Massanova and Felice Crocetto conceived and designed the study; Elena Cantone, Matteo Massanova, Fabrizio Corlianò, Fabio Esposito and Luigi Romano collected the data; Biagio Barone and Elena Cantone interpreted and analysed the data; Elena Cantone, Matteo Massanova and Biagio Barone wrote the manuscript; Davide Arcaniolo, Luigi Romano, Gaetano Motta, Elena Cantone, Biagio Barone and Antonio Celia revised the manuscript.The authors declare no conflict of interest.The present study protocol was reviewed and approved by the institutional review board of “Federico II” University of Naples (Reg No. 316/20). Informed consent was submitted by all subjects when they were enrolled.


Helicobacter pylori infection and virulence factors in the induction of CD55 and its association with histological changes of the human gastric mucosa remain incompletely understood. We hypothesised that CD55 would be increased during infection with more virulent strains of H. pylori, and with more marked gastric mucosal pathology. RT‐qPCR and immunohistochemical analyses of gastric biopsy samples from 42 H. pylori‐infected and 42 uninfected patients revealed that CD55 mRNA and protein were significantly higher in the gastric antrum of H. pylori‐infected patients, and this was associated with the presence of IM, but not atrophy, or inflammation. Increased gastric CD55 and IM were both linked with colonisation by vacA i1‐type strains independently of cagA status, and in vitro studies using isogenic mutants of vacA confirmed the ability of VacA to induce CD55 and sCD55 in gastric epithelial cell lines. siRNA experiments to investigate the function of H. pylori‐induced CD55 showed that CD55 knockdown in gastric epithelial cells partially reduced IL‐8 secretion in response to H. pylori, but this was not due to modulation of bacterial adhesion or cytotoxicity. Finally, plasma samples taken from the same patients were analysed for the soluble form of CD55 (sCD55) by ELISA. sCD55 levels were not influenced by IM and did not correlate with gastric CD55 mRNA levels. These results suggest a new link between active vacA i1‐type H. pylori, IM, and CD55, and identify CD55 as a molecule of potential interest in the management of IM as well as GC treatment. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.High‐level expression of decay‐accelerating factor, CD55, has previously been found in human gastric cancer (GC) and intestinal metaplasia (IM) tissues. Therapeutic effects of CD55 inhibition in cancer have been reported. However, the role of  Helicobacter pylori is the primary cause of gastric cancer (GC), the fifth most common malignancy worldwide and the fourth leading cause of cancer‐related death  assay  24 h after H. pylori co‐culture. In brief, after supernatants were harvested for ELISA, cells were incubated with fresh medium containing 0.5 mg/ml MTT for 3 h at 37 °C. Subsequently, the medium was removed and 500 μl of 0.04 m hydrochloric acid in isopropanol and 50 μl of 10% SDS were added to each well. The absorbance of solutions was measured at a wavelength of 595 nm. A decrease in absorbance indicates a reduction in the number of viable cells. For bacterial adhesion assays, cells were washed twice with PBS and harvested by scraping in 1 ml of PBS. Ten‐fold serial dilutions of cell suspensions were spotted onto blood agar plates and colonies counted after 3–5 days’ incubation under microaerobic conditions.AGS  and ACTB  (both Qiagen) with Power SYBR Green Master Mix (Thermo Fisher Scientific). Relative CD55 levels were calculated using the Pfaffl method [ACTB, and as fold‐differences compared with pooled antral biopsies from uninfected patients.Total RNA was extracted from gastric biopsies using an RNeasy Mini Kit . After DNase treatment using a TURBO DNA‐free Kit, RNA was reverse‐transcribed into cDNA using a High‐Capacity cDNA Reverse Transcription Kit (both Thermo Fisher Scientific). qPCR was performed on a Rotor‐Gene 3000 using QuantiTect Primer Assays for l method , normaliH. pylori. Immunostaining was performed using Novolink Polymer Detection Systems . In brief, after antigen retrieval with citrate buffer (pH 6.0) for 20 min, sections were incubated with rabbit anti‐human CD55 mAb , rabbit anti‐human CD4 mAb  or rat anti‐human Pax‐5 mAb  at 4 °C overnight. For Pax‐5 staining, sections were further incubated with rabbit anti‐rat IgG (Abcam) for 30 min at room temperature. After incubation with Rabbit Novolink polymer (anti‐rabbit Poly‐HRP‐IgG) for 30 min at room temperature, staining was visualised with DAB, followed by haematoxylin counterstain. Mucosal CD55 was assessed independently by two scientists and a histopathologist using light microscopy, blinded to the endoscopy findings, histopathological scores, and RT‐qPCR results. CD55 immunohistochemistry scores were calculated by multiplying staining intensity  by staining distribution , and observers’ scores were averaged. Staining on lymphoid aggregates was excluded from the scoring.Gastric biopsy sections were stained with H&E, blinded, and scored by an expert gastrointestinal (GI) pathologist for inflammation, atrophy, and IM, using the updated Sydney System . This grsCD55 and IL‐8 were quantified using the Human CD55/DAF ELISA Pair Set  and IL‐8 Human Uncoated ELISA kit (Thermo Fisher Scientific) respectively, following the manufacturers’ instructions.m PMSF. Cellular proteins (10–20 μg) were electrophoresed through 10% SDS‐PAGE gels, transferred to nitrocellulose membranes, and probed with anti‐CD55  and anti‐β‐actin  antibodies at 4 °C overnight. Membranes were then incubated with alkaline‐phosphatase‐conjugated goat anti‐rabbit secondary Ab  at room temperature for 1 h and visualised using BCIP/NBT substrate (Sigma‐Aldrich).After washing with PBS, cells were solubilised in radioimmunoprecipitation assay buffer containing 0.1 p < 0.05 was considered statistically significant.All statistical analyses were carried out using GraphPad Prism 9 software . The tests used are indicated in the figure legends. H. pylori infection was associated with CD55 expression in the gastric mucosa, RT‐qPCR was performed on patient biopsies. In the antrum, CD55 mRNA was significantly increased in H. pylori‐infected compared with uninfected patients  in a dose‐dependent manner . While significantly reduced sCD55 and CD55 proteins were seen in knockdown cells  cells, we found no association of CD55 or IM score with cagA status in gastric biopsies. Additionally, almost half of vacA i2 strains were cagA+, and IM and CD55 were present in three of four patients infected with cagA−vacA i1 strains. Therefore, the observed associations are likely to be CagA‐independent.Our data showed that both high CD55 and IM were more common in individuals infected with h others , we founH. pylori. The mechanism is unlikely to involve modulation of bacterial adhesion or cytotoxicity because bacterial attachment and cell viability were similar in CD55 knockdown and control cells. Additionally, gastric CD55 was enhanced in areas of IM which generally occur at a later stage of infection, suggesting that CD55 is not a main adhesin for H. pylori. We and others have previously shown that MAPK and/or NF‐κB pathways regulate H. pylori‐induced IL‐8 expression [et al demonstrated that H. pylori induces CD55 via activation of the p38 MAPK pathway independently of NF‐κB signalling in gastric epithelial cells [cagT4SS and VacA have been shown to activate the p38 MAPK pathway, but our previous data suggest that IL‐8 expression by gastric epithelial cell lines is cagT4SS‐dependent but independent of VacA [Results from our siRNA experiments suggest that CD55 partially regulates the IL‐8 response of epithelial cells to pression , 39, 40,pression . The woral cells , suggest of VacA , 43, whi of VacA , an inte of VacA . CDX2 ma of VacA , 47. FutH. pylori status. CD55 is expressed on the cell surface of nearly all peripheral blood cells and is present on a wide range of tissues [In our cohort, no association was found between plasma sCD55 and IM, AG or  tissues . Since w tissues ; therefo tissues .H. pylori‐infected human gastric mucosa and provide a new insight into the role of VacA in the development of GC. There is a great deal of interest in preventing the progression of IM to GC. Further longitudinal studies of the link between CD55 and progression of IM could demonstrate the potential of CD55 as a therapeutic target, as previously explored in colorectal cancer [In conclusion, our data strengthen the evidence for an association between CD55 and IM in the l cancer .KK, KR, JCA and IS conceived and designed the study. KK, AMZ, DPL, JLR, JCA and JT carried out the experiments. KK, AMZ, DPL and KR analysed and interpreted the data. All the authors were involved in writing the manuscript and approved the final version.Figure S1.CD55 mRNA in human gastric corpusFigure S2. CD55 is present in H. pylori‐induced lymphoid aggregatesFigure S3.H. pylori increases expression and secretion of CD55 in gastric epithelial cellsFigure S4. Characteristic morphological changes in gastric epithelial cells infected with H. pylori mutantsFigure S5. CD55 expression and secretion in gastric epithelial cells after infection with H. pylori strains of different vacA genotypesFigure S6. CD55 knockdown in gastric epithelial cellsClick here for additional data file.


P > 0.05). The relative risk for fatigue, muscle ache, or exercise intolerance was equal between persons with and without SCD . No episodes of metabolic crisis were recorded in non‐carnitine‐supplemented persons with MCADD and SCD. In some persons with MCADD, SCD resolved without carnitine supplementation. There is absence of real‐world evidence in favor of routine carnitine analysis and carnitine supplementation in the follow‐up of persons with MCADD.Our aim was to study the effect of secondary carnitine deficiency (SCD) and carnitine supplementation on important outcome measures for persons with medium‐chain Acyl–CoA dehydrogenase deficiency (MCADD). We performed a large retrospective observational study using all recorded visits of persons with MCADD in the University Medical Center Groningen, the Netherlands, between October 1994 and October 2019. Frequency and duration of acute unscheduled preventive hospital visits, exercise tolerance, fatigue, and muscle pain were considered important clinical outcomes and were studied in relation to (acyl)carnitine profile and carnitine supplementation status. The study encompassed 1228 visits of 93 persons with MCADD. >60% had SCD during follow‐up. This included only persons with severe MCADD. Carnitine supplementation and SCD were unrelated to the frequency and duration of the acute unscheduled preventive hospital visits ( The disorder has had a prevalence of 1:8000 in the Netherlands since the introduction of population newborn bloodspot screening (NBS).N‐N‐N‐trimethylaminobutyrate) facilitates the transport of activated long‐chain fatty acids from the cytoplasm to the mitochondrial matrix. In non‐vegetarians, approximately 75% of carnitine is provided by diet  and 25% from de novo biosynthesis from the amino acids' lysine and methionine. Only 0.5% of the carnitine circulates; plasma levels are very low (40–60 μmol/L) compared to tissue concentrations (2–3 mmol/kg in the muscle up to 800–1500 mmol/kg in the liver).Carnitine .2.2ACADM genotype historically associated with clinical ascertainment, or residual MCAD activity <10%. Mild MCADD was defined by an ACADM genotype that has never been associated with clinical ascertainment and residual MCAD activity >10%, as previously published.This was a monocenter, retrospective, observational cohort study of the plasma carnitine concentrations and clinical outcomes of all persons with MCADD with a recorded visit in the electronic health record system of the University Medical Center Groningen, Groningen, the Netherlands, between October 1994 and October 2019. Persons were excluded when (a) the diagnosis was established after death, (b) no plasma (acyl)carnitine profile was analyzed in our center, or (c) severe comorbidity likely interfered with outcome measures. Severe MCADD was defined by an 2.3Management of our MCADD population is based on the national clinical care pathway, of which the first version dated from 2012, and was recently updated.2.4Concentrations of TC‐ , C0‐ (free), C2‐ (acetyl‐), C6‐ (hexanoyl‐), C8‐ (octanoyl‐), and C10‐ (decanoyl‐) carnitine, as well as the C8/C10 ratio, were obtained from dried blood spots or blood plasma samples by flow‐injection tandem mass spectrometry.2.5Data were divided into age categories corresponding to important changes in growth and feeding patterns: neonates (0–6 days), “full lactation,” that is, receiving frequent feedings (6–8 bottles/day) and presenting with rapid growth (7–55 days), infants (56 days to 19 months), preschool (20 months to 4 years), school age (5–10 years), adolescence (11–17 years), and adulthood (18–80 years), based on previous studies on age‐related differences in AC concentrations.All analyses were performed using R . Descriptive statistics were used for all continuous data including means, medians, ranges (min‐max), standard errors (SE), and 95% confidence intervals (95% CI). Comparisons between groups with normally distributed data were done using the Student's T‐test if variances were equal, and with Welch two‐sample t‐test, if variances were unequal. In the case of non‐normal distribution, groups were compared using Wilcoxon rank‐sum tests with continuity correction. R packages. Linear mixed modeling was chosen as it can handle the non‐independent nature of our data  and the missing data (occurring due to the retrospective nature of our study). As fixed effects, we entered disease severity, gender, and the number of acute unscheduled preventive hospital visits  in the period before the visit into the model, without interaction terms. As the random effects, we entered patient and age categories (as described above 2.5). Model assumptions were verified by visual inspection of residuals versus fitted values and residuals Q‐Q plots. To meet the assumption of normality, AC data were normalized by log transformation. P‐values were obtained by restricted maximum likelihood ratio tests of the full model with effect in question against the model without effect in question. P‐values < 0.05 were considered significant.To study possible influences on the most disease‐specific AC for MCADD, we fitted linear mixed‐effect models (LMMs) with normalized total C, C0‐, C2‐, C6‐, C8‐, C10‐, and C8/C10 ratio using the “lme4”  and “lmerTest” 33.1SYT2 (OMIM:*600104), which led to long‐term hospitalization, mechanical ventilation, and prolonged nasogastric feeding. The case is described in detail elsewhere.The cohort encompassed 1228 visits of 93 persons with MCADD (representing 959 years of follow‐up) .A total of 476 AC profiles were analyzed, equaling a mean of 1 carnitine profile per patient every 2 years of follow‐up. Most persons with MCADD  displayed SCD at some point during follow‐up. This included only persons with severe MCADD. SCD was found in 24% of the measured profiles (116/476). SCD was relatively most prevalent among preschoolers and adults  of persons during 392 visits. On average, a carnitine dose of 35 mg/kg/day was given (range: 0.4–234 mg/kg/d). In 21% (24/116), SCD was observed during a visit despite carnitine supplementation (doses ranging from 8 to 38 mg/kg/d).3.2P > 0.05) . Gastroenteritis, fever, and vomiting were the main reasons for admittance. The median age at acute unscheduled preventive hospital visits was 2.0 years (range: 4 days to 27 years). Carnitine supplementation and SCD were not related to the frequency and duration of the acute unscheduled preventive hospital visits  , compared to non‐supplemented visits. In three persons, carnitine supplementation was (re)started or the dose was increased specifically for these symptoms. All reported improvement of complaints within 3–4 months, however, acylcarnitine profiles were not systematically analyzed before, during, and after symptoms. In the other eight persons, the indication for carnitine supplementation was either previous low‐normal C0 concentrations, previous SCD, or not documented.Specific symptoms such as fatigue, muscle ache, and exercise intolerance were recorded in 38 visits of 18 persons, all with severe MCADD. The median age at which these symptoms occurred was 12 years (range: 2.5–43 years). In 11 of these 18 persons, during 23 of the 38 visits, carnitine was supplemented with doses ranging between 7 and 46 mg/kg/d. The relative risk (RR) for these specific complaints during a visit while receiving carnitine supplementation is 3.2 . Conditional means of the C0 concentration are equal during life in persons with MCADD exhibiting and not exhibiting these symptoms at some point during follow‐up, irrespective of supplementation status  of these visits, SCD was found, with C0‐carnitine concentrations of 13.7, 5.4, 15.2, and 13.7 μmol/L (reference range: 16–55 μmol/L). The latter three profiles were analyzed while carnitine was supplemented in the respective doses of 7, 30, and 24 mg/kg/d. RR for specific complaints is equal for persons during visits where they have SCD compared to those having C0‐carnitine concentration in the range  were found deficient during multiple visits. No episodes of acute severe metabolic crisis were recorded in these persons . C0 concentrations fluctuated and sometimes normalized without interference Figure .2 ranged from 0.235 for C10 to 0.933 in C8/C10.The results of LMMs for disease‐specific AC can be seen in Table P‐value = 0.015) lower in persons with severe compared to mild MCADD. Also lower in severe persons with MCADD were concentrations of C0‐carnitine  and C2‐carnitine . Higher in severe persons were concentrations of C6‐carnitine , C8‐carnitine , and of the C8/10 ratio . Sex and acute unscheduled preventive hospital visits did not affect the acylcarnitine concentrations. We found that TC, C0, and C6 concentrations were more similar per patient and per age category . Variation in C2 and C10 was only explained by similarity in concentration by age category. Variation in C8 and C8/C10 was only explained by similarities in concentration per patient. Figure We found a significant effect of disease severity on AC profiles. TC was on average − 0.32 ± 0.25 log μmol/L  mice, increased liver carnitine concentrations were found in VLCADD mice versus healthy controls, despite lower plasma carnitine concentrations. The carnitine homeostasis in tissue may be maintained under metabolic stress through carnitine uptake from the plasma and stimulated carnitine biosynthesis.Besides the absence of real‐world evidence in favor of carnitine supplementation in persons with MCADD, several considerations can be taken into account. First, the lack of a clear benefit of carnitine supplementation may be explained by the degree of carnitine deficiency. Based on the KThe negative consequences of carnitine supplementation and carnitine profiling should also be considered. First, carnitine supplementation may aggravate the tissue accumulation of toxic AC in MCADD, as also seen in VLCADD mice.LMMs of our (acyl)carnitine data showed great differences between persons with mild and severe MCADD. We advocate the separate biochemical analysis of severe and mild persons with MCADD, especially in longitudinal analysis. Since mild persons have only been identified since the expansion of the NBS, this may confound results.We found C8 and C8/C10 to be relatively stable throughout life and within a patient, but they differed greatly between persons. Finding the origin of these individual differences between concentrations may also shed more light on the (patho)physiology of FAO(D). LMMs could prove of great value to the field of rare diseases in the future, as they can be adopted for the development of personalized medicine and as a data processing tool.Some methodological remarks should be recognized. The retrospective character and large time period covered by this study have to be taken into account when interpreting the results. The content and detail of the reviewed clinical notes are biased due to differences in metabolic specialists and time‐related available knowledge. Furthermore, a lack of interoperability of electronic health records leads to missing data on (preventive) hospital admittances in centers other than our own. Although it is unlikely that major clinical events or severe complications would be missed, the patient cohort was closely followed, and shared care with the local hospitals is well organized. This does underline that already available information is left unused due to technical and organizational issues. In rare diseases, each patient file can be recognized as an individual case report containing invaluable information. Adoption of a general format to report disease‐specific core outcomes measures during out‐patient clinic visits, as well as better interconnectivity between electronic patient records will increase the possibilities for effectiveness trials in MCADD.5with a clear clinical indication such as age‐inappropriate, unexplained, fasting intolerance, muscle weakness, or exercise intolerance. If carnitine supplementation is commenced, clinical and biochemical effects should be carefully monitored and documented by the treating physician.In conclusion, SCD is not associated with more frequent or prolonged acute unscheduled preventive hospital visits. It is recommended that (acyl)carnitine profiling and supplementation should only take place in persons with severe MCADD, The MD/Ph.D. scholarship of Emmalie Jager (MD/Ph.D. 18/55) and Pilot Project of Merit Schaafsma (PP 19–65) are funded by the Junior Scientific Masterclass from the University of Groningen, University Medical Center Groningen.Emmalie Jager, Merit Schaafsma, Melanie van der Klauw, Rebecca Heiner‐Fokkema, and Terry Derks declare that they have no conflict of interest.All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation  and with the Helsinki Declaration of 1975, as revised in 2000 (5). The Medical Ethical Committee of the University Medical Center Groningen stated that the Medical Research Involving Human Subjects Act was not applicable, official study approval by the Medical Ethical Committee was not required (METc 2019/119), and the study was approved for waived consent.This article does not contain any studies with animal subjects performed by any of the authors.Supplementary Figure S1: lifetime C0 concentrations of persons with MCADD who exhibited or not exhibited fatigue, muscle ache, or exercise intolerance during follow‐up. A. C0 concentrations with and without carnitine supplementation combined. B. C0 concentrations while receiving carnitine supplementation C. C0 concentrations when not receiving carnitine supplementation. The figure only includes C0 concentrations of severe patients. Blue line indicates conditional mean of persons with MCADD who exhibited specific symptoms during follow‐up, and black line indicates persons with MCADD who did not exhibit specific symptoms during follow‐up. Gray area show 95% CI of the respective conditional mean .Click here for additional data file.Supplementary Table S1: Acylcarnitine reference valuesSupplementary Table S2: Acylcarnitine profiles of deceased children with MCADDClick here for additional data file.


Pennisetum purpureum Schum. was used to explore the mitigation effects of exogenous strigolactone (SL) on drought stress during the seedling stage. The effects of different concentrations  of SL on the photosynthesis characteristics, growth performance, and endogenous abscisic acid (ABA) of P. purpureum under drought stress were studied.Drought is one of the main environmental factors limiting plant growth and development. P. purpureum growth. Compared with drought stress, the net photosynthesis rate, stomatal conductance, transpiration rate, and water-use efficiency of the leaves of P. purpureum after SL treatment significantly increased, thereby exerting a significant mitigation effect on the decrease in photosystem II maximum photochemical efficiency and the performance index based on light absorption caused by drought. Moreover, the exogenous application of SL can effectively increase the fresh and dry weight of the leaves and roots and the main-root length. After applying SL for 120 h, the ABA content of P. purpureum decreased significantly. The activity of key enzymes of photosynthesis significantly increased after 48 h of external application of SL to P. purpureum.Exogenous SL could effectively alleviate the inhibitory effect of drought stress on P. purpureum leaves under drought conditions and increase the antioxidant capacity of the leaves, thereby reducing the adverse effects of drought, promoting the growth of P. purpureum, and effectively improving the drought resistance of P. purpureum.SL treatment can improve the photosynthesis performance of  Drought is one of the most important environmental factors affecting plant growth and development . With thZea mays L.) under drought stress and found that SL improves the water relationship of maize seedlings, increases photosynthesis pigments and gas-exchange parameters, and improves antioxidant enzyme activity. Thus, the tolerance of maize seedlings to drought stress is enhanced. Ha et al. , Gs [μmol·(m2·s)− 1], Tr [mmol·(m2·s)− 1], Ci (μmol·mol− 1), and water-use efficiency  were measured in each treatment group. Five plants were measured for each treatment.The photosynthesis parameters of The maximum photochemical efficiency (Fv/Fm) and the performance index based on absorbed light energy (PIabs) were determined using a plant-efficiency analyzer. The top third unfolded leaf of the plant was selected, and the leaf was dark-adapted for 20 min before Chl fluorescence-parameter determination. Five plants were measured for each treatment.P. purpureum was rinsed with distilled water, and the leaves and roots were dried and cut. The fresh weight of P. purpureum was immediately weighed with an analytical balance. Then, the plant was dried to constant weight with an electric blast dryer at 105 °C, and its dry weight was obtained. Three plants were measured per treatment. The formula for calculating the water content was as follows: water content (%) = (fresh weight − dry weight) / (fresh weight) × 100.P. purpureum was measured in centimeters using a meter ruler .Three plants were taken from each treatment at 24, 48, and 120 h after SL treatment, and the length of the main root of Leaf and root samples were taken at 24, 48, and 120 h after SL treatment. Then, they were snap frozen in liquid nitrogen and transferred into a − 80 °C refrigerator. The leaf and root samples were ground into powder with liquid nitrogen, and 0.1 g of sample was loaded into a centrifuge tube. Then, 0.9 mL of PBS buffer was added, shaken well, centrifuged at 3000 g and 4 °C for 10 min, and prepared for use. Ten microliters of supernatant was collected for ABA content determination according to the instructions of a Phytohormone Abscisic Acid (ABA) ELISA Kit . Three plants were measured for each treatment.Leaf sampling was performed at 48 h after SL treatment. The samples were snap frozen in liquid nitrogen and transferred into a − 80 °C refrigerator. The leaf samples were ground into powder with liquid nitrogen, and 0.1 g of the sample was loaded into a centrifuge tube. After adding 1 mL of extraction solution, it was homogenized in an ice bath, centrifuged at 8000 g and 4 °C for 10 min, and placed on ice. Ten microliters of supernatant was collected to determine the key photosynthesis enzyme activities according to the instructions of a NADP-ME kit , a PEPC kit , and a PPDK kit . Three plants were measured for each treatment.P < 0.05). The analysis results were expressed as the mean and standard error.Data were statistically analyzed using SPSS 20.0 . One-way ANOVA and Duncan’s multiple comparison analysis were used to test the significance of differences between treatments (


P = 0.04) and clinical recurrence (P = 0.004) and appeared to have greatest prognostic value for patients with Grade Groups 4–5. In conclusion, when heterogeneity is considered, ERG protein is a robust prognostic biomarker for prostate cancer.Prognostic biomarkers for prostate cancer are needed to improve prediction of disease course and guide treatment decisions. However, biomarker development is complicated by the common multifocality and heterogeneity of the disease. We aimed to determine the prognostic value of candidate biomarkers transcriptional regulator ERG and related ETS family genes, while considering tumor heterogeneity. In a multisampled, prospective, and treatment‐naïve radical prostatectomy cohort from one tertiary center , we analyzed ERG protein , and RNA of several ETS genes in a subcohort . Intra‐ and interfocal heterogeneity was identified in 29% and 33% (ERG protein) and 39% and 27% (ETS RNA) of patients, respectively. ERG protein and ETS RNA was identified exclusively in a nonindex tumor in 31% and 32% of patients, respectively. ERG protein demonstrated independent prognostic value in predicting biochemical ( ERG and other ETS genes, is still unclear. Utilizing a multisampled biobank, we show that ERG expression is heterogeneous both within and between malignant foci in the same patient. Despite significant heterogeneity, we find that ERG is a biomarker for poor prognosis for patients with localized prostate cancer.The prognostic relevance of the most common mutations in prostate cancer, involving  BCRbiochemical recurrencecDNAcomplementary DNACIconfidence intervalCRclinical recurrenceTCcycle thresholdFFPEformalin‐fixed paraffin‐embeddedHRhazard ratioHGPINhigh‐grade prostatic intraepithelial neoplasiaIDC‐Pintraductal carcinoma of the prostateISUPInternational Society of Urological PathologyIQRinterquartile rangePCRpolymerase chain reactionPSAprostate‐specific antigenpT‐stagepathological tumor stageQ3third quartileREMARKReporting recommendations for tumor marker prognostic studiesRPradical prostatectomyRTreverse transcriptionTMAtissue microarray1There is an unmet need for prognostic biomarkers in prostate cancer to aid in predicting clinical outcome of primary disease and improve the precision of treatment decisions . CurrentERG, ETV1, ETV4, and FLI1 ., 9.ERG, patients , 11. Thepatients . ERG and pathway , 13. In ogenesis . It has ogenesis .TMPRSS2‐ERG has been associated with adverse histopathological features, for example, cribriform growth pattern , with a median of 16 (IQR: 12–22) PSA measurements collected for each patient. For patients without biochemical recurrence (BCR) and without persistently PSA, the median follow‐up time was 8.0 years (IQR: 7.1–8.6 years), with a median of 14 PSA measurements (IQR: 10–18) collected. BCR was defined as a postoperative PSA level ≥ 0.20 ng·mL2.3Histopathological re‐evaluation of RP specimens was performed according to the 2014 International Society of Urological Pathology (ISUP) Modified Gleason system  by two iFor all RP specimens, multifocality was assessed and it was determined from which focus each tissue sample was collected. Tumors were defined as different foci when clearly separated by at least 2–4 mm and showing different tissue morphology. The index tumor was defined as the focus with the highest pathological tumor (pT)‐stage. In cases with multiple foci with the same pT‐stage, the focus with the highest Gleason score, or in cases with two foci with the same Gleason score, the largest focus (in diameter), was defined as the index tumor.2.4Construction of tissue microarray (TMA) blocks was performed using FFPE tissue from the 506 patients with available FFPE tissue blocks, and the Tissue Arrayer  instrument, with 1.0 mm tissue cores and 80–120 tissue cores per recipient paraffin block. The Microtome HM355S  was used to cut 4 μm sections, and regions of interest were verified on hematoxylin–eosin stained sections.2.5in situ ERG protein expression. In total, 2047 tissue cores  could be evaluated, of which 1–11 malignant tissue cores (median: 3 tissue cores) and 0–6 benign tissue cores (median: 1 tissue core) from each patient. Multiple tissue cores from the same malignant tumor focus were available for 312 patients and from multiple foci from 156 patients.From the TMAs, 480 patients had at least one malignant sample that could be evaluated for In situ protein expression of ERG was assessed with immunohistochemistry on the TMAs using the fully automated Ventana Benchmark Ultra system, with anti‐ERG monoclonal antibody EPR3864  and Ventana UltraView Universal DAB Detection kit (Roche Tissue Diagnostics). Tissue from tonsils, liver, pancreas and appendix were used as controls for ERG immunohistochemistry. Endothelial cells were used as an internal positive control. ERG protein expression was visually scored and evaluated as positive or negative as previously described , but the association did not reach significance for BCR  in univariable analysis (Table P = 0.06) nor CR .To evaluate the association between ERG protein and clinical outcome, time‐to‐event analyses were performed Fig. . ERG prois Table . In multCI: 0.93–.24; P = is Table –D. An in3.4ERG, ETV1, ETV4, and FLI1) and their association with prognosis, in a largely overlapping subcohort  for ETV1, and 6% (5/85) for ETV4. Among malignant samples, 46% (165/359) had RNA overexpression of either ERG , ETV1 , or ETV4 . No samples displayed overexpression of FLI1. Overexpression of multiple ETS genes was detected in different malignant foci from 6% (2/31) of ETS‐positive patients with malignant samples from more than one focus. Among these, one patient was positive for both ERG and ETV4, and the other for ETV1 and ETV4. None had overexpression of multiple ETS genes in the same malignant focus. TMPRSS2‐ERG was detected in 47% (167/359) of malignant samples, with 56% (81/145) of patients being positive for TMPRSS2‐ERG in at least one malignant sample (Tables ERG RNA overexpression and TMPRSS2‐ERG status was concordant in 88% (128/145) of patients, whereas ERG RNA and TMPRSS2‐ERG were concordant with ERG protein in 90% (123/137) and 85% (116/137), respectively . Interfocal heterogeneity was identified in 34% (19/56) of patients for ETS and 27% (15/56) for ERG RNA overexpression, respectively. Among patients with interfocal heterogeneity of ETS expression, 32% (6/19) were exclusively ETS‐positive in a nonindex focus. ETS overexpression was associated with a younger age at time of surgery, higher pT‐stage, and reactive stroma  experienced BCR and 21% (15/70) CR. Similar proportions were identified in patients positive for ETV1 and/or ETV4, where 31% (5/16) experienced BCR and 13% (2/16) CR. There was no significant association between BCR or CR and RNA overexpression of ERG or ETS genes combined  [TMPRSS2‐ERG was detected. This has also been observed by others and could imply that the RNA methods are more sensitive, in that areas negative for ERG protein may not produce a sufficient amount of protein or a variant that is not recognized by the applied antibody [ERG expression is present even within benign tissue.Expression of y events , and TMP (HGPIN) . As we dantibody . AnotherERG RNA expression in malignant samples demonstrated a distinct separation into ‘high’ and ‘low’ groups, which supports the evaluation of ERG protein as either positive or negative. Other studies have also applied this scoring system [The results from analysis of g system . HoweverERG variants has gained increasing interest [ERG RNA transcripts isoforms can be expressed, resulting in at least 15 protein variants [Although beyond the scope of the current study, the prognostic relevance of certain interest . Multiplvariants . Some ofvariants . AccordiERG RNA overexpression, and TMPRSS2‐ERG was identified among malignant samples, in line with other studies [TMPRSS2 or RT‐PCR being a more sensitive method. The antibody used for immunohistochemistry has known cross‐reactivity with FLI1 protein, but this is an unlikely explanation as none of the samples had FLI1 RNA overexpression. Nonetheless, the high concordance demonstrates that the methods are largely interchangeable for the detection of ERG aberrations. As FFPE tissue is routinely collected, immunohistochemistry is the preferred method and could easily be implemented in most laboratories.A high concordance between ERG protein,  studies . The fewOverall, our results support the implementation of ERG protein assessment in the post‐RP setting to determine which patients require closer follow‐up and are potential candidates for adjuvant treatment. Due to the vast heterogeneity, all malignant foci should be evaluated. According to the European Association of Urology guidelines for prostate cancer , it is aet al. [The significant heterogeneity of ERG complicates its use as a biomarker in the diagnostic setting; however, a study by Shah et al. , suggest5In situ ERG protein expression is an independent predictor of BCR and CR in prostate cancer patients with undetectable PSA and who did not receive adjuvant treatment after surgery. Significant intra‐ and interfocal heterogeneity of ERG protein expression challenges previous accuracy of ERG status assessment. We conclude that implementation of ERG protein as a prognostic biomarker in the post‐RP setting while considering the vast heterogeneity may aid treatment decisions and improve patient outcomes.The authors declare no conflict of interest.ML, RAL, KA, UA, and RIS were all involved in conception and design. SGK, MB, KTC, ACB, and AVM performed acquisition of data. All authors were involved in analysis and interpretation of data. SGK and MB performed statistical analysis. RAL, KA, UA, and RIS were responsible for obtaining funding. ACB, AVM, and ML were involved in administrative, technical, or material support. ML, RAL, KA, UA, and RIS supervised the study.6https://publons.com/publon/10.1002/1878‐0261.13225.The peer review history for this article is available at Fig. S1. Flow chart of patient inclusion.Fig. S2. Prognostic relevance of overexpression of ERG RNA and ETS genes combined.Table S1. REMARK checklist (Reporting recommendations for tumor marker prognostic studies).Table S2. Clinicopathological and molecular characteristics for all patients. See separate Excel file.Table S3. Protein expression of ERG in all evaluable samples. See separate Excel file.Table S4. Univariable Cox regression analysis of ERG protein expression with biochemical recurrence and clinical recurrence as endpoints.Table S5. RNA expression of four ETS genes  and TMPRSS2‐ERG. See separate Excel file.Click here for additional data file.Table S6. Clinicopathological characteristics of the patient subcohort analyzed on the RNA level, stratified by ETS status.Table S7. Univariable Cox regression analysis of ETS RNA overexpression with biochemical recurrence and clinical recurrence as endpoints.Click here for additional data file.


High‐dose chemotherapy and autologous stem cell transplantation (ASCT) are too toxic for elderly patients with relapsed or refractory diffuse large B‐cell lymphoma (DLBCL). Therefore, effective and tolerable regimens for elderly patients are urgently needed. The present phase II study assessed the efficacy and safety of dose‐adjusted therapy with gemcitabine, dexamethasone, cisplatin, and rituximab (GDP‐R) in this population. ASCT‐ineligible elderly patients with relapsed or refractory DLBCL received dose‐adjusted GDP‐R in each 28‐day cycle for up to six cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints were complete response (CR) rate, progression‐free survival (PFS), and safety. Thirty‐three patients were enrolled and received dose‐adjusted GDP‐R. The median age was 75 years (range: 68‐87 years). The ORR was 82.8% , with a CR rate of 58.6% . At a median follow‐up of 20.9 months, the 2‐year PFS rate was 46.8%  and the 2‐year overall survival rate was 63.2% . The most frequently observed grade 4 adverse events were neutropenia (63.6%), thrombocytopenia (57.6%), and lymphocytopenia (39.4%). Dose‐adjusted GDP‐R is a promising salvage regimen for ASCT‐ineligible elderly patients with relapsed DLBCL after rituximab‐containing chemotherapy and warrants further investigation. Hayashi22.1This study was a multicenter, open‐label, single‐arm phase II trial (UMIN000015492). It was conducted in 20 Japanese centers belonging to the Japanese National Hospital Organization (J‐NHO). Protocol details have been published previously  . Baseline assessments included physical examination, standard laboratory tests, computed tomography (CT) scanning of the chest, abdomen, and pelvis, and if indicated, a bone marrow biopsy. Eligible patients were required to have measurable disease by CT scan or physical examination, an Eastern Cooperative Oncology Group performance status (PS) of 0‐3, and acceptable hematologic and biochemical parameters. Patients were excluded if they had previously received treatment with gemcitabine and cisplatin, had CNS involvement with DLBCL, had a history of hepatitis B virus, hepatitis C virus, or human immunodeficiency virus infection, or a medical condition that would interfere with the safe administration of the protocol chemotherapy.2 of body surface area per day on days 1 and 8 and cisplatin 75 mg/m2 on day 1, oral dexamethasone 40 mg per day on days 1 through 4, and rituximab 375 mg/m2 intravenously on days 1 through 8, with the expectation that there would be a synergistic effect between gemcitabine and rituximab.Three cycles of protocol therapy were administered every 28 days for up to six treatment cycles, depending on the response and toxicity, and consisted of intravenous gemcitabine 1000 mg/mPatients who had not achieved a complete response (CR) or a partial response (PR) after three treatment cycles were permitted to be withdrawn from the study. Treatment was designed to be delivered to patients in an outpatient setting and included a recommended minimum hydration schedule for cisplatin. Each participating center was responsible for determining policies for supportive care after treating patients with dose‐adjusted GDP‐R. Granulocyte colony‐stimulating factor was given daily if neutrophil counts decreased to less than 1000/μL.2.4Disease status assessments included physical examinations, CT scans, and bone marrow analysis. Tumor response evaluation was performed according to the Revised Response Criteria for Malignant Lymphoma . CT scan2.5The sample size calculation was reported previously . BrieflyThe efficacy analysis set consisted of eligible patients receiving protocol treatment after registration. The safety analysis set was defined as all patients receiving protocol treatment after registration. The point estimation and 90% confidence interval (CI) of the response rate were calculated. The incidence of AEs was calculated. PFS, OS, and time to response were calculated using the Kaplan‐Meier method. The Cox proportional hazards model was used in univariate analysis of PFS‐ and OS‐related factors. OS, according to the interim response after three cycles of treatment (CR + PR vs stable disease [SD] + progressive disease [PD]), was evaluated using the log‐rank test. Changes from baseline in the QOL‐ACD and SF‐36 health survey were determined by the Wilcoxon signed‐rank test. The significance level was .05 in the one‐tailed test for the primary endpoint and .05 in two‐tailed tests. Statistical analyses were performed using SAS version 9.4 .33.1Between January 2015 and December 2017, 33 patients older than 65 years with R/R transplant‐ineligible DLBCL were enrolled from 14 hospitals that belonged to the J‐NHO. This study was terminated on December 2017 because of planned enrollment periods. All diagnoses of biopsies were reclassified and DLBCL was confirmed by an experienced hematopathologist. One patient with a transformed follicular lymphoma and one patient without a confirmed diagnosis of a R/R DLBCL were excluded from the efficacy analysis. No patients received ASCT because of the physician's decision based on their advanced age. The median age was 75 years (range: 68‐87 years), and 19 out of 31 (61.3%) patients were male (Table 3.2P < .001). The CR rate was 58.6% . Regarding disease status at study entry, the ORR was 88.8% with relapse after more than 1 year after initial therapy (CR was achieved by 66.6%), 75.0% with relapse within less than 1 year after initial therapy (CR was achieved by 50.0%), and 66.6% with primary induction failure (CR was achieved by 33.3%). At a median follow‐up of 20.9 months (range: 1.2‐41.3 months), the 2‐year PFS and OS rates were 46.8% . In univariate analysis using prognostic variables, none of the following variables was predictive of PFS or OS to treatment: age, sex, IPI, and pathological markers, including non‐GCB, CD5, MIB‐1, and Bcl2 and c‐Myc IHC/FISH status. Only p53 status was predictive of both PFS and OS (Table At least one cycle of protocol therapy was administered to 33 patients. The median cycle of GDP‐R was 4 range: 1‐6). The overall response rate (ORR) after treatment was 82.8% . The lower boundary of 90% CI for response rates was above the threshold of 35%, thus meeting the protocol‐specified criterion of response rate to dose‐adjusted GDP‐R . The total median period of treatment was 177 days (range: 17‐331 days). The median period of patient admission to hospital was 70 days (range: 14‐102 days). The median period of outpatient visits for treatment was 81 days (range: 0‐218 days). The median ratio of inpatient hospital admissions and outpatient visits was 60% (range: 10‐80%).4To the best of our knowledge, this is the first study to evaluate dose‐adjusted GDP‐R for ASCT‐ineligible elderly patients with R/R DLBCL. The results confirmed our hypothesis that dose‐adjusted GDP‐R is an effective and feasible salvage regimen for elderly patients. The primary endpoint of the trial was met, and the ORR of dose‐adjusted GDP‐R was more effective than that found in previous trials.The population in this study was highly pretreated, including R‐CHOP, and patients had high‐risk DLBCL with a poor long‐term prognosis. The ORR was 82.8%, which is high, considering the R‐CHOP pretreatment, the high‐risk characteristics, and the poor prognosis of the study population. In our study, 58.1% of patients experienced recurrence after 1 year of completing primary therapy. Regarding the cell of origin, 80.6% of patients had the GCB subtype of DLBCL. Regarding pathological markers, we observed one patient who was double positive for Bcl‐2‐FISH and c‐Myc‐FISH. Selection bias may appear to account for the favorable results achieved with dose‐adjusted GDP‐R in the current study. In the trial by Crump et al , 27% of Prognosis of patients with R/R DLBCL is generally poor; drugs for salvage therapy have some cross‐resistance to standard chemotherapy regimens such as R‐CHOP. Regimens that contain an anthracycline such as doxorubicin, included in CHOP, are not suitable as second‐line chemotherapy because of the cardiac toxicity arising from the accumulation of anthracycline. The combination of gemcitabine and cisplatin may be an effective salvage therapy for R/R DLBCL after R‐CHOP. However, the optimal dose of GDP‐R has not been determined. The novel use of GDP‐R in this study showed promising response rates in elderly patients with R/R DLBCL. Dose‐adjusted GDP‐R had better outcomes in DLBCL patients because of the prolonged control of the disease after relapse.The 2‐year PFS rate after treatment with dose‐adjusted GDP‐R was 46.8%, which was noninferior compared with previous trials (Table S1). Hou et al reported that the 2‐year PFS rate in patients with R/R aggressive B‐cell non‐Hodgkin's lymphoma who received R‐GDP was 48.0% , but no Our study had several limitations. First, it was a nonrandomized phase II study with a small number of patients, which was not registered with a planned sample size. Second, 90.3% of the patients had a good PS (<2). Third, considering the feasibility of the clinical trial, this study was not designed to assess PFS as a primary endpoint. Nevertheless, our results showed promising efficacy and manageable toxicity of dose‐adjusted GDP‐R for ASCT‐ineligible elderly patients with R/R DLBCL, and this trial is an important initial step in developing a tailor‐made treatment strategy for elderly patients. To assess the QOL in elderly patients, we observed patient‐oriented QOL, duration of hospitalization, and total medical cost associated with dose‐adjusted GDP‐R treatment, which has clinically meaningful efficacy in elderly patients with R/R DLBCL. Comparing the results of the present study with published data is difficult, because no studies have been published to date in which dose‐adjusted GDP‐R was administered to elderly patients with R/R DLBCL, which was well tolerated without unexpected AEs or treatment‐related deaths.In summary, this novel therapy was well tolerated; incidence, severity, and type of AEs were acceptable compared with those observed previously , 19. DosSY contributed to the study design, data analysis, and manuscript preparation. AK, IC, HI, NS, NH, MS, TS, TK, TY, IY, SY, KS, TH, HT, KO, MT, AS, HI, and HN reviewed the manuscript. AS was responsible for data management. AK was responsible for statistical analysis.The protocol of this study was approved by the Clinical Research Central Ethics Review Board of the National Hospital Organization in October 2014. This study has been registered in the Clinical Trial Registry (UMIN‐CTR) (UMIN000015492). Prior to this study, the principal investigator or investigators obtained written informed consent based on patient free will.KO is a consultant to SRL. HI received research funding from Chugai. NS received research funding from Ono, A2 Healthcare, Astellas, Janssen, Merck Sharp & Dohme, Otsuka, Pfizer, PPD SNBL, Sumitomo Dainippon Pharma, Daiichi Sankyo, and Bristol‐Myers Squibb. IY and SY received research funding from Kyowa Kirin and Chugai. KS received research funding from Novartis, GlaxoSmithKline, Janssen, Abbvie, Takeda, Sanofi, Bristol‐Myers Squibb, Ono, Merck Sharp & Dohme, Alexion, Daiichi Sankyo, and Celgene. OK received research funding from Kyowa Kirin, Chugai, Celgene, and Daiichi Sankyo. HN received research funding from Bayer Yakuhin, Takeda, Kyowa‐Kirin, Esai, Bristol‐Myers Squibb, Ono, Zenyaku Kogyo, Solasia, AstraZeneca, SymBio, IQVIA service Japan, Mundipharma, Chugai, and Janssen. HI received honoraria from Novartis, Celgne, Astellas, and Janssen. IY received honoraria from Celgene, Mundipharma, Bristol‐Myers Squibb, Shire Japan, Jansen, Mochida, Merck Sharp & Dohme, Takeda, and Taiho and grants and personal fees from Kyowa Kirin and Chugai. SY received honoraria from Bristol‐Meyers Squibb, Takeda, Eisai, Otsuka, and Celgene. KS received honoraria from Takeda, Bristol‐Myers Squibb, Ono, and Celgene. HN received honoraria from Ono, Celgene, Takeda, Esai, Bristol‐Myers Squibb, Chugai, Mundipharma, Sanofi, Janssen, Zenyaku Kogyo, Novartis, Merck Sharp & Dohme, and Chordia Therapeutics. AK received personal fees from Bayer Yakuhin as a member of the data monitoring committee. All other authors declare no conflict of interest.Supporting InformationClick here for additional data file.