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Graduate students are increasingly expected to publish peer-reviewed scholarship during the course of their studies, yet predictable mentoring and education on academic publishing is not available to all graduate students. Although academic librarians are well positioned to offer such instruction, their efforts are not always informed by comprehensive investigations of what, and how, graduate students need to learn. This study used focus groups with graduate students and faculty mentors to explore strengths and gaps in current mentoring and learning practices, while also discovering and uncovering suggestions and opportunities for further development in education about scholarly publishing. Thematic analysis of the data revealed that current training and mentorship meet some, but not all, of students' needs and preferences. Future library instruction should employ a blended and compassionate approach to teaching about this complex topic, and this study offers a way forward as librarians-as-partners in scholarly communication.

Abstract Esophageal adenocarcinoma is a prominent example of cancer characterized by frequent amplifications in oncogenes. However, the mechanisms leading to amplicons that involve breakage-fusion-bridge cycles and extrachromosomal DNA are poorly understood. Here, we use 710 esophageal adenocarcinoma cases with matched samples and patient-derived organoids to disentangle complex amplicons and their associated mechanisms. Short-read sequencing identifies ERBB2, MYC, MDM2, and HMGA2 as the most frequent oncogenes amplified in extrachromosomal DNAs. We resolve complex extrachromosomal DNA and breakage-fusion-bridge cycles amplicons by integrating of de-novo assemblies and DNA methylation in nine long-read sequenced cases. Complex amplicons shared between precancerous biopsy and late-stage tumor, an enrichment of putative enhancer elements and mobile element insertions are potential drivers of complex amplicons’ origin. We find that patient-derived organoids recapitulate extrachromosomal DNA observed in the primary tumors and single-cell DNA sequencing capture extrachromosomal DNA-driven clonal dynamics across passages. Prospectively, long-read and single-cell DNA sequencing technologies can lead to better prediction of clonal evolution in esophageal adenocarcinoma.

Introduction Evaluating the safety and acceptability of reusing catheters for intermittent catheterisation (IC) is one of the top 10 continence research priorities identified by the UK James Lind Alliance Priority Setting Partnership in 2008. There are an estimated 50 000 IC users in England and this number is rising. Globally, both single-use catheters (thrown away after use) and multi-use/reusable ones (cleaned between uses) are used. Using multi-use catheters as well as single-use ones (mixed-use) could bring benefits (eg, reducing plastic waste and patients never running out of catheters) and offer more choice to users. Evidence is needed that mixed-use is at least as safe and acceptable as using only single-use catheters.Methods The MultICath Trial is a non-inferiority randomised controlled trial involving 578 participants. The aim is to compare mixed-use catheter management with single-use catheter management over 12 months. Participants are randomised on a 1:1 basis to either mixed-use catheter management, which includes an evidence-based cleaning method for the multi-use catheters (intervention) or single-use catheter management (control). Following randomisation, participants are followed up for 12 months. The primary outcome is at least one episode of microbiologically confirmed symptomatic urinary tract infection with help-seeking or self-help behaviour over the 12-month follow-up period. Laboratory analysis of patient-initiated urine samples is blind. Secondary outcomes include antibiotic use, microhaematuria, visible blood on catheter/in urine, quality of life and health economics. A qualitative sub-study to examine participant experiences using mixed-use is included.Ethics and dissemination Ethical review was undertaken by South Central-Hampshire A Research Ethics Committee and favourable opinion was granted on 12 July 2019 (reference: 19/SC/0334). Written, informed consent to participate was obtained from all participants. Results will be disseminated in peer-reviewed publications, in the National Institute for Health and Care Research journal library and to participants and the public via a lay summary published on the trial website.Trial registration number ISRCTN42028483.

Abstract Introduction Within 10 years of multiple sclerosis (MS) progression, nearly all women will have experienced symptoms associated with bladder, bowel and/or sexual health. Yet despite the impact these symptoms have on physical, psychological and social well‐being, it remains an underserved area within the UK healthcare system. Study Aim This research employs a participatory research approach framed within the principles of intersectional feminism to collaboratively investigate the lived experiences of pelvic floor dysfunction (PFD) and healthcare interactions among UK‐based women with MS. Setting and Participants Women residing in the United Kingdom with MS were invited to participate in online interviews facilitated by the primary author. Analysis A thematic framework analysis offering a structured yet adaptable approach to data collection and interpretation. Results One focus group involving four women with MS and seven individual, one‐to‐one interviews with women with MS provided insights into the challenges associated with navigating both MS and PFD. Four main themes included: Navigating MS and PFD; Cycles of Control; Mind, Mobility and Bladder Embodiment; Silenced Voices: The Impact of Taboos/Stigma/Dismissal on Preventing Access and Resistance through Collective Community. Six subthemes were also identified. Taken together, these themes cumulatively reflect PFD as an unmet healthcare need. Conclusion Our findings underscore negative healthcare experiences, inadequate information provision and unmet needs related to PFD, emphasising the compounding effects of gender and disability biases. Impact We hope that these insights can lay the groundwork for developing tailored therapeutic interventions and improved PFD healthcare for women with MS. Potential solutions include using existing MS support communities. Public Contributions Women with MS were actively involved in co‐producing interview scripts for one‐to‐one interviews. The primary author shared study findings at an MS group event, engaging in discussions with over 30 individuals, including people with MS and their loved ones. MS advocates played a pivotal role in contextualising the study within the broader lived experience of MS.

The recommendations in this article came from two coaching colleagues and professional friends who reflected on their coaching careers as part of an action research project. The recommendations in this article primarily come from the perspective of the lead author's coaching business experience, while the second author took on the role of providing feedback as the critical friend. It is hoped that this article will be of interest and value to coaches who are thinking of setting up their own sports coaching business.

Background Pelvic organ prolapse is common, causes unpleasant symptoms and negatively affects women’s quality of life. In the UK, most women with pelvic organ prolapse attend clinics for pessary care. Objectives To determine the clinical effectiveness and cost-effectiveness of vaginal pessary self-management on prolapse-specific quality of life for women with prolapse compared with clinic-based care; and to assess intervention acceptability and contextual influences on effectiveness, adherence and fidelity. Design A multicentre, parallel-group, superiority randomised controlled trial with a mixed-methods process evaluation. Participants Women attending UK NHS outpatient pessary services, aged ≥ 18 years, using a pessary of any type/material (except shelf, Gellhorn or Cube) for at least 2 weeks. Exclusions: women with limited manual dexterity, with cognitive deficit (prohibiting consent or self-management), pregnant or non-English-speaking. Intervention The self-management intervention involved a 30-minute teaching appointment, an information leaflet, a 2-week follow-up telephone call and a local clinic telephone helpline number. Clinic-based care involved routine appointments determined by centres’ usual practice. Allocation Remote web-based application; minimisation was by age, pessary user type and centre. Blinding Participants, those delivering the intervention and researchers were not blinded to group allocation. Outcomes The patient-reported primary outcome (measured using the Pelvic Floor Impact Questionnaire-7) was prolapse-specific quality of life, and the cost-effectiveness outcome was incremental cost per quality-adjusted life-year (a specifically developed health Resource Use Questionnaire was used) at 18 months post randomisation. Secondary outcome measures included self-efficacy and complications. Process evaluation data were collected by interview, audio-recording and checklist. Analysis was by intention to treat. Results Three hundred and forty women were randomised (self-management, n = 169; clinic-based care, n = 171). At 18 months post randomisation, 291 questionnaires with valid primary outcome data were available (self-management, n = 139; clinic-based care, n = 152). Baseline economic analysis was based on 264 participants (self-management, n = 125; clinic-based care, n = 139) with valid quality of life and resource use data. Self-management was an acceptable intervention. There was no group difference in prolapse-specific quality of life at 18 months (adjusted mean difference −0.03, 95% confidence interval −9.32 to 9.25). There was fidelity to intervention delivery. Self-management was cost-effective at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year gained, with an estimated incremental net benefit of £564.32 and an 80.81% probability of cost-effectiveness. At 18 months, more pessary complications were reported in the clinic-based care group (adjusted mean difference 3.83, 95% confidence interval 0.81 to 6.86). There was no group difference in general self-efficacy, but self-managing women were more confident in pessary self-management activities. In both groups, contextual factors impacted on adherence and effectiveness. There were no reported serious unexpected serious adverse reactions. There were 32 serious adverse events (self-management, n = 17; clinic-based care, n = 14), all unrelated to the intervention. Skew in the baseline data for the Pelvic Floor Impact Questionnaire-7, the influence of the global COVID-19 pandemic, the potential effects of crossover and the lack of ethnic diversity in the recruited sample were possible limitations. Conclusions Self-management was acceptable and cost-effective, led to fewer complications and did not improve or worsen quality of life for women with prolapse compared with clinic-based care. Future research is needed to develop a quality-of-life measure that is sensitive to the changes women desire from treatment. Study registration This study is registered as ISRCTN62510577. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/82/01) and is published in full in Health Technology Assessment; Vol. 28, No. 23. See the NIHR Funding and Awards website for further award information. Plain language summary Pelvic organ prolapse is a common and distressing condition experienced by large numbers of women. Prolapse is when the organs that are usually in the pelvis drop down into the vagina. Women experience a feeling of something coming down into the vagina, along with bowel, bladder and sexual problems. One possible treatment is a vaginal pessary. The pessary is a device that is inserted into the vagina and holds the pelvic organs back in their usual place. Women who use a vaginal pessary usually come back to clinic every 6 months to have their pessary removed and replaced; this is called clinic-based care. However, it is possible for a woman to look after the pessary herself; this is called self-management. This study compared self-management with clinic-based care. Three hundred and forty women with prolapse took part; 171 received clinic-based care and 169 undertook self-management. Each woman had an equal chance of being in either group. Women in the self-management group received a 30-minute teaching appointment, an information leaflet, a 2-week follow-up telephone call and a telephone number for their local centre. Women in the clinic-based care group returned to clinic as advised by the treating healthcare professional. Self-management was found to be acceptable. Women self-managed their pessary in ways that suited their lifestyle. After 18 months, there was no difference between the groups in women’s quality of life. Women in the self-management group experienced fewer pessary complications than women who received clinic-based care. Self-management costs less to deliver than clinic-based care. In summary, self-management did not improve women’s quality of life more than clinic-based care, but it did lead to women experiencing fewer complications and cost less to deliver in the NHS. The findings support self-management as a treatment pathway for women using a pessary for prolapse. Scientific summary Background Pelvic organ prolapse (hereafter prolapse) is the descent of some, or all, of the female pelvic organs from their usual position in the pelvis into the vagina. Prolapse is a common problem, with studies suggesting that up to 65% of women may be affected. Prolapse incidence increases with age. As the population ages, prolapse presents a growing health problem. Women who experience prolapse report bothersome symptoms that negatively affect their quality of life and body image. Symptoms include a feeling of ‘something coming down’ into the vagina; urinary, bowel and sexual symptoms; and pain. Prolapse can be treated conservatively or surgically. Between 10% and 30% of women who have prolapse surgery may need repeat surgery, and the controversy around the use of surgical mesh has brought the focus onto conservative treatment options. One conservative treatment option is vaginal pessary. The pessary is an inexpensive mechanical device that is inserted into the vagina to support the pelvic organs. Pessaries are widely used in the NHS, with two-thirds of women initially choosing a vaginal pessary to treat their prolapse symptoms. The current UK care pathway for women who use a pessary as treatment for prolapse is that the pessary is usually fitted at a gynaecological clinic, or occasionally at a general practitioner surgery, and the woman returns approximately every 6 months to have it removed and replaced with a new one. However, having to return to clinic every 6 months may be inconvenient for women, having a pessary permanently in situ may interfere with sexual intercourse, and the patient may require a review in clinic before 6 months because the pessary has fallen out or because of pessary complications (e.g. vaginal discomfort). An alternative to clinic-based pessary care is pessary self-management, whereby a woman removes and reinserts the pessary herself at home, thus offering her more control over her ability to maintain and improve her own health. Research in other clinical domains suggests that self-management is beneficial because people improve their self-efficacy (confidence) in looking after their own health. To the best of our knowledge, there is no current evidence on the effectiveness of pessary self-management for women with prolapse. The treatment of prolapse with self-care pessary (TOPSY) study aims to fill that evidence gap. Objective The TOPSY trial aimed to evaluate the clinical effectiveness and cost-effectiveness of self-management of a vaginal pessary on the prolapse-specific quality of life of women with pelvic organ prolapse when compared with clinic-based care. Clinic-based care is the standard operating model for many pessary services across the UK. The process evaluation undertaken concurrently with the trial aimed to assess, using a mixed-methods design, intervention acceptability, pathways to effectiveness, adherence to treatment and fidelity. Methods We undertook a parallel-group, multicentre, randomised controlled trial, with individual randomisation, which assessed the superiority of self-management compared with clinic-based pessary care for women who used a pessary for prolapse. Allocation was carried out remotely via a web-based computer system, with minimisation by age (< 65/≥ 65 years), pessary user type (new user/existing user) and centre. A sample size of 330 women (165 per group) was required to provide 90% power to detect a difference of 20 points in the Pelvic Floor Impact Questionnaire-7 score (which measures prolapse-specific quality of life) at 18 months after randomisation, assuming a standard deviation of 50, two-sided alpha of 0.05 and 20% loss to follow-up. Participants were recruited from 21 UK centres where pessary care was routinely provided. Women who were new pessary users (had used a pessary for ≤ 3 months) and existing users (had used a pessary for > 3 months) were identified by centre staff and via patient notes, clinic lists, caseloads and referral letters. Potentially eligible women were sent an invitation letter or approached in clinic by centre staff. Women were eligible for inclusion if they were aged ≥ 18 years, were using a pessary of any material or type (except shelf, Gellhorn or cube pessaries) and had retained the pessary for at least 2 weeks. Women were excluded if they had limited manual dexterity that would affect their ability to remove and replace their pessary; were judged by their healthcare team to have a cognitive deficit such that it was not possible for them to provide informed consent or to self-manage; were pregnant; or had insufficient understanding of the English language (the self-management intervention was only available in English). The primary outcome of effectiveness was prolapse-specific quality of life, measured using the Pelvic Floor Impact Questionnaire-7, and of cost-effectiveness was incremental cost per quality-adjusted life-year at 18 months post randomisation. Interim follow-ups were undertaken at 6 and 12 months. Secondary outcome measures included generic quality of life [measured using the EuroQol-5 Dimensions, five-level (EQ-5D-5L)]; pelvic floor symptoms (measured using the Pelvic Floor Distress Inventory-20); sexual function (measured using the prolapse/incontinence sexual questionnaire-IUGA-Revised); self-efficacy (measured using the General Self-efficacy Scale); pessary complications; pessary use; and pessary confidence. Resource use data were collected using a specifically developed health Resource Use Questionnaire. Study centres received a training visit during which the principles of self-management were explained and the intervention delivery staff were trained in the components of the intervention. Each centre also received a training manual that provided written guidance on the intervention. Women randomised to self-management received: a 30-minute self-management teaching appointment where they were taught to, and given the opportunity to try to, remove, clean and reinsert their own pessary a self-management information leaflet that provided written and diagrammatic information on pessary self-management a 2-week follow-up telephone call to assess if they had been able to remove, clean and reinsert their pessary since the teaching appointment and to assess any difficulties they experienced a telephone helpline number for their local clinical centre. Women in the clinic-based care group received routine appointments at which their pessary was removed and cleaned, or changed for a new one, and replaced by a healthcare professional. The interval between the appointments was determined by the usual practice of the centre. A concurrent mixed-methods process evaluation was undertaken to assess intervention acceptability, pathways to effectiveness, adherence to treatment and fidelity. Recruiting staff at centres were asked to audio-record a sample of their recruitment discussions. Staff delivering the intervention were asked to record a sample of self-management teaching appointments and 2-week follow-up telephone calls and to complete a checklist for every self-management teaching session undertaken to allow assessment of fidelity to the intervention. A subsample of women who were randomised in the trial and consented to take part in an additional interview study were interviewed at baseline and 18 months. Eligible women who declined to be randomised but were willing to take part in an interview study were also interviewed at baseline and 18 months. The Pessary Use Questionnaire included an open question about women’s experiences of their trial group. The interviews and open questions aimed to assess acceptability, adherence and pathways to effectiveness. Finally, recruiting centre staff and healthcare professionals who delivered the intervention were invited to take part in an interview to increase understanding of pathways to effectiveness and fidelity. A within-trial economic evaluation was conducted to compare the costs and benefits, measured in quality-adjusted life-years, of self-management with clinic-based care over the 18 months post randomisation. In addition, a decision-analytic model was developed using the trial data to extend the analysis over a 5-year period. Healthcare resource use data were collected from the clinic visit and telephone support case report forms and from the participant-completed Resource Use Questionnaire. Costs were attached to resource use from published sources. Health state utility values were elicited from responses to the EQ-5D-5L to estimate the difference in quality-adjusted life-years between the trial groups. The trial analysis followed the intention to treat principle, and the analyses of all study elements were documented in prespecified analysis plans. The qualitative analysis for the process evaluation followed framework analysis methods and, where appropriate, case study analytic methods. Results Key results: trial Three hundred and forty women were randomised: 169 to the self-management group and 171 to the clinic-based care group. At 18 months post randomisation, 291 questionnaires with valid primary outcome data were available: 139 (82.2%) in the self-management group and 152 (88.9%) in the clinic-based care group. There was no evidence of a difference between the groups in prolapse-specific quality of life (measured using the Pelvic Floor Impact Questionnaire-7) at 18 months (adjusted mean difference −0.03, 95% confidence interval −9.32 to 9.25). Sensitivity analysis of the primary outcome showed no significant difference between the groups under a range of different assumptions and prespecified sensitivity analyses. A subgroup analysis of the primary outcome showed no significant effect of trial group by subgroup interactions (subgroups were age < 65 vs. ≥ 65 years, new vs. existing pessary user and hysterectomy vs. no hysterectomy at baseline). At the 18-month follow-up, a greater proportion of pessary complications were reported in the clinic-based care group than in the self-management group (adjusted mean difference 3.83, 95% confidence interval 0.81 to 6.86). There was no difference between the groups in general self-efficacy, but women in the self-management group were more confident in their ability to manage pessary-related problems and to insert and remove their pessary. An analysis adjusting for clinic-based care appointments cancelled due to the COVID-19 pandemic did not alter the findings. Key results: process evaluation Self-management was reported to be an acceptable intervention to women and to healthcare professionals. Women (whether they received self-management or not) and healthcare professionals reported benefits from pessary self-management to women and the NHS and valued the possibilities provided to women who could self-manage their pessary, such as flexibility and independence in using the pessary as needed. There was fidelity to self-management intervention delivery and there was minimal variance in the delivery of clinic-based care across the study centres. Self-management delivery can be integrated within existing service structures. Interview data demonstrated that women’s adherence to their allocated group ranged from not adherent at all to completely adherent in all aspects, and this was the case in both groups. The COVID-19 pandemic did have an impact on adherence, especially among those in the clinic-based care group when clinic appointments were suspended, which led some women to remove their own pessary. Although the pandemic might have had some effect on adherence, multiple other contextual factors influenced adherence, such as good general health, which influenced it in both groups. Multiple contextual factors impacted on pathways to effectiveness for both trial groups. There was variance in women’s quality of life in both groups across the 18 months’ follow-up. The pessary itself influenced women’s quality of life, regardless of trial group. There was at least the potential for self-management to further enhance that quality of life over and above the influence of the pessary itself. Women in the self-management group had different self-efficacy from those in the clinic-based group. Women in the self-management group felt more confident in addressing common problems with their pessary, such as discharge or slippage, on their own without the need for additional clinic appointments. Key results: economic evaluation The within-trial economic analysis indicated that clinic-based care was dominated by self-management. There was no significant difference in the mean number of quality-adjusted life-years gained between self-management and clinic-based care (0.021), but the mean cost was lower for self-management than for clinic-based care (£578 vs. £728). The incremental net benefit estimated at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year gained was £564, with an 80.8% probability of cost-effectiveness. The modelling results are consistent with the trial analysis. The incremental net benefit at 5 years was estimated as £4221 and the probability that self-management is a cost-effective intervention was estimated as 69.7%. Key results: synthesis There was no evidence that self-management improved prolapse-specific or general quality of life more than clinic-based care. Although qualitative findings suggested that quality of life had the potential to be improved more in the self-management group, this did not translate beyond participant-level data. The proposed mechanism of action for the intervention was self-efficacy. General self-efficacy did not differ between the groups at 18 months. Women who self-managed were more confident in their abilities to insert and remove their pessary and to manage problems experienced with their pessary than women in the clinic-based care group. There was fidelity to the self-management and clinic-based care intervention delivery, with the groups receiving different interventions, confirming that the trial was a true test. There was variance in adherence to trial group by the women; approximately 40% of the clinic-based care group removed the pessary themselves at least once at some point during follow-up, and 34 women in the self-management group crossed over to clinic-based care. Women in the self-management group reported fewer complications than women in the clinic-based care group. Experience of complications led to a greater likelihood of women discontinuing pessary use. Conclusions Implications for health care Healthcare professionals and policy-makers can be confident that in offering self-management as an option to women who use a vaginal pessary to manage pelvic organ prolapse they are offering an acceptable intervention that will not make women’s quality of life better or worse than clinic-based care. Self-management will, however, reduce the pessary-related complications that women experience and will cost the NHS less to deliver than standard clinic-based care models. Self-management of vaginal pessaries should be offered as part of NHS services from the outset of pessary care and as part of routine, ongoing care. In offering self-management to women, healthcare professionals should explain the lower complication rates experienced by women who self-manage and the possible mechanisms that may lead to that reduction (such as women’s confidence in removing the pessary when experiencing discomfort). Healthcare professionals who deliver self-management training may wish to add further information about options for pessary removal into that training, as women found pessary removal more difficult than pessary insertion. Recommendations for research (in priority order) Future research is needed to identify constructs that are important to women in measuring their prolapse-specific quality of life. This may necessitate the generation of a new measure that has greater sensitivity to quality-of-life constructs beyond the symptomatic changes linked to the pessary itself. Future trials of self-management should test the effectiveness of self-management with a wide range of ethnic groups and with women of different abilities to assess its effectiveness in these populations. This may include the testing of devices that support pessary removal or insertion. Future research is needed that focuses on self-management follow-up. For example, can follow-up be women-initiated, or does it need to be planned at specific intervals? Future research on pessary self-management is needed to look at possible links between pessary continuation and complications, including which specific complications are more likely to lead to discontinuation. Study registration This study is registered as ISRCTN62510577. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/82/01) and is published in full in Health Technology Assessment; Vol. 28, No. 23. See the NIHR Funding and Awards website for further award information.

In this study, the success of 6,054 college students "screened" as twice-exceptional (2e; i.e., those with significantly discrepant math vs. reading scores on the ACT [formerly, American College Test] or SAT [formerly, Scholastic Aptitude Test]) was examined based on major selection and type of potential learning disability using a screening technique proposed by McCallum et al. There were no differences in high school grade point average, college grade point average, or first-year retention rates between students screened as 2e who had a major in line with their academic strength versus those who did not (p > 0.05). However, students screened as 2e based on an exceptionally high math score but a lower reading score yielded statistically significantly higher rates of retention (p < 0.05) than students screened as 2e with the reverse pattern of scores (i.e., gifted in reading with a potential learning disability in math). Implications for screening 2e students are discussed.

This article encourages thoughtful discussion on cross-disciplinary partnerships among those researchers, practitioners, and librarians engaged in the Scholarship of Teaching and Learning. Through personal experiences, examples from the literature, and the goal of meaningful collaboration, the authors describe four models of engagement with librarians in the Scholarship of Teaching and Learning. We propose that it is time for the Scholarship of Teaching and Learning and its practitioners to more fully engage with librarians because they bring complementary perspectives, powerful areas of expertise, and significant insights into students' learning experiences.

Background Up to 30% of children have constipation at some stage in their life. Although often short-lived, in one-third of children it progresses to chronic functional constipation, potentially with overflow incontinence. Optimal management strategies remain unclear. Objective To determine the most effective interventions, and combinations and sequences of interventions, for childhood chronic functional constipation, and understand how they can best be implemented. Methods Key stakeholders, comprising two parents of children with chronic functional constipation, two adults who experienced childhood chronic functional constipation and four health professional/continence experts, contributed throughout the research. We conducted pragmatic mixed-method reviews. For all reviews, included studies focused on any interventions/strategies, delivered in any setting, to improve any outcomes in children (0–18 years) with a clinical diagnosis of chronic functional constipation (excluding studies of diagnosis/assessment) included. Dual reviewers applied inclusion criteria and assessed risk of bias. One reviewer extracted data, checked by a second reviewer. Scoping review: We systematically searched electronic databases (including Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature) (January 2011 to March 2020) and grey literature, including studies (any design) reporting any intervention/strategy. Data were coded, tabulated and mapped. Research quality was not evaluated. Systematic reviews of the evidence of effectiveness: For each different intervention, we included existing systematic reviews judged to be low risk of bias (using the Risk of Bias Assessment Tool for Systematic Reviews), updating any meta-analyses with new randomised controlled trials. Where there was no existing low risk of bias systematic reviews, we included randomised controlled trials and other primary studies. The risk of bias was judged using design-specific tools. Evidence was synthesised narratively, and a process of considered judgement was used to judge certainty in the evidence as high, moderate, low, very low or insufficient evidence. Economic synthesis: Included studies (any design, English-language) detailed intervention-related costs. Studies were categorised as cost-consequence, cost-effectiveness, cost-utility or cost-benefit, and reporting quality evaluated using the consensus health economic criteria checklist. Systematic review of implementation factors: Included studies reported data relating to implementation barriers or facilitators. Using a best-fit framework synthesis approach, factors were synthesised around the consolidated framework for implementation research domains. Results Stakeholders prioritised outcomes, developed a model which informed evidence synthesis and identified evidence gaps. Scoping review 651 studies, including 190 randomised controlled trials and 236 primary studies, conservatively reported 48 interventions/intervention combinations. Effectiveness systematic reviews studies explored service delivery models (n = 15); interventions delivered by families/carers (n = 32), wider children’s workforce (n = 21), continence teams (n = 31) and specialist consultant-led teams (n = 42); complementary therapies (n = 15); and psychosocial interventions (n = 4). One intervention (probiotics) had moderate-quality evidence; all others had low to very-low-quality evidence. Thirty-one studies reported evidence relating to cost or resource use; data were insufficient to support generalisable conclusions. One hundred and six studies described implementation barriers and facilitators. Conclusions Management of childhood chronic functional constipation is complex. The available evidence remains limited, with small, poorly conducted and reported studies. Many evidence gaps were identified. Treatment recommendations within current clinical guidelines remain largely unchanged, but there is a need for research to move away from considering effectiveness of single interventions. Clinical care and future studies must consider the individual characteristics of children. Study registration This study is registered as PROSPERO CRD42019159008. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 128470) and is published in full in Health Technology Assessment; Vol. 28, No. 5. See the NIHR Funding and Awards website for further award information. Plain language summary Between 5% and 30% of children experience constipation at some stage. In one-third of these children, this progresses to chronic functional constipation. Chronic functional constipation affects more children with additional needs. We aimed to find and bring together published information about treatments for chronic functional constipation, to help establish best treatments and treatment combinations. We did not cover assessment or diagnosis of chronic functional constipation. This project was guided by a ‘stakeholder group’, including parents of children with constipation, people who experienced constipation as children, and healthcare professionals/continence experts. We carried out a ‘scoping review’ and a series of ‘systematic reviews’. Our ‘scoping review’ provides an overall picture of research about treatments, with 651 studies describing 48 treatments. This helps identify important evidence gaps. ‘Systematic reviews’ are robust methods of bringing together and interpreting research evidence. Our stakeholder group decided to structure our systematic reviews to reflect who delivered the interventions. We brought together evidence about how well treatments worked when delivered by families/carers (32 studies), the wider children’s workforce (e.g. general practitioner, health visitor) (21 studies), continence teams (31 studies) or specialist consultant-led teams (42 studies). We also considered complementary therapies (15 studies) and behavioural strategies (4 studies). Care is affected by what is done and how it is done. We brought together evidence about different models of delivering care (15 studies), barriers and facilitators to implementation of treatments (106 studies) and costs (31 studies). Quality of evidence was mainly low to very low. Despite numerous studies, there was often insufficient information to support generalisable conclusions. Our findings generally agreed with current clinical guidelines. Management of childhood chronic functional constipation should be child-centred, multifaceted and adapted according to the individual child, their needs, the situation in which they live and the health-care setting in which they are looked after. Research is needed to address our identified evidence gaps. Scientific summary Background Chronic functional constipation (CFC) in childhood is common; it is estimated to affect 5–30% of school-aged children, becoming chronic in around one-third of cases. CFC has negative effects on quality of life (QoL) of children, families and carers, with increasing impact as the child gets older. Although rarely life-threatening, CFC is an unpleasant and distressing condition, associated with a wide range of complications, including physical discomfort, missed school, poor school performance, social isolation and reduced involvement in group activities. More than a third of children with CFC will present clinically with behavioural problems as a result of the constipation. The healthcare costs of childhood CFC are significant. Treatments are usually directed at symptom control since limited diagnostics mean no underlying cause is identified in more than 95% of cases, thus limiting ability to stratify treatments. There are a number of different interventions available for the management of CFC; however, the optimal strategy for combining and implementing interventions for individual circumstances remain unclear. National Institute for Health and Care Research (NIHR) commissioned this work to address the question: ‘What are the most effective interventions, and combinations and sequences of interventions, for childhood chronic functional constipation (CFC), and how can they best be implemented?’ Objectives Specific research questions (RQs) answered by this project were: RQ1: What is the current evidence relating to management strategies for childhood CFC? (Scoping review). RQ2: What are the most effective childhood CFC strategies and combinations of strategies in relation to outcomes of importance to stakeholders and/or cost to the patient/NHS? [Systematic review (SR) of evidence of effectiveness and cost effectiveness]. RQ3: What factors are associated with implementation success or failure of childhood CFC strategies and combinations of strategies for different subgroups? (SR of factors affecting implementation). RQ4: What are the evidence gaps in childhood CFC management strategies? Design We conducted a three-stage pragmatic mixed-method study. In stage 1, we completed a broad, comprehensive scoping review. In stage 2, we conducted focused SRs evaluating effectiveness, cost effectiveness and factors affecting implementation. In stage 3, we integrated findings, generating interactive evidence maps, exploring complementarity between our findings and published clinical guidelines, and identifying evidence gaps. Methods Patient and public involvement Stakeholder involvement was central to our project. We formed a stakeholder group (SG) from across the UK, comprising people with lived experience of childhood CFC, parents of children with CFC, healthcare professionals and representatives of relevant charities. We adhered to key principles for research co-production. The SG provided continuous project oversight and completed specific activities. These activities included development of an intervention taxonomy and logic model, agreement on outcomes for the review, identifying evidence gaps and reaching consensus on clinical implications. Scoping review Our scoping review was based on a systematic search of several electronic databases including medical literature analysis and retrieval system online (MEDLINE), excerpta medica database (EMBASE) and Cumulative Index to Nursing and Allied Health Literature (CINAHL; January 2011 to March 2020), as well as searches of grey literature, contacting experts and forward citation tracking. We included papers, regardless of study design, which investigated, reported or discussed any strategy, delivered in any setting, aimed at improving any outcomes in children (aged 0–18 years) with a clinical diagnosis of CFC. We did not include studies of assessment/diagnosis. We included studies involving children with or without additional needs but excluded those with a recognisable cause of constipation such as anorectal malformation, Hirschsprung’s disease, intestinal nerve abnormalities, metabolic or endocrine causes. Eligible abstracts and full texts were independently reviewed by two reviewers. Data were extracted by one reviewer and cross-checked by a second. Two reviewers independently applied descriptive codes to categorise the type of study, aim/focus of the study, outcomes, types of interventions/intervention combinations, and availability of data relating to effectiveness, economics or implementation factors. In keeping with scoping review methodology, we did not formally assess research quality. Data were summarised within an evidence gap map. Systematic reviews of evidence of effectiveness For our SRs of evidence of effectiveness, we considered all studies identified in the scoping review and ‘tagged’ them as studies of effectiveness. We included any studies investigating effectiveness of any intervention, or combination of interventions, aimed at improving outcomes in children with CFC. Informed by our stakeholders, we grouped studies according to whether the intervention was one that would be delivered by families/carers (‘Level 0’), the wider children’s workforce (e.g. general practitioner, health visitor) (‘Level 1’), continence teams (‘Level 2’) or specialist consultant-led teams (‘Level 3’). We also considered different models of service delivery, and complementary and psychosocial therapies. For each different intervention, we adopted a hierarchical, step-wise approach to inclusion of different study designs. If there was a comprehensive SR, judged to be low risk of bias (ROB) [using risk of bias assessment tool for systematic reviews (ROBIS) criteria, assessed by two independent reviewers], this was also included. Where we included a SR, we also included any randomised controlled trials (RCTs) published after the date of the search in the review. Where there was no SR, we included RCTs and other primary studies of intervention effectiveness. Data were extracted on study methods, participant characteristics, intervention characteristics [using template for intervention description and replication (TIDieR) framework], outcomes and key findings. ROB was judged using tools appropriate to the study design [e.g. Cochrane ROB tool for RCTs, critical appraisals skills programme (CASP) tools for cohort studies, Joanna Briggs Institute (JBI) tools for qualitative evidence, Ways of Evaluating Important and Relevant Data (WEIRD) tool for other study designs]. Relevant meta-analyses within included SRs were updated with any new RCTs following the methods reported in the SR. A narrative synthesis of evidence of effectiveness for each intervention, delivered within ‘level’ 0 to 3 was presented, with a process of considered judgement used to judge certainty in the evidence as high, moderate, low, very low or insufficient evidence. Economic evaluation For our SR of economic studies, we considered any economic evidence identified in our scoping review and conducted additional searching of electronic databases and citation tracking following best practice guidance. We included all types of study detailing costs related to interventions aimed at children with CFC that were published in English, regardless of study design. One reviewer extracted data, including details of economic evaluations, and these were checked by a second reviewer. Studies were categorised as cost-consequence, cost-effectiveness, cost-utility or cost-benefit and their quality evaluated using the consensus health economic criteria (CHEC) checklist, and data were brought together into a narrative synthesis. Systematic review of factors affecting implementation For our SR of factors affecting implementation, we included studies which were identified in the scoping review as explicitly reporting data relating to key participant variables, barriers, facilitators, equity factors and adherence. One reviewer systematically identified, extracted and coded [using the consolidated framework for implementation research (CFIR)] barriers and facilitators, and a second reviewer checked this. We used a best fit framework synthesis approach combining deductive and inductive thematic approaches to identify barriers and facilitators. Data were brought together in a narrative synthesis organised around the CFIR domains. Integration of findings Our integration of findings from the SRs was informed by decisions taken by our stakeholders, including development of a logic model. We explored agreements between our findings and recommendations within previously published guidelines. We brought our findings together within interactive evidence maps, and systematically identified evidence gaps. Results The scoping review included 651 studies, including 190 RCTs and 236 primary studies. Forty-eight interventions (or combinations of interventions) were reported. Studies were mainly conducted in high-income countries; no studies from low-income countries were identified. The most frequently reported interventions were delivered by carers, prior to healthcare professional involvement (22%); these were primarily lifestyle interventions focused on diet. The least frequently reported were psychosocial interventions (3%). Children were recruited from a variety of settings including hospitals, clinical outpatients, and other community settings. Interventions were generally delivered face to face either at home or within a variety of hospital settings such as the emergency department. Interventions were rarely delivered in education settings (e.g. school-based settings) (n = 5) or residential care/looked after population (n = 1) settings. The most frequently reported outcome measurement was defaecation frequency, which was reported in one-third of studies within the scoping review. School attendance or absenteeism was the least frequently reported outcome (n = 8 studies). Our SRs of effectiveness included 32 studies (including 2 SRs) which explored effectiveness of interventions delivered by families/carers (‘Level 0’); 21 studies (including 2 SRs) which explored effectiveness of interventions delivered by wider children’s workforce (‘Level 1’); 31 studies (including 1 SR) which explored effectiveness of interventions delivered by continence teams (‘Level 2’); 42 studies (no SRs) which explored effectiveness of interventions delivered by specialist consultant-led teams (‘Level 3’); 15 studies (no SRs) which explored effectiveness of different models of service delivery; 15 studies (2 SRs) which explored effectiveness of complementary therapies; and 4 studies (1 SR) which explored effectiveness of psychosocial interventions. Interventions for which there was some evidence of potential benefit included, within Level 0: a trial of cows’ milk-free diet, educational interventions for parents, selenium supplements. Within Level 1: laxatives, physical exercise focused on pelvic floor muscle, combined pharmacological, diet and behaviour programme. Within Level 2: combined oral and enema therapy, transanal irrigation, biofeedback (for children with abnormal defaecation dynamics), combined treatment programmes. Within Level 3: botulinum toxin, antegrade continence enema (ACE)/Malone antegrade continence enema (MACE), sacral modulation. Models of care delivery which may be beneficial included nurse-led clinics, an algorithm, or care pathway, used in primary care settings, specialist (Level 2) services and web-based information, following an appointment with a specialist. Complementary therapies for which there was some evidence of effectiveness included: connective tissue manipulation (CTM) for children with cerebral palsy (CP), and some herbal/traditional medicines. There was some evidence in favour of behavioural therapy. Interventions which evidence suggests may not be beneficial include, probiotics, additional dietary fibre, increased fluid intake and biofeedback (for children with normal defaecation dynamics). Evidence relating to probiotics was judged to be moderate quality, but for all other interventions was considered low to very low quality. There was insufficient evidence to support conclusions relating to several other interventions. We identified 31 studies which reported some evidence relating to cost or resource use, of which 20 were cost-of-illness studies. Fewer than 30% of the studies employed a formal economic evaluation study design. Most studies were poorly reported with limited details. Data included in this review were insufficient to support any generalisable conclusions relating to cost or resource use. One hundred and six studies described multiple barriers and facilitators across the five domains of the CFIR framework. The most commonly reported factors related to ‘successfulness’ of an intervention included; whether the intervention was adaptable, flexible and offered an advantage over an alternative solution; understanding the tension for change (i.e. why clinicians and families felt that the changes were needed now); the taboo nature of constipation and the reluctance of children, families, healthcare professionals and wider society to openly engage in discussion about constipation; a lack of understanding of what children and their families need; self-efficacy, coupled with individual knowledge and beliefs; and engagement of champions to support children. Research gaps were identified through evidence maps and stakeholder discussions. Key topics considered priorities for future research relate to recognition of CFC; information provision; diet; laxatives and combinations of laxatives; behavioural therapy and psychological support. Future research studies should address what works for which individual child, and when, including children with and without additional needs. Research to explore the optimal delivery of services, including identification of key components and features of effective teams and criteria for referring children from one ‘level’ to the next, is needed. Conclusions We conducted a comprehensive review of all evidence relating to interventions, and combinations of interventions, for children with CFC. The finding from our review are generally in agreement with the current guideline recommendations, where recommendations exist. A significant proportion of interventions for which we found evidence had not been addressed within current guidelines. This project has highlighted that research in this field often does not adhere to recognised standards for conduct and reporting or consider the complexities of interventions for CFC. We found no evidence which gave us high certainty in the findings; and we only had moderate certainty relating to one intervention (probiotics, with evidence demonstrating that probiotics may not have any beneficial – or harmful – effect). Our certainty about all other findings was low to very low or, in many cases, we judged that the evidence was insufficient to support any generalised conclusions. The current evidence base rarely measured outcomes deemed of highest priority to children and families, and many studies failed to describe the complex nature of the treatments that a child may be receiving. This limits the conclusions that can be made from the current evidence. Further, the limitations within the evidence base reduce confidence in recommendations and create a barrier to implementation of best practice, impairing progress in efforts to improve outcomes for this group of children. Our findings do not indicate that changes are necessarily needed to the treatment recommendations within current clinical guidelines. However, management of childhood CFC is complex, and there is no simple ‘one size fits all’ approach. Clinical care and future studies must consider the individual characteristics of each child with constipation, and the context – or environment – within which they live. Key goals of successful management of CFC should be early recognition of symptoms and delivery of interventions by families/carers, achieved by providing children and families/carers with effective education and support from members of the wider children’s workforce (primary care services). Development, evaluation and implementation of strategies to enhance the delivery of services focused on individualised care, combining lifestyle and behavioural strategies with laxatives are a priority. To avoid further research waste, it is essential that future research addresses the questions which are of the highest priority to key stakeholders and has the highest possible standards of conduct and reporting. Future research studies should address what works for which individual child, and when, including children with and without additional needs. Future research into any interventions for childhood CFC should take into account relevant evidence relating to the development and evaluation of complex interventions. Study registration This study is registered as PROSPERO CRD42019159008. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 128470) and is published in full in Health Technology Assessment; Vol. 28, No. 5. See the NIHR Funding and Awards website for further award information.

Summary: Background: Prolapse affects 30–40% of women. Those using a pessary for prolapse usually receive care as an outpatient. This trial determined effectiveness and cost-effectiveness of pessary self-management (SM) vs clinic-based care (CBC) in relation to condition-specific quality of life (QoL). Methods: Parallel-group, superiority randomised controlled trial, recruiting from 16 May 2018 to 7 February 2020, with follow-up to 17 September 2021. Women attending pessary clinics, ≥18 years, using a pessary (except Shelf, Gellhorn or Cube), with pessary retained ≥2 weeks were eligible. Limited manual dexterity; cognitive deficit; pregnancy; or requirement for non-English teaching were exclusions. SM group received a 30-min teaching session; information leaflet; 2-week follow-up call; and telephone support. CBC group received usual routine appointments. The primary clinical outcome was pelvic floor-specific QoL (PFIQ-7), and incremental net monetary benefit for cost-effectiveness, 18 months post-randomisation. Group allocation was by remote web-based application, minimised on age, user type (new/existing) and centre. Participants, intervention deliverers, researchers and the statistician were not blinded. The primary analysis was intention-to-treat based. Trial registration: https://doi.org/10.1186/ISRCTN62510577. Findings: The requisite 340 women were randomised (169 SM, 171 CBC) across 21 centres. There was not a statistically significant difference between groups in PFIQ-7 at 18 months (mean SM 32.3 vs CBC 32.5, adjusted mean difference SM-CBC −0.03, 95% CI −9.32 to 9.25). SM was less costly than CBC. The incremental net benefit of SM was £564 (SE £581, 95% CI −£576 to £1704). A lower percentage of pessary complications was reported in the SM group (mean SM 16.7% vs CBC 22.0%, adjusted mean difference −3.83%, 95% CI –6.86% to −0.81%). There was no meaningful difference in general self-efficacy. Self-managing women were more confident in self-management activities. There were no reported suspected unexpected serious adverse reactions, and 31 unrelated serious adverse events (17 SM, 14 CBC). Interpretation: Pessary self-management is cost-effective, does not improve or worsen QoL compared to CBC, and has a lower complication rate. Funding: National Institute for Health and Care Research, Health Technology Assessment Programme (16/82/01).

The purpose of this paper is to demonstrate and describe why alternating treatments design (ATD) researchers should consider employing a no-treatment series during the alternating treatments phase. To identify limitations associated with excluding this design element, we obtained examples of ATD studies published in five school psychology journals published over 10 years. Next we read, scored, and analyzed these articles with our primary focus being authors' isolated and comparative effectiveness conclusions. After taking into account authors' relative effectiveness conclusions, we describe why some isolated treatment effectiveness conclusions may not be warranted because threats to internal validity were not controlled. Also, we describe how including a no-treatment series during the alternating treatments phase can address these limitations by allowing researchers to assess and possibly rule out many threats to internal validity. Discussion focuses on how including this design element may increase the number of studies validating specific interventions, yield better relative effectiveness conclusions, and prevent researchers and consumers of research from concluding that an intervention was effective when observed changes were caused by uncontrolled threats to internal validity.

Abstract Cancer cells undergo transcriptional reprogramming to drive tumor progression and metastasis. Using cancer cell lines and patient-derived tumor organoids, we demonstrate that loss of the negative elongation factor (NELF) complex inhibits breast cancer development through downregulating epithelial-mesenchymal transition (EMT) and stemness-associated genes. Quantitative multiplexed Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins (qPLEX-RIME) further reveals a significant rewiring of NELF-E-associated chromatin partners as a function of EMT and a co-option of NELF-E with the key EMT transcription factor SLUG. Accordingly, loss of NELF-E leads to impaired SLUG binding on chromatin. Through integrative transcriptomic and genomic analyses, we identify the histone acetyltransferase, KAT2B, as a key functional target of NELF-E-SLUG. Genetic and pharmacological inactivation of KAT2B ameliorate the expression of EMT markers, phenocopying NELF ablation. Elevated expression of NELF-E and KAT2B is associated with poorer prognosis in breast cancer patients, highlighting the clinical relevance of our findings. Taken together, we uncover a crucial role of the NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis.

The synaptonemal complex (SC) is a supramolecular protein scaffold that mediates chromosome synapsis and facilitates crossing over during meiosis. In mammals, SC proteins are generally assumed to have no other function. Here, we show that SC protein TEX12 also localises to centrosomes during meiosis independently of chromosome synapsis. In somatic cells, ectopically expressed TEX12 similarly localises to centrosomes, where it is associated with centrosome amplification, a pathology correlated with cancer development. Indeed, TEX12 is identified as a cancer-testis antigen and proliferation of some cancer cells is TEX12-dependent. Moreover, somatic expression of TEX12 is aberrantly activated via retinoic acid signalling, which is commonly disregulated in cancer. Structure-function analysis reveals that phosphorylation of TEX12 on tyrosine 48 is important for centrosome amplification but not for recruitment of TEX12 to centrosomes. We conclude that TEX12 normally localises to meiotic centrosomes, but its misexpression in somatic cells can contribute to pathological amplification and dysfunction of centrosomes in cancers.

Self-reported perceptions of the impact of acceleration through an early college entrance program at the University of Iowa National Academy of Arts, Sciences, and Engineering (NAASE), revealed the program's contribution to students' overall development. Responses from a sample of 76-gifted participants to a 64-item survey offered insights about accelerated college-aged students' perceptions of their intellectual and social growth, peer and family relationships, leadership ability, happiness, and peer acceptance. Self-perceptions of NAASE program effectiveness were generally positive. Not all abilities or skills were perceived as equally impacted as a function of participation in the NAASE program. Results add to the growing literature explicating the effects of participation in an early college entrance program on the development and peer relationships of gifted students. Implications are discussed for further research.

The psychometric integrity of a curriculum-based measure to screen for academic giftedness (Monitoring Instructional Responsiveness: Reading [MIR:R]) was evaluated by examining its ceiling, item gradient, and predictive capacity using 460 fourth grade students. Eighty fourth graders (17.39%) scored one standard deviation above the MIR:R mean. Ten fourth graders (2.17%) scored two or more standard deviations above the mean, indicating an adequate ceiling. Item gradients were sufficient, that is, one raw score change produced less than one-third of a standard deviation change in standard deviation units. The MIR:R accurately screened students who performed in the "advanced" range on an end-of-the-year measure (i.e., Tennessee Comprehensive Assessment Program [TCAP]). Results of a chi-square indicated that 78.3% were identified as non-gifted by both the TCAP and MIR:R and 5.9% were identified as gifted.

Abstract Background Finding the genetic causes of quantitative traits is a complex and difficult task. Classical methods for mapping quantitative trail loci (QTL) in miceuse an F2 cross between two strains with substantially different phenotype and an interval mapping method to compute confidence intervals at each position in the genome. This process requires significant resources for breeding and genotyping, and the data generated are usually only applicable to one phenotype of interest. Recently, we reported the application of a haplotype association mapping method which utilizes dense genotyping data across a diverse panel of inbred mouse strains and a marker association algorithm that is independent of any specific phenotype. As the availability of genotyping data grows in size and density, analysis of these haplotype association mapping methods should be of increasing value to the statistical genetics community. Results We describe a detailed comparative analysis of variations on our marker association method. In particular, we describe the use of inferred haplotypes from adjacent SNPs, parametric and nonparametric statistics, and control of multiple testing error. These results show that nonparametric methods are slightly better in the test cases we study, although the choice of test statistic may often be dependent on the specific phenotype and haplotype structure being studied. The use of multi-SNP windows to infer local haplotype structure is critical to the use of a diverse panel of inbred strains for QTL mapping. Finally, because the marginal effect of any single gene in a complex disease is often relatively small, these methods require the use of sensitive methods for controlling family-wise error. We also report our initial application of this method to phenotypes cataloged in the Mouse Phenome Database. Conclusion The use of inbred strains of mice for QTL mapping has many advantages over traditional methods. However, there are also limitations in comparison to the traditional linkage analysis from F2 and RI lines. Application of these methods requires careful consideration of algorithmic choices based on both theoretical and practical factors. Our findings suggest general guidelines, though a complete evaluation of these methods can only be performed as more genetic data in complex diseases becomes available.

Currently, control against bovine respiratory disease (BRD) primarily consists of mass administration of an antimicrobial upon arrival to facility, termed “metaphylaxis.” The objective of this study was to determine the influence of six different antimicrobials used as metaphylaxis on the whole blood host transcriptome in healthy steers upon and following arrival to the feedlot. One hundred and five steers were stratified by arrival body weight (BW = 247 ± 28 kg) and randomly and equally allocated to one of seven treatments: negative control (NC), ceftiofur (CEFT), enrofloxacin (ENRO), florfenicol (FLOR), oxytetracycline (OXYT), tildipirosin (TILD), or tulathromycin (TULA). On day 0, whole blood samples and BW were collected prior to a one-time administration of the assigned antimicrobial. Blood samples were collected again on days 3, 7, 14, 21, and 56. A subset of cattle (n = 6) per treatment group were selected randomly for RNA sequencing across all time points. Isolated RNA was sequenced (NovaSeq 6,000; ~35 M paired-end reads/sample), where sequenced reads were processed with ARS-UCD1.3 reference-guided assembly (HISAT2/StringTie2). Differential expression analysis comparing treatment groups to NC was performed with glmmSeq (FDR ≤ 0.05) and edgeR (FDR ≤ 0.1). Functional enrichment was performed with KOBAS-i (FDR ≤ 0.05). When compared only to NC, unique differentially expressed genes (DEGs) found within both edgeR and glmmSeq were identified for CEFT (n = 526), ENRO (n = 340), FLOR (n = 56), OXYT (n = 111), TILD (n = 3,001), and TULA (n = 87). At day 3, CEFT, TILD, and OXYT shared multiple functional enrichment pathways related to T-cell receptor signaling and FcεRI-mediated NF-kappa beta (kB) activation. On day 7, Class I major histocompatibility complex (MHC)-mediated antigen presentation pathways were enriched in ENRO and CEFT groups, and CEFT and FLOR had DEGs that affected IL-17 signaling pathways. There were no shared pathways or Gene Ontology (GO) terms among treatments at day 14, but TULA had 19 pathways and eight GO terms enriched related to NF- κβ activation, and interleukin/interferon signaling. Pathways related to cytokine signaling were enriched by TILD on day 21. Our research demonstrates immunomodulation and potential secondary therapeutic mechanisms induced by antimicrobials commonly used for metaphylaxis, providing insight into the beneficial anti-inflammatory properties antimicrobials possess.

In this study, the high school and college GPAs of college students who were screened as twice-exceptional were compared to college students screened as gifted and average college students. From a sample of 32,741 college students, those screened as gifted earned significantly higher means than students screened as twice-exceptional (2e) and the general college population on both high school and college GPA (p < 0.05); students screened as 2e earned high school and college GPA means higher than those from the general college population (p < 0.05). No mean college GPA differences were found between students screened as 2e with STEM majors and those with non-STEM majors GPA (p > 0.05), but STEM majors had higher high school mean GPAs than those with non-STEM majors (p < 0.001). Additionally, 2e students screened as having a reading learning disability (LD) yielded higher mean high school and college GPAs than 2e students screened as having a math LD (p < 0.001). Implications for advising are discussed.

Abstract Background Neurogenic lower urinary tract dysfunction is an abnormality in the presence of underlying neurologic disease. A recent systematic review and meta-analysis demonstrated that storage phase symptoms are the predominant symptoms among people with multiple sclerosis (PwMS). Transcutaneous tibial nerve stimulation (TTNS) is a non-invasive treatment for bladder storage symptoms; however, the potential efficacy of stimulation among PwMS is based on a small number of studies with the absence of high-quality evidence. The aim of this study was to evaluate the feasibility, acceptability, and safety of TTNS in PwMS using an affordable transcutaneous electrical nerve stimulation (TENS) unit. Methods A total of 23 participants with MS enrolled in the study. The primary outcomes included recruitment/retention rate, completion of the outcomes and the intervention, adherence to the protocol, adverse events, and acceptability of the intervention. The primary outcomes were assessed using diaries and a satisfaction questionnaire. The secondary outcomes included changes in urinary symptoms and quality of life assessed using a set of validated outcome measures including a 3-day bladder diary, PPIUS, ICIQ-OAB, and KHQ at baseline and post-intervention. Results Twenty participants completed the study. Three participants (13.04%) withdrew. All 20 participants completed the 6-week intervention and all the outcome measures (100%), with no reported adverse events. Participants were satisfied and found the unit acceptable. Three-day bladder diary showed changes in urinary frequency from a daily median of 10 times to 8 times and daily median urgency changed from 6 times at baseline to 2 times post-intervention. PPIUS showed changes in daily median sever urgency from 3 points (IQR=4) to 1 point (IQR=1) post-intervention. ICIQ-OAB total scores changed from 8 points (IQR=2.25) to 4 points (IQR=2.5) post-intervention. Median and mean scores of KHQ showed a clinical meaningful change of QoL in part-two and part-three of the questionnaire. Conclusions TTNS is feasible, safe, and acceptable for PwMS. Changes of urinary symptoms scores and QoL post-intervention suggested improvements. Future implications need to consider the treatment protocol including frequency of treatment sessions, duration of treatment, and the electrical stimulation parameters as well as the outcome measures followed in the current study for the implementation of the future pilot RCT. Trial registration ClinicalTrials.gov NCT04528784 . Registered on 27 August 2020. https://register.clinicaltrials.gov/prs/app/action/LoginUser?ts=1&cx=-jg9qo4 .

Teachers regularly apply independent group-oriented contingencies (e.g., each student who scored above 89% gets a reward) which are designed to enhance students' academic performance and achievement. In some instances, these contingencies are ineffective with low performing students. Numerous researchers have demonstrated that applying interdependent group-oriented contingencies (e.g., the entire class receives extra free time if the class average exceeds 89%) can meaningfully enhance mathematics performance across students. Research designed to evaluate the application of interdependent group-oriented bonus rewards on students' independent mathematic performance will be described and analyzed. Recommendations for applying these procedures will be provided. These recommendations focus on research-based procedures and strategies designed to maximize the effectiveness of interdependent contingencies while minimizing the negative side effects associated with these procedures.

Sandhu et al. report that the synaptonemal complex (SC) protein, TEX12, localises to centrosomes independently of the SC during meiosis. They also show that it provokes centrosome amplification in somatic cells, a pathology associated with cancer development.

Introduction: Concerns about radiation dose in computed tomography (CT) imaging have renewed interest in iterative reconstruction (IR), a technique which has the potential to produce images with less noise at lower radiation doses than traditional filtered back projection (FBP). This study aimed to assess whether application of IR could provide comparable quality sinus CT images to FBP at lower kilovolt (kV) and milliamp (mA) settings, and to establish optimal scan settings for sinus imaging. Methods: 30 sinus CT scans were performed on 5 cadaver heads at two kV setting and three mA settings. Each scan was reconstructed using FBP and 3 IR settings, yielding a total of 120 image series. Each image set was blinded and randomly reviewed by 3 rhinologists and 2 neuroradiologists. Using a 5-point Likert scale, 16 anatomical landmarks, were graded with respect to image quality. Data were assessed with respect to dose and IR settings using statistical analysis. Results: Higher kV and mAs settings produced significantly higher quality images for structure identification across all 16 landmarks; however, the suitability for surgery did not increase in a linear fashion and plateaued by a total radiation dose of 0.1201 mSv. IR algorithm did not provide a benefit in the overall score of scans at a fixed kV and mAs. Conclusions: Identification of structures in sinus CT imaging significantly correlates with the kV and mA and overall dose of radiation; however, IR did not provide additional benefit in the image quality. Blinded reviewers unanimously agreed that scans obtained at 100 mV and 120 mA were acceptable for surgery independent of IR.

The recommendations in this article came from two coaching colleagues and professional friends who reflected on their coaching careers as part of an action research project. The recommendations in this article primarily come from the perspective of the lead author's coaching business experience, while the second author took on the role of providing feedback as the critical friend. It is hoped that this article will be of interest and value to coaches who are thinking of setting up their own sports coaching business. [ABSTRACT FROM AUTHOR]

• Evidence of heart rate variability in delirium prediction in hospitalized patient. • Monitoring of standard deviation of NN may be useful for delirium identification. • High heart rate variability associated with acute brain dysfunction. Brain and heart interact through multiple ways. Heart rate variability, a non-invasive measurement is studied extensively as a predicting model for various health conditions including subarachnoid hemorrhage, cancer, and diabetes. There is limited evidence to predict delirium, an acute fluctuating disorder of brain dysfunction, as it poses a significant challenge in the intensive care unit (ICU) and post-operative setting. In this systematic review of 9 articles, heart rate variability indices were used to investigate the occurrence of post-operative and ICU delirium. This systematic review and meta -analysis reveal evidence of a strong predilection between postoperative and intensive care unit delirium and alterations in the heart rate variability, measured by mean differences for standard deviation of NN-intervals. Other heart rate variability indices [root mean squares of successive differences, low-frequency (LF), high-frequency (HF), and LF:HF ratio] showed lack of or very weak association. A non-invasive tool of brain and heart interaction may refine diagnostic predictions for acute brain dysfunctions like delirium in such population and would be an important step in delirium research. [ABSTRACT FROM AUTHOR]

Protein HilD of Salmonella Typhimurium coordinates motility and host cell invasion by upregulating flagellar genes and a secretion system. Here, Cooper et al. show that HilD also modulates swimming behaviour by upregulating a subunit of the chemotactic receptor array, and this is important for invasion of epithelial cells.

In mammalian cells, during transcription and replication, RNA:DNA hybrid structures known as R-loops can arise, posing as obstacles to replication fork progression. Here the authors reveal that the ATP-dependent chromatin remodelling INO80 complex promotes resolution of R-loops to prevent replication associated DNA damage in cancer cells.

Abstract Background Urinary incontinence (UI) is highly prevalent in nursing and residential care homes (CHs) and profoundly impacts on residents’ dignity and quality of life. CHs predominantly use absorbent pads to contain UI rather than actively treat the condition. Transcutaneous posterior tibial nerve stimulation (TPTNS) is a non-invasive, safe and low-cost intervention with demonstrated effectiveness for reducing UI in adults. However, the effectiveness of TPTNS to treat UI in older adults living in CHs is not known. The ELECTRIC trial aims to establish if a programme of TPTNS is a clinically effective treatment for UI in CH residents and investigate the associated costs and consequences. Methods This is a pragmatic, multicentre, placebo-controlled, randomised parallel-group trial comparing the effectiveness of TPTNS (target n = 250) with sham stimulation (target n = 250) in reducing volume of UI in CH residents. CH residents (men and women) with self- or staff-reported UI of more than once per week are eligible to take part, including those with cognitive impairment. Outcomes will be measured at 6, 12 and 18 weeks post randomisation using the following measures: 24-h Pad Weight Tests, post void residual urine (bladder scans), Patient Perception of Bladder Condition, Minnesota Toileting Skills Questionnaire and Dementia Quality of Life. Economic evaluation based on a bespoke Resource Use Questionnaire will assess the costs of providing a programme of TPTNS. A concurrent process evaluation will investigate fidelity to the intervention and influencing factors, and qualitative interviews will explore the experiences of TPTNS from the perspective of CH residents, family members, CH staff and managers. Discussion TPTNS is a non-invasive intervention that has demonstrated effectiveness in reducing UI in adults. The ELECTRIC trial will involve CH staff delivering TPTNS to residents and establish whether TPTNS is more effective than sham stimulation for reducing the volume of UI in CH residents. Should TPTNS be shown to be an effective and acceptable treatment for UI in older adults in CHs, it will provide a safe, low-cost and dignified alternative to the current standard approach of containment and medication. Trial registration ClinicalTrials.gov, NCT03248362. Registered on 14 August 2017. ISRCTN, ISRCTN98415244. Registered on 25 April 2018. https://www.isrctn.com/.