Perceptions of gender equity and markers of achievement in a National Institute for Health Research Biomedical Research Centre: a qualitative study.

BACKGROUND: The need to improve gender equity (GE) in academic medicine is well documented. Biomedical Research Centres (BRCs), partnerships between leading National Health Service (NHS) organizations and universities in England, conduct world-class translational research funded by the National Institute for Health and Care Research (NIHR). In 2011, eligibility for BRC funding was restricted to universities demonstrating sustained GE success recognized by the Athena SWAN Charter for Women in Science Silver awards. Despite this structural change, GE research in BRC settings is underdeveloped, yet critical to the acceleration of women's advancement and leadership. To explore both women's and men's perceptions of GE and current markers of achievement in a BRC setting. METHODS: Thematic analysis of data from two research projects: 53 GE survey respondents' free-text comments (34 women, 16 men), and 16 semi-structured interviews with women affiliated to the NIHR Oxford BRC. RESULTS: Four major themes emerged from the analysis: perceptions of the Athena SWAN Charter for Women in Science (GE policy); views on monitoring GE in BRCs; views on current markers of achievement in academia and GE; and recommendations for actions to improve GE in BRC settings. Monitoring of GE in BRCs was deemed to be important, but complex. Participants felt that current markers of achievement were not equitable to women, as they did not take contextual factors into account such as maternity leave and caring responsibilities. BRC-specific organizational policies and metrics are needed in order to monitor and catalyse GE. CONCLUSIONS: Markers of achievement for monitoring GE in BRCs should consider contextual factors specific to BRCs and women's career progression and professional advancement. GE markers of achievement should be complemented with broader aspects of equality, diversity and inclusion.

Translational researchers' training and development needs, preferences, and barriers: A survey in a National Institute for Health Research Biomedical Research Centre in the United Kingdom.

The objective was to identify translational researchers' training and development needs, preferences, and barriers to attending training. This cross-sectional study involved an online questionnaire survey. The research population comprised a convenience sample of translational researchers and support staff (N = 798) affiliated with the National Institute for Health Research Oxford Biomedical Research Centre. The response rate was 24%. Of 189 respondents, 114 were women (60%) and 75 were men (40%). The respondents were mainly research scientists (31%), medical doctors and dentists (17%), and research nurses and midwives (16%). Many of the respondents had attended at least one training course in the last year (68%). Training in statistics and data analysis was the most common training received (20%). Leadership training was the most wanted training (25%). Morning was the most preferred time of training (60%). Half a day was the ideal duration of a training course (41%). The main teaching hospital site was the most preferred location of training (46%). An interactive workshop was the most favored delivery style of training (52%). Most common barriers to attending training were the lack of time (31%), work (21%) and clinical commitments (19%), and family and childcare responsibilities (14%). Some differences in training needs, preferences, and barriers were found by gender and role, though these were not statistically significant. Translational researchers want short, easily accessible, and interactive training sessions during the working day. The training needs, preferences, and barriers to attending training need to be considered while developing inclusive training programs in biomedical research settings.

Rapid research response to the COVID-19 pandemic: perspectives from a National Institute for Health Biomedical Research Centre.

With over 5 million COVID-19 deaths at the time of writing, the response of research leaders was and is critical to developing treatments to control the global pandemic. As clinical research leaders urgently repurposed existing research programmes and resources towards the COVID-19 pandemic, there is an opportunity to reflect on practices observed in Biomedical Research Centre (BRC) settings. BRCs are partnerships between leading National Health Service organizations and universities in England conducting translational research for patient benefit funded by the National Institute for Health Research (NIHR). Oxford BRC-supported researchers have led the rapid set-up of numerous COVID-19 research studies at record speed with global impact. However, the specific contribution of BRCs to the COVID-19 pandemic in the literature is sparse. Firstly, we reflect on the strategic work of clinical research leaders, creating resilient NIHR research infrastructure to facilitate rapid COVID-19 research. Secondly, we discuss how COVID-19 rapid research exemplars supported by Oxford BRC illustrate "capacity", "readiness" and "capability" at an organizational and individual level to respond to the global pandemic. Rapid response research in turbulent environments requires strategic organizational leadership to create resilient infrastructure and resources. The rapid research exemplars from the Oxford BRC illustrate capability and capacity at an organizational and individual level in a dynamic environment to respond during the COVID-19 public health challenge. This response was underpinned by swift adaptation and repurposing of existing research resources and expertise by the Oxford BRC to deliver rapid research to address different aspects of COVID-19.

Gender parity in scientific authorship in a National Institute for Health Research Biomedical Research Centre: a bibliometric analysis.

OBJECTIVE: Scientific authorship is a vital marker of achievement in academic careers and gender equity is a key performance metric in research. However, there is little understanding of gender equity in publications in biomedical research centres funded by the National Institute for Health Research (NIHR). This study assesses the gender parity in scientific authorship of biomedical research. DESIGN: Descriptive, cross-sectional, retrospective bibliometric study. SETTING: NIHR Oxford Biomedical Research Centre (BRC). DATA: Data comprised 2409 publications that were either accepted or published between April 2012 and March 2017. The publications were classified as basic science studies, clinical studies (both trial and non-trial studies) and other studies (comments, editorials, systematic reviews, reviews, opinions, book chapters, meeting reports, guidelines and protocols). MAIN OUTCOME MEASURES: Gender of authors, defined as a binary variable comprising either male or female categories, in six authorship categories: first author, joint first authors, first corresponding author, joint corresponding authors, last author and joint last authors. RESULTS: Publications comprised 39% clinical research (n=939), 27% basic research (n=643) and 34% other types of research (n=827). The proportion of female authors as first author (41%), first corresponding authors (34%) and last author (23%) was statistically significantly lower than male authors in these authorship categories (p<0.001). Of total joint first authors (n=458), joint corresponding authors (n=169) and joint last authors (n=229), female only authors comprised statistically significant (p<0.001) smaller proportions, that is, 15% (n=69), 29% (n=49) and 10% (n=23) respectively, compared with male only authors in these joint authorship categories. There was a statistically significant association between gender of the last author with gender of the first author (p<0.001), first corresponding author (p<0.001) and joint last author (p<0.001). The mean journal impact factor (JIF) was statistically significantly higher when the first corresponding author was male compared with female (Mean JIF: 10.00 vs 8.77, p=0.020); however, the JIF was not statistically different when there were male and female authors as first authors and last authors. CONCLUSIONS: Although the proportion of female authors is significantly lower than the proportion of male authors in all six categories of authorship analysed, the proportions of male and female last authors are comparable to their respective proportions as principal investigators in the BRC. These findings suggest positive trends and the NIHR Oxford BRC doing very well in gender parity in the senior (last) authorship category. Male corresponding authors are more likely to publish articles in prestigious journals with high impact factor while both male and female authors at first and last authorship positions publish articles in equally prestigious journals.

Basic versus biofeedback-mediated intensive pelvic floor muscle training for women with urinary incontinence: the OPAL RCT.

BACKGROUND: Urinary incontinence affects one in three women worldwide. Pelvic floor muscle training is an effective treatment. Electromyography biofeedback (providing visual or auditory feedback of internal muscle movement) is an adjunct that may improve outcomes. OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of biofeedback-mediated intensive pelvic floor muscle training (biofeedback pelvic floor muscle training) compared with basic pelvic floor muscle training for treating female stress urinary incontinence or mixed urinary incontinence. DESIGN: A multicentre, parallel-group randomised controlled trial of the clinical effectiveness and cost-effectiveness of biofeedback pelvic floor muscle training compared with basic pelvic floor muscle training, with a mixed-methods process evaluation and a longitudinal qualitative case study. Group allocation was by web-based application, with minimisation by urinary incontinence type, centre, age and baseline urinary incontinence severity. Participants, therapy providers and researchers were not blinded to group allocation. Six-month pelvic floor muscle assessments were conducted by a blinded assessor. SETTING: This trial was set in UK community and outpatient care settings. PARTICIPANTS: Women aged ≥ 18 years, with new stress urinary incontinence or mixed urinary incontinence. The following women were excluded: those with urgency urinary incontinence alone, those who had received formal instruction in pelvic floor muscle training in the previous year, those unable to contract their pelvic floor muscles, those pregnant or < 6 months postnatal, those with prolapse greater than stage II, those currently having treatment for pelvic cancer, those with cognitive impairment affecting capacity to give informed consent, those with neurological disease, those with a known nickel allergy or sensitivity and those currently participating in other research relating to their urinary incontinence. INTERVENTIONS: Both groups were offered six appointments over 16 weeks to receive biofeedback pelvic floor muscle training or basic pelvic floor muscle training. Home biofeedback units were provided to the biofeedback pelvic floor muscle training group. Behaviour change techniques were built in to both interventions. MAIN OUTCOME MEASURES: The primary outcome was urinary incontinence severity at 24 months (measured using the International Consultation on Incontinence Questionnaire Urinary Incontinence Short Form score, range 0-21, with a higher score indicating greater severity). The secondary outcomes were urinary incontinence cure/improvement, other urinary and pelvic floor symptoms, urinary incontinence-specific quality of life, self-efficacy for pelvic floor muscle training, global impression of improvement in urinary incontinence, adherence to the exercise, uptake of other urinary incontinence treatment and pelvic floor muscle function. The primary health economic outcome was incremental cost per quality-adjusted-life-year gained at 24 months. RESULTS: A total of 300 participants were randomised per group. The primary analysis included 225 and 235 participants (biofeedback and basic pelvic floor muscle training, respectively). The mean 24-month International Consultation on Incontinence Questionnaire Urinary Incontinence Short Form score was 8.2 (standard deviation 5.1) for biofeedback pelvic floor muscle training and 8.5 (standard deviation 4.9) for basic pelvic floor muscle training (adjusted mean difference -0.09, 95% confidence interval -0.92 to 0.75; p = 0.84). A total of 48 participants had a non-serious adverse event (34 in the biofeedback pelvic floor muscle training group and 14 in the basic pelvic floor muscle training group), of whom 23 (21 in the biofeedback pelvic floor muscle training group and 2 in the basic pelvic floor muscle training group) had an event related/possibly related to the interventions. In addition, there were eight serious adverse events (six in the biofeedback pelvic floor muscle training group and two in the basic pelvic floor muscle training group), all unrelated to the interventions. At 24 months, biofeedback pelvic floor muscle training was not significantly more expensive than basic pelvic floor muscle training, but neither was it associated with significantly more quality-adjusted life-years. The probability that biofeedback pelvic floor muscle training would be cost-effective was 48% at a £20,000 willingness to pay for a quality-adjusted life-year threshold. The process evaluation confirmed that the biofeedback pelvic floor muscle training group received an intensified intervention and both groups received basic pelvic floor muscle training core components. Women were positive about both interventions, adherence to both interventions was similar and both interventions were facilitated by desire to improve their urinary incontinence and hindered by lack of time. LIMITATIONS: Women unable to contract their muscles were excluded, as biofeedback is recommended for these women. CONCLUSIONS: There was no evidence of a difference between biofeedback pelvic floor muscle training and basic pelvic floor muscle training. FUTURE WORK: Research should investigate other ways to intensify pelvic floor muscle training to improve continence outcomes. TRIAL REGISTRATION: Current Controlled Trial ISRCTN57746448. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 70. See the NIHR Journals Library website for further project information.

Urinary incontinence (accidental leakage of urine) is a common and embarrassing problem for women. Pregnancy and childbirth may contribute by leading to less muscle support and bladder control. Pelvic floor exercises and 'biofeedback' equipment (a device that lets women see the muscles working as they exercise) are often used in treatment. There is good evidence that exercises (for the pelvic floor) can help, but less evidence about whether or not adding biofeedback provides better results. This trial compared pelvic floor exercises alone with pelvic floor exercises plus biofeedback. Six hundred women with urinary incontinence participated. Three hundred women were randomly assigned to the exercise group and 300 women were randomised to the exercise plus biofeedback group. Each woman had an equal chance of being in either group. Women were offered six appointments with a therapist over 16 weeks to receive their allocated treatment. After 2 years, there was no difference between the groups in the severity of women's urinary incontinence. Women in both groups varied in how much exercise they managed to do. Some managed to exercise consistently over the 2 years and others less so. There were many factors (other than the treatment received) that affected a woman's ability to exercise. Notably, women viewed the therapists' input very positively. The therapists reported some problems fitting biofeedback into the appointments, but, overall, they delivered both treatments as intended. Women carried out exercises at home and many in the biofeedback pelvic floor muscle training group also used biofeedback at home; however, for both groups, time issues, forgetting and other health problems affected their adherence. There were no serious complications related to either treatment. Overall, exercise plus biofeedback was not significantly more expensive than exercise alone and the quality of life associated with exercise plus biofeedback was not better than the quality of life for exercise alone. In summary, exercises plus biofeedback was no better than exercise alone. The findings do not support using biofeedback routinely as part of pelvic floor exercise treatment for women with urinary incontinence.

Markers of achievement for assessing and monitoring gender equity in a UK National Institute for Health Research Biomedical Research Centre: A two-factor model.

BACKGROUND: The underrepresentation of women in academic medicine at senior level and in leadership positions is well documented. Biomedical Research Centres (BRC), partnerships between leading National Health Service (NHS) organisations and universities, conduct world class translational research funded by the National Institute for Health Research (NIHR) in the UK. Since 2011 BRCs are required to demonstrate significant progress in gender equity (GE) to be eligible to apply for funding. However, the evidence base for monitoring GE specifically in BRC settings is underdeveloped. This is the first survey tool designed to rank and identify new GE markers specific to the NIHR BRCs. METHODS: An online survey distributed to senior leadership, clinical and non-clinical researchers, trainees, administrative and other professionals affiliated to the NIHR Oxford BRC (N = 683). Participants ranked 13 markers of GE on a five point Likert scale by importance. Data were summarised using frequencies and descriptive statistics. Interrelationships between markers and underlying latent dimensions (factors) were determined by exploratory and confirmatory factor analyses. RESULTS: The response rate was 36% (243 respondents). Respondents were more frequently female (55%, n = 133), aged 41-50 years (33%, n = 81), investigators (33%, n = 81) affiliated to the BRC for 2-7 years (39.5%, n = 96). Overall participants ranked 'BRC senior leadership roles' and 'organisational policies on gender equity', to be the most important markers of GE. 58% (n = 141) and 57% (n = 139) respectively. Female participants ranked 'organisational policies' (64.7%, n = 86/133) and 'recruitment and retention' (60.9%, n = 81/133) most highly, whereas male participants ranked 'leadership development' (52.1%, n = 50/96) and 'BRC senior leadership roles' (50%, n = 48/96) as most important. Factor analyses identified two distinct latent dimensions: "organisational markers" and "individual markers" of GE in BRCs. CONCLUSIONS: A two-factor model of markers of achievement for GE with "organisational" and "individual" dimensions was identified. Implementation and sustainability of gender equity requires commitment at senior leadership and organisational policy level.

The impact of age on patient tolerance of mycophenolate following kidney transplantation.

BACKGROUND: In Scotland, standard maintenance immunosuppression following kidney transplantation consists of mycophenolate (MPA), tacrolimus and prednisolone irrespective of recipient age. We analyzed the tolerability of this immunosuppression regimen and the association with transplant outcomes. METHODS: A national, multicentre retrospective analysis of patients transplanted in 2015 and 2016, comparing graft function, acute rejection, significant infection rates and immunosuppression dosing between patients aged 18 and 59 years (Group 1) and ≥60 years (Group 2). RESULTS: Of the 490 patients, 26% were aged ≥60 years. Acute rejection (AR) rates at 1 year were 15% and 11% in Groups 1 and 2, respectively. Full-dose MPA was poorly tolerated with 53% in Group 1 and 77% in Group 2 requiring dose reduction or cessation. Female gender and age ≥60 years were independent predictors for MPA dose changes. One year following MPA dose reduction, AR risk was low (5%) in Group 2, however, those remaining on full dose MPA had a 79% increased rate of serious infections. CONCLUSION: The majority of renal transplant recipients aged ≥60 fail to tolerate full-dose MPA. In this group, MPA dose reduction is associated with low rejection rates, but full-dose MPA is associated with high infection rates. We suggest that a tailored approach to immunosuppression in elderly recipients incorporating lower doses of MPA may be appropriate.

A case report-Two manufacturers SAB testing kits can reveal different HLA antibody profiles-Identifying prozone and denatured antigen.

Recent reports have identified that the presence of non-native conformation HLA to which antibody can bind upon Luminex HLA Class I single antigen beads, can vary in levels between different manufacturers kits and that the prozone effect may also be specific to particular products. We present a case in which both prozone and non-native HLA reactive antibodies were observed, which raises important questions on how SAB assays are utilised, especially in the post-transplant monitoring setting. A 56-year old, highly sensitised female patient awaiting a regraft received a HLAi renal transplant. Post-transplant monitoring showed discordant results between two SAB manufacturers assays, with one assay identifying a potential de novo HLA DSA. HLA Class I antibody reactivity was observed which was directed towards the Bw6 public epitope, which is present upon HLA molecules encoded for by numerous HLA-B alleles. However in the day 19 post-transplant sample reactivity spread beyond the Bw6 epitope. To investigate the possibility of a prozone type effect influencing the testing kit the day 19 post-transplant sample was diluted 1:10 with PBS and reanalysed. After dilution the Bw6 reactivity was observed again, however the suspect de novo DSA still persisted. An analysis of the mismatched epitopes identified one manufacturer's assay as being confounded by the presence of denatured reactivity as well as prozone.

Understanding the Athena SWAN award scheme for gender equality as a complex social intervention in a complex system: analysis of Silver award action plans in a comparative European perspective.

BACKGROUND: Given the complex mix of structural, cultural and institutional factors that produce barriers for women in science, an equally complex intervention is required to understand and address them. The Athena SWAN Award Scheme for Gender Equality has become a widespread means to address barriers for women's advancement and leadership in the United Kingdom, Ireland, Australia, the United States of America and Canada, while the European Commission is exploring the introduction of a similar award scheme across Europe. METHODS: This study analyses the design and implementation of 16 departmental Athena SWAN Silver Action Plans in Medical Sciences at one of the world's leading universities in Oxford, United Kingdom. Data pertaining to the design and implementation of gender equality interventions were extracted from the action plans, analysed thematically, coded using categories from the 2015 Athena SWAN Charter Awards Handbook and synthesised against a typology of gender equality interventions in the European Research Area. The results were further analysed against the complexity research literature framework, where research organisations are perceived as dynamic systems that adapt, interact and co-evolve with other systems. RESULTS: Athena SWAN is a complex contextually embedded system of action planning within the context of universities. It depends on a multitude of contextual variables that relate in complex, non-linear ways and dynamically adapt to constantly moving targets and new emergent conditions. Athena SWAN Silver Action Plans conform to the key considerations of complexity - (1) multiple actions and areas of intervention with a focus on the complex system being embedded in local dynamics, (2) the non-linearity of interventions and the constantly emerging conditions, and (3) impact in terms of contribution to change, improved conditions to foster change and the increased probability that change can occur. CONCLUSIONS: To enact effective sustainable structural and cultural change for gender equality, it is necessary to acknowledge and operationalise complexity as a frame of reference. Athena SWAN is the single most comprehensive and systemic gender equality scheme in Europe. It can be further strengthened by promoting the integration of sex and gender analysis in research and education. Gender equality policies in the wider European Research Area can benefit from exploring Athena SWAN's contextually embedded systemic approach to dynamic action planning and inclusive focus on all genders and categories of staff and students.

Structural Transformation to Attain Responsible BIOSciences (STARBIOS2): Protocol for a Horizon 2020 Funded European Multicenter Project to Promote Responsible Research and Innovation.

BACKGROUND: Promoting Responsible Research and Innovation (RRI) is a major strategy of the "Science with and for Society" work program of the European Union's Horizon 2020 Framework Programme for Research and Innovation. RRI aims to achieve a better alignment of research and innovation with the values, needs, and expectations of society. The RRI strategy includes the "keys" of public engagement, open access, gender, ethics, and science education. The Structural Transformation to Attain Responsible BIOSciences (STARBIOS2) project promotes RRI in 6 European research institutions and universities from Bulgaria, Germany, Italy, Slovenia, Poland, and the United Kingdom, in partnership with a further 6 institutions from Brazil, Denmark, Italy, South Africa, Sweden, and the United States. OBJECTIVE: The project aims to attain RRI structural change in 6 European institutions by implementing action plans (APs) and developing APs for 3 non-European institutions active in the field of biosciences; use the implementation of APs as a learning process with a view to developing a set of guidelines on the implementation of RRI; and develop a sustainable model for RRI in biosciences. METHODS: The project comprises interrelated research and implementation designed to achieve the aforementioned specific objectives. The project is organized into 6 core work packages and 5 supporting work packages. The core work packages deal with the implementation of institutional APs in 6 European institutions based on the structural change activation model. The supporting work packages include technical assistance, learning process on RRI-oriented structural change, monitoring and assessment, communication and dissemination, and project management. RESULTS: The project is funded by Horizon 2020 and will run for 4 years (May 2016-April 2020). As of June 2018, the initial phase has been completed. The participating institutions have developed and approved APs and commenced their implementation. An observation tool has been launched by the Technical Assistance Team to collect information from the implementation of APs; the Evaluation & Assessment team has started monitoring the advancement of the project. As part of the communication and dissemination strategy, a project website, a Facebook page, and a Twitter account have been launched and are updated periodically. The International Scientific Advisory Committee has been formed to advise on the reporting and dissemination of the project's results. CONCLUSIONS: In the short term, we anticipate that the project will have a considerable impact on the organizational processes and structures, improving the RRI uptake in the participating institutions. In the medium term, we expect to make RRI-oriented organizational change scalable across Europe by developing guidelines on RRI implementation and an RRI model in biosciences. In the long term, we expect that the project would help increase the ability of research institutions to make discoveries and innovations in better alignment with societal needs and values. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/11745.

The Impact of Withdrawal of Maintenance Immunosuppression and Graft Nephrectomy on HLA Sensitization and Calculated Chance of Future Transplant.

BACKGROUND: The development of HLA antibodies towards a failing renal allograft is a barrier to retransplantation. This study aimed to compare the formation of HLA donor-specific antibodies (DSA) in patients undergoing graft nephrectomy and in those with a failed graft left in situ who had maintenance immunosuppression (IS) stopped, and assess the relative impact of IS cessation and graft nephrectomy on future relative chance of transplant (R-CoT). METHODS: A single-center retrospective study of patients with failed grafts between 2005 and 2015 was performed. Samples were tested for DSA pre-IS wean, post-IS wean, and post-IS cessation. Nephrectomy patients additionally had samples tested for DSA before and after nephrectomy. Calculated reaction frequency (cRF) was determined at each timepoint and entered into the UK Organ Donation and Transplant R-CoT calculator. RESULTS: Forty-one patients were included in the study: 24 with nephrectomy and 17 with a failed graft in situ. Patient demographics and duration of IS wean were similar between groups. There was a higher rate of blood transfusion (54% vs 24%) in nephrectomy patients. In patients whose graft remained in situ, cRF rose from 13% pre-IS wean to 40% post-IS wean and 62% after IS cessation. This equated to a reduction in mean R-CoT from 54% to 46% at 5 years. In patients undergoing nephrectomy mean cRF rose from 31% pre-IS wean to 69% post-IS wean and 89% post-IS cessation. Mean R-CoT fell from 54% to 42% at 5 years. CONCLUSIONS: A stepwise increase in cRF with reduced chance of transplant was observed in both groups as IS was withdrawn, with a similar pattern irrespective of graft nephrectomy. Calculated reaction frequency was higher in the nephrectomy group. The risks and benefits of stopping IS need to be carefully considered on an individual basis to maximize chance of future transplant.

Immunosuppressive treatment for proliferative lupus nephritis.

BACKGROUND: Cyclophosphamide, in combination with corticosteroids, has been first-line treatment for inducing disease remission for proliferative lupus nephritis, reducing death at five years from over 50% in the 1950s and 1960s to less than 10% in recent years. Several treatment strategies designed to improve remission rates and minimise toxicity have become available. Treatments, including mycophenolate mofetil (MMF) and calcineurin inhibitors, alone and in combination, may have equivalent or improved rates of remission, lower toxicity (less alopecia and ovarian failure) and uncertain effects on death, end-stage kidney disease (ESKD) and infection. This is an update of a Cochrane review first published in 2004 and updated in 2012. OBJECTIVES: Our objective was to assess the evidence and evaluate the benefits and harms of different immunosuppressive treatments in people with biopsy-proven lupus nephritis. The following questions relating to management of proliferative lupus nephritis were addressed: 1) Are new immunosuppressive agents superior to or as effective as cyclophosphamide plus corticosteroids? 2) Which agents, dosages, routes of administration and duration of therapy should be used? 3) Which toxicities occur with the different treatment regimens? SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 2 March 2018 with support from the Cochrane Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing any immunosuppressive treatment for biopsy-proven class III, IV, V+III and V+VI lupus nephritis in adult or paediatric patients were included. DATA COLLECTION AND ANALYSIS: Data were abstracted and the risks of bias were assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) and measures on continuous scales calculated as mean differences (MD) with 95% confidence intervals (CI). The primary outcomes were death (all causes) and complete disease remission for induction therapy and disease relapse for maintenance therapy. Evidence certainty was determined using GRADE. MAIN RESULTS: In this review update, 26 new studies were identified, to include 74 studies involving 5175 participants overall. Twenty-nine studies included children under the age of 18 years with lupus nephritis, however only two studies exclusively examined the treatment of lupus nephritis in patients less than 18 years of age.Induction therapy Sixty-seven studies (4791 participants; median 12 months duration (range 2.5 to 48 months)) reported induction therapy. The effects of all treatment strategies on death (all causes) and ESKD were uncertain (very low certainty evidence) as this outcome occurred very infrequently. Compared with intravenous (IV) cyclophosphamide, MMF may have increased complete disease remission (RR 1.17, 95% CI 0.97 to 1.42; low certainty evidence), although the range of effects includes the possibility of little or no difference.Compared to IV cyclophosphamide, MMF is probably associated with decreased alopecia (RR 0.29, 95% CI 0.19 to 0.46; 170 less (129 less to 194 less) per 1000 people) (moderate certainty evidence), increased diarrhoea (RR 2.42, 95% CI 1.64 to 3.58; 142 more (64 more to 257 more) per 1000 people) (moderate certainty evidence) and may have made little or no difference to major infection (RR 1.02, 95% CI 0.67 to 1.54; 2 less (38 less to 62 more) per 1000 people) (low certainty evidence). It is uncertain if MMF decreased ovarian failure compared to IV cyclophosphamide because the certainty of the evidence was very low (RR 0.36, 95% CI 0.06 to 2.18; 26 less (39 less to 49 more) per 1000 people). Studies were not generally designed to measure ESKD.MMF combined with tacrolimus may have increased complete disease remission (RR 2.38, 95% CI 1.07 to 5.30; 336 more (17 to 1048 more) per 1000 people (low certainty evidence) compared with IV cyclophosphamide, however the effects on alopecia, diarrhoea, ovarian failure, and major infection remain uncertain. Compared to standard of care, the effects of biologics on most outcomes were uncertain because of low to very low certainty of evidence.Maintenance therapyNine studies (767 participants; median 30 months duration (range 6 to 63 months)) reported maintenance therapy. In maintenance therapy, disease relapse is probably increased with azathioprine compared with MMF (RR 1.75, 95% CI 1.20 to 2.55; 114 more (30 to 236 more) per 1000 people (moderate certainty evidence). Multiple other interventions were compared as maintenance therapy, but patient-outcome data were sparse leading to imprecise estimates. AUTHORS' CONCLUSIONS: In this review update, studies assessing treatment for proliferative lupus nephritis were not designed to assess death (all causes) or ESKD. MMF may lead to increased complete disease remission compared with IV cyclophosphamide, with an acceptable adverse event profile, although evidence certainty was low and included the possibility of no difference. Calcineurin combined with lower dose MMF may improve induction of disease remission compared with IV cyclophosphamide, but the comparative safety profile of these therapies is uncertain. Azathioprine may increase disease relapse as maintenance therapy compared with MMF.

Outcome of Kidney Transplant in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVES: Kidney transplant outcomes in patients with antineutrophil cytoplasmic antibody-associated vasculitis are comparable with outcomes in patients transplanted for other causes. Here, we report our single center experience of kidney transplant in patients with this condition and a pooled analysis of published studies. MATERIALS AND METHODS: This retrospective study included all patients with end-stage kidney disease secondary to antineutrophil cytoplasmic antibody-associated vasculitis who received a kidney transplant between 1987 and 2013 in the East of Scotland. We examined patient and graft survival and disease recurrence after transplant. We also performed a pooled analysis of published literature. RESULTS: We identified 24 patients who received a total of 31 kidney allografts. Median age at first transplant was 45.5 years (range, 18-68 y), and median follow-up after transplant was 60 months (range, 0.5-226 mo). All patients were positive for antineutrophil cytoplasmic antibody (71% by proteinase 3 and 29% by myeloperoxidase) at diagnosis. Patient survival at 1 and 5 years was 92% and 88%, with corresponding death-censored allograft survival of 93% and 71%. Overall patient and allograft relapse rates were 0.022 and 0.016 relapse/patient-years. The pooled analysis comprised 20 studies (1169 patients). Patient/graft survival ranged from 64% to 80%/77% to 100% at 5 years and from 60% to 100%/59% to 84% at 10 years. Relapse rate was significantly higher in patients with positive antineutrophil cytoplasmic antibody at transplant (14% vs 5%; P = .042). CONCLUSIONS: Our experience shows that kidney transplant remains a safe option for patients with end-stage kidney disease secondary to antineutrophil cytoplasmic antibody-associated vasculitis. Disease relapse posttransplant is uncommon and associated with pretransplant relapse. Pooled analyses suggest that relapse rate is higher in patients with positive antineutrophil cytoplasmic antibody at transplant. Multicenter registry data are needed to define renal outcome predictors in antineutrophil cytoplasmic antibody-associated vasculitis.

Alpha-2 agonists for sedation of mechanically ventilated adults in intensive care units: a systematic review.

BACKGROUND: Care of critically ill patients in intensive care units (ICUs) often requires potentially invasive or uncomfortable procedures, such as mechanical ventilation (MV). Sedation can alleviate pain and discomfort, provide protection from stressful or harmful events, prevent anxiety and promote sleep. Various sedative agents are available for use in ICUs. In the UK, the most commonly used sedatives are propofol (Diprivan(®), AstraZeneca), benzodiazepines [e.g. midazolam (Hypnovel(®), Roche) and lorazepam (Ativan(®), Pfizer)] and alpha-2 adrenergic receptor agonists [e.g. dexmedetomidine (Dexdor(®), Orion Corporation) and clonidine (Catapres(®), Boehringer Ingelheim)]. Sedative agents vary in onset/duration of effects and in their side effects. The pattern of sedation of alpha-2 agonists is quite different from that of other sedatives in that patients can be aroused readily and their cognitive performance on psychometric tests is usually preserved. Moreover, respiratory depression is less frequent after alpha-2 agonists than after other sedative agents. OBJECTIVES: To conduct a systematic review to evaluate the comparative effects of alpha-2 agonists (dexmedetomidine and clonidine) and propofol or benzodiazepines (midazolam and lorazepam) in mechanically ventilated adults admitted to ICUs. DATA SOURCES: We searched major electronic databases (e.g. MEDLINE without revisions, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE and Cochrane Central Register of Controlled Trials) from 1999 to 2014. METHODS: Evidence was considered from randomised controlled trials (RCTs) comparing dexmedetomidine with clonidine or dexmedetomidine or clonidine with propofol or benzodiazepines such as midazolam, lorazepam and diazepam (Diazemuls(®), Actavis UK Limited). Primary outcomes included mortality, duration of MV, length of ICU stay and adverse events. One reviewer extracted data and assessed the risk of bias of included trials. A second reviewer cross-checked all the data extracted. Random-effects meta-analyses were used for data synthesis. RESULTS: Eighteen RCTs (2489 adult patients) were included. One trial at unclear risk of bias compared dexmedetomidine with clonidine and found that target sedation was achieved in a higher number of patients treated with dexmedetomidine with lesser need for additional sedation. The remaining 17 trials compared dexmedetomidine with propofol or benzodiazepines (midazolam or lorazepam). Trials varied considerably with regard to clinical population, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded outcome assessors. Compared with propofol or benzodiazepines (midazolam or lorazepam), dexmedetomidine had no significant effects on mortality [risk ratio (RR) 1.03, 95% confidence interval (CI) 0.85 to 1.24, I (2) = 0%; p = 0.78]. Length of ICU stay (mean difference -1.26 days, 95% CI -1.96 to -0.55 days, I (2) = 31%; p = 0.0004) and time to extubation (mean difference -1.85 days, 95% CI -2.61 to -1.09 days, I (2) = 0%; p < 0.00001) were significantly shorter among patients who received dexmedetomidine. No difference in time to target sedation range was observed between sedative interventions (I (2) = 0%; p = 0.14). Dexmedetomidine was associated with a higher risk of bradycardia (RR 1.88, 95% CI 1.28 to 2.77, I (2) = 46%; p = 0.001). LIMITATIONS: Trials varied considerably with regard to participants, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded assessors. CONCLUSIONS: Evidence on the use of clonidine in ICUs is very limited. Dexmedetomidine may be effective in reducing ICU length of stay and time to extubation in critically ill ICU patients. Risk of bradycardia but not of overall mortality is higher among patients treated with dexmedetomidine. Well-designed RCTs are needed to assess the use of clonidine in ICUs and identify subgroups of patients that are more likely to benefit from the use of dexmedetomidine. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014014101. FUNDING: The National Institute for Health Research Health Technology Assessment programme. The Health Services Research Unit is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates.

Markers of achievement for assessing and monitoring gender equity in translational research organisations: a rationale and study protocol.

INTRODUCTION: Translational research organisations (TROs) are a core component of the UK's expanding research base. Equity of career opportunity is key to ensuring a diverse and internationally competitive workforce. The UK now requires TROs to demonstrate how they are supporting gender equity. Yet, the evidence base for documenting such efforts is sparse. This study is designed to inform the acceleration of women's advancement and leadership in two of the UK's leading TROs--the National Institute for Health Research (NIHR) Biomedical Research Centres (BRCs) in Oxford and London--through the development, application and dissemination of a conceptual framework and measurement tool. METHODS AND ANALYSIS: A cross-sectional retrospective evaluation. A conceptual framework with markers of achievement and corresponding candidate metrics has been specifically designed for this study based on an adapted balanced scorecard approach. It will be refined with an online stakeholder consultation and semistructured interviews to test the face validity and explore practices and mechanisms that influence gender equity in the given settings. Data will be collected via the relevant administrative databases. A comparison of two funding periods (2007-2012 and 2012-2017) will be carried out. ETHICS AND DISSEMINATION: The University of Oxford Clinical Trials and Research Governance Team and the Research and Development Governance Team of Guy's and St Thomas' National Health Service (NHS) Foundation Trust reviewed the study and deemed it exempt from full ethics review. The results of the study will be used to inform prospective planning and monitoring within the participating NIHR BRCs with a view to accelerating women's advancement and leadership. Both the results of the study and its methodology will be further disseminated to academics and practitioners through the networks of collaborating TROs, relevant conferences and articles in peer-reviewed journals.

Belatacept for kidney transplant recipients.

BACKGROUND: Most people who receive a kidney transplant die from either cardiovascular disease or cancer before their transplant fails. The most common reason for someone with a kidney transplant to lose the function of their transplanted kidney necessitating return to dialysis is chronic kidney transplant scarring. Immunosuppressant drugs have side effects that increase risks of cardiovascular disease, cancer and chronic kidney transplant scarring. Belatacept may provide sufficient immunosuppression while avoiding unwanted side effects of other immunosuppressant drugs. However, high rates of post-transplant lymphoproliferative disease (PTLD) have been reported when belatacept is used in particular kidney transplant recipients at high dosage. OBJECTIVES: 1) Compare the relative efficacy of belatacept versus any other primary immunosuppression regimen for preventing acute rejection, maintaining kidney transplant function, and preventing death. 2) Compare the incidence of several adverse events: PTLD; other malignancies; chronic transplant kidney scarring (IF/TA); infections; change in blood pressure, lipid and blood sugar control. 3) Assess any variation in effects by study, intervention and recipient characteristics, including: differences in pre-transplant Epstein Barr virus serostatus; belatacept dosage; and donor-category (living, standard criteria deceased, or extended criteria deceased). SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 1 September 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials (RCT) that compared belatacept versus any other immunosuppression regimen in kidney transplant recipients were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data for study quality and transplant outcomes and synthesized results using random effects meta-analysis, expressed as risk ratios (RR) and mean differences (MD), both with 95% confidence intervals (CI).  Subgroup analyses and univariate meta-regression were used to investigate potential heterogeneity. MAIN RESULTS: We included five studies that compared belatacept and calcineurin inhibitors (CNI) that reported data from a total of 1535 kidney transplant recipients. Of the five studies, three (478 participants) compared belatacept and cyclosporin and two (43 recipients) compared belatacept and tacrolimus. Co-interventions included basiliximab (4 studies, 1434 recipients); anti-thymocyte globulin (1 study, 89 recipients); alemtuzumab (1 study, 12 recipients); mycophenolate mofetil (MMF, 5 studies, 1509 recipients); sirolimus (1 study, 26 recipients) and prednisone (5 studies, 1535 recipients).Up to three years following transplant, belatacept and CNI-treated recipients were at similar risk of dying (4 studies, 1516 recipients: RR 0.75, 95% CI 0.39 to 1.44), losing their kidney transplant and returning to dialysis (4 studies, 1516 recipients: RR 0.91, 95% CI 0.61 to 1.38), and having an episode of acute rejection (4 studies, 1516 recipients: RR 1.56, 95% CI 0.85 to 2.86). Belatacept-treated kidney transplant recipients were 28% less likely to have chronic kidney scarring (3 studies, 1360 recipients: RR 0.72, 95% CI 0.55 to 0.94) and also had better graft function (measured glomerular filtration rate (GFR) (3 studies 1083 recipients): 10.89 mL/min/1.73 m², 95% CI 4.01 to 17.77; estimated GFR (4 studies, 1083 recipients): MD 9.96 mL/min/1.73 m², 95% CI 3.28 to 16.64) than CNI-treated recipients. Blood pressure was lower (systolic (2 studies, 658 recipients): MD -7.51 mm Hg, 95% CI -10.57 to -4.46; diastolic (2 studies, 658 recipients): MD -3.07 mm Hg, 95% CI -4.83 to -1.31, lipid profile was better (non-HDL (3 studies 1101 recipients): MD -12.25 mg/dL, 95% CI -17.93 to -6.57; triglycerides (3 studies 1101 recipients): MD -24.09 mg/dL, 95% CI -44.55 to -3.64), and incidence of new-onset diabetes after transplant was reduced by 39% (4 studies (1049 recipients): RR 0.61, 95% CI 0.40 to 0.93) among belatacept-treated versus CNI-treated recipients.Risk of PTLD was similar in belatacept and CNI-treated recipients (4 studies, 1516 recipients: RR 2.79, 95% CI 0.61 to 12.66) and was no different among recipients who received different belatacept dosages (high versus low dosage: ratio of risk ratios (RRR) 1.06, 95% CI 0.11 to 9.80, test of difference = 0.96) or among those who were Epstein Barr virus seronegative compared with those who were seropositive before their kidney transplant (seronegative versus seropositive; RRR 1.49, 95% CI 0.15 to 14.76, test for difference = 0.73).The belatacept dose used (high versus low), type of donor kidney the recipient received (extended versus standard criteria) and whether the kidney transplant recipient received tacrolimus or cyclosporin made no difference to kidney transplant survival, incidence of acute rejection or estimated GFR. Selective outcome reporting meant that data for some key subgroup comparisons were sparse and that estimates of the effect of treatment in these groups of recipients remain imprecise. AUTHORS' CONCLUSIONS: There is no evidence of any difference in the effectiveness of belatacept and CNI in preventing acute rejection, graft loss and death, but treatment with belatacept is associated with less chronic kidney scarring and better kidney transplant function. Treatment with belatacept is also associated with better blood pressure and lipid profile and a lower incidence of diabetes versus treatment with a CNI. Important side effects (particularly PTLD) remain poorly reported and so the relative benefits and harms of using belatacept remain unclear. Whether short-term advantages of treatment with belatacept are maintained over the medium- to long-term or translate into better cardiovascular outcomes or longer kidney transplant survival with function remains unclear. Longer-term, fully reported and published studies comparing belatacept versus tacrolimus are needed to help clinicians decide which patients might benefit most from using belatacept.

Induction and maintenance treatment of proliferative lupus nephritis: a meta-analysis of randomized controlled trials.

BACKGROUND: Lupus nephritis accounts for ~1% of patients starting dialysis therapy. Treatment regimens combining cyclophosphamide with steroids preserve kidney function but have significant side effects. Newer immunosuppressive agents may have improved toxicity profiles. STUDY DESIGN: Systematic review and random-effects meta-analysis, searching MEDLINE (1966 to April 2012), EMBASE (1988-2011), and the Cochrane Renal Group Specialised Register. SETTING & POPULATION: Patients with biopsy-proven proliferative lupus nephritis (classes III, IV, V+III, and V+IV). SELECTION CRITERIA: Randomized controlled trials. INTERVENTION: Immunosuppressive treatment regimens used for induction and maintenance therapy of lupus nephritis. OUTCOMES: Mortality, renal remission and relapse, doubling of creatinine level, proteinuria, incidence of end-stage kidney disease, ovarian failure, alopecia, leukopenia, infections, diarrhea, vomiting, malignancy, and bladder toxicity. RESULTS: 45 trials (2,559 participants) of induction therapy and 6 (514 participants) of maintenance therapy were included. In induction regimens comparing mycophenolate mofetil (MMF) with intravenous cyclophosphamide, there was no significant difference in mortality (7 studies, 710 patients; risk ratio [RR], 1.02; 95% CI, 0.52-1.98), incidence of end-stage kidney disease (3 studies, 231 patients; RR, 0.71; 95% CI, 0.27-1.84), complete renal remission (6 studies, 686 patients; RR, 1.39; 95% CI, 0.99-1.95), and renal relapse (1 study, 140 patients; RR, 0.97; 95% CI, 0.39-2.44). MMF-treated patients had significantly lower risks of ovarian failure (2 studies, 498 patients; RR, 0.15; 95% CI, 0.03-0.80) and alopecia (2 studies, 522 patients; RR, 0.22; 95% CI, 0.06-0.86). In maintenance therapy comparing azathioprine with MMF, the risk of renal relapse was significantly higher (3 studies, 371 patients; RR, 1.83; 95% CI, 1.24-2.71). LIMITATIONS: Heterogeneity in interventions and definitions of remission and lack of long-term outcome reporting. CONCLUSIONS: MMF is as effective as cyclophosphamide in achieving remission in lupus nephritis, but is safer, with a lower risk of ovarian failure. MMF is more effective than azathioprine in maintenance therapy for preventing relapse, with no difference in clinically important side effects.

Treatment for lupus nephritis.

BACKGROUND: Cyclophosphamide, in combination with corticosteroids has been used to induce remission in proliferative lupus nephritis, the most common kidney manifestation of the multisystem disease, systemic lupus erythematosus. Cyclophosphamide therapy has reduced mortality from over 70% in the 1950s and 1960s to less than 10% in recent years. Cyclophosphamide combined with corticosteroids preserves kidney function but is only partially effective and may cause ovarian failure, infection and bladder toxicity. Several new agents, including mycophenolate mofetil (MMF), suggest reduced toxicity with equivalent rates of remission. This is an update of a Cochrane review first published in 2004. OBJECTIVES: To assess the benefits and harms of different immunosuppressive treatments in biopsy-proven proliferative lupus nephritis. SEARCH METHODS: For this update, we searched the Cochrane Renal Group's Specialised Register (up to 15 April 2012) through contact with the Trials' Search Coordinator using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing any treatments for biopsy-proven lupus nephritis in both adult and paediatric patients with class III, IV, V +III and V +IV lupus nephritis were included. All immunosuppressive treatments were considered. DATA COLLECTION AND ANALYSIS: Data were abstracted and quality assessed independently by two authors, with differences resolved by discussion. Dichotomous outcomes were reported as risk ratio (RR) and measurements on continuous scales reported as mean differences (MD) with 95% confidence intervals (CI). MAIN RESULTS: We identified 50 RCTs involving 2846 participants. Of these, 45 studies (2559 participants) investigated induction therapy, and six studies (514 participants), considered maintenance therapy.Compared with intravenous (IV) cyclophosphamide, MMF was as effective in achieving stable kidney function (5 studies, 523 participants: RR 1.05, 95% CI 0.94 to 1.18) and complete remission of proteinuria (6 studies, 686 participants: RR 1.16, 95% CI 0.85 to 1.58). No differences in mortality (7 studies, 710 participants: RR 1.02, 95% CI 0.52 to 1.98) or major infection (6 studies, 683 participants: RR 1.11, 95% CI 0.74 to 1.68) were observed. A significant reduction in ovarian failure (2 studies, 498 participants: RR 0.15, 95% CI 0.03 to 0.80) and alopecia (2 studies, 522 participants: RR 0.22, 95% CI 0.06 to 0.86) was observed with MMF. In maintenance therapy, the risk of renal relapse (3 studies, 371 participants: RR 1.83, 95% CI 1.24 to 2.71) was significantly higher with azathioprine compared with MMF. Multiple other interventions were compared but outcome data were relatively sparse. Overall study quality was variable. The internal validity of the design, conduct and analysis of the included RCTs was difficult to assess in some studies because of the omission of important methodological details. No study adequately reported all domains of the risk of bias assessment so that elements of internal bias may be present. AUTHORS' CONCLUSIONS: MMF is as effective as cyclophosphamide in inducing remission in lupus nephritis, but is safer with a lower risk of ovarian failure. MMF is more effective than azathioprine in maintenance therapy for preventing relapse with no increase in clinically important side effects. Adequately powered trials with long term follow-up are required to more accurately define the risks and eventual harms of specific treatment regimens.