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The clinical severity of sickle cell disease (SCD) is strongly influenced by the level of fetal haemoglobin (HbF) persistent in each patient. Three major HbF loci (BCL11A, HBS1L-MYB, and Xmn1-HBG2) have been reported, but a considerable hidden heritability remains. We conducted a genome-wide association study for HbF levels in 1006 Nigerian patients with SCD (HbSS/HbSβ0), followed by a replication and meta-analysis exercise in four independent SCD cohorts (3,582 patients). To dissect association signals at the major loci, we performed stepwise conditional and haplotype association analyses and included public functional annotation datasets. Association signals were detected for BCL11A (lead SNP rs6706648, β = -0.39, P = 4.96 × 10-34) and HBS1L-MYB (lead SNP rs61028892, β = 0.73, P = 1.18 × 10-9), whereas the variant allele for Xmn1-HBG2 was found to be very rare. In addition, we detected three putative new trait-associated regions. Genetically, dissecting the two major loci BCL11A and HBS1L-MYB, we defined trait-increasing haplotypes (P < 0.0001) containing so far unidentified causal variants. At BCL11A, in addition to a haplotype harbouring the putative functional variant rs1427407-'T', we identified a second haplotype, tagged by the rs7565301-'A' allele, where a yet-to-be-discovered causal DNA variant may reside. Similarly, at HBS1L-MYB, one HbF-increasing haplotype contains the likely functional small indel rs66650371, and a second tagged by rs61028892-'C' is likely to harbour a presently unknown functional allele. Together, variants at BCL11A and HBS1L-MYB SNPs explained 24.1% of the trait variance. Our findings provide a path for further investigation of the causes of variable fetal haemoglobin persistence in sickle cell disease., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: With the introduction of novel treatment options for benign prostatic hyperplasia (BPH), decision making regarding surgical management has become ever more complex. Factors such as clinical exposure, equipment availability, patient characteristics and hospital setting may affect what treatment is offered and an informed patient choice. The aim of this study was to investigate how urologists help patients make decisions regarding BPH management and whether their practice would differ if they were the patient themselves., Material and Methods: A 52-question survey presenting hypothetical clinical scenarios was distributed to European urologists and trainees/residents online and in person. In each scenario, regarding treatment options for BPH, the participant considered themselves firstly as the treating clinician and secondly as the patient themselves. Details regarding the participants' clinical experience, awareness of treatment options and exposure to these options were obtained., Results: There were 139 participants; 69.8% of whom were consultants, with 82.1% of participants having practiced urology for more than 5 years. A total of 59.7% of urologists consider themselves BPH specialists. Furthermore, 93.5% of those surveyed had performed transurethral resection of the prostate (TURP), whilst procedures performed the least by participants were minimally invasive surgical therapy (MIST) options. Only 17.3% had seen and 1.4% had performed all of the treatment options. When considering themselves as a patient within standard practice, there was a preference for HoLEP amongst participants., Conclusions: The majority of urologists surveyed had minimal experience to newer BPH techniques and MIST, suggesting that more exposure is required. A higher rate of HoLEP was chosen as a treatment option for urologists themselves as a patient than what they would choose as an option for their patients., Competing Interests: The authors declare no conflicts of interest., (Copyright by Polish Urological Association.)

Background: Recovery Colleges are a relatively recent initiative within mental health services. The first opened in 2009 in London and since then numbers have grown. They are based on principles of personal recovery in mental health, co-production between people with lived experience of mental health problems and professionals, and adult learning. Student eligibility criteria vary, but all serve people who use mental health services, with empirical evidence of benefit. Previously we developed a Recovery College fidelity measure and a preliminary change model identifying the mechanisms of action and outcomes for this group, which we refer to as service user students. The Recovery Colleges Characterisation and Testing (RECOLLECT) study is a five-year (2020-2025) programme of research in England. The aim of RECOLLECT is to determine Recovery Colleges' effectiveness and cost-effectiveness, and identify organisational influences on fidelity and improvements in mental health outcomes.  METHODS: RECOLLECT comprises i) a national survey of Recovery Colleges, ii) a prospective cohort study to establish the relationship between fidelity, mechanisms of action and psychosocial outcomes, iii) a prospective cohort study to investigate effectiveness and cost-effectiveness, iv) a retrospective cohort study to determine the relationship between Recovery College use and outcomes and mental health service use, and v) organisational case studies to establish the contextual and organisational factors influencing fidelity and outcomes. The programme has been developed with input from individuals who have lived experience of mental health problems. A Lived Experience Advisory Panel will provide input into all stages of the research., Discussion: RECOLLECT will provide the first rigorous evidence on the effectiveness and cost effectiveness of Recovery Colleges in England, to inform their prioritising, commissioning, and running. The validated RECOLLECT multilevel change model will confirm the active components of Recovery Colleges. The fidelity measure and evidence about the fidelity-outcome relationship will provide an empirically-based approach to develop Recovery Colleges, to maximise benefits for students. Findings will be disseminated through the study website (researchintorecovery.com/recollect) and via national and international Recovery College networks to maximise impact, and will shape policy on how Recovery Colleges can help those with mental health problems lead empowered, meaningful and fulfilling lives., (© 2022. The Author(s).)

Red blood cells (RBCs) lose plasma membrane in the spleen as they age, but the cells and molecules involved are yet to be identified. Sickle cell disease and infection by Plasmodium falciparum cause oxidative stress that induces aggregates of cross-linked proteins with N-linked high-mannose glycans (HMGs). These glycans can be recognised by mannose-binding lectins, including the mannose receptor (CD206), expressed on macrophages and specialised phagocytic endothelial cells in the spleen to mediate the extravascular haemolysis characteristic of these diseases. We postulated this system might also mediate removal of molecules and membrane in healthy individuals. Surface expression of HMGs on RBCs from patients who had previously undergone splenectomy was therefore assessed: high levels were indeed observable as large membrane aggregates. Glycomic analysis by mass spectrometry identified a mixture of Man 5-9 GlcNAc 2 structures. HMG levels correlated well with manual pit counts (r = 0.75-0.85). To assess further whether HMGs might act as a splenic reticuloendothelial function test, we measured levels on RBCs from patients with potential functional hyposplenism, some of whom exhibited high levels that may indicate risk of complications., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Trial Design: A randomised, parallel-group, double-blind, placebo-controlled multicentre study with health economic and nested qualitative studies to determine if mifepristone (Mifegyne ® , Exelgyn, Paris, France) plus misoprostol is superior to misoprostol alone for the resolution of missed miscarriage., Methods: Women diagnosed with missed miscarriage in the first 14 weeks of pregnancy were randomly assigned (1 : 1 ratio) to receive 200 mg of oral mifepristone or matched placebo, followed by 800 μg of misoprostol 2 days later. A web-based randomisation system allocated the women to the two groups, with minimisation for age, body mass index, parity, gestational age, amount of bleeding and randomising centre. The primary outcome was failure to pass the gestational sac within 7 days after randomisation. The prespecified key secondary outcome was requirement for surgery to resolve the miscarriage. A within-trial cost-effectiveness study and a nested qualitative study were also conducted. Women who completed the trial protocol were purposively approached to take part in an interview to explore their satisfaction with and the acceptability of medical management of missed miscarriage., Results: A total of 711 women, from 28 hospitals in the UK, were randomised to receive either mifepristone plus misoprostol (357 women) or placebo plus misoprostol (354 women). The follow-up rate for the primary outcome was 98% (696 out of 711 women). The risk of failure to pass the gestational sac within 7 days was 17% (59 out of 348 women) in the mifepristone plus misoprostol group, compared with 24% (82 out of 348 women) in the placebo plus misoprostol group (risk ratio 0.73, 95% confidence interval 0.54 to 0.98; p  = 0.04). Surgical intervention to resolve the miscarriage was needed in 17% (62 out of 355 women) in the mifepristone plus misoprostol group, compared with 25% (87 out of 353 women) in the placebo plus misoprostol group (risk ratio 0.70, 95% confidence interval 0.52 to 0.94; p  = 0.02). There was no evidence of a difference in the incidence of adverse events between the two groups. A total of 42 women, 19 in the mifepristone plus misoprostol group and 23 in the placebo plus misoprostol group, took part in an interview. Women appeared to have a preference for active management of their miscarriage. Overall, when women experienced care that supported their psychological well-being throughout the care pathway, and information was delivered in a skilled and sensitive manner such that women felt informed and in control, they were more likely to express satisfaction with medical management. The use of mifepristone and misoprostol showed an absolute effect difference of 6.6% (95% confidence interval 0.7% to 12.5%). The average cost per woman was lower in the mifepristone plus misoprostol group, with a cost saving of £182 (95% confidence interval £26 to £338). Therefore, the use of mifepristone and misoprostol for the medical management of a missed miscarriage dominated the use of misoprostol alone., Limitations: The results from this trial are not generalisable to women diagnosed with incomplete miscarriage and the study does not allow for a comparison with expectant or surgical management of miscarriage., Future Work: Future work should use existing data to assess and rank the relative clinical effectiveness and safety profiles for all methods of management of miscarriage., Conclusions: Our trial showed that pre-treatment with mifepristone followed by misoprostol resulted in a higher rate of resolution of missed miscarriage than misoprostol treatment alone. Women were largely satisfied with medical management of missed miscarriage and would choose it again. The mifepristone and misoprostol intervention was shown to be cost-effective in comparison to misoprostol alone., Trial Registration: Current Controlled Trials ISRCTN17405024., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 25, No. 68. See the NIHR Journals Library website for further project information.

Background: Urolithiasis patients often require frequent urinary tract imaging, leading to high radiation exposure. CT Kidney-Ureter-Bladder (CT-KUB) is the gold standard in urolithiasis detection, however it is thought to harbour significant radiation load. Urologists have therefore utilised abdominal radiographs (XR-KUB) as an alternative, though with markedly lower sensitivity and specificity. We present the first contemporary UK study comparing the effective doses of XR-KUBs with low dose CT-KUBs., Method: Fifty-three patients were retrospectively identified in a single centre who underwent both a XR-KUB and a CT-KUB in 2018. Effective-Dose was measured by converting the recorded 'Dose Area/Length Product' via the International Commission on Radiological Protection formula., Results: The average effective dose of XR-KUBs and low dose CT-KUBs were 5.10 mSv and 5.31 mSv respectively. Thirty-four percent (18/53) of patients had a XR-KUBs with a higher effective dose than their low dose CT-KUB. Patients with higher Weight, BMI and AP diameter had higher effective doses for both their XR and low dose CT-KUBs. All patients in our study weighing over 92 kg or with a BMI greater than 32 had a XR-KUBs with a higher effective dose than their low dose CT-KUB., Conclusion: This data supports moving away from XR-KUBs for the investigation of urolithiasis, particularly in patients with a high BMI.

Background: Around 60,000 babies are born preterm (prior to 37 weeks' gestation) each year in the UK. There is little evidence on the optimal birth mode (vaginal or caesarean section)., Objective: The overall aim of the CASSAVA project was to determine if a trial to define the optimal mode of preterm birth could be carried out and, if so, determine what sort of trial could be conducted and how it could best be performed. We aimed to determine the specific groups of preterm women and babies for whom there are uncertainties about the best planned mode of birth, and if there would be willingness to recruit to, and participate in, a randomised trial to address some, but not all, of these uncertainties. This project was conducted in response to a Heath Technology Assessment programme commissioning call (17/22 'Mode of delivery for preterm infants')., Methods: We conducted clinician and patient surveys ( n  = 224 and n  = 379, respectively) to identify current practice and opinion, and a consensus survey and Delphi workshop ( n  = 76 and n  = 22 participants, respectively) to inform the design of a hypothetical clinical trial. The protocol for this clinical trial/vignette was used in telephone interviews with clinicians ( n  = 24) and in focus groups with potential participants ( n  = 13)., Results: Planned sample size and data saturation was achieved for all groups except for focus groups with participants, as this had to be curtailed because of the COVID-19 pandemic and data saturation was not achieved. There was broad agreement from parents and health-care professionals that a trial is needed. The clinician survey demonstrated a variety of practice and opinion. The parent survey suggested that women and their families generally preferred vaginal birth at later gestations and caesarean section for preterm infants. The interactive workshop and Delphi consensus process confirmed the need for more evidence (hence the case for a trial) and provided rich information on what a future trial should entail. It was agreed that any trial should address the areas with most uncertainty, including the management of women at 26-32 weeks' gestation, with either spontaneous preterm labour (cephalic presentation) or where preterm birth was medically indicated. Clear themes around the challenges inherent in conducting any trial emerged, including the concept of equipoise itself. Specific issues were as follows: different clinicians and participants would be in equipoise for each clinical scenario, effective conduct of the trial would require appropriate resources and expertise within the hospital conducting the trial, potential participants would welcome information on the trial well before the onset of labour and minority ethnic groups would require tailored approaches., Conclusion: Given the lack of evidence and the variation of practice and opinion in this area, and having listened to clinicians and potential participants, we conclude that a trial should be conducted and the outlined challenges resolved., Future Work: The CASSAVA project could be used to inform the design of a randomised trial and indicates how such a trial could be carried out. Any future trial would benefit from a pilot with qualitative input and a study within a trial to inform optimal recruitment., Limitations: Certainty that a trial could be conducted can be determined only when it is attempted., Trial Registration: Current Controlled Trials ISRCTN12295730., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 25, No. 61. See the NIHR Journals Library website for further project information.

Objective: To assess the cost-effectiveness of mifepristone and misoprostol (MifeMiso) compared with misoprostol only for the medical management of a missed miscarriage., Design: Within-trial economic evaluation and model-based analysis to set the findings in the context of the wider economic evidence for a range of comparators. Incremental costs and outcomes were calculated using nonparametric bootstrapping and reported using cost-effectiveness acceptability curves. Analyses were performed from the perspective of the UK's National Health Service (NHS)., Setting: Twenty-eight UK NHS early pregnancy units., Sample: A cohort of 711 women aged 16-39 years with ultrasound evidence of a missed miscarriage., Methods: Treatment with mifepristone and misoprostol or with matched placebo and misoprostol tablets., Main Outcome Measures: Cost per additional successfully managed miscarriage and quality-adjusted life years (QALYs)., Results: For the within-trial analysis, MifeMiso intervention resulted in an absolute effect difference of 6.6% (95% CI 0.7-12.5%) per successfully managed miscarriage and a QALYs difference of 0.04% (95% CI -0.01 to 0.1%). The average cost per successfully managed miscarriage was lower in the MifeMiso arm than in the placebo and misoprostol arm, with a cost saving of £182 (95% CI £26-£338). Hence, the MifeMiso intervention dominated the use of misoprostol alone. The model-based analysis showed that the MifeMiso intervention is preferable, compared with expectant management, and this is the current medical management strategy. However, the model-based evidence suggests that the intervention is a less effective but less costly strategy than surgical management., Conclusions: The within-trial analysis found that based on cost-effectiveness grounds, the MifeMiso intervention is likely to be recommended by decision makers for the medical management of women presenting with a missed miscarriage., Tweetable Abstract: The combination of mifepristone and misoprostol is more effective and less costly than misoprostol alone for the management of missed miscarriages., (© 2021 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: In the last decade non-technical skills (NTS) have emerged as a vital area for improvement within surgery. This study aims to develop and evaluate a Non-technical Skills for Urological Surgeons (NoTSUS) training curriculum and assessment scale., Methods: This international, longitudinal and observational study began with a 3-round Delphi methodology to refine curriculum contents and rating scale. Sessions with up to four participants were delivered where each candidate undertook an independent scenario within the validated full immersion simulation environment. Candidates were assessed using both the NoTSS (Non-technical Skills for Surgeons) and NoTSUS rating scales by NTS-trained and non-trained experts. A post-training evaluation survey was distributed., Results: 62 participants comprising trainees (n = 43) and specialists (n = 19) undertook the NoTSUS course. The NoTSS and NoTSUS scales correlated well, with a mean difference of 3.3 in the overall total (p = 0.10, r = 0.53). However, there was significant differences in scores between the NoTSS-trained and non-trained raters (n = 28, p = 0.03). A one-way ANOVA test revealed significant improvement throughout the four simulation scenarios in each session (p = 0.02). The NoTSUS curriculum received positive feedback from participants and demonstrated educational value and acceptability., Conclusions: The NoTSUS curriculum has demonstrated high educational value for NTS training aimed at urologists, with marked improvement throughout sessions. Correlation of NoTSUS and NoTSS scales proves its suitability for evaluating NTS in future training. Demonstration of inter-rater reliability indicates that the scale is reliable for use in assessment by expert faculty members. Furthermore, qualitative feedback from participants suggests gain of transferrable skills over the course.

The physical and psychological effect of miscarriage is commonly underappreciated. The journey from diagnosis of miscarriage, through clinical management, to supportive aftercare can be challenging for women, their partners, and caregivers. Diagnostic challenges can lead to delayed or ineffective care and increased anxiety. Inaccurate diagnosis of a miscarriage can result in the unintended termination of a wanted pregnancy. Uncertainty about the therapeutic effects of interventions can lead to suboptimal care, with variations across facilities and countries. For this Series paper, we have developed recommendations for practice from a literature review, appraisal of guidelines, and expert group discussions. The recommendations are grouped into three categories: (1) diagnosis of miscarriage, (2) prevention of miscarriage in women with early pregnancy bleeding, and (3) management of miscarriage. We recommend that every country reports annual aggregate miscarriage data, similarly to the reporting of stillbirth. Early pregnancy services need to focus on providing an effective ultrasound service, as it is central to the diagnosis of miscarriage, and be able to provide expectant management of miscarriage, medical management with mifepristone and misoprostol, and surgical management with manual vacuum aspiration. Women with the dual risk factors of early pregnancy bleeding and a history of previous miscarriage can be recommended vaginal micronised progesterone to improve the prospects of livebirth. We urge health-care funders and providers to invest in early pregnancy care, with specific focus on training for clinical nurse specialists and doctors to provide comprehensive miscarriage care within the setting of dedicated early pregnancy units., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Miscarriage is generally defined as the loss of a pregnancy before viability. An estimated 23 million miscarriages occur every year worldwide, translating to 44 pregnancy losses each minute. The pooled risk of miscarriage is 15·3% (95% CI 12·5-18·7%) of all recognised pregnancies. The population prevalence of women who have had one miscarriage is 10·8% (10·3-11·4%), two miscarriages is 1·9% (1·8-2·1%), and three or more miscarriages is 0·7% (0·5-0·8%). Risk factors for miscarriage include very young or older female age (younger than 20 years and older than 35 years), older male age (older than 40 years), very low or very high body-mass index, Black ethnicity, previous miscarriages, smoking, alcohol, stress, working night shifts, air pollution, and exposure to pesticides. The consequences of miscarriage are both physical, such as bleeding or infection, and psychological. Psychological consequences include increases in the risk of anxiety, depression, post-traumatic stress disorder, and suicide. Miscarriage, and especially recurrent miscarriage, is also a sentinel risk marker for obstetric complications, including preterm birth, fetal growth restriction, placental abruption, and stillbirth in future pregnancies, and a predictor of longer-term health problems, such as cardiovascular disease and venous thromboembolism. The costs of miscarriage affect individuals, health-care systems, and society. The short-term national economic cost of miscarriage is estimated to be £471 million per year in the UK. As recurrent miscarriage is a sentinel marker for various obstetric risks in future pregnancies, women should receive care in preconception and obstetric clinics specialising in patients at high risk. As psychological morbidity is common after pregnancy loss, effective screening instruments and treatment options for mental health consequences of miscarriage need to be available. We recommend that miscarriage data are gathered and reported to facilitate comparison of rates among countries, to accelerate research, and to improve patient care and policy development., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Women who have had repeated miscarriages often have uncertainties about the cause, the likelihood of recurrence, the investigations they need, and the treatments that might help. Health-care policy makers and providers have uncertainties about the optimal ways to organise and provide care. For this Series paper, we have developed recommendations for practice from literature reviews, appraisal of guidelines, and a UK-wide consensus conference that was held in December, 2019. Caregivers should individualise care according to the clinical needs and preferences of women and their partners. We define a minimum set of investigations and treatments to be offered to couples who have had recurrent miscarriages, and urge health-care policy makers and providers to make them universally available. The essential investigations include measurements of lupus anticoagulant, anticardiolipin antibodies, thyroid function, and a transvaginal pelvic ultrasound scan. The key treatments to consider are first trimester progesterone administration, levothyroxine in women with subclinical hypothyroidism, and the combination of aspirin and heparin in women with antiphospholipid antibodies. Appropriate screening and care for mental health issues and future obstetric risks, particularly preterm birth, fetal growth restriction, and stillbirth, will need to be incorporated into the care pathway for couples with a history of recurrent miscarriage. We suggest health-care services structure care using a graded model in which women are offered online health-care advice and support, care in a nurse or midwifery-led clinic, and care in a medical consultant-led clinic, according to clinical needs., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Rationale: Teenage pregnancy has a high risk of poor outcomes for both mother and baby. Teenage girls have the poorest diets of any population group in the UK, which compounds the risk of poor pregnancy outcomes. Pregnant teenagers trust advice from their midwives, but midwives feel they do not have time, confidence, or knowledge to discuss nutrition., Objective: This study examined how the relationship between pregnant teenagers and their midwives could be utilised to deliver support to improve diet quality., Method: Qualitative interviews were conducted across three urban sites in the UK: Manchester, Doncaster, and Southampton with adolescent mothers and their midwives regarding diet and lifestyle, and what form of support would be helpful. In total, 106 young women and 20 midwives were interviewed. Most of the young mothers were 19 or younger (67%). Half had had their first child in the past year (52%) and 21% were pregnant during the study. Thematic analysis was used to identify ways to better support young mothers to eat well., Results: Young women found it difficult to prioritise healthy eating; they often felt isolated and not in control of their own lives and wanted support from their midwife. Midwives felt that it was their role to support young mothers with diet in pregnancy but were anxious about initiating conversations and felt they lacked clear guidance., Conclusions: Pregnant teenagers and their midwives lack reliable resources and strategies for healthy eating support. An effective intervention to improve pregnant teenagers' diet quality must empower, inform, and motivate young mothers and their midwives, and enable connections between young mothers., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In both sickle cell disease and malaria, red blood cells (RBCs) are phagocytosed in the spleen, but receptor-ligand pairs mediating uptake have not been identified. Here, we report that patches of high mannose N-glycans (Man 5-9 GlcNAc 2 ), expressed on diseased or oxidized RBC surfaces, bind the mannose receptor (CD206) on phagocytes to mediate clearance. We find that extravascular hemolysis in sickle cell disease correlates with high mannose glycan levels on RBCs. Furthermore, Plasmodium falciparum-infected RBCs expose surface mannose N-glycans, which occur at significantly higher levels on infected RBCs from sickle cell trait subjects compared to those lacking hemoglobin S. The glycans are associated with high molecular weight complexes and protease-resistant, lower molecular weight fragments containing spectrin. Recognition of surface N-linked high mannose glycans as a response to cellular stress is a molecular mechanism common to both the pathogenesis of sickle cell disease and resistance to severe malaria in sickle cell trait.

Sickle cell disease (SCD) presents a significant global health problem. At present there is no effective treatment, with most being supportive for its associated complications such as the vaso-occlusive crises that result from increased cell adhesion. Hypoxic sickle cells have previously shown greater phosphatidylserine (PS) exposure and oxidative damage, as well as being notably "stickier" suggesting that increased cell cohesion and adhesion to the blood vessel endothelium is a possible mechanism for vaso-occlusion. The present work uses the hybrid technique of atomic force microscopy nano-infrared spectroscopy (AFM-IR) to probe changes to the coefficient of friction and C-O IR intensity in SCD on a nanoscale for dried red blood cells (RBCs) fixed under conditions of hypoxia and correlates these observations with adhesive interactions at the membrane. Using functionalised AFM tips, it has been possible to probe adhesive interactions between hydrophilic and hydrophobic moieties exposed at the surface of the dried RBCs fixed under different oxygenation states and for different cell genotypes. The results are consistent with greater PS-exposure and oxidative damage in hypoxic sickle cells, as previously proposed, and also show strong correlation between localised oxidative damage and increased adhesion. A mechanistic explanation involving significant lipid tail disruption as a result of oxidative action, in combination with differing concentrations of externalised PS lipids, is proposed to explain the observed adhesion behaviour of each type of cell., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Phosphatidylserine (PS) exposure is increased in red cells from sickle cell anaemia (SCA) patients. Externalised PS is prothrombotic and attractive to phagocytes and activated endothelial cells and thus contributes to the anaemic and ischaemic complications of SCA. The mechanism of PS exposure remains uncertain but it can follow increased intracellular Ca 2+ concentration ([Ca 2+ ] i ). Normally, [Ca 2+ ] i is maintained at very low levels but in sickle cells, Ca 2+ permeability is increased, especially following deoxygenation and sickling, mediated by a pathway sometimes called P sickle . The molecular identity of P sickle is also unclear but recent work has implicated the mechanosensitive channel, PIEZO1. We used Yoda1, an PIEZO1 agonist, to investigate its role in sickle cells. Yoda1 caused an increase in [Ca 2+ ] i and PS exposure, which was inhibited by its antagonist Dooku1 and the PIEZO1 inhibitor GsMTx4, consistent with functional PIEZO1. However, PS exposure did not necessitate an increase in [Ca 2+ ] i . Two PKC inhibitors were also tested, chelerytherine chloride and calphostin C. Both reduced PS exposure whilst chelerytherine chloride also reduced Yoda1-induced increases in [Ca 2+ ] i . Findings are therefore consistent with the presence of PIEZO1 in sickle cells, able to mediate Ca 2+ entry but that PKC was also involved in both Ca 2+ entry and PS exposure.

Background: The anti-progesterone drug mifepristone and the prostaglandin misoprostol can be used to treat missed miscarriage. However, it is unclear whether a combination of mifepristone and misoprostol is more effective than administering misoprostol alone. We investigated whether treatment with mifepristone plus misoprostol would result in a higher rate of completion of missed miscarriage compared with misoprostol alone., Methods: MifeMiso was a multicentre, double-blind, placebo-controlled, randomised trial in 28 UK hospitals. Women were eligible for enrolment if they were aged 16 years and older, diagnosed with a missed miscarriage by pelvic ultrasound scan in the first 14 weeks of pregnancy, chose to have medical management of miscarriage, and were willing and able to give informed consent. Participants were randomly assigned (1:1) to a single dose of oral mifepristone 200 mg or an oral placebo tablet, both followed by a single dose of vaginal, oral, or sublingual misoprostol 800 μg 2 days later. Randomisation was managed via a secure web-based randomisation program, with minimisation to balance study group assignments according to maternal age (<30 years vs ≥30 years), body-mass index (<35 kg/m 2 vs ≥35 kg/m 2 ), previous parity (nulliparous women vs parous women), gestational age (<70 days vs ≥70 days), amount of bleeding (Pictorial Blood Assessment Chart score; ≤2 vs ≥3), and randomising centre. Participants, clinicians, pharmacists, trial nurses, and midwives were masked to study group assignment throughout the trial. The primary outcome was failure to spontaneously pass the gestational sac within 7 days after random assignment. Primary analyses were done according to intention-to-treat principles. The trial is registered with the ISRCTN registry, ISRCTN17405024., Findings: Between Oct 3, 2017, and July 22, 2019, 2595 women were identified as being eligible for the MifeMiso trial. 711 women were randomly assigned to receive either mifepristone and misoprostol (357 women) or placebo and misoprostol (354 women). 696 (98%) of 711 women had available data for the primary outcome. 59 (17%) of 348 women in the mifepristone plus misoprostol group did not pass the gestational sac spontaneously within 7 days versus 82 (24%) of 348 women in the placebo plus misoprostol group (risk ratio [RR] 0·73, 95% CI 0·54-0·99; p=0·043). 62 (17%) of 355 women in the mifepristone plus misoprostol group required surgical intervention to complete the miscarriage versus 87 (25%) of 353 women in the placebo plus misoprostol group (0·71, 0·53-0·95; p=0·021). We found no difference in incidence of adverse events between the study groups., Interpretation: Treatment with mifepristone plus misoprostol was more effective than misoprostol alone in the management of missed miscarriage. Women with missed miscarriage should be offered mifepristone pretreatment before misoprostol to increase the chance of successful miscarriage management, while reducing the need for miscarriage surgery., Funding: UK National Institute for Health Research Health Technology Assessment Programme., (This is an Open Access article under the CC BY-NC-ND 4.0 license.)

Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone supplementation may reduce the risk of miscarriage in women with recurrent or threatened miscarriage. Cochrane Reviews summarized the evidence and found that the trials were small with substantial methodologic weaknesses. Since then, the effects of first-trimester use of vaginal micronized progesterone have been evaluated in 2 large, high-quality, multicenter placebo-controlled trials, one targeting women with unexplained recurrent miscarriages (the PROMISE [PROgesterone in recurrent MIScarriagE] trial) and the other targeting women with early pregnancy bleeding (the PRISM [PRogesterone In Spontaneous Miscarriage] trial). The PROMISE trial studied 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% greater live birth rate with progesterone but with substantial statistical uncertainty. The PRISM trial studied 4153 women from 48 hospitals in the United Kingdom and found a 3% greater live birth rate with progesterone, but with a P value of .08. A key finding, first observed in the PROMISE trial, and then replicated in the PRISM trial, was that treatment with vaginal micronized progesterone 400 mg twice daily was associated with increasing live birth rates according to the number of previous miscarriages. Prespecified PRISM trial subgroup analysis in women with the dual risk factors of previous miscarriage(s) and current pregnancy bleeding fulfilled all 11 conditions for credible subgroup analysis. For the subgroup of women with a history of 1 or more miscarriage(s) and current pregnancy bleeding, the live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo (rate difference 5%; risk ratio, 1.09, 95% confidence interval, 1.03-1.15; P=.003). The benefit was greater for the subgroup of women with 3 or more previous miscarriages and current pregnancy bleeding; live birth rate was 72% (98/137) with progesterone vs 57% (85/148) with placebo (rate difference 15%; risk ratio, 1.28, 95% confidence interval, 1.08-1.51; P=.004). No short-term safety concerns were identified from the PROMISE and PRISM trials. Therefore, women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg twice daily. Women and their care providers should use the findings for shared decision-making., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage., Objectives: (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding., Design: A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding., Setting: A total of 48 hospitals in the UK., Participants: Women aged 16-39 years with early pregnancy bleeding., Interventions: Women aged 16-39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation., Main Outcome Measures: The primary outcome was live birth at ≥ 34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective., Results: A total of 4153 women from 48 hospitals in the UK received either progesterone ( n  = 2079) or placebo ( n  = 2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p  = 0.08). A significant subgroup effect (interaction test p  = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p  = 0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p  = 0.07); and three or more (72% in the progesterone group vs. 57% in the placebo group; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p  = 0.004). A significant post hoc subgroup effect (interaction test p  = 0.01) was identified in the subgroup of participants with early pregnancy bleeding and any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p  = 0.003). There were no significant differences in the rate of adverse events between the groups. The results of the health economics analysis show that progesterone was more costly than placebo (£7655 vs. £7572), with a mean cost difference of £83 (adjusted mean difference £76, 95% confidence interval -£559 to £711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as £3305 per additional live birth at ≥ 34 weeks of gestation., Conclusions: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall, but an important subgroup effect was identified. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks. For future work, we plan to conduct an individual participant data meta-analysis using all existing data sets., Trial Registration: Current Controlled Trials ISRCTN14163439, EudraCT 2014-002348-42 and Integrated Research Application System (IRAS) 158326., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 33. See the NIHR Journals Library website for further project information., Competing Interests: Jane P Daniels declares membership of the Clinical Trials Unit Standing Advisory Committee. Meenakshi Choudhary declares membership of Health Technology Assessment (HTA) Maternal, Newborn and Child Health (MNCH) Panel and the HTA Prioritisation Committee. Jane E Norman declares membership of the HTA MNCH Panel, that she currently receives funding from the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, that she participates in a Data Monitoring and Ethics Committee for GlaxoSmithKline plc (Brentford, UK) and that she is a paid consultant for Dilafor AB (Solna, Sweden). She was a member of the HTA and EME Editorial Board from 2012 to 2014. Caroline Overton declares that she was a Mylan clinical educator for general practitioner education about hormone replacement therapy and incorporated private practice in April 2017 (now called Bristol Women’s Clinic Ltd).

Background: High exhaled nitric oxide fraction ( F ENO ) levels are associated with greater risk of asthma exacerbation. However, it is not clear how F ENO can be used to guide safe reductions in inhaled corticosteroid (ICS) doses in asthma patients. This study assesses the ability of F ENO to guide ICS reductions., Methods: Systematic searching of electronic databases identified prospective observational studies and randomised controlled trials which recruited participants with mild-to-moderate asthma aged ≥12 years and measured F ENO before reducing ICS. We performed multilevel mixed-effects logistic regression in relation to acute exacerbations and estimated each participant's exacerbation risk using our logistic regression model., Results: We included data from seven out of eight eligible studies, representing 384 participants. ICS doses were halved in four studies and withdrawn in three studies. A baseline F ENO measurement of ≥50 ppb was associated with increased risk of exacerbations (crude OR 3.14, 95% CI 1.41-7.00, p=0.005; adjusted OR 3.08, 95% CI 1.36-6.98, p=0.007) and corresponded to an estimated exacerbation risk cut-off of 15%. Reducing ICS when estimated exacerbation risk was <15% versus <10% would result in fewer patients remaining on the same ICS dose (40 (10.4%) out of 384 versus 141 (36.7%) out of 384), but similar proportions of patients avoiding exacerbations (222 (91.4%) out of 243, 95% CI 87.1-94.6% versus 311 (90.4%) out of 344, 95% CI 86.8-93.3%)., Conclusion: In patients with mild-to-moderate asthma, gradual ICS reduction when F ENO is <50 ppb may help decrease ICS use without increasing exacerbations. Future research should aim to validate these findings in larger populations., Competing Interests: Conflict of interest: K. Wang reports grants from National Institute for Health Research, during the conduct of the study. Conflict of interest: J.Y. Verbakel has nothing to disclose. Conflict of interest: J. Oke has nothing to disclose. Conflict of interest: A. Fleming-Nouri has nothing to disclose. Conflict of interest: J. Brewin has nothing to disclose. Conflict of interest: N. Roberts has nothing to disclose. Conflict of interest: N. Harada reports personal fees from AstraZeneca, outside the submitted work. In addition, N. Harada has a patent Japanese Patent Application 2018-097070 pending. Conflict of interest: R. Atsuta has nothing to disclose. Conflict of interest: K. Takahashi reports grants and personal fees from Chugai Pharmaceutical Co., Ltd, grants and personal fees from Nippon Boehringer Ingelheim Co., Ltd, grants and personal fees from MSD K.K., grants from GlaxoSmithKline Consumer Healthcare Japan K.K., grants from Nippon Shinyaku Co., Ltd, grants from Tsumura & Co., grants and personal fees from Pfizer Inc., grants and personal fees from AstraZeneca K.K., grants and personal fees from Taiho Pharmaceutical Co., Ltd, grants from Astellas Pharma Inc., grants and personal fees from Kyorin Pharmaceutical Co., Ltd, grants from Kyowa Hakko Kirin Co., Ltd, grants and personal fees from Teijin Pharma Limited, grants from Mochida Pharmaceutical Co., Ltd, grants from Toyama Chemical Co., Ltd, grants from Sanofi K.K., grants and personal fees from Ono Pharmaceutical Co., Ltd, grants and personal fees from Nobelpharma Co., Ltd, grants and personal fees from Novartis Pharma K.K., grants from Shionogi & Co., Ltd, grants and personal fees from Eli Lilly Japan K.K., grants from Nipro Corporation, grants from Torii Pharmaceutical Co., Ltd, grants from MiZ Company Limited, personal fees from Sumitomo Dainippon Pharma Co., Ltd, personal fees from Bristol-Myers K.K., personal fees from Meiji Seika Pharma Co., Ltd, personal fees from Otsuka Pharmaceutical Co., Ltd, personal fees from Parexel International Corporation, personal fees from Eisai Co., Ltd, personal fees from Mitsubishi Tanabe Pharma, outside the submitted work. Conflict of interest: K. Mori has nothing to disclose. Conflict of interest: T. Fujisawa has nothing to disclose. Conflict of interest: T. Shirai has nothing to disclose. Conflict of interest: T. Kawayama has nothing to disclose. Conflict of interest: H. Inoue reports grants from Astellas, AstraZeneca, Boehringer-Ingelheim, Chugai Pharm, GlaxoSmithKline, Pfizer, Merck Sharp & Dohme, Novartis, Teijin-Pharma, personal fees from Astellas, AstraZeneca, Boehringer-Ingelheim, Chugai Pharm, GlaxoSmithKline, Kyorin, Merck Sharp & Dohme, Meiji Seika Pharma, Novartis, Otsuka, Pfizer, Taiho, outside the submitted work. Conflict of interest: S. Lazarus reports grants from NIH/NHLBI, during the conduct of the study; grants from NIH/NHLBI, grants from American Lung Association – Airway Clinical Research Centers Network (ALA-ACRC), outside the submitted work. Conflict of interest: S. Szefler reports other from Boehringer-Ingelheim, other from Genentech, other from GlaxoSmithKline, other from AstraZeneca, other from Daiichi Sankyo, grants from GlaxoSmithKline, other from Propeller Health, other from Sanofi, other from Regeneron, outside the submitted work. Conflict of interest: F. Martinez reports grants from NIH/NHLBI, grants from NIH/NIEHS, grants from NIH/NIAID, grants from NIH/Office of Director, grants from Johnson & Johnson, personal fees from Copeval, personal fees from Commense Inc, outside the submitted work. Conflict of interest: D. Shaw reports personal fees from AstraZeneca, GSK, TEVA and Novartis, outside the submitted work. Conflict of interest: I.D. Pavord reports personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Aerocrine, personal fees from Almirall, personal fees from Novartis, personal fees from GlaxoSmithKline, personal fees from Genentech, personal fees from Regeneron, speakers’ fees from Teva, speakers’ fees from Chiesi, advisory board fees from Sanofi, advisory board fees from Circassia, advisory board fees from Knopp, grants from NIHR, outside the submitted work. Conflict of interest: M. Thomas reports personal fees from GSK, personal fees from Novartis, personal fees from Boehringer Ingelheim, outside the submitted work; and recent membership of the BTS SIGN Asthma guideline steering group and the NICE Asthma Diagnosis and Monitoring guideline development group., (Copyright ©ERS 2020.)

Objectives: To assess the cost-effectiveness of progesterone compared with placebo in preventing pregnancy loss in women with early pregnancy vaginal bleeding., Design: Economic evaluation alongside a large multi-centre randomised placebo-controlled trial., Setting: Forty-eight UK NHS early pregnancy units., Population: Four thousand one hundred and fifty-three women aged 16-39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac., Methods: An incremental cost-effectiveness analysis was performed from National Health Service (NHS) and NHS and Personal Social Services perspectives. Subgroup analyses were carried out on women with one or more and three or more previous miscarriages., Main Outcome Measures: Cost per additional live birth at ≥34 weeks of gestation., Results: Progesterone intervention led to an effect difference of 0.022 (95% CI -0.004 to 0.050) in the trial. The mean cost per woman in the progesterone group was £76 (95% CI -£559 to £711) more than the mean cost in the placebo group. The incremental cost-effectiveness ratio for progesterone compared with placebo was £3305 per additional live birth. For women with at least one previous miscarriage, progesterone was more effective than placebo with an effect difference of 0.055 (95% CI 0.014-0.096) and this was associated with a cost saving of £322 (95% CI -£1318 to £673)., Conclusions: The results suggest that progesterone is associated with a small positive impact and a small additional cost. Both subgroup analyses were more favourable, especially for women who had one or more previous miscarriages. Given available evidence, progesterone is likely to be a cost-effective intervention, particularly for women with previous miscarriage(s)., Tweetable Abstract: Progesterone treatment is likely to be cost-effective in women with early pregnancy bleeding and a history of miscarriage., (© 2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.)

Background: Retained placenta following vaginal delivery is a major cause of postpartum haemorrhage. Currently, the only effective treatments for a retained placenta are the surgical procedures of manual removal of placenta (MROP) and uterine curettage, which are not universally available, particularly in low- and middle-income countries. The objective of the trial was to determine whether sublingual nitroglycerin spray was clinically effective and cost-effective for medical treatment of retained placenta following vaginal delivery., Methods and Findings: A randomised, placebo-controlled, double-blind trial was undertaken between October 2014 and July 2017 at 29 delivery units in the UK (Edinburgh, Glasgow, Manchester, Newcastle, Preston, Warrington, Chesterfield, Crewe, Durham, West Middlesex, Aylesbury, Furness, Southampton, Bolton, Sunderland, Oxford, Nottingham [2 units], Burnley, Chertsey, Stockton-on-Tees, Middlesborough, Chester, Darlington, York, Reading, Milton Keynes, Telford, Frimley). In total, 1,107 women with retained placenta following vaginal delivery were recruited. The intervention was self-administered 2 puffs of sublingual nitroglycerin (800 μg; intervention, N = 543) or placebo spray (control, N = 564). The primary clinical outcome was the need for MROP, assessed at 15 minutes following administration of the intervention. Analysis was based on the intention-to-treat principle. The primary safety outcome was measured blood loss between study drug administration and transfer to the postnatal ward or other clinical area. The primary patient-sided outcomes were satisfaction with treatment and side-effect profile, assessed by questionnaires pre-discharge and 6 weeks post-delivery. Secondary clinical outcomes were measured at 5 and 15 minutes after study drug administration and prior to hospital discharge. There was no statistically significant or clinically meaningful difference in need for MROP by 15 minutes (primary clinical outcome, 505 [93.3%] for nitroglycerin versus 518 [92.0%] for placebo, odds ratio [OR] 1.01 [95% CI 0.98-1.04], p = 0.393) or blood loss (<500 ml: nitroglycerin, 238 [44.3%], versus placebo, 249 [44.5%]; 500 ml-1,000 ml: nitroglycerin, 180 [33.5%], versus placebo, 224 [40.0%]; >1,000 ml: nitroglycerin, 119 [22.2%], versus placebo, 87 [15.5%]; ordinal OR 1.14 [95% CI 0.88-1.48], p = 0.314) or satisfaction with treatment (nitroglycerin, 288 [75.4%], versus placebo, 303 [78.1%]; OR 0.87 [95% CI 0.62-1.22], p = 0.411) or health service costs (mean difference [£] 55.3 [95% CI -199.20 to 309.79]). Palpitations following drug administration were reported more often in the nitroglycerin group (36 [9.8%] versus 15 [4.0%], OR 2.60 [95% CI 1.40-4.84], p = 0.003). There were 52 serious adverse events during the trial, with no statistically significant difference in likelihood between groups (nitroglycerin, 27 [5.0%], versus placebo, 26 [4.6%]; OR 1.13 [95% CI 0.54-2.38], p = 0.747). The main limitation of our study was the low return rate for the 6-week postnatal questionnaire. There were, however, no differences in questionnaire return rates between study groups or between women who did and did not have MROP, with the patient-reported use of outpatient and primary care services at 6 weeks accounting for only a small proportion (approximately 5%) of overall health service costs., Conclusions: In this study, we found that nitroglycerin is neither clinically effective nor cost-effective as a medical treatment for retained placenta, and has increased side effects, suggesting it should not be used. Further research is required to identify an effective medical treatment for retained placenta to reduce the morbidity caused by this condition, particularly in low- and middle-income countries where surgical management is not available., Trial Registration: ISRCTN.com ISRCTN88609453 ClinicalTrials.gov NCT02085213., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: FCD is named as Principal Investigator on government and charitable research grants to their institution which aim to improve pregnancy outcome. JEN is named as Principal Investigator on government and charitable research grants to their institution which aim to improve pregnancy outcome. In the last three years JEN has provided consultancy to pharma companies GSK and Dilafor; my institution was renumerated for this. JEN's institution has received travel and subsistence expenses from Merck to facilitate them speaking at a Merck sponsored symposium on metformin. JEN is on Subpanel A1 for REF, and on a Wellcome Trust Science interview panel, and receive personal renumeration for each. KFC is named as CoInvestigator on a charitable research grant about coronary syndrome. None of the other co-authors have declared any competing interests.

Background: Retained placenta is associated with postpartum haemorrhage and can lead to significant maternal morbidity if untreated. The only effective treatment is the surgical procedure of manual removal of placenta, which is costly, requires skilled staff, requires an operative environment and is unpleasant for women. Small studies suggest that glyceryl trinitrate may be an effective medical alternative., Objective: To determine the clinical effectiveness and cost-effectiveness of sublingual glyceryl trinitrate spray compared with placebo in reducing the need for manual removal of placenta in women with retained placenta after vaginal delivery following the failure of current management., Design: A group-sequential randomised double-blind placebo-controlled trial with a cost-effectiveness analysis., Setting: There were 29 obstetric units in the UK involved in the study., Participants: There were 1107 women (glyceryl trinitrate group, n  = 543; placebo group, n  = 564) randomised between October 2014 and July 2017., Interventions: Glyceryl trinitrate spray was administered to 541 women in the intervention group, and a placebo was administered to 563 women in the control group., Main Outcome Measures: Four primary outcomes were defined: (1) clinical - the need for manual removal of placenta, (2) safety - measured blood loss, (3) patient sided - satisfaction with treatment and side effects and (4) economic - cost-effectiveness of both treatments using the UK NHS perspective. Secondary clinical outcomes included a > 15% decrease in haemoglobin level, time from randomisation to delivery of placenta in theatre, the need for earlier manual removal of placenta than planned, increase in heart rate or decrease in blood pressure, requirement for blood transfusion, requirement for general anaesthesia, maternal pyrexia, and sustained uterine relaxation requiring additional uterotonics., Results: No difference was observed between the glyceryl trinitrate group and the control group for the placenta remaining undelivered within 15 minutes of study treatment (93.3% vs. 92%; odds ratio 1.01, 95% confidence interval 0.98 to 1.04; p  = 0.393). There was no difference in blood loss of > 1000 ml between the glyceryl trinitrate group and the control group (22.2% vs. 15.5%; odds ratio 1.14, 95% confidence interval 0.88 to 1.48; p  = 0.314). Palpitations were more common in the glyceryl trinitrate group than in the control group after taking the study drug (9.8% vs. 4.0%; odds ratio 2.60, 95% confidence interval 1.40 to 4.84; p  = 0.003). There was no difference in any other measures of patient satisfaction between the groups. There was no difference in costs to the health service between groups (mean difference £55.30, 95% confidence interval -£199.20 to £309.79). Secondary outcomes revealed that a fall in systolic or diastolic blood pressure, or an increase in heart rate, was more common in the glyceryl trinitrate group than in the control group (odds ratio 4.9, 95% confidence interval 3.7 to 6.4; p  < 0.001). The need for a blood transfusion was also more common in the glyceryl trinitrate group than in the control group (odds ratio 1.53, 95% confidence interval 1.04 to 2.25; p  = 0.033)., Conclusions: Glyceryl trinitrate spray did not increase the delivery of retained placenta within 15 minutes of administration when compared with the placebo, and was not cost-effective for medical management of retained placenta. More participants reported palpitations and required a blood transfusion in the glyceryl trinitrate group. Further research into alternative methods of medical management of retained placenta is required., Trial Registration: Current Controlled Trials ISRCTN88609453., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 70. See the NIHR Journals Library website for further project information., Competing Interests: Fiona C Denison has received funding from Dilafor AB (Solna, Sweden) outside the submitted work. Jane E Norman has received funding from Dilafor AB and GlaxoSmithKline plc (Middlesex, UK) outside the submitted work and declares membership of the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Maternal Newborn and Child Health Panel. Jane Norman was a member of the HTA and Efficacy and Mechanism Evaluation (EME) Editorial Board. John Norrie declares grants from the University of Aberdeen and the University of Edinburgh during the conduct of the study and membership of the following NIHR boards: Cardiopulmonary Resuscitation Decision-making Committee, HTA Commissioning Board, HTA Commissioning Sub-Board (Expression of Interest), HTA Funding Boards Policy Group, HTA General Board, HTA post-board funding teleconference, NIHR Clinical Trials Unit Standing Advisory Committee, NIHR HTA and EME Editorial Board and Pre-exposure Prophylaxis Impact Review Panel. Julia Lawton declares membership of the HTA General Board.

We investigated changes in the plasma proteome of children with sickle cell anaemia (SCA) associated with hydroxycarbamide (HC) use, to further characterize the actions of HC. Fifty-one children with SCA consented to take part in this study. Eighteen were taking HC at a median dose of 22 mg/kg, and 33 were not on HC. Plasma was analysed using an unbiased proteomic approach and a panel of 92 neurological biomarkers. HC was associated with increased haemoglobin (Hb) (89·8 vs. 81·4 g/l, P = 0·007) and HbF (6·7 vs. 15·3%, P < 0·001). Seventeen proteins were decreased on HC compared to controls by a factor of <0·77, and six proteins showed >1·3 increased concentration. HC use was associated with reduced haemolysis (lower α, β, δ globin chains, haptoglobin-related protein, complement C9; higher haemopexin), reduced inflammation (lower α-1-acid glycoprotein, CD5 antigen-like protein, ceruloplasmin, factor XII, immunoglobulins, cysteine-rich secretory protein 3, vitamin D-binding protein) and decreased activation of coagulation (lower factor XII, carboxypeptidase B2, platelet basic protein). There was a significant correlation between the increase in HbF% on HC and haemopexin levels (r = 0·603, P = 0·023). This study demonstrated three ways in which HC may be beneficial in SCA, and identified novel proteins that may be useful to monitor therapeutic response., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Spinal cord injury (SCI) patients are at increased risk of developing urolithiasis. Ureteroscopic management for stone disease in SCI patients is underreported. Endourologists face many challenges in the management of stone disease in SCI patients including decreased stone free rates (SFR), increased infection risk, increased complication rate, anatomical variation, increased comorbidity level and challenges to nursing care. We present our experience at a regional SCI centre., Methods: Retrospective data was collected from 2005-2017 from a single SCI unit for patients who underwent ureteroscopy for stone disease., Results: A total of 21 patients underwent 41 procedures, 7 cases being a planned multi-stage approach. Bladder management included sheath catheter, urethral catheter, suprapubic catheter, intermittent self-catheterisation, mitrofanoff, and ileal conduit. Spinal cord level was cervical (71%) or thoracic (29%), with American Spinal Injury Association (ASIA) grade classification A (86%), C (9%) and D (5%). Median follow-up time for patients was 46 months. Average stone size was 27 mm (range, 5-59 mm) access was achieved 98% of patients, with an access sheath used in 63%. The SFR was 47% with a recurrence rate (RR) of 42%. The complication rate was 24% all being Clavien Dindo grade 2., Conclusions: Ureteroscopy in SCI can be challenging and careful multidisciplinary team planning for intervention is needed. Ureteroscopy offers a useful treatment option for SCI, however, is associated with a lower SFR and greater complication rate compared to that of the general population., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Translational Andrology and Urology. All rights reserved.)

Oxidative damage to red blood cells (RBCs) may contribute to pathogenesis of sickle cell anemia. Reducing the deleterious effects of oxidants by exposing RBCs to a number of antioxidants has been shown to have protective effects against lipid and protein peroxidation. We hypothesize that antioxidants may also have beneficial effects on the abnormal membrane permeability of sickle cells. Increased cation permeability of these cells encourages HbS polymerization by causing RBC dehydration and also leads to externalization of the prothrombotic aminophospholipid phosphatidylserine (PS). Three antioxidants with different mechanisms of action were investigated - dithiothreitol, N -acetylcysteine, and quercetin. All three were found to inhibit the main cation pathways responsible for dehydration - the deoxygenation-induced cation conductance (or P sickle ), the Ca 2+ -activated K + channel (or Gardos channel), and the K + -Cl - cotransporter. They also reduced Ca 2+ -induced PS exposure and hemolysis. Findings provide evidence for additional beneficial actions of antioxidants in maintenance of rheology and reducing vascular adhesion and further inform the rationale for their clinical use.

Background: Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy., Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data., Results: A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P = 0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08). The incidence of adverse events did not differ significantly between the groups., Conclusions: Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: Direct access (DA) testing allows GPs to refer patients for investigation without consulting a specialist. The aim is to reduce waiting time for investigations and unnecessary appointments, enabling treatment to begin without delay., Aim: To establish the proportion of patients diagnosed with cancer and other diseases through DA testing, time to diagnosis, and suitability of DA investigations., Design and Setting: Systematic review assessing the effectiveness of GP DA testing in adults., Method: MEDLINE, Embase, and the Cochrane Library were searched. Where possible, study data were pooled and analysed quantitatively. Where this was not possible, the data are presented narratively., Results: The authors identified 60 papers that met pre-specified inclusion criteria. Most studies were carried out in the UK and were judged to be of poor quality. The authors found no significant difference in the pooled cancer conversion rate between GP DA referrals and patients who first consulted a specialist for any test, except gastroscopy. There were also no significant differences in the proportions of patients receiving any non-cancer diagnosis. Referrals for testing were deemed appropriate in 66.4% of those coming from GPs, and in 80.9% of those from consultants; this difference was not significant. The time from referral to testing was significantly shorter for patients referred for DA tests. Patient and GP satisfaction with DA testing was consistently high., Conclusion: GP DA testing performs as well as, and on some measures better than, consultant triaged testing on measures of disease detection, appropriateness of referrals, interval from referral to testing, and patient and GP satisfaction., (© British Journal of General Practice 2018.)

Silent cerebral infarction is the most common neurological abnormality in children with sickle cell anemia, affecting 30-40% of 14 year olds. There are no known biomarkers to identify children with silent cerebral infarcts, and the pathological basis is also unknown. We used an unbiased proteomic discovery approach to identify plasma proteins differing in concentration between children with and without silent cerebral infarcts. Clinical parameters and plasma samples were analysed from 51 children (mean age 11.8 years, range 6-18) with sickle cell anemia (HbSS). A total of 19 children had silent cerebral infarcts and 32 normal MRI; the children with silent infarcts had lower HbF levels (8.6 vs 16.1%, P =0.049) and higher systolic blood pressures (115 vs 108.6, P =0.027). Plasma proteomic analysis showed 13 proteins increased more than 1.3 fold in the SCI patients, including proteins involved in hypercoagulability (α2-antiplasmin, fibrinogen-γ chain, thrombospondin-4), inflammation (α2-macroglobulin, complement C1s and C3), and atherosclerosis (apolipoprotein B-100). Higher levels of gelsolin and retinol-binding protein 4 were also found in the population with silent infarcts, both of which have been linked to stroke. We investigated the genetic basis of these differences by studying 359 adults with sickle cell disease (199 with silent cerebral infarcts, 160 normal MRIs), who had previously undergone a genome-wide genotyping array. None of the genes coding for the differentially expressed proteins were significantly associated with silent infarction. Our study suggests that silent cerebral infarcts in sickle cell anemia may be associated with higher systolic blood pressure, lower HbF levels, hypercoagulability, inflammation and atherosclerotic lipoproteins., (Copyright© 2018 Ferrata Storti Foundation.)

One in four pregnancies ends in miscarriage, a distressing event which can cause significant psychosocial impacts for many women, and yet often remains unseen and unspoken. Many would-be mothers turn to the internet for information and emotional support, and to share their experiences. In this paper, we present the results from 12 semi-structured interviews with women, investigating how and what online information they searched for at the time of miscarriage. We found that women are passive information seekers, searching for causes and preventive strategies to inform future pregnancies. Women want information presented in an easy to understand manner that is not overly clinical, and informed by credible sources. Women also seek psychological support and emotional relief through reading about others' experiences and sharing their stories online. The findings from this study provide a unique insight into the support and information needs of women, and will be used to guide the content, design and functionality of web-based technologies for women experiencing miscarriage.

The early stages of sickle cell nephropathy (SCN) manifest in children with sickle cell anemia (SCA) as hyperfiltration and proteinuria. The physiological conditions of the renovascular system are among the most conducive to hemoglobin S polymerization in the body and will magnify small changes in red cell volume thus crucially modulating intracellular concentrations of hemoglobin S. This large cross-sectional study of children with sickle cell anemia measured glomerular filtration rates and microalbuminuria to report prevalence, clinical correlates and uniquely, association with key red cell cation transport mechanisms. One hundred and twelve patients (mean age 10.7 ± 4.1) were recruited. The prevalence of hyperfiltration and microalbuminuria was 98% and 15.1%, respectively. Glomerular filtration rates did not vary with age, but proteinuria became more prevalent with increasing age. Both features associated with markers of hemolysis, while elevated hemoglobin F was protective, but no association was seen with systolic or diastolic blood pressure. In multivariate analysis, both Gardos channel (β = 0.476, P  < 0.001) and KCl co-transporter (KCC; β = -0.216, P  = 0.009) activity, alongside age (β = 0.237, P  = 0.004), remained independently predictive for microalbuminuria. Increased activity of Gardos channel and P sickle positively associated with microalbuminuria, while increased KCC activity associated with a reduction in microalbuminuria. This study demonstrates a direct link between the abnormally active red cell cation transport systems in sickle cell disease and sickle organopathy. Small variations in the activity of these transport mechanisms predict for SCN and measurement of them may help identify those at risk, while pharmaceutical manipulation of these excessively active systems may ameliorate their risk., Competing Interests: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Stroke is one of the most severe complications to affect children with sickle cell anaemia (SCA). Transcranial doppler (TCD) is an accurate and non-invasive method to determine stroke risk. Randomised controlled trials have demonstrated the efficacy of chronic transfusion therapy in stroke prevention based on risk stratification determined by TCD velocities. This has led to the regular use of TCD monitoring for children with SCA in order to determine stroke risk. Significant resource allocation is necessary to facilitate training, quality assurance and failsafe arrangements for non-attenders. In a subgroup of patients, chronic transfusions for primary stroke prevention can be replaced by hydroxycarbamide therapy, provided careful monitoring is undertaken; including repeat TCD studies at frequent intervals. The authors propose an evidence-based algorithm for the management of abnormal TCD velocities and discuss the role of this test in other clinical contexts, such as in Haemoglobin SC disease., (© 2017 John Wiley & Sons Ltd.)

Introduction: A retained placenta is diagnosed when the placenta is not delivered following delivery of the baby. It is a major cause of postpartum haemorrhage and treated by the operative procedure of manual removal of placenta (MROP)., Methods and Analysis: The aim of this pragmatic, randomised, placebo-controlled, double-blind UK-wide trial, with an internal pilot and nested qualitative research to adjust strategies to refine delivery of the main trial, is to determine whether sublingual glyceryl trinitrate (GTN) is (or is not) clinically and cost-effective for (medical) management of retained placenta. The primary clinical outcome is need for MROP, defined as the placenta remaining undelivered 15 min poststudy treatment and/or being required within 15 min of treatment due to safety concerns. The primary safety outcome is measured blood loss between administration of treatment and transfer to the postnatal ward or other clinical area. The primary patient-sided outcome is satisfaction with treatment and a side effect profile. The primary economic outcome is net incremental costs (or cost savings) to the National Health Service of using GTN versus standard practice. Secondary outcomes are being measured over a range of clinical and economic domains. The primary outcomes will be analysed using linear models appropriate to the distribution of each outcome. Health service costs will be compared with multiple trial outcomes in a cost-consequence analysis of GTN versus standard practice., Ethics and Dissemination: Ethical approval has been obtained from the North-East Newcastle & North Tyneside 2 Research Ethics Committee (13/NE/0339). Dissemination plans for the trial include the Health Technology Assessment Monograph, presentation at international scientific meetings and publication in high-impact, peer-reviewed journals., Trial Registration Number: ISCRTN88609453; Pre-results., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: To identify and prioritise important research questions for miscarriage., Design: A priority setting partnership using prospective surveys and consensus meetings following methods advocated by the James Lind Alliance., Setting: UK., Participants: Women and those affected by miscarriage working alongside healthcare professionals., Results: In the initial survey, 1093 participants (932 women who have experienced miscarriage, 8 partners, 17 family members, friends or colleagues, 104 healthcare professionals and eight charitable organisations) submitted 3279 questions. A review of existing literature identified a further 64. Non-questions were removed, and the remaining questions were categorised and summarised into 58 questions. In an interim electronic survey, 2122 respondents chose their top 10 priorities from the 58 summary questions. The 25 highest ranked in the survey were prioritised at a final face-to-face workshop. In summary, the top 10 priorities were ranked as follows: research into preventative treatment, emotional aspects in general, investigation, relevance of pre-existing medical conditions, emotional support as a treatment, importance of lifestyle factors, importance of genetic and chromosomal causes, preconception tests, investigation after different numbers of miscarriage and male causal factors., Conclusions: These results should be the focus of future miscarriage research. Presently, studies are being conducted to address the top priority; however, many other priorities, especially psychological and emotional support, are less well researched areas. We hope our results will encourage both researchers and funders to focus on these priorities., Competing Interests: Competing interests: JB is chief executive of Tommy’s baby charity, which funds research to prevent and treat miscarriage. RS is chair of the Association of Early Pregnancy Units. BH-J is vice chair of the Miscarriage Association and represented them in the PSP. She works for Roche pharmaceuticals in clinical research, but Roche do not have any products or conduct research for miscarriage. LR is president of the Royal College of Obstetricians and Gynaecologists. AC is director of Tommy’s National Centre for Miscarriage Research at the University of Birmingham., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Current training modalities within ureteroscopy have been extensively validated and must now be integrated within a comprehensive curriculum. Additionally, non-technical skills often cause surgical error and little research has been conducted to combine this with technical skills teaching. This study therefore aimed to develop and validate a curriculum for semi-rigid ureteroscopy, integrating both technical and non-technical skills teaching within the programme., Methods: Delphi methodology was utilised for curriculum development and content validation, with a randomised trial then conducted (n = 32) for curriculum evaluation. The developed curriculum consisted of four modules; initially developing basic technical skills and subsequently integrating non-technical skills teaching. Sixteen participants underwent the simulation-based curriculum and were subsequently assessed, together with the control cohort (n = 16) within a full immersion environment. Both technical (Time to completion, OSATS and a task specific checklist) and non-technical (NOTSS) outcome measures were recorded with parametric and non-parametric analyses used depending on the distribution of our data as evaluated by a Shapiro-Wilk test., Results: Improvements within the intervention cohort demonstrated educational value across all technical and non-technical parameters recorded, including time to completion (p < 0.01), OSATS scores (p < 0.001), task specific checklist scores (p = 0.011) and NOTSS scores (p < 0.001). Content validity, feasibility and acceptability were all demonstrated through curriculum development and post-study questionnaire results., Conclusions: The current developed curriculum demonstrates that integrating both technical and non-technical skills teaching is both educationally valuable and feasible. Additionally, the curriculum offers a validated simulation-based training modality within ureteroscopy and a framework for the development of other simulation-based programmes.

Objective: Little integration of technical and nontechnical skills (e.g., situational awareness, communication, decision making, teamwork, and leadership) teaching exists within surgery. We therefore aimed to (1) evaluate the relationship between these 2 skill sets within a simulation-based environment and (2) assess if certain nontechnical skill components are of particular relevance to technical performance., Design: A prospective analysis of data acquired from a comparative study of simulation vs nonsimulation training was conducted. Half of the participants underwent training of technical and nontechnical skills within ureteroscopy, with the remaining half undergoing no training. All were assessed within a full immersion environment against both technical (time to completion, Objective Structured Assessment of Technical Skills, and task-specific checklist scores) and nontechnical parameters (Nontechnical Skills for Surgeons [NOTSS] rating scale). The data of whole and individual cohorts were analyzed using Pearson correlation coefficient., Setting: The trial took place within the Simulation and Interactive Learning Centre at Guy's Hospital, London, UK., Participants: In total, 32 novice participants with no prior practical ureteroscopy experience were included within the data analysis., Results: A correlation was found within all outcome measures analyzed. For the whole cohort, a strong negative correlation was found between time to completion and NOTSS scores (r = -0.75, p < 0.001), with strong positive correlations identified when NOTSS scores were compared with Objective Structured Assessment of Technical Skills (r = 0.89, p < 0.001) and task-specific checklist scores (r = 0.91, p < 0.001). Similar results were observed when each cohort was analyzed separately. Finally, all individual nontechnical skill components demonstrated a strong correlation with all technical skill parameters, regardless of training., Conclusions: A strong correlation between technical and nontechnical performance exists, which was demonstrated to be irrespective of training received. This may suggest an inherent link between skill sets. Furthermore, all nontechnical skill sets are important in technical performance. This supports the notion that both of these skills should be trained and assessed together within 1 curriculum., (Copyright © 2015 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the face, content and construct validity of the distributed simulation (DS) environment for technical and non-technical skills training in endourology. To evaluate the educational impact of DS for urology training., Subjects and Methods: DS offers a portable, low-cost simulated operating room environment that can be set up in any open space. A prospective mixed methods design using established validation methodology was conducted in this simulated environment with 10 experienced and 10 trainee urologists. All participants performed a simulated prostate resection in the DS environment. Outcome measures included surveys to evaluate the DS, as well as comparative analyses of experienced and trainee urologist's performance using real-time and 'blinded' video analysis and validated performance metrics. Non-parametric statistical methods were used to compare differences between groups., Results: The DS environment demonstrated face, content and construct validity for both non-technical and technical skills. Kirkpatrick level 1 evidence for the educational impact of the DS environment was shown. Further studies are needed to evaluate the effect of simulated operating room training on real operating room performance., Conclusions: This study has shown the validity of the DS environment for non-technical, as well as technical skills training. DS-based simulation appears to be a valuable addition to traditional classroom-based simulation training., (© 2014 The Authors BJU International © 2014 BJU International Published by John Wiley & Sons Ltd.)

Calcific uremic arteriolopathy or calciphylaxis is a rare condition that can present with clinical features similar to penile cancer. It is a diagnosis to consider in patients with end-stage renal failure (ESRF) presenting with a penile lesion. We describe one such case, where a patient with ESRF presented with a solid, tender penile mass and underwent surgery for presumed penile cancer. Histopathological analysis however confirmed a diagnosis of calcific uremic arteriolopathy, without evidence of malignancy. The clinical diagnosis of calcific uremic arteriolopathy relies on a high index of suspicion, and lesion biopsy is controversial due to a high risk of poor wound healing and sepsis. New treatment options are encouraging, and have been reported, albeit in small numbers. Delayed diagnosis can adversely affect both quality of life and prognosis in a condition with an extremely high mortality rate.

In the mythology of Ancient Greece, there was often a creative tension between the opposing forces of the gods Apollo and Dionysius, the two sons of Zeus. The Apollonian force was considered to be rational and lifegiving, whilst Dionysian forces were chaotic and elemental. Acute myeloid leukaemia is characterised by the clash of these forces: the chaotic proliferation of immature myeloid cells in the bone marrow overcomes the normal, orderly production of healthy blood cells. DNMT3A mutations occur early in the leukaemogenic process and may even act as "founder" mutations - the first step in a pathway towards malignant transformation. As such, these mutations may represent a Dionysian agent of disorder, inciting the chaotic myeloid proliferation and arrest of differentiation which are hallmarks of AML. This review will focus on the role of DNMT3A mutations in leukaemia pathogenesis, their influence on prognosis, and the potential for therapeutic targeting.

Epstein-Barr virus (EBV)-associated posttransplant lymphoma (PTLD) is a major cause of morbidity/mortality after hematopoietic stem cell (SCT) or solid organ (SOT) transplant. Adoptive immunotherapy with EBV-specific cytotoxic lymphocytes (CTLs), although effective in SCT, is less successful after SOT where lifelong immunosuppression therapy is necessary. We have genetically engineered EBV-CTLs to render them resistant to calcineurin (CN) inhibitor FK506 through retroviral transfer of a calcineurin A mutant (CNA12). Here we examined whether or not FK506-resistant EBV-CTLs control EBV-driven tumor progression in the presence of immunosuppression in a xenogeneic mouse model. NOD/SCID/IL2rγ(null) mice bearing human B-cell lymphoma were injected with autologous CTLs transduced with either CNA12 or eGFP in the presence/absence of FK506. Adoptive transfer of autologous CNA12-CTLs induced dramatic lymphoma regression despite the presence of FK506, whereas eGFP-CTLs did not. CNA12-CTLs persisted longer, homed to the tumor, and expanded more than eGFP-CTLs in mice treated with FK506. Mice receiving CNA12-CTLs and treated with FK506 survived significantly longer than control-treated animals. Our results demonstrate that CNA12-CTL induce regression of EBV-associated tumors in vivo despite ongoing immunosuppression. Clinical application of this novel approach may enhance the efficacy of adoptive transfer of EBV-CTL in SOT patients developing PTLD without the need for reduction in immunosuppressive therapy., (© 2014 by The American Society of Hematology.)

Introduction: Validation studies are an important part of simulator evaluation and are considered necessary to establish the effectiveness of simulation-based training. The widely used Bristol transurethral resection of prostate (TURP) simulator has not been formally validated., Objectives: Evaluation of the face, content, and construct validities of the Bristol TURP simulator as an endourology training tool., Design: Using established validation methodology, face, content, and construct validities were evaluated. Face and content validities were assessed using a structured quantitative survey. Construct validity was assessed by comparing the performance of experts and novices using a validated performance scale and resection efficiency., Participants and Setting: Overall, 8 novice urologists and 8 expert urologists participated in the study. The study was conducted in a dedicated surgical simulation training facility., Results: All 16 participants felt the model was a good training tool and should be used as an essential part of urology training (face validity). Content validity evaluation showed that most aspects of the simulator were adequately realistic (mean Likert scores 3.38-3.57/5); however, the model does not simulate bleeding. Experts significantly outperformed novices (p < 0.001) across all measures of performance, therefore establishing construct validity., Conclusions: The Bristol TURP simulator shows face, content, and construct validities, although some aspects of the simulator were not very realistic (e.g., bleeding). This study provides evidence for the continuing use of this simulator in endourology training., (Copyright © 2014 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Although a number of simulators have been introduced for prostate surgery, none have undergone validation for holmium laser enucleation of the prostate training. This study was carried out to assess the face and content validities as well as feasibility and acceptability of the new prostatic hyperplasia model and prostate surgery simulator for holmium laser enucleation of the prostate., Design: This is a prospective, observational, and comparative study. Participants were given a 30-minute video tutorial followed by a 45-minute simulation session, with one-to-one mentoring. A survey with qualitative and quantitative fields was used to evaluate their experience., Setting: This study was carried out in a 2-day modular teaching course hosted by the Holmium User Group at Cambridge University Hospitals, UK, and during the British Association of Urological Surgeons 2013 Annual Meeting., Participants: A total of 36 participants comprising 13 urology trainees and 23 senior urologists of varying levels from all around the globe were recruited., Results: Overall, 87% of the participants believed that holmium laser enucleation of the prostate was an effective method of treatment, simulation-based training, and assessment essential for patient safety and 84% believed a validated simulator would be useful for training. Of the participants, 97% agreed that the simulation should be implemented into training programs and only 31% felt it should be part of accreditation. Participants ranked all components of the simulator greater than 7 of 10 on a global rating scale and believed it was a feasible and acceptable method of training and assessment., Conclusions: The new simulator for holmium laser enucleation of the prostate has been demonstrated to be useful as a training tool. This study has established face and content validities of the simulator. Senior and trainee urologists believed the simulator was an acceptable tool for training and assessment and its use feasible for novice trainees to acquire skills and knowledge to a predetermined level of proficiency., (© 2013 Published by Association of Program Directors in Surgery on behalf of Association of Program Directors in Surgery.)

Simulation, if appropriately integrated into surgical training, may provide a time efficient, cost effective and safe method of training. The use of simulation in urology training is supported by a growing evidence base for its use, leading many authors to call for it to be integrated into the curriculum. There is growing evidence for the utilisation of part task (technical skills) simulators to shorten the learning curve in an environment that does not compromise patient safety. There is also evidence that non-technical skills affect patient outcomes in the operating room and that high fidelity team based simulation training can improve non-technical skills and surgical team performance. This evidence has strengthened the argument of surgical educators who feel that simulation should be formally incorporated into the urology training curriculum to develop both technical and non-technical skills with the aim of optimising performance and patient safety., (Copyright © 2013 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (PTLD) remains a major cause of morbidity and mortality after hematopoietic stem cell (HSCT) or solid organ transplant (SOT). Strategies to reconstitute immunity by adoptive transfer of EBV-specific cytotoxic T lymphocyte (CTL) therapy while highly effective in the HSCT setting where immunosuppression can be withdrawn have been less successful in the SOT setting where continued immunosuppression therapy is necessary. Additionally, the complexity and time taken to generate EBV-CTLs for adoptive transfer limit the clinical applicability. We have developed a system for the rapid generation of EBV-CTLs resistant to immunosuppression based on selection of interferon-gamma (IFN-γ) secreting EBV-CTLs and retroviral transduction with a calcineurin B mutant. With this methodology, EBV-CTLs resistant to the calcineurin inhibitor Tacrolimus (TAC) can be produced in 14 days. These CTLs show high specificity for EBV with negligible alloreactivity in both proliferation and cytotoxicity assays and are able to proliferate and secrete IFN-γ in response to antigen stimulation in the presence of therapeutic doses of TAC. This strategy will substantially facilitate clinical application of this approach for the treatment of PTLD in SOT recipients., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)