Staff Publication

Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT (2020)

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Type of publication:
Randomised controlled trial

Author(s):
Coomarasamy A.; Harb H.M.; Devall A.J.; Williams H.M.; Gallos I.D.; Ewer A.; Cheed V.; Roberts T.E.; Ogwulu C.B.; Middleton L.J.; Goranitis I.; Eapen A.; Daniels J.P.; Ahmed A.; Hinshaw K.; Bender-Atik R.; Bhatia K.; Bottomley C.; Kriedt K.; Jurkovic D.; Brewin J.; Choudhary M.; Crosfill F.; Deb S.; Duncan W.C.; Norman J.E.; Horne A.W.; Holland T.; Izzat F.; Johns J.; Ross J.; Lumsden M.-A.; Manda P.; Nunes N.; Overton C.E.; Quenby S.; Rao S.; Shahid A.; *Underwood M. ; Vaithilingham N.; Watkins L.; Wykes C.

Citation:
Health Technology Assessment (Winchester, England); Jun 2020; vol. 24 (no. 33); p. 1-70

Abstract:
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. OBJECTIVE(S): (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 400mg 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. RESULT(S): 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. CONCLUSION(S): 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.

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Ten-Year Results of FAST: A Randomized Controlled Trial of 5-Fraction Whole-Breast Radiotherapy for Early Breast Cancer (2020)

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Type of publication:
Randomised controlled trial

Author(s):
Brunt A.M.; Haviland J.S.; Sydenham M.; Bliss J.M.; *Agrawal R.K.; Algurafi H.; Alhasso A.; Barrett-Lee P.; Passant H.; Bliss P.; Bloomfield D.; Tremlett J.; Bowen J.; Donovan E.; Goodman A.; Harnett A.; Hogg M.; Kumar S.; Quigley M.; Sherwin L.; Stewart A.; Syndikus I.; Tsang Y.; Venables K.; Wheatley D.; Yarnold J.R.

Citation:
Journal of Clinical Oncology; October 2020, 38, no. 28, 3261-3272.

Abstract:
PURPOSE: Previous studies of hypofractionated adjuvant whole-breast radiotherapy for early breast cancer established a 15- or 16-fraction (fr) regimen as standard. The FAST Trial (CRUKE/04/015) evaluated normal tissue effects (NTE) and disease outcomes after 5-fr regimens. Ten-year results are presented. METHOD(S): Women >= 50 years of age with low-risk invasive breast carcinoma (pT1-2 pN0) were randomly assigned to 50 Gy/25 fr (5 weeks) or 30 or 28.5 Gy in 5 fr of 6.0 or 5.7 Gy (1 week). The primary end point was change in photographic breast appearance at 2 and 5 years; secondary end points were physician assessments of NTE and local tumor control. Odds ratios (ORs) from longitudinal analyses compared regimens. RESULT(S): A total of 915 women were recruited from 18 UK centers (2004-2007). Five-year photographs were available for 615/862 (71%) eligible patients. ORs for change in photographic breast appearance were 1.64 (95% CI, 1.08 to 2.49; P = .019) for 30 Gy and 1.10 (95% CI, 0.70 to 1.71; P = .686) for 28.5 Gy versus 50 Gy. alpha/beta estimate for photographic end point was 2.7 Gy (95% CI, 1.5 to 3.9 Gy), giving a 5-fr schedule of 28 Gy (95% CI, 26 to 30 Gy) estimated to be isoeffective with 50 Gy/25 fr. ORs for any moderate/marked physician-assessed breast NTE (shrinkage, induration, telangiectasia, edema) were 2.12 (95% CI, 1.55 to 2.89; P < .001) for 30 Gy and 1.22 (95% CI, 0.87 to 1.72; P = .248) for 28.5 Gy versus 50 Gy. With 9.9 years median follow-up, 11 ipsilateral breast cancer events (50 Gy: 3; 30 Gy: 4; 28.5 Gy: 4) and 96 deaths (50 Gy: 30; 30 Gy: 33; 28.5 Gy: 33) have occurred. CONCLUSION(S): At 10 years, there was no significant difference in NTE rates after 28.5 Gy/5 fr compared with 50 Gy/25 fr, but NTE were higher after 30 Gy/5 fr. Results confirm the published 3-year findings that a once-weekly 5-fr schedule of whole-breast radiotherapy can be identified that appears to be radiobiologically comparable for NTE to a conventionally fractionated regimen.

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First impressions of the foundation interim year 1 postings: positives, pitfalls, and perils (2020)

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Type of publication:
Journal article

Author(s):
Youssef S.; Zaidi S.; Varghese C.; Rajagopalan S.; *Shrestha S.

Citation:
Medical Education Online; Dec 2020; vol. 25 (no. 1)

Abstract:
COVID-19 has placed an increased burden on the NHS. Changes were made to expand patient capacity including hospital restructuring, cancellation of most elective surgeries and early graduation of final year medical students. 1 The UK foundation programme (UKFP) curated a new training position for graduates as foundation interim year 1 (FiY1) doctors, where they voluntarily work in paid positions prior to entering formal foundation year 1 (FY1) roles. 2 Expediting the process of fulfilling these positions, the General Medical Council facilitated early provisional registration of doctors. We discuss the positives, pitfalls, and perils of the new roles and the first impressions of three newly qualified FiY1 s in medical, obstetrics and gynaecology and surgical posts, a surgical FY1 doctor and a clinical supervisor in surgery.

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Randomized Trial of Ciprofloxacin Doxycycline and Hydroxychloroquine Versus Budesonide in Active Crohn's Disease (2021)

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Type of publication:
Randomised controlled trial

Author(s):
Rhodes J.M.; Subramanian S.; Martin K.; Probert C.; Flanagan P.K.; Horgan G.W.; Mansfield J.; Parkes M.; Hart A.; Dallal H.; Iqbal T.; *Butterworth J.; Culshaw K.

Citation:
Digestive Diseases and Sciences; Aug 2021; vol. 66 (no. 8); p. 2700-2711

Abstract:
Background: Increased mucosa-associated E. coli are present in Crohn's disease, but their role in pathogenesis is uncertain. Aim(s): To assess efficacy and safety of an antibiotic/hydroxychloroquine combination effective against E. coli inside macrophages. Method(s): Adults with moderately active disease (CDAI > 220-450 plus C reactive protein >= 5 mg/l and/or fecal calprotectin > 250 mug/g) were randomized to receive (open-label) oral budesonide (Entocort CR 9 mg/day 8 weeks, 6 mg/day 2 weeks, 3 mg/day 2 weeks) or oral ciprofloxacin 500 mg bd, doxycycline 100 mg bd, hydroxychloroquine 200 mg tds for 4 weeks, followed by doxycycline 100 mg bd and hydroxychloroquine 200 mg tds for 20 weeks. Primary endpoints were remission (CDAI <= 150) at 10 weeks, remission maintained to 24 weeks, and remission maintained to 52 weeks. Patients not responding (CDAI fall by > 70) by 10 weeks were invited to crossover onto the alternative therapy. Result(s): Fifty-nine patients were recruited across 8 sites. Including crossover, 39 patients received antibiotics/hydroxychloroquine and 39 received budesonide. At 10 weeks, 24 weeks, and 52 weeks on initial therapy, only 2/27, 2/27, and 1/27 were in remission on antibiotics/hydroxychloroquine compared with 8/32, 1/32, and 1/32 on budesonide (P = 0.092 at 10 weeks). Withdrawals by 10 weeks due to adverse events were seen in 15 receiving antibiotics/hydroxychloroquine and 6 budesonide. Results including crossover were more promising with 9/24 patients receiving antibiotics/hydroxychloroquine per protocol in remission by 24 weeks. No correlation was seen between response to antibiotics/hydroxychloroquine and ASCA/OmpC antibody status or disease location. Conclusion(s): Overall results with this antibiotic/hydroxychloroquine combination were unimpressive, but long-term remission is seen in some patients and justifies further study.

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Prospective validation of the RAPID clinical risk prediction score in adult patients with pleural infection: the PILOT study (2020)

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Type of publication:
Journal article

Author(s):
Corcoran J.P.; Psallidas I.; Hassan M.; Hallifax R.J.; Rahman N.M.; Dobson M.; Shaw R.; Hedley E.L.; Sabia A.; Robinson B.; Gerry S.; Collins G.S.; Piccolo F.; Popowicz N.D.; Koegelenberg C.F.; Saba T.; Saba J.; Daneshvar C.; Ward N.R.; Fairbairn I.; *Heinink R.; West A.; Stanton A.E.; Holme J.; Kastelik J.A.; Steer H.; Downer N.J.; Haris M.; Baker E.H.; Everett C.F.; Pepperell J.; Bewick T.; Yarmus L.; Maldonado F.; Khan B.; Hart-Thomas A.; Hands G.; Warwick G.; De Fonseka D.; Maskell N.A.; Munavvar M.; Guhan A.; Shahidi M.; Pogson Z.; Dowson L.; Davies H.E.; Yu L.-M.; Miller R.F.

Citation:
The European respiratory journal; 2020 Nov;56(5)

Abstract:
BACKGROUND: Over 30% of adult patients with pleural infection either die and/or require surgery. There is no robust means of predicting at baseline presentation which patients will suffer a poor clinical outcome. A validated risk prediction score would allow early identification of high-risk patients, potentially directing more aggressive treatment thereafter. OBJECTIVE(S): To prospectively assess a previously described risk score (RAPID – Renal (urea), Age, fluid Purulence, Infection source, Dietary (albumin)) in adults with pleural infection. METHOD(S): Prospective observational cohort study recruiting patients undergoing treatment for pleural infection. RAPID score and risk category were calculated at baseline presentation. The primary outcome was mortality at 3 months; secondary outcomes were mortality at 12 months, length of hospital stay, need for thoracic surgery, failure of medical treatment, and lung function at 3 months. RESULT(S): Mortality data were available in 542 of 546 (99.3%) patients recruited. Overall mortality was 10% (54/542) at 3 months and 19% (102/542) at 12 months. The RAPID risk category predicted mortality at 3 months; low-risk (RAPID score 0-2) mortality 5/222 (2.3%, 95%CI 0.9 to 5.7), medium-risk (RAPID score 3-4) mortality 21/228 (9.2%, 95%CI 6.0 to 13.7), and high-risk (RAPID score 5-7) mortality 27/92 (29.3%, 95%CI 21.0 to 39.2). C-statistics for the score at 3 and 12 months were 0.78 (95%CI 0.71 to 0.83) and 0.77 (95%CI 0.72 to 0.82) respectively. CONCLUSION(S): The RAPID score stratifies adults with pleural infection according to increasing risk of mortality and should inform future research directed at improving outcomes in this patient population.

The importance of skin biopsies: Sweet syndrome as a differential for 'acute painful red rash' in a patient with normal neutrophils and polymyalgia rheumatica on glucocorticoids (2020)

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Type of publication:
Journal article

Author(s):
Rajakulenthiran T.G.; Amarasena R.; Silva S.S.C.; *Singh R.; *Kelly S.

Citation:
Clinical Medicine, Journal of the Royal College of Physicians of London; Mar 2020; vol. 20, p. S25

Abstract:

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Stepped-wedge randomised trial of laparoscopic ventral mesh rectopexy in adults with chronic constipation: A randomised controlled trial (2020)

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Type of publication:
Conference abstract

Author(s):
Grossi U.; McAlees E.; Knowles C.H.; Stevens N.; Di Tanna G.L.; Marlin N.; *Lacy-Colson J.; Brown S.; Scott S.M.; Norton C.; Mason J.

Citation:
Techniques in Coloproctology; 2020; vol. 24 (no. 4); p. 373-374

Abstract:
Background: Laparoscopic ventral mesh rectopexy (LVMR) is an established treatment for external full-thickness rectal prolapse. However, its clinical efficacy in patients with internal prolapse is uncertain due to the lack of high-quality evidence.
Methods: An individual level, stepped-wedge randomised trial has been designed to allow observer blinded data comparisons between patients awaiting LVMR with those who have undergone surgery. Adults with symptomatic internal rectal prolapse, unresponsive to prior conservative management, will be eligible to participate. They will be randomised to three arms with different delays before surgery (0, 12 and 24 weeks). Efficacy outcome data will be collected at equally stepped time points (12, 24, 36 and 48 weeks). The primary objective is to determine clinical efficacy of LVMR compared to controls with reduction in the Patient Assessment of Constipation Quality of Life (PAC-QOL) at 24 weeks serving as the primary outcome. Secondary objectives are to determine: (1) the clinical effectiveness of LVMR to 48 weeks to a maximum of 72 weeks; (2) preoperative determinants of outcome; (3) relevant health economics for LVMR; (4) qualitative evaluation of patient and health professional experience of LVMR and (5) 30-day morbidity and mortality rates.
Results: An individual-level, stepped-wedge, randomised trial serves the purpose of providing an untreated comparison for the active treatment group, while at the same time allowing the waiting-listed participants an opportunity to obtain the intervention at a later date. Conclusions: In keeping with the basic ethical tenets of this design, the average waiting time for LVMR (12 weeks) will be shorter than that for routine services (24 weeks).

Metabolic stone screening - can education improve adherence to national guidelines? (2020)

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Type of publication:
Journal article

Author(s):
Ravindraanandan M.; *Jayawardena P.

Citation:
Journal of Endoluminal Endourology; Jan 2020; vol. 3 (no. 1)

Abstract:
Nephrolithiasis is a common urological disease affecting approximately 13% of the global population. Identifying a preventable cause during follow-up for stone formation is a necessary factor in reducing recurrence. The majority of kidney stones are comprised of calcium, with oxalate and phosphate compounds accounting for approximately 80% of stone formers. Serum analysis can be used to identify the levels of calcium in the blood, excluding metabolic causes for stones. Current NICE guidelines recommend performing a metabolic screen during an acute admission. Adherence to these guidelines from clinicians can be poor. We aim to see whether education can improve serum metabolic requests from clinicians in the UK. Method A case-control study was performed in a single rural district general hospital in the UK. Patients who presented with renal colic were analyzed retrospectively for four months, looking at serum metabolic screen requests. Two months of education was then delivered to acute departments, with a further prospective study performed following this for six months. Outcomes were then compared between both groups to see if there was an improvement in serum requests following the delivery of local education. Results A total of 124 patients were included in our study. 50 patients were analyzed in cohort A over a 4-month period. Complete serum analysis was performed on 22% (n=11) of patients. Incomplete serum analysis was performed on 58% (n-29) of patients with uric acid being missed on all of them. 10 patients had no metabolic serum analysis performed at all, with 1 patient having a previous history of stones. A total of 74 patients were analyzed in cohort B over a 6-month period. This was following the 2 months of departmental education given by urologists. Complete serum analysis was performed on 24% (n=18) of patients. Incomplete serum analysis was performed on 55% (n=41) of patients with uric acid being missed from all of them. The remaining 21% of patients (n=15) had no metabolic serum screen performed at all. There was no significant difference seen between both cohorts after comparing metabolic serum requests before and after department education for 2 months (p=0.7287). Conclusion Improving adherence to clinical guidelines for metabolic screening has proved difficult with departmental teaching alone, with very little improvement achieved. Nevertheless, formal face-to-face education is advocated to reinforce knowledge in junior doctors managing renal stones.

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Providing a safe and effective intravitreal treatment service: strategies for service delivery (2020)

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Type of publication:
Journal article

Author(s):
Amoaku W.; Bailey C.; Downey L.; Gale R.P.; Ghanchi F.; Hamilton R.; Mahmood S.; Menon G.; *Nosek J. ; Pearce I.; Yang Y

Citation:
Clinical Ophthalmology; 2020; vol. 14 ; p. 1315-1328

Abstract:
An aging population leads to increasing demand for medical retina services with chronic diseases being managed in long-term care pathways. Many hospital services struggle to deliver efficient and effective MR care due, at least in part, to infrastructure that does not expand responsively enough to meet the increased demand. A steering committee of retinal specialists from a variety of UK NHS hospital ophthalmology departments with experience of leading and managing NHS retinal services in the intravitreal era came together for the generation of this document to review and compile key aspects that should be considered when optimising intravitreal treatment capacity within MR services. This article aims to provide a useful collation and signposting of key published evidence, consensus and insights on aspects of delivering an intravitreal service, including treatment regimens, virtual clinics, staff training and governance, telemedicine and information technology, and data collection and key performance indicators. The objective is to equip ophthalmologic healthcare professionals with the necessary tools to develop and adapt their local service in the face of current and projected increased demand.

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The triple effect of the magseed for localisation of impalpable breast cancer: Significant reduction in re-excision rate, cost saving by reducing further surgery and high patient satisfaction (2020)

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Type of publication:
Conference abstract

Author(s):
*Lake B.; *Wilson M.; *Thomas G.; *Williams S.; *Usman T.

Citation:
European Journal of Surgical Oncology; Jun 2020; vol. 46 (no. 6); e12

Abstract:
Introduction: Traditionally impalpable breast cancers have been localised with image guided techniques of wire guidance or ultrasound marking. Magseed is a small magnetic seed which is changing practice of localisation of these cancers. The aim of this study was to see if the change of practice of localisation to Magseed affected patient outcome evaluated by re-excision rate, specimen weight and patient satisfaction. Method(s): A change of practice service evaluation was conducted at the Shrewsbury and Telford Hospital of all patients who had imaged guided wide local excision for impalpable breast cancer from July 2017 to August 2019. Data recorded included tumour demographics, localisation method, size of tumour and specimen weight. Evaluation of localisation methods included re-excision rates, type of further surgery, cost saving in reduction in re-excision, and patient satisfaction. Result(s): 2017/2018 226 Traditional guided WLE were performed. 2018/2019 90 traditional guided WLE, and 106 Magseed WLE were performed. Tumour demographics, size of tumour were similar for localisation methods. The introduction of Magseed in our practice has resulted in a significant reduction in overall re-excision rates from 22.4 to 12%, (z =2.6616 p.00782), and average specimen weight from 40 to 27g (t= -3.2364, P.000716). Cost saving analysis of further surgery showed a saving of 34,457 with 48% less further operations following change of practice. 98% of patients had a very good/excellent experience of Magseed. Conclusion(s): Magseed demonstrates a triple effect on patient outcome with significant reduction in re-excision rate, cost saving by reducing further surgery and high patient satisfaction.