Author: Jason Curtis

Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial (2020)

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Type of publication:
Randomised controlled trial

Author(s):
Chu, Justin J; Devall, Adam J; Beeson, Leanne E; Hardy, Pollyanna; Cheed, Versha; Sun, Yongzhong; Roberts, Tracy E; Ogwulu, C Okeke; Williams, Eleanor; Jones, Laura L; La Fontaine Papadopoulos, Jenny H; Bender-Atik, Ruth; Brewin, Jane; Hinshaw, Kim; Choudhary, Meenakshi; Ahmed, Amna; Naftalin, Joel; Nunes, Natalie; Oliver, Abigail; Izzat, Feras; Bhatia, Kalsang; Hassan, Ismail; Jeve, Yadava; Hamilton, Judith; Deb, Shilpa; Bottomley, Cecilia; Ross, Jackie; Watkins, Linda; *Underwood, Martyn; Cheong, Ying; Kumar, Chitra S; Gupta, Pratima; Small, Rachel; Pringle, Stewart; Hodge, Frances; Shahid, Anupama; Gallos, Ioannis D; Horne, Andrew W; Quenby, Siobhan; Coomarasamy, Arri

Citation:
Lancet; Sep 2020; vol. 396 (no. 10253); p. 770-778

Abstract:
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/m2vs ≥35 kg/m2), 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.

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Clozapine toxicity: a cautionary palliative care tale (2020)

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Type of publication:
Journal article

Author(s):
*Macfarlane, Michael; Shahab, Julita; *Willis, Derek

Citation:
BMJ Supportive & Palliative Care; Sep 2020; vol. 10 (no. 3); p. 312-313

Abstract:
OBJECTIVE: This case report presents an unusual case of clozapine toxicity secondary to reduced smoking habit mimicking a patient approaching end of life. METHODS: It is a cautionary tale for palliative care specialists, perhaps unaware of the effect of cigarette smoke on metabolism of this antipsychotic, to be aware of. RESULTS: Following specialist advice and change of antipsychotic medication, this patient's condition improved to the point that he was discharged from the hospice. CONCLUSION: Palliative care specialists should be aware that reducing cigarette consumption can alter metabolism of clozapine, potentially causing drug accumulation and toxicity with features which mimic deterioration towards end of life. Specialist advice should be sought in such a situation.

Assembly of alternative prothrombinase by extracellular histones initiate and disseminate intravascular coagulation (2020)

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Type of publication:
Journal article

Author(s):
Abrams, Simon Timothy; Su, Dunhao; Sahraoui, Yasmina; Lin, Ziqi; Cheng, Zhenxing; Nesbitt, Kate; *Alhamdi, Yasir; Harrasser, Micaela; Du, Min; Foley, Jonathan; Lillicrap, David; Wang, Guozheng; Toh, Cheng-Hock

Citation:
Blood; Jul 2020 [epub ahead of print]

Abstract:
Thrombin generation is pivotal to both physiological blood clot formation and pathological development of disseminated intravascular coagulation (DIC). In critical illness, extensive cell damage can release histones into the circulation, which can increase thrombin generation and cause DIC, but the molecular mechanism is not clear. Typically, thrombin is generated by the prothrombinase complex, comprising activated factor X (FXa), activated co-factor V (FVa) and phospholipids to cleave prothrombin in the presence of calcium. In this study, we found that in the presence of extracellular histones, an alternative prothrombinase could form without FVa and phospholipids. Histones directly bind to prothrombin fragments F1 and F2 specifically, to facilitate FXa cleavage of prothrombin to release active thrombin, unlike FVa which requires phospholipid surfaces to anchor the classical prothrombinase complex. In vivo, histone infusion into mice induced DIC, which was significantly abrogated when prothrombin fragments F1+F2 were infused prior to histones, to act as decoy. In a cohort of intensive care unit (ICU) patients with sepsis (n=144), circulating histone levels were significantly elevated in patients with DIC. These data suggest that histone-induced alternative prothrombinase without phospholipid anchorage may disseminate intravascular coagulation, and reveal a new molecular mechanism of thrombin generation and DIC development. In addition, histones significantly reduced the requirement for FXa in the coagulation cascade to enable clot formation in Factor VIII and IX-deficient plasma, as well as in Factor VIII-deficient mice. In conclusion, this study highlights a novel mechanism in coagulation with therapeutic potential in both targeting systemic coagulation activation as well as in correcting coagulation factor deficiency.

Non-HDL or LDL cholesterol in heterozygous familial hypercholesterolaemia: findings of the Simon Broome Register (2020)

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Type of publication:
Journal article

Author(s):
Soran H.; Durrington P.N.; Cooper J.A.; Humphries S.E.; *Capps N.; McDowell I.F.W.; Neil A.

Citation:
Current Opinion in Lipidology; August 2020, Volume 31, Issue 4, p. 167-175

Abstract:
PURPOSE OF REVIEW: The role of non-HDL-C in the identification and management of lipid disorders is not clearly defined, although UK guidelines recommend its wider use in assessing the need for lipid-lowering therapy and as a treatment target. RECENT FINDINGS: We examined the implications of the use of non-HDL-C as opposed to LDL-C in 253 people with hypercholesterolaemia before treatment and 573 after treatment in whom fasting total serum cholesterol, HDL-C and LDL-C had been recorded and the diagnosis of heterozygous familial hypercholesterolemia (heFH) was investigated by genetic testing. The difference and the limits of agreement between non-HDL-C and LDL-C calculated using the Friedewald formula were assessed in those with and without heFH-causing mutations. SUMMARY: There were 147 mutation-positive and 106 mutation-negative pretreatment participants and 395 mutation-positive and 178 mutation-negative patients receiving treatment. The difference between non-HDL-C and LDL-C pretreatment in mutation-positive people (mean LDL-C 7.73 mmol/l) was 0.67 mmol/l (95% CI 0.62-0.73) and posttreatment (mean LDL-C 4.71 mmol/l) was 0.62 mmol/l (95% CI 0.59-0.65) with wide limits of agreement of -0.02 to 1.37 and 0.07-1.18 mmol/l, respectively. Among patients with heterozygous familial hypercholesterolaemia, use of estimated LDL-C derived from non-HDL-C in place of calculated LDL-C may result in diagnostic misclassification and difficulty in assessing the true reduction in LDL-C with treatment, because of the wide inter-individual limits of agreement around the mean difference between non-HDL-C and LDL-C.

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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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