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Background Tubal ectopic pregnancies can cause significant morbidity or even death. Current treatment is with methotrexate or surgery. However, methotrexate treatment can fail in approximately 30% of women. Gefitinib, an epidermal growth factor receptor inhibitor, may improve the effects of methotrexate. We assessed the efficacy of administering oral gefitinib with methotrexate, versus methotrexate alone, to treat a tubal ectopic pregnancy. Objectives To test the hypothesis a combination of gefitinib with methotrexate can increase resolution of stable tubal ectopic pregnancy without the need for surgery, compared with methotrexate alone. Design A randomised, double-blind, placebo-controlled, multicentre, superiority trial. Setting Fifty UK hospitals. Participants A target of 328 women with a stable, tubal ectopic pregnancy. Intervention Women were randomised to combination of methotrexate and gefitinib or methotrexate and placebo. All participants received a single intramuscular dose of methotrexate 50 mg/m2 and were randomised in a 1:1 ratio of oral gefitinib (250 mg daily for 7 days) or placebo. Main outcome measures The primary outcome was surgical intervention for resolution of ectopic pregnancy. Secondary outcomes were the need for an additional dose of methotrexate, time to resolution of the ectopic pregnancy, number of treatment-associated hospital visits, safety and tolerability, acceptability of treatment and return to menses. Results Between 2 November 2016 and 6 October 2021, 328 women were randomly allocated to methotrexate and gefitinib (n = 165) or methotrexate and placebo (n = 163). Three women in the placebo group withdrew. Surgical intervention occurred in 30% (50/165) of the gefitinib group and in 29% (47/160) of the placebo group (adjusted risk ratio 1.15, 95% confidence interval 0.85 to 1.58; adjusted risk difference −0.01, 95% confidence interval −0.10 to 0.09; p = 0.37). Without surgical intervention, median time to resolution was 28.0 days in the gefitinib group and 28.0 days in the placebo group (subdistribution hazard ratio 1.03, 95% confidence interval 0.75 to 1.40). The need for additional methotrexate doses, number of additional hospital visits, participant acceptability, time to return of menses and serious adverse events were similar in both groups. Diarrhoea and rash were more common in the gefitinib group. Conclusions The addition of gefitinib to standard medical management with methotrexate to treat tubal ectopic pregnancy is not clinically effective as it does not reduce subsequent surgical intervention and is associated with higher rates of reported symptoms than placebo. Limitations We were unable to investigate how different gefitinib doses or modes of delivery would impact on the results. Future work Questions that remain unaddressed relate to the use of methotrexate and gefitinib combination treatment for other extrauterine and uterine ectopic pregnancy, such as caesarean scar pregnancies, or in the management of choriocarcinoma. Trial registration This trial is registered as ISRCTN 67795930 and EudraCT 2015-005013-76. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme and will be published in full in Efficacy and Mechanistic Evaluation; Vol. 10, No. 1. The gefitinib and placebo were supplied by Astra Zeneca. See the NIHR Journals Library website for further project information. Plain language summary What was the question? A tubal ectopic pregnancy is where a fertilised egg is not growing in the womb. The pregnancy cannot be saved and the woman is at risk of losing her fallopian tube and if this pregnancy is left to grow can even die. Current treatment is with methotrexate or surgery. An operation can happen because either the ectopic pregnancy has ruptured and caused internal bleeding, the medical treatment has not worked and the ectopic pregnancy needs to be removed or the patient can chose to have an operation. However, methotrexate treatment can fail in approximately 30% of women. We carried out research to see if the addition of a new drug (gefitinib, a drug used for lung cancer) to methotrexate could lower the number of women needing an operation to remove their ectopic pregnancy. What did we do? We involved 328 women with a stable tubal ectopic pregnancy, who were being treated medically with methotrexate, and randomly assigned them to have methotrexate alone or a combination of methotrexate and gefitinib. The gefitinib was taken in tablet form for 7 days, and the methotrexate was given as an injection. We followed the women up in line with their clinical care until their ectopic pregnancy resolved or they had surgery to remove the ectopic pregnancy. What did we find? The addition of gefitinib to methotrexate did not reduce the number of women who required surgery to remove their ectopic pregnancy. More women taking gefitinib experienced side effects, such as a facial rash or diarrhoea. What does this mean? Treatment with methotrexate remains the only drug treatment option for ectopic pregnancy. More research is needed. Scientific summary Background Tubal ectopic pregnancy (EP) can cause significant morbidity or even death. Current treatment is with methotrexate (MTX) or surgery. However, MTX treatment can fail in approximately 30% of women. Preclinical studies have shown that tubal implantation sites express high levels of epidermal growth factor receptor (EGFR) and that gefitinib (an EGFR antagonist) augments MTX-induced regression of pregnancy-like tissue. Clinical evidence from uncontrolled phase I and II trials has raised the possibility that a combination of MTX and gefitinib could be a more effective medical treatment than MTX alone to treat stable tubal EP. Objectives To test the hypothesis, a combination of gefitinib with MTX can increase resolution of stable tubal EP without the need for surgery, compared with MTX alone. Design A randomised, double-blind, placebo-controlled, multicentre, superiority trial. Setting This trial took place in 50 hospitals in the UK. Participants A target of 328 women with a stable, tubal EP. Intervention Participants were randomly assigned in a 1:1 ratio to receive either gefitinib and MTX or matched placebo and MTX with the use of minimisation to balance trial-group assignments according to baseline human chorionic gonadotropin levels (

Background: Chronic limb-threatening ischaemia with ischaemic pain and/or tissue loss., Objective: To examine the clinical and cost-effectiveness of a vein bypass-first compared to a best endovascular treatment-first revascularisation strategy in preventing major amputation or death., Design: Superiority, open, pragmatic, multicentre, phase III randomised trial., Setting: Thirty-nine vascular surgery units in the United Kingdom, and one each in Sweden and Denmark., Participants: Patients with chronic limb-threatening ischaemia due to atherosclerotic peripheral arterial disease who required an infra-popliteal revascularisation, with or without an additional more proximal infra-inguinal revascularisation procedure, to restore limb perfusion., Interventions: A vein bypass-first or a best endovascular treatment-first infra-popliteal, with or without an additional more proximal infra-inguinal revascularisation strategy., Main Outcome Measures: The primary outcome was amputation-free survival. Secondary outcomes included overall survival, major amputation, further revascularisation interventions, major adverse limb event, health-related quality of life and serious adverse events., Methods: Participants were randomised to a vein bypass-first or a best endovascular treatment-first revascularisation strategy. The original sample size of 600 participants (247 events) was based on a hazard ratio of 0.66 with amputation-free survival rates of 0.72, 0.62, 0.53, 0.47 and 0.35 in years 1-5 in the best endovascular treatment-first group with 90% power and alpha at p  = 0.05. The sample size was revised to an event-based approach as a result of increased follow-up time due to slower than anticipated recruitment rates. Participants were followed up for a minimum of 2 years. A cost-effectiveness analysis was employed to estimate differences in total hospital costs and amputation-free survival between the groups. Additionally, a cost-utility analysis was carried out and the total cost and quality-adjusted life-years, 2 and 3 years after randomisation were used., Results: Between 22 July 2014 and 30 November 2020, 345 participants were randomised, 172 to vein bypass-first and 173 to best endovascular treatment-first. Non-amputation-free survival occurred in 108 (63%) of 172 patients in the vein bypass-first group and 92 (53%) of 173 patients in the best endovascular treatment-first group [adjusted hazard ratio 1.35 (95% confidence interval 1.02 to 1.80); p  = 0.037]. Ninety-one (53%) of 172 patients in the vein bypass-first group and 77 (45%) of 173 patients in the best endovascular treatment-first group died [adjusted hazard ratio 1.37 (95% confidence interval 1.00 to 1.87)]. Over follow-up, the economic evaluation discounted results showed that best endovascular treatment-first was associated with £1690 less hospital costs compared to vein bypass-first. The cost utility analysis showed that compared to vein bypass-first, best endovascular treatment-first was associated with £224 and £2233 less discounted hospital costs and 0.016 and 0.085 discounted quality-adjusted life-year gain after 2 and 3 years from randomisation., Limitations: Recruiting patients to the Bypass versus Angioplasty in Severe Ischaemia of the Leg Trial-2 trial was difficult and the target number of events was not achieved., Conclusions: A best endovascular treatment-first revascularisation strategy was associated with better amputation-free survival, which was largely driven by fewer deaths. Overall, the economic evaluation results suggest that best endovascular treatment-first dominates vein bypass-first in the cost-effectiveness analysis and cost-utility analysis as it was less costly and more effective than a vein bypass-first strategy., Future Work: The Bypass versus Angioplasty in Severe Ischaemia of the Leg Trial-2 investigators have a data sharing agreement with the BEst Surgical Therapy in patients with Chronic Limb threatening Ischaemia investigators. One output of this collaboration will be an individual patient data meta-analysis., Study Registration: Current Controlled Trials ISRCTN27728689., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/35/45) and is published in full in Health Technology Assessment ; Vol. 28, No. 65. See the NIHR Funding and Awards website for further award information.

Background: Second trimester miscarriage and preterm birth is a significant global problem. Surgical cervical cerclage is performed to prevent pregnancy loss and preterm birth. It utilises either a monofilament or braided suture. It is hypothesised that a braided material becomes colonised with pathogenic bacteria that causes vaginal dysbiosis, infection and cerclage failure., Objectives: The primary objective of the study was to examine the effectiveness of using a monofilament suture material as opposed to a braided suture material on pregnancy loss in women requiring a vaginal cervical cerclage., Design: Superiority open randomised controlled trial., Setting: Seventy-five maternity sites across the UK., Participants: Women experiencing a singleton pregnancy requiring a cervical cerclage., Interventions: Monofilament suture or braided suture., Main Outcome Measures: The primary outcome was pregnancy loss (miscarriage and perinatal mortality, including any stillbirth or neonatal death in the first week of life). Secondary outcomes included the core outcome set for preterm birth., Methods: Women were randomised on a 1 : 1 basis to monofilament or braided cerclage utilising a bespoke randomisation service with minimisation dependent on the site, indication for cerclage, intention to use progesterone and planned surgical technique. The inclusion criteria were three or more previous mid-trimester losses or preterm births, insertion of a cerclage in a previous pregnancy, a history of a mid-trimester loss or preterm birth with a shortened cervical length in the current pregnancy or in women who clinicians deemed at risk of preterm birth. The exclusion criteria were an emergency or rescue cerclage, age of < 18 years, being unable to give informed consent or the cerclage having to be placed abdominally. The original sample size was calculated based on a relative risk reduction of 41% from a pregnancy loss rate of 19% in the braided group to 11% in the monofilament group with 90% power and alpha at p = 0.05. The independent data monitoring committee noted a lower-than-anticipated pooled event rate within the trial and recommended an increase in sample size to 2050. The outcome data were collected using clinical record forms from the maternal and neonatal medical records and reported to Birmingham Clinical Trials Unit., Results: A total of 2049 women were randomised, after withdrawals and loss to follow-up, data on 1005 women in the monofilament group and 993 women in the braided group were included. The baseline demographics between the groups were similar. There was no evidence of a difference in pregnancy loss rates between the monofilament and braided groups (80/1003 vs. 75/993; adjusted risk ratio: 1.05, 95% confidence interval: 0.79 to 1.40; adjusted risk difference: 0.002, 95% confidence interval: -0.02 to 0.03)., Limitations: The trial did not collect long-term paediatric outcomes. There were no safety concerns., Conclusions: There was no evidence of a difference in pregnancy loss between a monofilament suture and a braided suture., Future Work: Long-term follow-up of neonates born within the C-STICH (cerclage suture type for an insufficient cervix and its effects on health outcomes) trial., Trial Registration: This trial is registered as ISRCTN15373349., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/04/107) and is published in full in Health Technology Assessment ; Vol. 28, No. 40. See the NIHR Funding and Awards website for further award information.

Objective: The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL)-2 trial enrolled participants with chronic limb threatening ischaemia who required an infrapopliteal, with or without a femoropopliteal, revascularisation procedure to restore limb perfusion. Participants randomised to a vein bypass (VB) first revascularisation strategy were over one third more likely than those randomised to a best endovascular treatment (BET) first revascularisation strategy to die from any cause during a median follow up of 40.0 (interquartile range 20.9, 60.6) months. The aim of the present study was to describe the timing and causes of death in BASIL-2 as a first step towards trying to better understand why randomisation to a VB first revascularisation strategy was associated with this excess mortality., Methods: A 10 person international panel comprising vascular and endovascular surgeons as well as vascular interventional radiologists, who had all been principal investigators in BASIL-2, took part in a modified Delphi consensus exercise to adjudicate the primary cause of death and, in particular, whether the cause was primarily cardiac or non-cardiac., Results: In 151 of 168 deaths (89.9%), the Delphi panel achieved a consensus regarding the cause of death being probably cardiac or non-cardiac. In the BET group, 16 of 77 deaths (21%) were classified as probably cardiac compared with 32 of 91 (35%) in the VB group (unadjusted subdistribution hazard ratio 2.16, 95% confidence interval [CI] 1.20 - 3.87; unadjusted cause specific hazard ratio 2.15, 95% CI 1.19 - 3.90). At the point of randomisation, 64 of 344 (18.6%), 40 of 342 (11.7%), and 37 of 344 (10.8%) participants had a previous myocardial infarction (MI), percutaneous coronary intervention (PCI), and coronary artery bypass graft (CABG), respectively. There was no evidence of varying treatment effects for cause of death in subgroup analyses of previous PCI, CABG, or MI., Conclusion: The excess mortality observed in the VB first revascularisation strategy group in BASIL-2 was largely due to deaths that were adjudicated by the Delphi panel as probably primarily cardiac. These excess cardiac deaths were observed throughout follow up and there was no evidence of non-proportional hazards. Further work is ongoing to try to better understand the reasons for these findings., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The Bypass versus Angioplasty in Severe Ischaemia of the Leg-2 (BASIL-2) randomised controlled trial has shown that, for patients with chronic limb threatening ischaemia (CLTI) who require an infrapopliteal (IP) revascularisation a vein bypass (VB) first revascularisation strategy led to a 35% increased risk of major amputation or death when compared with a best endovascular treatment (BET) first revascularisation strategy. The study aims are to place the BASIL-2 trial within the context of the CLTI patient population as a whole and to investigate the generalisability of the BASIL-2 outcome data., Methods: This was an observational, single centre prospective cohort study. Between 24 June 2014 and 31 July 2018, the BASIL Prospective Cohort Study (PCS) was performed which used BASIL-2 trial case record forms to document the characteristics, initial and subsequent management, and outcomes of 471 consecutive CLTI patients admitted to an academic vascular centre. Ethical approval was obtained, and all patients provided fully informed written consent. Follow up data were censored on 14 December 2022., Results: Of the 238 patients who required an infrainguinal revascularisation, 75 (32%) had either IP bypass (39 patients) or IP BET (36 patients) outside BASIL-2. Seventeen patients were initially randomised to BASIL-2. A further three patients who did not have an IP revascularisation as their initial management were later randomised in BASIL-2. Therefore, 95/471 (20%) of patients had IP revascularisation (16% outside, 4% inside BASIL-2). Differences in amputation free survival, overall survival, and limb salvage between IP bypass and IP BET performed outside BASIL-2 were not subject to hypothesis testing due to the small sample size. Reasons for non-randomisation into the trial were numerous, but often due to anatomical and technical considerations., Conclusion: CLTI patients who required an IP revascularisation procedure and were subsequently randomised into BASIL-2 accounted for a small subset of the CLTI population as a whole. For a wide range of patient, limb, anatomical and operational reasons, most patients in this cohort were deemed unsuitable for randomisation in BASIL-2. The results of BASIL-2 should be interpreted in this context., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Study Question: What is the capacity of the change between Day 1 and Day 4 post-treatment serum human chorionic gonadotropin (hCG) levels for predicting single-dose methotrexate treatment success in tubal ectopic pregnancy?, Summary Answer: Any fall in Days 1-4 serum hCG signified an 85% (95% CI 76.8-90.6) likelihood of treatment success for women with tubal ectopic pregnancy (initial hCG of ≥1000 and ≤5000 IU/l) managed with single-dose methotrexate., What Is Known Already: For those with tubal ectopic pregnancy managed by single-dose methotrexate, current guidelines advocate intervention if Days 4-7 hCG fails to fall by >15%. The trajectory of hCG over Days 1-4 has been proposed as an early indicator that predicts treatment success, allowing early reassurance for women. However, almost all prior studies of Days 1-4 hCG changes have been retrospective., Study Design, Size, Duration: This was a prospective cohort study of women with tubal ectopic pregnancy (pre-treatment hCG of ≥1000 and ≤5000 IU/l) managed with single-dose methotrexate. The data were derived from a UK multicentre randomized controlled trial of methotrexate and gefitinib versus methotrexate and placebo for treatment of tubal ectopic pregnancy (GEM3). For this analysis, we include data from both treatment arms., Participants/materials, Setting, Methods: Participants were categorized according to single-dose methotrexate treatment success or failure. Treatment success for this analysis was defined as complete and uneventful resolution of tubal ectopic pregnancy to serum hCG <30 IU/l following single-dose methotrexate treatment without additional treatment. Patient characteristics of the treatment success and failure groups were compared. Changes in Days 1-4, 1-7, and 4-7 serum hCG were evaluated as predictors of treatment success through receiver operating characteristic curve analysis. Test performance characteristics were calculated for percentage change ranges and thresholds including optimal classification thresholds., Main Results and the Role of Chance: A total of 322 women with tubal ectopic pregnancy were treated with single-dose methotrexate. The overall single-dose methotrexate treatment success rate was 59% (n = 189/322). For any fall in serum hCG on Days 1-4, likelihood ratios were >3, while for any fall of serum hCG >20% on Days 1-7, likelihood ratios reached 5. Any rise of serum hCG on Days 1-7 and 4-7 strongly reduced the chance of success. Any fall in Days 1-4 hCG predicted single-dose methotrexate treatment success with a sensitivity of 58% and specificity 84%, resulting in positive and negative predictive values of 85% and 57%, respectively. Any rise in Days 1-4 serum hCG <18% was identified as an optimal test threshold that predicted treatment success with 79% sensitivity and 74% specificity, resulting in 82% positive predictive value and 69% negative predictive value., Limitations, Reasons for Caution: Our findings may be limited by intervention bias resulting from existing guidelines which influences evaluation of hCG changes reliant on Day 7 serum hCG levels., Wider Implications of the Findings: Examining a large prospective cohort, we show the value of Days 1-4 serum hCG changes in predicting single-dose methotrexate treatment success in tubal ectopic pregnancy. We recommend that clinicians provide early reassurance to women who have a fall or only a modest (<18%) rise in Days 1-4 serum hCG levels, that their treatment will likely be effective., Study Funding/competing Interest(s): This project was supported by funding from the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership (grant reference number 14/150/03). A.W.H. has received honoraria for consultancy for Ferring, Roche, Nordic Pharma and AbbVie. W.C.D. has received honoraria from Merck and Guerbet and research funding from Galvani Biosciences. L.H.R.W. has received research funding from Roche Diagnostics. B.W.M. is supported by a NHMRC Investigator grant (GNT1176437). B.W.M. also reports consultancy for ObsEva and Merck and travel support from Merck. The other authors declare no competing interests., Trial Registration Number: This study is a secondary analysis of the GEM3 trial (ISRCTN Registry ISRCTN67795930)., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Lay Summary: An ectopic pregnancy occurs when an embryo implants outside of the uterus, usually in a fallopian tube. When detected early, treatment is often with a medication called methotrexate. When methotrexate does not work, surgery is required. A recent clinical trial of ectopic pregnancy treatment (called GEM3) found that adding a drug called gefitinib to methotrexate did not reduce the need for surgery. We have used data from the GEM3 trial, combined with data collected 12 months after the trial finished, to investigate post-methotrexate pregnancy outcomes. We found no difference in pregnancy rates, pregnancy loss rates and recurrent ectopic pregnancy rates between those treated medically only and those who subsequently also needed surgery. The surgical technique used also did not affect pregnancy rates. This research provides reassurance that women with ectopic pregnancies treated medically who need surgery have similar post-treatment pregnancy outcomes to those treated successfully medically.

Objectives: To address optimal timing of birth for women with chronic or gestational hypertension who reach term and remain well., Study Design: Pragmatic, non-masked randomised trial., Inclusion: maternal age ≥16 years, chronic or gestational hypertension, singleton pregnancy, live fetus, 36 +0 -37 +6 weeks' gestation, and able to give documented informed consent., Exclusion: contraindication to either trial arm (e.g., pre-eclampsia or another indication for birth at term), blood pressure (BP) ≥ 160/110 mmHg until controlled, major fetal anomaly anticipated to require neonatal care unit admission, or participation in another timing of birth trial. Randomisation (1:1 ratio, minimised for key prognostic variables: site, hypertension type, and prior Caesarean) to 'planned early term birth at 38 +0-3 weeks' or 'usual care at term' (revised from 'expectant care until at least 40 +0 weeks', Aug 2022)., Outcomes: Maternal co-primary: composite of 'poor maternal outcome' (severe hypertension, maternal death, or maternal morbidity). Neonatal co-primary: neonatal care unit admission for ≥4 h. Each co-primary is measured until primary hospital discharge or 28 days post-birth (whichever is earlier). Key secondary: Caesarean birth., Analysis: Sample of 1080 participants (540/arm) will detect an 8% reduction in the maternal co-primary (90% power, superiority hypothesis), and give 94% power for a between-group non-inferiority margin of difference of 9% in the neonatal co-primary. Analysis will be by intention-to-treat. Ethics approval has been obtained (NHS Health Research Authority London Fulham Research Ethics Committee, 18/LO/2033)., Conclusions: The study will provide data for women to make informed choices about their care and allow health systems to plan services., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Chronic limb-threatening ischaemia is the severest manifestation of peripheral arterial disease and presents with ischaemic pain at rest or tissue loss (ulceration, gangrene, or both), or both. We compared the effectiveness of a vein bypass first with a best endovascular treatment first revascularisation strategy in terms of preventing major amputation and death in patients with chronic limb threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion., Methods: Bypass versus Angioplasty for Severe Ischaemia of the Leg (BASIL)-2 was an open-label, pragmatic, multicentre, phase 3, randomised trial done at 41 vascular surgery units in the UK (n=39), Sweden (n=1), and Denmark (n=1). Eligible patients were those who presented to hospital-based vascular surgery units with chronic limb-threatening ischaemia due to atherosclerotic disease and who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion. Participants were randomly assigned (1:1) to receive either vein bypass (vein bypass group) or best endovascular treatment (best endovascular treatment group) as their first revascularisation procedure through a secure online randomisation system. Participants were excluded if they had ischaemic pain or tissue loss considered not to be primarily due to atherosclerotic peripheral artery disease. Most vein bypasses used the great saphenous vein and originated from the common or superficial femoral arteries. Most endovascular interventions comprised plain balloon angioplasty with selective use of plain or drug eluting stents. Participants were followed up for a minimum of 2 years. Data were collected locally at participating centres. In England, Wales, and Sweden, centralised databases were used to collect information on amputations and deaths. Data were analysed centrally at the Birmingham Clinical Trials Unit. The primary outcome was amputation-free survival defined as time to first major (above the ankle) amputation or death from any cause measured in the intention-to-treat population. Safety was assessed by monitoring serious adverse events up to 30-days after first revascularisation. The trial is registered with the ISRCTN registry, ISRCTN27728689., Findings: Between July 22, 2014, and Nov 30, 2020, 345 participants (65 [19%] women and 280 [81%] men; median age 72·5 years [62·7-79·3]) with chronic limb-threatening ischaemia were enrolled in the trial and randomly assigned: 172 (50%) to the vein bypass group and 173 (50%) to the best endovascular treatment group. Major amputation or death occurred in 108 (63%) of 172 patients in the vein bypass group and 92 (53%) of 173 patients in the best endovascular treatment group (adjusted hazard ratio [HR] 1·35 [95% CI 1·02-1·80]; p=0·037). 91 (53%) of 172 patients in the vein bypass group and 77 (45%) of 173 patients in the best endovascular treatment group died (adjusted HR 1·37 [95% CI 1·00-1·87]). In both groups the most common causes of morbidity and death, including that occurring within 30 days of their first revascularisation, were cardiovascular (61 deaths in the vein bypass group and 49 in the best endovascular treatment group) and respiratory events (25 deaths in the vein bypass group and 23 in the best endovascular treatment group; number of cardiovascular and respiratory deaths were not mutually exclusive)., Interpretation: In the BASIL-2 trial, a best endovascular treatment first revascularisation strategy was associated with a better amputation-free survival, which was largely driven by fewer deaths in the best endovascular treatment group. These data suggest that more patients with chronic limb-threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion should be considered for a best endovascular treatment first revascularisation strategy., Funding: UK National Institute of Health Research Health Technology Programme., Competing Interests: Declaration of interests AWB reports salary part paid by a National Institute for Health (NIHR) and Care Research Health Technology Assessment (HTA) BASIL-2 grant; payment expert advice and testimony from NHS Resolution, His Majesty's Coroners, National Crime Agency, UK, Scotland, Wales, and Northern Ireland Governments, and various law firms, outside of the submitted work; and payment to his institution and personal honoraria for committee work from NIHR HTA and NICE. GRB reports salary part paid by a NIHR HTA BASIL-2 grant; the BASIL-2 grant also paid mileage for visiting patients in the BASIL-2 trial for follow-up assessments. AD reports honoraria from Boston Scientific, Cordis, Medalliance, and Abbott. KH reports honoraria from Le Maitre and Bayer. STR reports payment for expert testimony from McCollum Consultants; consulting fees from 3M, Bayer, and Avita; speaker fees from 3M, Bayer, Avita, and Terumo; travel support Bayer and Terumo; and is an advisory board member for 3M, Bayer, and Avita. AS reports honoraria and institutional grant support from Shockwave and Abbott and unpaid committee work for NICE. HZ reports an institutional grant from Abbott and honoraria from Limflow, Abbott, Boston Scientific, Bentley, Cook Medical, and Medtronic. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Many people do not regularly participate in physical activity, which may negatively impact their health. Current physical activity guidelines are focused on promoting weekly accumulation of at least 150 min of moderate to vigorous intensity physical activity (MVPA). Whilst revised guidance now recognises the importance of making small changes to physical activity behaviour, guidance still focuses on adults needing to achieve at least 150 min of MVPA per week. An alternative 'whole day' approach that could motivate the public to be more physically active, is a concept called Snacktivity™. Instead of focusing on achieving 150 min per week of physical activity, for example 30 min of MVPA over 5 days, Snacktivity™ encourages the public to achieve this through small, but frequent, 2-5 min 'snacks' of MVPA throughout the whole day., Methods: The primary aim is to undertake a feasibility trial with nested qualitative interviews to assess the feasibility and acceptability of the Snacktivity™ intervention to inform the design of a subsequent phase III randomised trial. A two-arm randomised controlled feasibility trial aiming to recruit 80 inactive adults will be conducted. Recruitment will be from health and community settings and social media. Participants will be individually randomised (1:1 ratio) to receive either the Snacktivity™ intervention or usual care. The intervention will last 12 weeks with assessment of outcomes completed before and after the intervention in all participants. We are interested in whether the Snacktivity™ trial is appealing to participants (assessed by the recruitment rate) and if the Snacktivity™ intervention and trial methods are acceptable to participants (assessed by Snacktivity™/physical activity adherence and retention rates). The intervention will be delivered by health care providers within health care consultations or by researchers. Participants' experiences of the trial and intervention, and health care providers' views of delivering the intervention within health consultations will be explored., Discussion: The development of physical activity interventions that can be delivered at scale are needed. The findings from this study will inform the viability and design of a phase III trial to assess the effectiveness and cost-effectiveness of Snacktivity™ to increase physical activity., Trial Registration: ISRCTN: 64851242., (© 2023. The Author(s).)

Background: Tubal ectopic pregnancies can cause substantial morbidity or even death. Current treatment is with methotrexate or surgery. Methotrexate treatment fails in approximately 30% of women who subsequently require rescue surgery. Gefitinib, an epidermal growth factor receptor inhibitor, might improve the effects of methotrexate. We assessed the efficacy of oral gefitinib with methotrexate, versus methotrexate alone, to treat tubal ectopic pregnancy., Methods: We performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Participants diagnosed with tubal ectopic pregnancy were administered a single dose of intramuscular methotrexate (50 mg/m 2 ) and randomised (1:1 ratio) to 7 days of additional oral gefitinib (250 mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. This trial is registered at the ISRCTN registry, ISCRTN 67795930., Findings: Between Nov 2, 2016, and Oct 6, 2021, 328 participants were allocated to methotrexate and gefitinib (n=165) or methotrexate and placebo (n=163). Three participants in the placebo group withdrew. Surgical intervention occurred in 50 (30%) of 165 participants in the gefitinib group and in 47 (29%) of 160 participants in the placebo group (adjusted risk ratio 1·15, 95% CI 0·85 to 1·58; adjusted risk difference -0·01, 95% CI -0·10 to 0·09; p=0·37). Without surgical intervention, median time to resolution was 28·0 days in the gefitinib group and 28·0 days in the placebo group (subdistribution hazard ratio 1·03, 95% CI 0·75 to 1·40). Serious adverse events occurred in five (3%) of 165 participants in the gefitinib group and in six (4%) of 162 participants in the placebo group. Diarrhoea and rash were more common in the gefitinib group., Interpretation: In women with a tubal ectopic pregnancy, adding oral gefitinib to parenteral methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions., Funding: National Institute of Health Research., Competing Interests: Declaration of interests AWH has received funding from Roche Diagnostics, and honoraria for consultancy for Ferring, Roche, Nordic Pharma, AbbVie, Benevolent AI, and GSK. ST is named on patents relating to use of epidermal growth factor receptor inhibitors to treat ectopic pregnancy and is on an advisory board for the Menzies Medical Research Institute. WCD has received honoraria from Merck and Guerbet and research funding from Galvani Biosciences. BWM reports consultancy for ObsEva and Merck and travel support from Merck. LHRW has received grant funding from National Institute of Health Research (NIHR) Health Technology Assessment (HTA) and Roche Diagnostics. TH has received honoraria from Olympus for teaching. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Miscarriage in the second trimester and preterm birth are significant global problems. Vaginal cervical cerclage is performed to prevent pregnancy loss and preterm birth. We aimed to determine the effectiveness of a monofilament suture thread compared with braided suture thread on pregnancy loss rates in women undergoing a cervical cerclage., Methods: C-STICH was a pragmatic, randomised, controlled, superiority trial done at 75 obstetric units in the UK. Women with a singleton pregnancy who received a vaginal cervical cerclage due to a history of pregnancy loss or premature birth, or if indicated by ultrasound, were centrally randomised (1:1) using minimisation to receive a monofilament suture or braided suture thread for their cervical cerclage. Women and outcome assessors were masked to allocation as far as possible. The primary outcome was pregnancy loss, defined as miscarriage, stillbirth, or neonatal death in the first week of life, analysed in the intention-to-treat population (ie, all women who were randomly assigned). Safety was also assessed in the intention-to-treat population. The trial was registered with ISRCTN, ISRCTN15373349., Findings: Between Aug 21, 2015, and Jan 28, 2021, 2049 women were randomly assigned to receive a monofilament suture (n=1025) or braided suture (n=1024). The primary outcome was ascertained in 1003 women in the monofilament suture group and 993 women in the braided suture group. Pregnancy loss occurred in 80 (8·0%) of 1003 women in the monofilament suture group and 75 (7·6%) of 993 women in the braided suture group (adjusted risk ratio 1·05 [95% CI 0·79 to 1·40]; adjusted risk difference 0·002 [95% CI -0·02 to 0·03])., Interpretation: Monofilament suture did not reduce rate of pregnancy loss when compared with a braided suture. Clinicians should use the results of this trial to facilitate discussions around the choice of suture thread to optimise outcomes., Funding: National Institute of Health Research Health Technology Assessment Programme., Competing Interests: Declaration of interests VHM is a National Institute for Health and Care Research (NIHR) clinical lecturer and has received an honorarium from Hologic. JD reports membership of the NIHR Clinical Trials Unit Standing Advisory Committee (May 1, 2016, to Sept 30, 2023). JEN is a member of the Health Technology Assessment (HTA) Maternal, Neonatal and Child Health Panel; receives funding from NIHR Efficacy and Mechanism Evaluation programme; participates in a Data Monitoring and Ethics Committee for GlaxoSmithKline; and is a paid consultant for DILAFOR. RKM receives funding from NIHR HTA and programme grants for Applied Health Research schemes; is a steering committee member of the Saving Babies Lives Care Bundle; and a paid Clinical Advisory Board member for Surepulse (a company designing neonatal monitors). All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: As a pragmatic randomised timing-of-birth trial, WILL adapted its trial procedures in response to the COVID-19 pandemic. These are reviewed here to inform post-pandemic trial methodology., Methods: The trial (internal pilot) paused in March 2020, re-opened in July 2020, and is currently recruiting in 37 UK NHS consultant-led maternity units. We evaluated pandemic adaptations made to WILL processes and surveyed sites for their views of these changes (20 sites, videoconference)., Results: Despite 88% of sites favouring an electronic investigator site file (ISF), information technology requirements and clinical trial unit (CTU) operating procedures mandated the ongoing use of paper ISFs; site start-up delays resulted from restricted access to the CTU. Site initiation visits (SIVs) were conducted remotely; 50% of sites preferred remote SIVs and 44% felt that it was trial-dependent, while few preferred SIVs in-person as standard procedure. The Central team felt remote SIVs provided scheduling and attendance flexibility (for sites and trial staff), the option of recording discussions for missing or future staff, improved efficiency by having multiple sites attend, and time and cost savings; the negative impact on rapport-building and interaction was partially mitigated over time with more familiarity with technology and new ways-of-working. Two methods of remote consent were developed and used by 30/37 sites and for 54/156 recruits. Most (86%) sites using remote consenting felt it improved recruitment. For remote data monitoring (5 sites), advantages were primarily for the monitor (e.g. flexibility, no time constraints, reduced cost), and disadvantages primarily for the sites (e.g. document and access preparation, attendance at a follow-up meeting), but 81% of sites desired having the option of remote monitoring post-pandemic., Conclusions: COVID adaptations to WILL trial processes improved the flexibility of trial delivery, for Central and site staff, and participants. Flexibility to use these strategies should be retained post-pandemic., Trial Registration: ISRCTN77258279. Registered on 05 December 2018., (© 2022. The Author(s).)

Background: Many people do not meet the recommended health guidance of participation in a minimum of 150-300 min of moderate intensity physical activity per week, often promoted as at least 30 min of physical activity on 5 days of the week. This is concerning and highlights the importance of finding innovative ways to help people to be physically active each day. Snacktivity™ is a novel approach that aims to encourage people to do small, 2-5 min bouts of physical activity 'snacks' throughout the whole day, such that they achieve at least 150 min of moderate intensity activity per week. However, before it can be recommended, there is a need to explore whether the concept is acceptable to the public., Methods: A survey to assess the views of the public about Snacktivity™ was distributed to adult patients registered at six general practices in the West Midlands, UK and to health care employees in the same region., Results: A total of 5989 surveys were sent to patients, of which 558 were returned (9.3%). A further 166 surveys were completed by health care employees. A total of 85% of respondents liked the Snacktivity™ concept. The flexibility of the approach was highly rated. A high proportion of participants (61%) reported that the ability to self-monitor their behaviour would help them to do Snacktivity™ throughout their day. Physically inactive participants perceived that Snacktivity™ would help to increase their physical activity, more than those who were physically active (OR = 0.41, 95% CI: 0.25-0.67). Approximately 90% of respondents perceived that Snacktivity™ was easy to do on a non-working day compared to 60% on a working day. Aerobic activity 'snacks' were preferred to those which were strength based., Conclusions: The Snacktivity™ approach to promoting physical activity was viewed positively by the public and interventions to test the merits of such an approach now need to be developed and tested in a variety of everyday contexts., (© 2022. The Author(s).)