BACKGROUND:Vaginal cervical cerclage and progesterone are established treatments for prevention of pregnancy loss and prematurity. There is limited data to assess the effect of these treatments in combination. The objective of this study was to investigate the association between progesterone and no progesterone treatment on pregnancy outcomes in women at high risk of preterm birth who had received a vaginal cervical cerclage. METHODS AND FINDINGS:This is a secondary post-hoc analysis of women recruited to the C-STICH randomised controlled trial, which recruited in 75 obstetric units in the UK between 2015 and 2021. In the C-STICH trial, women with a singleton pregnancy, receiving a vaginal cervical cerclage due to a history of pregnancy loss or premature birth, or if indicated by ultrasound, were randomised to cerclage with braided or monofilament suture, with a primary outcome of pregnancy loss, defined as miscarriage, stillbirth, or neonatal death in the first week of life. In this secondary analysis, the primary outcome was pregnancy loss, defined as miscarriage and perinatal mortality, including any stillbirth or neonatal death in the first week of life. Secondary maternal outcomes included miscarriage and previable neonatal death; stillbirth; gestational age at delivery; preterm pre labour rupture of membranes, and sepsis. Secondary neonatal outcomes included early/late neonatal death and sepsis. For each outcome, regression models were fitted adjusting for prespecified prognostic variables. From the 2,048 women recruited to C-STICH, 1943 (95%) women had a vaginal cerclage placed and available progesterone data. Of these, 834 (43%) women received progesterone and 1,109 (57%) did not receive progesterone. In women with primary outcome data available, in our predefined analysis pregnancy loss occurred in 49 (5.9%) of 832 women who received progesterone and 91 (8.3%) of 1,103 women who did not receive progesterone (adjusted* risk ratio 0.70 (95% confidence interval (CI) [0.50, 0.99]); adjusted risk difference -0.02 (95% CI [-0.04, -0.001], *adjusted for indication, obstetric history, surgical technique, and maternal age). Further exploratory analysis excluding women who had termination of pregnancy for foetal anomaly demonstrated a nonsignificant reduction in the risk of pregnancy loss. Key limitations of this study include a nonrandomised trial design and unknown confounding relating to variation in progesterone use. CONCLUSION:In women with a vaginal cervical cerclage and concomitant progesterone there appears to be an association with a reduced risk of pregnancy loss. This combination therapy may be an important opportunity to further reduce the risk of pregnancy loss in this high-risk cohort.

Background:For women with chronic or gestational hypertension who remain well, early term birth (at 37-38 weeks' gestation) may reduce maternal complications, caesareans and stillbirths, but it may increase neonatal morbidity compared with expectant care. Expectant care may increase costs. There are no high-quality data to guide care, which currently involves maternal-fetal surveillance and intervention for maternal or fetal compromise, which may be rapid or unexpected. Objective:To investigate optimal timing of birth for women with chronic or gestational hypertension who reach term and remain well. Design:Pragmatic, unmasked, multicentre randomised trial with a health economic analysis. Setting:Fifty United Kingdom hospitals. Participants: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), blood pressure ≥ 160/110 mmHg until controlled, major fetal anomaly anticipated to require neonatal care unit admission or participation in another timed birth trial. Interventions:Planned early term birth at 38+0-3 weeks' (intervention) or 'usual care at term' (control, revised from 'expectant care until at least 40+0 weeks', August 2022). Main outcome measures:Maternal coprimary: composite of 'poor maternal outcome' (severe hypertension, maternal death or maternal morbidity and superiority hypothesis). Neonatal coprimary: neonatal care unit admission ≥ 4 hours (non-inferiority hypothesis). Each coprimary is measured until primary hospital discharge or 28 days post birth (whichever is earlier). Key secondary: caesarean birth. Randomisation:1 : 1 ratio, minimised for key prognostic variables: site, hypertension type and prior caesarean. Blinding:It was not possible to mask care providers or participants to the intervention. For the coprimary maternal outcome, there was local site principal investigator/delegate sign-off based on review, masked to allocated group, of primary case notes. Results:From 2019 to 2022, 403 participants were randomised (37% of target 1080) to intervention (n = 201) or control (n = 202). The funder stopped the trial during the coronavirus disease discovered in 2019 pandemic for delayed recruitment. In the intervention (vs. control) group, birth was a median of 0.9 weeks earlier (38.4, interquartile range 38.3-38.6 vs. 39.3, interquartile range 38.7-39.9 weeks). There was no evidence of a difference in 'poor maternal outcome' (13% vs. 12%, respectively; adjusted risk ratio 1.16, 95% confidence interval 0.72 to 1.87). For 'neonatal care unit admission ≥ 4 hours', the intervention was considered to be non-inferior to control, as the adjusted risk difference, 95% confidence interval upper bound did not cross the 8% pre-specified non-inferiority margin (7% vs. 7%, respectively; adjusted risk difference 0.003, 95% confidence interval -0.05 to +0.06), although event rates were lower than estimated. There was no evidence of a difference in caesarean (29% vs. 36%, respectively; adjusted risk ratio 0.81, 95% confidence interval 0.61 to 1.08). Limitations:Recruitment was 37% of the anticipated sample size (as above). Conclusions:Despite being unable to recruit to target in this study, we observed that most women with chronic or gestational hypertension required labour induction and planned birth at 380-3 weeks (vs. usual care), which resulted in birth an average of 6 days earlier and there were no differences in poor maternal outcome or neonatal morbidity. Our findings provide reassurance about planned birth at 380-3 weeks as a clinical option for these women. Future work:An individual participant data meta-analysis is planned to address whether the intervention (vs. control) reduces caesarean; low adverse event rates would make unfeasible mounting another randomised trial. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/167/123.

Objective To determine which primary endovascular revascularisation strategy represents the most clinically effective treatment for patients with chronic limb threatening ischaemia who require endovascular femoro-popliteal, with or without infra-popliteal, revascularisation. Design Three arm, open label, pragmatic, multicentre, randomised, phase 3 superiority trial (BASIL-3). Setting 35 UK NHS vascular units. Participants Patients with chronic limb threatening ischaemia who required endovascular femoro-popliteal, with or without infra-popliteal, revascularisation. Interventions Participants were randomly assigned (1:1:1) to femoro-popliteal plain balloon angioplasty with or without bare metal stenting (PBA±BMS), drug coated balloon angioplasty with or without bare metal stenting (DCBA±BMS), or drug eluting stenting (DES) as their first revascularisation strategy. Main outcome measures The primary outcome was amputation free survival defined as time to first major amputation or death from any cause. Secondary outcomes included the composite components of the primary outcome, major adverse limb events, major adverse cardiac events, and other prespecified clinical and patient reported outcome measures. Serious adverse events were collected up to 30 days after the first revascularisation procedure. Results Between 29 January 2016 and 31 August 2021, 481 participants were randomised (167 (35%) women, mean age 71.8 years (standard deviation 10.8)). Major amputation or death occurred in 106 of 160 (66%) participants in the PBA±BMS group, 97 of 161 (60%) in the DCBA±BMS group, and 93 of 159 (58%) in the DES group (adjusted hazard ratios: PBA±BMS v DCBA±BMS: 0.84, 97.5% confidence interval 0.61 to 1.16, P=0.22; PBA±BMS v DES: 0.83, 0.60 to 1.15, P=0.20). No differences in serious adverse events were reported between the groups. Conclusions Neither DCBA±BMS nor DES conferred significant clinical benefit over PBA±BMS in the femoro-popliteal segment in patients with chronic limb threatening ischaemia undergoing endovascular femoro-popliteal, with or without infra-popliteal, revascularisation. Trial registration ISRCTN registry ISRCTN14469736

BACKGROUND:Procedural management of early pregnancy loss (EPL) involves removing any residual pregnancy tissue from the uterus. Clinical evidence and guidance are clear that antibiotic treatment is needed for women experiencing EPL, with signs and symptoms of infection. However, it is less clear whether prophylactic antibiotics are routinely required during procedural management in those without features of infection. OBJECTIVES:To evaluate the effectiveness of routine antibiotic prophylaxis for women undergoing uterine evacuation procedures to manage early pregnancy loss. SEARCH METHODS:We searched the Cochrane Fertility Regulation Review Group trials register, CENTRAL, MEDLINE, Embase, Global Health (Ovid), Scopus (conference abstracts only), and grey literature in October 2023. We checked references and contacted study authors and experts in the field to identify additional studies. SELECTION CRITERIA:We included randomised controlled trials comparing prophylactic antibiotics with placebo or no treatment. Trials with a cluster-randomised design and trials published only in abstract form were also eligible for inclusion. We included all types of EPL managed with surgical uterine evacuation. There was no gestational age limit. We excluded women with signs and symptoms of infection. DATA COLLECTION AND ANALYSIS:Two review authors independently assessed trials for inclusion and risk of bias, extracted and checked data for accuracy, and assessed the certainty of evidence using the GRADE approach. We contacted the authors of the ongoing trial for additional information. MAIN RESULTS:We included six RCTs with a total of 4371 participants undergoing uterine evacuation procedures to manage EPL. Prophylactic antibiotics may have little or no effect on uterine infection after uterine evacuation for EPL compared with placebo or no treatment, but this evidence was uncertain (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.47 to 1.28; I² = 50%; 6 studies, 4371 participants; low-certainty evidence).   Sensitivity analysis of three studies including 3737 participants (85% of total participants) showed that when only studies with low risk of bias were meta-analysed, the effect was larger and of high certainty, resulting in a 43% reduction in the risk of developing a uterine infection (RR 0.57, 95% CI 0.37 to 0.86; I² = 0%; 3 studies, 3737 participants; high-certainty evidence). Both the overall estimate and the sensitivity analysis limited to studies with low risk of bias were consistent with a reduction in uterine infection with prophylactic antibiotics. A single study reported on adverse effects. Prophylactic antibiotics likely result in little or no difference in the risk of vomiting (RR 1.20, 95% CI 0.61 to 2.38; 1 study, 3404 participants; moderate-certainty evidence), and likely result in little or no difference in the risk of having diarrhoea (RR 0.92, 95% CI 0.51 to 1.65; 1 study, 3404 participants; moderate-certainty evidence). Prophylactic antibiotics may increase the risk of allergy (RR 3.01, 95% CI 0.12 to 73.76; 1 study, 3404 participants; low-certainty evidence); the study reported no cases of anaphylaxis (very low-certainty evidence). Prophylactic antibiotics may reduce the need for antibiotic treatment to treat infection, but the evidence is very uncertain (RR 0.94, 95% CI 0.54 to 1.64; I2 = 63%; 3 studies, 3574 participants; very low-certainty evidence). Meta-analysis of three studies also found that prophylactic antibiotics may reduce hospitalisation for treatment of infection, but the effect was very uncertain (RR 0.76, 95% CI 0.40 to 1.46; I² = 0%; 3 studies, 3859 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS:When all studies were considered, the evidence suggested that routine antibiotic prophylaxis may reduce uterine infection amongst women undergoing uterine evacuation procedures to manage early pregnancy loss (EPL), but the evidence is of low certainty. It is important to note that the quality of the evidence included was seriously affected by poor follow-up and high non-compliance with antibiotic prophylaxis. A sensitivity analysis based on three trials assessed to have low risk of bias (85% of the total participants), demonstrated a larger effect size with high certainty, resulting in a 43% reduction in the risk of uterine infection rates with antibiotic prophylaxis. Prophylactic antibiotics may reduce hospitalisation for treatment of infection, and may reduce the need for a course of antibiotics to treat infection after uterine evacuation procedures to treat EPL, but this evidence is very uncertain. Data were limited and uncertain with regard to potential adverse effects, such as vomiting, diarrhoea, allergy, and anaphylaxis.

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.

IntroductionIn liver cirrhosis, acute variceal bleeding (AVB) is associated with a 1-year mortality rate of up to 40%. Data on early or pre-emptive transjugular intrahepatic portosystemic stent–shunt (TIPSS) in AVB is inconclusive and may not reflect current management strategies. Randomised controlled trial of EArly transjugular intrahepatiC porTosystemic stent–shunt in AVB (REACT-AVB) aims to investigate the clinical and cost-effectiveness of early TIPSS in patients with cirrhosis and AVB after initial bleeding control.Methods and analysisREACT-AVB is a multicentre, randomised controlled, open-label, superiority, two-arm, parallel-group trial with an internal pilot. The two interventions allocated randomly 1:1 are early TIPSS within 4 days of diagnostic endoscopy or secondary prophylaxis with endoscopic therapy in combination with non-selective beta blockers. Patients aged ≥18 years with cirrhosis and Child-Pugh Score 7–13 presenting with AVB with endoscopic haemostasis are eligible for inclusion. The primary outcome is transplant-free survival at 1 year post randomisation. Secondary endpoints include transplant-free survival at 6 weeks, rebleeding, serious adverse events, other complications of cirrhosis, Child-Pugh and Model For End-Stage Liver Disease (MELD) scores at 6 and 12 months, health-related quality of life, use of healthcare resources, cost-effectiveness and use of cross-over therapies. The sample size is 294 patients over a 4-year recruitment period, across 30 hospitals in the UK.Ethics and disseminationResearch ethics committee of National Health Service has approved REACT-AVB (reference number: 23/WM/0085). The results will be submitted for publication in a peer-reviewed journal. A lay summary will also be emailed or posted to participants before publication.Trial registration numberISRCTN85274829; protocol version 3.0, 1 July 2023.

Background Shiga-toxin-producing Escherichia coli haemolytic uraemic syndrome affects ~100 United Kingdom children each year. Around half need dialysis, a quarter develop serious complications with long-term consequences and ~3% die. No effective intervention is known; however, some studies report eculizumab, effective in atypical haemolytic uraemic syndrome, may be effective. Objectives To determine whether the severity of Shiga-toxin-producing Escherichia coli haemolytic uraemic syndrome is less in those given eculizumab. Design Randomised, double-blind, placebo-controlled, parallel-group trial with internal pilot phase and nested mechanistic laboratory studies. Setting Paediatric nephrology units in 12 United Kingdom hospitals. Participants Children aged 6 months to < 19 years weighing ≥ 5 kg, with presumed Shiga-toxin-producing Escherichia coli haemolytic uraemic syndrome, including ‘injury’ or ‘failure’ category of the acute kidney injury paediatric risk/injury/failure/loss/end criteria. Intervention Participants were randomised in a 1 : 1 ratio to receive intravenous eculizumab or placebo on day 1 and 8. All received meningococcal vaccination and prophylactic antibiotics. Main outcome measures The primary outcome measure was a multidomain clinical severity score, reflecting morbidity until day 60. Secondary outcome measures included survival, duration of renal replacement therapy, persistent neurological defect (day 60) and presence of chronic kidney disease at 1 year. Mechanistic studies assessed complement activation and vascular endothelial growth factor profiles in plasma ± urine samples. In vitro cell co-culture work assessed the effect of Shiga toxin on endothelial cells. Results Thirty-six participants from 10 sites were randomised: 17 to eculizumab and 19 to placebo. The target sample size was 134 participants – recruitment stopped early due to low recruitment (factors included reduced incidence and limited out-of-hours research infrastructure) and the COVID-19 pandemic. The mean clinical severity score for participants randomised to eculizumab was 11.5 (standard deviation 8.4) compared to 14.6 (standard deviation 7.7) for participants randomised to placebo (adjusted mean difference: −2.5, 95% confidence interval −7.8 to 2.8, p = 0.3). Five participants (three eculizumab, two placebo) experienced an adverse event; there were seven serious adverse events in six participants (five eculizumab, one placebo). Urinary complement factor H and vascular endothelial growth factor levels were high initially and subsequently normalised. Shiga toxin caused a podocyte-dependent decrease in endothelial cell factor H levels. Conclusions and limitations There was no significant difference in mean clinical severity score between eculizumab and placebo groups – since the trial was underpowered, this cannot be interpreted as evidence of no effect. No significant safety concerns were observed. With further validation, the Eculizumab in Shiga-toxin-producing Escherichia coli Haemolytic Uraemic Syndrome clinical severity score may be an outcome measure for future trials. Our results imply that Shiga toxin causes complement-dependent glomerular endothelial cell injury through its action on podocytes and subsequent cellular cross-talk. Future work We will continue to investigate cross talk between podocytes and endothelial cells after exposure to Shiga toxin and further develop plasma/urine biomarkers for diagnosis of Shiga-toxin-producing Escherichia coli haemolytic uraemic syndrome. Trial registration This trial is registered as EudraCT-2016-000997-39 and ISRCTN89553116. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 14/48/43) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 11. See the NIHR Funding and Awards website for further award information. Plain language summary Why did we do this study? Annually, approximately 100 United Kingdom children develop Shiga-toxin-producing Escherichia coli haemolytic uraemic syndrome after infection with a diarrhoea-causing bug. The bug makes a toxin (Shiga toxin) that damages blood vessels, especially in the kidneys. Half need dialysis (artificial kidney support), about a quarter suffer fits or a stroke and about 3% die. Most children fully recover, but about a quarter suffer permanent kidney or brain damage. There are no known effective treatments. Eculizumab, a medicine which blocks part of the immune system called complement, may work. What was the question? Does eculizumab reduce the severity of Shiga-toxin-producing Escherichia coli haemolytic uraemic syndrome? What did we do? We planned to recruit 134 children, but difficulties with recruitment and the COVID-19 pandemic meant the study was stopped early after 36 children had been recruited; 17 received eculizumab, 19 received a dummy medicine (placebo). We compared children in each group using a score that measured how their kidneys and other organs were affected. We studied samples of their blood and urine, and also how Shiga toxin damages kidney cells in the laboratory. What did we find? The severity of illness was similar in both groups; however, because we only studied a small number of children, we cannot be sure this means that eculizumab does not work. Eculizumab appeared to be safe in this condition. In the blood and urine samples, we saw evidence that complement is involved in the illness. We also discovered a new way that Shiga toxin damages kidney cells. What does this mean? We have been unable to show whether eculizumab is a worthwhile treatment for children with this condition. However, we have learnt lots about how the illness is caused and hope these results can be combined with other studies to give us a clearer answer. Scientific summary Background Shiga-toxin-producing Escherichia coli haemolytic uraemic syndrome affects around 100 UK children each year, following gastrointestinal infection with Shiga-toxin-producing E. coli. Around half of affected children will need dialysis, about a quarter develop serious complications with long-term consequences and about 3% die. All patients require long-term follow-up because of the risk of developing chronic kidney disease (CKD). No intervention has definitively been shown to reduce morbidity or mortality in this condition, and therefore treatment is supportive. Case reports and case series suggest that eculizumab (Soliris®, Alexion Pharmaceuticals, Boston, MA), an inhibitor of the complement system and an effective treatment for the related condition, atypical haemolytic uraemic syndrome, may be effective in this condition. Until very recently, there were no published data regarding the efficacy and safety of eculizumab in Shiga-toxin-producing E. coli haemolytic uraemic syndrome, and yet despite this its use has risen globally. A recent randomised phase 3 clinical trial reported comparison of eculizumab with placebo in 100 children with Shiga-toxin-producing E. coli haemolytic uraemic syndrome (Garnier A, Brochard K, Kwon T, Sellier-Leclerc A-L, Lahoche A, Allain Launay E, et al. Efficacy and safety of Eculizumab in pediatric patients affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: a randomized, placebo-controlled trial. J Am Soc Nephrol 2023;34:1561–73). Patients with severe multi-organ involvement were excluded. Four patients in the placebo group were withdrawn and subsequently received eculizumab. There was no difference between treatment groups in the proportion of children who required renal replacement therapy 48 hours after randomisation, In addition, no differences between groups were seen in the secondary outcome measures of extra-renal manifestations, duration of hospitalisation and mortality. During follow up, there was a slight difference in the proportion who exhibited renal sequelae at 12 months post randomisation (20 patients in the eculizumab group (43.48%) and 29 patients (64.44%) in the placebo group (P = 0.04). The authors concluded that eculizumab seemed to have no impact on the course of acute kidney injury and interpreted the 12-month follow-up data with caution. No data have been published which include the role of eculizumab in patients with severe manifestations of disease in a controlled setting. Objectives of the main trial The Eculizumab in Shiga-toxin-producing Escherichia coli Haemolytic Uraemic Syndrome (ECUSTEC) trial was designed to test the hypothesis that treatment with eculizumab reduces the severity of Shiga-toxin-producing E. coli haemolytic uraemic syndrome in children aged 6 months–< 19 years. We also wanted to assess the safety of eculizumab and test the hypothesis that treatment with eculizumab reduces the incidence of CKD following Shiga-toxin-producing E. coli haemolytic uraemic syndrome. Objectives of the mechanistic substudies The mechanistic component of the trial had the following objectives: to investigate the time course of systemic complement activation in Shiga-toxin-producing E. coli haemolytic uraemic syndrome and its relation to the severity of disease to determine whether thrombotic microangiopathy (TMA) in Shiga-toxin-producing E. coli haemolytic uraemic syndrome occurs via a Shiga-toxin-mediated reduction in podocyte vascular endothelial growth factor (VEGF) production, leading to loss of complement regulation to test whether neutrophils derived from patients with acute Shiga-toxin-producing E. coli haemolytic uraemic syndrome deliver Shiga toxin to podocytes to assess whether any genetic variations in patients with Shiga-toxin-producing E. coli haemolytic uraemic syndrome point to novel pathogenic mechanisms. Methods Design The trial was a randomised, double-blind, placebo-controlled, parallel-group trial of two doses of eculizumab in children (aged 6 months–< 19 years) with Shiga-toxin-producing E. coli Haemolytic Uraemic Syndrome. The trial had an internal pilot phase and included nested mechanistic laboratory studies and a cost-effectiveness evaluation, although the latter was not undertaken following the trial being stopped early. The mechanistic substudies were optional; all participants in the main trial were offered the opportunity to participate in the substudies, which involved providing blood and urine samples over the first 30 days of the trial. Participant blood and urine samples were used to explore the evidence for, and time course of, complement activation in this condition. Using both patient samples and an in vitro cell co-culture model, evidence was sought to support the hypothesis that Shiga toxin causes a glomerular TMA as a consequence of its effect on podocyte VEGF production. This included measurement of patient urine and plasma complement factor H (CFH) and VEGF and plasma complement activation products [by both enzyme-linked immunosorbent assay (ELISA) and a novel degradomics technique]. In the co-culture experiments, glomerular endothelial cells were exposed to Shiga toxin in the presence and absence of podocytes. Setting The trial was conducted in 12 sites in NHS hospital settings across the UK with the support of 88 Patient Identification Centres. Participants Informed consent was sought from parents/guardians of eligible children (those aged 6 months–< 19 years weighing ≥ 5 kg, with a clinical diagnosis of Shiga-toxin-producing E. coli haemolytic uraemic syndrome, including acute kidney injury (AKI) equivalent to the ‘injury’ or ‘failure’ category of the paediatric risk/injury/failure/loss/end criteria). Eligible young people aged 16–18 years provided their own consent for participation in the trial, with assent from younger children if appropriate (according to age). Screening and randomisation Screening began as soon as possible after a diagnosis of Shiga-toxin-producing E. coli haemolytic uraemic syndrome was suspected. Once eligibility was confirmed and informed consent obtained, the participants were commenced on prophylactic antibiotics, and unless contra-indicated or already administered, participants were also vaccinated against meningococcal infection. Participants were then randomised into the ECUSTEC trial via a secure online central randomisation system. Participants were randomised at the level of the individual in a 1 : 1 ratio to either eculizumab or placebo, which was commenced as soon as possible after randomisation. A minimisation algorithm was used to ensure balance in the treatment allocation over the following variables: centre, severity of AKI and hydration status. To avoid predictability in the randomisation, a random element was included in the minimisation algorithm, so that each patient had a probability (unspecified here), of being randomised to the opposite treatment that they would have otherwise received. Intervention Each participant received two intravenous infusion doses of either eculizumab (dose according to first two doses of induction regimen for atypical haemolytic uraemic syndrome) or placebo. The first dose was given as soon as possible after randomisation (designated day 1), with the second dose given 7 days later (i.e. on day 8). They also received vaccination against meningococcal disease and an 8-week course of antibiotic prophylaxis. The participants, parents/guardians, clinical staff and research teams were blind to randomised treatment allocation throughout the study. Outcome measures Primary The ECUSTEC clinical severity score (CSS), a purpose-developed, multidomain score comprising severity of AKI and extrarenal events. A single score is assigned at day 60 to reflect cumulative morbidity up until that point. The score ranges from 1 to 69 with higher scores indicating greater disease severity. Secondary Overall survival. Duration of renal replacement therapy (days). Duration of thrombocytopenia (number of consecutive days until platelet count > 150 × 109/l). Duration of haemolysis (number of days until lactate dehydrogenase within local centre reference range). Number of packed red blood cell transfusions required and volume (ml/kg). Duration markers of inflammation present (number of days until neutrophil cell count and C-reactive protein are in normal range for that centre). Persistent neurological defect at day 60 measured by structured expert assessment to include central nervous system examination, vision, hearing and neuropsychological assessment. CKD at 52 weeks (a composite end point of the presence of hypertension, albuminuria or estimated glomerular filtration rate (eGFR) < 90 ml/minute/1.73 m2 at 52 weeks). eGFR measurement using a centralised cystatin C assay at 52 weeks. Mechanistic studies Urine CFH levels. Urine VEGF levels. Presence of urine markers of podocyte damage (nephrin and Wilms tumour-1). Plasma VEGF and factor H levels. Plasma complement activation products (Bb, C3a, C4a and sC5b9 by ELISA and C3 and C4 activation markers by degradomics). Glomerular endothelial surface levels of factor H and C3d (a marker of complement activation) in a co-culture models of human conditionally immortalised podocytes and glomerular endothelial cells exposed to Shiga toxin. Whole exome sequencing and serum anti-factor H antibody levels. Results The target sample size was 134 participants, but recruitment was stopped early due to low recruitment and the impact of the COVID-19 pandemic. At the point the trial was stopped, 108 children had been screened for participation, of whom 87 were deemed eligible to participate. Thirty-six children were consented and randomised; 17 were randomised to eculizumab and 19 were randomised to placebo. One participant withdrew from the trial and one participant died. The majority of baseline data of the participants were comparable across the two groups; however, the participants in the placebo group were slightly older and consequently heavier than those in the eculizumab group. Reasons for slow recruitment included a fall in the incidence of Shiga-toxin-producing E. coli haemolytic uraemic syndrome during the trial period (up to a 37% reduction) and a lack of out-of-hours infrastructure for undertaking acute interventional clinical trials in children. The mean CSS at day 60 for participants randomised to eculizumab was 11.5 [standard deviation (SD) 8.4] compared to 14.6 (SD 7.7) for participants randomised to placebo [adjusted mean difference: −2.5, 95% confidence interval (CI) −7.8 to 2.8, p = 0.3]. Five participants (three eculizumab, two placebo) experienced an adverse event, and there were seven serious adverse events (SAEs) in six participants (five eculizumab, one placebo). None of the SAEs were considered related to the trial treatment. Mechanistic substudies Of the 36 participants recruited to the main trial, 32 consented to take part in the mechanistic studies and provided blood and/or urine samples. In anuric patients, only blood samples were collected. Urine factor H and vascular endothelial growth factor levels in serial samples The highest urine factor H levels were at day 1 (150 ng/ml), diminishing by day 4 (30 ng/ml), and completely normalising by day 30 (undetectable). The highest urine VEGF levels were at day 1 (average 1300 ng/ml) and by day 30 the levels were below 20 ng/ml. Markers of podocyte damage Western blots of urine cell pellets showed acute podocyte loss during active disease, which recovered by day 8. Plasma factor H and vascular endothelial growth factor levels No difference was seen for plasma levels of either factor H or VEGF at day 1 or day 30. Plasma degradomics analysis In a sample of five patients, N-termini consistent with complement C3 and C4 activation were much more abundant at day 1 compared with day 3. In vitro cell co-culture In response to Shiga toxin, there was a reduction in glomerular endothelial factor H levels, accompanied by evidence of complement activation (increased C3d levels) and this was critically dependent on the presence of podocytes. Shiga toxin had no effect when added to endothelial cells alone. Plasma complement activation products Mean plasma levels of Bb were elevated in both groups at baseline (4.38 mcg/ml in the eculizumab group and 10.38 mcg/ml in the placebo group, normal range 0.48–1.62 mcg/ml). They were also elevated at day 2 (5.91 mcg/ml in the eculizumab group and 4.09 mcg/ml in the placebo group) and day 4 (4.90 mcg/ml in the eculizumab group and 3.16 mcg/ml in the placebo group). At day 6 and day 8, Bb levels remained elevated in the placebo group (6.21 and 3.47 mcg/ml respectively) but were normal in the eculizumab group. In both groups, mean Bb levels were in the normal range at day 30. Mean plasma levels of C3a were elevated in both groups at baseline and at days 2 and 4. At days 6 and 8, mean levels remained elevated in the placebo group while mean levels in the eculizumab group were in the normal range. Levels were in the normal range for both groups by day 30. Mean plasma levels of C4a were elevated at all time points in both groups but fell significantly at day 30. Mean levels were 3852, 3026, 3423, 3067, 3425 and 1623 ng/ml at days 1, 2, 4, 6, 8 and 30 in the eculizumab group (normal range 110–699 ng/ml) and 3970, 3573, 2673, 4348, 2844 and 1992 ng/ml at the same respective time points in the placebo group. Mean plasma levels of sC5b9 were normal in both groups at all time points with the exception of day 4 and day 6 in the placebo group, which were elevated (487 and 514 ng/ml respectively, normal range 95–467 ng/ml). In the placebo group, a linear relationship was not established between CSS and baseline Bb (r = 0.43, p = 0.2); C3a (r = −0.16, p = 0.7); C4a (r = 0.15, p = 0.7) or sC5b9 (r = −0.17, p = 0.7). Similarly, a linear relationship was not established between CSS and the maximum value of Bb (r = 0.45, p = 0.1); C3a (r = 0.15, p = 0.6); C4a (r = 0.23, p = 0.4) or sC5b9 (r = −0.22, p = 0.5). Delivery of Shiga toxin to podocytes from patient-derived neutrophils Insufficient patient samples were obtained to complete this part of the work. Genetic variations in patients with Shiga-toxin-producing Escherichia coli haemolytic uraemic syndrome Data from whole exome sequencing have been obtained and analysis is ongoing. Conclusions In children with Shiga-toxin-producing E. coli haemolytic uraemic syndrome, the mean CSSs at day 60 were similar between those randomised to eculizumab and those randomised to placebo. However, since the trial was stopped early and did not recruit to the planned sample size, this cannot be interpreted as evidence of no effect. In order to deliver successful clinical trials of investigational medicinal products in acutely unwell children, a review of out-of-hours paediatric research infrastructure may be required. In the mechanistic substudies, we have established that urine factor H and VEGF levels are sensitive measures of early disease activity, and have demonstrated complement activation in patient serum using both ELISA and sophisticated proteomics technology. Urine factor H and VEGF levels and plasma degradomics for C3 and C4 proteins could all be further explored as new biomarkers of acute Shiga-toxin-producing E. coli haemolytic uraemic syndrome. Our co-culture cell work has demonstrated that podocyte cross-talk is responsible for factor H and complement activation levels on endothelial cells. Collectively this strongly supports the mechanistic hypothesis of a complement-mediated disease driven via the podocyte as the target cell. Trial registration This trial is registered as EudraCT2016-000997-39 and ISRCTN89553116. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 14/48/43) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 11. 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.

BACKGROUND:Chronic or gestational hypertension complicates approximately 7% of pregnancies, half of which reach 37 weeks' gestation. Early term birth (at 37 to 38 weeks) may reduce maternal complications, cesareans, stillbirths, and costs but may increase neonatal morbidity. In the WILL Trial (When to Induce Labour to Limit risk in pregnancy hypertension), we aimed to establish optimal timing of birth for women with chronic or gestational hypertension who reach term and remain well. METHODS AND FINDINGS:This 50-centre, open-label, randomised trial in the United Kingdom included an economic analysis. WILL randomised women with chronic or gestational hypertension at 36 to 37 weeks and a singleton fetus, and who provided documented informed consent to "Planned early term birth at 38+0-3 weeks" (intervention) or "usual care at term" (control). The coprimary outcomes were "poor maternal outcome" (composite of severe hypertension, maternal death, or maternal morbidity; superiority hypothesis) and "neonatal care unit admission for ≥4 hours" (noninferiority hypothesis). The key secondary was cesarean. Follow-up was to 6 weeks postpartum. The planned sample size was 540/group. Analysis was by intention-to-treat. A total of 403 participants (37.3% of target) were randomised to the intervention (n = 201) or control group (n = 202), from 3 June 2019 to 19 December 2022, when the funder stopped the trial for delayed recruitment. In the intervention (versus control) group, losses to follow-up were 18/201 (9%) versus 15/202 (7%). In each group, maternal age was about 30 years, about one-fifth of women were from ethnic minorities, over half had obesity, approximately half had chronic hypertension, and most were on antihypertensives with normal blood pressure. In the intervention (versus control) group, birth was a median of 0.9 weeks earlier (38.4 [38.3 to 38.6] versus 39.3 [38.7 to 39.9] weeks). There was no evidence of a difference in "poor maternal outcome" (27/201 [13%] versus 24/202 [12%], respectively; adjusted risk ratio [aRR] 1.16, 95% confidence interval [CI] 0.72 to 1.87). For "neonatal care unit admission for ≥4 hours," the intervention was considered noninferior to the control as the adjusted risk difference (aRD) 95% CI upper bound did not cross the 8% prespecified noninferiority margin (14/201 [7%] versus 14/202 [7%], respectively; aRD 0.003, 95% CI -0.05 to +0.06), although event rates were lower-than-estimated. The intervention (versus control) was associated with no difference in cesarean (58/201 [29%] versus 72/202 [36%], respectively; aRR 0.81, 95% CI 0.61 to 1.08. There were no serious adverse events. Limitations include our smaller-than-planned sample size, and lower-than-anticipated event rates, so the findings may not be generalisable to where hypertension is not treated with antihypertensive therapy. CONCLUSIONS:In this study, we observed that most women with chronic or gestational hypertension required labour induction, and planned birth at 38+0-3 weeks (versus usual care) resulted in birth an average of 6 days earlier, and no differences in poor maternal outcome or neonatal morbidity. Our findings provide reassurance about planned birth at 38+0-3 weeks as a clinical option for these women. TRIAL REGISTRATION:isrctn.com ISRCTN77258279.

Background Vaginal cervical cerclage and progesterone are established treatments for prevention of pregnancy loss and prematurity. There is limited data to assess the effect of these treatments in combination. Objective To investigate the association between progesterone and no progesterone treatment on pregnancy outcomes in women at high risk of preterm birth who have received a vaginal cervical cerclage. Study Design This is a secondary analysis of women recruited to the CSTICH trial, which recruited in 75 obstetric units in the UK. The primary outcome was pregnancy loss, defined as miscarriage and perinatal mortality, including any stillbirth or neonatal death in the first week of life. Secondary maternal outcomes included miscarriage and previable neonatal death; stillbirth; gestational age at delivery; preterm pre labour rupture of membranes and sepsis. Secondary neonatal outcomes included early/late neonatal death and sepsis. For each outcome, regression models were fitted adjusting for pre-specified prognostic variables. Results 1943 women had a vaginal cerclage placed, with available progesterone data. From the 2048 women recruited to CSTICH; 843 (43%) women received progesterone and 1109 (57%) did not receive progesterone. Pregnancy loss occurred in 49 (5.9%) of 832 women who received progesterone and 91 (8.3%) of 1103 women who did not receive progesterone (adjusted risk ratio 0.70, 95% confidence interval (CI): 0.50 to 0.99; adjusted risk difference -0.02, 95% CI: -0.04 to -0.001). Conclusion There appears to be an association with progesterone use in women who receive a vaginal cervical cerclage and a reduction in pregnancy loss. This combination therapy may be an important opportunity to further reduce the risk of pregnancy loss in this high risk cohort. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols ### Funding Statement The author(s) received no specific funding for this work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Uk NHS research ethics committee I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data underlying the results presented in the study are available from The University of Birmingham clinical trials unit by contacting the lead author as per the correspondence details.

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 pound 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 pound and 2233 pound 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

Graphical abstract 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.

Abstract Study question How effective is the change between day 1 and 4 post-treatment serum hCG level at predicting single-dose methotrexate treatment success in tubal ectopic pregnancy (tEP)? Summary answer Any fall in day 1–4 serum hCG signifies an 85% (95%CI 76.8–90.6) likelihood of treatment success for tEP managed with single-dose methotrexate. What is known already For those with tEP managed by single-dose methotrexate, current guidelines advocate intervention if day 4–7 hCG fails to fall by ≥ 15%. The trajectory of hCG over day 1–4 has been proposed as an early indicator that predicts treatment success, allowing early reassurance for women. However, almost all prior studies of day 1–4 hCG change have been small or retrospective. Study design, size, duration This was a prospective cohort study of women with tEP (pre-treatment hCG of ≥ 1000 IU/L and ≤5000 IU/L) managed with single-dose methotrexate. The data were derived from a UK multicentre randomised controlled trial of methotrexate and gefitinib versus methotrexate and placebo for treatment of tEP (GEM3). For this analysis, we include data from both treatment arms. Participants/materials, setting, methods Participants were categorised by single-dose methotrexate treatment success or failure. Treatment success for this analysis was defined as complete tEP resolution to serum hCG <30 IU/L following single-dose methotrexate treatment only. Patient characteristics between groups were compared. Changes in day 1–4, 1–7 and 4–7 serum hCG were evaluated as predictors of treatment success through receiver operating characteristic (ROC) curve analysis. Test performance characteristics were calculated for percentage reduction thresholds including optimal thresholds. Main results and the role of chance A total of 322 women with tEP and hCG ≥1000 IU/L and ≤5000 IU/L were treated with single-dose methotrexate. The overall single-dose methotrexate treatment success rate was 59% (n = 189/322). Day 1–4, 1–7 and 4–7 serum hCG change predicted single-dose methotrexate treatment success with ROC area under curve 0.80 (95% CI 0.74–0.85), 0.86 (95% CI 0.81–0.91) and 0.89 (95% CI 0.85–0.93) respectively. Any fall between day 1 and day 4 hCG predicted single-dose methotrexate treatment success with a positive predictive value of 85%, negative predictive value 57%, sensitivity 58%, specificity 84%, positive likelihood ratio 3.6 and negative likelihood ratio 0.5. A less than 18% rise in day 1–4 serum hCG was identified as an optimal classification threshold and predicted treatment success with 82% positive predictive value, 69% negative predictive value, 79% sensitivity, 74% specificity, positive likelihood ratio 3.0 and negative likelihood ratio 0.3. 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 This large prospective cohort demonstrates the value of day 1–4 serum hCG changes in predicting single-dose methotrexate treatment success in tEP. We recommend clinicians provide early reassurance to women who have fall or modest (<18%) rise in day 1–4 serum hCG that their treatment will likely be effective. Trial registration number This study is a secondary analysis of the GEM3 trial (ISRCTN Registry ISRCTN67795930).

Abstract 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).

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.

ABSTRACT Preterm birth complicates approximately 10% of pregnancies worldwide. It can lead to neonatal mortality or lifelong complications for those babies who survive. One cause of preterm birth is cervical insufficiency, which affects up to 1% of pregnant women and can be treated with the placement of vaginal cervical cerclage. There are 2 techniques for cervical cerclage: the modified Shirodkar cerclage, which involves dissecting the bladder and placing a suture around the supravaginal cervix with the suture thread buried, and the McDonald cerclage, which involves inserting the suture thread as high as possible around the upper section of the cervix. The effectiveness of either technique is dependent on perioperative decisions, such as suture thread choice. One UK survey found that 87% of clinicians prefer to use braided thread, with 13% preferring monofilament thread. The preference for braided thread was due to its easy handling and concerns that monofilament thread is difficult to remove if it becomes embedded in the cervix. However, an observational, nonrandomized systemic review suggested that monofilament thread was better than braided thread to prevent pregnancy loss (7% vs 18.9%; risk ratio [RR], 0.34; 95% confidence interval [CI], 0.18–0.63). Additional evidence suggests that monofilament thread is superior because braided thread could serve as a reservoir for bacteria, causing vaginal dysbiosis and increasing the risk of pregnancy loss. There are no randomized clinical trials to inform the choice of suture thread to prevent pregnancy loss. The aim of this study was to compare the effectiveness of monofilament suture thread to braided suture thread on pregnancy loss in women undergoing cervical cerclage. This was a superiority randomized clinical trial, conducted at 75 obstetric units in the United Kingdom between August 21, 2015, and January 28, 2021. Included were women aged 18 years and older with singleton pregnancies, who required vaginal cervical cerclage. Excluded were women who required emergency or rescue cerclage, needed immediate suture insertion, or had ruptured or visible membranes, as well as those who did not have a cerclage placed vaginally. Eligible women were randomized to receive either monofilament thread or braided thread. Women were followed up until 28 days postdelivery or hospital discharge, whichever came first. Preterm neonates were followed up until delivery or discharge, and babies born at term were followed up 28 days postdelivery or hospital discharge, whichever came first. A total of 2049 women were randomized to the monofilament suture thread group (n = 1025) or the braided suture thread group (1024). The intention-to-treat analysis included 1003 women in the monofilament group and 993 women in the braided group. No significant differences were observed in the rate of pregnancy loss between the monofilament group and braided group (8% vs 7.6%, respectively; RR, 1.05; 95% CI, 0.79–1.40; adjusted risk difference, 0.002; 95% CI, −0.02 to 0.03; P = 0.73). Insertion complications occurred in 4% of women in the monofilament group and 3% in the braided suture group. Women in the monofilament group experienced more removal complications than the braided group (RR, 1.25; 95% CI, 1.15–1.36). No significant differences were observed in maternal secondary outcomes or neonatal outcomes. In conclusion, there was no difference in the rate of pregnancy loss when using monofilament suture thread or braided suture thread in women undergoing cervical cerclage.

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/m2) 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 1middot15, 95% CI 0middot85 to 1middot58; adjusted risk difference -0middot01, 95% CI -0middot10 to 0middot09; p=0middot37). Without surgical intervention, median time to resolution was 28middot0 days in the gefitinib group and 28middot0 days in the placebo group (subdistribution hazard ratio 1middot03, 95% CI 0middot75 to 1middot40). 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.Copyright (c) 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Abstract Background Approximately one in ten women have high blood pressure during pregnancy. Hypertension is associated with adverse maternal and perinatal outcomes, and as treatment improves maternal outcomes, antihypertensive treatment is recommended. Previous trials have been unable to provide a definitive answer on which antihypertensive treatment is associated with optimal maternal and neonatal outcomes and the need for robust evidence evaluating maternal and infant benefits and risks remains an important, unanswered question for research and clinical communities. Methods The Giant PANDA study is a pragmatic, open-label, multicentre, randomised controlled trial of a treatment initiation strategy with nifedipine (calcium channel blocker), versus labetalol (mixed alpha/beta blocker) in 2300 women with pregnancy hypertension. The primary objective is to evaluate if treatment with nifedipine compared to labetalol in women with pregnancy hypertension reduces severe maternal hypertension without increasing fetal or neonatal death or neonatal unit admission. Subgroup analyses will be undertaken by hypertension type (chronic, gestational, pre-eclampsia), diabetes (yes, no), singleton (yes, no), self-reported ethnicity (Black, all other), and gestational age at randomisation categories (11 + 0 to 19 + 6, 20 + 0 to 27 + 6, 28 + 0 to 34 + 6 weeks). A cost-effectiveness analysis using an NHS perspective will be undertaken using a cost-consequence analysis up to postnatal hospital discharge and an extrapolation exercise with a lifetime horizon conditional on the results of the cost-consequence analysis. Discussion This trial aims to address the uncertainty of which antihypertensive treatment is associated with optimal maternal and neonatal outcomes. The trial results are intended to provide definitive evidence to inform guidelines and linked, shared decision-making tools, thus influencing clinical practice. Trial registration EudraCT number: 2020–003410-12, ISRCTN: 12,792,616 registered on 18 November 2020.