RATIONALE:Induction of labour (IoL) aims to initiate labour when the risks of continuing pregnancy outweigh the benefits. Over 10 methods are currently available, yet the most effective and safest method remains unclear. OBJECTIVES:To compare the benefits and harms of various cervical ripening and IoL methods at or beyond term labour and to rank the methods. SEARCH METHODS:We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, and the WHO ICTRP until 1 February 2023. ELIGIBILITY CRITERIA:We included randomised controlled trials (RCTs) evaluating IoL methods among women with a live fetus at or beyond term labour (gestational age ≥ 37 weeks). We focused on the methods currently recommended by international guidelines and those proposed by previous Cochrane reviews. OUTCOMES:Our critical outcomes included failure to achieve vaginal delivery within 24 hours, caesarean section due to any causes, caesarean section due to non-reassuring fetal status, uterine hyperstimulation with changes in the heartbeat of the baby before birth, perinatal death, and severe neonatal morbidity. RISK OF BIAS:We assessed bias and trustworthiness using the Cochrane RoB 1 tool and the Cochrane Pregnancy and Childbirth Trustworthiness Tool (CPS-TST), respectively. The final analyses only included trials that met the CPS-TST. SYNTHESIS METHODS:We performed pair-wise meta-analyses using a random-effects model and network meta-analyses (NMA) with a frequentist approach. We reported analyses and results separately for two populations: 1) women without a previous caesarean section and a mix of women with or without a previous caesarean section (where more than 50% of participants had no previous caesarean section), and 2) women with a previous caesarean section. We used risk ratio (RR) and mean difference (MD) to present treatment effects with 95% confidence intervals (CIs). We assessed the certainty of evidence for critical outcomes using the GRADE approach for NMA. We used the surface under the cumulative ranking curve (SUCRA) to estimate treatment ranking. INCLUDED STUDIES:The analysis included 106 RCTs assessing 13 IoL methods among 30,348 women. Most trials (84.9%) were conducted in inpatient settings. Only two RCTs recruited women with previous caesarean section, and seven RCTs recruited a mix of women with or without a previous caesarean section. SYNTHESIS OF RESULTS:We evaluated the effects of the following IoL methods: vaginal misoprostol (≤ 50 μg), oral misoprostol (≤ 50 μg), sublingual or buccal misoprostol (≤ 50 μg), controlled-release misoprostol vaginal pessary, vaginal dinoprostone (tablet or gel), controlled-release dinoprostone vaginal pessary, oxytocin (alone), nitric oxide donors, balloon catheters, osmotic cervical dilators, oxytocin plus amniotomy (Oxytocin+Amniotomy), balloon catheters plus oxytocin (Balloon+Oxytocin), balloon catheters plus vaginal/oral misoprostol (≤ 50 μg) (Balloon+Misoprostol ≤ 50 μg), and inactive methods (placebo, no intervention, and expectant management). The following results show the relative effects of NMA for four of the six critical outcomes among women without previous caesarean section and a mix of women with or without previous caesarean section. The findings of women with previous caesarean section are not presented here due to limited evidence. We used vaginal misoprostol (≤ 50 μg) as the reference method for presenting results, where data for this method were available in the network. 1) Failure to achieve vaginal delivery within 24 hours There was no clear evidence that any of the methods were more effective than vaginal misoprostol (≤ 50 μg) in reducing the risk of this outcome. Oxytocin+Amniotomy (RR 0.41, 95% CI 0.14 to 1.24, 22.4% fewer, moderate-certainty evidence), Balloon+Misoprostol ≤ 50 μg (RR 0.85, 95% CI 0.60 to 1.19, 5.7% fewer, high-certainty evidence), and Balloon+Oxytocin (RR 0.94, 95% CI 0.71 to 1.26, 2.3% fewer, low-certainty evidence) likely resulted in little to no difference in this outcome compared with vaginal misoprostol (≤ 50 μg). Despite the comparable relative treatment effects between some methods and vaginal misoprostol (≤ 50 μg), these three methods ranked highest. 2) Caesarean section due to non-reassuring fetal status There was no clear evidence that any of the methods were more effective than vaginal misoprostol (≤ 50 μg) in reducing the risk of this outcome. Balloon+Oxytocin (RR 0.77, 95% CI 0.47 to 1.25, 2.0% fewer, moderate-certainty evidence), controlled-release dinoprostone vaginal pessary (RR 0.86, 0.62 to 1.18, 1.2% fewer, low-certainty evidence), and balloon catheters (RR 0.88, 95% CI 0.70 to 1.11, 1.0% fewer, low-certainty evidence) may result in little to no difference in this outcome when compared with vaginal misoprostol (≤ 50 μg). Despite the comparable relative treatment effects between all methods and vaginal misoprostol (≤ 50 μg), these three methods ranked highest. 3) Uterine hyperstimulation with changes in the heartbeat of the baby before birth Nitric oxide donors (RR 0.05, 95% CI 0.01 to 0.47, 3.9% fewer, moderate-certainty evidence), osmotic cervical dilators (RR 0.07, 95% CI 0.01 to 0.42, 3.8% fewer, moderate-certainty evidence), balloon catheters (RR 0.38, 95% CI 0.21 to 0.69, 2.5% fewer, moderate-certainty evidence), and oral misoprostol (≤ 50 μg) (RR 0.62, 95% CI 0.39 to 0.99, 1.6% fewer, moderate-certainty evidence) probably reduce this outcome compared with vaginal misoprostol (≤ 50 μg). When compared with inactive interventions (placebo, no intervention, or expectant management), vaginal misoprostol (≤ 50 μg) (RR 3.47, 95% CI 1.16 to 10.35) probably increases the risk of this outcome. The three highest-ranked methods were nitric oxide donors, osmotic cervical dilators, and inactive methods (placebo, no intervention, and expectant management). 4) Perinatal death There was no clear evidence for this outcome, as it was rare (10 cases reported across trials). AUTHORS' CONCLUSIONS:For women without previous caesarean section and a mix of women with or without previous caesarean section, there was no clear evidence that any of the IoL methods were more effective than vaginal misoprostol (≤ 50 μg) for the outcomes of failure to achieve vaginal delivery within 24 hours, caesarean section due to non-reassuring fetal status, and perinatal death. Nitric oxide donors, osmotic cervical dilators, balloon catheters, and oral misoprostol (≤ 50 μg) probably reduce the risk of uterine hyperstimulation with changes in the heartbeat of the baby before birth. FUNDING:This review had no dedicated funding. REGISTRATION:Protocol (2023): https://doi.org/10.1002/14651858.CD015234.

Excessive bleeding after childbirth, known as postpartum haemorrhage (PPH), can turn an uncomplicated birth into a catastrophe. Each year, PPH occurs in an estimated 27 million women worldwide-17 million after vaginal birth and 10 million during or after caesarean birth. An estimated 43 000 women die from PPH annually, translating to a death every 12 min. The pooled prevalence of PPH at vaginal birth is 12·6% (95% CI 10·1-15·2) and at caesarean birth 30·9% (95% credible interval 24·9-37·6), based on the conventional definition of PPH. Common causes of PPH are uterine atony, genital tract trauma, retained placenta, abnormal placentation, and coagulopathy. Risk factors include caesarean birth, multiple pregnancy, anaemia, high maternal BMI, previous PPH, female genital mutilation, sepsis, pre-eclampsia, macrosomia, and inadequate antenatal care. In addition to being the leading cause of maternal mortality worldwide, the consequences of PPH include serious morbidities such as severe anaemia, hysterectomy, organ failure, and long-term psychological trauma. The global economic burden of PPH is estimated at US$10·4 billion (95% credible interval $9·8-13·2 billion) annually, consisting of $3·6 billion ($3·2-6·2 billion) for health systems and $6·8 billion ($6·2-7·5 billion) for societies. Based on a rigorous review of the evidence, WHO has recently redefined PPH as objectively measured blood loss of at least 300 mL plus an abnormal haemodynamic sign, or objectively measured blood loss of at least 500 mL, whichever occurs first. This new definition prioritises early PPH diagnosis and treatment to avert life-threatening maternal outcomes. Comprehensive efforts to address missed opportunities in the prevention, diagnosis, and treatment of PPH are needed to improve outcomes. These efforts include addressing the unmet need for contraception, mitigating modifiable risks such as anaemia, avoiding caesarean sections that are not medically indicated, using effective single uterotonic prophylaxis for all births and combination prophylaxis for women at high risk of PPH, ensuring accurate and objective measurement of blood loss for early PPH diagnosis, and promptly implementing treatment with an evidence-based bundle. The PPH Roadmap (2023-30) provides a global framework for action.

BACKGROUND:Postpartum haemorrhage (excessive bleeding after birth) is a leading cause of maternal mortality and morbidity worldwide. However, there is no global consensus on which clinical markers best define excessive bleeding or reliably predict adverse maternal outcomes. The aim of this study was to assess the prognostic accuracy of clinical markers of postpartum bleeding in predicting maternal mortality or severe morbidity. METHODS:In this individual participant data meta-analysis, eligible datasets were identified through a global call for data issued by WHO and systematic searches of PubMed, MEDLINE, Embase, the Cochrane Library, and WHO trial registries (from database inception to Nov 6, 2024). Studies were eligible if they included at least 200 participants with objectively measured blood loss or other clinical markers of haemodynamic instability, and reported at least one clinical outcome of interest. Individual participant data were requested for all eligible studies. For each dataset, we computed the prognostic accuracy of each clinical marker to predict a composite outcome of maternal mortality or severe morbidity (blood transfusion, surgical interventions, or admission to intensive care unit). Five clinical markers were assessed: measured blood loss, pulse rate, systolic blood pressure, diastolic blood pressure, and shock index. Results were meta-analysed through two-level mixed-effects logistic regression models, with a bivariate normal model used to generate summary accuracy estimates. Clinical marker and threshold selections were informed by a WHO expert consensus process, which placed emphasis on maximising prognostic sensitivity (preferably >80%) over prognostic specificity (preferably ≥50%). This meta-analysis was registered on PROSPERO (CRD420251034918). FINDINGS:We identified 33 potentially eligible datasets and successfully obtained and analysed full data for 12 datasets, comprising 312 151 women. At the conventional threshold of 500 mL, measured blood loss had a summary prognostic sensitivity of 75·7% (95% CI 60·3-86·4) and specificity of 81·4% (95% CI 70·7-88·8) for predicting the composite outcome. The preferred sensitivity threshold was reached at 300 mL (83·9% [95% CI 72·8-91·1]), although at the expense of reduced specificity (54·8% [95% CI 38·0-70·5]). Prognostic performance improved with a decision rule that combined the use of either blood loss thresholds less than 500 mL (≥300 mL to ≥450 mL) and any abnormal haemodynamic sign (pulse rate >100 beats per min, systolic blood pressure <100 mm Hg, diastolic blood pressure <60 mm Hg, or shock index >1·0) or 500 mL or more of blood loss, with sensitivities ranging from 86·9% to 87·9% and specificities from 66·6% to 76·1%. INTERPRETATION:Measured blood loss below the conventional threshold, combined with abnormal haemodynamic signs, accurately predicts women at risk of death or life-threatening complications from postpartum bleeding and could support earlier postpartum haemorrhage diagnosis and treatment. FUNDING:The Gates Foundation and UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction.

RATIONALE:Postpartum haemorrhage (PPH) is a major cause of maternal mortality worldwide. The combination of accurate diagnosis and effective treatment is necessary to improve outcomes. There is uncertainty about which combination of diagnostic and treatment strategies is most effective. OBJECTIVES:To assess the comparative effectiveness of various combinations of 'diagnostic and treatment' strategies for PPH in women giving birth, and rank them. To explore the relative effects of various diagnostic strategies, when the treatment strategies are the same or similar. To explore the relative effects of various treatment strategies, when the diagnostic strategies are the same or similar. SEARCH METHODS:We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform to 18 October 2024. ELIGIBILITY CRITERIA:Randomised controlled trials or cluster-randomised trials comparing the effects of different combinations of 'diagnostic and treatment' strategies for PPH were eligible. We included studies of women having vaginal or caesarean birth in any setting. OUTCOMES:Critical outcomes were: PPH ≥ 500 mL within 24 hours after birth; additional blood loss of ≥ 500 mL following diagnosis of PPH and within 24 hours after birth; PPH ≥ 1000 mL within 24 hours after birth; need for blood transfusion; use of additional uterotonics, and PPH treatment rate. Important outcomes included maternal death. RISK OF BIAS:We used the Cochrane risk of bias tool (RoB 1). SYNTHESIS METHODS:At least two review authors independently assessed trials for inclusion, trustworthiness, risk of bias, and certainty of the evidence using GRADE. We calculated direct and indirect effect estimates, where possible, for critical and important outcomes. Due to limited data, we were unable to perform pairwise meta-analyses and network meta-analyses for the available combinations, or generate rankings. INCLUDED STUDIES:We included five trials (10 trial arms, 236,771 women); all included women giving birth vaginally and four had a hospital setting. The combinations of diagnostic and treatment strategies were: visual estimation-based diagnosis plus usual care for treatment; 3-option trigger PPH diagnosis with calibrated drape (1. clinical concern, or 2. blood loss ≥ 300 mL to < 500 mL plus abnormal observations, or 3. blood loss ≥ 500 mL) plus MOTIVE (uterine Massage, Oxytocics, Tranexamic acid, IntraVenous fluids, and Examination and Escalation of care) treatment bundle; 2-option trigger PPH diagnosis with calibrated drape (1. clinical concern, or 2. blood loss ≥ 500 mL) plus MOTIVE treatment bundle; calibrated drape-based diagnosis plus usual care for treatment; gravimetric method-based diagnosis plus usual care for treatment; MaternaWell tray-based diagnosis plus usual care for treatment. SYNTHESIS OF RESULTS:3-option trigger PPH diagnosis plus MOTIVE bundle versus visual estimation-based diagnosis plus usual care (direct evidence; 1 study, 170,956 participants) reduces PPH ≥ 500 mL (RR 0.48, 95% CI 0.39 to 0.58; high-certainty evidence), and PPH ≥ 1000 mL (RR 0.34, 95% CI 0.26 to 0.44; high-certainty). Moderate-certainty evidence suggests it probably makes little or no difference to the need for blood transfusion (RR 0.82, 95% CI 0.62 to 1.08) or additional uterotonics (RR 1.19, 95% CI 0.94 to 1.50), and maternal death (RR 0.73, 95% CI 0.36 to 1.48). 2-option trigger PPH diagnosis plus MOTIVE bundle versus visual estimation-based diagnosis plus usual care (direct evidence; 1 study, 39,176 participants) reduces PPH ≥ 500 mL (RR 0.73, 95% CI 0.60 to 0.89; high-certainty). It probably makes little or no difference to PPH ≥ 1000 mL (RR 0.88, 95% CI 0.69 to 1.12; moderate-certainty), and the need for blood transfusion (RR 1.06, 95% CI 0.55 to 2.04; moderate-certainty), and may make little or no difference to maternal death (RR 1.01, 95% CI 0.00 to 4.0 × 107; low-certainty). High-certainty evidence suggests it increases the need for additional uterotonics (RR 3.54, 95% CI 2.27 to 5.52). 3-option trigger PPH diagnosis plus MOTIVE bundle versus 2-option trigger PPH diagnosis plus MOTIVE bundle (indirect evidence) reduces PPH ≥ 500 mL (RR 0.65, 95% CI 0.49 to 0.86; high-certainty), PPH ≥ 1000 mL (RR 0.38, 95% CI 0.27 to 0.55; high-certainty), and the need for additional uterotonics (RR 0.34, 95% CI 0.20 to 0.55; high-certainty). It probably makes little or no difference to the need for blood transfusion (RR 0.78, 95% CI 0.38 to 1.59; moderate-certainty), and may make little or no difference to maternal death (RR 0.72, 95% CI 0.00 to 2.9 × 107; low-certainty). Calibrated drape-based diagnosis plus usual care (in a European setting (E)) versus visual estimation-based diagnosis plus usual care (E) (direct evidence; 1 study, 25,381 participants) probably makes little or no difference to the need for blood transfusion (RR 0.83, 95% CI 0.57 to 1.21; moderate-certainty). Gravimetric method-based diagnosis plus usual care versus calibrated drape-based diagnosis plus usual care (direct evidence; 1 study, 1195 participants) reduces PPH ≥ 500 mL (RR 0.54, 95% CI 0.32 to 0.90; high-certainty), and may make little or no difference to need for blood transfusion (RR 1.00, 95% CI 0.06 to 15.94; low-certainty). MaternaWell tray-based diagnosis plus usual care versus calibrated drape-based diagnosis plus usual care (direct evidence; 1 study, 63 participants) may make little or no difference to PPH ≥ 500 mL (RR 0.61, 95% CI 0.11 to 3.38; low-certainty), and PPH ≥ 1000 mL (RR 0.30, 95% CI 0.01 to 7.19; low-certainty). Gravimetric method-based diagnosis plus usual care versus MaternaWell tray-based diagnosis plus usual care (indirect evidence) may make little or no difference to PPH ≥ 500 mL (RR 0.89, 95% CI 0.15 to 5.35; low-certainty). No data were available for other critical and important outcomes. AUTHORS' CONCLUSIONS:Both 3-option trigger PPH diagnosis plus MOTIVE bundle and 2-option trigger PPH diagnosis plus MOTIVE bundle were more effective than visual estimation-based diagnosis plus usual care (direct evidence). 3-option trigger PPH diagnosis plus MOTIVE bundle was more effective than 2-option trigger PPH diagnosis plus MOTIVE bundle (indirect evidence). As the treatment strategy (MOTIVE bundle) is the same in these combinations, the increased effectiveness is likely due to the 3-option trigger PPH diagnosis, which adds blood loss of ≥ 300 mL to < 500 mL in the drape plus abnormal clinical observations as a PPH diagnostic trigger. None of the comparisons demonstrated differences in blood transfusion or maternal mortality outcomes. Future research should assess the effectiveness of combination diagnostic and treatment strategies in non-hospital settings, and for women having a caesarean birth. Studies should provide more data on side effects, and maternal experience of care. FUNDING:Gates Foundation REGISTRATION: PROSPERO (CRD42024600189).

RATIONALE:Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic agents can prevent PPH. The current World Health Organization (WHO) recommendation for preventing PPH is 10 IU (international units) of intramuscular or intravenous oxytocin. Several uterotonics prevent PPH, but there remains uncertainty about the most effective agent with the fewest side effects. This is an update of a review first published in April 2018, and incorporates trustworthiness screening of eligible trials. OBJECTIVES:To identify the most effective uterotonic agent(s) to prevent PPH with the fewest side effects, and generate a ranking according to their effectiveness and side effect profile. SEARCH METHODS:On 5 February 2024, we searched CENTRAL, MEDLINE, Embase and CINAHL in collaboration with the Cochrane Information Specialist. ELIGIBILITY CRITERIA:All randomised controlled trials (RCTs) or cluster-RCTs that compared the effectiveness and side effects of uterotonic agents with other uterotonic agents, placebo or no treatment for preventing PPH were eligible for inclusion. We screened eligible trials for trustworthiness. We included randomised trials published only as abstracts if we could retrieve sufficient information; we excluded quasi-randomised trials. OUTCOMES:Primary outcomes were PPH ≥ 500 mL and PPH ≥ 1000 mL. Secondary outcomes included use of additional uterotonics, blood transfusion, vomiting, hypertension, and fever. RISK OF BIAS:We used RoB 1 to assess risk of bias. SYNTHESIS METHODS:At least three review authors independently assessed trials for inclusion, trustworthiness, risk of bias, and certainty of evidence using GRADE. We estimated the relative effects and rankings for the primary and secondary outcomes. We reported primary outcomes for prespecified subgroups, stratified by mode of birth (caesarean versus vaginal), setting (hospital versus community), prior risk of PPH (high versus low), dose of misoprostol (≥ 600 μg versus < 600 μg), and regimen of oxytocin (bolus versus bolus plus infusion versus infusion only). We performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available agents. INCLUDED STUDIES:The network meta-analysis included 122 trials (121,931 women), involving seven uterotonic agents and placebo or no treatment, conducted across 48 high-, middle- and low-income countries. Most were in a hospital setting (115/122, 94%), with women having a vaginal birth (87/122, 71%). SYNTHESIS OF RESULTS:Relative effects from the network meta-analysis suggested that all agents, except injectable prostaglandins, for which data were limited, were effective for preventing PPH ≥ 500 mL compared with placebo or no treatment. The two highest-ranked agents were ergometrine plus oxytocin and misoprostol plus oxytocin. Compared with oxytocin, ergometrine plus oxytocin reduces PPH ≥ 500 mL (risk ratio (RR) 0.76, 95% confidence interval (CI) 0.64 to 0.90, high-certainty evidence), and misoprostol plus oxytocin probably reduces PPH ≥ 500 mL (RR 0.70, 95% CI 0.57 to 0.87; moderate-certainty evidence). Carbetocin (high-), injectable prostaglandins (moderate-) and ergometrine (low-certainty evidence) have similar effects compared with oxytocin. The evidence for misoprostol is very low certainty. All agents, except ergometrine and injectable prostaglandins, for which data were limited, were effective for preventing PPH ≥ 1000 mL compared with placebo or no treatment. Ergometrine plus oxytocin, and misoprostol plus oxytocin were the highest-ranked agents. Compared with oxytocin, carbetocin and injectable prostaglandins (both moderate-certainty evidence), and misoprostol plus oxytocin (low-certainty evidence) make little or no difference to PPH ≥ 1000 mL. Misoprostol may be less effective in preventing PPH ≥ 1000 mL compared with oxytocin (RR 1.24, 95% CI 1.06 to 1.46; low-certainty evidence). The certainty of evidence for ergometrine and ergometrine plus oxytocin was very low. Compared with oxytocin, misoprostol plus oxytocin probably reduces the use of additional uterotonics (RR 0.55, 95% CI 0.42 to 0.72, moderate-certainty evidence), and carbetocin (RR 0.74, 95% CI 0.59 to 0.94; low-certainty evidence), and ergometrine plus oxytocin may reduce the use of additional uterotonics (RR 0.68, 95% CI 0.56 to 0.83; low-certainty evidence). Misoprostol (low-certainty evidence) makes little or no difference to this outcome. Misoprostol plus oxytocin probably reduces the risk of needing a blood transfusion (RR 0.40, 95% CI 0.28 to 0.58; moderate-certainty-evidence), and ergometrine plus oxytocin may reduce the risk of blood transfusion compared with oxytocin (RR 0.73, 95% CI 0.56 to 0.96, low-certainty evidence). Carbetocin (moderate-certainty evidence) and misoprostol (low-certainty evidence) probably make little or no difference to this outcome compared with oxytocin. All uterotonic agents, except for carbetocin, were associated with increased risks of side effects compared with oxytocin. Misoprostol may increase the likelihood of nausea, vomiting and fever, and probably increases the risk of diarrhoea. Injectable prostaglandins may increase the likelihood of diarrhoea. Ergometrine probably increases the likelihood of nausea and vomiting, and may increase the likelihood of hypertension, headache, and diarrhoea. Ergometrine plus oxytocin may increase the likelihood of nausea, vomiting, and diarrhoea. Misoprostol plus oxytocin probably increases the likelihood of nausea, vomiting and diarrhoea, and may increase the likelihood of fever. Analyses of the prespecified subgroups did not reveal important subgroup differences. Evidence for outcomes not presented above but reported in the summary of findings tables was very low certainty. AUTHORS' CONCLUSIONS:Most agents are effective for preventing PPH when compared with placebo or no treatment. Ergometrine plus oxytocin, and misoprostol plus oxytocin may be more effective than the current standard oxytocin. All agents, except for carbetocin, are associated with an increased risk of some side effects compared with oxytocin. FUNDING:Supported by UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a cosponsored programme executed by the WHO (Award No. HQHRP2220228-22.1-74309). REGISTRATION:Cochrane Library; Registration number: CD011689 and protocol [and previous versions] available via DOI: 10.1002/14651858.CD011689 [DOI: 10.1002/14651858.CD011689.pub3 and DOI: 10.1002/14651858.CD011689.pub2].

Type 1 diabetes is characterised by the immune-mediated destruction of pancreatic beta cells. We aimed to determine the effectiveness of immunotherapies for preserving residual beta cell function in newly diagnosed (stage 3) type 1 diabetes. Searches were carried out in MEDLINE, Embase, Cochrane CENTRAL and trial registries until 31st Jul 2024. RCTs of immunotherapies to preserve beta cells in newly diagnosed type 1 diabetes were included. Data were extracted using a bespoke, piloted extraction sheet. Risk of bias was assessed using Cochrane Risk of Bias Tool 1. A random effects network meta-analysis was undertaken in R. The primary outcome was C-peptide. Interventions were analysed by class. Sixty trials were included (4597 patients, 32 intervention classes). Forty-one trials of 42 interventions were eligible for network meta-analysis. Eleven interventions demonstrated statistically significantly higher levels of C-peptide than placebo at 12 months, mesenchymal stem cells (autologous and Wharton’s jelly-derived cells), azathioprine, interferon-alpha (5000 IU), autologous dendritic cells, anti-TNF golimumab, low-dose ATG, 3 mg 1-course anti-CD3 teplizumab, baricitinib, cyclosporin and 9/11 mg 2-course anti-CD3 teplizumab but with substantial heterogeneity present (I2 = 66

BACKGROUND:An understanding of the causes of postpartum haemorrhage is needed to provide appropriate treatment and services. Knowledge of the risk factors for postpartum haemorrhage can help address modifiable risk factors. We did a systematic review and meta-analysis to identify and quantify the various causes and risk factors for postpartum haemorrhage. METHODS:In this systematic review and meta-analysis, we did a systematic literature search in MEDLINE, Embase, Web of Science, Cochrane Library, and Google Scholar for cohort studies of postpartum haemorrhage from Jan 1, 1960, to Nov 30, 2024 without language restrictions. At least two authors independently undertook study selection, data extraction, and quality assessment. Population-based cohort studies available in English were eligible. Rates of postpartum haemorrhage causes as well as crude and adjusted odds ratios (ORs) for risk factors were pooled using a random-effects model. Risk factors were classified as having weak, moderate, or strong association based on the pooled ORs: weak (OR >1 to 1·5), moderate (OR >1·5 to 2), and strong (OR >2). This study is registered with PROSPERO, CRD42023479686. FINDINGS:We synthesised data from 327 studies, including 847 413 451 women with no restriction on age, race, or ethnicity. Most studies were of high methodological quality. The pooled rates of the five commonly reported causes of postpartum haemorrhage were uterine atony (70·6% [95% CI 63·9-77·3]; n=834 707 women, 14 studies), genital tract trauma (16·9% [9·3-24·6]; n=18 449 women, six studies), retained placenta (16·4% [12·3-20·5]; n=235 021 women, nine studies), abnormal placentation (3·9% [0·1-7·6]; n=29 638 women, two studies), and coagulopathy (2·7% [0·8-4·5]; n=236 261, nine studies). The pooled rate of women with multiple postpartum haemorrhage causes was 7·8% (95% CI 4·7-10·8; n=666, two studies). Risk factors with a strong association with postpartum haemorrhage included anaemia, previous postpartum haemorrhage, caesarean birth, female genital mutilation, sepsis, no antenatal care, multiple pregnancy, placenta praevia, assisted reproductive technology use, macrosomia with a birthweight of more than 4500 g, and shoulder dystocia. Risk factors with moderate association with postpartum haemorrhage included BMI ≥30 kg/m2, COVID-19 infection, gestational diabetes, polyhydramnios, pre-eclampsia, and antepartum haemorrhage. Risk factors with weak association with postpartum haemorrhage included Black and Asian ethnicity, BMI 25-29·9 kg/m2, asthma, thrombocytopenia, uterine fibroids, antidepressant use, induction of labour, instrumental birth, and premature rupture of membranes. INTERPRETATION:The finding that uterine atony is the commonest cause of postpartum haemorrhage supports the WHO recommendation for all women giving birth to be given prophylactic uterotonics. Knowledge of risk factors with a strong association with postpartum haemorrhage can help to identify women at high risk of postpartum haemorrhage who could benefit from enhanced prophylaxis and treatment. The importance of multiple concurrent causes of postpartum haemorrhage supports the use of treatment bundles. FUNDING:Gates Foundation.

Left ventricular assist devices (LVADs) can extend life and improve quality of life among advanced heart failure patients ineligible for transplantation (destination therapy). High-quality evidence on the cost effectiveness of LVADs compared with optimal medical management is needed to inform policy. This study identifies economic evaluations of LVADs for destination therapy and assesses their methodological quality. The review followed Centre for Review and Dissemination guidelines for methods, and PRISMA standards for reporting, and was registered on PROSPERO (CRD42020158987). Six databases were searched for studies published up to October 2024. Full economic evaluations of LVADs for destination therapy were included. Two reviewers independently conducted study selection, data extraction and quality assessment using validated tools. The study identified 14 economic evaluations, including 10 modelling studies. Most studies were from the US and UK. There was substantial variation in model structure, methods, and cost estimates. Only seven studies used a lifetime horizon. Resource use was typically estimated based on data from small single-centre samples. Overall quality was moderate due to key limitations such as insufficient time horizons, omitting complications and costs, and limited consideration of uncertainty. Only two studies examined severity, and none assessed cost effectiveness by patient age. Most studies found LVADs not to be cost effective compared with medical management except for two UK-based evaluations. This review reveals important limitations in the current evidence on the cost effectiveness of LVADs as destination therapy. More comprehensive, robust evaluations are needed to inform policy decisions.

Background Chronic kidney disease (CKD) is associated with comorbidities and altered pharmacokinetics, making appropriate prescribing, and monitoring necessary to minimise drug-related problems (DRPs). Therefore, this study aimed to describe the drug-utilisation pattern in hospitalised CKD patients.Methods An observational study was conducted in hospitalised adult (≥18 years old) CKD patients in the UK using WHO prescribing indicators, from November 2021 to April 2022 in a large teaching hospital in England from admission until discharge. This study used STATA version 16 for analysis.Results The mean number of drugs per prescription was 11.1(±5), the percentage of encounters resulting in the prescription of an antibiotic was 62%, the percentage of drugs prescribed by generic name was 90%, the percentage of encounters resulting in the prescription of an injection was 94%, and the percentage of drugs prescribed from essential drugs list or formulary was 89%. The most frequent drug group prescribed Alimentary Tract and Metabolism was 22%. Longer hospital stays, admission to a renal ward, and the number of comorbidities were independently associated with polypharmacy.Conclusion Not all prescribing indicators evaluated in this study were in full compliance with WHO recommendations. Polypharmacy was found in most participants which might require interventions to avoid DRPs. Further research is needed to evaluate factors associated with prescribing in the CKD population and prescriber perspectives on decision-making in the context of available guidelines and patient factors.

This study was aimed to evaluate the impact of community pharmacy (CP)-based medication therapy management (MTM) program on clinical and humanistic outcomes in patients with uncontrolled diabetes. An open label, parallel-group randomised controlled trial was undertaken at a community pharmacy in Riyadh city, Kingdom of Saudi Arabia. Patients with a diagnosis of uncontrolled diabetes (HbA1c of >= 8%) meeting the eligibility criteria were randomised to receive either the MTM programme provided by pharmacists or standard care. The primary outcome was change in HbA1c over 6 months. Secondary outcomes included: changes in clinical parameters (blood pressure (BP), lipid profile, serum creatinine (SCr) and albumin-to- creatinine ratio (ACR)), types of drug-related problems (DRPs), health service utilization (HSU), adherence, diabetes distress and overall patient satisfaction with the service at 6-month. A sufficiently powered sample of 160 participants with a mean age was 50 years (SD +/- 11.9) was recruited. The majority of the patients (68.1%) were male and had diabetes for more than eight years [IQR 3, 14]. After adjusting for baseline HbA1c, compared to the control group, the mean HbA1c level was 0.02% (p = 0.929) and 0.2% (p = 0.47) lower in the intervention arm at 3-month and 6-month respectively. However, these differences were not statistically significant. Nonetheless, within each arm, there was a significant improvement in HbA1c from baseline. Furthermore, the intervention arm demonstrated improvement in BP control (SBP lowered by 3.2 mmHg (p = 0.05) and DBP lowered by 3.8 mmHg (p = 0.008)). During the study period, none of the participants in the intervention group reported hospitalization or ER visits compared to 14 patients in the control group [OR 0.069 (95% CI 0.004, 1.3)]. Patient satisfaction as measured by Patient Satisfaction with Pharmacist Services Questionnaire 2.0 (PSPSQ 2.0) was significantly higher among MTM program participants compared to standard care (p = 0.00001). Patients in the MTM program were eight times more likely to be adherent compared to the patients in the standard care [OR 7.89 (95% CI 3.6, 17.4)]. MTM program metrics showed that per patient, the pharmacists spent a median of 35 [IQR 30, 44.5] minutes at the initial visit and 20 [IQR 10, 25] minutes during the 6-month visit. The number of DRPs had significantly dropped in the intervention arm at 3 and 6-month (p = 0.0001). In conclusion, CP-based MTM program can improve health outcomes and prevent hospitalisations in patients with diabetes. These findings support the implementation of CP-based MTM services for patients with diabetes in the Kingdom of Saudi Arabia.

Background Selected patients with advanced heart failure ineligible for heart transplantation could benefit from left ventricular assist device therapy as ‘destination therapy’. There is evidence of the efficacy of destination therapy; however, it is not currently commissioned within the United Kingdom National Health Service due to the lack of economic evidence. Objective What is the clinical and cost-effectiveness of a left ventricular assist device compared to medical management for patients with advanced heart failure ineligible for heart transplantation (destination therapy)? Methods A systematic review of evidence on the clinical and cost-effectiveness of left ventricular assist devices as destination therapy was undertaken including, where feasible, a network meta-analysis to provide an indirect estimate of the relative effectiveness of currently available left ventricular assist devices compared to medical management. For the systematic reviews, data sources searched (up to 11 January 2022) were Cochrane CENTRAL, MEDLINE and EMBASE via Ovid for primary studies, and Epistemonikos and Cochrane Database of Systematic Reviews for relevant systematic reviews. Trial registers were also searched, along with data and reports from intervention-specific registries. Economic studies were identified in EconLit, CEA registry and the NHS Economic Evaluation Database (NHS EED). The searches were supplemented by checking reference lists of included studies. An economic model (Markov) was developed to estimate the cost-effectiveness of left ventricular assist devices compared to medical management from the United Kingdom National Health Service/personal social service perspective. Deterministic and probabilistic sensitivity analyses were conducted to explore uncertainties. Where possible, all analyses focused on the only currently available left ventricular assist device (HeartMate 3TM, Abbott, Chicago, IL, USA) in the United Kingdom. Results The clinical effectiveness review included 134 studies (240 articles). There were no studies directly comparing HeartMate 3 and medical management (a randomised trial is ongoing). The currently available left ventricular assist device improves patient survival and reduces stroke rates and complications compared to earlier devices and relative to medical management. For example, survival at 24 months is 77% with the HeartMate 3 device compared to 59% with the HeartMate II (MOMENTUM 3 trial). An indirect comparison demonstrated a reduction in mortality compared to medical management [relative risk of death 0.25 (95% confidence interval 0.13 to 0.47); 24 months; this study]. The cost-effectiveness review included 5 cost analyses and 14 economic evaluations covering different generations of devices and with different perspectives. The reported incremental costs per quality-adjusted life-year gained compared to medical management were lower for later generations of devices [as low as £46,207 (2019 prices; United Kingdom perspective; time horizon at least 5 years)]. The economic evaluation used different approaches to obtain the relative effects of current left ventricular assist devices compared to medical management from the United Kingdom National Health Service/personal social service perspective. All gave similar incremental cost-effectiveness ratios of £53,496–58,244 per quality-adjusted life-year gained – lifetime horizon. Model outputs were sensitive to parameter estimates relating to medical management. The findings did not materially differ on exploratory subgroup analyses based on the severity of heart failure. Limitations There was no direct evidence comparing the clinical effectiveness of HeartMate 3 to medical management. Indirect comparisons made were based on limited data from heterogeneous studies regarding the severity of heart failure (Interagency Registry for Mechanically Assisted Circulatory Support score distribution) and possible for survival only. Furthermore, the cost of medical management of advanced heart failure in the United Kingdom is not clear. Conclusions Using cost-effectiveness criteria applied in the United Kingdom, left ventricular assist devices compared to medical management for patients with advanced heart failure ineligible for heart transplant may not be cost-effective. When available, data from the ongoing evaluation of HeartMate 3 compared to medical management can be used to update cost-effectiveness estimates. An audit of the costs of medical management in the United Kingdom is required to further decrease uncertainty in the economic evaluation. Study registration This study is registered as PROSPERO CRD42020158987. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128996) and is published in full in Health Technology Assessment; Vol. 28, No. 38. See the NIHR Funding and Awards website for further award information. Plain language summary The majority of patients with advanced heart failure would be unsuitable for heart transplantation due to their age and comorbidities but selected patients could benefit from a left ventricular assist device. Left ventricular assist device therapy for such patients is known as ‘destination therapy’. This is a long-term therapy that involves implanting a battery-powered pump to support the patient’s heart. The purpose of this project was to collect and assess the research evidence on the effectiveness of left ventricular assist devices when used for destination therapy, and to estimate value for money compared to medical management from the United Kingdom National Health Service/personal social service perspective. This research identified that the currently available left ventricular assist device improves patient survival as well as reducing stroke rates and complications compared to earlier devices and relative to medical management. However, there is uncertainty in the evidence due to the absence of studies directly comparing the current device to medical therapy alone. An ongoing clinical trial is currently assessing this. It also means there is uncertainty about whether left ventricular assist devices could provide value for money as determined currently for the United Kingdom National Health Service. Scientific summary Background Heart failure is a debilitating, progressive syndrome characterised by the inability of the heart to pump blood around the body. Pharmacological treatments are used as first-line treatment but may eventually become less effective and left ventricular assist devices (LVADs) or heart transplant (HT) are considered. LVADs are frequently used as bridge to transplant (BTT) or bridge to candidacy (BTC). However, some patients are ineligible for HT and either continue on medical management (MM) or could have a LVAD implanted as ‘destination therapy’ (DT). LVAD as DT is not currently commissioned within the United Kingdom National Health Service (UK NHS). The costs of LVADs are high, especially when compared to the alternative MM, but may also offer significant benefit in terms of survival. It is important to determine whether LVADs are both clinically and cost-effective as DT to inform decision-making from the UK NHS/personal social service (PSS) perspective on their potential as long-term treatment for advanced heart failure patients ineligible for HT. Aims and objectives What is the clinical and cost-effectiveness of a LVAD compared to MM for advanced heart failure (AHF) patients ineligible for HT (DT)? The specific objectives to address this aim were to undertake: – a systematic review of available evidence on the clinical effectiveness of a LVAD as DT, including a network meta-analysis (NMA) to provide an indirect estimate of the relative effectiveness of currently available LVADs compared to MM; – a systematic review of available economic evidence on the use of a LVAD as DT; and – the development of an economic model to estimate the cost-effectiveness of a LVAD compared to MM from the UK NHS/PSS perspective. Due to the withdrawal of the HeartWare ventricular assist device (HVAD) during the undertaking of this research, the analyses primarily focus on the HeartMate 3™ (Abbott, Chicago, IL, USA) device, the only LVAD available in the UK at this time. Methods Systematic review of clinical effectiveness A systematic review was undertaken of all LVADs as DT and reporting followed the general principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The review was registered on PROSPERO (CRD42020158987). Eligibility criteria Studies of patients over 16 years of age with AHF who received any type of LVAD as DT were included. The review considered all devices, but the analysis focused on the HM3 device due to the recent withdrawal of the HeartWare HVAD (Medtronic, Dublin, Republic of Ireland). Eligible comparators (where relevant) were MM and other LVADs. Outcomes were survival, quality of life (QoL), hospitalisations, major events, complications and functional status. Study designs eligible were any clinical trial (whether randomised, non-randomised or single arm), observational studies (cohort, case-controls and case series) and reports from patient registries [e.g. INTERMACS, International Registry for Mechanically Assisted Circulation (IMACS)]. Studies were eligible if 50 or more DT patients were included. Systematic reviews were included and used to identify any additional potentially relevant primary studies. Searches and study selection Databases were searched from inception to 20 May 2020, with an updated search on 11 January 2022. Databases searched included Cochrane Library (CENTRAL), MEDLINE and EMBASE via Ovid, Epistemonikos, Cochrane Library of Systematic Reviews and World Health Organization (WHO) clinical trials portal (for ongoing studies). There were no restrictions by language or date of publication. Two reviewers independently undertook title and abstract screening and full-text selection via Covidence (Veritas Health Innovation, Melbourne, VIC, Australia). Disagreements were resolved by a third reviewer or consensus and reasons for exclusion were recorded. Risk of bias, data extraction and synthesis Quality assessment and data extraction were completed by one reviewer and checked by a second. Appropriate risk-of-bias tools dependent upon study design were applied. A hierarchical approach to synthesis was undertaken to avoid double-counting of studies with overlapping patient data and to manage the large volume of evidence. Randomised controlled trials (RCTs) and controlled non-randomised trials were considered in the first instance. Registry reports and uncontrolled observational studies were used to supplement findings for all outcomes. Data were tabulated and analysed in a narrative approach by device, and forest plots without summary estimates were presented (and where appropriate the feasibility of meta-analysis was considered). A network meta-analysis was considered for the main outcomes to produce an indirect comparison of the HM3 device (across LVAD generations) to MM, but only carried out for survival. Systematic review of cost-effectiveness A systematic review of the cost-effectiveness of LVADs was carried out utilising the same search strategy, and at the same time as the clinical effectiveness review, with the addition of three further specialist economics database searches in EconLit, Cost-Effectiveness Analysis (CEA) registry and the NHS Economic Evaluation Database (NHS EED). Appropriate risk-of-bias tools were applied and a narrative synthesis was undertaken. Economic evaluation The systematic reviews’ findings were used to inform the development of a cost–utility analysis (CUA), from the NHS/PSS perspective, using a Markov model with a lifetime horizon and 1-month cycles. Along with evidence from the reviews, the model was informed by guidance from clinical specialists, patients and commissioners. All costs used were in 2019 prices, and a discount rate of 3.5% was applied as per the national UK guidelines. To produce the base case, mortality risks for MM and LVAD arms required some assumptions and several methods for estimating the risks were identified. Two of these were primarily utilised: non-comparative net weight estimates and comparative estimates mapped to LVAD data from the recent relevant HM3 trial (MOMENTUM). The analysis was repeated incorporating a small probability of LVAD DT recipients transitioning to HT eligibility. The potential impacts of the severity of heart failure on cost-effectiveness were explored by considering subgroupings of profiles based on the INTERMACS classification. Uncertainty was explored via both deterministic and probabilistic sensitivity analyses, paying specific attention to the life expectancy and ongoing costs. Results Systematic review of clinical effectiveness There were 240 articles from 134 studies included in the clinical effectiveness review (5 randomised trials, 1 non-randomised trial, 86 observational studies, reports from 5 registries, 5 ongoing studies and 32 systematic reviews). Of the six trials that were included, only one of these assessed the HM3 and this was in comparison to the previous generation HeartMate II device (MOMENTUM RCT). The majority of HM3 data comes from this trial, with minimal additional data contributions from registry reports or observational studies of single cohorts. The MOMENTUM study was considered as having some concerns regarding risk of bias; however, this was primarily due to the per-protocol analysis for the DT participants and most other domains were considered low risk. There were 624 DT patients in the MOMENTUM 3 trial in total, with a mean age of 63 [standard deviation (SD) 12], 82.2% male and 52.1% INTERMACS level 3. At the longest follow-up point (24 months) survival was 76.7% in HM3 DT patients compared to 59% in HeartMate II patients. Clear and significant improvements in QoL from baseline were reported at 12 months and maintained at 24 months in the HM3 group; however, this was similar in the HeartMate II group. Major events and complications were present in both groups by the 24-month follow-up. There were eight stroke events per 100 patient-years in the HM3, as well as one pump thrombosis event and 70 bleeding events per 100 patient-years. These were all lower than that of the HeartMate II group. Rehospitalisations were also significantly lower in HM3 patients. While some reports included HM3 patients, there were no HM3 specific data reported in any patient registry reports. One observational study reported that HM3 patients (n = 15) had 0 pump thrombosis events in 24 months of follow-up. While it was not the focus due to withdrawal, survival levels were lower in the HeartWare HVAD trials when compared to the HM3 in the MOMENTUM trial and there were concerns with the stroke rates reported in the evidence. Risk of bias across the included trials varied with all but two studies reporting an overall high risk of bias or with some concerns for at least one outcome. The evidence contained within the remaining trials, observational studies and registry reports mostly relate to devices other than HM3. This evidence is summarised in the main part of this report. Indirect comparison of HeartMate 3 and medical management As there were no studies directly comparing HM3 and MM, indirect comparisons of the trial data were required utilising MM data from the older REMATCH trial (the first RCT comparing the first-generation HeartMate device to MM). Data were available to link through available studies for the survival outcome only. The network meta-analysis demonstrated a reduction in the risk of mortality, relative risk of death of 0.25 [95% confidence interval (CI) 0.13 to 0.47] 24 months, with the HM3 compared to MM. Systematic review of cost-effectiveness There were 19 studies reported in 20 articles included in the cost-effectiveness review: 5 cost analyses and 14 economic evaluations. Nine studies were US-based and four were UK-based. Most of the studies aimed to compare the health and cost outcomes of LVADs with MM. Most economic evaluations (n = 12) used a CUA approach and only two conducted a CEA. Markov-based modelling was applied in eight studies. The perspective, where stated, was the service provider in most studies. Healthcare resource use was usually estimated based on small numbers of patients from a single centre, which resulted in variability. In the studies comparing LVAD with MM for DT patients, the incremental cost per quality-adjusted life-year (QALY) gained estimates ranged between £46,207 and £238,401 in 2019 prices over a time horizon of 5 years or longer and from different perspectives. The overall quality of the studies was considered poor to moderate. Some limitations were limited consideration of uncertainty, insufficient time horizon and lack of consideration of some key complications and cost components. Only one study looked at the impact of disease severity on cost-effectiveness. More recent evaluations tended to have lower estimates of incremental cost-effectiveness, presumably reflecting better clinical outcomes of more recent devices. Two recent studies estimated the cost-effectiveness from a UK perspective, deriving incremental cost-effectiveness ratios of £47,361 and £46,207 per QALY gained for the HeartWare device (device withdrawn in 2021) and the HM3 device, respectively compared to MM. Economic evaluation The economic evaluation found similar results for each base case: Non-comparative net weight estimates approach: LVAD would produce an additional 2.86 QALYs per person, increase life expectancy by 3.73 years and the incremental cost to the NHS would be £152,735 per person. Incremental cost-effectiveness ratio (ICER): £53,496. Comparative estimates mapped to LVAD in MOMENTUM approach: LVAD would produce an additional 2.51 QALYs per person, increase life expectancy by 3.06 years and the incremental cost to the NHS would be £146,275 per person. ICER: £58,244. At a willingness to pay threshold of £50,000 per QALY gained, LVADs would not be considered cost-effective compared to MM for AHF patients ineligible for HT. The same applied when severity weighted ICER estimates based on QALY shortfall methods were used. The deterministic sensitivity analysis showed that inclusion of the probability of becoming eligible for a HT did not change these findings. Furthermore, the findings did not differ in subgroup analyses based on severity of heart failure. Model outputs were most sensitive to estimates related to outpatient costs for both LVAD and MM. Conclusions LVADs have significantly improved over time and the currently available HM3 LVAD is considered clinically effective in patients with end-stage heart failure ineligible for transplant, offering survival of over 75% at 2 years of follow-up with reduced complications and major events in comparison to older devices. However, the device compared to MM may not be considered cost-effective when using methods of defining this for end of life in the UK. Future research Currently, no RCT has been published that compares the HM3 device to MM; however, there is an ongoing trial (SweVAD) comparing the two, which is due to complete final study follow-up in December 2023. This randomised trial, undertaken in Sweden, should allow for relative effects to be determined between the two interventions. This will ultimately enable more robust data to be used to update the current model, rather than relying upon indirect comparisons with wide uncertainty. However, further issues around the true cost of MM are still present due to the lack of recent data on these costs in the UK. An audit of MM costs in DT patients in the UK would address this. Issues also persist in developing reliable subgroup analyses based on severity profiles to aid identification of whether a LVAD is (more) cost-effective for some groups of DT patients. Future trials and other studies should report results by patient severity profiles (e.g. INTERMACS classification), and if registry/observational studies then also by device implanted. Study registration This study is registered as PROSPERO CRD42020158987. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128996) and is published in full in Health Technology Assessment; Vol. 28, No. 38. See the NIHR Funding and Awards website for further award information.

Effective summarization of long documents is a challenging task. When addressing this challenge, Graph and Cluster-Based methods stand out as effective unsupervised solutions. Graph-Based Unsupervised methods are widely employed for summarization due to their success in identifying relationships within documents. Cluster-Based methods excel in minimizing redundancy by grouping similar content together before generating a concise summary. Therefore, this paper merges Cluster-Based and Graph-Based methods by applying language models for Unsupervised Extractive Summarization of long documents. The approach simultaneously extracts key information while minimizing redundancy. First, we use BERT-based sentence embeddings to create sentence clusters using k-means clustering and select the optimum number of clusters using the elbow method to ensure that sentences are categorized based on their semantic similarities. Then, the TextRank algorithm is employed within each cluster to rank sentences based on their importance and representativeness. Finally, the total similarity score of the graph is used to rank the clusters and eliminate less important sentence groups. Our method achieves comparable or better summary quality and reduced redundancy compared to both individual Cluster-Based and Graph-Based methods, as well as other supervised and Unsupervised baseline models across diverse datasets.

OBJECTIVES:Left Ventricular Assist Devices (LVADs) for destination therapy (DT) are used in many countries but in some, like the UK, LVADs are not commissioned due to uncertainty around their cost-effectiveness. Existing economic evaluations of LVADs for these patients have limitations. This study aimed to estimate the cost-effectiveness of LVADs as destination therapy, compared to optimal medical therapy, in the UK. METHODS:A cost-utility analysis from a UK healthcare perspective was conducted, using a Markov model. The model incorporated the impact of major events and complications. Sub-group analyses considered different severities of heart failure on cost-effectiveness. Uncertainty was measured in deterministic and probabilistic sensitivity analyses. RESULTS:LVAD produced additional 2.78 (95% CI 2.46-3.14) QALYs at an incremental cost of £152,329 (95% CI £125,665 - £181,812) compared to medical management, giving an incremental cost-effectiveness ratio (ICER) of £54,748 per QALY. The ICER remained above the accepted thresholds of cost-effectiveness in the UK if a small proportion of patients receiving LVAD becomes eligible for a heart transplant and for all subgroups based on heart failure severity. The deterministic sensitivity analysis showed that the ongoing outpatient costs had a significant impact on the results. CONCLUSIONS:Our analysis found that LVADs are not cost-effective as destination therapy in the UK if a willingness to pay threshold of £50,000 per QALY gained or disease severity modifiers, were applied. Robust data on ongoing costs for LVAD and medical management are needed.

Due to increasing life expectancy, almost half of people with type 2 diabetes are aged 65 years or over worldwide. When metformin alone does not control blood sugar, the choice of which second-line therapy to prescribe next is not clear from currently available evidence. The existence of frailty and comorbidities in older adults further increases the complexity of medical decision-making. As only a relatively small proportion of trials report results separately for older adults, the relative efficacy and safety of second-line therapies in older adults with type 2 diabetes mellitus are unknown and require further investigation. This individual participant data (IPD) network meta-analysis evaluates the relative efficacy and safety of second-line therapies on their own or in combination in older adults with type 2 diabetes mellitus. All relevant published and unpublished trials will be identified. Studies published prior to 2015 will be identified from two previous comprehensive aggregate data network meta-analyses. Searches will be conducted in CENTRAL, MEDLINE, and EMBASE from 1st January 2015 onwards, and in clinicaltrials.gov from inception. Randomised controlled trials with at least 100 estimated older adults (≥ 65 years) receiving at least 24 weeks of intervention that assess the effects of glucose-lowering drugs on mortality, glycemia, vascular and other comorbidities outcomes, and quality of life will be eligible. The screening and data extraction process will be conducted independently by two researchers. The quality of studies will be assessed using the Cochrane risk of bias tool 2. Anonymised IPD of all eligible trials will be requested via clinical trial portals or by contacting the principal investigators or sponsors. Received data will be reanalysed where necessary to standardise outcome metrics. Network meta-analyses will be performed to determine the relative effectiveness of therapies. With the increasing number of older adults with type 2 diabetes worldwide, an IPD network meta-analysis using data from all eligible trials will provide new insights into the optimal choices of second-line antidiabetic drugs to improve patient management and reduce unnecessary adverse events and the subsequent risk of comorbidities in older adults. PROSPERO CRD42021272686.

Objective: To examine the association between periconceptual maternal diet and miscarriage risk among women with recurrent miscarriages. Design: Prospective multicentre cohort study (Tommy's Net). Setting: Three university hospital research centres in the United Kingdom. Population: 1035 women with a baseline history of two or more miscarriages. Methods: We analysed baseline dietary data from a 10-item Food Frequency Questionnaire (FFQ). For individual food category analyses, we used multivariable Poisson regression following adjustment for maternal confounders and paternal dietary patterns. For whole diet analyses, ordinal principal component analysis (PCA) was used to identify common dietary patterns. Results were presented as relative risks (RR) with 95% confidence intervals (CI) and accompanying p-values. Main Outcome Measures: Miscarriage rate, defined as the rate of spontaneous pregnancy loss (< 24 weeks of gestation) relative to the total number of pregnancies (miscarriages and live births). Results: High consumption of fruit and nuts (almonds and walnuts) was associated with lower miscarriage risk (fruit 226/662 (34.1%) vs. 38/77 (49.4%), RR 0.66, 95% CI 0.51 to 0.85, p = 0.001; nuts 47/152 (30.9%) vs. 220/613 (35.9%), RR 0.73, 95% CI 0.54 to 0.98, p = 0.039). High red meat intake was associated with a possible increase in miscarriage risk (6/12 (50.0%) vs. 165/469 (35.2%), RR 1.86, 95% CI 1.10 to 3.16, p = 0.022). The association with miscarriage risk was unclear for other food groups, including fresh vegetables, white meat, fish, dairy, eggs, soya and chocolate, due to imprecise point estimates. Through PCA, we identified three data-derived dietary patterns. Yet, no distinct relationship emerged between these dietary patterns and miscarriage risk. Conclusions: A maternal diet rich in fresh fruits and nuts is associated with a lower miscarriage risk among women with a history of recurrent miscarriage. Trail Registration: Tommy's Net (ISRCTN17732518) https://www.isrctn.com/ISRCTN17732518. Analysis plan (OSF zp7cs) https://osf.io/zp7cs.

We thank Pirtea et al. (2023) and Alsbjerg and Humaidan (2023) for their interest in our article and have addressed below the points we deemed pertinent. In our original review (Melo et al., 2021), we found a wide range of serum progesterone thresholds below which live birth or ongoing pregnancy rates appeared to be diminished in frozen embryo treatment (FET). The evidence was heterogeneous, even among articles reporting exclusively on cycles using vaginal progesterone for luteal phase support. It is important to note that in that publication, rather than suggesting that serum progesterone measurements 10 ng/ml were the level for which to strive, we simply reported that among studies investigating cut-offs lower than 10 ng/ml (which ranged from 8.06 to 9.43 ng/ml), higher serum progesterone levels than the specified threshold were associated with improved outcomes (Melo et al., 2021). There is a subtle yet crucial difference between these two statements. Rounding it up to 10 ng/ml would have simplistically ignored the cut-off heterogeneity we identified in our review. Our most recent study attempted to investigate what happens in an unselected population of participants presenting for FET, irrespective of (but adjusting for) cycle regimen (Melo et al., 2022). Overall, for serum progesterone levels lower than 7.8 ng/ml, the evidence identified a reduction in live birth rates, which was consistent with the findings of our systematic review. Our article does not suggest that 7.8 ng/ml should be the revised cut-off. Instead, we state that our findings support the aforementioned evidence for thresholds lower than 10 ng/ml. Where our analyses differed from much of the existing evidence was in the way we evaluated serum progesterone as a continuous variable, thus minimizing loss of data and statistical power (Altman and Royston, 2006). We discussed extensively the limitations of our cohort in our article, including its pragmatic nature, which we tackled by adjusting our analyses for clinically important confounders, the variation in sample timing, and the difficulties in reaching the sample size originally planned (Melo et al., 2022). We agree with Alsbjerg and Humaidan (2023) that the low sample size resulted in imprecision, warranting further studies on this important topic, particularly in non-vaginal routes of progesterone administration. Our study is not unique in identifying evidence of a non-linear association between serum progesterone and treatment outcomes in FET. In the first published cohort on this topic, Yovich et al. (2015) found an optimum range of serum progesterone in FET cycles using vaginal progesterone (70–99 nmol/l or 22–31.1 ng/ml), above which there was a decline in live birth rate. Similarly, Kofinas et al. (2015) showed that in women receiving intramuscular progesterone for luteal phase support in FET, participants with serum progesterone levels above 20 ng/ml exhibited lower rates of ongoing pregnancy or live birth and an increased rate of miscarriage. Alsbjerg et al. (2020) later demonstrated that in FET cycles primed with vaginal and rectal progesterone, serum progesterone levels above 14 ng/ml appeared to negatively affect treatment outcomes. More recently, in a prospective study evaluating combined vaginal and intramuscular progesterone in FET, Alyasin et al. (2021) identified a reduction in live birth rate for serum progesterone levels above 32.5 ng/ml. The aforementioned studies varied in their FET regimens and found a wide range of serum progesterone thresholds (14–32.5 ng/ml) above which there may have been a negative association with live birth rate. In our own study, we demonstrated that serum progesterone levels below the 10 centile were overall associated with a reduction in live birth. However, we also observed a decrease in live birth rates in women exclusively receiving subcutaneous progesterone who exhibited higher serum measurements. In this subgroup, our adjusted analysis suggested that progesterone levels above 16.3 ng/ml may have been associated with a reduction in effectiveness, which contrasted with the shape of the relationship between serum progesterone and live birth for all other cycle regimens. We acknowledge this finding differs from some of the existing literature—but not all, as demonstrated above. Further, we believe that constructing an argument based on publications from 40 years ago with sample sizes smaller than ours and focusing on average serum progesterone levels in interventional studies, does little to advance the scientific discussion on this topic. This is particularly important within the realm of serum hormone measurements, for which the overwhelming scientific consensus is that optimum ranges exist. It could be argued that suggesting progesterone would be unique by exhibiting no upper serum limit of effectiveness and safety is in fact what truly defies ‘biological plausibility’. Given the conflicting evidence in the available literature, further research examining this specific relationship would be important. We described our findings in a balanced and well-thought-out manner, including all subgroups of FET regimens in the box aimed for patients. Suggesting we focused exclusively on a potential negative effect of higher serum in women receiving solely subcutaneous progesterone is a misrepresentation of our words, which we chose carefully. We also note that our statement that

Background It is estimated that approximately 300,000 people are experiencing homelessness in England. The aim of this study was to evaluate key causes and long-term trends of emergency departments (EDs) and in hospital inpatient admissions of persons experiencing homelessness in England. Methods ED and hospital inpatient admissions data were obtained from Hospital Episode Statistics (HES) covering all National Health Service (NHS) England hospitals. Anyone identified or declared to be experiencing homelessness during the service usage are recorded in HES datasets. Data were extracted for the 10-year study period and compared to the general population, which includes all patients attending the ED or admitted to inpatient care in England. Results Drug- and alcohol-related causes contribute to the most frequent reasons for attendance and admissions of persons experiencing homelessness in the ED and inpatient respectively. A total of 30,406 ED attendances were recorded for persons experiencing homelessness in the year 2018/2019 (+ 44.9% rise vs 2009/10) of which injuries and poisoning respectively represented 21.8% and 17.9% of all persons experiencing homelessness presentations to the ED. Poisoning (including drug overdose) represented only 1.9% of all attendances by the general population during the same study year (rate ratio vs general populations 9.2 95% CI 9.0–9.4). High mortality rates were observed in relation to presentations attributed to drug- and alcohol-related causes. A total of 14,858 persons experiencing homelessness inpatient admissions were recorded in 2018/2019 (+ 68.6% vs 2009/2010). Psychoactive substance use constituted 12.7% of all admissions in 2018/2019 compared to 0.4% of in the general populations (rate ratio: 33.3, 95% CI : 31.9–34.7). There was a 44.3% rise in the number of admissions related to poisoning in the study period amongst persons experiencing homelessness in England (vs 14.2% in general population). Conclusion Marked disparities around primary causes of ED and inpatient admissions were identified between persons experiencing homelessness and the general population. There is a continued need for prevention measures to reduce the prevalence of drug and alcohol, injury and poisoning-related admissions to the ED, enhanced service provision at the community level, and multisector collaborations. These initiatives should maximise opportunities for early interventions and improve outcomes for persons experiencing homelessness, including increased accessibility of healthcare and mental health services, particularly in areas that demonstrate increasing ED and inpatient attendance rates over time.

We believe that there is sufficient evidence from basic science, longitudinal cohort studies and randomised controlled trials which validates the low-density lipoprotein cholesterol (LDL-C) or lipid hypothesis. It is important that we can communicate details of the cardiovascular disease (CVD) risk reduction that the average patient could expect depending on the scale of LDL-C decrease following lipid lowering therapy. It is also essential that residual risk (ResR) of CVD be highlighted. To achieve this aim by using existing trial evidence, we developed mathematical models initially for relative risk reduction (RRR) and absolute risk (AR) reduction and then showed that despite optimising LDL-C levels, a considerable degree of ResR remains that is dependent on AR. Age is significantly associated with AR (odds ratio: 1.02, 95% confidence intervals: 1.01-1.04) as was previously demonstrated by analysing the Whickham study cohort using a logistic regression model (age remaining significant even when all the other significant risk factors such as sex, smoking, systolic blood pressure, diabetes and family history were included in the regression model). A discussion of a paper by Ference et al. provided detailed evidence of the relationship between age and AR, based on lifetime LDL-C exposure. Finally, we discussed non-traditional CVD risk factors that may contribute to ResR based on randomised controlled trials investigating drugs improving inflammation, thrombosis, metabolic and endothelial status.

Background: Although the pharmacological approach may help with motor symptoms in Parkinson's disease (PD), they are clearly not the complete solution. Thus, for the treatment of PD motor symptoms, physical activity has been proposed as an effective intervention. Methods: A systematic search in MEDLINE, Web of Science, Scopus, and Cochrane Central Register of Controlled Trials databases was conducted to identify randomized controlled trials testing the effectiveness of exercise interventions on motor symptoms of PD. Physical exercise interventions were divided into 9 categories: endurance, resistance, combined, balance, dance, alternative exercises, body weight supported, sensorimotor interventions including endurance exercise, and sensorimotor interventions not including endurance exercise. A pairwise meta-analysis for direct and indirect comparisons between intervention and control/nonintervention groups was carried out. Results: Fifty-six studies met the inclusion criteria, including 2740 participants, aged between 57.6 and 77.7 years. Results showed that sensorimotor training including endurance (effect size [ES]−1.09; 95% confidence interval [CI], −1.68 to −0.50), resistance (ES−0.82; 95% CI, −1.23 to −0.41), and dance (ES−0.64; 95% CI, −1.24 to −0.05) were the most effective physical activity interventions for mitigating PD motor symptoms. Conclusion: Physical activity interventions are an effective strategy for the management of motor symptoms in patients with PD. Among the different exercise intervention programs, those including more complex and demanding activities (sensorimotor training including endurance, resistance, and dance) seem to be the most effective physical activity interventions.