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Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB–IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0–2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin–carboplatin, or 15 mg/kg every 21 days combined with gemcitabine–carboplatin or paclitaxel–carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4–9·3) in the standard chemotherapy group and 11·8 months (10·8–12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41–0·65; log-rank p<0·0001). Most common grade 3–4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. Hoffmann–La Roche and Associazione Italiana per la Ricerca sul Cancro.

SummaryBackgroundAdding immunotherapy to first-line chemotherapy might improve outcomes for patients with advanced or recurrent endometrial cancer. We aimed to compare carboplatin and paclitaxel versus avelumab plus carboplatin and paclitaxel as first-line treatment with avelumab given concurrent to chemotherapy and as maintenance after the end of chemotherapy. MethodsMITO END-3 is an open-label, randomised, controlled, phase 2 trial conducted at 31 cancer institutes, hospitals, and universities in Italy. Eligible patients were aged 18 years or older with histologically confirmed advanced (FIGO stage III–IV) or recurrent endometrial cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and no previous systemic anticancer therapy as primary treatment for advanced or metastatic disease. Participants were randomly assigned (1:1) using a computerised minimisation procedure stratified by centre, histology, and stage at study entry, to either receive carboplatin (area under the curve [AUC] 5 mg/mL × min) and paclitaxel (175 mg/m 2; standard group) intravenously every 3 weeks for six to eight cycles or avelumab (10 mg/kg intravenously) added to carboplatin and paclitaxel (experimental group) every 3 weeks and then every 2 weeks as a single maintenance treatment after the end of chemotherapy until disease progression or unacceptable toxicity. Patients, treating clinicians, and those assessing radiological examinations were not masked to study treatment. The primary endpoint was investigator-assessed progression-free survival, measured in the intention-to-treat (ITT) population. Patients who received at least one dose of study drug were included in the safety analysis. Experimental group superiority was tested with 80% power and one-tailed α 0·20. This trial is registered with ClinicalTrials.gov ( NCT03503786) and EudraCT (2016–004403–31). FindingsFrom April 9, 2018, to May 13, 2021, 166 women were assessed for eligibility and 39 were excluded. 125 eligible patients were randomly assigned to receive carboplatin and paclitaxel (n=62) or avelumab plus carboplatin and paclitaxel (n=63) and included in the ITT population. The median follow-up was 23·3 months (IQR 13·2–29·6) and was similar between the two groups. 91 progression-free survival events were reported, with 49 events in 62 patients in the standard group and 42 events in 63 patients in the experimental group. The median progression-free survival was 9·9 months (95% CI 6·7–12·1) in the standard group and 9·6 months (7·2–17·7) in the experimental group (HR of progression or death 0·78 [60% CI 0·65–0·93]; one-tailed p=0·085). Serious adverse events were reported more frequently in the experimental group (24 vs seven events in the standard group); neutrophil count decrease was the most frequent grade 3–4 adverse event (19 [31%] of 61 patients in the experimental group vs 26 [43%] of 61 patients in the standard group). Two deaths occurred in the experimental group during treatment (one respiratory failure following severe myositis [possibly related to treatment] and one cardiac arrest [not related to treatment]). InterpretationAdding avelumab to first-line chemotherapy deserves further testing in patients with advanced or recurrent endometrial cancer, although consideration of mismatch repair status is warranted. FundingPfizer.

To assess the potential impacts of impoundments on sensitive stream species, such as the Topeka shiner (Notropis topeka) and hornyhead chub (Nocomis biguttatus), I conducted a review of existing scientific literature. A substantial body of literature indicates that construction of dams has a negative impact on native stream fishes. In general, an impoundment can reduce the quantity and quality of stream habitat, alter reproductive and feeding behavior of fishes, and increase the number and sizes of predatory fish within a stream system. These impacts suggest a negative relationship between impoundments and obligate stream species, such as the Topeka shiner and hornyhead chub.

A re-evaluation of the status of fishes in Kansas suggests that 54 of the 116 native species should be assigned special conservation status due to substantial declines in distribution or abundance and/or their rarity in the state. Nine species are recommended for retention in their existing status of endangered, threatened, or species in need of conservation. We recommend elevated conservation status for 44 additional species, and provide information on trends in distribution and abundance for these taxa. A single species, the Arkansas River Shiner, Notropis girardi, is considered to be extirpated recently from Kansas.

A re-evaluation of the status of fishes in Kansas suggests that 54 of the 116 native species should be assigned special conservation status due to substantial declines in distribution or abundance and /or their rarity in the state. Nine species are recommended for retention in their existing status of endangered, threatened, or species in need of conservation. We recommend elevated conservation status for 44 additional species, and provide information on trends in distribution and abundance for these taxa. A single species, the Arkansas River Shiner, Notropis girardi, is considered to be extirpated recently from Kansas.

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. 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. 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. 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. Gates Foundation.

This study presents a comprehensive methodology for the detection and characterization of fractures in geological samples using X-ray computed tomography (CT). By combining convolution-based image processing techniques with advanced neural network-based segmentation, the proposed approach achieves high precision in identifying complex fracture networks. The method was applied to a marly limestone sample from the Maiolica Formation, part of the Umbria–Marche stratigraphic succession (Northern Apennines, Italy), a geological context where fractures often vary in size and contrast and are frequently filled with minerals such as calcite or clays, making their detection challenging. A critical part of the work involved addressing multiple sources of uncertainty that can impact fracture identification and measurement. These included the inherent spatial resolution limit of the CT system (voxel size of 70.69 μm), low contrast between fractures and the surrounding matrix, artifacts introduced by the tomographic reconstruction process (specifically the Radon transform), and noise from both the imaging system and environmental factors. To mitigate these challenges, we employed a series of preprocessing steps such as Gaussian and median filtering to enhance image quality and reduce noise, scanning from multiple angles to improve data redundancy, and intensity normalization to compensate for shading artifacts. The neural network segmentation demonstrated superior capability in distinguishing fractures filled with various materials from the host rock, overcoming the limitations observed in traditional convolution-based methods. Overall, this integrated workflow significantly improves the reliability and accuracy of fracture quantification in CT data, providing a robust and reproducible framework for the analysis of discontinuities in heterogeneous and complex geological materials.

Background Chronic obstructive pulmonary disease (COPD) is commonly associated with anxiety/depression which can affect self-management and quality of life. The TANDEM trial evaluated a cognitive behavioural approach intervention targeting COPD-related symptoms of anxiety and/or depression, comprising up to eight one-to-one sessions delivered by respiratory healthcare professionals prior to pulmonary rehabilitation (PR). The intervention showed no improvement in anxiety/depression or uptake/completion of PR. We present patient perspectives of the intervention to help understand these results. Method Semi-structured individual interviews, using a semi-structured topic guide informed by Sekhon’s Theoretical Framework of Acceptability, were conducted with 19 patients between September 2019 and April 2020. The interviews were audio-recorded, transcribed verbatim and analysed thematically. Results The following could have limited the impact of the intervention: (1) The lives of patients were complex and commonly affected by competing comorbidities or other external stressors which they managed through previously adopted long-standing coping strategies. (2) Some patients were reluctant to talk about their mood despite the Facilitators' training and person centred-skills which aimed to enable patients to talk freely about mood. (3) The intervention handouts and ‘home-practice’ were perceived as helpful for some, but not suitable for all. (4) Many patients perceived improvements in their physical and mental health, but this was not sustained due to a mix of personal and external factors, and some did not perceive any benefits. (5) PR non-attendance/non-completion was a result of personal and PR service-related reasons. (6) Discussing COPD and mental health with the Facilitator was a novel experience. Many patients felt that TANDEM could be of benefit if it was offered earlier on/at different time points in the COPD illness journey. Conclusion We found the delivery of TANDEM prior to PR was not helpful for patients with advanced COPD often experiencing other comorbidities, and/or difficult personal/external events. These patients already utilised long-standing coping strategies to manage their COPD. Holistic interventions, that address the impact of COPD in relation to wider aspects of a patients’ life, may be more beneficial. Trial registration ISRCTN Registry 59,537,391. Registration date 20 March 2017.

Timely detection and treatment of postpartum hemorrhage (PPH) are crucial to prevent complications or death. A calibrated blood-collection drape can help provide objective, accurate and early diagnosis of PPH, and a treatment bundle can address delays or inconsistencies in the use of effective interventions. Here we conducted an economic evaluation alongside the E-MOTIVE trial, an international, parallel cluster-randomized trial with a baseline control phase involving 210,132 women undergoing vaginal delivery across 78 secondary-level hospitals in Kenya, Nigeria, South Africa and Tanzania. We aimed to assess the cost-effectiveness of the E-MOTIVE intervention, which included a calibrated blood-collection drape for early detection of PPH and a bundle of first-response treatments (uterine massage, oxytocic drugs, tranexamic acid, intravenous fluids, examination and escalation), compared with usual care. We used multilevel modeling to estimate incremental cost-effectiveness ratios from the perspective of the public healthcare system for outcomes of cost per severe PPH (blood loss ≥1,000 ml) avoided and cost per disability-adjusted life-year averted. Our findings suggest that the use of a calibrated blood-collection drape for early detection of PPH and bundled first-response treatment is cost-effective and should be perceived by decision-makers as a worthwhile use of healthcare budgets. ClinicalTrials.gov identifier: NCT04341662 . An economic evaluation of the E-MOTIVE intervention for postpartum hemorrhage (PPH) compared with usual care in 210,132 women, carried out from a healthcare system perspective, uncovered the cost per case of severe PPH prevented and cost per disability-adjusted life-year averted.

Postpartum haemorrhage (PPH) is the leading cause of global maternal deaths, accounting for 30-50% of maternal deaths in sub-Saharan Africa. Most PPH-related deaths are preventable with timely detection and initiation of care, which may be facilitated by using a clinical care bundle. We explore influences on current PPH detection and management and on the future implementation of a new PPH bundle (E-MOTIVE) in low-resource, high-burden settings. Semi-structured qualitative interviews based on the Theoretical Domains Framework were conducted with 45 healthcare providers across nine hospitals in Nigeria, Kenya and South Africa, to identify barriers and enablers to current PPH detection and management and future implementation of a new PPH care bundle. Data were analysed using thematic and framework analysis. The Behaviour Change Wheel was used to identify potential interventions to address identified barriers and enablers. Influences on current PPH detection and management fell under 12 domains: Environmental Context and Resources (drug and staff shortages), Skills (limited in-service training), Knowledge (variable understanding of the recommended practice), Behaviour Regulation (limited quality improvement culture), Beliefs about Consequences (drawbacks from inaccurate detection), Emotion (stress from the unpredictability of PPH), Social Influence (teamwork), Memory, Attention and Decision-making (limited guideline use), Social/Professional Role and Identity (role clarity), Beliefs about Capabilities (confidence in managing PPH), Reinforcement (disciplinary procedures) and Goals (PPH as a priority). Influences on bundle uptake included: Beliefs about Consequences (perceived benefits of new blood loss measurement tool), Environmental Context and Resources (high cost of drugs and new tools), Memory, Attention and Decision-making (concerns about whether bundle fits current practice), Knowledge (not understanding 'bundled' approach), Social Influence (acceptance by women and staff) and Intention (limited acceptance of 'bundled' approach over existing practice). These influences were consistent across countries. Proposed interventions included: Education, Training, Modelling (core and new skills), Enablement (monitoring uptake), Persuasion (leadership role) and Environmental Restructuring (PPH emergency trolley/kit). A wide range of individual, socio-cultural and environmental barriers and enablers to improving PPH detection and management exist in these settings. We identified a range of interventions that could improve PPH care and the implementation of new care bundles in this context. ClinicalTrials.gov : NCT04341662.