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Time-lapse imaging systems for embryo incubation and selection might improve outcomes of in-vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) treatment due to undisturbed embryo culture conditions, improved embryo selection, or both. However, the benefit remains uncertain. We aimed to evaluate the effectiveness of time-lapse imaging systems providing undisturbed culture and embryo selection, and time-lapse imaging systems providing only undisturbed culture, and compared each with standard care without time-lapse imaging. We conducted a multicentre, three-parallel-group, double-blind, randomised controlled trial in participants undergoing IVF or ICSI at seven IVF centres in the UK and Hong Kong. Embryologists randomly assigned participants using a web-based system, stratified by clinic in a 1:1:1 ratio to the time-lapse imaging system for undisturbed culture and embryo selection (time-lapse imaging group), time-lapse imaging system for undisturbed culture alone (undisturbed culture group), and standard care without time-lapse imaging (control group). Women were required to be aged 18–42 years and men (ie, their partners) 18 years or older. Couples had to be receiving their first, second, or third IVF or ICSI treatment and could not participate if using donor gametes. Participants and trial staff were masked to group assignment, embryologists were not. The primary outcome was live birth. We performed analyses using the intention-to-treat principle and reported the main analysis in participants with primary outcome data available (full analysis set). The trial is registered on the International Trials Registry (ISRCTN17792989) and is now closed. 1575 participants were randomly assigned to treatment groups (525 participants per group) between June 21, 2018, and Sept 30, 2022. The live birth rates were 33·7% (175/520) in the time-lapse imaging group, 36·6% (189/516) in the undisturbed culture group, and 33·0% (172/522) in the standard care group. The adjusted odds ratio was 1·04 (97·5% CI 0·73 to 1·47) for time-lapse imaging arm versus control and 1·20 (0·85 to 1·70) for undisturbed culture versus control. The risk reduction for the absolute difference was 0·7 percentage points (97·5% CI –5·85 to 7·25) between the time-lapse imaging and standard care groups and 3·6 percentage points (–3·02 to 10·22) between the undisturbed culture and standard care groups. 79 serious adverse events unrelated to the trial were reported (n=28 in time-lapse imaging, n=27 in undisturbed culture, and n=24 in standard care). In women undergoing IVF or ICSI treatment, the use of time-lapse imaging systems for embryo culture and selection does not significantly increase the odds of live birth compared with standard care without time-lapse imaging. Barts Charity, Pharmasure Pharmaceuticals, Hong Kong OG Trust Fund, Hong Kong Health and Medical Research Fund, Hong Kong Matching Fund.

IntroductionDespite advances in the management, Pancreato-Biliary (PB) cancers are associated with poor 5-year survival. Due to their location and the initial non-specific symptoms, time to diagnosis is significantly higher compared to other cancers. Standard-of-care confirmation of diagnosis is through brush cytology, which is often inadequate. Hence, patients often undergo multiple procedures to reach definitive diagnosis. Tissue acquisition through either bile duct biopsies or endoscopic ultrasound (EUS) guided needle biopsies improve the diagnostic yield. We evaluated the diagnostic yield of all cytology and biopsy in PB cancer.MethodsAll consecutive patients who were investigated for bile duct strictures between January 2022 and January 2024 in Nottingham University Hospitals NHS Trust were reviewed. Patients were included if they either had biliary brushing or biopsies acquired via endoscopic retrograde cholangiopancreatography (ERCP), EUS or percutaneous transhepatic cholangiogram (PTC). Repeat procedures on the same patient were counted only if repeat sampling was done. Patient demographics, cytology results, histology results and final multidisciplinary meeting (MDM) diagnosis were collected. Cytology was considered as positive for cancer if it was reported as C5; MDM diagnosis, which is based on imaging, histopathology, tumour markers was considered the definitive diagnosis. Sensitivity, specificity, positive predictive and negative predictive values (PPV, NPV) were calculated for both cytology and biopsy using SPSS software.Results315 consecutive PTC, EUS and ERCP procedures were reviewed; of these, 106 did not include sampling and were excluded. Two hundred nine procedure samples from 179 patients were included in the analysis. The median age was 72 (IQR 17.0); the majority were males (n=104, 58%). The sensitivity, specificity, PPV and NPV for cytology and biopsies are described below. Abstract P224 Table 1Type of cancer Sample type Sensitivity% Specificity% PPV% NPV% All PB cancers Biopsy 88.3 91.0 96.5 69.7 Cytology 73.2 90.1 95.8 51.2 Combined 89.9 90.1 96.4 76.7 Pancreas Biopsy 89.8 93.1 95.8 67.4 Cytology 70.9 95.3 95.3 51.4 Combined 70.2 97.9 95.5 53.0 CCA Biopsy 93.8 74.5 86.5 93.4 Cytology 91.4 58.1 74.2 83.4 Combined 93.2 72.1 85.0 86.7 The average number of brushings were similar between PTC and ERCP (1.26 [SD 0.75] vs 1.08 [SD 0.43]); similarly, the average number of PTC procedures and ERCP procedures required to obtain a diagnosis sample were similar (1.35 [SD0.79] vs. 1.21 [SD0.53])ConclusionsThe diagnostic yield of biopsy specimens is significantly better compared to cytology for all PB cancers together and individually. Obtaining biopsy specimens may lead to earlier diagnosis, minimize the number of procedures required and aid molecular analysis.

IntroductionNeurodegenerative disorders (NDDs) represent an unprecedented public health burden. These disorders are clinically heterogeneous and therapeutically challenging, but advances in discovery science and trial methodology offer hope for translation to new treatments. Against this background, there is an urgent unmet need for biomarkers to aid with early and accurate diagnosis, prognosis and monitoring throughout the care pathway and in clinical trials.Investigations routinely used in clinical care and trials are often invasive, expensive, time-consuming, subjective and ordinal. Speech data represent a potentially scalable, non-invasive, objective and quantifiable digital biomarker that can be acquired remotely and cost-efficiently using mobile devices, and analysed using state-of-the-art speech signal processing and machine learning approaches. This prospective case–control observational study of multiple NDDs aims to deliver a deeply clinically phenotyped longitudinal speech dataset to facilitate development and evaluation of speech biomarkers.Methods and analysisPeople living with dementia, motor neuron disease, multiple sclerosis and Parkinson’s disease are eligible to participate. Healthy individuals (including relatives or carers of participants with neurological disease) are also eligible to participate as controls. Participants complete a study app with standardised speech recording tasks (including reading, free speech, picture description and verbal fluency tasks) and patient-reported outcome measures of quality of life and mood (EuroQol-5 Dimension-5 Level, Patient Health Questionnaire 2) every 2 months at home or in clinic. Participants also complete disease severity scales, cognitive screening tests and provide optional samples for blood-based biomarkers at baseline and then 6-monthly. Follow-up is scheduled for up to 24 months. Initially, 30 participants will be recruited to each group. Speech recordings and contemporaneous clinical data will be used to create a dataset for development and evaluation of novel speech-based diagnosis and monitoring algorithms.Ethics and disseminationDigital App for Speech and Health Monitoring Study was approved by the South Central—Hampshire B Ethics Committee (REC ref. 24/SC/0067), NHS Lothian (R&D ref. 2024/0034) and NHS Forth Valley (R&D ref. FV1494). Results of the study will be submitted for publication in peer-reviewed journals and conferences. Data from the study will be shared with other researchers and used to facilitate speech processing challenges for neurological disorders. Regular updates will be provided on the Anne Rowling Regenerative Neurology Clinic web page and social media platforms.Trial registrationClinicalTrials.gov NCT06450418 (pre-results).

Although it is important that stem cell therapies are advanced into the clinic, their safety must be continually evaluated. This review, the result of an Innovative Medicines Initiative SafeSciMET workshop with support from the UK Regenerative Medicine Platform, held at the University of Liverpool, outlines the known risks of stem cell therapeutics and discusses how they can be assessed and managed through preclinical and clinical trials to ensure the safest possible development of new products. The field of stem cell therapeutics is moving ever closer to widespread application in the clinic. However, despite the undoubted potential held by these therapies, the balance between risk and benefit remains difficult to predict. As in any new field, a lack of previous application in man and gaps in the underlying science mean that regulators and investigators continue to look for a balance between minimizing potential risk and ensuring therapies are not needlessly kept from patients. Here, we attempt to identify the important safety issues, assessing the current advances in scientific knowledge and how they may translate to clinical therapeutic strategies in the identification and management of these risks. We also investigate the tools and techniques currently available to researchers during preclinical and clinical development of stem cell products, their utility and limitations, and how these tools may be strategically used in the development of these therapies. We conclude that ensuring safety through cutting‐edge science and robust assays, coupled with regular and open discussions between regulators and academic/industrial investigators, is likely to prove the most fruitful route to ensuring the safest possible development of new products.

ObjectiveTo determine the incidence of venous thromboembolism in patients with advanced epithelial ovarian cancer undergoing neoadjuvant chemotherapy in UK gynecological cancer centers. Secondary outcomes included incidence and timing of venous thromboembolism since cancer presentation, impact on cancer treatment, and mortality.MethodsAll UK gynecological cancer centers were invited to participate in this multi-center retrospective audit through the British Gynecological Cancer Society. Data were captured on all patients undergoing neoadjuvant chemotherapy for International Federation of Gynecology and Obstetrics (FIGO) stage III/IV epithelial ovarian cancer within a 12-month period during 2021–2022. Patients on anticoagulation prior to cancer presentation were excluded. Patients who were diagnosed with venous thromboembolism between cancer presentation and commencing neoadjuvant chemotherapy were also excluded from our analysis of venous thromboembolism rates from neoadjuvant chemotherapy.ResultsFourteen UK gynecological cancer centers returned data on 660 eligible patients. The median age was 67 years (range 34–96). In total, 131/660 (19.8%) patients were diagnosed with venous thromboembolism from cancer presentation until discharge following cytoreductive surgery. Between commencing neoadjuvant chemotherapy and post-operative discharge, 65/594 (10.9%) patients developed venous thromboembolism (median 11.3%, IQR 5.9–11.3); 55/594 (9.3%) during neoadjuvant chemotherapy, 10/594 (1.7%) during post-operative admission. There was no significant difference across centers (p=0.47). Of these 65 patients, 44 (68%) were diagnosed with pulmonary embolism and 30 (46%) with deep-vein thrombosis (nine had both), including in major abdominal/pelvic vessels, with 36 (55%) presenting symptomatically and 29 (45%) diagnosed incidentally on imaging. Venous thromboembolism resulted in mortality (n=3/65, 5%), and delays/changes/cancelation of treatment (n=18/65, 28%).ConclusionAcross a large, representative sample of UK gynecological cancer centers, one in five patients undergoing neoadjuvant chemotherapy were diagnosed with a potentially preventable venous thromboembolism, including one in nine diagnosed after commencing chemotherapy. This led to adverse clinical consequences for one third, including delay to oncological treatment and mortality. This high venous thromboembolism rate justifies the consideration of thromboprophylaxis in this patient group.

This paper is part of a larger community health study aimed at delineating the determinants of health in Sarnia. The paper specifically investigates Sarnia residents' daily lived experiences, perceptions of and responses to living within the St. Clair River \"Area of Concern\" (AOC) as designated by the federal government based on the hypothesis that relatively high levels of environmental pollution in the region are negatively influencing human health. Results from in-depth interviews (N = 27) show that residents of Sarnia are conflicted by the elevation of awareness about environmental health threats by being labelled within an AOC. Residents use their emotional and sensual experiences to adopt appropriate coping strategies to live within a contaminated community. In contextualizing their everyday lived realities, residents argued that living in an AOC demands personal acceptance of the conditions in Sarnia and awareness of \"bad air days\" to cope with pollution exposure. Yet, residents were not willing to abandon Sarnia because of their cultural, social, and economical attachments to the place they call home. These findings suggest the need for local health policies that incorporate local concerns and perceptions of how environmental pollution affects people's experiences and well-being. There is a necessity to involve community members as central participants in the process of policy making.

To determine the incidence of venous thromboembolism in patients with advanced epithelial ovarian cancer undergoing neoadjuvant chemotherapy in UK gynecological cancer centers. Secondary outcomes included incidence and timing of venous thromboembolism since cancer presentation, impact on cancer treatment, and mortality. All UK gynecological cancer centers were invited to participate in this multi-center retrospective audit through the British Gynecological Cancer Society. Data were captured on all patients undergoing neoadjuvant chemotherapy for International Federation of Gynecology and Obstetrics (FIGO) stage III/IV epithelial ovarian cancer within a 12-month period during 2021-2022. Patients on anticoagulation prior to cancer presentation were excluded. Patients who were diagnosed with venous thromboembolism between cancer presentation and commencing neoadjuvant chemotherapy were also excluded from our analysis of venous thromboembolism rates from neoadjuvant chemotherapy. Fourteen UK gynecological cancer centers returned data on 660 eligible patients. The median age was 67 years (range 34-96). In total, 131/660 (19.8%) patients were diagnosed with venous thromboembolism from cancer presentation until discharge following cytoreductive surgery. Between commencing neoadjuvant chemotherapy and post-operative discharge, 65/594 (10.9%) patients developed venous thromboembolism (median 11.3%, IQR 5.9-11.3); 55/594 (9.3%) during neoadjuvant chemotherapy, 10/594 (1.7%) during post-operative admission. There was no significant difference across centers (p=0.47). Of these 65 patients, 44 (68%) were diagnosed with pulmonary embolism and 30 (46%) with deep-vein thrombosis (nine had both), including in major abdominal/pelvic vessels, with 36 (55%) presenting symptomatically and 29 (45%) diagnosed incidentally on imaging. Venous thromboembolism resulted in mortality (n=3/65, 5%), and delays/changes/cancelation of treatment (n=18/65, 28%). Across a large, representative sample of UK gynecological cancer centers, one in five patients undergoing neoadjuvant chemotherapy were diagnosed with a potentially preventable venous thromboembolism, including one in nine diagnosed after commencing chemotherapy. This led to adverse clinical consequences for one third, including delay to oncological treatment and mortality. This high venous thromboembolism rate justifies the consideration of thromboprophylaxis in this patient group.

Background Organizational and clinician characteristics are important considerations for the implementation of evidence-based recommendations into primary care practice. The introduction of Canadian dementia practice guidelines and Alzheimer strategies offers a unique context to study which of the organizational and clinician characteristics align with good quality care in primary care practices. Methods To evaluate the quality of dementia care, we carried out a retrospective chart review in randomly selected patients with a diagnosis of dementia and who had a visit during a 9-month period in 33 primary care practices. We collected data on indicators that were based on existing Canadian evidence-based recommendations to measure a quality of dementia care score. In addition, four questionnaires were administered: two questionnaires to evaluate the organizational characteristics of the practices (dementia-specific and general organization) and two to evaluate the clinician characteristics (one for family physicians and one for nurses). Primary care practices were stratified into tertiles based on their average quality of dementia care score (low, moderate, high). The differences between the groups organizational and clinician questionnaires scores were analyzed descriptively and visually. Results The mean overall scores for each questionnaire were higher in the high quality of dementia care group. When looking at the breakdown of the overall score into each characteristic, the high-quality group had a higher average score for the dementia-specific organizational characteristics of “access to and coordination with home and community services”, “financial support”, “training”, “coordination and continuity within the practice”, and “caregiver support and involvement”. The characteristic “Leadership” showed a higher average score for the moderate and high-quality groups than the low-quality group. In both clinician questionnaires, the high group scored better in “attitudes towards the Alzheimer’s plan” than the other two groups. Conclusions These results suggest that investing in organizational characteristics specifically aimed at dementia care is a promising avenue to improve quality of dementia care in primary care. These results may be useful to enhance the implementation of evidence-based practices and improve the quality of dementia care.

Protein S (PS), the critical plasma cofactor for the anticoagulants tissue factor (TF) pathway inhibitor (TFPI) and activated protein C (APC), circulates in two functionally distinct pools: free (anticoagulant) or bound to complement component 4b-binding protein (C4BP) (anti-inflammatory). Acquired free PS deficiency is detected in several viral infections, but its cause is unclear. Here, we identified a shear-dependent interaction between PS and von Willebrand Factor (VWF) by mass spectrometry. Consistently, plasma PS and VWF comigrated in both native and agarose gel electrophoresis. The PS/VWF interaction was blocked by TFPI but not APC, suggesting an interaction with the C-terminal sex hormone binding globulin (SHBG) region of PS. Microfluidic systems, mimicking arterial laminar flow or disrupted turbulent flow, demonstrated that PS stably binds VWF as VWF unfolds under turbulent flow. PS/VWF complexes also localized to platelet thrombi under laminar arterial flow. In thrombin generation-based assays, shearing plasma decreased PS activity, an effect not seen in the absence of VWF. Finally, free PS deficiency in COVID-19 patients, measured using an antibody that binds near the C4BP binding site in SHBG, correlated with changes in VWF, but not C4BP, and with thrombin generation. Our data suggest that PS binds to a shear-exposed site on VWF, thus sequestering free PS and decreasing its anticoagulant activity, which would account for the increased thrombin generation potential. As many viral infections present with free PS deficiency, elevated circulating VWF, and increased vascular shear, we propose that the PS/VWF interaction reported here is a likely contributor to virus-associated thrombotic risk.