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The Institute of Biomedical Engineering and Nuffield Department of Obstetrics and Gynaecology receives Grand Challenges Explorations Grant for Groundbreaking Research in Global Health and Development.
Amyloid-β disrupts APP-regulated protein aggregation and dissociation from recycling endosomal membranes.
Secretory proteins aggregate into non-soluble dense-core granules in recycling endosome-like compartments prior to regulated release. By contrast, aberrantly processed, secreted amyloid-β (Aβ) peptides derived from amyloid precursor protein (APP) form pathological extracellular amyloidogenic aggregations in late-stage Alzheimer's disease (AD). By examining living Drosophila prostate-like secondary cells, we show that both APP and Aβ peptides affect normal biogenesis of dense-core granules. These cells generate dense-core granules and secreted nanovesicles called Rab11-exosomes via evolutionarily conserved mechanisms within highly enlarged secretory compartments with recycling endosomal identity. The fly APP homologue, APP-like (APPL), associates with these vesicles and the compartmental limiting membrane, from where its extracellular domain modulates protein aggregation. Proteolytic release of this domain permits mini-aggregates to coalesce into a large central dense-core granule. Mutant Aβ expression disrupts this process and compartment motility, and increases aberrant lysosomal targeting, mirroring previously unexplained early-stage pathological events in AD. It also promotes cell-to-cell propagation of these endolysosomal defects, again phenocopying changes observed in AD. Our data therefore demonstrate physiological roles for APP in membrane-dependent protein aggregation, involving molecular mechanisms, which when disrupted by Aβ peptides, trigger Alzheimer's disease-relevant pathologies.
A new paradigm of islet adaptations in human pregnancy: insights from immunohistochemistry and proteomics
Abstract Physiological changes during pregnancy support foetal growth, including adaptations in pancreatic islets to maintain glucose homeostasis. We investigate these adaptations using rare, high-quality pancreatic tissue from pregnant human donors and matched controls. We profile islets from pregnant donors using proteomics and assess α- and β-cell characteristics, as well as prolactin receptor and serotonin 2B receptor expression. Proteomic profiling of microdissected human islets identifies 7546 proteins but shows minimal differences in protein expression. In pregnancy, we show that islet area increases 1.9-fold, α- and β-cell areas increase 4.3- and 1.9-fold, driven by an increase in cell number rather than hypertrophy. Prolactin receptor expression is higher in α but not β cells, and serotonin 2B receptor is undetectable in β cells. Glucagon-like peptide-1 abundance increases 2.9-fold in α cells. These findings indicate that the molecular mechanisms driving pregnancy-induced islet adaptations in humans differ from those in mice, highlighting the need for human-based studies.
The global scope and components of family-centred care for preterm infants: An umbrella review.
Preterm birth is the leading cause of under-five mortality. Family-centred care (FCC) interventions may improve outcomes related to prematurity and may be used to address this issue to achieve the Sustainable Development Goals. We aimed to consolidate the scope of evidence and components of FCC interventions for preterm infants globally and see its relevance for low-resource settings. We conducted an umbrella review informed by the Joanna Briggs Institute (JBI) guidelines. Systematic literature reviews evaluating FCC in the preterm or high-risk infant population and their families were identified from six databases. Keywords included "family-centred care", "premature infants", "neonatal intensive care unit", and their relevant synonyms. Quality appraisal was conducted using the JBI Critical Appraisal Checklist for Systematic Reviews and Research Syntheses and data extraction performed to an agreed table. Thematic analysis was carried out to categorise the components of FCC interventions. Forty-four reviews were included in the umbrella review. Outcomes were observed on the parents in 40 studies, the infant in 19, the health care provider in 13, and the health system in 7. Most studies focused on inpatient settings (79.6%) and were conducted primarily in high-income countries (92.3%). The components identified were general FCC, health system design, parent support, partnership in care, and information and communication. Overall, FCC interventions have a positive impact on parental, infant, and health system outcomes, with consistent reporting of FCC impact on parental well-being and satisfaction, infant length of stay, feeding and growth, and hospital readmission rates. FCC interventions have the potential to improve preterm infant health system outcomes. To maximise impact, FCC interventions need to be further explored in low-resource and post-discharge settings, where the burden of premature infant morbidity and mortality is highest. Evidence in both these settings is scarce. Future research efforts should aim to close these evidence gaps.
Innovations and strategies for effective implementation of post pregnancy contraception services: Learnings from the FIGO PPIUD initiative.
The global unmet need for contraception continues to be unacceptably high at 218 million. The vast majority of these are women living in low and middle income countries, with a particularly high unmet need in the postpartum period. The FIGO PPIUD initiative demonstrated that it is feasible to embed counselling on contraception and insertion of PPIUD in maternity services. Implementation of these services was greatly enhanced by ensuring that counselling was culturally sensitive and appropriately given through specifically trained individuals, that task sharing was maximized in order to increase access, and that a high fundal placement was achieved resulting in low expulsion rates. Financing for contraception in LMICs is currently precarious and vulnerable to international politics. PPIUD is highly cost-effective. Expansion of contraception services including PPIUD has the potential to impact positively on climate change and a country's development profile if expanded on a large scale.
Genetic and reproductive strategies to prevent mitochondrial diseases.
Mitochondrial DNA (mtDNA) diseases pose unique challenges for genetic counselling and require tailored approaches to address recurrence risks and reproductive options. The intricate dynamics of mtDNA segregation and heteroplasmy shift significantly impact the chances of having affected children. In addition to natural pregnancy, oocyte donation, and adoption, IVF-based approaches can reduce the risk of disease transmission. Prenatal diagnosis (PND) and preimplantation genetic testing (PGT) remain the standard methods for women carrying pathogenic mtDNA mutations; nevertheless, they are not suitable for every patient. Germline nuclear transfer (NT) has emerged as a novel therapeutic strategy, while mitochondrial gene editing has increasingly become a promising research area in the field. However, challenges and safety concerns associated with all these techniques remain, highlighting the need for long-term follow-up studies, an improved understanding of disease mechanisms, and personalized approaches to diagnosis and treatment. Given the inherent risks of adverse maternal and child outcomes, careful consideration of the balance between potential benefits and drawbacks is also warranted. This review will provide critical insights, identify knowledge gaps, and underscore the importance of advancing mitochondrial disease research in reproductive health.
Prenatal detection of congenital heart defects using the deep learning-based image and video analysis: protocol for Clinical Artificial Intelligence in Fetal Echocardiography (CAIFE), an international multicentre multidisciplinary study.
INTRODUCTION: Congenital heart defect (CHD) is a significant, rapidly emerging global problem in child health and a leading cause of neonatal and childhood death. Prenatal detection of CHDs with the help of ultrasound allows better perinatal management of such pregnancies, leading to reduced neonatal mortality, morbidity and developmental complications. However, there is a wide variation in reported fetal heart problem detection rates from 34% to 85%, with some low- and middle-income countries detecting as low as 9.3% of cases before birth. Research has shown that deep learning-based or more general artificial intelligence (AI) models can support the detection of fetal CHDs more rapidly than humans performing ultrasound scan. Progress in this AI-based research depends on the availability of large, well-curated and diverse data of ultrasound images and videos of normal and abnormal fetal hearts. Currently, CHD detection based on AI models is not accurate enough for practical clinical use, in part due to the lack of ultrasound data available for machine learning as CHDs are rare and heterogeneous, the retrospective nature of published studies, the lack of multicentre and multidisciplinary collaboration, and utilisation of mostly standard planes still images of the fetal heart for AI models. Our aim is to develop AI models that could support clinicians in detecting fetal CHDs in real time, particularly in nonspecialist or low-resource settings where fetal echocardiography expertise is not readily available. METHODS AND ANALYSIS: We have designed the Clinical Artificial Intelligence Fetal Echocardiography (CAIFE) study as an international multicentre multidisciplinary collaboration led by a clinical and an engineering team at the University of Oxford. This study involves five multicountry hospital sites for data collection (Oxford, UK (n=1), London, UK (n=3) and Southport, Australia (n=1)). We plan to curate 14 000 retrospective ultrasound scans of fetuses with normal hearts (n=13 000) and fetuses with CHDs (n=1000), as well as 2400 prospective ultrasound cardiac scans, including the proposed research-specific CAIFE 10 s video sweeps, from fetuses with normal hearts (n=2000) and fetuses diagnosed with major CHDs (n=400). This gives a total of 16 400 retrospective and prospective ultrasound scans from the participating hospital sites. We will build, train and validate computational models capable of differentiating between normal fetal hearts and those diagnosed with CHDs and recognise specific types of CHDs. Data will be analysed using statistical metrics, namely, sensitivity, specificity and accuracy, which include calculating positive and negative predictive values for each outcome, compared with manual assessment. ETHICS AND DISSEMINATION: We will disseminate the findings through regional, national and international conferences and through peer-reviewed journals. The study was approved by the Health Research Authority, Care Research Wales and the Research Ethics Committee (Ref: 23/EM/0023; IRAS Project ID: 317510) on 8 March 2023. All collaborating hospitals have obtained the local trust research and development approvals.
Effect of supine or semi-recumbent positions on arterial stiffness among pregnant women
Objective: We aimed to evaluate whether there was a difference in arterial stiffness measurements in supine and semirecumbent positions among pregnant women. Methods: This was a cross-sectional study in four public hospitals in Uganda. Women were interviewed to capture demographic data and obstetric history before undergoing arterial stiffness examinations using the Arteriograph device (TensioMed, Budapest, Hungary) in supine and semirecumbent positions. Three consecutive measurements were acquired per position and were transformed to gestational age adjusted z-scores for analysis using a two-sample t-test, paired t-test and Pearson correlation coefficients. Results: We included 194 pregnant women, with median age of 25 years (interquartile rage (IQR), 21–29), and body mass index of 23.9 kg/m2 (IQR, 21.1–27.6). None was smoking or had renal and cardiac diseases. The procedure failure rate was less than 3 %. There were no significant differences in measurements between supine and semirecumbent positions at 11–42 weeks. We found a strong positive correlation between hemodynamic indices performed in supine and semirecumbent positions: aortic pulse wave velocity z-scores (r = 0.84 (95 % CI, 0.77–0.89)) and aortic augmentation index z-scores (r = 0.95 (95 % CI, 0.92–0.97)) at 11–27 weeks’ gestation, and central systolic blood pressure z-scores (r = 0.81 (95 % CI, 0.72–0.87)) and mean arterial pressure z-scores (r = 0.84 (95 % CI, 0.77–0.89)) at 28–42 weeks’ gestation. Repeated measurements taken in same position were strongly correlated throughout gestation. Conclusion: Arterial stiffness parameters measured in supine and semirecumbent positions were comparable and had very minimal failure rates. As a supine position is often not tolerated well in late gestation, our study suggests that pregnant women could assume a semirecumbent position during Arteriograph test procedures between 11 and 42 weeks of gestation.
WERF Endometriosis Phenome and Biobanking Harmonisation Project for Experimental Models in Endometriosis Research (EPHect-EM-Organoids): endometrial organoids as an emerging technology for endometriosis research
The aetiology of endometriosis remains poorly understood. In vitro model systems provide the opportunity to identify the mechanisms driving disease pathogenesis using human cells. Three-dimensional models, particularly organoid systems, have revolutionized how we study epithelial biology and are powerful tools for modelling endometriosis. As an emerging model system, it is important to define protocols and identify the remaining challenges surrounding endometrial organoid culture to increase reproducibility and scientific rigour in endometriosis research. The World Endometriosis Research Foundation (WERF) established an international working group comprised of experts using in vitro approaches for the study of endometriosis. This working group harmonized protocols and documentation of existing and emerging organoid systems to maximize comparison and replication across the field and guide specific research hypotheses testing. This evaluation of organoid protocols, limitations, challenges, and alternative approaches assessed both published and grey literature papers across several disciplines pertinent to endometriosis research. Recommendations for protocol and documentation harmonization are presented, and we created the first-ever decision tree diagram to guide and facilitate the selection of existing models best suited for specific areas of endometriosis research. Rigorous and systematic assessment of emerging organoid systems, recognizing the inferential strengths and limitations of these approaches, is vital for endometriosis research. This comprehensive review of the benefits, limitations, and utilization of organoid models, as well as the consequent integration of protocols and documentation, will contribute to the scientific knowledge base by maximizing the reproducibility, comparability, and interpretation of research studies in endometriosis. Additionally, these newly developed protocols and documentation should serve as a resource for, and facilitate collaboration between, endometriosis investigators using organoids in their research methods.
WERF Endometriosis Phenome and Biobanking Harmonisation Project for Experimental Models in Endometriosis Research (EPHect-EM-Pain): methods to assess pain behaviour in rodent models of endometriosis
Pain is a debilitating symptom of endometriosis, and its mechanisms are often explored using rodent models. However, a lack of harmonization amongst models and behavioural measures, in addition to inconsistent reporting, might limit the overall clinical relevance and hinder translation of findings. An additional challenge is accurately linking rodent behaviour to human experiences of endometriosis. This study aimed to: (i) review current measures of pain-associated behaviours used in endometriosis studies; (ii) recommend best practices for each method and their suitability to study endometriosis-associated pain; and (iii) develop internationally agreed-upon standard operating procedures ('EPHect-EM-Pain SOPs'). The World Endometriosis Research Foundation (WERF) assembled an international working group, from which a 'pain behaviour working group' consisting of experts in the field was established. The group used additional consultation from experimental pain model scientists in the broader field. Stimulus-evoked (reflexive) and stimulus-independent (spontaneous) measures are currently used to assess pain-associated behaviours in rodents with experimental endometriosis. All existing methods offer advantages and limitations regarding ethological relevance, output quality, and equipment/training requisites. Internationally standardized pain SOPs as well as summary documentation outlining the minimum and standard requirements for several behavioural measures were developed, as well as consensus recommendations on experimental designs and documentation. To more closely reflect the lived experiences of those with endometriosis, the consortium recommends that, following validation, multiple types of pain-related and/or parallel rodent behaviours (e.g. anxiety) should be quantified as surrogate outcome measures for endometriosis-associated pain. These harmonized methods and documentation for endometriosis research will facilitate essential comparisons among studies, improve translational applicability, and provide a superior holistic view of animal (and thus human) wellbeing.
WERF Endometriosis Phenome and Biobanking Harmonisation Project for Experimental Models in Endometriosis Research (EPHect-EM-Heterologous): heterologous rodent models
Endometriosis, defined as the growth of endometrial-like tissues outside the uterus, is a common disease among women. Numerous in vivo rodent models of endometriosis have been developed to explore multiple aspects of this poorly understood disease. Heterologous models utilize human endometrial tissues engrafted into immunocompromized mice, while homologous models engraft rodent endometrium into immunocompetent mice or rats. Heterologous models of endometriosis more closely replicate the human disease; however, the murine humoral immune response must be suppressed to prevent rejection of the xenograft tissue. Although the innate immune system remains intact, suppression of the humoral response leads to a markedly different local and systemic immune environments compared to humans. Despite this limitation, experiments using heterologous models have contributed significantly to our understanding of endometriosis establishment and progression, the pre-clinical effectiveness of various therapeutic strategies, and genetically modifiable host factors that contribute to disease. Unfortunately, a lack of harmonization of the models used by different laboratories has impeded the reproducibility and comparability of results between groups. Therefore, the World Endometriosis Research Foundation (WERF) formed an international working group of experts in heterologous models of endometriosis to develop guidelines and protocols that could contribute to unifying experimental approaches across laboratories. Nine critical variables were identified: (i) mouse strain; (ii) human tissue type; (iii) hormonal status of the human tissue donor; (iv) human tissue preparation; (v) method and location of tissue placement; (vi) hormonal status of the recipient animal; (vii) whether or not mice were engrafted with human immune cells; (viii) endpoint assessments; and (ix) number and type of replicates. Herein, we outline important considerations for each major variable and make recommendations for unification of approaches. Widespread adoption of harmonized protocols and implementation of standardized documentation and reporting should further improve the reproducibility and translation of experimental findings both within and between laboratories.