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Nuffield Department of Women's & Reproductive Health sits within the Medical Sciences Division of the University of Oxford. The department encompasses multi-disciplinary research across four overarching themes; Cancer, Global Health, Maternal & Fetal Health and Reproductive Medicine & Genetics
Exploring pathophysiological insights to improve diagnostic utility of ultrasound markers for distinguishing placenta accreta spectrum from uterine-scar dehiscence.
OBJECTIVE: Accurate differentiation between placenta accreta spectrum (PAS) and uterine-scar dehiscence with underlying non-adherent placenta is often challenging, even for PAS experts, both prenatally and intraoperatively. We investigated the use of standardized two-dimensional grayscale ultrasound and Doppler imaging markers in differentiating between these closely related, yet distinct, conditions. METHODS: This was a retrospective cohort study conducted in two centers with specialized PAS services. All consecutive women with at least one previous Cesarean delivery and a current pregnancy with a low-lying placenta or placenta previa, for whom detailed prenatal ultrasound, management and outcome information was available for review by the research team, were included. PAS was diagnosed clinically by the abnormal adherence of the placenta to the uterus. The PAS cases were classified using the International Federation of Gynecology and Obstetrics clinical classification. Grade 1 was considered low-grade PAS while Grades 2 and 3 were classified as high-grade PAS. The ultrasound markers were categorized according to their underlying pathophysiology, including lower uterine segment (LUS) remodeling, uteroplacental vascular remodeling and serosal hypervascularity. The combined ultrasound features were analyzed among the PAS and non-PAS subgroups using the chi-square test or Fisher's exact test, and univariable and multivariable logistic regression analysis. Additionally, receiver-operating-characteristics (ROC) curves were used to evaluate the diagnostic accuracy of the combined ultrasound features in differentiating between high-grade PAS and uterine-scar dehiscence. RESULTS: Out of the 150 cases retrieved, six cases were excluded for not meeting the eligibility criteria. The included 144 cases comprised 89 cases of PAS, 23 cases of uterine-scar dehiscence and 32 cases of uncomplicated low-lying placenta or placenta previa. Among the PAS cases, there were 16 cases of low-grade PAS and 73 of high-grade PAS. Combined signs of LUS remodeling were present in most cases of uterine-scar dehiscence (20/23 (87.0%)) and high-grade PAS (67/73 (91.8%)) (P = 0.444), while these signs were absent in cases of low-grade PAS (0/16) and uncomplicated low-lying placenta or placenta previa (0/32). A subgroup analysis of cases with all LUS remodeling features present revealed that the combined signs of serosal hypervascularity (adjusted odds ratio (aOR), 41.2 (95% CI, 7.5-225.3)) and uteroplacental vascular remodeling (aOR, 116.0 (95% CI, 15.3-878.3)) were significantly associated with high-grade PAS. Diagnostic accuracy testing within this subgroup revealed an area under the ROC curve (AUC) of 0.90 (95% CI, 0.81-0.99), sensitivity of 89.6% (95% CI, 79.7-95.7%) and specificity of 90.0% (95% CI, 68.3-98.8%) for the diagnosis of high-grade PAS when all signs of uteroplacental vascular remodeling were present. If both signs of serosal hypervascularity were present, the AUC was 0.84 (95% CI, 0.74-0.95) with a sensitivity of 83.6% (95% CI, 72.5-91.5%) and specificity of 85.0% (95% CI, 62.1-96.8%) for the diagnosis of high-grade PAS. CONCLUSIONS: The combined ultrasound markers of LUS remodeling are common in both high-grade PAS and uterine-scar dehiscence, while the combined features of abnormal vascularity (uteroplacental vascular remodeling and serosal hypervascularity) are specific to high-grade PAS. Understanding these pathophysiological differences would enhance the diagnostic accuracy of ultrasound in distinguishing between these two conditions. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
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.
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.