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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
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.
WERF Endometriosis Phenome and Biobanking Harmonisation Project for Experimental Models in Endometriosis Research (EPHect-EM-Homologous): homologous rodent models
In vivo models of endometriosis enable the discovery and preclinical testing of new therapies. Several rodent models of endometriosis exist, but a lack of harmonization impedes reproducibility and comparability of results among investigators. Homologous models are advantageous as they allow the contribution of the immune system/inflammation to be studied. We reviewed published homologous rodent models of endometriosis to develop standard operating procedures ('EPHect-EM-Homologous-SOPs') to guide and facilitate the choice and implementation of these models and harmonize documentation to enhance interpretation and comparability of results. The World Endometriosis Research Foundation (WERF) established an international working group of experts in models of endometriosis and formed a working sub-group to discuss homologous rodent models of endometriosis. A systematic literature review and detailed analysis of protocols was performed. The identified models have advantages and limitations regarding physiological relevance and utility. To harmonize key variables for endometriosis rodent models, the working group focused on species and animal strains, placement of ectopic tissue, uterine tissue volume, method of induction, hormonal status, and uterine tissue 'type'. A decision tree and recommendations on model use were developed for mice and rats to serve as guides for the use of harmonized EPHect-EM-Homologous-SOPs, experimental design, reporting standards, and research of question-dependent key variables. No 'ideal' homologous model of endometriosis was identified. The choice of model for specific research should be guided according to a best-fit strategy. Harmonization of SOPs, documentation, and reporting standards will improve replicability and translational applicability of studies and better highlight where de novo model creation is needed.
Prevalence and types of errors in the electronic health record: protocol for a mixed systematic review.
INTRODUCTION: In countries with access to the electronic health record (EHR), both patients and healthcare professionals have reported finding errors in the EHR, so-called EHRrors. These can range from simple typos to more serious cases of missing or incorrect health information. Despite their potential detrimental effect, the evidence on EHRrors has not been systematically analysed. It is unknown how common EHRrors are or how they impact patients and healthcare professionals. METHODS AND ANALYSIS: A mixed systematic review will be carried out to address the research gap. We will search PubMed, Web of Science and CINAHL for studies published since 2000, which report original research data on patient-identified and healthcare professional-identified EHRrors. We will analyse (1) the prevalence of EHRrors, (2) the types of EHRrors and (3) their impact on care. Quantitative and qualitative findings will be synthesised following the Joanna Briggs Institute Framework for Mixed Systematic Reviews. Identified studies will be critically appraised for meta-biases and risk of bias in individual studies. The confidence in the emerging evidence will be further assessed through the Grading of Recommendations Assessment, Development and Evaluation approach. Findings will be contextualised and interpreted involving an international team of patient representatives and practising healthcare professionals. ETHICS AND DISSEMINATION: The study will not involve collection or analysis of individual patient data; thus, ethical approval is not required. Results will be published in a peer-reviewed publication and further disseminated through scientific events and educational materials. PROSPERO REGISTRATION NUMBER: CRD42024622849.
Small for Gestational Age sub-groups have differential morbidity, growth and neurodevelopment at age 2: the INTERBIO-21st Newborn Study.
BACKGROUND: Small for Gestational Age (SGA) is a complex perinatal syndrome associated with increased neonatal morbidity, mortality, and impaired childhood growth and neurodevelopment. Current classifications rely primarily on birth weight, which does not capture the heterogeneity of the condition nor predict long-term health outcomes. Here we aim to identify and characterise distinct SGA sub-groups and assess their neonatal and early childhood health trajectories. OBJECTIVES: To refine the classification of SGA by identifying sub-groups based on maternal, fetal, and environmental factors and evaluating their associations with neonatal morbidity, growth, and neurodevelopment at age 2. STUDY DESIGN: Prospective Cohort Study. In six countries worldwide, between 2012 and 2018, the INTERBIO-21st Study enrolled SGA and non-SGA newborns defined by the <10th centile of international standards with moderate (≥3rd to <10th centile) and severe (<3rd centile) SGA sub-groups; we assessed their growth, health, nutrition, motor development, and neurodevelopment up to age 2. We used 2-step cluster analysis to identify SGA sub-groups, and a probabilistic approach to choose the optimal sub-group model based on a statistical measure of fit. We performed logistic regression analysis (OR; 95% CI) to assess health and development outcomes among sub-groups using the non-SGA as reference group, adjusting for key confounders. RESULTS: We enrolled 5153 non-SGA and 1549 SGA newborns: moderate (≥3rd to <10th centile) SGA=947 and severe (<3rd centile) SGA=602). We identified nine SGA sub-groups: 'no main condition detected' (29.0%); 'previous low birth weight (LBW)/preterm birth (PTB)' (14.6%); 'severe maternal disease' (12.0%); 'maternal short stature (11.6%); 'hypertensive disorders' (9.6%); 'extrauterine infection' (6.8%); 'previous miscarriage(s)' (6.5%); 'smoking' (5.2%), and 'maternal under-nutrition' (4.7%). Severe SGA newborns in the 'severe maternal disease' (OR: 3.2; 95% CI, 1.8-6.0), 'previous LBW/PTB' (OR: 2.8; 95% CI, 1.6-4.8), and 'smoking' (OR: 5.4; 95% CI, 1.3-21.8) sub-groups had increased risk of neonatal and long-term morbidity, and low anthropometric measures at age 2 as compared to the non-SGA group. Moderate SGA newborns in the "hypertensive disorders" sub-group had increased risk of neonatal morbidity (OR: 2.6; 95% CI, 1.5-4.6), and higher odds of scoring <10th centile of normative values in language (OR: 3.5; 95%CI, 1.0-12.0) and positive behavior (OR: 2.2; 95%CI, 1.1-4.5). The 'severe maternal disease' sub-group had also higher risk of deficit (<10th centile of normative values) in language (OR: 5.7; 95%CI, 1.3-24.8), positive behavior (OR: 3.4; 95%CI, 1.5-7.6). CONCLUSIONS: SGA comprises heterogeneous sub-groups with distinct patterns of neonatal morbidity, postnatal growth, and neurodevelopmental outcomes up to age 2.
OXSeg: Multidimensional Attention UNet-Based Lip Segmentation Using Semi-Supervised Lip Contours
Lip segmentation plays a crucial role in various domains, such as lip synchronization, lip-reading, and diagnostics. However, the effectiveness of supervised lip segmentation is constrained by the availability of lip contour in the training phase. A further challenge with lip segmentation is its reliance on image quality, lighting, and skin tone, leading to inaccuracies in the detected boundaries. To address these challenges, we propose a sequential lip segmentation method that integrates attention UNet and multidimensional input. We unravel the micro-patterns in facial images using local binary patterns to build multidimensional inputs. Subsequently, the multidimensional inputs are fed into sequential attention UNets, where the lip contour is reconstructed. We introduce a mask generation method that uses a few anatomical landmarks and estimates the complete lip contour to improve segmentation accuracy. This mask has been utilized in the training phase for lip segmentation. To evaluate the proposed method, we use facial images to segment the upper lips and subsequently assess lip-related facial anomalies in subjects with fetal alcohol syndrome (FAS). Using the proposed lip segmentation method, we achieved a mean dice score of 84.75%, and a mean pixel accuracy of 99.77% in upper lip segmentation. To further evaluate the method, we implemented classifiers to identify those with FAS. Using a generative adversarial network (GAN), we reached an accuracy of 98.55% in identifying FAS in one of the study populations. This method could be used to improve lip segmentation accuracy, especially around Cupid’s bow, and sheds light on distinct lip-related characteristics of FAS.
Latent Profiles of Early Language Development in a Large Finnish-Speaking Sample of the FinnBrain Birth Cohort Study.
PURPOSE: Research on early language development has primarily used two categories to group at-risk children, differing by the age at which risk is identified. Late talkers are toddlers with late onset of language development, some of whom may catch up with peers. Developmental language disorder is used to refer to children above the age of 4 years. To this day, the longitudinal relationship between the two categories remains unclear. In this study, we explored early language trajectories in a large birth cohort using exploratory methodology to gain better understanding of the types and prevalence of language trajectories from 14 months to 5 years of age, with particular interest in risk trajectories that cluster statistically. METHOD: We conducted latent profile analysis (LPA) on seven language variables collected between 1 and 5 years of age (N = 1,281). Multinomial logistic regression procedure was used to identify child and family characteristics that predicted profile memberships. RESULTS: The LPA yielded three profiles of language development described as persistent low, stable average, and stable high. Female sex, longer duration of pregnancy, and higher maternal socioeconomic status increased the odds of belonging to the stable high-language profile, whereas male sex and not being first born increased the odds of belonging to persistent low language profile. CONCLUSIONS: Contrary to previous research, we did not observe increasing or decreasing profiles, suggesting that toddler language difficulties tend to persist at age 5 years, at least in this birth cohort. This suggests commencing language intervention early instead of the wait-and-see approach. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.29441471.
Genome-wide associations spanning 194 in-hospital drug dosage change phenotypes highlight diverse genetic backgrounds in concurrent drug therapy
As populations get older and medicine consumption rises, the rate of concurrent drug use and polypharmacy among patients is increasing. Polypharmacy is known to complicate therapy and increase the risk of drug-drug interactions, the individuality of which remain largely unexplored. Here, we perform a series of genome-wide association studies to identify variants associated with dosage changes during episodes of concurrent drug therapy. We extracted in-hospital drug prescription records from 847,537 patients in a population-wide Danish hospital cohort. Using imputed genotype data from the Copenhagen Hospital Biobank and the Danish Blood Donor Study we then performed a series of genome-wide association analyses across 194 drug pair phenotypes fulfilling selection criteria. We identified 51 genome-wide significant (p < 5E-08) loci, 49 so far unreported in any genome-wide association studies, associated with dosage changes across 42 different drug pair phenotypes. 49 of the identified loci were unique to the respective drug pairs. Through annotation of the identified loci, expression quantitative trait loci analyses, and gene-based tests we found links to 57 distinct genes, several of which have previously been associated with disease. This study identifies genes that may modulate response to drug therapy in the context of polypharmacy. Our findings reveal distinct patterns of genetic variation across different drug pairs, suggesting a diverse set of genes involved in drug efficacy and drug response. This study may give a better understanding of the individuality of such mechanisms and may aid the development personalized treatment approaches.
Sub-cellular level resolution of common genetic variation in the photoreceptor layer identifies continuum between rare disease and common variation.
Photoreceptor cells (PRCs) are the light-detecting cells of the retina. Such cells can be non-invasively imaged using optical coherence tomography (OCT) which is used in clinical settings to diagnose and monitor ocular diseases. Here we present the largest genome-wide association study of PRC morphology to date utilising quantitative phenotypes extracted from OCT images within the UK Biobank. We discovered 111 loci associated with the thickness of one or more of the PRC layers, many of which had prior associations to ocular phenotypes and pathologies, and 27 with no prior associations. We further identified 10 genes associated with PRC thickness through gene burden testing using exome data. In both cases there was a significant enrichment for genes involved in rare eye pathologies, in particular retinitis pigmentosa. There was evidence for an interaction effect between common genetic variants, VSX2 involved in eye development and PRPH2 known to be involved in retinal dystrophies. We further identified a number of genetic variants with a differential effect across the macular spatial field. Our results suggest a continuum between common and rare variation which impacts retinal structure, sometimes leading to disease.
BayesPiles
We address the problem of exploring, combining, and comparing large collections of scored, directed networks for understanding inferred Bayesian networks used in biology. In this field, heuristic algorithms explore the space of possible network solutions, sampling this space based on algorithm parameters and a network score that encodes the statistical fit to the data. The goal of the analyst is to guide the heuristic search and decide how to determine a final consensus network structure, usually by selecting the top-scoring network or constructing the consensus network from a collection of high-scoring networks. BayesPiles, our visualisation tool, helps with understanding the structure of the solution space and supporting the construction of a final consensus network that is representative of the underlying dataset. BayesPiles builds upon and extends MultiPiles to meet our domain requirements. We developed BayesPiles in conjunction with computational biologists who have used this tool on datasets used in their research. The biologists found our solution provides them with new insights and helps them achieve results that are representative of the underlying data.
Ovarian culture with mouse serum improves follicle development compared with fetal bovine serum, showing the importance of as yet unidentified factors in follicle growth
Context For survivors of childhood blood cancer, fertility preservation through ovarian tissue cryopreservation (OTC) and reimplantation is not recommended because of the risk of reintroducing malignant cells. Since a robust in vitro ovarian tissue culture system does not exist for humans, new approaches are needed. Aims To investigate new approaches to in vitro follicle growth, our aim was to determine whether mouse serum (MS) could support follicle development better in mouse ovaries in vitro compared to fetal bovine serum (FBS). Methods Neonatal ovaries were cultured for 14 days in either MS or FBS. Follicle development and health were assessed by histological and molecular analyses. Anti-Müllerian hormone (AMH) and laminin were analysed using immunohistochemistry. Key results MS supported the development of primordial follicles to preantral follicles, whereas those in FBS did not develop beyond primary. Ovaries cultured in MS had fewer atretic follicles than those in FBS. There were more AMH-positive follicles in MS-cultured than in FBS-cultured ovaries, more primary follicles that were AMH-positive and, AMH-positive primary follicles contained more AMH-positive granulosa cells than those cultured in FBS. Finally, ovaries cultured in either MS or FBS contained laminin; however, the follicle basal lamina (FBL) in MS ovaries were more defined. Conclusions MS better supported follicle development, health, and function than did BS, indicating that MS contains additional factors important for follicle development in mice. Implications These findings demonstrated that as-yet-unknown factors exist that are important for in vitro follicle development, and we need to define them, and explore the role of these molecules in human studies.
Two-year follow-up study (PRIMROSE 3) to assess bone mineral density in subjects with uterine fibroids completing the PRIMROSE 1 and PRIMROSE 2 linzagolix trials.
STUDY QUESTION: How important was the change in lumbar spine (L1-L4), femoral neck, and total hip bone mineral density (BMD) from post-treatment baseline values to 24 months after the end of treatment in PRIMROSE 1 and PRIMROSE 2 study participants? SUMMARY ANSWER: In the present study (PRIMROSE 3), mean percentage changes in lumbar spine BMD from the post-treatment baseline to month 24 (primary endpoint) were small in most treatment groups and similar to variations in the placebo group. WHAT IS KNOWN ALREADY: Due to its mechanism of action, some BMD decreases are observed with oral GnRH antagonist treatment, depending on the dose administered and addition or not of add-back therapy (ABT) (1 mg oestradiol and 0.5 mg norethisterone acetate). In PRIMROSE 1 and PRIMROSE 2, no significant changes in BMD were observed in any of the three anatomic sites investigated (lumbar spine, femoral neck, and total hip) in any of the treated groups but one. Indeed, at 24 weeks, mean differences were most pronounced in the lumbar spine in participants given 200 mg linzagolix alone. STUDY DESIGN SIZE DURATION: PRIMROSE 3 is a long-term follow-up study on BMD in subjects who completed at least 20 weeks of treatment in the main linzagolix trials (PRIMROSE 1 or PRIMROSE 2) and underwent dual-energy X-ray absorptiometry (DEXA) within 35 days of their last treatment (week 24 or week 52 [extension study]). The primary endpoint was the change in lumbar spine (L1-L4), femoral neck, and total hip BMD from post-treatment baseline values to 24 months after the end of treatment in PRIMROSE 1 and PRIMROSE 2 study participants. The secondary endpoint was the change in lumbar spine (L1-L4), femoral neck, and total hip BMD from pre-treatment baseline values to 24 months after the end of treatment. The study involved an eligibility visit and up to three follow-up consultations at 12, 18 and/or 24 months after the end of treatment in either PRIMROSE 1 or PRIMROSE 2. PARTICIPANTS/MATERIALS SETTING METHODS: Patients given an end-of-treatment DEXA scan within 35 days of their last treatment were invited to participate in the PRIMROSE 3 study. Those who were pregnant or unable to undergo a DEXA scan on the same type of equipment as used for the end-of-treatment DEXA scan in PRIMROSE 1 or PRIMROSE 2 were not eligible for this trial. A total of 137 subjects were screened, 134 (97.8%) of whom were enrolled and 130 (94.9%) included in the safety analysis set. Subject groups were small and ranged from 7 subjects (placebo group) to 30 subjects (200 mg/200 mg+ABT group). Most subjects (n = 110, 80.3%) completed the study by evaluation of their BMD by DEXA at 2 years post-treatment.This study (EudraCT number: 2021-000452-19) was conducted at 3 sites in Bulgaria, 4 sites in the Czech Republic, 4 sites in Hungary, 1 site in Latvia, 6 sites in Poland, 1 site in Romania, 5 sites in Ukraine, and 32 sites in the USA. MAIN RESULTS AND THE ROLE OF CHANCE: The most notable percentage increase from the end of treatment to month 24 was in the 200 mg/200 mg+ABT treatment group, which was also the group showing the greatest mean percentage BMD loss during linzagolix treatment. This marked upturn in BMD after cessation of treatment demonstrated the crucial role of ABT.Percentage changes in lumbar spine BMD from the pre-treatment baseline to month 24 (secondary endpoint) remained above -2% in all linzagolix treatment groups. Small BMD modifications observed from both the post-treatment and pre-treatment baseline to month 24 after the end of therapy may not have any clinically relevant impact on overall bone health of linzagolix-treated individuals, since the Z-score of most subjects was within the expected range for age. In addition, changes in BMD values and Z-scores in the linzagolix treatment groups were mostly within the same range as in the placebo group. LIMITATIONS REASONS FOR CAUTION: The number of patients is relatively small. Since interpretation of results from the month-12 and month-18 visits is limited due to the small number of subjects in each treatment arm at corresponding time points, giving rise to high data variability, this manuscript focuses on the month-24 visit only. WIDER IMPLICATIONS OF THE FINDINGS: It can be assumed that the small BMD changes observed from both the post-treatment and pre-treatment baseline to month 24 after cessation of therapy may not have any clinically relevant impact on overall bone health of linzagolix-treated individuals.Changes in BMD values and Z-scores in the linzagolix treatment groups were mostly within the same range as in the placebo group, indicating that there are no long-term consequences on BMD after the end of linzagolix treatment. STUDY FUNDING/COMPETING INTERESTS: Funding for the PRIMROSE studies was provided by ObsEva (Geneva, Switzerland). Analysis of data was partially supported by ObsEva (Geneva, Switzerland), Theramex (London, UK), and Kissei (Japan). Grant 5/4/150/5 was awarded to M.-M.D. by the FNRS.J.D. was a member of the scientific advisory board of ObsEva and Preglem until 2023 and reports consulting fees from ObsEva, Gedeon Richter, and Theramex. F.P. has received consulting fees and honoraria for lectures from Theramex. H.T. has received grants from Abbvie, reports consulting fees from ObsEva and Gedeon Richter, has a patent on endometriosis biomarkers owned by Yale University, and was a past president of American Society of Reproductive Medicine (ASRM). C.B. was a member of the independent data monitoring board for the PRIMROSE trials and member of the advisory board for Spirit 1 and 2 trials. He was also the Chair for the ESHRE endometriosis guideline committee. Consulting fees from Myovant and Theramex went to the University of Oxford. S.B. has received consulting fees and honoraria for lectures from Theramex. F.C.H. reports consulting fees and honoraria for lectures, presentations, or educational events from Theramex and Gedeon Richter and receiving honoraria for participation in a data safety monitoring board for Organon. M.P. was a principal investigator in the ObsEva-sponsored PRIMROSE 2 and 3 trials. E.B. and S.H. are employees of Theramex. M.-M.D. has received fees for lectures from Gedeon Richter and Theramex. TRIAL REGISTRATION NUMBER: EudraCT number: 2021-000452-19.
MCAT: Visual Query-Based Localization of Standard Anatomical Clips in Fetal Ultrasound Videos Using Multi-Tier Class-Aware Token Transformer
Accurate standard plane acquisition in fetal ultrasound (US) videos is crucial for fetal growth assessment, anomaly detection, and adherence to clinical guidelines. However, manually selecting standard frames is time-consuming and prone to intra- and inter-sonographer variability. Existing methods primarily rely on image-based approaches that capture standard frames and then classify the input frames across different anatomies. This ignores the dynamic nature of video acquisition and its interpretation. To address these challenges, we introduce Multi-Tier Class-Aware Token Transformer (MCAT); a visual query-based video clip localization (VQ-VCL) method to assist sonographers by enabling them to capture a quick US sweep. By then providing a visual query of the anatomy they wish to analyze, MCAT returns the video clip containing the standard frames for that anatomy, facilitating thorough screening for potential anomalies. We evaluate MCAT on two ultrasound video datasets and a natural image VQ-VCL dataset based on Ego4D. Our model outperforms state-of-the-art methods by 10% and 13% mtIoU on the ultrasound datasets and by 5.35% mtIoU on the Ego4D dataset, using 96% fewer tokens. MCAT’s efficiency and accuracy have significant potential implications for public health, especially in low- and middle-income countries (LMICs), where it may enhance prenatal care by streamlining standard plane acquisition, simplifying US based screening, diagnosis and allowing sonographers to examine more patients.
FGFR2 Genetic Variant C.1019A > G p.(Tyr340Cys) in a Fetus with Pfeiffer Type II Syndrome Diagnosed by a Combination of 3D Ultrasound Phenotyping and DNA Sequencing
AbstractA 38-year-old woman was referred at 20 weeks' gestation for multiple fetal anomalies detected on routine ultrasound screening. Initial findings included dolichocephaly, ventriculomegaly, craniofacial abnormalities, and limb anomalies, which led to the suspicion of a skeletal dysplasia. While microarray analysis was normal, rapid fetal exome sequencing identified a de novo pathogenic variant in the FGFR2 gene (c.1019A > G p.(Tyr340Cys)). Initially classified as a variant of uncertain significance due to initial ultrasound suspicion, targeted three and four dimensional ultrasound phenotyping revealed characteristic features of Pfeiffer syndrome type 2, including cloverleaf skull, proptosis, hypertelorism, broad thumbs and big toes, and radial-humeral synostosis. This case demonstrates the crucial interplay between advanced genetic testing and detailed ultrasound assessment in prenatal diagnosis. Accurate interpretation of genetic variants requires meticulous ultrasound phenotyping in a multidisciplinary setting, particularly for complex and rare conditions such as Pfeiffer syndrome type 2.