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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
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.
Definition and diagnostic criteria of retained products of conception following first-trimester pregnancy loss: a systematic review.
Retained products of conception (RPOC) is a common complication following first-trimester pregnancy loss. However, there are no formal recommendations regarding the diagnosis of RPOC. This systematic review aimed to synthesise and critically appraise the existing evidence on the definition and diagnostic criteria for RPOC. We registered this systematic review prospectively with PROSPERO (CRD42023444456). A comprehensive literature search was conducted in October 2024 using the following databases: Embase (OVID), Medline (OVID), Global Health, CINAHL on EBSCOhost, Cochrane Central and Web of Science. Databases were searched using free-text keywords and subject headings for the key concepts of 'early', 'miscarriage' and 'retained'. Data were extracted and 2 by 2 tables populated. Risk of bias and quality assessments were performed using the QUADAS-2 tool. The literature search yielded 2,014 articles that were screened for eligibility, resulting in the inclusion of 17 studies in the final analysis. Ultrasound scan was the primary diagnostic tool, used in 16 of the 17 included studies. Ultrasound diagnostic markers included: endometrial thickness (ET), the presence of hyperechoic or echogenic material, and colour flow Doppler. One study used persistent bleeding for more than 14 days as the primary diagnostic marker. There was significant variation in the diagnostic thresholds used and no single ultrasound marker demonstrated consistent reliability in diagnosing RPOC. The findings of this review highlight the limitations of ultrasound as a standalone diagnostic tool for RPOC. Given the lack of clear diagnostic criteria, clinicians should integrate ultrasound findings with clinical symptoms to improve diagnostic accuracy. RPOC appears to be a distinct pathology within the spectrum of early pregnancy loss, characterised by the persistence of pregnancy tissue within the uterine cavity despite initial management which distinguishes it from incomplete miscarriage. This review provides a foundation for future research and calls for a Delphi consensus to refine the diagnosis and management of RPOC.
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.
Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images.
Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.
Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.
Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.
Comparison of Associations with Different Macular Inner Retinal Thickness Parameters in a Large Cohort: The UK Biobank.
PURPOSE: To describe and compare associations with macular retinal nerve fiber layer (mRNFL), ganglion cell complex (GCC), and ganglion cell-inner plexiform layer (GCIPL) thicknesses in a large cohort. DESIGN: Cross-sectional study. PARTICIPANTS: We included 42 044 participants in the UK Biobank. The mean age was 56 years. METHODS: Spectral-domain OCT macular images were segmented and analyzed. Corneal-compensated intraocular pressure (IOPcc) was measured with the Ocular Response Analyzer (Reichert, Corp., Buffalo, NY). Multivariable linear regression was used to examine associations with mean mRNFL, GCC, and GCIPL thicknesses. Factors examined were age, sex, ethnicity, height, body mass index (BMI), smoking status, alcohol intake, Townsend deprivation index, education level, diabetes status, spherical equivalent, and IOPcc. MAIN OUTCOME MEASURES: Thicknesses of mRNFL, GCC, and GCIPL. RESULTS: We identified several novel independent associations with thinner inner retinal thickness. Thinner inner retina was associated with alcohol intake (most significant for GCIPL: -0.46 μm for daily or almost daily intake compared with special occasion only or never [95% confidence interval (CI), 0.61-0.30]; P = 1.1×10-8), greater social deprivation (most significant for GCIPL: -0.28 μm for most deprived quartile compared with least deprived quartile [95% CI, -0.42 to -0.14]; P = 6.6×10-5), lower educational attainment (most significant for mRNFL: -0.36 μm for less than O level compared with degree level [95% CI, -0.45 to 0.26]; P = 2.3×10-14), and nonwhite ethnicity (most significant for mRNFL comparing blacks with whites: -1.65 μm [95% CI, -1.86 to -1.43]; P = 2.4×10-50). Corneal-compensated intraocular pressure was associated most significantly with GCIPL (-0.04 μm/mmHg [95% CI, -0.05 to -0.03]; P = 4.0×10-10) and was not associated significantly with mRNFL (0.00 μm/mmHg [95% CI, -0.01 to 0.01]; P = 0.77). The variables examined explained a greater proportion of the variance of GCIPL (11%) than GCC (6%) or mRNFL (7%). CONCLUSIONS: The novel associations we identified may be important to consider when using inner retinal parameters as a diagnostic tool. Associations generally were strongest with GCIPL, particularly for IOP. This suggests that GCIPL may be the superior inner retinal biomarker for macular pathophysiologic processes and especially for glaucoma.
FFPred 3: feature-based function prediction for all Gene Ontology domains.
Predicting protein function has been a major goal of bioinformatics for several decades, and it has gained fresh momentum thanks to recent community-wide blind tests aimed at benchmarking available tools on a genomic scale. Sequence-based predictors, especially those performing homology-based transfers, remain the most popular but increasing understanding of their limitations has stimulated the development of complementary approaches, which mostly exploit machine learning. Here we present FFPred 3, which is intended for assigning Gene Ontology terms to human protein chains, when homology with characterized proteins can provide little aid. Predictions are made by scanning the input sequences against an array of Support Vector Machines (SVMs), each examining the relationship between protein function and biophysical attributes describing secondary structure, transmembrane helices, intrinsically disordered regions, signal peptides and other motifs. This update features a larger SVM library that extends its coverage to the cellular component sub-ontology for the first time, prompted by the establishment of a dedicated evaluation category within the Critical Assessment of Functional Annotation. The effectiveness of this approach is demonstrated through benchmarking experiments, and its usefulness is illustrated by analysing the potential functional consequences of alternative splicing in human and their relationship to patterns of biological features.