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The Manchester buckle study: 15-year outcomes and predictive factors for success in scleral buckling for primary rhegmatogenous retinal detachment
Get PDFAims: To assess the long-term anatomical and visual outcomes of primary scleral buckle (SB) surgery for rhegmatogenous retinal detachment (RRD) and identify predictors of surgical and functional success. Methods: All primary SB procedures performed at Manchester Royal Eye Hospital between January 2008 and December 2023 were reviewed retrospectively. Preoperative, intraoperative and postoperative data were extracted from electronic records. Primary end-points were single-surgery anatomical success (SSAS) and final best-corrected visual acuity (BCVA); univariate and multivariate regression analyses examined predictive variables and complications. Results: 608 eyes were included. SSAS was achieved in 515 eyes (85%) and final anatomical success in 602 eyes (99%). Mean BCVA improved from 0.62±0.85 to 0.32±0.49 logarithm of the minimum angle of resolution (logMAR) (p40 years (OR 0.55, 95% CI 0.37 to 0.83; p=0.004), macula-off status (OR 0.65, 95% CI 0.44 to 0.97; p=0.034) and ocular trauma (OR 0.40, 95% CI 0.19 to 0.82; p=0.012) independently reduced SSAS. For visual outcomes, macula-off detachment (β=+0.36; p<0.001) and ocular trauma (β=+0.42; p<0.001) were independent predictors of worse postoperative BCVA. The most common complications were subretinal haemorrhage (4.6%), inadvertent deep sutures (3.9%) and postoperative ocular hypertension (7.4%). Conclusions: Primary SB provided high anatomical success, significant visual improvement and a favourable safety profile in this large single-centre study. Age above 40 years, macula-off status and ocular trauma predicted poorer SSAS; trauma and macula-off status were also associated with worse postoperative BCVA on multivariate logistic regression
Expanding the phenotypic spectrum of MECOM-associated syndrome: rare variants are associated with syndromic pulmonary arterial hypertension
Get PDFBackground: MECOM encodes a developmental and haematopoietic transcription factor associated with a rare early-onset syndrome including bone marrow failure, skeletal and other congenital anomalies. Heterozygous de novo variants are the primary cause. We previously identified MECOM as a candidate gene for paediatric pulmonary arterial hypertension (PAH) using trio exome sequencing. Methods: To test the role of MECOM in paediatric PAH and further define the clinical phenotype of MECOM-associated syndrome, we queried GeneMatcher and screened rare disease databases for individuals with predicted deleterious MECOM variants. We analysed the clinical spectrum of patients, performed protein modelling of genetic variants and assessed cardiopulmonary expression. Results: We identified 15 individuals with MECOM variants, including 11 unrelated probands and 8 de novo variants. 11 individuals had severe or mild thrombocytopenia, 9 had skeletal issues, 8 had cardiac anomalies, 6 had PAH and 10 had additional conditions. Three were diagnosed in utero and died in the neonatal period. All missense variants map to the zinc finger 6 or zinc finger 8/9 region, a known hotspot for MECOM-associated syndrome. Protein modelling predicted that both regions are DNA-binding, and that the variants may interfere with binding to a VEGFR2/KDR enhancer. Data from LungMAP showed that MECOM is primarily expressed in pulmonary arterial endothelial cells. Conclusion: Rare MECOM variants are associated with early-onset syndromic PAH. PAH monitoring should be considered for all individuals with rare MECOM variants. We speculate that the pathogenetic mechanism for PAH and cardiac defects may be impaired VEGFR2/KDR signalling
Barriers to accessing perinatal mental health services in ethnically diverse women in the UK
Get PDFBackground: Mental health problems are common among women during the perinatal period (here defined as during pregnancy and the 2 years after birth), affecting up to 20% of women. Although there are effective treatments for perinatal mental health problems, ethnically diverse women who are at higher risk of developing perinatal mental health problems are less likely to access treatment for their perinatal mental health problems. This study explored perceptions of perinatal mental health problems and barriers to accessing treatment amongst a sample of ethnically diverse women with current or past experiences who did not receive help from a specialist team. Methods: This study is qualitative primary research. Twenty-eight women living in England who reported they struggled with emotional and mental health challenges during their perinatal period but did not receive assistance from the specialist perinatal mental health team were recruited from community groups and adverts. Women participated in online interviews, which were transcribed. NVIVO was used to support a thematic analysis. Results: The study revealed that substantial barriers to seeking help arise from women’s interactions with their healthcare professionals. When women feel a lack of trust, experience discrimination, or sense judgment from healthcare providers, they are less inclined to seek assistance. However, the motivation to seek help is significantly shaped by community perceptions of perinatal mental health issues, particularly for those women who have made efforts to access support. Women had a positive experience in peer support groups. Conclusion: A significant barrier to accessing perinatal mental health services for ethnically diverse women is experiences with health professionals. Moreover, women from ethnically diverse groups may encounter additional problems regarding help-seeking due to cultural influences and attitudes towards mental health and motherhood roles. Hence, the intricate interplay between cultural factors and healthcare experiences highlights the urgent need for a more culturally competent approach to perinatal mental health services
Human Endometriotic Lesion‐Derived Small Extracellular Vesicles Impair Macrophage Function in the Peritoneal Microenvironment
Get PDFEndometriosis (EM) is a chronic inflammatory disease that affects ∼10% of women during reproductive age. It is characterised by ectopic (ECT) growth of endometrial‐like tissue mainly in the pelvic cavity. Small extracellular vesicles (sEVs) mediate cellular interactions, but their function remains poorly understood in the pathogenesis of EM. 3D endometrial epithelial organoids (EEOs) from ECT lesions and eutopic (EUT) endometrium from EM patients and controls were established to investigate sEVs. Multiplex bead‐based flow cytometry revealed CD133/1 and EpCAM as dominant markers on EEO‐sEVs, with ECT EEO‐sEVs showing upregulation of CD44, CD29 and downregulation of EpCAM compared to EUT EEO‐sEVs. Peritoneal fluid (PF)‐sEVs displayed high and correlated CD133/1 and EpCAM expression, indicating a major contribution from endometrial epithelial (EE) cells, alongside sEVs of lymphocyte and endothelial origin. Functionally, both ECT EEO‐sEVs and PF‐sEVs from EM patients significantly suppressed macrophage phagocytosis, as assessed by pH‐sensitive fluorescent bioparticles. The effect was reversed by CD47 blockade. The coexpression of CD47 with CD133/1 and EpCAM on PF‐sEVs indicates the involvement of EE cell‐derived sEVs in CD47/SIRP‐α mediated suppression. This study provides the first thorough characterisation of EE‐derived sEVs utilising EEO models in EM and demonstrates their potential immunomodulatory role in the peritoneal microenvironment via CD47/SIRP‐α signalling
Chile, Argentina and the Bretton Woods System (1945-1973)
Get PDFThis thesis analyses how Latin America’s Southern Cone actively and strategically navigated the Bretton Woods international monetary system (1945–1973). Aiming to re-centre traditional accounts focused on industrialised economies, it shows how Chile and Argentina engaged and shaped global financial developments in the postwar era. Central to those interactions were the countries’ fragile external positions and their ISI models, which remained at odds with global non-discriminatory norms. Drawing upon a vast range of archival sources, from government agencies to major trading partners’ records, this dissertation is divided into three main parts. Part I explores how the Southern Cone navigated the complex postwar dollar shortage and the emergence and consolidation of currency blocs. Chapter 1 delves into Chile’s use of a discriminatory system of multiple exchange rates, while Chapter 2 analyses the unfolding and crisis of what this thesis refers to as the ‘bilateral-nationalistic’ strategy in Argentina. Part II focuses on the global transition towards multilateralism, normally signalled by currency convertibility of major industrial countries. In the Southern Cone, such a shift took the form of stabilisation programmes aimed at modernising the countries’ import-substitution models and buttressed by unprecedented levels of international cooperation (Chapters 3 and 4). Finally, Part III examines the eventful final decade of the Bretton Woods order, which roughly coincided with the Southern Cone’s industrial heyday. It shows how a combination of improved trade conditions and international assistance enabled both Chile (Chapter 5) and Argentina (Chapter 6) to enjoy a comfortable external position and assist America with its balance of payments constraints in the late 1960s. Taken together, the three parts of this thesis reveal a more complex architecture of the postwar order, portraying it as a truly global system deeply embedded in cooperation and multilateralism
Controlling quantum systems at the pulse level: cavity QED and beyond
Get PDFThis thesis addresses challenges in the experimental realisation of optical quantum computing with atom-cavity platforms and develops techniques for experimental quantum control that generalise across a range of quantum modalities. Within the framework of cavity quantum electrodynamics (cQED), methods are developed and numerically validated for fast and precise control of single atoms to generate photonic states of interest. In particular, we consider the generation of high-repetition-rate n-photon bursts and time-bin entangled states. These photonic resources are essential for applications such as boson sampling, multi-photon interference, optical quantum computing, and quantum-enhanced metrology. Experimental improvements in coherent population transfer are demonstrated using adaptive pulse shaping with acousto-optic modulators.
Beyond photon generation, the thesis introduces general-purpose pulse-level techniques, including pulse distortion correction, memory-efficient pulse compression, and machine learning-based optimisation. These methods are shown to be transferable to other platforms, such as neutral atom arrays and superconducting qubits. A particular contribution is the implementation of scalable pulse generation using fixed-point compressed pulse representations on FPGA hardware, achieving substantial memory savings while maintaining high fidelity in simulations of quantum operations. Additionally, reinforcement learning is presented as a powerful tool for optimising complex quantum dynamics, with state-of-the-art results demonstrated across various simulated systems. Throughout the thesis, theoretical developments are supported by numerical simulations and partial experimental validation, providing important insights for the development of future quantum technologies
Genome-wide analysis of extended-spectrum beta-lactamase-producing Escherichia coli from seafood in Bangladesh: population structure, resistome, virulome, and global dissemination patterns
Get PDFObjectives: This study aimed to identify multilocus sequence type (MLST), serotype, average nucleotide identity (ANI), antimicrobial resistance genes (ARGs), virulence genes (VGs), and mobile genetic elements (MGEs) from whole-genome sequences of 10 Escherichia coli isolated from seafood in Bangladesh and compared them with the global datasets of beta-lactamase-producing E. coli. Methods: Ten E. coli isolates (crab = 3, shrimp = 1, tuna = 6) were subjected to whole-genome sequencing using Oxford Nanopore Technologies (Oxford, UK). In-silico bioinformatics analyses were performed using online tools and Linux-based commands. A systematic advanced search in PubMed identified 722 global genomes of beta-lactamase-producing E. coli for comparative analysis. A population structure and global phylogeny were constructed to illustrate the current status of beta-lactamase-producing E. coli from diverse sources (seafood, human, aquatic, wastewater, and environmental) across countries, based on their STs, ARGs, VGs, MGEs, and serotypes. Results: Bioinformatics analysis revealed that most isolates displayed unique sequence types (STs) and core genome sequence types (cgSTs), while three isolates shared both ST1431 and cgST104784, indicating close genetic relatedness supported by ANI analysis. In shrimp and tuna isolates, both O and H antigens were detected, whereas crab isolates carried either O or H antigens. Pangenome analysis identified 56.4% strain-specific genes, 34.2% dispensable genes, and 9.4% core genes, with functions categorized into clusters of orthologous groups (COGs). Several ARGs, including beta-lactamase genes (CTX-M-15, AmpC, blaDHA-1), were detected across isolates, with crabs harboring the highest number. The VGs were more common in tuna isolates. Plasmids were only detected in crabs (Col440I, IncFIA, IncFIB(pHCM2), and ColRNAI) carrying qnrB4, dfrA17, qacE, mph(A), sul1, blaDHA-1 ARGs, but were absent in shrimp and tuna. Population structure analysis showed that ST345 in Bangladesh closely matched wastewater (Czech Republic) and human (USA) isolates. Some STs overlapped with international records, while others appeared novel, suggesting limited global distribution. Globally, wastewater and human isolates from the Czech Republic showed the greatest similarity to our strains. Conclusion: These findings underscore the potential role of seafood in disseminating beta-lactamase-producing E. coli, highlighting the urgent need for integrated surveillance to mitigate antimicrobial resistance risks in humans, animals, and the food chain
Wnt‐dependent spatiotemporal reprogramming of bone marrow niches drives fibrosis
Get PDFBone marrow fibrosis is the most extensive matrix remodeling of the microenvironment and can include de novo formation of bone (osteosclerosis). Spatiotemporal information on the contribution of distinct bone marrow niche populations to this process is incomplete. We demonstrate that fibrosis‐inducing hematopoietic cells cause profibrotic reprogramming of perivascular CXCL12‐abundant reticular (CAR) progenitor cells, resulting in loss of their hematopoiesis‐support and upregulation of osteogenic and pro‐apoptotic programs. In turn, peritrabecular osteolineage cells (OLCs) are activated in an injury‐specific, Wnt‐dependent manner, comparable to skeletal repair. OLCs fuel bone marrow fibrosis through their expansion and skewed differentiation, resulting in osteosclerosis and expansion of Ly6a+ fibroblasts. NCAM1 expression marks peritrabecular OLCs and their expansion into the central marrow is specific for fibrosis in mice and patients. Peritrabecular stromal β‐catenin expression is linked to fibrosis in patients, and inhibition of Wnt signaling reduces bone marrow fibrosis and osteosclerosis, possibly being a clinically relevant therapeutic target
Structural basis for domain coupling in heteromeric glycine receptors revealed by an atypical allosteric agonist
Get PDFGlycine receptors (GlyRs), pentameric ligand-gated ion channels (pLGICs), mediate sensory and motor functions. GlyR functional states are well characterized; however, structural details of transitions between states remain undefined. Here, we determined cryo-electron microscopy structures of GlyRα1β (with gephyrin E-domain) at varying concentrations of ivermectin, a transmembrane domain (TMD) allosteric agonist, and at saturating concentrations of strychnine, a competitive antagonist at the extracellular domain (ECD). Electrophysiology shows that ivermectin activates GlyR even with strychnine present. Structures with both ligands reveal intermediate states featuring a desensitized TMD and an ECD between closed and desensitized conformations, providing insights into domain cooperativity and ligand efficacy. Molecular dynamics simulations show how ivermectin affects strychnine dynamics. These data support a model where ivermectin activates GlyRs through a concerted and near-symmetric TMD mechanism, whereas allosteric ECD motions are graded and spatially heterogeneous. These findings reveal unanticipated features of GlyR gating and establish principles of allosteric modulation applicable to pLGICs
Molecular characterisation of the placental-pancreatic islet axis
Get PDFDuring pregnancy adaptive changes support foetal growth and prepare the mother for childbirth. This includes the pancreatic islets, in which insulin secretion from β cells doubles by the third trimester. When these adaptations fail, gestational diabetes mellitus can occur, negatively impacting outcomes. These islet adaptations are closely linked to placental growth, with insulin secretion increasing as the placenta develops and returning to normal post-delivery. In mouse models, placental signals, such as hormones and extracellular vesicles (EVs), enhance islet function and β-cell mass. However, it remains unclear if these mechanisms apply to humans. This thesis investigates islet changes during human pregnancy ex vivo, using rare pancreatic tissue from pregnant women, and explores the role of placental small EVs (psEVs) in β-cell biology using a human-based model system. In the first part of the study, human islets were isolated using laser capture microdissection and analysed via liquid chromatography-mass spectrometry (LC-MS/MS), generating the largest dataset of proteins from islets isolated from pregnant women to date with over 7,000 proteins detected. Comparative analysis between pregnant and non-pregnant samples identified differences in only four proteins. Immunohistochemistry, coupled with unbiased computational analysis, revealed that whole islet, α-, and β-cell areas increased during pregnancy due to an increase in cell number, similar to findings in mice. However, unlike in mice, serotonin 2B receptor was absent in human β cells, and prolactin receptor expression remained unchanged. A notable increase in glucagon-like peptide-1 (GLP-1) within α cells was observed, which may enhance β-cell function through paracrine signalling. In the second part of the study, psEVs were isolated from human placentae and their effects tested in vitro on a human β-cell line, EndoC-βH3. psEVs increased β-cell insulin gene expression and insulin content but did not enhance glucose-stimulated insulin secretion. Proteomic analysis via LC-MS/MS identified an increase in Annexin A1 (ANXA1) in psEV-treated Endoc-βH3 cells, suggesting a potential mechanistic role in psEV-mediated effects. In conclusion, islet adaptations in human pregnancy differ to those in mice and psEVs increase insulin content potentially through ANXA1